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RELATED APPLICATION
[0001] This application claims the benefit of priority from U.S. provisional patent application Ser. No. 60/663,558 entitled “Collapsible Storage System” and currently co-pending.
FIELD OF INVENTION
[0002] This invention relates to storage systems. In particular, it relates to a storage system of a chest and drawers. More specifically, though not exclusively, this invention relates to collapsible storage systems having the ability to be flattened for shipment, and reconfigured into a rigid storage container for use.
BACKGROUND OF INVENTION
[0003] Chests and drawers for storage have existed for many years and in many forms. One problem with traditional chests and drawers is that if they are not in use for a time they merely occupy space that could be used for other purposes. Therefore, there is a need for a chest and drawers that would occupy little space when not in use.
[0004] The need for a storage system that can be efficiently transported is becoming more and more apparent as the economy becomes more global, and the cost of transporting goods increases with the ever-soaring costs of fossil fuels. As a result if these fossil fuel costs, the price of products transported becomes largely dependent on the distance the product is transported, the location of the manufacturing, the location of the retail sales, and the method of transportation. In some cases, the transportation costs of a product could contribute more than twenty five percent (25%) of the retail price.
[0005] In light of the above, it would be advantageous to provide products which can be easily shipped in the smallest volume as possible. More specifically, since freight is often shipped in containers, the minimization of the physical volume of a product is often more critical than the actual weight of the product. Products used for storage are often plagued by the air volume of the containers themselves.
[0006] Because there is no advantage to shipping products containing air and wasting valuable cargo space, the present invention was devised to provide a collapsible storage system which can overcome the storage and transport challenges of fixed storage devices.
SUMMARY OF THE INVENTION
[0007] The present invention includes a collapsible storage chest that is formed to receive a number of collapsible storage boxes, or drawers. Each of the elements of the present invention is capable of being collapsed to a substantially flat configuration to enable the efficient packaging, shipping, warehousing, and distribution of the invention.
[0008] The collapsible containers of the present invention include four side-walls hinged together in the form of a parallelogram which may be positioned into a rectangular configuration; and by folding acutely two opposing hinges, collapsed into a flat configuration.
[0009] The hinges may be actual metal pin hinges, may be effective hinges by sewn seams in material-covered side-walls, or may be formed by spaces between the rigid portions of the side-walls. The bottom panel of the container is a pliable material which may be separated along a diagonal between diagonally separated hinges, and flexible enough to allow the collapse of the container an opposite diagonal direction.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] The novel features of this invention, as well as the invention itself, both as to its structure and its operation, will be best understood from the accompanying drawings, taken in conjunction with the accompanying description, in which similar reference characters refer to similar parts, and in which:
[0011] FIG. 1 is a top perspective view of the small collapsible storage container;
[0012] FIG. 2 is a top view of the small collapsible storage container;
[0013] FIG. 3 is a left side view of the small collapsible storage container;
[0014] FIG. 4 is a bottom view of the small collapsible storage container;
[0015] FIG. 5 is a front view of the small collapsible storage container;
[0016] FIG. 6 is a back view of the small collapsible storage container;
[0017] FIG. 7 is a right-side view of the small collapsible storage container;
[0018] FIG. 8 is a perspective view of the small collapsible storage container shown in a semi-collapsed configuration;
[0019] FIG. 9 is a perspective view of the collapsible storage chest of the present invention having three collapsible storage boxes installed with one removed for clarity; and
[0020] FIG. 10 is a front view of the collapsible storage chest showing the diagonal zipper along the back panel to allow for the collapsing of the storage chest to a substantially flat configuration.
DESCRIPTION OF THE INVENTION
[0021] Referring initially to FIG. 1 , a top perspective view of the collapsible storage container is shown and designated 100 . Container 100 includes a back 102 , a right side 104 , and left side 106 , a front 108 formed with a handle slot 110 , and having bottom panels 112 and 114 attached together with a zipper 116 .
[0022] As shown in this configuration, the sides are attached together to form a hinge. Specifically, sides 102 and 106 are attached with hinge 124 , sides 102 and 104 are attached with hinge 122 , sides 104 and 108 are attached with hinge 128 , and sides 108 and 106 are attached with hinge 126 . These hinges allow the angles between the sides to vary from ninety degrees to facilitate the collapsing of the storage container as shown and discussed in conjunction with FIG. 8 below.
[0023] FIG. 2 is a top view of the collapsible storage container and shows the bottom panels 112 and 114 attachable together with a zipper 116 having a zipper slide 118 . It is to be appreciated that the zipper 116 is shown in its usable configuration with the two bottom portions zipped together to make the bottom panel sufficiently rigid to maintain the sides 102 , 104 , 106 and 108 in a substantially rectangular form. If the zipper is opened, the storage container may collapse in direction 117 to a substantially flat configuration for easy storage. It may be reconfigured to its usable state by merely re-closing the zipper 116 to re-establish the sides in a rectangular configuration.
[0024] FIG. 3 is a left side view of the collapsible storage container. FIG. 4 is a bottom view of the collapsible storage container showing the orientation of the zipper 116 , and a handle 120 used to advance the zipper slide 118 along the zipper 116 to change the configuration of the container. As shown in this Figure, the handle 120 is on the bottom of the container, however, it is to be appreciated that the handle may be placed inside the container. Further, although the zipper is shown as a fastener in this preferred embodiment of the present invention, it is to be appreciated that any variety of fasteners may be used in the present invention without departing from the invention. For instance, Velcro hook-and-loop fasteners, snaps, buttons, ties, etc., may be used to fasten bottom panels 112 and 114 together.
[0025] Referring to FIG. 5 , a front view of the collapsible storage container is shown and front side 108 is formed with a cut-out handle 110 . It is to be appreciated that other shapes may be used for the handle, such as finger-holes, or a handle may be attached to the front 108 (not shown).
[0026] FIG. 6 is a back view, and FIG. 7 is a right side view of the collapsible storage container.
[0027] Referring to FIG. 8 , a perspective view of the collapsible storage container shown in a semi-collapsed configuration. In order to collapse the storage container, zipper 116 must be opened to allow for the separation of bottom panels 112 and 114 . As shown, these panels are flexible enough to allow for the movement of the sides 102 , 104 , 106 and 108 into a trapezoidal configuration. When fully collapsed, sides 104 and 106 are directly adjacent each other, or separated only by panels 112 and 114 . This collapsed configuration provides for the very compact storage of the container in a flat package, readily usable simply by re-orienting the sides into a rectangular position and zipping bottom panels 112 and 114 together.
[0028] Referring to FIG. 9 , a perspective view of the collapsible storage chest of the present invention is shown and generally designated 200 . Storage chest 200 includes a frame 202 and a drawer 204 . Chest 200 is formed having a top 206 , a bottom 208 , a left side 210 , and a right side 212 . Also shown is a center support 214 extending between left side 210 and right side 212 to support drawers 204 .
[0029] Frame 202 is formed with hinges 230 , 232 , 234 , and 236 which provide for the collapsing of the frame to a substantially flat configuration. Drawers 220 , 222 , 224 and 226 are similar to drawer 100 discussed above, and likewise collapsible.
[0030] Referring now to FIG. 10 , a front view of the collapsible storage chest 200 showing the diagonal zipper 240 having slide 242 separating two back panels 242 and 246 . The zipper 240 along the back panel to allows for the collapsing of the storage chest to a substantially flat configuration. Once un-zipped, the frame 202 may collapse in direction 248 .
[0031] The storage system of the present invention may be made of any material capable of supporting the structure shown herein. No limitation as to the materials is contemplated except that the materials chosen for the sides must be substantially rigid, and the materials chosen for the bottom must be somewhat flexible when in the un-zipped configuration in order to allow for the collapsing of the sides together.
[0032] While the particular collapsible storage containers as herein shown and disclosed in detail is fully capable of obtaining the objects and providing the advantages herein before stated, it is to be understood that it is merely illustrative of the presently preferred embodiments of the invention and that no limitations are intended to the details of construction or design herein shown other than as described in the appended claims. | A collapsible storage chest is formed to receive a number of collapsible storage boxes, or drawers. The chest and boxes or drawers are capable of being collapsed to a substantially flat configuration to enable the efficient packaging, shipping, warehousing, distribution and reconstitution of them. | 0 |
BACKGROUND OF THE INVENTION
The present invention relates to an apparatus and process for breaking up soil used for the cultivation of plants.
In an apparatus of this type, breaking up agriculturally utilized soil is effected by means of a probe, whereby by means of a rapid-closing gate valve and an injection valve compressed air and a substrate, respectively, are driven suddenly into the soil. The rapid-closing gate valve is located in an upper and the injection valve in a lower area of an intermediate reservoir containing substrate. The rapid-closing valve is followed by an injector pipe. When the rapid-closing valve is in an open position, the injector pipe is raised from an injection valve seat of the intermediate reservoir to open the injection valve. The rapid-closing valve, in order to be opened and closed, is connected with the piston of a first pneumatic cylinder and the injector pipe and with the piston of a second pneumatic cylinder by means of a tie rod. In order to produce a periodic release of the injector valve, the pressure action in the injector pipe is connected with a third dynamic pressure chamber of the compressed air cylinder limited by the piston. Control pressure lines are connected with both pneumatic cylinders.
In practical applications of the apparatus it is necessary to maintain the injection valve closed with great force and closed as tightly as possible until the injection valve is opened. It is also necessary that the opening of the injection valve take place exactly following the breaking up of the soil. When the injection valve is open, the propping substrate should enter the air flow coming from the injector pipe without clogging or the like, and as free of interference as possible. After the injection of the substrate into the soil, the injection valve should be closed by the dynamic pressure in the shortest time possible.
SUMMARY OF THE INVENTION
It is an object of the present invention to further develop an apparatus of the above-described type and a process using the apparatus and adapted to heterogeneous soil conditions. It is an object to increase the sensitivity of the pressure dependent control functions in order to obtain optimum process behavior. Particularly, the time difference between the opening of the rapid-closing gate valve and the injection valve should be determined accurately, in view of their separate functions.
This object is attained with an apparatus and with a process using the apparatus according to the present invention.
It has been found that, following opening of the injection valve, a pressure of between 2 and 3 bars is generated in the injection chamber, in spite of the high velocity of the air flow. During the time in which this counter pressure is developed, no substrate can come in contact with the flow of air and therefore cannot be entrained by it. This is not entirely satisfactory because, shortly after the injection valve is opened the maximum velocity of the air at the corresponding residual pressure provides the air flow with its maximum transport capacity. At the same instant, the crevices, cracks and pores of the soil are widened to their maximum extent. The propping substrate may be entrained by the air flow and injected by the probe into soil broken up by the impact of a preceding air blast only following the equalization of the pressure between the reservoir and the air jet. At this time, however, the air pressure has been reduced significantly, so that the velocity of the air has also been reduced and the injection of rendered substrate less than optimal.
A further object of the present invention consists of developing an apparatus so that optimum penetration and propping of the broken soil volume is achieved, preferably with a high air pressure and particularly with a high air velocity.
Further objects, features, and advantages of the present invention will become apparent from the brief description of the preferred embodiments which follows, when considered together with the attached drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings:
FIG. 1 shows a partially sectioned lateral view of an apparatus according to the invention, with the figure being extended and laterally offset as indicated to show the ram and the probe;
FIG. 2 is an enlarged sectional view of the time valve for one of the working chambers of the apparatus according to FIG. 1;
FIG. 3 shows the time valve in a partially-sectioned lateral view according to FIG. 2, but in the opposite functional position;
FIG. 4 shows a partially sectioned lateral view of a pneumatic spring integrated into the compressed air cylinder of the apparatus according to FIG. 1;
FIG. 5 shows a partially sectioned lateral view of a further embodiment of the apparatus according to the invention, and
FIG. 6 shows a lateral view of the principal actuating valve block of the apparatus according to FIG. 1, enlarged.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The apparatus 1 according to the invention shown in FIG. 1 is intended for breaking up soil used for the cultivation of plants. Compressed air produced by a compressor is injected suddenly at a depth of approximately 50-90 cm in the form of an eruptive blast. In this manner the soil is broken up or loosened within defined areas and, more particularly, made permeable in structurally predetermined fracture lines, so that the soil structure is not damaged as in conventional ploughing. By means of apparatus 1, the fine canals produced in the soil may be supported with propping materials immediately following the blast. In addition to the propping materials, fertilizers or curing substances may be introduced into the canals of the loosened area by means of compressed air. In view of the simultaneous introduction of oxygen an optimum preparation of the soil is obtained.
The apparatus 1 comprises an intermediate funnel-shaped reservoir 2 made of a transparent synthetic plastic or a metal, and including a bottom part 3 and an upper part 4. The bottom part 3 and the upper part 4 are screwed together by means of threads 5. A mounting fitting 6 is provided on the bottom part 3 of the internediate reservoir 2. An inner tube 7, which rotates about its axis, is located in the fitting 6. The inner tube 7 is associated with a probe tube 8 for insertion in the ground. The apparatus 1 has a ram 9 operated with compressed air, and an anvil 10 for forcing the probe tube 8 into the ground.
An injection valve 11 is provided in a tapered end of the bottom part 3 of the reservoir 2. The valve 11 comprises an injector valve seat 12 of the bottom part 3 and a conical, jet-like compressed air outlet 13 of an injector pipe 14. The pipe passes through the inner space 15 and the central axis of the intermediate reservoir 2. The reservoir 2 is where the substrate to be introduced into the soil is stored.
A relief valve 16 is located on the upper part 4 of the intermediate reservoir 2. A tubular sleeve 17 is also arranged on the upper part 4, which projects into the inner space 15, and wherein the injector tube 14 is supported in an axially displaced manner and sealed by means of an annular gasket 18.
Coaxially with the longitudinal axis of the intermediate reservoir 2, a rapid closing valve 19 is located on the upper wall of the reservoir. The valve comprises a valve cone 21 seated on a valve seat 22. A tie rod 20 passes through the rapid closing valve 19. The open upper end 24 of the injector tube 14 is fastened with a screw nut 25 at the lower end of the tie rod 20. Fine adjustment of the exact sealing function of the injection valve 11 may be obtained by means of the screw nut 25.
An orifice 26 of the connecting fitting for the compressed air supplied by the compressor is provided, directly above the valve cone 21, in a wall of the housing of the rapid closing valve 19.
A pneumatic cylinder, for the sake of clarity pneumatic cylinder 28, is screwed onto the tubular valve housing 27 of the rapid-closing valve. A piston 29 is axially displaceably guided in the cylinder 28. A pressure chamber 30 is located under the piston 29, while a counter pressure chamber 31 is disposed above the piston 29. A downwardly extending tubular piston rod 32 is arranged on the piston 29. The piston rod 32 is guided tightly in a sleeve 33. The valve cone 21 of the rapid closing valve 19 is fastened to the lower end of the piston rod 32.
Another pneumatic or compressed air cylinder 34 is screwed on top of the pneumatic cylinder 28, and lies on a projection of the central long axis of the reservoir 2. Compressed air cylinder 34 is generally similar in configuration to the pneumatic cylinder 28. A piston 35 is axially displaceably guided in cylinder 34. The piston 35 limits in the downward direction a working chamber 36 and includes a downwardly directed piston tube 37.
The piston tube 37 is supported tightly in a sleeve 38 and has no stroke function but performs merely guiding and sealing roles.
The tightly guided tie rod 20 is mounted at the upper end of the piston tube 37. The tie rod 20 comprises an air conduit 39 in the form of a continuous, longitudinal bore, such that a free air passage exists through the piston 35 to a dynamic pressure chamber 40 located above it. The tie rod 20 is screwed at its upper end with the piston tube 37. The piston tube 37 is in turn screwed together with the piston 35 by means of a protruding screw end. The housing 41 of the compressed air cylinder 34 is closed off on top by a screw cap 42. The piston 35 comprises a dynamic pressure surface 43 on top which acts in the downward direction. The piston 35 also has working surface 44 on the bottom which acts in the upward direction. The surface 44 is smaller by the diameter of the piston tube 37 than the dynamic pressure surface 43.
A control pressure line 45 is connected to pneumatic cylinder 28 at the lower pressure chamber 30; and a further control pressure line 46 is connected with the pneumatic cylinder 28 at the upper counter pressure chamber 31. In addition, a control pressure line 47 is provided on the compressed air cylinder 34 at the lower working chamber 36, and a compressed air line 48 is provided at the upper dynamic pressure chamber 40. Control pressure lines 46, 47 communicate with the pressure in the inner tube 7 by means of the air line 39.
A pilot valve 49 is located in the compressed air line 48 leading to the upper dynamic pressure chamber 40. Pilot valve 49 may be actuated by means of a control pressure line 50. FIG. 1 clearly shows that the compressed air line 48, actuable by means of the pilot valve 49, is connected with the top of the compressed air cylinder at the screw cap 42 of the compressed air cylinder. Line 48 opens coaxially with the air line 39 into the dynamic pressure chamber 40 and is directly connected with the air space in the inner tube 7 by means of the air line 39.
It is also clearly seen in FIG. 1 that the air line 39 is extended downward toward the inner tube 7 as a pressure transducer line 51. The air line 39 follows the shortest path, and has an approximately constant cross section from the compressed air outlet 13 of the injector tube 14 along the axis of the intermediate reservoir 2, and through the pressure transducer line 51 and the hollow tie rod 20 to the upper dynamic pressure chamber 40. Specifically, the pressure transducer line 51 has the configuration of a tube. The line 51 is arranged to be an extension of the air line 39 in the injector tube 14. The compressed air conducted through the compressed air line 48 from above into the dynamic pressure chamber 40, is guided through the pressure transducer line 51 separately from the compressed air conducted downward through the rapid closing valve 19 in the injector tube 14, to the compressed air outlet 13 at the injector valve seat 12. Improved sensitivity of the pressure dependent control functions is obtained even if the compressed air conducted through the compressed air line 48 into the dynamic pressure chamber 40 is passed through the air line 39 or pressure transducer line 51 to the upper area of the intermediate reservoir 2. It is, however, particularly advantageous to extend the pressure transducer line as far as possible downward to the probe 8. It may be favorable to pass the pressure transducer line 51 into the inner tube 7 or to permit it to project into the tube 7.
The control pressure line 45 leading to the lower pressure chamber 30 of the pneumatic cylinder 28 is connected with an outlet 52 of a 5/2 distributing valve 53. The control pressure line 47 leading to the lower working chamber 36 of the compressed air cylinder 34 and the control pressure line 50 leading to the pilot valve 49 branch off the control pressure line 45 and are therefore also connected with the outlet 52 of the 5/2 distributing valve 53. The control pressure line 46 leading to the upper counter pressure chamber 31 of the pneumatic cylinder 28 is connected with a another outlet 54 of the 5/2 distributing valve 53. The valve 53 thus has five connections and two switching positions.
A time valve 55, the details of which are shown in FIGS. 2 and 3, is located in the control pressure line 47 leading to the lower working chamber 36 of the compressed air cylinder 34. The time valve 55 is accurately adjustable and serves to provide individual adaptation to differential soil conditions in order to attain a pressure buildup in the lower pressure chamber 36 of the compressed air cylinder 34 which is optimally timed. As seen in particular in FIG. 2 and 3, the time valve 55 has a housing 56 containing two parallel chambers 57, 58 each having a valve seat 59 at the respective ends thereof. A valve body 60 is located in the chamber 57, while a valve part 61 is placed in the other chamber 58. The valve body 60 and the valve part 61 have the same approximate configuration and are guided in an axially displaceable manner, but are arranged in opposite directions. The valve body 60 is coordinated with the valve seat 59 provided at the inlet 62 of the time valve 55, while the valve part 61 is coordinated with the valve seat 59 provided at the outlet 63 of the time valve 55. A connecting channel 64 for air supply is located between the outlet 63 and the chamber 57. A transverse channel 65 leading from the chamber 58 to the inlet 62 is provided in the housing 56 for the return flow of air. A helical spring 66 for biasing the valve body 60 against the valve seat 59 of the inlet 62 is associated with the valve body 60. The spring 66 is supported opposite to the valve seat 59 on an adjusting screw 67. The screw 67 has a knurled head 68 for manual rotation so that the force of the spring 66 may be finely adjusted. The adjusting screw 67 may be locked by means of a counter nut 69. The valve part 61 located in the chamber 58 is associated with a helical spring element 70. The force of the spring element 70 is only large enough to enable the valve body to perform its intended checking function, to ensure that there is no delay in the relief of the working chamber 36 of the compressed air cylinder 34, and to ensure that the lowest possible residual pressure is generated.
The force of the spring 66 may be adjusted conveniently so that the valve body 60 is lifted from the valve seat 59 of the inlet 62 within a range of from about 0.5 to 8 bar. The pressure and velocity of the air supply at outlet 63 from the time valve 55 for the opening of the injection valve 11 may thus be accurately determined.
The time valve 55 thus makes it possible to affect the time of the pressure buildup in the working chamber 36 and thereby the magnitude of the pressure. Consequently, the breaking-up process may be accurately adjusted to different soil conditions encountered in actual practice, so that a high capacity of the process is assured.
In the operating position shown in FIG. 3 the compressed air flows back and may be almost completely relieved, i.e. the injection valve 11 is closing. The compressed air therefore escapes through the 5/2 distributing valve 53.
Referring to FIG. 1 a pneumatic spring 71 is provided for closing the rapid-closing valve 19. The spring 71 is shown enlarged in FIG. 4. The pneumatic spring 71 is supplied with compressed air through the control pressure line 46 connected with the counter pressure chamber 31. A pressure chamber 72, transfixed by the hollow tie rod 20, is formed in the piston rod 32. A piston 73 is mounted on the tie rod 20. An air inlet 74 with a gasket 75 acting as a check valve is located on the upper side of the pneumatic spring 71 facing the counter pressure chamber 31 of the pneumatic cylinder 28. The gasket 75 is located in the pressure chamber 72 of the piston tube 32 and has an approximately V shaped cross section. Two sealing lips of the gasket 75 diverge downwardly, sealing the tie rod 20 on the inside and the pressure chamber 72 on the outside. A support and guide disk 76 is located on the downward-pointing V opening of the gasket 75 which essentially has the configuration of a standard groove ring. One end of a helical holding spring 77 abuts the disk 76. The piston 73 of the pneumatic spring 71 also has a gasket 78 with a V-shaped cross section. The gasket 78 is placed so that the V opening of the diverging sealing lips points upward. Here again, a support disk 79 for the lower end of the support spring 77 is provided. An annular gasket 80 is disposed at the bottom of the pressure chamber 72 of the pneumatic spring 71 facing the rapid closing valve 19. Gasket 80 has the same configuration in cross section as the gaskets 75 and 78 and comprises two downward-pointing V shaped divergent sealing lips. The gasket 80 abuts against a support disk 81 mounted on the piston tube 32.
The hollow tie rod 20 has an axial relief canal 82 so disposed that, when the injection valve 11 is open, the tie rod 20 is axially and upwardly displaced so that the relief canal 82 bridges the sealing lip of the gasket 75. The pressure thus escapes through the inlet 74, the counter pressure chamber 31, the control pressure line 46 and the 5/2 distributing valve 53. An additional closing spring 83 for the rapid-closing valve is provided on the piston rod 32 of the pneumatic spring 71.
The holding spring 77 of the pneumatic spring 71 is strong enough to retain the upper gasket 75 while the compressed air is flowing in from above. The closing force of the groove ring is very small, so that the air is able to enter the pressure chamber 72 through the air inlet 74 even at approximately 0.2 bar. The gasket 75 has the function of a check valve. The outer closing spring 83 provides a safe closure at the onset of the compressed air accumulation in front of the rapid closing valve 19.
When the probe is inserted in the soil, the probe pipe 8 is opened initially. An actuating valve for the compressed air source, conventional and not shown, permits the compressed air to be passed through the 5/2 distributing valve 53, thus subsequently pneumatically closing the rapid closing valve 19 and the injection valve 11. The compressed air penetrates through the air inlet 74 and the upper gasket 75 into the pressure chamber 72. The pressure on the piston 73 applies a closing force of a magnitude (20 bar, for example) that otherwise could not be attained with a mechanical spring in view of the tight space conditions and the resulting restricted dimensions.
At the instant the soil is broken up pressure declines in the dynamic pressure chamber 40. The pressure, built up in the working chamber 36 by means of the time valve, now opens the injection valve 11. The relief canal 82 of the tie rod 20 thereby bridges the upper gasket 75. The compressed air spring force thus is reduced to zero so that only the slight force of the holding spring 77 remains. The outer closing spring 83 is then able to close the rapid closing valve 19.
Because the pilot valve 49 receives its actuating pulse from the control pressure line 50, it opens simultaneously with the rapid closing valve 19. Air therefore flows through the compressed air line 48 parallel and simultaneously with the compressed air flowing through the rapid closing valve 19 so that the air arrives downward at the same time through the pressure transducer line 51. The dynamic pressure generated by the impact of the compressed air on the surrounding soil slows the air flowing from the pressure transducer line 51 upon its exit from the compressed air outlet 13. The dynamic pressure chamber 40 is thereby very rapidly supplied with the necessary pressure so that the closing of the injection valve 11 may be effected rapidly and in a very responsive manner. By means of the compressed air coming from the pilot valve 49 and flowing through the pressure transducer line 51 from top to bottom an increase in the actuating force and valve operations absolutely free of interference may be obtained. The flow of air only cannot introduce dirt or cause clogging in the pressure transducer line 51 and the air line 39, even when dusty substrates are employed.
The second upper piston cylinder thus actuates the injection valve 11 completely independently of the actuation of the rapid closing valve 19. The pressure transducer line 51 connects the inner tube 7 of the probe pipe 8 with the upper dynamic pressure chamber 40 of the upper piston cylinder. Thereby, controlled by the process pressure, the pressure transducer line 51 effects the reliable closing and the optimum opening of the injection valve 11 in all types and conditions of soil.
The advantage obtained by the process and apparatus of the present invention is that the soil to be utilized for the cultivation of plants may be loosened better and more effectively than with conventional ploughs or the like. Substantially less energy is required than in ploughing. A further essential advantage is that with the apparatus according to the invention an optimum propping up of the ground fissures and soil cracks is obtained by the immediate introduction of a substrate. In particular, after repeated application a dense supply artery network is obtained, making it possible in a later cultivating process to perform merely a surface preparation of seed beds, so that although a highly economical and ecologically favorable working process is provided.
A further advantage of the process is that densified or otherwise diseased soils with standing cultures, for example orchards or vineyards, forests, and trees grown alongside streets, may be loosened, cured and made permeable.
The embodiment of the apparatus shown in FIGS. 5 and 6 corresponds in basic configuration to the apparatus 1 according to FIG. 1 to 4. The parts of the apparatus 101 identified by the symbols 102 to 141 and 143 to 155 correspond to the parts 2 to 41 and 43 to 55 of the apparatus 1 described in detail above, so that a repeated description may be omitted here. In place of the screw cap 42, however, a piston slide valve 142 is provided in the apparatus 101 and the pneumatic spring (heretofore 71) carries the symbol 156 in the apparatus 101.
The upper piston slide valve 142 comprises a housing 158 and a piston rod 159 disposed in the housing 158. The piston rod 159 is displaceable in the direction of the center axis and is connected with the tie rod 120. A threaded nut 160 is provided. The nut 160 is screwed onto a tubular part 161 protruding into the dynamic pressure chamber 140 around the hollow tie rod 120. In order to make possible the free passage of air from the dynamic pressure chamber 140 into the hollow tie rod 120, a transverse bore 162 is provided. The bore 162 is formed both in the tubular part 161 and the threaded nut 160.
An inlet chamber 163 and an outlet chamber 164 are provided in the housing 158 of the piston slide valve 142. The inlet chamber 163 comprises an air inlet 165 for the air supply 166. The outlet chamber 164 comprises an air outlet 167, to which a pressure line 168 is connected. Approximately in the center of the housing 158 there is a gasket 169 that separates the inlet chamber 163 and the outlet chamber 164 from each other. The piston rod 159 passes through the gasket 169 and is tightly surrounded by it. The piston rod 159 has a tapering part 170 in the middle of its length. The cross section of the part 170 is smaller than the cross section of the rest of the rod parts extending below and above. In the closing position of the piston slide valve 142, the upper part of the piston rod 159 is within the area of the gasket 159. The inlet chamber 163 and the outlet chamber 164 are thus tightly separated from each other. The tapered part 170 is located entirely in the area of the inlet chamber 163. In the opening position of the piston slide valve 142, the piston rod 159 is moved upward above the piston 135 and far enough so that the tapered part 170 is in the area of the gasket 169 and both in the inlet chamber 163 and the outlet chamber 164. This assures the free passage of air from the air inlet 165 through the piston slide valve 142 to the air outlet 167.
Two spacer sleeves 171, 172 are disposed coaxially and above one another in the piston slide valve 142. The lower spacer sleeve 171 is located in the inlet chamber 163 while the upper spacer sleeve 172 is positioned in the outlet chamber 164. Between the two spacer sleeves 171, 172 the gasket 169 is supported approximately in the center of the housing 158. On the opposing ends of the spacer sleeves 171, 172, i.e. in the lower terminal area of the inlet chamber 163 and in the upper terminal area of the outlet chamber 164, additional gaskets 173, 174 are arranged, which preferably have exactly the same configuration as the center gasket 169 and which again tightly surround the piston rod 159. In order to assure a high degree of tightness, even in case of very high air pressure, for example 120 bar, the gaskets 169, 173, 174 of the piston slide valve are in the form of so-called groove ring gaskets with V shaped cross sections. The gaskets 169, 173, 174 are positioned so that the opening side of the V shape is directed toward the side on which the high air pressure is applied, so that the lips extending downward in the V shape are pressured increasingly with rising pressures against the adjacent sealing surfaces. A satisfactory sealing effect is thus always ensured.
In order for the compressed air to be able to pass from the air inlet 165 to the air outlet 167, a plurality of radial air passage orifices 175 are provided in the two spacer sleeves 171, 172 in which the piston rod 159 is axially guided. To obtain satisfactory operation and optimum performance of the process, it may be advantageous to introduce the air supply 166 to the piston slide valve 142 separately from the air supply for the other parts of the apparatus. The air supply 166 could thus be supplied from a compressed air reservoir independently of the compressed air supplied to the opening 148.
A plurality of air nozzles 178 is arranged on the intermediate reservoir 102, all of which are connected with the pressure line 168 coming from the piston slide valve 142. The air nozzles 178 are located on the bottom part 103 and extend into the inner space 115. The air nozzles 178 are arranged in two different planes above one another for optimum acceleration of the substrate. The plane of the air nozzles 178 closest to the injection valve 111 is located approximately in the lower quarter of the intermediate reservoir 102. The upper plane of air nozzles 178 is located approximately in the central area of the intermediate reservoir 102. It has been found that it may be particularly advantageous to provide a total of seven or eight air nozzles 178 on the intermediate reservoir 102, e.g. four air nozzles 178 are located in the lower plane and three or four in the upper plane. In the drawing, only the air nozzles 178 arranged on the left and the right side are visible, while the rear nozzles 178 are hidden by the injector pipe 114 and the front nozzles are not seen because of the sectioned representation. The air nozzles 178 are arranged on the circumference of the intermediate reservoir 102, preferably in approximately equal intervals. It may be appropriate for certain applications to provide more or less than eight air nozzles 178, and it may be advantageous in certain conditions to place the nozzles 178 in more than one two planes. It is possible to arrange the air nozzles 178 in one plane arcuately offset with respect to the nozzles in another plane, so that the nozzles 178 of the upper plane are able to blow into the gaps existing between the nozzles 178 of the lower plane.
As seen in the drawing, the air nozzles 178 are bent approximately at right angles and arranged so that the outlet 179 is located in the vicinity of the inner surface 180 of the intermediate reservoir 102. The air nozzles 178 are aligned with their outlet 179 so that a flow of compressed air 181 exiting from the outlet 179 blows parallel to the inner surface 180 and in the direction of the compressed air outlet 113. The flow of compressed air 181 produces a high air velocity in the nozzles 178, preferably by its nearly independent high air pressure which is little affected by the actual process. This velocity is capable of accelerating the substrate particles, even if they have a high specific gravity, in the manner required. The substrate located in the reservoir 102 may be thus injected into the air flow with the injection valve 111 open, in any amount desired and entrained by the air flow, further reliably accelerated if necessary, for delivery into the opened soil and distributed in the most favorable manner possible.
At the instant the soil is broken up, pressure declines over the entire process path. The abrupt pressure decrease in the dynamic pressure chamber 140 opens the injection valve 111. At the instant the injection valve 111 opens, the piston slide valve 142 is also opened by the necessary upward movement of the piston rod 159, so that the air supply 166 passes into the pressure line 168 and to the air nozzles 178. The flow of compressed air 181 exiting from the air nozzles 178 entrains the substrate in the reservoir 102 with a high velocity and acts against the counter pressure resulting upon the opening of the injection valve 111. In the intermediate reservoir 102, the flow 181 of compressed air produces a pressure level that forces the substrate to flow downward out of the reservoir 102 immediately upon the opening of the injection valve 111. The substrate particles are thus accelerated by the eight air nozzles 178 into the injection stream. The injection jet transports the substrate particles precisely during the most efficient initial phase of the substrate insertion.
The substrate is transported under a high pressure and with great velocity into the farthest and smallest fissures and cracks of the newly broken soil. The permeation of the soil volume is thereby significantly improved, and the propping substrate, which can comprise fertilizers or curing substances for example, are carried into the soil with an equal or reduced consumption of energy and with an optimum distribution of the substances. These improvements are especially important for the restoration of all environmentally damaged stands of trees, for example in public parks, road side greenery and in forests.
According to a further feature of the invention, it may be advantageous for the optimum penetration and propping of the broken soil volume, preferably under a high air pressure and particularly at a high air velocity, to provide an air inlet 182 opening into the inner space 115 of the intermediate reservoir 102. The air inlet 182 is connected to air pressure line 183 and is intended to produce an over-pressure prior to the opening of the injection valve 111 and thus prior to the opening of the rapid closing valve 119 for blasting compressed air into the soil. The overpressure is produced in the intermediate reservoir 102 and applied to the substrate in the reservoir 102 in the direction of the compressed air outlet 113.
As seen in FIG. 5, the air inlet 182 passes through the wall of the reservoir 102 approximately in its central area and extends in the form of a bent pipe in an upward direction to the cover wall of the upper part 104, so that the air outlet 184 is located above the substrate even if the reservoir 102 is full. The overpressure in the intermediate reservoir 102 is able to cooperate with the flow 181 of compressed air of the air nozzles 178, thereby transporting the substrate more effectively toward the compressed air outlet 113. The overpressure may also be provided without the flow 181 of the nozzles 178 and used to effect the accelerated exit of the substrate according to the process of the present invention.
The overpressure produced by the air inlet 182 in the intermediate reservoir 102 prior to the breakup of the soil is at least high enough to equalize the counter pressure resulting upon opening of the injection valve 111. The counter pressure originates in the inner tube 107 and acts in the direction of the inner space 115 of the reservoir 102. Because of the equalization of pressure, the counter pressure from the inner tube 107 thus cannot act in the inner space 115. Rather, the substrate is pressured directly into the flow of compressed air 113 by the overpressure. The exposure of the substrate to the overpressure is effected conveniently shortly prior to the opening of the injection valve 111. The abrupt introduction of the compressed air into the soil is actuated immediately following the attainment of the overpressure.
The air pressure introduced through the over-pressure line 183 should correspond at least to the jet pressure generated by the opening of the injection pipe 114. According to experience, this amounts to between 2 and 3 bar. In special cases it may, however, be much higher.
The compressed air for the buildup of the over-pressure in the intermediate reservoir 102 is controlled by a ball valve 185 located in the over-pressure line 183. As is seen in FIG. 6, the ball valve 185 is equipped with an actuating lever 186 for manual operation. The ball valve 185 is located on a compact valve block 187. The valve block comprises the distributing valve 153 serving to break up the soil, a valve 188 to open and close the probe tube 108, a valve 189 provided for the raising and lowering of the probe apparatus with the aid of two lift cylinders, for example, and a valve 190 for the actuation of the ram 109. The valves 188, 189 and 190 have appropriate handles 191 for their actuation.
The distributing valve 153 is coupled with the ball valve 185 by means of a linkage 192 so that a slave valve 193 is obtained. The linkage 192 is therefore attached with one end 194 to the actuating lever 186 and with its other end 195 to an opener 196 of the 5/2 distributing valve 153.
When the actuating lever 186 is pivoted upward in the direction of the arrow by approximately 45° corresponding to a first opening path 197, the ball valve 185 is opened far enough so that compressed air flows through the overpressure line 183 and the air inlet 182 into the inner space 115 of the intermediate reservoir 102, until the necessary overpressure is built up in the inner space 115. In this first opening path 197 the opener 196 of the 5/2 distributing valve 153, which preferably is in the form of a piston slide, remains in its closed position. If now the actuating lever 186 is pivoted further upwardly over a second opening path 198 approximately to the vertical in the direction of the arrow, the ball valve 185 is opened further, and, simultaneously, the opener 196 is displaced to the right in the drawing by the linkage 192. The distributing valve 153 is now also opened, whereupon the pressure blast is initiated to break up the soil. Following the introduction of the substrate into the broken soil the actuating lever 186 is pivoted back into the initial position shown, so that the ball valve 185 is closed. In the process, the opener 196 may also be forcibly entrained to the left by means of the linkage 192 to close the distributing valve 153. In another preferred embodiment, the opener 196 may be pressured, for example by the force of a spring, to the left into the closing position.
The air supply for the ball valve 185 may be provided from a separate compressed air reservoir, not shown, and optimized by means of pressure reducers.
In view of the overpressure built up prior to the opening of the injection valve 111 in the intermediate reservoir 102 the counter pressure originating in the air jet 113 cannot act in the direction of the inner space 115. No air movement can thus take place from the air jet into the intermediate reservoir 102. Consequently, the substrate, especially heavy substrates, may be mixed without delay immediately following the breaking of the soil into the air jet 113 and inserted into the soil. | Apparatus and method for breaking up soil and introducing a substrate into the broken up soil. The substrate is contained in a reservoir. A series of pneumatic cylinders acting in timed sequence function to first open a rapid-closing valve for introducing a blast of compressed air for forcing a probe into the ground for breaking up the soil. The rapid-closing valve is then closed, a pressure drop sensed, and an injection valve opened to pressurize the reservoir to inject substrate into the fissures formed during the break up of the soil. The substrate may comprise fertilizers, curing substances or filling materials which, together with the compressed air with which they are injected, serve to better condition the soil for cultivation. If desired, additional compressed air lines may communicate with the interior of the reservoir for ensuring a positive pressure in the reservoir to carry out substrate injection. | 0 |
BACKGROUND OF THE INVENTION
Field of the Invention
This invention relates generally to a machine for burying and turning under the rice straw in a rice paddy.
Once the rice has been harvested from the rice paddy, traditionally the fields have had to be drained and allowed to dry so that the stalks, straw and stubble can be burned. Burning has been considered a necessity because parasitic action will invade the rice straw that has not been burned and destroy future new unharvested rice crops.
Admittedly a certain but very small percentage of rice straw has been harvested for other uses but by comparison the vast majority of rice straw left in the field must be burned off. Ecologically speaking to burn off these rice fields having stubble therein has been undesirable from a smog point of view, and indeed farmers have been restricted as to the days they are allowed to perform the burning.
The essence of this invention therefore, is to provide a machine which avoids the necessity of burning the rice stubble, thereby avoiding the undesirable ecological contamination, and also providing the farmer with more freedom to clear his field when he wants to. This is made possible by the structure to be described hereinafter in which the rice stubble is cut and buried in the mud covered over and left in water, thereby providing an environment hostile to the parasites.
Accordingly it is an object of this invention to provide a means for rice farmers to clear their land for subsequent plantings without the need for burning the stubble in the field.
It is another object of this invention to reduce the pollution attendant with burning rice fields by not burning them at all, plowing them under instead.
Other objects and advantages will become apparent in the following specification when considered in light of the attached drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a top plan view of the tractor showing the drum wheel assembly;
FIG. 2 is a side view thereof;
FIG. 3 is a front view of the tractor assembly as seen in FIG. 1;
FIG. 4 is an end view of the tractor;
FIG. 5 is a three quarter view of the wheel assembly showing the structural details therein; and
FIG. 6 is a side view of the wheel showing its effect on rice stalks in a rice paddy.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now to the figures in which like reference numerals indicate like parts throughout, the tractor is generally denoted by numeral 1.
FIGS. 1 through 4 generally show the tractor which has front and rear drum wheels denoted by numeral 4. FIGS. 5 and 6 show the details of these two wheels. On the outer periphery of wheel or drum 4 there are disposed knives 2 which as seen in FIG. 6 are depicted as being straight, they may be curved in either the forward or rearward direction. These knives are preferably six inches long and are supported on the cage drum by a plurality of triangular brace members 3. The cage drum is approximately six feet in diameter.
FIG. 6 shows the stages of compaction for the rice straw as effected by the knife and brace member. At stages A through C it will be observed that the rice stubble has been pushed below the surface of the mud and has been compacted down. Removal of the support brace and knife member is seen in stages D and E. The turbulance caused by the inner action of the drum brace and knife member has caused the opening into which the stubble has been put to start to collapse, and fill back up with mud. Stages F, G and H depict the equilibrium that is reached by having the knife blades cut and coact with the rice stubble and bury it under the ground.
It is important to reemphasize that the rice stubble has to be completely buried as well as inundated, for only if a minor portion of rice stubble is left exposed to the air and is left out standing in the water, it will be susceptible to parasitic attack which will infest and ruin subsequent rice crops. This is why that even today the state of the art for clearing rice fields has been to drain the field let the straw and stubble dry out and then burn it.
The front and rear drums 4 are supported and carried on an axle 15 which in turn is fastened to arms 6 which are disposed at the extremities of the axle. Arms 6 are connected to each other along the top portion of the tractor by brace members 13 for the front portion and 14 for the rear portion respectively. The orientation of the front and rear drum wheel members is regulated by the damping system denoted by the numerals 7 and 8. These may be a conventional shock absorber type of arrangement, or it may encompass a variable damping system to alter the motion of the front and rear cage wheels depending upon the terrain. The front and rear portions of the tractor are additionally fastened as seen in FIG. 2 at points 9 and 10 by a universal type coupling which permits substantial freedom of motion for the front and rear portions relative to each other, and this is a desirable feature since the tractor must climb over levees built to retain water in the paddies.
The front and rear drum wheels are self propelled by means of a hydrostatic drive which is incorporated within the drums 4 of the front and rear drum wheels. Hydraulic lines 5 communicate with the hydrostatic propulsion system which is generally denoted by numeral 12 best seen in FIG. 5. The hydrostatic actuation mechanism is run off of the diesel motor which sits on top of the tractor.
From the foregoing it will be apparent that the rice paddies can be plowed under and the rice shaft will be assured of being completely buried by virtue of the action of the knives which cuts and buries the straw most beneficially while the water is still in the paddy. This provides additional benefit for farmers who don't have to go to the additional expense of draining their fields. It will also be noted that the contour of the knives may also have a bent or curved portion to accommodate different soil conditions.
Having thus described the preferred embodiment of the invention it should be understood that numerous structural modifications and adaptations may be resorted to without departing from the spirit of the invention. | Disclosed herein is a self propelled drum wheel tractor for use in puddling rice paddies. A pair of drums having a plurality of knife elements disposed thereon serve to bury or puddle the rice stalk, while the field is still flooded. | 1 |
PRIORITY CLAIM
[0001] This application claims priority from European patent application No. 05425676.3, filed Sep. 28, 2005, which is incorporated herein by reference.
TECHNICAL FIELD
[0002] An embodiment of the present invention relates to a process for manufacturing thick suspended structures of semiconductor material, in particular that can be used as inertial (or seismic) masses in micro-electromechanical devices such as integrated accelerometers, to which the following description will make reference without this, however, implying any loss in generality.
BACKGROUND
[0003] Processes for manufacturing thick suspended structures of semiconductor material are known to the art. Said processes initially envisage providing a layer of semiconductor material, and etching the layer of semiconductor material from the back, for example via an anisotropic wet chemical etch in TMAH (Tetra-Methyl Ammonium Hydroxide), so as to define a thick structure having a desired shape. Then, a covering layer is joined, for example via anodic bonding, to the layer of semiconductor material, underneath the structure previously defined. In particular, the covering layer has a recess in a position corresponding to said structure so that, following upon bonding between the two layers, the structure will be suspended above a cavity.
[0004] By way of example, FIG. 1 shows an accelerometer 1 of a piezoresistive type, comprising a thick suspended structure, in particular an inertial mass, made as described above.
[0005] In detail, the accelerometer 1 comprises a first layer 2 and a second layer 3 , bonded to one another, for example, via anodic bonding. The first layer 2 is made of semiconductor material, whilst the second layer 3 may be made of semiconductor material, or, alternatively, of glass or plastic.
[0006] The first layer 2 comprises a bulk region 4 and an inertial mass 5 , mechanically connected to the bulk region 4 via thin and deformable connection structures 6 . The inertial mass 5 is formed via a TMAH etching of the first layer 2 , made from the back; with the same etching the connection structures 6 are defined. The second layer 3 has a function of covering and mechanical support, and has a cavity 8 , in a position corresponding to the inertial mass 5 , so as to ensure freedom of movement for the inertial mass 5 . Piezoresistive detection elements 9 , for example constituted by regions doped by diffusion, are made in the connection structures 6 and connected in a bridge circuit.
[0007] During operation, an acceleration sensed by the accelerometer 1 causes a displacement of the inertial mass 5 . Consequently, the connection structures 6 , fixed to the inertial mass 5 , undergo deformation, and the resistivity of the piezoresistive detection elements 9 varies accordingly, unbalancing the bridge circuit. Said unbalancing is then detected by a suitable electronic circuit, which derives therefrom the desired acceleration measurement.
[0008] The described manufacturing process is rather complex, due to the presence of a wet etching to be carried out from the back of a layer of semiconductor material, and the need to provide a bonding with a covering layer. For this reason, micro-electromechanical devices comprising suspended structures formed through said process may be characterized by large overall dimensions and high costs.
SUMMARY
[0009] An embodiment of the present invention is a process for manufacturing thick suspended structures of semiconductor material that will enable the aforementioned disadvantages and problems to be overcome, and in particular that will have a reduced complexity and lower production costs.
[0010] Consequently, according to an embodiment of the present invention, a process for manufacturing a suspended structure of semiconductor material and a semiconductor structure comprising a suspended structure of semiconductor material are provided.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] For a better understanding of embodiments of the present invention, an embodiment is now described, purely by way of non-limiting example and with reference to the attached drawings.
[0012] FIG. 1 is a cross-sectional view of a micro-electromechanical structure of a known type.
[0013] FIG. 2 is a top plan view of a wafer of semiconductor material, in an initial step of a process for manufacturing a suspended structure, according to an embodiment of the present invention.
[0014] FIG. 3 is a cross-sectional view at an enlarged scale of details of the wafer of FIG. 2 , taken along the line III-III, according to an embodiment of the invention.
[0015] FIGS. 4-8 are cross-sectional views of the wafer of semiconductor material in subsequent steps of the manufacturing process according to an embodiment of the invention.
DETAILED DESCRIPTION
[0016] A process for manufacturing thick suspended structures of semiconductor material is now described. This process is based, in part, upon the process described in the European patent application 04 425 197.3, which is incorporated by reference.
[0017] FIG. 2 (which, like the subsequent figures, is not drawn to scale) shows a wafer 10 of semiconductor material, in particular monocrystalline silicon of an N type with (100) orientation of the crystallographic plane, which comprises a bulk region 11 .
[0018] In an initial step of the manufacturing process, a resist layer is deposited on a top surface 10 a of the wafer 10 , and it is defined so as to form a mask 12 (see also the cross-sectional view of FIG. 3 ). In detail, the mask 12 covers an approximately square area having sides I of, for example, 300 μm, with the sides parallel to the flat ( 110 ) of the wafer 10 . The mask 12 has a lattice structure 12 a (as may be seen from the enlarged detail of FIG. 2 ), defining a plurality of openings 13 of an approximately square shape. The openings 13 have sides t of approximately one micron, for example, 0.8 μm, and the distance d between opposite sides of adjacent openings 13 is also approximately one micron, for example, 0.8 μm.
[0019] Using the mask 12 ( FIG. 4 ), an anisotropic dry chemical etching of the wafer 10 is then carried out, to form deep trenches 14 in a position corresponding to the openings 13 . The depth of the deep trenches 14 is of the order of microns or of tens of microns (for example, 10 μm), and the deep trenches 14 are separated from one another by walls 15 of semiconductor material, which form together a single separation structure, having a section corresponding to the lattice structure 12 a.
[0020] Next, the mask 12 is removed, and an epitaxial growth is performed in a de-oxidizing atmosphere (typically, in an atmosphere with a high hydrogen concentration, preferably with trichlorosilane—SiHCl 3 ). Due to the epitaxial growth, a silicon closing layer 16 is formed (shown only in FIG. 5 ), which has a thickness of the order of microns (for example, 5 μm) and closes the deep trenches 14 at the top, entrapping the gas present therein. In particular, before the deep trenches 14 are closed at the top, a growth of silicon occurs therein, causing a reduction in the dimensions of said trenches. At the end of the epitaxial growth, the deep trenches 14 consequently have an oval cross section elongated in a direction perpendicular to the top surface 10 a.
[0021] A first thermal annealing treatment is then carried out in an atmosphere containing hydrogen or another inert gas (for example, nitrogen or argon) or else a combination of hydrogen and of another inert gas, at high temperature (around or higher than 1000° C.) for a first time interval, which lasts some minutes or some tens of minutes. Advantageously, the first thermal annealing treatment is carried out in a hydrogen atmosphere, at a temperature of 1200° C., and the first time interval is no longer than 30 minutes.
[0022] The high temperature promotes a migration of the silicon atoms of the walls 15 , which tend to move into a position of lower energy. In particular, the silicon atoms migrate through adjacent lattice positions, preserving the lattice structure of perfect crystal of the silicon. On account of said migration, the individual deep trenches 14 evolve towards conformations with lower surface energy, for example, from oval shapes to shapes of a spherical type, and then merge together to form a single buried cavity 17 , which is uniform and entirely contained and insulated within the wafer 10 ( FIG. 6 ). For example, the buried cavity 17 has a thickness of 2 μm and a square cross section with sides of 300 μm. The main internal walls, i.e., the top and bottom walls, of the buried cavity 17 are substantially parallel to one another and to the top surface 10 a of the wafer 10 . A surface region 18 of semiconductor material remains above the buried cavity 17 ; this surface region 18 is constituted in part by epitaxially grown silicon atoms and in part by migrated silicon atoms, and has a first thickness w 1 (in a direction orthogonal to the top surface 10 a ). For example, said surface region 18 can form a thin membrane, which is suspended in a flexible and deformable way above the buried cavity 17 .
[0023] Next, according to an embodiment of the present invention, a second thermal annealing treatment is carried out at high temperature (around or above 1000° C.) for a second time interval, having a duration of tens of minutes or of some hours. The conditions and operative parameters of the second thermal annealing treatment may coincide with those of the first thermal treatment; i.e., the second treatment may also made in hydrogen atmosphere and at a temperature of 1200° C.; in addition, the duration of the second time interval may be longer than 30 minutes.
[0024] Due to the second thermal annealing treatment, a further migration of the silicon atoms occurs: in particular, the silicon atoms of the bulk region 11 that “face” the inside of the buried cavity 17 migrate and are displaced, in the direction indicated by the arrows in FIG. 7 , towards a central portion 18 a of the surface region 18 . The resulting effect is that, whereas the ends of the buried cavity 17 remain substantially at the same depth with respect to the top surface 10 a of the wafer 10 , the centre of the buried cavity 17 progressively shifts towards the bulk region, moving away from the top surface 10 a . The buried cavity 17 consequently assumes a profile having, in a section orthogonal to the top face 10 a , a central stretch substantially parallel to the top face 10 a , and lateral stretches, joined to the central stretch, inclined with respect to the top face 10 a by an angle α of approximately 30°. The thickness of the central portion 18 a of the surface region 18 progressively increases, and the surface region 18 is “strengthened” until it forms a suspended structure 20 , of large thickness (i.e., of tens of microns, for instance, more than 10 μm, or, more than 50 μm), above the buried cavity 17 . In particular, the suspended structure 20 has a central portion 20 a and lateral portions 20 b , which surround the central portion 20 a . The central portion 20 a has a second thickness w 2 greater than the thickness of the lateral portions 20 b and than the first thickness w 1 of the surface region 18 . In addition, the suspended structure 20 has a bottom portion (adjacent to the buried cavity 17 ) having substantially the shape of a truncated pyramid turned upside down, and a top portion (adjacent to the top surface 10 a ) substantially corresponding to the surface region 18 . In particular, the side walls of the truncated pyramid are inclined by the angle α (of 30°) with respect to the top surface 10 a of the wafer 10 , and the height of the pyramid is equal to the difference w 2 -w 1 between the second thickness and the first thickness.
[0025] Proceeding further with the second thermal annealing treatment, the migration of the silicon atoms continues, and thus the dimensions of the inclined side walls and the second thickness w 2 of the suspended structure 20 increase, until the semiconductor structure of FIG. 8 is obtained, with the suspended structure 20 that has a bottom portion having substantially the shape of a pyramid turned upside down, and with the buried cavity 17 that has a V-shaped profile in a section transverse to the top face 10 a.
[0026] The second thickness w 2 , as likewise the shape (whether of a truncated pyramid or of a pyramid), of the suspended structure 20 is consequently a function of the duration of the second time interval, i.e., of the duration of the second thermal annealing treatment: for example, in one embodiment FIG. 7 corresponds to a duration of 60 minutes, whilst FIG. 8 corresponds to a duration of 6 hours. The value of the second time interval that leads to the formation of the suspended structure of FIG. 8 (i.e., to the end of the process of migration of the silicon atoms) depends, as may be inferred, upon the starting dimensions of the surface region 18 a , or, in a similar way, upon the sides I of the mask 12 . In addition, also the value of the second thickness w 2 at the end of the process of migration is linked to the dimensions of the surface region 18 a by simple trigonometric relations; for example, given a side I of 300 μm, said value is approximately equal to 90 μm.
[0027] Advantageously, given the substantial uniformity of conditions and of operating parameters of the first and second thermal annealing treatments, just one thermal annealing treatment may be carried out, so that the second treatment is a continuation of the first treatment, with a total duration of the single thermal annealing treatment equal to the sum of the first and second time intervals. In general, said total duration is more than 30 minutes, for example between 60 and 600 minutes. The formation of the surface region 18 is in this case only an initial step of a single migration process of the silicon atoms, which then leads to the formation of the suspended structure 20 .
[0028] The suspended structure 20 can advantageously be used within a micro-electromechanical structure, for example as inertial mass in an accelerometer. In this case, in a way not illustrated, the manufacturing process can proceed with the formation of thin and deformable connection structures between the suspended structure and the bulk region 11 of the wafer 10 , and with the formation of transduction elements, for example of a piezoresistive type, in said connection structures.
[0029] The described manufacturing process has numerous advantages.
[0030] In particular, it does not involve bonding steps, in so far as the suspended structure 20 and the underlying buried cavity are formed within a single monolithic body of semiconductor material, with advantages in terms of manufacturing costs and complexity.
[0031] The suspended structure 20 can thus advantageously be used in semiconductor structures, for example as inertial mass in accelerometers of a resistive or capacitive type, or else in cantilever accelerometers (in this lafter case, the suspended structure 20 is carried by a beam, in a position corresponding to one end thereof, and is suspended above the buried cavity). The resulting semiconductor structures have small overall dimensions, given the absence of bonding between different layers and of wet etches carried out from the back.
[0032] It is moreover possible to control the thickness (and the shape) of the resulting suspended structures in a precise way according to the duration of the thermal annealing treatment.
[0033] The manufacturing process described enables integration of integrated circuits of a CMOS type within the suspended structure 20 (in a per se known manner which is not illustrated).
[0034] Finally, modifications and variations may be made to what is described and illustrated herein, without thereby departing from the scope of the present invention.
[0035] For example, the step of epitaxial growth that leads to closing of the deep trenches 14 at the top ( FIG. 5 ) may not be envisaged. In fact, it is possible to obtain closing of the deep trenches 14 via the subsequent thermal annealing treatment and the consequent migration of the silicon atoms of the walls 15 .
[0036] In the described manufacturing process wafers of semiconductor material of a P type, instead of an N type, may be used in an altogether equivalent way. The orientation of the crystallographic plane is advantageously (100), in so far as experimental tests have sometimes shown difficulty in obtaining the same structures starting from wafers with (111) orientation. In particular, in the case of (111) orientation, the deep trenches 14 may not merge into a single buried cavity 17 during the thermal annealing treatment.
[0037] As an alternative to what has been described, via the mask 12 a hard mask can be obtained, for example made of oxide, which can then be used for the etching of the wafer 10 that leads to the formation of the deep trenches 14 .
[0038] The structure of the mask 12 (or, in an equivalent way of the aforesaid hard mask) and the shape of the walls 15 and of the deep trenches 14 can vary with respect to what is illustrated. For example, the mask 12 can have a structure that is complementary to the one illustrated in FIG. 2 and can comprise a plurality of portions of a polygonal shape (for example, square or hexagonal), arranged in a regular way to define an opening shaped like a (square or honeycomb) lattice. More in general, the walls 15 can be constituted by thin structures capable of enabling complete migration of the silicon atoms during the annealing step that leads to the formation of the buried cavity 17 . The masks 12 having a lattice structure are, however, the most advantageous for use in the manufacturing process described.
[0039] Finally, the area over which the mask 12 extends may have different shapes; for example, it may have a rectangular or a generically polygonal shape.
[0040] Moreover, the structure 10 , or a die or IC in which the structure is located, may compose part of an electronic system such as the air-bag-firing system of an automobile. | A process for manufacturing a suspended structure of semiconductor material envisages the steps of: providing a monolithic body of semiconductor material having a front face; forming a buried cavity within the monolithic body, extending at a distance from the front face and delimiting, with the front face, a surface region of the monolithic body, said surface region having a first thickness; carrying out a thickening thermal treatment such as to cause a migration of semiconductor material of the monolithic body towards the surface region and thus form a suspended structure above the buried cavity, the suspended structure having a second thickness greater than the first thickness. The thickening thermal treatment is an annealing treatment. | 1 |
BACKGROUND
[0001] The present disclosure concerns the technical field of garments and worn apparel. More particularly, the present configuration is in the technical field of garment/fabric/synthetic material that can be worn and serve as a carrying backpack.
[0002] A backpack (also called rucksack, knapsack, packsack, or pack) is, in its simplest form, a cloth sack carried on one's back and secured with two straps that go over the shoulders, but there can be exceptions. Lightweight types of backpacks are sometimes worn on only one shoulder strap. The present invention is an exception that can be worn like a vest with or without sleeves.
SUMMARY
[0003] A wearable luggage appliance for carrying goods of the wearer distributes the weight of the carried goods across the front and back of the wearer for mitigating a gravitational load conventionally borne by shoulder straps on the shoulders of a wearer. The luggage appliance includes integrated front and back portions connected by continuous side panels that distribute downward forces exerted on cargo or items disposed in compartments on the back portions onto the front portion. Heavy loads on a conventional back-disposed carrying appliance (i.e. backpack) typically concentrated loads on shoulder straps that tend to apply downward and backward forces on the shoulders and upper body of the wearer. The wearable luggage appliance redistributes these rear loads across the front (chest and torso) of the wearer by an integrated vest construction having continuous seams across the shoulders and sides (around armholes) for evenly distributing the downward and backward forces, reducing wearer fatigue and pressure concentrated on the shoulders.
[0004] Configuration herein are based, in part, on the observation that conventional wearable luggage appliances employ shoulder straps for supporting the weight of a carried load. The shoulder straps distribute the load substantially on the shoulder of the wearer. Accordingly, conventional approaches suffer from the shortcoming that the wearer's back and relevant skeletal and muscular structures bear much or all of the weight from conventional worn luggage appliances (e.g. backpacks). Conventional approaches may employ a strap or tether on a lower portion, but such a tether serves merely to keep the load in place, and is not structural or load bearing. For example, backpack straps keep the load close to the wearers back, but do not distribute the load to a front panel that bears the weight across the front torso (chest and abdomen) of the wearer. Even if drawn tightly, such straps merely increase tension on the lower abdomen, and do not assist in load bearing capacity because they do not distribute the load tension across a larger portion of the torso. Similarly, so-called “fanny” packs focus tension on a lower portion of the abdomen, and do not direct the load toward the upper front torso.
[0005] Accordingly, configurations herein substantially overcome the above described shortcomings of conventional wearable luggage appliances by distributing tension forces resulting from a load on the rear upper torso (back) across the front torso of the wearer, thus relieving the downward force on the shoulders and back caused with conventional backpacks. A weight dispersion panel, that may be selectively zippered or otherwise closeable, integrates tension from a load carried on the rear torso and/or shoulders to the front torso of the wearer such that carried loads are more evenly distributed, therefore reducing musculoskeletal strain and associated discomfort.
[0006] The present appliance may be defined as a device that serves both as a backpack and a vest for users to use for carrying load with ease and using the front pockets on the vest for other carrying purposes. Backpacks are often preferred to handbags for carrying heavy loads or carrying any sort of equipment, because of the limited capacity to carry heavy weights for long periods of time in the hands. Large backpacks, used to carry loads over 10 kg (22 lbs), usually offload the largest part (up to about 90%) of their weight onto padded hip belts, leaving the shoulder straps mainly for stabilizing the load. This improves the potential to carry heavy loads, as the hips are stronger than the shoulders, and also increases agility and balance, since the load rides nearer the wearer's own center of mass. However, such a construction tends to focus substantial tension on the lower abdomen or beltline where the hip belts engage.
[0007] In further detail, in a particular configuration as discussed further below, the disclosed approach teaches a wearable containment appliance including a front portion and a back portion, in which the front and back portions are integrated for encircling a torso of the wearer, and at least one containment receptacle on the back portion for containing weighted items. The containment receptacle (containment) is typically at least one textile pouch or pocket for containing articles. The containment attaches by textile straps or panels to at least one weight dispersion panel on the front portion for spreading forces exerted by the back portion across the front portion, in which the front portion engages the front torso of the wearer. In this manner, the weight dispersion panel combines and integrates tension resulting from the weight of the containment and disperses or spreads the weight (force) across a larger area on the front torso.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] The foregoing and other objects, features and advantages of the invention will be apparent from the following description of particular embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention.
[0009] FIG. 1 is a perspective view of a commonly used vest (front and back) and a backpack.
[0010] FIG. 2 is an exterior view of the three sections of a vest, the middle section of the vest includes the drawing of a backpack as a genesis of the invention. This is a combination of FIG. 1 ;
[0011] FIG. 3 is a plan view of the exterior of the back view of the present invention;
[0012] FIG. 4 is a back view of the present invention with a hood version;
[0013] FIG. 5 is a back view of an unfurled garment according to a further configuration;
[0014] FIG. 6 is an inside front view of the garment of FIG. 5 ; and
[0015] FIG. 7 is a side profile view of the garment of FIGS. 5 and 6 around a wearer.
DETAILED DESCRIPTION
[0016] A weight dispersing wearable containment appliance, in a particular configuration, takes the form of a supportive vest integrated with a back worn storage appliance having the appearance of a backpack which may be employed with or without sleeves and may be worn like any typical, ordinary or specialized device of any style for the optional purpose of a carrying load and maybe worn as a fashion in any setting. Such an appliance, or device, takes the appearance of a backpack, for purposes such as hiking and camping, and may also be employed for everyday use such as by students for carrying books and the like. In contrast to conventional hiking equipment, a rigid, bulky frame is not required, further facilitating usage as an everyday carrying appliance such as a briefcase, purse or duffel bag. The various configurations may also be provided with a plurality of different color variations.
[0017] Conventional backpacks are typically either large or exceedingly difficult to maneuver from the back. It is difficult to move these devices into a house or office because they are large and heavy. Moving such devices typically requires several strong persons, or a sturdy wheeled vehicle such as a reinforced wagon or hand cart. The difficulties of bringing such a device into a house or office are multiplied when stairs must be climbed. Further, it is not an uncommon experience to realize that the device cannot pass through the doorway without widening. Further, the devices cannot readily be moved from spot to spot once inside a room,
[0018] A vest is a garment covering the upper body. The term has different global meanings, for example a waistcoat has a full vertical opening in the front which fastens with buttons or snaps. Both single-breasted and double-breasted waistcoats exist, regardless of the formality of dress, but single-breasted ones are more common. In a three piece suit, the cloth used matches the jacket and trousers.
[0019] Such a vest may commonly be defined as a sleeveless under-jacket. This is called a waistcoat in the UK and many Commonwealth countries, or a vest in the U.S. and Canada. It is often worn as part of formal attire, or as the third piece of a lounge suit. Other sleeveless jackets also exist in different forms. The term “vest” may refer to other outer garments, such as a sports tank top, or a padded sleeveless jacket popular for hunting, commonly known as a hunting vest. Another common variant is the fishing vest which carries a profusion of external pockets for carrying fishing tackle. The term jerkin is also used to refer to this sort of sleeveless outdoor coat. A sweater vest is an American and Canadian English term. Such a garment may also be called a slipover, sleeveless sweater, or tank top (which may also refer to a type of sleeveless shirt). Banyan is an Indian garment and it is commonly called a vest in Indian English. All these variations can be made with the same style of combination of vest and backpack.
[0020] The advantages of the present approach include, without limitation, that the wearable appliance is easy to distribute a load on the back, hip and shoulder without excessive or disproportionate pressure exertion on one region of the upper body. It is easy to remove and consolidated when passing through security check points. Configurations disclosed herein generally will hang on a hook or clothes hanger when stored in a closet or locker through most doorways without any widening. Further, the various configurations may easily be unzipped unbuttoned at any time. In a broad embodiment, the present configuration includes a vest-like backpack apparatus which may be sleeved or sleeveless.
[0021] Referring to FIGS. 1-7 , in a particular configuration, the disclosed wearable containment appliance includes a front portion and a back portion, such that the front and back portions are integrated for encircling a torso of the wearer and at least one containment receptacle on the back portion for containing weighted items. The apparatus further includes at least one weight dispersion panel on the front portion for spreading forces exerted by the back portion across the front portion. In further detail, the front portion may define a vest attached to the back portion along a continuous side panel, and the back portion defines a backpack having a plurality of pockets or similar storage receptacles. The weight dispersing portion is adapted to carry downward force exerted on the wearer from the containment receptacle, therefore avoiding a concentrated and rearward force exerted on the wearer from the back portion by the tension carried to the weight dispersing panel.
[0022] FIG. 1 is a perspective view of a commonly used prior art vest (front and back) and a conventional backpack. Referring to FIG. 1 , a vest 1000 closes along a front seam 1001 to form a continuous garment. A backpack 1010 employs shoulder straps 1011 for bearing the load of a payload contained within.
[0023] FIG. 2 is an exterior view of the three sections of the wearable containment appliance disclosed herein. Referring to FIG. 2 , a back portion 100 is a textile or other suitable flexible material for engaging the rear torso of a wearer. A containment 102 , which may include multiple pockets or compartments 104 is attached to the back portion and may be continuous such that the back portion 100 is one of several sides of each of the pockets 104 . The containment compartments 104 on the back portion are adapted for containing weighted items. A plurality of side portions 110 , 112 attach to the back portion at side seams 114 , 116 , and are adapted to completely encircle the torso of the wearer at front seams 120 , thereby forming a front portion. Upon closure of the front portion, the front and back portions 100 become integrated for encircling a torso of the wearer. The side seams 114 , 116 are configured to transfer tension from the back portion 100 to the side portions 110 , 112 and, in turn, to the front seam 120 . Selective closures engage to secure the front seam, discussed further below. Similarly, shoulder straps 130 interconnect the front and back portion 100 for bearing a downward force (continuity shown by dotted lines 132 ). Closure of the front seam 120 defines a weight dispersion panel on the front portion for spreading forces exerted by the back portion across the front portion.
[0024] FIG. 3 is a plan view of the exterior of the back view of the present invention. Referring to FIG. 3 , the back 100 includes pockets 104 in various configurations. The back portion 100 of the containment 102 may defines a backpack having a plurality of pockets 104 .
[0025] FIG. 4 is a back view of the present invention with a hood version being worn by a wearer 140 . Referring to FIGS. 2-4 , the back portion 100 and side portions 110 , 112 encircle the wearer 140 at the torso and chest. Particular configurations may also include a hood 136 .
[0026] FIG. 5 is a back view of an unfurled garment according to a further configuration. Referring to FIGS. 2 , 3 and 5 , the back portion 100 integrates with a left side portion 110 and a right side portion 112 via seams 150 , which may be stitched, molded, fused, glued or attached by other suitable means. The side panels 110 , 112 are engageable by attachments 152 - 1 , 152 - 2 ( 152 generally), which define a suitable fastening mechanism extending from the side portions 110 , 112 , as a wrap around panel 110 - 1 , 112 - 1 to define the weight dispersion panel 154 , defined by integrated portions 154 - 1 , 154 - 2 . The attachments 152 extend from the side panels via straps 156 for securement at the front torso.
[0027] The backpack includes at least one pocket 104 , defined by a main zipper compartment, and a small miscellaneous pocket 104 ′, as well as others, may be included. Hand pockets 148 and front slip pockets 149 complement a plurality of pockets 104 . A zipper compartment expander 105 , as is common with soft-sided luggage appliances, may also be employed. Armholes 158 are reinforced to further “snug” the tension of the weight dispersion panel 154 .
[0028] FIG. 6 is an inside front view of the garment of FIG. 5 . Referring to FIGS. 5 and 6 , a zipper 170 - 1 , 170 - 2 ( 170 generally), affixes both front panels 110 , 112 in addition to the attachments 152 , for providing a continuous seam along the integrated portions 154 - 1 , 154 - 2 defining the weight dispersion panel 154 . Closure of the integrated portions facilitates tension distribution along the full torso from abdomen to chest of the wearer 140 .
[0029] A plurality of back supports 160 , such as resilient cushioning (foam, polyester, or other) enhances comfort and support for maintaining tension along the weight dispersion panel 154 . Interior zipper pockets 162 may also be provided.
[0030] FIG. 7 is a side profile view of the garment of FIGS. 5 and 6 around a wearer the wearer 140 . The zipper 170 is operable by a handle 170 ′, and may extend to the neckline of the wearer 140 for maximizing the area of the weight dispersion panel 154 . By joining the side panels 110 , 112 to integrate the integrated portions 154 - 1 , 154 - 2 along the front seams 120 from the attachments 152 and extending to an upper travel range of the zipper 170 , the range 154 ′ of the weight dispersion panel 154 is effectively maximized to the torso length of the wearer 140 . Other inclusions are an extension zipper 180 and miscellaneous pouch 182 to the main zipper pocket 104 and other pockets.
[0031] Therefore, the weight dispersion panel 154 occupies a front portion defining a vest attached to the back portion along a continuous side panel 110 , 112 . The weight dispersion panel 154 is adapted to carry downward force exerted on the wearer 140 from the containment receptacle 104 . The integration of the front and back 100 portions therefore avoids a concentrated and rearward force exerted on the wearer 140 from the back portion 100 by the tension carried to the weight dispersion panel 154 . The weight dispersion panel 154 therefore includes a plurality of selectively engageable panels, 154 - 1 , 154 - 2 although additional or unitary panels could be employed, such that the selectively engageable panels 154 - 1 , 154 - 2 maintain tension with the back portion 100 when engaged via the attachment 152 and the zipper (or other) closure 170 . The weight dispersion panel 154 is adapted to effectively distribute weight across the front torso (chest and abdomen) of the wearer 140 , and the weight dispersion panel 154 avoids concentration of the transferred force at the lower torso and beltline of the wearer 140 .
[0032] While the straps 156 facilitate integration of the front and back portion 100 by maintaining tension between the front and back portions 100 , the weight is distributed across the torso by the weight distribution panel 154 in the front and the wrap around panels 110 - 1 , 112 - 1 . In contrast to conventional approaches, such as fanny packs and beltline straps, the weight dispersion panel 154 distributes tension across the full area of the front torso engaged by the range 154 ′ of the weight dispersing panel, while the conventional approaches simply increase compression on the abdomen of the wearer without providing any “lift.” Conventional backpack straps keep the load close to the wearers back, but do not distribute the load to a front panel that bears the weight across the front torso (chest and abdomen) of the wearer.
[0033] The wrap around panels 110 - 1 , 112 - 1 may comprise a continuous flexible panel between the front and back portions 100 for integrating the front and back portion 100 , such that the straps maintain tension between the front and back portions along a continuous seam 150 . The seam 150 maintains tension along the side panel 110 , 112 , rather than just at the location of the straps 156 . The engagement of the weight distribution panel (front) employs a combination of the attachments 152 and the zipper 170 , effectively providing a selective closure for engagement and disengagement of a plurality of panels 154 defining the front portion, such that the engaged panels 154 - 1 , 154 - 2 define the weight dispersion panel 154 for accommodating the tension resulting from the spread forces. Alternate arrangements for the selective closure may include a unitary or combination of zipper, snaps, hook and loop, buttons, and latch.
[0034] The disclosed appliance distributes weight from the containment in such a manner that user fatigue and stress is mitigated. Accordingly, the appliance performs a method for dispersing weight across an upright torso of a carrier, or wearer 140 , by disposing a load in a containment 102 on the torso, in which the containment 102 has an upper attachment such as shoulder straps 130 for supporting the containment 102 on the torso. The appliance transfers forces from the containment 104 to an opposed side of the torso (front of the wearer 140 ) by engaging the containment with a lower support defined by the weight dispersion panel 154 , such that the lower support encircles the torso of the wearer 140 . The lower support is adapted for tensioning to effectively transfer the load from the containment 104 to the opposed side, and is also adapted for tensioning the upper attachment (straps 30 ) by interconnecting the upper attachment to the lower support on the opposed side, as the zipper 170 is closed to define the weight dispersion panel 154 as covering the front of the wearer 140 .
[0035] Interconnection of the straps 130 and weight distribution panels 154 is for linking tensioned loads exerted on the containment 102 , such that the linking transfers the load to the opposed side, i.e. the front of the wearer 140 . The disclosed arrangement disposes the containment 102 on a rear torso of a wearer 140 , such that the opposed side is defined by a front torso of the wearer 140 .
[0036] As indicated above, lower support further comprises a plurality of panels (weight distribution panel portions 154 - 1 , 154 - 2 ), each adapted to engage the front torso, such that the panels 154 -N are adapted for selective engagement via the zipper 170 for establishing the tension. Upon closure, the panels 154 - 1 , 154 - 2 tension the wrap around panels 110 - 1 , 112 - 1 , forming a complete tensioned enclosure encircling the torso of the wearer 140 .
[0037] Tensioning the lower support defined by the panels 154 - 1 , 154 - 2 may further include selectively engaging closures such as the attachments 152 between the panels 154 - 1 , 154 - 2 defining the lower support. As indicated above, such a selective closure may include a latch mechanism as shown, and at least one of zipper, snaps, hook and loop, or buttons. It should be noted that although both the attachments 152 of the straps, and the closure of the engageable panels 154 - 1 , 154 - 2 contribute to a system of weight distribution, and that either could be employed alone for transferring and distributing loads as disclosed above. The engaged panels 154 - 1 , 154 - 2 therefore define a weight dispersion panel adapted to distribute weight across the front torso (chest and abdomen) of the wearer 140 , such that the weight dispersion panels 154 avoid concentration of the transferred force at the lower torso and beltline of the wearer 140 .
[0038] While the foregoing written description of the invention enables one of ordinary skill to make and use what is considered presently to be the best mode thereof, those of ordinary skill will understand and appreciate the existence of variations, combinations, and equivalents of the specific embodiment, method, and examples herein. The invention should therefore not be limited by the above described embodiment, method, and examples, but by all embodiments and methods within the scope and spirit of the invention as claimed. The disclosed apparatus has been particularly shown and described with references to embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims. | A wearable luggage appliance for carrying goods of the wearer distributes the weight of the carried goods across the front and back of the wearer for mitigating a gravitational load conventionally borne by shoulder straps on the shoulders of a wearer. The luggage appliance includes integrated front and back portions connected by continuous side panels that distribute downward forces exerted on cargo or items disposed in compartments on the back portions onto the front portion. Heavy loads on a conventional back-disposed carrying appliance (i.e. backpack) typically concentrate loads on shoulder straps that tend to apply downward and backward forces on the shoulders and upper body of the wearer. The wearable luggage appliance redistributes these rear loads across the front (chest and torso) of the wearer by an integrated vest construction having continuous seams across the shoulders and sides for evenly distributing the downward and backward forces, reducing wearer fatigue. | 0 |
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Patent Application Ser. No. 60/065,044 filed Nov. 11, 1997 and entitled IMPROVED STRADDLE ARM FOR RIDER REACH FORK LIFT TRUCK which is incorporated herein by reference.
BACKGROUND OF THE INVENTION
The present invention relates in general to fork lift trucks and, more particularly, to an improved straddle arm for supporting the forward end of such trucks while permitting free movement of forks carried by the trucks. While the present invention is generally applicable to fork lift trucks, it is described herein with reference to a rider reach fork lift truck, for which it is particularly applicable and initially being used.
Rider reach fork lift trucks are typically provided with a pair of forwardly extending straddle arms mounted outside the forks where they do not impede the lowering of the forks, and any load supported upon the forks, to the floor. The straddle arms carry one or more wheels to support the weight of the truck of course including any load carried by the forks. In prior art trucks, straddle arms are attached to a truck by means of a lateral member which is typically a box structure formed by a pair of L-shaped or U-shaped steel components welded together.
FIG. 1 shows one example of prior art straddle arm construction. A straddle arm 1 is welded to a lateral member 2 which in turn is welded to a mast assembly 3 at the forward end of a power unit 4 . The lateral member 2 is made of two components which are welded together at the front 5 of the lateral member 2 and at the rear 6 of the lateral member in substantially the same manner. The truck supporting force applied to wheels at the forward end of the straddle arm 1 results in a considerable amount of torque being transferred through the lateral member 2 to the mast assembly 3 such that the lateral member 2 must be substantial and securely welded .
There is an ongoing need to improve lift truck design to provide more efficient structure s and manufacturing techniques.
SUMMARY OF THE INVENTION
With regard to straddle arms for lift trucks, this need is currently met by the invention of the present application wherein the lateral member of each straddle arm is formed from a cylindrical section of steel pipe or tubing. Advantageously, the cylindrical tubing section is continuous in its circumference, thereby evenly distributing the torque which is transferred from the forwardly extending portion of the straddle arm to the mast assembly. Further, the cylindrical tubing section does not have to be constructed by welding two components together so that it eliminates the two weldments necessary for construction of the prior art lateral member and thereby reduces the time of construction. As an additional advantage, the straddle arm of the present application presents a smooth, rounded shape at the point of attachment of the arm to the mast assembly which is visually appealing.
In accordance with one aspect of the present invention, a fork lift truck comprises power unit and a mast assembly secured to the power unit. A pair of forks are mounted to the mast assembly and movable in height between a lowered position and plurality of raised positions. A pair of straddle arms are spaced outwardly from the forks and secured to opposite sides of the mast assembly. Each of the straddle arms comprises an arm member extending forwardly from the power unit, and a lateral cylindrical member extending axially between the arm member and the mast assembly to couple the arm member to the mast assembly. Each of the straddle arms may further comprise a torque arm coupled between the arm member and the lateral cylindrical member.
Preferably, the torque arm comprises a teardrop shaped solid steel member having a rounded end which tapers to a generally pointed end, the member including a cutout toward the generally pointed end for receiving the arm member. The arm member and the torque arm are welded together such that an inside surface of the arm member and an inside surface of the torque arm are flush with one another to define an inner surface for engaging the lateral cylindrical member. A first end of the lateral cylindrical member is welded to the inner surface and a second end of the lateral cylindrical member is welded to the mast assembly. The first and second ends of the lateral cylindrical member can be beveled to facilitate welding the lateral cylindrical member to the mast assembly and to the surface of the arm member and the torque arm.
In accordance with another aspect of the present invention, a straddle arm for a fork lift truck comprises an elongated arm member, a cylindrical member, and a torque arm coupled to the arm member and the cylindrical member. Preferably, the torque arm is a teardrop shaped solid steel member having a rounded end and a pointed end and including a cutout in the pointed end for receiving the elongated arm member therein. The elongated arm member and the torque arm are combined and welded together to form a surface for engaging a first end of the cylindrical member. The first end of the cylindrical member is welded to the surface formed by combining the elongated arm member and the torque arm. Both the first end of the cylindrical member and a second end thereof can be beveled to facilitate welding at the first and second ends.
In accordance with still another aspect of the present invention, a method of making a fork lift truck comprises providing a power unit and securing a mast assembly to the power unit. A pair of forks are mounted to the mast assembly for movement in height between a lowered position and a plurality of raised positions. A cylindrical member is secured to each side of the mast assembly so that axes of the cylindrical members are generally horizontal and the cylindrical members extend outwardly from the mast assembly. An arm member is coupled to each of the cylindrical members so that the arm members are spaced outwardly from the forks. Preferably, the step of coupling an arm member to each of the cylindrical members comprises providing a teardrop shaped torque arm member having a rounded end which tapers to a generally pointed end and forming a cutout in the torque arm toward the generally pointed end for receiving the arm member. The arm member is welded to the torque arm with an inside surface of the arm member and an inside surface of the torque arm being flush with one another to define an inner surface for engaging the cylindrical member. The cylindrical member is welded to the inner surface. Preferably, the method further comprises beveling first and second ends of the cylindrical members to facilitate welding the cylindrical members
It is, thus, an object of the present invention to provide an improved straddle arm for a fork lift truck including a cylindrical member for coupling an arm member to a mast assembly of the truck.
Other objects and advantages of the invention will be apparent from the following description, the accompanying drawings and the appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a prior art straddle arm construction for a fork lift truck;
FIG. 2 is a perspective view of a rider reach fork lift truck incorporating the present invention;
FIG. 3 is a side elevational view of the rider reach truck of FIG. 2;
FIG. 4 is a rear perspective view of the left straddle arm and mast assembly of the rider reach truck of FIG. 2;
FIG. 5 is a front perspective view of the left straddle arm and mast assembly of the rider reach truck of FIG. 2; and
FIG. 6 is an exploded front view of the left straddle arm of the rider reach truck of FIG. 2 with the mast assembly.
DETAILED DESCRIPTION OF THE INVENTION
FIGS. 2 and 3 show a rider reach truck 10 , specifically a 42 inch wide model 5000 rider reach truck manufactured by Crown Equipment Corporation. The truck 10 includes a power unit 15 including a battery compartment 20 , an operator's compartment 25 , a mast assembly 30 , an overhead guard 35 , and a pair of forks 40 carried by a fork carriage mechanism 45 .
The truck 10 is supported at four points which are provided by a steerable, powered wheel 50 located at the left rear of the power unit 15 as shown in FIG. 2., a caster wheel 55 located at the right rear of the power unit 15 as shown in FIG. 2, and two sets of outrigger wheels 60 supported on a pair of straddle arms 70 (only one of which, the left straddle arm, is shown in the drawings) extending from the mast assembly 30 at the front of the truck 10 . The straddle arms 70 are attached at the lower end of the mast assembly 30 and extend laterally outwardly to allow the forks 40 , and any loads/pallets carried thereby, to be lowered to the floor between the straddle arms 70 without interference.
As shown in FIGS. 4-6, each of the straddle arms 70 is formed from a forwardly extending solid steel bar or arm member 72 . A pair of bearing plates 74 is attached to the forward end of the arm member 72 with wheels 60 supported for rotation between the pair of bearing plates 74 . A torque arm 76 is coupled between the arm member 72 and the mast assembly 30 and, as shown in FIGS. 4-6, is teardrop shaped having a rounded end 76 A which tapers to a generally pointed end 76 B. The torque arm 76 is a solid steel component, approximately 3 inches thick, that includes a cut-out 85 into which the forwardly extending arm 72 is placed and then welded to the torque arm 76 .
In the illustrated embodiment, the mast assembly 30 includes a vertically extending member, a side plate 34 and a transverse plate 36 . The side plate 34 is welded to the vertical member 32 around its periphery illustrated at 35 and plates 34 and 36 are welded together. A lateral cylindrical member 80 extends between the arm member 72 and the mast assembly 30 . When the arm member 72 and the torque arm 76 are welded together, an inside surface of the arm member 72 and an inside surface of the torque arm 76 are flush with one another to define an inner surface for engaging the cylindrical member 80 . The inside surfaces of the torque arm 76 and the arm member 72 , i.e., the inner surface, is welded to a first end 80 A of the cylindrical member 80 around its periphery illustrated at 83 while a second end 80 B of the cylindrical member 80 is welded to the mast assembly 30 or, more precisely for the illustrated embodiment, to the side plate 34 around its periphery illustrated at 82 . Preferably, the ends 80 A, 80 B of the cylindrical member 80 are beveled to facilitate welding the cylindrical member 80 to the plate 34 and to the inside surfaces of the torque arm 76 and the arm member 72 , see FIG. 6 .
The torque arm 76 and cylindrical member 80 thus transfer weight from the wheels 60 at the forwardly extending portion of the straddle arm to the mast assembly 30 with the torque being evenly distributing by the construction of the straddle arm of the present application.
Thus, in the present invention, a strong, visually appealing straddle arm is provided, which requires fewer assembly steps than the prior art.
Having thus described the invention of the present application in detail and by reference to preferred embodiments thereof, it will be apparent that modifications and variations are possible without departing from the scope of the invention defined in the appended claims. | Each straddle arm of a lift truck is formed from a cylindrical section of steel pipe or tubing which is continuous in its circumference, to evenly distribute the torque which is transferred from a forwardly extending portion of the straddle arm to a mast assembly of the truck. | 1 |
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This is divisional of U.S. application Ser. No. 15/066,818 filed Mar. 10, 2016, which is a divisional of U.S. application Ser. No. 14/791,622 filed Jul. 6, 2015, now U.S. Pat. No. 9,315,550, which is a divisional of U.S. application Ser. No. 13/551,878 filed Jul. 18, 2012, now U.S. Pat. No. 9,101,687, which is a continuation-in-part application of U.S. application Ser. No. 12/729,046 filed Mar. 22, 2010, now U.S. Pat. No. 8,586,539, which is a continuation-in-part application of U.S. application Ser. No. 10/521,628 filed Sep. 8, 2005, now U.S. Pat. No. 7,700,721 (all herein incorporated by reference), which is the U.S. National Stage of International Application No. PCT/GB2003/003016, filed Jul. 15, 2003 (published in English under PCT Article 21(2)), which in turn claims the benefit of Great Britain patent application no. 0216286.5 filed Jul. 15, 2002.
FIELD
[0002] This disclosure relates to novel supramolecular aggregates, polymers and networks made by beta-sheet self-assembly of rationally-designed complementary peptides, and their uses as for example as responsive industrial fluids (oil exploration), as personal care products, as tissue reconstruction devices (e.g., dental reconstructive devices), or as controlled drug delivery systems.
BACKGROUND
[0003] International Patent Application No WO 96/31528 (Boden et al.) describes novel rationally designed peptides which self-assemble in one dimension to form beta sheet tape-like polymers. The tapes above a critical peptide concentration (typically above 0.3% v/v peptide) become physically entangled and gel their solutions in organic solvents or in water. The monomeric or single peptide gels possess the specific property of being programmable to switch from the gel state to a fluid or stiffer gel state in response to external chemical or physical triggers. The self-assembly of peptides into beta tape aggregates follows a hierarchical system, as the concentration of peptide increases they will begin to form beta tapes, as the concentration of peptide increases further two beta tapes will interact with each other to form a ribbon, as the concentration of peptide increases yet further ribbons will interact with each other to form fibrils and finally if the concentration increases high enough fibrils can interact to form fibres.
[0004] It has recently been found that the tapes having chemically distinct opposing surfaces can give rise to an hierarchy of other self-assembled, supramolecular structures as a function of increasing peptide concentration: ribbons (two stacked tapes), fibrils (many ribbons stacked together) and fibres (entwined fibrils). All these beta-sheet polymers appear twisted because of the peptide chirality. A theoretical model has been developed which rationalises this self-assembly process of beta-sheet forming peptides using a set of energetic parameters ε j . The magnitudes of ε j define the peptide concentration ranges over which each type of polymer will be stable.
[0005] Complementary peptide gels are a special case of peptide gels. The main differences between single peptide gels and complementary peptide gels are that in single peptide gels, gelation can be triggered by specific environmental conditions typically specific pH and/or salinity. This property can create a problem in the case of usage of peptide gels in medical applications, i.e. the peptide fluid solution eg in pure water, hits the physiological solution and immediately transforms into a gel, which can act like a gel plug, preventing further diffusion of the peptide solution to fill a large cavity or to form an interpenetrated network inside another porous matrix for example a decellularised tissue matrix. In the case of the complementary peptide gels, it is possible to overcome this problem by administering first peptide A which is in a low viscosity fluid monomeric state, this is then followed by administering the complementary peptide B which is also in a low viscosity fluid monomeric state. In this case, the formation of the peptide gel network only takes place by the coexistence of A and B in the same volume and their interaction and self-assembly ( FIG. 1 ), rather by the presence of any other chemical or physical conditions of the solution, i.e. pH, salinity or specific counterions e.g., Ca+2. This makes complementary peptide gelation in situ a much more reliable event and much more likely to happen in the whole space that is available rather than only at the entrance point of a cavity or only on the surface of a porous material.
[0006] A further difference between single peptide and complementary peptide self-assembly is that the latter typically relies on complementary intermolecular electrostatic interactions. This causes very high affinity between adjacent self-assembling peptides, much higher than it would normally by achieved by single peptide self-assembly. Since the affinity between complementary peptides is expected to be higher than for single peptides, then the critical concentration (c*tape) for tape self-assembly will be expected to be much lower for complementary peptides than for single peptide tapes. The magnitude of c*tape ( FIG. 2 ) relates to how fast or how slow a peptide gel will dissolve out of the injection site in situ. Peptide gels that are required to have as long a lifetime as possible in vivo, must have as low c*tape value as possible. Therefore complementary peptides provide a way to form an injectable gel in situ that will be expected to be much more long lived and therefore acting for much longer in vivo, than their corresponding single peptide gels.
[0007] A yet further difference between single peptide tapes and complementary peptide tapes is that the complementary ones provide a lot more surface versatility than single peptide gels because they consist of alternating peptides A and B ( FIG. 3 ). Therefore they provide new opportunities to control distances between functional groups and to introduce new surface functionalities, thus extending the possible bioactive properties of this class of peptide gels.
SUMMARY
[0008] We have shown that by appropriate peptide design we can produce polymers comprising tapes, ribbons, fibrils or fibres by simply mixing a pair of complementary peptides irrespective of controllable environmental conditions or changes such as the pH, the ionic strength of the solution or temperature. In particular, complementary peptides can be designed which, when combined, self-assemble to form one or other of these polymers.
[0009] We have recently discovered that this hierarchy of polymers can be formed by mixing complementary peptides together (alternating co-polymers). For example, we have shown that complementary peptide P 11 -13 and P 11 -14 (Table 1A and 1B) when contacted together immediately undergo gelation, in all cases of the complementary peptides of the present invention apart from P 11 -26/27, gelation took place instantly upon mixing of the separate fluid monomeric peptide solutions at all concentration equal to or higher than c*gel. The formed gel remained stable over time confirming apparent equilibrium behaviour, the complementary peptides of the present invention provide significant advantages over the prior art monomeric peptides having an overall net charge of +/−2 as there is no requirement for controlling environmental conditions such as pH, salinity or presence of specific counterions such as Ca ++ .
[0010] According to the present invention there is provided alternate co-polymer beta-sheet polymeric tapes, ribbons, fibrils and fibres made by the self-assembly of more than one complementary peptides. The complementarity of the peptide originating from their charges e.g., net positive charge on one peptide and net negative charge on the other peptide to provide an overall net charge of +/−2 per pair of complementary peptides and under standard physiological conditions of pH and salt.
[0011] Reference herein to complementary peptides indicates that the overall net charge of a combination of separate solutions of peptides is either +/−2, it has been found that the overall net charge of, for example the negative −2 (P 11 -13/14) or positive +2 (P 11 -28/29), makes little difference in the gelation, morphology and self-assembly behaviours of the complementary peptides. However, completely polar complementary peptides don't form gels in physiological solutions, rather they tend to phase separate from solution, possibly either due to many defects forming during the self assembly process or due to very strong hydrogen bond interactions between then multiple —CONH 2 groups on the surfaces of these tapes.
[0012] Thus, provided herein is a material comprising ribbons, fibrils or fibres characterised in that each of the ribbons, fibrils or fibres have an antiparallel arrangement of peptides in a β-sheet tape-like substructure.
[0013] When the material substantially comprises fibrils, the fibrils may be comprised in a network of fibrils interconnected at fibre-like junctions.
[0014] Also provided is a material wherein the material comprises self assembling complementary peptides (SACPs) wherein the SACPs form a tape in an aqueous medium and is made up of 3 or more polar/neutral amino acids and a plurality of charged amino acids but wherein the overall net charge is +/−2 per pair of complementary peptides.
[0015] The polar/neutral amino acids, which may be the same or different, can be selected from the group including glutamine, serine, asparagine, ornithine, threonine, tyrosine, glutamic acid, phenylalanine and tryptophan.
[0016] We further provide a material wherein the complementary peptides are overall +2 positively charged per pair of peptides and form a gel when the first of the complementary monomeric peptides contacts its complementary second monomeric peptide (P 11 -28/29). Alternatively, we provide a material wherein the complementary peptides are overall −2 negatively charged per pair of peptides (P 11 -13/14; P 11 -30/31; P 11 -26/27) and form a gel when the first and second complementary peptides of the pair make contact with one another.
[0017] We further provide a material wherein the amino acid chain is extended to include a bioactive peptide sequence, or wherein the amino acid chain is attached to a therapeutically active molecule.
[0018] The material may comprise SACPs which forms ribbons and/or fibrils in an aqueous solution and wherein the SACPS has a primary structure in which at least 50% of the amino acids comprise an alternating structure of polar and apolar amino acids.
[0019] The polar amino acids include from 4 to 6 charged amino acids per 11 amino acids. Preferably, the SACPs are selected from the group comprising: P 11 -13/14 (SEQ ID NOs: 2 and 3); P 11 -26/27 (SEQ ID NOs: 4 and 5); P 11 -28/29 (SEQ ID NOs: 6 and 7) and P 11 -30/31 (SEQ ID NOs: 8 and 9).
[0020] Exemplary complementary peptides of the present disclosure are recited in Tables 1A- and 1B.
[0000]
TABLE 1A
Primary structures of rationally designed
complementary peptides.
Peptide
SEQ
Name
Primary Structure*
ID NO:
P 11 -4
CH 3 CO—Q—Q—R—F—E—W—E—F—E—Q—Q—NH 2
1
P 11 -13
CH 3 CO—E—Q—E—F—E—W—E—F—E—Q—E—NH 2
2
P 11 -14
CH 3 CO—Q—Q—O—F—O—W—O—F—O—Q—Q—NH 2
3
P 11 -26
CH 3 CO—Q—Q—O—Q—O—Q—O—Q—O—Q—Q—NH 2
4
P 11 -27
CH 3 CO—E—Q—E—Q—E—Q—E—Q—E—Q—E—HN 2
5
P 11 -28
CH 3 CO—O—Q—O—F—O—W—O—F—O—Q—O—NH 2
6
P 11 -29
CH 3 CO—Q—Q—E—F—E—W—E—F—E—Q—Q—NH 2
7
P 11 -30
CH 3 CO—E—S—E—F—E—W—E—F—E—S—E—NH 2
8
P 11 -31
CH 3 CO—S—S—O—F—O—W—O—F—O—S—S—NH 2
9
*The N— and C— termini of the peptides are always blocked with CH 3 CO— and NH 2 — respectively.
O symbolizes ornithine amino acid side chains.
[0000]
TABLE 1B
Self assembling complementary peptides.
One letter
Affect
amino acid
being
Peptide
code
Charge
studied
Structure
P 11 -13
AcEQEFEWEFEQENH 2
−6
N/A
P 11 -14
AcQQOFOWOFOQQNH 2
+4
N/A
P 11 -26
AcQQOQOQOQOQQNH 2
+4
Polarity
P 11 -27
AcEQEQEQEQEQENH 2
−6
Polarity
P 11 -28
AcOQOFOWOFOQONH 2
+6
Charge
P 11 -29
AcQQEFEWEFEQQNH 2
−4
Charge
P 11 -30
AcESEFEWEFESENH 2
−6
Serine
P 11 -31
AcSSOFOWOFOSSNH 2
+4
Serine
[0021] The peptides provided herein are preferably 11 residues in length.
[0022] Preferably, in each complementary pair the amino acids at positions 2, 4, 6, 8, and 10 are the same. For example, the complementary pair P 11 -13/14 each have glutamine, phenylalanine, tryptophan phenylalanine and glutamine at positions 2, 4, 6, 8, 10 respectively as has the complementary pair P 11 -28/29. The complementary peptides of P 11 -26/27 have glutamine at all five positions and P 11 -30/31 has serine, phenylalanine, tryptophan, phenylalanine and serine at positions 2, 4, 6, 8, 10 respectively.
[0023] Preferably the amino acid at position 2 is either glutamine or serine, at position 4 it is either phenylalanine or glutamine, at position 6 it is either tryptophan or glutamine, at position 8 it is either phenylalanine or glutamine and at position 10 it is either serine or glutamine.
[0024] Preferably, the amino acid residues at positions 10 and 11 of one of the complementary monomeric peptides are the same and are selected from the group comprising serine (SS) or glutamine (QQ) Peptides P 11 -14/26/29 each have glutamine at positions 10 and 11 whereas P 11 -31 has serine at the terminal two positions.
[0025] Preferably, the amino acid residue at position 4 is either phenylalanine or glutamine.
[0026] Preferably, the amino acid residues at positions 4 and 5 are selected from the pairs of the group comprising phenylalanine and glutamic acid, phenylalanine and ornithine, glutamine and glutamic acid and glutamine and ornithine.
[0027] Preferably, the terminal hydrogen bond group is either —CONH 2 or OH. The presence of —CONH 2 hydrogen bonding moieties (P 11 -13/14 and P 11 -28/29) on the surface of the tapes appear to be more efficient than —OH hydrogen bond moieties (P 11 -30/31) in creating gels with lower c*gel with much more well defined tape self-assembly and lower c*tape therefore providing a potentially longer lifetime in vivo.
[0028] The material may be suitable for use in, inter alia, tissue engineering, cell culture medium, and/or dental treatment. The complementary peptides of the present invention are considered as ideal candidates for regenerative medicine as self assembly does not occur until both monomers are mixed together which makes application within the body more achievable and overcomes the problem of gel plug formation.
[0029] We also provide a material wherein the material comprises self assembling complementary peptides (SACPs) wherein the SACPS forms a tape in an aqueous medium and wherein each complementary peptide is made up of 3 or more polar/neutral amino acids and a plurality of charged amino acids.
[0030] In some examples, the SACPS are isolated. An “isolated” biological component (such as a protein) has been substantially separated or purified away from other biological components present in the cell of an organism, or the organism itself, in which the component may naturally occur, such as other chromosomal and extra-chromosomal DNA and RNA, proteins and cells. In addition, proteins that have been “isolated” include proteins purified by standard purification methods. The term also embraces proteins prepared by recombinant expression in a host cell as well as chemically synthesized proteins. For example, an isolated SACP is one that is substantially separated from other peptides.
[0031] The polar/neutral amino acids, which may be the same or different, may be selected from the group including glutamine, serine, asparagine, ornithine, threonine, tyrosine, glutamic acid, tryptophan and phenylalanine.
[0032] In one example, the SACPs have a polar amino acid selected from the group consisting of serine, threonine, tyrosine, asparagine, and glutamine.
[0033] The apolar amino acids, which may be the same or different, are selected from the group including phenylalanine, leucine, isoleucine, valine and tryptophan.
[0034] We further provide a material wherein the amino acid chain is extended to include a bioactive peptide sequence, or wherein the amino acid chain is attached to a therapeutically active molecule.
[0035] We also provide a material wherein the SACPs are soluble and may comprise a ratio of net charged amino acids to total amino acids of from 6:11 to 4:11.
[0036] The material may be suitable for use in, inter alia, tissue engineering, cell culture medium, and/or dental treatment.
[0037] We further provide a material wherein the complementary peptide tapes are made up of 3 or more polar amino acids of which some are charged amino acids wherein the ratio of charged amino acids to total amino acids is 4:11 or greater.
[0038] Also provided is a composition that includes ribbons, fibrils or fibres and wherein the complementary peptides are present at a concentration of at least 1 mg/ml in the composition (for example 1 mg/ml to 100 mg/ml, 1 mg/ml to 60 mg/ml, 1 mg/ml to 50 mg/ml, 1 mg/ml to 35 mg/ml, 15 mg/ml to 15 mg/ml or 20 mg/ml to 35 mg/ml and any other integers therebetween). Each of the ribbons, fibrils or fibres has an antiparallel arrangement of peptides in a β-sheet tape-like substructure, wherein each pair of complementary peptides comprises a net −2 or a +2 charge, and wherein the peptide is selected from the group comprising P 11 -13/14 (SEQ ID NOs: 2 and 3); P 11 -26/27 (SEQ ID NOs: 4 and 5); P 11 -28/29 (SEQ ID NOs: 6 and 7) and P 11 -30/31 (SEQ ID NOs: 8 and 9). as set forth in Table 1A.
[0039] The foregoing and other features of the disclosure will become more apparent from the following description of the figures.
BRIEF DESCRIPTION OF THE FIGURES
[0040] FIG. 1 illustrates the mixing of monomeric complementary peptides that are originally in separate, low viscosity solutions, triggers peptide self-assembly and instant gelation.
[0041] FIG. 2 shows a typical self-assembly curve, indicating the onset point for self-assembly.
[0042] FIG. 3 represents a complementary peptide tape.
[0043] FIG. 4 shows the Fourier Transform Infrared Spectroscopy (FITR) analysis for the complementary peptides P 11 -13/14 in isolation and in combination.
[0044] FIGS. 5A and 5B show TEM images of the complementary peptides P 11 -13/14. FIG. 5A shows 15 mg/ml times dilution magnification of FIG. 5B 15 mg/ml at 15 times dilution magnification of 52,000 times.
[0045] FIGS. 6A-6C show TEM images of the complementary peptides P 11 -30/31. FIG. 6A shows 20 mg/ml diluted 15 times, magnification 52,000 times, FIG. 6B 20 mg/ml diluted 15 times magnification of 52,000 times and FIG. 6C 20 mg/ml diluted 15 times, magnification of 39,000 times.
[0046] FIGS. 7A-7C show SEM images of the complementary peptides P 11 -13/14 30 mg/ml at magnification of (A) 5,000, (B) 10,000 and (C) 35,000 times.
[0047] FIGS. 8A-D show SEM images of the complementary peptides P 11 -30/31 15 mg/ml at magnification of (A) 70,000, (B) 20,000, (C) 10,000 times and (D) 5,000 times.
[0048] FIG. 9 shows the Elastic modulus, Viscous modulus and Phase Angle versus Shear strain for P 11 -30/31 in physiological solution and temperature.
[0049] FIGS. 10A-10B show luminescent count toxicity studies in BHK and 3T3 cells for isolated complementary peptides (A) and combined complementary peptides (B).
SEQUENCE LISTING
[0050] The protein sequences listed in the accompanying sequence listing are shown using standard letter abbreviations for proteins. The Sequence Listing is submitted as an ASCII text file, created on Jul. 12, 2016 8 KB, which is incorporated by reference herein.
[0051] SEQ ID NO: 1 is the amino acid sequence for P11-4.
[0052] SEQ ID NO: 2 is the amino acid sequence for P11-13.
[0053] SEQ ID NO: 3 is the amino acid sequence for P11-14.
[0054] SEQ ID NO: 4 is the amino acid sequence for P11-26.
[0055] SEQ ID NO: 5 is the amino acid sequence for P11-27.
[0056] SEQ ID NO: 6 is the amino acid sequence for P11-28.
[0057] SEQ ID NO: 7 is the amino acid sequence for P11-29.
[0058] SEQ ID NO: 8 is the amino acid sequence for P11-30.
[0059] SEQ ID NO: 9 is the amino acid sequence for P11-31.
DETAILED DESCRIPTION
[0060] The singular forms “a,” “an,” and “the” refer to one or more than one, unless the context clearly dictates otherwise. For example, the term “comprising a peptide” includes single or plural peptide and is considered equivalent to the phrase “comprising at least one peptide.” The term “or” refers to a single element of stated alternative elements or a combination of two or more elements, unless the context clearly indicates otherwise. As used herein, “comprises” means “includes.” Thus, “comprising A or B,” means “including A, B, or A and B,” without excluding additional elements.
[0061] Unless explained otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and not intended to be limiting.
[0062] We have also shown that above a certain peptide concentration c I/N (isotropic to nematic transition concentration) the semi-rigid ribbons, fibrils and fibres can align and thus transform their initially isotropic solution into a nematic liquid crystalline solution. The transition of the solution to the nematic liquid crystalline state happens at lower concentrations for more rigid polymers.
[0063] We have also shown that as the peptide concentration increases even further there is a second transition from a fluid nematic liquid crystalline solution to a self-supporting nematic gel, which is formed by the entwining of the fibrils
[0064] We have discovered that the alignment of these polymers (tapes, ribbons, fibrils and fibres) can be improved significantly by shearing or application of external magnetic field to the peptide solution. Subsequent gelation locks the aligned polymers into place and preserves their alignment for a long time (typically weeks) even after the polymer solution is removed from the magnetic field or after the end of shearing. Shearing or external magnetic field (superconducting magnet with a field strength of 7T) have been found indeed to improve the alignment of fibrils in aqueous solutions, as shown by monitoring the birefringence of the solution using cross polars. The improved polymer alignment in solution has been preserved for several weeks after the end of shearing or of the application of the magnetic field.
[0065] Provided is a method of producing nematic liquid crystalline solutions and gels of alternating copeptide beta-sheet tapes, ribbons, fibrils or fibres with improved polymer alignment and thus improved optical properties (i.e., increased liquid crystallinity and birefringence), by shearing the peptide solutions or by subjecting them to other external forces such as electric and magnetic fields.
[0066] These peptide liquid crystalline solutions and gels can be formed in organic solvents or in water depending on the peptide design. The design of the complementary peptide primary structure is necessary to achieve compatibility between the surface properties of the peptide polymers and the solvent. For example, self-assembling beta-sheet forming peptides with predominantly hydrophobic amino acid side-chains are required to form nematic solutions and gels in moderately polar solvents, whilst peptides which form tapes with at least one polar side are required to obtain nematic solutions and gels in water.
[0067] The fibrils and fibres are alignable and can therefore form nematic gels. Therefore, the fibrils and fibres can be spun to make, for example, high tensile strength fibres, cf. Kevlar®. Also, they can be used to make highly ordered scaffolds for tissue engineering or templates for the growth of inorganic matrices, or as matrices for the alignment of biomolecules, e.g., in NMR spectroscopy.
[0068] Until recently, formation of these polymers has been limited to relatively simple solutions (e.g., pure solvents or low ionic strength solutions). We have now discovered that it is possible to rationally design pairs of complementary peptides which will form soluble polymers (e.g., tape, ribbons, fibrils and fibres) once they have been mixed together or allowed to contact one another.
[0069] The stages of complementary peptide design for formation of soluble beta-sheet polymers and gel scaffolds are:
1) for production of single tapes, design the peptide following the criteria in the International Patent Application No. PCT/GB96/00743. To produce stable single tapes in cell media, both sides of tapes should be covered by predominantly polar groups. 2) for production of ribbons, fibrils and fibres, one sides of the tape should be different from the other, e.g. one predominantly polar and the other predominantly apolar. The polar sides should also be able to weakly interact with each other e.g. through hydrogen-bonding sites provided for example by glutamine or asparagines side chains. 3) To ensure all these polymers are soluble, some repulsion between polymers must be created. This can be electrostatic repulsion between like charges on the polymers. Alternatively, it can be steric repulsions created by flexible solvophilic chains decorating the peptide polymers such as polyethylene glycol chains when water is the preferred solvent. These PEG segments can be attached on amino acid side-chains or on the peptide termini.
[0073] By way of illustration, we include the following example:
[0074] A large number (dozens) of systematically varied peptides (typically 7-30 residues long) have been studied for soluble polymer and gel formation. All of these peptides can self-assemble to form beta-sheet polymers in certain low-ionic strength media, but most were found to precipitate out of solution in cell media. Only complementary peptides with a approximate net +2 or −2 charge per peptide pair, were able to form soluble polymers in gel cell media (The amount of net charge necessary per peptide to keep its complementary polymers soluble will vary depending on the overall surface properties and solubility of the peptide tapes it forms).
[0075] The fibrils entwine and form a three dimensional network and turn their solution into a homogeneous self-supporting gel at peptide concentration higher than 1 to 5 mg/ml. The gel remains stable for at least several weeks at room temperature.
[0076] The gel can be broken by mechanical agitation. The time it takes to reform depends on the complementary peptide concentration, ranging from seconds for a 15 mg/ml peptide gel, to hours for a 1 mg/ml peptide gel.
[0077] Thus, peptide fibrils and gels with a variety of chemical properties can be produced by complementary peptide design. For example, the type of charge (+ or −) of the polymer may be crucial for the polymer matrix-cell interactions. The nature of the neutral polar side-chains can also be varied to fine-tune and maximise the favourable polymer-cell interactions, and the polymer stability in vivo.
[0078] The fibrils and gels can reform after sterilisation using an autoclave. Thus autoclaving is a viable method to sterilise these peptide gels. This is significant, since sterilisation is a prerequisite for the use of these materials with cells in vitro or in vivo. Other alternative sterilisation methods that can also be used are filtration of the initially monomeric peptide solutions or gamma irradiation.
[0079] Although the peptide design procedure stated above can be used to design either tapes or higher order aggregates (i.e., ribbons, fibrils and fibres) the more robust fibrils and fibres are potentially more useful for production of complementary peptide scaffolds for tissue engineering. The reason is that the fibrils being much stronger structural units than e.g., tapes, can support cells in three dimensions without significant breakage for a long time. In addition, the highly packed nature of the fibrils, protects the peptides from enzymatic degradation, and can increase significantly the lifetime of the scaffold in vivo.
[0080] The peptide gels are formed with a very low complementary peptide concentration (typically at or above 5 mg/ml), which corresponds to 0.003 volume fraction of peptide and 0.997 volume fraction of solvent in the gel, which means that the gels contain mainly solvent. Thus, encapsulated cells in these gels, have a lot of room available to grow, to communicate with each other and nutrients, oxygen, and various metabolites can diffuse almost freely in and out of the gel network.
[0081] The opportunities that these new biomaterials provide for tissue engineering in vitro and in vivo are enormous. A large number of different cells can be encapsulated in these polymer scaffolds.
[0082] Complementary peptides can be designed to have a self-assembling domain followed by at least one bioactive domain. Thus, polymeric gel scaffolds can be formed in cell media, decorated with specific bioactive sequences (e.g., RGD sequence) which will control the interactions of the scaffold with a particular type of cell, and also influence the growth differentiation state and function of the encapsulated cells.
[0083] The complementary peptide polymers (especially so the more rigid fibrils and fibres) can be preferentially aligned by shearing or application of magnetic field. Thus, anisotropic polymer scaffolds can be obtained which when they are seeded with cells, they can be particularly important for the control of cell type, cell-cell interactions and shape of the growing tissue.
[0084] The cells can be encapsulated in the polymer matrix in a variety of different ways. For example:
1) disruption of gel by mechanical agitation, mixing with the cells, and encapsulation of the cells as the gel matrix reforms around them. 2) Mix the cells with an initially fluid first monomeric peptide solution in cell media, followed by triggered gel formation on contact with its complementary peptide.
[0087] Possibly the most effective way of encapsulating cells in the peptide scaffolds is using alternating copeptides.
[0088] It is seen that the alternating copeptide systems offer a unique way of encapsulating cells in the peptide scaffolds without the need to change the pH, ionic strength and counter ion concentration of the cell solutions. This can be done by mixing the cells with one of the initial monomeric peptide solutions, and subsequently adding the complementary peptide solution.
[0089] The heteropeptide polymers scaffolds also offer the advantage of combining different functionalities on the same polymers, and extending the chemical and periodic features of homopeptide polymers. For example one peptide component of the polymer may have a bioactive peptide bound to it, whilst its other complementary peptide compound may have a drug molecule bound on it.
[0090] The ribbons, fibrils and/or fibres of the disclosure exhibit significant tensile strength, controlled, inter alia, by how many tapes make up the ribbons, fibrils or fibres, especially in the longitudinal direction of the fibril or fibre. Such strength has been estimated to be in the order of that of a conventional covalent bond. Furthermore, since the fibrils and/or fibres are biodegradable, because of their peptide content, they are especially advantageous in that they may be constructed into a biodegradable scaffold. Such scaffolds may comprise a weave, knit or plait of the fibrils or fibres of the disclosure.
[0091] Scaffolds can also be constructed using a combination of the complementary peptide polymers and other commercial polymers (such as cotton and wool fibres), to obtain materials with a desirable combination of mechanical, chemical and biochemical properties, and low production cost.
[0092] Alignment of the microscopic fibrils followed by subsequent lateral association of the fibrils can result in the formation of macroscopic oriented fibre mats.
[0093] The peptide fibrils and/or fibres can be engineered to control the chemical and bioactive properties of synthetic polymer fibres. The methodology has the advantage of harnessing and combining existing expertise on manufacturing at low-cost well controlled fibrous structures with desirable mechanical properties, with the opportunity of designing their bioactivity, biocompatibility and other chemical properties. Such new materials can have exciting applications in biomedical fields such as in tissue engineering, wound healing and tissue adhesion.
Products and Applications
Industrial Applications
[0094] Modification of the physical and chemical properties of a surface in a controlled way, e.g., wetting properties; for example, for anti-icing applications.
[0095] Also for controlling the interaction of oil/water with clay surfaces, and the stabilising the clay itself, an important issue when, e.g., dealing with fractures in oil wells. The stability of the peptide polymers can be controlled by peptide design. Thus, by increasing the number of amino acid residues per peptide and also the number of favourable intermolecular interactions between amino acid side-chains, complementary peptide polymers with increased stability and strength can be obtained. In addition, ribbons, fibrils and fibres can be increasingly more stable polymers compared to single tapes. Thus, the right polymers can be produced by complementary peptide design to form gels stable in the high temperature of the oil wells. These gels can for example provide significant mechanical support at a specific site of the oil well.
[0096] Receptor or receptor binding sites can be engineered by complementary peptide design into the ribbons, fibrils and/or fibres, providing materials for use as sensors or as biocatalysts, or as separation media in biotechnology applications.
[0097] The peptide tapes, ribbons, fibrils and fibres can be used as templates for the production of nanostructured inorganic materials with chiral pores. The dimensions, pitch and chirality of the pores can be controlled by peptide design to control the properties of the polymer aggregate. The orientation of the pores can also be controlled by alignment of the polymers in nematic states. These nanostructured materials have important applications as chiral separation media.
[0098] The fibres of the disclosure are advantageous because, inter alia, they possess similar properties to other known peptide fibres, for example, KEVLAR® which consists of long molecular chains produced from poly-paraphenylene terephthalamide. Thus the fibres of the disclosure exhibit the following features; high tensile strength at low weight, high modulus, high chemical resistance, high toughness, high cut resistance, low elongation to break, low thermal shrinkage, high dimensional stability, flame resistant and self extinguishing.
[0099] Therefore, the fibres of the disclosure can be processed into various forms, for example, continuous filament yarns, staple, floc, cord and fabric.
[0100] The processed fibres may possess the following characteristics: continuous filament yarn, high tensile strength, processable on conventional looms, twisters, cord forming, stranding and serving equipment; staple, very high cut resistance, spun on conventional cotton or worsted spinning equipment, precision cut short fibres, processable on felting and spun lace equipment; pulp-wet and dry, floc, precision cut short fibres, high surface area, miscible in blend composites, thermal resistance, excellent friction and wear resistance; cord, high tensile strength and modulus at low specific weight, retention of physical properties at high and low temperature extremes, very low heat shrinkage, very low creep, good fatigue resistance; fabric, excellent ballistic performance at low weights; and excellent resistance to cuts and protrusion combined with comfortable wear and excellent friction and wear performance against other materials.
[0101] The peptide fibrils and fibres of the disclosure may have a variety of applications, for example, in adhesives and sealants, e.g. thixotropes; in ballistics and defence, e.g., anti-mine boots, gloves—cut resistance police and military, composite helmets, and vests—bullet and fragmentation; in belts and hoses, e.g. automotive heating/cooling systems, automotive and industrial hoses, and automotive and industrial synchronous and power transmission belts; in composites, e.g., aircraft structural body parts and cabin panels, boats, and sporting goods; in fibre optic and electro-mechanical cables, e.g., communication and data transmission cables, ignition wires, and submarine, aerostat and robotic tethers; in friction products and gaskets, e.g., asbestos replacement, automotive and industrial gaskets for high pressure and high temperature environments, brake pads, and clutch linings; in protective apparel, e.g. boots, chain saw chaps, cut resistant industrial gloves, helmets—fireman and consumer (bicycle), and thermal and cut protective aprons, sleeves, etc; in tires, e.g. aircraft, automobiles, off-road, race, and trucks; and in ropes and cables, e.g., antennae guy wires, fish line, industrial and marine utility ropes, lifting slings, mooring and emergency tow lines, netting and webbing, and pull tapes.
Biomedical and Biomaterial Applications
[0102] Biocompatible surfaces: Bioresponsive and biocompatible surfaces to promote or to prevent adhesion, spreading and growth of endothelial cells in medical implant materials. Biocompatible surface coatings for devices such as stents, valves and other structures introduced into biological systems. Biocompatible surface coatings for dental implants and intra-oral appliances e.g. dental prosthesis.
[0103] Tissue engineering: The peptide fibrils and/or fibres of the disclosure can be used in the construction of a biodegradable three-dimensional scaffold for use in attaching cells to produce various tissues in vivo and in vitro.
[0104] Thus according to a further feature of the disclosure we provide a three-dimensional scaffold comprising fibres or fibrils of the disclosure in cell medium. As mentioned above such scaffolds of the peptide fibrils and/or fibres are advantageous in that they can be used to support cells in the growth and/or repair of tissue. The nature of such cells may vary depending upon the nature of the tissue of interest. For example, the cells may be ligamentum cells for growing new ligaments, tenocytes for growing new tendon. Alternatively, the cells may be chondrocytes and/or other stromal cells, such as chondrocyte or osteoblast or other progenitor cells.
[0105] Therefore, according to a yet further feature of the disclosure we provide a three-dimensional scaffold comprising fibres or fibrils as hereinbefore described which scaffold is seeded with cells.
[0106] The methods of the disclosure therefore result in the efficient production of new ligament, tendon, cartilage, bone, skin, etc in vivo.
[0107] The cells may themselves be cultured in the matrix in vitro or in vivo. The cells may be introduced into the implant scaffold before, during or after implantation of the scaffold. The newly grown tissue can be used to hold the scaffold in place at the site of implantation and also may provide a source of cells for attachment to the scaffold in vivo.
[0108] The ability of the polymers to break allowing the free ends to self assemble enables, for example, scaffolds to be formed in situ and also to respond (by breaking and reforming) to the growing tissue. Also monomeric peptides may be injected at the site of choice and then chemically triggered to create, for example, a gel in situ.
[0109] Thus, according to a further feature of the disclosure we provide a method of tissue repair which comprises seeding a three-dimensional fibre matrix as hereinbefore described with appropriate cells.
[0110] For a tendon or ligament to be constructed, successfully implanted, and function, the matrices must have sufficient surface area and exposure to nutrients such that cellular growth and differentiation can occur following implantation. The organisation of the tissue may be regulated by the microstructure of the matrix. Specific pore sizes and structures may be utilised to control the pattern and extent of fibrovascular tissue in growth from the host, as well as the organisation of the implanted cells. The surface geometry and chemistry of the scaffold matrix may be regulated to control the adhesion, organisation, and function of implanted cells or host cells.
[0111] In an exemplary embodiment, the scaffold matrix is formed of peptides having a fibrous structure which has sufficient interstitial spacing to allow for free diffusion of nutrients and gases to cells attached to the matrix surface until vascularisation and engraftment of new tissue occurs. The interstitial spacing is typically in the range of 50 nm to 300 microns. As used herein, “fibrous” includes one or more fibres that is entwined with itself, multiple fibres in a woven or non-woven mesh, and sponge-like devices.
[0112] Nerve tissue engineering: The fibrils and/or fibres can be used to provide paths/tracks, to control and guide the direction of growth or movement of molecules or cells. This may be useful for nerve tissue repair as well as for growth and formation of bone tissue (tissue engineering).
[0113] Bone tissue engineering: Biomineralisation using the peptide ribbons, fibrils and/or fibres as a template for the nucleation and growth of inorganic materials is important in bone tissue engineering and dental applications etc. The self assembled peptide structures have been shown to be effective as templates for hydroxyapatite crystallisation, as shown in the later examples.
[0114] Self-assembling complementary peptides may increase mineral gain via their ability to nucleate hydroxyapatite de novo and/or by decreasing mineral dissolution via stabilisation of mineral surfaces. They are therefore candidate materials for use in both caries treatment and prevention, in treatment for dentina sensitivity, in control of ectopic calcification and in treatment or prevention of bone defects and deterioration, such as that experienced in osteoporosis or in periodontitis.
[0115] The use of peptides, e.g., self assembling complementary peptides (SACPs), as scaffolds in in situ tissue engineering of bone is novel per se.
[0116] Thus according to a further aspect of the disclosure provided is a method of tissue engineering, e.g., tissue repair, such as of bone repair, which comprises the use of SACPs as a scaffold.
[0117] Artificial skin: Network structures formed from the peptide ribbons, fibrils or fibres can be used to generate artificial skin or to promote skin re-growth in vivo.
[0118] Drug delivery: pH and ion responsive ribbons, fibrils, fibres, gels or liquid crystals are potentially useful in drug encapsulation and release and by designing an appropriate network programmable release rates may be achieved.
Personal Care Products
[0119] Dental applications: Peptide ribbons, fibrils and/or fibres are of use in the protection of teeth, as carriers for delivery of active substances to promote dental repair, as templates/scaffolds for the in situ nucleation of hydroxyapatite within tooth porosities (e.g., caries lesions, dentine), as agents for the treatment and/or prevention of caries (enamel/dentine and marginal caries around restorations), as agents for the treatment and prevention of tooth sensitivity and as carriers for the delivery of active substances into teeth. In addition, the peptide structures are of application in the treatment of dentinal/tooth staining, sensitivity and other symptoms experienced in gingival recession. The use of self assembled complementary peptide structures in caries treatment is demonstrated in the later examples.
[0120] The prior art describes use of an amphiphilic peptide as a scaffold for ordered deposition of mineral imitating crystal orientation in bone collagen This amphiphilic peptide assembles to give a structure which forms fibrils which are stabilised by covalent modification. The assembly of this peptide differs from the self assembled peptides described here in that the assembly is driven by amphiphilic forces, rather than by very specific attractions between matched groups in the separate peptide chains. The amphiphilic peptide described is not suitable for treatment in vivo as the assembly must take place at low pH (pH<4) and the covalent modification takes place under conditions hostile to living tissues. The self assembled complementary peptide ribbons, fibrils and fibres described in this application differ in that they can be designed such that assembly is triggered merely by contacting each of the complementary peptides rather than by environmental conditions such as a pH with no subsequent reaction under hostile conditions is necessary.
[0121] The prior art also describes use of casein phosphopeptides in dental application These species are not self assembling peptides as described in this application. As shown in the examples, the self assembled peptides described in this application show improved performance in mineralisation of caries like lesions of enamel under simulated oral conditions compared with the casein phosphopeptides.
[0122] In particular, we provide a method as hereinbefore described wherein the method comprises the prevention, treatment and/or alleviation of dental caries. Thus the method may comprise the mineralisation or remineralisation of a dental cavity or the suppression of leakage around existing restorations. Alternatively, the method may comprise suppression of demineralisation.
[0123] In particular, we provide a method as hereinbefore described wherein the method comprises the prevention, treatment and/or alleviation of tooth sensitivity. Thus the method may comprise the remineralisation of a dental cavity, white spot lesions or exposed dentine. Alternatively, the method may comprise suppression of demineralisation, thus preventing development of tooth sensitivity.
[0124] Skin treatments: The controlled formation of peptide ribbons, fibrils and/or fibres can be of benefit in skincare and dermatological applications for both cosmetic and medical benefit. Benefits may include skin protection, improvement in skin feel, improvement of skin strength, increased suppleness, delivery of active or beneficial substances, moisturization, improved appearance and anti-ageing effects.
[0125] Hair care products: Peptide ribbons, fibrils and/or fibres can be of benefit in hair care to improve hair condition, strength, feel, suppleness, appearance and moisturisation. Peptides which form such structures in application can be beneficial ingredients in hair shampoos, conditioners, dyes, gels, mousses and other dressings.
[0126] In another aspect of the disclosure responsive networks can be used to deliver perfumes, vitamins and/or other beneficial agents to the skin and/or hair.
Example 1
Synthesis, Purification and Sterilisation of Peptides
[0127] Complementary peptides were synthesized using standard 9-fluorenylmethoxycarbonyl (FMOC) chemistry protocols as described in Aggeli et al. ( J. Mat. Chem., 7:1135, 1997). Peptides were purified by reversed-phase HPLC using a water-acetonitrile gradient in the presence of 0.1% trifluoroacetic acid or ammonia as buffer A and 10% buffer A in acetonitrile as buffer B. Mass spectrometry showed the expected molecular weights. Peptides were sterilized in the dry state using γ-irradiation (2.5 MRad) with a Gammacell 1000 Elite irradiator. TEM and mass spectrometry were used to assess any damage to the peptide structure and fibril formation.
[0128] Four pairs of systematically varied complementary peptides were designed following the design criterion of +2/−2 net charge per peptide pair that applies to single peptide gels in physiological solutions. In all cases, the individual peptides were found to be monomeric random coils and to form low viscosity solutions. Upon mixing, most of the complementary pairs led to instant gelation in physiological solution conditions, confirming that the +2/−2 net charge can be used as a design criterion not only for single peptides but also for complementary peptide gels.
Example 2
Comparative Gelation Studies
[0129] Samples of all complementary pairs P 11 -13/14, P 11 -26/27, P 11 -28/29 and P 11 -30/31 were prepared at concentrations of 2, 3, 5, 10, 15, 20 and 30 mg/ml. Peptides were weighed out (Mettler AE 240 balance) and diluted to produce the correct concentration, taking peptide purity into account, using DMEM solution (for dilution volumes and peptide weights of all sample produced see appendix 2). Small amounts of acid (HCl 1M, 0.5M or 0.1 M) and base (NaOH 1M, 0.1M) were added and gentle heating applied when the peptide did not fully dissolve. The monomer solutions were combined in a 1:1 molar ratio to produce a mixture of the 2 complementary peptides, once mixed the room samples were placed in an incubator (Labnet Mini Incubator, 9 litre, analogue, gravity convection) heated to 37° C. and left to reach equilibrium. Observations were carried out once a day over a one week period to determine the concentration at which gelation occurs therefore ascertaining when the system is at equilibrium. Table 2 below shows the comparative gelation studies in 2-30 mg mL-1 range of concentrations:
[0000]
TABLE 2
C* gel in
C*gel in
physiological
physiological
Hydrogen
solution and
solution and
Peptide
Net
Hydrophobic
bonding
37° C./
20° C./
pair
charge
character
groups
mg mL−1
mg mL−1
P11-13/
−2
Amphiphilic
—CONH2
7.5 ± 2.5
5.5 ± 1.5
14
P11-28/
+2
Amphiphilic
—CONH2
7.5 ± 2.5
4.0 ± 1.0
29
(and
17.5 ± 2.5)
P11-30/
−2
Amphiphilic
—OH
12.5 ± 2.5
27.5 ± 2.5
31
P11-26/
−2
Completely
—CONH2
na
Na
27
polar
[0130] In all cases apart from P 11 -26/27 gelation took place instantly upon mixing of the separate fluid peptide solutions at all concentration equal to or higher than c*gel. The formed gel remained stable over time during the observation time which was 1 week, confirming apparent equilibrium behaviour. Repeat experiments established full reproducibility of the reported behaviours. P11-13/14 gel also exhibited coloured birefringence when examined between cross polars, which is evidence of long range order in the material, ie the tapes partially align to form micro domains in the material with a common director for each microdomain. This may have important implications for the biological activity of the peptides, eg in the case of biomineralisation for the control of the direction of growth of hydroxypatite crystals. Birefringence was not reliably observed for the other pairs of peptides although further more detailed studies may show different results in the future. In the case of P11-28/29, two different c*gel values were observed in two different types of physiological like solutions, therefore these experiments will have to be repeated; however the overall gelation behaviour of this pair is likely to be very similar to P11-13/14 one. P11-13/14 and P11-28/29 have lower gelation concentrations compared to P11-30/31 and P11-26/27 did not form gels at all in physiological solutions, instead it tended to precipitate out of solution.
Example 3
Transmission Electron Microscopy Studies
[0131] The room temperature D 2 O samples of all four complementary peptide pairs of concentration 15, 20, 30 mg/ml underwent TEM analysis. The samples in TEM are required to be very thin, around 40-60 nm thick, and are supported on a thin copper mess which offers a reasonable viewing area and are conductive enabling discharge of excess electrical charge produced by the electron beam to the microscope column. The copper grids are covered in a ultra thin carbon film which serves as an electron transparent support for the sample. Two small volumes of each sample were transferred to two different sample vials and diluted with D 2 O to produce two samples one with 15 and 50 times diluted. This dilution was carried out to ensure the sample, which when applied to the copper grids, would be thin and have a decreased salt content enabling the production of good TEM images. Carbon coated copper grids (Athene hexagonal 400 mesh copper 3.05 mm) were exposed to UV light for 30 minutes to charge the surface and ensure adhesion of sample to the surface. One drop of sample was applied to the carbon coated copper grids and left for one minute then the excess was removed using filter paper. The same process was repeated using 4% uranyl acetate solution but left for only 20 seconds. Uranyl acetate is used as a negative stain; it deflects the electron beam resulting in a dark section on the final image. A biological based sample, such as the peptides used in this research, does not absorb much of the uranyl acetate due to surface tension interactions which prevent it from penetrating the peptide aggregate and results in electrons being transmitted through the sample and reaching the detector. The grid surface is covered in the uranyl acetate which blocks the transmittance of electrons and produces the contrast between sample and background. Samples were then loaded into the TEM instrument (Philips CM10 operating at 80 kV) and pictures taken at various magnifications (39 k, 52 k and 73K). Once the image had been captured onto the film it was scanned onto a PC where it was then processed using Image J software to determine what type of aggregates were present and their widths. TEM studies revealed that P11-13/14 ( FIG. 5 ) and P11-28/29 formed well defined, distinct aggregates of tapes with widths 4±1 and 6±1 respectively. P11-30/31 ( FIG. 6 ) formed much looser associations of tapes (rather amorphous bundles), similar was also the behavior of P11-26/27 under the TEM.
Example 4
Scanning Electron Microscopy Studies
[0132] Samples of 15 mg/ml and 30 mg/ml in DMEM were produced for P 11 -13/14 and P 11 -30/31 using the same method previously outlined for the incubated DMEM samples. A small amount of gel was applied to the copper shim, with the excess liquid removed, and then frozen in liquid nitrogen. The samples were then freeze-dried (Peltier stage attached to a Polaron coating unit) and loaded with the stage running at approximately −65° C. and left for one hour. The stage is then warmed 10° C. every 30 minutes until room temperature is reached. Once dried the g majority of the gel is knocked off leaving a small amount in contact with the copper shim which is then mounted using carbon rods onto stubs. These were then splutter coated with approximately 3 nm of gold/palladium. The sample was then mounted into the SEM instrument and the images taken. The resulting images were processed using the Image J software to determine the width of the pores in the gel and also the width of the strands that produce the pores. SEM studies showed that P11-13/14 gel network consists of pore size of 900±750 at 15 mg mL-1 and 700±500 at 30 mg mL-1 ( FIG. 7 ). Similar results were also obtained for P11-30/31 ( FIG. 8 ).
Example 5
Spectroscopic (Mainly) FTIR Analysis
[0133] Samples for Fourier Transform Infrared Spectroscopy (FITR) analysis at both room and physiological temperature were prepared for P 11 -13/14, P 11 -26/27, P 11 -28/29 and P 11 -30/31 at concentrations of 2, 3, 5, 10, 15, 20 and 30 mg/ml. The peptide was dissolved in D 2 O (Aldrich Deuterium oxide, 99.9 atom % D) 130 mM NaCl (Fisher Scientific) solution to produce a known concentration of monomer solution in mg/ml. Gentle heating and, if required, small amounts of dilute DCI (Aldrich 35 wt. % in D 2 O, 99 atom % D) and NaOD (Aldrich 40 wt. % in D 2 O, 99 atom % D) were added to aid dissolution and correct the pD to near physiological conditions The monomer solutions of each peptide were combined, using a Gilson Pipetman P200, with a volume of its complementary peptide to produce a 1:1 molar ratio at a known overall concentration. D 2 O was used instead of H 2 O as its absorption in the amide I band is weak 13 and 130 mM NaCl is required to reproduce the ionic strength of physiological conditions allowing comparison with the DMEM samples. The purity of both P 11 -13 and P 11 -14 was 70.6% and 72.6% and so although not exactly 1:1 molar ratios were produced it is within a reasonable range. The concentrations produced were 3.8, 7.3, 10.8, 14.3 and 21.4 mg/ml. FIG. 4 shows the original and band filtered spectra for single and combined complementary peptides P11-13/14. The FTIR studies revealed that all the mixed complementary peptide solutions had very high content of beta-sheet (65-85%) even in the lowest concentration studied (5 mg mL-1). Further NMR studies at much lower concentrations revealed that c*tape for P11-13/14 and for P11-28/29 are very similar and in the region of 10-50 uM. This is much lower that c*tape for P11-4 which is at 400 uM. P11-30/31 c*tape is higher than 50 uM but still lower than 400 uM (further studies are required to define it accurately). Thus all complementary peptide pairs studied here have lower c*tape compared to P11-4, and therefore are likely to have much longer lifetime in vivo compared to “golden standard” P11-4 peptide.
Example 6
Mechanical Studies
[0134] Mechanical studies established that the complementary peptide gels can have significant mechanical strength when considering that they are classified under soft matter. In particular P11-30/31 gels were characterised by a plateau elastic modulus of 4,000-5,000 Pa and a viscous modulus of 400-500 Pa. FIG. 9 shows the Elastic modulus, Viscous modulus and Phase Angle versus Shear strain for P11-30/31. Preliminary evidence suggests that depending on peptide design, the mechanical properties of the resulting complementary peptide gels may vary from as low as 20 Pa to as high as 80,000 Pa for the plateau elastic modulus. This wide range of mechanical properties give the opportunity to select gels of optimal mechanical strength to suit the requirements of different applications. For example in cases of applications of peptide gels as scaffolds for cell growth, different cell types require scaffolds with different mechanical strengths (stronger or softer) in order to thrive in them.
Example 7
Cytotoxicity Studies
[0135] Detailed cytotoxicity studies using the extract cytotoxicity method against two different cell types showed that all complementary peptides are biocompatible in their monomeric, low viscosity solution state and they don't show any statistical difference from the control sample. Self-assembling tapes of complementary peptide pairs were also tested for biocompatibility using the same method. All pairs were again found biocompatible with no statistically significant difference between any of these pairs and the control samples ( FIG. 10 ). | There is described a material comprising tapes, ribbons, fibrils or fibres characterized in that each of the ribbons, fibrils or fibres have an antiparallel arrangement of peptides in a β-sheet tape-like substructure wherein the material comprises a pair of self assembling complementary polypeptides. | 0 |
BACKGROUND OF THE INVENTION
The present invention relates generally to the field of film winding. More particularly the invention relates to taking a flat film and winding it upon a hollow core so that the film wound on the core is essentially flat. The method and apparatus of this invention is directed towards steps and mechanism to achieve a high degree of flatness of the film rolled on the core by allowing the core to be in especially close proximity to a bed roll from which it receives the film.
Multiple web winders for films, which winders wind more than one web in the same web path, have traditionally had to compromise film flatness because of the physical limitations of the winder apparatus. Ideally the film being wound is placed up against a bed roll and is kept in close tolerance to the bed roll to have an essentially wrinkle free film. In order to accomplish this result most effectively, the bed roll would have to run against the film surface being wound upon the core. However, it is difficult to control the forces between the bed roll and the core in such a way as to minimize compression of the wound film. None of the prior art technology teaches how to sufficiently balance the forces of the core to the bed roll, nor to adjust for the fact that a core changes diameter as it is being wound with the film. Also a factor in multiple web winders is that there is customarily a plurality of mandrels in the winder system and the rolls of more than one mandrel may be touching the bed roll at any given moment, each exerting a different pressure with respect to the bed roll. Because of these factors, prior art winders of multiple webs have allowed the cores to be spaced a distance from the bed roll. This is to compensate for the constantly varying core diameter as it is having film wound upon it and to allow automatic core feeding and removal. The result has been that films which are wound upon such a core customarily have a surface which is wrinkled to the degree that it is highly noticed by the consumer, a wound roll diameter which is unnecessarily large, and other undesirable attributes.
An answer to obtaining a high degree of film flatness with the use of a plastic film winder has been found in sufficiently and automatically counterbalancing the relative forces between the bed roll and the core as the core is being wound and its diameter constantly changing so that close contact between bed roll and the core upon which the film is being wound is maintained even when more than one core is in proximity to the bed roll. The present invention provides such a solution.
BRIEF DESCRIPTION OF THE INVENTION
In the arrangement of the film winder of the present invention a turret mechanism carries a plurality of core support mandrels which successively move into proximity with the bed roll to pick up film coming off of the bed roll to be wrapped on a core carried by the mandrels. The turret support is pivotal about a point so that the core wrapped on each mandrel pushes against the bed roll as it engages the bed roll and travels along the circumferential surface of the bed roll while picking up film being wound upon the core. The force of the core against the bed roll and the counteracting force of the bed roll against the core carried by the mandrel is balanced by a mechanism which acts through a turret lever arm extending from the pivot point and fixedly secured to the turret. The turret lever arm is connected linearly to a ratio multiplier pulley which itself is linearly connected to a turret balancing cam. Movement of the arm is controlled by the movement of the turret lever arm as each core on a mandrel engages the bed roll and is counterbalanced by either a counterweight or equivalent component. The linear relationship between the ratio multiplying pulley and the turret balancing cam varies as the lever arm moves because of the cam surface of the turret balancing cam. The radius from a pivot point of the cam to the linear element, which can be a cable, results in an automatic adjustment of the forces between the core containing mandrels as it engages the bed roll of the winder.
The action of the turret balancing cam together with the counterweight, the ratio multiplying pulley and the action of the turret lever arm permit the turret support element to respond through mechanical mechanisms as each core on a mandrel engages the bed roll so that the amount of forces between the core and the mandrels and a bed roll are just sufficient to permit close contact between the core and the bed roll as the film is being wound. This provides exceedingly flat film on the finished wrapped core.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGURE 1 is a schematic elevational view of the apparatus of the present invention, showing in broken lines what happens as a core upon the mandrel rotates about a turret support.
DETAILED DESCRIPTION OF THE INVENTION
FIGURE 1 illustrates schematically a film apparatus 10 constructed according to the concepts of the present invention. FIGURE 1 is in effect a side-elevational view of one end of the apparatus, the other end being a mirror image. The basic elements of the apparatus comprise a partially broken away main frame 12 carrying a support bracket 14, a turret side support 16 and a bed roll 18. Turret 16 is supported by pivot tube 20 carried on the frame 12 so that the turret can move back and forth about the turret pivot point 22 as shown by the arrow A. Also carried by turret support 16 is a mandrel spider 24 pivoting about the turret at mandrel pivot point shaft 26, each of the mandrel spider arms 28 carrying a mandrel 30, the successive mandrels carrying the letters 30A, 30B, 30C, 30D, 30E and 30F. Each of the mandrels carry a film core 32 upon which is wrapped a film 34 coming from bed roll 18. As the mandrel passes along a winding path 36 to the position occupied by mandrel 30B the film 34 is wrapped on the core 30A to complete the desired quantity of film upon the core. The winding path 36 essentially follows the curvature of the bed roll. It has been found advantageous to have mandrel acceleration during indexing, i.e., movement of mandrel A from position I to II with an immediately following indexing pause at position III during winding. The indexing accelerates the core to the bed roll surface speed to effect winding. Such acceleration and pausing can be effected by any conventional mechanism such as a Geneava gear mechanism 26' operating turret shaft 26 shown hidden on FIGURE 1, which Geneva gear is typified by that taught in U.S. Pat. No. 2,769,600.
To obtain flat film winding it is desired to maintain the core 32 against the bed roll including the film being wound thereon or in especially close proximity thereto during a substantial portion of the winding path. However, in bringing the core and bed roll in such a proximate relationship, the core should not be resting against the bed roll with such force that the film is compressed upon the roll so as to cause the film to be difficult to separate from its many wound layers or to distort the film by high compression forces. The applicants have achieved a method for providing the desired forces which are generally in the range of about 25 lbs in a direction radially directed at the bed roll from the core carrying mandrel surface.
To achieve the proper forces, attached to the turret support directly or through pivot tube 20 is turret lever arm 38. Carried by support bracket 14 is a ratio multiplying pulley 40 having a large hub 42 and a small hub 44. Rotatable about hub 44 and fixed to arm 38 is a main turret support cable 46. Main turret support cable 46 can be made adjustable in length by a mechanism as simple as a turnbuckle or its equivalent.
Also supported by a bracket 14 by means not shown is a turret balancing cam 48 which rotates about pivot point 50 as pulley 40 rotates about its pivot point 51. A linking cable 52 traveling around the outer periphery 42 of pulley 40 also travels about outer periphery 54 of turret balancing cam 48. Suspended from a smaller inner pulley 56 by cable 58 can be a counterweight 60 or its essential equivalent. Preferably turret balancing cam 48 carries on a shaft 56 another cam 59 having a mirror image and disposed at 180° with respect to cam 48 so that a smooth vibratory-free action is obtained upon movement of the balancing cam 48 about its pivot point 50. The counterbalancing cam 59 has no function other than counterbalancing cam 48 and carries no cable.
In operation mandrel 30A after it picks up a core 32, travels first to position I, rapidly accelerates to position II to obtain the same speed as the bed roll and then picks up the film 34. It then travels along winding path 36 where there is a pause at position III so that the bed roll is in intimate contact with the film being wound upon the core during virtually the complete wind. The core with its wound film then comes off the bed roll at position IV where the film is cut. The mandrel is then taken to position V and the core with its wound film is removed from the mandrel. When the mandrel 30A reaches position II it causes the turret support 16 to move in the direction of arrow B away from the bed roll 18 which in turn causes the turret lever arm to move upwardly in the direction shown by the arrow C, which latter action is transmitted by cable 46 to the small wheel 44 of pulley multiplier 40. This in turn causes the pulley 40 to rotate about pivot point 51 in the direction of arrow D causing the linking cable 52 to move in the direction of arrow E, which in turn causes the turret balancing cam 48 to rotate in the direction of arrow F. As this operation occurs the forces delivered to the bed roll 18 by the weight of the turret support 16 and all of its components are counterbalanced and automatically adjusted so as to obtain minimum forces while the mandrel 30A, core 32 and film 34 the core is carrying, move along the winding path 36. As the balancing cam 48 rotates, the radius from the pivot point 50 to the surface 54 of the balancing cam where it is engaged by cable 52 varies so as to compensate in proportion to the forces between the mandrel 30A and its contents as it moves from position II to position IV.
With the mechanism of this present invention varying forces are automatically compensated for and it is possible to maintain the proper clearance between the mandrel and its contents regardless of the roll size and the thickness of the film carried thereon. This results in an especially flat film which is highly desirable for the reasons heretofore stated.
Other modifications of the present invention are possible and could still be within the scope of the appending claims and it should be understood that other details and variations of the particular mechanism and its operation as taught may be possible without affecting the scope and protection herein afforded. | A film winder apparatus and method to minimize wrinkles during film winding comprising provision of balancing and counterbalancing mechanisms so that forces involved when cores are engaged by a bed roll occurring during film winding are effectively minimized while allowing the core to be in intimate contact with the bed roll. | 1 |
CROSS-REFERENCE TO RELATED APPLICATION
This is a continuation-in-part of application Ser. No. 08/102,284 filed Aug. 5, 1993 now U.S. Pat. No. 5,344,211.
FIELD OF THE INVENTION
The present invention relates in general to backrests, and more particularly an adjustable backrest having independent adjustment of lumbar and upper back height and curvature, as well as overall height adjustment to fit different size patients.
BACKGROUND OF THE INVENTION
Adjustable backrests or supports are well known in the art. U.S. Pat. No. 5,112,106 (Asbjornsen et al) discloses a backrest comprising a central spine or rail to which a lumbar support cushion and head cushion are connected via a sliding element. The sliding element is connected to the rail or spine via a ratchet-like connection. The '106 Patent is of interest for teaching the concept of height adjustable lumbar support where the adjusting means is connected to a spine for sliding engagement therewith.
U.S. Pat. No. 2,756,809 (Endresen) discloses a back support comprising a metal sheet with adjustable lumbar and upper-back portions. A screw adjusts the concavity of the upper-back portion while a further screw adjusts the convexity of the lumbar support portion. A pair of cross bars are provided for supporting and securing the lumbar and upper back portions of the sheet to the backrest. The two adjustment screws are mounted on a pair of sliding plates to provide vertical adjustment of the lumbar support area and the upper-back support area. Accordingly, this patent is of interest for teaching independent height and curvature adjustment of the lumbar support and upper-back support portions of a backrest.
Additional references are known which pertain to adjustable back support or backrests, as follows: U.S. Pat. Nos. 2,843,195; 3,241,879; 3,762,769; 4,153,293; 4,452,458; 4,541,670; 4,601,514; 4,632,454; 4,722,569; 4,909,568; 4,915,448; 4,968,093; 5,026,116; and 5,197,780, as well international patent application No. PCT/AU91/00487 (BackCare and Seating Pty. Ltd.).
While the known prior art backrests disclose the provision of lumbar and upper-back support members with independently adjustable curvature and positioning, none of the known prior art teaches the combinations of height adjustment, lumbar height and curvature adjustment, upper-back curvature and position adjustment and side-to-side mobility. The provision of these features in a backrest is important to ensure proper fitting of the backrest for adult bodies of different height and shapes. Furthermore, human beings tend not to be static but like to move or "fine tune" their sitting positions. The known prior art backrests do not provide adequate side-to-side mobility for such movement. Nor do they allow for the convenient minor adjustment of support. In addition, the known prior art back supports are generally bulky or heavy to carry and occupy excessive space at the bottom portions thereof, thereby leaving very little room to sit on a chair.
SUMMARY OF THE INVENTION
According to the present invention, a backrest is provided in which lumbar height and curvature adjustment are provided along with overall height adjustment to fit different sized persons. Additionally, upper-back curvature and height adjustment are provided along with side adjustment to suit each half side of the human back (i.e. for accommodating different torso shapes). Also, side-to-side mobility is provided to accommodate twisting movements of the human back which are common when a person is sitting (e.g. turning to reach something, or "fine tuning" of one's sitting position). Furthermore, according to the backrest of the present invention a slight hollow is provided just above the base of the backrest to allow for curvature and space so that the backrest does not occupy excessive space on a chair.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of the backrest according to the present invention resting on a chair;
FIG. 2 is a cross section along lines II--II of FIG. 1;
FIG. 3 is a rear perspective view of the backrest according to the present invention;
FIGS. 4A and 4B are cross sectional views along the lines IV--IV of FIG. 3 showing curvature adjustment of the lumbar support and upper back support of the backrest according to the present invention;
FIG. 5 is a front perspective view of the backrest according to the present invention with the back pad shown in phantom;
FIG. 6 an exploded front perspective view of the structural details of the backrest according to the present invention;
FIG. 7 is a perspective view of the backrest according to an alternative embodiment of the present invention;
FIG. 8 is a rear perspective view, partly broken, of the backrest according to the alternative embodiment;
FIGS. 9A and 9B are cross sectional views along the lines IX--IX of FIG. 8 showing curvature adjustment of the lumbar support and upper back support of the backrest according to the alternative embodiment;
FIG. 10 is a front perspective view of the backrest according to the alternative embodiment with the back pad shown in phantom; and
FIG. 11 is an exploded front perspective view of the structural details of the backrest according to the alternative embodiment.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Turning first to FIG. 1, the backrest of the present invention is shown comprising a generally triangular upper portion 1 and base portion 3 resting on the seat of chair C. The triangular profile of upper portion 1 facilitates side-to-side movement of a person using the backrest of the present invention. Also, the hollow portion between the portion 1 and base portion 3 ensures that the backrest does not occupy excessive space on the chair C.
Turning to the remaining FIGS. 2-6, the details of construction of the preferred embodiment are illustrated. A spine 5, preferably of rigid aluminum, forms a central support portion of the backrest to which all other parts are attached. The spine 5 is fabricated to form a pair of cylindrical channels 7 and 9 intermediate a groove 11. As will be discussed in greater detail below, the spine 5 also includes a plurality of slots and apertures for the connection and securing of the various other parts.
A lumbar spring 13 has a projection 15 from a bottom end thereof which is shaped so as to be received in a clip 17. The clip 17 is riveted into spine 5 via a rivet 19 or other suitable attachment means. Thus, the lower portion of lumbar spring 13 is rigidly connected to the spine 5. As will be discussed in greater detail below, an upper portion of the lumbar spring 13 contains a projection 21 which is adapted to slide within the groove 11 of the spine 5 to permit curvature adjustment of the lumbar spring 13.
A cross bar 23 is provided in the form of a flat piece of metal (e.g. steel) which in conjunction with the back pad 49 and lateral adjustment straps 51 and 53 (discussed below), contributes to side-to-side lateral support of the backrest. The cross bar 23 is attached to back pad 4a as discussed in greater detail below.
An adjustment strap 25 is provided with a clip 27 at one looped end thereof and a D-ring 29 at an opposite looped end thereof. The end with clip 27 is dimensioned to pass through an aperture 31 in the spine of 5 as shown by the arrow in FIG. 6 such that the clip 27 may be secured to one of a plurality of slots 33 in the spine.
At the other end, the projection 21 of lumbar spring 13 is dimensioned to pass through D-ring 29 which remains on an opposite side of the spine 5 from the clip 27 and is adapted to slide within the groove 11 thereof, as will be discussed in greater detail below.
According to an important aspect of the present invention, curvature of the lumbar spring 13 may be adjusted. Turning to FIGS. 4A and 4B, the manner of such adjustment is shown. In order to adjust the curvature of spring 13, the clip 27 at the lower looped end of adjustment strap 25 is removed from one of the slots 33 in spine 5 by pulling downwardly against the tension of the spring 13 and releasing. Pulling of the adjustment strap 25 is facilitated by the loop 39 through which a finger may be inserted. Once the clip 27 has been removed from the slot 33, as shown in FIG. 4B, curvature of the lumbar spring 13 may be decreased by allowing the adjustment strap 25 to be released upwardly toward the slot 31 in spine 5. Alternatively, as shown in FIG. 4B, by pulling downwardly on the adjustment strap 25, D-ring 29 pulls the projection 21 of lumbar spring 13 downwardly, thereby increasing the curvature of the spring in the direction of the arrow.
An upper back spring 35 is provided having a slot 37 at a base portion thereof through which the projection 21 is adapted to be inserted (shown best in FIGS. 5 and 6).
According to another important aspect of the invention, independent curvature of the upper back spring 35 is also provided. A cylindrical tube 41 is capped on both sides via end caps 43, and is secured to the spine 5 via retention spring 45 which slides within the groove 11 and which is riveted to the upper back support tube 41 via rivet 47. By pushing the tube 41 downwardly in the direction of the arrow in FIG. 4B, the upper back spring 35 assumes a greater degree of curvature (ie. concavity), as illustrated. In addition, the tube 41 may be easily removed in order to remove any curvature in the upper back spring 35.
A back pad 49 (FIG. 5) is provided with a pair of adjustment straps 51 and 53 having hook and loop type fasteners thereon (i.e. velcro™) which pass through a pair of slots 55 in the back pad 49 in order to adjust the contour of back pad 49, as discussed in greater detail below. Each of these straps is independently and individually adjustable of each other allowing for precise side-to-side contouring.
The back pad 49 is connected to the upper spring 35 via a screw (not shown) or other attachment means passing through holes 57 and 59 (FIG. 5). The back pad 49 is connected at a lower end thereof to a further retention spring 61 which slides within the groove 11. Back pad 49 is connected to retention spring 61 via rivet 63 and hole 65 (FIG. 5). Thus, the back pad 49 is free to move upwardly and downwardly relative to the spine 5 as a result of the sliding connection of retention spring 61, upper back support spring 35 and cross bar 23 which is mounted to lumbar support spring 13.
As shown in FIGS. 1, 2 and 3, the back pad 49 is covered by a suitable fabric and foam cover 67 which provides a soft cushion for receiving the human back, the overall vertical profile of the cushion being dictated by the curvatures of the lumbar support spring 13, upper back support spring 35 and back pad curvature adjustment straps 51 and 53. As shown in FIG. 3, the back pad adjustment straps are attached via rivets or other suitable means to the back pad 49 via apertures 69, and extend through the rear of the fabric and foam cushion 67 via slots 71 and 73 for connection rearwardly of the backrest to suitable hook-and-loop (i.e. Velcro™) fasteners 75 (see FIGS. 2 and 3). By pulling on the adjustment straps 51 and 53, the curvature of the back pad 49 and hence the cushion 67 covering it, is caused to increase in the direction of the arrows shown in FIG. 3.
The back pad 49 is of generally deltoid shape and preferably fabricated from plastic panel to allow free shoulder rotation and upper back twisting.
The base portion 3 of the backrest includes a wire foot 77 covered with self skinning plastic foam 79. As shown in FIG. 6, cylindrical end portions of the wire foot 77 are adapted to slide within the cylindrical holes 7 and 9 (FIG. 2) of the spine 5 for upward and downward sliding movement of the wire foot 77 as shown with reference to the arrows at the bottom of FIG. 3. The wire foot 77 is secured in place relative to spine 5, after height adjustment, by means of a pair of screws 80 and corresponding nuts 82.
A self skinning wire head 81 is inserted into the tubular grooves 7 and 9 at the top of spine 5 to provide a pleasing aesthetic finish and an integral carrying handle. The wire head 81 is secured within spine 5 via a pair of screws 83 and corresponding nuts 85 which cause the grooves 7 and 9 to close around the wire head 81. In order to assemble the backrest according to the present invention, cross bar 23 is first attached to the lumbar spring 13 using very high bond tape, or other suitable material, as discussed above. The Velcro™ adjustment straps 51 and 53 and the cross bar 23 are then riveted to back pad 49. Lumbar spring 13 and upper back spring 35 are hooked together as shown in FIG. 6, and the upper back spring 35 is riveted to the back pad 49 as discussed with reference to FIG. 5. The retention spring 61 is riveted to the back pad 49 through hole 65 (FIG. 5).
Clip 27 is then riveted to the lumbar adjustment strap 25, forming a loop 39.
Wire foot 77 is inserted into the spine 5 and fastened into place with machine screws 80 and nuts 82. Loop 29 is hooked to the lumbar spring 13 and this assembly is then made to slide into the channel 11 in the spine 5. The lumbar adjustment strap 25 is then inserted through the D-shaped loop and riveted to the end thereof, and the opposite looped end 39 of the strap 25 is pushed through slot 31 at the back of the spine 5. The assembly comprising lumbar spring 13, D-shaped loop 29 and upper back spring 35 is pulled downwardly to allow the retention spring 61 to slide into the spine 5 from the bottom. The assembly is then pulled back up and the bottom end 15 of the lumbar spring 13 is hooked into clip 17.
Next, the retention spring 45 is riveted to the upper back support tube 41. End caps 43 are inserted into the sides of the upper back support tube 41, and the assembly comprising the upper back support spring 35 and retention spring 45 are inserted into the channel 11 of spine 5 from the top.
The wire head 81 is then inserted into the top of the spine 5, the fabric and foam cover 67 is placed over the back pad 49, and the various straps 25, 51 and 53 are adjusted for personal setting.
An alternative embodiment of the invention is illustrated in FIGS. 7-11. The alternative embodiment is similar in many respects to the embodiment shown in FIGS. 1-6. Where the features are identical, no additional description is provided herein, and the same reference numerals have been used in FIGS. 1-6 and FIGS. 7-11 to identify like components.
In the alternative embodiment, the wire head 81A is provided with a rubberized sleeve for enveloping the protruding top portion of the wire head, rather than completely encapsulating the wire head 81 as in the embodiment in FIG. 1-6.
The spine 5 is of slightly modified design in that cylindrical channels into which the ends of the wire head 81A are inserted, have been created in the spine, thereby eliminating the requirement for screws 83 and nuts 85 (FIGS. 1-6).
In the alternative embodiment, spring 35A has been shortened and the material from which it is fabricated (eg. plastic) is strengthened relative to the spring 35 in the embodiment of FIGS. 1-6, so as to provide the same level of resiliency as in the embodiment of FIGS. 1-6.
The back pad 49 is connected to anchoring spring 35A via a pair of nuts and bolts (FIG. 10) which pass through a pair of holes 59A in back pad 49 and a pair of holes 57A in spring 35A, thereby replacing the single holes 57 and 59 in the embodiment of FIGS. 1-6.
The method of securing the lumbar spring 13 for a predetermined amount of curvature is substantially modified in the embodiment of FIGS. 7-11, resulting in the elimination of slots 33. In the alternative embodiment, one end of a first adjustment strap 25 is connected to the spine 5 via a rivet 28 and the other end is connected to a friction buckle 33A. The strap 25 passes upwardly from buckle 33A along the rear side of the spine 5, through aperture 31 in the spine, through loop 37B of spring 35A, and down to the rivet 28. One end of a second adjustment strap 26 is connected at 65A to a bottom portion of back pad 49, passes through slot 33B and is then threaded through friction buckle 33A, for permitting adjustment and then tightening of the strap 26 in position. The end of strap 26 which is connected to the back pad 49 at 65A is folded back on itself, and is rivetted for securing the end of the strap to the back pad. The use of a buckle (e.g. LADDER LOCK™) provides easier and finer adjustment of the lumbar spring 13 and upper spring 35A than is provided with the hook and slot arrangement in the embodiment of FIGS. 1-6.
Since the lower portion of back pad 49 is secured via strap 26, the retention spring 61 and rivet 63 have been eliminated from the alternative embodiment.
In the alternative embodiment, hook-and-loop fasteners 75A are attached directly to the cross-bar 23, rather than to the foam backrest.
The position adjustment of wire foot 77A is simplified in the alternative embodiment by replacing the two screws 80 (FIGS. 3 and 6), with a single thumb screw 80A which projects into the channel 9 for insertion into one of the circular apertures 78 in wire foot 77A, thereby locking the wire foot in position.
The plastic foam 79 of the embodiment shown in FIG. 1-6 is replaced in the alternative embodiment by a rubber sleeve 79A, in a similar manner as discussed above with reference to wire head 81A.
The cross bar 23 is more securely fastened in the alternative embodiment via a plurality of nuts and bolts (not shown), wherein the bolts are inserted through ten holes 69 extending through the back pad 49 and corresponding holes through cross bar 23, instead of four holes in the embodiment of FIGS. 1-6.
The screw 47 (FIGS. 4A, 4B and 6) is replaced in the alternative embodiment by a rivet 47A, while the retention spring 45 is replaced by a flat member 45A having a pair of holes.
In the alternative embodiment, the end 21 of lumbar spring 13 is no longer bent and the overall shape of the lumbar spring differs from that in the embodiment of FIGS. 1-6. Furthermore, the method of attaching the lumbar spring 13 to spring member 35A is modified from the embodiment of FIGS. 1-6, as shown best with reference to FIGS. 9A, 9B and 10. Specifically, the upper end 21 of lumbar spring 13 is inserted through slot 37A in spring 35A, while the opposite end 15A rests in clip 17A. The clip 17A is secured to the spine 5 via nuts 19B and bolts 19A.
In operation, by pulling downwardly on strap 26, buckle 33A is pulled downwardly which, in turn, causes strap 25 to pull down spring member 35A via loop 37B. This causes the lumbar spring 13 to flex, thereby increasing the curvature thereof.
Although specific design features are changed in the alternative embodiment over the embodiment shown in FIGS. 1-6, the general principle of operation remains the same.
In summary, according to the present invention, an adjustable backrest is provided having independent lumbar height and depth adjustment, overall height adjustment to fit different sized patients, mid-back curve height adjustment, side adjustment to suit each half of a patient's back, upper back side-to-side mobility so that the patient can turn from side-to-side, and a hollow portion just above the base to allow curvature and room so that the backrest of the present invention does not occupy excessive space on the chair. Furthermore, the backrest according to the preferred embodiment is portable, and can be affixed to office chairs, car seats, wheelchairs, etc, or can be made an integral part thereof.
Other embodiments and modifications of the invention are contemplated. For example, in a further alternative embodiment the backrest of the present invention may be incorporated integrally within a chair, rather than being portable as provided in the preferred embodiment. This further alternative embodiment nonetheless offers all of the advantages of independent adjustability provided by the preferred embodiment. This and all other modifications and embodiments are believed to be within the sphere and scope of the invention as defined by the claims appended hereto. | An adjustable backrest for supporting a human back comprising a spine member; a lumbar support member projecting from the spine member; a back pad resting on the lumbar support member for supporting the human back; means for adjusting curvature of the lumbar support member and means for adjusting curvature of different portions of the back pad to accommodate different shapes of the human back; means for providing side-to-side mobility of the back pad to accommodate twisting movement of the human back. | 1 |
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of priority from U.S. Provisional Patent Application No. 60/552,806 filed on Mar. 12, 2004 and entitled UNDERWATER DATA COMMUNICATION AND INSTRUMENT RELEASE MANAGEMENT SYSTEM, the entire contents of which are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This invention generally relates to apparatus and methods for underwater communication and, more particularly, to apparatus and methods by which data can be acquired by a topside unit from an instrument package remotely located underwater and/or the instrument package can be released by command from the topside unit.
BACKGROUND OF THE INVENTION
[0003] With packages moored below or beneath the surface of water, it is desirable to have a remotely controlled release mechanism for disengaging the packages from their moorings thus allowing them to rise to the surface for retrieval or to sink below toward the bottom. Such apparatus have commonly been used with subsea data collecting instruments, especially where such instruments are anchored at significant depths. Such instruments are typically connected to or integrated with a flotation device. At shallow depths, the flotation device may be kept at the surface for easy retrieval by surface vessels. When the submerged package is at more significant depths or it is desired that the submerged package not be easily sighted at the water surface, it is typical to secure the package and flotation device completely below the water by attaching it to a mooring via an intermediate, acoustically triggered, release.
[0004] Prior release mechanisms have been remotely triggered with acoustic communications devices using narrowly limited and discrete sets of signals. For instance, a typical device might accommodate a few discrete frequencies that, when detected by the release mechanism, cause it to disengage from the mooring apparatus and allow the disconnected package to float to the surface for retrieval.
[0005] Another desirable feature to have with underwater packages is the ability to transfer large amounts of data between them and the surface while such packages remain submerged. There are currently available advanced apparatus and methods for communicating large amounts of voice and other data through water, facilitated by what are typically referred to as underwater modems. These underwater modems generally provide the same functionality as those commonly used for global network communications across telephone, microwave, radio and other mediums. Underwater modems currently provide a dynamic means for high-rate data transfer between land, above-water and underwater vessels, and instruments such as those used for collecting information about undersea conditions.
[0006] Thus, current practice is to use multiple communications links and protocols from surface to sub sea units to retrieve data from undersea packages, communicate with their various components, and issue commands to release mechanisms. These practices are redundant and result in inefficient and costly apparatus comprised of multiple battery/power sources and communications instruments both below and above the surface.
[0007] Consequently, there is a need to be able to efficiently and effectively acquire data from submerged instrument packages and also release them from their underwater moorings for retrieval, and it is a primary object of the present invention to address this need.
[0008] Other objects of the invention will, in part, appear hereinafter and, in part, be obvious when the following detailed description is read in connection with the drawings.
SUMMARY OF THE INVENTION
[0009] The present invention is directed to an underwater data communications and instrument package release management system and associated method. The present invention comprises a release and an underwater modem apparatus integrated in a single waterproof housing having one-end adapted to be releasably attached to an underwater mooring and the other preferably attached to a buoyant instrumentation package. The modem is adapted for bi-directional communications and for providing a means for controlling and monitoring the release apparatus. The modem also is adapted for receiving and transmitting complex data and commands to and from attached instruments.
[0010] An embodiment of the invention includes a cylindrical housing to permit safe enclosure of a release mechanism and acoustic modem at significant underwater depths. At one end, the housing includes a means releasably latching to an attachment, the attachment typically being part of a means for tethering and anchoring the housing and combined loads to the seafloor. Also within the housing is included the acoustic modem, a processing unit for interpreting and directing commands and data between the modem and other components, and a long-life battery. The processing unit includes a means for connecting with internal or external instruments. Instruments can alternatively be contained within the housing or attached externally via a tethering arrangement. External instruments typically are electrically connected to interior housing components using water-sealed or sealable communication wires and ports. Data gathering instruments can be stored within positively buoyant spheres and, while the sphere is secure to the housing of the release, the instruments are wired to the processor and modem components of the invention. This avoids the necessity of having a modem component within or integrally combined with the spheres or their internal instruments.
[0011] Various embodiments of acoustic underwater modems can be selected for adaptation with the invention. Many such modems are sold by Benthos, Inc., North Falmouth, Mass., including acoustic modems for either shallow-water or deep-water use and those that use various data transmission modes. Incorporated within these modems are features designed to accommodate the dense and irregular medium of seawater. Such modems adopt various known techniques for signal modulation such as Frequency Shift Keying (FSK) or Phase Shift Keying (PSK), including various known adaptations of these techniques such as Multiple Frequency Shift Keying (MFSK) or Multi-byte Phase Shift Keying (MPSK). Typically included are Doppler correction techniques to compensate for signal distortion created by motion between transmitters and receivers. The transmitters of these modems can alternatively be adapted for directional or omni-directional radiation. These modems also may be adapted with many of the features that today's standard telephony-based modems include, such as data compression, buffering, and/or error correction.
[0012] One embodiment of the modem component would include a processing unit for directing data and commands between the modem and various instruments, including the release mechanism. A wide variety of microprocessors and micro-controllers are available that can readily be programmed for such use.
[0013] For use as a surface communication means with the underwater modem, a portable surface component may be provided with a dunkable transducer. This component is typically employed on a surface vessel with the dunkable transducer towed or otherwise resident beneath the water surface. The surface component contains its own underwater modem component that acts to transmit and receive data to and from other underwater remotely located modems. The surface component provides a means for storing and transferring such data to and from other various surface components, such as a personal computer (“PC”) via an RS-232 port or other communications means.
[0014] An embodiment of a surface unit can be adapted for use with common or customized software packages that are installable on personal computers (including laptops). This software is adapted to act as an interface for an operator to transmit data and commands to control the release mechanism and other various instruments connected to an underwater modem. The software may also be used to receive, present and store data retrieved through the modem.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] The structure, operation and methodology of the invention, together with other objects and advantages thereof, may best be understood by reading the detailed description in connection with the drawings in which each part has an assigned label or numeral that uniquely identifies it wherever it appears in the various drawings and wherein:
[0016] FIG. 1 is a diagrammatic side elevational view showing in block form an underwater data communications and instrument release according to an embodiment of the invention connected to a spherical float-instrument package;
[0017] FIG. 2 is a diagrammatic view illustrating the underwater data communications and instrument release management system according to an embodiment of the present invention as it is deployed;
[0018] FIG. 3 is a diagrammatic side view of the top-surface components according to an embodiment of the present invention as shown in FIG. 2 ;
[0019] FIG. 4 is a view of a main screen for an embodiment of the computer software component of the present invention;
[0020] FIGS. 5A and 5B are views of software screens for configuring the modem component of the present invention;
[0021] FIG. 6 is a view of a software screen that graphically displays data communicated from instruments attached to underwater modems;
[0022] FIG. 7 is a view of a software display screen for remotely controlling and monitoring the status of the release mechanism component of the present invention;
[0023] FIG. 8 is a diagrammatic exploded view showing in more detail an embodiment of the internal components of the modem and release apparatus;
[0024] FIG. 9A is a diagrammatic side elevational view of an actuating release mechanism according to an embodiment of the invention; and,
[0025] FIG. 9B is a diagrammatic elevational view of a release latch that is actuated by the mechanism shown in FIG. 9A .
DETAILED DESCRIPTION
[0026] Reference is now made to FIG. 1 , which illustrates an underwater release 10 that comprises part of the data communications and instrument release management system of the invention. Underwater release 10 includes a variety of internal components that reside in a protective, preferably cylindrical, waterproof housing 15 including a release mechanism 40 adapted to mechanically actuate a latch assembly 52 to which an underwater load, such as an anchoring or mooring means can be attached. To the top end of underwater release 10 is attached a spherical instrument package 90 that has positive buoyancy. Instrument package 90 is attached to underwater release 10 via a cable 62 .
[0027] Also residing in housing 15 is a modem 100 that serves to provide communications between underwater release 10 and a topside or surface base unit. Modem 100 connects via cabling 24 to a controller unit 20 . Controller unit 20 , which comprises a controller board 21 , CPU 23 , and memory 25 , interprets and translates commands and data to and from instruments 70 that are located in instrument package 90 and release mechanism 40 , including commands for actuating release mechanism 40 . A long-life battery 30 provides power for modem 100 , controller unit 20 and release mechanism 40 . Controller unit 20 is preferably programmed to monitor the power level of battery 30 , so that when power levels fall below a predetermined threshold, instruments and other components are turned off and only commands for “waking” the modem to actuate the release mechanism 40 are processed by controller board 20 . Modem 100 connects to an external transmitter/receiver or transducer 50 , which delivers and receives acoustic signals to and from other transmitters and receivers. Transmitter/receiver 50 is partially protected from external physical interference by caged housing shield 60 . Power may also be provided by an external battery pack or by an undersea generator.
[0028] As mentioned earlier, underwater release 10 is connected to spherical float/instrument package 90 via underwater tethering means 62 selected from among many strong and corrosive-resistant type materials that are available for this purpose. Controller board 20 is connected to an external communications interface 80 , selected from among any suitable water-shielded multi-pin variations commercially available. Interface 80 connects to an underwater cable 82 that, in turn, connects to a data port 72 to provide a communications link between modem 100 and instruments 70 . A sensor port 74 provides a means for a sensor 76 to access and collect data from the surrounding undersea environment. Within float/instrument package 90 is a sufficient vacuum to assist in providing the necessary sealing force for keeping its two hemispherical halves together. Seawater displacement causes instrument package 90 to be buoyant thereby allowing it and underwater release 10 to ascend to the surface when release mechanism 40 is detached from its underwater mooring.
[0029] Reference is now made to FIGS. 2 and 3 , which diagrammatically show the underwater data communications and instrument release management system of the invention deployed in its native operating environment. A top surface or topside modem 200 ( FIG. 3 ) and its components are transported and alternatively powered by seagoing vessel 215 . Towed below seagoing vessel 215 is transducer 230 that provides a means for transmitting and receiving underwater acoustic signals to and from other acoustic underwater remotely located devices such as underwater release 10 . Underwater release 10 is shown tethered to spherical float/instrument package 90 and held below the surface by a mooring 250 .
[0030] Reference is now made to FIG. 3 , which shows a side elevational view of the top surface components of the invention as they are deployed in FIG. 2 . Topside modem 200 connects to underwater transducer 230 via a cable 220 or alternatively via a port 222 , and underwater cable 232 . Underwater transducer 230 provides a means for transmitting and receiving underwater acoustic signals to other underwater modems, similar to that shown in FIG. 2 . Topside modem 200 can provide its own integrated operator interface or alternatively be remotely managed by a separate computer 210 , which can be connected to modem 200 by various available means such as cable 202 . Cable 202 could, for example, be terminated by various types of connectors including RS-232, Ethernet, and USB. Modem 200 and computer 210 may alternatively be connected by wireless means such as wireless Ethernet.
[0031] Reference is now made to FIG. 4 , which shows an embodiment of the main screen of a software component of the invention, which resides in computer 210 . The main screen provides a graphical user interface (GUI) for initializing communications between topside and underwater modems, automating desired sequences of communications between such modems, allowing basic commands to be transmitted between modems via a terminal window, and providing a means for retrieving various diagnostic parameters of modems, such as baud rate, power level, and signal strength. The Main Screen provides a user access to the various other specific functions and screens of the software, such as diagnostic screens (See FIGS. 5A-5B ), instrument communication and data viewing screen (See FIGS. 6 ), and underwater release status and control display screen (See FIGS. 7 ).
[0032] Reference is now made to FIGS. 5A and 5B , which show configuration screens for topside and underwater modems allowing a user to set operating modes such as maximum baud rate, timeouts, packet sizes, wakeup parameters, bandwidth, and transmission frequencies.
[0033] Reference is now made to FIG. 6 , which shows an embodiment of a screen for displaying and transferring instrument data and checking an instrument's communications status. Information such as temperature, depth, salinity, current strength, and positional data can be displayed.
[0034] Reference is now made to FIG. 7 , which shows an embodiment of a screen for viewing the status of a release mechanism and providing a means for an operator to remotely actuate the release. This screen also permits attitude information about the underwater release to be conveyed.
[0035] Software for generating the foregoing screens and other functions may be implemented in well-known manners in any suitable computer language.
[0036] Reference is now made to FIG. 8 , which shows an exploded and further detailed diagrammatic variation of a subassembly of the modem and release components packaged for easy insertion into waterproof housing 15 according to an embodiment of the invention. As best seen in FIG. 8 , the end cap assembly 52 including modem release mechanism 40 attach to the remaining elements via a chassis connector 250 . A battery tube 254 receives battery 30 and is held in place via a battery pack cover plate 252 . An electronics tube 256 is adapted to receive controller board 20 , and an end plate 258 covers the outboard end of the electronics tube 256 . FIG. 8 demonstrates in particular a variation of how the controller unit 20 and modem 100 components can be arranged within the apparatus housing, wherein labeled P.C. boards 260 and 262 , can alternatively comprise and/or combine each of said controller and modem components. The end cap assembly 52 along with the elements of the release mechanism 40 complete the other end of the subassembly. Release mechanism 40 comprises a motor driven screw and push rod arrangement 300 shown in FIG. 9A that operates a pivoting latch member 302 shown in FIG. 9B .
[0037] The modems of the invention adopt various known communications protocols or techniques for signal modulation such as Frequency Shift Keying (FSK) or Phase Shift Keying (PSK), including various known adaptations of these techniques such as Multiple Frequency Shift Keying (MFSK) or Multi-byte Phase Shift Keying (MPSK). Typically included are Doppler Correction techniques to compensate for signal distortion created by motion between transmitters and receivers. The transmitters of the modems can alternatively be adapted for directional or omni-directional radiation. The modems also may be adapted with many of the features that today's standard telephony-based modems include, such as data compression, buffering, and/or error correction. Preferably included in the communications protocol to improve data transmission are:
[0038] 1 of 4 MFSK:_ An advanced modulation scheme, which allows for high speed data transmission (up to 2400 baud). 1 of 4 MFSK is bandwidth efficient, fast and_relatively simple to encode.
[0039] Hadamard MFSK: An advanced modulation scheme used to minimize the effects of frequency dependent fading. This scheme also allows the system to operate at a lower signal to: noise ratio (SNR) by working reliably at lower transmit power levels.
[0040] In addition to 1 of 4 MSFK and Hadamard MFSK, the acoustic modems incorporate three other methods for increased data reliability. These include data redundancy, convolutional coding and a multipath guard period. All three methods are user selectable and can be applied when using either modulation scheme.
[0041] Data Redundancy: A technique in which the same data bits are transmitted two or more times (user selectable) in the same data frame. Data reliability is increased through repetition and frequency diversity.
[0042] Convolutional coding: An error correction technique in which a Viterbi algorithm is implemented to detect and correct received bit errors. An effective technique for use in high multipath environments. This feature allows the user to incorporate a selectable delay period between data frames. This brief delay allows time for the multipath to die down in the communication channel before sending out the next data frame.
[0043] Customer Selectable Frequency Range: The system can be configured to operate within one of three standard frequency ranges: 9-14 kHz (LF), 15-20 kHz (MF), and 25-30 kHz (HF).
[0044] Customer Selectable Transducer Arrays: Each of the acoustic modems (topside and sub sea) can be configured to include a directional, omni directional, or line array transducer.
[0045] An embodiment of the modem component would include a processor for directing data and commands between the modem and various instruments, including the release mechanism. A wide variety of microprocessors and micro-controllers are available that can readily be programmed for such use or a general-purpose desktop or laptop computer, preferably ruggedized, can be programmed. The software resident in such microprocessors or computers can be implemented using any suitable language, including but not limited to, C, C ++ , Fortran, Visual Basic, assembler language or combinations thereof.
[0046] Based on the disclosure of the invention, other variants of it will be evident to those skilled in the art. For example, it should be apparent that the system can be used without a separate buoyant instrument package since it can be used separately a just a communication and release apparatus. When used without a separate buoyant instrument package, it should be apparent that buoyancy needs to be added if the apparatus is to be to ascend to the surface after release. Such buoyancy can be provided by integrating it with the apparatus housing or attaching is as an external component to an attachment arrangement provided on the housing. The buoyancy could in either case be inflatable. It is intended that such variants be within the scope of the claimed subject matter. | A data communications and underwater release management system for acquiring data from remote positively buoyant instrumentation packages moored underwater through the use of an intervening mechanical release coupled at one end to the buoyant instrumentation package and at the other to the mooring. A topside modem system provides bidirectional communication with an undersea modem commonly housed with the release to permit data generated from the instrumentation to be conveyed topside and/or send command signals to release the instrumentation package so that it can ascend to the surface for recovery, repair, or refitting. Power is supplied via an on-board battery whose energy level is monitored and directed when below a threshold value to operate only the mechanical release. | 1 |
BACKGROUND OF THE INVENTION
The invention relates generally to fastener drive tools, and more particularly to anvil-type or hammer drive, powder actuated tools.
Many types of fastener drive tools and like explosively actuated equipment have been developed over the years, and such tools have generally had complex mechanisms for firing pin operation, for ejecting or extracting spent cartridge shells and for meeting safety standards. Recent developmental trends are toward improved low velocity tools of the type in which a piston ram member is explosively driven to actuate a nail or like fastener into a workpiece such as concrete or wood. One type of low velocity tool is described in U.S. Pat. No. 3,066,302, which tool uses a pistol-type firing pin mechanism having a trigger and sear to trip a spring-loaded firing pin that is cocked by compressing the muzzle end of the tool telescopically rearwardly within the tool housing. Many such pistol-type low velocity tools are disclosed in the prior art.
Another type of low velocity tool is described in U.S. Pat. No. 4,025,029, which tool, like the present invention, is a hammer-activated, powder actuated stud driver. Such hammer drive tools are conventionally operated by placing the muzzle end of the tool against the workpiece and striking the rear end of the tool with a hammer to fire the cartridge or like powder charge. Hammer drive tools heretofore, while simple in construction and operation, have been inherently dangerous due to the fact that a loaded tool could be fired if accidentally dropped. U.S. Pat. No. 3,688,964 discloses another low velocity hammer drive tool designed for caseless powder loads and having some safety features.
SUMMARY OF THE INVENTION
The present invention comprises a low velocity, powder actuated tool of the type utilized in construction and other trades, and particularly adapted for use in the home, shop or the like by semi-skilled persons.
The principal object of the present invention is to provide a novel fastener drive tool of the hammer drive or impact type; one that is of simple, rugged construction and eliminates the complex and expensive forms of closure, trigger, sear, firing pin, cartridge holding and ejection and like mechanisms of prevalent tool design.
Another object is to provide a powder actuated tool that is highly efficient in operation and provides exceptional safety standards against drop-fire and other accidental tool discharge incidents. A more specific objective is to provide triple safety means requiring positive manual operation as well as substantial striking force to accomplish firing actuation of the tool.
Still another object is to provide a hammer drive tool that meets the three safety requirements of the American National Safety Code.
These and still other objects and advantages will become more apparent hereinafter.
BRIEF DESCRIPTION OF THE DRAWINGS
For purposes of illustration and disclosure, the invention is embodied in the parts and in the arrangements and combinations of parts hereinafter described and claimed.
In the accompanying drawings which form part of the specification and wherein like numerals refer to like parts wherever they occur:
FIG. 1 is a longitudinal cross-sectional view of a hammer drive, powder actuated tool in the expanded or loading position thereof;
FIG. 2 is a longitudinal cross-sectional view of the tool in its compressed condition at the instant of powder detonation;
FIG. 3 is an enlarged fragmentary cross-sectional view taken substantially along line 3--3 of FIG. 1;
FIG. 4 is an enlarged fragmentary cross-sectional view taken substantially along line 4--4 of FIG. 2, but being rotated 90° for correct depiction; and
FIG. 5 is an enlarged fragmentary cross-sectional view taken substantially along line 5--5 of FIG. 1, but being rotated 90° for correct depiction.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring to the drawings wherein the hammer drive, powder actuated tool 10 is illustrated as a presently preferred embodiment of the present invention, the tool 10 comprises a main cylindrical housing member 11 having a rear firing pin bore section 12 and a front barrel bore section 13 with an intermediate breech or loading area 14. A primary solid anvil member 17 is rigidly secured in the firing pin bore 12 of the main housing 11 by a cross pin 18, and a "floating" firing pin assembly 19 is housed in the firing pin section 12 between the primary anvil mass 17 and the breech or loading area 14, as will be defined more fully hereinafter. A safety lever assembly 20 is pivotally mounted on the main housing 11 intermediate to the firing pin section 12 and breech area 14, and one of its purposes is to limit or restrict free floating forward movement of the firing pin assembly 19 toward the breech section 13. The main housing 11 has a lateral breech opening 21 for access to the inner breech or loading area 14 for purposes of cartridge ejection and reloading of the tool 10. The main housing 11 is provided with a two-piece outer resilient hand grip or housing covering 22 which circumscribes the rear firing pin section 12 and is associated with the safety lever assembly 20, as will be described.
A barrel ram guide member 23 is slidably mounted in the front barrel section 13 of the main housing 11, the guide member having a bore 24 in which a barrel extension 25 is threadedly engaged at the muzzle end. The barrel extension 25 has a bore 26 concentric with the ram guide bore 24 and an annular shoulder 27 is formed between the bores 24 and 26. The ram guide 23 also has a breech plug 28 threadedly engaging the breech end of the bore 24, the breech plug 28 having an ignition cavity 29 for receiving a powder cartridge C (see FIG. 1) or like powder charge. A ram or piston member 30 has an enlarged head 31 with a close tolerance sliding fit in the ram guide bore 24, and an axially extending cylindrical ram or piston rod 32 is slidably positioned in the barrel extension bore 26 with a free or working end therein for engagement with a fastener F. The ram head member 31 has an annular steel or like O-ring seal 35, and an annular abutment shoulder 36 on the head member 31 defines the end of the recess between the piston rod 32 and the ram guide bore 24. The ram and ram guide members 30 and 23 comprise fastener drive means for orienting the fastener member F in the tool 10 and for driving such fastener F into a workpiece (not shown) in a conventional manner readily apparent to those skilled in the art. The ram head 31 is also provided with an axially extending ejection pin 37 for dislodging spent cartridge shells C from the ignition cavity 29.
An important feature of the tool 10 comprises frictional abutment means 38 adjacent to the muzzle end of the main barrel housing 11. The ram guide member 23 has a longitudinal slot 39 extending a major portion of the guide member length, and an arcuate transverse slot 40 is formed in the main housing wall 11 to thereby accommodate a spring clip 41 forming part of the frictional abutment means 38, see FIGS. 1 and 3. The spring clip 41 has a U-shaped central body 42 extending radially inwardly through the ram guide slot 39 into the recess for abutment by the ram head shoulder 36, and arcuate friction wings 43 are formed as outward re-entrant curves from the opposed walls of this central body 42, FIG. 3. The frictional abutment means 38 also includes a spring steel retainer band 45 having an inner end flange 46 received between the spaced walls of the spring clip central body 42 to maintain the band 45 in circumscribing relationship around the muzzle end of the main housing 11.
Referring to FIG. 2, the tool 10 is shown in its fully compressed firing position with the ram 30 and ram guide 23 being retracted in telescopic relation within the main housing 11 and the firing pin assembly being compressed in the condition of the tool 10 at the precise instant that a hammer driven force is applied to the primary anvil member 17 to detonate the powder charge C in the breech plug 29. It will be understood by those skilled in the art that the force exerted upon the ram head 31 drives the ram 30 axially in the ram guide 23 and barrel extension 25 so that the working end 33 drives the fastener F from the muzzle end of the barrel extension 25 into the workpiece (not shown). Thus, when the tool has been fired, the ram 30 will naturally be positioned in the ram guide 23 leftwardly of the position shown in FIGS. 1 and 2 until the piston guide is also moved leftwardly (as in FIG. 1) to its expanded, re-loading position. This action is carried out by snapping the muzzle end of the tool outwardly in a swinging movement to throw the ram guide outwardly in the main housing bore 13 against the frictional force exerted therebetween by the spring clip wings 43 of the spring clip 41. In this movement the ram guide 23 moves to its fully extended loading position with the frictional abutment means 38 engaging the end of slot 39, and the ram 30 is also engaged with its abutment shoulder 36 against the U-shaped central body 42 of the spring clip. Thus, in the FIG. 1 position of the tool 10, the ejection pin 37 projects into the cartridge or ignition cavity 29 of the breech plug 28 to eject the spent cartridge shell, which is dropped through the breech opening 21 by inverting the tool 10 from its FIG. 1 position. It will be readily apparent that the frictional abutment means 38 return the ram and ram guide members 30 and 23 to their loading relationship for inserting a new fastener F in the muzzle end of the barrel extension 25 and a cartridge C in the ignition cavity 29 of the breech plug 28. The frictional abutment means 38 also prevents relative rotation of the ram guide member 23 in the main housing 11, and the spring clip 41 and retainer band 45 act frictionally between the ram guide member 23 and main housing 11 to maintain the ram guide frictionally in any adjusted axial position. The steel friction spring 35 between the ram head 31 and ram guide bore 24 maintains the adjusted axial position of the ram 30 in the ram guide member 23.
Referring particularly to FIGS. 1, 4 and 5, the firing pin mechanism of the tool 10 includes the primary anvil member 17 having a centrally projecting impact or anvil block 49 with striking face 50, and a strong drop-spring 51 is positioned on the anvil block 49 and extends concentrically forwardly in the firing pin bore 12 to oppose movement of the ram guide 23 and its cartridge carrying breech plug 28 toward firing position. The spring 51 has a substantial force of approximately 25 to 30 ft. lbs., which is several times the weight of the tool and thereby forms a first safety mechanism to substantially obviate drop-fire incidents. The "floating" firing pin assembly 19 includes a secondary anvil mass or plug 52 slidably positioned in the firing pin bore section 12 of the main housing 11, and a circular firing pin 53 is integrally formed on its forward face in the breech area 14 and is axially aligned with the ignition chamber 29 of the ram guide member 23. The secondary anvil and firing pin member 52,53 is biased forwardly toward the breech area 14 by the strong or "heavy" drop-spring 51, but a stop key or pin 54 projects radially from the secondary anvil member 52 and is guided in a longitudinal slot 55 in the main housing wall 12 to limit forward movement of the firing pin assembly 19 toward the breech area 14.
The firing pin assembly 19 also includes secondary safety means associated with the secondary anvil 52. The anvil 52 is bored through, at 56, on opposite sides of the firing pin 53 and is counterbored from the back, at 57, and receives a pair of diametrally disposed headed studs or safety rivets 58. The rivets 58 are biased by firing pin safety springs 61 positioned in the counterbore 57 and retained therein by a tempered closure anvil block or plate 62, which is welded to the back surface of the anvil plug 52 and serves to retain the forward end of the drop-spring 51. The secondary anvil member 52 also has a forwardly projecting annular shoulder 63 at its periphery, which is adapted to interfit with an annular peripheral recess 64 in the breech plug 28 thereby forming a sealing arrangement at the point of firing contact of the firing pin 53 with a cartridge C. It may be noted that the firing pin 53 has a complete centerfire fit with the percussion flange of the cartridge C, and firing indentation of the cartridge C by penetration of the firing pin is controlled by the sealing arrangement. The safety stud springs 61 are also of substantial force or "heavy," each being about the same magnitude as the drop-spring 51 (approximately 28 ft. lbs.) whereby the combined spring forces to be overcome to fire the tool 10 substantially eliminate accidental firing incidents.
The safety lever assembly 20 comprises the third safety device of the present tool 10, and comprises an elongated lever body 66 longitudinally disposed along the firing pin section 12 of the housing 11 and contained within the davity section 65 formed in the resilient covering 22 therefor. A safety latch or lug 67 is formed substantially at right angles on the forward end of the lever body 66 and extends radially inwardly of the cylindrical main housing 11 through a transverse slot 68 and defines the forwardmost limit of the firing pin assembly 19 as a secondary stop to the limit plug 54. More importantly, the latch 67 acts to prevent accidental rearward movement of the ram guide member 23 as will be described. The other end of the lever body 66 is provided with a handle 70 extending outwardly of the resilient covering 22, and the lever body 66 is hinged or pivoted on the main housing 11 on a fulcrum mounting lug 69 intermediate to the latch 67 and the outwardly extending handle portion 70. A wrap-around spring 71 or the like compresses the latch member 67 inwardly to form the safety abutment in the main housing bore, and the spring 71 is overcome by depressing the handle 70 radially inwardly against the hand grip covering 22. It will be apparent that the handle-fulcrum-latch relationship can be modified to provide optimum safety lever action.
In the extended, loading position of the tool 10 as shown in FIG. 1, a new cartridge C is inserted into the ignition cavity 29 thereby pressing against the ejection plug 37 and axially moving the entire ram 30 slightly to the left, where the ram 30 is held in position with the ram guide 23 by the friction sealing spring 35. A fastener F is inserted in the muzzle end of barrel extension bore 26 against the ram work face 33, and the fastener drive and guide means 30,23 is moved rearwardly toward the firing pin section 13 to close the breech opening 21 and position the breech plug 28 of the ram guide 23 against the ends of the safety guide rivets or studs 58, which project axially beyond the safety lever latch 68, FIG. 1. Although the safety lever mechanism 20 forms the only positive interference safety device, that prevents unrestricted axial movement of the guide means 23 and firing pin assembly 19 into contacting or firing abutment, the combined force of the two firing pin safety springs is approximately 56 ft. lbs. and effectively prevents compressive firing action by the operator or other inadvertent compressive forces of great magnitude, such as accidental drop-fire incidents. Therefore, it will be seen that in the normal sequence of compression, the drop-spring 51 would first become compressed to bring the ram guide 23 into abutment with the safety latch 68 before the firing pin safety springs 61 will give way to striking engagement between the firing pin 53 and cartridge C in the breech plug 28.
In actual operation, when the tool 10 is positioned against a workpiece (not shown) and ready for firing, the ram and ram guide 30,23 will be telescoped into the barrel housing with the breech plug 28 abutting the ends of the safety rivets 58. The safety lever handle 70 is then depressed to pivot the latch 68 out of the barrel bore 14 against the action of spring 71, and the primary anvil 17 is struck solidly by a heavy hammer (not shown) weighing about one pound or greater. It is again emphasized that the hammer force must overcome the 25 to 30 ft. lbs. force of the spring 51 to drive the primary and secondary anvil members 17 and 52,62 together and also overcome the combined forces of firing pin safety springs 61 to provide firing contact of the firing pin 53 against the cartridge C, as shown in FIG. 2.
It will thus be readily apparent that the two firing pin safety studs 58 and springs 61, as positioned immediately adjacent to the firing pin 53 and acting in opposition to relative firing actuation, assure the deliberate and safe operation of the tool 10 and assure against substantially all inadvertent tool mishaps. From the foregoing description it will be readily apparent that the present fastener drive tool 10 meets the various objectives of simplicity, safety and efficiency in construction, handling and operation. The essential simplification of the invention pertains to the "floating" secondary anvil 52 that is spring loaded by a "heavy" spring 51 away from the primary anvil mass 17, and in the provision of a positive safety latch 20 that is manually retractable to condition the tool for firing. It may be noted that the handle 70 of the safety lever 20 is positioned radially inwardly of the large end flange of the resilient hand grip 22 so that it is also protected against release do to accidental dropping incidents. Various changes and modifications of the tool 10 will be apparent to those skilled in the art without departing from the inventive concept. Accordingly, the invention is limited only by the scope of the claims which follow. | A hammer drive, powder actuated tool having a main barrel housing, fastener drive and guide means telescopically slidable in one end of the housing and having a muzzle end for orienting a fastener and a breech end for orienting a fastener-driving powder charge, the other end of said main housing having first anvil means thereon, second anvil means including firing pin means, spring means of substantial force biasing said first and second anvil means apart, and movable safety means disposed between the breech end of said fastener drive and guide means and said firing pin means preventing unrestricted axial movement therebetween and contact between said firing pin and powder charge. | 1 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a sheet feeder for feeding printed sheets to a conveying device. The sheet feeder has a gripper drum with at least one gripper for removing the printed sheets one at a time from a stack; a pocket, which is permanently mounted essentially in the peripheral area of the gripper drum and in which the printed sheets can be aligned against a stop with the fold forward and set down on the conveying device with reversal of direction; and a decelerating device, which slows the speed of the printed sheets downstream towards the stop.
2. Description of the Related Art
Sheet feeders of this type are known especially as signature feeders of gathering and stitching machines. These have a gripper drum, with which printed sheets in a stack are tipped at a front edge, gripped and guided one at a time to stops, also known as register stops, on which the printed sheets are aligned. During this process, the sheets are held in the peripheral area of the drum by guides, which form a pocket and are mounted in a stationary way. The printed sheets are pulled from this pocket one at a time by their rear edges and opened with opening drums. They are then set down in roof-like fashion on a gathering line.
The printed sheets are often provided with an overlay fold to allow them to be opened. The different length of the front side and rear side of the folded printed sheets thus allows central opening. During the further processing of the gathered printed sheets, these overlay folds must be cut off in a cutting device to realize a clean appearance of the printed products. The overlay fold thus serves only for correct processing of the printed sheets and ultimately winds up as waste, which, of course, must be kept low. Conflicting with this goal is the fact that in a high-speed sheet feeder, the printed sheets strike at high speed in the pocket and do not have time to stabilize in this position. Especially the end of the printed sheet that is located in the pocket thus lies unsteadily and inexactly, which makes it more difficult to realize reliable gripping and opening with the smaller overlay fold that is desired. Therefore, in high-capacity sheet feeders, the overlay fold must be made longer than would be desirable from the standpoint of waste production.
To stabilize the printed sheets in the pocket, the sheet feeder disclosed by EP 0 716 995 A has a pocket with a rubber stop, which is meant to dampen the impact of the printed sheets. In the sheet feeder described by DE 197 38 920 A, an endless belt is provided, which is intended to stabilize the printed sheets in the pocket with frictional contact.
SUMMARY OF THE INVENTION
The object of the invention is to create a sheet feeder of the aforementioned type, which is intended to allow reliable gripping and opening of the sheets at their rear edge at high processing speeds.
In a sheet feeder of this general type, the solution to this problem is provided by the fact that the decelerating device has at least one secondary stop, which rotates in the same direction as the gripper drum, has a slower speed than the gripper drum for slowing down the printed sheets, and on which the printed sheets are slowed down upstream of the stop.
In the sheet feeder of the invention, the printed sheets are slowed down significantly by the secondary stop before the stop is reached. The speed at which the printed sheets strike the stop in the pocket is thus significantly lower than the speed of the printed sheets after they have been pulled from the stack. Before the change in direction, the printed sheets are thus decelerated in two stages. The speed can be reduced, for example, by half on the secondary stop. Since the printed sheets strike the stop at a reduced speed in the pocket, the end of the sheet, i.e., the rear edge of the printed sheet, is positioned much more steadily and exactly. Therefore, the overlay fold can be made shorter, which reduces the amount of waste, since in most cases the overlay fold is cut off. Due to the lower speed of the printed sheets in the pocket, the rear edge or the overlay fold can thus be gripped more reliably, and the printed sheet can be opened. The stop in the pocket is also acoustically quieter, which is another advantage. The sheet feeder of the invention is thus quieter at the same output.
In accordance with a further development of the invention, it is provided that the one or more secondary stops bring the slowed printed sheet into the vicinity of the pocket. The printed sheet remains with its front edge on the secondary stop until it is slowed down on the stop. To this end, in accordance with another refinement of the invention, it is provided that the one or more secondary stops have holding means for gripping the front edge of the braked printed sheet. The front edge of the printed sheet can be gripped especially reliably if, in accordance with another refinement of the invention, the holding means have a spring element for gripping one printed sheet at a time. The front edge of the printed sheet can then be gripped on the secondary stop. This allows especially reliable transfer of the braked printed sheets to the pocket.
In accordance with another further development of the invention, it is provided that the one or more secondary stops are located on a lever. The lever allows simple and nevertheless reliable control of the secondary stop. This is especially simple and reliable if, in accordance with a further development of the invention, the lever is rotatably mounted on a driven disk. Preferably, two disks of this type are provided, with the gripper drum arranged between the two disks. Naturally, before the printed sheets strike the secondary stop, they are released. In this refinement, the printed sheets are thus slowed down on two levers arranged some distance apart.
In accordance with a further development of the invention, it is provided that the lever is a two-armed lever and that the one or more secondary stops are located at the rear end of the lever. The lever can be controlled, for example, by a cam disk. A suitable cam roller, which runs on the cam of the cam disk, is then mounted on the front end of the lever. Naturally, if there are two levers, two such cam disks can be provided accordingly. The cam disks are rigidly mounted.
In accordance with a further development of the invention, it is provided that the one or more secondary stops are controlled in such a way that they are swiveled into a position that is shifted back relative to the periphery of the gripper drum after the pocket with respect to the direction of flow and that they are swiveled to the periphery of the gripper drum before the pocket to slow down the printed sheets. In this connection, the secondary stop is preferably swiveled radially inward or radially outward. If the secondary stop is swiveled inward into an inactive position, the printed sheets can be moved past the secondary stop. If the secondary stop is swiveled into the peripheral area of the gripper drum, printed sheets which follow strike this secondary stop.
In accordance with a further development of the invention, at least two, preferably three, and even more preferably four or more than four secondary stops are provided, which are spaced apart from one another. They are preferably spaced equal distances apart.
In accordance with a further development of the invention, the secondary stop has a speed of rotation that is about 50% of the speed of rotation of the gripper drum. The speed of impact of the printed sheets on the stop of the pocket can thus be essentially halved.
In accordance with a further development of the invention, it is provided that at least one secondary stop can be swiveled outward upstream of the pocket in such a way that it deflects the trailing end of a preceding printed sheet radially outward. This secondary stop thus acts here not as a stop for slowing a printed sheet but rather as a guide device for guiding the rear edge into the intended position for the reversal of direction. The aforesaid end of the sheet is already being deflected outward by gravity. However, this deflection is guided by the secondary stop and thus takes place more precisely.
The printed sheets are preferably provided with a leading fold and are preferably so-called signatures. The sheet feeder of the invention preferably has opening drums, with which the printed sheets, after the aforesaid reversal of direction has occurred, are opened, so that they can be set down on the conveying device. However, this is not absolutely necessary. In principle, after the reversal of direction, the printed sheets can also be further conveyed unopened.
The sheet feeder of the invention is suitable especially for a gathering and stitching machine. However, use for a gathering and stitching machine is not absolutely necessary.
Other advantageous features are specified in the dependent claims and the following description and are apparent from the drawings.
The various features of novelty which characterize the invention are pointed out with particularity in the claims annexed to and forming a part of the disclosure. For a better understanding of the invention, its operating advantages, specific objects attained by its use, reference should be had to the drawing and descriptive matter in which there are illustrated and described preferred embodiments of the invention.
BRIEF DESCRIPTION OF THE DRAWING IN THE DRAWING
FIG. 1 is a schematic view of a sheet feeder of the invention.
FIG. 2 is a cross section through part of the sheet feeder of the invention along line II-II of FIG. 1 .
FIG. 3 is a schematic partial view of the sheet feeder of the invention.
FIG. 4 is schematic view of a lever that forms a secondary stop.
FIG. 5 shows schematically the transfer of a printed sheet to a bin.
DETAILED DESCRIPTION OF THE INVENTION
The sheet feeder 1 shown in FIG. 1 has a gripper drum 2 , with which printed sheets 7 are separated and removed from a stack 6 in a way which in itself is already well known. The printed sheets 7 are preferably signatures and have a front edge 8 and a rear edge 9 . The printed sheet is usually folded at the front edge 8 . The rear edge 9 is furnished with an overlay fold. To separate the printing sheets 7 , a suction device 11 or other suitable type of gripping device is provided.
The gripper drum 2 has several grippers 12 which in themselves are already well known. Each gripper 12 can be rotated about its axis 13 under automatic control. These grippers 12 seize each separated printed sheet 7 by its front edge and convey it on a peripheral area 17 formed by the gripper drum 2 in the direction of the arrow 14 and thus in the counterclockwise direction in FIG. 1 . In a lower area of the gripper drum 2 , a supporting lever 25 is installed, which can be swiveled about an axis of rotation 26 between the positions indicated by the solid lines and the broken lines. The supporting lever 25 serves to guide small formats. After this supporting lever 25 , the printed sheets 7 , with the folded front edge 8 forward, are fed into an essentially stationary pocket 15 , which is formed by several guides. The pocket 15 is thus mounted on a frame, which is not shown here. In principle, however, the pocket 16 could also be provided with limited movement, so that, for example, if the printed sheets 7 become jammed, it could give way. A stop 16 , which the front edges 8 of the printed sheets 7 strike, is located near the pocket 15 . To accommodate different formats, the stop 16 can be shifted in the peripheral direction, as indicated by the double arrow 29 . FIG. 3 shows a stop 16 ′ that is adjusted for a comparatively small format.
If a printed sheet 7 is located in the stop position against the stop 16 , it is seized at its rear edge 9 by a gripper 27 of an opening drum 3 and pulled out of the pocket 15 with reversal of its direction. The gripper 27 or the two grippers 27 that are provided here are swiveled about an axis 28 under automatic control. The opening drum 3 cooperates with another opening drum 4 to open the printed sheet gripped at its rear edge 9 and set it down on a gathering chain 5 or other conveying device. In this operation, the opening drums 3 and 4 are driven in the directions of the arrows 30 and 31 . The gathering chain 5 is especially part of a gathering and stitching machine, the rest of which is not shown here. In principle, the gathering chain 5 can also be some other type of conveying device. The printed sheets 7 can also be dropped onto the conveying device unopened.
As FIG. 2 shows, the gripper drum 1 is mounted on a shaft 33 , which is driven and controlled by a drive (not shown). A gripper disk 37 is mounted nonrotatably on this shaft 33 , and the aforementioned grippers 12 are supported on the gripper disk 37 in such a way that they can rotate about an axis of rotation 13 . The grippers 12 are controlled by a toothed segment 48 on a cam 38 , on each of which a cam roller 43 rests. The cam 38 is mounted on a support 32 , which is joined with a feeder table 36 or the machine frame. When the shaft 33 rotates, the grippers 12 are controlled in such a way that they seize or release a printed sheet 7 at the desired moment.
The gripper disk 37 is disposed between two secondary stop disks 40 , each of which is nonrotatably joined with sleeves 44 , which are arranged coaxially with the shaft. The sleeves 44 are synchronously driven by a drive (not shown here). It is also possible for the secondary stop disks to be driven by their own drive, for example, a servomotor. This makes it possible to optimize the sequence of motions of the secondary stops and/or to reduce the number of secondary stops. With a suitable gear ratio, this drive can simultaneously serve as the drive for the shaft 33 . The secondary stop disks 40 each serve to support four levers 18 , which, as shown in FIG. 1 , are two-armed levers. As shown in FIG. 2 , these levers 18 are each rotatably supported, with an axis of rotation 19 , on one of the two secondary stop disks 40 . At one end, each of the levers 18 has a cam roller 20 , which runs on a cam 24 of a cam disk 39 . The two cam disks 39 are also rigidly connected with the support 32 . The course of the cam 24 is shown in FIG. 1 as a dot-dash line. Instead of a cam disk 39 , other control mechanisms can also be used for controlling the levers 18 .
In addition, the levers 18 have a secondary stop 21 at one end, as shown in FIGS. 1 and 4 . The secondary stop 21 has a more or less conically tapering recess 23 , which is bounded on one side by a spring element 22 and on the other side by a tongue 46 . The spring element 22 is designed especially as a leaf spring. The recess 23 is arranged some distance from the axis of rotation 19 and at the opposite end of the lever 18 from the cam roller 20 . Each two-armed lever 18 thus has the cam roller 20 at one end and the aforesaid secondary stop 21 at the other end. The spring element 22 and the tongue 46 form holding means, with which the decelerated printed sheet 7 can be seized by its front edge 8 .
The two secondary stop disks 24 are driven in the same direction as the gripper disk 37 . However, the speed of rotation of the two secondary stop disks 40 is slower than the speed of rotation of the gripper disk 37 . If the gripper disk 37 is driven at a speed V, then the two secondary stop disks 40 are driven at a speed V′. The speed V′ is significantly lower than the speed V. The two secondary stop disks 40 are driven at the same speed and synchronously with each other. In the illustrated embodiment, the speed V′ is 50% of the speed V. However, other speed ratios are also possible here; in particular, the speed V can be varied by a controlled drive during a rotation of the secondary stop disks.
The cam 24 has an inwardly curved area 24 ′, which is located approximately in the 4 o'clock position in FIG. 1 . In this area 24 ′, the cam rollers 20 thus move radially inward and then radially outward again. Accordingly, the secondary stop 21 first moves radially outward and then radially inward again. The outward movement causes the secondary stop 21 to enter the peripheral region 17 , on which the printed sheets 7 are also being conveyed. The corresponding secondary stop 21 is now controlled in such a way that, upstream of the stop 16 or upstream of the pocket 15 , it forms a stop for a printed sheet 7 trailing it.
Since the levers 18 are moved at a lower speed than the printed sheets 7 , the aforementioned printed sheet 7 is slowed down on the secondary stop 21 to the speed of the secondary stop 21 . Since, as explained earlier, two secondary stop disks 40 are provided, a printed sheet 7 simultaneously strikes two levers 18 or two secondary stops 21 that are some distance apart. Before the printed sheet 7 hits the two secondary stops 21 , it is released by the corresponding gripper 12 . The two levers 18 , on which the printed sheet 7 is stopped, now guides this printed sheet 7 farther until it reaches the pocket 15 , in which the printed sheet is finally slowed down to a speed of zero on the stop 16 .
If the front edge 8 of a printed sheet 7 runs into the two secondary stops 21 , it then passes under the spring element 22 until finally, at the end of the recess 23 , it is gripped by said spring element 22 and thus stabilized. This is shown in FIGS. 4 and 5 . In this way, the slowed printed sheet 7 can be safely transferred to the pocket 15 in the direction of the arrow 47 , as shown in FIG. 5 . If the printed sheet 7 has been slowed to a speed of zero on the stop 16 , then the corresponding lever 18 can immediately detach itself from the printed sheet 7 due to the spring action of the spring element 22 and thus continue to be moved with undiminished speed.
The end of the lever 18 , on which the secondary stop 21 is mounted, has a finger-like construction, as FIG. 4 shows, and has a curved outer guide surface 45 . This guide surface 45 makes it possible, by suitable control of the lever 18 , to guide the rear edge 9 of a printed sheet 7 that is entering the pocket 15 in order to transfer the overlay fold 10 to one of the grippers 27 . The given lever 18 does not act as a secondary stop in this case but rather acts to guide the given printed sheet 7 , as just described. This process will now be described in greater detail with reference to FIG. 3 .
As FIG. 3 shows, the rear edge 9 of a printed sheet 7 that has entered the pocket 15 is moved radially outward, which allows it to be gripped by one of the grippers 27 . This radially outwardly directed movement basically occurs even without the guidance of a lever 18 . However, the lever 18 assists this movement by the swiveling movement shown in FIG. 3 . In this movement, the aforesaid guide surface 45 is moved radially outward beyond the peripheral area 17 upstream of the guide roller 41 . This movement begins as soon as the corresponding cam roller 20 moves into the aforementioned area 24 ′ of the cam 24 . The guide surface 25 then briefly moves in the outward direction and then back in the inward direction. Approximately in the vicinity of the guide roller 41 , the guide surface 45 is again located in the peripheral area 17 .
FIG. 1 shows three printed sheets 7 a , 7 b , and 7 c in different phases during the transfer from the stack 6 to the opening drums 3 and 4 . A gripper 12 grips the front edge 8 of the printed sheet 7 a approximately in the 10 o'clock position. The lever 18 , whose secondary stop 21 is located in the vicinity of the front edge 8 , is inactive at this time.
The front edge 8 of the printed sheet 7 b is located at the secondary stop 21 of the lever 18 ″. The printed sheet 7 b has thus been slowed or is being slowed. The printed sheet 7 is guided by the supporting lever 25 and is now being transferred on the stop 21 of the lever 18 ″ to the pocket 15 . This transfer is also shown in FIG. 5 . When the rear edge 9 of the printed sheet 7 b has left the supporting lever 25 , this rear edge 9 is guided by the following lever 18 ′ in such a way, as explained above, that this rear edge 9 can be securely gripped by one of the grippers 27 .
The rear edge 9 of the printed sheet 7 c has already been gripped by a lever 27 and is being pulled by this lever 27 out of the pocket 15 by the rotational motion of the opening drum 3 . Finally, the printed sheet 7 c is opened by means that are already well known and dropped on the gathering chain 5 .
The function of the lever 18 ′ as a guide device is advantageous during the transfer of the printed sheets 7 to the opening drums but is not essential to the invention. It would thus be conceivable to have a design in which the rear edge 9 is deflected in a way that in itself is already well known and is then gripped by a gripper 27 .
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. | A sheet feeder for feeding printed sheets to a conveying device, with a gripper drum that has at least one gripper for removing the printed sheets one at a time from a stack; a pocket is permanently mounted essentially in the peripheral area of the gripper drum wherein the printed sheets are aligned against a stop with the fold forward and set down on the conveying device with reversal of direction; and with a decelerating device for slowing the speed of the printed sheets downstream towards the stop. The decelerating device has at least one secondary stop, which rotates in the same direction as the gripper drum, has a slower speed than the gripper drum for slowing down the printed sheets, and on which the printed sheets are slowed down upstream of the stop. | 1 |
TECHNICAL FIELD
This invention generally relates to medical devices for drainage of fluids, and more specifically to ureteral stents.
BACKGROUND INFORMATION
Ureteral stents are used to assist urinary drainage from the kidney to the urinary bladder in patients with a ureteral obstruction or injury, or to protect the integrity of the ureter in a variety of surgical manipulations. Stents may be used to treat or avoid ureteral obstructions (such as ureteral stones or ureteral tumors) which disrupt the flow of urine from the kidneys to the bladder. Serious obstructions may cause urine to back up into the kidneys, threatening renal function. Ureteral stents may also be used after endoscopic inspection of the ureter to prevent obstruction of the ureter by swelling of the ureteral wall caused by the surgical procedure.
Ureteral stents typically are tubular in shape, terminating in two opposing ends: a kidney distal end and a bladder proximal end. One or both of the ends may be coiled in a pigtail or J-shape to prevent the upward and/or downward migration of the stent due, for example, to physiological movements. A kidney end coil resides within the lumen of the kidney, known as the renal pelvis, and is designed to prevent stent migration down the ureter and into the bladder. The bladder-end coil resides in the bladder and is designed to prevent stent migration upward toward the kidney. The bladder coil is also used to aid in retrieval and removal of the stent. Regions such as the trigone region in the bladder and the region of the ureter near the bladder known as the ureteral-vesical junction are particularly sensitive to irritation by foreign objects. Commonly used bladder-end coils contact and irritate the trigone region causing discomfort to the patient. Similarly, the proximal region of the stent contacts the ureteral-vesical junction causing irritation and discomfort to the patient particularly during voiding. Additionally, ureteral stents, particularly the portion positioned within the ureteral-vesical junction and inside the bladder, may produce adverse effects including blood in the urine, a continual urge to urinate, strangury, and flank pain accompanying reflux of urine up the stent (e.g., when voiding). Such effects occur as pressure within the bladder is transmitted to the kidney. In short, while providing drainage from the kidney to the bladder, stents may also cause or contribute to significant patient discomfort and serious medical problems.
SUMMARY OF THE INVENTION
The present invention relates to a ureteral stent that reduces patient discomfort and urine reflux. In particular, the invention relates to a foam segment, disposed at the proximal end of the stent, which reduces urine reflux and minimizes contact with the trigone region and ureteral-vesical junction. When the stent is placed within the urinary system of a patient, the foam segment is located within the ureteral-vesical junction, and also in the bladder itself. The foam segment, constructed from a soft and compressible open-cell or reticulated foam material, for example, minimizes the amount of irritation to the ureteral-vesical junction and the trigone region. Also, the foam segment, which is present within or blocks the opening of the stent lumen, partially occludes the stent lumen. This partial occlusion of the lumen prevents the rapid flow of urine through the stent to the kidney during urine reflux.
The foam segment also forms a proximal retention structure that is positioned in the urinary bladder when the stent is in use and functions to restrain the migration of the stent towards the kidney. The stent also includes a distal retention structure, which when the stent is installed in the patient, is generally located in the renal pelvis and functions to prevent the migration of the stent down the ureter into the urinary bladder.
In one aspect, the invention relates to a ureteral stent that includes an elongated member that defines a lumen extending therethrough, a distal retention structure that is defined by a distal region of the elongated member, and a foam segment that extends from a proximal end of the elongated member and is in fluid communication with the lumen.
In one embodiment, the foam segment includes a proximal retention structure. The proximal retention structure prevents the migration of the stent upward towards a kidney. In another embodiment, a distal portion of the foam segment is contained within the lumen of the elongated member. In yet another embodiment, a portion of the foam segment is attached to an outer surface of a proximal end of the elongated member. In further embodiments, the foam segment may include an open-cell foam, a reticulated foam, or a closed-cell foam.
In another embodiment, an outer dimension of the proximal retention structure that is substantially perpendicular to a longitudinal axis of the elongated member is larger than the diameter of the elongated member. A proximal retention structure with such an outer dimension prevents the proximal retention structure from entering into a ureter. In various embodiments, the proximal retention structure may include a funnel shape, a conical shape or a spherical shape, for example. In yet another embodiment, an outer dimension of the distal retention structure that is substantially perpendicular to a longitudinal axis of the elongated member is larger than the diameter of the elongated member. A distal retention structure with such an outer dimension prevents the distal retention structure from entering into a ureter. In one embodiment the distal retention structure includes a coiled shape.
In one embodiment, the elongated member of the ureteral stent includes an outer diameter ranging from about 6 to about 12 French. In another embodiment, the elongated member may include a biocompatible plastic.
In one embodiment of the invention, the foam segment further includes a coaxial member that defines a lumen extending therethrough. The coaxial member is fixed within the foam segment, by a bonding process, for example. In another embodiment, the foam segment of the ureteral stent defines a lumen extending therethrough.
In another aspect, the invention relates to a method for draining urine from a kidney. The method first requires providing a ureteral stent such as previously described. The stent is then inserted into a ureter of a patient. In one embodiment, the stent is positioned such that at least a portion of the distal retention structure resides within a kidney. In another embodiment, the stent is positioned such that at least a portion of the foam segment of the stent resides within a ureteral-vesical junction. In another embodiment, the foam segment includes a proximal retention structure. The proximal retention structure is positioned in the bladder thus preventing the migration of the proximal end of the stent out of a urinary bladder.
In another aspect, the invention relates to a method of positioning a ureteral stent within a patient. The method includes providing a ureteral stent as previously described. The method then includes positioning the stent within a patient using a guide wire and a pusher. First, the stent is mounted over a guide wire already positioned within the body and then is pushed along the guide wire utilizing a pusher to locate the stent within the ureter of a patient. The shape of the pusher, particularly the distal end of the pusher, conforms to a shape of a proximal end of the ureteral stent. This allows the pusher to effectively transfer the necessary force to the proximal end of the stent to position the stent within the patient. Once the stent is properly located within patient, the guide wire is removed from the patient. The pusher may also be removed from the patient after the procedure.
In one embodiment, the method further includes inserting the guide wire into a urinary tract of the patient. The guide wire may be inserted into the urinary tract prior to inserting the stent into the urinary tract. In another embodiment, the method further includes positioning the distal retention structure within a kidney. The distal retention structure prevents the stent from migrating down the ureter and into the urinary bladder. In yet another embodiment, the foam segment of the stent includes a proximal retention structure, and the method further includes positioning the proximal retention structure in a urinary bladder. The proximal retention structure prevents the stent from migrating out of the bladder and up the ureter. In yet another embodiment, mounting the stent over a guide wire includes inserting the guide wire within a lumen of the elongated member.
The foregoing and other aspects, embodiments, features, and advantages of the invention will become apparent from the following description, figures, and claims.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings, like reference characters generally refer to the same parts throughout the different views. Also, the drawings are not necessarily to scale, emphasis generally being placed upon illustrating the principles of the invention.
FIGS. 1A and 1B depict an embodiment of a ureteral stent of the invention, with FIG. 1A showing the device positioned in a ureter with a distal region in a kidney and a proximal region in a ureteral-vesical junction and bladder, and FIG. 1B showing the device outside of the body.
FIGS. 2A-D depict an embodiment of a proximal region of a ureteral stent of the invention in longitudinal cross-section in different configurations within the ureter and urinary bladder. FIG. 2A depicting a proximal retention structure distant from the ureteral-vesical junction, and FIG. 2B depicting the proximal retention structure flushed with the ureteral-vesical junction. FIGS. 2C and 2D depicts the cross-sectional structure of reticulated and open-cell foam, respectively, that forms the foam segment and proximal retention structure.
FIGS. 3A-D depict various embodiments of a proximal region of the ureteral stent of the invention in longitudinal cross-section.
FIGS. 4A and 4B depicts other embodiments of a proximal region of a ureteral stent in longitudinal cross-section positioned in the ureter and urinary bladder.
FIGS. 5A-D depict various steps involving a guide wire, a pusher and a ureteral stent in longitudinal cross-section positioned in the ureter and urinary bladder, as occurs during installation of the stent.
DESCRIPTION
This invention generally relates to a ureteral stent that, when positioned within a urinary tract of a patient, significantly reduces discomfort to the patient. The stent of the present invention includes an elongated member and an attached foam segment. The foam segment extends from a proximal end of the elongated member, and a distal retention structure exists at a distal region of the elongated segment.
The wall of the elongated member, including the distal retention structure, may be constructed of a biocompatible plastic such as but not limited to any of polyester, nylon based biocompatible polymers, polytetrafluoroethylene polymers, silicone polymers, polyurethane polymers, polyethylene polymers, and thermoplastic polymers, for example. The wall of the elongated member is of sufficient thickness to resist the pressure from the adjacent tissue caused by a tumor, peristalsis, or swelling, for example, that would collapse the ureter if not for the presence of the stent. In contrast to the trigone region and the ureteral-vesical junction, the renal pelvis and the majority of the ureter are relatively insensitive to irritation by the presence of foreign objects. This allows for the use of a relatively stiff plastic in regions of the stent, such as the elongated member and distal retention structure, that contact these relatively insensitive regions of the body.
The foam segment, which contacts the sensitive trigone region and ureteral-vesical junction, is constructed of a foam material that is highly compressible and flexible and generally reduces irritation caused by the stent on these areas. Additionally, to further reduce irritation, the foam segment may be shaped to minimize contact with the trigone region in the bladder, for example. The foam segment also minimizes patient discomfort by reducing urine reflux from the bladder to the renal pelvis, particularly during voiding of the bladder. During voiding, the ureteral orifice to the bladder constricts and closes to prevent urine from flowing up the ureter as the bladder compresses to force urine out of the bladder. When the stent is in place in the body, the foam segment traverses the ureteral orifice to the bladder and is generally located within the ureteral-vesical junction. Due to the high compressibility of the foam segment, the ureteral orifice can compress the region of the foam segment traversing the orifice and effectively block the flow of urine into the ureter.
In addition, the foam segment prevents urine reflux by obstructing the rapid passage of urine through the foam segment and into the elongated member of the stent. In contrast, a stent with an unobstructed lumen allows substantially free movement of urine from the bladder, through the elongated member of the stent and into the renal pelvis. In order for urine to flow through the stent of the present invention the urine must flow through the portion of the foam segment that resides within the lumen of the elongated member and the portion that blocks the lumen opening at the proximal end of the elongated member. The foam segment slows the flow of urine by forcing urine to filter through the network of small channels and passageways present in the structure of the foam. The foam segment provides adequate drainage of urine from the kidney to the bladder, to which urine generally flows at a slow rate by wicking or dripping, while acting as a barrier to the rapid flow of urine from the bladder to the kidney, which occurs during urine reflux.
Referring to FIGS. 1A and 2B, a ureteral stent 100 includes an elongated member 102 defining a lumen 101 . The stent 100 also includes a foam segment 106 extending from the proximal end 105 of the elongated member 102 and in fluid communication with the lumen 101 of the elongated member 102 . The distal region of the elongated member 102 forms a distal retention structure 104 . The elongated member 102 is generally located within the ureter 108 and the distal retention structure 104 is located in the renal pelvis 110 . The foam segment 106 but not the elongated member 102 is located within the ureteral-vesical junction 114 and in the urinary bladder 112 when the stent 100 is properly positioned in the patient.
The stent 100 of the present invention minimizes patient discomfort by reducing the force and surface of contact between the stent 100 and the ureteral-vesical junction 114 and trigone region of the urinary bladder wall 116 . The foam segment 106 , which is more pliable, flexible, supple and compressible than the plastic tubing of elongated member 102 , is the portion of the stent 100 that contacts these sensitive areas of the body. The foam segment 106 is less irritating or abrasive to the ureteral-vesical junction 114 and trigone region thus making the stent 100 more comfortable to the patient. However, the foam segment 106 is also sufficiently resilient to be shaped and formed as a proximal retention structure 107 . The proximal retention structure 107 may be shaped to minimize contact with the trigone region and thus reduce the irritation caused by the contact.
The stent 100 also minimizes patient discomfort by providing a barrier to urine flowing through the stent 100 from the bladder 112 into the renal pelvis 110 . Urine must flow through the portion of the foam segment 106 that is present in the lumen 101 . In FIG. 1B, the boundaries of the distal retention structure 104 , elongated segment 102 and foam segment 106 are depicted. The length of overlap between the elongated segment 102 and foam segment 106 determines the amount of the foam segment 106 present inside the lumen 101 . The amount of overlap may be varied depending on the density and type of the foam, the desired rate of urine flow through the stent 100 , and the shape of the foam segment 106 , for example. The foam segment 106 , due to its high compressibility, lessens the resistance to the closing or constricting of the ureteral orifice to the bladder 112 during bladder voiding, and thus further assists in preventing urine reflux.
FIGS. 2A and 2B show schematic representation of the operation of the proximal retention structure 107 at the ureteral orifice. In FIG. 2A, the ureteral stent 100 is positioned in the patient so that the foam segment 106 and not the elongated segment 108 is within the ureteral-vesical junction 114 . The foam segment 106 , constructed from a compressible and flexible foam material, causes less irritation to the ureteral-vesical junction 114 than the elongated segment 108 , which is constructed from a noncompressible and less flexible plastic material. In FIG. 2B, the ureteral stent 100 retracts towards the kidney and the proximal retention structure 107 of the foam segment 106 contacts the inner surface of the urinary bladder wall 116 preventing further movement of the ureteral stent 100 up the ureter 108 and towards the kidney. Movement of the ureteral stent 100 within the patient occurs by the expansion and contraction of the ureter caused by normal day-to-day activities of the patient. The proximal retention structure 107 and distal retention structure 104 maintain the stent 100 in the ureter 108 by restricting the movement of the stent 100 away from the urinary bladder 112 and kidney, respectively.
FIGS. 2C and 2D depict the microstructure of the reticulated and open-cell foam, respectively, that forms the foam segment 106 . Both types of foam possess a structure that includes a plurality of curved and interconnecting passageways or channels that prevent the direct movement of urine through the foam segment 106 . The structure of open-cell foam 106 (FIG. 2D) includes a plurality of cavities. The shape and size of the cavities may be fairly uniform or may vary. The cavities generally have one or more openings to one or more of the adjacent cavities. The arrangement of cavities produces foam that includes multiple passageways and channels that allows for the movement of liquids or gases therethrough. The multiple passageways and channels in reticulated foam 106 (FIG. 2C) are formed by the spaces created by a plurality of fibers bonded together in a network. The foam segment 106 located at least partially within and extending from the lumen 101 of the ureteral stent 100 slows the rate of fast or turbulent urine flow from retrograde pressure coming from the bladder 112 as it forces urine to travel through its plurality of small tortuous passageways. The foam segment 106 , however, does not interfere with slow rates of urine flowing from the kidney into the bladder 112 .
Referring to FIGS. 3A-D, embodiments of the present invention may further include a lumen 118 that extends through and may be oriented co-axially with the foam segment 106 . The lumen 118 is in fluid communication with the lumen 101 of the elongated segment 102 . The lumen 118 may be formed by removing a core of foam material from the foam segment 106 . The lumen 118 increases the rate at which urine flows through the foam segment 106 by providing an unobstructed or large channel for urine to flow. The increased capacity for urine flow through the foam segment 106 increases the rate at which urine can flow through the stent 100 from the kidney to the bladder 112 . However, the increased capacity for urine flow may be insufficient to allow substantial urine reflux. Urine reflux is further prevented in these embodiments by the collapsing of the surrounding flexible walls of the foam segment 106 that define the lumen 118 . As the walls of the lumen 118 collapse, the cross-sectional area of the lumen 118 significantly decreases thus preventing a rapid flow of urine through the foam segment 106 and the stent 100 .
Additionally, a coaxial member 120 that defines a lumen 118 may be inserted into the foam segment 106 . The coaxial member 120 may be substantially tubular and may be bonded to the foam segment 106 fixing it in place. The coaxial member 120 reinforces the foam segment 106 by providing an embedded structural support of greater strength than the foam material alone. The coaxial member 120 may be of sufficient tensile strength to prevent the foam segment 106 from tearing during the grasping and pulling of the foam segment 106 during removal of the stent 100 . More particularly, the coaxial member 120 may function to increase stiffness to the proximal retention structure 107 of the foam segment 106 , in FIG. 3B for example. The coaxial member 120 may flare out on the surface of the proximal retention structure 107 thus conferring greater stiffness to the base of the cone-shaped portion of the proximal retention structure 107 , in FIG. 3B for example. The lumen 118 defined by the foam segment 106 or the coaxial member 120 may function as a passageway for inserting a guide wire or cannula, for example, into the stent 100 during insertion, removal or repositioning of the stent in the body.
Embodiments of the foam segment 106 that include a lumen 118 (lumen 118 being defined either by the coaxial member 120 or the foam segment 106 , for example) can be made of a closed-cell foam. The structure of closed-cell foam includes cavities or spaces in the material forming the foam, but the majority of the cavities or spaces are not interconnected, and the lack of interconnection between the cavities or spaces prevents the efficient flow of a liquid or gas through the closed-cell foam. When the foam segment 106 comprises closed-cell foam, it may not allow for sufficient drainage of urine through the stent 100 unless the lumen 118 is present in the foam segment 106 to allow for a sufficient flow of urine.
In FIGS. 3C and 3D, the proximal retention structure 107 may be in the shape of a sphere or a cone with a thin skirt 109 attached to the edge of the base of the cone. The foam segment 106 may be shaped in various ways to produce a proximal retention structure 107 that prevents the movement of the ureteral stent up the ureter 108 and minimizes or avoids contact with the trigone region.
In FIGS. 4A-B, the foam segment 106 is fixed to the exterior surface of the elongated segment 102 . In this embodiment, a portion of the foam segment 106 need not exist within the elongated segment 102 . Additionally, the foam segment 106 may include a lumen 118 . The lumen 118 may be defined by the foam segment 106 or by a coaxial member 120 .
Referring to FIGS. 5A-D, the method of positioning a ureteral stent 100 within a patient is illustrated in a schematic with cross-sectional views of portions of the ureter 108 and urinary bladder 112 . Draining urine from the kidney or ureter 108 may be accomplished by inserting a ureteral stent 100 according to the invention over a guide wire 122 with a pusher 124 , through the urethra and urinary bladder 112 to the final position in the ureter 108 . A guide wire 122 (FIGS. 5A and 5B) assists in the installation of the stent by providing a mechanical means of directing the stent 100 into the patient. The guide wire 122 is inserted into the body, through the urinary bladder 112 and ureter 108 until reaching the renal pelvis (FIG. 5 A). Once the guide wire 122 is positioned in the patient, the stent 100 is inserted into the patient over the guide wire 122 , which remains outside the body (FIG. 5 B). The distal retention structure 104 is straightened as the guide wire is inserted through the lumen 101 and the stent 100 is moved along the length of the guide wire 122 and into the body with a pusher 124 . In stent 100 embodiments that lack a lumen 118 , alternative methods for passing the guide wire 122 through the foam segment 106 exist. The guide wire 122 may be passed through naturally occurring passageways or channels of the foam or through a channel formed by piercing the foam segment 106 . The pusher 124 includes a lumen that is configured to accept a guide wire 122 and the proximal retention structure 107 (shown in a collapsed state in FIG. 5 B). The guide wire 122 or a cannula may be used to temporarily straighten the distal retention structure.
Once the ureteral stent 100 is properly positioned, the guide wire 122 may be removed (FIG. 5 C). The distal retention structure is constructed from resilient material that regains its initial shape after distortion. The ureteral stent 100 may also be inserted into the patient by use of an endoscope, ureteroscope, or a cytoscope, for example.
Once the stent 100 is positioned in the ureter 108 , the pusher 124 may be withdrawn from the body of the patient (FIG. 5 D). The ureteral stent 100 is positioned in the ureter 108 so that the distal retention structure is seated in the renal pelvis and the proximal retention structure 107 is located in the urinary bladder 112 . Proper placement of the ureteral stent 100 positions the foam segment 106 within the ureteral-vesical junction 114 thus relieving irritation to this region and decreasing urine reflux.
Referring again to FIGS. 2A, 2 B, 3 A-D, 4 A and 4 B, the proximal retention structure 107 of the foam segment 106 may adopt a variety of shapes. Referring to FIGS. 5 B and 5 C, the pusher 124 abuts and applies a force against the proximal end 105 of the elongated segment 102 and the foam segment 106 to push the stent 100 into the body of the patient. To facilitate positioning of the stent 100 in the patient's body, the distal region of a pusher 124 conforms to the proximal end 105 of the elongated segment 102 and the foam segment 106 . This allows for the force applied to the pusher 124 to be effectively transferred to the ureteral stent 100 during installation of the stent 100 . Also, the lumen of the pusher 124 is large enough to house the foam segment 106 in a compressed state (FIGS. 5 B and 5 C). The lumen of the pusher 124 may include various inner diameters to conform to the various embodiments of the proximal retention structure 107 and foam segment 106 .
Referring again to FIGS. 1A and 1B, the elongated member 102 is constructed by the extrusion of a biocompatible plastic such as but not limited to any of polyester, nylon based biocompatible polymers, polytetrafluoroethylene polymers, silicone polymers, polyurethane polymers, polyethylene polymers, and thermoplastic polymers, for example. The foam segment 106 may include reticulated foam (FIG. 2 C), open-cell foam (FIG. 2 D), closed-cell foam, and generally any material(s) that is/are functionally and/or structurally equivalent to the disclosed foams. The material(s) used to form the foam segment 106 may include urethane polymers, and one or more of the biocompatible plastics identified above in connection with the elongated member 102 , and any generally similar material(s). The construction of the stent 100 includes bonding the foam segment 106 to the elongated member 102 . The bonding of these two components may be performed by heat bonding. Heat bonding functions by partially melting the plastic on the surface of a structure, allowing the melted plastic to contact and adhere to a surface of another component, and allowing the plastic to cool and harden and thus form a bond. Heat bonding methods that include radio frequency bonding, induction heating and conduction heating may be used. The plastic of the foam segment 106 may be selected to melt at a similar temperature as the plastic of the elongated member 102 so that both components of the stent 100 are melted during the heat bonding process. Alternatively, either the foam segment 106 or elongated member 102 may be constructed from plastic with a lower melting temperature than the other component in order that only the component with the lower melting temperature melts during the bonding process.
Alternatively, the foam segment 106 and elongated member 102 may be bonded by the use of a bonding solvent, such as cyclohexanone and methylethylketone, for example. The bonding solvent acts by dissolving the plastic on the surface of the elongated member 102 , for example. The foam segment 106 adheres to the dissolved plastic of the elongated member 102 . The solvent may then be removed allowing for the dissolved plastic of the elongated member 102 to harden and thus complete the bonding process with the foam segment 106 .
The bonding of the foam segment 106 to the elongated member 102 is facilitated by the use of a mandrel, for example. The bonding process includes the insertion of a mandrel into the foam segment 106 , followed by the insertion of the foam segment 106 and mandrel into the elongated member 102 . The mandrel compresses the foam segment 106 against the inner wall of the elongated member 102 thus facilitating the bonding of the two components. In embodiments of the invention in which the foam segment 106 is bonded to the outer wall of the elongated member 102 (FIGS. 4 A and 4 B), a pinching device may be used to compress the foam segment 106 against the outer wall of the elongated member 102 during the bonding process.
Embodiments of the foam segment 106 which include a coaxial member 120 (FIGS. 3A-3D, 4 A and 4 B) may be constructed by bonding the foam segment 106 to the elongated member 102 followed by inserting and bonding the coaxial member 120 in the foam segment 106 . Alternatively, the coaxial member 120 may be inserted and bonded in the foam segment 106 prior to the insertion of the foam segment 106 into the elongated member 102 . The coaxial member 120 may be bonded in the foam segment 106 by methods similar to those described for bonding the foam segment 106 to the elongated member 102 .
Having thus described certain embodiments of the present invention, various alterations, modifications, and improvements will be apparent to those of ordinary skill. Such alterations, modifications, and improvements are intended to be within the spirit and scope of the invention. Accordingly, the foregoing description of embodiments of the invention is not intended to be limiting. | A ureteral drainage stent is designed to be placed in a patient's ureter and extend into a patient's bladder. An elongated tubular segment includes a distal retention structure for placement in the renal cavity, and a proximal retention structure constructed at least partly from a foam material and for placement in a urinary bladder. A central lumen connects at least one opening in the distal retention structure to the foam proximal retention structure. The foam proximal retention structure typically extends along at least a lower part of the ureter, across the ureteral-vesical junction, and into the bladder, to provide drainage through multiple networked channels. | 0 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the field of mass communication techniques, and more particularly to advertising display technologies and to the exploitation of surfaces, such as sports fields, which have not previously been used for advertising displays.
2. Description of the Prior Art
During events which take place on grass fields, in particular sports events, many advertising panels usually border the field. The grass itself, however, although it is the place that the public sees most frequently, and is the largest surface that the spectators have before their eyes, does not carry any advertisements. The only marks which are printed on the grass are those related to the sport played on the field.
SUMMARY OF THE INVENTION
It is accordingly an objective of the invention to utilize the previously unused surface of a sports field for advertising display purposes by making possible the marking of messages, especially advertising messages, on the grass surface itself, without creating confusion with the sport markings.
It is another objective of the invention to provide a method for marking the grass with signs, such as letters forming words, names or numbers, or images, and to provide an apparatus capable of making such markings.
The invention has both method and apparatus embodiments.
In a first method embodiment of the invention, a preferred method of marking grass fields, especially sports fields, involves directing a part of the blades of a grass surface in one direction, and orienting or leaving oriented in at least one other direction at least another part of the blades of the grass surface so that at least one of the parts constitutes an image or sign.
In a second method embodiment of the invention, the method of the first embodiment is implemented by orienting the blades of at least a part of the grass surface by means of one or several brushes.
In a third method embodiment of the invention, the method of the second embodiment is implemented by using rotating brushes.
In a fourth method embodiment of the invention, the method of the first embodiment is implemented by orienting the blades of at least a part of the grass surface by means of one or several rollers.
In a fifth embodiment of the invention, the method of the first embodiment is implemented by orienting the blades of grass surfaces by means of one or several brushes and by means of one or several rollers.
In a sixth embodiment of the invention, the method of the three last above described embodiments involves dividing the model of the image or sign to be marked on the grass surface into several points, dividing the grass surface into several sectors, and commanding the action, and especially the lowering, the raising and/or the rotation of the brushes and/or the rollers in connection with the position of the brushes and/or rollers on definite sectors which correspond to definite points of the model of the sign or image to be marked on the grass surface.
In a seventh embodiment of the invention, the method of the last above described embodiment involves commanding the action, and especially the lowering, the raising and/or the rotation of the brushes and/or rollers, using a computer in which are inserted the model or models of the signs or images to mark on the grass surface, the model or models being divided in several points, the position of the brushes and/or rollers with regard to the position of the sectors of the grass surface and instructions which command the action with regard to the position of the brushes and/or rollers.
In a further version of the above described seventh embodiment of the invention, the preferred method involves using an apparatus on which are fixed the brushes or rollers, registering the position of the apparatus on the grass surface through sensors which detect magnetizable bodies that are deposited or buried at definite places on or under said grass surface.
In a further version of the above described seventh embodiment of the invention, the preferred method includes the steps of using an apparatus on which brushes or rollers are fixed and registering the position of the apparatus on the grass surface by means of a device which is able to emit and receive electromagnetic or sonic waves.
In a particular embodiment of that latter version, the device is able to receive signals from geostationary satellites.
The preferred apparatus for marking grass fields, in a first embodiment, includes wheels for moving the apparatus, brushes and/or rollers, and means for lowering down to the grass and raising from the grass, so that they do not touch grass any more, at least some of said brushes and/or rollers.
In a second apparatus embodiment, the preferred apparatus includes brushes which rotate and means for making the brushes rotate in two directions.
In a third embodiment of the preferred apparatus, which is a variant of the second embodiment, the apparatus includes means for lowering down to the grass and for raising from the grass, so that they do not touch the grass any more, at least some of the rotating brushes.
In a fourth embodiment of the preferred apparatus, the brushes and/or rollers according to one of the above apparatus embodiments are assembled in groups.
In a fifth embodiment of the preferred apparatus, at least a part of the rollers are mounted on one or more rotating barrels so that they can freely rotate.
In a sixth embodiment of the preferred apparatus the brushes and/or the rollers and/or the groups of brushes and/or rollers are staggeredly fixed to the apparatus.
In a seventh apparatus embodiment, the preferred apparatus according to one of the above described embodiments includes means for raising the wheels, and rollers which are able to support and to move the apparatus when the wheels have been raised up.
In an eighth apparatus embodiment, the preferred apparatus according to the seventh above described embodiment includes at least one engine which sets in motion the rollers which support the apparatus and a steering device for directing the apparatus when the wheels have been raised up.
In a ninth apparatus embodiment, the preferred apparatus according to the seventh or the eighth embodiments involves an arrangement for setting each roller or group of rollers and each brush or group of brushes in motion by a separate engine.
In a tenth apparatus embodiment, the preferred apparatus according to one of the above described embodiments comprises an odometer actuated by the rollers which support the apparatus or by a wheel which rolls on the grass surface and which registers the position of said apparatus on said grass surface.
In an eleventh apparatus embodiment, the preferred apparatus according to one of the four last above described embodiments is characterized in that the rotation axes of the wheels are perpendicular to the rotation axes of the rollers and/or brushes.
According to a variant of all of the above described apparatus embodiments, the preferred apparatus includes a computer in which the model or models of the image or images or of the sign or signs to be marked on the grass surface, as well as the position of the apparatus on the grass surface, are entered in the computer, the apparatus further including means by which the computer can actuate the brushes and/or the rollers according to the entries so that at least a part of the blades of the grass surface are oriented in a direction which is different from the direction of the other blades, so that at least a part of the grass surface constitutes an image or a sign which corresponds to the image or to the sign entered in the computer.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic plan view of an apparatus according to a preferred embodiment of the invention.
FIG. 2 is a schematic lateral view of the apparatus shown in FIG. 1.
FIG. 3 is a schematic plan view of an apparatus according to a further embodiment of the invention.
FIG. 4 is a schematic lateral view of the preferred apparatus shown in FIG. 3.
FIG. 5 is a schematic plan view of a variant of the preferred apparatus shown in FIG. 3, in which the brushes are staggeredly placed.
FIG. 6 is a schematic lateral view of the preferred apparatus shown in FIG. 5.
FIG. 7 is a schematic plan view of a variant of the preferred apparatus shown in FIGS. 1 and 2, in which the brushes have been replaced by rollers.
FIG. 8 is a schematic lateral view of the preferred apparatus shown in FIG. 7.
FIG. 9 is a schematic plan view of a variant of the apparatus shown in FIGS. 7 and 8, in which the rollers are staggered.
FIG. 10 is a schematic lateral view of the preferred apparatus shown in FIG. 9.
FIG. 11 is a schematic plan view of a further embodiment of the variant shown in FIGS. 7 and 8, in which the rollers are mounted on rotating barrels.
FIG. 12 is a schematic lateral view of the preferred apparatus shown in FIG. 11.
FIG. 13 is a schematic plan view of the apparatus shown in FIGS. 11 and 12 in which the rotating barrels bearing the rollers are staggered.
FIG. 14 is a schematic lateral view of the apparatus shown in FIG. 13.
FIG. 15 is a schematic plan view of a further embodiment of the preferred apparatus, in which the rollers which do not support the apparatus are mounted on rotating barrels.
FIG. 16 is a schematic lateral view of the preferred apparatus shown in FIG. 15.
FIG. 17 is a schematic plan view of a variant of the preferred apparatus shown in FIGS. 15 and 16, in which the rotating barrels bearing the rollers have been staggered.
FIG. 18 is a schematic lateral view of the preferred apparatus shown in FIG. 17.
FIG. 19 is a schematic plan view of a variant of the preferred apparatus shown in FIGS. 15 and 16, in which the rotating barrels have been fixed on both sides of the supporting rollers.
FIG. 20 is a schematic lateral view of the preferred apparatus shown in FIG. 19.
FIG. 21 is a schematic plan view of a variant of the preferred apparatus shown in FIG. 15, in which the non-supporting rollers mounted on rotating barrels have been replaced by rotating brushes.
FIG. 22 is a schematic lateral view of the preferred apparatus shown in FIG. 21.
FIG. 23 is a schematic plan view of a variant of the preferred apparatus shown in FIG. 17, in which the rotating barrels which bear rollers have been replaced by rotating brushes.
FIG. 24 is a schematic lateral view of the preferred apparatus shown in FIG. 23.
FIG. 25 is a schematic plan view of a variant of the preferred apparatus shown in FIG. 19, in which the rotating barrels which bear rollers have been replaced by rotating brushes.
FIG. 26 is a schematic lateral view of the preferred apparatus shown in FIG. 25.
FIG. 27 is a plan view of a variant of the preferred apparatus shown in FIG. 25, in which the rotating brushes have been staggered and the power of the engine is transmitted through belts.
FIG. 28 is a cross section according to A--A of the preferred apparatus shown in FIG. 27.
FIG. 29 is a cross section according to B--B of the preferred apparatus shown in FIG. 27.
FIG. 30 is a cross section according to C--C of the preferred apparatus shown in FIG. 27.
FIG. 31 is a diagram of an electronic and electric command device for the preferred apparatus.
FIG. 32 shows a grass surface divided into several sectors with a mark imprinted with dots in chosen sectors, the whole of the dots forming the mark.
FIG. 33 shows a network of metallic cables or wires which is buried under the grass surface and which allows positioning the apparatus on the grass surface.
FIG. 34 shows a sports field with four surfaces to mark and two transceivers which allow positioning the apparatus on the grass surface.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the embodiment schematically shown in FIGS. 1 and 2, the apparatus according to the invention is equipped with four wheels 1 and with a range of brushes 2, the bristles of which are vertically directed towards the grass. The wheels are used to move the apparatus to the grass surface to the work area to be marked, and to move it on the surface. The wheels are moved by one or several engines, which are preferably electrical, and which are not shown here, and are equipped with a steering device. Each brush can be lowered down to the grass and raised above the grass by raising and lower means 1b. When the apparatus passes onto the grass surface to work, the brushes are lowered down when necessary. Each brush preferably has a width which corresponds to that of a definite sector of the surface to be worked.
In a preferred method embodiment utilizing this simple apparatus, the grass surface to be marked is handled like a network of small sectors 13, which are preferably quadrangular, as shown in FIG. 32. If the width of the surface be marked is larger than the length of the row of brushes, it is useful to work the surface in several parallel strips 14, the width of which corresponds to the length of the range of brushes of the apparatus. The grass surface shown in FIG. 32 is so divided into four strips, the width of which corresponds to eight sectors, this latter number corresponding itself to the number of brushes with which the apparatus is equipped.
In operation, the apparatus rolls along the first strip and, when a brush passes over a sector to be marked, it is brought down to the grass and directs the grass blades as it goes by, up to the moment when it is raised up above the grass. FIG. 32 shows that, on the fourth strip, the third brush of the range is brought down on the twelfth and the thirteenth sectors from the left, and is raised afterwards, so marking the grass of the two sectors by directing their grass blades. A part of the letter A is thus imprinted in the grass.
The rest of the grass surface can of course remain as it was before, without any treatment. However, it is much preferable to have the apparatus pass a first time with all the brushes down, in one way, in order to direct all the grass blades on the whole strip. Afterwards, the apparatus runs on the same strip in the other direction, and the brushes are brought down only on the sectors which compose the sign or the image to be depicted. In that way, the blades are directed, approximately, in only two directions, which gives a sharper image. Once the first strip has been worked, the apparatus is put again on the starting line, at the beginning of the second strip, which is parallel and adjacent to the first strip, and the process is started again, until the whole grass surface is worked.
In the embodiment of FIGS. 3 and 4, the brushes 2 are still in one row, but they can rotate independently from each other in either direction. Likewise, the brushes can be braked or stopped, or can rotate freely, independently from each other. When a brush is locked or is rotating backwards, the grass blades bow in the direction of the run of the apparatus. When a brush is rotating forward, at a speed which is greater than the speed of the apparatus, the grass blades bow in an opposite direction. The apparatus can therefore work a whole strip in one pass. When the apparatus reaches the end of a strip, it turns back and immediately starts working the next strip, in the opposite way.
On the way to the surface to be marked, one can let the brushes rotate freely, if the apparatus is not equipped with a device by means of which the brushes can be raised up. In certain cases, it might, however, be useful to equip the apparatus with such a brush raising device.
FIGS. 5 and 6 show an embodiment in which the brushes are staggeredly fixed to the apparatus, which makes assembly of the transmissions and control devices easier, and makes it possible to work the whole grass surface, without any gaps. An automatic device, of a conventional type, makes the brushes work at the right time, in spite of their staggered position.
In the embodiment shown in FIGS. 7 and 8, the row of brushes is replaced by a row of rollers 3 which are mounted on their axes so that they can freely rotate. In the embodiment of FIGS. 9 and 10, the rollers are staggered and fixed. An automatic device, of a conventional type, makes it possible to lower respective rollers at the right time in spite of their staggered position. The rollers of FIGS. 7 and 8 have a central division which makes it possible to support the rollers on central bearings or ball bearings, while the rollers of FIGS. 9 and 10 are supported by bearings which are placed on each side of the rollers. In both embodiments, the rollers are mounted on a device 1b which makes it possible to bring them down and raise them up independently from each other. In both embodiments, the functioning of the apparatus is the same as that of the apparatus shown in FIGS. 1 and 2. In other words, it is necessary to make the apparatus pass twice on the same strip if one wishes to work the whole surface.
In the embodiment shown in FIGS. 11 and 12, the row of brushes shown in FIGS. 3 and 4 are replaced by a row of rotating barrels 15 on the periphery of which rollers 3 are mounted so that they can freely rotate around axes which are parallel to that of the barrel. The barrels 15 can rotate in two ways, or be braked or stopped, independently from each other, by means of engines which are not shown. When a barrel is stopped or rotates backwards, the grass blades lean in the same direction as the run of the apparatus. When the barrel rotates forward, at a speed which is higher than that of the apparatus, the grass blades lean in an opposite direction. The apparatus can therefore work a whole strip in one way. When it has arrived at the end of a strip, it turns back and immediately begins to work the next strip, in the opposite way. The apparatus is preferably equipped with a device which makes it possible to raise the barrels in order to avoid damage to them during the way to and from the grass surface.
FIGS. 13 and 14 show a version of this latter embodiment, in which the rotating barrels 15 are staggeredly placed with the advantages mentioned above in connection with FIGS. 5 and 6. In this version, the device adapts the functioning of the barrels to the space which is between the barrels.
In the embodiment schematically shown in FIGS. 15 and 16, the apparatus has eight barrels 15 which bear rollers 3, and moreover has four rollers 3 arranged in pairs. The axes of the wheels 1 are perpendicular to the axes of the rollers. The apparatus has means for raising the wheels, so that the apparatus can be supported by the two pairs of rollers. The apparatus is brought to the grass surface to be marked by means of the wheels which are down. When the apparatus has arrived, the wheels are raised up and the apparatus moves perpendicularly to its direction of arrival on the grass surface by means of the two pairs of rollers which are driven by one or more engines. The two rollers of each pair are separated by a small space which avoids friction. It is easy to make the apparatus turn by braking the rollers located on the same side of the apparatus, which is possible by means of a differential mounted on the transmission. A differential is not necessary in the case when each roller is driven by a separate engine.
The device which makes it possible to raise and to lower the wheels is not shown here. It is a conventional device, like many others which have been in existence for decades in some models of trucks (semi-trailers) or planes (landing gears).
The length of each pair of rollers and of the rotating barrels 15 corresponds to the width of a strip 14 of the grass surface. All the blades of the grass of the strip are first directed by the supporting rollers in the direction of the run of the apparatus. Then, the rotating barrels pass and give a different or an identical direction to the blades, depending on the direction and speed of their rotation, as explained in connection with FIGS. 11 and 12. A strip can therefore be worked in one way. However, if one wishes to work the next strip on the way back, it is necessary to turn the apparatus around in order to avoid deletion by the supporting rollers of the markings made by the rotating barrels, as the supporting barrels would follow the rotating barrels if the apparatus was not turned around.
FIGS. 17 and 18 show a variant of this latter embodiment, in which the rotating barrels are staggered to obtain the advantages mentioned in connection with FIGS. 5 and 6, and 13 and 14. In this variant, a device also adapts the functioning operation of the barrels to the space which is between the two rows of barrels.
FIGS. 19 and 20 show a variant of the embodiment of FIGS. 15 and 16, in which the two pairs of supporting rollers are bordered on two sides by two rows of rotating barrels which bear rollers. The presence of a row of barrels on each side of the supporting rollers makes it possible to mark the next strip on the way back, without turning back the apparatus. In principle, however, it is preferable to work each strip in the same way to obtain as uniform a direction as possible for the grass blades.
In a variant which is not shown here, the apparatus in the embodiment of FIGS. 19 and 20 has rotating barrels staggeredly mounted, with the above described advantages.
FIGS. 21 to 26 show variants of the embodiments shown in FIGS. 15 to 20, in which the barrels have been replaced by rotating brushes. Like the barrels in the preceding embodiments, each rotating brush can rotate in either direction independently of the other brushes.
FIGS. 27 to 30 show the features of the apparatus schematically shown in FIGS. 25 and 26, with the difference that the brushes are staggered, with all of the advantages noted above deriving from such arrangement.
Each rotating brush 2 can freely rotate around the axis 7 and is driven by a belt 4 which drives the brush by means of a pulley 10 which is attached to the brush. Each belt 4 is driven by an engine 11, which is preferably electrical, and which is independent of the other engines. The brushes are placed at such a height that they penetrate the layer of grass, but do not touch the soil. The axes 7 which support the brushes are fixed by their ends to the main chassis 5. Each pair of supporting rollers is supported by an axis 6. The supporting rollers freely rotate around the axis. At each end of each axis are pulleys 10 each pulley being fixed to a supporting roller 3. Belts 4 transmit the rotation of the engines to the rollers. Each belt is driven by an independent engine 11. Each engine drives the belt through a train of gears 12. The axes which support the rollers, as well as the engines and the trains of gears, are fixed to a secondary chassis 8. This secondary chassis 8 is fixed to a main chassis 5 through the medium of a ball bearing 9 which makes it possible for the secondary chassis to turn in a small angle to steer the apparatus. As each roller is driven by an independent engine, a differential is superfluous.
The engines are electrical and are powered by an accumulator. Of course, other types of engines could be used, but they would be less convenient. Likewise, it would be possible to use transmission means other than belts and pulleys, for example chains or gears.
The engines and the transmissions which drive the rollers give the apparatus, thanks to a high gear reduction, a speed which is approximately constant, and which is equivalent to that of a walking man even if the weight changes.
The engines for the rollers are started manually, by switches commanded by the driver. For the first strip, the driver can manually command the steering device, which makes it possible to make the two secondary chassis pivot with regard to the main chassis. For the next strips, the computer automatically steers the apparatus.
Each of the engines which drive the brushes is controlled and actuated by a computer according to the position of the brushes on the grass surface. The data which are transmitted to the computer are registered on a RAM card. FIG. 31 gives a diagram of the relations between the various electric or electronic devices which drive the apparatus. The torque necessary to make a brush rotate, whether in a direction corresponding to the direction of the apparatus or in the contrary direction, is more or less constant, depending on the elasticity of the bristles of the brush.
In comparison with the above described versions in which the wheels cannot be raised up, the advantage of this preferred embodiment lies in a better distribution of the weight, preventing the wheels from marking furrows in the ground. In comparison with the versions in which the brushes are replaced by barrels with rollers, this embodiment avoids the large weight and dimensions of the barrels.
Of course, in each contemplated embodiment, the number of devices may vary according to the needs of the user, including the number of rollers, barrels, brushes, engines, pulleys or wheels.
In the preferred embodiments, the method for marking grass fields is automatically carried out by a computer. The image or images, or the sign or signs, for example a name or a word constituting a trademark, which must be printed on the grass, are entered in the computer. The image or images and/or the sign or signs are marked at points which correspond to a division of the grass surface into several sectors 13.
The driver first places the apparatus on the starting line 15, and then drives it manually along the first strip. The apparatus is equipped with a device which deposits small balls made of ferromagnetic metal on an edge of the strip, i.e. on the left of the apparatus in the embodiment shown in FIG. 33, at regular intervals, for example at the limit of each sector 13. The apparatus is moreover equipped with magnetic sensors which are connected to the computer, and with a magnetic device by means of which the balls are recuperated on the way. The balls are deposited in the path of the apparatus on the first strip. The computer commands the dropping of the balls and actuates the brushes and/or rollers at the moment when the apparatus is in a definite position.
In order to determine this position, on the first pass, the preferred method is to use an odometer which is connected and driven by one or more rollers which support the apparatus, or by a wheel attached to the apparatus and which freely rolls on the grass. The odometer may be a common odometer of the type used, for example, in automobiles. The odometer transmits its data to the computer, which transmits its instructions to the engines according to the program entered by the driver. During passage on the second strip, the sensors transmit to the computer the data they collect concerning the position of the apparatus with regard to that of the balls, so that the odometer is no longer required. The position of the balls not only defines the direction given to the apparatus, but also the moment when the brush or roller must be actuated to give the grass blades the required direction in a definite sector, as well as the positions at which the balls are to be deposited in a new line along the second strip.
As the apparatus recovers the balls deposited on the edge of the first strip, it deposits balls on the edge of the second strip. Of course, these balls can be the same balls which are transferred by the apparatus from the border of the first strip to the border of the second strip. After having worked the second strip, the driver again places the apparatus on the starting line, at the beginning of the next strip and the process starts again. When the apparatus has arrived at the last strip, the computer stops the ball depositing device, while the ball collecting device still collects the balls deposited on the border of the preceding strip.
In another embodiment of the preferred method, the computer commands the marking of a line in the grass, on the edge of the strip. On the next strip, the driver drives the apparatus along the marked line. The line is preferably marked in such a way that the passing of the apparatus for the working of the next strip deletes it. In other words, it is necessary that the apparatus passes along the marked line. At the same time as the apparatus deletes this first line, it makes a second one, at the edge of the second strip. This second line is deleted by the passing of the apparatus on the third strip. The process starts again until the whole surface has been worked.
A further embodiment of the preferred method involves burying in the ground, some centimeters under the surface, a metallic network which corresponds to the edges of the strips and to the starting and arrival lines, as shown in FIG. 33. The apparatus is equipped with sensors which transmit the position of the apparatus to the computer. A measuring device informs the computer and the driver of any difference between the real position and the desired position entered in the computer. Here too, the steering can be automatic or manual.
In a further embodiment of the preferred method, transceivers are placed on the ground and on the apparatus. Such devices can measure the distance and/or the angle which makes it possible for the computer to calculate the position of the apparatus with regard to the transceivers placed on the ground. FIG. 34 schematically shows that such transceivers could be placed at points A and B. Either microwave, ultrasonic, or infrared transceivers could be used in such a system. Here too, the steering can be automatic or manual.
Lastly, it is possible to use a system in which transceivers are on satellites, as is the case with the GPS system. Other embodiments, modifications, and variations thereof will also occur to those skilled in the art, and thus it is intended that the invention not be limited by the above description, but rather that it be defined solely by the appended claims. | An advertising display method involves marking grass sports fields by bending the grass blades in definite zones and bending or leaving them straight in other zones in order to form an image or a word. The difference in the direction given to the grass blades is quite visible to the spectator. The grass blades are directed by means of an apparatus mounted on rollers which runs on the grass surface. The apparatus also has brushes and/or additional rollers which rotate to straighten the grass blades on definite sectors. The sectors form an image or the letters of a words. The engines which drive the apparatus and the brushes and/or rollers are electrical and are controlled by a computer. The image or word to represent on the grass, as well as the position of the apparatus on the surface to work, are entered in the memory of a computer. | 0 |
BACKGROUND OF THE INVENTION
This invention relates generally to athletic equipment and particularly to instructional equipment for golfing. A number of things are crucial for good golfing. A golfer must have the correct stance when he addresses the ball, and he must have the proper swing when he strikes the ball. While a large number of devices have been developed which enable the golfer to practice striking the ball in places other than on the golf course itself, no device has been developed which enables the golfer to analyze what he is doing right or wrong concerning his stance and swing. The golfer of course can see that he has hooked, sliced or shanked the ball, but he can tell very little from this about how to change his stance or the movements which he makes during his swing. A second person such as a golf pro at the local golf club must observe the golfer and relay to the golfer comments concerning the golfer's stance and swing.
When a golfer has a proper stance and swing, his head does not move from the time he addresses the ball until after he has completed his swing. To teach the golfer to hold his head steady, a second person usually must place a hand upon the golfer's head while the golfer is practicing, and this must ordinarily be done at the golf course.
Since certain types of instruction concerning the golfer's swing really can be give only at a golf course, and since such instruction involves observations of the golfer and communication thereof to the golfer by a second person, the instructional process can be cumbersome and inconvenient. A method or device whereby the golfer is enabled to instruct himself at convenient times and locations is to be much preferred.
SUMMARY OF THE INVENTION
A self-instruct golf analyzer has a base and an indicator mechanism. The indicator mechanism includes first and second perpendicularly intersecting planar members. The indicator mechanism is affixed to the base such that the first planar member defines a plane oblique to the ground while the second planar member defines a plane normal to the ground. The upper edges of the planar members form an inverted T-shape, and the front and rear surfaces of the first planar member and the left and right surfaces of the second planar member are not visible, when the golfer has assumed a correct stance adjacent the base and is gazing at the indicator mechanism. The front, rear, left and right surfaces have different colors which, when detected by the golfer during his swing, indicate improper head and body movement.
It is an object of this invention to provide a self-instruct golf analyzer which can be used by golfers of any height with clubs of any given loft.
It is also an object of this invention to provide a self-instruct golf analyzer which will enable the golfer to practice his swing at any place or time convenient to the golfer.
Another object of this invention is to provide a self-instruct golf analyzer which will enable the golfer to detect instantly any deviation of his head, and therefore improper body movement, during his swing, and to analyze and correct his swing to attain a steady head without a second person having to be present to make observations and communications thereof.
A further object of this invention is to provide a self-instruct golf analyzer which is simple of construction and economical of manufacture yet sturdy and capable of achieving the aforementioned objects.
These objects and other features and advantages of the self-instruct golf analyzer of this invention will become readily apparent upon referring to the following description, when taken in conjunction with the appended drawing.
BRIEF DESCRIPTION OF THE DRAWING
The self-instruct golf analyzer of this invention is illustrated in the drawing wherein:
FIG. 1 is a side elevational view of the first embodiment of the analyzer of this invention;
FIG. 2 is a top plan view of the first embodiment of the analyzer of this invention;
FIG. 3 is a front elevational view of the first embodiment of the analyzer of this invention;
FIG. 4 is a top perspective view of the first embodiment of the analyzer depicting the proper sighting taken by a golfer using the analyzer;
FIG. 5 is a perspective view of the second embodiment of the analyzer;
FIG. 6 is a fragmentary, top perspective view of the second embodiment of the analyzer depicting the proper sighting taken by a golfer using the analyzer; and
FIG. 7 is a fragmentary, perspective view of a modification of the second embodiment of the analyzer.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now to the drawing, the self-instruct golf analyzer of this invention is illustrated generally at 11 in FIG. 1. The analyzer 11 more particularly includes a base member 12 and an indicator mechanism 13.
Referring to FIGS. 1, 2 and 3, the base member 12 is flat and substantially rectangular in shape, having front and rear edge 14, 15. The base 12 may be other than rectangular in shape. The bottom surface 16 of the base 12 engages the ground or floor. The top surface 17 of the base 12 is very dark in color, preferably black. A pair of circular ball simulating areas 18, preferably white in color, are disposed upon the upper surface 17. The areas 18 are located toward the front edge 14, one area 18 being on each side of a line which is perpendicular to and bisects both edges 14, 15. The areas 18 are so oriented that the line which is defined by the centers of the areas 18 is also parallel to the front and rear edges 14, 15.
The indicator mechanism 13 includes a front, transverse plane 19. The front plane 19 at the lower edge thereof is affixed to the upper surface 17 of the base 12 directly over the line defined by the centers of the areas 18. Both areas 18 are thereby bisected by the plane 19. The front plane 19 is parallel to the front edge 14 and extends upwardly from the base 12, at an angle of about 65° from the top surface 17 as measured from that part of the surface 17 adjacent the front edge 14, to terminate in a upper edge 20. The front surface 21 of the plane 19 is a contrasting color, perhaps blue, to the black and white of the top surface 17 and areas 18. The rear surface 22 of the plane 19 is another contrasting color, perhaps green.
The indicator mechanism 13 also includes a longitudinal plane 23. The plane 23 is attached to the base 12 perpendicular to the upper surface 17 and extends upwardly therefrom to terminate in an upper edge 24. The plane 23 is attached to the base 12 directly over the line which is perpendicular to and bisects the front and rear edges 14, 15. The plane 23 also is attached to the transverse plane 19 and bisects the rear surface 22, the upper edges 20, 24 forming a "T" when viewed in plan (FIG. 2). The longitudinal plane 23 has left and right facing sides 25, 26. Again, these sides 25, 26 are of contrasting colors, the left side 25 being orange and the right side 26 being yellow perhaps.
The areas 18 are divided such that the front half of each area 18 is within the portion of the surface 17 extending between the front edge 14 and the intersection of the plane 19 with the surface 17. The rear half of each area 18 is within the portion of the surface 17 extending between the rear edge 15 and the intersection of the plane 19 with the surface 17. The rear halves of areas 18 are separated by the plane 23, the rear half of one area 18 being in the portion of surface 17 fronting the left side 25, and the rear half of the other area 18 being disposed in the portion of surface 17 fronting the right side 26.
A second embodiment of the analyzer of this invention 11 is generally shown in FIG. 5. The base assembly 12' includes a block member 27 having a lowr surface which engages the ground or floor and an upper surface 28. The block 27 has a bore 29 formed therein at an angle to the surface 28. A tightening screw 31 penetrates through the upper surface 28 and into the bore 29. A support arm 32 at one end thereof is rotatably received by the bore 29, and the tightening screw 31 is movable to engage and secure the arm 32 within the bore 29. The arm 32 extends upwardly from the block 27 at an angle to the surface 28 to terminate in an upper end having a slot 33 formed therein. The plane 23, adjacent the edge which is opposite the edge of attachment to the plane 19, is slidably received within the slot 33. The plane 23 is pivotally attached to the arm 32 by a bolt 34 and secured in a desired orientation, as by means of a wing nut 36.
The second embodiment of the analyzer of this invention 11 may be modified. The plane 19 may be semi-circular in conformation, retaining the upper edge 20 and having a lower, arcuate edge 37, as shown in FIG. 7. The arm 32 may be upwardly arcuate in conformation, the radius of curvature thereof being taken from a center point located below the arm 32.
Use of the analyzer of this invention 11 is illustrated in FIGS. 4 and 6. If the golfer-user is practicing indoors at home, the first embodiment of the analyzer 11, shown in FIGS. 1 through 4, is used. If the golfer-user is practicing outdoors or any place where he may swing a golf club to strike a ball 38, the second embodiment of the analyzer 11, shown in FIGS. 5 and 6, is used.
Where the first embodiment of the analyzer 11 is used, the golfer-user places the analyzer in a appropriate place, the bottom 16 engaging the floor, and assumes his regular golfing stance. The golfer uses one of the areas 18 as a simulation of an actual golf ball, right-handed golfers concentrating on the area 18 which is disposed to the left of plane 23 fronting upon side 25, left-handed golfers concentrating on the area 18 which is disposed to the right of plane 23 fronting upon side 26. The golfer takes a stance whereby he is facing the front edge 14 and surface 21, and he should see the top edges 20, 24 only and not the sides 21, 22, 25, 26, FIG. 4 illustrates the view which the golfer should have when he has assumed his proper stance for addressing the ball. It will be noted that the edges 20, 24 by their intersection direct the golfer to concentrate on the position upon the golf ball, here simulated by one of the areas 18, which the head of a club should strike with a correct swing.
The golfer then practices his swing while noting which colors he sees during his swing. If the golfer sees blue (front side 21), he is either leaning backwards or lowering his head during his swing. If the golfer sees green (rear side 22), he is leaning forward or raising his head during his swing. Should the golfer see yellow (right side 26) or orange (left side 25), he is swaying his body to the right or left during his swing. A combination of colors would indicate some combination of the aforementioned movements.
In general, cool colors (blue, green) indicate forward and backward movements while hot colors (orange, yellow) indicate sideways movements. The colors of the planes 21, 22, 25, 26 are contrasting and are very visible against the black color of the surface 17. By analyzing the colors which become visible to him during his swing, the golfer can correct his stance and swing such that he properly addresses and strikes a golf ball. During a proper swing, the golfer should see nothing other than the top edges 20, 24 marking the rear edge of a simulated ball area 18 against the black background of the surface 17.
While the golfer uses the first analyzer 11, shown in FIGS. 1 through 4, where he is practicing his swing without using a golf club or ball, the second analyzer 11, shown in FIGS. 5 and 6, is used where the golfer actually uses his clubs and strikes a ball 38. As before, the golfer places the ball 38 and assumes his stance, addressing the golf ball 38 in his normal manner. The arm 32 displaces the indicator mechanism 13 forward of the base assembly 12' such that a golf ball 38 may be placed upon the ground and struck with a golf club without the club striking the analyzer 11. Where the plane 19 having the arcuate edge 37 is employed, passage of the club beneath the indicator mechanism 13 is further facilitated. As shown in FIG. 6 (the case of a right-handed golfer being illustrated), the golfer should see the edges 20, 24, and his attention should be focused upon the rear edge of the golf ball 38, to which the intersection of the edges 20, 24 direct. As before, the golfer takes note of the colors he sees while swinging to strike the ball 38. He then analyzes the colors to ascertain bodily movements by him which must be eliminated in order to properly swing and strike the ball 38.
The 65° angle of the transverse plane 20 with respect to the surface 17 is suited to most persons when using a driver. When assuming a normal correct stance, the golfer will see the analyzer 11 as shown in FIG. 4. For persons taller than about 6'3" (190 cms), or where clubs of short lengths and greater loft such as seven, eight and nine irons and pitching and sand wedges are used, the angle should be greater than 65°. For persons shorter than about 5'7" (170 cms) the angle should be smaller than 65°. Separate forms of the analyzer 11 can be used by different height groupings of golfers or for different club lengths by each individual golfer. Alternately, shims (not shown may be placed underneath the base 12 adjacent the front edge 14 or rear edge 15 to change the angle of the plane 19 with respect to the floor. The seccond form of analyzer 11, shown in FIGS. 5 and 6, has an indicator mechanism 13 which can be adjusted such that the angle which the plane 19 makes with respect to the ground is either about 65° or is greater or less than 65°.
During the foregoing description concerning the angle of the plane 19, it has been assumed that the golfer is using a normal golf stance. For those instances where an individual golfer through study and instruction has developed an unusual golf stance, the correct angle of the plane 19 is determined by the golfer first assuming his stance. A second person then adjusts the analyzer 11 such that the golfer views the edges 20, 24 as shown in FIG. 4 or FIG. 6. Notice is then taken of how the analyzer 11 is adjusted, and thereafter the golfer himself may set up the analyzer whenever he desires to practice his swing.
From the foregoing it can be seen that both forms of the analyzer 11 can be used by golfers of any height with clubs of any particular loft. The individual golfer can self-determine through use of the analyzer 11 any deviation of his head during the course of his swing. Movements of the head are detected at the moment of occurrence during the swing. The individual can determine corrections to be made to his swing in order to obtain a steady head. More cumbersome methods, whereby a second individual places his hand upon the head of the golfer to teach the golfer to keep his head steady or merely watches and then communicates his observations to the golfer, are thereby eliminated. The golfer, by using different embodiments of the analyzer 11, may practice his swing virtually anywhere. Thus it can be seen that the objects of this invention have been attained.
Although two embodiments of the self-instruct golf analyzer 11 have been disclosed herein, it is to be remembered that various modifications and alternate constructions can be made thereto without departing from the full scope of the invention, as defined in the appended claims. | A base having a lower, ground-engageable portion and an upper portion. An indicator mechanism is formed by first and second perpendicularly intersecting planar members. Each of the outer planar surfaces of the planar members includes a distinctive color, and each color is different from the others. The first planar member defines a plane oblique to the ground while the second planar member defines a plane normal to the ground. The indicator mechanism is attached to the upper portion of the base. When the golfer assumes a golfing stance adjacent the base and gazes at the indicator mechanism, the upper edges of the planar members form an inverted T-shape, the side surfaces of the planar members not being visible. | 0 |
This is a continuation of application Ser. No. 410,863, filed Aug. 23, 1982, now abandoned, which is a continuation of application Ser. No. 125,217, filed Feb. 27, 1980, now abandoned.
BACKGROUND OF THE INVENTION
The present invention relates to a method of and a machine for planting seeds in general and more particularly to a machine of this type which is also capable of breaking up the soil prior to the actual planting operation.
There are already known various machines of the type here under consideration which are capable of both breaking up the soil and planting seeds therein. Such conventional machines are either towed behind a tractor or self-propelled to move over the field to be tilled, include at their front portion either stationary tools, such as plowing blades or cultivator tines, or movable tools such as disks rotating about a horizontal axis or prongs or similar tools orbiting around vertical axes. Immediately behind these breaking-up tools, there are provided arrangements which cause the seeds to be planted to become deposited on, or penetrate into the ground. Such arrangements, which usually are constructed as tubes, more often than not, discharge the seeds at a zone where the soil broken up by the breaking-up tool descends onto the ground. It is also known to equip the conventional machines of this type with a compacting roller which serves the dual purpose of compacting the upper layer of the soil at the region of deposition of the seeds, and of controlling the working depth of the breaking-up tools.
Experience with these conventional machines has shown that they are disadvantageous in several respects. One of the serious drawbacks of these conventional machines is that the seeds are not deposited in or on the ground under conditions which would be most conducive to their subsequent growth. As a matter of fact, the depth below the surface at which the seeds planted by the conventional machine are located varies within relatively wide limits. This is due partly to the fact that the seeds already deposited on or travelling toward the ground are entrained by the soil travelling rearwardly from the breaking-up tools for joint travel therewith in the rearward direction, and partly to the fact that the seeds become deposited on soil which has been previously broken up or loosened but which has not been tamped or compacted prior to the deposition of the seeds thereon. As a result of the latter situation, the seeds can fall into cracks or other gaps in the ground, such as gaps present between adjacent soil granules or aggregates. It is well known that a seed which is situated more than 10-15 cms. below the upper surface of the ground after the planting does not germinate. In addition thereto, if the upper layer of the soil is too loose, moisture from the subsoil is hindered in rising toward the seeds due to capillary action so that the seeds may be deprived of the moisture needed for their growth. On the other hand, if the upper layer of the soil is too loose, the latter dries out very rapidly after being moistened by rain or other precipitation, which also impedes the growth of the plants from the seeds.
SUMMARY OF THE INVENTION
Accordingly, it is one of the principal objects of the present invention to avoid the disadvantages of the prior art.
More particularly, it is an object of the present invention to develop a machine which performs a method of planting seeds which is not possessed of the disadvantages of the conventional seed-planting methods.
A further object of the present invention is to provide a seed-planting machine which performs a method which renders it possible to plant the seeds under optimum conditions for their subsequent growth.
A concomitant object of the present invention is to develop a machine which is simple in construction, inexpensive to manufacture, easy to use, and reliable in operation.
Other objects of the invention will in part be obvious and in part appear hereinafter.
With the above and other objects of the invention in view, one feature of the present invention resides in a machine which performs a method of planting seeds into the ground, which comprises the steps of breaking up the ground, moving and lifting a top layer of soil off the thus broken ground, so that a lower layer of the ground is uncovered, providing a tamping of the uncovered lower layer free of any of the top layer immediately previously removed from the soil during said moving and lifting step, placing seeds onto the uncovered and tamped lower layer, depositing the lifted soil of the top layer in the form of a loose-consistency covering layer onto the uncovered and tamped lower layer and onto the seeds placed thereon for covering the latter, and compacting the deposited covering layer.
A particular advantage of this method is that the quantity of soil which has been lifted off the ground is returned to the lower layer of the ground, only after the same has been tamped and the seeds deposited thereon, as a layer of uniform thickness. Thus, all seeds are located at the same depth below the final surface since their deposition on the already tamped ground prevented them from descending to lower depths into cracks or the like, and the layer of soil deposited on top of the seeds is uniform throughout.
The machine of the present invention which is capable of performing the above method is movable in a forward direction over a ground, and comprises break-up means positioned forwardly for breaking up the ground, soil conveyance means including a soil lifting device disposed rearwardly of said break-up means operative for moving and lifting a top layer of soil off the thus broken ground, so that a lower layer of the ground is uncovered, said soil lifting device comprises a plurality of tools rotatable about an axis transverse to said forward direction, tamping means located rearwardly of said soil lifting device and including a tamping roller rotatable about an axis transverse to said forward direction said tamping roller being adapted for providing a tamping of the uncovered lower layer free of any of the top layer immediately previously removed from the soil by said soil conveyance means, seed emplacement means for placing seeds on the tamped lower layer, said soil conveyance means conveying the lifted soil upwardly and so as to deposit it on the ground to the rear of said seed emplacement means, and compacting means rearwardly of said tamping means, for compacting the deposited covering layer, whereby the lifted soil is deposited in the form of a loose-consistency covering layer onto the tamped layer, and onto the seed placed on the tamped surface.
When the machine is constructed in the above-discussed manner, there are obtained several important advantages. One of the more important advantages is that the seeds are covered by a layer of soil having a substantially uniform thickness after the seeds have been placed on a substantially level surface which has been tamped by the action of the tamping roller. Another advantage obtained when the machine of the present invention is employed is that it is possible to cover the seeds with a layer of soil which has a predetermined, preferably relative fine, granularity. Additionally, it is possible, when using the present invention, to avoid mixing of the seeds with the soil intended for covering such seeds, in that the seeds are placed on the tamped ground ahead of the location at which the soil previously lifted off the ground descends onto the ground.
The fact that the layer of soil onto which the seeds are placed is tamped prior to the placing of the seeds brings about the double advantage of reducing excessive drying of the subsoil even during a period of drought and of permitting the moisture contained in the subsoil to rise to the seeds due to capillary forces. As a result of the employment of the machine of the present invention, there is obtained a situation where the seeds are situated at a depth at which, on the one hand, they can be reached by the moisture rising through the subsoil due to capillary forces and needed for their germination and growth and, on the other hand, they are accessible to the heat and air passing through the layer of soil covering the same, so that all conditions needed for germination of such seeds and growth of the plants therefrom are met.
Another advantage of the machine according to the present invention, is that it is possible to vary the types of seedlings, or to adjust the machine to different types of seeds, in dependence on the distance at which the seeds are placed behind the tamping roller. If the seeds are placed immediately behind the tamping roller on the leveled and tamped surface, sufficient time is available for the seeds to spread out before they are covered by the layer of previously lifted soil and an effect is obtained as if the seeds were distributed at random even though, in fact, the seeds are placed on the tamped surface in a row.
In contrast thereto, when the seeds are delivered to a zone which is more spaced from the tamping roller and closer to the zone at which the previously lifted soil descends onto the tamped surface, the seeds do not have sufficient time available to them to become scattered over the tamped surface. As a result of this, the seeds will remain in the original rows as placed on the tamped surface, or substantially so, at the time at which they are covered by the descending previously lifted soil, so that the end effect is planting of the seeds in rows.
The invention accordingly comprises the features of construction, combination of elements and arrangement of parts, as well as the several steps and the relation of one or more of such steps with respect to each of the others, which will be exemplified in a construction and the detailed disclosure hereinafter set forth and the scope of the application of which will be indicated in the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a somewhat diagrammatic side elevational view of a first embodiment of the machine according to the present invention;
FIG. 2 is a view similar to FIG. 1 but of a modified embodiment of the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring now to the drawings in detail, and first to FIG. 1 thereof, it may be seen that the machine according to the invention includes a frame 1. The frame 1 is provided, at its front end, with brackets 2 and 3 or similar mounting elements by means of which the machine can be attached to a tractor (which is not shown in the drawings) or a similar apparatus for advancing the machine in the direction of an arrow A. A bin or hopper 4 which accommodates a supply of seeds (such as grain) is mounted on the frame 1 by means of supports 5 and 6, at an elevated position.
A rotating soil breaking-up cutter 29, having blades 30 which orbit about an axis of the cutter 29 in a direction of an arrow r is capable of penetrating into the ground to a depth B of about 25-30/cms., and is mounted at the front portion of the frame 1. This cutter 29 is capable of breaking up or otherwise disintegrating the topsoil to the depth B. This breaking up cutter 29 which is mounted on the frame 1 of the machine is driven in rotation by means of a chain transmission 31 trained about a sprocket wheel 32 of a crankcase 33 which is directly connected to the implement powering output of the tractor which pulls the machine of the present invention in the direction indicated by the arrow A. The breaking-up cutter 29, the axis of rotation of which extends substantially horizontally and at a right angle to the direction A of movement of the machine, is covered by a hood 34 having a rear portion 35 which is pivotably mounted on the remainder of the hood 34. This rear portion 35 slightly levels the terrain broken up by the blades 30 of the breaking-up cutter 29. The blades 30 are advantageously arranged in a helix around the axis of rotation of the breaking-up cutter 29.
A lifting cutter 10 of a smaller diameter than the breaking-up cutter 29 is mounted on the frame 1 rearwardly of the breaking-up cutter 29 for rotation about an axis extending below the frame 1 and substantially horizontally and at a right angle to the direction A of forward movement of the machine. This lifting cutter 10 is fastened to the frame 1 by means of braces 11 and is provided with lifting tools, such as blades 12, capable of lifting a predetermined quantity of the soil which has been previously broken up by the breaking-up cutter 29. Blades 12 are rotatable about an axis transverse to the forward direction A. The lifting tools provided on lifting cutter 10 may be in the form of blades, as illustrated, or may be in such other forms as are known to those skilled in the art for lifting soil, for example, teeth, prongs, spades, etc. The axis of rotation of the lifting cutter 10 and the dimensions of the latter are so selected that the free ends of the blades 12 penetrate below the surface of the ground which has been broken up by the breaking-up cutter 29, to a depth of about 5-10 cms.
In addition to lifting the soil, the blades 12 also serve for crushing the soil which they lift. To achieve this, the lifting cutter 10 is rotated in a direction indicated by an arrow f at an elevated rotational speed, being driven in rotation by a chain transmission 13, to give an example. The chain transmission 13 is set in motion by means of a crank case 14 which is mounted on the frame 1 and which is connected to the crank case 33 by a shaft 36.
The soil lifted by the lifting cutter 10 and travelling upwardly of its axis of rotation is thrown rearwardly between two hoods 37 and 38 which extend one above the other.
A soil amount controlling device 21 is provided in front of the lower hood 37 and serves for controlling the amount of soil lifted by the blades 12 of the lifting cutter 10 which is permitted to penetrate between the two hoods 37 and 38. This controlling device 21 is constituted by a plate 22 extending transversely of the machine over the entire width thereof and perpendicularly to the layer of soil lifted by the lifting cutter 10. The position of this plate 22 may be adjusted so that the amount of soil thrown rearwardly by the lifting cutter 10, may be adjusted. To achieve this, the adjustable plate 22 can be displaced closer to or farther away from the upper hood 38 in order to reduce or increase the aperture through which the soil thrown rearwardly by the blades 12 of the lifting cutter 10 can enter the space between the hoods 37 and 38.
A tamping roller 23 which, as illustrated, includes two end disks and a plurality of transverse bars extending between the end disks, is mounted below the hood 37. This tamping roller 23 extends perpendicularly to the direction A of advancement of the machine and parallel to the axis of rotation of the lifting cutter 10, and is fastened to the frame 1 of the machine by means of arms 24 located at the two ends of the tamping roller 23. Inasmuch as the tamping roller 23 is located forwardly of the discharge zone of the layer of soil thrown rearwardly by the lifting cutter 10, it is capable of tamping the soil which has previously been broken up by the breaking-up cutter 29, ahead of the zone at which the soil lifted by the lifting cutter 10 descends on the tamped ground.
The bin 4 communicates with tubes 25 which pass through the hoods 38 and 37 and have their discharge ends located immediately rearwardly of the tamping roller 23. These tubes 25 convey seeds 26 originally contained in the bin 4 toward the tamped surface of the ground. The seeds 26 may be distributed among the various tubes 25 by a conventional distributing device which has not been illustrated in the drawings and which is energized, for instance, by the tamping roller 23. As sufficient amount of time is available to the seeds 26 to become uniformly distributed over the tamped ground when the discharge ends of the tubes 25 are placed quite closely behind the tamping roller 23, the effect is reminiscent of planting the seeds 26 at random.
According to an important aspect of the present invention, the seeds 26 are placed onto a layer of a thickness C which has been previously tamped by the tamping roller 23, before being covered by the soil which has been previously lifted by the lifting cutter 10 and thrown rearwardly by said lifting cutter 10. As a result of the presence of the controlling or calibrating device 21 arranged immediately rearwardly of the lifting cutter 10, it is possible to precisely control the quantity of soil which will cover the seeds 26, which renders it possible to cover such seeds 26 with a layer of soil having a thickness D which is as uniform as possible. The thickness D of this covering layer is so chosen that the best possible conditions of growth of plants from the seeds 26 are obtained.
In addition thereto, the fact that the seeds 26 are placed onto the ground previously tamped by the tamping roller 23 between the latter and the area of descent of the previously lifted soil onto the ground and onto the seeds 26 with the purpose of covering the latter, renders it possible to avoid mixing of the seeds 26 with the descending soil. This guarantees that each seed 26 is located at always the same depth below the surface of the ground, at a location where it is acccessible to the moisture rising from the subsoil and to the heat from sun or the ambient atmosphere penetrating through the layer covering the seeds 26.
As also shown in FIG. 1 the machine of the present invention may be equipped with a compacting roller 27 which rolls on the ground owing to the forward movement of the machine and which is mounted on the arms 24 supporting the tamping roller 23 by means of additional arms 28. The purpose of this compacting roller 27 is to slightly compact the soil layer which covers the seeds 26 so as to improve the conditions for growth of the latter.
A deflector 39 enclosing a predetermined angle with the hood 38 is provided at the rear portion of the hood 38. The function of this deflector 39 is to deflect the soil advancing between the hoods 37 and 38 onto the ground and to simultaneously crush the soil particles or granules. The angle of inclination of the deflector 39 relative to the hood 38 is advantageously adjustable, independently of adjustment of the position of the hood 38 which is fastened to the frame 1 of the machine by means of braces 40, the lower ends of which are provided with means for fastening the hood 38 in respective lowered or raised positions.
FIG. 2 illustrates an embodiment of the machine according to the present invention which is similar to that discussed with reference to FIG. 1 in so many respects that only those parts appearing for the first time in FIG. 2 will be discussed in some detail, while the common parts will be identified by the same reference numerals.
As illustrated in FIG. 2, the modified machine according to the invention comprises a rotatable harrow 41 provided with teeth 42 and mounted at the forward region of the machine. Each harrow 41 has two of the teeth 42 which orbit about the respective vertical axis of the harrow 41. The axes of rotation of the harrows 41 are substantially aligned perpendicularly to the forward direction A of the machine. The rotatable harrow 41 is mounted on the frame 1 and is set in rotary motion by a transmission which has been omitted from the drawing in order not to unduly encumber the same, the transmission being energized from a crankcase 33 which is directly connected to the implement-energizing output shaft of the tractor. As the teeth 42 revolve about the axis of the harrow 41, they crush the soil and throw the same in the rearward direction of the machine. A grating 43 is located rearwardly of the harrow 41 and lets fine soil granules pass therethrough while retaining huge soil granules or agglomerations and stones in front thereof. This avoids the possibility that blades 12 of the lifting cutter 10 could lift such agglomerations or stones and throw the same rearwardly of the machine.
The lifting cutter 10 resembles the one described in connection with FIG. 1 and functions in the same manner and for the same purpose so that it need not be discussed in detail herein. However, it is to be mentioned that the blades 12 of the lifting cutter 10 lift the soil from rearwardly of the grating 43 and advance such soil upwardly of the axis of rotation of the cutter 10 and into the space between two hoods 44 and 45. The hood 44 is similar to that discussed above in connection with FIG. 1 and indicated at 38. This hood 44 is held in place by braces 40 which are equipped with means for holding the hood 44 at different distances from the hood 45. In order to avoid possible clogging of the space between the hoods 44 and 45 by the soil, a forward portion 46 of the hood 45, which carries the controlling or measuring device 21, is set in forward and rearward motion by a reciprocatory mechanism, as indicated by an arrow v. This forward and rearward motion is caused by a connecting rod 47 which is pivotally connected, on the one hand, to the lifting cutter 10 and, on the other hand, to the forward portion 46 of the hood 45. The portion 46 extends from behind the lifting cutter 10 to above the tamping roller 23 and is guided, on the one hand, by resting on a transverse rod 48 of the frame 1 and, on the other hand, by resting on a fixed portion 49 of the hood 45. Inasmuch as the speed of rotation of the lifting cutter 10 is rather high, the forward portion 46 of the hood 45 will oscillate at a correspondingly high frequency, which, on the one hand, avoids the possibility of undesired ahderence of soil to the hood 45 and, on the other hand, enhances the movement of the soil toward the rear of the machine.
The hood 45 again extends over and covers the tamping roller 23 in the same manner as discussed above in connection with FIG. 1. The fixed end 49 of the hood 45 which extends rearwardly beyond the tamping roller 23 is formed with notches or slots which accommodate the tubes 25. In this manner, the seeds 26 may be delivered through the tubes 25 onto the surface of the tamped layer of the thickness C previously tamped by the tamping roller 23. Herein, the discharge end of each tube 25 is located as close as possible to the point of descent of the soil previously lifted by the lifting cutter 10 onto the tamped ground, so that the type of seed distribution obtained as a result of the operation of the machine shown in FIG. 2 resembles that obtained in sowing in a row. This is attributable to the fact that the seeds 26 do not have sufficient time available to them to distribute themselves on the tamped surface, inasmuch as they are immediately covered by a layer of soil having a thickness D which is as uniform as possible, without becoming mixed with this soil layer.
This covering soil layer may advantageously be slightly compacted due to the action thereon by a rounded lower portion 50 of the hood 44, which, in a sense, performs the same function as the roller 27 illustrated in FIG. 1. The positions of the free ends of the tubes 25 are adjustable from close to the tamping roller 23 to close to the zone at which the previously lifted soil reaches the tamped ground.
Even though several modifications of the invention have been described above in connection with FIGS. 1 and 2, it is quite clear that the various elements or components of these modifications could be combined with one another in a manner different from that discussed above. So, for instance, the hood 37 which extends from rearwardly of the lifting cutter 10 to above the roller 23, as shown in FIG. 1, could be employed in the machine of FIG. 2 after omitting the mechanism which causes the forward portion 46 of the hood 35 to vibrate. Similarly, the machine of FIG. 2 could be equipped with the compacting roller 27 shown in FIG. 1. In addition thereto, it is equally possible to situate the discharge ends of the tubes 25 which convey the seeds 26 onto the tamped surface in the immediate vicinity of the zone at which the soil dislodged by the lifting cutter 10 returns to the ground. In this manner, planting in rows can be obtained even in the machine of FIG. 1. Similarly, the machine of FIG. 2 could be modified to achieve planting at random by transferring the discharge ends of tubes 25 closer to the tamping roller 23.
Finally, it is to be mentioned that a machine according to the invention may also be used for planting seeds 26 without being equipped with the breaking-up tools 29 or 41 which has been discussed above. In that case, the ground must be prepared for planting which means that at least the uppermost layer of the soil must have been crushed or broken up prior to the use of such a machine. | A machine for planting seeds includes a rotary soil lifting device which lifts broken-up soil, a tamping roller which tamps the remaining broken-up soil, an arrangement for placing seeds onto the upper surface of the tamped layer of the ground, and an arrangement for conveying the soil lifted by the soil lifting device past and upwardly of the tamping roller and for depositing this soil onto the tamped surface and onto the seeds placed thereon as a layer of uniform thickness. A compacting roller may be used to compact the soil of this layer after the formation of the latter, and the machine includes breaking-up tools of the fixed or rotating type mounted at the front region of the machine for breaking up the soil prior to and to a depth sufficient for the performance of the lifting operation by the soil lifting device. The conveying arrangement may include two hoods which together define a passage through which the lifted soil advances upwardly of and beyond the tamping roller. The discharge ends of tubes which constitute parts of the seed placing arrangement may be moved closer to the tamping roller to allow the seeds to spread out in random fashion, or closer to the area at which the lifted soil descends onto the ground to achieve planting in rows. | 0 |
[0001] This application claims priority to U.S. Patent Application Ser. No. 60/736,540, filed Nov. 14, 2005.
BACKGROUND OF THE INVENTION
[0002] The present invention relates generally to methods of treating cancer and, more specifically, to a biodegradable core-shell nano-sized gels (nanogels) that can be used for cancer-drug delivery or cancer-tissue imaging.
[0003] Cancer is the second leading cause of death in the United States. Each year more than 1.2 million Americans are diagnosed with cancer, and less than half can survive five years. Annual medical costs for cancer treatment account for billions of dollars in the US alone. Chemotherapy, which uses chemical agents (anticancer drugs) to kill cancer cells, is one of the primary methods of cancer treatment. Unfortunately, these anticancer drugs have limited selectivity for cancer and are inherently toxic to both cancer and normal tissues. As a result, anticancer drugs can cause severe side effects and damage to healthy tissues. For example, cisplatin is a well-known metal complex that exhibits high antitumor activity [Rosenberg et al., 1969; Takahara et al., 1995]. However, it has significant toxicity, in particular, acute as well as chronic nephrotoxicity [von Hoff et al., 1979; Pinzani et al., 1994]. Other common side effects of anticancer drugs include decrease in the number of white blood cells (increasing risk of infection), red blood cells (losing energy) and platelets (risk for bruising and bleeding) as well as nausea, vomiting, hair loss, etc. Furthermore, the high glomerular clearance of the anticancer drugs leads to an extremely short circulation period in the blood compartment [Siddik et al., 1987].
[0004] Most importantly, treatments in conventional dosage form of these drugs may lead to initial cancer regression, but soon the cancer becomes insensitive to the drugs, causing cancer progression and death. The primary reason for the treatment failure is cancer's intrinsic and acquired drug resistance [Pastan and Gottesman, 1991; Gottesman, 2002]. When a conventional drug dose is administered intravenously, the drug molecules distribute throughout the body and some drug molecules reach the cancer interstititium. Some are taken up by cancer cells via diffusion, transport and endocytosis. On the other hand, cancer cells have various mechanisms by which they become resistant to the drugs, such as loss of a cell surface receptor or transporter for a drug to slow down the drug influx, specific metabolism of a drug, alteration by mutation or drug detoxification to consume the drugs, and the like [Gottesman, 2002]. A major mechanism of multidrug resistance is an energy-dependent drug efflux transporter, the P-glycoprotein (P-gp) pump located in cell membrane [Gottesman, 2002]. P-gp pumps are very efficient in detecting and binding a large variety of hydrophobic drugs as they enter the plasma membrane. These pumps then transport the drugs out of the cells [Bogman et al., 2001; Gottesman, 2002]. As a consequence of the slowed drug entry but efficient drug removal by the P-gp pumps and the drug consumption by other forms of drug resistance, the effective drug concentration in cytoplasm is well below the cell-killing threshold, resulting in a limited therapeutic efficacy.
[0005] The goal of this invention is to increase the drug selectivity for cancer and to overcome the cancer drug resistance toward enhanced therapeutic efficacy and reduced toxicity to healthy tissue.
SUMMARY OF THE INVENTION
[0006] The present invention relates to degradable nanogels for the delivery of drugs. The nanogels are made of a polymer that has a water-soluble polymer chain containing carboxylic acid moieties and poly(ethylene glycol) (PEG) or other water-soluble polymer chains attached to the polymer chain and having the generic structure of FIG. 1 . The water-soluble side chains have a molecular weight preferably between 300 and 50,000 and most preferably between 2000 and 5000. The polymers are useful as drug carriers and as imaging agents, and can overcome cancer drug resistance leading to enhanced therapeutic efficacy and reduced toxicity of the cancer drug to healthy tissue. In a particular application of the present invention, the polymer complexes with the cancer drug cisplatin to form core shell type gels with a size from 1 nm to 2000 nm.
BRIEF DESCRIPTION OF THE FIGURES
[0007] FIG. 1 is a scheme of the generic structure of the polymeric compound claimed in this invention.
[0008] FIG. 2 is a scheme of the synthesis of 2,2-bis(acryloxymethyl)propionic acid.
[0009] FIG. 3 is a scheme of the synthesis of PEG macromonomer and poly (β-aminoester)-graft-PEG by polycondensation of 2,2-bis(acryloxymethyl)propionic acid.
[0010] FIG. 4 is a scheme of the formation of core-shell nanogel of the poly (β-aminoester) and CDDP.
[0011] FIG. 5 is a graph of the size distribution of the CDDP-induced nanogels.
[0012] FIG. 6 is a graph of the cytotoxicity of the polymers (P2K-25P, P25K-50P) and their nanogels at COOH/Pt of 3 (P2K-25-3 and P2K-50-3); cisplatin equivalent dose is 0.25.
[0013] FIG. 7 is a graph of tumor formation in SKOV-3 xenografted nude mice treated with cisplatin and with the nanogels (P2K-25-3 and P2K-50-3); A is the average number of tumors present per cm of mesentery tissue; B is the average diameters of tumors present; C is the tumor area as a ratio of the total area.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0014] Drug Example
[0015] Cis-dichiorodiamineplatinum (II) (cisplatin or CDDP) is an example of an anticancer drug that can induce cancer drug resistance. [Scanlon, 1991.] Kataoka and co-workers incorporated cisplatin into block copolymer micelles to circumvent the drug resistance. The micelle-encapsulated cisplatin had an improved cytotoxicity. [Noshiyama, 2003; Nishiyama, 1999; Nishiyama, 2001.]
[0016] Nanogel Example
[0017] We synthesized a water-soluble carboxylic acid-containing poly(ester) grafted with PEG side chains. In water, CDDP complexes with the carboxylic acid of the poly(ester) and forms nanogel domains of about 100-200 nm that can be used for controlled delivery of CCDP or other drugs to cancer tissue.
[0018] Synthesis of 2,2-bis(acryloxymethyl)propionic Acid:
[0019] The reaction scheme for producing 2,2-bis(acryloxymethyl)propionic acid is illustrated in FIG. 1 . 2,2-bis(hydroxymethyl) propionic acid (10.1 g, 0.075 mol) was stirred at 0-5° C. in dried dichloromethane. Triethylamine (15.2 g, 0.15 mol) was added with stirring. Acryloyl chloride (13.64 g, 0.15 mol) was added dropwise to the solution in 1.5 h. The resulting mixture was stirred for 0.5 h and then filtered. The filtrate was concentrated by removal of the solvent under vacuum and the residue was dissolved in 50 ml Na 2 CO 3 aqueous solution (10% w/v). Hydrochloric acid (6N) was then dropped in with vigorous stirring, until the pH reached 2.0. Finally, dichloromethane (3×50 ml) was added to the solution. The dichloromethane solution was then concentrated by removal of the solvent under vacuum. The crude product was recrystallized with ethyl acetate/hexane mixed solvent and yielded the 2,2-bis(acryloxymethyl)propionic acid as white crystals. 1 H NMR (CDCl 3 , 400 MHz) δ=11.47 (s, 1H); 5.7-6.8 (m, 6H), 4.4 (s, 4H), 1.38 (s, 3H).
[0020] Synthesis of PEG Macromonomer:
[0021] The reaction scheme for synthesizing the PEG macromonomer is illustrated in FIG. 2 . Poly(ethylene glycol) methy ether (Mn ca. 2000) (10.0 g, 0.005 mol) and 2,2-bis(acryloxymethyl)propionic acid (3.03 g, 0.0125 mmol), N,N-dicyclohexylcarbodiimide (DCC) (2.588 g, 0.0125 mol), 4-dimethylaminopyridine (0.152 g, 0.00125 mol) and a polymerization inhibitor were dissolved in 50 ml of dry dichioromethane and stirred at room temperature for 72 h. The mixture was then filtered and washed with a small volume of dichioromethane. The filtrate was precipitated in ether, and purified by reprecipitation to give the product as white powder.
[0022] Synthesis of Poly(ester)-graft-PEG:
[0023] The reaction scheme for synthesizing poly(ester)-graft-PEG is illustrated in FIG. 2 . 2,2-Bis(acryloxymethyl)propionic acid (0.242 g. 0.001 mol), PEG macromonomer (2.224 g, 0.001 mol) and piperazine (0.172 g. 0.002 mol) were dissolved in 20 ml of N,N-dimethylformamide and stirred at room temperature for 7 days. The molecular weight and polydispersity of the polymer were measured by GPC and calibrated with PEG standards.
[0024] Preparation of Nanogels:
[0025] The reaction scheme for synthesizing the nanogels is illustrated in FIG. 3 . Poly(β-aminoester)-graft-PEG and CDDP were dissolved in distilled water ([COOH]/[CDDP]=7.4) and stirred for a certain period of time at room temperature or heated at 70° C. for 10 minutes and then kept stirring at room temperature for 12 h. The size of the formed nanogels was evaluated by Nanosizer (Malvern Instruments).
[0026] Poly(ester)-graft-PEG Examples
[0027] The graft copolymers with PEG side chains (M n =2000) was prepared by direct condensation. The PEG chain density was controlled by the molar ratio of 2,2-bis(acryloxymethyl)propionic acid to the PEG macromonomer. The pendent carboxyl acid groups are used for the complexation with CDDP. Composition of the copolymer was measured with 1 HNMR by the ratio of the OCH 2 CH 2 signal intensity in PEG (3.60 ppm) and that of CH 3 − in 2,2-bis(acryloxymethyl)propionic acid (1.38 ppm). Polyester-graft-PEG with varied contents can be synthesized in a similar method.
TABLE 1 Poly(ester)-graft-PEG copolymers with different PEG chain lengths and PEG unit feed ratios Composition P2K-25 P2K-50 P5K-25 P5K-50 (mol %) feed NMR feed NMR feed NMR feed NMR mPEG 25 26.5 50 44.4 25 25.2 50 36.2 Carboxyl acid 75 73.5 50 55.6 75 74.8 50 63.8
[0028] Characterization of the CDDP-Induced Formation of Nanogels.
[0029] The PEG grafted polymer and CDDP reacted in distilled water. The carboxylic groups of the graft-copolymer complexed with CDDP, and thus the polymer was crosslinked to form the gel core, while the PEG chains formed the hydrophilic corona ( FIG. 3 ). The average size was 220-240 nm ( FIG. 4 ). Heating can decrease the size of the nanogel. When heated at 70° C. for ten minutes, the average size of the nanogels was reduced to 150-160 nm. The nanogels are negatively charged. The negatives and the PEG outer layer impart “stealth properties” to the nanogels suitable for in vivo drug delivery to cancerous tissues via the EPR effect. Particularly, the polymers alone showed no or little cytotoxicity.
[0030] The cisplatin-containing nanogels had low in vitro cytotoxicity to SKOV-3 ovarian cancer cells compared to free cisplatin. Similar phenomena were reported in the cisplatin-containing micelles and other water soluble cisplatin conjugates (Cabral et al. 2005; Nishiyama et al. 2003a; Nishiyama et al. 2003b; Nishiyama et al. 1999). However, the nanogels had similar in vivo anticancer activity to cisplatin tested in nude mice inoculated with SKOV-3 tumors. Grafting targeting groups to the nanogels is expected to further increase the anticancer activity.
[0031] In conclusion, the reaction of CDDP and PEG-grafted copolymer in distilled water led to the spontaneous formation of CDDP-incorporated micelles. The size of the micelles can be reduced by heating. These nanogels are useful for drug delivery.
[0032] The foregoing description and drawings comprise illustrative embodiments of the present inventions. The foregoing embodiments and the methods described herein may vary based on the ability, experience, and preference of those skilled in the art. Merely listing the steps of the method in a certain order does not constitute any limitation on the order of the steps of the method. The foregoing description and drawings merely explain and illustrate the invention, and the invention is not limited thereto, except insofar as the claims are so limited. Those skilled in the art who have the disclosure before them will be able to make modifications and variations therein without departing from the scope of the invention.
REFERENCES
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Nishiyama, N., Yokoyama, M., Aoyagi, T., Okano, T., Sakurai, Y., Kataoka, K., Langmuir, 15(1999), 377-383.
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Nishiyama, N., Okazaki, S., Cabral, H., Miyamoto, M., Kato, Y., Sugiyama, Y., Nishio, K., Matsumura, Y., Kataoka, K., Cancer Res., 63(2003), 8977-8983.
Pastan, I. and Gottesman, M. M. Multidrug resistance, Annu. Rev. Med. 42 (1991), 277-286.
Pinzani, V.; Bressolle, F.; Hang, L. J.; Galtier, M.; Blayac, J. P.; Balmes, P. Cisplatin-induced renal toxicity and toxicity-modulating strategies—a review, Cancer Chemother. Pharmacol. 35(1994), 1-9.
Rosenberg, B.; VanCamp, L.; Trosko, J. E.; Mansour, V. H. Platinum compounds: a new class of potent antitumor agents, Nature 222(1969), 385.
Scanlon, K. J.; Kashani-Sabet, M.; Tone, T.; Funato, T. Pharmacol. Therap. 52(1991), 385-406.
Takahara, P. M.; Rosenzweig, A. C.; Frederick, C. A.; Lippard, S. J. Crystal-structure of double-stranded DNA containing the major adduct of the anticancer drug cisplatin, Nature 377(1995), 649-652.
Von Hoff, D. D.; Schilsky, R.; Reichert, C. M.; Reddick, R. L.; Rozencweig, M.; Young, R. C.; Muggia, F. M. Toxic effects of cis-dichlorodiammineplatinum(II) in man, Cancer Treat. Reports 63(1979), 1527-1531. | A nano-sized hydrogel is made of a water-soluble chain containing carboxylic acid moieties and polyethylene side chains. Such a nanogel is applicable as a cancer-drug delivery agent or an imagining agent, where either a cancer drug, such as cisplatin, or an imaging agent, such as Gd3+. The complexation of the cancer drug or the imaging agent with the carboxyl moieties leads to the hydrogel formation. | 0 |
BACKGROUND OF THE PRESENT INVENTION
The present invention is novel compounds, which are derivatives of benzoic acid and benzoic acid ester--having antiinflammatory activity for the treatment of arthritis, asthma, Raynaud's disease, inflammatory bowel disorders, trigeminal or herpetic neuralgia, inflammatory eye disorders, psoriasis, and/or having analgesic activity for the treatment of dental pain and headache, particularly vascular headache, such as migraine, cluster, and mixed vascular syndromes, as well as nonvascular, tension headache. Thus, the present invention is also a pharmaceutical composition comprising the novel compounds together with a pharmaceutically acceptable carrier or methods of use of such compounds for treatment of the above noted conditions.
Among known compounds are benzoic acid derivations in which the derivative is limited to a substituent having a (naphthoxy)isobutyramido containing group and for which compounds an antiphlogistic activity is disclosed. See U.S. Pat. No. 4,183,954. Additionally O. Exner, et al. discloses N-(4-carboxybenzyl)acetamide in "Quantitative Evaluation of the Inductive Effect," Coll. Czech. Chem. Commun. 27, 2299 (1962). But no teaching to activity or utility for the compound is indicated by Exner, et al.
Compounds related to capsaicin are disclosed in a series of patents. The compounds are thus not benzoic acid derivatives but have various amido, sulfonylamido or amidosulfonyl and thioamido linkages in combination with a benzyl or a benzyl analog moiety. Such compounds are found in U.S. Pat. No. 4,313,958, that claims the use of capsaicin; U.S. Pat. No. 4,460,602; U.S. Pat. No. 4,401,663; European Patent Application No. 0,132,113; U.S. Pat. No. 4,424,203; European Patent Application No. 0,132,114; European Patent Application No. 0,132,346 and European Patent Application No. 0,132,115 as well as European Patent Application Nos. 0,149,554 and 0,149,545. Of these European Patent Applications Nos. 0,132,115; 0,132,346; 0,132,114; 0,132,115, 0,149,544 and 0,149,545 include a short chain acyl group on the benzyl moiety. U.S. Pat. No. 3,992,540 discloses 3-quinoline-carboxamides. Analgesia is disclosed as an activity for the compounds of the references. However, none of the references teach the compounds having the moieties such as benzoic acid moieties and their substituents, or particularly the combination of moieties, of the present invention.
DETAILED DESCRIPTION OF INVENTION
The novel compounds of the present invention have the following structural formula: ##STR1## wherein: (a) R 1 is tetrazolyl or COOR' wherein R' is H or lower alkyl of 1 to 4 carbons, inclusive;
(b) B is ##STR2## (c) X and Y are independently H or lower alkyl of 1 to 4 carbons, inclusive;
(d) R 2 is alkylene, alkenylene, alkynylene branched or linear chains of 1 to 11 carbons, inclusive;
(e) Q is CH 3 , COOH, Br, NH 2 , H, imidazolyl, cyclohexyl, ##STR3## and nontoxic, pharmaceutically acceptable base or acid addition salts thereof, with the proviso that when B is (B 1 ) and Q is H, then R 2 is not methylene.
The term "lower alkyl of 1 to 4 carbons" means a straight or branched hydrocarbon chain up to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl.
The terms alkylene, alkenylene and alkynylene are divalent hydrocarbon straight or branched chains containing one or more single, double or triple carbon to carbon bonds, respectively.
Preferred embodiments of the present invention contain COOH as shown in the following formula (II): ##STR4## wherein X, Y, B, R 2 and Q are all as defined above. More preferred embodiments of the present invention are compounds of formula II wherein B is B 1 and X, Y, R 2 and Q are as defined above. The most preferred embodiment of the present invention is the compund N-(4-carboxybenzyl)nonanamide. The preferred method of use is for treating headaches, particularly migraines.
Examples of suitable acids for the preparation of the acid solution salts are inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as acetic acid, benzoic acid, tartaric acid, fumaric acid, succinic acid, maleic acid, arginine acid, lactic acid, tartaric acid, and sulfonic acids such as methansulfonic acid, ethansulfonic acid, benzenesulfonic acid of p-toluenesulfonic acid.
The base salts of the present inventions include those safe for topical or systemic administration, such as sodium, potassium, calcium, magnesium, and ammonium salts or the like.
Generally, the preparation of the compounds of the present invention is represented by the following scheme: ##STR5## wherein R 1 , X, Y, B, R 2 Q are as defined above the Hal is chloro, bromo, or iodo, but preferably chloro.
The preparation uses standard synthetic techniques used in the examples or analogous to those used in the examples hereinafter. The starting materials for the preparation are readily available, known or can be prepared by known methods.
The compositions containing the compounds of the formula (I') ##STR6## wherein: (a) R 1 is tetrazolyl or COOR' wherein R' is H or lower alkyl of 1 to 4 carbons, inclusive;
(b) B is ##STR7## (c) X and Y are independently H or lower alkyl of 1 to 4 carbons, inclusive;
(d) R 2 is alkylene, alkenylene, alkynylene branched or linear chains of 1 to 11 carbons, inclusive;
(e) Q is CH 3 , COOH, Br, NH 2 , H, imidazolyl, cyclohexyl, ##STR8## and nontoxic, pharmaceutically acceptable base or acid addition salts thereof, are comprised of an analgesic or antiinflammatory effective amount of a compound of formula I' as defined above or their pharmaceutically acceptable base or acid addition salts and a pharmaceutically acceptable carrier. Such compositions may be one of a broad range of known forms for topical or systemic administration.
The methods of use are for the treatment in mammals, particularly in humans, of various conditions such as enumerated above either for diseases known as inflammatory or for pain. An ordinarily skilled physician would recognize such conditions. The compounds of formula I are active in animal tests which are generally recognized as predictive for antiinflammatory or analgesic activity. Regardless of the route of administration selected, the compounds of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to the pharmaceutical art. In general a preferred method of administration is, however, by oral dosage forms.
The compounds can be administered in such unit oral dosage forms as tablets, capsules, pills, powders, or granules. They may also be administered rectally or vaginally in such forms as suppositories or bougies. They may also be introduced parenterally, (e.g., subcutaneously, intravenously, or intramuscularly), using forms known to the pharmaceutical art.
An effective but nontoxic amount of the compound of formula I or the salts thereof is employed in treatment. The dosage regimen for treating inflammation or pain by the compounds of formula I and their salts as described above is selected in accordance with a variety of factors including the type, age, weight, sex, and medical condition of the subject, the severity of the inflammation or pain, the route of administration and the particular compound employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
Initial dosages of the compounds of the invention are ordinarily in the area of 1 mg/kg up to at least 100 mg/kg per dose orally, preferably 30 to 100 mg/kg orally are given. Each dose is given for one to four times daily or as needed. When other forms of administration are employed equivalent doses are administered.
An illustrative example of the activity for use as described above for the novel compounds of the present invention is an ED 50 of 33.03 mg/kg for the compound of Example 1 described in the following material when administered in a test based on that of Koster et al. [Fed. Proc., Vol. 18 (1959), p. 412] in which the peritoneal injection of acetic acid to mice provokes repeated stretching and twisting movements which persist for more than 6 hrs. Analgesics prevent or surpress these syndromes which are considered to be an exteriorization of a diffuse abdominal pain. A 1% solution of acetic acid in water is used at a dose of 0.01 ml/g or 100 mg/kg of acetic acid to release the syndrome.
The Example 1 compound is subcutaneously administered 30 minutes before the acetic acid injection and the mice are fasted 24 hrs before the start of the test. The stretching for the mice is observed and totaled for each mouse in a 15 minute observation period starting just after the acetic acid injection. The results are expressed as mg/kg which amount produces the desired inhibition of stretching or "writhing" in 50 percent of a population.
Additionally, the same Example 1 compound was effective at a dose of 100 mg/kg administered i.p. in reducing the inflammatory response to an injection of carrageenan into the rat foot pad. This is a commonly employed standard assay for the identification of antiinflammatory activity, based on the method described by Winter et al. (Proc. Soc. Exptl. Biol. N.Y. vol 111 (1962), p. 544).
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following Examples will further illustrate the invention, without limiting it thereto.
Examples
EXAMPLE 1
N-(4-Carboxybenzyl)nonanamide
Methyl 4-(aminomethyl)benzoate hydrochloride (6.0 g, 0.03 moles) is treated with 50 mL 1N NaOH and the mixture extracted with ether (3×50 mL). The combined ether extracts are dried with anhydrous potassium carbonate and evaporated to leave the amine base as a white solid. This residue is dissolved in 100 mL methylene chloride, to which is added 2.85 g pyridine. Nonanoyl chloride (6.36 g, 0.036 moles) in 10 mL methylene chloride is then added dropwise to the mixture with stirring over a 5 min period. The thick pasty mass which formed after a few minutes is stirred at room temperature for 45 min, at which time 30 mL saturated sodium bicarbonate is carefully added. The mixture is stirred vigorously for 15 min, after which the layers are separated and the organic layer extracted with 2N HCl (30 mL), and dried over anhydrous sodium sulfate. Evaporation of the solvent leaves a waxy residue which is crystallized from isopropyl ether as colorless plates, m.p. 94.5°- 95.5° C.
The crystalline product (2.0 g) is dissolved in tetrahydrofuran (30 mL) to which is added 1N NaOH (10 mL). The heterogeneous mixture is stirred overnight at room temperature. The resulting clear solution is made acidic by addition of 2N HCl, and the mixture partitioned between chloroform (250 mL) and water (200 mL). The chloroform layer is dried over sodium sulfate and evaporated to leave a waxy residue, which is crystallized as colorless needles from methanol/water. A yield of 1.36 g, of the desired product N-(4-carboxybenzyl)nonamide is obtained. M.p. 178°-179.5° C.
In a procedure analogous to that described in Example 1 above but using the appropriate acid chloride the following compounds are prepared.
EXAMPLE 2
N-(4-Carboxybenzyl)decanamide sodium salt, m.p. 250° C.
EXAMPLE 3
N-(4-Carboxybenzyl(heptanamide), m.p. 179°-180° C.
EXAMPLE 4
N-(4-Carboxybenzyl)octanamide, m.p. 180° C.
EXAMPLE 5
N-(4-Carboxybenzyl)phenylacetamide, m.p. 220°-221° C.
EXAMPLE 6
N-(4-Carboxybenzyl)-4-hydroxy-3-methoxycinnamamide, m.p. 233°-234° C.
EXAMPLE 7
N-(4-Carboxybenzyl)-4-phenylbutyramide
4-(Aminomethyl)benzoic acid (3.6 g) is suspended in methylene chloride (100 mL), to which 15 mL triethylamine is added. Chlorotrimethylsilane (10 mL) is then added and the mixture allowed to stir at room temperature for 1 hr. The mixture is then cooled in an ice bath and 4-phenylbutyryl chloride (5.3 g) in methylene chloride (10 mL) is added dropwise and the resulting mixture stirred for 30 min at 0° C., followed by an additional 3 hrs at ambient temperature. The mixture is treated with 75 mL 1N HCl, after which the organic layer is separated and extracted with 1N HCl. The precipitate which had formed is recovered by filtration and recrystallized two times from methanol/1N HCl to give pure N-(4-carboxybenzyl)-4-phenylbutyramide. M.p. 178°-179° C.
A procedure analogous to that described in Example 7 using the appropriate starting material produces the following compound:
EXAMPLE 8
N-(4-Carboxybenzyl)undecanamide, m.p. 179°-180° C.
EXAMPLE 9
N-(4-Carboxylbenzyl)-(2-naphthoxy)acetamide
(2-Naphthoxy)acetic acid (8.5 g) is suspended in 160 mL methylene chloride and treated with 1,1'-carbonyldiimidazole (6.8 g) which is added in small portions. After stirring for 3 hrs at room temperature under a nitrogen atmosphere, the mixture is added dropwise to a previously prepared solution of alpha-amino-p-toluic acid (1.4 g), chlorotrimethylsilane (10 mL), and triethylamine (11 mL) in 250 mL methylene chloride at 0° C. The final mixture is stirred at room temperature under a nitrogen atmosphere overnight. The mixture is combined with 200 mL 1N HCl and shaken, after which the resultant precipitate is collected by suction filtration. The precipitate is recrystallized from methanol/2N HCl, m.p. 188°-189° C. as N-(4-carboxybenzyl)-(2-naphthoxy)acetamide.
EXAMPLE 10
N-(4-Carboxybenzyl)cinnamide
1,1'-Carbonyldiimidazole (3.71 g) is added to an ice-cold stirred solution of cinnamic acid (3.13 g) in 30 mL tetrahydrofuran. After stirring for an additional 1 hr, methyl 4-(aminomethyl)benzoate hydrochloride (4.7 g) and triethylamine (3.23 mL) are added and the final mixture stirred while immersed in an ice water bath for an additional 30 min, followed by stirring overnight at room temperature. After removal of the solvent by rotary evaporation, the residue is taken up in chloroform (250 mL) and extracted with water (200 mL), 1N HCl (3×50 mL), water (100 mL), saturated sodium bicarbonate (100 mL), brine (100 mL) and the final chloroform layer dried over anhydrous magnesium sulfate. After evaporation of the solvent in vacuo, the crude product (2.74 g) is suspended in 100 mL tetrahydrofuran and 20 mL 2N NaOH and the mixture stirred at room temperature overnight. The mixture is then made acidic by addition of excess 1N HCl, and the precipitate recovered by filtration. After washing the filter cake with water and pressing to remove as much water as possible, the white solid is crystallized from methanol/2N HCl as N-(4-carboxybenzyl)cinnamide, m.p. 238°-239° C.
A procedure analogous to that described in Example 10 using an appropriate starting material produces the following compound:
EXAMPLE 11
N-(4-Carboxybenzyl)cyclohexylacetamide, m.p. 223°-224° C.
EXAMPLE 12
N-(4-Carboxybenzyl)butyramide
4-(Aminomethyl)benzoic acid (3.0 g) is suspended in pyridine (15 mL) and the mixture cooled in an ice water bath. Butyric anhydride (9.2 mL) is added dropwise to the stirred suspension over a 20 min period. The ice bath is removed and the mixture stirred at room temperature overnight. The mixture is poured into 150 mL ice water and made acidic (pH 1.5) by addition of concentrated HCl. The precipitate is recovered by suction filtration and recrystallized from ethyl acetate to produce N-(4-carboxybenzyl)butyramide, m.p. 186.5°-187.5° C.
EXAMPLE 13
N-(4-Carboxybenzyl)hexanamide
Hexanoic acid (3.06 g) in 20 mL acetonitrile is treated with N-methylmorpholine (2.9 mL) and the mixture cooled to -20° C. with stirring. Ethyl chloroformate (2.8 mL) is then added dropwise, keeping the temperature below or at -20° C. After stirring for an additional 40 min at that temperature, the solution is transferred to a cooled (-15° C.) solution of alpha-amino-p-toluic acid (2.0 g), triethylamine (15 mL), a chlorotrimethylsilane (5.0 mL) in methylene chloride (60 mL; prepared as described in Example 7). After the addition is complete, the mixture is stirred at 5° C. for 4 hrs, followed by overnight stirring at room temperature. After removal of the solvents by evaporation, the residue is redissolved in methylene chloride (100 mL) and extracted with 1N HCl (2×50 mL) and brine (2×50 mL). The organic layer is dried over magnesium sulfate and evaporated, leaving N-(4-carboxybenzyl)hexanamide as an off-white solid. The N-(4-carboxybenzyl)hexanamide product is crystallized from methanol/2N HCl, m.p. 178°-179° C.
EXAMPLE 14
N-1-(1-(4-Carboxyphenyl)ethyl)nonanamide
Step 1. 4-(1-aminoethyl)benzoic acid
4-Acetylbenzoic acid (4.1 g) is dissolved in 50 mL ammonia-saturated methanol. Raney nickel catalyst (1.5 g; activity grade III) is then added and the mixture reduced under hydrogen atmosphere (4750 psi) at 80° C. for 17 hrs. After removal of the catalyst by suction filtration, the filtrate is evaporated and the residue dissolved in H 2 O. The solution is passed through a 2.5×15 cm column of Dowex-50X8-400 resin (H + form) and eluted with 1N NH 4 OH. Evaporation of the eluate leaves a residue (2.9 g) which is recrystallized from H 2 O/acetone and characterized as 4-(1-aminoethyl)benzoic acid, m.p.>300° C.
Step 2. N-1-(1-(4-Carboxyphenyl)ethyl)nonanamide
The 4-(1-aminoethyl)benzoic acid as prepared above in Step 1 (1.5 g) is suspended in 30 mL methylene chloride containing 2.13 g pyridine and cooled to 0° C. Nonanoyl chloride (1.7 g) is dissolved in 5 mL methylene chloride and added dropwise with stirring to the cooled solution. After allowing the mixture to warm to room temperature, the mixture is allowed to stir an additional 2 hrs. Treatment with 1N HCl (40 mL) produces a solid residue at the interface of the two liquid phases, which is recovered by filtration and recrystallized from methanol/water as N-1-(1-(4-carboxyphenyl)ethyl)nonanamide, m.p. 178°-180° C.
EXAMPLE 15
N-(4-carboxybenzyl)-N-methylnonanamide
Step 1. 4-(methylaminomethyl)benzoic acid hydrochloride
4-Carboxybenzaldehyde (10 g) is dissolved in 50 mL aqueous methylamine (30%). Raney nickel (5 g) is added and the mixture treated with hydrogen at 1500 psi and 100° C. for 17 hrs. Removal of the catalyst by suction filtration and evaporation of the filtrate left a solid residue, which is redissolved in 2N HCl (50 mL). The solution is extracted with ethyl acetate (50 mL) and chloroform (50 mL) and the resultant aqueous layer evaporated to dryness. The residue is vacuum dried at 60° C. for 4 hrs and recrystallized from methanol/ethyl acetate to yield 7.65 g 4-(methylaminomethyl)benzoic acid hydrochloride, m.p. 225°-261° C.
Step 2. N-(4-Carboxybenzyl-N-methylnonamide)
The 4-(methylaminomethyl)benzoic acid hydrochloride prepared in Step 1 above (2.0 g) is suspended in 5 mL pyridine and cooled in ice water. Nonanoyl chloride (1.8 g) is added dropwise with stirring, and the final solution allowed to stir at room temperature for 18 hrs. The clear solution is treated with 2N HCl (15 mL), and partitioned between chloroform and water (50 mL each). The aqueous layer is again extracted with chloroform (25 mL) and the combined organic layers dried (Na 2 SO 4 ) and evaporated to leave a clear viscous oil which solidifies on standing. The solid is crystallized from ethyl acetate/hexanes as N-(4-carboxybenzyl)-N-methylnonanamide, m.p. 79.5°-81° C.
EXAMPLE 16
N-((4-(1-Tetrazol-5-yl)phenyl)methyl)nonanamide
To a solution of 4-(aminomethyl)benzonitrile (5.0 g, 0.038 moles) in 100 mL chloroform is added 3.82 g (0.038 moles) triethylamine. A solution of nonanoyl chloride (6.68 g, 0.038 moles) in 10 mL chloroform is then added dropwise with stirring over a 10 min period and the final mixture stirred at room temperature for 18 hrs. The mixture is extracted with water (100 mL), saturated NaHCO 3 (50 mL), 2N HCl (50 mL), dried over Na 2 SO 4 and evaporated to leave 10.2 g crude N-(4-cyanobenzyl)nonanamide. This crude product is taken up in 50 mL dimethylformamide, to which is added 2.47 g (0.038 moles) sodium azide and 2.03 g (0.038 moles) ammonium chloride. The final mixture is heated at 90°-110° C. for 4 hrs. after cooling, the mixture is diluted with water (350 mL) and the resultant precipitate recovered by suction filtration, washed with water, and vacuum dried. Recrystallization from ethyl acetate left N-[[4-(1H-tetrazol-5-yl)phenyl]methyl]nonanamide (2.6 g), m.p. 185°-187° C. | Novel benzoic acid or benzoic acid ester derivatives, pharmaceutical compositions and methods of use thereof are the present invention. Utility is for the treatment of arthritis, asthma, Raynaud's disease, inflammatory bowel disorders, trigeminal or herpetic neuralgia, inflammatory eye disorders, psoriasis, dental pain, and headaches, particularly vascular headache, such as migraine, cluster, mixed vascular syndromes, as well as nonvascular, tension headaches. | 2 |
CROSS REFERENCES TO RELATED APPLICATIONS
The present application claims priority to U.S. Provisional Patent Application No. 60/710,308, filed Aug. 22, 2005.
This invention was made in the performance of a Cooperative Research and Development Agreement with the Department of the Air Force. The Government of the United States has certain rights to use the invention.
FIELD OF THE INVENTION
The present invention relates to nanocomposites formed from the combination of repeat sequence protein polymers and layered silicates. The invention also provides for methods for the synthesis of such nanocomposite materials.
BACKGROUND OF THE INVENTION
The combination of polymers and inorganic filler materials is known for the production of nanocomposite materials with improved mechanical, thermal and barrier properties as compared to the unmodified polymer. A detailed discussion of nanocomposites can be found in Ajayan, P. M., Nanocomposite Science and Technology (Wiley, 2003).
The combination of polymers with layered silicates, also known as smectite clays or phyllosilicates, has been exploited as a means for the synthesis of nanocomposites. Comprehensive reviews on the subject are Alexandre and Dubois (2001) and Pinnavaia, T. J.; Beall, G. W. Polymer Clay Nanocomposites Wiley New York, 2000. Smectite clays are described in Grim, R. E. Clay Mineralology 2 nd edition; McGraw-Hill: New York 1968.
Several methods for the synthesis of polymer clay nanocomposites have been described in the art, for example Nylon/clay composites first described by Usuki et al. (1993). A. Usuki, et al., “Synthesis of nylon 6-clay hybrid”, J. Mater. Res., vol. 8, No. 5, May 1993, pp. 1179-1184. In this process nylon and montmorillonite are combined at high temperature to give an exfoliated nanocomposite with improved material properties relative to the polymer alone.
A biodegradable thermoplastic material comprising a natural polymer, a plasticizer and an exfoliated clay having a layered structure and a cation exchange capacity of from 30-350 milliequivalents per 100 grams is described in U.S. Pat. No. 6,811,599 B2. The natural polymer is a polysaccharide.
A smectite clay modified with an organic chemical composition and a polymer is described in U.S. Pat. No. 6,521,690.
Nanocomposites formed from phyllosilicates and the synthetic homopolymer poly-L-lysine have been described. (Krikorian, V. et al. J. Polym. Sci. B: Polym. Phys. 2002, 40, 2579). Soy protein isolate has also been incorporated into nanocomposites containing sodium montmorillonite clay (Chen, P. and Zhang, L. Biomacromolecules, 2006, 7, 1700).
Proteins make up the main structural elements of most organisms, using complex sequences of amino acids that lead to wide arrays of functionalities. One of the most intensely studied structural proteins, Bombyx mori silkworm silk, has generated significant interest because of its remarkable mechanical properties, which rival even spider silk. Elastin, another well-known structural protein, is found predominantly in the body's arterial walls, the lungs, intestines, and skin. Silk elastin like protein (SELP) is a recombinant protein consisting of alternating blocks of silk-like and elastin-like amino acids. The mechanical properties of recombinant proteins like SELP are often inferior to structural proteins found in nature.
The use of recombinant proteins in in-vivo applications and in applications outside of the body may demand improvements and alterations in a wide variety of properties, including high temperature mechanical behavior.
SUMMARY OF THE INVENTION
The invention is directed to compositions comprising nanocomposites of a phyllosilicate and one or more repeat sequence protein polymers. In one embodiment of the invention, the phyllosilicate is Na + Montmorillonite (MMT), a smectite clay and the repeat sequence protein polymer is a co-polymer comprising sequences derived from silk and elastin termed SELP. In yet another embodiment of the invention the repeat sequence protein polymer is a chemically modified SELP analogue whereby the protein is reacted with succinic anhydride. In another embodiment of the invention the phyllosilicate is attapulgite. In yet another embodiment of the invention, an additive, for example, a plasticizer, or a protein cross linking agent, or a plasticizer and a cross linking agent is added to the phyllosilicate and the repeat sequence protein polymer.
The compositions of the present invention are nanocomposites that demonstrate material property alterations and/or enhancements relative to the RSPP alone.
The nanocomposites are dispersions of phyllosilicate sheets within a protein matrix. The dispersion, or exfoliation, is achieved by interactions between the positively charged lysine residues of the protein and the negatively charged phyllosilicate sheets, in addition to other polar functionalities within the protein structure.
Without wishing to be bound by any particular theory, it is believed that the electrostatic character of the protein dominates long-range particle-particle interactions, and that the hydrogen bonding character of the protein dominates local interactions between the protein and the phyllosilicate material. Specifically, cationic charged proteins result in an exfoliated morphology, while the presence of anionic protein residues affects the morphology of the nanocomposite by generating repulsive interactions with MMT sheets that may result in a weak clustering or agglomeration of MMT in solution that manifests as at least some non-uniformity in the solid state.
The nanocomposites of the present invention may be tailored to have altered and/or improved elasticity as shown by elastic modulus values that are at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, and at least 90% greater than the elastic modulus values of the RSPP alone. The nanocomposites also may be designed to have altered tensile properties, altered morphology, altered zeta potential, and or altered coefficient of thermal expansion.
The protein-based nanocomposite of repeat sequence protein polymer and phyllosilicate produces a repeat sequence protein polymer with mechanical properties suitable for use of the composite as suture material, as a tissue scaffold, artificial tissue, or biodegradable structural material, including industrial materials.
The nanocomposites of the present invention may also retain variable percentages of the water, or other solvents used to make the nanocomposites as well as other additives selected to tailor properties of the nanocomposites.
This invention also describes methods for the formation of nanocomposites consisting of a phyllosilicate and a repeat sequence protein polymers. The method comprises suspending a phyllosilicate in deionized water or buffered water, with or without an additional solvent; and adding a repeat sequence protein polymer to the phyllosilicate suspension with mixing and/or sonication. The resulting mixture may be cast into a vessel and allowed to dry.
The amount of SELP material added to the phyllosilicate suspension may be selected to provide a nanocomposite with desired material properties. For example, a nanocomposite with desired elastic modulus values, or tensile strength values, may be made by varying the amount of SELP in the composite.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph showing X-ray scattering curves for nanocomposites of the present invention.
FIG. 2 is low and high magnification transmission electron microscopy (TEM) images of nanocomposites of the present invention.
FIGS. 3A and 3B are, respectively, graphs showing the elastic modulus and the coefficient of thermal expansion (CTE) of nanocomposites of the present invention.
FIG. 4 is a graph showing the zeta potential for aqueous suspensions of a phyllosilicate having increasing concentrations of repeat sequence protein polymer.
FIG. 5 is low and high magnification TEM images of nanocomposites of the present invention.
FIG. 6 is a graph showing stress-strain curves for nanocomposites of the present invention, with a table listing the elastic modulus (GPa) and percent elongation to break (%) calculated from the curves.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to compositions that are nanocomposites of a phyllosilicate material and one or more repeat sequence protein polymers. In one embodiment of the invention, the phyllosilicate material is a smectite clay, for example, montmorillonite (MMT) clay, and the repeat sequence protein polymer is a co-polymer having sequences derived from silk and elastin, termed SELP. In yet another embodiment of the invention the repeat sequence protein polymer is a chemically modified SELP analogue whereby the protein is reacted with succinic anhydride.
The nanocomposites of the present invention are highly exfoliated materials produced under controlled conditions. The invention further includes methods for the formation of nanocomposites of a phyllosilicate and a repeat sequence protein polymer. The method suspends a phyllosilicate clay in water with or without a solvent; adds a repeat sequence protein polymer to the phyllosilicate suspension with mixing and/or sonication. The resulting mixture may be cast into a vessel and dried, retaining varying amounts of water or other solvent. Additives may be used and added to select properties of the nanocomposites.
DEFINITIONS
For purposes of this invention, the following definitions shall apply:
“Elastic modulus”, or modulus of elasticity means a measurement that expresses the ability of a material to return to its original dimension after the removal of stresses, calculated by the formula E=S/δ, where S is the unit stress and δ is the unit strain. The nanocomposites of the present invention have an elastic modulus that is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, and at least 90% greater than the elastic modulus of the RSPP without the addition of the phyllosilicate material.
An “Exfoliated nanocomposite” means a composite morphology where the layers of the phyllosilicate component are dispersed or displaced from the generally intercalated layered structure found in the starting phyllosilicate material. A “highly exfoliated nanocomposite” exhibits a morphology that is generally homogeneous because substantial layer dispersion has occurred so that the composite cannot be shown to have distinct phyllosilicate and RSPP phases.
Without wishing to be bound by any particular theory, it is believed that the electrostatic character of the protein dominates long-range particle-particle interactions, and that the hydrogen bonding character of the protein dominates local interactions between the protein and the phyllosilicate material. Specifically, cationic charged proteins result in an exfoliated morphology, while the presence of anionic protein residues affects the morphology of the nanocomposite by generating repulsive interactions with MMT sheets that may result in a weak clustering or agglomeration of MMT in solution that manifests as at least some non-uniformity in the solid state.
“Material properties” means tensile strength, elastic modulus, morphology, and altered and/or improved thermal properties.
The nanocomposites of the present invention demonstrate an alteration and/or improvement, when compared to repeat sequence protein polymers alone, of one or more material properties.
A “nanocomposite” means a composite composed of two or more physically distinct materials in close contact, where at least one of the two or more phases exhibits at least one dimension that is in the nanometer size range (i.e. smaller than 100 nanometers). The close contact between phases in a nanocomposite underlies the unique properties of this class of materials relative to conventional composite materials. Ajayan, P. M., Nanocomposite Science and Technology (Wiley, 2003).
“Tensile Strength” as applied to a composite film means the maximum stress which can be applied in a tension test prior to breakage (failure) of the film. Tensile strength is expressed in Pascals (MPa) or pounds per square inch (psi).
“Percent elongation-to-break”, sometimes referred to as strain to break, is the strain on a material when it breaks and is expressed as a percent. Tensile properties includes tensile strength and percent elongation-to-break.
“Zeta potential” means the electrical potential that is generated by the accumulation of ions at the surface of a colloidal particle.
Repeat Sequence Protein Polymers
The repeat sequence protein polymer (RSPP) can be any modified polypeptide with at least one distinct domain repeated throughout the entire sequence two or more times.
The at least two distinct repeating domains of the RSPPs suitable for the present invention may be derived from a natural, chemically synthesized and/or modified, recombinant protein, or mixtures thereof. For example, the repeating sequence units may be derived from modifying a natural structure supporting materials such as silk, elastin, and collagen. Alternatively, the repeating sequence units may be derived from synthetic structures.
One skilled in the art will appreciate the various naturally occurring proteins containing repeating sequence units, which can be modified and used for designing and producing the repeat sequence protein polymers of the present invention, any of which may be employed herein. Specifically, there are more than six hundred repeating amino acid sequence units known to exist in biological systems. The natural OR synthetic protein repeating amino acid sequence units are derived by making modifications to elastin, collagen, abductin, byssus, extensin, flagelliform silk, dragline silk, gluten high molecular weight subunit, titin, fibronectin, leminin, gliadin, glue polypolypeptide, ice nucleating protein, keratin mucin, RNA polymerase II, resilin or a mixture thereof.
RSPP repeating sequence units for the natural or synthetic materials listed above are described and the amino acid sequences are shown in WO 04080426A1, which is incorporated herein in its entirety.
The repeat sequence protein polymer (RSPP) formula comprises:
T y [(A n ) x (B) b (A′ n ′) x ′(B′) b′ (A″ n ″) x ″] i T′ y ′
wherein: T and T′ each comprise an amino acid sequence of from about 1 to about 100 amino acids, wherein the amino acid sequence of T′ is the same as or different from the amino acid sequence of T; y and y′ are each an integer from 0 to 1, wherein the integer of y′ is the same as or different from the integer of y; A, A′ and A″ are each individual repeating amino acid sequence units comprising from about 3 to about 30 amino acids, wherein the amino acid sequence of A′ and the amino acid sequence of A″ are the same as or different from the amino acid sequence of A; n, n′, and n″ are each integers of at least 2 and not more than 250; x, x′ and x″ are each 0 or an integer of at least 1, wherein each integer varies to provide for at least 30 amino acids in the A′, A′ and A″ individual amino acid sequence repeating units, and wherein the integer of x′ and the integer of x″ are the same as or different from the integer of x and x, x′, and x″ cannot all be zero; B and B′ each comprise an amino acid sequence of from about 4 to about 50 amino acids, wherein the amino sequence of B′ is the same as or different from the amino acid sequence of B; b and b′ are each an integer from 0 to 3, wherein the integer of b′ is the same as or different from the integer of b; and i is an integer from 1 to 500.
The repeating amino acid sequence units may comprise identical repeating sequence units or may comprise different repeating sequence unit combinations, which join together to form a block copolymer or an alternating block copolymer. Additionally, the individual repeating amino acid sequence units of the repeat sequence protein polymer comprise from about 3 to about 30 amino acids or from about 3 to about 8 amino acids. Moreover, the same amino acid may appear at least twice in the same repeating sequence unit.
It will be further understood by those having skill in the art that the repeat sequence protein polymers of the present invention may be monodispersed or polydispersed. For purposes of defining and describing the present invention, “monodispersed” polymers are polymers having a single defined molecular weight. For purposes of defining and describing the present invention, “polydispersed” polymers are polymers that have been subjected to proteolysis or other means of subdivision, or were produced or modified in such a manner as to give rise to a distribution of molecular weights.
In one embodiment, the copolymers are combinations of silk units and elastin units to provide silk-elastin copolymers having properties distinctive from polymers having only the same monomeric unit.
A silk-elastin polymer, SELP47K, may be used as the repeat sequence protein polymer of the present invention. The SELP47K is a homoblock protein polymer that consists exclusively of silk-like crystalline blocks and elastin-like flexible blocks. SELP47K is a modified material of 70% proline, valine, and alanine, and has hydrophobic characteristics. The repeat sequence protein polymer may also comprise SELP 47-E13, SELP 47R-3, SELP 47K-3, SELP 47 E-3, SELP 67K, and SELP 58.
In one embodiment of the invention, the structure of the silk elastin-like protein is Head-(S 2 E 3 E K E 4 S 2 ) 13 -Tail (SEQ ID NO:6), where S is the silk-like sequence of amino acids GAGAGS (SEQ ID NO:1), E is the elastin-like sequence GVGVP (SEQ ID NO:2), and E K is the elastin like sequence modified with a lysine residue GKGVP (SEQ ID NO:3). The head sequence of amino acids is MDPVVLQRRD WENPGVTQLN RLAAHPPFAS DPM (SEQ ID NO:4) and the tail sequence is GAGAM DPGRYQDLRS HHHHHH (SEQ ID NO:5). The copolymer contains 886 amino acids, with 832 amino acids in the repeating sequence unit. The SELP47K has a molecular weight of about 70,000 Daltons, and a pI of 10.5. The properties of other SELP variants are shown below in Table 1.
TABLE 1
SELP variants, properties.
Number of
Lysine
Molecular
Isoelectric
SEQ ID
Variant Name
Subunits
Substitution
Weight (Da)
Point
NO
SELP47E
13
Glutamic
70,212
4.16
7
Acid
SELP47K-3
3
none
20,748
9.52
8
SELP47R-3
3
Arginine
20,960
10.5
9
SELP47E-3
3
Glutamic
20,879
5.9
10
Acid
SELP27K
13
none
59,401
10.53
SELP37K
13
none
64,605
10.53
SELP58
13
none
74,765
6.7
11
SELP67K
13
none
80,347
10.53
12
One skilled in the art will appreciate the various methods for producing the repeat sequence protein polymers of the present invention, any of which may be employed herein. For example, the repeat sequence protein polymer may be produced by generally recognized methods of chemical synthesis, for example, L Andersson et. al., Large - scale synthesis of peptides , Biopolymers 55(3), 227-50 (2000)); genetic manipulation (for example, J. Cappello, Genetically Engineered Protein Polymers, Handbook of Biodegradable Polymers, Domb, A. J.; Kost, J.; Wiseman, D. (Eds.), Harvard Academic Publishers, Amsterdam; pages 387-414); and enzymatic synthesis (for example, C. H. Wong & K. T. Wang, New Developments in Enzymatic Peptide Synthesis , Experientia 47 (11-12), 1123-9 (1991)). For example, the repeat sequence protein polymers of the present invention may be produced using the methods described in U.S. Pat. Nos. 5,243,038; 6,355,776; and WO 07080426A1 the disclosures of which are incorporated by reference herein. In another example, the repeat sequence protein polymers may be produced utilizing non-ribosomal peptide synthase (for example, H. V. Dohren, et al., Multifunctional Peptide Synthase, Chem. Rev. 97, 2675-2705 (1997).
The E. coli strains containing a specific silk-elastin repeat sequence protein copolymer SELP47K, SELP37K and SELP27K recombinant DNA were also obtained from Protein Polymer Technologies, Inc. of San Diego, Calif. SELP67K, SELP58, SELP37K and SELP27K variant proteins were produced in 14 L fed batch culture using standard SELP47K production protocols, as described above. Proteins were purified and characterized as follows: 40 grams of cell pastes collected from 14 L cultures were lysed via French-press followed by the addition of polyethyleneimine (0.8 w/v %). Centrifugation was used to separate the cellular debris from the cell extract. SELP polymers were precipitated from the cell extract using ammonium sulfate (30% saturation), collected by centrifugation and reconstituted in water.
The protocol used for the genetic engineering of variants SELP47E, SELP47K-3, SELP47R-3, and SELP47E-3 is a modification of a commercially available kit designed to create single base pair changes in multiple sites along a particular DNA sequence (QUIKCHANGE® Multi (Site-Directed Mutagenesis Kit), Stratagene cat #200513). The standard protocol involves the construction of single direction 5′ phosphorylated primers that will hybridize to plasmid template regions of interest and incorporate point mutations. Thermocycling is employed that includes a ligation reaction designed to link the multiple primers during each round of synthesis.
Phyllosilicates
The layered silicate materials suitable for the present invention are phyllosilicates, frequently referred to as smectite clays. Phyllosilicates have a multiple layer structure with the layers having a thickness of between about 3 Angstroms to about 10 Angstroms. Each two-dimensional layer is made up of two silica tetrahedra sheets arranged on either side of an octahedral alumina sheet. The multiple layers are separated by cations. A number of phyllosilicates have a cation exchange capacity of between 20 and 250 mEq per 100 g.
The layered phyllosilicates are swellable clays in that they expand when exposed to liquids such as water, or other solvents with the ability to act as hydrogen bond acceptors and/or donors, thereby increasing the space between the layers. Examples include, but are not limited to montmorillonite, bentonite, hectorite, saponite, beidellite, attapulgite, and stevensite.
In one embodiment, the phyllosilicate is sodium montmorillonite, or its ion exchanged form, which may be obtained in the sodium form by utilizing naturally occurring clay. Sodium montmorillonite consists of negatively charged, 1 nm thick aluminosilicate layers with exchangeable sodium cations on the surface. The sheets are approximately 100 nm in diameter. In another embodiment of the present invention, the phyllosilicate is attapulgite.
Those skilled in the art will recognize that phyllosilicate clays that have been processed to remove non-clay materials can be converted to the sodium form if desired by either running a clay slurry through a cation exchange resin; or, by forming a mixture of clay, water and a water-soluble sodium compound and subjecting the mixture to shear.
The concentration by weight of phyllosilicate used in the present nanocomposite invention is about 0.1 to about 9-9%, about 0.1 to about 50%, about 1% to about 20%, about 1% to about 10%, and about 4% to about 6%.
The nanocomposites may retain variable amounts of the water or other solvents used to make the composites. For instance, the nanocomposites may retain from about 0.1% to about 90%, about 1% to about 50%, about 1% to about 25%, about 1% to about 15%, about 1% to about 10%, about 5% to about 20%, and about 5% to about 10% of water or other solvents.
The nanocomposites may include additives to tailor and vary properties. For instance, additives may be salts, onium ions, plasticizers, anti-microbials, reinforcing agents, protein cross linking agents, growth factors, preservatives, nanoparticles, nanofibres, chaotropic agents and electrolytes.
Plasticizers decrease the glass transition temperature of nanocomposite films and improve film flexibility, particularly at room temperature. The concentration of such plasticizers is from about 2 wt % to about 10 wt % of the total solids in suspension. Suitable plasticizers include polyethylene glycol (PEG) and a mono-, poly-, or di-saccharide, for example, trehalose. Common families of molecules that may also be used to plasticize nanocomposite films include adipic acid derivatives, azeic acid derivatives, benzoic acid derivatives, diphenyl derivatives, citric acid derivatives, epoxides, glycolates, isophthalic acid derivatives, maleic acid derivatives, phosphoric acid derivatives, phthalic acid derivatives, polyesters, trimelitates, etc. Specifically, water soluble plasticizers can be used such as citrate esters, triethyl citrate, triacetin, diethyl phthalate, glycerol, polyalkylene glycols such as polyethylene glycol, trehalose, polysaccharaides, polysuccinimide and poly aspartate.
Protein crosslinkers such as glutaraldehyde can be used to stabilize the films from solvent attack, as well as increase the effective molecular weight. Concentrations of approximately 0.6% to approximately 4% are typically used for glutaraldehyde crosslinking. Other homofunctional and heterobifunctional protein crosslinkers that react primarily with protein amines, sulfhydryls and carboxyl groups may be used. Homobifunctional protein crosslinkers that react with sulfhyhryl groups include 1,4-bis[3-(2-pyridyldithio)propionamido]butane (DPDPB), bis[2-(N-succinimidyl-oxycarbonyloxy)ethyl]sulfone(BSOCOES), ethylene glycol disuccinate di(N-succinimidyl)ester (EGS). Dimethyl 3,3′-dithiopropionimidate dihydrochloride is a homobifunctional reagent which typically reacts with primary amines to form amidine bonds. Bis[2-(4-azidosalicylamido)ethyl]disulfide (BASED) is a photoactive crosslinker with amine reactivity. Sebacic acid bis(N-succinimidyl)ester (DSS) is a homobifunctional crosslinker with amine reactivity. Sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate) (SulfoSMCC) is a heterobifunctional crosslinker that interacts with amine and sulfhydryl groups. Dithiobis(succinimidylpropionate) (DSP) is homobifunctional and reactive towards amino groups. Spacer arms can be used in these molecules if the distance between reactive groups in the protein is unknown. Intermediate crosslinkers such as ethyl-3-(dimethylaminopropyl)carbodiimide (EDC) can also be used to modify reactive groups for later crosslinking or functionalization.
The following examples are included to illustrate embodiments of the invention and are not intended to be limiting thereof.
EXAMPLES
Example 1
Production of Silk-Elastin Like Protein (SELP)
Monodispersed silk-elastin protein polymer SELP47K was produced by fermenting a recombinant E. coli strain to produce a cell-paste containing monodispersed SELP47K as described in US2004/0180027A1. The cell-paste is placed in ice cold water and homogenized to make the cell extract. The cell-extract is mixed with polyethyleneimine and a filter-aid and allowed to sit at 7° C. for one hour. The polyethyeleneimine causes precipitation of cell debris and a significant amount of E. coli proteins. The SELP47K containing reaction mixture is then filtered using a Rotary Drum Vacuum Filter (RVDF). The filtered SELP47K solution is then mixed with ammonium sulfate to 25% saturation, which leads to precipitation of SELP47K. Precipitated SELP47K and mother liquor is mixed with a filter-aid and again filtered using RVDF. The RVDF cake containing SELP47K and filter-aid is mixed with cold water to dissolve the SELP47K. This precipitation and solubilization step is repeated to improve the purity profile of the SELP47K. Purified monodispersed SELP47K is then water-exchanged until the conductivity of SELP solution reached 50 μS/cm 2 . The monodispersed SELP solution was then concentrated to 10% wt/vol and then lyophilized to make powdered monodispersed SELP47K protein polymer. The material was stored at −70° C. until needed for application testing.
Example 2
Preparation of Succinylated SELP
Succinylated SELP was prepared from a solution of SELP (0.7 g) in 25% aqueous acetonitrile (10 mL) that was treated with succinic anhydride (152 mg) at room temperature. Sodium hydroxide solution (3M) was added dropwise in order to maintain the pH between 7 and 8 during the course of the reaction. After 3 hours an aliquot was found to be unreactive towards ninhydrin indicating the derivatization of the available amino functionalites. The sample was dialyzed against water (3×2 L) overnight and then freeze dried to give a spongy white solid (0.62 g).
Example 3
Preparation of the RSPP/Phyllosilicate Solutions and Films
Cloisite® Na+ Montmorillonite (MMT) phyllosilicate in powder form (Southern Clay, cation exchange capacity [CEC] 92 meq/100 g) was added to deionized water to form 0.1-1.0 wt % suspensions. The water/MMT suspensions were then sonicated using a probe sonicator for approximately 10 minutes. For zeta potential measurements, SELP in powder form was slowly added to the MMT suspensions. For preparation of thin films, SELP was dissolved in deionized water to form a 5 wt % solution, and was added to the MMT suspension. The mixtures were then cast into polystyrene weighing dishes and dried for several days. The resulting films were freestanding, optically clear, approximately 5 cm in diameter, and the total amount of solid in each film was approximately 100 mg. The final amounts of MMT in the nanocomposite material were 0%, 2%, 4%, 6%, 8% and 10% on a dry weight basis.
Nanocomposites using the phyllosilicate attapulgite in powder form were also prepared by adding the attapulgite to deionized water and then mixing the suspension with SELP. Films were prepared as described above.
Example 4
Methods for Characterizing Material Properties of the Nanocomposite
Zeta Potential
Zeta potential measurements of the nanocomposite liquid solvent mixtures were performed on a ZetaPALS instrument (Brookhaven Instruments Corp., NY) at room temperature. At each MMT concentration, the average value was taken from 10 measurements. 0.01 wt % and 0.1 wt % MMT in water suspensions were stirred overnight, and then allowed to settle for several days. Samples for zeta potential measurements were then taken from the supernatant of the settled suspensions. SELP or succinylated SELP powder was added to the suspensions in various amounts. The zeta potential results were generally similar for both the 0.01 and 0.1 wt % suspensions at the same relative concentrations.
X-Ray Diffraction Profiles
Small angle x-ray scattering profiles were collected at beamline X27C of a National Synchrotron Light Source instrument with an evacuated beam path, a camera length of 1870 mm, an x-ray wavelength of 0.1366 nm, and a Mar-CCD (Charge coupled device) large area detector (Mar USA, Evanston, Ill.). Wide angle scattering was done using a Rigaku™ rotating anode operating at 50 kV with a Statton camera (camera length 73 mm), imaging plates held under vacuum, and an x-ray wavelength of 0.15418 nm. Two-dimensional patterns were analyzed using the Fit2D software (A. Hammersley, European Synchrotron Radiation Facility).
Transmission Electron Microscopy (TEM)
Transmission electron microscopy was performed on a Philips™ CM200-FEG instrument operating at 200 kV. Films were cut into ˜25 mm 2 size sections, embedded in Spurr (Electron Microscopy Sciences, Hatfield, Pa.) epoxy and cured at room temperature overnight. Cross sectional microtomy was done in on a RMC PowerTome™ with a diamond knife at room temperature. Section thickness was 100-150 nm.
Tensile Tests
Films were cut into strips approximately 5×35 mm for tensile strength testing. Five tests were run on each sample concentration. The slope of the stress-strain curve at 0.25% strain was used to calculate the elastic modulus. The percentage elongation to break, or strain to break was also measured as a percentage value.
Thermal Mechanical Analysis
In thermal mechanical analysis, the coefficient of thermal expansion (CTE) was measured as the slope of the sample's length at constant stress vs. temperature curve, divided by the original length of the sample. This slope was measured over a 2° C. temperature span in the rubbery regime (>200° C.)
Example 5
Material Properties of the Nanocomposites
X-Ray Diffraction
FIG. 1 b shows scattering curves in the small-angle and wide-angle regimes. There was no interlayer spacing near 1.2 nm, as is seen in the MMT powder control. Peaks arising from the interatomic (intra-sheet) MMT spacings as well as the broad peaks from the SELP can be seen at scattering vector (q) values greater than 1 nm −1 . In the small angle regime (q<1 nm −1 ) there is a very uniform scattering profile with no evidence for peaks at these larger length scales.
The results indicate that there is no intermediate structure, where the protein chains are intercalated between the MMT sheets in an ordered fashion. The WAXS regime (q>1 nm −1 ) shows that the SELP is not crystalline, as shown be the absence of the characteristic silk I peak at d=0.72 nm as well as the lack of any clear silk II β-sheet peaks.
TEM
FIG. 2 shows TEM micrographs from 150 nm thick cross-sections of 2%, 4% and 8% MMT in SELP nanocomposite samples. The high magnification micrographs (2b, d, f) show that the MMT is dispersed well in the SELP matrix, with the individual, 1 nm thick, MMT sheets visible. The density of MMT also appears to be quite uniform across the films from top to bottom, and along their length for several hundreds of microns ( FIGS. 2 a, c, e ).
The TEM and X-ray diffraction data both support the findings of a highly exfoliated structure.
Tensile Properties
Film tensile tests showed an elastic modulus for the SELP alone control films of 2 GPa ( FIG. 3 a ) and tensile strengths greater than 50 Mpa (Data not shown). As MMT concentration increased, an increase in the elastic modulus to nearly 3 GPa was seen up to loadings of 4-6%. At MMT loadings above 4-6%, the modulus dropped. While the modulus of the films was increased at 4% MMT, the films were found to be more brittle, with the percent elongation to break, or strain to break, decreasing from 0.044 (4.4%) at 0% MMT to 0.012 (1.2%) at 4% MMT.
Differential Scanning Calorimetry
Differential Scanning Calorimetry (DSC) showed no significant shift in the SELP glass transition with the addition of MMT. The T g remained near 180° C. regardless of the amount of MMT present, and this value is similar to the T g measured from dry films and fibers of silk and elastin.
Thermal Properties
Thermal mechanical analysis (TMA) was used to determine the coefficient of thermal expansion (CTE) in the rubbery region (>200° C.). The CTE showed a decrease with increasing amounts of MMT from 94×10 −3 ° C. −1 in the SELP only control to as low as 49×10 −3 ° C. −1 at 8% MMT loading ( FIG. 3 b ). While DSC showed no evidence for a T g shift, the temperature at which the samples transitioned from glassy to rubbery behavior, as measured from the intersection of the slopes of the sample length vs. temperature curves in the glassy and rubbery regions, was seen to increase significantly with increasing MMT concentration. This temperature increased from 193° C. in the SELP to 213° C. in the 10% MMT/SELP samples.
Zeta Potential
FIG. 4 shows a plot of zeta potential at various weight ratios of SELP/MMT. The zeta potential of the pure MMT suspension and the SELP solution are plotted on the log-linear plot at SELP/MMT relative concentrations of 0.0001 and 10000, respectively. The zeta potential of sodium MMT in water, at a concentration of 0.1 wt %, is −42 mV (Southern™ Clay Na + , 92 meq/100 g). The size of the MMT sheets, as measured by the median in the log-normal distribution of sizes measured from light scattering, was 90 nm. As SELP is added into the suspension in higher concentrations, the effective size and surface charge of the MMT sheets remains relatively unaltered until the weight ratio of SELP/MMT reaches about 1. The surface charge decreases in magnitude as SELP is adsorbed onto the MMT, the zeta potential goes toward zero, and is then neutralized at a SELP/MMT weight ratio of 8:1. The zeta potential of the system does not go far into the positive regime with the continued addition of SELP, because of the low overall positive charge of the protein (only 13 positively charged lysines out of 886 total residues). The zeta potential of the SELP solution (0.5-1 wt %) was measured to be +3 mV. The exfoliated composites had SELP/MMT weight ratios varying from 10:1 to 50:1, and it can be seen in FIG. 4 that the MMT charge is neutralized by the adsorbed protein at these ratios.
In the SELPsucc nanocomposites we see good dispersion at the nanometer length scale, as we saw in the SELP nanocomposites. X-ray scattering shows no MMT interlayer spacing and no intercalation peak. On larger length scales, however, some macroscopic phase separation in the SELPsucc can be seen, especially in low magnification TEM images. FIG. 5 shows electron micrographs of the SELPsucc samples and clear regions of MMT-rich and protein rich regions can be seen.
In aqueous solution, absorption of SELP on MMT sheets seems to readily occur, irrespective of a small fraction of ionic residues. However, these residues play a dominate role in determining the morphology of the nanocomposite because the anionic residues generate repulsive interactions with MMT sheets resulting in a weak clustering or agglomeration of MMT in solution that manifests in non-uniformity in the solid state.
Example 6
Preparation of Plasticized RSPP Nanocomposite Films
Plasticizers, including polyethylene glycol (PEG) and trehalose were used to decrease the glass transition temperature of the films and to improve film flexibility at room temperature. SELP solutions with MMT in deionized water were prepared as in example 3, and PEG (molecular weight 200 g/mol) was added in concentrations ranging from 2-10 wt % of the total solids in suspension. Samples were made containing 3% w/w of MMT, 2% w/w of PEG, and 95% w/w SELP were made and the tensile strength of these samples were compared to the tensile strength of SELP alone, as shown in FIG. 6 . Common families of molecules that may also be used to plasticize these nanocomposite films include adipic acid derivatives, azeic acid derivatives, benzoic acid derivatives, diphenyl derivatives, citric acid derivatives, epoxides, glycolates, isophthalic acid derivatives, maleic acid derivatives, phosphoric acid derivatives, phthalic acid derivatives, polyesters, trimelitates, etc. Specifically, water soluble plasticizers can be used such as citrate esters, triethyl citrate, triacetin, diethyl phthalate, glycerol, polyalkylene glycols such as polyethylene glycol, trehalose, polysaccharides, polysuccinimide and poly aspartate.
Example 7
Preparation of Cross-Linked RSPP Nanocomposite Films
Protein crosslinkers were used to stabilize the films from solvent attack, as well as increase the effective molecular weight. After SELP/MMT films made according to Example 3 were dried, they were submerged in a 2.5 vol. % glutaraldehyde solution to crosslink for 18 hours. Concentrations of approximately 0.6%-4% were typically used for glutaraldehyde crosslinking. The films were then submerged in DI water for 2 hours for rinsing and subsequently dried. Concentrations of approximately 0.6% to approximately 4% are typically used for glutaraldehyde crosslinking. | Nanocomposites of repeat sequence protein polymers and phyllosilicates demonstrated improved material properties, for example, improved elasticity, and are useful as suture, tissue scaffolding, and biodegradable composite materials. | 0 |
BACKGROUND OF THE INVENTION
[0001] The present invention relates to a process for producing 1,1,1-trifluoroacetone that is useful as an intermediate of pharmaceuticals and agricultural chemicals, or as a reagent for introducing fluorine-containing groups.
[0002] 1,1,1-trifluoroacetone is known to be obtained by various methods. It is described in J. Chem. Soc. (Lond.) 1956, 835 that 1,1,1-trifluoroacetone is synthesized by a Grignard reaction between trifluoroacetic acid and magnesium methyliodide. This Grignard reaction must be conducted in an anhydrous state. In addition, it is also described in Tetrahedron, 20, 2163 (1964) that trifluoroacetone can be synthesized by decarbonating trifluoroacetoethyl acetate in sulfuric acid. It is described in Tetrahedron Lett. Vol. 24 (No. 5), 507-510, 1983 that difluoromethylketones are obtained at considerably high yield as a result of reducing chlorodifluoroketones, which are represented by CF 2 ClC(=O)R (wherein R is a group not containing halogen) by zinc and methanol in tetrahydrofuran.
[0003] Japanese Patent Publication 2000-336057A, corresponding to Japanese Patent Application 11-147670, discloses a process for producing 1,1,1-trifluoroacetone by reacting 3,3-dichloro-1,1,1-trifluoroacetone with zinc in a solvent of a proton donor. In this process, it is necessary to have a relatively large amount of zinc.
SUMMARY OF THE INVENTION
[0004] It is an object of the present invention to provide a process for producing 1,1,1-trifluoroacetone, which is suitable for an industrial-scale production.
[0005] According to the present invention, there is provided a process for producing 1,1,1-trifluoroacetone. This process comprises conducting a hydrogenolysis of a halogenated trifluoroacetone, which is represented by the general formula (1), by a hydrogen gas in the presence of a catalyst comprising a transition metal,
[0006] where X represents a chlorine, bromine or iodine, and n represents an integer from 1 to 3.
[0007] According to the present invention, it is possible to obtain 1,1,1-trifluoroacetone with a high yield by using the above special catalyst in hydrogenolysis of the halogenated trifluoroacetone (e.g., 3,3-dichloro-1,1,1-trifluoroacetone) by a hydrogen gas.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0008] The hydrogenolysis can be conducted by a gas phase reaction between the halogenated trifluoroacetone (gas) and a hydrogen gas using a reactor for flow method.
[0009] The halogenated trifluoroacetone used as a starting material in the process of the present invention may be a hydrate, alcohol addition product, gem-diol, acetal or hemiacetal, or their aqueous or alcohol solutions, of a halogenated trifluoroacetone represented by the general formula (1), as indicated in the following formulas, although an aqueous solution of the hydrate is preferable due to its ease of handling:
[0010] where X and n are the same as previously defined in the general formula (1), m represents an integer, R 1 represents an alkyl group, and each R 2 independently represents a hydrogen atom or alkyl group.
[0011] The halogenated trifluoroacetone can be 3-chloro-1,1,1-trifluorocetone, 3,3-dichloro-1,1,1-trifluoroacetone, or 3,3,3-trichloro-1,1,1-trifluoroacetone. These compounds can be synthesized by known processes. For example, they can be obtained by fluorinating pentachloroacetone by hydrogen fluoride in the presence of a transition metal or the like as a catalyst. Furthermore, decarboxylation of a trifluoroacetoacetic ester is known.
[0012] As stated above, the halogenated trifluoroacetone used as a starting material in the process of the present invention may be a hydrate in which a halogenated trifluoroacetone represented by the general formula (1) has hydrated to have an arbitrary number of water molecules. In the process, it is preferable to use the halogenated trifluoroacetone in the form of an aqueous solution, since its handling is easy and thereby the reaction procedures can be simplified. The existence of water is not an obstacle to the reaction, but the existence of unnecessary water is not preferable from the viewpoint of energy consumption.
[0013] As stated above, the catalyst used in the hydrogenolysis comprises a transition metal. This transition metal is preferably a noble metal such as ruthenium, palladium, platinum, iridium, and rhodium. Further examples of the transition metal other than noble metal are nickel, copper and iron. Of these, palladium and platinum are preferable. The transition metal is preferably supported on a support such as activated carbon, alumina, silica-alumina, and silica. Of these, activated carbon is preferable. It is particularly preferable to use a catalyst containing an activated carbon supporting thereon palladium or platinum. The way of making the transition metal to be supported on the support is not particularly limited. For example, it is possible to immerse a support in a solution of a transition metal compound or to spray this solution to a support, followed by drying and then reduction with hydrogen gas. The transition metal compound may be in the form of chloride, bromide, fluoride, oxide, nitrate, sulfate or carbonate. The transition metal may be in an amount of about 0.1-10 g, preferably 0.2-5 g, per 100 ml of the support. If it is less than 0.1 g, both conversion of the halogenated trifluoroacetone and yield of 1,1,1-trifluoroacetone may become too low. An amount of greater than 5 g may not be preferable from the economical viewpoint.
[0014] The reaction temperature may be 50° C. or higher, preferably 70° C. or higher, more preferably 90° C. or higher, still more preferably 100° C. or higher, further preferably 105° C. or higher. Furthermore, the reaction temperature may be 350° C. or lower, preferably 250° C. or lower, more preferably 200° C. or lower, still more preferably 150° C. or lower, further preferably 120° C. or lower. Therefore, the reaction temperature range may be 50-350° C., preferably 70-250° C., more preferably 90-120° C. If it is lower than 50° C., both conversion of the halogenated trifluoroacetone and yield of 1,1,1-trifluoroacetone may be lowered. If it is higher than 350° C., fluorine atom hydrogenolysis and/or hydrogenation of carbonyl group may proceed. With this, yield of 1,1,1-trifluoroacetone may be lowered.
[0015] The molar ratio of hydrogen (hydrogen gas) to the halogenated trifluoroacetone may be varied depending on the number of the halogen atoms (other than fluorine) of the halogenated trifluoroacetone. This ratio may be in a range of 1.5-50, preferably 2-10, more preferably 2.5-5. If it is less than 1.5, conversion of the halogenated trifluoroacetone may not be sufficiently high. Even if it is greater than 50, conversion of the halogenated trifluoroacetone may not improve further. Furthermore, this is not preferable from the economical viewpoint, due to the necessity of recovering the unreacted hydrogen gas. It is optional to make nitrogen gas coexistent with the other reagents in the reaction system in order to adjust the reaction and to suppress the catalyst deterioration.
[0016] It is preferable that the hydrogenolysis is conducted by using a reactor made of a material lined with a lining material selected from of borosilicate glasses, tetrafluoroethylene resins, chlorotrifluoroethylene resins, vinylidene fluoride resins, perfluoroalkyl vinyl ether (PFA) resins and carbon, when water exists in the reaction system. When water does not exist in the reaction system by using a halogenated trifluoroacetone that is not hydrated, it is possible to use iron, stainless steel, nickel and Hastelloy (trade name) for the reactor in addition to the above-mentioned lining material.
[0017] The way of conducting the hydrogenolysis is not particularly limited. For example, it can be conducted by the following flow method. At first, a reactor for flow method, which is resistant against the reaction conditions of the hydrogenolysis, is charged with a transition metal supported catalyst. Then, the reactor is heated from outside, and hydrogen gas is allowed to flow through a reaction tube. When the reaction tube's inside temperature reaches a predetermined temperature, the halogenated trifluoroacetone is introduced into a vaporizer for vaporizing the same and then into the reaction tube together with the hydrogen gas. A mixture of gas and/or liquid flowing out of the reaction tube is absorbed into water. Alternatively, it is cooled down and collected in the form of liquid. It is optional to separately introduce the halogenated trifluoroacetone and water into the reaction tube.
[0018] The resulting 1,1,1-trifluoroacetone can be purified by a conventional purification method used for hydrogenolysis products obtained from fluorinated compounds. For example, a reaction product containing 1,1,1-trifluoroacetone (in the form of liquid or gas), which has flowed out of the reactor together with hydrogen chloride, is cooled down. After that, hydrogen chloride is removed from the reaction product by distillation or gas-liquid phase separation. Then, the remaining acid component is removed from the product with a basic substance or the like. After that, the target product, 1,1,1-trifluoroacetone of high purity, is obtained by rectification.
[0019] The following nonlimitative catalyst preparations are illustrative of the present invention.
Catalyst Preparation 1
[0020] At first, a 200-ml eggplant-type flask was charged with 35 g of a granular activated carbon (a coconut husk carbon of a particle diameter of 4-6 mm) made by Takeda Chemical Industries, Ltd. having a trade name of GRANULAR SHIRO SAGI G2X-4/6. Then, about 120 ml of an about 20% nitric acid aqueous solution was added to the flask. After that, the flask was allowed to stand still for about 3 hr, thereby to conduct a nitric acid treatment of the activated carbon. Separately, 0.83 g of palladium (II) chloride, PdCl 2 , was dissolved in 5 g of a 24% hydrochloric acid, to prepare a palladium chloride solution. This palladium chloride solution was poured on the activated carbon contained in the flask. Then, this flask was allowed to stand still for 2 days. Then, the activated carbon, impregnated with the palladium chloride solution, was subjected to vacuum drying with an evaporator by increasing the bath temperature to 150° C. Then, the dried activated carbon was put into a reaction tube having a diameter of 25 mm, an axial length of 400 mm, and a capacity of about 200 ml. Then, while nitrogen was allowed to flow through the reaction tube at a rate of 200-300 ml/min, the reaction tube was heated from 150° C. to 300° C. by increasing the set temperature of the reaction tube stepwise by 50° C., in order to bake the activated carbon. The reaction tube temperature was maintained at 300° C. for 1 hr in order to further bake the same, and then the set temperature was decreased to 150° C. After that, while nitrogen and hydrogen were allowed to flow therethrough at respective rates of 50 ml/min and 50 ml/min, the reaction tube temperature was increased again to 300° C. by increasing its set temperature stepwise by 30° C. for conducting reduction. With this, there was prepared a first catalyst having an activated carbon carrying thereon 0.5% of palladium, based on the weight of the activated carbon.
Catalyst Preparation 2
[0021] At first, a 200-ml eggplant-type flask was charged with 35 g of the same granular activated carbon as that of Catalyst Preparation 1. Separately, 0.46 g of hexachloroplatinic (IV) acid hexahydrate, H 2 PtCl 6 .6H 2 O, was dissolved in 100 ml of 30% hydrochloric acid, to prepare a hexachloroplatinic acid solution. This solution was poured on the activated carbon contained in the flask. Then, this flask was allowed to stand still for 2 days. Then, the same procedures as those of Catalyst Preparation 1 were conducted, thereby preparing a second catalyst having an activated carbon carrying thereon 0.5% of platinum, based on the weight of the activated carbon.
[0022] The following nonlimitative examples are illustrative of the present invention.
EXAMPLE 1
[0023] At first, a tubular reactor made of glass was charged with 50 ml of the first catalyst (0.5% Pd on activated carbon) obtained in Catalyst Preparation 1. Then, the reactor was heated to 110° C., while hydrogen gas was allowed to flow through the reactor at a rate of 80 ml/min by downflow. A 3,3-dichloro-1,1,1-trifluoroacetone aqueous solution (water content: 25%) was introduced into a vaporizer at a rate of 0.2 g/min, thereby vaporizing this solution. The resulting vapor was mixed with hydrogen, and the mixture was introduced into the reactor after the reactor's inside temperature became stable. Then, the reaction was conducted for 5 hr. During the reaction, liquid and gas flowing out of the reactor were introduced into 10 g of water cooled at 0° C., thereby collecting them. The collected product in an amount of 47.2 g was found by Karl Fischer's method to contain 52.4% of water. Furthermore, it was found by gas chromatography to contain organic components of 98.4% of 1,1,1-trifluoroacetone, 0.1% of 1,1-difluoroacetone, 0.5% of 1-fluoroacetone, 0.4% of acetone and others. These percentages are areal percentages in chromatogram.
EXAMPLE 2
[0024] Example 1 was repeated except in that the flow rate of hydrogen gas was 65 mmin, thereby collecting 53.8 g of a product. The collected product was found by Karl Fischer's method to contain 42.3% of water. Furthermore, it was found by gas chromatography to contain organic components of 97.7% of 1,1,1-trifluoroacetone, 0.4% of 1,1-difluoroacetone, 1.3% of 1-fluoroacetone, 0.3% of acetone and others.
EXAMPLE 3
[0025] Example 1 was repeated except in that the flow rate of hydrogen gas was 100 ml/min, thereby collecting 49.1 g of a product. The collected product was found by Karl Fischer's method to contain 52.8% of water. Furthermore, it was found by gas chromatography to contain organic components of 97.5% of 1,1,1-trifluoroacetone, 1.1% of 1,1-difluoroacetone, 0.5% of 1-fluoroacetone, 0.4% of acetone and others.
EXAMPLE 4
[0026] At first, a tubular reactor made of glass was charged with 50 ml of the first catalyst (0.5% Pd on activated carbon) obtained in Catalyst Preparation 1. Then, the reactor was heated to 110° C., while hydrogen gas was allowed to flow through the reactor at a rate of 80 ml/min by downflow. An aqueous solution (water content: 15%) of a raw material mixture containing 8.2% of 3-chloro-1,1,1-trifluoroacetone, 88.8% of 3,3-dichloro-1,1,1-trifluoroacetone, and 2.4% of 3,3,3-trichloro-1,1,1-trifluoroacetone was introduced into a vaporizer at a rate of 0.2 g/min, thereby vaporizing this solution. The resulting vapor was mixed with hydrogen, and the mixture was introduced into the reactor after the reactor's inside temperature became stable. Then, the reaction was conducted for 5 hr. During the reaction, liquid and gas flowing out of the reactor were introduced into 20 g of water cooled at 0° C., thereby collecting them. The collected product in an amount of 56.9 g was found by Karl Fischer's method to contain 45.6% of water. Furthermore, it was found by gas chromatography to contain organic components of 97.9% of 1,1,1-trifluoroacetone, 0.4% of 1,1-difluoroacetone, 0.5% of 1-fluoroacetone, 0.6% of acetone and others.
EXAMPLE 5
[0027] Example 1 was repeated except in that the first catalyst was replaced with the second catalyst (0.5% Pt on activated carbon) obtained in Catalyst Preparation 2 and that the water cooled at 0° C. was in an amount of 14 g, thereby collecting 64.2 g of a product. The collected product was found by Karl Fischer's method to contain 46.3% of water. Furthermore, it was found by gas chromatography to contain organic components of 99.0% of 1,1,1-trifluoroacetone, 0.1% of 1,1-difluoroacetone, 0.1% of 1-fluoroacetone, 0.3% of acetone and others.
EXAMPLE 6
[0028] At first, a tubular reactor made of glass was charged with 500 ml of the first catalyst (0.5% Pd on activated carbon) obtained in Catalyst Preparation 1. Then, the reactor was heated to 95° C., while hydrogen gas was allowed to flow through the reactor at a rate of 500 ml/min by downflow. A raw material mixture containing 9.6% of 3-chloro-1,1,1-trifluoroacetone, 84.0% of 3,3-dichloro-1,1,1-trifluoroacetone, and 3.9% of 3,3,3-trichloro-1,1,1-trifluoroacetone was introduced into a vaporizer at a rate of 1.5 g/min, thereby vaporizing the mixture. The resulting vapor was mixed with hydrogen, and the mixture was introduced into the reactor after the reactor's inside temperature became stable. Then, the reaction was conducted for 6 hr. During the reaction, liquid and gas flowing out of the reactor were introduced into 500 g of water cooled at 0° C., thereby collecting them. The collected product in an amount of 909 g was found by Karl Fischer's method to contain 55.0% of water. Furthermore, it was found by gas chromatography to contain organic components of 98.1% of 1,1,1-trifluoroacetone, 0.7% of 1,1-difluoroacetone, and others.
EXAMPLE 7
[0029] At first, a tubular reactor made of glass was charged with 10 ml of the second catalyst (0.5% Pt on activated carbon) obtained in Catalyst Preparation 2. Then, the reactor was heated to 110° C., while hydrogen gas was allowed to flow through the reactor at a rate of 80 ml/min by downflow. An aqueous solution (water content: 15%) of a raw material mixture containing 8.2% of 3-chloro-1,1,1-trifluoroacetone, 88.8% of 3,3-dichloro-1,1,1-trifluoroacetone, and 2.4% of 3,3,3-trichloro-1,1,1-trifluoroacetone was introduced into a vaporizer at a rate of 0.16 g/min, thereby vaporizing the mixture. The resulting vapor was mixed with hydrogen, and the mixture was introduced into the reactor after the reactor's inside temperature became stable. Then, the reaction was conducted for 1 hr. During the reaction, liquid and gas flowing out of the reactor were introduced into 10 g of water cooled at 0° C., thereby collecting them. The collected product in an amount of 16.1 g was found by Karl Fischer's method to contain 61.2% of water. Furthermore, it was found by gas chromatography to contain organic components of 96.7% of 1,1,1-trifluoroacetone, 1.5% of 3-chloro-1,1,1-trifluoroacetone, and others.
EXAMPLE 8
[0030] At first, a tubular reactor made of glass was charged with 50 ml of the second catalyst (0.5% Pt on activated carbon) obtained in Catalyst Preparation 2. Then, the reactor was heated to 110° C., while hydrogen gas was allowed to flow through the reactor at a rate of 80 ml/min by downflow. 3,3-dichloro-1,1,1-trifluoroacetone was introduced into a vaporizer at a rate of 0.18 g/min, thereby vaporizing this compound. The resulting vapor was mixed with hydrogen, and the mixture was introduced into the reactor after the reactor's inside temperature became stable. Then, the reaction was conducted for 1 hr. During the reaction, liquid and gas flowing out of the reactor were introduced into 10 g of water cooled at 0° C., thereby collecting them. The collected product in an amount of 17.4 g was found by Karl Fischer's method to contain 55.9% of water. Furthermore, it was found by gas chromatography to contain organic components of 95.4% of 1,1,1-trifluoroacetone, 3.0% of 3-chloro-1,1,1-trifluoroacetone, and others.
[0031] The entire disclosure of each of Japanese Patent Applications No. 2000-043869 filed on Feb. 22, 2000 and No. 2000-309649 filed on Oct. 10, 2000, including specification, claims and summary, is incorporated herein by reference in its entirety. | A process for producing 1,1,1-trifluoroacetone includes the step of conducting a hydrogenolysis of a halogenated trifluoroacetone, which is represented by the general formula (1), by a hydrogen gas in the presence of a catalyst containing a transition metal,
where X represents a chlorine, bromine or iodine, and n represents an integer from 1 to 3. It is possible to obtain 1,1,1-trifluoroacetone with a high yield by using the special catalyst. | 2 |
This application claims the benefit of U.S. Provisional Application No. 60/860,195, filed Nov. 20, 2006, which is hereby incorporated by reference.
FIELD OF THE INVENTION
The present invention relates generally to amide containing azatricyclic metalloprotease inhibiting compounds, and more particularly to azatricyclic amide MMP-13, MMP-8, MMP-3 and MMP-2 inhibiting compounds.
BACKGROUND OF THE INVENTION
Matrix metalloproteinases (MMPs) and aggrecanases (ADAMTS=a disintegrin and metalloproteinase with thrombospondin motif) are a family of structurally related zinc-containing enzymes that have been reported to mediate the breakdown of connective tissue in normal physiological processes such as embryonic development, reproduction, and tissue remodelling. Over-expression of MMPs and aggrecanases or an imbalance between extracellular matrix synthesis and degradation has been suggested as factors in inflammatory, malignant and degenerative disease processes. MMPs and aggrecanases are, therefore, targets for therapeutic inhibitors in several inflammatory, malignant and degenerative diseases such as rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, multiple sclerosis, gingivitis, corneal epidermal and gastric ulceration, atherosclerosis, neointimal proliferation (which leads to restenosis and ischemic heart failure) and tumor metastasis.
The ADAMTSs are a group of proteases that are encoded in 19 ADAMTS genes in humans. The ADAMTSs are extracellular, multidomain enzymes functions include collagen processing, cleavage of the matrix proteoglycans, inhibition of angiogenesis and blood coagulation homoeostasis ( Biochem. J. 2005, 386, 15-27 ; Arthritis Res. Ther. 2005, 7, 160-169 ; Curr. Med. Chem. Anti - Inflammatory Anti - Allergy Agents 2005, 4, 251-264).
The mammalian MMP family has been reported to include at least 20 enzymes ( Chem. Rev. 1999, 99, 2735-2776). Collagenase-3 (MMP-13) is among three collagenases that have been identified. Based on identification of domain structures for individual members of the MMP family, it has been determined that the catalytic domain of the MMPs contains two zinc atoms; one of these zinc atoms performs a catalytic function and is coordinated with three histidines contained within the conserved amino acid sequence of the catalytic domain. MMP-13 is over-expressed in rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, breast carcinoma, squamous cell carcinomas of the head and neck, and vulvar squamous cell carcinoma. The principal substrates of MMP-13 are fibrillar collagens (types I, II, III) and gelatins, proteoglycans, cytokines and other components of ECM (extracellular matrix).
The activation of the MMPs involves the removal of a propeptide, which features an unpaired cysteine residue complexed with the catalytic zinc (II) ion. X-ray crystal structures of the complex between MMP-3 catalytic domain and TIMP-1 and MMP-14 catalytic domain and TIMP-2 also reveal ligation of the catalytic zinc (II) ion by the thiol of a cysteine residue. The difficulty in developing effective MMP inhibiting compounds comprises several factors, including choice of selective versus broad-spectrum MMP inhibitors and rendering such compounds bioavailable via an oral route of administration.
MMP-3 (stromelysin-1; transin-1) is another member of the MMP family ( FASEB J. 1991, 5, 2145-2154). Human MMP-3 was initially isolated from cultured human synoviocytes. It is also expressed by chondrocytes and has been localized in OA cartilage and synovial tissues ( Am. J. Pathol. 1989, 135, 1055-64).
MMP-3 is produced by basal keratinocytes in a variety of chronic ulcers. MMP-3 mRNA and Protein were detected in basal keratinocytes adjacent to but distal from the wound edge in what probably represents the sites of proliferating epidermis. MMP-3 may thus prevent the epidermis from healing ( J. Clin. Invest. 1994, 94, 79-88).
MMP-3 serum protein levels are significantly elevated in patients with early and long-term rheumatoid arthritis ( Arthritis Rheum. 2000, 43, 852-8) and in osteoarthritis patients ( Clin. Orthop. Relat. Res. 2004, 428, 272-85) as well as in other inflammatory diseases like systemic lupus erythematosis and ankylosing spondylitis ( Rheumatology 2006, 45, 414-20).
MMP-3 acts on components of the ECM as aggrecan, fibronectin, gelatin, laminin, elastin, fibrillin and others and on collagens of type III, IV, V, VII, IX, X ( Clin. Orthop. Relat. Res. 2004, 428, 272-85). On collagens of type II and IX, MMP-3 exhibits telopeptidase activity ( Arthritis Res. 2001, 3, 107-13 ; Clin. Orthop. Relat. Res. 2004, 427, S118-22). MMP-3 can activate other MMP family members such as MMP-1, MMP-7, MMP-8, MMP-9 and MMP-13 ( Ann. Rheum. Dis. 2001, 60 Suppl 3:iii62-7).
MMP-3 is involved in the regulation of cytokines and chemokines by releasing TGFβ 1 from the ECM, activating TNFα, inactivating IL-1β and releasing IGF ( Nat. Rev. Immunol. 2004, 4, 617-29). A potential role for MMP-3 in the regulation of macrophage infiltration is based on the ability of the enzyme to convert active MCP species into antagonistic peptides ( Blood 2002, 100, 1160-7).
MMP-8 (collagenase-2; neutrophil collagenase; EC 3.4.24.34) is another member of the MMP family ( Biochemistry 1990, 29, 10628-34). Human MMP-8 was initially located in human neutrophils ( Biochemistry 1990, 29, 10620-7). It is also expressed by macrophages, human mucosal keratinocytes, bronchial epithelial cells, ginigival fibroblasts, resident synovial and articular chondrodrocytes mainly in the course of inflammatory conditions ( Cytokine & Growth Factor Rev. 2006, 17, 217-23).
The activity of MMP-8 is tightly regulated and mostly limited to the sites of inflammation. MMP-8 is expressed and stored as an inactive pro-enzyme in the granules of the neutrophils. Only after the activation of the neutrophils by proinflammatory mediators, MMP-8 is released and activated to exert its function.
MMP-8 plays a key role in the migration of immune cells to the sites of inflammation. MMP-8 degrades components of the extracellular matrix (ECM) such as collagen type I, II, III, VII, X, cartilage aggrecan, laminin-5, nidogen, fibronectin, proteoglycans and tenascin, thereby facilitating the cells migration through the ECM barrier. MMP-8 also influences the biological activity of its substrates. Through proteolytic processing of the chemokines IL-8, GCP-2, ENA-78, MMP-8 increases the chemokines ability to activate the infiltrating immune cells. While MMP-8 inactivates the serine protease inhibitor alpha-1 antitrypsin through its cleavage ( Eur. J. Biochem. 2003, 270, 3739-49 ; PloS One 2007, 3, 1-10 ; Cytokine & Growth Factor Rev. 2006, 17, 217-23).
MMP-8 has been implicated in the pathogenesis of several chronic inflammatory diseases characterized by the excessive influx and activation of neutrophils, including cystic fibrosis ( Am. J. Resprir. Critic. Care Med 1994, 150, 818-22), rheumatoid arthritis ( Clin. Chim. Acta 1996, 129-43), chronic periodontal disease ( Annals Med. 2006, 38, 306-321) and chronic wounds ( J. Surg. Res. 1999, 81, 189-195).
In osteoarthritis patients, MMP-8 protein expression is significantly elevated in inflamed human articular cartilage in the knee and ankle joints ( Lab Invest. 1996, 74, 232-40 ; J. Biol. Chem. 1996, 271, 11023-6).
The levels of activated MMP-8 in BALF is an indicator of the disease severity and correlates with the airway obstruction in patients with asthma, COPD, pulmonary emphysema and bronchiectasis ( Lab Invest. 2002, 82, 1535-45 ; Am. J. Respir. Crit. Care Med 1999, 159, 1985-91 ; Respir. Med. 2005, 99, 703-10 ; J. Pathol. 2001, 194, 232-38).
SUMMARY OF THE INVENTION
The present invention relates to a new class of azatricyclic amide containing pharmaceutical agents which inhibits metalloproteases. In particular, the present invention provides a new class of metalloprotease inhibiting compounds that exhibit potent MMP-13 inhibiting activity and/or activity towards MMP-8, MMP-3 and MMP-2.
The present invention provides several new classes of amide containing azatricyclic metalloprotease compounds, which are represented by the following general formula:
wherein all variables in the preceding Formula (I) are as defined hereinbelow.
The azatricyclic metalloprotease inhibiting compounds of the present invention may be used in the treatment of metalloprotease mediated diseases, such as rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, cancer (e.g. but not limited to melanoma, gastric carcinoma or non-small cell lung carcinoma), inflammation, atherosclerosis, multiple sclerosis, chronic obstructive pulmonary disease, ocular diseases (e.g. but not limited to ocular inflammation, retinopathy of prematurity, macular degeneration with the wet type preferred and corneal neovascularization), neurologic diseases, psychiatric diseases, thrombosis, bacterial infection, Parkinson's disease, fatigue, tremor, diabetic retinopathy, vascular diseases of the retina, aging, dementia, cardiomyopathy, renal tubular impairment, diabetes, psychosis, dyskinesia, pigmentary abnormalities, deafness, inflammatory and fibrotic syndromes, intestinal bowel syndrome, allergies, Alzheimers disease, arterial plaque formation, oncology, periodontal, viral infection, stroke, atherosclerosis, cardiovascular disease, reperfusion injury, trauma, chemical exposure or oxidative damage to tissues, chronic wound healing, wound healing, hemorroid, skin beautifying, pain, inflammatory pain, bone pain and joint pain, acne, acute alcoholic hepatitis, acute inflammation, acute pancreatitis, acute respiratory distress syndrome, adult respiratory disease, airflow obstruction, airway hyperresponsiveness, alcoholic liver disease, allograft rejections, angiogenesis, angiogenic ocular disease, arthritis, asthma, atopic dermatitis, bronchiectasis, bronchiolitis, bronchiolitis obliterans, burn therapy, cardiac and renal reperfusion injury, celiac disease, cerebral and cardiac ischemia, CNS tumors, CNS vasculitis, colds, contusions, cor pulmonae, cough, Crohn's disease, chronic bronchitis, chronic inflammation, chronic pancreatitis, chronic sinusitis, crystal induced arthritis, cystic fibrosis, delayed type hypersensitivity reaction, duodenal ulcers, dyspnea, early transplantation rejection, emphysema, encephalitis, endotoxic shock, esophagitis, gastric ulcers, gingivitis, glomerulonephritis, glossitis, gout, graft vs. host reaction, gram negative sepsis, granulocytic ehrlichiosis, hepatitis viruses, herpes, herpes viruses, HIV, hypercapnea, hyperinflation, hyperoxia-induced inflammation, hypoxia, hypersensitivity, hypoxemia, inflammatory bowel disease, interstitial pneumonitis, ischemia reperfusion injury, kaposi's sarcoma associated virus, liver fibrosis, lupus, malaria, meningitis, multi-organ dysfunction, necrotizing enterocolitis, osteoporosis, chronic periodontitis, periodontitis, peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD), pre-term labor, polymyositis, post surgical trauma, pruritis, psoriasis, psoriatic arthritis, pulmatory fibrosis, pulmatory hypertension, renal reperfusion injury, respiratory viruses, restinosis, right ventricular hypertrophy, sarcoidosis, septic shock, small airway disease, sprains, strains, subarachnoid hemorrhage, surgical lung volume reduction, thrombosis, toxic shock syndrome, transplant reperfusion injury, traumatic brain injury, ulcerative colitis, vasculitis, ventilation-perfusion mismatching, and wheeze.
In particular, the azatricyclic metalloprotease inhibiting compounds of the present invention may be used in the treatment of MMP-13, MMP-8, MMP-3 and MMP-2 mediated osteoarthritis and may be used for other MMP-13, MMP-8, MMP-3 and MMP-2 mediated symptoms, inflammatory, malignant and degenerative diseases characterized by excessive extracellular matrix degradation and/or remodelling, such as cancer, and chronic inflammatory diseases such as arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, abdominal aortic aneurysm, inflammation, multiple sclerosis, and chronic obstructive pulmonary disease, and pain, such as inflammatory pain, bone pain and joint pain.
The present invention also provides azatricyclic metalloprotease inhibiting compounds that are useful as active ingredients in pharmaceutical compositions for treatment or prevention of metalloprotease—especially MMP-13, MMP-8, MMP-3 and MMP-2—mediated diseases. The present invention also contemplates use of such compounds in pharmaceutical compositions for oral or parenteral administration, comprising one or more of the azatricyclic metalloprotease inhibiting compounds disclosed herein.
The present invention further provides methods of inhibiting metalloproteases, by administering formulations, including, but not limited to, oral, rectal, topical, intravenous, parenteral (including, but not limited to, intramuscular, intravenous), ocular (ophthalmic), transdermal, inhalative (including, but not limited to, pulmonary, aerosol inhalation), nasal, sublingual, subcutaneous or intraarticular formulations, comprising the azatricyclic metalloprotease inhibiting compounds by standard methods known in medical practice, for the treatment of diseases or symptoms arising from or associated with metalloprotease, especially MMP-13, MMP-8, MMP-3 and MMP-2, including prophylactic and therapeutic treatment. Although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. The compounds from this invention are conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
The azatricyclic metalloprotease inhibiting compounds of the present invention may be used in combination with a disease modifying antirheumatic drug, a nonsteroidal anti-inflammatory drug, a COX-2 selective inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, a biological response modifier or other anti-inflammatory agents or therapeutics useful for the treatment of chemokines mediated diseases.
DETAILED DESCRIPTION OF THE INVENTION
One aspect of the invention relates to a compound of Formula (I):
wherein
R 1 in each occurrence is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, and heterocycloalkyl fused heteroarylalkyl,
wherein R 1 is optionally substituted one or more times, or
wherein R 1 is optionally substituted by one R 16 group and optionally substituted by one or more R 9 groups;
R 2 is selected from hydrogen and alkyl, wherein alkyl is optionally substituted one or more times or R 1 and R 2 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S(O) x , or NR 50 and which is optionally substituted one or more times;
R 4 in each occurrence is independently selected from R 10 , hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, haloalkyl, CF 3 , (C 0 -C 6 )-alkyl-COR 10 , (C 0 -C 6 )-alkyl-OR 10 , (C 0 -C 6 )-alkyl-NR 10 R 11 , (C 0 -C 6 )-alkyl-NO 2 , (C 0 -C 6 )-alkyl-CN, (C 0 -C 6 )-alkyl-S(O) y OR 10 , (C 0 -C 6 )-alkyl-S(O) y NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 CONR 11 SO 2 R 30 , (C 0 -C 6 )-alkyl-S(O) n R 10 , (C 0 -C 6 )-alkyl-OC(O)R 10 , (C 0 -C 6 )-alkyl-OC(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(═NR 10 )NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 C(═NR 11 )NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)OR 10 , (C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)NR 10 SO 2 R 11 , (C 0 -C 6 )-alkyl-C(O)—NR 11 —CN, O—(C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , S(O) n —(C 0 -C 6 )-alkyl-C(O)OR 10 , S(O) n —(C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)NR 10 —(C 0 -C 6 )-alkyl-NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 —C(O)R 10 , (C 0 -C 6 )-alkyl-NR 10 —C(O)OR 10 , (C 0 -C 6 )-alkyl-NR 10 —C(O)—NR 10 R 10 , (C 0 -C 6 )-alkyl-NR 10 —S(O) y NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 —S(O) y R 10 , O—(C 0 -C 6 )-alkyl-aryl and O—(C 0 -C 6 )-alkyl-heteroaryl,
wherein each R 4 group is optionally substituted one or more times, or
wherein each R 4 group is optionally substituted by one or more R 14 groups, or
wherein optionally two R 4 groups, when taken together with the nitrogen or carbon to which they are attached complete a 3- to 8-membered saturated ring or multicyclic ring or unsaturated ring containing carbon atoms and optionally containing one or more heteroatom independently selected from O, S(O) x , N, or NR 50 and which is optionally substituted one or more times, or
optionally two R 4 groups together at one saturated carbon atom form ═O, ═S, ═NR 10 or ═NOR 10 ;
R 5 is independently selected from hydrogen, alkyl, C(O)NR 10 R 11 , aryl, arylalkyl, SO 2 NR 10 R 11 and C(O)OR 10 wherein alkyl, aryl and arylalkyl are optionally substituted one or more times;
R 8 is independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, R 10 and NR 10 R 11 wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted one or more times;
R 9 in each occurrence is independently selected from R 10 , hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, CHF 2 , CF 3 , OR 10 , SR 10 , COOR 10 , CH(CH 3 )CO 2 H, (C 0 -C 6 )-alkyl-COR 10 , (C 0 -C 6 )-alkyl-OR 10 , (C 0 -C 6 )-alkyl-NR 10 R 11 , (C 0 -C 6 )-alkyl-NO 2 , (C 0 -C 6 )-alkyl-CN, (C 0 -C 6 )-alkyl-S(O) y OR 10 , (C 0 -C 6 )-alkyl-P(O) 2 OH, (C 0 -C 6 )-alkyl-S(O) y NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 CONR 11 SO 2 R 30 , (C 0 -C 6 )-alkyl-S(O) n R 10 , (C 0 -C 6 )-alkyl-OC(O)R 10 , (C 0 -C 6 )-alkyl-OC(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(═NR 10 )NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 C(═NR 11 )NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 C(═N—CN)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(═N—CN)NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 C(═N—NO 2 )NR 10 R 11 , (C 0 -C 6 )-alkyl-C(═N—NO 2 )NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)OR OR 11 , (C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)NR 11 SO 2 R 11 , C(O)NR 10 —(C 0 -C 6 )-alkyl-heteroaryl, C(O)NR 10 —(C 0 -C 6 )-alkyl-aryl, S(O) 2 NR 11 —(C 0 -C 6 )-alkyl-aryl, S(O) 2 NR 11 —(C 0 -C 6 )-alkyl-heteroaryl, S(O) 2 NR 10 -alkyl, S(O) 2 —(C 0 -C 6 )-alkyl-aryl, S(O) 2 —(C 0 -C 6 )-alkyl-heteroaryl, (C 0 -C 6 )-alkyl-C(O)—NR 11 —CN, O—(C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , S(O)—(C 0 -C 6 )-alkyl-C(O)OR 10 , S(O)—(C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)NR 10 —(C 0 -C 6 )-alkyl-NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 —C(O)R 10 , (C 0 -C 6 )-alkyl-NR 11 —C(O)OR 10 , (C 0 -C 6 )-alkyl-NR 10 —C(O)—NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 —S(O) y NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 —S(O) y R 11 , O—(C 0 -C 6 )-alkyl-aryl and O—(C 0 -C 6 )-alkyl-heteroaryl,
wherein each R 9 group is optionally substituted, or
wherein each R 9 group is optionally substituted by one or more R 14 groups;
R 10 and R 11 in each occurrence are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted one or more times, or R 10 and R 11 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S(O) x , or NR 50 and which is optionally substituted one or more times;
R 14 is independently selected from hydrogen, alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclylalkyl and halo, wherein alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times.
R 16 is selected from cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, heterocycloalkyl fused heteroarylalkyl, (i) and (ii):
wherein cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, and heterocycloalkyl fused heteroarylalkyl are optionally substituted one or more times;
R 17 is selected from R 1 , R 4 and R 21 ;
R 21 is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, and
wherein R 21 is optionally substituted one or more times, or
wherein R 21 is optionally substituted by one or more R 9 groups;
R 30 is selected from alkyl and (C 0 -C 6 )-alkyl-aryl, wherein alkyl and aryl are optionally substituted;
R 50 in each occurrence is independently selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R 80 , C(O)NR 80 R 81 , SO 2 R 80 and SO 2 NR 80 R 81 , wherein alkyl, aryl, and heteroaryl are optionally substituted one or more times;
R 80 and R 81 in each occurrence are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted, or R 80 and R 81 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally a heteroatom selected from O, S(O) x , —NH, and —N(alkyl) and which is optionally substituted one or more times;
E is selected from a bond, CR 10 R 11 , O, NR 5 , S, S═O, S(═O) 2 , C(═O), N(R 10 )(C═O), (C═O)N(R 10 ), N(R 10 )S(═O) 2 , S(═O) 2 N(R 10 ), C═N—OR 11 , —C(R 10 R 11 )C(R 10 R 11 )—, —CH 2 —W 1 — and
L a is independently selected from CR 9 and N;
L b is independently selected from C and N with the proviso, that both L b are not N, and that the bond between L b and L b is optionally a double bond only if both L b are C;
L c is selected from a single bond or an acyclic, straight or branched, saturated or unsaturated hydrocarbon chain having 1 to 10 carbon atoms, optionally containing 1 to 3 groups independently selected from —S—, —O—, NR 0 —, —NR 10 CO—, —CONR 10 —, —S(O) n —, —SO 2 NR 10 —, —NR 10 SO 2 —, NR 10 SO 2 NR 10 —, —NR 10 CONR 10 —, —OC(O)NR 10 —, —NR 10 C(O)O—, which replace a corresponding number of non-adjacent carbon atoms, and wherein the hydrocarbon chain is optionally substituted one or more times;
Q is a 4- to 8-membered ring selected from cycloalkyl, heterocycloalkyl or a 5- or 6-membered ring selected from aryl and heteroaryl,
wherein Q is optionally substituted one or more times, or
wherein Q is optionally substituted one or more times with R 4 , or
wherein Q is fused via two of its adjacent atoms, which are selected from N and C with a further cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, aryl and heteroaryl system, which is optionally independently substituted one or more times;
U is selected from C(R 5 R 10 ), NR 5 , O, S, S═O and S(═O) 2 ;
W 1 is selected from O, NR 5 , S, S═O, S(═O) 2 , N(R 10 )(C═O), N(R 10 )S(═O) 2 ; and S(═O) 2 N(R 10 );
X is selected from a bond and (CR 10 R 11 ) w E(CR 10 R 11 ) w ;
X 1 is independently selected from O, S, NR 10 , N—CN, NCOR 10 , N—NO 2 , or N—SO 2 R 10 ;
g and h are independently selected from 0-2;
w is selected from 0-4;
x is selected from 0 to 2;
y is selected from 1 and 2;
the dotted line optionally represents a double bond; and
N-oxides, pharmaceutically acceptable salts, prodrugs, formulations, polymorphs, tautomers, racemic mixtures and stereoisomers thereof.
In one embodiment, in conjunction with any above or below embodiments, Q is phenyl or thiophene that is fused via two of its adjacent atoms with a further cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, aryl and heteroaryl system, which is optionally independently substituted one or more times.
In another embodiment, in conjunction with any above or below embodiments, L a is N.
In another embodiment, in conjunction with any above or below embodiments, L a is N; and L b is C.
In another embodiment, in conjunction with any above or below embodiments, the compound has the structure:
wherein Q′ is a fused cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, aryl or heteroaryl.
In another embodiment, in conjunction with any above or below embodiments, Q′ is a fused cycloalkyl.
In another embodiment, in conjunction with any above or below embodiments, Q′ is a fused heterocycloalkyl.
In another embodiment, in conjunction with any above or below embodiments, Q′ is a fused heterobicycloalkyl.
In another embodiment, in conjunction with any above or below embodiments, Q′ is a fused cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, aryl or heteroaryl.
In another embodiment, in conjunction with any above or below embodiments, Q′ is a fused phenyl.
In another embodiment, in conjunction with any above or below embodiments, Q′ is a fused heteroaryl.
In another embodiment, in conjunction with any above or below embodiments, the compound is selected from:
In another embodiment, in conjunction with any above or below embodiments, R 8 is H.
In another embodiment, in conjunction with any above or below embodiments, R 17 is selected from
wherein:
R 6 is selected from R 9 , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C(O)OR 10 , CH(CH 3 )CO 2 H, (C 0 -C 6 )-alkyl-COR 10 , (C 0 -C 6 )-alkyl-OR 10 , (C 0 -C 6 )-alkyl-NR 10 R 11 , (C 0 -C 6 )-alkyl-NO 2 , (C 0 -C 6 )-alkyl-CN, (C 0 -C 6 )-alkyl-S(O) y OR 10 , (C 0 -C 6 )-alkyl-P(O) 2 OH, (C 0 -C 6 )-alkyl-S(O) y NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 CONR 11 SO 2 R 30 , (C 0 -C 6 )-alkyl-S(O) x R 10 , (C 0 -C 6 )-alkyl-OC(O)R 10 , (C 0 -C 6 )-alkyl-OC(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(═NR 10 )NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 C(═NR 11 )NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 C(═N—CN)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(═N—CN)NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 C(═N—NO 2 )NR 10 R 11 , (C 0 -C 6 )-alkyl-C(═N—NO 2 )NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)OR 10 , (C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)NR 10 SO 2 R 11 , C(O)NR 10 —(C 0 -C 6 )-alkyl-heteroaryl, C(O)NR 10 —(C 0 -C 6 )-alkyl-aryl, S(O) 2 NR 10 —(C 0 -C 6 )-alkyl-aryl, S(O) 2 NR 10 —(C 0 -C 6 )-alkyl-heteroaryl, S(O) 2 NR 10 -alkyl, S(O) 2 —(C 0 -C 6 )-alkyl-aryl, S(O) 2 —(C 0 -C 6 )-alkyl-heteroaryl, (CO—C 6 )-alkyl-C(O)—NR 11 —CN, O—(C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , S(O) x —(C 0 -C 6 )-alkyl-C(O)OR 10 , S(O) n —(C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)NR 10 —(C 0 -C 6 )-alkyl-NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 —C(O)R 10 , (C 0 -C 6 )-alkyl-NR 10 —C(O)OR 10 , (C 0 -C 6 )-alkyl-NR 10 —C(O)—NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 —S(O) y NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 —S(O) y R 11 , O—(C 0 -C 6 )-alkyl-aryl and O—(C 0 -C 6 )-alkyl-heteroaryl, wherein each R 6 group is optionally substituted by one or more R 14 groups;
R 9 is independently selected from hydrogen, alkyl, halo, CHF 2 , CF 3 , OR 10 , NR 10 R 11 , NO 2 , and CN, wherein alkyl is optionally substituted one or more times;
In another embodiment, in conjunction with any above or below embodiments, R 1 is selected from:
wherein:
R 18 is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR 10 R 11 , CO 2 R 10 , OR 10 , OCF 3 , OCHF 2 , NR 10 CONR 10 R 11 , NR 10 COR 11 , NR 10 SO 2 R 11 , NR 10 SO 2 NR 10 R 11 , SO 2 NR 10 R 11 and NR 10 R 11 , wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl are optionally substituted one or more times;
R 25 is selected from hydrogen, alkyl, cycloalkyl, C(O)NR 10 R 11 and haloalkyl, wherein alkyl, cycloalkyl, and haloalkyl are optionally substituted one or more times;
B 1 is selected from NR 10 , O and S;
D 2 , G 2 , L 2 , M 2 and T 2 are independently selected from CR 18 and N; and
Z is a 5- to 8-membered ring selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted one or more times.
In another embodiment, in conjunction with any above or below embodiments, R 1 is selected from:
In another embodiment, in conjunction with any above or below embodiments, R 1 is selected from:
wherein:
R 12 and R 13 are independently selected from hydrogen, alkyl and halo, wherein alkyl is optionally substituted one or more times, or optionally R 12 and R 13 together form ═O, ═S, ═NR 10 or ═NOR 10 ;
R 18 is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR 10 R 11 , CO 2 R 10 , OR 10 , OCF 3 , OCHF 2 , NR 10 CONR 10 R 11 , NR 10 COR 11 , NR 10 SO 2 R 10 , NR 10 SO 2 NR 10 R 11 , SO 2 NR 10 R 11 and NR 10 R 11 , wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times;
R 19 is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR 10 R 11 , CO 2 R 10 , OR 10 , OCF 3 , OCHF 2 , NR 10 CONR 10 R 11 , NR 10 COR 11 , NR 10 SO 2 R 11 , NR 10 SO 2 NR 10 R 11 , SO 2 NR 10 R 11 and NR 10 R 11 , wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times, or optionally two R 19 groups together at one carbon atom form ═O, ═S, ═NR 10 or ═NOR 10 ;
R 25 is selected from hydrogen, alkyl, cycloalkyl, C(O)NR 10 R 11 and haloalkyl, wherein alkyl, cycloalkyl, and haloalkyl are optionally substituted one or more times;
J and K are independently selected from CR 10 R 18 , NR 10 , O and S(O) x ;
A 1 is selected from NR 10 , O and S(O) x ; and
D 2 , G 2 , J 2 , L 2 , M 2 and T 2 are independently selected from CR 18 and N.
In another embodiment, in conjunction with any above or below embodiments, R 1 is selected from:
In another embodiment, in conjunction with any above or below embodiments, R 1 is selected from:
wherein:
R 18 is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR 10 R 11 , CO 2 R 10 , OR 10 , OCF 3 , OCHF 2 , NR 10 CONR 10 R 11 , NR 10 COR 11 , NR 10 SO 2 R 11 , NR 10 SO 2 NR 10 R 11 , SO 2 NR 10 R 11 and NR 10 R 11 , wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times;
R 19 is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR 10 R 11 , CO 2 R 10 , OR 10 , OCF 3 , OCHF 2 , NR 10 CONR 10 R 11 , NR 10 COR 11 , NR 10 SO 2 R 10 , NR 10 SO 2 NR 10 R 11 , SO 2 NR 10 R 11 and NR 10 R 11 , wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times, or optionally two R 19 groups together at one carbon atom form ═O, ═S, ═NR 10 or ═NOR 11 ;
R 25 is selected from hydrogen, alkyl, cycloalkyl, CONR 10 R 11 and haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times;
L 2 , M 2 , and T 2 are independently selected from CR 18 and N;
D 3 , G 3 , L 3 , M 3 , and T 3 are independently selected from N, CR 18 , (i) and (ii)
with the proviso that one of L 3 , M 3 , T 3 , D 3 , and G 3 is (i) or (ii);
B 1 is selected from the group consisting of NR 10 , O and S(O) x ; and
Q 2 is a 5- to 8-membered ring selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, which is optionally substituted one or more times with R 19 .
In another embodiment, in conjunction with any above or below embodiments, R 1 is selected from:
In another embodiment, in conjunction with any above or below embodiments, R 1 is selected from:
In another embodiment, in conjunction with any above or below embodiments, R 1 is selected from:
In another embodiment, in conjunction with any above or below embodiments, the compounds have the structure:
N-oxides, pharmaceutically acceptable salts, prodrugs, formulations, polymorphs, tautomers, racemic mixtures and stereoisomers thereof.
Another aspect of the invention relates to a pharmaceutical composition comprising an effective amount of the compound according to any of the above or below embodiments.
Another aspect of the invention relates to a method of treating a metalloprotease mediated disease, comprising administering to a subject in need of such treatment an effective amount of a compound according to any of the above or below embodiments.
In another embodiment, in conjunction with any above or below embodiments, the disease is selected from rheumatoid arthritis, osteoarthritis, inflammation, atherosclerosis and multiple sclerosis.
Another aspect of the invention relates to a pharmaceutical composition comprising:
A) an effective amount of a compound according to any of the above or below embodiments;
B) a pharmaceutically acceptable carrier; and
C) a drug, agent or therapeutic selected from: (a) a disease modifying antirheumatic drug; (b) a nonsteroidal anti-inflammatory drug; (c) a COX-2 selective inhibitor; (d) a COX-1 inhibitor; (e) an immunosuppressive; (f) a steroid; (g) a biological response modifier; and (h) a small molecule inhibitor of pro-inflammatory cytokine production.
Another aspect of the invention relates to a method of inhibiting a metalloprotease enzyme, comprising administering a compound according to any of the above or below embodiments.
In another embodiment, in conjunction with any above or below embodiments, the metalloproteinase is selected from MMP-2, MMP-3, MMP-8, and MMP-13.
In another embodiment, in conjunction with any above or below embodiments, the disease is selected from the group consisting of: rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, cancer (e.g. but not limited to melanoma, gastric carcinoma or non-small cell lung carcinoma), inflammation, atherosclerosis, chronic obstructive pulmonary disease, ocular diseases (e.g. but not limited to ocular inflammation, retinopathy of prematurity, macular degeneration with the wet type preferred and corneal neovascularization), neurologic diseases, psychiatric diseases, thrombosis, bacterial infection, Parkinson's disease, fatigue, tremor, diabetic retinopathy, vascular diseases of the retina, aging, dementia, cardiomyopathy, renal tubular impairment, diabetes, psychosis, dyskinesia, pigmentary abnormalities, deafness, inflammatory and fibrotic syndromes, intestinal bowel syndrome, allergies, Alzheimers disease, arterial plaque formation, oncology, periodontal, viral infection, stroke, atherosclerosis, cardiovascular disease, reperfusion injury, trauma, chemical exposure or oxidative damage to tissues, wound healing, hemorroid, skin beautifying, pain, inflammatory pain, bone pain and joint pain, acne, acute alcoholic hepatitis, acute inflammation, acute pancreatitis, acute respiratory distress syndrome, adult respiratory disease, airflow obstruction, airway hyperresponsiveness, alcoholic liver disease, allograft rejections, angiogenesis, angiogenic ocular disease, arthritis, asthma, atopic dermatitis, bronchiectasis, bronchiolitis, bronchiolitis obliterans, burn therapy, cardiac and renal reperfusion injury, celiac disease, cerebral and cardiac ischemia, CNS tumors, CNS vasculitis, colds, contusions, cor pulmonae, cough, Crohn's disease, chronic bronchitis, chronic inflammation, chronic pancreatitis, chronic sinusitis, crystal induced arthritis, cystic fibrosis, delayed type hypersensitivity reaction, duodenal ulcers, dyspnea, early transplantation rejection, emphysema, encephalitis, endotoxic shock, esophagitis, gastric ulcers, gingivitis, glomerulonephritis, glossitis, gout, graft vs. host reaction, gram negative sepsis, granulocytic ehrlichiosis, hepatitis viruses, herpes, herpes viruses, HIV, hypercapnea, hyperinflation, hyperoxia-induced inflammation, hypoxia, hypersensitivity, hypoxemia, inflammatory bowel disease, interstitial pneumonitis, ischemia reperfusion injury, kaposi's sarcoma associated virus, lupus, malaria, meningitis, multi-organ dysfunction, necrotizing enterocolitis, osteoporosis, chronic periodontitis, periodontitis, peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD), pre-term labor, polymyositis, post surgical trauma, pruritis, psoriasis, psoriatic arthritis, pulmatory fibrosis, pulmatory hypertension, renal reperfusion injury, respiratory viruses, restinosis, right ventricular hypertrophy, sarcoidosis, septic shock, small airway disease, sprains, strains, subarachnoid hemorrhage, surgical lung volume reduction, thrombosis, toxic shock syndrome, transplant reperfusion injury, traumatic brain injury, ulcerative colitis, vasculitis, ventilation-perfusion mismatching, and wheeze.
Another aspect of the invention relates to the use of a compound according to any of the above or below embodiments for the manufacture of a medicament for treating an metalloprotease mediated disease.
In another embodiment, in conjunction with any of the above or below embodiments, the metalloprotease mediated disease is selected from the group consisting of MMP-2, MMP-3, MMP-8 and MMP-13 mediated diseases.
The specification and claims contain listing of species using the language “selected from . . . and . . . ” and “is . . . or . . . ” (sometimes referred to as Markush groups). When this language is used in this application, unless otherwise stated it is meant to include the group as a whole, or any single members thereof, or any subgroups thereof. The use of this language is merely for shorthand purposes and is not meant in any way to limit the removal of individual elements or subgroups as needed.
The terms “alkyl” or “alk”, as used herein alone or as part of another group, denote optionally substituted, straight and branched chain saturated hydrocarbon groups, preferably having 1 to 10 carbons in the normal chain, most preferably lower alkyl groups. Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkenyl, alkynyl, aryl (e.g., to form a benzyl group), cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH 2 —CO—), substituted carbamoyl ((R 10 )(R 11 )N—CO— wherein R 10 or R 11 are as defined below, except that at least one of R 10 or R 11 is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (—SH).
The terms “alkyl” or “alk”, as used herein alone or as part of another group, denote optionally substituted, straight and branched chain saturated hydrocarbon groups, preferably having 1 to 10 carbons in the normal chain, most preferably lower alkyl groups. Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkenyl, alkynyl, aryl (e.g., to form a benzyl group), cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH 2 —CO—), substituted carbamoyl ((R 10 )(R 11 )N—CO— wherein R 10 or R 11 are as defined below, except that at least one of R 10 or R 11 is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (—SH).
The terms “lower alk” or “lower alkyl” as used herein, denote such optionally substituted groups as described above for alkyl having 1 to 4 carbon atoms in the normal chain.
The term “alkoxy” denotes an alkyl group as described above bonded through an oxygen linkage (—O—).
The term “alkenyl”, as used herein alone or as part of another group, denotes optionally substituted, straight and branched chain hydrocarbon groups containing at least one carbon to carbon double bond in the chain, and preferably having 2 to 10 carbons in the normal chain. Exemplary unsubstituted such groups include ethenyl, propenyl, isobutenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH 2 —CO—), substituted carbamoyl ((R 10 )(R 11 )N—CO— wherein R 10 or R 11 are as defined below, except that at least one of R 10 or R 11 is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (—SH).
The term “alkynyl”, as used herein alone or as part of another group, denotes optionally substituted, straight and branched chain hydrocarbon groups containing at least one carbon to carbon triple bond in the chain, and preferably having 2 to 10 carbons in the normal chain. Exemplary unsubstituted such groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH 2 —CO—), substituted carbamoyl ((R 10 )(R 11 )N—CO— wherein R 10 or R 11 are as defined below, except that at least one of R 10 or R 11 is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (—SH).
The term “cycloalkyl”, as used herein alone or as part of another group, denotes optionally substituted, saturated cyclic hydrocarbon ring systems, containing one ring with 3 to 9 carbons. Exemplary unsubstituted such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, and cyclododecyl. Exemplary substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
The term “bicycloalkyl”, as used herein alone or as part of another group, denotes optionally substituted, saturated cyclic bridged hydrocarbon ring systems, desirably containing 2 or 3 rings and 3 to 9 carbons per ring. Exemplary unsubstituted such groups include, but are not limited to, adamantyl, bicyclo[2.2.2]octane, bicyclo[2.2.1]heptane and cubane. Exemplary substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
The term “spiroalkyl”, as used herein alone or as part of another group, denotes optionally substituted, saturated hydrocarbon ring systems, wherein two rings of 3 to 9 carbons per ring are bridged via one carbon atom. Exemplary unsubstituted such groups include, but are not limited to, spiro[3.5]nonane, spiro[4.5]decane or spiro[2.5]octane. Exemplary substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
The term “spiroheteroalkyl”, as used herein alone or as part of another group, denotes optionally substituted, saturated hydrocarbon ring systems, wherein two rings of 3 to 9 carbons per ring are bridged via one carbon atom and at least one carbon atom is replaced by a heteroatom independently selected from N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized. Exemplary unsubstituted such groups include, but are not limited to, 1,3-diaza-spiro[4.5]decane-2,4-dione. Exemplary substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
The terms “ar” or “aryl”, as used herein alone or as part of another group, denote optionally substituted, homocyclic aromatic groups, preferably containing 1 or 2 rings and 6 to 12 ring carbons. Exemplary unsubstituted such groups include, but are not limited to, phenyl, biphenyl, and naphthyl. Exemplary substituents include, but are not limited to, one or more nitro groups, alkyl groups as described above or groups described above as alkyl substituents.
The term “heterocycle” or “heterocyclic system” denotes a heterocyclyl, heterocyclenyl, or heteroaryl group as described herein, which contains carbon atoms and from 1 to 4 heteroatoms independently selected from N, O and S and including any bicyclic or tricyclic group in which any of the above-defined heterocyclic rings is fused to one or more heterocycle, aryl or cycloalkyl groups. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom.
Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolinyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, oxindolyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl.
Further examples of heterocycles include, but not are not limited to, “heterobicycloalkyl” groups such as 7-oxa-bicyclo[2.2.1]heptane, 7-aza-bicyclo[2.2.1]heptane, and 1-aza-bicyclo[2.2.2]octane.
“Heterocyclenyl” denotes a non-aromatic monocyclic or multicyclic hydrocarbon ring system of about 3 to about 10 atoms, desirably about 4 to about 8 atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur atoms, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. Ring sizes of rings of the ring system may include 5 to 6 ring atoms. The designation of the aza, oxa or thia as a prefix before heterocyclenyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The heterocyclenyl may be optionally substituted by one or more substituents as defined herein. The nitrogen or sulphur atom of the heterocyclenyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. “Heterocyclenyl” as used herein includes by way of example and not limitation those described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”, 82:5566 (1960), the contents all of which are incorporated by reference herein. Exemplary monocyclic azaheterocyclenyl groups include, but are not limited to, 1,2,3,4-tetrahydrohydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Exemplary oxaheterocyclenyl groups include, but are not limited to, 3,4-dihydro-2H-pyran, dihydrofuranyl, and fluorodihydrofuranyl. An exemplary multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl.
“Heterocyclyl,” or “heterocycloalkyl,” denotes a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 carbon atoms, desirably 4 to 8 carbon atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur. Ring sizes of rings of the ring system may include 5 to 6 ring atoms. The designation of the aza, oxa or thia as a prefix before heterocyclyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The heterocyclyl may be optionally substituted by one or more substituents which may be the same or different, and are as defined herein. The nitrogen or sulphur atom of the heterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
“Heterocyclyl” as used herein includes by way of example and not limitation those described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”, 82:5566 (1960). Exemplary monocyclic heterocyclyl rings include, but are not limited to, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
“Heteroaryl” denotes an aromatic monocyclic or multicyclic ring system of about 5 to about 10 atoms, in which one or more of the atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur. Ring sizes of rings of the ring system include 5 to 6 ring atoms. The “heteroaryl” may also be substituted by one or more substituents which may be the same or different, and are as defined herein. The designation of the aza, oxa or thia as a prefix before heteroaryl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. A nitrogen atom of a heteroaryl may be optionally oxidized to the corresponding N-oxide. Heteroaryl as used herein includes by way of example and not limitation those described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”, 82:5566 (1960). Exemplary heteroaryl and substituted heteroaryl groups include, but are not limited to, pyrazinyl, thienyl, isothiazolyl, oxazolyl, pyrazolyl, furazanyl, pyrrolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, benzoazaindole, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, benzthiazolyl, dioxolyl, furanyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, oxazinyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinazolinyl, quinolinyl, tetrazinyl, tetrazolyl, 1,3,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, thiatriazolyl, thiazinyl, thiazolyl, thienyl, 5-thioxo-1,2,4-diazolyl, thiomorpholino, thiophenyl, thiopyranyl, triazolyl and triazolonyl.
The phrase “fused” means, that the group, mentioned before “fused” is connected via two adjacent atoms to the ring system mentioned after “fused” to form a bicyclic system. For example, “heterocycloalkyl fused aryl” includes, but is not limited to, 2,3-dihydro-benzo[1,4]dioxine, 4H-benzo[1,4]oxazin-3-one, 3H-Benzooxazol-2-one and 3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one.
The term “amino” denotes the radical —NH 2 wherein one or both of the hydrogen atoms may be replaced by an optionally substituted hydrocarbon group. Exemplary amino groups include, but are not limited to, n-butylamino, tert-butylamino, methylpropylamino and ethyldimethylamino.
The term “cycloalkylalkyl” denotes a cycloalkyl-alkyl group wherein a cycloalkyl as described above is bonded through an alkyl, as defined above. Cycloalkylalkyl groups may contain a lower alkyl moiety. Exemplary cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclopentylethyl, cyclohexylpropyl, cyclopropylpropyl, cyclopentylpropyl, and cyclohexylpropyl.
The term “arylalkyl” denotes an aryl group as described above bonded through an alkyl, as defined above.
The term “heteroarylalkyl” denotes a heteroaryl group as described above bonded through an alkyl, as defined above.
The term “heterocyclylalkyl,” or “heterocycloalkylalkyl,” denotes a heterocyclyl group as described above bonded through an alkyl, as defined above.
The terms “halogen”, “halo”, or “hal”, as used herein alone or as part of another group, denote chlorine, bromine, fluorine, and iodine.
The term “haloalkyl” denotes a halo group as described above bonded though an alkyl, as defined above. Fluoroalkyl is an exemplary group.
The term “aminoalkyl” denotes an amino group as defined above bonded through an alkyl, as defined above.
The phrase “bicyclic fused ring system wherein at least one ring is partially saturated” denotes an 8- to 13-membered fused bicyclic ring group in which at least one of the rings is non-aromatic. The ring group has carbon atoms and optionally 1-4 heteroatoms independently selected from N, O and S. Illustrative examples include, but are not limited to, indanyl, tetrahydronaphthyl, tetrahydroquinolyl and benzocycloheptyl.
The phrase “tricyclic fused ring system wherein at least one ring is partially saturated” denotes a 9- to 18-membered fused tricyclic ring group in which at least one of the rings is non-aromatic. The ring group has carbon atoms and optionally 1-7 heteroatoms independently selected from N, O and S. Illustrative examples include, but are not limited to, fluorene, 10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 2,2a,7,7a-tetrahydro-1H-cyclobuta[a]indene.
The term “pharmaceutically acceptable salts” refers 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 basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Examples therefore may be, but are not limited to, sodium, potassium, choline, lysine, arginine or N-methyl-glucamine salts, and the like.
The pharmaceutically acceptable salts include the conventional non-toxic salts or the 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 those derived from inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as, but not limited to, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Organic solvents include, but are not limited to, nonaqueous media like ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa., 1990, p. 1445, the disclosure of which is hereby incorporated by reference.
The phrase “pharmaceutically acceptable” denotes those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
The phrase “pharmaceutically acceptable carrier” denotes media generally accepted in the art for the delivery of biologically active agents to mammals, e.g., humans. Such carriers are generally formulated according to a number of factors well within the purview of those of ordinary skill in the art to determine and account for. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and, the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, well known to those of ordinary skill in the art. Non-limiting examples of a pharmaceutically acceptable carrier are hyaluronic acid and salts thereof, and microspheres (including, but not limited to poly(D,L)-lactide-co-glycolic acid copolymer (PLGA), poly(L-lactic acid) (PLA), poly(caprolactone (PCL) and bovine serum albumin (BSA)). Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources, e.g., Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, the contents of which are incorporated herein by reference.
Pharmaceutically acceptable carriers particularly suitable for use in conjunction with tablets include, for example, inert diluents, such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents, such as croscarmellose sodium, cross-linked povidone, maize starch, or alginic acid; binding agents, such as povidone, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example celluloses, lactose, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with non-aqueous or oil medium, such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.
The compositions of the invention may also be formulated as suspensions including a compound of the present invention in admixture with at least one pharmaceutically acceptable excipient suitable for the manufacture of a suspension. In yet another embodiment, pharmaceutical compositions of the invention may be formulated as dispersible powders and granules suitable for preparation of a suspension by the addition of suitable excipients.
Carriers suitable for use in connection with suspensions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate); and thickening agents, such as carbomer, beeswax, hard paraffin or cetyl alcohol. The suspensions may also contain one or more preservatives such as acetic acid, methyl and/or n-propyl p-hydroxy-benzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
Cyclodextrins may be added as aqueous solubility enhancers. Preferred cyclodextrins include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of α-, β-, and γ-cyclodextrin. The amount of solubility enhancer employed will depend on the amount of the compound of the present invention in the composition.
The term “formulation” denotes a product comprising the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical formulations of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutical carrier.
The term “N-oxide” denotes compounds that can be obtained in a known manner by reacting a compound of the present invention including a nitrogen atom (such as in a pyridyl group) with hydrogen peroxide or a peracid, such as 3-chloroperoxy-benzoic acid, in an inert solvent, such as dichloromethane, at a temperature between about −10-80° C., desirably about 0° C.
The term “polymorph” denotes a form of a chemical compound in a particular crystalline arrangement. Certain polymorphs may exhibit enhanced thermodynamic stability and may be more suitable than other polymorphic forms for inclusion in pharmaceutical formulations.
The compounds of the invention can contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. According to the invention, the chemical structures depicted herein, and therefore the compounds of the invention, encompass all of the corresponding enantiomers and stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.
The term “racemic mixture” denotes a mixture that is about 50% of one enantiomer and about 50% of the corresponding enantiomer relative to all chiral centers in the molecule. Thus, the invention encompasses all enantiomerically-pure, enantiomerically-enriched, and racemic mixtures of compounds of Formulas (I) and (II).
Enantiomeric and stereoisomeric mixtures of compounds of the invention can be resolved into their component enantiomers or stereoisomers by well-known methods. Examples include, but are not limited to, the formation of chiral salts and the use of chiral or high performance liquid chromatography “HPLC” and the formation and crystallization of chiral salts. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972); Stereochemistry of Organic Compounds, Ernest L. Eliel, Samuel H. Wilen and Lewis N. Manda (1994 John Wiley & Sons, Inc.), and Stereoselective Synthesis A Practical Approach, Mihaly Nogradi (1995 VCH Publishers, Inc., NY, N.Y.). Enantiomers and stereoisomers can also be obtained from stereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
“Substituted” is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O) group, then 2 hydrogens on the atom are replaced.
Unless moieties of a compound of the present invention are defined as being unsubstituted, the moieties of the compound may be substituted. In addition to any substituents provided above, the moieties of the compounds of the present invention may be optionally substituted with one or more groups independently selected from:
C 1 -C 4 alkyl;
C 2 -C 4 alkenyl;
C 2 -C 4 alkynyl;
CF 3 ;
halo;
OH;
O—(C 1 -C 4 alkyl);
OCH 2 F;
OCHF 2 ;
OCF 3 ;
ONO 2 ;
OC(O)—(C 1 -C 4 alkyl);
OC(O)—(C 1 -C 4 alkyl);
OC(O)NH—(C 1 -C 4 alkyl);
OC(O)N(C 1 -C 4 alkyl) 2 ;
OC(S)NH—(C 1 -C 4 alkyl);
OC(S)N(C 1 -C 4 alkyl) 2 ;
SH;
S—(C 1 -C 4 alkyl);
S(O)—(C 1 -C 4 alkyl);
S(O) 2 —(C 1 -C 4 alkyl);
SC(O)—(C 1 -C 4 alkyl);
SC(O)O—(C 1 -C 4 alkyl);
NH 2 ;
N(H)—(C 1 -C 4 alkyl);
N(C 1 -C 4 alkyl) 2 ;
N(H)C(O)—(C 1 -C 4 alkyl);
N(CH 3 )C(O)—(C 1 -C 4 alkyl);
N(H)C(O)—CF 3 ;
N(CH 3 )C(O)—CF 3 ;
N(H)C(S)—(C 1 -C 4 alkyl);
N(CH 3 )C(S)—(C 1 -C 4 alkyl);
N(H)S(O) 2 —(C 1 -C 4 alkyl);
N(H)C(O)NH 2 ;
N(H)C(O)NH—(C 1 -C 4 alkyl);
N(CH 3 )C(O)NH—(C 1 -C 4 alkyl);
N(H)C(O)N(C 1 -C 4 alkyl) 2 ;
N(CH 3 )C(O)N(C 1 -C 4 alkyl) 2 ;
N(H)S(O) 2 NH 2 );
N(H)S(O) 2 NH—(C 1 -C 4 alkyl);
N(CH 3 )S(O) 2 NH—(C 1 -C 4 alkyl);
N(H)S(O) 2 N(C 1 -C 4 alkyl) 2 ;
N(CH 3 )S(O) 2 N(C 1 -C 4 alkyl) 2 ;
N(H)C(O)O—(C 1 -C 4 alkyl);
N(CH 3 )C(O)O—(C 1 -C 4 alkyl);
N(H)S(O) 2 O—(C 1 -C 4 alkyl);
N(CH 3 )S(O) 2 O—(C 1 -C 4 alkyl);
N(CH 3 )C(S)NH—(C 1 -C 4 alkyl);
N(CH 3 )C(S)N(C 1 -C 4 alkyl) 2 ;
N(CH 3 )C(S)O—(C 1 -C 4 alkyl);
N(H)C(S)NH 2 ;
NO 2 ;
CO 2 H;
CO 2 —(C 1 -C 4 alkyl);
C(O)N(H)OH;
C(O)N(CH 3 )OH:
C(O)N(CH 3 )OH;
C(O)N(CH 3 )O—(C 1 -C 4 alkyl);
C(O)N(H)—(C 1 -C 4 alkyl);
C(O)N(C 1 -C 4 alkyl) 2 ;
C(S)N(H)—(C 1 -C 4 alkyl);
C(S)N(C 1 -C 4 alkyl) 2 ;
C(NH)N(H)—(C 1 -C 4 alkyl);
C(NH)N(C 1 -C 4 alkyl) 2 ;
C(NCH 3 )N(H)—(C 1 -C 4 alkyl);
C(NCH 3 )N(C 1 -C 4 alkyl) 2 ;
C(O)—(C 1 -C 4 alkyl);
C(NH)—(C 1 -C 4 alkyl);
C(NCH 3 )—(C 1 -C 4 alkyl);
C(NOH)—(C 1 -C 4 alkyl);
C(NOCH 3 )—(C 1 -C 4 alkyl);
CN;
CHO;
CH 2 OH;
CH 2 O—(C 1 -C 4 alkyl);
CH 2 NH 2 ;
CH 2 N(H)—(C 1 -C 4 alkyl);
CH 2 N(C 1 -C 4 alkyl) 2 ;
aryl;
heteroaryl;
cycloalkyl; and
heterocyclyl.
In some cases, a ring substituent may be shown as being connected to the ring by a bond extending from the center of the ring. The number of such substituents present on a ring is indicated in subscript by a number. Moreover, the substituent may be present on any available ring atom, the available ring atom being any ring atom which bears a hydrogen which the ring substituent may replace. For illustrative purposes, if variable R X were defined as being:
this would indicate a cyclohexyl ring bearing five R X substituents. The R X substituents may be bonded to any available ring atom. For example, among the configurations encompassed by this are configurations such as:
These configurations are illustrative and are not meant to limit the scope of the invention in any way.
Biological Activity
The inhibiting activity towards different metalloproteases of the heterocyclic metalloprotease inhibiting compounds of the present invention may be measured using any suitable assay known in the art. A standard in vitro assay for measuring the metalloprotease inhibiting activity is described in Examples 1700 to 1706. The heterocyclic metalloprotease inhibiting compounds show activity towards MMP-2, MMP-3, MMP-8, MMP-12, MMP-13, ADAMTS-4 and/or ADAMTS-5.
The heterocyclic metalloprotease inhibiting compounds of the invention have an MMP-13 inhibition activity (IC 50 MMP-13) ranging from below 0.2 nM to about 20 μM, and typically, from about 0.2 nM to about 1 μM. Heterocyclic metalloprotease inhibiting compounds of the invention desirably have an MMP inhibition activity ranging from about 0.2 nM to about 20 nM. Table 1 lists typical examples of heterocyclic metalloprotease inhibiting compounds of the invention that have an MMP-13 activity lower than 100 nM (Group A) and from 100 nM to 20 μM (Group B).
TABLE 1
Summary of MMP-13 Activity for Compounds
Group
Ex. #
A
1, 2/25, 2/29, 2/33, 2/52, 2/67, 2/89, 2/90, 2/94, 2/95, 2/103,
2/104, 2/107, 2/108, 2/113, 2/114, 2/117, 2/118, 2/119, 2/120,
2/121, 2/122, 2/125, 2/126, 2/129, 2/131, 2/132, 2/145, 2/152,
2/153, 2/166, 2/167, 2/169, 2/170, 2/171, 2/173, 2/174, 2/175,
2/176, 2/188, 2/208, 2/209, 2/210, 2/211, 2/219, 2/224, 2/231,
2/240, 2/245, 2/246, 2/251, 2/255, 2/267, 2/290, 2/309, 2/313,
2/316, 2/332, 2/354, 2/359, 2/367, 3/382, 2/413, 2/417, 2/526,
2/528, 3, 4/14, 4/15, 15, 15/2, 15/4, 15/5, 19, 22, 22/1, 22/2,
26, 28, 41, 42/2, 43
B
2/24, 2/34, 2/130, 2/143, 2/144, 2/146, 2/291, 2/292, 2/294,
2/302, 2/305, 2/307, 2/319, 2/323, 2/327, 2/328, 2/333, 2/344,
2/352, 2/355, 2/368, 2/383, 2/384, 2/428, 2/433, 2/530, 2/538,
39/7, 39/20
Some heterocyclic metalloprotease inhibiting compounds of the invention have an MMP-8 inhibition activity (IC 50 MMP-8) ranging from below 5 nM to about 20 μM, and typically, from about 10 nM to about 2 μM. Heterocyclic metalloprotease inhibiting compounds of the invention desirably have an MMP inhibition activity ranging below 100 nM. Table 2 lists typical examples of heterocyclic metalloprotease inhibiting compounds of the invention that have an MMP-8 activity lower than 250 nM (Group A) and from 250 nM to 20 μM (Group B).
TABLE 2
Summary of MMP-8 Activity for Compounds
Group
Ex. #
A
1, 2/25, 2/33, 2/52, 2/94, 2/95, 2/103, 2/104, 2/107, 2/113,
2/114, 2/117, 2/118, 2/121, 2/122, 2/125, 2/126, 2/131, 2/132,
2/152, 2/153, 2/166, 2/167, 2/169, 2/170, 2/171, 2/174, 2/175,
2/176, 2/188, 2/209, 2/211, 2/218, 2/223, 2/224, 2/230, 2/240,
2/251, 2/255, 2/267, 2/269, 2/313, 2/413, 4/14, 4/15, 15, 15/2,
19, 22/1, 26, 42/2, 43/1
B
2/129, 2/130, 2/173, 2/290, 2/292, 2/316, 2/382, 2/383, 2/384,
2/387, 2/417, 2/428, 2/433, 2/528, 2/529, 2/538, 3, 15/3, 22,
22/2, 39/7, 39/20, 41, 42, 42/1
Some heterocyclic metalloprotease inhibiting compounds of the invention have an MMP-3 inhibition activity (IC 50 MMP-3) ranging from below 10 nM to about 20 μM, and typically, from about 50 nM to about 2 nM. Heterocyclic metalloprotease inhibiting compounds of the invention desirably have an MMP inhibition activity ranging below 100 nM. Table 3 lists typical examples of heterocyclic metalloprotease inhibiting compounds of the invention that have an MMP-3 activity lower than 250 nM (Group A) and from 250 nM to 20 μM (Group B).
TABLE 3
Summary of MMP-3 Activity for Compounds
Group
Ex. #
A
2/103, 2/104, 28, 42/2, 43
B
2/95, 2/107, 2/108, 2/132, 2/171, 2/188, 2/208, 2/209, 2/210,
2/211, 2/212, 2/231, 2/232, 2/236, 2/240, 2/245, 3, 4/15, 15,
15/2, 19, 22, 22/1, 22/2, 26, 39/7, 42/1
The synthesis of metalloprotease inhibiting compounds of the invention and their biological activity assay are described in the following examples which are not intended to be limiting in any way.
Schemes
Provided below are schemes according to which compounds of the present invention may be prepared.
In some embodiments the compounds of Formula (I) and (II) are synthesized by the general methods shown in Scheme 1 to Scheme 3.
Route A
An carbonic acid and amino substituted compound (e.g. 4-amino-nicotinic acid) is condensed (e.g. EtOH/reflux) with chloro-oxo-acetic acid ethyl ester as previously described e.g. in WO2005/105760 in pyridine to give an oxazine ethyl ester (Scheme 1). This intermediate is then converted into the corresponding pyrimidine derivative using a suitable reagent (e.g. NH 4 OAc, HOAc, EtOH/80° C.). For example, when ring Q is a pyridine ring. the compound can be obtained according this route A.
Route B
An ester and amino substituted compound (e.g. 2-amino-benzoic acid ethyl ester) is condensed (e.g. 4N HCl, dioxane/50° C.) with ethyl cyanoformate as previously described e.g. in WO2005/105760, to give a 1,3-pyrimidine-4-one ethyl ester (Scheme 1).
Route C
An carboxamide and amino substituted compound (e.g. 2-amino-benzamide) is condensed with an suitable reagent (e.g oxalic acid diethyl ester or acetic acid anhydride as described in DD272079A1 or chloro-oxo-acetic acid ethyl ester as described in J. Med. Chem. 1979, 22(5), 505-510) to give a 1,3-pyrimidine-4-one ethyl ester (Scheme 1).
Saponification (e.g. aqueous LiOH) of the 1,3-pyrimidine-4-one derivative of Scheme 1 above gives the corresponding bicyclic carboxylic acid (Scheme 2). Activated acid coupling (e.g. EDCI/HOAt) with R 1 R 2 NH (e.g. 6-aminomethyl-4H-benzo[1,4]oxazin-3-one) in a suitable solvent gives the desired amide. The saponification/coupling step can be combined by stirring the ester with the free amine at elevated temperature (e.g. 200° C., 15 min) under microwave irradiation.
A substituted ketone (e.g. tetrahydrothiophen-3-one) is condensed (e.g. toluene/reflux with Dean-Stark apparatus) with ethyl cyanoacetate, acetic acid and ammonium acetate to afford the desired ethyl ester-cyano substituted double bond. (Scheme 3). This intermediate is then converted into the corresponding thiophene derivative using suitable reagents (e.g. sulphur, Et 2 NH, EtOH/50° C.) as previously described e.g. in J. prakt. Chem. 1973, 315, 39-43 or Monatsh. Chem. 2001, 132, 279-293.
The Knoevenage/cyclisation step can be combined by stirring the ketone with ethyl cyanoacetate, sulphur and a base (e.g. Et 3 N) in a suitable solvent (e.g EtOH/50° C.), following the Gewald type reaction as described e.g. in J. prakt. Chem. 1973, 315, 39-43 or Bioorg. Med. Chem. 2002, 10, 3113-3122.
In compounds, where the one L b in formula (I) is a nitrogen atom, the following procedure can be applied (Scheme 4).
For example, N-(pyrazol-3-yl)acetamide acetate can be cyclizised with carbonic acid diethyl ester to 2-methylpyrazolo[1,5a]-s-triazine-4-one ( J. Heterocycl. Chem. 1985, 22, 601-634) and further oxidized to the corresponding acid (e.g. by SeO 2 and then oxone).
In ring Q of the product in Scheme 1 to Scheme 4, further functional group manipulation can be applied (e.g. J. March, Advanced Organic Chemistry, Wiley&Sons), e.g. palladium catalyzed halogen-cyanide exchange or nucleophilic substitution.
EXAMPLES AND METHODS
All reagents and solvents were obtained from commercial sources and used without further purification. Proton spectra ( 1 H-NMR) were recorded on a 400 MHz and a 250 MHz NMR spectrometer in deuterated solvents. Purification by column chromatography was performed using silica gel, grade 60, 0.06-0.2 mm (chromatography) or silica gel, grade 60, 0.04-0.063 mm (flash chromatography) and suitable organic solvents as indicated in specific examples. Preparative thin layer chromatography was carried out on silica gel plates with UV detection.
Preparative Examples are directed to intermediate compounds useful in preparing the compounds of the present invention.
Preparative Example 4
Step A
2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylic acid methyl ester (1 g) was dissolved in a 4M solution of HCl in 1,4-dioxane (20 mL) and cyanoacetic acid ethyl ester (0.6 mL) was added. The mixture was stirred at 40° C. overnight, concentrated and purified by extraction with ethyl acetate from an aqueous solution to afford the title compound (1.3 g, 99%). [MH] + =265.
Preparative Examples 5/7 to 5/106
Following similar procedures as described in the Preparative Examples 4 except using the amines indicated in Table I.2 below, the following compounds were prepared.
TABLE I.2
Ex. #
amine
product
yield
5/7
59% [MH] + = 275
5/10
n.d. [MH] + = 294
5/35
74% [MH] + = 306
5/36
36% [MH] + = 322
5/41
88% [MH] + = 329
5/43
46% [MH] + = 357
5/45
89% [MH] + = 337
5/47
100% [MH] + = 293
5/48
27% [MH] + = 297
5/49
100% [MH] + = 283
5/51
95% [MH] + = 307
5/53
100% [MH] + = 297
5/59
84% [MH] + = 331
5/60
96% [MH] + = 355
5/63
7% [MH] + = 281
5/64
28% [MH] + = 394
5/69
n.d. [MH] + = 406
5/71
97% [MH] + = 351
5/72
96% [MH] + = 337
5/73
35% [MH] + = 295
5/74
30% (cryst from, CH 2 Cl 2 - cyclohexane) [MH] + = 311
5/76
38% [MH] + = 365
5/87
100% [MH] + = 351
5/88
69% [MH] + = 351
5/89
n.d. [MH] + = 323
5/91
100% [MH] + = 351
5/95
35% [MH] + = 400
5/106
n.d. [MH] + = n.d.
Preparative Example 9
Step A
A solution of the commercially available 4-Isopropyl-phenylamine (1.35 g) and N-Bromosuccinimide (2.0 g) in benzene (20 mL) was stirred at room temperature. After 12 h, the precipitated solid was filtered off, and the filtrate was concentrated and purified by chromatography (silica, hexane/EtOAc) to afford the title compound (1.8 g, 89%). [MH] + =214.
Step B
A solution of the intermediate from Step A above (800 mg), xantphos (36 mg), Pd 2 (dba) 3 (20 mg), triethylamine (1.4 mL) in methanol (10 mL) was heated in autoclave under carbon monoxide at 50 psi at 100° C. for 6 h. The solution was concentrated and purified by chromatography (silica, hexane/EtOAc) to afford the title compound (360 mg, 49%). [MH] + =194.
Preparative Example 10/4
Following similar procedures as described in the Preparative Example 9 except using the aniline derivative indicated in Table I.4 below, the following compounds were prepared.
TABLE I.4
Ex. #
aniline
product
yield
10/4
10% [MH] + = 259
Preparative Example 11
Step A
To a solution of the Preparative Example 4 above (503 mg) in THF (20 mL) was added 1M aqueous LiOH (5 mL). The resulting mixture was stirred at room temperature for 1 h, concentrated and neutralized with 1M aqueous HCl. The residue was filtered off and used without further purification (420 mg, 87%). [MH] + =237.
Preparative Examples 12/9-12/104
Following a similar procedure as described in the Preparative Example 11 except using the ester indicated in Table I.5 below, the following compounds were prepared.
TABLE I.5
Ex. #
ester
product
yield
12/9
>99% [MH] + = 247
12/12
n.d. [MH] + = 266
12/13
83% [MH] + = 251
12/43
n.d. [MH] + = 278
12/44
92% [MH] + = 294
12/49
31% [MH] + = 301
12/51
78% [MH] + = 329
12/54
56% [MH] + = 309
12/56
68% [MH] + = 265
12/57
100% [MH] + = 269
12/58
69% [MH] + = 255
12/60
84% [MH] + = 279
12/62
65% [MH] + = 269
12/68
89% [MH] + = 303
12/69
100% [MH] + = 327
12/73
100% [MH] + = 253
12/77
45% [MH] + = 366
12/84
n.d. [MH] + = 378
12/85
63% [MH] + = 323
12/86
18% [MH] + = 309
12/87
74% [MH] + = 267
12/89
93% [MH] + = 283
12/91
63% [MH] + = 337
12/92
91% [MH] + = 323
12/93
70% [MH] + = 323
12/94
21% (2 steps) [MH] + = 295
12/96
47% [MH] + = 323
12/97
68% [MH] + = 352
12/104
92% [MH] + = 372
Preparative Example 13
Step A
A degassed suspension of commercially available 6-Bromo-4H-benzo[1,4]oxazin-3-one (8.39 g), Zn(CN) 2 (3.46 g) and Pd(PPh 3 ) 4 (2.13 g) in DMF (70 mL) was stirred in a oil bath (80° C.) overnight. The mixture was cooled to room temperature and then poured into water (500 mL). The precipitate was collected by suction, air dried, washed with pentane, dissolved in CH 2 Cl 2 /MeOH (1:1), filtered through an silica pad and concentrated to yield a yellow solid (5.68 g, 89%). [MH] + =175.
Step B
To an ice cooled solution of the title compound from Step A above (5.6 g), di-tert-butyl dicarbonate (14.06 g) and NiCl 2 .6H 2 O (1.53 g) in MeOH, NaBH 4 (8.51 g) was added in portions. The mixture was vigorously stirred for 1 h at 0° C. and 1 h at room temperature. After the addition of diethylenetriamine (3.5 mL) the mixture was concentrated, diluted with EtOAc, washed subsequently with 1N HCl, saturated aqueous NaHCO 3 and saturated aqueous NaCl, dried (MgSO 4 ), concentrated to afford the title compound as an off-white solid (7.91 g, 88%). [M+Na] + =397.
Step C
The title compound from Step B above (7.91 g) was dissolved in a 4M solution of HCl in 1,4-dioxane (120 mL), stirred for 14 h, concentrated, suspended in Et 2 O, filtered and dried to afford the title compound as an off-white solid (5.81 g, 96%). [M-NH 3 Cl] + =162.
Preparative Example 14
Step A
A solution of commercially available 7-cyano-1,2,3,4-tetrahydroisoquinoline (2.75 g), K 2 CO 3 (3.60 g) and benzylchloroformate (2.7 mL) in THF/H 2 O was stirred overnight and then concentrated. The residue was diluted with EtOAc, washed with 10% aqueous citric acid, saturated aqueous NaHCO 3 and brine, dried (MgSO 4 ) and concentrated. The residue was dissolved in MeOH (100 mL) and di-tert-butyl dicarbonate (7.60 g) and NiCl 2 .6H 2 O (400 mg) was added. The solution was cooled to 0° C. and NaBH 4 (2.60 g) was added in portions. The mixture was allowed to reach room temperature and then vigorously stirred overnight. After the addition of diethylenetriamine (2 mL) the mixture was concentrated, diluted with EtOAc, washed subsequently with 10% aqueous citric acid, saturated aqueous NaHCO 3 and saturated aqueous NaCl, dried (MgSO 4 ), concentrated and purified by chromatography (silica, CH 2 Cl 2 /MeOH) to afford the title compound as a colorless oil (1.81 g, 26%). [MH] + =397.
Preparative Example 15
Step A
A mixture of the title compound from the Preparative Example 14 (1.81 g) and Pd/C (10 wt %, 200 mg) in EtOH (50 mL) was hydrogenated at atmospheric pressure overnight, filtered and concentrated to a volume of ˜20 mL. 3,4-Diethoxy-3-cyclobutene-1,2-dione (0.68 mL) and NEt 3 (0.5 mL) were added and the mixture was heated to reflux for 4 h. Concentration and purification by chromatography (silica, cyclohexane/EtOAc) afforded a slowly crystallizing colorless oil. This oil was dissolved in EtOH (20 mL) and a 28% solution of NH 3 in H 2 O (100 mL) was added. The mixture was stirred for 3 h, concentrated, slurried in H 2 O, filtered and dried under reduced pressure. The remaining residue was dissolved in a 4M solution of HCl in 1,4-dioxane (20 mL), stirred for 14 h, concentrated, suspended in Et 2 O, filtered and dried to afford the title compound as an off-white solid (1.08 g, 92%). [M-Cl] + =258.
Preparative Example 16
Step A
Tetrahydrothiophen-3-one (1 g), ethyl cyanoacetate (1.44 g), acetic acid (70 μL) and ammonium acetate (30 mg) in toluene were heated to reflux in presence of a Dean-Stark overnight. After concentration of the mixture, a purification by chromatography (silica cyclohexane/EtOAc 9/1) afforded a yellow oil (1.04 g, 54%). [MH] + =198.
Preparative Examples 17/1 to 17/20
Following similar procedures as described in the Preparative Examples 16 except using the ketones indicated in Table I.6 below, the following compounds were prepared.
TABLE I.6
Ex. #
Ketone
product
yield
17/1
27% [MH] + = 212
17/2
n.d. [MH] + = 309
17/5
n.d. [MH] + = n.d.
17/7
93% [MH] + = 266
17/8
83% [MH] + = 252
17/9
37% [MH] + = 210
17/10
n.d. [MH] + = 226
17/12
n.d. [MH] + = 280
17/13
40% [MH] + = 266
17/14
n.d. [MH] + = 266
17/15
n.d. [MH] + = 238
17/17
41% [MH] + = 266
17/20
n.d. [MH] + = n.d.
Preparative Example 18
Step A
A mixture of the title compound from the Preparative Example 16 (0.5 g) and sulfur (86 mg) in MeOH (5 mL) were heated at 50° C. Diethylamine (135 μL) was added slowly and the mixture was stirred at 50° C. for 2 h. After concentration of the mixture, a purification by chromatography (silica cyclohexane/EtOAc 9/1) afforded a orange solid (345 mg, 59%). [MH] + =230.
Preparative Examples 18/1 to 18/21
Following similar procedures as described in the Preparative Examples 18 except using the adduct indicated in Table I.7 below, the following compounds were prepared.
TABLE I.7
Ex. #
adduct
product
yield
18/1
43% [MH] + = 244
18/2
62% (2 steps) [MH] + = 341
18/5
98% (2 steps) [MH] + = 353
18/7
82% [MH] + = 298
18/8
65% [MH] + = 284
18/9
80% [MH] + = 242
18/10
92% (2 steps) [MH] + = 258
18/12
47% (2 steps) [MH] + = 312
18/13
79% [MH] + = 298
18/14
38% (2 steps) [MH] + = 298
18/15
62% (2 steps) [MH] + = 270
18/17
61% [MH] + = 298
18/21
30% (2 steps). [MH] + = 347
Preparative Example 19
Step A
Ethyl-2-amino-6-terbutoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxylate (0.5 g) was dissolved in a 4M solution of HCl in 1,4-dioxane (20 mL) and nitriloacetic acid ethyl ester (0.25 mL) was added. The mixture was stirred at 50° C. for 3 h and concentrated. The decarboxylation of the ester was observed. This product was used in the following step without further purification. [MH] + =280.
Step B
The title compound of Step A above was dissolved in DMF and triethylamine (0.32 mL) was added. Di-tert-butyl dicarbonate (0.5 g) was added and the mixture was stirred at room temperature for 1 h. The solvent was removed by evaporation. The residue was dissolved in dichloromethane and washed with water, dried and evaporated to give the title compound (580 mg) as a yellow solid. [MH] + =380.
Preparative Example 20
Step A
Tetrahydro-2H-pyran-4-one (1 g) was placed in methanol in presence of barium oxide (0.1 g). Nitrosomethylurethane (1.3 g) was added slowly to the reaction mixture. During the addition, barium oxide (0.2 g) was added by small portion. The reaction was stirred 3 hours at room temperature and then filtrated. The methanol was evaporated, diethyl ether was then added to the residue, a precipitate was formed. The mixture was filtrated and diethyl ether evaporated to afford the title compound (790 mg, 70%) as a yellow oil. [MH] + =115.
Preparative Example 20/1
Following similar procedures as described in the Preparative Examples 20, except using the educt indicated in Table I.13 below, the following compounds were prepared.
TABLE I.13
Ex. #
Educt
product
yield
20/1
76% [MH] + = 143
Example 1
Step A
To a solution of the title compound from Preparative Example 11 above (30 mg), EDCI (50 mg) and HOAt (22 mg) in DMF (10 mL) were added N-methylmorpholine (50 μL) and the title compound from the Preparative Example 13 (50 mg). The mixture was stirred overnight and then concentrated. The remaining residue was suspended in 10% aqueous citric acid and the residue was filtered to afford the title compound as an off white solid (38 mg, 74%). [MH] + =397.
Example 1a
Step A
To a solution of the title compound from Preparative Example 12/16 above (9.5 mg), HATU (23.3 mg) and HOAt (8.2 mg) in DMA (200 μL) was added a 0.1 M solution of morpholine in DMA/pyridine(1:1, 440 μL). The resulting mixture was agitated (˜600 rpm) at room temperature for 4 h, concentrated and purified by HPLC(RP-C18, ACN/H 2 O) to afford the title compound. [MH] + =305.
Examples 2/24-2/547
Following similar procedures as described in the Examples 1 (method A) or 1a (method B), except using the amines and acids indicated in Table II.1 below, the following compounds were prepared.
TABLE II.1
method,
Ex. #
amine, acid
product
yield
2/24
A, 95% [MH] + = 407
2/25
A, 26% [MH] + = 407
2/29
A, 12% [MH] + = 426
2/30
A, n.d. [MH] + = 426
2/33
A, 29% [MH] + = 411
2/34
A, 77% [MH] + = 411
2/52
A, 85% [MH] + = 476
2/67
A, 76% [MH] + = 486
2/89
A, 27% [MH] + = 438
2/90
A, 63% [MH] + = 517
2/94
A, 83% [MH] + = 454
2/95
A, 70% [MH] + = 533
2/103
A, 81% [MH] + = 461
2/104
A, 64% [MH] + = 540
2/107
A, 85% [MH] + = 489
2/108
A, quant. [MH] + = 489
2/113
A, 40% [MH] + = 469
2/114
A, 88% [MH] + = 548
2/117
A, 93% [MH] + = 425
2/118
A, 98% [MH] + = 504
2/119
A, 65% [MH] + = 429
2/120
A, 76% [MH] + = 508
2/121
A, 86% [MH] + = 415
2/122
A, 91% [MH] + = 494
2/125
A, 68% [MH] + = 439
2/126
A, 43% [MH] + = 518
2/129
A, 31% [MH] + = 420
2/130
A, 10% [MH] + = 422
2/131
A, 77% [MH] + = 429
2/132
A, 31% [MH] + = 508
2/143
A, 80% [MH] + = 463
2/144
A, 5% [MH] + = 542
2/145
A, 27% [MH] + = 487
2/146
A, 74% [MH] + = 566
2/152
A, 45% [MH] + = 413
2/153
A, 60% [MH] + = 492
2/166
A, 75% [MH] + = 440
2/167
A, 99% [MH] + = 530
2/168
A, 40% [MH] + = 620
2/169
A, 34% [MH] + = 587
2/170
A, 50% [MH] + = 608
2/171
A, 78% [MH] + = 526
2/172
A, 26% [MH] + = 454
2/173
A, 23% [MH] + = 468
2/174
A, 80% [MH] + = 548
2/175
A, 39% [MH] + = 544
2/176
A, 36% [MH] + = 562
2/177
A, 86% [MH] + = 562
2/178
A, 76% [MH] + = 562
2/188
A, n.d. [MH] + = 538
2/208
A, 25% [MH] + = 483
2/209
A, 22% [MH] + = 562
2/210
A, 7% [MH] + = 469
2/211
A, 79% [MH] + = 427
2/212
A, 87% [MH] + = 506
2/218
A, 66% [MH] + = 443
2/219
A, 56% [MH] + = 522
2/223
A, 61% [MH] + = 478
2/224
A, 58% [MH] + = 554
2/225
A, 34% [MH] + = 482
2/230
A, 48% [MH] + = 534
2/231
A, 87% [MH] + = 496
2/232
A, 70% [MH] + = 519
2/236
A, 98% [MH] + = 497
2/237
A, 78% [MH] + = 482
2/238
A, 80% [MH] + = 582
2/239
A, 79% [MH] + = 468
2/240
A, 69% [MH] + = 468
2/245
A, 26% [MH] + = 391
2/246
A, 10% [MH] + = 391
2/249
A, 67% [MH] + = 526
2/250
A, 69% [MH] + = 526
2/251
A, 90% [MH] + = 506
2/252
A, 96% [MH] + = 483
2/253
A, 16% [MH] + = 454
2/254
A, 26% [MH] + = 468
2/255
A, 25% [MH] + = 497
2/256
A, 86% [MH] + = 525
2/257
A, 85% [MH] + = 483
2/258
A, 43% [MH] + = 454
2/259
A, 20% [MH] + = 468
2/260
A, 30% [MH] + = 482
2/261
A, 14% [MH] + = 492
2/262
A, 78% [MH] + = 454
2/263
A, 60% [MH] + = 468
2/264
A, 23% [MH] + = 455
2/266
A, 95% [MH] + = 483
2/267
A, 96% [MH] + = 468
2/268
A, 57% [MH] + = 482
2/269
A, 72% [MH] + = 496
2/270
A, 85% [MH] + = 512
2/289
B, n.d. [MH] + = 315
2/290
B, n.d. [MH] + = 343
2/291
B, n.d. [MH] + = 289
2/292
B, n.d. [MH] + = 343
2/293
B, n.d. [MH] + = 303
2/294
B, n.d. [MH] + = 277
2/295
B, n.d. [MH] + = 303
2/296
B, n.d. [MH] + = 325
2/297
B, n.d. [MH] + = 331
2/298
B, n.d. [MH] + = 334
2/299
B, n.d. [MH] + = 263
2/300
B, n.d. [MH] + = 317
2/301
B, n.d. [M-TFA] + = 306
2/302
B, n.d. [MH] + = 403
2/303
B, n.d. [MH] + = 249
2/304
B, n.d. [MH] + = 339
2/305
B, n.d. [MH] + = 357
2/306
B, n.d. [M-TFA] + = 318
2/307
B, n.d. [MH] + = 365
2/308
B, n.d. [MH] + = 292
2/309
B, n.d. [M-TFA] + = 326
2/310
B, n.d. [MH] + = 339
2/311
B, n.d. [MH] + = 339
2/312
B, n.d. [MH] + = 318
2/313
B, n.d. [MH] + = 357
2/314
B, n.d. [MH] + = 404
2/315
B, n.d. [MH] + = 409
2/316
B, n.d. [MH] + = 383
2/317
B, n.d. [M-TFA] + = 506
2/318
B, n.d. [MH] + = 383
2/319
B, n.d. [MH] + = 357
2/320
B, n.d. [MH] + = 357
2/321
B, n.d. [MH] + = 401
2/322
B. n.d. [MH] + = 365
2/323
B, n.d. [MH] + = 346
2/324
B, n.d. [MH] + = 365
2/325
B, n.d. [MH] + = 351
2/326
B, n.d. [MH] + = 351
2/327
B, n.d. [MH] + = 368
2/328
B, n.d. [M-TFA] + = 402
2/329
B, n.d. [MH] + = 368
2/330
B, n.d. [MH] + = 332
2/331
B, n.d. [MH] + = 376
2/332
B, n.d. [MH] + = 427
2/333
B, n.d. [MH] + = 381
2/334
B, n.d. [MH] + = 393
2/335
B. n.d. [MH] + = 399
2/336
B, n.d. [MH] + = 393
2/337
B, n.d. [M-TFA] + = 368
2/338
B, n.d. [MH] + = 375
2/339
B, n.d. [MH] + = 393
2/340
B, n.d. [MH] + = 343
2/341
B, n.d. [MH] + = 345
2/342
B, n.d. [MH] + = 345
2/343
B, n.d. [MH] + = 319
2/344
B, n.d. [MH] + = 331
2/345
B, n.d. [M-TFA] + = 410
2/346
B, n.d. [MH] + = 367
2/347
B, n.d. [MH] + = 353
2/348
B, n.d. [MH] + = 353
2/349
B, n.d. [MH] + = 353
2/350
B, n.d. [MH] + = 345
2/351
B, n.d. [MH] + = 319
2/352
B, n.d. [MH] + = 381
2/353
B, n.d. [M-TFA] + = 410
2/354
B, n.d. [MH] + = 365
2/355
B, n.d. [M-TFA] + = 424
2/356
B, n.d. [MH] + = 409
2/357
B, n.d. [M-TFA] + = 326
2/358
B, n.d. [M-TFA] + = 340
2/359
B, n.d. [M-TFA] + = 410
2/360
B, n.d. [M- (TFA) 2 ] + = 423
2/361
B, n.d. [MH] + = 409
2/362
B, n.d. [MH] + = 333
2/363
B, n.d. [MH] + = 367
2/364
B, n.d. [M-TFA] + = 315
2/365
B, n.d. [MH] + = 331
2/366
B, n.d. [MH] + = 317
2/367
B, n.d. [MH] + = 410
2/368
B, n.d. [M-TFA] + = 394
2/369
B, n.d. [MH] + = 332
2/370
B, n.d. [MH] + = 374
2/371
B, n.d. [MH] + = 374
2/372
B, n.d. [MH] + = 389
2/376
A, 87% [MH] + = 532
2/382
B, n.d. [MH] + = 370
2/383
B, n.d. [MH] + = 340
2/384
B, n.d. [MH] + = 356
2/385
B, n.d. [MH] + = 348
2/386
B, n.d. [MH] + = 356
2/387
B, n.d. [MH] + = 356
2/388
B, n.d. [MH] + = 354
2/389
B, n.d. [MH] + = 384
2/390
B, n.d. [MH] + = 426
2/391
B, n.d. [MH] + = 368
2/392
B, n.d. [MH] + = 356
2/393
B, n.d. [MH] + = 356
2/394
B, n.d. [MH] + = 384
2/395
B, n.d. [MH] + = 384
2/396
B, n.d. [MH] + = 384
2/397
B, n.d. [MH] + = 356
2/398
B, n.d. [MH] + = 400
2/399
B, n.d. [MH] + = 372
2/400
B, n.d. [MH] + = 455
2/401
B, n.d. [MH] + = 384
2/402
B, n.d. [MH] + = 384
2/403
B, n.d. [MH] + = 383
2/404
B, n.d. [MH] + = 383
2/405
B, n.d. [MH] + = 340
2/406
B, n.d. [MH] + = 406
2/407
B, n.d. [MH] + = 382
2/408
B, n.d. [MH] + = 396
2/409
B, n.d. [MH] + = 383
2/410
B, n.d. [MH] + = 397
2/411
B, n.d. [MH] + = 397
2/412
B, n.d. [MH] + = 410
2/413
B, n.d. [MH] + = 450
2/414
B, n.d. [MH] + = 478
2/415
B, n.d. [MH] + = 394
2/416
B, n.d. [MH] + = 464
2/417
B, n.d. [MH] + = 468
2/418
B, n.d. [MH] + = 482
2/419
B, n.d. [MH] + = 482
2/420
B, n.d. [MH] + = 416
2/421
B, n.d. [MH] + = 490
2/422
B, n.d. [MH] + = 372
2/423
B, n.d. [MH] + = 351
2/424
B, n.d. [M-TFA] + = 368
2/425
B, n.d. [MH] + = 390
2/426
B, n.d. [MH] + = 412
2/427
B, n.d. [MH] + = 412
2/428
B, n.d. [MH] + = 384
2/429
B, n.d. [MH] + = 400
2/430
B, n.d. [MH] + = 400
2/431
B, n.d. [MH] + = 388
2/432
B, n.d. [MH] + = 368
2/433
B, n.d. [MH] + = 378
2/434
B, n.d. [MH] + = 342
2/435
B, n.d. [MH] + = 420/422
2/436
B, n.d. [MH] + = 425
2/437
B, n.d. [MH] + = 395
2/438
B, n.d. [MH] + = 402
2/439
B, n.d. [MH] + = 412
2/440
B, n.d. [M-TFA] + = 365
2/441
B, n.d. [MH] + = 392
2/442
B, n.d. [MH] + = 392
2/443
B, n.d. [MH] + = 351
2/444
B, n.d. [MH] + = 388
2/445
B, n.d. [MH] + = 404
2/446
B, n.d. [MH] + = 455
2/447
B, n.d. [MH] + = 384
2/448
B, n.d. [MH] + = 419
2/449
B, n.d. [MH] + = 384
2/450
B, n.d. [M-TFA] + = 357
2/451
B, n.d. [MH] + = 294
2/452
B, n.d. [MH] + = 360
2/453
B, n.d. [MH] + = 306
2/454
B, n.d. [MH] + = 462
2/455
B, n.d. [M-TFA] + = 347
2/456
B, n.d. [MH] + = 306
2/457
B, n.d. [MH] + = 370
2/458
B, n.d. [MH] + = 320
2/459
B, n.d. [MH] + = 280
2/460
B, n.d. [MH] + = 446
2/461
B, n.d. [MH] + = 320
2/462
B, n.d. [MH] + = 320
2/463
B, n.d. [MH] + = 330
2/464
B, n.d. [MH] + = 320
2/465
B, n.d. [MH] + = 394
2/466
B, n.d. [MH] + = 419
2/467
B, n.d. [MH] + = 308
2/468
B, n.d. [MH] + = 364
2/469
B, n.d. [MH] + = 376
2/470
B, n.d. [MH] + = 337
2/471
B, n.d. [MH] + = 405
2/472
B, n.d. [MH] + = 418/420
2/473
B, n.d. [M-TFA] + = 328
2/474
B, n.d. [MH] + = 294
2/475
B, n.d. [MH] + = 322
2/476
B, n.d. [MH] + = 418/420
2/477
B, n.d. [M-TFA] + = 407
2/478
B, n.d. [M-TFA] + = 321
2/479
B, n.d. [MH] + = 294
2/480
B, n.d. [MH] + = 274
2/481
B, n.d. [MH] + = 368
2/482
B, n.d. [MH] + = 386
2/483
B, n.d. [M-TFA] + = 452
2/484
B, n.d. [MH] + = 466
2/485
B, n.d. [MH] + = 320
2/486
B, n.d. [M-TFA] + = 411
2/487
B, n.d. [M-TFA] + = 411
2/488
B, n.d. [MH] + = 404/406
2/489
B, n.d. [MH] + = 348
2/490
B, n.d. [MH] + = 315
2/491
B, n.d. [M-TFA] + = 355
2/492
B, n.d. [MH] + = 292
2/493
B, n.d. [MH] + = 368
2/494
B, n.d. [MH] + = 462
2/495
B, n.d. [MH] + = 422/424
2/496
B, n.d. [MH] + = 342
2/497
B, n.d. [MH] + = 399
2/498
B, n.d. [MH] + = 362
2/499
B, n.d. [MH] + = 362
2/500
B, n.d. [MH] + = 306
2/501
B, n.d. [MH] + = 306
2/502
B, n.d. [MH] + = 292
2/503
B, n.d. [MH] + = 292
2/504
B, n.d. [M-TFA] + = 375
2/505
B, n.d. [M-TFA] + = 319
2/506
B, n.d. [MH] + = 447
2/507
B, n.d. [M-TFA] + = 333
2/508
B, n.d. [MH] + = 390
2/509
B, n.d. [M-TFA] + = 423
2/510
B, n.d. [MH] + = 336
2/511
B, n.d. [MH] + = 383
2/512
B, n.d. [MH] + = 383
2/513
B, n.d. [MH] + = 333
2/514
B, n.d. [MH] + = 358
2/515
B, n.d. [MH] + = 433
2/516
B, n.d. [MH] + = 304
2/517
B, n.d. [MH] + = 318
2/518
B, n.d. [M-TFA] + = 345
2/519
B, n.d. [M-TFA] + = 328
2/520
B, n.d. [MH] + = 447
2/521
B, n.d. [M-TFA] + = 330
2/522
B, n.d. [MH] + = 382
2/523
B, n.d. [MH] + = 410
2/524
B, n.d. [MH] + = 410
2/525
B, n.d. [MH] + = 410
2/526
B, n.d. [MH] + = 390
2/527
B, n.d. [M- (TFA) 2 ] + = 396
2/528
B, n.d. [M- (TFA) 2 ] + = 428
2/529
B, n.d. [M- (TFA) 2 ] + = 412
2/530
B, n.d. [MH] + = 419
2/531
B, n.d. [MH] + = 358
2/532
B, n.d. [MH] + = 358
2/533
B, n.d. [MH] + = 346
2/534
B, n.d. [MH] + = 358
2/535
B, n.d. [MH] + = 340
2/536
B, n.d. [M-TFA] + = 349
2/537
B, n.d. [MH] + = 415
2/538
B, n.d. [MH] + = 459
2/539
B, n.d. [MH] + = 411
2/540
B, n.d. [MH] + = 415
2/541
B, n.d. [MH] + = 433
2/542
B, n.d. [MH] + = 411
2/543
B, n.d. [MH] + = 436
2/544
B, n.d. [MH] + = 454
2/545
B, n.d. [MH] + = 383
2/546
B, n.d. [MH] + = 426
2/547
B, n.d. [MH] + = 416
Example 3
Step A
To a solution of the title compound from Step A above (200 mg) in THF (3 mL) was added 1M aqueous LiOH (1.2 mL). The resulting mixture was stirred at room temperature 3 h, concentrated and suspended in 1M aqueous HCl. The residue was filtered off and used without further purification (150 mg, 80%). [MH] + =469.
Examples 4/4-4/19
Following a similar procedure as described in Example 3, except using the ester indicated in Table II.2 below, the following compounds were prepared.
TABLE II.2
Ex. #
Ester
4/4
4/9
4/10
4/11
4/14
4/15
4/17
4/18
4/19
Ex. #
product
yield
4/4
70% [MH] + = 441
4/9
66% [MH] + = 606
4/10
68% [MH] + = 574
4/11
99% [MH] + = 455
4/14
65% [MH] + = 520
4/15
65% [MH] + = 441
4/17
40% [MH] + = 455
4/18
72% [MH] + = 455
4/19
66% [MH] + = 467
Example 15
Step A
To the title compound from Step A above (55 mg) was added a 4M solution of HCl in 1,4-dioxane (3 mL). The reaction mixture was stirred at room temperature overnight and concentrated to afford the title compound (29 mg, 58%). [MH] + =526.
Examples 15/2-15/5
Following a similar procedure as described in the Example 15, except using the protected product indicated in Table II.7 below, the following compounds were prepared.
TABLE II.7
Ex. #
educt
15/2
15/3
15/4
15/5
Ex. #
product
Yield
15/2
50% [MH] + = 498
15/3
16% [MH] + = 426
15/4
69% [MH] + = 426
15/5
46% [MH] + = 412
Example 19
Step A
To DMF (5 mL) was added 2M oxalylchloride in dichloromethane (250 μL) at 0° C. Then a solution of the title compound from Example 2/166 (200 mg) in DMF (2 mL) was added and the mixture was stirred for 6 h at 0° C. After adding pyridine (150 μL) the mixture was stirred for additional 2 h at room temperature. The mixture was concentrated and the remaining residue was suspended in 1M HCl and filtered to afford the title compound as an off white solid (192 mg, 99%). [MH] + =422.
Example 22
Step A
The title compound from example 2/119 (9 mg) was placed in a mixture acetic acid/acetic acid anhydride (1:1). Hydrogen peroxide (6 μL) was added and the reaction mixture was heated at 100° C. for 4 h and then stirred at room temperature overnight. After evaporation, water was added and the residual product was filtrated and dried to afford the title compound (7 mg, 72%). [MH] + =461.
Example 22/1 and 22/2
Following a similar procedure as described in Example 22, except using the educt indicated in Table II.9 below, the following compounds were prepared.
TABLE II.9
Ex. #
educt
22/1
22/2
Ex. #
product
Yield
22/1
80% [MH] + = 475
22/2
89% [MH] + = 461
Example 26
Step A
The title compound from Example 2/218 (15.8 mg) was dissolved in DMSO, then H 2 O 2 (˜1 mL) was added and the mixture was stirred at room temperature for 3 h, evaporated, slurried with water and filtered to afford the title compound (13.8 mg, 84%) as a colourless solid. [MH] + =459.
Example 28
Step A
To a solution of 9-oxo-8,9-dihydro-1,3-dioxa-6,8-diaza-cyclopenta[a]naphthalene-7-carboxylic acid ethyl ester (32 mg) in ethanol (1 mL) were added triethyl amine (40 μL) and the title compound from the Preparative Example 13 (30 mg). The mixture was heated at 180° C. in a microwave oven for 1 h and then concentrated. The remaining residue was purified by silica gel chromatography (10% methanol in methylene chloride) to give a yellow solid (45 mg, 95%). [MH] + =395.
Example 39/7 and 39/20
Following similar procedures as described in Examples 28 except using the amines and the ester indicated in Table II.14 below, the following compounds were prepared.
TABLE II.14
Ex. #
amine; ester
39/7
39/20
Ex. #
product
Yield
39/7
20% [MH] + = 428
39/20
19% [MH] + = 401
Example 41
Step A
The title compound from Example 2/376 above was stirred in a solution of HBr in glacial acid (33 wt %) at room temperature for 2 h. Evaporation afford the title compound. [MH] 30 =398.
Example 42
Step A
To a solution of the title compound from Example 41 (9.6 mg) in pyridine (200 μL) was added acetyl chloride (3 μL) at room temperature. The mixture was stirred for 2 h at room temperature and evaporated. The resulting residue was purified by HPLC to afford the title compound. (2.2 mg; 25%, [MH] + =440).
Example 42/1 and 42/2
Following a similar procedure as described in Example 42 above, except using amines and acid chlorides as indicated in the Table II.15 below, the following compounds were prepared.
TABLE II.15
Ex. #
amine; acid chloride
42/1
42/2
Ex. #
product
Yield
42/1
9% [MH] + = 508
42/2
29% [MH] + = 476
Example 43
Step A
To a solution of the title compound from Example 41 (15 mg) above in DMA (500 μL) was added 2-bromo-pyrimidine (10 mg). The mixture was heated in a sealed tube at 100° C. (microwave) for 5 min. Purification by HPLC afforded the title compound. (6.1 mg; 33%, [MH] + =476).
Example 43/1
Following a similar procedure as described in Example 43 above, except using amine and benzyl bromide as indicated in the Table II.16 below, the following compound was prepared.
TABLE II.16
Ex. #
amine; benzyl bromide
43/1
Ex. #
product
yield
43/1
14% [MH] + = 488
Example 1700
Assay for Determining MMP-13 Inhibition
The typical assay for MMP-13 activity is carried out in assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl 2 and 0.05% Brij-35. Different concentrations of tested compounds are prepared in assay buffer in 50 μL aliquots. 10 μL of a 50 nM stock solution of catalytic domain of MMP-13 enzyme (produced by Alantos or commercially available from Invitek (Berlin), Cat.# 30100812) is added to the compound solution. The mixture of enzyme and compound in assay buffer is thoroughly mixed and incubated for 10 min at room temperature. Upon the completion of incubation, the assay is started by addition of 40 GAL of a 12.5 μM stock solution of MMP-13 fluorescent substrate (Calbiochem, Cat. No. 444235). The time-dependent increase in fluorescence is measured at the 320 nm excitation and 390 nm emission by automatic plate multireader. The IC 50 values are calculated from the initial reaction rates.
Example 1701
Assay for Determining MMP-3 Inhibition
The typical assay for MMP-3 activity is carried out in assay buffer comprised of 50 mM MES, pH 6.0, 10 mM CaCl 2 and 0.05% Brij-35. Different concentrations of tested compounds are prepared in assay buffer in 50 μL aliquots. 10 μL of a 100 nM stock solution of the catalytic domain of MMP-3 enzyme (Biomol, Cat. No. SE-109) is added to the compound solution. The mixture of enzyme and compound in assay buffer is thoroughly mixed and incubated for 10 min at room temperature. Upon the completion of incubation, the assay is started by addition of 40 μL of a 12.5 μM stock solution of NFF-3 fluorescent substrate (Calbiochem, Cat. No. 480-455). The time-dependent increase in fluorescence is measured at the 330 nm excitation and 390 nm emission by an automatic plate multireader. The IC 50 values are calculated from the initial reaction rates.
Example 1702
Assay for Determining MMP-8 Inhibition
The typical assay for MMP-8 activity is carried out in assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl 2 and 0.05% Brij-35. Different concentrations of tested compounds are prepared in assay buffer in 50 μL aliquots. 10 μL of a 50 nM stock solution of activated MMP-8 enzyme (Calbiochem, Cat. No. 444229) is added to the compound solution. The mixture of enzyme and compound in assay buffer is thoroughly mixed and incubated for 10 min at 37° C. Upon the completion of incubation, the assay is started by addition of 40 μL of a 10 μM stock solution of OmmiMMP fluorescent substrate (Biomol, Cat. No. P-126). The time-dependent increase in fluorescence is measured at the 320 nm excitation and 390 nm emission by an automatic plate multireader at 37° C. The IC 50 values are calculated from the initial reaction rates.
Example 1703
Assay for Determining MMP-12 Inhibition
The typical assay for MMP-12 activity is carried out in assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl 2 and 0.05% Brij-35. Different concentrations of tested compounds are prepared in assay buffer in 50 μL aliquots. 10 μL of a 50 nM stock solution of the catalytic domain of MMP-12 enzyme (Biomol, Cat. No. SE-138) is added to the compound solution. The mixture of enzyme and compound in assay buffer is thoroughly mixed and incubated for 10 min at room temperature. Upon the completion of incubation, the assay is started by addition of 40 μL of a 12.5 μM stock solution of OmniMMP fluorescent substrate (Biomol, Cat. No. P-126). The time-dependent increase in fluorescence is measured at the 320 nm excitation and 390 nm emission by automatic plate multireader at 37° C. The IC 50 values are calculated from the initial reaction rates.
Example 1704
Assay for Determining Aggrecanase-1 Inhibition
The typical assay for aggrecanase-1 activity is carried out in assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl 2 and 0.05% Brij-35. Different concentrations of tested compounds are prepared in assay buffer in 50 μL aliquots. 10 μL of a 75 nM stock solution of aggrecanase-1 (Invitek) is added to the compound solution. The mixture of enzyme and compound in assay buffer is thoroughly mixed. The reaction is started by addition of 40 μL of a 250 nM stock solution of aggrecan-IGD substrate (Invitek) and incubation at 37° C. for exact 15 min. The reaction is stopped by addition of EDTA and the samples are analysed by using aggrecanase ELISA (Invitek, InviLISA, Cat. No. 30510111) according to the protocol of the supplier. Shortly: 100 μL of each proteolytic reaction are incubated in a pre-coated micro plate for 90 min at room temperature. After 3 times washing, antibody-peroxidase conjugate is added for 90 min at room temperature. After 5 times washing, the plate is incubated with TMB solution for 3 min at room temperature. The peroxidase reaction is stopped with sulfurous acid and the absorbance is red at 450 nm. The IC 50 values are calculated from the absorbance signal corresponding to residual aggrecanase activity.
Example 1705
Assay for Determining Inhibition of MMP-3 Mediated Proteoglycan Degradation
The assay for MMP-3 activity is carried out in assay buffer comprised of 50 mM MES, pH 6.0, 10 mM CaCl 2 and 0.05% Brij-35. Articular cartilage is isolated fresh from the first phalanges of adult cows and cut into pieces (˜3 mg). Bovine cartilage is incubated with 50 nM human MMP-3 (Chemikon, cat.# 25020461) in presence or absence of inhibitor for 24 h at 37° C. Sulfated glycosaminoglycan (aggrecan) degradation products (sGAG) are detected in supernatant, using a modification of the colorimetric DMMB (1,9-dimethylmethylene blue dye) assay (Billinghurst et al., 2000, Arthritis & Rheumatism, 43 (3), 664). 10 μL of the samples or standard are added to 190 μL of the dye reagent in microtiter plate wells, and the absorbance is measured at 525 nm immediately. All data points are performed in triplicates.
Example 1706
Assay for Determining Inhibition of MMP-3 Mediated Pro-Collagenase 3 Activation
The assay for MMP-3 mediated activation of pro-collagenase 3 (pro-MMP-13) is carried out in assay buffer comprised of 50 mM MES, pH 6.0, 10 mM CaCl2 and 0.05% Brij-35 (Nagase; J. Biol. Chem. 1994 Aug. 19; 269(33):20952-7).
Different concentrations of tested compounds are prepared in assay buffer in 5 μL aliquots. 10 μL of a 100 nM stock solution of trypsin-activated (Knäuper V., et al., 1996 J. Biol. Chem. 271 1544-1550) human pro-MMP-3 (Chemicon; CC1035) is added to the compound solution. To this mixture, 35 μL of a 286 nM stock solution of pro-collagenase 3 (Invitek; 30100803) is added to the mixture of enzyme and compound. The mixture is thoroughly mixed and incubated for 5 h at 37° C. Upon the completion of incubation, 10 μL of the incubation mixture is added to 50 μL assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl 2 and 0.05% Brij-35 and the mixture is thoroughly mixed.
The assay to determine the MMP-13 activity is started by addition of 40 μL of a 10 μM stock solution of MMP-13 fluorogenic substrate (Calbiochem, Cat. No. 444235) in assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl 2 and 0.05% Brij-35 (Knäuper, V., et al., 1996 . J. Biol. Chem. 271, 1544-1550). The time-dependent increase in fluorescence is measured at 320 nm excitation and 390 nm emission by an automatic plate multireader at room temperature. The IC 50 values are calculated from the initial reaction rates. | The present invention relates generally to azatriocyclic containing pharmaceutical agents, and in particular, to azatricyclic metalloprotease inhibiting compounds. More particularly, the present invention provides a new class of azatricyclic MMP-3, MMP-8 and/or MMP-13 inhibiting compounds, that exhibit an increased potency and selectivity in relation to currently known MMP-13, MMP-8 and MMP-3 inhibitors. | 2 |
FIELD OF THE INVENTION
The present invention relates generally to a Biologically Accelerated Treatment (BAT) media support frame apparatus used to contain biofilm support media for the treatment of wastewater. In particular, the present invention is directed toward a support frame which allows fast and efficient periodic media cleaning so as to maintain high treatment efficiencies and lower costs associated with periodic media cleaning as compared with currently used techniques.
BACKGROUND AND DESCRIPTION OF THE RELATED ART
It has become increasingly important to treat wastewater in an efficient manner so as to protect the health and well being of humankind. In past years the treatment of wastewater has advanced considerably to include the use of chemical and biological agents. In this light it has become common practice to treat wastewater with biologically active organisms that digest, and thus, eliminate organic material from wastewater. These biologically active organisms grow as a biofilm on media which act as carriers for the biologically active organisms. It is common practice to mount the media onto a supporting structure and submerge the supporting structure into the flow path of wastewater for treatment therein. The biofilm continues to grow overtime as it ingests organic material from the wastewater. The biofilm eventually proliferates to the extent that it hinders passage of wastewater through the biofilm media. Therefore, the need to clean the media in an efficient manner becomes critical. Unfortunately, the cleaning of media has not followed the same advancement as the treatment of the wastewater. To this extent many media support structure designs make it difficult to clean the media outside the treatment compartment or tank. In many instances these inadequacies will lead to inefficient wastewater treatment processes. Thus, there is a definite need for a media supporting apparatus that will allow the operator of a treatment facility to efficiently and easily clean, maintain and, if necessary remove, the media from the treatment compartment or tank.
Media supporting structures have been known and used in the treatment of wastewater for many years. Currently used supporting structures, however, have several shortcomings that are difficult to overcome, and in many instances can be a hindrance, when treating wastewater. These shortcomings lead to problems which range from difficulty in cleaning the media to the inability to vary the size of the supporting structures for various wastewater treatment applications.
Specifically, supporting structures which are currently utilized in the field do not lend themselves to easy reconfiguration of their sizes hence allowing only a definitive amount of media to be mounted thereon during wastewater treatment. These supporting structure configurations do not lend themselves to the adaptability and diversity needed in facilities ranging from small-sized home plants to middle-sized commercial tanks to large municipal wastewater treatment plants. In particular, sections of supporting structures cannot be varied in size to accommodate, amongst other applications, differing sizes of media so as to allow the positioning of media into small openings within areas of a tank for the treatment of wastewater. For example, U.S. Pat. No. 4,149,972 to Iwai et al. discloses a wastewater apparatus which comprises thin fan-shaped media sheets which are assembled using spacers. A tubular member is then inserted through holes in the media sheets to form an assembly of sheets. The assembly of sheets is radially disposed about a shaft which, in turn, forms a circular rotary body. In this embodiment the design does not allow for varying sizes of the media sheets and thus the assembly of sheets is fixed in size, thereby creating the inability to position the assembly of sheets in small areas that would otherwise accumulate wastewater.
A further example of a supporting means that does not allow for variation in size is U.S. Pat. No. 4,810,377 to Kato et al. which discloses a clarification device in which media is disposed in an upward direction from the bottom of a purifier tank. The biofilm media are divided into a plurality of assemblies to simplify removal from the purifier tank. The purifier tank has a top opening which accommodates several covers. In this configuration the purifier tank can only accommodate specific amounts of media for the treatment of wastewater. Additionally, the purifier tank is unable to be varied in size, thus not allowing the assembly to be positioned in smaller treatment compartments or tanks.
A further shortcoming of currently used supporting structures is the inability to maintain and clean the media at periodic intervals without incurring large expenditures of time and labor. In this regard, supporting structures are designed so as to make it difficult to periodically maintain and clean the media. Specifically, referring once again to the Iwai et al, reference, it is difficult to disassemble the apparatus so as to thoroughly maintain and clean the media sheets. To remove and thoroughly clean the media sheets the structure must be removed from the wastewater, completely disassembled, cleaned, reassembled and reintroduced to the wastewater. This procedure, and more particularly the disassembling of media sheets, spacers and tubular members, is time consuming, laborious, and inefficient.
Additional weaknesses in the currently used supporting structures include the lack of structural strength of media against external forces when mounted on the supporting structures. To this extent currently used supporting structures predispose the media to design criteria that render the media incapable of withstanding external forces. Generally, these design criteria force the media to be designed in thin sheets that are incapable of sustaining vertical and horizontal external forces. These supporting structures are varied in design and account for the majority of designs in the field.
Other systems using media support frames include those disclosed in U.S. Pat. Nos. 3,231,490 to Fry; 3,301,401 to Hall; 3,617,541 to Pan; 3,962,087 to Hartmann; 4,137,171 to Yokata; 4,165,281 to Kuriyama, et al.; 4,177,147 to Roberts; 4,267,051 to Uhlmann; 4,333,893 to Clyde; 4,416,993 to Benjes, et al.; 4,859,321 to Iida; and, 5,073,256 to Sieksmeyer, et al. These media support structures also suffer from the same shortcomings as described above.
Therefore, in light of the above shortcomings a new media support frame structure is needed which would be capable of easily varying its size to accommodate various wastewater plant applications and which would allow easy periodic cleaning, inspection, and maintenance. The new media support frame apparatus would also accommodate various sizes, configurations, and designs of media that can withstand external forces. U.S. Pat. No. 5,388,316 to MacLaren discloses media sheets bound together by tubes. This patent presents a novel method of cleaning the media and is incorporated herein by reference.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide a BAT media support frame that may be easily placed at any location in a treatment compartment or tank.
It is a further object of the present invention to provide a BAT media support frame that can be quickly and easily configured to fit into any treatment compartment or tank by fitting a number of frames horizontally or vertically and then locking them together by simple locking devices.
It is still a further object of the present invention to provide a BAT media support frame that can be easily removed from the treatment compartment or tank by lifting hooks.
It is yet a further object of the present invention to provide a BAT media support frame that allows media to be designed to withstand external forces.
It is another object of the present invention to provide a BAT media support frame that will allow media to be easily placed therein and removed.
It is still another object of the present invention to provide a BAT media support frame that will allow media blocks to be kept at varying depths in the BAT media support frame.
It is yet another object of the present invention to provide a BAT media support frame that will accommodate varying sizes of media blocks.
It is an additional object of the present invention to provide a BAT media support frame that prevents media in the BAT media support frame from floating in the treatment compartment or tank.
It is still an additional object of the present invention to provide a BAT media support frame that allows the media to be easily cleaned.
It is yet an additional object of the present invention to provide a BAT media support frame that can be easily replaced in the wastewater treatment compartment or tank.
These and other objects and advantages of the present invention will be apparent to those persons skilled in the art upon examination of the detailed description of the invention, the drawing figures, and the appended claims.
The present invention comprises a frame which may include legs, lock bars, snap locks, lock bar supports, lifting hooks, and cross-members. The inclusion and number of the above components will be determined by the size and shape of the frame. The media support frame can be designed to fit the dimensions of any treatment compartment or tank. In furtherance of this concept, the media support frame will be able to accommodate any location of a treatment compartment or tank by varying its dimensions, placing the media support frames side by side and/or stacking them in a vertical position. The latter two scenarios would be accomplished by utilizing locking devices to connect support frames in the stacked and/or side by side positions. In some applications, such as in high pressure head flows, the media support frames will be fixed to the walls in the treatment compartment or tank by the locking devices. In light of the above, it will now be possible to place the media support frame or frames in any treatment compartment or tank for maximum utilization.
Subsequent to the configuring of the media support frame, media will be placed therein. The media will be loaded until it reaches a certain depth in relation to the media support frame and will be preferably supported by at least one cross-member located at the bottom and each side of the frame. The configuration of the frame allows the media to be stacked in a vertical or a horizontal manner as well as accommodating media of different sizes. As mentioned earlier, the number of cross-members will be determined by the size of the frame--a larger dimension frame will require more cross-members. Lock bars or other restraint devices will then be positioned over the media to prevent the media from floating in the treatment compartment or tank. Thereafter, the supporting frame and media will be lowered into the treatment compartment or tank, preferably by lifting hooks. The lifting hooks will also allow easy removal of the supporting frame and media for periodic inspection, maintenance, and cleaning.
After a certain period of operation, the operator may have to clean the media that is located in the supporting frame. To accomplish this periodic cleaning the operator may utilize one of the following four techniques:
1. Pump the mixed liquor out of the treatment vessel and wash the media by spraying it with water;
2. Use air bubbles to wash down the biofilm and pump the settled biofilm to another treatment unit;
3. Use the pump cycle to force the biofilm to drip down from the media surface using the gravity method and pump the settled biofilm to another treatment unit; or
4. Remove the media blocks from the treatment compartment or tank, either with or without the frame, and wash the media outside of the treatment compartment or tank.
The latter method will usually be utilized in smaller covered plants; however, it may be effectuated at any size plant which is covered or not covered.
To effectuate technique number four it will be necessary to initiate the following cleaning procedures:
a. Open the lock bar;
b. Remove the media from the supporting frame and hence the treatment compartment or tank;
c. Clean the media in a unit;
d. Reload the media into the media supporting frame; and
e. Lock the lock bar.
This method of cleaning can vary slightly for other applications including, amongst other applications, small and large covered plants as well as small and large non covered plants. This variation will include lifting the entire media support frame from the treatment compartment or tank prior to the removal of the media from the frame. After the media is cleaned as referenced in steps a through e, the entire media support frame will be submerged into the treatment compartment or tank. The lifting of the media support frame and the subsequent submerging of the same into the treatment compartment or tank will be accomplished by the use of the lifting hooks. Another variation includes lifting the entire media support frame from the treatment compartment or tank and cleaning the media while it is disposed within the support frame. It is preferred to use these latter methods in smaller plants that are not covered or a larger plants that are not covered.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an isometric diagram of the BAT media support frame.
FIG. 2 is a side view diagram of the BAT media support frame.
FIG. 3 is a plan view diagram of the BAT media support frame.
FIG. 4 is an end view diagram of the BAT media support frame.
FIG. 5 is a plan view diagram of a snap lock.
FIG. 6 is a schematic diagram of a lock bar.
FIG. 7 is a plan view diagram of a lock bar.
DETAILED DESCRIPTION OF THE INVENTION
The detailed description of the present invention is based on a free standing BAT media support frame (hereinafter referred to as a "media support frame") for use in a home wastewater treatment compartment or tank (hereinafter referred to as a "treatment plant") which is designed to process 500 gallons of fluid a day. All numbers and dimensions that are used in this description are based on a free standing media system that can accommodate such a treatment plant while utilizing at least eight media blocks. The dimensions of the media support frame, including legs, lock bars, snap locks, lock bar supports, lifting hooks, cross-members, elbows, tee connectors, pipes, and other dimensions and quantities specified may vary with the size and type of treatment plant contemplated for use with the present invention. Therefore, numbers and dimensions specified herein are not to be construed as limitations on the scope of the present invention but are meant to be merely illustrative of one particular application. For example, it is contemplated that the components of the media support frame may be assembled in different quantities and arrangements so as to accommodate any size and shape of wastewater treatment tank or plant. Further, more than one frame may be combined to form an array of neighboring frames, if appropriate.
FIG. 1 demonstrates a free standing media support frame which will be utilized in a home treatment plant. In the preferred embodiment the frame 1 is assembled using segments of pipe 7 which are preferably constructed from a lightweight, non-rusting material such as PVC. The segments of pipe 7 on the frame 1 form a top, a bottom, ends, and sides which, in turn, form a polyhedron shape. The shape of the frame 1 and the quantity of frames used will depend on the configurations and dimensions of the specific treatment plant; however, in the preferred embodiment the top, bottom, ends, and sides of the frame 1 will have a rectangular shape. The top, bottom, ends, and sides of the frame 1 are connected together by various coupling devices.
In the preferred embodiment as depicted in FIG. 1 the top, bottom, two ends, two sides, and legs are connected by several coupling devices. In the preferred embodiment the shape of the sides, ends, bottom, and top form a rectangular shape. For example, the ends are formed by pipe segments connected in a rectangular shape, with legs 2 extending downward from the bottom of the ends, as shown. The two sides are defined by pipe segments that are attached to the two ends. The bottom, two ends, and two sides are reinforced by x shaped cross-members, cross braces, or other reinforcement constructions. These reinforcement constructions hold the media in place and lend structural support to the frame against external forces. The top of the frame 1 is defined by the top pipe segments of the ends and sides. The top pipe segments of the sides are lower than the top segments of pipe of the ends, defining a step sequence wherein there is a higher portion and a lower portion. The higher portions are located at the top pipe segments of the ends and the lower portions are located at the top pipe segments of the sides. The bottom of the frame 1 is defined by the bottom pipe segments of the ends and sides. The bottom pipe segments of the sides can be higher, lower, or the same height as the bottom pipe segments of the ends. All pipe segments are rigidly connected to form the frame 1. The connections are made, for example, using elbows, tee connectors, or other coupling devices.
On the higher portion of the top of frame 1 are lifting hooks 4 which are connected to segments of the pipe 7 of the frame 1. At least one lifting hook 4 will be placed on each higher portion of the top of the frame 1 to facilitate the simple removal of the frame 1 from the treatment plant for the periodic cleaning, maintenance, and inspection of media blocks. The above configuration of lifting hooks 4 are preferred; however, in alternative embodiments any number or configuration of lifting hooks 4 or other graspable implements that facilitate the lifting of the media support frame will suffice. Thus, due to the flexibility in the shape and number of the elements of the present embodiment, the frame 1 can be easily located in any portion of a treatment tank for high efficiency.
FIG. 1 further shows lock bar supports 5 on the top of the frame 1. In the preferred embodiment two lock bar supports 5 will be mounted on each lower portion of the top of the frame 1 by tee connectors 9. In alternative embodiments, the lock bar supports 5 may be placed at other locations of the frame 1. The lock bars 6 are employed to prevent the media block from floating in the treatment plant as well as to keep the media block at a certain depth in the frame 1. The operator of the treatment plant may also utilize the lock bar supports 5 as lifting handles when the necessity arises, such as when the configuration of frame 1 forecloses the isolated use of the lifting handles 5. The lock bar 6 is coupled to each lock bar support 5 by hinges 13. The lock bar 6 may also be coupled to any portion of the frame 1 depending on the convenience and practicality for the particular application. The hinges 13 allow the user to easily move the lock bars 6 so as to obtain simple access to the media block within the frame 1. Other movable restraining devices may be used with or in place of the disclosed lock bars. Note that the quantity of the above components used will be determined by the size and application of the frame 1. In light of the above embodiment, the reduction in labor, costs, and time associated with cleaning, maintenance, and inspection will be substantially reduced.
It is also seen from FIG. 1 that the cross-members 3 are coupled to the sides, ends, and bottom of the frame 1. The cross-members 3, in conjunction with the lock bars 6, are designed to hold the media block in the frame 1. It is preferable to assemble the cross-members in an x configuration; however, any pattern that retains the media block within the frame 1 will be acceptable. In the preferred embodiment the cross-members 3 are attached to the to the frame 1 by, for example elbows 8 and the tee connectors 9. In the present illustration one cross-member 3 will be placed on each side and end of the frame 1 and two cross-members 3 will be placed on the bottom of the frame 1. In the preferred embodiment, the cross-members 3 are constructed from the pipe 7 similar to the rest of the frame 1. The number and placement of the cross-members 3, the tee connectors 9, and the elbows 8 will vary according to the dimensions and application of the frame 1.
FIG. 2 illustrates a side view of the frame 1 with several media blocks 11 disposed therein. The frame 1 is designed to support the media blocks 11 of varying sizes and in varying combinations. These combinations may include arrangements of small blocks or orderly stacked blocks. Media blocks 11 are supported in the frame 1 by the cross-members 3 on the bottom, ends, sides, and at least one lock bar 6. At least one cross-members 3 will be located at each side, end, and bottom of the frame 1. It is preferred that the media blocks 11 be stacked to the same height as the lock bar 6 so that the media blocks 11 will be securely dispensed within the frame 1. The above configuration will prevent the media blocks 11 from floating within the treatment plant thus achieving maximum efficiency.
As shown in FIG. 3 the lock bar 6 is connected to a lock bar support 5. In this portrayal the lock bars 6 are in a locked position thus securing the media blocks 11 within the frame 1. In order to properly and effectively facilitate the inspection, cleaning, or maintenance of the media block 11, the user will simply:
1. Unlock the lock bar 6;
2. Lift the media block 11 from the frame 1;
3. Clean, inspect, or maintain the media block 11;
4. Replace the media block 11 in the frame 1; and
5. Secure the lock bar 6 to the lock bar support 5 (or other portions of the frame 1 depending on the convenience and practicality for the particular application).
During this process the media support frame will remain within the wastewater treatment plant. This method will be usually be employed with small plants that are covered. If there is a large plant (or a small plant that is not covered) the user will simply:
1. Remove the media support frame from the treatment plant;
2. Unlock the lock bar 6;
3. Lift the media block 11 from the frame 1;
4. Clean, inspect, or maintain the media block 11;
5. Replace the media block 11 in the frame 1;
6. Secure the lock bar 6 to the lock bar support 5 (or other portions of the frame 1 depending on the convenience and practicality for the particular application); and
7. Replace the media support frame in the treatment plant.
In the alternative, the operator may clean, inspect, or maintain the media in the following manner:
1. Remove the media support frame from the treatment plant;
2. Clean, inspect or maintain the media block 11 within the frame 1;
3. Replace the media support frame in the treatment plant.
To accomplish the removal of the media support frame the user will lift the frame 1 by the lifting hooks 4. As stated previously, the operator of the treatment plant may also utilize the lock bar supports 5 as lifting handles when the necessity arises. Using the lock bar supports 5 as a lifting point will allow the operator simple removal of the media support frame under conditions that would make the isolated use of the lifting hooks 4 impracticable.
FIG. 4 depicts the lifting hooks 4 located at the higher portion of the frame 1. The number and location of the lifting hooks 4 will vary according to the convenient and practical application of the media support frame. The variation of the lifting hooks 4 will be based on several variables including, but not limited to, the size, shape, and weight of the media support frame. The number of the lifting hooks 4 can also vary according to the number of media blocks 11--more lifting hooks 4 will be used when bulky or heavy media blocks 11 are disposed within the frame 1. FIG. 4 further depicts the location of the lifting hooks 4 so as to facilitate ease in the removal of the media support frame when cleaning, maintaining, or inspecting the media blocks 11. It is preferred, as illustrated in FIG. 4, that the cross-members 3 be connected to the tee connectors 9 by elbows 8 which in turn are coupled to the frame 1 at all corners. This configuration gives the media support frame a substantial amount of support so as to withstand external loads. The cross-members it will be manufactured from segments of pipe 7 to further strengthen frame 1.
As shown, FIG. 5 demonstrates a snap lock 12 connecting two pipes 7. When more than one media support frame is used in a treatment plant the snap lock 12 will connect the pipes 7 of adjoining frames 1 together securely locking them in place. The snap lock 12 can be made in several variations for locking purposes. These variations can include, amongst others, two prong tension locks, three prong tension locks, four prong tension locks, latch locks, hinged locks, lock groove locks, and any other locking device. The snap lock 12 can be utilized when the flames 1 are stacked in a vertical fashion or side by side. The frame 1 is designed to permit the snap lock 12 to connect to any portion of the pipe 7 to adjoining portions of the pipe 7 located on an adjacent frame 1. The snap lock 12 allows for further versatility of the media support frame by allowing the media support frame to accommodate any treatment plant configuration.
As shown in FIG. 6 and FIG. 7, the lock bar 6 can be connected to the frame 1 by a hinge 13. In the preferred embodiment, the hinge is a section of tubing that fits around the frame section and is free to swivel about the frame section. It is preferred that the hinge 13 be swivel mounted on a lock bar support 5. In this configuration the lock bar 6 will have two ends. The first end of the lock bar 6 will be connected to the hinge 13 and the second end of the lock bar 6 will accommodate a latch 14 or other device for removably locking the lock bar 6 onto the pipe 7. Referring now to FIG. 7 it is noted that the hinge 13 and the latch 14 can be fashioned in different shapes and sizes. The hinge 13, however, must be larger in diameter than then the outside diameter of the pipe 7 or the lock support 5. The swivel mounted hinge will allow easy access to the media blocks 11 when the operator attempts to clean, maintain, or inspect the same.
Preferred and alternate embodiments of the present invention have now been described in detail. It is to be noted, however, that this description of these specific embodiments is merely illustrative of the principles underlying the inventive concept. It is therefore contemplated that various modifications of the disclosed embodiments will, without departing from the spirit and scope of the invention, be apparent to persons of ordinary skill in the art. | An apparatus and method for cleaning, inspecting and maintaining media disposed within a biological aeration treatment media support frame. The apparatus consists of a frame connected to legs, x shaped cross-members, lifting hooks, lock bar supports and lock bars. The x shaped cross-members are mounted to the sides and bottom of the frame for the support of media as well as contributing to the strength of the frame thus protecting it from external forces. The lifting hooks permit the operator of the biological aeration treatment support frame to remove the frame in an effortless manner when cleaning, maintaining and inspecting the media. The lock bars are supported by the lock bar supports, which, in turn, maintain the media within the frame hence not allowing the media to float around in the wastewater treatment compartment. The lock bar support handle can also be used as a lifting hook. The lock bars are swivel mounted on the lock bar support to allow easy access to the media. This access will allow the operator to easily remove the media from the frame for cleaning, maintaining or inspecting the media when the removal of the entire apparatus is not required. | 2 |
BACKGROUND OF THE INVENTION
This invention relates to epoxy resin compositions. In a specific embodiment, the invention relates to latent-curing epoxy resin compositions which can be pre-mixed and stored but cure rapidly under subsequently-imposed curing conditions.
Polyester resins are often fabricated into molded parts using a sheet molding compound (SMC) technique. In this process, a styrene solution of carboxyl-terminated polyester is mixed with a peroxide (or other initiator), a thickening agent such as magnesium oxide, and a filler such as calcium carbonate or clay. This liquid mixture is then mixed with chopped fiberglass between two sheets of polyethylene film, and air bubbles are removed by squeeze rolls. Over 1-2 days, the viscosity increases from an initial value near 1 Pa.s to several thousand Pa.s. The increase in viscosity is caused by reaction of the carboxyl end groups of the polyester with magnesium oxide to form polymeric magnesium carboxylates. The viscosity reaches a plateau after the magnesium oxide is consumed. The SMC then has a leathery consistency, suitable for draping into a mold. The viscosity remains relatively constant for three months or longer, which constitutes the "molding window" of the SMC. If the viscosity is too low, liquid resin will squirt out of the mold during molding. If the viscosity becomes too high, the SMC will be "boardy" and difficult to drape, and it may not have sufficient flow to fill the mold completely.
Almost all commercially-available polyester resins have values of heat distortion temperature (HDT) below 120° C., while much higher HDT's can be obtained with epoxy resins. An epoxy resin processable as SMC by polyester-type techniques would therefore be highly desirable. To prepare such a material would be difficult, however, because of the different cure behavior of polyesters and epoxies. Polyester resins cure by a radical mechanism based on dissociation of an initiator to give radicals which initiate copolymerization of the styrene diluent with the maleate and fumarate groups of the polyester chain. The decomposition rate of most radical initiators is very sharply dependent on temperature. Epoxy resins cure with almost all curing agents by ionic processes which are much less temperature dependent. Hence it is much more difficult with epoxies than with polyesters to obtain a stable mixture at room temperature which cures rapidly at high temperatures.
Styrene-diluted epoxy systems cured with trimellitic anhydride (TMA) have been used to produce epoxy-based SMC for certain high-temperature applications. However, the viscosity of such systems continues to increase after reaching the desired level instead of forming a plateau. The molding window of this SMC is only about 2 days unless it is refrigerated, making it impossible to ship the SMC. Other epoxy curing agents such as aromatic amines give similarly short molding windows.
It is therefore an object of the invention to provide a latent-curing epoxy resin system suitable for use in sheet-molding applications.
BRIEF SUMMARY OF THE INVENTION
According to the invention, a composition is provided comprising a curable epoxy resin, a reactive diluent, a phenolic curing agent for the epoxy resin, and an isocyanate. The composition is stable at room temperature for extended periods, and cures to form a part which has good high-temperature properties.
DETAILED DESCRIPTION OF THE INVENTION
The invention composition includes an epoxy resin. The epoxy resin component of the composition can be any curable resin having, on the average, more than one vicinal epoxide group per molecule. The epoxy resin can be saturated or unsaturated, aliphatic, cycloaliphatic, aromatic or heterocyclic, and may bear substituents which do not materially interfere with the curing reaction.
Suitable epoxy resins include glycidyl ethers prepared by the reaction of epichlorohydrin with a compound containing at least one hydroxyl group carried out under alkaline reaction conditions. The epoxy resin products obtained when the hydroxyl group-containing compound is bisphenol-A are represented below by structure I wherein n is zero or a number greater than 0, commonly in the range of 0 to 10, preferably in the range of 0 to 2. ##STR1## Other suitable epoxy resins can be prepared by the reaction of epichlorohydrin with mononuclear di- and trihydroxy phenolic compounds such as resorcinol and phloroglucinol, selected polynuclear polyhydroxy phenolic compounds such as bis(p-hydroxyphenyl)methane and 4,4'-dihydroxybiphenyl, or aliphatic polyols such as 1,4-butanediol and glycerol.
Epoxy resins suitable for the invention compositions have molecular weights generally within the range of 86 to about 10,000, preferably about 200 to about 1500. The commercially-available epoxy resin EPON® Resin 828, a reaction product of epiclorohydrin and 2,2-bis(4-hydroxyphenylpropane (bisphenol-A) having a molecular weight of about 400, an epoxide equivalent (ASTM D-1652) of about 185-192, and an n value (from formula I above) of about 0.2, is presently the preferred epoxy resin because of its low viscosity and commercial availability.
The invention composition includes a reactive monomer selected from unsaturated aromatic monomers, esters or amides of ethylenically unsaturated carboxylic acids, cyano-containing compounds, vinyl esters, N-vinyl amides and allyl-containing compounds. Examples of unsaturated aromatic monomers include vinyl aromatic monomers such as styrene, alpha-methyl styrene, and p-methyl styrene; halo- and nitro-substituted styrenes such as vinyl toluene, chlorostyrene, bromostyrene, and nitrostyrene; divinylbenzene; t-butylstyrene; 2-vinylpyridine; and vinylnaphthalene. Styrene and mixtures of styrene and divinylbenzene are preferred.
Suitable unsaturated monocarboxylic acid esters include the alkyl esters of ethylenically unsaturated acids such as acrylic acid, methacrylic acid, crotonic acid, alpha-phenylacrylic acid, alpha-cyclohexylacrylic acid, maleic acid, cyanoacrylic acid, methoxyacrylic acid, and the like. Very preferred acids are acrylic acid and methacrylic acid. Accordingly, suitable such esters include methyl methacrylate, ethyl acrylate, butyl acrylate, butyl methacrylate, isobutyl methacrylate, and the like wherein side chains may contain halogen, e.g., 2,3-dibromopropyl acrylate and pentachlorophenyl methacrylate.
Very preferred comonomers include the polyacrylate and polymethacrylate esters of polyols containing more than one terminal acrylate or methacrylate group. These esters are the acrylic and methacrylic acid esters of aliphatic polyhydric alcohols such as, for example, the di- and polyacrylates and the di- and polymethacrylates of alkylene glycols, polyoxyalkylene glycols, alicyclic glycols and higher polyols, such as ethylene glycol, triethylene glycol, tetraethylene glycol, tetramethylene glycol, hexanediol, trimethylolethane, trimethylolpropane, pentaerythritol, dipentaerythritol, tripentaerythritol and the like, or mixtures of these with each other or with their partially esterified analogs.
Typical compounds include but are not limited to trimethylolpropane triacrylate, trimethylolethane triacrylate, trimethylolpropane trimethacrylate, trimethylolethane trimethacrylate, tetramethylene glycol dimethacrylate, ethylene glycol dimethacrylate, triethylene glycol dimethacrylate, pentaerythritol triacrylate, pentaerythritol tetraacrylate, 1,6-hexanediol diacrylate, 1,6-hexanediol dimethacrylate, dipentaerythritol tetraacrylate, dipentaerythritol pentaacrylate, and the like. Particularly preferred esters are neopentyl glycol dimethacrylate, trimethylolpropane trimethacrylate, trimethylolpropane triacrylate, pentaerythritol triacrylate, and 1,3-butylene dimethacrylate.
Suitable unsaturated carboxylic acid amides include acrylamide, N,N'-dimethylacrylamide, diacetone acrylamide, N-isopropylacrylamide, and N,N'-dimethylmethacrylamide, for example.
Suitable cyano-compounds are acrylonitrile, methacrylonitrile and halogenated acrylonitriles, for example.
Suitable vinyl esters include vinyl acetate, vinyl benzoate and divinyl adipate. Suitable N-vinyl amides include N-vinylpyrrolidone, N-vinyl-N-methylacetamide and N,N'-divinyl-N,N'-dimethyladipamide.
Suitable allyl monomers include diallyl phthalate, triallyl isocyanurate, diallyl isophthalate and diethylene glycol bis(allylcarbonate).
The described reactive monomers will be blended with the polyepoxide component of the invention composition in an amount within the range of about 5 to about 75, preferably about 10 to about 50, weight percent, based on the weight of the epoxy resin.
The invention composition preferably contains a free radical initiator for the reactive monomer(s). Examples of such initiators include peroxides, such as benzoyl peroxide, tertiary butyl hydroperoxide, ditertiary butyl peroxide, hydrogen peroxide, potassium peroxydisulfate, bis(methylcyclohexyl)peroxide, cumene hydroperoxide, acetyl benzoyl peroxide, Tetralin hydroperoxide, phenylcyclohexane hydroperoxide, tertiary butyl peroxyacetate, dicumyl peroxide, tertiary butyl peroxybenzoate, and the like, and mixtures thereof; azo compounds such as 2,2'-azobisisobutyronitrile, dimethyl 2,2'-azobisisobutyrate, 2,2'-azobis(2,4-dimethylvaleronitrile), 2,2'-azobisisobutyramide, 2,2'-azobis(2-acetoxypropane), and the like. Particularly preferred initiators include the dialkyl peroxides, tertiary alkyl hydroperoxides, and alkyl esters of peroxycarboxylic acids. Especially useful peroxides include tertiary butyl peroxy(2-ethylhexanoate) and 2,5-bis(tertiary butyl peroxy)-2,5-dimethylhexane. The optimum amount of free-radical initiator can vary over a broad range depending on the amount of the particular unsaturated monomer used and the type of curing agent present. In general, a curing amount for the reactive monomer is employed. One skilled in the art would simply adjust the amounts of a particular initiator to suit existing process conditions.
The invention composition includes a phenolic curing agent for the epoxy resin. The phenolic curing agent will preferably have a functionality greater than about 1.75. The preferred curing agents are phenolic novolacs prepared by reacting a monohydroxy phenol such as phenol or o-cresol, or a dihydroxy phenol such as resorcinol or bisphenol-A with formaldehyde in acid solution. The phenolic novolac curing agent will be present in the composition in an amount effective to cure the epoxy resin, which will generally be a stoichiometric amount of about 0.75 to about 1.25 equivalents per equivalent of epoxy resin. In terms of weight percent, the curing agent will be present in an amount generally from about 10 to about 70 weight percent, preferably about 15 to about 50, most preferably about 15 to about 40, based on the combined weight of epoxy resin and curing agent.
The invention composition includes an isocyanate. Preferred isocyanates can be represented by the formula
R--N═C═O].sub.n
in which R is a mono- or multivalent C 1-20 hydrocarbyl moiety which can be substituted with non-interfering functionalities, such as halide, and may contain heteroatomic bridging moieties such as --S--, --O--, CONH, or CO, for example, and n is equal to the valence of R. Examples of suitable isocyanates include 4,4'-diisocyanatodiphenylmethane, toluene diisocyanate, hexamethylene diisocyanate, α,α,α',α'-tetramethyl-α,α'-xylylene diisocyanate, and the oligomeric isocyanates prepared by treating anilineformaldehyde oligomers with an excess of phosgene.
The amount of isocyanate compound present will vary depending on the properties desired in the final product, but the composition will generally contain from about 15 to about 150, preferably about 30 to about 60, weight percent isocyanate compound, based on the weight of the epoxy resin.
EXAMPLE 1
A series of experiments was performed to evaluate the properties of isocyanate-containing epoxy-based compositions according to the invention. Formulations were prepared by combining a resin component containing a liquid diglycidyl ether of bisphenol-A (WPE about 185-192), trimethylolpropane trimethacrylate reactive monomer (TMPTMA), and isocyanate (Isonate 143L, a 4,4'-diisocyanatodiphenylmethane modified with carbodiimide linkages to make it liquid at room temperature); with a curing agent component containing CRJ-406 o-cresol novolac from Schenectady Chemicals, styrene, Lupersol 101 peroxide, Fikure 62-U (phenyldimethyl urea) and, in some cases, dibutyltin diacetate or dibutyltin dilaurate catalyst. The formulations and tested properties are shown in Table 1.
EXAMPLE 2
Formulations were prepared as in Example 1, except that an isocyanate based on an aniline-formaldehyde oligomer containing an average of 3.1 isocyanate groups per molecule (PAPI 135 from Dow) was used, and the epoxy resin was a diglycidyl ether of BPA having a WPE of about 178-186. Formulations and results are shown in Runs 12, 13 and 14 of Table 1.
EXAMPLE 3
The resin component and curing agent component were reformulated to determine if shelf life of the formulations could be improved. The resin component for Runs 15, 16 and 17 contained a liquid diglycidyl ether of bisphenol-A (WPE 178-186) epoxy resin, o-cresol novolac (CRJ-406), styrene, divinylbenzene or TMPTMA and (in Runs 15 and 16) 0.03 phr hydroquinone. The curing agent component contained isocyanate, Lupersol 101 and the urea compound. Results are shown in Runs 15, 16 and 17 of Table 1.
TABLE 1__________________________________________________________________________ISOCYANATE-THICKENED PHENOLIC-CURED RESINS.sup.(a, b)__________________________________________________________________________ Lupersol Fikure Tin Time (hours)- Epoxy TMPTMA, Isocyanate, CRJ 406, Styrene 101 62-U Catalyst Brookfield vis.Run Resin Parts Parts Parts Parts Parts Parts Parts (mPa · s), ˜25° C.__________________________________________________________________________1 100 40 60.sup.(h) 73 40 0.5 0.88 0-1900, 2-2100, 4-25202 100 40 60.sup.(h) 73 40 0.5 0.88 0.27.sup.(d) Cured immediately to rubbery gel3 100 40 30.sup.(h) 73 40 0.48 0.88 0-2480, 2-3000, 4-4200, 6-48004 100 40 30.sup.(h) 73 40 0.48 0.85 0.27.sup.(d) Cured immediately to tacky gel5 100 40 73 40 0.48 0.89 0-2050, 2-2500 4-3200, 6-40006 100 40 30.sup.(h) 73 40 0.48 0.887 100 40 30.sup.(h) 73 40 0.48 0.88 0.057.sup.(e) Cured immediately to soft tacky gel8 100 40 90.sup.(h) 73 40 0.48 0.839 100 40 90.sup.(h) 73 40 0.48 0.83 0.069.sup.(e) Cured immediately to soft gel10 100 40 120.sup.(h) 73 40 0.48 0.9011 100 40 120.sup.(h) 73 40 0.48 0.90 0.075.sup.(e) Cured immediately to soft gel12 100 40 40.sup.(i) 75 50 0.49 0.92 0.009.sup.(e) 0-87513 100 40 30.sup.(i) 75 50 0.50 0.92 0.009.sup.(e) 0-88814 100 40 20.sup.(i) 75 50 0.49 0.92 0.009.sup.(e) 0-85015 100 41.sup.(c) 60.sup.(i) 75 27 0.49 1.0 0-723, 1.23-868, 3.23-146516 100 41.sup.(c) 30.sup.(i) 75 27 0.25 0.5 0-804, 1.16-850, 3.13-109517 100.sup.(g) 40 60.sup.(h) 73 40 0.5 0.88__________________________________________________________________________ Gel Time, HDT 150° C. 264 psi Run Sec. °C. Comments__________________________________________________________________________ 1 159, 168 Hard gel after 1 month 2 Hard gel after 1 month 3 134, 132 Soft tacky gel after 21/2 months-"melts" at 150° C. 4 Soft tacky gel after 21/2 months-"melts" at 150° C. Non-melting after 11 months 5 118, 114 Liquid after 11 months 6 >10 min. .sup.(f) Soft tacky gel after 9 months-melts @ 150° C. 7 Non-melting after 9 months 8 >10 min. .sup.(f) Hard, non-melting after 1 month 9 Hard solid after 1 week 10 >10 min. .sup.(f) Hard (but melting) gel after 1 month 11 Hard solid after 1 week 12 .sup.(f) Stiff gel after 1 week, not melting at 175° C. 13 .sup.(f) Stiff gel after 1 week, not melting at 175° C. 14 .sup.(f) Soft gel after 1 week, melting at 175° C. and regelling in 100 seconds 15 29 .sup.(f) 16 50 .sup.(f) 17 >450 168, 169 Tg (Rheometrics) 198°__________________________________________________________________________ C. .sup.(a) Cure cycle: 1 hour @ 120° C. followed by 2 hours @ 170° C. .sup.(b) All components mixed together before aging. .sup.(c) Divinylbenzene used instead of TMPTMA. .sup.(d) Dibutyltin diacetate. .sup.(e) Dibutyltin dilaurate. .sup.(f) HDT bars were filled with voids. .sup.(g) Cure cycle: 1 hour @ 100° C. followed by 2 hours @ 150-180° C. .sup.(h) Isonate 143L. .sup.(i) PAPI 135. | A composition comprising a curable epoxy resin, a reactive diluent, a curing agent for the epoxy resin, and an isocyanate compound is stable at room temperature for extended periods of time and cures to form a part which has good high-temperature properties. | 2 |
BACKGROUND OF THE INVENTION
It has been known in the prior art to provide a mounting arrangement for conveyor belt cleaners whereby the cross-shaft on which the belt cleaners are mounted was adapted to be rotated to one of a number of preselected orientations. This was accomplished by movement of a lever arm connected to the cross-shaft and the subsequent locking of the arm and shaft against further rotation. Such an arrangement, although operative to achieve the desired result, has certain drawbacks which prevent it from being as effective as it should be. It must be recognized that in the majority of conveyor belt installations space and access are at a premium. The prior art arrangement required the operator to exert substantial torque, sometime in excess of 200 foot-pounds, in an area which is generally cluttered. This often makes it difficult for the operator to be able to grasp the handle in a position that would permit him to have the leverage to exert this kind of force. Such an arrangement also presents a problem as to where the assembly can be mounted so as to minimize interference with the access door provided in the conveyor housing. To be able to open the access door and frequently inspect the cleaner is important to insure continuous operation of the belt cleaner.
SUMMARY OF THE INVENTION
The present invention provides a radial ratchet arrangement for incremental rotation of the cross-shaft which supports the belt cleaner blades. As a result of the radial ratchet arrangement provided the overall torque required to change the belt cleaner blade tension is reduced and the ratchet arrangement allows the ratchet handle to be positioned at any convenient angle for rotation. The present invention includes a spur gear connected to the cross-shaft external to the conveyor belt housing and a locking pawl associated with the spur gear which, in its lock position, permits rotation of the spur gear and cross-shaft in only one direction. This arrangement provides for easy removal of the entire cross-shaft assembly when repair or replacement of the cleaner blades is required.
DESCRIPTION OF THE DRAWINGS
FIG. 1 is a fragmentary perspective view of the belt conveyor and cleaning and mounting arrangement of the present invention.
FIG. 2 is a sectional view taken substantially on the line 2--2 of FIG. 1.
FIG. 3 is a side view of the ratchet arrangement shown in FIG. 2 with the wrench removed.
FIG. 4 is a fragmentary end view of a portion of the belt conveyor and mounting arrangement taken from the delivery end.
DESCRIPTION OF THE PREFERRED EMBODIMENT
FIG. 1 shows, in perspective, the discharge end portion of a conveyor belt 20 here selected as representative of typical conveyors, having an upper or delivery run 22 and a lower or return run 24, the belt being trained as usual about a drum or roller 26 conventionally carried in a frame (not shown) within a housing 28. The housing is provided with an access door 30 which allows the operator to inspect the belt cleaning operation. Frequent inspection is important to insure continuous operation of the belt cleaner. Adjacent the access door a slot 31 is formed in the housing 28 the purpose for which will be described later.
A belt cleaner assembly 32 is provided consisting of a cross-shaft 34 which is disposed below and substantially transverse to the direction of travel of the return run 24 as indicated by the arrow. Carried on the shaft 34 is a plurality of mounting means 36, each of which is designed to support a rodlike member or arm 38 to which is affixed a blade 40. The mounting of the blade may be effected by a pair of nuts 42 or by any of a number of commonly accepted mounting methods. It is to be understood that any of a variety of arrangements may be substituted for mounting the blade 40 to the arm 38 or for mounting the arm 38 to the shaft 34 without affecting the scope of the present invention. In the embodiment illustrated a torsion mount is provided between the arm 38 and the shaft 34. The arm 38 is threaded into a nut 44 which is welded or otherwise rigidly attached to a sleeve-like portion or tubular part 46. A U-shaped bracket 48 is rigidly affixed to the cross-shaft 34 by means of a bolt 50 or some other suitable fastening. The bracket 48 includes a pair of ears 52 extending radially from the shaft and a fastener 54 here illustrated as a nut and bolt extending therebetween parallel to the axis of the cross-shaft 34. An annular elastomeric member 56 is disposed between the fastener 54 and the inner periphery of the tubular part 46 to elastically resist twisting and deflection of the arms relative to the shaft. The spring action from the torsion mount withstands the impacts from high speed belts and still keeps the blades in proper position. It is to be noted that adjacent pairs of brackets 48 and 48A are radially staggered with respect to each other to provide for a slight overlap between the adjacent blades 40 and 40A.
A radial ratchet tensioning arrangement 58 is illustrated for incrementally rotating the shaft 34 to bias the cleaner blades 40 against the bottom surface of the lower run 24 to thereby effect a scraping and cleaning operation for removing excess material from the conveyor belt.
As best shown in FIG. 2 the shaft 34 extends through a portion of one side wall 60 of the conveyor housing 28. Arbitrarily we will designate this side of the conveyor housing the "operator" side although the mounting arrangement can be reversed if, due to the location of the housing or surrounding environment, better access is provided on the other side.
As best shown in FIGS. 2 and 3 a first mounting flange 62 is positioned adjacent the wall 60 and is secured thereto by a plurality of bolts 64 or other suitable removable fasteners. Welded to the mounting flange is a threaded collar 66 extending therefrom. The flange 62 defines an aperture 68 therein through which the shaft 34 extends. A similar aperture 70 is defined in the wall 60 for the same purpose.
A rotary gear element 72 is illustrated including a spur gear 74 and a hub member 76 axially extending therefrom. The gear element 72 defines a circular opening 78 extending entirely therethrough and through which the shaft 34 is slidably received. The spur gear and hub are illustrated as a unitary member but may be provided as separate elements if so desired.
A pair of set screws 80 are received within a pair of threaded bores 82 radially disposed in the hub member 76. The set screws are adapted to engage the shaft 34 and prevent relative movement, either rotational or axial, between the shaft and the rotary element.
A coupling 84 is illustrated which is adapted to transfer torque from a torque applying member to the shaft 34. The coupling 84 includes a housing 86 defining an annular internal wall 88 and further defining a square shaped axially extending opening 90 in the outward end thereof. The internal wall 88 is designed to slide over the end of the shaft 34. A pair of set screws 92 are shown positioned within a pair of threaded bores 94 radially disposed in the housing 86. The set screws are adapted to engage the shaft 34 and prevent relative movement either rotational or axial between the coupling 84 and the shaft 34.
A torque applying member 96 is illustrated in the form of a standard, reversible ratchet wrench. The wrench 96 has an outwardly extending square head projection 98 adapted to be received within the opening 90 for transmitting torque to the coupling 84 and therethrough to the shaft 34. It should be apparent that torque could also be transmitted to the shaft by means of a coupling which, instead of utilizing a square internal opening as 90, provides a square shaped, axially extending male projection which can be inserted into a ratchet wrench which has a square head female opening formed in its face.
As best illustrated in FIG. 3 a locking pawl mechanism 100 is provided which, when in one position, will allow one way rotation of the spur gear 74. The mechanism includes an L shaped locking pawl 102 with a handle 104 extending therefrom, a pivot post 106 affixed to the mounting plate 62 and a spring loaded lock member 108 cooperative with the locking pawl 102.
The pawl 102 includes a finger-like end 110 which is adapted to interfit between adjacent teeth of the spur gear 74. Both side walls 112 of the included angle of the pawl 102 are adapted to contact and pivotally rock about the pivot post 106. A flat face 114 is formed on the outer periphery of the pawl 102 where the outer walls are joined.
The lock member 108 includes a hollow cylinder 116 threaded at one end 118 and adapted to be threaded into the collar 66. A ball type detent 120 is spring biased into engagement with the pawl 102. When the pawl 102 assumes the full line position shown in FIG. 3 rotation of the spur gear 74 is permitted only in the clock-wise direction. Any counterclockwise rotation is prevented as can be readily seen. When the cylinder 118 is unscrewed to a position allowing the pawl 102 to assume the dotted line position shown in FIG. 2, the detent 120 engages the flat face 114. The end 110 is held away from engagement with the teeth of the spur gear 74 and free rotation of the gear 74 and shaft 34 is permitted.
The arrangement for mounting the shaft 34 on the side away from the operator is best illustrated in FIG. 4. A side wall 122 of the conveyor housing 28 is provided with an opening 124 through which the shaft 34 extends. A mounting flange 126 is shown positioned adjacent the sidewall 122 and removably secured thereto. The mounting flange also includes an opening 128 through which the shaft 34 extends. An annular collar 130 is slidably positioned along the shaft 34 until it abuts the mounting flange 126. A pair of set screws 132 are threaded into the collar and are tightened until they grippingly engage the shaft 34 to prevent axial movement of the shaft with respect to the sidewall 122.
The operation of the present invention is substantially as follows. Under normal circumstances, the mounting flange 126 on the side of the conveyor housing opposite from the operator side is left affixed to the side wall 122 and is not removed. When the belt cleaner assembly 32 is to be mounted the shaft 34 is inserted through the access door 30. The end of the shaft 34 is inserted through the opening 124 in the side wall 122 and through the opening 128 in the mounting flange 126. The collar 120 is then slid over the end of the shaft 34 and set screws 132 are tightened to secure the collar to the shaft. The other end of the shaft 34 is positioned within the groove 31 formed in the "operator" side of the housing and the mounting flange 62 is slid over the end of the shaft 34 and secured to the side wall 60 of the conveyor housing by means of the bolts 64. The rotary gear element 72 is then slid over the end of the shaft until it abuts the mounting flange 62. The set screws 80 are then tightened to grippingly engage the shaft 34 thereby preventing relative movement between the gear element and the shaft. Next the coupling 84 is positioned over the end of the shaft 34 and the set screws 92 are tightened to grip the shaft. The projection 98 of the radial ratchet wrench 96 is then inserted into the opening 90 of the coupling 84. The handle of the ratchet is then rotated in a clockwise direction thereby rotating the shaft 34 and the mounting assembly carried by the shaft. As illustrated in FIG. 3, when the locking pawl mechanism is in the lock position, as illustrated by the full lines in FIG. 3, the rotary gear element 72 is permitted to rotate in a clockwise direction only. Rotation in the counterclockwise direction is prevented by means of the lcoking mechanism 100.
The operator continues to rotate the handle of the ratchet wrench 96 until the belt scraper blades have engaged the lower portion of the return run 24. Additional rotation of the shaft by the ratchet wrench will increase the tension on the arm members 38 until the desired tension has been achieved. As can be seen the shaft may be rotated in small increments to increase this tension.
When the operator determines that the belt cleaner blades should be repaired or replaced the procedure for removal of the cross-shaft 34 and the belt cleaner assembly 32 is reversed. The wrench 96 is removed, the coupling 84 is slid off the end of the shaft, the rotary gear element 72 is removed from the shaft, the collar 130 is removed from the other end of the shaft, the mounting flange 62 is disassembled from the side wall 60 and the shaft and cleaner assembly is removed from the conveyor housing 28 by means of the access door 30. At this time all or some of the individual wiper blades may be removed and replaced.
Various features of the invention have been particularly shown and described in connection with the illustrated embodiments of the invention, however, it must be understood that these particular arrangements merely illustrate and that the invention is to be given its fullest interpretation within the terms of the appended claims. | A mounting and support arrangement for conveyor belt cleaners which provides for selective incremental rotation of a cross-shaft on which is carried a plurality of belt cleaner blades suspended from mounting arms. A radial ratchet and pawl arrangement is provided exterior to the housing of the conveyor belt to be cleaned which provides for rotation of the shaft to bias the cleaner blades against the belt until the desired blade pressure is attained. A locking pawl secures the shaft against counter-rotation. | 1 |
FIELD OF THE INVENTION
Non-scratching abrasives for cleaning and polishing moderately soft metal surfaces such as, aluminum, copper, brass and bronze.
BACKGROUND OF THE INVENTION
This invention relates to a cleansing aid, including the process of fabricating same, adapted for home use in the cleansing of kitchen utensils and the like. More particularly, the invention relates to the structure of and process for making a cleansing aid in the form of a pad presenting highly effective and durable abrasive surfaces, and optionally having incorporated therewith a water-soluble cleansing agent, Further, said pad may optionally include means for retaining liquified cleansing agent within the pad to thereby prevent unnecessary wastage of the cleansing agent.
A cleansing or scouring pad of the type above referred to should ideally represent a combination of several functional and physical characteristics. It is, of course, desired that the outer surfaces of the pad provide a good abrasive action, be of an open or lofty structure so as not to mat or become clogged by the dirt, grease or other material removed in the cleansing operation and furthermore be of a rust-free material.
DISCUSSION OF THE PRIOR ART
For decades, the cleaning material of choice for metal surfaces of moderate softness has been steel wool of various grades, sold with or without soap. While pads of such material are excellent cleaners, they suffer from well known problems which heretofore have not been fully overcome. Unless stainless steel is used, the pads rust rapidly after initial use, they do not retain the soap well after the initial use and the steel fibers tend to break and embed themselves into the skin of the hand of the user.
It is desirable that the pad of sufficient resilience so as to be comfortable to handle and also capable or conforming to irregular contours in the article or utensil to be cleansed. The pad may be provided with its own self-contained supply of a
A web of abrasive material of the sort above described has heretofore been described in U.S. Pat. No. 2,327,199, issued to Clarence Robert Loeffler, issued Aug. 17, 1943, and in the U.S. Pat. No. 2,334,572, to R. L. Melton, et al., issued Nov. 16, 1943.
The seminal improvement in this technology is set forth in U.S. Pat. No. 2,958,593 to Hoover et al., assigned to 3M Corporation. This disclosed a class of products sold by the assignee under their trade mark "Scotch Brite" and associated marks. These products, as well as developments thereof, such as Klecker et al. U.S. Pat. No. and Fitzer U.S. Pat. No. 4,227,350, have the disadvantage that while they clean well they cannot be effectively used on metallic cookware surfaces as they are too abrasive and cause unsightly scratches. They particularly scratch aluminum and copper cookware surfaces. Similarly they cannot be used on soft coatings such as those of PTFE (or Teflon, (Trademark of DuPont Corp., Wilmington, Del.)).
Improved cleaning aids of the interior pad type are disclosed in U.S. Pat. No. 3,284,963, issued Nov. 15, 1966, to Samuel Lanham, et. al. While the Lanham product constituted an advance over the art, both it and the Hoover device are not suitable for polishing metals particularly moderately soft metals. Thus while Lanham states that any suitable abrasive may be used he, in fact, only mentions aluminum oxide, silicon carbide and the like which clean metal surfaces, but also scratch them in an unacceptable manner.
It would therefore be desirable to provide abrasive pads having the desirable qualities of steel wool pads without the aforesaid disadvantages, which could be used for the cleaning and polishing of moderately soft metal surfaces, in particular those of copper, brass, bronze and especially aluminum.
SUMMARY
There is provided an open low density abrasive article adapted for the cleaning of all metallic surfaces and particularly moderately soft metallic surfaces, suitably non-ferrous surfaces such as copper, brass, bronze and, in particular, aluminum surfaces comprising in one embodiment a lofty open non-woven three dimensional web form of a plurality of interlaced randomly extending flexible durable, tough, resilient organic fibers having a diameter of from about 25 to about 250 microns.
These web fibers are firmly adhesively bonded together at points where they cross and contact each other to form a three-dimensionally integrated structure throughout said web, and abrasive particles generally evenly distributed on each fiber within said web and are firmly bonded to the web fibers by a relatively hard binder, the interstices between adjacent fibers being open and substantially unfilled by binder or abrasive. Thus, there is defined throughout said article a tri-dimensionally extending network of intercommunicating voids constituting the major portion of the volume of the said article.
The article is flexible and readily compressible and, upon release of pressure capable of recovering substantially completely to its initial form. In addition to the web substrate, there may be utilized foam substrate from foams selected from the group comprising urethane foams, polypropylene, polyethylene, polyvinyl alcohol, silicone rubber, neoprene, or natural rubber latex foams. Density ranges of these foams are typically between 0.015-0.1 g/cm 3 .
Woven fabrics can also be used as carriers for the abrasive materials. All fabric constructions may be considered for specific applications, in particular is Terry Fabric of the surface density range from 100 g/m 2 to 410 g/m 2 , and open or textured weave fabrics such as ducks, twills, oznabergs, and leno weaves. These materials may be woven of natural or synthetic fibers, but of particular advantage are cotton, polyester, or nylon. Typical surface density appropriate for this application are fabrics from 45 g/m 2 to 340 g/m 2 . (i.e., weight/surface area).
A wide variety of engineered non-woven fabrics can be used to advantage as abrasive carriers, among them are those produced by spun bonded, fiber entangled, thermal and chemical bonded, spun-laced, print bonded, and needle punched. These materials may be made from natural or synthetic fibers or blends there of, non-wovens of rayon, polyester, or nylon can be used to particular advantage of a surface density of 75 g/m 2 to 285 g/m 2 .
Papers of various kinds can be used as carriers for the abrasives described depending on specific applications. Naturally substrate normally used for sandpaper applications would be suitably of surface density of 100 g/m 2 to 1 kg/m 2 .
An example of such paper would have the following specifications: A weight of 117 g/m 2 , type-Kraft and/or treated with zinc chloride, thickness-0.075 cm. Other papers of high wet strength can also be used.
The abrasive is applied to non web materials, i.e., fabrics (woven and non-woven) by coating them with a suitable adhesive resin followed by spraying dry abrasive powder.
Provided it is not water soluble, the sole criterion for the abrasive is that it may be defined by any one of the measures of hardness selected from the group of measures consisting of a) Mho's 4.5-6.3, b) Rockwell B 60-85, c) Brinell 95-142, or d) Knoop 120-180. As long as the aforesaid hardness criteria are met, the actual chemical nature of the abrasive is unimportant. In certain embodiments, the abrasive layer may be associated with a lubricant which may, but need not be a soap and/or sponge-like material.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
For use as abrasive web material for the abrasive coating, it has been found that synthetic fibers such as nylon and polyesters (e.g., Dacron) are particularly well suited. The uniformity and quality of such types of fibers can be closely controlled. Also, these fibers retain substantially their desired physical properties when wet with water or oil. However, various natural fibers which are flexible, resilient, durable, and tough can also be utilized in the web material. The resulting extremely open fibrous construction exhibits a remarkably effective action. It is essentially non-clogging and non-filling in nature, particularly when used in conjunction with liquids such as water and oils. Furthermore, it can be readily cleaned upon simple flushing with a rinsing liquid, dried and left for substantial periods of time and then reused with all its original properties intact. The structure of the web is flexible and readily compressible and upon release of compression returns substantially completely to the initial uncompressed form.
When a further cleansing or lubricating material retention layer is used either as a second lamina or third or inner lamina between two outer web lamina of the pad, it is preferably formed of a foamed synthetic, thermoplastic material, such as for example polyurethane form or the like which may be either of the polyester or polyether type. Due to the cellular structure of this foamed material, the inner web is highly flexible and compressible, thereby adding resilience to the overall pad, the cellular structure furthermore enabling the web to readily absorb the retain water which is not characteristic of the outer laminae of the pad. Thus, as the pad is wetted in preparation for use, the wetting of the water-soluble cleansing agent preferably incorporated therewith may liquify or emulsify a portion of the cleansing or lubricating agent, thus causing the solution to become absorbed in the pores and cellular structure of the foamed inner web material. Thereafter as the pad is put to use, the inner lamina of foam material is somewhat compressed causing the solution of cleansing or lubricating agent to be exuded from the foam material and applied to the surface of the article being cleansed. Upon reuse of the pad, after having dried, the introduction of water thereto first saturates the inner foamed web and thus places in solution the film of cleansing agent lining the pores and cells of the form material thereby minimizing the amount of additional cleansing agent required.
The second as well as the intermediate or inner lamina of the foam web material when used also serves as an effective means for binding the laminae or plies of the composite pad into a unified and integral structure.
In accordance with one embodiment of pad structure the bonding of the three laminae is achieved by application of both heat and pressure at only the border area of the pad so as to produce a fin-sealed edge or lip comprised of the three pad laminae bound together in a compressed state. In this embodiment the application of heat also acts as a resin binder on the two outer laminae so as to effect a binding of the fibers of said outer laminae in a compressed state.
According to another embodiment of the invention, the bonding of the three laminae is achieved through a flame lamination technique by which heat is applied to the entire surface on both sides of the inner web of foamed material, whereupon each outer ply is brought into contact with a respective heated surface with a force sufficient to effect a surface bond and furthermore enabling the web to readily absorb the retain water which is not characteristic of the outer laminae of the pad. Thus, as the pad is wetted in preparation for use, the wetting of the water-soluble cleansing agent preferably incorporated therewith liquifies a portion of the cleansing agent, thus causing the solution to become absorbed in the pores and cellular structure of the foamed inner web material. Thereafter as the pad is put to use, the inner lamina of foam material is somewhat compressed causing the solution of cleansing agent to be exuded from the foam material and applied to the surface of the article being cleansed. Upon reuse of the pad, after having dried, the introduction of water thereto first saturates the inner foamed web and thus places in solution the film of cleansing agent lining the pores and cells of the form material thereby minimizing the amount of additional cleansing agent required.
In the case of each embodiment, the bonding of the several laminae into an integral product is accomplished without the addition of any glue, adhesive or other binding additives which might tend to impair the permeability or free flow of water from one lamina to the other at their respective interfaces.
The cleansing or lubricating agent which may be incorporated in a pad or other substrate is a soap or synthetic detergent, or a combination thereof in a solid or semisolid form. The use of soap per se or a combination being preferred.
To amplify the function of polishing the metal surfaces, using substrates containing abrasives as previously described, in combination with a lubricating agent greatly increases polishing ability over the abrasive webs alone. It has been found that soaps, or soaps, in conjunction with detergents are superior lubricating agents than detergents alone.
It has also been found that waxes, and particular carnauba wax, are excellent lubricating agents alone or dispersed within soaps, or soap detergent mixtures when used in conjunction with the abrasive webs of this invention. It has been found that lubricants, suitably fatty acid lubricants, particularly stearic acid, when applied to the individual abrasive particles before applying these abrasive particles to the heretofore mentioned webs either alone or with soaps and soap detergent mixtures, yield superior results. Also, a natural wax when admixed with water, can be sprayed in a very thin film on the surface of the particles or the completed abrasive webs.
An article of the present invention may comprise a soap solid at ambient temperature. A large number of such soaps are available in commerce. Such soaps, as well as the foregoing waxes or lubricants, may be coated over all of the fibers by, say, immersion into a bath of liquid soap or, more suitably, injected in the liquid state into the interior of the article.
The soap may be disposed between a second or an inner web of foamed material and one of the outer webs of abrasive material. Alternatively, the cleansing agent is heated to a liquid state, injected into the inner web and permitted to solidify on cooling. It will be understood by those skilled in the art that where the flame sealing embodiment is employed, the cleansing material will tend to be melted into the inner web. Suitably, the amount of soap is between 25 and 75% by weight of the entire article.
The abrasive material is finely divided, water insoluble abrasive which complies with the aforementioned hardness criteria, having a size range of about 10 to about 300 microns. It may be a metal, a naturally occurring mineral or a glass. Suitable materials include copper alloy, iron, nickel alloy or steel, especially finely divided stainless steel. Spherical glass beads are also useful both per se and in conjunction with other abrasives. Suitably the abrasive material is coated at a density of between about 140 and about 250 g/m 2 of gross area. The term gross area means the area obtained by, say, multiplying the breadth times the width of a given rectangular surface. It does not mean the actual surface area provided by each individual fibre, which would be a very substantially larger amount.
The abrasive particles may be sprayed onto the outer webs in a particle binder through spray nozzles prior to the cutting step. Alternatively, and preferably, a binder is sprayed onto the needle punched web and the abrasive powder sprayed onto said coating. Optionally, an upper coating of binder is applied and the entire web is cured. Thereafter, if desired, the cleansing agent is added and the pads cut to desired size or the foamed synthetic thermoplastic layer is attached to a single web or laminated between two webs and the cleansing agent added. As binders there may be employed any suitable binders which set to a resin which is substantially insoluble in water and organic solvents after evaporation of the aerosol carrier therefore.
This technique of application is equally applicable when, in place of a web the substrate is a foam pad, a woven or non-woven fabric or a substantially water resistant paper.
It is therefore an object of this invention to improve upon a cleansing aid in the form of an abrasive pad and adaptable for home use in scouring kitchen utensils made of metals, such as moderately soft metals such as aluminum, bronze, brass or copper. Improvements in scouring utensils of stainless steel can also be used.
It is a further object of this invention to provide a cleansing aid in the form of a scouring pad having a self-contained supply of cleansing agent incorporated therewith.
It is also an object of this invention to provide an abrasive scouring pad with means for preventing unnecessary waste of the cleansing agent incorporated therewith.
It is a still further object of the invention to provide an improved method for fabricating a cleansing aid in the form of an abrasive scouring pad which may have incorporated therewith a self-contained cleansing agent.
Further objects of the invention, together with the features contributing thereto and the advantages accruing therefrom, will be apparent from the following description when read in conjunction with the drawings wherein:
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a side elevational sectional view of a scouring pad according to one embodiment of the instant invention.
FIG. 2 is a side elevational sectional view of a scouring pad according to a second embodiment of the invention.
FIG. 3 is a side elevational sectional view of a third embodiment.
FIG. 4 is a side elevational sectional view of a scouring pad according to still another modification of the third embodiment of the invention.
FIG. 5 is a plan of the pad shown in FIG. 4 at section 5--5.
FIG. 6 is a side elevational sectional view of a scouring pad according to still another modification of the third embodiment of the invention showing the presence of a soap module.
FIG. 7 is a diagrammatic view illustrating the process for fabricating scouring pads according to FIGS. 4 and 5 of the instant invention; and
FIG. 8 is a more detailed view in enlarged scale of a part of the pad fabricating equipment illustrated in FIG. 7.
DETAILED DESCRIPTION OF THE DRAWINGS
Referring now in particular to FIG. 1, it will be seen that a pad 100 in accordance with the first embodiment of the invention comprises web material 110. The initially substantially non-abrasive web material 110 is comprised of a plurality of individual fibers 112 randomly oriented, non-woven, and loosely held together at the points where they contact one another by needle punching. The web material 110 presents an open, lofty and somewhat resilient structure possessing extremely low density and containing a network of many relatively larger intercommunicating voids.
Referring now in particular to FIG. 2, it will be seen that a pad 200, in accordance with this embodiment of the invention comprises a laminate structure which includes upper lamina 210 of web material and a further lamina 220 of a synthetic sponge-like foamed plastic material, joined thereto at surface 222.
Referring now in particular to FIGS. 3, a pad 300 in accordance with these embodiments of the invention comprises a sandwich laminate structure which includes upper lamina 210 of web material, a further lamina 320 of a synthetic sponge-like foamed plastic material joined thereto at 322 and a further lower layer of web material 311, joined to said foam lamina 320 at 324.
Referring now in particular to FIGS. 4 through 5, a pad 400 in accordance with these embodiments of the invention comprises a laminate structure which includes upper lamina 410 of web material, a further lamina 420 of a synthetic sponge-like foamed plastic material and a further lower layer of web material 411, which is sealed at the edges to provide a scraping edge 419.
In the embodiments of FIGS. 1-5 which contain a cleansing agent 330, the cleansing agent may be disposed over the fibers of the outer web, suitably by dipping into said cleansing agent in the liquid phase.
Alternatively, in the embodiments of FIGS. 2-5, a discrete amount of cleansing agent may be disposed within the pad at the interfaces 222, 322, 324 or 424 between the foam lamina 220, 320 or 420 and the web lamina 210, 310 or 410 respectively. Alternatively within the foam laminae 220, 320 or 420 is a water soluble cleansing agent 330 which may be either a soap, synthetic detergent, or a combination of both. The cleansing agent is introduced to the pad during fabrication thereof as a pasty, semisolid deposit which may, however, before usage, depending upon the length of time between fabrication of the pad and usage, dry out and become solid so as to constitute a thin tablet or wafer. The cleansing agent could, however, if desired, be initially incorporated into the pad structure in a solid tablet or wafer form.
The foam lamina 220, 320 or 420 comprises a web of foamed plastic material such as polyurethane or the like. Such materials are flexible and compressible thereby providing added resilience to the overall pad structure. Such material is also, due to its cellular structure, higher absorbent, thereby enabling it to serve as a reservoir for retaining the cleansing agent in liquified form after application of water thereto. In use, pressure applied to the pad incident to the scrubbing action compresses the foam material of the inner lamina causing it to exude the retained solution of cleansing agent which thereupon flows freely through the open structure of the outer lamina of the pad to the pad outer surface to assist and complement the abrasive action of the pad in removing the dirt, grease or other foreign substances from the article being cleaned.
In the form of pad illustrated in FIGS. 4 and 5, the border areas of the three laminae 410, 420 and 411 are bound together under application of suitable heat and pressure at said border areas to form a heat seal bond firmly securing the respective laminae into a unified and integral pad structure. Application of a suitable degree of heat to the border area of the pad when under compression breaks down the cellular structure of the foamed thermoplastic material of the inner lamina 420 to render it more dense while fusing thereto the web material of the outer laminae 410, 411. At the same time, the fibers 110 of the outer laminae become bound together by the binder incorporated therewith under the influence of the heat to result in a fin-sealed lip or edge 429 as shown. The fin-sealed edge constitutes a relatively thin and rigid pad portion having, after coating, a good abrasive surface thereby being particularly effective and useful for reaching into small cracks, crevices or other small openings in the article or utensil to be cleaned, which type of openings could not be effectively cleaned in the absence of such a fin-sealed edge on the pad. Also, by binding the respective laminae together in this manner, it will be apparent that the interface between the major portions of the inner and outer laminae contain no impediment to the free flow or intercommunication of water or cleansing solution therebetween.
The detailed structure of the devices of the present invention is readily illustrated by reference by FIG. 6. To the needle punched web 316 is added a binder, preferably resin, which coats each fiber along its length and particularly at the juncture points between the respective fibers is sprayed onto the web. Thereafter there is distributed along each fiber within the web material (but not exclusively present at said globules 314) are also fine particles of abrasive material 316 such as stainless steel powder, glass spheres and materials of similar hardness as defined above, the abrasive particles being adhered to the web structure by the said particle binder and preferably concentrated at or near the outer surface of the webs. If desired a further coat of binder 318 is applied over the abrasive 316. The soap module 326, in this modification, lies between web 310 and foam 320.
The thickness of the web material constituting respective laminae of the pad is not critical and may be varied without substantially impairing the usefulness of the pad as a cleansing pad. Typically, the laminae of web material may have a thickness of about 0.6 to 1.25 cm., with the thickness of the foamed plastic material constituting the foam laminae of the pad being about 0.3 to 0.6 cm. Pads comprised of laminae having the foregoing thickness dimensions have been found to be of an overall thickness which renders them highly effective as cleansing aids, and convenient to handle.
The fiber batt of 40 denier polyester can be formed using a variety of standard techniques known to one skilled in the art. A Rando-weber or a textile card equipped with a cross-lapper can be used to form the base web to the desired weight and thickness. Once formed, the web is ready for the application of bonding agents or alternately, the web can be fed into a needle punch machine to lightly tack the fibers together prior to applying bonding agents. The light punching of the fibers yields a web with significantly higher strength. The web can then be sprayed with resin to facilitate handling.
Alternatively, a web may be purchased commercially.
The resinated non-woven substrate roll is positioned on a delivery stand and fed to a base coat spray apron fitted with flat wire belt, and passed directly under an horizontal transverse reciprocator. The reciprocation is set at a predetermined rate and is fitted with a automatic recirculating airless gun and is also equipped with an on/off switch controlled by a programmable logic controller and inductive proximity limit switches to spray only a portion of the width substrate passing between the sprocket centers of the reciprocator. A wet coating is then supplied to it by an airless pump to provide the wet base coat required.
Immediately after the base coat spray apron, the wet substrate passes under a coating machine which has been modified to handle the dry abrasive powders. The abrasive powder is delivered onto the wet substrate across the width when it passes from the base coat to top coat spray apron.
A top coat spray apron similar to the base coat one carries the wet substrate with powder under a pneumatic cable cylinder horizontal transverse machine set at a predetermined rate is fitted with a conventional air atomizing automatic spray gun, equipped with an air nozzle and fluid nozzle. A pressure feed tank delivers the wet top coat to the gun. Fluid and atomizing air pressures are adjusted to deliver the top coat, if desired.
Immediately after the top coat spray apron, the wet substrate enters a gas fired and conveyorized oven to dry and cure the coating onto the substrate.
A take-up cart equipped with two wooden rolls moving in the same direction winds the coated substrate up into a roll when a cardboard core is positioned above the two rolls. After the first side is coated, the process is repeated for the opposite side.
FIG. 7 depicts the process for fabricating the above described pad of FIGS. 4 and 5. As shown, elongate sheets of fibrous web material 610, 611 are supplied from spools 31, 33 thereof, a sheet of foamed thermoplastic material 620 being supplied from a spool 32 thereof. The sheets are continuously withdrawn from their respective spools at a uniform rate, the sheet of web material 611 being fed through a suitably driven pair of feed rolls 35 while the other sheet of web material 610 and the sheet of foamed thermoplastic web material 620 are similarly fed by suitably driven feed rolls 36, 37 respectively. The sheet 610 is thereafter supported by a series of rolls 38, the sheet 620 being thereafter supported by a series of rolls 39. As the sheet 611 is fed into the nip of feed rolls 41 it is brought into contact with the sheet 620, the two sheets thereafter being fed in superposed relation beneath a dispenser 42 which is charged with the cleansing agent and deposits measured amounts thereof intermittently at spaced increments both laterally and longitudinally relative to the upper surface of sheet 620. As the two sheets 611, 620 enter the nip of feed rolls 45, the upper surface of sheet 620 is brought into contact with sheet 6 which overlies the deposits of cleansing agent, the three sheets thereafter being fed in superposed relation to one another into a die-cutting press 50. Feed through the die-cutting press is intermittent in synchronism with the cyclic operation of the press, the momentary interruption of feed being compensated for by permitting the combined sheets to develop a loop between the feed rolls 45 and the press.
For fabricating the pads according to the FIG. 1 embodiment thereof, the sealing press 50 operating to compress and heat seal the three sheets 611, 611 and 620 in a plurality of oval patterns to form the fin-seal edge 18 of the individual pad structure, after the sealing step the abrasive is sprayed on by jets 71 or 72. In the second stage of the operation, a cutting press 58 operates to cut or sever the three sheets at the heat sealed area so as to separate the individual pads from the elongate sheet material, which pads are then directed to a suitable conveying mechanism 51 for delivery of the completed pads to another location. The heat sealing and cutting pattern effected by the press on the sheets of web material can be seen in FIG. 6 which shows a section of the sheet material remaining as scrap after individual pads have been separated therefrom. The individual pads are cut out from a pattern in which they are aligned in a series of transverse rows, the adjacent rows being relatively offset from one another in the interests of minimizing waste of the web material from which the pads are formed. It will of course be understood that the spacing of the areas cut away from the sheets to produce the individual pads is arranged to coincide with the placement of the cleansing agent deposited by the dispenser 42, so that each of the resulting pads will have incorporated therewith a deposit of said cleansing agent.
FIG. 8 illustrates in greater detail the portion of the press effective in the first stage of operation for heat sealing the sheet material to form the fin-seal edge of the individual pads. As shown, the mechanism includes opposed heating dies 52 mounted in heated blocks 53 each provided with a plurality of electrical resistance heat cartridges 54. The blocks 53 are supported on posts 55 of heat insulating material, the posts 55 associated with the lower die being mounted on a stationary portion 56 of the press, the posts associated with the upper die being secured to a reciprocally driven portion 57 of the press. Preferably, heating of the web material is also achieved dielectrically by radio frequency energy supplied from a radio frequency pulse generator 60, the output of the generator being transmitted to the upper die 52 through a flexible conductor 61 connected thereto. Shorting out of the radio frequency energy across the gap between the dies 52 is prevented by coating the edge of the dies with a hard dielectric substance 62 such as a ceramic or the like. The use of dielectric heating by radio frequency energy lessens the time to heat the web material to the desired temperature. It also avoids the tendency which would otherwise exist for the dies to stick to the web material.
For fabricating the pad according to the FIGS. 2 and 3 embodiment, a slightly modified process is employed. According to this modified process for the FIG. 2 embodiment, a gas burner manifold 65 provided with a series of gas jets is disposed so as to direct a flame on the undersurface of sheet 620 immediately prior to its being brought into contact with sheet 611 at the nip of the feed rolls 41. Accordingly, as the sheets 611 and 620 pass between the rolls 41 and the heated surface of sheet 620 starts to cool, the two sheets become flame laminated over their entire abutting surfaces.
For the FIG. 3 embodiment, a similar gas burner manifold 66 is disposed so as to direct a flame over the entire upper surface of sheet 620 immediately prior to its being brought into contact with sheet 610 by the feed rolls 45. Accordingly, as sheets pass between rolls 45, sheet 610 becomes surface bonded to the upper surface of sheet 620, the three sheets being thereby bonded one to another at their respective interfaces as they are fed into the press 50. In this modified process the press 52 performs only a single stage operation of severing individual pads from the elongate sheets. The heretofore described first stage of press operation, employed for producing pads of the FIG. 1 embodiment, not being employed in the modified process for producing pads in accordance with the FIG. 2 and 3 embodiment thereof.
Although there has been shown and described what are considered to be preferred embodiments of the invention, it is of course understood that obvious changes or variations could be made from the forms and techniques specifically described and disclosed herein without departing from the spirit of the invention. It is therefore intended that the invention be not limited to the precise forms and techniques herein shown and described nor to anything less than the whole of the invention as hereinafter claimed.
EXAMPLES cl Example 1
Fiber batt formation
The fiber batt of 40 denier polyester can be formed using a variety of standard techniques known to one skilled in the art. A Rando-weber, Model D, (manufactured by Rando Machine Co., Macedon, N.Y.,) or a textile card equipped with a cross-lapper can be used to form the base web to the desired weight and thickness. Once formed, the web is ready for the application of bonding agents or alternately, the web can be fed into a needle punch machine to lightly tack the fibers together prior to applying bonding agents. The light punching of the fibers yields a web with significantly higher strength. The web is then lightly sprayed with an acrylic resin to facilitate handling.
Alternately, a web may be purchased commercially with the following specifications.
Weight--2.5 mg./cm 2
Fiber--100% 40 Denier Polyester
Binder--Rohm & Haas TR 407
Fiber/Binder Ratio--80/20
Thickness--1.90 cm.
Among the suppliers of this material are E. R. Carpenter Co., Russelville, Ky.; Moldan Corp., York S.C., and Kemwove Inc., Charlotte, N.C.
Example 2
Scrub Puff Coating Procedure
a) First Base Coat
The resinated non-woven substrate roll is positioned on a delivery stand and fed to a base coat spray apron fitted with a 2.5×2.5 cm mesh flat wire belt, moving at 1.93 cm./min. The substrate passes directly under an Horizontal Transverse Reciprocator Machine (DeVilbiss Type TYDB-508). The reciprocation is set at 15 strokes/min. and is fitted with a Automatic Recirculating Airless Gun (Binks Model 560) and is also equipped with an on/off switch controlled by a programmable logic controller and inductive proximity limit switches to spray only the 111.76 cm. width substrate passing between the 200 cm. sprocket centers of the reciprocator. (0.53 cm.) orifice size is used in the gun. A wet coating (see Table I) is then supplied to it by an Airless Pump, (Aro Model 650465-811), rated at 20:1 fluid pressure to air inlet pressure. Approximately 2-8 Kg/cm 2 psi inlet pressure delivers the 2.099-3.205 g/m 2 wet base coat required.
b) Abrasive Coating
Immediately after the base coat spray apron, the wet substrate passes under a Christy Machine Company "Coat-O-Matic", Model 60"-DI-S, with modified to handle the dry abrasive powders. These modifications include an extra fine diamond knurled 3.175/cm diameter rotary dispensing shaft, additional density plate studs to hopper body, internal head pressure relief plate, additional front brush, and an alternate slide adjuster having a 111.76/cm symmetrical dispensing width. The abrasive powder (see Table I) is delivered onto the wet substrate across the width when it passes from the base coat to top coat spray apron. A setting of approximately 21% setting on the motor drive fitted to the rotary shaft delivers the 560 g/min. abrasive powder required for the 2.234 g/m 2 dry coat.
c) Second On Top Coat
A top coat spray apron similar to the base coat one and moving at 4.194/cm/min. carries the wet substrate with powder under a Pneumatic Cable Cylinder Horizontal Transverse Machine (Reciprocator). This reciprocator is set at approximately 70 strokes/min. and is fitted with a Binks Model 610 conventional air atomizing automatic spray gun, equipped with a #63 PE Air Nozzle and #63 Fluid Nozzle. A Pressure Feed Tank (DeVilbiss Type QM 5095-3), delivers the wet top coat (see Table I) to the gun. Fluid and atomizing air pressures are adjusted to deliver 148.-.1765 mg/m 2 top coat.
Immediately after the top coat spray apron, the wet substrate enters a Sargent-Serial #2034--gas fixed and conveyorized 4.267 m long oven, set at 162° C. and 193.55 cm., to dry and cure the coating onto the substrate.
A take-up cart equipped with two wooden rolls moving in the same direction winds the coated substrate up into a roll when a cardboard core is positioned above the two rolls. After the first side is coated, the process is repeated for the opposite side.
Example 3
Soap and Soap/Detergent Loading
Under mild agitation, there is added enough Armour Dial #7344 crushed soap pellets to water at 82° C. to make a 30% solids solution. The soap solution is cooled to room temperature and injected into a device of Example 2 (wt. 4.4 g.) with a syringe. The soap is allowed to dry to yield a device of 11.5 gms. wt.
In accordance with the above procedure, to the solution is added 4.49 gms. ±7 an equal volume of Joy (trademark of Colgate-Polmolive) dishwashing detergent. Upon drying, a similar product is obtained.
Example 4
Detergent Loading
Full strength Joy (trademark of Colgate-Polmolive) dishwashing detergent is poured directly onto the device of Example 2. The detergent was allowed to dry to yield a device of 10 gms. wt.
Example 5
Carnauba Wax
54° C. water are premixed with 0.63 grams of Methocel F4M to make a high viscosity gel. The premix is cooled to room temperature and 23 grams of Duramul 0814--a 35% solid aqueous dispersion of Carnauba Wax (manufactured by Astor Wax Corp) is added. A portion (25 ml) of the formulation is injected into a device of Example 2 with a syringe to provide, on drying, a device of 15.3 gms wt.
Example 6
Woven And Non-woven Substrates
a) A typical abrasive formulation of the present invention comprises:
______________________________________ Wet Dry*______________________________________Water 100 --Methocell KHMS 3.5 3.5HA-12 acrylic emulsion 60 27SCM 304 stainless steel coated 62.9 62.9with lithium stearate______________________________________ (*Net weight after drying)
b) Utilizing the procedures of Example 2a. The formulation of section (9) above is applied to woven or non-woven substrate.
i) Woven: Terrycloth (234 g/m 2 ) was coated with 175 g/m 2 per side (one or two) of the above abrasive formulation.
ii) Non-woven: A natural cellulosic wipe (110 g/m 2 ) was coated with 88 g/m 2 per side (one or two with the above formulation).
In accordance with the above procedure any of the above substrates listed herein can be similarly coated. Similarly, in place of SCM 304 any of the above abrasives listed in Table I which fall within the permitted parameters may be employed.
Comparison of Polishing Capability of Certain Abrasives
Controls A through Q
In accordance with the procedure of Example 2 the following abrasives were coated onto the substrates listed below:
A: Shelblast AD-10.5B, walnut shells; B: Novaculite 200 mesh sand; C: 180 mesh silicon carbide; D: 280 mesh silicon carbide; E: 280 mesh alumina; F: 200 mesh olivine sand. G: 100 mesh, stainless steel powder #304-LSC, SCM Corp., Cleveland, Ohio; H: ampal 611 atomized aluminum powder, United States Bronze Powders, Inc., Flemington, N.J. I: #2224 soda lime glass spheres, Potters Industries, Inc., Hasbrouck Heights, N.J.; J: 1 (ss) stainless steel flake #316, United States Bronze Powders, Inc., and 1 (gls) #3000 glass spheres, Potters Industries, Inc., * these abrasives were not sprayed on after the base coat but mixed in with the base coat and sprayed on with it; K: 434 unannealed stainless steel powder, SCM Corp.; L: iron alloy powder #4600, SCM Corp., Cleveland, Ohio; M: #2227 soda lime glass spheres, Potters Industries, Inc., Hasbrouck Heights, N.J.; N: stainless steel powder #316-L, SCM Corp., Cleveland, Ohio; O: annealed stainless steel powder #410-L, SCM Corp., Cleveland, Ohio; P: microcrystalline silicon dioxide, grade 200, Illinois Minerals Company, Cairo, Ill.; Q: stainless steel powder #304-L, SCM Corp., Cleveland, Ohio.
Substrates: PE/U 94.8 gm/m 2 needle punched polyester heat sealed to urethane foam; U: urethane foam.
Other components: Rhoplex HA12 is a water-based acrylic polymer, manufactured by Rohm and Haas Co., Philadelphia, Pa. Astromel 6A and 8A are methylated melamine formaldehyde resins, manufactured by Astro Industries, Inc., Morganton, N.J. Cymel 301 is a hexamethoxymethylamine cross-linking agent, manufactured by American Cyanamid Co., Wayne, N.J. Luconyl Blue 708, a blue pigment dispersion, manufactured by BASF Corporation, Parsippany, N.J. AL 190 WD is a water dispersible aluminum paste, manufactured by United States Bronze Powders, Inc., Flemington, N.J. MD200 is a non-leafing grade aluminum powder, manufactured by Alcan-Toyo America, Inc., Naperville, Ill. Silane A1106 is an aqueous solution of an aminoalkyl silicone, manufactured by Union Carbide Corp., Danbury, Conn. Swift 22005 is a one component moisture cure polyurethane adhesive, manufactured by Swift Adhesives, Downers Grove, Ill.
The resulting materials were tested for polishing/scratching qualities. The results are listed in Tables 1 (a), (b) and (c) below together with the appropriate base and top coat components and amounts. Sample 1 is urethane foam coated on both sides. Samples 2,3,6,8-12, 16 and 18 are sandwiches of web material with web on each side (FIG. 3), 1st and 2nd refer to the exposed sides of the web. Samples 4 and 5 are single laminates (FIG. 2), and samples 13, 14 and 15 are urethane foam coated on one side only.
While the substrates used were needle punched polyester and urethane foam and needle punched polyester is preferred, it is apparent that equal polishing results could be obtained by applying the abrasives in the hardness range indicated above to other substrates such as woven and non-woven cloths, polyethylene, or vinyl foams, various wet strength papers, sponges and the like.
TABLE 1 (a)__________________________________________________________________________POLISHING/SCRATCH TEST RESULTS 1 2 3 4 5 6__________________________________________________________________________Abrasive A B C D E FSubstrate U PE/U PE/U PE/U PE/U PE/URhoplex HA 12 250 250 250 300 250 250AstroMel NW6A 100 100AstroMel NW8A 100 120Cymel 303/*307 100 100*Water 300 60.020% aq NH.sub.4 Cl 20BASFlucBlu 708 1AL190WD 10 60 60 45 45MD200 30.6Silane A1106 3 3Swift 22005 50Sides bottom top 1st 2nd 1st 2nd 1st 2ndSurface area cm.sup.2 103 103 161 161 8361 8361 161 161 161 161Wet base wt, g. 7.31 3.0 3.48 120 194 2.4 2.2 1.81 1.73Abrasive wt. g. 0.5 2.4 2.8 27.6 41.5 1.01 1.3 1.31 1.01Top Coat Wt. g. 0.45 0.28 0.33 20.0 25.9 0.5 0.35 1.1 0.4Knoop Hardns. 2500 2500 2050Mho's Hardns. 3-4 7 6-7RockwellB Hrd.Result non- agrssve scrtch severe scrtch too too too agrssve abrasive agrssve agrssve__________________________________________________________________________ Abrasives: A:Shelblast AD10.5B, walnut shells; B:Novaculite 200 mesh sand C: 180 mesh silicon carbide; D:280 mesh silicon carbide; E: 280 mesh alumina; F: 200 mesh olivine sand. Substrates: PE/U 94.8 gm/m.sup.2 needle punched polyester heat sealed to urethane foam. U: urethane foam.
TABLE 1 (b)__________________________________________________________________________ 7 8 9 10 11__________________________________________________________________________Abrasive G H I J KSubstrate PE/U PE/U PE/U PE/U PE/URhoplex HA 12 250 250 250 250 250AstroMel NW6A 100 100 100 100 100AstroMel NW8ACymel 303Water 40 40 40 10020% aq NH.sub.4 ClBASFluc Blu 708AL190WD/900L* 45 45 45 25* 45MD2000St Steel Flk316L 72Glass Sph#3000 100Sides 1st 2nd 1st 2nd 1st 2nd 1st 2nd 1st 2ndSurface area cm.sup.2 161 161 161 161 161 161 161 161 161 161Wet base wt, g. 3.34 2.48 3.21 2.78 3.31 2.85 3.78 4.21 2.38 2.14Abrasive wt. g. 1.25 1.30 2.65 2.65 2.91 2.91 1.23 1.07Top Coat Wt. g. 0.2 0.77 0.63 0.81 0.66 0.87 0.17 0.17Knoop Hardns.Mho's Hardns. 2.0-2.9 6 6.0.sup.glsRockwell B Hrd. 66 60.sup.ssResult like Brillo No effect good polish v. gd polish more scratch than G__________________________________________________________________________ Abrasives: G: 100 mesh, stainless steel powder #304LSC, SCM Corp, Cleveland OH; H: Ampal 611 atomized aluminum powder, US Bronze Co., Flemington NJ; I: #2224 soda lime glass spheres, Potters Industries, Hasbrouck Heights, NJ; J: .sup.1 (ss) stainless steel flake #316, US Bronze Co, and .sup.2 (gls) #3000 glass spheres, Potters Ind. *these abrasives were not sprayed on after the base coat but mixed in with the base coat and sprayed on with it; K: 434 unannealed stainle ss steel powder, SCM Corp.;
TABLE 1 (c)__________________________________________________________________________ 12 13 14 15 16 17__________________________________________________________________________Abrasive L M N O P QSubstrate PE/U U U U U PE/URhoplex HA 12 250 250AstroMel NW6A 100 100AstroMel NW8ACymel 303Water20% ag NH.sub.4 ClBASFluc Blu 208AL190WD 45 10 45MD2000Silane A1106Swift 22005 50 50 50 50Sides 1st 2nd 1st 2ndSurface area cm.sup.2 161 161 103 103 103 103 161 161Wet base wt, g. 0.93 1.10 7.88 8.43 7.34 8.51 0.98 0.99Abrasive wt. g. 1.18 1.17 4.35 4.41 4.31 0.57 1.18 1.12Top Coat Wt. g. 0.12 0.12 0.062 0.062Knoop Hardns.Mho's Hardns. 6.0 6.5Rockwell B Hrd. 80 60 96 66Result better than G good almost as not gd excess good polish polish gd as 304.sup.ss as 304 scrtch__________________________________________________________________________ Abrasives: L: iron alloy powder #4600, SCM Corp, Cleveland OH; M: #2227 soda lime glass spheres, Potters Industries, Hasbrouck Heights, NJ; N: stainless steel powder #316L, SCM Corp, Cleveland OH; O: annealed stainless steel powder #410L, SCM Corp, Cleveland OH; P: microcrystalline silicon dioxide, grade 200, Illinois Mineral Inc., Cairo, IL; Q: stainles steel powder #304L, SCM Corp, Cleveland OH;
Comparison to Klecker U.S. Pat. No. 4,078,340
Controls R-T
Following the guidelines of U.S. Pat. No. 4,078,340, souring pads using Navajo FFFF pumice, Gemstar's Camel Carb (calcium carbonate) and Illinois Mineral's Imsil A-25, microcrystalline silice were prepared and evaluated to determine their polishing properties on aluminum panels.
R-Pumice as an Abrasive
______________________________________Component Weight (g)______________________________________Water 242.0Foammaster AP 0.5Methocel F4M 6.0Rhoplex HA-121 25.0Astro Mel NW-6A 62.5Luc Green 936 1.0Navajo FFFF Pumice 64.6 501.6______________________________________
S-Calcium Carbonate an Abrasive
______________________________________Component Weight (g)______________________________________Water 242.0Methocel F4M 6.0Rhoplex HA-12 125.0Astro Mel NW-6A 62.5Luc Green 936 2.0Camel Carb (CaCO.sub.3) 64.6 502.1______________________________________
Applied 16.6 grams to a 4"×4" piece of 8.6 oz/yd 2 needle punched polyester. The coating was dried in a 300° F. oven for one hour.
T-Silica as an Abrasive
______________________________________Component Weight (g)______________________________________Water 242.0Methocel F4M 6.0Rhoplex HA-12 125.0Astro Mel NW-64 62.5Luc Green 936 2.0Imsil A-25 64.6 502.1______________________________________
Applied 15.3 grams to a 4"×4" piece of 8.6 oz./yd. 2 needle punched polyester. The coating was dried in a 300° F. for one hour.
A polishing test was performed on Ryerson #3003 aluminum panels. A panel was scoured using a 2% solution of Joy with a moderate amount of hand pressure. These abrasives did not provide good polishing properties in comparison to stainless steel and steel wool. However, the scouring pad containing Pumice was rated fair compared to calcium carbonate, which were rated as ineffective and silica which was unacceptable due to scratching.
Haze Reflection Measurement.
In order to determine the relative efficacy of certain lubricants, in particular soaps and detergents. Devices of Example 2 coated 304-LSC, S.S. Powder, (lithium stearate stainless steel powder) 100 Mesh, and Steel Wood (Grade #1 Medium Course) were utilized to polish Ryerson #3003 aluminum panels under an approximately 2% aqueous solution or suspension of these lubricants. The resulting panels were examined by a Spectrogard Color System spectrophotometer (manufactured by Gardner Laboratories, Silver Spring, Md.). The significant reading is the Y reading. Values of Y>30 are not acceptable.
The results for controls LA-LR are summarized in Table 3 below.
TABLE 3__________________________________________________________________________MEASUREMENT OF HAZE REFLECTION(MACHINE CONDITIONS: 1964 cie 10°,CIE ILLUMINANT,D65 (DAYLIGHT)SPECULAR COMPONENT EXCLUDED.) *POLISHING PROP.PANELSCOURING TRISTIMULUS VALUES 1 = BEST,ID PAD FORMULATION CIE X, Y, Z 20 = WORST__________________________________________________________________________LL STEEL WOOL 1.98% SOS Soap 17.40, 18.17, 20.13 1LN STEEL WOOL 1.99% aqueous solution of Armour Dial #7344 18.45, 19.58, 22.14 2 Zonyl FST (0.2% Zonyl FST based on total solids)LK STEEL WOOL 1.98% aqueous solution of Armour Dial # 7344 19.64, 20.84, 23.56 3LM STEEL WOOL 1.98% aqueous solution of Joy 20.48, 21.76, 24.68 4LT STEEL WOOL 2.0% aq. soln of Ajax (Colgate-Palmolive 21.65, 23.00, 26.13 5 dishwashing detergent)LA SCRUB PUFF 1.98% aqueous solution of Armour Dial # 7344 23.01, 24.37, 27.86 6LB SCRUB PUFF 1.98% aqueous solution of SOS soap 24.56, 25.99, 28.80 7LQ STEEL WOOL 20% aqueous solution of Bio Soft D-62 (LHS) 28.03, 29.72, 32.86 8LD SCRUB PUFF 99% aqueous solution of Armour Dial # 7344 28.37, 30.00, 32.94 9 Zonyl FST, 0.2% Zonyl FST based on total solidsLR STEEL WOOL 2.0% aqueous solution of sodium Lauryl sulfates 29.15, 30.94, 34.79 10LC SCRUB PUFF 1.93% aqueous solution of Joy (P & G) 36.38, 38.51, 42.26 11LG SCRUB PUFF 2.0% aqueous solution of Bio Soft D-62 (LAS) 40.20, 42.50, 45.97 12LJ SCRUB PUFF 2.0% aqueous solution of Ajax (Colgate Palmolive) 41.44, 43.81, 47.52 13LH SCRUB PUFF 2.0% aqueous solution of sodium Lauryl sulfate 44.34, 46.18, 49.56 14LI SCRUB PUFF 2.0% aqueous solution of lauramine oxide 46.92, 47.47, 52.34 15LO STEEL WOOL Water 47.21, 49.89, 53.58 16LF SCRUB PUFF 2.0% aq solution of Triton X-100 48.33, 50.98, 54.01 17LE SCRUB PUFF Water 52.22, 52.94, 52.63 18LS STEEL WOOL 2.0% aqueous solution of lauramine oxide 52.36, 55.26, 58.94 19LP STEEL WOOL 2.0% aqueous solution of Triton X-100 52.40, 55.30, 58.68 20__________________________________________________________________________ *Lowest Y value indicates the least amount of surface haze. (maximum polish). Steel wool means steel wool pad of grade #1, medium course, Scru Puff means a device substantially as produced by Example 2. | An open low density abrasive article adapted for the cleaning of aluminum or similar surfaces comprising a lofty open non-woven three dimensional web form of a plurality of interlaced randomly extending flexible durable, tough, resilient organic fibers said web fibers being firmly adhesively bonded together at points where they cross and contact each other to form a three-dimensionally integrated structure throughout said web, and abrasive particles distributed within said web and firmly bonded to the web fibers by a relatively hard binder, the interstices between adjacent fibers being open and substantially unfilled by binder or abrasive, there being defined throughout said aricle a tridimensionally extending network of intercommunicating voids constituting the major portion of the volume of the said article, said article being flexible and readily compressible and, upon release of pressure capable of recovering substantially completely to its initial form, wherein said abrasive is defined by any one of the measures of hardness selected from the group of measures consisting of a) Mho's 4.5-6.3, b) Rockwell B60-85, c) Brinell 95-142, d) Knoopp 120-180. In certain embodiments, the abrasive layer may be associated with sponge-like material and/or a cleansing or lubricating agent suitably a soap. | 1 |
BACKGROUND OF THE INVENTION
[0001] Sensory signals play an important role in communicating key benefits to the consumer. For example, when using toothpaste there is typically no immediate signal that the product has worked as promised or clone anything during use. A visual cue., such as the foam changing color from white to blue could dramatically improve this perception but the art reports that such technologies may not be currently feasible.
[0002] Moreover, a need exists to control the rate at which this color change occurs so that the signal could be used to ensure consumer compliance (e.g., to ensure a child has brushed adequately).
BRIEF SUMMARY OF THE INVENTION
[0003] The invention includes a composition that includes a film. The film is composed of a first shielding polymer layer, a middle decorative layer, and a second shielding polymer layer. The first and the second shielding layers obscure at least a portion of the middle decorative layer.
[0004] Also included are methods of using the compositions in an oral care, personal care, or home care regimen.
DETAILED DESCRIPTION OF THE INVENTION
[0005] As used throughout, ranges are used as a shorthand for describing each and every value that is within the range. Any value within the range can be selected as the terminus of the range. In addition, all references cited herein are hereby incorporated by reference in their entireties, in the event of a conflict in a definition in the present disclosure and that of a cited reference, the present, disclosure controls.
[0006] The invention broadly encompasses oral care compositions, personal care compositions, and home care compositions. Oral care compositions include compositions such as toothpaste, personal care compositions include such things as lotions and shower gels, and home care compositions include such things as all-purpose cleaning solutions and dish detergents. Other exemplary compositions are disclosed elsewhere herein.
[0007] The invention also encompasses an oral care composition that includes a film. The film includes at least a first and a second shielding polymer layer and a middle-decorative polymer layer that is placed between the first and the second shielding layers. The oral care composition may be in any form, including toothpaste, a gel, a mouthrinse, a lozenge, a floss, a tooth tape, a ship, a confection, or a varnish.
[0008] The shielding layers, of which there are at least two, serve to obscure the visual aspect of the decorative layer(s), such that prior to contact with and/or mechanical manipulation in the oral cavity, the true visual aspect of the decorative layer is not apparent. By “obscure” it is intended to include shielding layers which presence over the decorative layer and/or which subsequent absence alters the visual aspect of the film and/or the overall composition. For example, the shielding layers may be opaque and visually shield the decorative layer; the shielding layers may be translucent or transparent but colored, so that the absence of the shielding layer results is a perceived color change of the film; the shielding layers may even be clear, if, the decorative layer contains a component that changes color when exposed to the oral cavity (by removal of the shielding layers), such as a pH or temperature sensitive agent. Alternatively, the shielding layer may be shielding a compound agent in the decorative layer, that, upon release alters an aesthetic of the overall composition, such compound(s) or agents may be visually discernable or not within the decorative layer.
[0009] The shielding lavers may discontinuous or they may provide coverage for the entire area of the decorative layer. The film may contain more than one decorative layer.
[0010] The diagram below further illustrates this material, which may be prepared by sequential casting of film slurries or by any other manner in the art.
[0011] In one embodiment, the shielding layers comprise at least hydroxypropyl methylcellulose (HPMC), glycerin, and titanium oxide. In another embodiment, the shielding layers comprise at least HPMC, glycerin, and titanium oxide. In another embodiment, the middle decorative polymer layers comprise at least HPMC, glycerin, and a pigment. In certain embodiments, a pigment of the decorative middle layer is red, blue, green or mixtures thereof, but any color is suitable. A composition may comprise more than two shielding layers.
[0012] In an embodiment, any of the polymer layers may comprise hydroxylpropyl cellulose (HPC). Any of the polymer layers may comprise one or more of a pigment, FD&C color, and lake color, and various color-Imparting compounds, among other things.
[0013] The oral care compositions can include various ingredients such as at least one abrasive, at least one fluoride source, at least one agent to increase the amount of foam, at least one surfactant, at least one vitamin, at least one polymer, at least one flavoring agent; at least one enzyme, at least one humectant, and/or at least one preservative and combinations thereof.
[0014] The invention also encompasses a method of apprising a user of completion of teeth brushing including applying an oral care composition as described herein comprising a first shielding polymer layer, at least one middle decorative polymer layer, and a second shielding polymer layer, wherein the first and second opaque layers collectively conceal at least a portion of the at least one middle decorative layer to the teeth, brushing the teeth and oral care composition to cause a foam, observing a distinct color change in the oral care composition. In certain embodiments, the color change is in the overall composition or in the foam produced by use of the composition.
[0015] For example, when the formulations are used In the normal manner, the film rapidly dissolves, allowing the colorant or pigment to become increasingly prominent. Foam changes color from white to decorative within one minute. This effect can also be illustrated by the change of a 1:3 slurry of toothpaste in water from white to decorative as me toothpaste Is distributed and the film dissolves. The degree of color change can be easily changed by increasing or decreasing the quantity of film in the formula.
[0016] In certain embodiments, an abrasive is present in the composition in an amount of about 1 to 20 wt % . In certain embodiments, the fluoride source is present in an amount of about 0.01 to 5 wt. % . In certain embodiments, the agent to increase the amount of foam is present in an amount of about 1 to 90 wt. %. In certain embodiments, the flavoring agent in an amount of about 0.01 to 5 wt. %. In certain embodiments, the tape or strip further includes at least one humectant in an amount of about 0.01 to 5 wt. %.
[0017] The oral care compositions may further include one or more fluoride ion sources. A wide variety of fluoride ion-yielding materials can be employed as sources of soluble fluoride in the present compositions. Examples of suitable fluoride ion-yielding materials are found In U.S. Pat. No. 3,535,421, to Briner et al.; U.S. Pat. No. 4,885,155, to Parran, Jr. et al. and U.S. Pat. No. 3,678,154, to Widder et al., incorporated herein by reference.
[0018] Representative fluoride ion sources include, but are not limited to, stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate, sodium monfluorophosphate (MFP), ammonium fluorosilicate, as well as tin fluorides, such as stannous fluoride and stannous chloride, and combinations thereof. Certain particular embodiments include stannous fluoride or sodium fluoride as well as mixtures thereof.
[0019] In certain embodiments, the oral care composition of the invention may also contain a source of fluoride ions or fluorine-providing ingredient hi amounts sufficient to supply about 25 ppm to 5,000 ppm of fluoride ions.
[0020] Fluoride ion sources may be added to the compositions of the invention at a level of from about 0.01 % to 3.0% in one embodiment or from about 0.03% to 1.0%, by weight of the composition in another embodiment.
[0021] The oral care compositions of the invention also may include an agent to increase the amount of foam that is produced when the strip or tape adhered to the oral cavity is brushed.
[0022] Illustrative examples of agents that increase the amount of foam include, but are not limited to polyoxyethylene and certain polymers including, but not limited to, alginate polymers.
[0023] The polyoxyethylene may increase the amount of foam and the thickness of the foam generated by the oral care composition of the present invention. Polyoxyethylene is also commonly known as polyethylene glycol (“PEG”) or polyethylene oxide. The polyoxyethylenes suitable for this invention will have a molecular weight of about 200,000 to about 7,000,000. In one embodiment the molecular weight will be from about 600,000 to about 2,000,000 and in another embodiment from about 800,000 to about 1,000,000. Polyox® is the hade name for the high molecular weight polyoxyethylene produced by Union Carbide.
[0024] The polyoxyethylene may be present in an amount from about 1 % to 90%, in one embodiment from about 5% to 50% and in another embodiment from about 10% to 20% by weight of the oral care carrier component of the oral care compositions of the present invention.
[0025] Another agent optionally included in the oral care tape or strips of the invention is a surfactant or a mixture of compatible surfactants. Suitable surfactants are those which are reasonably stable throughout a wide pH range, for example, anionic, cationic, nonionic or zwitterionic surfactants.
[0026] Suitable surfactants are described more fully, for example, in U.S. Pat. No. 3,959,458, to Agricola et al.; U.S. Pat. No. 3,937,807, to Haefele; and U.S. Pat. No. 4,051,234, to Gieske et al., which are incorporated herein by reference.
[0027] In certain embodiments, the anionic surfactants useful herein include the water-soluble salts of alkyl sulfates having from 10 to 18 carbon atoms in the alkyl radical and the water-soluble salts of sulfonated monoglycerides of fatty acids having from 10 to 18 carbon atoms. Sodium lauryl sulfate, sodium lauroyl sarcosinate and sodium coconut monoglyceride sulfonates are examples of anionic surfactants of this type. Mixtures of anionic surfactants may also be utilized.
[0028] In another embodiment, cationic surfactants useful in the present invention can be broadly defined as derivatives of aliphatic quaternary ammonium compounds having one long alkyl chain containing from about 8 to 18 carbon atoms such as lauryl trimethylammonium chloride, cetyl pyridinium chloride, cetyl trimethylammonium bromide, di-isobutylphenoxyethyldimethylbenzylammonium chloride, coconut alkyltrimethylammonium nitrite, cetyl pyridinium fluoride, and mixtures thereof.
[0029] Illustrative cationic surfactants are the quaternary ammonium fluorides described in U.S. Pat. No. 3,535,421, to Briner et al, herein incorporated by reference. Certain cationic surfactants can also act as germicides in the compositions.
[0030] Illustrative nonionic surfactants mat can be used in the compositions of the invention can be broadly defined as compounds produced by the condensation of alkylene oxide groups (hydrophilic in nature) with an organic hydrophobic compound which may be aliphatic or alkylaromatic in nature. Examples of suitable nonionic surfactants Include, but are not limited to, the Pluronics, polyethylene oxide condensates of alkyl phenols, products derived from the condensation of ethylene oxide with the reaction product of propylene oxide and ethylene diamine, ethylene oxide condensates of aliphatic alcohols, long chain tertiary amine oxides, long chain tertiary phosphine oxides, long chain dialkyl sulfoxides and mixtures of such materials.
[0031] In certain embodiments, zwitterionic synthetic surfactants useful in the present invention can be broadly described as derivatives of aliphatic quaternary ammonium, phosphomium, and sulfonium compounds, in which the aliphatic radicals can be straight chain or branched, and wherein one of the aliphatic substituents contains from about 8 to 18 carbon atoms and one contains an anionic water-solubilizing group, e.g., car boxy, sulfonate, sulfate, phosphate or phosphorate. Illustrative examples of the surfactants suited for inclusion into the composition include, but are not limited to, sodium alkyl sulfate, sodium lauroyl sarcosinate, cocoamidopropyl betaine and polysorbate 20, and combinations thereof.
[0032] The surfactant or mixtures of compatible surfactants can be present in the compositions of the present invention from about 0.1% to about 5.0%, In another embodiment from about 0.3% to about 3.0% and in another embodiment from about 0.5% to about 2.0% by weight of the total composition. The dosage of surfactant in the individual strip or tape (i.e., a single dose) Is about 0.001 to 0.05% by weight, 0.003 to 0.03% by weight, and in another embodiment about 0.005 to 0.02 % by weight.
[0033] Flavoring agents which are used in the practice of the present invention include, but are not limited to, essential oils as well as various flavoring aldehydes, esters, alcohols, and similar materials. Examples of the essential oils include oils of spearmint, peppermint, wintergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemon, lime, grapefruit, and orange. Also useful are such chemicals as menthol, carvone, and anethole. Certain embodiments employ the oils of peppermint and spearmint.
[0034] The flavoring agent is incorporated in the oral composition at a concentration of about 0.1 to about 5% by weight and about 0.5 to about 1.5% by weight.
[0035] The oral care compositions of the invention also may optionally include one or more chelating agents able to complex calcium found in the cell walls of the bacteria. Binding of this calcium weakens the bacterial cell wall and augments bacterial lysis.
[0036] Another group of agents suitable for use as chelating agents in the present invention are the soluble pyrophosphates. The pyrophosphate salts used in the present compositions can be any of the alkali metal pyrophosphate salts. In certain embodiments, salts include tetra alkali metal pyrophosphate, dialkali metal diacid pyrophosphate, trialkali metal monoacid pyrophosphate and mixtures thereof, wherein the alkali metals are sodium or potassium. The salts are useful in both their hydrated and unhydrated forms. An effective amount of pyrophosphate salt useful in the present composition is generally enough to provide at least 1.0% pyrophosphate ions, from about 1.5% to about 6%, from about 3.5% to about 6% of such ions. The dosage chelating agent in the individual ship or tape (i.e., a single dose) is about 0.01 to 0.6% by weight and in another embodiment about 0.035 to 0.06 % by weight.
[0037] The oral care strips or tape compositions of the invention also optionally include one or more polymers. Such materials are well known in the art, being employed in the form of their free acids or partially or fully neutralized water soluble alkali metal (e.g. potassium and sodium) or ammonium salts. Certain embodiments include 1:4 to 4:1 copolymers of maleic anhydride or acid with another polymerizable ethylenically unsaturated monomer, for example, methyl vinyl ether (methoxyethylene) having a molecular weight (M.W.) of about 30,000 to about 1,000,000. These copolymers are available for example as Gantrez AN 139(M.W. 500,000), AN 119 (M.W. 250,000) and S-97 Pharmaceutical Grade (M.W. 70,000), of GAP Chemicals Corporation.
[0038] Other polymers include those such as the 1:1 copolymers of maleic anhydride with ethyl acrylate, hydroxyethyl methacrylate, N-vinyl-2-pyrollidone, or ethylene, the latter being available for example as Monsanto EMA No. 1103, M.W. 10,000 and EMA Grade 61, and 1:1 copolymers of acrylic acid with methyl or hydroxyethyl methacrylate, methyl or ethyl acrylate, isobutyl vinyl ether or N-vinyl-2-pyrrolidone.
[0039] Suitable generally, are polymerized olefinically or ethylenically unsaturated carboxylic acids containing an activated carbon-to-carbon olefinic double bond and at least one carboxyl group, that is, an acid containing an olefinic double bond which readily functions in polymerization because of its presence in the monomer molecule either in the alpha-beta position with respect to a carboxyl group or as part of a terminal methylene grouping. Illustrative of such acids are acrylic, methacrylic, ethacrylic, alpha-chloroacrylic, crotonic, beta-acryloxy propionic, sorbic, alpha-chlorsorbic, cinnamic, beta-styrylacrylic, muconic, itacontic, citraconic, mesaconic, glutaconic, aconitic, alpha-phenylacrylic, 2-benzyl acrylic, 2-cyclohexylacrylic, angelic, umbellic, fumaric, maleic acids and anhydrides. Other different olefinic monomers copolymerizable with such car boxy lie monomers include vlnylacetate, vinyl chloride, dimethyl maleate and the like. Copolymers contain sufficient carboxylic salt groups for water-solubility.
[0040] A further class of polymeric agents includes a composition containing homopolymers of substituted acrylamides and/or homopolymers of unsaturated sulfonic acids and salts thereof, in particular where polymers are based on unsaturated sulfonic acids selected from acrylamidoalykane sulfonic acids such as 2-acrylamide 2methylpropane sulfonic acid having a molecular weight from 1,000-2,000,000, described in U.S. Pat. No. 4,842,847, Jun. 27, 1989 to Zahid, incorporated herein by reference.
[0041] Another useful class of polymeric agents includes polyamino acids, particularly those containing proportions of anionic surface-active ammo acids such as aspattic acid, glutamic acid and phosphoserine, as disclosed in U.S. Pat. No. 4,866,161 Sikes et al., incorporated herein by reference.
[0042] The oral care compositions of the invention may also optionally include one or more enzymes. Useful enzymes include any of the available proteases, glucanohydrolases, endoglycosidases, amylases, mutanases, lipases and mucinases or compatible mixtures thereof. In certain embodiments, the enzyme is a protease, dextranase, endoglycosidase and mutanase. In another embodiment, the enzyme is papain, endoglycosidase or a mixture of dextranase and mutanase. Additional enzymes suitable for use in the present invention are disclosed in U.S. Pat. No. 5,000,939 to Dring et al., U.S. Pat. No. 4,992,420; U.S. Pat. No. 4,355,022; U.S. Pat. No. 4,154,815; U.S. Pat. No. 4,058,595; U.S. Pat. No. 3,991,177; and U.S. Pat. No. 3,696,191 all incorporated herein by reference. An enzyme of a mixture of several compatible enzymes in the current invention constitutes from about 0.002% to about 2.0% in one embodiment or from about 0.05% to about 1.5% in another embodiment or in vet another embodiment from about 0.1% to about 0.5%.
[0043] Water may also be present in the oral compositions of the invention. Water, employed in the preparation of commercial oral compositions should be deionized and free of organic impurities. Water commonly makes up the balance of the compositions and includes from about 10% to 50%, about 20% to 40% or about 10% to 15% by weight of the oral compositions. This amount of water includes the free water which is added plus that amount which is introduced with other materials such as with sorbitol or any components of the invention.
[0044] In preparing oral care compositions, it is sometimes necessary to add some thickening material to provide a desirable consistency. In certain embodiments, the thickening agents are carboxyvinyl polymers, carrageenan, hydroxyethyl cellulose and water soluble salts of cellulose ethers such as sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose. Natural gums such as karaya, gum arable, and gum tragacanth can also be incorporated. Colloidal magnesium aluminum silicate or finely divided silica can be used as component of the thickening composition to further improve the composition's texture. Thickening agents in an amount from 0.5% to 5.0% by weight of the total composition can be used.
[0045] Within certain embodiments of the oral compositions, it is also desirable to incorporate a humectant to prevent the composition from hardening upon exposure to air. Certain humectants can also impart desirable sweetness or flavor to dentifrice compositions. The humectant, on a pure humectant basis, generally includes from about 15% to 70% in one embodiment or from about 30% to 65% In another embodiment by weight of the dentifrice composition.
[0046] Suitable humectants include edible polyhydric alcohols such as glycerine, sorbitol, xylitol, propylene glycol as well as other polyols and mixtures of these humectants. Mixtures of glycerine and sorbitol may be used in certain embodiments as the humectant component of the toothpaste compositions herein.
[0047] In addition to the above described components, the embodiments of this invention can contain a variety of optional dentifrice ingredients some of which are described below. Optional ingredients include, for example, but are not limited to, adhesives, sudsing agents, flavoring agents, sweetening agents, additional antiplaque agents, abrasives, and coloring agents. These and other optional components are further described in U.S. Pat. No. 5,004,597, to Majeti; U.S. Pat. No. 3,959,458 to Agricola et al. and U.S. Pat. No. 3,937,807, to Haefele, all being incorporated herein by reference.
[0048] The present invention in its method, aspect involves applying to the oral cavity a safe and effective amount of the compositions described herein. These amounts, for example, from about 20 mm 2 to 2000 mm 2 of the strip or tape, is kept in the mouth from about 15 seconds to about 12 hours. In addition, the oral, care strip or tape can be left alone to clean the teeth or can be used with a brush.
EXPERIMENTAL EXAMPLES
Example 1
Disintegration Test
[0049] In various embodiments, the composition of the present Invention passes a disintegration test. In a preferable Disintegration Test, one gram of a composition comprising a. sample of film fragments is placed on top of a 2 inch (50.8 mm) magnetic star bar. The stir bar is placed into a transparent vessel, such as s 500 ml beaker containing 300 ml of water at 30° C. The water comprising the stir bar is then, analyzed for the presence of broken and unbroken film fragments. The analysis can include straining the water through a mesh that is less than half an original long dimension of the film shape. This test will show if any pieces did not break up.
Example 2
Color-Change Formula
[0050] Examples 2 Illustrates an illustrative embodiment showing the multi-layer color change formula (white→blue).
[0000]
TABLE 1
Opaque White Layer 1
Slurry Weight
Weight % of
Ingredients
%
Solids
Opaque White Layer 1
Water
71.500
Methocel HPMC E5
10.300
36.140
Methocel HPMC E50
2.900
10.175
TiO 2
5.800
20.351
Propylene Glycol
9.000
31.579
Tween 80
0.500
1.754
Total
100.000
100.000
[0000]
TABLE 2
Blue Color Layer 2
Slurry Weight
Weight % of
Ingredients
%
Solids
Blue Color Layer 2
Water
71.500
Methocel HPMC E5
10.300
36.140
Methocel HPMC E50
2.900
10.175
Blue pigment
5.800
20.351
Propylene Glycol
9.000
31.579
Tween 80
0.500
1.754
Total
100.000
100.000
[0000]
TABLE 3
Opaque White Layer 3
Slurry Weight
Weight % of
Ingredients
%
Solids
Opaque White Layer 3
Water
71.500
Methocel HPMC E5
10.300
36.140
Methocel HPMC E50
2.900
10.175
TiO 2
5.800
20.351
Propylene Glycol
9.000
31.579
Tween 80
0.500
1.754
Total
100.000
100.000
Example 3
Preparation of Multi-Layer Color Change Formula of Example 2
[0051] Layer 1 was cast 1 mil then dried in a 90° C. oven for 10 minutes. Layer 2 was cast over layer 1 at 1 mil men dried in the same manner. Layer 3 was cast at 3 mil and the final composition dried at 100° C. for another 10 minutes. The films appeared white to off-white. When cut into small pieces and formulated in a toothpaste (formula below).
Example 4
Full Toothpaste with Color Change Film
[0052] Examples 4 illustrates an illustrative embodiment showing a full toothpaste of a multi-layer color change formula.
[0000]
TABLE 4
Full Toothpaste with color change film
Ingredient
Example 1, Wt. %
Polyethylene glycol 600 (PEG-12)
1.026
TiO 2
0.001
Sodium CMC
0.513
Sorbitol
70.77
Water
8.682
Sodium saccharin
0.359
Sodium fluoride
0.226
Silica abrasive (Zeodent 114)
8.205
Silica thickener (Zeodent 165)
8.205
Flavor oil
0.513
Sodium lauryl sulfate
0.5
Color Change Film (white-blue-white, triple layer)
1
[0053] When the full formulations are used in the normal manner, the film rapidly dissolves, allowing the colorant to become increasingly prominent. In the illustrative example, foam color changes from white to dark blue within one minute. This effect may be illustrated by the change of a 1:3 slurry of toothpaste in water from white to blue as the toothpaste is distributed and the film dissolves. The degree of color change can be easily changed by increasing or decreasing the quantity of film in the formula.
[0054] Other colors or effects are easily substituted, by replacing the pigments in the above example:
Example 5
Red Color Change Toothpaste
[0055] Replace Blue Pigment in Layer 2 with Iron Oxide or D&C Red #30.
Example 6
Green Color Change Toothpaste
[0056] Replace Blue Pigment in Layer 2 with Pigment Green 7.
Example 7
Toothpaste with Delayed Release of Gold Sparkle
[0057] Replace blue pigment in Layer 2 with Iron Oxide-based colorants on TiO 2 -coated mica (available from various manufacturers, such as under the Timeron trade name from Presperse)
Example 8
Toothpaste with Delayed Release of Tingle Sensation
[0058] Replace 5% formula glycerin in Layer 2 with Tingle Sensate (from IFF).
Example 9
Blue Color Change/Toothpaste
[0059] Replace pigment in the middle layer with take color.
[0000]
TABLE 5
Components of blue color change dentifrice.
Ingredients
Slurry Weight %
Weight % of Solids
An example of blue color layer 2 using
FD&C blue No. 1 lake instead of pigment
Water
86.1
Hydroxylpropyl cellulose (HPC)
4.5
32.374
PEG 600
2.0
14.388
Propylene Glycol
0.2
1.439
Tween 80
0.2
1.439
FD&C blue No. 1 lake
7.0
50.360
Total
100.000
100.000
[0060] The color change may be from a white composition to a colored composition. However, it will be understood that the color change may also be from one color to another. In some embodiments, a subsequent color can supplant a previous color. In other embodiments, a subsequent different color may result from combination of a second pigment being combined with a first pigment.
[0061] For example, a different colored base, such as a light green base, can be combined with white-blue-white triple layer film in the toothpaste. The color change will be from green to blue.
[0062] In another example, instead of the white-colored-white film set forth above, a triple layer film can have one color in the outer layers (i.e., layers 1 and 3), and another color in middle layer. For example, a composition may have a yellow-blue-yellow film scheme. The triple layer film appears yellow, but the resultant foam will change color to blue or green (upon the mixing of the yellow and blue layers).
[0063] In other illustrative embodiments alternate film formulations would ensure stability and dissolvability with use. Tuning the dissolving and release could be easily done by Increasing the thickness of the respective layers.
[0064] A number of references have been cited, the entire disclosures of which are incorporated herein by reference. | The invention relates to personal care products containing multilayer films with decorative layers and may impart a noticeable color change. The invention is applicable in products including type toothpaste, soaps, and other products until diluted with water (or saliva). | 1 |
BACKGROUND
1. Technical Field
The present invention relates to a liquid ejection apparatus which performs a drawing operation by ejecting a liquid from a nozzle of inkjet recording devices, display manufacturing devices, electrode forming devices, biochip manufacturing devices, etc.
2. Related Art
In the related art, the inkjet printers (hereinafter, referred to as ‘printer’) suitable for performing a printing operation on a sheet of paper is known as a liquid (ink) ejecting apparatus. Generally, the printer is configured such that a head provided with a fine nozzle for ejecting a liquid (ink) is movably arranged while facing a paper.
In the printers, if the ink in nozzle become dehydrated, it makes difficult to perform a normal ejection. Therefore, the technick or recovering from drying and suppress the drying, becomes important. Essentially, a printer has a cap for sealing (capping) a nozzle opening, so the printer is made to suppress drying of ink in the nozzle by performing capping during non-operating time.
Additionally, it is also well known printers that recovers and sustains a ejection capability by ejecting ink outside a sheet of paper when a drawing is operated at start, end or in the meanwhile and thereby exchanging to new ink from old ink which is progressed drying in a nozzle. The ejection for nozzle maintenance is called a preliminary ejection operation, and most of the ejection is performed into the cap.
In the related art, an absorber is provided to sustain ink inside the cap. The sealing space by the capping is kept in high humidity by the moisture of the ink sustained in the absorber. Nevertheless, in the printer accompanied with the preliminary ejection operation as mentioned above, sometimes the preliminary ejected ink is more accelerated drying inside nozzle when the nozzle is capped. That is, because a moisturizer (glycerin etc.) of the ink accompanied with progression of preliminary ejection history is accumulated to the absorber in condition of missing the sustaining moisture. Therefore, it acts actively to deprive of moisture from the ink in the nozzle when capping is operating.
To consider the above, first, the applicant of the present application filed about the invention related to a cap structure of no-remaining ink inside the cap. (Patent Document 1)
Patent Document 1: JP-A-2003-251828
However, in patent document 1 related to the cap, the cap suppress the trouble from moisturizer in the ink described above. By contrast there is no moisture sustaining function at the same time, as a result the cap is not possible enough to suppress drying in the nozzle under long abandoned period.
Further, in the configuration of the cap remaining the absorber, even if a forced discharge of the preliminary ejected ink by using a suction unit communicated with the cap is tried to operate, since that ink has high viscosity already to lose the large amount of moisture, the ink may not be almost ejected.
SUMMARY
An advantage of some aspects of the invention is to provide a liquid ejection apparatus capable of appropriately suppressing drying a liquid inside a nozzle in state of capping. The advantage can be attained as at least one of the following aspects.
A first aspect of the invention provides a liquid ejection apparatus comprising: an ejection head that ejects a liquid from a nozzle; a cap that can seal an opening of the nozzle; an absorber disposed in the cap; a preliminary ejection unit (first ejection unit) that performs a preliminary ejection operation (first ejection operation) toward the cap for maintenance of the nozzle; a suction unit that sucks the liquid from the cap; a replenishing ejection unit (second ejection unit) that performs a replenishing ejection operation (second ejection operation) for replenishing the cap with a liquid before the suction; and a capping unit that covers the opening of the nozzle by the cap after the replenishing ejection operation is performed.
According to the liquid ejection apparatus of the invention, after new liquid is replenished to the absorber (replenishing ejection operation) then suction is operated. Therefore old (humid component disappears and moisturizer is contained a lot) liquid accumulated to the absorber by the preliminary ejection operation is cleaned and flow out by using new liquid and thus the old liquid is appropriately discharged. A part of the replenishing liquid is sustained to the absorber. Whereby the preliminary ejected old liquid do not promote drying in the nozzle. Further in the nozzle opening when capped, the drying in the nozzle is properly suppressed by humid component of the liquid sustained to the absorber.
The humid component of liquid represents a main solvent component and, the moisturizer represents an addition component having characteristics to sustain the humid component.
Preferably, in the liquid ejection apparatus, an amount of the liquid ejected by the replenishing ejection operation is larger than an amount of moisturizing component in the liquid contained in the absorber by the preliminary ejection operation.
According to the liquid ejection apparatus of the invention, the moisturizer accumulated to the absorber can be appropriately discharged.
It is preferable that, in the liquid ejecting, the replenishing ejection unit performs the replenishing ejection operation just before a main power supply is turned off.
According to the liquid ejection apparatus of the invention, in a situation assuming that a non-operation state is left for long time, the discharge of the moisturizer in the absorber is operated, and therefore the drying in the nozzle can be properly suppressed.
It is preferable that, in the liquid ejection apparatus, a plurality of the nozzles and caps are provided to correspond to a plurality of liquid types, and the replenishing ejection unit sets an amount of the liquid ejected by the replenishing ejection operation every liquid type.
According to the liquid ejection apparatus of the invention, a humidity retention component can be efficiently washed by replenishing liquid of the proper amount every corresponding liquid type.
It is preferable that, in the liquid ejection apparatus, the suction unit performs the suction after the replenishing ejection operation is performed and a predetermined waiting time elapses.
According to the liquid ejection apparatus of the invention, by the replenishing ejection operation, the suction is operated after the elapse of the waiting time to mix the moisturizer accumulated to the absorber, therefore the moisturizer in the absorber can be efficiently discharged.
It is preferable that, in the liquid ejection apparatus, the apparatus further includes a history managing unit that manages a history related to the preliminary ejection operation, and the replenishing ejection unit performs the replenishing ejection operation under a condition based on the history.
If the history of the preliminary ejection is progressed, an old moisturizer is sustained a lot to the absorber, then drying promotion in the nozzle during capping is occurred, or it is hard to wash the humidity retention component. According to the liquid ejection apparatus of the invention, based on the history information related to the preliminary ejection operation, the moisturizer can be discharged in appropriate condition.
It is preferable that, in the liquid ejection apparatus, the replenishing ejection unit performs the replenishing ejection operation with an amount of the liquid based on the history.
According to the liquid ejection apparatus of the invention, by replenishing liquid of the proper amount every corresponding amount of the humidity retention component accumulated to the absorber, the humidity retention component can be efficiently washed.
It is preferable that, in the liquid ejection apparatus, the replenishing ejection unit performs the replenishing ejection operation at a time based on the history.
According to the liquid ejection apparatus of the invention, by performing the suction accompanied with the liquid replenishing in the proper time reflecting to the preliminary ejection history, the moisturizer in the absorber can be efficiently discharged.
It is preferable that, in the liquid ejection apparatus, the history managing unit manages information on an accumulated amount of the liquid ejected by the preliminary ejection operation.
According to the liquid ejection apparatus of the invention, based on the history information that appropriately reflecting to the state of the humidity retention component accumulated to absorber, the humidity retention component in the absorber can be efficiently discharged.
It is preferable that, in the liquid ejection apparatus, the history managing unit manages an accumulated time of a drawing operation.
According to the liquid ejection apparatus of the invention, based on the history information that appropriately reflecting to the state of the moisturizer accumulated to absorber, the humidity retention component in the absorber can be efficiently discharged.
It is preferable that, the liquid ejection apparatus further includes a drying history managing unit that manages a drying history of the liquid contained in the absorber by the preliminary ejection operation, and the replenishing ejection unit performs the replenishing ejection operation with an amount of the liquid based on the drying history.
According to the liquid ejection apparatus of the invention, the replenishing ejection operation is performed with the proper ejection amount considering the drying state of the liquid accumulated to absorber, whereby the moisturizer sustained the liquid can be efficiently discharged.
It is preferable that, the liquid ejection apparatus further includes a temperature detection unit that detects an ambient temperature, and the replenishing ejection unit performs the replenishing ejection operation with an amount of the liquid based on the ambient temperature.
According to the liquid ejection apparatus of the invention, the replenishing ejection operation is performed with the proper ejection amount considering a viscosity change of the liquid by the ambient temperature, whereby the humidity retention component in the absorber can be efficiently discharged.
The present disclosure relates to the subject matter contained in Japanese patent application Nos. JP 2006-021984 filed on Jan. 31, 2006 and JP 2006-102945 filed on Apr. 4, 2006, which are expressly incorporated herein by reference in its entirety.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will be described with reference to the accompanying drawings, wherein like numbers reference like elements.
FIG. 1 is schematic perspective view illustrated a whole configuration of the liquid ejection apparatus.
FIG. 2 is a partially-exploded side view illustrated a peripheral configuration of the cap.
FIG. 3 is a block diagram illustrated an electrical configuration of the liquid ejection apparatus.
FIG. 4 is a flow chart illustrated a processing related to a drawing operation.
FIG. 5 is a flow chart illustrated a processing related to nozzle maintenance at that time of main power off.
FIG. 6 is a flow chart illustrated a processing related to the drawing operation in Modified Example 1.
FIG. 7 is a block diagram illustrated an electrical configuration of the liquid ejection apparatus in the second embodiment.
FIG. 8 is a flow chart illustrated a processing related to the drawing operation in the second embodiment.
DESCRIPTION OF EXEMPLARY EMBODIMENTS
Hereinafter, appropriate embodiment of the invention is minutely illustrated with reference to an attached drawing.
The embodiment mentioned below is, appropriate detailed examples of the invention, therefore there are technically preferable a lot of limitations. However, in description mentioned below, if there is no description about that the invention is limited, the scope of the invention is not limited to these embodiments. Also, in the reference drawings mentioned below, for convenience of an illustration, there is a case that length and width scale of a member or a portion is differently illustrated compare to a practical object.
(Configuration of Liquid Ejection Apparatus)
First Embodiment
First, the configuration of the liquid ejection apparatus is illustrated to refer to FIG. 1 , FIG. 2 and FIG. 3 .
FIG. 1 is schematic perspective view illustrating a whole configuration of the liquid ejection apparatus. FIG. 2 is a partially-exploded side view illustrating peripheral configuration of the cap. FIG. 3 is a block diagram illustrating an electrical configuration of the liquid ejection apparatus.
In FIG. 1 , a printer 1 as the liquid ejection apparatus, is provided with a guide frame 3 formed of steel plate, a transport roller 4 carrying a sheet of paper 2 , a ejection head 10 having a nozzle surface 10 a set up with fine nozzle in parallel, a maintenance unit 5 for maintaining the nozzle of the ejection head 10 . The ejection head 10 is equipped on a carriage 6 and made to operate reciprocating motion (scanning) with following a guide road 8 . A guide frame 3 sets a basis of the whole device by rigidity and weight and has a function as an electrical earth.
In the carriage 6 , ink cartridges 7 a to 7 d that receive respectively a coloring ink of four colors as liquid is equipped and the coloring ink (ink) of each color is supplied respectively to the ejection head 10 . And, performing discharge control for the each nozzle of the ejection head 10 through synchronizing with scanning of the carriage 6 and carrying of the sheet of paper 2 (drawing operation), image is formed on the sheet of paper 2 by ink liquid droplets.
The maintenance unit 5 includes, a cap 11 being capable of sealing (capping) the nozzle opening through close contacting the nozzle surface 10 a of the ejection head 10 and a wiper blade 12 as a plate shaped member made of rubber etc. The cap 11 is available not only playing a role to protect nozzle from dust or dry, but also operating the maintenance. In addition, wiper blade 12 is available to wipe the ink sticking on the nozzle surface 10 a.
In FIG. 2 , the ejection head 10 includes a nozzle 21 set up in parallel with line shape on nozzle surface 10 a corresponding to each ink, and a pressure generating chamber 22 that communicates to each nozzle 21 . A part of the wall of the pressure generating chamber 22 is deflected by piezoelectric elements etc., and the ink is ejected by pressure generating in the pressure generating chamber 22 that is caused by operation of the piezoelectric element.
The cap 11 is a box shaped member having an opening on a side opposed to the ejection head 10 . The cap 11 has elasticity at an edge portion 11 a of the cap opening. Therefore, the opening of the nozzle 21 can be sealed (capping) by closely contacting the edge portion 11 a to the surface 10 a . Furthermore, inside the cap 11 , an absorber 13 formed of sponge and non-woven fabric is arranged. The reason is for sustaining high humidity inside the cap 11 in state of capping by the absorber 13 having the ink sustaining function.
The cap 11 is supported by the slider apparatus not to be illustrated, and move in up down direction (direction to places both near and far from the nozzle surface 10 a ) operating together with a movement in scanning direction of the ejection head 10 . Thus, the capping and the releasing of that can be performed freely by scanning control of the ejection head 10 .
In a lower portion of the cap 11 , a communication pipe 11 b is formed. The communication pipe 11 b is connected to one edge section of a communication tube 14 . The communication tube 14 , considering that the cap 11 is set up configuration to be possible to move by the slider apparatus, is preferable to have proper flexibility. In state of the capping, considering to form communicating space with sealing space in the cap 11 , the communication tube 14 is preferable to be made of material that makes hardly vapor permeation through side walls.
The other edge section of the communication tube 14 , is connected to a suction pump 15 (illustration that express schematically) as a suction unit. In the suction pump 15 , tube pump that is small and has good efficiency is properly available. The suction pump 15 is capable of not only suction (suction in the nozzle) the ink from inside the nozzle 21 in capping state but also suction (suction in the cap) the pooled ink inside the cap in no-capping state. The suctioned ink is received in a waste ink tank 17 trough a waste ink tube 16 communicating with the outlet of the suction pump 15 .
The suction in the nozzle, in case that the ink in the nozzle 21 is dried to be solid or impossible to discharge because of the high viscosity, discharging the dried ink by force, performed as an object to recover ejection capacity. Moreover, the suction in the cap performed as an object to recover the ejected ink in the cap 11 by suction in the nozzle or recover the ejected ink by the preliminary ejection operation (the detailed content is mentioned later).
In FIG. 3 , the printer 1 includes a control unit 120 that operate various kinds of controls related to operations. The control unit 120 connected to host computer 119 through external interface (I/F) 121 . Also through the internal I/F 122 , the unit is connected to a ejection drive circuit 131 of the ejection head 10 , scanning motor 104 to perform scanning drive of the carriage 6 (reference in FIG. 1 ), a transport motor 105 for driving the transport roller 4 (reference in FIG. 1 ), and a pump motor 106 for driving the suction pump 15 (reference in FIG. 2 ).
The control unit 120 includes a CPU 123 , a RAM 124 functioning as a buffer memory of data related to a work memory of the CPU 123 or discharge control, a ROM 125 memorizing each kinds of control information, a transmit circuit 126 generating clock signal (CK), and a drive signal generating circuit 127 to generate drive signal (COM). The ROM 125 can be available to be capable of rewriting such as an EEPROM.
The ejection drive circuit 131 includes a shift register circuit including a shift register 132 , a latch circuit 133 , and a switch 135 , also the drive circuit is composed to apply selectively drive signal (COM) to each of the piezoelectric element 136 . The drive signal (COM) is composed by combination of pulses of electric charge and discharge.
A printing operation is performed to transmit the data such as the drawing pattern data of bitmap type that illustrate arrangement of ink drops in the sheet of paper 2 (reference in FIG. 1 ), to the control unit 120 from host computer 119 . At that time, the control unit, decoding the drawing pattern data, generates nozzle data that is ON/OFF information of the every nozzle.
A nozzle data signal (SI) that changes from nozzle data into serial signals, synchronize the clock signal (CK) and is transmitted to the shift register circuit. As the result, the ON/OFF information of the every nozzle is memorized to each of the shift register 132 . The nozzle data related to ┌ON┘ information latched in the latch circuit 133 by a latch signal (LAT), is transformed to pre determined voltage signal in level shifter 134 and is supplied to a switch 135 .
As a result, the drive signal (COM) is applied to the piezoelectric element 136 corresponding to ┌ON┘ and then the ink is ejected from the nozzle. The discharge control (drawing control) based on the drawing pattern data is performed periodically through synchronizing with the scan location of the ejection head 10 .
The control unit 120 , in such a way to interleave the drawing control process, makes to generate the corresponding nozzle data signal (SI) or the drive signal (COM) etc. then might make to perform the preliminary ejection operation or replenishing ejection operation. That is, control unit 120 has the function as the preliminary ejection unit (first ejection unit) and the replenishing ejection unit (second ejection unit) of the invention.
Herein, the preliminary ejection operation (first ejection operation) is a ejection toward the cap 11 before and after the drawing operation or in the meanwhile as the object of the nozzle maintenance, and the ejection is performed as an object of attempting recovery and sustenance of the ejection capacity through replacing old ink in the nozzle to new ink, or improving humidity retention in case of the capping by supplying moisture to absorber 13 (reference in FIG. 2 ).
The replenishing ejection operation (second ejection operation) is an ejection performed for replenishing ink to the absorber 13 (reference in FIG. 2 ) prior to suction in the cap. The replenishing ejection operation likewise the preliminary ejection operation is the ejection performed for the cap 11 (reference in FIG. 2 ). Yet the replenishing ejection operation is performed with suction inside the cap. Also, an ejection amount per one operation is set up with about several to dozen times comparing to the preliminary ejection operation.
(Nozzle Maintenance of the Liquid Ejection Apparatus)
Hereinafter, the nozzle maintenance of the liquid ejection apparatus is illustrated through flow charts of FIG. 4 , FIG. 5 referring to FIG. 2 , FIG. 3 .
FIG. 4 is, a flow chart illustrating a processing related to the drawing operation. FIG. 5 is, a flow chart illustrating a processing related to nozzle maintenance at that time of main power off.
The printer 1 , in non-operating time, is made in the state that the nozzle 21 is capped (capping condition). If the printer 1 receives a drawing command from the host computer 119 , the printer 1 performs a processing as following with the flow chart illustrating in FIG. 4 .
The control unit 120 , first releases the capping by an operation of the scanning motor 104 (step S 1 ), thereafter performs the preliminary ejection operation for the cap 11 (step S 2 ), renewals the history parameter (step S 3 ), and performs to initialize a cycle timer (step S 4 ).
The preliminary ejection operation in step S 2 , in state of capping, is performed in an object of the recovery for the ejection capacity by ejecting the ink progressed drying from inside the nozzle 21 . According to various kinds of the ink, such the preliminary ejection operation might be controlled not to operate, referring to processing time from the nearest drawing operation, the preliminary ejection operation might be controlled to decide whether the preliminary ejection operation perform or not.
The history parameter in step S 3 is one illustrating to parameters about the history of the preliminary ejection, in detail, illustrating that integrate the accumulated discharge amount for the every preliminary ejection operation. The history parameter can be set up with not only the value corresponding to a number of the ejected ink drops, consuming ink amount, but also the value corresponding to the recovery (ejection drive recovery, operation recovery) of the preliminary ejection operation. In the cases, the history parameter can be set up with the value corresponding to any one of one nozzle unit, one ink kind unit, the whole nozzle unit. As mentioned before, the control unit 120 has a function as a history managing unit for managing the history of the preliminary ejection operation by the history parameter.
The cycle timer in step S 4 is a timer for deciding a performance time of the preliminary ejection operation (step S 9 ) that performs periodically in the meanwhile of the drawing operation. As illustrated in the flow chart in FIG. 4 , the cycle timer is counted to set right after of the preliminary ejection operation (step S 2 and step S 9 ) as a starting time of reckoning.
After S 4 , the control unit 120 operates drawing control for 1 scanning amount (step S 5 ), thereafter the unit decide whether drawing pattern data remains or not (step S 6 ).
In step S 6 , when it is judged that the drawing pattern data is no remaining, the control unit 120 operates the nozzle maintenance processing (step S 15 to S 17 ) for finishing of the drawing operation. That is, after the preliminary ejection operation (step S 15 ) inside the cap, and the renewal of the history parameter (step S 16 ) is performed, protecting of the nozzle 21 is attempted by the capping (step S 17 )
In the step S 15 , the preliminary ejection operation is performed for moisturizing the absorber 13 in the cap 11 . As the result, the sealing space in the capping state sustains a high humid state, the ink drying in the nozzle 21 is suppressed properly.
In step S 6 , when it is judged that the drawing pattern data is no remaining, the control unit 120 decides whether or not the cycle timer value is the predetermined value or more (step S 7 ).
In step S 7 , when it is judged that the cycle timer value is less than the predetermined value, the processing mentioned above is repeated by returning to the processing of already mentioned step S 5 . In other words, drawing control (step S 5 ) in unit of the scanning is repeated more than once until that the cycle timer reaches the determined value.
In step S 7 , when it is judged that the cycle timer value is the predetermined value or more, the control unit 120 decides whether or not the history parameter is less than a predetermined value (step S 8 ).
In step S 8 , when it is judged that the history parameter value is less than predetermined value, the control unit 120 operates the nozzle maintenance processing (step S 9 to S 11 ) for sustaining ejection capacity during the drawing operation. That is, with the preliminary ejection operation in the cap 11 (step S 9 ), it is performed the cycle timer initialization (step S 10 ) and the history parameter renewal (step S 11 ).
In the step 9 , the preliminary ejection operation is performed in the purpose of forcedly replacing old ink in the nozzle 21 progressed drying into new ink. As the result, ink ejection of the lowest limit is secured whether or not the ejection is performed based on the drawing pattern data. Therefore, ejection capacity is sustained properly during the drawing operation.
After step S 11 , the processing mentioned above is repeated by returning to the processing of already mentioned step S 5 . Likewise, the preliminary ejection operation (step S 9 ) is performed periodically during the drawing operation.
In step S 8 , when it is judged that the history parameter value is the predetermined value or more, the control unit 120 operates the processing for forcedly discharging about the accumulated ink to the absorber 13 . That is, the replenishing ejection operation (step S 12 ) into the cap 11 and the suction in the cap (step 13 ) are continuously performed. Herein, the expression mentioned above, “are continuously performed” is used, but that means both of the operations are performed as an integral manner, in actuality, the suction in the cap (step 13 ) is performed when a predetermined waiting time has elapsed after the replenishing ejection operation (step S 12 )
In the condition of rising history parameter value caused by the preliminary ejection operation (step S 2 .S 9 .S 15 ) that is performed periodically, the ink included to the absorber 13 by the preliminary ejection operation is in the state of high viscosity with missing a lot of moisture. Such the old ink missing moisture, by the function of the moisturizer (glycerin etc.) of the ink inside acts to promote a drying in the nozzle 21 in the capping state. The suction in the cap of the step S 13 is performed in order to discharge compulsorily the old ink that has such an unwanted effect.
The old ink having high viscosity is hard to discharge because of decrease in liquidity, in this embodiment, to perform the suction in the cap (step S 13 ) after replenishing a lot of ink to the absorber 13 by replenishing ejection operation (step S 12 ), the discharge capacity of the old ink has been raised. Because the accumulated old ink to the absorber 13 is cleaned by the replenishing ejected new ink and thus ejected properly. The reason providing the waiting time between the replenishing ejection operation (step S 12 ) and the suction in the cap (step S 13 ) is in consideration to make higher the discharge capacity for the old ink caused by mixing the new ink replenishing ejected with the old ink having high viscosity.
Further, the new ink that is replenishing ejected, after the suction in the cap (step S 13 ), a part of the ink is sustained to the absorber 13 , and plays a role to sustain the capped sealing space inside with high humidity
The ink ejection amount by replenishing ejection operation (step S 12 ), is preferably to set up larger amount than the an amount of moisturizing component of the ink accumulated to the absorber 13 , and more preferably, the replenishing ejection amount is about 2 to 3 times (weight ratio) as large as the amount of moisturizing component. In the embodiment, the ink containing moisturizer in 10 to 20 weight % (according to ink types, the content ratio is different) has been available. The ink corresponding to 50% of whole ink amount that is preliminary ejected in the cap 11 is made to operate the replenishing ejection operation (step S 12 ).
By the replenishing ejection operation (step S 12 ) and the suction in the cap (step S 13 ), since most of the old ink accumulated to the absorber 13 is discharged, the history parameter is initialized in step S 14 . Because the history parameter is an index of the accumulated ink amount to the absorber 13 by the preliminary ejection operation. In the same reason, the initialization of the history parameter is performed when the nozzle suction operation is activated for removing of the solidified ink or air bubbles inside the nozzle 21 .
After step S 14 , the processing mentioned above is repeated again with returning step S 5 . That is, the forced discharge (step S 12 , S 13 ) from the cap 11 of the preliminary ejected ink is performed periodically when the time reaches the predetermined value.
The periodically forced discharge (step S 12 , S 13 ) of the old ink referring to the history parameter is performed in order to increase in an efficiency of the old ink discharge. The reason is, if the old ink is too much accumulated to the absorber 13 , the ink replenishment of great large amount is needed for discharging the ink or the enough discharge is impossible.
The Printer 1 finishing the drawing operation is waiting the command from host computer 119 etc. in the no-operation state itself, whereby the processing of step S 1 to S 17 mentioned above is performed in case of receiving the re-command about new drawing. In this case, the history parameter keeps being used as an end point value of the drawing operation at the last time.
On the contrary, when the main switch off operation of the printer 1 is performed by the not shown hardware switch, the printer 1 performs the processing following the flow chart illustrated in FIG. 5 .
The control unit 120 first releases the capping by the drive of the scanning motor 104 (step S 21 ). And then the unit obtains the history parameter (step S 22 ), and based on the obtained history parameter, set up an amount of liquid ejected by the replenishing ejection operation (step S 23 ). And, under the set ejection amount, the replenishing ejection operation (step S 24 ) and thereafter suction in the cap (step S 25 ) are performed. And the history parameter is initialized (step S 26 ), then capping is performed (step S 27 ).
Likewise, when main power is off, independent of the history parameter value at a point in time, the ink discharge operation that combines the replenishing ejection operation (step S 24 ) and the suction in the cap (step 25 ) is performed. When the main power is off, thereafter it is assumed that the printer 1 does not operate for a long time. Consequently it is an object of appropriate drying prevention in the nozzle 21 caused by discharging the accumulated old ink to the absorber 13
In addition, the replenishing ejection operation in step S 24 is performed based on the ejection amount set referring to the history parameter. That is, corresponding to the old ink amount accumulated to the absorber 13 , the necessary and sufficient ink in order to clean the old ink is replenished. As the result, it is considered that the ink in replenishing ejection operation (step S 24 ) is not unnecessarily wasted. Corresponding to an amount of liquid ejected by the replenishing ejection operation (step S 24 ), the optimization is also attempted so that drive amount of the pump motor 106 related to suction in the cap (step S 25 ) is variable.
Modified Example 1
Next, about Modified Example 1, it is illustrated as focus on differences with embodiment mentioned above following the flow chart in FIG. 6 .
FIG. 6 is illustrated that the processing related to drawing operation in Modified Example 1
In Modified Example 1, about the processing related to the preliminary ejection operation (step S 33 , S 34 , S 37 , S 39 , S 40 , S 44 ) or drawing control (step S 35 ) and the processing for end judgment of drawing operation (step S 36 ), that is the same as the embodiment mentioned before, so the description is omitted.
In Modified Example 1, the performance judgment (step S 38 ) of the replenishing ejection operation (step S 41 ) and the suction in the cap (step S 42 ), is performed based on the history timer. The history timer is a timer that records accumulation of time of the drawing operation. Since the preliminary ejection operation (step S 33 , S 39 , S 44 ) related to drawing operation generally performs in periodic, the history related to the preliminary ejection operation is counted as an indirect managing unit. As Modified Example 1, the history related to the preliminary ejection operation is possible to manage indirectly by related time and so on.
The history timer, in detail, starts the count (step S 32 ) just after the capping release (step S 31 ) and finishes the count (step S 45 ) just before the capping (step S 46 ). The history timer sustains after the one drawing operation, but the timer is initialized when the suction in the cap (step S 42 ) or the nozzle suction operation is performed (step S 43 ).
Modified Example 2
Next, about Modified Example 2, it is illustrated as focus on differences with embodiment mentioned above.
In Modified Example 2, the caps that perform capping the nozzle corresponding to every ink types are independently or separately provided, and made to perform the preliminary ejection operation, replenishing ejection operation or suction in the cap for every ink types. In the case, the ejection amount in the replenishing ejection operation is set up every corresponding ink types. That is, containing moisture amount is different according to corresponding ink types, whereby the differences are developed in the proper replenish ink amount required in cleansing from the absorber, therefore the unnecessary consumption of ink is suppressed by attempting the optimization in the replenishing ejection operation. In this case, the history parameter illustrating the preliminary ejection history might be allowed to count for every ink types.
The proper amount of the replenishing ink required in the old ink cleansing, since the amount is affected from the component except for the moisturizer (color material etc.), is preferably optimized considering such the fact. For example, because a pigment ink compared with a dye ink has not good characteristics in liquidity when moisture was missed, an amount of liquid ejected by the replenishing ejection operation performing for the cap corresponding to pigment ink is set up larger than an amount of liquid ejected by the replenishing ejection operation performing for the cap corresponding to dye ink.
Second Embodiment
Next, referring to FIG. 2 FIG. 7 , FIG. 8 , about Second Embodiment of the invention, it is illustrated as focus on differences with First Embodiment.
FIG. 7 is a block diagram illustrating that an electrical configuration of the liquid ejection apparatus in Second Embodiment. FIG. 8 is a flow chart illustrated that the processing related to drawing operation in Second Embodiment.
In FIG. 7 , the printer 1 is equipped with the thermistor 140 as a temperature detection unit in the ejection head 10 . Detecting a peripheral ambient temperature, operation control (the detailed content is mentioned later) based on the detected ambient temperature is performed by the control unit 120 . The printer 1 , receiving the drawing command from the host computer 119 , operates processing related to drawing operation following the flow chart illustrated in FIG. 8 .
That is, the printer 1 , releases the capping (step S 131 ), performs the preliminary ejection operation toward the cap 11 in order to operate nozzle maintenance (discharge of the ink having the high viscosity during the capping) (step S 132 ), and renewals history parameter A (step S 133 ). Herein, the history parameter A is, a parameter related to accumulated ejection amount of the preliminary ejection operation, as the completely same as the history parameter in the First Embodiment.
After step S 133 , the printer 1 performs required drawing control (step S 134 ), whereby the printer 1 decides whether the time reaches the required preliminary ejection time (corresponding to the time that the cycle timer in first Embodiment reaches the predetermined value) or not (step S 135 ). Herein, if the time reaches the required preliminary ejection time, then the printer 1 proceeds to step S 136 . If the time does not reach the required preliminary ejection time, then printer 1 proceeds to step S 141 and decides whether or not the drawing pattern data remains.
In step S 141 , if it is judged that drawing pattern data is remained, the flow mentioned above is repeated by returning the step S 134 again. if it is judged that drawing pattern data is not remained, the printer 1 performs the preliminary ejection operation (step S 147 ) in an object to the nozzle maintenance (retention of humidity in the cap 11 during the capping), and the renewal of the parameter A (step S 148 ), whereby the printer 1 finishes the sequence flow by the capping (step S 149 ).
In step S 136 , it is judged whether or not parameter A is less than a predetermined value. In case that the history parameter is less than the predetermined value in the step S 136 , printer 1 performs the preliminary ejection operation (step S 137 ) in an object of nozzle maintenance (discharge of the ink having the high viscosity during the drawing operation). Whereby printer 1 renews the history parameter A (step S 138 ). Furthermore, the ambient temperature is detected by the thermistor 140 (step S 139 ), and based on the detected temperature, the renewal of a history parameter B is performed (step S 140 ).
After step S 140 , it proceeds to the processing for the step S 141 . As a result, if there is a possibility that the drawing pattern data is remained, until the history parameter A reaches predetermined value, the preliminary ejection operation (step S 137 ) is periodically repeated. Accompanied with that, the preliminary ejected ink to the absorber 13 of the cap 11 is gradually accumulated up, also the history parameter A value that indicates the accumulated ejection amount related to the preliminary ejection operation gradually increases
Herein, the history parameter B related to step S 140 is, a parameter taking a charge drying history of the ink accumulated to the absorber 13 by the preliminary ejection operation, in the embodiment, a parameter reflecting to estimated value of the accumulated evaporation loss for the moisture in the ink. More in detail, assuming the moisture evaporation is caused from the absorber 13 in predetermined speed corresponding to the ambient temperature detected (step S 139 ) by the thermistor 140 , the control unit 120 calculates (renew) the accumulated evaporation loss for every performance time of the preliminary ejection operation (step S 137 ). That is, the thermistor 140 and the control unit 120 constitutes the drying history managing unit of the invention
The moisture evaporation speed based on calculating of the history parameter B, is variable value according to not only the ambient temperature but also the opening area of the cap 11 or a type of absorber 13 (material, foam, density, etc.) because of this, the control unit 120 , reads out the evaporation speed data obtained by pre-experiment from ROM 125 (reference in FIG. 3 ), and sets up to perform calculating the history parameter B.
In step S 136 , when the history parameter is the predetermined value or more, the printer 1 performs the processing (step S 142 to S 146 ) that compulsorily discharges the old ink accumulated to the absorber 11 by the preliminary ejection operation. In detail, the processing is performed as mentioned below.
That is, the ambient temperature is detected by the thermistor 140 (step S 142 ), and based on the detected ambient temperature and the history parameter B, the operation conditions (ejection amount etc.) for thereafter performed step S 144 to S 145 are set up (step S 143 ). And, the replenishing ejection operation (step S 144 ) is performed under the set operation condition, the suction in the cap (step S 145 ) is performed when waiting time is elapsed, and thereby the old ink accumulated to the absorber 13 is discharged. Whereby, since the ink state to the absorber 13 is initialized, the history parameters A, B reflecting to the ink 2 state are initialized (step S 146 ) and it proceeds to the processing of the step S 141 .
In the step S 143 , based on ambient temperature and history parameter B, an amount of liquid ejected by the replenishing ejection operation (step S 144 ), awaiting time after the replenishing ejection operation, and a drive amount of the pump motor 106 for suction in the cap (step S 145 ) are setup. In particular, the lower ambient temperature, and the larger history parameter B value (the larger accumulated evaporation), the replenishing ejection operation (step S 144 ) is operated with the larger ejection, whereby long waiting time is passed, the drive amount is increased and the suction in the cap (step S 145 ) is operated. The reason is that, the lower temperature, the ink (including the ink related to the replenishing ejection operation) viscosity more increases. Additionally, the more ink drying to the absorber 13 is progressed, the ink viscosity (the concentration of the moisture occupying in the ink) is more increased. Accordingly, it is considered that the ink discharge from the absorber 13 becomes difficult in that condition.
In this manner, by the printer 1 in Second Embodiment, based on the ambient temperature or the ink drying history (history parameter B) of the absorber 13 , the replenishing ejection operation or suction in the cap is performed under the more fine operation condition, therefore the old ink accumulated to the absorber 13 is efficiently discharged, that drying in the nozzle is appropriately suppressed when capped.
The invention is not limited in the embodiment mentioned above.
For example, the invention is, that being the history of the preliminary ejection is an presupposition, but the aspect related to performance of the preliminary ejection operation is not limited in the embodiment mentioned above, and if there is a possibility to have an object of a nozzle maintenance, it is possible to modify and add for the a lot of variable condition.
In addition, it is possible that modify freely in the range of unchanging an intent of the invention for the replenishing ejection operation and the performance time of the suction in the cap or the judgment condition.
About liquid drying history in the absorber, considering about not only the evaporation during the drawing operation, but also the evaporation during capping, it may be possible to calculate the value. By not only the ambient temperature but also humidity history, it may be possible to manage drying history.
The invention can be applied to drawing devices using industrial way, in this case, a humid component of liquid may contain not only water but also organic solvent.
The each configuration of the each embodiment can properly combine each of them, omit or combine into another configuration not to illustrate. | A liquid ejection apparatus includes: an ejection head that ejects a liquid from a nozzle; a cap that can seal an opening of the nozzle; an absorber disposed in the cap; a first ejection unit that allows to perform a first ejection operation toward the cap for maintenance of the nozzle; a suction unit that sucks the liquid from the cap; a second ejection unit that allows to perform a second ejection operation for replenishing the cap with a liquid before the suction, and a capping unit that covers the opening of the nozzle by the cap after the second ejection operation is performed. | 1 |
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a divisional of U.S. patent application Ser. No. 09/687,428, filed on Oct. 13, 2000, by Samuel Achilefu et al., now U.S. Pat. No. 6,663,847 published on Dec. 16, 2003, the disclosure of which is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
This invention relates to novel optical probes for use in physiological function monitoring, particularly indole and benzoindole compounds.
BACKGROUND OF THE INVENTION
Dynamic monitoring of physiological functions of patients at the bedside is highly desirable in order to minimize the risk of acute renal failure brought about by various clinical, physiological, and pathological conditions (C. A. Rabito, L. S. T. Fang, and A. C. Waltman, Renal function in patients at risk with contrast material - induced acute renal failure: Noninvasive real - time monitoring, Radiology 1993, 18, 851-854; N. L. Tilney, and J. M. Lazarus, Acute renal failure in surgical patients: Causes, clinical patterns, and care, Surgical Clinics of North America , 983, 63, 357-377; B. E. VanZe, W. E. Hoy, and J. R. Jaenike, Renal injury associated with intravenous pyelography in non - diabetic and diabetic patients, Annals of Internal Medicine , 1978, 89, 51-54; S. Lundqvist, G. Edbom, S. Groth, U. Stendahl, and S.-O. Hietala, Iohexol clearance for renal function measurement in gynecologic cancer patients, Acta Radiologica , 1996, 37, 582-586; P. Guesry, L. Kaufman, S. Orlof, J. A. Nelson, S. Swann, and M. Holliday, Measurement of glomerular filration rate by fluorescent excitation of non - radioactive meglumine iothalamate, Clinical Nephrology , 1975, 3, 134-138). This monitoring is particularly important in the case of critically ill or injured patients because a large percentage of these patients face the risk of multiple organ failure (MOF), resulting in death (C. C. Baker et al., Epidemiology of Trauma Deaths, American Journal of Surgery , 1980, 144-150; R. G. Lobenhofer et al., Treatment Results of Patients with Multiple Trauma: An Analysis of 3406 Cases Treated Between 1972 and 1991 at a German Level I Trauma Center, Journal of Trauma , 1995, 38, 70-77). MOF is a sequential failure of lung, liver, and kidneys, and is incited by one or more severe causes such as acute lung injury (ALI), adult respiratory distress syndrome (ARDS), hypermetabolism, hypotension, persistent inflammatory focus, or sepsis syndrome. The common histological features of hypotension and shock leading to MOF include tissue necrosis, vascular congestion, interstitial and cellular edema, hemorrhage, and microthrombi. These changes affect the lung, liver, kidneys, intestine, adrenal glands, brain, and pancreas, in descending order of frequency (J. Coalson, Perspectives on Sepsis and Septic Shock , Ed. Sibbald and Sprung, Chap. 3, 1996, pp 27-59. The transition from early stages of trauma to clinical MOF is marked by the extent of liver and renal failure and a change in mortality risk from about 30% to about 50% (F. B. Cerra, Multiple Organ Failure Syndrome. In New Horizons: Multiple Organ Failure , D. J. Bihari and F. B. Cerra (Eds). Society of Critical Care Medicine , Fullerton, Calif., 1989, pp. 1-24).
Serum creatinine measured at frequent intervals by clinical laboratories is currently the most common way of assessing renal function and following the dynamic changes in renal function which occur in critically ill patients (P. D. Doolan, E. L. Alpen, and G. B. Theil, A clinical appraisal of the plasma concentration and endogenous clearance of creatinine, American Journal of Medicine , 1962, 32, 65-79; J. B. Henry (Ed). Clinical Diagnosis and Management by Laboratory Methods , 17 th Edition , W. B. Saunders, Philadelphia, Pa. 1984); C. E. Speicher, The right test: A physician's guide to laboratory medicine , W. B. Saunders, Philadelphia, Pa., 1989). These values are frequently misleading, since age, state of hydration, renal perfusion, muscle mass, dietary intake, and many other clinical and anthropometric variables affect the value. In addition, a single value returned several hours after sampling is difficult to correlate with other important physiologic events such as blood pressure, cardiac output, state of hydration and other specific clinical events (e.g., hemorrhage, bacteremia, ventilator settings and others). An approximation of glomerular filtration rate can be made via a 24-hour urine collection, but this requires 24 hours to collect the sample, several more hours to analyze the sample, and a meticulous bedside collection technique. New or repeat data are equally cumbersome to obtain. Occasionally, changes in serum creatinine must be further adjusted based on the values for urinary electrolytes. osmolality, and derived calculations such as the “renal failure index” or the “fractional excretion of sodium.” These require additional samples of serum collected contemporaneously with urine samples and, after a delay, precise calculations. Frequently, dosing of medication is adjusted for renal function and thus can be equally as inaccurate, equally delayed, and as difficult to reassess as the values upon which they are based. Finally, clinical decisions in the critically ill population are often as important in their timing as they are in their accuracy.
Exogenous markers such as inulin, iohexol, 51 Cr-EDTA, Gd-DTPA, or 99m Tc-DTPA have been reported to measure the glomerular filtration rate (GFR) (P. L. Choyke, H. A. Austin, and J. A. Frank, Hydrated clearance of gadolinium - DTPA as a measurement of glomerular filtration rate, Kidney International , 1992, 41, 1595-1598; M. F. Tweedle, X. Zhang, M. Fernandez, P. Wedeking, A. D. Nunn, and H. W. Strauss, A noninvasive method for monitoring renal status at bedside, Invest. Radial ., 1997, 32, 802-805; N. Lewis, R. Kerr, and C. Van Buren, Comparative evaluation of urographic contrast media, insulin, and 99m Tc - DTPA clearance methods for determination of glomerular filtration rate in clinical transplantation, Transplantation, 1989, 48, 790-796). Other markers such as 123 I and 125 I labeled o-iodohippurate or 99m Tc-MAG 3 are used to assess tubular secretion process (W. N. Tauxe, Tubular Function , in Nuclear Medicine in Clinical Urology and Nephrology , W. N. Tauxe and E. V. Dubovsky, Editors, pp. 77-105, Appleton Century Crofts, East Norwalk, 1985; R. Muller-Suur, and C. Muller-Suur, Glomerular filtration and tubular secretion of MAG 3 in rat kidney, Journal of Nuclear Medicine , 1989, 30, 1988-1991). However, these markers have several undesirable properties such as the use of radioactivity or ex-vivo handling of blood and urine samples. Thus, in order to assess the status and to follow the progress of renal disease, there is a considerable interest in developing a simple, safe, accurate, and continuous method for determining renal function, preferably by non-radioactive procedures. Other organs and physiological functions that would benefit from real-time monitoring include the heart, the liver, and blood perfusion, especially in organ transplant patients.
Hydrophilic, anionic substances are generally recognized to be excreted by the kidneys (F. Roch-Ramel, K. Besseghir, and H. Murer, Renal excretion and tubular transport of organic anions and cations, Handbook of Physiology, Section 8 , Neurological Physiology, Vol. II , E. E. Windhager, Editor, pp. 2189-2262, Oxford University Press, New York, 1992; D. L. Nosco, and J. A. Beaty-Nosco, Chemistry of technetium radiopharmaceuticals 1 : Chemistry behind the development of technetium -99 m compounds to determine kidney function, Coordination Chemistry Reviews , 1999, 184, 91-123). It is further recognized that drugs bearing sulfonate residues exhibit improved clearance through the kidneys (J. Baldas, J. Bonnyman, Preparation, HPLC studies and biological behavior of techentium -99 m and 99 mTcN 0- radiopharmaceuticals based on quinoline type ligands, Nuc. Med. Biol ., 1999, 19, 491-496; L. Hansen, A. Taylor, L., L. G. Marzilli, Synthesis of the sulfonate and phosphonate derivatives of mercaptoacetyltriglycine, X - ray crystal structure of Na 2 [ReO ( mercaptoacetylglycylglycylaminomethane - sulfonate )]3 H 2 O, Met .- Based Drugs , 1994, 1, 31-39).
Assessment of renal function by continuously monitoring the blood clearance of exogenous optical markers, viz., fluorescein bioconjugates derived from anionic polypeptides, has been developed by us and by others (R. B. Dorshow, J. E. Bugaj, B. D. Burleigh, J. R. Duncan, M. A. Johnson, and W. B. Jones, Noninvasive fluorescence detection of hepatic and renal function, Journal of Biomedical Optics , 1998, 3, 340-345; M. Sohtell et al., FITC-Inulin as a Kidney Tubule Marker in the Rat, Acta. Physiol. Scand ., 1983, 119, 313-316, each of which is expressly incorporated herein by reference). The main drawback of high molecular weight polypeptides is that they are immunogenic. In addition, large polymers with narrow molecular weight distribution are difficult to prepare, especially in large quantities. Thus, there is a need in the art to develop low molecular weight compounds that absorb and/or emit light that can be used for assessing renal, hepatic, cardiac and other organ functions.
SUMMARY OF THE INVENTION
The present invention overcomes these difficulties by incorporating hydrophilic anionic or polyhydroxy residues in the form of sulfates, sulfonates, sulfamates and strategically positioned hydroxyl groups. Thus, the present invention is related to novel dyes containing multiple hydrophilic moieties and their use as diagnostic agents for assessing organ function.
The novel compositions of the present invention comprise dyes of Formulas 1 to 6 which are hydrophilic and absorb light in the visible and near infrared regions of the electromagnetic spectrum. The ease of modifying the clearance pathways of the dyes after in vivo administration permits their use for physiological monitoring. Thus, blood protein-binding compounds are useful for angiography and organ perfusion analysis, which is particularly useful in organ transplant and critical ill patients. Predominant kidney clearance of the dyes enables their use for dynamic renal function monitoring, and rapid liver uptake of the dyes from blood serves as a useful index for the evaluation of hepatic function.
As illustrated in FIGS. 1-7 , these dyes are designed to inhibit aggregation in solution by preventing intramolecular and intermolecular induced hydrophobic interactions.
The present invention relates particularly to the novel compounds comprising indoles of the general Formula 1
wherein R 3 , R 4 , R 5 , R 6 , and R 7 , and Y 1 are independently selected from the group consisting of —H, C1-C10 alkoxyl, C1-C10 polyalkoxyalkyl, C1-C20 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, saccharides, amino, C1-C10 aminoalkyl, cyano, nitro, halogen, hydrophilic peptides, arylpolysulfonates, C1-C10 alkyl, C1-C10 aryl, —SO 3 T, —CO 2 T, —OH, —(CH 2 ) a SO 3 T, —(CH 2 ) a OSO 3 T, —(CH 2 ) a NHSO 3 T, —(CH 2 ) a CO 2 (CH 2 ) b SO 3 T, —(CH 2 ) a OCO(CH 2 ) b SO 3 T, —(CH 2 ) a CONH(CH 2 ) b SO 3 T, —(CH 2 ) a NHCO(CH 2 ) b SO 3 T, —(CH 2 ) a NHCONH(CH 2 ) b SO 3 T, —(CH 2 ) a NHCSNH(CH 2 ) b SO 3 T, —(CH 2 ) a OCONH(CH 2 ) b SO 3 T, —(CH 2 ) a PO 3 HT, —(CH 2 ) a PO 3 T 2 , —(CH 2 ) a OPO 3 HT, —(CH 2 ) a OPO 3 T 2 , —(CH 2 ) a NHPO 3 HT, —(CH 2 ) a NHPO 3 T 2 , —(CH 2 ) a CO 2 (CH 2 ) b PO 3 HT, —(CH 2 ) a CO 2 (CH 2 ) b PO 3 T 2 , —(CH 2 ) a OCO(CH 2 ) b PO 3 HT, —(CH 2 ) a OCO(CH 2 ) b PO 3 T 2 , —(CH 2 ) a CONH(CH 2 ) b PO 3 , —(CH 2 ) a CONH(CH 2 ) b PO 3 T 2 , —(CH 2 ) a NHCO(CH 2 ) b PO 3 HT, —(CH 2 ) a NHCO(CH 2 ) b PO 3 T 2 , —(CH 2 ) a NHCONH(CH 2 ) b PO 3 HT, —(CH 2 ) a NHCONH(CH 2 ) b PO 3 T 2 , —(CH 2 ) a NHCSNH(CH 2 ) b PO 3 HT, —(CH 2 ) a NHCSNH(CH 2 ) b PO 3 T 2 , —(CH 2 ) a OCONH(CH 2 ) b PO 3 HT, and —(CH 2 ) a OCONH(CH 2 ) b PO 3 T 2 , —CH 2 (CH 2 —O—CH 2 ) c —CH 2 —OH, —(CH 2 ) d —CO 2 T, —CH 2 —(CH 2 —O—CH 2 ) e —CH 2 —CO 2 T, —(CH 2 ) f —NH 2 , —CH 2 —(CH 2 —O—CH 2 ) g —CH 2 —NH 2 , —(CH 2 ) h —N(R a )—(CH 2 ) i —CO 2 T, and —(CH 2 ) j —N(R b )—CH 2 —(CH 2 —O—CH 2 ) k —CH 2 —CO 2 T; W 1 is selected from the group consisting of —CR c R d , —O—, —NR c , —S—, and —Se; a, b, d, f, h, i, and j independently vary from 1-10; c, e, g, and k independently vary from 1-100; R a , R b , R c , and R d are defined in the same manner as Y 1 ; T is either H or a negative charge.
The present invention also relates to the novel compounds comprising benzoindoles of general Formula 2
wherein R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and Y 2 are independently selected from the group consisting of —H, C1-C10 alkoxyl, C1-C10 polyalkoxyalkyl, C1-C20 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, saccharides, amino, C1-C10 aminoalkyl, cyano, nitro, halogen, hydrophilic peptides, arylpolysulfonates, C1-C10 alkyl, C1-C10 aryl, —SO 3 T, —CO 2 T, —OH, —(CH 2 ) a SO 3 T, —(CH 2 ) a OSO 3 T, —(CH 2 ) a NHSO 3 T, —(CH 2 ) a CO 2 (CH 2 ) b SO 3 T, —(CH 2 ) a OCO(CH 2 ) b SO 3 T, —(CH 2 ) a CONH(CH 2 ) b SO 3 T, —(CH 2 ) a NHCO(CH 2 ) b SO 3 T, —(CH 2 ) a NHCONH(CH 2 ) b SO 3 T, —(CH 2 ) a NHCSNH(CH 2 ) b SO 3 T, —(CH 2 ) a OCONH(CH 2 ) b SO 3 T, —(CH 2 ) a PO 3 HT, —(CH 2 ) a PO 3 T 2 , —(CH 2 ) a OPO 3 HT, —(CH 2 ) a OPO 3 T 2 , —(CH 2 ) a NHPO 3 HT, —(CH 2 ) a NHPO 3 T 2 , —(CH 2 ) a CO 2 (CH 2 ) b PO 3 HT, —(CH 2 ) a CO 2 (CH 2 ) b PO 3 T 2 , —(CH 2 ) a OCO(CH 2 ) b PO 3 HT, —(CH 2 ) a OCO(CH 2 ) b PO 3 T 2 , —(CH 2 ) a CONH(CH 2 ) b PO 3 HT, —(CH 2 ) a CONH(CH 2 ) b PO 3 T 2 , —(CH 2 ) a NHCO(CH 2 ) b PO 3 HT, —(CH 2 ) a NHCO(CH 2 ) b PO 3 T 2 , —(CH 2 ) a NHCONH(CH 2 ) b PO 3 HT, —(CH 2 ) a NHCONH(CH 2 ) b PO 3 T 2 , —(CH 2 ) a NHCSNH(CH 2 ) b PO 3 HT, —(CH 2 ) a NHCSNH(CH 2 ) b PO 3 T 2 , —(CH 2 ) a OCONH(CH 2 ) b PO 3 HT, and —(CH 2 ) a OCONH(CH 2 ) b PO 3 T 2 , —CH 2 (CH 2 —O—CH 2 ) c —CH 2 —OH, —(CH 2 ) d —CO 2 T, —CH 2 —(CH 2 —O—CH 2 ) e —CH 2 —CO 2 T, —(CH 2 ) f —NH 2 , —CH 2 —(CH 2 —O—CH 2 ) g —CH 2 —NH 2 , —(CH 2 ) h —N(R a )—(CH 2 ) i —CO 2 T, and —(CH 2 ) j —N(R b )—CH 2 —(CH 2 —O—CH 2 ) k —CH 2 —CO 2 T; W 2 is selected from the group consisting of —CR c R d , —O—, —NR c , —S—, and —Se; a, b, d, f, h, i, and j independently vary from 1-10; c, e, g, and k independently vary from 1-100; R a , R b , R c , and R d are defined in the same manner as Y 2 ; T is either H or a negative charge.
The present invention also relates to the novel composition comprising cyanine dyes of general Formula 3
wherein R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , Y 3 , and Z 3 are independently selected from the group consisting of —H, C1-C10 alkoxyl, C1-C10 polyalkoxyalkyl, C1-C20 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, saccharides, amino, C1-C10 aminoalkyl, cyano, nitro, halogen, hydrophilic peptides, arylpolysulfonates, C1-C10 alkyl, C1-C10 aryl, —SO 3 T, —CO 2 T, —OH, —(CH 2 ) a SO 3 T, —(CH 2 ) a OSO 3 T, —(CH 2 ) a NHSO 3 T, —(CH 2 ) a CO 2 (CH 2 ) b SO 3 T, —(CH 2 ) a OCO(CH 2 ) b SO 3 T, —(CH 2 ) a CONH(CH 2 ) b SO 3 T, —(CH 2 ) a NHCO(CH 2 ) b SO 3 T, —(CH 2 ) a NHCONH(CH 2 ) b SO 3 T, —(CH 2 ) a NHCSNH(CH 2 ) b SO 3 T, —(CH 2 ) a OCONH(CH 2 ) b SO 3 T, —(CH 2 ) a PO 3 HT, —(CH 2 ) a PO 3 T 2 , —(CH 2 ) a OPO 3 HT, —(CH 2 ) a OPO 3 T 2 , —(CH 2 ) a NHPO 3 HT, —(CH 2 ) a NHPO 3 T 2 , —(CH 2 ) a CO 2 (CH 2 ) b PO 3 HT, —(CH 2 ) a CO 2 (CH 2 ) b PO 3 T 2 , —(CH 2 ) a OCO(CH 2 ) b PO 3 HT, —(CH 2 ) a OCO(CH 2 ) b PO 3 T 2 , —(CH 2 ) a CONH(CH 2 ) b PO 3 HT, —(CH 2 ) a CONH(CH 2 ) b PO 3 T 2 , —(CH 2 ) a NHCO(CH 2 ) b PO 3 HT, —(CH 2 ) a NHCO(CH 2 ) b PO 3 T 2 , (CH 2 ) a NHCONH(CH 2 ) b PO 3 HT, —(CH 2 ) a NHCONH(CH 2 ) b PO 3 T 2 , —(CH 2 ) a NHCSNH(CH 2 ) b PO 3 HT, —(CH 2 ) a NHCSNH(CH 2 ) b PO 3 T 2 , —(CH 2 ) a OCONH(CH 2 ) b PO 3 HT, and —(CH 2 ) a OCONH(CH 2 ) b PO 3 T 2 , —CH 2 (CH 2 —O—CH 2 ) c —CH 2 —OH, —(CH 2 ) d —CO 2 T, —CH 2 —(CH 2 —O—CH 2 ) e —CH 2 —CO 2 T, —(CH 2 ) f —NH 2 , —CH 2 —(CH 2 —O——(CH 2 ) g —CH 2 —NH 2 , —(CH 2 ) h —N(R a )—(CH 2 ) i —CO 2 T, and —(CH 2 ) j —N(R b )—CH 2 —(CH 2 —O—CH 2 ) k —CH 2 —CO 2 T; W 3 and X 3 are selected from the group consisting of —CR c R d , —O—, —NR c , —S—, and —Se; V 3 is a single bond or is selected from the group consisting of —O—, —S—, —Se—, and —NR a ; a, b, d, f, h, i, and j independently vary from 1-10; c, e, g, and k independently vary from 1-100; a 3 and b 3 vary from 0 to 5; R a , R b , R c , and R d are defined in the same manner as Y 3 ; T is either H or a negative charge.
The present invention further relates to the novel composition comprising cyanine dyes of general Formula 4
wherein R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , Y 4 , and Z 4 are independently selected from the group consisting of —H, C1-C10 alkoxyl, C1-C10 polyalkoxyalkyl, C1-C20 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, saccharides, amino, C1-C10 aminoalkyl, cyano, nitro, halogen, hydrophilic peptides, arylpolysulfonates, C1-C10 alkyl, C1-C10 aryl, —SO 3 T, —CO 2 T, —OH, —(CH 2 ) a SO 3 T, —(CH 2 ) a OSO 3 T, —(CH 2 ) a NHSO 3 T, —(CH 2 ) a CO 2 (CH 2 ) b SO 3 T, —(CH 2 ) a OCO(CH 2 ) b SO 3 T, —(CH 2 ) a CONH(CH 2 ) b SO 3 T, —(CH 2 ) a NHCO(CH 2 ) b SO 3 T, —(CH 2 ) a NHCONH(CH 2 ) b SO 3 T, —(CH 2 ) a NHCSNH(CH 2 ) b SO 3 T, —(CH 2 ) a OCONH(CH 2 ) b SO 3 T, —(CH 2 ) a PO 3 HT, —(CH 2 ) a PO 3 T 2 , —(CH 2 ) a OPO 3 HT, —(CH 2 ) a OPO 3 T 2 , —(CH 2 ) a NHPO 3 HT, —(CH 2 ) a NHPO 3 T 2 , —(CH 2 ) a CO 2 (CH 2 ) b PO 3 HT, —(CH 2 ) a CO 2 (CH 2 ) b PO 3 T 2 , —(CH 2 ) a OCO(CH 2 ) b PO 3 HT, —(CH 2 ) a OCO(CH 2 ) b PO 3 T 2 , —(CH 2 ) a CONH(CH 2 ) b PO 3 HT, —(CH 2 ) a CONH(CH 2 ) b PO 3 T 2 , —(CH 2 ) a NHCO(CH 2 ) b PO 3 HT, —(CH 2 ) a NHCO(CH 2 ) b PO 3 T 2 , —(CH 2 ) a NHCONH(CH 2 ) b PO 3 HT, —(CH 2 ) a NHCONH(CH 2 ) b PO 3 T 2 , —(CH 2 ) a NHCSNH(CH 2 ) b PO 3 HT, —(CH 2 ) a NHCSNH(CH 2 ) b PO 3 T 2 , —(CH 2 ) a OCONH(CH 2 ) b PO 3 HT, and —(CH 2 ) a OCONH(CH 2 ) b PO 3 T 2 , —CH 2 (CH 2 —O—CH 2 ) c —CH 2 —OH, —(CH 2 ) d —CO 2 T, —CH 2 —(CH 2 —O—CH 2 ) e —CH 2 —CO 2 T, —(CH 2 ) f —NH 2 , —CH 2 —(CH 2 —O—CH 2 ) g —CH 2 —NH 2 , —(CH 2 ) h —N(R a )—(CH 2 ) i —CO 2 T, and —(CH 2 ) j —N(R b )—CH 2 —(CH 2 —O—CH 2 ) k —CH 2 —CO 2 T; W 4 and X 4 are selected from the group consisting of —CR c R d , —O—, —NR c , —S—, and —Se; V 4 is a single bond or is selected from the group consisting of —O—, —S—, —Se—, and —NR a ; a 4 and b 4 vary from 0 to 5; a, b, d, f, h, i, and j independently vary from 1-10; c, e, g, and k independently vary from 1-100; R a , R b , R c , and R d are defined in the same manner as Y 4 ; T is either H or a negative charge.
The present invention also relates to the novel composition comprising cyanine dyes of general Formula 5
wherein R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , Y 5 , and Z 5 are independently selected from the group consisting of —H, C1-C10 alkoxyl, C1-C10 polyalkoxyalkyl, C1-C20 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, saccharides, amino, C1-C10 aminoalkyl, cyano, nitro, halogen, hydrophilic peptides, arylpolysulfonates, C1-C10 alkyl, C1-C10 aryl, —SO 3 T, —CO 2 T, —OH, —(CH 2 ) a SO 3 T, —(CH 2 ) a OSO 3 T, —(CH 2 ) a NHSO 3 T, —(CH 2 ) a CO 2 (CH 2 ) b SO 3 T, —(CH 2 ) a OCO(CH 2 ) b SO 3 T, —(CH 2 ) a CONH(CH 2 ) b SO 3 T, —(CH 2 ) a NHCO(CH 2 ) b SO 3 T, —(CH 2 ) a NHCONH(CH 2 ) b SO 3 T, —(CH 2 ) a NHCSNH(CH 2 ) b SO 3 T, —(CH 2 ) a OCONH(CH 2 ) b SO 3 T, —(CH 2 ) a PO 3 HT, —(CH 2 ) a PO 3 T 2 , —(CH 2 ) a OPO 3 HT, —(CH 2 ) a OPO 3 T 2 , —(CH 2 ) a NHPO 3 HT, —(CH 2 ) a NHPO 3 T 2 , —(CH 2 ) a CO 2 (CH 2 ) b PO 3 HT, —(CH 2 ) a CO 2 (CH 2 ) b PO 3 T 2 , —(CH 2 ) a OCO(CH 2 ) b PO 3 HT, —(CH 2 ) a OCO(CH 2 ) b PO 3 T 2 , —(CH 2 ) a CONH(CH 2 ) b PO 3 HT, —(CH 2 ) a CONH(CH 2 ) b PO 3 T 2 , —(CH 2 ) a NHCO(CH 2 ) b PO 3 HT, —(CH 2 ) a NHCO(CH 2 ) b PO 3 T 2 , —(CH 2 ) a NHCONH(CH 2 ) b PO 3 HT, —(CH 2 ) a NHCONH(CH 2 ) b PO 3 T 2 , —(CH 2 ) a NHCSNH(CH 2 ) b PO 3 HT, —(CH 2 ) a NHCSNH(CH 2 ) b PO 3 T 2 , —(CH 2 ) a OCONH(CH 2 ) b PO 3 HT, and —(CH 2 ) a OCONH(CH 2 ) b PO 3 T 2 , —CH 2 (CH 2 —O—CH 2 ) c —CH 2 —OH, —(CH 2 ) d —CO 2 T, —CH 2 —(CH 2 —O—CH 2 ) e —CH 2 —CO 2 T, —(CH 2 ) f —NH 2 , —CH 2 —(CH 2 —O—CH 2 ) g —CH 2 —NH 2 , —(CH 2 ) h —N(R a )—(CH 2 ) i —CO 2 T, and —(CH 2 ) j —N(R b )—CH 2 —(CH 2 —O—CH 2 ) k —CH 2 —CO 2 T; W 5 and X 5 are selected from the group consisting of —CR c R d , —O—, —NR c , —S—, and —Se; V 5 is a single bond or is selected from the group consisting of —O—, —S—, —Se—, and —NR a ; D 5 is a single or a double bond; A 5 , B 5 and E 5 may be the same or different and are selected from the group consisting of —O—, —S—, —Se—, —P—, —NR a , —CR c R d , CR c , alkyl, and —C═O; A 5 , B 5 , D 5 , and E 5 may together form a 6 or 7 membered carbocyclic ring or a 6 or 7 membered heterocyclic ring optionally containing one or more oxygen, nitrogen, or a sulfur atom; a, b, d, f, h, i, and j independently vary from 1-10; c, e, g, and k independently vary from 1-100; a 5 and b 5 vary from 0 to 5; R a , R b , R c , and R d are defined in the same manner as Y 5 ; T is either H or a negative charge.
The present invention also relates to the novel composition comprising cyanine dyes of general Formula 6
wherein R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 and R 58 , Y 6 , and Z 6 are independently selected from the group consisting of —H, C1-C10 alkoxyl, C1-C10 polyalkoxyalkyl, C1-C20 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, saccharides, amino, C1-C10 aminoalkyl, cyano, nitro, halogen, hydrophilic peptides, arylpolysulfonates, C1-C10 alkyl, C1-C10 aryl, —SO 3 T, —CO 2 T, —OH, —(CH 2 ) a SO 3 T, —(CH 2 ) a OSO 3 T, —(CH 2 ) a NHSO 3 T, —(CH 2 ) a CO 2 (CH 2 ) b SO 3 T, —(CH 2 ) a OCO(CH 2 ) b SO 3 T, —(CH 2 ) a CONH(CH 2 ) b SO 3 T, —(CH 2 ) a NHCO(CH 2 ) b SO 3 T, —(CH 2 ) a NHCONH(CH 2 ) b SO 3 T, —(CH 2 ) a NHCSNH(CH 2 ) b SO 3 T, —(CH 2 ) a OCONH(CH 2 ) b SO 3 T, —(CH 2 ) a PO 3 HT, —(CH 2 ) a PO 3 T 2 , —(CH 2 ) a OPO 3 HT, —(CH 2 ) a OPO 3 T 2 , —(CH 2 ) a NHPO 3 HT, —(CH 2 ) a NHPO 3 T 2 , —(CH 2 ) a CO 2 (CH 2 ) b PO 3 HT, —(CH 2 ) a CO 2 (CH 2 ) b PO 3 T 2 , —(CH 2 ) a OCO(CH 2 ) b PO 3 HT, —(CH 2 ) a OCO(CH 2 ) b PO 3 T 2 , —(CH 2 ) a CONH(CH 2 ) b PO 3 HT, —(CH 2 ) a CONH(CH 2 ) b PO 3 T 2 , —(CH 2 ) a NHCO(CH 2 ) b PO 3 HT, —(CH 2 ) a NHCO(CH 2 ) b PO 3 T 2 , —(CH 2 ) a NHCONH(CH 2 ) b PO 3 HT, —(CH 2 ) a NHCONH(CH 2 ) b PO 3 T 2 , —(CH 2 ) a NHCSNH(CH 2 ) b PO 3 HT, —(CH 2 ) a NHCSNH(CH 2 ) b PO 3 T 2 , —(CH 2 ) a OCONH(CH 2 ) b PO 3 HT, and —(CH 2 ) a OCONH(CH 2 ) b PO 3 T 2 , —CH 2 (CH 2 —O—CH 2 ) c —CH 2 —OH, —(CH 2 ) d —CO 2 T, —CH 2 —(CH 2 —O—CH 2 ) e —CH 2 —CO 2 T, —(CH 2 ) f —NH 2 , —CH 2 —(CH 2 —O—CH 2 ) g —CH 2 —NH 2 , —(CH 2 ) h —N(R a )—(CH 2 ) i —CO 2 T, and —(CH 2 ) j —N(R b )—CH 2 —(CH 2 —O—CH 2 ) k —CH 2 —CO 2 T; W 6 and X 6 are selected from the group consisting of —CR c R d , —O—, —NR c , —S—, and —Se; V 6 is a single bond or is selected from the group consisting of —O—, —S—, —Se—, and —NR a ; D 6 is a single or a double bond; A 6 , B 6 and E 6 may be the same or different and are selected from the group consisting of —O—, —S—, —Se—, —P—, —NR a , —CR c R d , CR c , alkyl, and —C═O; A 6 , B 6 , D 6 , and E 6 may together form a 6 or 7 membered carbocyclic ring or a 6 or 7 membered heterocyclic ring optionally containing one or more oxygen, nitrogen, or sulfur atom; a, b, d, f, h, i, and j independently vary from 1-10; c, e, g, and k independently vary from 1-100; a 6 and b 6 vary from 0 to 5; R a , R b , R c , and R d are defined in the same manner as Y 6 ; T is either H or a negative charge.
The inventive compositions and methods are advantageous since they provide a real-time, accurate, repeatable measure of renal excretion rate using exogenous markers under specific yet changing circumstances. This represents a substantial improvement over any currently available or widely practiced method, since currently, no reliable, continuous, repeatable bedside method for the assessment of specific renal function by optical methods exists. Moreover, since the inventive method depends solely on the renal elimination of the exogenous chemical entity, the measurement is absolute and requires no subjective interpretation based on age, muscle mass, blood pressure, etc. In fact it represents the nature of renal function in this particular patient, under these particular circumstances, at this precise moment in time.
The inventive compounds and methods provide simple, efficient, and effective monitoring of organ function. The compound is administered and a sensor, either external or internal, is used to detect absorption and/or emission to determine the rate at which the compound is cleared from the blood. By altering the R groups, the compounds may be rendered more organ specific.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 : Reaction pathway for the preparation of indole derivatives.
FIG. 2 : Reaction pathway for the preparation of benzoindole derivatives.
FIG. 3 : Reaction pathway for the preparation of indocarbocyanine derivatives.
FIG. 4 : Reaction pathway for the preparation of benzoindocarbocyanine derivatives.
FIG. 5 : Reaction pathway for the preparation of robust indocarbocyanine derivatives.
FIG. 6 : Reaction pathway for the preparation of robust benzoindocarbocyanine derivatives.
FIG. 7 : Reaction pathway for the preparation of long-wavelength absorbing indocarbocyanine derivatives.
FIG. 8 a : Absorption spectrum of indoledisulfonate in water.
FIG. 8 b : Emission spectrum of indoledisulfonate in water.
FIG. 9 a : Absorption spectrum of indocarbocyaninetetrasulfonate in water.
FIG. 9 b : Emission spectrum of indocarbocyaninetetrasulfonate in water.
FIG. 10 a : Absorption spectrum of chloroindocarbocyanine in acetonitrile.
FIG. 10 b : Emission spectrum of chloroindocarbocyanine in acetonitrile.
FIG. 11 : Blood clearance profile of carbocyanine-polyaspartic (10 kDa) acid conjugate in a rat.
FIG. 12 : Blood clearance profile of carbocyanine-polyaspartic (30 kDa) acid conjugate in a rat.
FIG. 13 : Blood clearance profile of indoledisulfonate in a rat.
FIG. 14 : Blood clearance profile of carbocyaninetetrasulfonates in a rat.
DETAILED DESCRIPTION
In one embodiment of the invention, the dyes of the invention serve as probes for continuous monitoring of renal function, especially for critically ill patients and kidney transplant patients.
In another aspect of the invention, the dyes of the invention are useful for dynamic hepatic function monitoring, especially for critically ill patients and liver transplant patients.
In yet another aspect of the invention, the dyes of the invention are useful for real-time determination of cardiac function, especially in patients with cardiac diseases.
In still another aspect of the invention, the dyes of the invention are useful for monitoring organ perfusion, especially for critically ill, cancer, and organ transplant patients.
The novel dyes of the present invention are prepared according the methods well known in the art, as illustrated in general in FIGS. 1-7 and described for specific compounds in Examples 1-11.
In one embodiment, the novel compositions, also called tracers, of the present invention have the Formula 1, wherein R 3 , R 4 , R 5 , R 6 and R 7 , and Y 1 are independently selected from the group consisting of —H, C1-C5 alkoxyl, C1-C5 polyalkoxyalkyl, C1-C10 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, mono- and disaccharides, nitro, hydrophilic peptides, arylpolysulfonates, C1-C5 alkyl, C1-C10 aryl, —SO 3 T, —CO 2 T, —OH, —(CH 2 ) a SO 3 T, —(CH 2 ) a OSO 3 T, —(CH 2 ) a NHSO 3 T, —(CH 2 ) a CO 2 (CH 2 ) b SO 3 T, —(CH 2 ) a OCO(CH 2 ) b SO 3 T, —CH 2 (CH 2 —O—CH 2 ) c —CH 2 —OH, —(CH 2 ) d —CO 2 T, —CH 2 —(CH 2 —O—CH 2 ) e —CH 2 —CO 2 T, —(CH 2 ) f —NH 2 , —CH 2 —(CH 2 —O—CH 2 ) g —CH 2 —NH 2 , —(CH 2 ) h —N(R a )—(CH 2 ) i —CO 2 T, and —(CH 2 ) j —N(R b )—CH 2 —(CH 2 —O—CH 2 ) k —CH 2 —CO 2 T; W 1 is selected from the group consisting of —CR c R d , —O—, —NR c , —S—, and —Se; a, b, d, f, h, l, and j independently vary from 1-5; c, e, g, and k independently vary from 1-20; R a , R b , R c , and R d are defined in the same manner as Y 1 ; T is a negative charge.
In another embodiment, the novel compositions of the present invention have the general Formula 2, wherein R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and Y 2 are independently selected from the group consisting of —H, C1-C5 alkoxyl, C1-C5 polyalkoxyalkyl, C1-C10 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, mono- and disaccharides, nitro, hydrophilic peptides, arylpolysulfonates, C1-C5 alkyl, C1-C10 aryl, —SO 3 T, —CO 2 T, —OH, —(CH 2 ) a SO 3 T, —(CH 2 ) a OSO 3 T, —(CH 2 ) a NHSO 3 T, —(CH 2 ) a CO 2 (CH 2 ) b SO 3 T, —(CH 2 ) a OCO(CH 2 ) b SO 3 T, —CH 2 (CH 2 —O—CH 2 ) c —CH 2 —OH, —(CH 2 ) d —CO 2 T, —CH 2 —(CH 2 —O—CH 2 ) e —CH 2 —CO 2 T, —(CH 2 ) f —NH 2 , —CH 2 —(CH 2 —O—CH 2 ) g —CH 2 —NH 2 , —(CH 2 ) h —N(R a )—(CH 2 ) i —CO 2 T, and —(CH 2 ) j —N(R b )—CH 2 —(CH 2 —O—CH 2 ) k —CH 2 —CO 2 T; W 2 is selected from the group consisting of —CR c R d , —O—, —NR c , —S—, and —Se; a, b, d, f, h, l, and j independently vary from 1-5; c, e, g, and k independently vary from 1-20; R a , R b , R c , and R d are defined in the same manner as Y 2 ; T is a negative charge.
In another embodiment, the novel compositions of the present invention have the general Formula 3, wherein R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , Y 3 , and Z 3 are independently selected from the group consisting of —H, C1-C5 alkoxyl, C1-C5 polyalkoxyalkyl, C1-C10 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, mono- and disaccharides, nitro, hydrophilic peptides, arylpolysulfonates, C1-C5 alkyl, C1-C10 aryl, —SO 3 T, —CO 2 T, —OH, —(CH 2 ) a SO 3 T, —(CH 2 ) a OSO 3 T, —(CH 2 ) a NHSO 3 T, —(CH 2 ) a CO 2 (CH 2 ) b SO 3 T, —(CH 2 ) a OCO(CH 2 ) b SO 3 T, —CH 2 (CH 2 —O—CH 2 ) c —CH 2 —OH, —(CH 2 ) d —CO 2 T, —CH 2 —(CH 2 —O—CH 2 ) e —CH 2 —CO 2 —T, —(CH 2 ) f —NH 2 , —CH 2 —(CH 2 —O—CH 2 ) g —CH 2 —NH 2 , —(CH 2 ) h —N(R a )—(CH 2 ) i —CO 2 T, and —(CH 2 ) j —N(R b )—CH 2 —(CH 2 —O—CH 2 ) k —CH 2 —CO 2 T; W 3 and X 3 are selected from the group consisting of —CR c R d , —O—, —NR c , —S—, and —Se, V 3 is a single bond or is selected from the group consisting of —O—, —S—, —Se—, and —NR a ; a, b, d, f, h, i, and j independently vary from 1-5; c, e, g, and k independently vary from 1-50; a 3 and b 3 vary from 0 to 5; R a , R b , R c , and R d are defined in the same manner as Y 3 ; T is either H or a negative charge.
In another embodiment, the novel compositions of the present invention have the general Formula 4, wherein R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , Y 4 , and Z 4 are independently selected from the group consisting of —H, C1-C5 alkoxyl, C1-C5 polyalkoxyalkyl, C1-C10 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, mono- and disaccharides, nitro, hydrophilic peptides, arylpolysulfonates, C1-C5 alkyl, C1-C10 aryl, —SO 3 T, —CO 2 T, —OH, —(CH 2 ) a SO 3 T, —(CH 2 ) a OSO 3 T, —(CH 2 ) a NHSO 3 T, —(CH 2 ) a CO 2 (CH 2 ) b SO 3 T, —(CH 2 ) a OCO(CH 2 ) b SO 3 T, —CH 2 (CH 2 —O—CH 2 ) c —CH 2 —OH, —(CH 2 ) d —CO 2 T, —CH 2 —(CH 2 —O—CH 2 ) e —CH 2 —CO 2 T, —(CH 2 ) f —NH 2 , —CH 2 —(CH 2 —O—CH 2 ) g —CH 2 —NH 2 , —(CH 2 ) h —N(R a )—(CH 2 ) i —CO 2 T, and —(CH 2 ) j —N(R b )—CH 2 —(CH 2 —O—CH 2 ) k —CH 2 —CO 2 T; W 4 and X 4 are selected from the group consisting of —CR c R d , —O—, —NR c , —S—, and —Se; V 4 is a single bond or is selected from the group consisting of —O—, —S—, —Se—, and —NR a ; a 4 and b 4 vary from 0 to 5; a, b, d, f, h, i, and j independently vary from 1-5; c, e, g, and k independently vary from 1-50; R a , R b , R c , and R d are defined in the same manner as Y 4 ; T is either H or a negative charge.
In another embodiment, the novel compositions of the present invention have the general Formula 5, wherein R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , Y 5 , and Z 5 are independently selected from the group consisting of —H, C1-C5 alkoxyl, C1-C5 polyalkoxyalkyl, C1-C10 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, mono- and disaccharides, nitro, hydrophilic peptides, arylpolysulfonates, C1-C5 alkyl, C1-C10 aryl, —SO 3 T, —CO 2 T, —OH, —(CH 2 ) a SO 3 T, —(CH 2 ) a OSO 3 T, —(CH 2 ) a NHSO 3 T, —(CH 2 ) a CO 2 (CH 2 ) b SO 3 T, —(CH 2 ) a OCO(CH 2 ) b SO 3 T, —CH 2 (CH 2 —O—CH 2 ) c —CH 2 —OH, —(CH 2 ) d —CO 2 T, —CH 2 —(CH 2 —O—CH 2 ) e —CH 2 —CO 2 T, —(CH 2 ) f —NH 2 , —CH 2 —(CH 2 —O—CH 2 ) g —CH 2 —NH 2 , —(CH 2 ) h —N(R a )—(CH 2 ; —CO 2 T, and —(CH 2 ) j —N(R b )—CH 2 —(CH 2 —O—CH 2 ) k —CH 2 —CO 2 T; W 5 and X 5 are selected from the group consisting of —CR c R d , —O—, —NR c , —S—, and —Se; V 5 is a single bond or is selected from the group consisting of —O—, —S—, —Se—, and —NR a D 5 is a single or a double bond; A 5 , B 5 and E 5 may be the same or different and are selected from the group consisting of —O—, —S—, —NR a , —CR c R d , CR c , and alkyl; A 5 , B 5 , D 5 , and E 5 may together form a 6 or 7 membered carbocyclic ring or a 6 or 7 membered heterocyclic ring optionally containing one or more oxygen, nitrogen, or sulfur atom; a, b, d, f, h, i, and j independently vary from 1-5; c, e, g, and k independently vary from 1-50; a 5 and b 5 vary from 0 to 5; R a , R b , R c , and R d are defined in the same manner as Y 5 ; T is either H or a negative charge.
In yet another embodiment, the novel compositions of the present invention have the general Formula 6, wherein R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , Y 6 , and Z 6 are independently selected from the group consisting of —H, C1-C5 alkoxyl, C1-C5 polyalkoxyalkyl, C1-C10 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, mono- and disaccharides, nitro, hydrophilic peptides, arylpolysulfonates, C1-C5 alkyl, C1-C10 aryl, —SO 3 T, —CO 2 T, —OH, —(CH 2 ) a SO 3 T, —(CH 2 ) a OSO 3 T, —(CH 2 ) a NHSO 3 T, —(CH 2 ) a CO 2 (CH 2 ) b SO 3 T, —(CH 2 ) a OCO(CH 2 ) b SO 3 T, —CH 2 (CH 2 —O—CH 2 ) c —CH 2 —OH, —(CH 2 ) d —CO 2 T, —CH 2 —(CH 2 —O—CH 2 ) e —CH 2 —CO 2 T, —(CH 2 ) f —NH 2 , —CH 2 —(CH 2 —O—CH 2 ) g —CH 2 —NH 2 , —(CH 2 ) h —N(R a )—(CH 2 ) i —CO 2 T, and —(CH 2 ) j —N(R b )—CH 2 —(CH 2 —O—CH 2 ) k —CH 2 —CO 2 T; W 6 and X 6 are selected from the group consisting of —CR c R d , —O—, —NR c , —S—, and —Se; V 6 is a single bond or is selected from the group consisting of —O—, —S—, —Se—, and —NR a ; D 6 is a single or a double bond; A 6 , B 6 and E 6 may be the same or different and are selected from the group consisting of —O—, —S—, —NR a , —CR c R d , CR c , and alkyl; A 6 , B 6 , D 6 , and E 6 may together form a 6 or 7 membered carbocyclic ring or a 6 or 7 membered heterocyclic ring optionally containing one or more oxygen, nitrogen, or sulfur atom; a, b, d, f, h, i, and j independently vary from 1-5; c, e, g, and k independently vary from 1-50; a 5 and b 5 vary from 0 to 5; R a , R b , R c , and R d are defined in the same manner as Y 6 ; T is either H or a negative charge.
The dosage of the tracers may vary according to the clinical procedure contemplated and generally ranges from 1 picomolar to 100 millimolar. The tracers may be administered to the patient by any suitable method, including intravenous, intraperitoneal, or subcutaneous injection or infusion, oral administration, transdermal absorption through the skin, or by inhalation. The detection of the tracers is achieved by optical fluorescence, absorbance, or light scattering methods known in the art (Muller et al. Eds, Medical Optical Tomography , SPIE Volume IS11, 1993, which is expressly incorporated herein by reference) using invasive or non-invasive probes such as endoscopes, catheters, ear clips, hand bands, surface coils, finger probes, and the like. Physiological function is correlated with the clearance profiles and rates of these agents from body fluids (R. B. Dorshow et al., Non - Invasive Fluorescence Detection of Hepatic and Renal Function, Bull. Am. Phys. Soc . 1997, 42, 681, which is expressly incorporated by reference herein).
The organ functions can be assessed either by the differences in the manner in which the normal and impaired cells remove the tracer from the bloodstream, by measuring the rate or accumulation of these tracers in the organs or tissues, or by obtaining tomographic images of the organs or tissues. Blood pool clearance may be measured non-invasively from convenient surface capillaries such as those found in an ear lobe or a finger, for example, using an ear clip or finger clip sensor, or may be measured invasively using an endovascular catheter. Accumulation of the tracer within the cells of interest can be assessed in a similar fashion. The clearance of the tracer dyes may be determined by selecting excitation wavelengths and filters for the emitted photons. The concentration-time curves may be analyzed in real time by a microprocessor. In order to demonstrate feasibility of the inventive compounds to monitor organ function, a non-invasive absorbance or fluorescence detection system to monitor the signal emanating from the vasculature infused with the compounds is used. Indole derivatives, such as those of Formulas 1-6, fluoresce at a wavelength between 350 nm and 1300 nm when excited at the appropriate wavelength as is known to, or readily determined by, one skilled in the art.
In addition to the noninvasive techniques, a modified pulmonary artery catheter can be used to make the necessary measurements (R. B. Dorshow, J. E. Bugaj, S. A. Achilefu, R. Rajagopalan, and A. H. Combs, Monitoring Physiological Function by Detection of Exogenous Fluorescent Contrast Agents , in Optical Diagnostics of Biological Fluids IV , A. Priezzhev and T. Asakura, Editors, Procedings of SPIE 1999, 3599, 2-8, which is expressly incorporated by reference herein). Currently, pulmonary artery catheters measure only intravascular pressures, cardiac output and other derived measures of blood flow. Critically ill patients are managed using these parameters, but rely on intermittent blood sampling and testing for assessment of renal function. These laboratory parameters represent discontinuous data and are frequently misleading in many patient populations. Yet, importantly, they are relied upon heavily for patient assessment, treatment decisions, and drug dosing.
The modified pulmonary artery catheter incorporates an optical sensor into the tip of a standard pulmonary artery catheter. This wavelength specific optical sensor can monitor the renal function specific elimination of an optically detectable chemical entity. Thus, by a method analogous to a dye dilution curve, real-time renal function can be monitored by the disappearance of the optically detected compound. Modification of a standard pulmonary artery catheter only requires making the fiber optic sensor wavelength specific, as is known to one skilled in this art. Catheters that incorporate fiber optic technology for measuring mixed venous oxygen saturation currently exist.
The present invention may be used for rapid bedside evaluation of renal function and also to monitor the efficiency of hemodialysis. The invention is further demonstrated by the following examples. Since many modifications, variations, and changes in detail may be made to the described embodiments, it is intended that all matter in the foregoing description and shown in the accompanying drawings be interpreted as illustrative and not in a limiting sense.
EXAMPLE 1
Synthesis of Indole Disulfonate
FIG. 1 , Compound 5, Y 7 =SO 3 − ; X 7 =H; n=1
A mixture of 3-methyl-2-butanone (25.2 mL), and p-hydrazinobenzenesulfonic acid (15 g) in acetic acid (45 mL) was heated at 110° C. for 3 hours. After reaction, the mixture was allowed to cool to room temperature and ethyl acetate (100 mL) was added to precipitate the product, which was filtered and washed with ethyl acetate (100 mL). The intermediate compound, 2,3,3-trimethylindolenium-5-sulfonate ( FIG. 1 , compound 3) was obtained as a pink powder in 80% yield. A portion of compound 3 (9.2 g) in methanol (115 mL) was carefully added to a solution of KOH in isopropanol (100 mL). A yellow potassium salt of the sulfonate was obtained in 85% yield after vacuum-drying for 12 hours. A portion of the 2,3,3-trimethylindolenium-5-sulfonate potassium salt (4 g) and 1,3-propanesultone (2.1 g) was heated in dichlorobenzene (40 mL) at 110° C. for 12 hours. The mixture was allowed to cool to room temperature and the resulting precipitate was filtered and washed with isopropanol. The resulting pink powder was dried under vacuum to give 97% of the desired compound.
Other compounds prepared by a similar method described above include polyhydroxyl indoles such as
EXAMPLE 2
Synthesis of Indole Disulfonate
FIG. 1 , Compound 5, Y 7 =SO 3 − ; X 7 =H; n=2
This compound was prepared by the same procedure described in Example 1, except that 1,4-butanesultone was used in place of 1,3-propanesultone.
EXAMPLE 3
Synthesis of Benzoindole Disulfonate
FIG. 2 , Compound 8Y, 7 , Y 8 =SO 3 − ; X 7 =H; n=2
This compound was prepared by the same procedure described in Example 1, except that hydrazinonaphthalenedisulfonic acid was used in place of hydrazinobenzenesulfonic acid.
Other compounds prepared by a similar method include polyhydroxyindoles such as:
EXAMPLE 4
Synthesis of Benzoindole Disulfonate
FIG. 2 , Compound 8, Y 7 , Y 8 =SO 3 − ; X 7 =OH; n=4
This compound was prepared by the same procedure described in Example 1, except that 3-hydroxymethyl-4-hydroxyl-2-butanone was used in place of 3-methyl-2-butanone.
EXAMPLE 5
Synthesis of Bis(ethylcarboxymethyl)indocyanine Dye
A mixture of 1,1,2-trimethyl-[1H]-benz[e]indole (9.1 g, 43.58 mmoles) and 3-bromopropanoic acid (10.0 g, 65.37 mmoles) in 1,2-dichlorobenzene (40 mL) was heated at 110° C. for 12 hours. The solution was cooled to room temperature and the red residue obtained was filtered and washed with acetonitrile:diethyl ether (1:1) mixture. The solid obtained was dried under vacuum to give 10 g (64%) of light brown powder. A portion of this solid (6.0 g; 16.56 mmoles), glutaconaldehyde dianil monohydrochloride (2.36 g, 8.28 mmoles) and sodium acetate trihydrate (2.93 g, 21.53 mmoles) in ethanol (150 mL) were refluxed for 90 minutes. After evaporating the solvent, 40 mL of 2 N aqueous HCl was added to the residue and the mixture was centrifuged and the supernatant was decanted. This procedure was repeated until the supernatant became nearly colorless. About 5 mL of water:acetonitrile (3:2) mixture was added to the solid residue and lyophilized to obtain 2 g of dark green flakes. The purity of the compound was established with 1 H-NMR and liquid chromatography/mass spectrometry (LC/MS).
EXAMPLE 6
Synthesis of Bis(pentylcarboxymethyl)indocyanine Dye
A mixture of 2,2,3-trimethyl-[1H]-benz[e]indole (20 g, 95.6 mmoles) and 6-bromohexanoic acid (28.1 g, 144.1 mmoles) in 1,2-dichlorobenzene (250 mL) was heated at 110 C for 12 hours. The green solution was cooled to room temperature and the brown solid precipitate formed was collected by filtration. After washing the solid with 1,2-dichlorobenzene and diethyl ether, the brown powder obtained (24 g, 64%) was dried under vacuum at room temperature. A portion of this solid (4.0 g; 9.8 mmoles), glutaconaldehyde dianil monohydrochloride (1.4 g, 5 mmoles) and sodium acetate trihydrate (1.8 g, 12.9 mmoles) in ethanol (80 mL) were refluxed for 1 hour. After evaporating the solvent, 20 mL of a 2 N aqueous HCl was added to the residue and the mixture was centrifuged and the supernatant was decanted. This procedure was repeated until the supernatant became nearly colorless. About 5 mL of water:acetonitrile (3:2) mixture was added to the solid residue and lyophilized to obtain about 2 g of dark green flakes. The purity of the compound was established with 1 H-NMR, HPLC, and LC-MS.
EXAMPLE 7
Synthesis of Polyhydroxyindole Sulfonate
FIG. 3 , Compound 13, Y 7 , Y 8 =O 3 − ; X 7 =OH; n=2
Phosphorus oxychloride (37 ml, 0.4 mole) was added dropwise with stirring to a cooled (−2° C.) mixture of dimethylformamide (DMF, 0.5 mole, 40 mL) and dichloromethane (DCM, 40 mL), followed by the addition of acetone (5.8 g, 0.1 mole). The ice bath was removed and the solution refluxed for 3 hours. After cooling to room temperature, the product was either partitioned in water/DCM, separated and dried, or was purified by fractional distillation. Nuclear magnetic resonance and mass spectral analyses showed that the desired intermediate, 10, was obtained. Reaction of the intermediate with 2 equivalents of 2,2,3-trimethyl-[H]-benz[e]indolesulfonate-N-propanoic acid and 2 equivalents of sodium acetate trihydrate in ethanol gave a blue-green solution after 1.5 hours at reflux. Further functionalization of the dye with bis(isopropylidene)acetal protected monosaccharide is effected by the method described in the literature (J. H. Flanagan, C. V. Owens, S. E. Romero, et al., Near infrared heavy - atom - modified fluorescent dyes for base - calling in DNA - sequencing application using temporal discrimination. Anal. Chem ., 1998, 70(13), 2676-2684).
EXAMPLE 8
Synthesis of Polyhydroxyindole Sulfonate
FIG. 4 , Compound 16, Y 7 , Y 8 =SO 3 − , X 7 =H; n=1
Preparation of this compound was readily accomplished by the same procedure described in Example 6 using p-hydroxybenzenesulfonic acid in the place of the monosaccharide, and benzoindole instead of indole derivatives.
EXAMPLE 9
Synthesis of Polyhydroxyindole Sulfonate
FIG. 5 , Compound 20, Y 7 , Y 8 =H; X 7 =OH; n=1
The hydroxyindole compound was readily prepared by a literature method (P. L. Southwick, J. G. Cairns, L. A. Ernst, and A. S. Waggoner, One pot Fischer synthesis of (2,3,3-trimethyl-3-H-indol-5-yl)-acetic acid derivatives as intermediates for fluorescent biolabels. Org. Prep. Proced. Int. Briefs , 1988, 20(3), 279-284). Reaction of p-carboxymethylphenylhydrazine hydrochloride (30 mmol, 1 equiv.) and 1,1-bis(hydroxymethyl)propanone (45 mmol, 1.5 equiv.) in acetic acid (50 mL) at room temperature for 30 minutes and at reflux for 1 gave (3,3-dihydroxymethyl2-methyl-3-H-indol-5-yl)-acetic acid as a solid residue.
The intermediate 2-chloro-1-formyl-3-hydroxymethylenecyclohexane was prepared as described in the literature (G. A. Reynolds and K. H. Drexhage, Stable heptamethine pyrylium dyes that absorb in the infrared. J. Org. Chem ., 1977, 42(5), 885-888). Equal volumes (40 mL each) of dimethylformamide (DMF) and dichloromethane were mixed and the solution was cooled to −10° C. in acetone-dry ice bath. Under argon atmosphere, phosphorus oxychloride (40 mL) in dichloromethane was added dropwise to the cool DMF solution, followed by the addition of 10 g of cyclohexanone. The resulting solution was allowed to warm up to room temperature and heated at reflux for 6 hours. After cooling to room temperature, the mixture was poured into ice-cold water and stored at 4° C. for 12 hours. A yellow powder was obtained. Condensation of a portion of this cyclic dialdehyde (1 equivalent) with the indole intermediate (2 equivalents) was carried out as described in Example 5. Further, the functionalization of the dye with bis (isopropylidene)acetal protected monosaccharide was effected by the method described in the literature (J. H. Flanagan, C. V. Owens, S. E. Romero, et al., Near infrared heavy - atom - modified fluorescent dyes for base - calling in DNA - sequencing application using temporal discrimination. Anal. Chem ., 1998, 70(13), 2676-2684).
EXAMPLE 10
Synthesis of Polyhydroxylbenzoindole Sulfonate
FIG. 6 , Compound 22, Y 7 , Y 8 =H; X 7 =OH; n=1
A similar method described in Example 8 was used to prepare this compound by replacing the indole with benzoindole derivatives.
EXAMPLE 11
Synthesis of Rigid Heteroatomic Indole Sulfonate
FIG. 7 , Compound 27, Y 7 , Y 8 , X 7 =H; n=1
Starting with 3-oxo-4-cyclohexenone, this heteroatomic hydrophilic dye was readily prepared as described in Example 8.
EXAMPLE 12
Minimally Invasive Monitoring of the Blood Clearance Profile of the Dyes
A laser of appropriate wavelength for excitation of the dye chromophore was directed into one end of a fiber optic bundle and the other end was positioned a few millimeters from the ear of a rat. A second fiber optic bundle was also positioned near the same ear to detect the emitted fluorescent light, and the other end was directed into the optics and electronics for data collection. An interference filter (IF) in the collection optics train was used to select emitted fluorescent light of the appropriate wavelength for the dye chromophore.
Sprague-Dawley or Fischer 344 rats were anesthetized with urethane administered via intraperitoneal injection at a dose of 1.35 g/kg body weight. After the animals had achieved the desired plane of anesthesia, a 21 gauge butterfly with 12″ tubing was placed in the lateral tail vein of each animal and flushed with heparinized saline. The animals were placed onto a heating pad and kept warm throughout the entire study. The lobe of the left ear was affixed to a glass microscope slide to reduce movement and vibration.
Incident laser light delivered from the fiber optic was centered on the affixed ear. Data acquisition was then initiated, and a background reading of fluorescence was obtained prior to administration of the test agent.
The compound was administered to the animal through a bolus injection in the lateral tail vein. The dose was typically 0.05 to 20 μmole/kg of body weight. The fluorescence signal rapidly increased to a peak value, then decayed as a function of time as the conjugate cleared from the bloodstream.
This procedure was repeated with several dye-epetide conjugates in normal and tumored rats. Representative profiles are shown in FIGS. 6-10 .
While the invention has been disclosed by reference to the details of preferred embodiments of the invention, it is to be understood that the disclosure is intended in an illustrative rather than in a limiting sense, as it is contemplated that modifications will readily occur to those skilled in the art, within the spirit of the invention and the scope of the appended claims. | Highly hydrophilic indole and benzoindole derivatives that absorb and fluoresce in the visible region of light are disclosed. These compounds are useful for physiological and organ function monitoring. Particularly, the molecules of the invention are useful for optical diagnosis of renal and cardiac diseases and for estimation of blood volume in vivo. | 2 |
AREA OF THE INVENTION
[0001] This invention relates compositions and methods for preventing or reducing the onset of symptoms of pulmonary diseases, or treating or reducing the severity of pulmonary diseases. In particular it relates to compositions and methods for treating pulmonary diseases mediated by phosphodiesterase 4 (PDE4) by administering a PDE4 inhibitor with other pharmaceutically active agents which affect pulmonary function.
BACKGROUND OF THE INVENTION
[0002] Identification of novel therapeutic agents for treating pulmonary diseases is made difficult by the fact that multiple mediators are responsible for the development of the disease. Thus, it seems unlikely that eliminating the effects of a single mediator could have a substantial effect on all three components of chronic asthma. An alternative to the “mediator approach” is to regulate the activity of the cells responsible for the pathophysiology of the disease.
[0003] One such way is by elevating levels of cAMP (adenosine cyclic 3′,5′-monophosphate). Cyclic AMP has been shown to be a second messenger mediating the biologic responses to a wide range of hormones, neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973]. When the appropriate agonist binds to specific cell surface receptors, adenylate cyclase is activated, which converts Mg +2 -ATP to cAMP at an accelerated rate.
[0004] Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of cAMP would produce beneficial effects including: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation. Hence, compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells. The principal cellular mechanism for the inactivation of cAMP is hydrolysis of the 3′-phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs).
[0005] It has been shown that a distinct cyclic nucleotide phosphodiesterase (PDE) isozyme, PDE IV, is responsible for cAMP breakdown in airway smooth muscle and inflammatory cells. [Torphy, “Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmatic Agents” in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989]. Research indicates that inhibition of this enzyme not only produces airway smooth muscle relaxation, but also suppresses degranulation of mast cells, basophils and neutrophils along with inhibiting the activation of monocytes and neutrophils. Moreover, the beneficial effects of PDE IV inhibitors are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as would be the case in vivo. Thus PDE IV inhibitors would be effective in the lung, where levels of prostaglandin E 2 and prostacyclin (activators of adenylate cyclase) are elevated. Such compounds would offer a unique approach toward the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on the market.
[0006] In addition, it could be useful to combine therapies in light of the fact that the etiology of many pulmonary diseases involves multiple mediators. In this invention there is presented the combination of a PDE 4 inhibitor and an inhaled long-acting beta agonist for treating pulmonary diseases, particularly COPD or asthma.
SUMMARY OF THE INVENTION
[0007] In a first aspect this invention relates to a method for treating a pulmonary disease by administering to a patient in need thereof an effective amount of a PDE 4 inhibitor and a long-acting beta adrenergic bronchodilator either in a single combined form, separately, or separately and sequentially where the sequential administration is close in time, or remote in time.
[0008] In a second aspect this invention relates to a composition for treating a pulmonary disease comprising an effective amount of a PDE4 inhibitor, an effective amount of a long-acting beta adrenergic bronchodilator and a pharmaceutically acceptable excipient.
[0009] In a third aspect this invention relates to a method for preparing a composition which is effective for preventing the symptoms of treating a pulmonary disease which method comprises mixing an effective amount of a PDE4 inhibitor and a long-acting beta adrenergic bronchodilator with a pharmaceutically acceptable excipient.
DETAILED DESCRIPTION OF THE INVENTION
[0010] The combination therapy contemplated by this invention comprises administering a PDE4 inhibitor with a long-acting beta adrenergic bronchodilator to prevent onset of a pulmonary disease event or to treat an existing condition. The compounds may be administered together in a single dosage form. Or they may be administered in different dosage forms. They may be administered at the same time. Or they may be administered either close in time or remotely, such as where one drug is administered in the morning and the second drug is administered in the evening. The combination may be used prophylactically or after the onset of symptoms has occurred. In some instances the combination(s) may be used to prevent the progression of a pulmonary disease or to arrest the decline of a function such as lung function.
[0011] The PDE4 inhibitor useful in this invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act in as PDE4 inhibitor, and which are only PDE4 inhibitors, not compounds which inhibit other members of the PDE family as well as PDE4. Generally it is preferred to use a PDE4 antagonists which has an IC 50 ratio of about 0.1 or greater as regards the IC 50 for the PDE IV catalytic form which binds rolipram with a high affinity divided by the IC 50 for the form which binds rolipram with a low affinity.
[0012] PDE inhibitors used in treating inflammation and as bronchodilators, drugs like theophylline and pentoxyfyllin, inhibit PDE isozymes indiscriminently in all tissues. These compounds exhibit side effects, apparently because they non-selectively inhibit all 5 PDE isozyme classes in all tissues. The targeted disease state may be effectively treated by such compounds, but unwanted secondary effects may be exhibited which, if they could be avoided or minimized, would increase the overall therapeutic effect of this approach to treating certain disease states. For example, clinical studies with the selective PDE 4 inhibitor rolipram, which was being developed as an antidepressant, indicate it has psychotropic activity and produces gastrointestinal effects, e.g., pyrosis, nausea and emesis.
[0013] It turns out that there are at least two binding forms on human monocyte recombinant PDE 4 (hPDE 4) at which inhibitors bind. One explanation for these observations is that hPDE 4 exists in two distinct forms. One binds the likes of rolipram and denbufylline with a high affinity while the other binds these compounds with a low affinity. The preferred PDE4 inhibitors of for use in this invention will be those compounds which have a salutary therapeutic ratio, i.e., compounds which preferentially inhibit cAMP catalytic activity where the enzyme is in the form that binds rolipram with a low affinity, thereby reducing the side effects which apparently are linked to inhibiting the form which binds rolipram with a high affinity. Another way to state this is that the preferred compounds will have an IC 50 ratio of about 0.1 or greater as regards the IC 50 for the PDE 4 catalytic form which binds rolipram with a high affinity divided by the IC 50 for the form which binds rolipram with a low affinity. Examples of such compounds are:
[0014] Papaverine—1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxyisoquinoline;
[0015] Trequinsin—2,3,6,7-tetrahydro-2-(mesitylimino)-9,10-dimethoxy-3-methyl-4H-primido[6,1-α]isoquinoline-4-one;
[0016] Dipyrimadole—the generic name for 2,2′,2″,2′″-[(4,8-dipiperidinopyrimido[5,4-d]pyrimidine-2-6-diyl)dinitrilo]tetraethanol;
[0017] (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone;
[0018] (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone,
[0019] 3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N2-cyano-S-methylisothioureido]benzyl)-2-pyrrolidone,
[0020] cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylate];
[0021] cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol];
[0022] (R)-(+)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate;
[0023] (S)-(−)-ethyl [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate,
[0024] Most preferred are those PDE4 inhibitors which have an IC 50 ratio of greater than 0.5, and particularly those compounds having a ratio of greater than 1.0. Preferred compounds are trequinsin, dipyridamole, and papaverine. Compounds such as cis-[cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylate], 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one, and cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol] are examples of structures which bind preferentially to the low affinity binding site and which have an IC 50 ratio of 0.1 or greater.
[0025] Reference is made to co-pending U.S. application Ser. No. 08/456,274 filed May 31, 1995 and its parent a PCT application published Jan. 5, 1995 as W)95/00139 for a methods and techniques which can be used to identify compound which have a high/low IC 50 ratio of 0.1 or greater as referred to in the proceeding paragraph. This co-pending application, U.S. Ser. No. 08/456,274 is incorporated herein by reference as if set out in full herein.
[0026] The several specific compounds set out above which do not have a generic or trade name can be made by the processed described in co-pending U.S. patent applications U.S. Ser. No. 862,083 filed Oct. 30, 1992; U.S. Ser. No. 862,111 filed Oct. 30, 1992; U.S. Ser. No. 862,030 filed Oct. 30, 1992; and U.S. Ser. No. 862,114 filed Oct. 30, 1992 or their progeny or U.S. patent(s) claiming priority from one or more of these applications. Each of these applications or related patents is incorporated herein by reference in full as if set out in this document.
[0027] The beta adrenergic bronchodilator, β 2 -adrenergic agonists really, used in this invention will be a long-acting compound. Any compound of this type can be used in this combination therapy approach. By long-lasting it is meant that the drug will have an affect on the bronchi that lasts around 6 hours or more, up to 12 hours in some instances. To illustrate, certain resorcinols such as metaproterenol, terbutaline, and fenoterol can be combined with a PDE4 inhibitor in the practice of this invention. Further examples of useful beta adrenergic bronchodilators is the likes of two structurally related compounds, albuterol {racemic (∝ 1 -[(t-butylamino)methyl]-4-hydroxy-m-xylene-∝, ∝′-diol)} and formoterol {(R*, R*)-(±)N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]ethyl]phenyl]formamide}.
[0028] Metaproterenol is the subject of U.S. Pat. No. 3,341,594 and is commercially available under the trade names of Alotec, Alupent, Metaprel or Novasmasol. Terbutaline is described in U.S. Pat. No. 3,938,838 and is available commercially as Brethine from Novartis. The preparation of fenoterol is described in U.S. Pat. No. 4,341,593. It is sold under several trade names, including Airum, Berotec, Dosberotec and Partusisten. Albuterol is sold under the trademark Proventil® by Schering Corporation. Formoterol is described in U.S. Pat. No. 3,994,974 and is available commercially under the names Atock and Foradil.
[0029] A preferred combination therapy is that of formoterol and cis-[cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylate].
[0030] These drugs, the beta agonists, are usually administered as an oral or nasal spray or aerosol, or as an inhaled powder. Usually these drugs are not administered systemically or by injection. The PDE4 inhibitors can be administered orally or by inhalation (orally or internasally) This invention contemplates either co-administering both drugs in one delivery form such as an inhaler, that is putting both drugs in the same inhaler. Alternatively one can put the PDE4 inhibitor into pills and package them with an inhaler that contains the beta agonist. Formulations are within the skill of the art.
[0031] It is contemplated that both active agents would be administered at the same time, or very close in time. Alternatively, one drug could be taken in the morning and one later in the day. Or in another scenario, one drug could be taken twice daily and the other once daily, either at the same time as one of the twice-a-day dosing occurred, or separately. Preferably both drugs would be taken together at the same time.
[0032] The foregoing statements and examples are intended to illustrate the invention, not to limit it. Reference is made to the claims for what is reserved to the inventors hereunder. | This invention relates to treating pulmonary diseases such as chronic obstructive pulmonary disease or asthma by administering a phosphodiesterase 4 inhibitor in combination with beta adrenergic bronchodilator. | 0 |
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application No. 61/581,784, filed Dec. 30, 2011, the disclosure of which is hereby incorporated by reference in its entirety.
FIELD
[0002] The field of this disclosure relates generally to air intake systems for aircraft and related methods, and more particularly, to heated screens and anti-icing systems for aircraft engine air intakes.
BACKGROUND
[0003] This section is intended to introduce various aspects of art that may be related to various aspects of the present disclosure, which are described and/or claimed below. This discussion should be helpful in providing background information to facilitate a better understanding of the various aspects of the present invention. These statements are to be read in this light, and not as admissions of prior art.
[0004] An engine for aircraft propulsion requires intake air that is free from contaminants to provide for efficient combustion and avoid damage to internal engine components. Some known compressors and turbines are designed with small clearances between moving parts that maximize efficiency, but which also increase vulnerability to damage of engine parts from small foreign particles. Contamination of intake air, even in a small amount, may cause premature wear on engine components, increases maintenance costs, and degrades operational performance and reliability. Aircraft are exposed to contaminants when operating at low altitudes where air is frequently contaminated with material from the ground, such as sand and dust. This problem may be worse for helicopters and for tiltrotor aircraft due to rotor downwash and prolonged low-altitude operation. This problem may also be worse for fixed wing aircraft operating from unimproved airfields. Aircraft, including tiltrotor aircraft, also have a higher operating altitude than conventional helicopters and are thereby more frequently exposed to icing conditions in flight. Such conditions can cause ice to form in and around the engine intake, and this ice may damage the engine if allowed to enter the engine. A better system for preventing ice and contaminants from entering the engine is needed.
SUMMARY
[0005] In one aspect, an aircraft includes a fuselage and wings mounted on opposite sides of the fuselage for sustained forward flight. An engine is mounted in the fuselage or at least one of the wings and includes an air intake. At least a portion of the air intake generally faces the forward direction for receiving intake air during forward flight. A filter assembly is mounted adjacent the air intake and disposed to impinge air and block objects from passing therethrough. A heated screen includes a heater embedded therein and is mounted adjacent the air intake and upstream of the engine such that ice entering the air intake contacts the heated screen before entering the engine. A power source is provided to supply power to the heater.
[0006] In another aspect, a filter and anti-icing system for an air intake of an aircraft engine includes a filter assembly disposed to impinge air and block objects from passing therethrough. A heated screen is mounted adjacent the filter such that ice contacts the screen before entering the engine. The heated screen includes a heat conducting plate embedded therein. A power source is provided to supply power to the heater.
[0007] Various refinements exist of the features noted in relation to the above-mentioned aspects. Further features may also be incorporated in the above-mentioned aspects as well. These refinements and additional features may exist individually or in any combination. For instance, various features discussed below in relation to any of the illustrated embodiments may be incorporated into any of the above-described aspects, alone or in any combination.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] The drawings are not to scale and certain features may be exaggerated for ease of illustration.
[0009] FIG. 1 is a perspective view of an aircraft (V-22) according to one embodiment of the present disclosure.
[0010] FIG. 2 is a perspective view of an engine of the aircraft of FIG. 1 .
[0011] FIG. 3 is a cross-section of an engine intake area of the engine of FIG. 2 .
[0012] FIG. 4 is an enlarged view of a portion of FIG. 3 .
[0013] FIG. 5 is a front view of another aircraft (C-130) according to another embodiment.
[0014] FIG. 6 is a front view of still another aircraft (C-17) according to another embodiment.
[0015] FIG. 7 is a front view of yet another aircraft according to another embodiment.
DETAILED DESCRIPTION
[0016] FIG. 1 illustrates an embodiment of an aircraft 100 , and in this embodiment, the aircraft is a tiltrotor aircraft, such as a V-22 Osprey, though other aircraft or helicopters may use the systems of the present disclosure. For example, other aircraft may include those similar to a C-130 (aircraft 200 in FIG. 5 ), or a C-17 (aircraft 300 in FIG. 6 ), or a tri-jet (aircraft 400 in FIG. 7 ). Other engine configurations, including single engine aircraft and aircraft with nose-mounted engines, are contemplated within the present disclosure. Note that embodiments of this disclosure may be advantageous for nose-mounted engines due to the proximity of the intake to the ground.
[0017] Aircraft 100 in FIG. 1 generally includes a fuselage 102 , wings 103 , rotor blades 104 , and an aircraft engine 106 mounted in a nacelle 107 . The tiltrotor aircraft is configured such that the rotation axis of each rotor blade is independently and sequentially tiltable between a generally vertical position for generally vertical flight and a generally horizontal position for forward flight. The engine may be, for example, a turbine engine, a piston engine, or another type of engine suitable for causing rotation of rotor blades 104 and thereby providing thrust for the aircraft 100 . The fuselage 102 defines a forward direction 108 , as designated in FIG. 1 . Each aircraft engine 106 includes an intake 110 for receiving air through a main opening 111 of the nacelle 107 for receiving air flow for use by the aircraft engine in a combustion process. It should be appreciated that other embodiments may include a different number of intakes for receiving intake air usable in a combustion process. In this embodiment, intake 110 is shown facing generally upward for hovering or vertical takeoff. Once in flight, the engine and rotor are capable of tilting forward so that the main axis of the engine is parallel to the forward direction 108 for forward movement or flight of aircraft 100 . In forward flight, intake air flows into the main opening 111 ( FIGS. 2-3 ) and then into the intake 110 .
[0018] As illustrated in FIG. 3 , each nacelle of the aircraft 100 includes filter system 112 (one filter system for each intake) including filter media 124 . It should be appreciated that other embodiments may include a different number of filter assemblies. Prior filter systems for aircraft include those shown in co-assigned U.S. Pat. Nos. 6,595,742; 6,824,582; 7,192,462; 7,491,253; and 7,575,014, all of which are incorporated herein by reference.
[0019] An exemplary filter system 112 is illustrated in FIGS. 2-4 . Each of the filter systems 112 is adjacent a respective one of the intakes 110 . Intake air passes through the filter system 112 prior to entering the air intake 110 of aircraft engine 106 . In other words, the filter system 112 is disposed to impinge air and block objects from entering the intake 110 . The filter system 112 is structured to filter intake air to remove containments therefrom, prior to permitting the intake air to enter the air intake 110 of the aircraft engine 106 .
[0020] Filter system 112 extends around the nacelle 107 forward of the engine inlet. The filter assembly 114 generally defines a substantially annular cross-section. More particularly, in this example embodiment, the filter system 112 defines a cylindrical filter assembly, as shown in FIG. 3 . In this embodiment, the filter assembly is substantially conformal to the contour of the nacelle to reduce or eliminate potential drag on the aircraft caused by the filter system, and thereby minimize or eliminate any “performance penalty” caused by the system.
[0021] The filter system 112 includes filter media 124 disposed at least partially about a circumference of the filter assembly 114 for removing contaminants from intake air entering the interior through the filter media 124 . A variety of configurations (e.g., size, shape, number of elements, orientation, etc.) of filter media 124 may be included in filter system embodiments. In this embodiment, filter media may include two or more filter elements. The filter elements are configured to remove particles from the intake air, as described in the patents referenced above, including sand, dust, or other particles which may be prevalent in various operating environments for aircraft 100 .
[0022] A suitable bypass of this embodiment includes a door or valve 126 disposed generally forward of the filter assembly 114 and intake 110 . In this embodiment, the valve is a butterfly valve pivotable about a pivot pin 127 mounted laterally or transverse to the flow of air into the nacelle 107 and into the intake 110 . An actuator (not shown) is operable to move or pivot the valve from a closed position for directing air through the filter assembly, to an open position for allowing unfiltered air to enter the intake 110 directly, without filtering the air. When closed and the engine is operating, the bypass inhibits unfiltered air from entering the engine, e.g., when the aircraft is hovering, or when the aircraft is near the ground. The bypass may be such that it substantially seals out air and thereby prevents unfiltered air from entering the engine. It is also contemplated that the bypass may have partially opened/closed positions to allow some unfiltered air into the intake 110 .
[0023] Referring to FIGS. 3 and 4 , a de-icing or anti-icing system includes a heated screen 130 for reducing or eliminating ice in the engine intake area (e.g., when the engine is in operation). The screen 130 is mounted in the nacelle 107 of the aircraft 100 . The heated screen 130 includes a plate 132 with holes 134 therethrough and a heater 136 (e.g., a heating element, a heat conducting plate or conductive element). In this embodiment, the plate 132 is made of a composite material. More particularly, the plate 132 includes a composite matrix, which may include carbon fiber. The plate 132 may suitably be made using a resin transfer molding (RTM) process with interlaying or interwoven heating elements, or made of an interlayered RTM. Alternatively, the plate 132 may include a heated metal plate or metal screen. The heater 136 may suitably be embedded between adjacent layers of composite material. As shown, the heater 136 is disposed about midway through the composite matrix, and extends substantially the entire length of the plate. The heater 136 is electrically connected to a power source for powering the heater, and may be connected to a controller as described below.
[0024] As shown, the screen 130 is positioned in the nacelle 107 between an inner edge 138 of the nacelle and the intake 110 . The screen of this embodiment is positioned adjacent the filter assembly 114 . In this embodiment, the screen 130 is positioned in the nacelle such that water or ice entering the nacelle must contact the screen before entering the engine when the bypass 126 is closed. The screen 130 is generally annular and in this embodiment is disposed to have an angle, e.g., a diverging angle, from the inner edge 138 of the nacelle to the intake 110 .
[0025] In this embodiment, holes 134 are formed through the plate 132 to allow air or water to flow from an upper surface of the plate to a lower surface. In this way, water can flow from the plate. Because it is water, rather than ice, it will not damage the engine if it passes through to the engine.
[0026] The heated screen 130 of this embodiment includes limited or no fasteners. Among other advantages, the risk of a loose or broken fastener entering the engine intake and damaging the engine is reduced due to the absence of fasteners.
[0027] In some embodiments, a sensor (not shown) on or adjacent the screen detects ice on the screen and/or may detect conditions under which ice is likely to form. For example, the sensor is operable to detect at least one of temperature of the screen or formation of ice on the screen. The aircraft 100 includes a controller (not shown) to control one or more functions of aircraft 100 . The controller may include or be integrated into, for example, an air vehicle computer or controller. The heating element is connected to the controller so that the controller is operable to energize the heating element to inhibit formation of ice on the replacement filter system 112 . In this exemplary embodiment, the heated screen and the sensor thereon are connected to and responsive to the controller 136 . More specifically, in one example, when the sensor signals the controller that there is ice on the screen, the controller activates the heater to thereby melt the ice on the screen or to prevent ice from forming. Note that in other embodiments, a sensor disposed on the aircraft remote from the screen may signal the controller that the aircraft is in icing conditions, and this signal may cause the controller to activate the heater in the screen to avoid ice formation or build-up.
[0028] The heater 136 may include multiple sections that may be powered or activated separately and independently of one another. For example, certain or discrete sections of the heater 136 may be activated, while other sections remain de-activated to conserve power. A controller may be included that selects which sections to activate depending on the conditions. The icing conditions may be indicated to the controller by the above-described sensor or other sensors.
[0029] In use, intake air may enter the interior through the forward opening or through the filter. Water may enter the inside of the nacelle 107 , e.g., through the main opening and collect on the screen 130 . This water that enters the nacelle 107 tends to collect on the screen. When the aircraft is flying in icing conditions, the water may freeze on surfaces of the nacelle 107 , including the screen 130 , and form ice. Or, ice may enter the nacelle through the opening and settle on the screen. In either situation, the heater 136 is activated, either by the controller or by the aircraft operator, to cause melting of any ice formed on the screen.
[0030] When introducing elements of the present invention or the embodiment(s) thereof, the articles “a”, “an”, “the” and “said” are intended to mean that there are one or more of the elements. The terms “comprising”, “including” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements.
[0031] As various changes could be made in the above constructions without departing from the scope of the invention, it is intended that all matter contained in the above description and shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense. | An aircraft includes a fuselage and wings mounted on opposite sides of the fuselage for sustained forward flight. An engine is mounted in the fuselage or at least one of the wings and includes an air intake. At least a portion of the air intake generally faces the forward direction for receiving intake air during forward flight. A filter assembly is mounted adjacent the air intake and disposed to impinge air and block objects from passing therethrough. A heated screen includes a heater and is mounted adjacent the air intake and upstream of the engine such that ice entering the air intake contacts the heated screen before entering the engine. A power source is provided to supply power to the heater. | 1 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to a medical product with a textile component, for example a wound compress, having the features of a multiplicity of openings, with at least two patterns of holes with groups of openings, the diameter of one opening of one hole pattern deviating from the diameter of an opening of another hole pattern in each case by about at least a factor of 5 from one another.
2. Description of the Related Art
In the medical sector, a number of textile products are known which are intended to externally promote wound healing, for example. Known medical products such as wound compresses consist for example of woven fabric, which has the disadvantage that it has a hard surface which adapts poorly to the wound. For this reason, many wound compresses are made up of knitted fabrics which are soft per se. They also have some degree of moisture absorbency. The softness of knitted fabrics arises from the movement of the threads within the interfacing. These abovementioned wound products have the disadvantage that they harden because of exudates emerging from the wound and thus lose their functional ability.
Known compresses have semipermeable membranes of polyurethane which permit the passage and exchange of gases and fluids and have in particular nonadhesive materials on the surface facing the wound in order to prevent them from firmly sticking to the wound. This very type of compress is not able to specifically promote the angiogenesis which is achieved with the surface structure according to the invention. U.S. Pat. No. 5,465,735 describes such a multi-layer wound dressing with a dense nonwoven which is intended in particular to permit less sticking to the wound.
SUMMARY OF THE INVENTION
Further possible uses of medical products with a textile component are, for example, the treatment of abdominal wall defects in the groin area or for strengthening soft tissue in other places. A corresponding technique is described in U.S. Pat. No. 5,569,273 which describes a hexagonal net structure of polypropylene monofilament yarns. Large openings are constructed between adjacent vertical mesh rows, into which body tissue can grow into the implant because of the pore structure. However, this product does not promote angiogenesis.
EP 870 820 discloses a nonadhesive wound dressing which, across its active area, has depressions containing a pharmaceutical carrier substance. The depressions are intended only for receiving and delivering an active substance. The nonadhesion of the wound dressing is emphasized.
Finally, EP 931 012 describes a compress which is used for treating wounds in a moist environment and which, by means of an appropriate choice of dressing material, is likewise intended not to adhere to the wound.
Taking this prior art as a basis, it is an object of the invention to make available a medical product which is of the type set out in the introduction and which specifically influences and promotes angiogenesis and the healing process associated with the latter.
It is also an aim of the invention to ensure that such a medical product also remains soft in its textile component even after prolonged contact with the wound.
A further aim of the invention is to ensure that the rigidness of such a medical product can be preset individually at the time of production.
Finally, it is also a further object of the invention to improve angiogenesis and consequently the tissue regeneration in leg ulcers, for example.
According to the invention, this object is achieved by the fact that the surface has a multiplicity of openings, there being at least two patterns of holes with groups of openings, the diameter of one opening of one hole pattern deviating from the diameter of an opening of another hole pattern in each case by about at least a factor of 5 from one another.
The advantage for the patient of using medical products according to the invention lies in the more rapid wound healing, in the reduction of the pain associated with wound treatment, in the shorter time spent in an inpatient department, and in the fact that the cost of treating such wounds is considerably reduced, which is important to the economy. These advantages are achieved by adapting the structural and mechanical properties of the medical product to the properties of the tissue in question.
In the case of leg ulcers, the main focus of wound healing lies in the regeneration of a physiologically functional vascular system. Wound healing is to be seen in the context of scar tissue formation. An intensive scar tissue formation inconveniences the patient because of the poor cosmetic aspect and in particular because of limited mobility. Both of these lead to personal anxiety and in many cases to disability. When the wound has healed, there is unfortunately connective scar tissue left in which the collagen matrix is reconstructed in compact parallel bundles, whereas the meshwork in undamaged skin has mechanically better properties.
Rapid vascularization can lead to uncontrolled formation of the skin capillary system. The capillaries themselves influence the orientation of the collagen fibers.
Mechanical signals in the form of the exertion of a controlled pull on the cells in the wound bed can represent an important activator of the wound response. Mechanical influences on the wound also play a part in collagen genesis because modified stresses during wound closure influence scarring. It is assumed that in order to form a normal collagen architecture a defined physiological mechanical stimulation is required with respect to loading and orientation. In the case of scar tissue, by contrast, the anisotropy of the collagen network and the dimensions of the collagen fibers are increased.
In contrast to the feature of nonadhesion to the wound bed, on which feature emphasis is placed in the prior art, growth of tissue into the medical article is here desired and advantageous.
The invention makes available a wound treatment system developed on a textile basis which controls tissue formation and positively influences angiogenesis by acting as a framework. The support for the layer according to the invention is dependent on the application. The use of the medical products according to the invention is possible in many areas. One area of use concerns the treatment of large wounds, burns or in surgical applications, for example for hernia meshes. These procedures require treatment systems which make it possible to minimize scar formation. At the same time, it is also possible for the medical products to include mannose-6-phosphate or other collagen-regulating means, or factors which promote tissue regeneration, for example growth factors of the TGF-b family.
The medical product can be used in many applications where the embroidery-specific properties such as the controlled mechanical properties of an embroidery, the local variation in the mechanical design and the specific porosity can be of great advantage. In addition to the stated compresses and hernia meshes, these include abdominal wall replacements, artificial blood vessels and artificial ligaments. In the case of the latter, the embroidery technique can be used to pass from a first specific structure, where the ligament is to grow on and where load transmission takes place, to a second and different structure in the ligament area. A further application is the formation of augmentation embroideries for reconstruction of the jaw bone in the dental sector.
Depending on the desired mechanical and structural properties of the textile, different yarn types are used. These can include fibrous, multifilament or monofilament yarns, which can also be untreated, antimicrobially pretreated, gel-coated and can be present in different titers.
By using embroidery technology, the knot size and the nature of the linking can likewise be preset.
The invention is described in more detail below on the basis of illustrative embodiments.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a diagrammatic cross section through a medical article according to one illustrative embodiment of the invention,
FIG. 2 is a diagrammatic plan view of a portion of the embroidered surface of a medical article according to the invention, and
FIG. 3 is an enlarged sectional view of the area of a pore according to FIG. 2 .
FIG. 1 shows a medical article 1 according to the invention in a diagrammatic cross section. This medical article is made up of three layers, for example. A base layer remote from the wound consists of compact woven fabric 10 which has an antibacterial action. This also controls the oxygen and water content at the same time.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
A spacer layer 11 with high shear force takeup consisting of gel-modified yarns permits absorption and desorption and the mechanical binding of the compress material. The shear force takeup permits the distribution of local pressure loads, that is to say it has a cushion function and permits stress distribution, which leads to uniform loading of the wound surface and thus avoids negative local stresses. Lastly, the compress 1 has an embroidered layer 12 . The fabric 11 is designed as a spacer in relation to the antibacterial layer 10 and as a material which takes up exudate. On this fabric 11 , which is advantageously formed as a knit, lies the separately produced embroidered layer 12 which is preferably connected at its side edges to the compress 1 , for example by ultrasonic welding. Reference number 13 denotes stimulation points which are formed in the layer 12 , particularly in the embroidery technique. In the form represented, they form flat to semi-round protuberances, stimulation points 13 , facing toward the wound surface and they can also protrude from the side facing away from the wound surface. The stimulation points 13 can all be the same size or can differ in size individually or in groups. The word “size” in this case refers both to the height above and below the surface of the embroidery and also to the surface area in the plan view of the figures. Gradients in size can be provided, for example with the stimulation points 13 with the largest surface area and the smallest thickness in the middle of an embroidery, and the stimulation points 13 with the smallest surface area and the greatest thickness at the edges of the embroidery. Any other combination of thicknesses and surface areas can be used.
An embroidered structure 12 and thus an angiopolar layer is thus provided near the wound. An angiopolar layer is a layer which permits the specific oriented growth of blood vessels into a structure and thus influences the density and orientation of the blood vessels in the regenerated tissue. This embroidered structure 12 introduces morphological features into wound treatment which induce and stimulate a specific angiogenesis within the framework and thus form the physiological basis for tissue renewal.
The textile architecture 11 and 12 creates optimum mechanical support, forms a reservoir for exudates and permits optimum control of moisture and gas transport.
With the embroidery technique, highly architectured three-dimensional textile structures are obtained which are needed for structural functions, for example pore pattern, for angiogenesis. The embroidery technique permits any desired use of materials in base fabrics.
FIG. 2 shows a diagrammatic plan view of a portion of the embroidered surface 12 of a medical article 1 according to the invention. The structures designated with reference number 14 are openings which are provided in the embroidered pattern and which are substantially diamond-shaped here. In other configurations, these shapes can also be rectangular, round, elliptic or have another shape.
To positively stimulate angiogenesis, it is particularly advantageous that the openings at the center of the compress 1 have the greatest aperture area and form corresponding cavities. In the illustrative embodiment according to FIG. 2, a gradient is provided with which the diameters 17 of the openings provided decrease from the center to the edges.
The openings 14 are arranged in a regular pattern in the illustrative embodiment shown. The embroidery technology also permits an irregular arrangement of the openings 14 according to further objectives, in particular with a variation in size.
The fabric 11 mentioned with reference to FIG. 1 and lying behind the embroidered surface 12 acts as a spacer and distributes the weight upon loading in order to prevent decubitus ulcers. The predetermined hole cross sections 17 have a size forming a cavity suitable for a blood coagulum. They are therefore a support for the tissue-regenerating element.
The embroidered surface, of which FIG. 3 shows a section of the area of a pore 14 according to FIG. 2, has mesoscopic openings 24 in addition to the apertures or pores 14 .
The macroscopic apertures or pores 14 are produced by a plurality of links and have a size of the order of 1 to 2 millimeters edge length. They serve for ingrowth of tissue plugs and as a reservoir for the blood coagulum from the freshly bleeding wound.
The mesoscopic openings 24 permit ingrowth of individual blood vessel stems and have a size of approximately 100 to 500 micrometers. They are produced by interfacing of two yarn elements.
Also shown here in diagrammatic representation are microscopic openings 34 with a diameter in the range of 5 to 50 micrometers which permit the ingrowth of cells and cell aggregates with capillaries if necessary. These openings 34 are between different filaments.
On a still smaller scale, small cavities in the range of 0.5 to 5 micrometers are present between individual filaments, and only extracellular matrix, for example collagen material, can be deposited in these.
The openings 14 , 24 and 34 form groups of hole patterns. The openings 14 , the openings 24 and the openings 34 are greater or smaller in relation to another group of openings by a factor of approximately at least 5. Within each group the openings can to a certain extent be the same size or can be of different sizes. The distribution can be regular or also random in the sense that a device for embroidering a textile material controls the random distribution of the openings on the whole surface of the textile material with the aid of a random number generator.
Reference number 13 denotes an embroidery point which, in the illustrative embodiment shown, lies between two edges of the diamond-shaped openings 14 . This embroidery point 13 is three-dimensional relative to the drawing plane and thus the plane of the embroidered layer 12 and has in particular a section protruding by 3 to 5 mm. In the illustrative embodiment shown, this is almost semispherical, but can also have other three-dimensional structures.
For example, this embroidery point can also be three-dimensional on the side pointing toward the knitted spacer, in particular in order to form an abutment.
In contrast to known knits, the regular arrangement of the embroidery shown in the figures is not system-related and instead can be changed as desired in accordance with the use on the basis of the embroidery technique. Thus, sequences of large and small apertures 14 are possible. As is shown in FIG. 2, these can have a gradient. The sequence of embroidery points 13 and openings 14 is purely functional and not dictated by the manufacturing technology of the textile fabric.
It is also possible that the apertures or pores 14 are spanned by a continuous thread 18 according to FIG. 3, which for example runs from knot to knot in the embroidery of knots 13 .
The interplay of the different hole sizes of the openings 14 , 24 , 34 favorably influences the ingrowth of blood vessels, so-called angiogenesis. Main growths have a size of 0.5 to 1 mm here. By means of the embroidery points it is possible to create a mechanical stimulation in the wound bed, which affords an advantageous design of the embroidered compress material.
Monofilaments, multifilaments or mixtures of these can be used in the embroidery process. The strength of the embroidery can be determined through the choice of yarn and the specified pattern. An advantage over a knit is that the thread cannot move in the interfacings, that is to say the mechanical properties of the embroidery are defined by the arrangements of the interfacings and are hardly affected by the incorporation of exudate or extracellular matrix into the thread, which leads to the interfacings sticking together. In knits, by contrast, the mechanical properties are mainly defined by the movability of the thread through the open interfacing. Thus, an adhesive exudate leads to an increase in the rigidness of the textile in some circumstances far more than an order of size. This is a considerable disadvantage for the medical product since the mechanical properties which are crucial for its medical functionality can no longer be controlled. Stiffening can cause local loading conditions which can lead to local tissue necrosis.
In addition to the use of the embroidered element on a textile base such as a compress, other possible uses can also be envisaged. This can include the use of the embroidered surface material on a metallic or ceramic base or other wound-treating elements. The embroidery technique makes it possible to produce suitable surface elements for each individual case.
Having described presently preferred embodiments of the invention, it is to be understood that it may be otherwise embodied within the scope of the appended claims. | The present invention relates to a medicinal product with a textile component such as a wound compress having a surface containing a multiplicity of openings arranged in at least two hole patterns. The diameter of one opening of one hole pattern deviates from the diameter of an opening of another hole pattern by about at least a factor of 5. Better wound healing is achieved by adapting the structural and mechanical characteristics of the medicinal product to the characteristics of the target tissue. | 0 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a rotary type injection orientation blow molding machine which can perform operations from injection molding of a preform formed of a synthetic resin to orientation blow molding of a hollow molded article.
2. Description of the Prior Art
The molding machines of this kind include one type in which a rotary disk on the machine bed is held by a base plate secured by a tie bar, and an injection mold is moved with respect to a hold mold on the lower side of the rotary disk to effect clamping, and include another type in which a mold is fixed, and a base plate is moved together with a rotary disk to effect clamping.
In the molding machine of the base plate-fixed type, since the injection mold is vertically moved, the injection apparatus cannot always be placed in nozzle touch with the mold, and it is necessary to move the injection apparatus backward after every completion of injection. Therefore, it takes time for the injection molding, which comprises a bottleneck in improving the molding cycle. Furthermore, both the injection core and mold need be clamped, as a consequence of which a larger clamping device is required.
On the other hand, in the molding machine of the base plate movable type, since the injection mold is fixed, the aforementioned problem can be overcome. However, it is necessary to move the clamping plate provided with the injection core up and down so as not to be delayed in the movement of the base plate, and the moving stroke thereof is larger than in the case of the fixed type. Therefore, it takes time for open and closing the mold, which comprises a bottle-neck in shortening the molding cycle.
OBJECT OF THE INVENTION
This invention has been contemplated in view of the above. An object of the invention to provide, in a molding machine of the type in which the base plate side is moved, a new rotary type injection orientation blow molding machine capable of vertically moving the clamping plate at a high speed.
SUMMARY OF THE INVENTION
According to a first feature of the present invention, there is provided a rotary type injection orientation blow molding machine in which a horizontal base plate is vertically movably provided on a machine bed with required portions of a peripheral edge thereof inserted into tie bars stood standing upright on the machine bed, a transfer plate rotatably mounted on the underside of said base plate and having hold molds at three locations of the lower surface thereof, a drive device located in the central portion in the upper portion of the base plate to intermittently rotate the transfer plate by a predetermined angle, a vertical clamping device and an injection mold with stop positions of said hold molds serving as an injection molding portion, an orientation blow molding portion and a releasing portion, a blow mold and orientation blow device, and a releasing device are provided at predetermined locations on the machine bed or the base plate, wherein a frame for connecting upper ends of said tie bars with each other and a fixed plate downwardly having a clamping cylinder of said clamping device are integrally molded, said fixed plate being secured to the tie bars on both sides of the injection molding portion, a clamping ram is connected to a vertically movable clamping plate inserted into both the tie bars, and a base-plate vertically moving cylinder is provided between a beam member integrally mounted between said machine bed and a peripheral edge of the base plate or between the frame of the tie bars and the fixed plate of the clamping device, and a cover member for the drive device in the central portion of the base plate.
According to a second feature of the present invention, said clamping device comprises a clamping cylinder wherein an inner diameter of an upper chamber is larger than an inner diameter of a lower chamber, the lower chamber is communicated with a parallel charge cylinder on the side of the cylinder and both the chambers are communicated by a bypass provided with a closing valve; a booster ram extended through a central portion of the clamping cylinder, a cylindrical clamping ram having a piston having an outer diameter matched to said lower chamber at the upper end thereof and having said booster ram inserted thereinto, a clamping plate having an injection core at the lower side thereof and vertically movably inserted into the tie bars on the both sides, and a piston rod of the charge cylinder connected to the clamping plate together with said claimping ram.
BRIEF DESCRIPTION OF THE DRAWINGS
The drawings show embodiments of a rotary type injection blow molding machine according to this invention.
FIG. 1 is a plan view of the molding machine, a part of which is cut away;
FIG. 2 is a side view when the mold is opened;
FIG. 3 is a longitudinal sectional side view of an injection molding portion and an orientation blow molding portion during molding;
FIG. 4 is a longitudinal sectional front view of the injection molding portion;
FIG. 5 is a longitudinal sectional side view of an injection molding portion and an orientation blow molding portion when the mold is opened;
FIG. 6 is a longitudinal sectional side view of an injection molding portion and an orientation blow molding portion during molding according to another embodiment; and
FIG. 7 is a partly longitudinal sectional side view of an upper portion of a molding machine according to still another embodiment
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the drawings, reference numeral 1 designates a machine bed, 2 a horizontal base plate above the machine bed, 3 a transfer plate rotatably embraced in the underside of the base plate 2, and 4 a seat plate on the machine bed.
Tie bars 5 are stand vertically upright at four portions of the seat plate 4, and peripheral edges of the base plate are slidably inserted into the tie bars 5. Insert holes are bored in three portions of the transfer plate 3, and hold molds 6 also serving as a mold forming a mouth portion of a preform are radially closeably mounted on the lower surface of the transfer plate at the portions of the insert holes.
A drive device 7 for intermittently rotating the transfer plate 3 every 120° leftwise is provided in the central portion at the upper portion of the base plate. Stop positions of the hold molds 6 of the transfer plate 2 are set to be an injection molding portion, an orientation blow molding portion and a releasing portion, respectively. Core insert portions 8 are bored, and a clamping device 9, an orientation blow device 10 and a releasing device 11 are disposed in order on said portions.
A fixed plate 12 of the clamping device 9 is formed integral with a frame 13 for connecting upper ends of the tie bars 5 to each other, the fixed plate 12 being mounted over the upper ends of a pair of tie bars 5 on the both sides of the injection molding portion. A clamping cylinder 14 is downwardly integrally formed at the upper portion of the fixed plate 12, and a charge cylinder 15 for pressurized oil and a bypass 16 vertically communicated within the clamping cylinder are provided on both sides thereof.
The inner diameter of the upper chamber of the clamping cylinder is larger than the inner diameter of the lower chamber, the lower chamber being communicated with the charge cylinder 15, and a booster ram 18 having a piston inserted into a cylindrical clamping ram 17 is positioned in the central portion therein. A piston 19 of the clamping ram 17 has the outer diameter water-tightly fitted into the lower chamber, and the clamping ram 17 is moved downward due to the pressurized oil within the cylinder according to a difference in pressure receiving area between the upper surface and lower surface of the piston.
The bypass 16 is interiorly provided with a valve 20 which defines upper and lower supply and discharge ports connected to a hydraulic circuit (not shown) if necessary and which opens and closes the bypass (see FIG. 3).
The clamping cylinder 17 and a pair of piston rods 21 of the charge cylinder 15 on the both sides are connected to a clamping plate 22 vertically movably inserted over both the tie bars 5, and an injection core 23 is mounted on the underside of the clamping plate 22.
Reference numeral 24 designates a base-plate vertically moving cylinder. The cylinders 24 are provided on a seat plate externally of the tie bar 5 of the injection molding portion and on a seat plate between the orientation blow molding portion and the releasing portion, and their piston rods 25 are connected to the edge side of the base plate 2.
Reference numeral 26 designates an injection mold, which is secured to a pedestal 29 vertically movably provided by a limit pin 27 and a spring member 28 on the seat plate 4. A lock 31 always placed in nozzle touch with an injection device 30 is secured to the seat plate interiorly of the pedestal 29.
An air or hydraulically operated core insert cylinder 32 and an orientation cylinder 33 are provided on the base plate 2 of the orientation blow molding portion 10, and a blow core 36 interiorly provided with an orientation rod 35 is mounted under a bed plate 34 having a piston rod 32a connected thereto.
A blow mold 37 is provided on the seat plate. The blow mold 37 is radially closeably provided together with a clamping cylinder 41 on a support bed 40 connected to a ram 39 of an air or hydraulically operated elevating device 38 installed underside of the seat plate.
An air or hydraulically operated releasing cylinder 42 is provided on the base plate of the releasing portion 11. Wedge members 45 entered from the base plate and an opening 44 (see FIG. 1) of the transfer plate to force open the hold mold 6 are mounted on both ends of a bed plate 43 connected to a piston rod of the cylinder 42.
Reference numeral 46 designates a preform and 47 denotes a molded article.
In an embodiment shown in FIG. 7, the base-plate vertically moving cylinder 24 is mounted on a beam member 48 integrally mounted over the frame 3 and a central portion on the fixed plate side of the clamping device 9, the piston rod 25 is connected to a cover member 48 of the drive device in the central portion of the base plate, and the base plate 2 is moved up and down in the central portion.
In the molding machine having the construction as described above, when the piston rod 25 of the base-plate vertically moving cylinder 24 is contracted, the base plate 2 together with the transfer plate 3 moves down, and in the injection molding portion, the hold mold 6 is fitted into an upper opening of the cavity of the injection mold 26. In the orientation molding portion 10, the hold mold 6 is positioned at the central portion of the blow mold 37.
When during the downward movement of the base plate 2, pressure oil is supplied from a supply port in the bypass 16 on the side to the clamping cylinder 14, the clamping ram is moved downward due to a difference in pressure received by the piston 19 to downwardly move the injection core 23 together with the clamping plate 22. Since the piston rod 21 of the charge cylinder 15 is pulled downward due to the downward movement of the clamping plate 22, pressure oil within the charge cylinder is delivered from the lower chamber to the clamping cylinder 14. Such a delivery is continued till the piston 19 is fitted into the lower chamber, and the pressure oil within the chamber is fed toward the upper chamber because of presence of a clearance around the piston 19. Therefore, even if pressure oil is present in the lower chamber, it will not act as a resistance, and the clamping ram 17 is moved down at a high speed.
When the piston 19 is fitted into the lower chamber, oil-pressure resistance is produced therein so that the descending speed of the clamping ram 17 slows down. When at that time, the bypass 16 is closed to let pressure oil in the lower chamber escape from a discharge port at the lower portion of the bypass to the hydraulic circuit, the mode is switched to clamping.
During the course of clamping, in the orientation blow molding portion 10, closing and clamping of the blow mold 37 are carried our. Then, this step is shifted to injection molding of the preform 46 and orientation blow molding of the molded article 47.
Upon completion of the molding, the blow mold 37 is opened, and a supply of pressure oil into the clamping cylinder is stopped, and when the bypass 16 is opened to supply pressure oil to the booster ram 18, the clamping ram 17 is moved upward together with the clamping plate 22 by the pressure oil fed under pressure into the clamping ram. At the same time, the piston rod 21 is also forced upward through the clamping plate 22, and therefore, pressure oil within the clamping cylinder is pumped up into the charge cylinder 15 via the bypass 16. Therefore, pressure oil in the upper chamber comprises no resistance so that the clamping ram 17 is moved upward at a high speed.
When the piston 25 of the base-plate vertically moving cylinder 24 is extended in synchronism with the upward movement of the clamping ram 17, the base plate 2 is moved upward together with the transfer plate 3 having the preform 46 held by the hold mold 6, and the injection core 13 is removed during such upward movement.
The difference in level of the injection mold 36 and the blow mold 37 can be adjusted by vertically changing the position of the blow mold 37.
In molding of a short preform 46, a moving stroke of the clamping ram 17 is restricted, and therefore, the injection core 23 is mounted by applying a block 50 having a predetermined thickness to compensate for the stroke to the clamping plate 22.
This invention has a configuration as mentioned above, and even in the case where the base plate is moved upward together with the transfer plate, mold opening can be done at a high speed. Moreover, since the injection device may be always placed in nozzle touch with the injection mold, there is a feature that the molding cycle time is materially shortened. | A rotary type injection orientation blow molding machine. A horizontal plate is vertically movably provided on a machine bed with portions of a peripheral edge thereof inserted into tie bars standing upright on the machine bed. A transfer plate is rotatably mounted on the underside of the base plate and has hold molds at these locations on the lower surface thereof. A drive device located in the central portion in the upper portion of the base plate intermittently rotates the transfer plate by a predetermined angle. A vertical clamping device and an injection mold with stop positons of the hold molds serve as an injection molding portion, an orientation blow molding portion and a releasing portion, respectively, a blow mold and orientation blow device, and a releasing device. | 1 |
FIELD OF THE INVENTION
[0001] The invention relates to imidazonaphthyridine, imidazopyridine and imidazoquinoline compounds that have immune response modulating activity and that contain a dye moiety, in particular, a fluorescent dye moiety. The invention also relates to methods of preparing the dye labeled compounds.
BACKGROUND OF THE INVENTION
[0002] Compounds that are labeled or tagged have long been used in the chemical and biological sciences. Such compounds can be used in a variety of ways. For example, by labeling a compound that is known to be biologically active, one can more readily identify metabolites of the compound, one can determine the binding and/or receptor sites for the molecule, one can determine how long the compound remains in the body or other system, and so on.
[0003] One known way to label compounds is by attaching a dye marker to the compound. This is typically done by grafting a dye moiety onto the biologically active molecule or by incorporating the dye moiety into the biologically active molecule during its synthesis. It is important that the labeled compound retain the critical properties of the unlabeled compound such as selective binding to a receptor or nucleic acid, activation or inhibition of a particular enzyme, or ability to incorporate into a biological membrane. There are a wide variety of dye moieties available, including for example, dipyrrometheneboron difluoride dyes, fluorescein, fluorescein derivatives, rhodamine, rhodamine derivatives and Texas Red.
[0004] The imidazonaphthyridines, imidazopyridines and imidazoquinolines are part of a unique class of immune response modifier compounds that have the ability to induce the biosynthesis of interferon and other cytokines. See, for example, Gerster, U.S. Pat. No. 4,689,338; Gerster et al., U.S. Pat. No. 4,929,624; Gerster, U.S. Pat. No. 5,268,376; Gerster et al., U.S. Pat. No. 5,389,640; Nikolaides et al., U.S. Pat. No. 5,352,784; Lindstrom et al., U.S. Pat. No. 5,494,916.; and International Publication WO 99/29693. Dyes, particularly fluorescent dyes, are typically relatively large, bulky molecules and it is possible that such a large substituent may impair the compound's ability to bind or otherwise interact with the subject cells in a manner that causes biologic response.
SUMMARY OF THE INVENTION
[0005] We have discovered a class of dye labeled imidazonaphthyridine, imidazopyridine or imidazoquinoline compounds that retain their ability to induce cytokines. These compounds employ a spacer group to separate the dye moiety from the active core of the compound so that the bulky dye group does not interfere with the biological activity of the molecule. The compounds of the invention have the generic formula (I):
[0006] wherein:
[0007] R 1 is a spacer group;
[0008] R 2 is hydrogen, alkyl, hydroxyalkyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amidoalkyl, alkylamidoalkyl, dialkylamidoalkyl, alkanoylalkyl, azidoalkyl, carbamoylalkyl, alkyl optionally interrupted by a heteroatom; alkenyl, alkenyloxyalkyl; cycloalkylalkyl, heterocycloalkyl; aryl, aralkyl, aralkenyl, heteroarylalkyl, in which aryl is optionally substituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo, amino, alkylamino or dialkylamino; aroylalkyl, or heteroaroylalkyl;
[0009] R 3 and R 4 are each independently hydrogen, alkyl, alkoxy of 1 to 4 carbon atoms, halo, amino, alkylamino, dialkylamino, or when taken together, R 3 and R 4 form a fused aryl or heteroaryl group that is optionally substituted by one or more substituents selected from alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo, amino, alkylamino, dialkylamino, hydroxy and alkoxymethyl; or
[0010] R 3 and R 4 form a fused 5- to 7-membered saturated ring, optionally containing one or more heteroatoms and optionally substituted by one or more substituents selected from alkyl of 1 to 4 carbon atoms, amino, halo and haloalkyl of 1 to 4 carbon atoms; and
[0011] DYE is a dye moiety, with the proviso that the dye moiety is not dansyl; or a pharmaceutically acceptable acid addition salt thereof.
[0012] The invention additionally provides methods of preparing the dye labeled imidazonaphthyridine, imidazopyridine and imidazoquinoline compounds.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] [0013]FIG. 1 is a histogram plot of the fluorescence intensity from cells incubated with fluorescent dye alone.
[0014] [0014]FIG. 2 is a histogram plot of the fluorescence intensity from cells incubated with a labeled compound of the invention where the label is the dye used in the incubation of FIG. 1.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0015] As mentioned above, the invention provides dye labeled immune response modifying compounds of formula (I):
[0016] wherein:
[0017] R 1 is a spacer group;
[0018] R 2 is hydrogen, alkyl, hydroxyalkyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amidoalkyl, alkylamidoalkyl, dialkylamidoalkyl, alkanoylalkyl, azidoalkyl, carbamoylalkyl, alkyl optionally interrupted by a heteroatom; alkenyl, alkenyloxyalkyl, cycloalkylalkyl, heterocycloalkyl; aryl, aralkyl, aralkenyl, heteroarylalkyl, in which aryl is optionally substituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo, amino, alkylamino or dialkylamino; aroylalkyl, or heteroaroylalkyl;
[0019] R 3 and R 4 are each independently hydrogen, alkyl, alkoxy of 1 to 4 carbon atoms, halo, amino, alkylamino, dialkylamino, or when taken together, R 3 and R 4 form a fused aryl or heteroaryl group that is optionally substituted by one or more substituents selected from by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo, amino, alkylamino, dialkylamino, hydroxy and alkoxymethyl; or
[0020] R 3 and R 4 form a fused 5- to 7-membered saturated ring, optionally containing one or more heteroatoms and optionally substituted by one or more substituents selected from alkyl of 1 to 4 carbon atoms, amino, halo and haloalkyl of 1 to 4 carbon atoms; and
[0021] DYE is dye moiety, with the proviso that the dye moiety is not dansyl; or a pharmaceutically acceptable acid addition salt thereof.
[0022] In this document, the following terms have the meanings assigned to them below unless otherwise noted:
[0023] Alkyl and alkenyl groups contain from 1 to 8 (or 2 to 8) carbon atoms and may be straight chain or branched. Cycloalkyl groups can contain from 3 to 8 ring members and may be optionally substituted by alkyl groups. Heterocyclic groups can contain from 3 to 8 ring members and from 1 to 3 heteroatoms independently selected from O, S, and N.
[0024] Aryl groups are carbocyclic aromatic rings or ring systems. Heteroaryl groups are aromatic rings or ring systems that contain from 1 to 6 heteroatoms independently selected from O, S, and N. A preferred aryl group is benzene. Preferred heteroaryl groups are single rings that have 5 or 6 members and 1 to 4 heteroatoms independently selected from O, S and N.
[0025] Heteroatoms are O, S, or N.
[0026] The term “oyl” is used to indicate the presence of a carbonyl group in the radical. For example, “aroyl” is used to refer to an aromatic group that is attached by a carbonyl group to the remainder of the structure.
[0027] The spacer group is an organic linking group that allows a dye moiety to be attached to an imidazonaphthyridine, imidazopyridine or imidazoquinoline compound without substantially reducing its biological activity. Although the invention is not bound by any theory of operation, it is thought that the spacer group places enough distance between the active core of the molecule and the bulky dye moiety such that the dye moiety does not interfere with the interactions between the active core and the cells that result in cytokine induction. The spacer group can therefore be any divalent organic linking group that does not itself interfere with the biological activity of the molecule and that allows a dye moiety to be included in the molecule without substantially reducing its biological activity. In this context, a compound's biological activity has not been significantly impaired if the labeled compound induces interferon or tumor necrosis factor biosynthesis when tested at a concentration less than or equal to about 50 μg/ml according to Test Method 1 provided below.
[0028] One preferred spacer group has the structural formula (II):
[0029] Preferably, when the spacer group has formula (II) the methylene group that is outside the brackets is attached to the dye moiety.
[0030] Another preferred spacer group has the structural formula (III):
[0031] The dye moiety can be derived from any of the known dyes, particularly fluorescent dyes, with the proviso that the dye moiety is not dansyl. Examples of suitable types of dyes include dipyrrometheneboron difluoride dyes, fluorescein, fluorescein derivatives, rhodamine, rhodamine derivatives and Texas Red. Many dipyrrometheneboron difluoride (4,4-difluoro-4- bora-3a,4a-diaza-s-indacene) dyes are known, see for example, Haugland, et al, U.S. Pat. No. 4,774,339; Kang, et al. U.S. Pat. No. 5,187,288; Haugland et al., U.S. Pat. No. 5,248,782; and Kang et al., U.S. Pat. No. 5,274,113. Many of the dipyrromethenboron difluoride dyes are commercially available from Molecular Probes, Inc., Eugene, Oreg. under the tradename BODIPY® fluorophores. Preferred dye moieties include fluorescein and 4,4-difluoro-5,7dimethyl-4-bora -3a,4a-diaza-s-indacene which has the following structure.
[0032] Preferred compounds of formula (I) include N-[2-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1l-yl)ethyl]-6-[(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-propionyl)amino]hexanoamide which has the following structure:
[0033] 5-{[({4-[4-amino-2-(2-methoxethyl)-1H-imidazo[4,5-c]quinolin- 1-yl]lbutyl}amino) carbonthioyl]amino}-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid which has the following structure:
[0034] and 5-{[({2-[4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}amino) carbonthioyl]amino}-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid which has the following structure:
[0035] Compounds of the invention may be prepared according to the method shown in Reaction Scheme I below. An imidazonaphthyridine, imidazopyridine or imidazoquinoline of Formula IV is reacted with a dye derivative of Formula V to provide a compound of Formula I. R A and R B both contain functional groups which are selected to react with each other. For example, if R A contains a primary amine, then a dye derivative wherein R B contains an acyl azide, aldehyde, anhydride, carbonyl halide, halide, haloacetamide, imido ester, isocyanate, isothiocyanate; maleimide, succinimidyl ester or sulfonyl chloride is selected. R A and R B are selected such that they react to provide the desired spacer group R 1 (e.g., If R A is —CH 2 CH 2 NH 2 and R B is —(CH 2 ) 2 C(O)NH(CH 2 ) 5 COOH then R 1 will be —CH 2 CH 2 NHC(O)(CH 2 ) 5 NHC(O)(CH 2 ) 2 —). Methods for preparing compounds of Formula IV where R A contains a functional group are known. See for example, Gerster, U.S. Pat. No. 4,689,338; Gerster et al., U.S. Pat. No. 4,929,624; Gerster, U.S. Pat. No. 5,268,376; Gerster et al., U.S. Pat. No. 5,389,640; Nikolaides et al., U.S. Pat. No. 5,352,784; Lindstrom et al., U.S. Pat. No. 5,494,916; Andre, et. al, U.S. Pat. No. 4,988,815; Gerster, U.S. Pat. No. 5,367,076; Gerster, U.S. Pat. No. 5,175,296; Nikolaides et. al., U.S. Pat. No. 5,395,937; Gerster et. al., U.S. Pat. No. 5,741,908; Lindstrom, U.S. Pat. No. 5,693,81 1; Nanba et al., U.S. Pat. No. 6,069,149, the disclosures of which are incorporated by reference herein. See also, International Publication WO 99/29693. Many dye derivatives containing a reactive functional group are commercially available (e.g. BODIPY® fluorophores, fluorescein isothiocyanate, 5-carboxyfluorescein) or may be prepared by known synthetic routes. See for example, Haugland, et al, U.S. Pat. No. 4,774,339; Kang, et al. U.S. Pat. No. 5,187,288; Haugland et al., U.S. Pat. No. 5,248,782;and Kang et al., U.S. Pat. No. 5,274,113, the disclosures of which are incorporated by reference herein. The reaction will generally be conducted by combining a solution of the compound of Formula IV in a suitable solvent such as pyridine or dimethyl sulfoxide with a solution of the dye derivative of Formula V in a suitable solvent such as pyridine or dimethylsulfoxide. The reaction may be run at ambient temperature or at an elevated temperature. The product of Formula I is then isolated and purified using conventional methods.
[0036] The examples below are provided to illustrate the invention, but are not intended to limit it in any way.
CYTOKINE INDUCTION IN HUMAN CELLS—TEST METHOD 1
[0037] An in vitro human blood cell system is used to assess cytokine induction by compounds of the invention. Activity is based on the measurement of interferon and tumor necrosis factor (α) (IFN and TNF, respectively) secreted into culture media as described by Testerman et. al. in “Cytokine Induction by the Immunomodulators Imiquimod and S27609”, Journal of Leukocyte Biology, 58, 365-372 (Sep., 1995).
[0038] Blood Cell Preparation for Culture
[0039] Whole blood from healthy human donors is collected by venipuncture into EDTA vacutainer tubes. Peripheral blood mononuclear cells (PBMCs) are separated from whole blood by Histopaque®-1077 (Sigma Chemicals, St. Louis, Mo.) density gradient centrifugation. The PBMCs are washed twice with Hank's Balanced Salts Solution (Sigma) and are then suspended at 2×10 6 cells/mL in RPMI 1640 medium containing 10% fetal bovine serum, 2 mM L-glutamine and 1% penicillin/streptomycin solution (RPMI complete). 1 mL portions of PBMC suspension are added to 12 or 24 well flat bottom sterile tissue culture plates.
[0040] Compound Preparation
[0041] The compounds are solubilized in ethanol, dimethyl sulfoxide or pyrogen free water then diluted with tissue culture water, 0.01N sodium hydroxide or 0.01N hydrochloric acid (The choice of solvent will depend on the chemical characteristics of the compound being tested.). Ethanol or DMSO concentration should not exceed a final concentration of 1% for addition to the culture wells. The compounds are generally tested using a concentration range from about 0.01 μg/mL to about 50 μg/mL.
[0042] Incubation
[0043] The solution of test compound is added to the wells containing 1 ml of PBMCs in media. The plates are covered with plastic lids, mixed gently and then incubated for 24 hours at 37° C. with a 5% carbon dioxide atmosphere.
[0044] Separation
[0045] Following incubation the cell-free culture supernatant is removed with a sterile polypropylene pipet and transferred to a 12×75 mm polypropylene tube. The tubes are then centrifuged at 1000 rpm (˜800 xg) for 10 to 15 minutes at 4° C. The supernatant is removed and placed into 2 mL sterile freezing vials. Samples are maintained at −70° C. until analyzed for cytokines.
[0046] Interferon Analysis/Calculation
[0047] Interferon concentrations are determined by bioassay using A549 human lung carcinoma cells challenged with encephalomyocarditis. The details of the bioassay method have been described by G. L. Brennan and L. H. Kronenberg in “Automated Bioassay of Interferons in Micro-test Plates”, Biotechniques, June/July, 78, 1983, incorporated herein by reference. Briefly stated the method is as follows: A549 cells are incubated with dilutions of IFN standard or test samples at 37° C. for 24 hours. The incubated cells are then infected with an inoculum of * encephalomyocarditis virus. The infected cells are incubated for an additional 24 hours at 37° C. before quantifying for viral cytopathic effect. The viral cytopathic effect is quantified by staining of the wells with a vital dye such as crystal violet followed by visual scoring of the plates. Results are expressed as alpha reference units/mL based on the value obtained for an NIH Human Leukocyte IFN standard.
[0048] Tumor Necrosis Factor (α) Analysis
[0049] Tumor necrosis factor (α) (TNF) concentration is determined using an ELISA kit available from Genzyme, Cambridge, Mass. The results are expressed as pg/ml.
CYTOKINE INDUCTION IN HUMAN CELLS—TEST METHOD 2
[0050] An in vitro human blood cell system is used to assess cytokine induction. Activity is based on the measurement of interferon and tumor necrosis factor (α) (IFN and TNF, respectively) secreted into culture media as described by Testerman et. al. In “Cytokine Induction by the Immunomodulators Imiquimod and S-27609”, Journal of Leukocyte Biology, 58, 365-372 (September, 1995).
[0051] Blood Cell Preparation for Culture
[0052] Whole blood from healthy human donors is collected by venipuncture into EDTA vacutainer tubes. Peripheral blood mononuclear cells (PBMCs) are separated from whole blood by density gradient centrifugation using Histopaque®-1077. The PBMCs are washed twice with Hank's Balanced Salts Solution and then are suspended at 3-4×10 6 cells/mL in RPMI complete. The PBMC suspension is added to 48 well flat bottom sterile tissue culture plates (Costar, Cambridge, Mass. or Becton Dickinson Labware, Lincoln Park, N.J.) containing an equal volume of RPMI complete media containing test compound.
[0053] Compound Preparation
[0054] The compounds are solubilized in dimethyl sulfoxide (DMSO). The DMSO concentration should not exceed a final concentration of 1% for addition to the culture wells. The compounds are generally tested at concentrations ranging from 0.12 to 30 μM.
[0055] Incubation
[0056] The solution of test compound is added at 60 μM to the first well containing RPMI complete and serial 3 fold dilutions are made in the wells. The PBMC suspension is then added to the wells in an equal volume, bringing the test compound concentrations to the desired range (0.12 to 30 μM). The final concentration of PBMC suspension is 1.5-2×10 6 cells/mL. The plates are covered with sterile plastic lids, mixed gently and then incubated for 18 to 24 hours at 37° C. in a 5% carbon dioxide atmosphere.
[0057] Separation
[0058] Following incubation the plates are centrifuged for 5-10 minutes at 1000 rpm (˜200 ×g) at 4° C. The cell-free culture supernatant is removed with a sterile polypropylene pipet and transferred to sterile polypropylene tubes. Samples are maintained at −30 to −70° C. until analysis. The samples are analyzed for interferon (α) and for tumor necrosis factor (α) by ELISA
[0059] Interferon (α) and Tumor Necrosis Factor (α) Analysis by ELISA
[0060] Interferon (α) concentration is determined by ELISA using a Human Multi-Species kit from PBL Biomedical Laboratories, New Brunswick, N.J. Results are expressed in pg/mL.
[0061] Tumor necrosis factor (α) (TNF)concentration is determined using ELISA kits available. from Genzyme, Cambridge, Mass.; R&D Systems, Minneapolis, Minn.; or Pharmingen, San Diego, Calif. Results are expressed in pg/mL.
Preparation of an Unlabeled Compound of Formula IV
[0062] 2-(4-Amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethaneamine trihydrochloride
[0063] Part A
[0064] Thionyl chloride (32.3 mL, 0.4338 mole) and N,N-dimethylformamide (32 mL, 0.4338 mole) were added sequentially to a suspension of 4-hydroxy-3-nitroquinoline (75 g, 0.3944 mole) in dichloromethane (750 ml). The reaction mixture was heated at reflux for about 2½ hours and then held at ambient temperature overnight. The reaction mixture was chilled in an ice bath and then a mixture of triethylamine (82.5 mL, 0.5916 moles) and ethanolamine (35.7 mL, 0.5916 mole) in dichloromethane was slowly added. The reaction mixture was heated at reflux for several hours and then an additional 0.5 equivalents of both triethylamine and ethanolamine were added. The reaction mixture was refluxed for an additional hour then held at ambient temperature overnight. The resulting solid was isolated by filtration, washed first with dichloromethane then with water, and dried to provide 75 g of 2-[(3-nitro-4-quinolinyl)amino]ethanol.
[0065] Part B
[0066] 2-[(3-Nitro4-quinolinyl)amino]ethanol (6 g) was combined with ethanol (200 mL) and platinum on carbon catalyst. The mixture was hydrogenated on a Parr apparatus. This procedure was repeated four additional times using a total of 30 g of starting material. The mixtures from all five hydrogenations were combined and then filtered through a layer of Celite® filter aid to remove the catalyst. The filtrate was concentrated under vacuum to provide crude 2-[(3-amino-4-quinolinyl)amino]ethanol.
[0067] Part C
[0068] The crude material from Part B was combined with ethoxyacetic acid (13.4 g). The mixture was heated using an oil bath until the reaction was complete. The mixture was cooled to ambient temperature and then diluted with water and made basic with sodium hydroxide (6N). The mixture was extracted 3 times with dichloromethane. The extracts were combined, washed with water, dried with magnesium sulfate and then filtered. The filtrate was concentrated under vacuum to provide 30.8 g of crude 2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol.
[0069] Part D
[0070] Peracetic acid (25 mL of 32%) was added to a mixture of the material from Part C and methyl acetate (350 mL). The reaction mixture was heated at 54° C. until thin layer chromatography indicated that all of the starting material had been consumed. The reaction mixture was cooled to ambient temperature. A solid was isolated by filtration, washed with methyl acetate and then dried to provide 28.5 g of 2-ethoxymethyl-1-(2-hydroxyethyl)-1H-imidazo[4,5-c]quinoline 5N oxide (crop 1). The filtrate was concentrated under vacuum. The residue was diluted with aqueous sodium bicarbonate and then extracted 3 times with dichloromethane. The extracts were combined, washed once with aqueous sodium bicarbonate, washed twice with water, dried with magnesium sulfate, filtered and then concentrated under vacuum to provide 1.6 g of additional product (crop 2).
[0071] Part E
[0072] Crops 1 and 2 from Part D were combined and mixed with dichloromethane (600 mL). Concentrated ammonium hydroxide (450 mL) was added. The reaction mixture was cooled in an ice bath and then p-toluenesulfonyl chloride (22 g) was slowly added to the mixture. The reaction mixture was stirred at ambient temperature overnight. Thin layer chromatography indicated the presence of a trace of starting material so 1 g of p-toluenesulfonyl chloride was added and the reaction mixture was stirred for an additional hour. A solid was isolated by filtration, washed with dichloromethane and then dried to provide 20.2 g of crude 4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol. A 1 g portion of this material was dissolved in acetone (about 10 mL). Hydrogen chloride/methanol (1 g/5 mL) was added until the solution became acidic. A precipitate formed immediately. The mixture was heated on a steam bath for 10 minutes. The solid was isolated by filtration, washed with acetone and then recrystallized from methanol/acetone to provide 0.7 g of 4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol hydrochloride as an off-white solid. Analysis: Calculated for C 15 H 19 CIN 4 O: %C, 55.81; %H, 5.93; %N, 17.36; Found: %C, 55.91; %H, 5.90; %N, 17.35.
[0073] Part F
[0074] Thionyl chloride (5 mL) and 4-amino-2-ethoxymethyl-1H-imidaz[4,5-c]quinoline-1-ethanol (1 g) were combined and heated on a steam bath until thin layer chromatography (20% methanol/ethyl acetate) showed the disappearance of starting material. The reaction mixture was cooled to ambient temperature and then slowly poured into a mixture of ice and water. The mixture was neutralized with sodium bicarbonate and then extracted 3 times with dichloromethane. The extracts were combined, washed 3 times with aqueous sodium bicarbonate, dried with magnesium sulfate, filtered and then concentrated under vacuum. Acetone (about 10 mL) was added to the residue followed by methanolic hydrogen chloride (about 1 mL). The mixture was refluxed and a precipitate formed. The reaction mixture was cooled to ambient temperature. The precipitate-was isolated by filtration and then washed with acetone. The solid was dissolved in hot methanol and then precipitated by the addition of acetone. The precipitate was isolated by filtration, washed with water and then dried to provide 1-(2-chloroethyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride. Analysis: Calculated for C 15 H 18 CIN 4 : %C, 52.80; %H, 5.32; %N, 16.42; Found: %C, 52.67; %H, 5.21; %N, 16.29.
[0075] Part G
[0076] Sodium azide (14.7 g) was added to a solution of 1-(2-chloroethyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (22.8 g prepared according to the method of Part F) in N,N-dimethylformamide (75 mL). The reaction mixture was heated at reflux for several hours and then allowed to cool to ambient temperature overnight. The reaction mixture was poured into water (100 ml) and then extracted 3 times with ethyl acetate. The extracts were combined, washed 3 times with water, dried over magnesium sulfate, filtered and then concentrated to dryness under vacuum to provide crude 1-(2-azidoethyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine as an oil.
[0077] Part H
[0078] Platinum on carbon catalyst was added to a solution of the crude material from Part G in ethanol (250 mL). The mixture was reduced on a Parr apparatus. The bottle was evacuated several times to remove nitrogen and the progress of the reaction was monitored by thin layer chromatography. The reaction mixture was filtered through a layer of Celite® filter aid to remove the catalyst and the filter pad was washed with warm ethanol. The filtrate was concentrated under vacuum to provide an oil which was purified by column chromatography (silica gel eluting with methanol/ethyl acetate). An attempt to recrystallize the purified oil produced a precipitate which was isolated by filtration. The filtrate was concentrated under vacuum to provide an oil. The oil was dissolved in ethanol. A portion was removed for later use. The remainder was combined with 10% hydrogen chloride in ethanol and refluxed. The mixture was cooled in an ice bath and then filtered to isolate the resulting solid. The solid was recrystallized from ethanol to provide 2-(4-amino-2-ethoxymethyl- 1H-imidazo[4,5-c]quinolin-1yl)ethaneamine trihydrochloride. Analysis: Calculated for C 15 H 22 Cl 3 N 5 O: %C, 45.64; %H, 5.62; %N, 17.74; Found: %C, 46.14; %H, 5.64; %N, 17.83.
Example 1—Preparation of a Labeled Compound of Formula I
N-[2-(4-Amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-6-[(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-propionyl) amino]hexanoamide
[0079] A solution containing 6-((4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-propionyl)amino)hexanoic acid, succinimidyl ester (5 mg, BODIPY® FL-X,SE from Molecular Probes) dissolved in dimethyl sulfoxide (1 mL) was combined with 2-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethanamine trihydrochloride (2.5 mg). Pyridine (5 drops) was added and the reaction mixture was shaken overnight at ambient temperature. The reaction mixture was purified by high performance liquid chromatography using a Bondapak C 18 12.5 nm reverse phase column (available from Waters, Milford, Mass.) eluting with a composite gradient of acetonitrile in water. In a typical elution, the acetonitrile content was increased from 5% to 30% during the initial 15 minutes, followed by a 10 minute isocratic elution at 30% acetonitrile, a 5 minute gradient to 50% acetonitrile, then a 5 minute isocratic elution at 50% acetonitrile. All solvents contained 0.1% trifluoroacetic acid. The fractions containing the labeled compound were initially identified by comparing chromatograms of the free fluorophore and the unlabeled compound with that of the reaction mixture. The fractions containing the labeled compound were then collected, pooled and lyophilized. The labeled compound had a molecular mass of 672.08 as determined by electrospray mass spectroscopy. The calculated mass is 672.35 based on the proposed empirical formula C 35 H 45 N 8 O 3 BF 2 . The uv-visible absorption spectra showed absorption bands at 505 nm and 325 nm which are characteristic of the fluorescent label and of the unlabeled compound respectively.
[0080] The labeled compound of Example 1 and the unlabeled intermediate (2-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethaneamine trihydrochloride) were tested side by side for their ability to induce cytokine biosynthesis using Test Method 1 described above. The compound of Example 1 was solubilized in ethanol. The unlabeled intermediate was solubilized in tissue culture water. The results are shown in the table below.
Cytokine Induction Labeled Compound Concentration of Example 1 Unlabeled Intermediate (μg/ml) TNF (pg/ml) IFN (U/ml) TNF (pg/ml) IFN (U/ml) 10 Not run Not run 2640 140 3 869 62 538 81 1 369 421 49 2878 0.3 73 2878 0 2878 0.1 46 554 0 421 0.03 42 47 Not run Not run 0.01 0 16 Not run Not run
Flow Cytometry Analysis
[0081] Whole blood was collected by venipuncture into EDTA vacutainer tubes from healthy human donors. PBMCs were separated from whole blood by ficoll hypaque (Sigma Chemicals, St. Louis, Mo.) density gradient centrifugation as described in Testerman. The PBMCs were suspended at 2×10 6 cells/mL in RPMI 1640 medium containing 10% fetal bovine serum, 2 mM L-glutamine and penicillin/streptomycin solution (RPMI complete). The cells were then incubated in 12×75 mm polypropylene tubes for 1 hour at 37° C. with either the labeled compound of Example 1 or with the BODIPY fluorophore used to prepare the labeled compound. Following incubation the cells were washed two times with staining buffer (Dulbecco's Phosphate Buffered Saline without calcium and magnesium, 1% heat inactivated fetal bovine serum, and 0.1% sodium azide). The cells were suspended in staining buffer and transferred to 12×75 mm polystyrene tubes for analysis by flow cytometry. Binding to mononuclear cells was determined by fluorescence using a FACScan flow cytometer (purchased from Becton Dickinson).
[0082] The histograms of FIGS. 1 and 2 plot the fluorescence intensity with the more highly fluorescent cell populations being seen further to the right. The peak area labeled as M3 in the histograms indicates the fluorescence binding to the monocyte population in the peripheral blood mononuclear cells. These monocytes have been shown to be a major cell producing cytokines in response to the imidazoquinolines (Gibson et. al. In “Cellular Requirements for Cytokine Production in Response to the Immunomodulators Imiquimod and S-27609”, Journal of Interferon and Cytokine Research, 15, 537-545 (1995). The histogram of FIG. 1 was obtained from cells incubated with the BODIPY fluorophore. The histogram of FIG. 2 was obtained from cells incubated with the BODIPY labeled compound of Example 1. These histograms demonstrate that the labeled compound of Example 1 binds to human peripheral blood mononuclear cells whereas the BODIPY fluorophore by itself does not and that monocytes bind more effectively than other PBMCs
[0083] The labeled compound of Example 1 did not show significant binding to monocytes when incubated with human PBMCs at 4° C. for 1 hour. A histogram similar to that of FIG. 1 was obtained indicating that binding is likely intracellular.
Preparation of an Unlabeled Compound of Formula IV
4-(4-Amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butaneamine
[0084] Part A
[0085] Phosphorous oxychloride (30 mL, 0.32 mole) was slowly added over a period of 1 hour to a solution of 3-nitroquinolin4-ol (50 g, 0.26 mole) in N,N-dimethylformamide (150 mL). The reaction mixture was heated on a steam bath for half an hour and then poured over a mixture of ice and water. The resulting solid was isolated by filtration and then suspended in chloroform (750 mL). The suspension was heated on a steam bath and then filtered while still hot. The filtrate was poured into a separatory funnel and the chloroform layer was separated from the residual water. Triethylamine (29 mL) was added to the chloroform layer followed by the slow addition of tert-butyl N-(4-aminobutyl)carbamate. The reaction was monitored by thin layer chromatography. When all of the starting material was gone, the reaction mixture was washed with water, dried over magnesium sulfate and then concentrated under vacuum to provide 66 g of 1,1-dimethylethyl N-{4-[(3-nitroquinolin-4-yl)amino]butyl}carbamate as a yellow solid.
[0086] Part B
[0087] Platinum on carbon (3.6 g of 5%) was added to a solution of 1,1-dimethylethyl N-{4-[(3-nitroquinolin-4-yl)amino]butyl}carbamate (36.1 g, 100 mmol) in toluene (1.5 L). The mixture was hydrogenated at 50 psi (3.5 Kg/cm 2 ) for 3 hours. The reaction mixture was filtered through a layer of Celite® filter aid to remove the catalyst. The filtrate was concentrated under vacuum to provide 30.1 g of crude 1,1-dimethylethyl N-{4-[(3-aminoquinolin-4-yl)amino]butyl}carbamate as a gooey orange syrup.
[0088] Part C
[0089] Under a nitrogen atmosphere, a solution of the material from Part B in dichloromethane (1 L) was cooled to 0° C. Triethylamine (13 mL, 93.3 mmol)) was added. Methoxypropionyl chloride (11.5 g, 91.2 mmol) was added over a period of 10 minutes. The ice bath was removed. After 1 hour the reaction mixture was concentrated to provide a pale orange solid. This material was combined with ethanol (1 L) and triethylamine (39 mL). The mixture was heated at about 75° C. overnight. The reaction mixture was allowed to cool to ambient temperature and then it was concentrated under vacuum to provide an oil. The oil was combined with diethyl ether (750 mL), stirred for about 15 minutes and then filtered. The filtrate was concentrated under vacuum to provide 34.5 g of crude 1,1-dimethylethyl N-[4-(2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate as a brown syrup.
[0090] Part D
[0091] Under a nitrogen atmosphere, 3-chloroperbenzoic acid (12.86 g of >77%) was added to a solution of 1,1-dimethylethyl N-[4-(2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate (21.3 g, 53.5 mmol) in dichloromethane (200 mL). The reaction mixture was allowed to stir at ambient temperature overnight. Additional 3-chloroperbenzoic acid (200 mg of >77%) was added. After about 2 hours the reaction mixture was washed with water, aqueous sodium bicarbonate, water and finally with brine. The organic layer was dried over sodium sulfate and then concentrated under nitrogen to provide 22 g of crude 1-{4-[(1,1-dimethylethylcarbonyl)amino]butyl}-2-(2-methoxyethyl)- 1H-irnidazo[4,5-c]quinoline-5N-oxide as a sticky syrup.
[0092] Part E
[0093] Concentrated ammonium hydroxide (˜50 mL) was added to a solution of the material from Part D in dichloromethane (200 mL). Under a nitrogen atmosphere, the reaction mixture was cooled to 0° C. Tosyl chloride (10.2 g, 53.5 mmol) was added with rapid stirring over a period of 10 minutes. The ice bath was removed and the reaction mixture was allowed to stir at ambient temperature. The layers were separated. The organic layer was washed with 1% sodium carbonate (3X), water and brine; dried over sodium sulfate and then concentrated under vacuum to provide 20.0 g of crude 1,1-dimethylethyl N-[4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate as a mustard yellow solid.
[0094] Part F
[0095] A mixture of 1,1-dimethylethyl N-[4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate (18.0 g) and hydrogen chloride/ethanol (40 mL of 2M) was heated to about 70° C. After 90 minutes another 40 mL of hydrogen chloride/ethanol was added. After about an additional hour, the reaction mixture was allowed to cool while being purged with nitrogen to remove excess hydrogen chloride. The reaction mixture was concentrated to near dryness. The residue was triturated with diethyl ether. The resulting solid was isolated by filtration and then dried under high vacuum to provide 15.8 g of the dihydrochloride salt as a light brown solid.
[0096] A portion of the salt (10 g) was dissolved in water. The solution was adjusted to pH 11 by the addition of ammonium hydroxide and then it was extracted several times with chloroform. The extracts were combined and concentrated under vacuum. The residue was slurried with toluene and then concentrated to dryness (3X) to provide 6.6 g of 4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butaneamine as a brown/yellow solid.
Example 2—Preparation of a Labeled Compound of Formula I
5-{[({4-[4-Amino-2-(2-methoxethyl)-1H-imidazo[4,5-c]quinolin- 1-yl]butyl }amino) carbonthioyl]amino}-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic Acid
[0097] A solution of 4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butaneamine (0.11 g, 0.35 mmol) in warm pyridine (2 mL) was slowly added to a solution of fluorescein-5-isothiocyanate (0.138 g, 0.35 mmol) in warm pyridine (2 mL). The reaction mixture was maintained at ambient temperature overnight. The reaction mixture was quenched with methanol (15 mL) and then stirred for an hour. The resulting solid was isolated by filtration, slurried with boiling methanol, and then dried to provide 0.12 g of the desired product, as an orange solid, m.p. >245°. Analysis by both thin layer chromatography and high performance liquid chromatography indicated pure product. Analysis: Calculated for C 38 H 34 N 6 O 6 S: %C, 64.94; %H, 4.88; %N, 11.96; Found: %C, 61.33; %H, 5.09; %N, 11.39. High resolution mass spectroscopy: TM=703.2339 Da., MM=703.2315 Da.
Preparation of an Unlabeled Compound of Formula IV
2-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethaneamine
[0098] Part A
[0099] Triethylamine (66.8 g, 0.66 mmol) was added to a solution of tert-butyl (N-2-aminoethyl)carbamate (55.0 g, 0.34 mmol) in anhydrous dichloromethane (500 mL). 4-Chloro-3-nitroquinoline (68.2 g, 0.33 mmol) was slowly added. The reaction mixture exothermed. The reaction mixture was allowed to stir overnight. The resulting precipitate was isolated by filtration and rinsed with water to provide a yellow solid. The filtrate was washed with water, dried over magnesium sulfate and then concentrated to provide a yellow solid. The two batches of solid were combined, slurried with hexane, filtered and then dried to provide 101 g of 1,1-dimethylethyl N-{2-[(3-nitroquinolin-4-yl)amino]ethyl }carbamate as a yellow solid.
[0100] Part B
[0101] Platinum on carbon (1.0 g of 10%) and sodium sulfate (2 g) were added to a slurry of 1,1-dimethylethyl N-{2-[(3-nitroquinolin-4-yl)amino]ethyl}carbamate (100 g, 0.30 mol) in toluene (500 mL). The reaction vessel was placed on a Parr apparatus under 50 psi (3.5 Kg/cm 2 ) hydrogen pressure overnight at ambient temperature. The reaction mixture was filtered through a layer of Celite® filter aid to remove the catalyst. The filtrate was concentrated under vacuum to provide 73 g of 1,1-dimethylethyl N-{2-[(3-aminoquinolin-4-yl)amino]ethyl}carbamate as a dark gold oil. Thin layer chromatography (silica gel; 10% methanol in dichloromethane) analysis indicated that the material was pure.
[0102] Part C
[0103] Trimethylorthovalerate (5.9 g, 36.4 mmol) was added with stirring to a solution of 1,1-dimethylethyl N-{2-[(3-aminoquinolin-4-yl)amino]ethyl}carbamate (10.0 g, 33.1 mmol) in anhydrous toluene (100 mL). The reaction mixture was heated to reflux. A 10 mL portion of toluene was removed using a Dean Stark trap and the reaction mixture was maintained for 36 hours. An additional 40 mL of toluene was removed and then the reaction was allowed to cool to ambient temperature with continued stirring. The resulting precipitate was isolated by filtration and dried to provide 6.2 g of 1,1-dimethylethyl N-[2-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate as a tan solid. Thin layer chromatography (silica gel; 10% methanol in dichloromethane) analysis indicated that the material was pure.
[0104] Part D
[0105] 3-Chloroperbenzoic acid (5.15 g of 60%, 17.9 mmol) was slowly added with vigorous stirring to a solution of 1,1-dimethylethyl N-[2-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (6.0 g, 16.3 mmol) in chloroform (60 mL). The reaction mixture was maintained at ambient temperature overnight and then it was quenched with aqueous sodium carbonate (250 mL of 1%). The layers were separated. The organic layer was dried over magnesium sulfate and then concentrated under vacuum to provide ˜6.3 g of 1-{2-[(1,1-dimethylethylcarbonyl)amino]ethyl}-2-butyl- 1H-imidazo[4,5-c]quinoline-5N-oxide as a tan foam.
[0106] Part E
[0107] A solution of 1-{2-[(1,1-dimethylethylcarbonyl)amino]ethyl}-2-butyl-1H-imidazo[4,5-c]quinoline-5N-oxide (39 g, 101 mmol) in chloroform (300 mL) was cooled in an ice bath. Trichloroacetyl isocyanate (21 g, 112 mmol) was added with stirring. The reaction mixture was maintained at ambient temperature overnight. The reaction mixture was quenched with concentrated ammonium hydroxide (40 mL) and then stirred at ambient temperature for 4 hours. Water was added to the reaction mixture. The layers were separated. The organic layer was dried over magnesium sulfate and then concentrated under vacuum to provide a gold oil. This material was recrystallized from 90% isopropanol to prove 30.2 g of 1,1-dimethylethyl N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c ]quinolin-1-yl)ethyl]carbamate.
[0108] Part F
[0109] Trifluoroacetic acid (100 mL) was added with stirring to a solution of 1,1 -dimethylethyl N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (30.0 g, 78.2 mmol) in acetonitrile (100 mL). The reaction mixture was maintained at ambient temperature for 24 hours and then it was concentrated under vacuum. The residue was dissolved in a minimal amount of water and the pH of the solution was adjusted to pH 13 using 10% sodium hydroxide. The resulting precipitate was isolated by filtration and dried under high vacuum to provide 18.1 g of 2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethaneamine as an off-white solid, m.p. 196-199° C.
Example 3—Preparation of a Labeled Compound of Formula I
5-{[({2-[4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}amino) carbonthioyl]amino}-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic Acid
[0110] A solution of fluorescein-5-isothiocyanate (778 mg, 2.0 mmol) in pyridine (5 mL) was added to a solution of 2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethaneamine (566 mg, 2.0 mmol) in pyridine (5 mL). The reaction mixture was heated at reflux for 30 minutes and then poured into water (50 mL). The resulting orange solid was isolated by filtration, dried under high vacuum and then recrystallized from pyridine to provide 0.76 g of the desired product as an orange solid, m.p. >245°. Analysis by high performance liquid chromatography indicated pure product. Analysis: Calculated for C 37 H 32 N 6 O 5 S: %C, 66.06; %H, 4.79; %N, 12.49; Found: %C, 63.03; %H, 4.89; %N, 12.59. High resolution mass spectroscopy: TM=673.2233 Da., MM=673.2251 Da.
[0111] The labeled compounds of Examples 2 and 3 were tested for their ability to induce cytokine biosynthesis using Test Method 2 described above. The results are shown in the table below where a “+” indicates that the compound induced the indicated cytokine at that particular concentration and a “−” indicates that the compound did not induce the indicated cytokine at that particular concentration.
Cytokine Induction Concentration Example 2 Example 3 (μg/ml) TNF IFN TNF IFN 30 + + + + 10 + + − + 3.33 + − − − 1.11 − − − − 0.37 − − − − 0.12 − − − − 0.041 − − − − 0.014 − − − − | Dye labeled imidazonaphthyridine, imidazopyridine and imidazoquinoline compounds having immune response modulating activity are disclosed. The compounds are useful, inter alia, for determining the binding and/or receptor sites of the molecules. | 2 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a secondary recovery process for recovering hydrocarbons from a subterranean hydrocarbon-bearing formation penetrated by an injection well and a production well wherein a fluid such as water saturated with a gas is utilized to displace hydrocarbons in the formation toward a production well.
2. Prior Art
The production of petroleum products is usually accomplished by drilling into a hydrocarbon-bearing formation and utilizing one of the well-known recovery methods for the recovery of the hydrocarbons. However, it is recognized that these primary recovery techniques may recover only a minor portion of the petroleum products present in the formation particularly when applied to reservoirs of viscous crudes. Even the use of improved recovery practices involving heating, miscible flooding, water flooding and steam processing may still leave up to 70-80 percent of the original hydrocarbons in place.
Thus, many large reserves of petroleum fluids from which only small recoveries have been realized by present commercial recovery methods, are yet to reach a potential recovery approaching their estimated oil-in-place.
Water flooding is one of the more widely practiced secondary recovery methods. A successful water flood may result in recovery of 30-50 percent of the original hydrocarbons left in place. However, generally the application of water flooding to many crudes results in much lower recoveries.
The newer development in recovery methods for heavy crudes is the use of steam injection which has been applied in several modifications, including the "push-pull" technique and through-put methods, and has resulted in significant recoveries in some areas. Crude recovery of this process is enhanced through the beneficial effects of the drastic viscosity reduction that accompanies an increase in temperature. This reduction in viscosity facilitates the production of hydrocarbons since it improves their mobility, i.e., it increases their ability to flow.
However, the application of these secondary recovery techniques to depleted formations may have major quantities of oil-in-place, since the crude is tightly bound to the sand particles of the formation, that is, the sorptive capacity of the sand for the crude is great. In addition, interfacial tension between the immiscible phases results in entrapping crude in the pores, thereby reducing recovery. Another disadvantage is the tendency of the aqueous drive fluid to finger, since its viscosity is considerably less than that of the crude, thereby reducing the efficiency of the processes. Another disadvantage is the tendency of the aqueous drive fluid to remove additional gas by diffusion from the in-place oil thus further reducing the already lowered formation oil volume and increasing the viscosity of the oil.
This is a definite need in the art for a water flooding process in which the aqueous fluid forced through the formation does not remove gas from the in-place oil.
SUMMARY OF THE INVENTION
This invention relates to a process for recovering hydrocarbons from a subterranean hydrocarbon-bearing formation penetrated by an injection well and a production well which comprises:
a. injecting into the formation via an injection well a driving fluid comprising water saturated at the injection pressure with a gas selected from the group consisting of natural gas, air, carbon dioxide, flue gas, ammonia and mixtures thereof.
b. forcing the said fluid through the formation and
c. recovering hydrocarbons through the production well.
DETAILED DESCRIPTION OF THE INVENTION
Prior to practicing the process of this invention it is sometimes desirable to open up a communication path through the formation by a hydraulic fracturing operation. Hydraulic fracturing is a well-known technique for establishing a communication path between an injection well and a production well. Fracturing is usually accomplished by forcing a liquid such as water, oil or any other suitable hydrocarbon fraction into the formation at pressures of from about 300 to about 3000 psig which are sufficient to rupture the formation and to open up channels therein. By use of this method it is possible to position the fracture at any desired vertical location with respect to the bottom of the oil-filled zone. It is not essential that the fracture planes be horizontally oriented, although it is of course preferable that they be. After the fracture has been established, and without diminishing the fracture pressure, a propping agent may be injected into the fracture in order to prevent healing of the fracture which would destroy its usefulness for fluid flow communication purposes. Gravel, metal shot, glass beads, sand, etc. and mixtures thereof are generally employed as propping agents. Which sand is utilized as the propping agent particles have a Tyler mesh size of from about 8 to about 40 are preferred (i.e., from about 0.016 to about 0.093 inches).
In the next step of the process of this invention the driving fluid is prepared by saturating water with gas such as natural gas, air, carbon dioxide, flue gas, ammonia and mixtures thereof at pressure of about 100 to about 6000 psi and at a temperature of about 40° to about 150° F. Generally the injection pressure will vary from about 300 to about 3000 psig. The temperature of the gas-saturated water injected into the formation via the injection well can likewise be varied over a wide-range and generally will be from about 40° to about 150° F. and preferably from about 70° to about 100° F.
If desired, the driving fluid, that is the gas-saturated water employed may comprise alkaline gas-saturated water or an alkaline, gas-saturated, water composition containing a minor amount of a solubilizing agent. The advantageous results achieved with the aqueous alkaline medium used in the process of this invention are believed to be derived from the wettability improving characteristics of the alkaline agent and when the solubilizing agent is employed it is believed that the advantageous results are derived from the solubilizing action on the crude oil and especially on the asphaltene fractions. The solubilizing agent is believed to be effective in releasing the crude from the pore surface or sand surfaces as the case may be so that the surface can be exposed to the alkaline agent.
Useful alkaline agents include compounds selected from the group consisting of alkali metal hydroxides, alkaline earth metal hydroxides, and a basic salts of the alkaline metal or alkaline earth metals which are capable of hydrolyzing in an aqueous medium to a given alkaline solution. The concentration of the alkaline agent employed is generally from about 0.001 to 0.5 molar. Also, alkaline materials such as sodium hypochlorite are highly effective as alkaline agents. Examples of these especially useful alkaline agents include sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, sodium hypochlorite, sodium carbonate, and potassium carbonate.
A wide variety of solubilizing agents are useful in the process of this invention including water-soluble oxyalkylated, nitrogen-containing aromatic compounds where preferably the initiator, i.e., the aromatic compound, contains not more than 12 carbon atoms and the number of oxyalkyl units is about 5 to about 60. One especially useful group of the water-soluble, oxyalkylated, nitrogen-containing aromatic compounds are those having the formula:
R (OR').sub.a OH,
wherein R is selected from the group consisting of: ##STR1## wherein R' is alkylene of from 2 to 4 inclusive carbon atoms and a is an integer of from about 5 to about 50 and preferably from about 5 to about 20. These novel water-soluble, oxyalkylated products can be conveniently prepared by a number of processes well-known in the art and one method for their preparation is more completely described in U.S. Pat. No. 3,731,741 which is incorporated herein by reference in its entirety.
Another group of solubilizing agents which are highly useful in the process of this invention include block-type oxyalkylated compounds of the formula:
R(OC.sub.3 H.sub.6).sub.b (OC.sub.2 H.sub.4).sub.c OH
a block-type oxyalkylated compound wherein R is selected from the group consisting of: ##STR2## b is from about 3 to about 20, c is from about 10 to about 50 and wherein the sum of b plus c is not more than about 60.
Typical water-soluble, oxyalkylated nitrogen-containing solubilizing agents include ethoxylated-8-hydroxy quinolines of the general formula: ##STR3## wherein a is, for example, 5, 8, 11 or 25. Propoxylated 8-quinoline sulfonic acid compounds of the formula: ##STR4## where a is for example 5, 12, or 14, are also highly useful solubilizing agents.
Another group of water-soluble, oxyalkylated, nitrogen-containing solubilizing agents which are highly useful in the process of this invention include compounds of the formula: ##STR5## wherein R' is alkylene of from 2 to 5 carbon atoms and d is an integer of from about 5 to about 50. All of the water-soluble, oxyalkylated, nitrogen-containing solubilizing compounds set out above can be prepared in the same manner as described in U.S. Pat. No. 3,731,741 which is incorporated herein in its entirety. Typical compounds of this group include: ##STR6##
A wide variety of surfactants such as linear alkylaryl sulfonates, alkyl poly-ethoxylated sulfates, etc. may also be included as a part of the driving fluid composition.
This invention is best understood by reference to the following example which is offered only as an illustrative embodiment of this invention and is not intended to be limitative.
EXAMPLE I
In a field in which the primary production has already been exhausted, an injection well is completed in the hydrocarbon bearing formation and perforations are formed between the interval of 8910-8930 feet. A production well is drilled approximately 405 feet distance from the injection well, and perforations are similarly made in the same hydrocarbon bearing formation at 8915-8935 feet.
The hydrocarbon bearing formation in both the injection well and the production well is hydraulically fractured using conventional techniques, and a gravel-sand mixture is injected into the fracture to hold it open and prevent healing of the fracture.
In the next step water saturated with natural gas at a temperature 60° F. and 5000 psig made alkaline with sodium hypochlorite and containing 0.002 weight percent of a solubilizing agent of the formula: ##STR7## is injected into the formation at this same pressure and at a rate of 1 barrel per minute. Injection of the driving fluid is continued at the rate of 1 barrel per minute and the production of oil via the production well gradually increases. Injection is continued and at the end of 60 days the rate of production is substantially greater than with water injection alone. | Hydrocarbons are recovered from subterranean formations by injecting into a hydrocarbon bearing formation via an injection well a fluid comprising water saturated with a gas such as natural gas, carbon dioxide, etc., forcing the said fluid through the formation and recovering hydrocarbons through a production well. | 2 |
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation in part of application Ser. No. 09/611,464 filed Jul. 7, 2000, now abandoned, entitled: Apparatus and Method for the Manufacture of Rice-Based Food Additive, which is a continuation-in-part of PCT application PCT/US98/25610 filed Dec. 3, 1998 entitled: Apparatus and Method for the Manufacture of Reduced and Low Fat Pasta Filata Cheese which is a continuation-in-part of U.S. application Ser. No. 08/869,114 filed Jun. 4, 1997 entitled: Apparatus and Method for the Manufacture of Reduced and Low Fat Pasta Filata Cheese, now U.S. Pat. No. 5,952,030, all hereby incorporated by reference.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Background of the Invention
The invention relates generally to an ingredient, apparatus and method for the production of high moisture food items, and in particular, to an apparatus and process for incorporating rice-stabilized water into food items including cheese and sausage.
Interest in reduced and low fat foods that nevertheless maintain the mouth feel, and texture of the original foods has led to interest in replacing fat with fat mimetics and increasing the moisture content of these foods so as to dilute fat with water.
The simple introduction of additional water to most products is not successful because of problems of product rheology, water release in storage and changed functionality. For these reasons, gums may be added to stabilize or bind the water in the product. The introduction of substantial amounts of gum may make a product less appealing and some consumers may avoid products with gums in favor of what is considered more “natural” ingredients.
The parent application to the present case describes a method of making of low fat pasta filata cheese by incorporating a water-rice mixture into the cheese at the kneading stage. It was found that this rice mixture allowed significant amounts of moisture to be added to cheese, thereby diluting fat, without adversely affecting the texture for which such cheeses including mozzarella cheese are prized.
The inventors have since discovered that the rice mixture may be used to significantly increase the water content of a variety of foods, not only pasta filata cheeses, but also other cheese and cheese products, sausages and the like. By incorporating and stabilizing water, the food retains its functionality, flavor and texture with reduced fat on a wet basis.
BRIEF SUMMARY OF THE INVENTION
The present invention provides a commercially practical method of high percentage augmentation of the moisture in food products. The invention combines rice grains and heated water and subjects the mixture to high shear to liquefy it without substantial release of water. This mixture is added to the desired food product while in liquefied form.
Although the inventors do not wish to be bound by a particular theory, this high shear method of producing a liquefied rice mixture is believed to preserve the structure of rice necessary to its water holding capacity. Further, this method is readily adapted to large process volumes and may use low cost rice as opposed to more expensive rice flours.
Specifically then, the present invention provides a method of manufacturing an augmented moisture food product using the steps of combining rice grains and heated water in a ratio allowing substantially complete absorption of the water within the rice grains. The mixture is then subjected to a high shear to liquefy the mixture without substantial release of water from the rice and then combined with the low moisture food ingredient.
Thus, it is one object of the invention to provide a natural and low cost method of stabilizing water to be introduced into food products to reduce their fat content or for other purposes.
The step of shearing the mixture of rice may include circulating the rice and water in a vessel with a high shear mixer and pumping the rice and water through a shear pump.
Thus, it is another object of the invention to provide a method of on-site preparation of a rice blend that is amenable to processes where occasional storage and transfer is required. The shear pump may recirculate the rice mixture to keep it liquefied and may be used to easily transport the rice mixture through standard pipes in liquefied form to where it will be needed.
The vessel may have heated walls and the method may include the step of scraping the inner surface of the walls of the heated vessel during the processing of the rice mixture. Thus, it is another object of the invention to provide for a simplified preparation of the rice mixture in a single vessel.
The food ingredient to which the rice mixture is added may be pasta filata cheese, other cheese and cheese products, or sausage meat.
Thus, it is another object of the invention to provide a general purpose, natural food substitute that may be used in a variety of products.
The rice grains and water may stand in the ratio of substantially one to two by weight.
Thus, it is another object of the invention to provide for extremely high water capacity in the rice mixture.
The foregoing and other objects and advantages of the invention will appear from the following description. In the description, reference is made to the accompanying drawings which form a part hereof and in which there is shown by way of illustration a preferred embodiment of the invention. Such embodiment does not necessary represent the full scope of the invention, however, and reference must be made to the claims herein for interpreting the scope of the invention.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
FIG. 1 is a simplified perspective view of the apparatus of the present invention for producing a reduced and low-fat pasta filata cheese showing a multiple auger heating system for the rice-based cheese substitute and a spray nozzle positioned over a hopper receiving standard pasta filata cheese and communicating with an upwardly extending kneading vessel;
FIG. 2 is a cross sectional view of the kneading vessel and spray nozzle of FIG. 1 taken along lines 2 — 2 of FIG. 1 showing the internal auger and the path of standard pasta filata cheese into the upwardly opening hopper;
FIG. 3 is a detailed fragmentary cross-sectional view taken along lines 3 — 3 of FIG. 1 showing two kneading augers within the kneading chamber of FIG. 2 in intermeshed counter rotating configuration;
FIG. 4 is a block diagram of the apparatus of FIGS. 1-3 showing the path of the rice cheese substitute and standard pasta filata cheese during the process;
FIG. 5 is a cross-sectional view of a preparation vessel that provides an alternative method for the manufacture of the rice cheese substitute;
FIG. 6 shows an arrangement of a manufacturing line employing two kneading vessels of FIG. 2, two of the manufacturing vessels of FIG. 5 and two modified vessels similar to that of FIG. 5 providing holding tanks, together allowing for continuous manufacture of the pasta filata cheese of the present invention;
FIG. 7 is a perspective view of a cheese volume flow meter such as may be used with the present invention for determining the flow rate of cheese or other material so as to provide a basis for automatic control of the ratio of the rice/cheese blend and cheese in the auger system of FIGS. 1 and 6;
FIG. 8 is a simplified cross-sectional view along lines 8 — 8 of FIG. 7 showing the pin wheel for measuring linear flow of the cheese and thickness gauge for gauging its cross-sectional area to determine total volume; and
FIG. 9 is a figure similar to that of FIG. 6 showing use of the rice blend in the manufacture of cream cheese.
DETAILED DESCRIPTION OF THE INVENTION
Apparatus and Process
Referring now to FIGS. 1 and 4, a reduced and low-fat cheese manufacturing apparatus 10 includes a motor-driven grinder 12 of conventional design having a hopper 14 sized to receive blocks of a rice mixture 16 whose preparation will be described in detail below. An auger 18 (shown in FIG. 4) is positioned within the grinder 12 and driven by motor 20 to force the semi-solid rice mixture 16 past a cutter head 21 so as to be macerated and extruded as indicated by arrow 22 for receipt by a second hopper 24 . The second hopper 24 opens into one end of a tubular heating chamber 26 which includes a second auger 28 driven by motor 30 to move the macerated rice mixture 16 along the length of the tubular heating chamber 26 from the hopper 24 to an exit port 31 at the opposite end of the tubular heating chamber 26 . The tubular heating chamber 26 is jacketed by a concentric hot water jacket 32 through which heated water 34 is passed. The heated water 34 is given a temperature so as to heat the macerated rice mixture 16 to approximately 120 degrees Fahrenheit as it passes along tubular heating chamber 26 .
When the rice mixture 16 reaches exit port 31 , it is sufficiently liquefied so that it may be received by a metering pump 36 of conventional design which provides a precise volume flow of the rice mixture 16 into connecting pipe 38 leading to a second tubular heating chamber 40 . Second tubular heating chamber 40 is similar in construction to tubular heating chamber 26 having a generally cylindrical lumen holding a third auger 42 driven by a motor 44 to move the liquefied cheese rice substitute from connecting pipe 38 to an exit port 46 . Again, second tubular heating chamber 40 has a hot water jacket 48 regulated to adjust the rice mixture 16 to a temperature from 185-190 degrees Fahrenheit. The heated and liquefied rice mixture 16 exits port 46 to valve 50 which may recirculate the rice mixture 16 through recirculation pipe 52 back to hopper 24 so as to constantly keep the rice mixture 16 flowing and heated, even if cheese is not actively being processed.
When pasta filata cheese is being processed, the rice mixture 16 passes through tube 56 to a spray nozzle 58 . The nozzle 58 is a length of pipe having a plurality of holes drilled in its lower surface to provide an orifice through which a rice mixture 16 may exit.
Referring now to FIGS. 1, 2 , and 4 , the reduced and low fat cheese manufacturing apparatus 10 may be positioned to receive standard pasta filata cheese 60 directly from a stretching machine, but prior to its molding, chilling, or brining. Ideally, the pasta filata cheese 60 is delivered from the stretcher (not shown) at a temperature of approximately 140 degrees Fahrenheit and has a fully formed fiber structure. The pasta filata cheese 60 drops into hopper 62 at the base of an upwardly sloping kneading chamber 64 . Referring in particular to FIG. 4, the kneading chamber 64 is jacketed with a concentric steam jacket 74 adjusted to a temperature of approximately 140 degrees Fahrenheit, but beneath the melting point of the cheese mixture 72 . The spray nozzle 58 is positioned above the hopper so that the liquefied and heated rice mixture 16 may be sprayed upon the surface of the pasta filata cheese 60 as it enters the hopper 62 . The flow rate of the pasta filata cheese 60 and the rice mixture 16 from nozzle 58 may be adjusted so that the combined pasta filata cheese 60 and rice mixture 16 (cheese mixture 72 ) is as high as 10-25% rice mixture 16 by weight.
Referring now to FIGS. 2 and 3, positioned within the kneading chamber 64 are twin augers 66 having helical vanes 68 passing in helixes of opposite “hand” around shafts 70 so that the vanes 68 may intermesh while the shafts 70 turn in opposite directions. A motor 76 turns the augers 66 through a conventional gear drive as will be understood to those of ordinary skill in the art. The augers 66 so turning provide a generally upward motion to the mixture of the pasta filata cheese 60 and the rice mixture 16 through the kneading chamber 64 .
The clearance between the vanes 68 and the walls of the kneading chamber 64 and the pitch and speed of the augers 66 is adjusted so that the cheese mixture 72 is stretched and folded between the augers and the inside of the kneading chamber 64 without cutting, so that the fibers of the cheese are preserved, yet coated uniformly with the rice mixture 16 . Generally, the augers 66 provide a similar action to hand kneading in which the palm of the hand is pressed against a lump of dough of cheese to roll it along a hard surface, stretching and compressing the cheese back upon itself.
At the upper end of the kneading chamber 64 is an exit opening through which the cheese mixture 72 exits as a reduced and low-fat pasta filata cheese. It may then be received by a molder chiller or brining tank of conventional design.
The reduced and low-fat cheese manufacturing apparatus 10 is generally instrumented and controlled through a control panel 80 providing control for the speed of the metering pump 36 of the motors 30 , 44 , and 76 and of valves necessary to hold the temperatures of the hot water jackets 74 , 48 , and 32 within the range as described. The heated water 34 may be provided by a steam heat exchanger 82 shown in FIG. 4 which provides heated water 34 directly to hot water jacket 48 which may then be cooled and transmitted to jackets 74 and 32 by metering valve 84 .
The Rice Mixture
The rice mixture 16 is formed principally of rice and water mixed and heated until it reaches a gel-like consistency. Preferably, the rice may be crushed in a grinder to a consistency of approximately two-millimeter particle size. A ribbon blender may then be used to mix the rice with approximately two hundred percent water by weight while it is heated to 160 degrees Fahrenheit for at least thirty minutes. The rice is then allowed to cool for approximately one hour with blending while other ingredients are added until it has reached approximately 70 degrees Fahrenheit. It is then molded into forty-pound blocks and refrigerated. The blocks are fed into the hopper 14 of the reduced and low-fat cheese manufacturing apparatus 10 as they are needed.
Although the exact composition of the rice mixture may vary, in a preferred embodiment, the rice mixture is compounded of the following ingredients:
TABLE I
Ingredient
Percent by weight
Water
39%
Rice
37.2%
Corn syrup
7.1%
Whey powder
4.8%
B950 food starch
4.8%
Maltrin M040
4.8%
Salt
1.0%
Cheddar flavor
0.5%
Guar Gum
0.8%
The composition of the rice mixture 16 with respect to its minor ingredients may be varied, particularly with respect to emulsifiers and flavoring agents.
In yet another embodiment, the rice/cheese substitute may be formulated for a substantially higher percentage of water.
TABLE II
Typical Batch
Ingredient
Percentage by Weight
Amounts
Long grain white rice
28%
300 lbs.
Water
60%
650 lbs.
GPC-Maltrin®
3-6%
50 lbs.
M200 Corn Syrup Solids
GPC-Maltrin®
2.5-5%
40 lbs.
M040 Maltodextrin
GPC-Pure-Set®
2.5-5%
40 lbs.
B950 Food Starch-
Modified
In preparing this blend, the equipment described above with respect to FIGS. 5 and 6 may be used with 650 lbs. of water added to the heated vessel 90 and brought to a boiling temperature of 212° F. Three hundred pounds of rice may be added to the heated vessel 90 , the rice being generally intact or naturally broken rice kernels without grinding or similar preprocessing. Heat may be introduced into the vessel 90 and the rice may be cooked for 25 minutes after which the scraper blades 128 and high shear mixer head 116 are started. The remaining ingredients are then added and the mixture agitated and sheared for ten additional minutes. Finally, the rice mixture 16 is pumped through shear pump 132 to be circulated for 20 minutes.
On-Site Manufacture of the Rice-Based Cheese Substitute
Referring now to FIG. 5 in an alternative embodiment, the of the grinder 12 , tubular heating chamber 26 and tubular heating chamber 40 (shown in FIG. 4) previously used to prepare a premanufactured semi-solid rice mixture 16 , may be replaced and the need for premanufacturing avoided by using a batch operated heated vessel 90 on-site.
The heated vessel 90 is a double-walled container having a cylindrical inner wall 92 surrounded coaxially by a cylindrical outer wall 94 . The walls 92 and 94 continue around a lower base of their respective cylinders to culminate in an axial drain port 96 providing a passage from a mixing volume 98 surrounded by the inner wall 92 . The inner wall 92 and outer wall 94 define between them a steam jacket volume 100 into which steam may be introduced and extracted through ports 102 . In this manner, the inner wall 92 may be heated to a controlled temperature so as to heat the material contained within the mixing volume 98 .
An upper cover 104 joins the inner wall 92 and outer wall 94 at their upper edges and covers the mixing volume 98 . Cover 104 is breached by access hatch 106 into which
ingredients as will be described may be introduced. A smaller entrance port 108 through cover 104 allows for the recirculation of material from inside the volume 98 out through the drain port 96 and back into the entrance port 108 as will also be described.
Mounted on top of the cover 104 is a shear mixer motor 110 driving a shaft 112 piercing the cover 104 and terminating within the volume 98 at a high shear mixer head 116 . Such mixer heads 116 are well known in the art and are commercially available from Admix of Manchester, N.H., United States under the tradename Rotosolver. During operation, the high shear mixer head 116 will rotate as indicated by arrow 118 .
The shaft 112 may be off center to the center axis of the cylindrical volume 98 to allow for the passage of a scraper shaft 120 through cover 104 along the center axis. The scraper shaft 120 is driven by scraper motor 122 also mounted on top of cover 104 . The scraper shaft 120 terminates at its lower end at a bearing 124 axially aligned with the drain port 96 but supported above the drain port 96 so as not to obstruct it. Scraper shaft 120 rotates about its extent as driven by the scraper motor 122 and as indicated by arrow 121 .
Extending symmetrically and radially outward from the lower end of the scraper shaft 120 , above the bearing 124 , are scraper arms 126 which follow along and above the portion of the inner wall 92 forming the lower base and along and inside the portion of the inner wall 92 forming cylindrical vertical walls. Scraper blades 128 are attached along the arms 126 between the arms and the inner wall 92 so as to scrape along the inner wall 92 preventing overheating of material immediately adjacent to the heated inner walls 92 . Scraper blades 128 are staggered with respect to the opposing arm 126 so as to provide essentially uniform coverage of the inner wall 92 adjacent to steam jacket volume 100 .
During operation, rice grains and heated water may be introduced through access hatch 106 . Preferably, the rice grains are unground rice comprising whole grains and broken grains such as naturally occur during grain shipping and handling. Other ingredients according to the table provided above may also be added at this time.
Steam introduced into the steam jacket volume 100 maintains the mixture at between 185 and 190° F. while it is blended with the high shear mixer head 116 and prevented from caking to the inner wall 92 by scraper blades 128 .
Referring now to FIG. 6 during blending, the mixture may be extracted from drain port 96 to be pumped by positive displacement pump 130 and then by shear pump 132 through valve 134 back into entrance port 108 providing additional shearing of the mixture and its constant recirculation. Still referring to FIG. 6, two such vessels 90 and 90 ′ may be arranged to operate in tandem so that one vessel may be cleaned or refitted while the other vessel is creating the rice water blend. By means of valve 134 , (or valve 134 ′ on tank 90 ′), the contents of the vessels 90 and 90 ′, respectively, may be pumped to a pasteurizing tank 136 (or 136 ′) being identical to vessels 90 and 90 ′ except for the absence of the shear mixer motor 110 , shaft 112 , and high shear mixer head 116 . Tanks 136 and 136 ′ include inlet ports 137 , 137 ′ connected each to an outlet of valves 134 or 134 ′.
The pasteurizing tanks 136 , 136 ′ may each have a positive feed pump 140 (or 140 ′) receiving mixture from the tank 136 or 136 ′ through drain ports 139 or 139 ′, respectively,
corresponding generally to drain port 96 as pumped by the pumps 140 or 140 ′ to valves 142 or 142 ′ for recirculation back into the tanks 136 , 136 ′. Valves 142 and 142 ′ provide the rice water mixture to two way valves 146 and 146 ′ which may direct the mixture either of hopper 62 or 62 ′ of two corresponding kneading chambers 64 or 64 ′ or to a second inlet on the other valve 146 , 146 ′.
Thus, vessels 90 and 90 ′ may be operated on a batch or intermittent basis with their product shunted to respective pasteurizing tanks 136 or 136 ′ for pasteurizing and holding. Tanks 136 and 136 ′ may hold the cheese rice substitute until it is needed and then via valves 142 and 142 ′ set to provide either of the kneading chambers 164 or 164 ′ with the mixture. As have been previously described, each kneading chamber 164 or 164 ′ includes an auger 66 or 66 ′ for kneading the rice water mixture into pasta filata cheese.
It will be understood, therefore, that the kneading chambers 64 and 64 ′ may be operated on an essentially continuous basis with the rice cheese substitute being manufactured in batches in vessels in 90 and 90 ′. Further the operation of the equipment need not be halted for cleaning operations of the vessels 90 , 90 ′, 136 or 136 ′ as dual flow paths exist to either of the kneading chambers 64 or 64 ′.
Referring now to FIGS. 7 and 8, a cheese flow meter 170 useful for metering the rice mixture 16 into the cheese 60 or other food base includes an entrance aperture 172 through which cheese 60 may be introduced prior to the introduction of the rice mixture 16 .
The cheese 60 travels along guiding trough 174 which terminates at an end lip 176 which may communicate with the hopper 62 shown in FIGS. 1, 2 and 6 of the kneading chamber 64 . The trough 174 provides a generally rectangular cross-section defined between a bottom horizontal wall and upstanding sidewalls. An open upper face of the trough 174 is partially covered by a pivoting gauge plate 178 hinging about an axis 180 generally perpendicular to the longitudinal extent of the trough 174 and the travel of the cheese 60 .
As pivoted, the gauge plate 178 may have one end follower 182 resting lightly upon the surface of the cheese 60 as it moves through the trough 174 , the gauge plate 178 angularly pivoting with movement of the follower end 182 up and down as the height of the mass of cheese 60 changes.
A sensor end of the gauge plate 178 opposite the follower end 182 with respect to the axis 160 may include a proximity sensing target 184 adjacent to a proximity sensor 186 positioned thereabove. The operation of the proximity sensor target 184 and proximity sensor 186 is to provide a measure of the height of follower end 182 above the bottom of the trough 174 and thus an electronic measurement of the height of the cross-section of cheese 60 flowing through the trough 174 .
Thus, it will be understood that insofar as the cheese 60 as it flows and spreads generally the full width of the bottom wall of the trough 174 , the height of the follower end 182 above the bottom of the trough 174 , together with knowledge of the width of the trough 174 , provides a measurement of the cross-sectional area of the cheese 60 passing over the lip 176 .
The follower end 182 of the gauge plate 178 may support rotatable pinwheels 188 being disks generally mounted for rotation along axis 190 parallel to axis 180 . The periphery of the disks including radially extending pins 192 that may engage the surface of the cheese 60 as it passes above the lip 176 but beneath the follower end 182 . The pin wheels 188 are free to rotate as the cheese 60 moves thus measuring in their rotation, a linear distance or velocity of cheese 60 passing over the lip 176 .
The rotation of the pin wheels 188 may be detected by an electronic rotation sensor 196 of conventional design and provided to a microprocessor or microcontroller (not shown) together with the signal from the proximity sensor 186 to provide a volume rate or total volume of cheese flowing past lip 176 .
This volumetric rate may be used to control a metering valve 50 prior to nozzle 58 to, in turn, control the ratio or rice mixture 16 to cheese 60 on an automatic basis. It will be understood that the cheese flow meter 170 may be used for a variety of materials other than pasta filata cheese where such metering is required.
Cream Cheese
Referring now to FIG. 9, the rice blend of the present invention may find application in the manufacture of low fat cream cheese which begins with the culturing of a starter mix being, for example, in the case of low fat cottage cheese, skim milk 200 contained in a culturing silo 202 . The starter mix may be incubated at 89° to 92° Fahrenheit with a bacterial starter culture suitable for cream cheese manufacture and preferably calf rennet according to techniques well known in the art. The culturing may continue for 6-8 hours until a PH of 4.6 is reached.
At this time the curd is broken up, cooked to 130F. to 170 Fahrenheit, and pumped by pump 204 into cream cheese separator 206 being a centrifugal type separation apparatus such as are available from a variety of different manufacturers and well known in the art. The separator 206 is operated so as to remove whey through whey outlet 208 and to provide a curd material having 40% to 60% moisture content by weight.
The moisture-reduced curd is then homogenized between 2500 and 3000 psi by homoginizer 207 . The homogenized cream cheese is received by a blender 210 , for example, a double agitator type blender. The blender 210 also receives the rice/water mixture at 140 to 160 degrees Fahrenheit as described above through valve 146 and the curd and rice/water mixture are blended at 120 to 170 degrees Fahrenheit. The rice/water mixture may be added to the moisture-reduced curd in an amount of 0% to 30%. During the blending process, salt may be added to the product.
Optional homogenization may occur at this time.
From the mixer the completed low fat cream cheese may be run through a heat exchanger 216 to cool it down or may be hot packed using hot pack equipment well known in the art.
Processed Meats—Sausages
Originally, sausage was produced in order to preserve excess meat. Today sausage is produced to meet the unique texture and flavor supplied by these products. Being meat products these foods typically have high fat and cholesterol. The industry is always searching for ways to maintain flavor and textural characteristics of these products while reducing fat and cholesterol.
Sausages are prepared in a variety of methods but typical procedures indicate chilled meat is blended with a solution of seasonings, water, and cure which is a preservative such as nitrates. The combined ingredients may include gums or alginates to help firm the product. Once the final mixture is made, the products are placed in a casing and cured by smoke and heat until an internal temperature of 155 F. is reached.
The use of rice mixture allows the sausage producers to dilute the fat and cholesterol, while maintaining flavor and texture characteristics. Another advantage of the rice mixture is that the use of gums or alginates are reduced or eliminated. Using a rice mixture also produces a more friendly ingredient statement.
The above description has been that of a preferred embodiment of the present invention, it will occur to those that practice the art that many modifications may be made without departing from the spirit and scope of the invention. In order to apprise the public of the various embodiments that may fall within the scope of the invention, the following claims are made. | A method of producing high moisture content food products provides for introduction of rice stabilized water at high percentages with respect to the base food. The rice stabilized water is produced by cooking rice and water to saturation and then liquefying it with high shear reducing water loss. | 0 |
BACKGROUND OF THE INVENTION
[0001] The invention relates to a product which comprises sorbic acid and at least one bacteriocin and can be used on its own in feedstuffs or mixed with other feedstuff additives in agricultural livestock rearing.
[0002] Antibiotics are frequently used to improve performance in the animal feed sector. In some cases, very similar or identical substances are used in human medicine. The use of antibiotics in the animal nutrition sector is suspected in principle of being responsible for the dangers derived from resistant bacteria, which may also endanger human health in the long term. It is therefore necessary to look for products about which there are fewer health doubts for this purpose of use. Thus, in other sectors too there is increasing replacement of substances about which there are physiological and epidemiological health doubts or else which are harmful for the environment, such as, for example, antibiotics, formaldehyde-emitting materials, halogenated substances, and many others, by materials about which there are fewer doubts, for example in human foods, feedstuffs, pet food, silages, pomace or other waste materials from the food industry. The purpose of these materials is, on the one hand, aimed at maintaining the value of the actual product. However, on the other hand, it is also intended to improve the hygienic condition thereof and achieve a longer shelf life.
[0003] It is known that sorbic acid can be employed for preserving feedstuffs. Sorbic acid (trans,trans-2,4-hexadienoic acid) is a colorless solid compound which dissolves only slightly in cold water and is used around the world as a preservative. The principle of action is determined by sorbic acid in undissociated form. Sorbic acid therefore displays its best effect in the acidic pH range. Sorbic acid and its salts have a very good microbiostatic, antimycotic action. At the same time, as unsaturated fatty acid, sorbic acid is virtually nontoxic, which has been proven by very extensive data and by the decades of use of this acid in the human food sector, in animal feeds, inter alia.
[0004] Besides sorbic acid, other organic acids have also been employed for some years for preserving feedstuffs and for improving feed hygiene. The hygienic quality in particular of feed for young animals must meet special requirements. This is why some organic acids are approved without a limitation on the maximum amount, on the basis of the national legal provisions concerning feedstuffs.
[0005] Bacteriocins are specific inhibitors which are secreted by microorganisms and are lethal for other microorganisms—principally bacteria. Bacteriocins are peptides, polypeptides, proteins or substances which have at least proteinogenic structures and are composed of amino acids. It is moreover possible for these bacteriocins which are composed of amino acids also to contain unusual amino acids such as, for example, lanthionine or β-methyllanthionine. For example, pediocin L50 contains other modified amino acids (L. M. Cintas et al., “Isolation and Characterization of Pediocin L50, a New Bacteriocin from Pediococcus acidilactici with a Broad Inhibitory Spectrum”, Applied and Environmental Microbiology, July 1995, pages 2643-2648).
[0006] Microorganisms which produce bacteriocin frequently occur naturally, for example in milk and dairy products (cf. for example, E. Rodriguez et al., “Diversity of bacteriocins produced by lactic acid bacteria isolated from raw milk”, International Dairy Journal 10 (2000) 7-15). Such microorganisms are moreover continually being isolated from other foodstuffs such as meat and meat products (cf. for example, Food Science and Technology International (1998) 4, 141-158).
[0007] The microorganisms which secrete bacteriocins have often already been used for several centuries—often unknowingly—for producing foodstuffs in that the bacteria which are intentionally added as so-called protective cultures inhibit, by their secretion products, other bacteria which cause spoilage, are toxic, unwanted or hazardous in other ways. A well-known bacteriocin is nisin. This is produced commercially and has also been employed for some years as foodstuff additive against certain microorganisms which cause so-called “late blowing” in cheese.
[0008] The fundamental disadvantage of using bacteriocins is that they are active only against certain groups of microorganisms, in particular against close relatives. In addition, bacteriocins are unstable in the foodstuff and decompose after a certain time, so that no activity is available any longer.
[0009] The other organic acids known as addition to feedstuffs have the disadvantage that some of them are volatile, have unpleasant odors and, in addition, corrosive effects. The performance-improving effects which can be achieved with them are associated with considerable disadvantages in handling.
[0010] The object accordingly was to provide a stable addition which is easy to handle, has a preservative effect and improves performance but does not have these disadvantages.
BRIEF DESCRIPTION OF THE INVENTION
[0011] This object is achieved by a product (composition) which comprises sorbic acid and at least one bacteriocin. The bacteriocin(s) may be employed as such but it is also perfectly possible to employ live or dead microorganisms which produce or contain these bacteriocins. It is preferred to use bacteriocin-producing microorganisms which occur naturally, for example in dairy or meat products. Microorganisms to be employed according to the invention are only those which produce bacteriocins. The table detailed below contains species of microorganisms which may or may not produce bacteriocins (for example Bacillus cereus ); these can accordingly be employed only if they produce bacteriocins. The bacteriocin-producing or -containing microorganisms or the bacteriocins themselves can also be employed in encapsulated form or bound to carriers. It is moreover possible to use products which contain bacteriocins in effective concentrations or detectable amounts. This also includes mixtures of such products, for example with whey proteins or common salt. Available products of this type are, for example ALTA2341 (Quest Biotechnology, Inc., Sarasota, U.S.A.) Microgard (Rhône Poulenc, Courbevois, France).
DETAILED DESCRIPTION OF THE INVENTION
[0012] The bacteriocins/microorganisms mentioned in the following table are preferably employed.
Microorganisms Bacteriocins Aeromonas hydrophila sakacin A or P Lactobacillus sakei Bacillus cereus lactocin-S, lactostrepcin-5, pediocin-A, pediocin-AcH, sakacin-A Bacillus coagulans nisin Bacillus licheniformis Bacillus stearothermophilus Clostridium bifermentans Lactococcus lactis Bacillus pumilis thermophillin Bacillus subtilis , 168, JH642 subtilin, lacticin-481, nisin, thermophillin, subtilosin Bronchothrix thermospacta curvacin-A, pediocin-AcH, sakacin-A, sakacin-P Carnobacterium divergens Carnobacterium piscicola UI 49, carnocin UI 49, carnobacteriocin A, LV 17 or LV 61 B1 and B2; piscicolin 61 Clostridium botulinum nisin, pediocin-A, reuterin, sakacin-A Clostridium butyricum nisin, reuterin Clostridium perfringens nisin, pediocin-A, pediocin-AcH, pediocin-VTT, reuterin, thermophillin Clostridium sporogens nisin, pediocin-A Clostridium tyrobutricum lacticin-481, lactocin-S, pediocin- AcH Enterococcus faecalis Enterococcus faecalis 226, INIA 4 enterocin 226NWC, AS-48 Enterococcus faecalis S-48 bacteriocin Bc-48 Enterococcus faecium , BFE 900, enterocin 1146, B, A, Cal, ON- 157, CTC492, cal 1, NIAI157, A, B, P, P, L50A, L50B L 50, G 16, AA13, T136 Enterococcus spp. enterococcins (I-V) Escherichia coli reuterin, thermophillin Fusobacterium mortiferum, (e.g.: “FM1025”) Lactobacillus acidophilus lactocicin Lactobacillus acidophilus 11088, lactacin F, lacidin, acidolin, acido- OSU 133, 2181, DDS1, LAPT, phillin, acidophilucin A, bacteriocin 1060, M46, N2, TK8912, M46, lactacin B, acidocin 8912, lactacin B Lactobacillus amylovorus amylovorin L471 DCE 471 Lactobacillus bavaricus MI401 bavaricin A Lactobacillus bulgaricus bulgarican Lactobacillus brevis lactobacillin Lactobacillus brevis brevicin Lactobacillus casei B80 caseicin 80, caseicin LHS Lactobacillus casei LHS Lactobacillus curvatus LTH 1174, curvacin A, 13 SB 13 Lactobacillus delbrückii ssp. bulgarican bulgaricus Lactobacillus delbrueckii subsp. lacticin B lactis JCM 1106, JCM 1107, JCM 1248 Lactobacillus fermentum 466 bacteriocin 446, proteid Lactobacillus gasseri gassericin A Lactobacillus helveticus lactocin 27 Lactobacillus helveticus 1829, helveticin V-1829, helveticin J, 481, LP27 lactocin 27 Lactobacillus plantarum , A2, BN, plantaricin A and D, lactolin, plantar- C-11, LPCO-10, LPCO-10, icin BN, A, S, 406, -B, SIK-83, 35 d MI406, NCDO 1193, SIK-83, 35 d, CTC 305, Lactobacillus reuteri LA6 reutericin 6 Lactobacillus sakei , Lb 706, L45, sakacin-A, lactocin S, sakacin P, LTH 673, CTC 494, CTC 372, sakacin K and T 148 Lactococcus lactis subsp. diplococcin, lactostrepcin 5, cremoris , -202, -9B4, -346, lactococcin A, B and M, Bac I, II, III -9B4, 4G6, LMG 2130, LMG2081, and IV, lactococcin A, G, lacticin JW 3 Lactococcus lactis subsp. lactis lactostrepcin 1, 2, 3, 4 and DR, lact- 10, 300, 71, ADRIA 85LO30, icin 481, dricin, bac V, VI and VII CNRZ 481, DRC1, 6F3 Lactococcus lactis subsp. lactis nisin A ATCC 11454 Lactococcus lactis subsp. lactis nisin Z NIZO 22186 Lactococcus lactis subsp. lactis bac VIII var. diacetyictis 6F7 Lactococcus lactis subsp. lactis lactocin D, bacteriocin S50, bac var. diacetyictis DPC938, S50 WM4 and WM4 Leuconostoc carnosum e.g.: Lm1 leucococin Lcm1 Leuconostoc dextranicum Leuconostoc geldium e.g.: leucocin A-UAL 187 UAL 187 Leuconostoc gelidium Leuconostoc mesenteroides Leuconostoc mesenteroides mesenterocin 52, 5, Y105 subsp. mesenteroides FR52, UL5, Y105 Leuconostoc paramesenteroides leuconocin S OX Listeria innocua lacticin-481, lactosin-S, pediocin-A, pediocin-AcH Listeria ivanovii pediocin-A, pediocin-AcH, pediocin- PAC10 Listeria monocytogenes spp. carnobacteriocin A & B, curvacin-A, enterocin-1146, lactacin-B, lacticin- 481, leucocin-A, nisin, pediocin-A, pediocin AcH, pediocin-JD, pediocin- PA-1, pediocin-PAC10, pediocin- VVT, piscicolin-61, reuterin, sakacin- A, sakacin-P Listeria seeligeri pediocin-A Listeria welchii lacticin-481, pediocin-A Mycobacterium tuberculosis nisin Pediococcus acidilactic e.a. H, E, pediocin AcH F, M Pediococcus acidilactic JD1-23, pediocin JD, PA-1, SJ-1 PAC 1.0, SJ-1, Pediococcus pentosaceus pediocin A, N5p FBB-61, L-7230, N5p Proteus mirabillis nisin Pseudomonas aeruginosa thermophillin Pseudomonas fluorescens Salmonella enteritidis reuterin, thermophillin Salmonella infantis pseudiocin-VVT, reuterin Salmonella typhimurium reuterin, thermophillin Shigella sp. reuterin, thermophillin Staphylococcus aureus nisin, lacticin-481, pediocin-A, pediocin-AcH, plantarcin-SIK83, sakacin-A, thermophillin Staphylococcus carnosus curvacin, lacticin-481, lactocin-S pediocin-AcH Staphylococcus epidermidis nisin Staphylococcus simulans nisin Streptococcus thermophilus thermophillin 13, bacteriocin St10, Sfi13, St10, STB40, STB78 bacteriocin STB40, bacteriocin STB78 Yersinia enterocolitica thermophlillin
[0013] The bacteriocins are obtained by known processes, for example by simple precipitation using ammonium sulfate, gel filtration (Sephadex G-50), cation exchange chromatography (CM-cellulose), RP-HPLC, adsorption/desorption centrifugation, vortex flow filtration or other technically suitable methods (see Parente E. and Ricciardi A., Appl. Microbiol. Biotechnol. 1999, 52, 628-638).
[0014] The product of the invention contains from 90.00 to 99.90% by weight, preferably 95.00 to 99.99% by weight, sorbic acid. Percentages by weight are based in this case on the total weight of the product.
[0015] The bacteriocin(s) are expediently present in the product of the invention in amounts such that from 2.5 to 50 mg/kg, preferably 5 to 40 mg/kg, in particular 10 to 20 mg/kg, are present in the animal feed. Preparations which contain bacteriocins are added in appropriately higher dosage (if, for example, the preparation contains 2.5% bacteriocin as active substance, then preferably from 400 to 800 mg/kg thereof are employed). If bacteriocin-producing microorganisms or combinations thereof are employed in the products of the invention, these are preferably present in amounts which correspond to about 10 6 to 10 10 microorganisms per g of feedstuff. It is also possible to use spray-dried products for this purpose. The bacteriocin content in the animal feed should in this case likewise be from 2.5 to 50 mg/kg, preferably 5 to 40 mg/kg, in particular 10 to 20 mg/kg.
[0016] Carriers which can be used both for the sorbic acid and for the bacteriocin or the microorganisms are organic or inorganic materials. These include, for example, starch and other polysaccharides such as cellulose. To improve dispersion in mixtures with sorbic acid, it is also possible for the bacteriocins to be present in the mixtures in salts such as common salt or mineral salts or else whey powder or other products of milk processing.
[0017] A further possibility is for the bacteriocins or the microorganisms to be provided with microcapsules/microspheres in order thus to resist unwanted effects of digestive juices. It is possible in this case for the sorbic acid to be put, separate from the bacteriocins, into the microspheres or else into one of the outer layers of a microcapsule in such a way that sorbic acid is released earlier and leads, for example in the stomach, to a marked reduction in pH, but the bacteriocins are not released until later in the gastrointestinal tract. A mixture of encapsulated bacteriocins and sorbic acid is also possible. Examples suitable for the encapsulation are gelatin, lecithins, steairates, alginates, tragacanth, xanthan, carrageenan, cassia gum, gum arabic, maltodextrins, modified starches, celluloses, mono- and diglycerides of edible fatty acids esterified with organic acids or unesterified, solid triglycerides with, preferably, saturated fatty acids such as tripalmitin, solid fatty acids such as palmitic acid or mixtures thereof.
[0018] Employed as carrier and for stabilizing the products are >0 to 10% by weight, preferably 2.5 to 7.5% by weight (based on the product), of carrier materials, alone or in combination.
[0019] The product of the invention is produced by, for example, mechanical mixing of the sorbic acid and bacteriocins, bacteriocin mixtures, preparations which contain bacteriocins, or live or dead microorganisms which have produced bacteriocins. If the product of the invention comprises a carrier, it is expedient for the microorganism extracts, which are liquid where appropriate, initially to be applied to the carrier, expediently in a commercially available tumbler mixer or other conventional mixer, and then for the sorbic acid and the other solid ingredients to be added.
[0020] Examples of suitable animal feedstuffs are green fodder, silages, dried green fodder, roots, tubers, fleshy fruits, grains and seeds, brewer's grains, pomace, brewer's yeast, distillation residues, milling byproducts, byproducts of the production of sugar and starch and oil production and various food wastes. Feedstuffs of these types may be mixed with certain feedstuff additives (e.g. antioxidants) or mixtures of various substances (e.g. mineral mixes, vitamin mixes) for improvement. Specific feedstuffs are also adapted for particular species and their stage of development. This is the case, for example, in piglet rearing. Prestarter and starter feed are used here. The product of the invention can be added to the animal feedstuff directly or else mixed with other feedstuff additives or else be added via premixes to the actual feedstuff. The product can be admixed dry with the feed, be added before further processing (e.g. extrusion) or be metered in and dispersed in the mixture. An additional possibility is to add the individual ingredients of the product separately to individual ingredients of the feedstuff. It is expedient to use for these purposes product concentrations between 0.25 and 7.5% by weight (based on the feed), preferably 0.75 to 4.0% by weight.
[0021] The product can be added as sole additive to the animal feedstuffs, for example for cattle, poultry, rabbit or sheep rearing, particularly preferably to prestarter and starter feeds for piglets, or be used mixed with other feed additives for these stock. Feedstuffs having the product of the invention are moreover suitable as milk replacers for the early weaning of lambs or calves.
[0022] Surprisingly, the products of the invention do not show the disadvantages described above. On the contrary, the products show good handling properties. In addition, effective acidification of the feed is achieved. It is moreover possible, surprisingly, for there to be a beneficial effect on the growth performance of young stock even with relatively small amounts of product.
[0023] The products of the invention are in a solid state of aggregation. The present invention avoids the problems which otherwise arise with the handling of the liquid acids previously used. The product of the invention is also able to improve the hygienic status in that unwanted organisms and spoilage microbes, which may otherwise consume nutrients present, are suppressed.
[0024] It has been found, surprisingly, that a marked improvement in performance in relation to growth rate and feed conversion can be achieved by adding even small amounts of products of the invention in piglet rearing. To ensure a significant nutritional activity, it is expedient to add products of the invention in amounts of from 0.25 to 7.5% by weight, based on the feed, preferably from 0.75 to 4.0% by weight.
[0025] The invention is illustrated below by means of examples.
EXAMPLE 1
[0026] 0.0075 to 0.015 kg (corresponding to a concentration of at least 20 mg/kg bacteriocin in the feed) of a product from Lactococcus lactis subsp. cremoris and Lactobacillus plantarum, which has been sprayed with whey powder, dried and enriched with bacteriocins, is mixed with 1.0 kg of sorbic acid in a double cone blender with tumbling movements over a period of about 15 min. The homogeneous mixture is mixed with 100 kg of piglet feed of the following composition (the following data in % by weight).
Fish meal 4.00 Extracted soybean meal 18.50 Barley 40.00 Wheat 33.00 Vegetable oil 1.90 L-Lysine HCl 0.2 DL-Methionine 0.1 L-Threonine 0.1 Mineral feed 2.2
EXAMPLE 2
[0027] 0.08 kg of a mixture of nisin (Nisaplin Aplin & Barrett, Dorset, U.K.) with whey proteins and common salt, which contains 2.5 percent of pure substance (equivalent to about 1×10 6 IU/g or 1×10 6 Reading units/g), is mixed with 0.92 kg of sorbic acid in a double cone mixer with tumbling movements over a period of about 15 min to achieve a uniform mixture. This mixture is mixed with 100 kg of piglet feed of the following composition (the following data are in % by weight).
Extracted soybean meal 22.00 Barley 40.00 Wheat 31.00 Vegetable oil 2.90 L-Lysine HCl 0.40 DL-Methionine 0.10 L-Threonine 0.10 Mineral feed 3.50
[0028] It was found that a marked improvement in performance in relation to growth rate and feed conversion is achieved even by addition of these amounts of products of the invention in piglet rearing. | The present invention relates to a product for use in animal feedstuffs. The product comprises sorbic acid and live or dead microorganisms which secrete bacteriocins, or the bacteriocins themselves or combinations thereof and, where appropriate, a carrier. The invention further relates to the use of the product on its own in feedstuffs or in a mixture with other feed additives for improving the hygienic status of the feed and for improving performance in agricultural livestock rearing. | 0 |
BACKGROUND
Electroconvulsive shock, or ECS, is known to induce amnesia in a significant number of individuals subjected thereto. Studies on this type of amnesia in animals have resulted in the discovery of a number of compounds which at least ameliorate and, in some cases, virtually reverse, ECS-induced amnesia.
These compounds and their pharmaceutically acceptable formulations are also of value in treating senility.
INVENTION
A group of novel compounds have been shown to be effective in treating subjects suffering from ECS-induced amnesia. These novel compounds contain fused hetero-N-cyclic rings and conform to one of the general formula: ##STR1## wherein R is --H, --C(O)CH 3 , --C(O)C(CH 3 ) 3 , --C(O)C 3 H 7 , --C(O)CH 2 C 6 H 6 , --Si(CH 3 ) 2 C(CH 3 ) 3 , --Si(C 6 H 5 ) 2 CH 3 or --Si(--C 6 H 5 ) 2 --C(CH 3 ) 3 .
Compounds of formula (I) and pharmaceutically-acceptable formulations thereof, have utility as discussed above. Mixtures of compounds conforming to formula (I) can be used.
In addition, the compounds of the invention exist as dextro- and levorotatory optical isomers. These isomers as well as geometric isomers of structure (I) are contemplated as exhibiting similar biological activity. Mixtures of isomers, e.g., racemic mixtures, are useful.
ADVANTAGES
The compounds of the instant invention show promise as cognition activators and memory enhancers.
Furthermore, they are produced from well-known chemical intermediates, such as the methyl ester of 4-nitrobutanoic acid. The synthesis of this intermediate is described in U.S. Pat. No. 2,342,119 to H. A. Bruson. The disclosure of that patent is hereby incorporated by reference.
Other aspects and advantages of the invention will become apparent after a consideration of the following description and claims.
DESCRIPTION OF THE INVENTION
The invention provides a novel group of compounds and pharmaceutical formulations containing those compounds individually or in mixtures of cis- and trans- or other isomers. Generally, the subject compounds conform to formula (I) set out above.
The optical and geometric isomers of compounds of formula (I) and pharmaceutically-acceptable materials derived therefrom are also usefully biologically.
The subject compounds are new chemical entities and are 2-hydroxy-dihydro-1H-pyrrolizine-3,5(2H,6H)-dione and derivatives thereof. Generally, they are the dione, O-substituted derivatives thereof, and esters thereof.
Among the compounds and mixtures encompassed by the invention are: mixtures of cis- and trans-2-hydroxy-1H-pyrrolizine-3,5(2H,6H)-diones; mixtures of cis- and trans-2-acetoxy-dihydro-1H-pyrrolizine-3,5(2H,6H)-dione; mixtures of cis- and trans-2-butyroxy-dihydro-1H-pyrrolizine-3,5(2H,6H)-dione; mixtures of cis- and trans-dihydro-2-pivaloxy-1H-pyrrolizine-3,5(2H,6H)-dione; mixtures of cis- and trans-2-t-butyldiphenylsilyloxy-dihydro-1H-pyrrolizine-3,5(2H,6H)-dione; mixtures of cis- and trans-2-t-butyldimethylsilyloxy-dihydro-1H-pyrrolizine-3,5(2H,6H)-dione; mixtures of cis- and trans-2-carbobenzoxy-dihydro-1H-pyrrolizine-3,5(2H,6H)-dione and the like. Combinations containing one or several of these are contemplated.
Solvates and hydrates, as well as other pharmaceutically acceptable materials prepared from any of the compounds discussed above, are also within the scope of the invention. In general, the hydrated and/or solvated forms which use suitable solvents are equivalent to the anhydrous forms.
Where a plane of symmetry cannot be drawn through the molecular structure of the compounds or derivatives thereof, the compounds exist as d,l-isomers and the biological activity may reside in either or both of the isomers. In addition, because the parent structure dihydro-1H-pyrrolizine-3,5(2H,6H)-dione molecular is not flat but is bent down on each side of the nitrogen 7-alpha-carbon atom axis, the 2-substituent can be on either the exo- or the endo- side of the molecule.
The use of techniques conventionally used to treat or modify the subject compounds in order to render them more suitable for pharmaceutical use is contemplated.
PREPARATORY SCHEMES
The compounds of the invention are generally prepared using one or more of the following schemes. The compounds set forth are merely exemplary. Reasonable extrapolation to encompass the use of analogous reagents is within the purview of the skilled artisan.
Typical schemes include: ##STR2## Me=methyl, Ph=phenyl,
Et=ethyl,
Ac=CH 3 C(O)-- ##STR3## Ph=phenyl, Et=ethyl,
Ac=CH 3 C(O)-- ##STR4## φ=phenyl, et=ethyl,
t-Bu=tertiary butyl,
Ac=CH 3 (C(O)-- ##STR5## Bn=benzyl, DMAP=4-dimethylaminopyridine,
Et=ethyl,
Ac=CH 3 C(O)-- ##STR6## t-Bu=tertiary butyl, HOAc=acetic acid
DOSAGE FORMS
The novel compounds disclosed herein, and pharmaceutically acceptable entities derived therefrom, are generally employed as active ingredients in compositions to be administered in unit dosage form.
Dosage forms will generally be of solid, semisolid, liquid or vaporous character. Useful dosage forms include, but are not limited to, tablets, capsules, lozenges, and pills as well as powders and aqueous and nonaqueous solutions and suspensions packaged in containers containing either one or some larger number of dosage units and capable of being subdivided into individual doses by such means as measurement into a teaspoon or other measuring device or container.
One or more suitable excipients, such as carriers, stabilizers, colorants, perfumes, flavoring agents, taste-making agents, and the like can be used in the subject compositions. Optionally, other active ingredients, i.e., one or more additional therapeutic agents, can be used in combination with the biologically active substances disclosed herein.
Useful carriers or diluents to be employed in compositives containing the subject compounds include a wide variety of materials. In general, any pharmaceutical diluent or carrier which does not significantly decrease the effectiveness of the active component(s) can be used.
Useful diluents include: sugars, such as lactose and sucrose; starches, such as corn starch and potato starch; cellulose derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methyl cellulose, and cellulose acetate phthalate; gelatin; talc; stearic acid; anhydrous magnesium stearate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma; propylene glycol; glycerine; sorbitol; polyethylene glycol; water; agar; alginic acid; as well as other compatible substances typically used in pharmaceutical formulations.
The compounds and derivatives disclosed herein can be incorporated into formulations to be administered via a variety of routes. For example, suitable salts and esters of the compounds of Formula I or the compounds themselves can be used in parenteral formulations.
In some cases, it is advantageous to employ the active ingredient in solid, e.g., powder, form, which solid form is subsequently combined with a suitable medium, e.g., an isotonic solution, prior to administration. The use of conventional pharmaceutical excipients and other therapeutic agents in such a medium is contemplated.
When topical, e.g., transdermal, administration is desired, the use of one or more active ingredient(s) with one or more carriers, surfactants, penetration enhancers or the like is suggested. Likewise, formulations for buccal or rectal administration can be made.
Solutions or suspensions of the drugs encompassed by the instant disclosure can be administered orally via syrups, elixirs, lozenges, chewable materials, and the like.
Nasal administration can be carried out by combining the active ingredient(s) with a suitable carrier and using appropriate packaging.
The percentage of active ingredient in the foregoing compositions can be varied within wide limits. However, it is generally present in a concentration of at least 10% in a primarily solid composition and at least 2% in a primarily liquid composition. The most satisfactory compositions are those in which a much higher proportion of the active ingredient is present.
The compositions of the invention preferably contain from about 1 to about 500 mg, preferably from about 5 to about 100 mg, of the active ingredient per dosage unit so that the entire amount to be administered during a day can be made up from a reasonable number of dosage units.
The estimated mammalian dosage for a 70 kg subject is from about 1 to about 1500 mg/day about (0.014 mg to about 21.4 mg/kg of weight per day), preferably about 25 to about 750 mg/day (about 36 mg to about 10.7 mg/kg of weight per day), optionally administered in divided proportions. Human subjects are preferred.
EXAMPLE I
Preparation of cis- and trans-2-acetoxy-dihydro-1H-pyrrolizine-3,5(2H,6H)-dione
A solution of 3.74 g of 4-hydroxy-5-oxo-2-pyrrolidinepropanoic acid methyl ester and 5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid methyl ester in 20 ml of 1N aqueous sodium hydroxide solution is heated to 60° C. for two hours. The reaction mixture is concentrated at reduced pressure and 20.4 g of acetic anhydride, 3.03 g of triethyl amine and 2.5 g of 4-dimethylaminopyridine are added. The resulting solution is heated at 90° C. for 16 hours. The solution is filtered and concentrated. Fifty cc of toluene are added and the mixture is reconcentrated. This operation is repeated five times and the resulting oil is chromatographed over SiO 2 (elution with chloroform:2-propanol; 97:3) to yield cis- and trans-2-acetoxy-dihydro-1H-pyrrolizine-3,5(2H,6H)-dione as a white solid with mp 88°-96° C. NMR (CDCl 3 ) and 5.53 (dd, 1/2H), 2.15 (d, 3H). IR (KBr) 2992, 1785, 1753, 1701, 1463, 1448, 1385, 1319, 1281, 1257, 1223.
EXAMPLE II
Preparation of cis- and trans-2-butyroxy-dihydro-1H-pyrrolizine-3,5-(2H,6H)dione.
A solution of 3.74 g of 4-hydroxy-5-oxo-2-pyrrolidinepropanoic acid methyl ester and 5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid methyl ester in 20 ml of 1N aqueous sodium hydroxide solution is heated to 60° C. for six hours. The reaction mixture is concentrated at reduced pressure and 4.0 g of butyric anhydride, 20 ml of toluene, and 2.5 g of 4-dimethylaminopyridine are added. The resulting solution is heated at 90° C. for three hours. The solution is filtered and concentrated. Fifty cc of toluene are added and the mixture is reconcentrated. The chloroform soluble material is chromatographed over SiO 2 (elution with chloroform:2-methanol; 97:3) to yield cis- and trans-2-butyroxy-dihydro-1H-pyrrolizine-3,5(2H,6H)-dione as a white solid with mp 145°-152° C. NMR (CDCl 3 ) and 5.54 (m, 1/2H), 5.24 (m, 1/2H), 4.22 (m, 1H), 2.94-0.73 (m, 13H). IR (cm.sup. -1) 2965, 2930, 2875, 1790, 1742, 1710, 1460, 1415, 1385, 1310, 1270.
EXAMPLE III
Preparation of cis- and trans-2-pivaloxydihydro-1H-pyrrolizine-3,5-(2H,6H)dione
A solution of 3.74 g of 4-hydroxy-5-oxo-2-pyrrolidinepropanoic acid methyl ester and 5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid methyl ester in 20 mil of 1N aqueous sodium hydroxide solution is heated to 60° C. for two hours. The reaction mixture is concentrated at reduced pressure and 4.7 g of pivalic anhydride, 20 ml of toluene, and 2.5 g of 4-dimethylaminopyridine are added. The resulting solution is heated at 90° C. for 16 hours. The solution is filtered and concentrated. Fifty cc of toluene are added and the mixture is reconcentrated. This operation is repeated five times and the resulting oil is chromatographed over SiO 2 (elution with chloroform:2-methanol; 97:3) to yield cis- and trans-2-pivaloxy-dihydro-1H-pyrrolizine-3,5(2H,6H)-dione as a white solid with mp 75°-77° C. NMR (CDCl 3 ) and 4.13 (m, 1H), 3.54 (m, 1H), 2.57-1.05 (m, 6H), 1.50 (s, 9H). IR (cm -1 ) 2945, 2875, 1780, 1750, 1710, 1590, 1510, 1435, 1355, 1255.
EXAMPLE IV
Preparation of cis- and trans-2-t-butyl-diphenylsilyloxy-dihydro-1H-pyrrolizine-3,5(2H,6H)-dione
A solution of 5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid (1.73 g), t-butyl-diphenylsilyl chloride (11 g), and imidazole (5.4 g) is allowed to stir in dimethylformamide (50 ml) for six hours at room temperature. The solution is diluted with water (100 mL) and extracted with diethyl ether (4×100 mL). The combined extracts are concentrated and the oil is dissolved in methanol (50 mL) and a 10% aqueous solution of potassium carbonate (50 mL) is added and the solution is stirred 18 hours. The solution is concentrated and washed with saturated brine (50 mL) and extracted with diethyl ether (4×75 mL). The combined extracts are dried and concentrated to an oil. The oil is dissolved in acetic anhydride (50 mL) and the solution is heated at 90° C. for two hours. The solution is filtered hot, concentrated, and the residue purified by chromatography on SiO 2 (elution with chloroform:methanol; 99:1) to yield cis- and trans-2-t-butyl-diphenyllsilyloxy-dihydro-1H)-pyrrolizine-3,5(2H,6H )-dione as a white solid with mp 155°-156° C. NMR (CDCl 3 ) and 7.60 (m, 10H), 4.66 (m, 1/2H), 4.40 (dd, 1H), 3.86 (m, 1/2H), 2.77-1.55 (m, 6H), 1.08 (s, 9H). IR (KBr) 3074, 2933, 1858, 1791, 1705, 1591, 1474, 1430, 1380, 1313, 1279.
EXAMPLE V
Preparation of cis- and trans-2-t-butyl-dimethylsilyloxy-dihydro-1H-pyrrolizine-3,5(2H,6H)-dione
A solution of 5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid methyl ester (5.6 g) in 1.0M sodium hydroxide solution (30 mL) is stirred at 60° C. for two hours. The solution is treated with 3.0M hydrochloric acid (10 mL) and concentrated at reduced pressure. The 5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid is treated with t-butyldimethylsilyl chloride (18 g) and imidazole (14 g) in dimethylformamide (120 mL) at room temperature with stirring for 18 hours. Water (300 mL) is added and the solution is extracted with diethyl ether (3×400 mL). The combined extracts are dried and concentrated. The oil is dissolved in methanol and a 20% solution of potassium carbonate (100 ml) is added. The solution is stirred two hours at room temperature and concentrated. Brine (100 mL) is added and the solution is made strongly acidic with concentrated hydrochloric acid (10 mL). The solution is extracted with diether ether (3×200 mL), dried, concentrated, and the oil is dissolved in acetic anhydride (150 ml). Triethylamine (94.5 ml) is added and the solution is heated at 90° C. for two hours. The solution is filtered hot and concentrated. Toluene is added and the solution is reconcentrated. Chromatography on SiO 2 elution with chloroform:methanol; 97:3, yields cis- and trans-2-t-butyldimethylsilyloxy-dihydro-1H-pyrrolizine-3,5-(2H,6H)-dione as a white solid with mp 156°-158° C. NMR (CDCl 3 ) and 4.62 (m, 1/2H), 4.43 (m, 1H), 4.06 (m, 1/2H), 2.83-1.63 (m, 6H), 1.05 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H). IR (KBr) 2930, 2859, 1782, 1702, 1474, 1377, 1314, 1281.
EXAMPLE VI
Preparation of 2-Hydroxy-dihydro-1H-pyrrolizine-3,5(2H,6H)-dione
A solution of 2-t-butyldimethylsilyloxy-dihydro-1H-pyrrolizine-3,5(2H,6H)-dione (2.1 g) in acetic acid:water, 3:1 (18 ml) is stirred at 60° C. for six hours. The solution is cooled, concentrated, toluene added and the solution reconcentrated. The oil is triturated with anhydrous ethyl ether and filtered to yield 2-hydroxy-dihydro-1H-pyrrolizine-3,5(2H,6H)-dione as a white solid with mp 135°-140° C. NMR (CDCl 3 ) and 5.48 (m, 1H), 4.47 (m, 1H), 4.10 (b.s., 1H), 2.93-1.36 (m, 6H). IR 3310, 2860, 1770, 1710, 1655, 1410, 1372, 1307, 1275.
PREPARATION OF NEW STARTING MATERIALS
A. Preparation of 5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid methyl ester
A suspension of 40 g of 4,5-dihydro-5-methoxycarbonyl-3-isoxazolepropanoic acid methyl ester and 2.0 g of PtO 2 in 400 ml of methanol is placed under a hydrogen atmosphere with agitation. After H 2 absorption is complete, the solution is filtered and the solvent removed under reduced pressure to give an oil. The oil is triturated with anhydrous diethyl ether to yield 5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid methyl ester as a white solid with mp 87°-90° C. NMR (CDCl 3 ) and 6.94 (s, 1H), 4.38 (m, 1H), 3.96 (d, 1H), 3.73 (m, 1H), 3.70 (s, 3H), 2.44-1.81 (m, 6H). Ir(KBr) 3330, 3200, 2980, 1734, 1696, 1436, 1416, 1400, 1382, 1362, 1313, 1297, 1246, 1212.
B. Preparation of 4-hydroxy-5-oxo-2-pyrrolidinepropanoic acid t-butyl ester
A suspension of 40 g of 4,5-dihydro-5-t-butoxycarbonyl-3-isoxazole-propanoic acid methyl ester and 2.0 g of PtO 2 /C in 400 ml of methanol is placed under a hydrogen atmosphere with agitation. After H 2 absorption is complete, the solution is filtered and the solvent removed under reduced pressure to give an oil. The oil is triturated with anhydrous diethyl ether to yield 4-hydroxy-5-oxo-2-pyrrolidinepropanoic acid t-butyl ester as a white solid with mp 94°-95° C. NMR (CDCl 3 ) and 6.83 (s, 1H), 4.42 (m, 1H), 3.93 (s, 1H), 3.70 (m, 1H), 2.78-1.66 (m, 6H), 1.47 (s, 9H). IR (KBr) 3320, 2980, 1732, 1705, 1456, 1417, 1353, 1368, 1295, 1260, 1214.
C. Preparation of 5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid t-butyl ester
A suspension of 105 of 4,5-dihydro-5-methoxycarbonyl-3-isoxazolepropanoic acid t-butyl ester and 2.0 g of PtO 2 /C in 1 L of methanol is placed under a hydrogen atmosphere with agitation. After H 2 absorption is complete, the solution is filtered and the solvent removed under reduced pressure to give an oil. The oil is titurated with anhydrous diethyl ether and filtered to yield 5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid t-butyl ester as a white solid with mp 110°-112° C. NMR (CDCl 3 ) and 6.38 (s, 1H), 4.13 (m, 1H), 3.87 (m, 1H), 3.27 (d, 1H), 2.47-1.60 (m, 6H), 7.53 (s, 9H). IR (KBr) 3460, 3245, 2978, 2938, 1723, 1686, 1426, 1392, 1372, 1318, 1277, 1256, 1209.
D. Preparation of 5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid
5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid, methyl ester (1.87 g), and Amberlite (IR--120 H + ) (1.9 g) in 20 ml of water is warned at 60° C. for 36 hours, filtered, and the solvent removed under reduced pressure. The resulting solid is washed with ethyl acetate and filtered to yield 5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid. NMR (DMSO D6 ) and 7.89 (d, J=11 Hz, 1HO, 5.35 (bs, 1H), 3.99 (m, 1HO, 3.44 (m, 1/2H), 3.30 (m, 1/2H), 2.48-1.21 (m, 6H). IR (cm -1 ) 3370, 3280, 2940, 1694, 1355, 1213, 1120.
E. Preparation of 4-hydroxy-5-oxo-2-pyrrolidine-propanoic acid
4-Hydroxy-5-oxo-2-pyrrolidinepropanoic acid t-butyl ester (1.87 g) and trifluoracetic acid (1.2 g) in 10 ml of N,N-dimethylformamide was heated at 100° C. until disappearance of starting material by thin layer chromatography. After concentration under reduced pressure, the resulting solid is washed with acetone and filtered to give 4-hydroxy-5-oxo-2-pyrrolidinepropanoic acid with mp 129°-132° C. NMR (DMSO D6 ) and 12.14 (s, 1H), 7.96 (d, J=5 Hz, 1H), 5.37 (m, 1H), 4.00 (m, 1H), 2.60-1.09 (m, 6H). IR (cm -1 ) 3420, 3080, 2030, 2920, 1698, 1494, 1387, 1284.
F. Preparation of 5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid benzyl ester
5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid (1.1 g), triethylamine (1.2 g), N-N-dimethylaminopyridine (1.5 g), and benzyl chloroformate (17 g) in 40 ml tetrahydrofuran is heated at reflux for 16 hours. After cooling and filtering off the triethylamine-hydrochloride, the solution was concentrated and chromatographed on SiO 2 (elution with methanol:chloroform; 3:97) to yield 5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid, benzyl ester mp 95°-96° C. NMR (CDCl 3 ) and 7.37 (s, 5H), 7.93 (d, 1H), 5.40 (s, 1H), 1.70 (m, 2H). IR (KBr) 3330, 3200, 1733, 1691, 1497, 1456, 1389, 1351, 1287, 1216.
G. Preparation of 4-nitrobutanoic acid t-butyl ester
To a stirred solution of 226 g (3.7 moles) of nitromethane and 5 g of aqueous 40% Triton B in 35 ml of t-butyl alcohol was added dropwise 56.7 g (0.53 moles) of t-butylacrylate. The reaction was cooled with an ice bath thought the reaction did not warm considerably. After stirring at room temperature for 18 hours, the solution was diluted with diethyl ether (500 ml) and washed with sat NH 4 Cl solution (2×200 ml). After drying over MgSO 4 , the solution was concentrated in vacuo and distilled.
Fraction 1
56-63 C. 0.15 mm 34.6 g 34% [4-nitrobutanoic acid t-butyl ester]
Fraction 2
142-148 C. 0.05 mm 19.6 g 12% [4-nitroheptanedioic acid di-t-butylester]
Fraction 1
NMR(CDCl 3 ) 4.50 (t, J=6H 2 , 2H), 2.40 (m, 4H), 1.43 (s, 9H)
IR (cm -1 ) 2975, 2940, 1736, 1555, 1483, 1460, 1440
Fraction 2
NMR(CDCl 3 ) 4.57 (m, 1H), 2.16 (m, 8HO), 1.46 (s, 9H),
IR (cm -1 ) 2981, 2938, 1731, 1554, 1458, 1425, 1395, 1370
H. Preparation of 4,5-Dihydro-5-(methoxycarbonyl)-3-isoxazolepropanoic acid methyl ester
A solution of 23.8 g of 4-nitrobutyric acid methyl ester (made in accordance with Bruson, U.S. Pat. No. 2,342,119) 39.6 g of methyl acrylate, 0.2 g triethyl amine in 200 ml of toluene is stirred and treated dropwise with 23.8 g of phenyl isocyanate. The mixture is stirred for 72 hours at room temperature and heated at 90° C. for two hours. The mixture is cooled, filtered to remove the diphyl urea, and concentrated under reduced pressure. The resulting oil is chromatographed on SiO 2 (elution with hexane:ethyl-acetate; 75:25) to yield 4,5-dihydro-5-(methoxycarbonyl)-3-isoxazolepropanoic acid methyl ester as a colorless oil. NMR (CDCl 3 ) and 4.93 (t, J=9 Hz, 1H), 3.72 (s, 3H), 3.63 (s, 3H), 3.20 (d, J-9 Hz, 2H9, 2.61 (s, 4H). IR (KBr) 2956, 2851, 1739, 1632, 1439, 1367, 1340, 1215. IR (cm -1 ).
I. Preparation of 4,5-dihydro-5-(methoxycarbonyl)-3-isoxazolepropanoic acid t-butyl ester
A solution of 18.9 g of 4-nitrobutyric acid t-butyl ester, 8.6 g of methyl acrylate, 0.2 g triethyl amine in 200 ml of toluene is stirred and treated dropwise with 27.4 g of phenyl isocyanate. The mixture is stirred for 72 hours at room temperature and heated at 90° C. for two hours. The mixture is cooled, filtered to remove the diphenyl urea, and concentrated under reduced pressure. The resulting oil is chromatographed on SiO 2 (elution with hexane:ethylacetate; 75:25) to yield 4,5-dihydro-5-(methoxycarbonyl)-3-isoxazolepropanoic acid t-butyl ester as a colorless oil. NMR (CDCl 3 ) and 5.00 (t, J=9 Hz, 1H), 3.77 (s, 3HO, 3.28 (d, J=9 Hz, 2H), 2.58 (s, 4H), 1.42 (s, 9H). IR (cm -1 ) 2955, 2910, 1728, 1545, 1437, 1385, 1370, 1340, 12155, 1215.
J. Preparation of 4,5-dihydro-5-(t-butoxycarbonyl)-3-isoxazolepropanoic acid methyl ester
A solution of 105 g of 4-nitrobutyric acid methyl ester (Bruson U.S. Pat. No. 2,342,119), 64 g of t-butyl acrylate, 1 ml triethyl amine in 200 ml of toluene is stirred and treated dropwise with 137 g of phenyl isocyanate. The mixture is stirred for 72 hours at room temperature and heated at 90° C. for two hours. The mixture is cooled, filtered to remove the diphenyl urea, and concentrated under reduced pressure. The resulting oil is chromatographed on elution with hexane:ethyl-acetate; 75:25) to yield 4,5-dihydro 5-(t-butoxycarbonyl)-3-isoxazolepropanoic acid methyl ester as a colorless oil. NMR (CDCl 3 ) and 4.87 (t, J=9 Hz, 1H), 3.70 (s, 3H), 3.20 (d, J=9 Hz, 2HO, 2.67 (s, 4H), 1.47 (s, 9H). IR (cm -1 ) 2970, 1740, 1600, 1556, 1445, 1396, 1373, 1340, 1300, 1262, 1230.
EFFECTIVENESS AGAINST ECS-INDUCED AMNESIA
The effectiveness of the aforementioned compounds is determined by a test designed to show a compound's ability to reverse amnesia produced by electroconvulsive shock. The test is fully described in U.S. Pat. No. 4,145,347, which is herein incorporated by reference. The only differences between the test set out in the patent and the instant test being that the test compounds in the present instance are administered orally and the length of the electroconvulsive shock is 1.0 seconds in duration.
The following criteria are used in interpreting the percent of amnesia reveral scores: 40 percent or more (active=A), 25 to 39 percent (borderline=C) and 0 to 24 percent (inactive=N).
The percent of amnesia reversal of orally administered cis- and trans-2-acetoxy-dihydro-1H-pyrrolizine-3,5(2H,6H)-dione follows:
______________________________________Amnesia Reversal %mg/kg1 10 100______________________________________50 (A) 14 (N) 60 (A)______________________________________
Reasonable variations, such as those which would occur to a skilled artisan, can be made herein without departing from the scope of the invention. | Novel derivatives of substituted pyrrolizine diones, isomers, and pharmaceutically acceptable derivatives thereof, have therapeutic utility for reducing amnesia induced by electroconvulsive shock and for treating senility. | 2 |
DESCRIPTION
[0001] The invention concerns an apparatus for the simultaneous dialysis of a plurality of liquid samples, which are contained in sample wells in a sample plate, and have been brought to this sample plate for a dialysis separation by at lest one semipermeable membrane which is in contact with a dialysate. Such a dialysis system can find general application where, for analytical purposes, specifically a plurality of liquid microsamples is to be investigated regarding their the macro-molecular apportionment and from which microsamples, low molecular weight molecules, which would disturb the analysis, must be separated. The separation is to be carried out in an efficient, easily manipulated manner and at the lowest possible expense. Beyond this, the dialysis system is to be applied advantageously in order to concentrate macromolecular containing microsamples quickly, protectively and without substantial loss. A further area of application is the buffering of samples, especially in the range of the DNA-treatment, for the investigation of proteins and in the case of sequentially occurring enzymatic reactions.
[0002] In recent years, highly parallel screening techniques, such as High Throughput Screening=HTS and Ultra High Throughput Screening=UHTS, have been showing up as analytical methods very frequently in analytical work. This has been especially aided by the efforts of the pharmaceutical industry for the capture of targets for the development of newer pharmaceuticals. Also, the proteomanic analysis is vigorously developing itself, and enables a very high sample throughput for the characterization of a multiplicity of proteins of a proteome with biological modifications both in various conditions, such a healthy and ill. Beyond this, the said proteomic analysis is an indispensable aid for many application ranges in biochemical and biotechnical research with high throughput analyses, for example, for the characterization of enzymes in regard to their activity, for the characterization of analytical and preparative chromatographic separations, for the mass centered renaturation of protein samples and for the characterization of nucleic acids.
[0003] These high throughput procedures have led, in their general range, to acceptable auxiliary technologies for the development of special analysis procedures. For example, these group themselves around a microtiter of 8×12 analysis positions in the basic area of a well plate of about 12.6×8.6 cm. At the present time, attention is given to a trend for even further compression of the analysis positions on the same basic area of n×8×12, where n can equal 4, or even 16 and further to more densely compacted multiple well plates. Very frequently, the materials of interest can be macromolecular substances such as DNA and its fractionates, proteins, peptides, glycoprotein and synthetic macromolecules as well as combinations of these substances.
[0004] Two additional and new procedures, MALDI-MS (Matrix Assisted Laser Desorption Ionization Mass Spectrometry) and ESI-MS (Electrospray Ionization Mass Spectrometry) have been recently developed in the last few years, and have proved themselves as excellent procedures for HTS/UHTS and for the proteomic analysis. In this case, especially in combination with protease digestion methods. In general, a strong tendency toward miniaturization of the methods of analysis must be recognized. Many procedures for the high-throughput screening method show a strong demand for sample preparation with high requirements. Some of the requirements are listed below:
1. the samples may contain only a low concentration of salt or detergent, or the samples must be found in a specific millieu of ionization, 2. the samples, which lie in the μl-volume range, must be treated in a highly parallelized manner, in order to guarantee the required analysis frequency, The treatment must be carried out, uniformly and under standardized conditions for all samples, 3. the recovery for these microsamples in the process of the sample preparation, must be satisfactorily high, and 4. frequently, samples of biological material must be protectively concentrated before the analysis, in order to achieve the necessary desired level of concentration.
[0009] For the removal of low-molecular substances, for the transfer of the samples into a defined millieu and for the concentration of macromolecular materials, excellent results have been acquired with the dialysis procedure requiring the use of semi permeable membranes. Consequently, there has arisen a greater number firms offering dialysis procedures, which, for example, can be found collected together under the address of http://biosupplynet.com.
[0010] The principal effort of the firms and the inventors for the improvement of the dialysis technology, addresses those problems, which relate to the practical manipulation of the technology. Some of the problems to be overcome are: mixing, recovery of macromolecules, difficulties with the speed of the dialysis process, and operations which are connected with small volumes, i.e., in the μl-range.
[0011] Where the MALDI and the ESI-MS procedures are concerned, the present state of the technology finds the removal of salts, detergents and other contaminating substances necessary.
[0012] Possibilities, which could improve the quality of the essential mixing of a dialysis solution, are described in U.S. Pat. No. 5,183,564 and in U.S. Pat. No. 6,176,609. U.S. Pat. No. 6,176,609 in particular describes a general procedure for mixing in a plurality of vessels. Giving consideration to the universal trend for miniaturization, a series of solutions were suggested. Also, U.S. Pat. No. 6,039,871 teaches of equipment which can be looked at as being disposable and the dialysis of 10 to 100 μl samples is foreseen as being in special vessels which can be encapsulated, one in the other. In U.S. Pat. No. 5,733,442 a closed microdialysis system is proposed, which is marked by microchambers, which can be screwed together, and possess two dialysis membranes and a special stirring device.
[0013] The difficulties which arise in connection with recovery of small analyte volumes is given attention by the inclusion of a special capture chamber in U.S. Pat. No. 6,217,772.
[0014] In the documents U.S. Pat. No. 5,783,075 and U.S. Pat. No. 5,503,741 a proposal for floating dialysis in vessels of a special configuration is made known. Where the floating dialysis is concerned, there are also offerings from the firm PGC, the firm Daigger and the firm Pierce, where the widely publicized slide dialysis system is treated.
[0015] In order to increase the rapidity of the dialysis, giving consideration to the ESI-MS technology, a capillary dialysis system is taught by U.S. Pat. No. 5,954,959.
[0016] Where a multiplicity of samples must be treated, proposals are put forth in U.S. Pat. No. 4,450,076. In these proposals the dialysis vessel is placed about a central axle, and is turned by means of rotation. Offers from PGC Scientifics Corp. bring forward a central axis oriented, equilibrium chamber, which is sealed by Teflon coated screws. Pierce Biotechnology, Inc. offers a microdialysis system for 12×20−100 μl volumes.
[0017] The proposed solutions of the problem, however, are not adaptable to the demands of higher throughputs, such as are necessary for HTS, UHTS and for proteomic analysis because of the following, because they:
1. are not acceptable for highly parallel microplate technology especially where corresponding liquid treatment is necessary, 2. a simultaneous and essentially uniform dialysis executed for all samples in a greater sample count in the μl range is prohibited, 3. a satisfactorily sufficient recovery of these small volumes fro secondary analytical procedures is not allowable, 4. a correspondingly high dialysis speed is not provided, 5. the volumes required for the dialysate are inadequately large, or 6. because of their complicated manner of application, the said solutions are not practical in routine operation with a high throughput.
[0024] Thus, the invention has the purpose, of dialysing simultaneously a multiplicity of micro samples in the μl-range essentially uniformly, wherein the manipulation is easily carried out and at as low a cost as possible, whereby these dialyses can be executed quickly and, if required, in an automatized manner, within the requirements of the modem screen and analysis methods.
[0025] In the case of a large throughput of samples, the dialysis permits a sufficiently high recovery of small volumes for secondary analytical procedures.
[0026] In accord with the purpose of the present invention, there is proposed an apparatus for the simultaneous dialysis of a plurality of liquid samples, wherein:
there is included a dialysis vessel with a dialysate as well as means for the inflow and outflow of the dialysate, which remain in connection with a level control, there is included at least one sample plate, which is either immersed in, or is in contact with, the surface of the dialysate, as well as being held by holding elements, in or on the surface of the dialysate, with a matrix (n×8×12) arrangement of a plurality of equal sample wells, which arrangement is acceptable and known for liquid handling technique in microplate technology and said wells have holding capacities for microliter volumes, whereby, of the sample wells, respectively, the upper ends are open and the lower ends are closed by a semipermeable membrane lying in a plane, and the sample plate in the area of the said matrix of the matrix of the sample wells has no gas barrier forming or supporting zones or elements which extend beyond the plane of the semipermeable membrane and the said sample plate 3 has, in its rim areas, elements, such as openings for the release of air imprisoned by touching contact with the dialysate, and besides the above, the said apparatus contains means for the movement of the plate and the dialysate.
[0030] Enabled by the acceptability of the sample plate used in the dialysis system, for the said liquid handling technique for the microplate technology of liquid, samples can be prepared with a high degree of throughput in accord with this technology, then subsequently be employed for their purpose and finally recovered for further use. With the special design of the sample plate, those air barriers which obstruct the dialysis upon the immersion of, or the displacement of the plate into or onto the dialysate surface are avoided. Should procedurally evolved gases migrate into the contact zone between the dialysate and the sample plate, then these can be forced out by deaerating apparatuses, so that in any case, an unbroken contact can be assured between the dialysate and the sample plate without the said gas barriers, such as air bubbles and the like. This disturbance-free contact is an essential presupposition for simultaneous and essentially uniform dialysis for each of the large number of samples in the μl range. This effect is essentially supported by the movement of the sample liquids and the dialysate, so that, predominately, no secondary membrane formation between the dialysate and the sample volumes can form and the dialysis can continue with unbroken continuity. To serve this purpose, the dialysis vessel possesses at least one entry and one exit opening, in order that the materials which are accumulated in the dialysate can again be continuously expelled from the said dialysate and continually a dialysate with equal dialysis acceptance power remains available in the system. The entry and exit flows are, meanwhile, connected by a level control, in order to hold constant the conditions of dialysis on the semipermeable contact between the sample liquid and the dialysate, thus maintaining the above advantages with consideration for level control.
[0031] By means of the movement of not only the dialysate, but also of the sample liquid, this movement being done by a known shaking device, with which the sample plate is connected, not only is the high dialysis effectivity itself attained, but also special usages, notably dialysis-effectivity is achieved. Of the latter, a dialysis of detergents which form micellla, is already enabled.
[0032] With the above stated features, the realization of variously designed dialysis systems is enabled, wherein the said dialysis systems can carry out different applications, either manually or with automatic drive, these being independent therefrom, as to whether the sample plate, for instance, by means of a pivot or a shaking arm lies on the dialysis vessel or floats in the dialysate which is present in the container.
[0033] In the most simple case, without limiting the invention, the sample plate may consist of a plate with cylindrical recesses or wells in the receiving means for microliter volumes. On the underside of the sample plate are the borings (sample containing recesses) either respectively closed by a common or by individual dialysis membranes, which, for example, are adhesively held on the underside of the plate. They may also be welded, bonded, or sprayed on. The dialysis membranes can also consist of more than one layer.
[0034] A cover or an adhesive film of a releasable closure of the upper end of the sample vessel protects the sample material which is in the sample wells, and blocks any evaporation and contamination of the small quantity of sample in the microliter range.
[0035] Described and explained in the subordinate claims, are a multitude of advantageous embodiments of the invented features. In this way, the dialysis vessel with the accepted sample plate becomes an integral part of a circulation system. In such a circulation system, for example, with a pump controlled, recycling apparatus, it is possible that an ion-exchange device or a detergent capturing adsorber could be placed. Such an addition would hold the concentration of the substances which are to be removed from the dialysate to a very small level, and thereby the speed of the dialysis procedure would be increased and the necessary volumes of the dialysate would be simultaneously minimized. Also the use of bound substances which form complex substances is possible, in order to remove metal ions.
[0036] In the following, the invention is described and explained with the aid of embodiments as shown in the drawing. There is shown in:
[0037] FIG. 1 : A sample plate, secured at the base of a dialysis vessel by feet,
[0038] FIG. 2 : An apparatus with a floating holder of the sample plate on the surface of the dialysate,
[0039] FIG. 3 : A dialysis vessel with the holder of the sample plate in accord with FIG. 1 , with both entry and exit fittings for the dialysate.
[0040] FIG. 4 : A dialysis vessel with a sample plate in a circulation system for the removal of interfering substances from the dialysate,
[0041] FIG. 5 : An apparatus for dialysis, wherein the sample plate is held in a shaking device to create turbulence in said dialysis apparatus,
[0042] FIG. 6 : A floating holding means for the sample plate (see FIG. 2 ) with conical sample wells,
[0043] FIG. 7 : A sequential run of a procedure to transfer dialyzed sample material subjected to centrifugation out of the sample plate with conical sample wells into a receiving plate with cylindrical wells,
[0044] FIG. 8 : A second sequential run of a procedure similar to FIG. 7 , showing a sealing means between the sample plate and the receiving plate, and
[0045] FIG. 9 : A graph showing the conductivity of the dialysate during a period of dialysis.
[0046] In FIG. 1 is shown a dialysis container 1 with a dialysate 2 therein. On the bottom of, and within the dialysis container, is to be found a sample plate 3 , which is secured by a holder 4 . This sample plate 3 consists of a plate shaped, basic body in which, and within the specifications of a known liquid handling technique for acceptable microplate technology, is placed an 8×12 matrix of aligned cylindrical wells 5 for the acceptance of sample material 6 , the content of each well being in the microliter range.
[0047] On the underside of the sample late 3 is found a dialysis membrane 7 , this membrane being semipermeable, common to all sample wells and secured on the rims thereof by adhesive. By means of this dialysis membrane 7 , each individual portion of the sample material 6 , which is within the wells 5 , stands respectively in contact with the dialysate 2 . For this purpose, the sample plate 3 is so supported by the holder 4 , that the said plate 4 is immersed, with its dialysis membrane 7 , into the dialysate. By means of the dialysis membrane 7 , the exchange of small molecules is possible, in accord with the exclusion threshold, since a concentration equilibrium between the dialysate 2 and the liquids of the sample material 6 is in force. The removal of the said small molecules out of the material 6 of the samples is accomplished by the effort of the said solutions to establish the mentioned equilibrium between the two compartments. Large molecules are restrained from passing through the dialysis membrane 7 .
[0048] The plane of the dialysis membrane 7 incorporates, in a way, also the lowest level of the sample plate 3 , during its operation in accord with its application. There exists in this matrix area of the sample wells 5 no zones or elements for stabilization fastening, manipulation or the like, or even yet areas dependent upon fabrication, which would protrude from the sample plate 3 outward and beyond, which would contactingly impinge on the dialysate 2 , or be immersed therein. Further the arrangement is such that no extension of the said zones or elements exist, which would interfere with the uniformly running dialysis process by introducing air or creating air barriers.
[0049] By means of a known magnetic stirrer 8 on the bottom of the dialysis container 1 , the dialysate is held in motion, in order that a concentration gradient on the dialysis membrane 7 be held as small as possible and also to accelerate the dialysis. An adhesive foil 9 , serving as a releasable closure of the upper rims of the sample wells 5 , protects the sample material 6 which is found therein and prevents an evaporation or a contamination of the sample very small volumes.
[0050] FIG. 2 depicts a construction, which is very similar to that of FIG. 1 . The difference, in this case, is that the sample plate 3 is not supported by foot or structural holding elements 4 rigidly connected to the bottom of the dialysis container 1 , but is held by means of a framelike, float element 10 directly on the surface of the dialysate. This is accomplished in such a manner, that the dialysis membrane 7 lies on this surface. This mode of holding is independent of the level of the dialysate 2 in the dialysis container 1 .
[0051] Additionally, the sample plate 3 has air escape openings 11 , which allow gas collecting under the sample plate 3 to bleed out, thereby assuring an unbroken contact of the dialysis membrane 7 with the surface of the dialysate 2 . This complete contact coverage forms the necessary preparation for a simultaneous and essentially uniformly completed dialysis for each sample of this large number of samples in the μl-volume range.
[0052] Because the sample plate 3 , at least in the matrix area of the sample wells 5 , possesses no elements (for holding or the like), which would protrude downward beneath the plane of the dialysis membrane 7 and thus immerse themselves in the dialysate 2 or cause turbulence in the same, either of which would disturb the desired uniformity of simultaneous analyses, very quickly essential characteristics for value-determining usage of the sample plate 3 in a dialysis system were immediately taken advantage of, in order to avoid air locks, or at least not to support them, in the contact zone of the dialysate 2 against the sample plate 3 . If, nevertheless, gases evolved from processing appeared in this zone, then, these gases, as mentioned above, could disperse through the air escape openings 11 and emerge above trough the sample plate 3 . Instead of the air escape openings 11 , other gas dispersing elements were given consideration, such as edge phase-changing, or the like. To enhance clarity, details of the air escape openings 11 (or other deaeration equipment) were not explicitly shown in each figure presentation.
[0053] FIG. 3 shows an apparatus for dialysis, wherein the sample plate 3 (as in FIG. 1 ) is supported in the interior of the dialysis container 1 on the floor thereof by means of feet or standard holding devices 4 . The dialysis container 1 possesses in this case, a feed fitting 12 as well as a outlet fitting 13 for the dialysate 2 . The level of the dialysate 2 is regulated by means of an adjustable float 14 with a float actuated valve 15 . In this case, the float 14 is guided to be vertically movable in a float track 16 . The advantage of this, is to be found in the continuous content balancing of the dialysate 2 . In this way, the adjustment of a concentration equilibrium between the dialysate 2 and the respective sample material 6 contained in the wells 5 can be avoided, also the speed of the dialysis is greater and the removal of low molecular substances from the sample material 6 is fundamentally improved. Naturally, the float valve system ( 12 - 17 ) can be replaced by an electronic level controller which regulates the feed at inlet 12 .
[0054] FIG. 4 shows an apparatus for dialysis, wherein the dialysis container 1 , which is shown in top view, demonstrates the therein placed sample plate 3 (see FIGS. 1 and 3 ), and shows the inlet 12 as well as the outlet 13 as being components of the circulation system for the through-flow of the dialysate 2 . The exchange of the dialysate 2 not carried out, as in the apparatus of FIG. 3 , through an open system, but rather by the dialysate 2 being transported by a pump 17 , through a filter cartridge 18 and into a line 19 , with the circulation system being completed by passage through the dialysis container 1 . The direction of the dialysate 2 is indicated by an arrow, whereby the black arrows symbolize the exit flow of the dialysate 2 . Upon its exit out of the dialysis container 1 , the dialysate 2 , for example, can be enriched with ions and/or detergents from the sample material 6 . By means of one or more sorbents in the filter cartridge 18 , these components can be removed from circulation. The cleaned dialysate 2 thus migrates, as the white arrows show, back into the dialysis container 1 . Advantageously, here, the ubiquitous applicability of the dialysate 2 contributes to:
(a) the said avoidance of the adjustment of a concentration equilibrium, between the dialysate 2 and the sample material 6 held respectively in the sample wells 5 and (b) the thereto connected advantages for dialysis (see the embodiment example of FIG. 3 ).
[0057] FIG. 5 depicts an apparatus for dialysis (once again sectional profile and top views), wherein the sample plate 3 is neither anchored to the bottom of the dialysis container 1 (see FIG. 1 ) nor is it floating on the dialysate 2 surface in the said dialysis container 1 (see FIG. 2 ). Rather the sample plate 3 is held by a holder 20 , which is also connected to a shaking device 22 through a shaker arm 21 . The shaker 22 serves, as the white, crossed arrows indicate, for the horizontal movement of the sample plate 3 along the surface of the dialysate 2 and also moves the sample plate 3 within the amplitude and frequency limits as directed for a shaker installed for microtiter sample plates as these limits are defined for laboratory operation. In this way, the sample material 6 found in the sample wells 5 of the sample plate 3 is thoroughly mixed, which acts against the establishment of concentration gradients in the said sample material 6 , as well as in the dialysate 2 , which the shaker 8 also affects. This has the favorable advantage, that the somewhat hindering construction of secondary membranes, which are necessary for many dialysis processes, may be omitted. Also, the transporting away of gas bubbles in the area of the membrane is favored by this shaking motion.
[0058] The advantage of this apparatus is, that not only is the recirculation and cleaning associated with the content balance of the dialysate 2 , as is described for the embodiments of FIG. 3, 4 , omitted, but also the speed and completeness of the dialysis is improved. To preserve clarity, a combined presentation with the said, and previously described embodiments, is not specifically illustrated in the attached drawings. In an additional embodiment example, not shown here, the motion of the samples and dialysate can be carried out with the same positive effects also by being coupled with an ultrasonic mixer.
[0059] FIG. 6 shows (likewise in sectional profile and top views) an apparatus for dialysis, wherein the sample plate 3 , as is the case in FIG. 2 , floats on the surface of the dialysate 2 . The sample plate 3 does not possess, as was the case in the previously described embodiments, sample wells with cylindrically parallel walls, but sample wells 5 a which are conically tapered, in the form of a cone frustum with respectively larger lower openings, which are closed by the dialysis membrane 7 . The said wells 5 a have, in comparison to the lower openings, smaller upper openings. The smaller upper openings create an advantageous shape-closure (see FIG. 7 ) for the transfer of the sample material 6 after the dialysis (following the dialysis) into the individual well volumes, in the same matrix in another sample receiver plate. This procedure is in accord with known microtiter plate technology. Easily recognizable in the top view presentation of FIG. 6 is adhesive foil 9 over the matrix arrangement of the sample wells 5 a , which foil prevents evaporation, spilling, and contamination of the sample material 6 , which is in the wells 5 a during the dialysis or can occur even during transport.
[0060] FIGS. 7, 8 show, schematically, respectively in sectional views through the plate, a sequential run of the procedure through centrifugation, out of the sample plate 3 with conical sample wells (see FIG. 6 ) into a receiver plate 23 with cylindrical wells. The receiving plate 23 , in an upset position, is placed on top of the sample plate 3 , whereupon the two are turned over in common. By means of centrifugation, the sample material 6 , which is originally in the sample plate 3 is transferred to the receiver plate 23 . Subsequently, the sample plate 3 and the receiver plate 23 are taken apart. As a centrifugal device, the known laboratory centrifuge for microtiter plates can be used. In FIG. 7 , the upper openings of the wells 5 are smaller than the openings of the sample container of the receiver plate 23 which confronts them. On this account, the already described satisfactory shape-fit assures the penetrative interconnection as shown in the drawing 7 . Conversely, in FIG. 8 , we see the confronting well openings of the sample plate 3 and the receiving plate 23 respectively equal in size. In this case, a required tighter shape fit is assured by means of an intermediately inserted sealing means 24 between the sample plate 3 and the sample plate 23 .
[0061] In the following four embodiments is shown, how, with the described apparatuses, different substances can be dialyzed.
APPLICATION EXAMPLE NO. 1
[0062] Low-molecular substances in 96 samples such as p-nitrophenol (p-NP) and sodium chloride, are to be uniformly removed, in short dialysis periods, wherein the reception of the sample plate 3 in a shaking device (see FIG. 5 ) is provided and which said plate 3 , in accord with FIG. 4 , is connected into a circulating system for the dialysate 2 .
[0063] For this situation, into the 8×12 dialysis wells, which are closed with a VSMP Millipore membrane (0.025 μm), each 100 μl of a 1.5 mM p-NP solution in 50-mM diethanol-amine buffer pH=9.8 (DEA), which, in addition, contains 750 mM NaCl, is pipetted and dialyzed against a volume, which is only 11 times greater than a volume of 110 ml deionized water for 2 hours. The dialysate 2 is circulated by a hose pump. In the circuit is integrated a deionizing column (Eco Pac, 10 ml, Bio Rad) (see FIG. 4 ). During the dialysis, the sample plate 3 is continually shaken, which sample plate is closed with adhesive foil 9 and is fastened in the holder 20 of the shaping apparatus (see FIG. 5 ). The effectivity of the separation of the lower molecular nitrophenols following the dialysis is checked with the absorbencies of the outlet solution. The absorbency measurement of the outlet solution, which emerges from the dialysis, is carried out with a DEA-buffer solution, pH=9.8 in a microtiter plate and the absorbencies read off on a display. For the absorbency measurement of the 96 dialyzed samples, 3 aliquots are taken by pipette from the sample plate 3 , with 50 mM DEA-buffer solution pH=9.8, mixed in a microtiter plate and measured in a display.
[0064] The comparison of the absorbency in the 96 positions of the dialysis module is shown in Table 1. The measured absorbencies have been reduced by the blind buffer value.
TABLE 1 Comparison of the Absorbencies at 405 nm (A 405 ) before and after Dialysis A 405 Analysis Dilution Solution Factor Av. Val. Analysis Samples (n = 96) Solution A 405 Total p-NP(%) p-NP pre Dialysis 0.397 ± 0.005 30 11.910 100 p-NP post Dialysis 0.028 ± 0.002 3.75 0.105 0.88
[0065] The values indicate, that under the described conditions, more than 99% of the p-NP can be removed. The distribution of the absorbency values after the dialysis show, that the dialysis speed in all 96 dialysis wells is very much the same. Besides the comparison of the absorbencies before and after the dialysis, the conductivities of the employed samples were measured and were compared with the conductivities after the dialysis of the 96 dialysis wells. From these values a residual capability of conductivity was determined, in relation to the outlet solution of 0.2%, which, in any case, confirms the effectivity of the dialysis.
APPLICATION EXAMPLE NO. 2
[0066] For the removal of lower molecular ions from proteins, in 8×11 positions of the sample plate 3 , per well, 75 μl of concentrated solution of an alkaline phosphatase (14.5 μg/ml) was added to IM DEA buffer pH=9.8, and dialyzed for one hour against a large volume of 470 ml deionized water. The sample plate 3 , which is placed as a floating element 10 on a polysterol framing, and floats on the dialysate 2 , which is kept in motion by the magnetic stirrer 8 (see FIG. 2 ). The continuous removal of the low molecular substances in the sample wells 5 is monitored by the measurement of the conductivity (see FIG. 9 ) in the said dialysate 2 .
[0067] After 60 minutes of dialyzation, 60% of the ions which can be dialyzed have been removed. The determination of the enzymatic activities of the alkaline phosphatase in the 88 occupied dialyzation wells of the sample plate 3 and a comparison of the enzymatic activity with the outlet solution yielded a recovery of the enzymatic activity of 90.4+4.3%.
APPLICATION EXAMPLE NO. 3
[0068] On the example of Triton X-100 (TX-100), the point is to determine, if it is possible to remove this much used detergent by dialysis from analysis samples. To this end the sample plate 3 is, respective by wells, charged with 7511 of a 0.5% aqueous solution of Triton X-100 and dialyzed for 8 hours vs tap water. The sample plate 3 was closed by adhesive foil 9 , and again placed in the holder 20 of the shaker apparatus (see FIG. 5 ) for continuous agitation. During this part of the operation, the same was immersed in 170 ml of tap water as a dialysate 2 , which was renewed at flow rate of 170 Ml/min in a circulation system in accord with FIG. 4 .
[0069] In order to capture eventual volume changes, the sample plate 3 was weighed before and after the dialysis. For the determination of the effectivity of the removal of the Triton by dialysis, aliquots were taken by multipipettes from the dialysis containers of the module, mixed in a microtiter plate with 30% n-propanol and measured in a fluorescence display at an excitation wave length of 270 nm from an emission wave length of 310 nm. The Triton X-100 which was subjected to dialyzation, after dilution in 30% n-propanol was measured under the same conditions in a microtiter plate. For the correction of the measured values and for the regulation of the linearity of the range of measurement, both the propanol solution in 56 positions of the microtiter plate (blind values) and three standard concentrations of Triton X-100, between 12.5 and 50 μM under the same conditions were measured. The results are summarized in Table 2. The measured average values were reduced by the determined propanol blind value:
Dilution Fluorescent Factor Analysis Solution Analysis Fluorescence Samples Av. Val. (n = 96) Solution Total TX-100 (%) TX-100 739.6 ± 11.83 201 148 660 100 pre Dialysis TX-100 62.39 ± 6.24 30 1 872 1.26 post Dialysis
The measured fluorescences following the dialysis in the 96 dialysis wells of the sample plate 3 show, that under the described conditions, 98.7% of the Triton X-100 was uniformly removed from all 96 of the dialysis wells.
APPLICATION EXAMPLE NO. 4
[0071] The sample plate 3 can also be employed for the simultaneous concentration of 96 samples. For this purpose, in accord with each well, 100 μl of a 0.3% Dextra-blueing solution with a multi-pipette was placed in the sample wells 5 of the sample plate 3 . The sample plate 3 was subsequently fixed on the floating frames 10 (see FIG. 2 ) of polysterol, which were laid on 100 ml of a 30% aqueous polyethylene glycol solution (PEG 40 000). After 45 minutes, the volume reduction was quantitatively determined. To this, from 88 out of the 96 positions was taken, per position, 30 μl with a multi-pipette and transferred into a microtiter plate, which, per container, contained 120 μl 50 mM DEA-buffer solution. In the remaining 8 positions of the microtiter plate, instead of the sample solution, each was given 30 μl reference solution (0.3% Dextra-blueing solution). The microtiter plate was then, after intensive mixing, measured in a display at 620 nm. A comparison of the determined absorbency of samples and reference solution shows, under the described conditions, the measured absorbency.
TABLE 3 Comparison of the Absorbency of Dextra Blueing before and after concentration Samples A 620 Reference Solution 0.291 ± 0.012 (n = 8) Samples after Concentration 0.465 ± 0.020 (n = 88)
[0072] The absorbencies have increased by a factor of 1 . 6 . That means, that after 45 minutes the volume of the samples is reduced by 37 . 5 μl, and indeed relatively uniformly, as may be seen by the distribution.
APPLICATION EXAMPLE NO. 5
[0073] For the dialysis of plasmid DNA, in a 96 well dialysis-plate, 110 μl of the samples having plasmid DNA pc DNA3.1hcSΔE44-N63(6.5 kb) was treated against buffer Tris 10 mM pH 8 and subjected to shaking and mixing. To the samples, paranitrophenol (PNP) was added in the end concentration of 978 μM and the reduction of the concentration was measured respectively after two and four hours.
[0074] The content of DNA in the samples was likewise determined after two and four hours in, respectively, eight parallel samples of a concentration with the aid of optical density. The detection was carried out at 400 nm for PNP and 260 nm for the plasmid DNA.
[0075] The table below shows the balance of the plasmid-DNA: That is, the concentrations were computed with a standard series of plasmids by optical density.
[0076] Table:
After 4-hour Output DNA Dialyzation, DNA in μg/ml in μg/ml 5 4.55 10 9.32 50 50.79
[0077] The balance of PNP in the samples, as per a standard series for the samples where n=32:
PNP after 2 hour PNP after 4 hour Item Output PNP Dialysis Dialysis Concentration in the 978.6 38.96 0.56 sample in μM Standard deviation 1.01 4.6 0.60 in μM % from output 100 3.9 0.06
Reference Numbers and Corresponding Components
1 Dialysis container 2 Dialysate 3 Sample plate 4 Holder 5 Well, ( 5 a conical tapered well) 6 Material of the sample 7 Dialysis membrane 8 Magnetic stirrer 9 Adhesive foil 10 Float element 11 Air escape opening 12 Entry fitting (feed) 13 Outlet fitting (exit) 14 Float 15 Float valve 16 Float guide 17 Pump 18 Filter cartridge 19 Line, for circulation of liquid 20 Holder ( FIG. 5 ) 21 Shaker arm 22 Shaker 23 Receiving plate (receives contents of 3 ) 24 Sealing means | The invention elates to a device for the simultaneous dialysis of a number of fluid samples, comprising a vessel for the dialysis fluid, with an inlet and outlet, a fill-level regulation and a sample plate ( 3 ) with a number of similar sample vessels ( 5 ) of μl range size, arranged in a raster (n×8×12), the upper ends of which are open and the lower ends of which are sealed by a semi-permeable membrane ( 7 ) lying in a plane. In the raster region of the sample vessels ( 5 ), the sample plate has no regions or elements which extend beyond the plane of the membrane ( 7 ), or which form or support gas barriers after dipping in the dialysis fluid ( 2 ). The sample plate ( 3 ) comprises elements in the boundary region thereof for the escape of air after dipping in the dialysis fluid. Both sample fluids and dialysis fluids are agitated. | 1 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to PCT/eP2014/060952 filed May 27, 2014, which in turn claims priority to European Patent Application No. 13172553.3 filed Jun. 18, 2013, both of which are hereby incorporated in its entirety.
TECHNICAL FIELD
[0002] The present invention relates to the technology of producing a three-dimensional article by means of selective laser melting (SLM). It refers to a method for producing an article or at least a part of such an article preferably made of a gamma prime (γ′) precipitation hardened nickel base superalloy with a high volume fraction (>25%) of gamma-prima phase or of a non-castable or difficult to machine material and to an article made with said method. More particularly, the method relates to producing of new or repairing of used and damaged turbine components.
BACKGROUND
[0003] Gas turbine components, such as turbine blades, often have complex three-dimensional geometries that may have difficult fabrication and repair issues.
[0004] The build-up of material on ex-service turbine components, for example during reconditioning, is usually done by conventional build-up welding such as tungsten inert gas (TIG) welding or laser metal forming (LMF). The use of these techniques is limited to materials with acceptable weldability such as for solution-strengthened (e.g. IN625, Heynes230) or gamma-prime strengthened nickel-base superalloys with low to medium amount of Al and Ti (e.g. Haynes282). Nickel-base superalloys with high oxidation resistance and high gamma-prime content (>25 Vol.-% ), that means with a high combined amount of at least 5 wt.-% Al and Ti, such as IN738LC, MarM-247 or CM-247LC are typically difficult to weld and cannot be processed by conventional build-up welding without considerable micro-cracking. The gamma-prime phase has an ordered FCC structure of the L12 type and form coherent precipitates with low surface energy. Due to the coherent interface and the ordered structure, these precipitates are efficient obstructions for dislocation movement and strongly improve the strength of the material even at high temperature. The low surface energy results in a low driving force for growth which is the reason for their long-term high temperature stability. In addition to the formation of gamma-prime phase, the high Al content results in the formation of a stable surface oxide layer resulting in superior high temperature oxidation resistance. Due to the extraordinary high temperature strength and oxidation resistance, these materials are preferably used in highly stressed turbine components. Typical examples of such gamma-prime strengthened nickel-base superalloys are: Mar-M247, CM-247LC, IN100, In738LC, IN792, Mar-M200, B1900, Rene80 and other derivatives
[0005] With conventional build-up welding techniques, for example TIG or LMF these gamma-prime strengthened superalloys can hardly be processed without considerable formation of microcracks.
[0006] Different cracking mechanism have been identified in the literature. Cracking can occur during the final stage of solidification, where dendrite formation inhibits the backfilling of liquid, resulting in crack initiation in the isolated sections. This mechanism is called “solidification cracking” (SC). So-called “Liquation cracking” (LC) occurs when dissolution of precipitates in the heat affected zone is retarded due to the fast heat-up during welding. As a result, the precipitates still exist at temperatures where they are not thermodynamically stable and an eutectic composition is formed at the interface region. When the temperature exceeds the relatively low eutectic temperature this interface regions melts and wets the grain boundaries. These weakened grain boundaries cannot anymore accommodate the thermal stresses, resulting in crack formation. Cracking can also occur in the solid state when previously processed layers are reheated to a temperature at which precipitations can form. The precipitation results in stress formation due to volumetric changes, in increased strength and in loss of ductility. Combined with the superimposed thermal stresses, the rupture strength of the material can be locally exceeded and cracking occurs. This mechanism is referred to as “strain-age cracking” (SAC).
[0007] Due to the high fraction of precipitates and the resulting high mechanical strength, the ability to relax thermal stresses is strongly reduced. For this reason gamma-prime precipitation hardened superalloys are especially prone to these cracking mechanisms and very difficult to weld.
[0008] Another issue is that state-of-the-art reconditioning processes often take a long time due to the many process steps involved. In the repair of turbine blades for example, crown plate replacement, tip replacement and/or coupon repair require different process steps. This results in high costs and long lead times.
[0009] The efficiency of a gas turbine increases with increasing service temperature. As the temperature capability of the used materials is limited, cooling systems are incorporated into turbine components. Different cooling techniques exist such as film cooling, effusion cooling or transpiration cooling. However, the complexity of the cooling system is limited by the fabrication process. State-of-the-art turbine components are designed with respect to these limited fabrication processes, which impede in most cases the optimal technical solution. Transpiration cooling has currently limited applications, as those porous structure have problems coping with the mechanical and thermal stresses.
[0010] Another drawback of conventional turbine blades is that they require the extraction of the cast core and must therefore have an open crown tip. The crown tip must subsequently be closed by letter box brazing, which is an additional critical step during fabrication. Additionally to these geometric restrictions, the state-of-the-art fabrication processes are often limited in the material choice and require castable or weldable material.
[0011] It is also known state of the art that abradable coatings or honeycombs are added on vanes and heat shields in order to avoid gas leakage which would result in decreased efficiency. The turbine blade tip cuts into this abradable structure during the running-in process, which results in a good sealing. However, due to the high abrasive effect of the turbine blade tip, the abradable layer is often strongly damaged during this process and therefore often requires complete replacement after each service interval. Due to limited material choice, oxidative losses of tip is a further common problem.
[0012] Selective laser melting (SLM) for the direct build-up of material on new or to be repaired/reconditioned turbine components has several advantages and can overcome the shortcomings mentioned above.
[0013] Due to the extremely localized melting and the resulting very fast solidification during SLM, segregation of alloying elements and formation of precipitates is considerably reduced. This results in a decreased sensitivity for cracking compared to conventional build-up welding techniques. In contrast to other state-of-the-art techniques, SLM allows the near-net shape processing of non-castable, difficult to machine or difficult to weld materials such as high Al+Ti containing alloys (e.g. IN738LC). The use of such high temperature strength and oxidation resistant materials significantly improves the properties of the built-up turbine blade section.
[0014] Porosity is a known phenomenon in the field of additive manufacturing, such as SLM. Apart from medical applications, the appearance of porosity is an effect that has to be minimized because porosity affects material properties such as strength, hardness and surface quality negatively. The SLM process parameters are therefore usually, especially for gas turbine components, optimized for highest density. Residual porosity is considered detrimental and therefore unwanted.
[0015] In contrast to casting and conventional repair techniques (e.g. build-up welding), SLM offers a much higher design freedom and allows the production of very complex structures (“complexity for free”). In addition, the use of SLM can reduce the amount of process steps, by combination of different repair processes in one single process.
[0016] In document WO 2009/156316 A1 a method for producing a component with coating areas by means of selective laser melting is disclosed. The coating areas have a composition that differs from the composition of the substrate material. This is accomplished by intermittently introducing a reactive gas that reacts with the powder material during SLM process. Therefore, during production of the component, layer regions arise, which can ensure particular functions of the component, for example a hardened surface.
[0017] Document EP 2319641 A1 describes a method to apply multiple materials with a selective laser melting process which proposes the use of foils/tapes/sheets or three-dimensional reforms instead of different powder for a second and additional material different from the previous (powder based) to be applied. These foils, tapes, sheets or preforms can be applied on different sections/portions of three-dimensional articles, for example on edges with abrasive materials, or on surfaces to improve the heat transfer, so that an adjustment of the microstructure/chemical composition with respect to the desired properties of the component/article can be achieved.
[0018] Document US2008/0182017 A1 discloses a method for laser net shape manufacturing a part or repairing an area of a part by deposition a bead of a material, wherein the deposited material may be varied or changed during the deposition such that the bead of material is formed of different materials.
[0019] Document EP 2586548 A1 describes a method for manufacturing a component or a coupon by means of selective laser melting SLM with an aligned grain size distribution dependent on the distribution of the expected temperature and/or stress and/or strain of the component during service/operation such that the lifetime of the component is improved with respect to a similar component with substantially uniform grain size.
SUMMARY
[0020] It is an object of the present invention to provide an efficient method for producing an article or at least a part of such an article made of a gamma prime (γ′) precipitation hardened nickel base superalloy with a high volume fraction (>25%) of gamma-prima phase, which is difficult to weld, or of a non-castable or difficult to machine material and to an article made with said method. More particularly, the method relates to producing of new or repairing of used and damaged turbine components.
[0021] According to the preamble of independent claim 1 the method is related to producing a three-dimensional article or at least a part of such an article made of a gamma prime (γ′) precipitation hardened nickel base superalloy with a high volume fraction (>25%) of gamma-prima phase which is a difficult to weld superalloy, or made of a cobalt base superalloy, or of a non-castable or difficult to machine metal material by means of selective laser melting (SLM), in which the article is produced by melting of layerwise deposited metal powder with a laser beam. The method is characterized in that the SLM processing parameters are selectively adjusted to locally tailor the microstructure and/or porosity of the produced article or a part of the article and therefore to optimize desired properties of the finalized article/part of the article.
[0022] The three-dimensional article or at least a part of such an article produced with a method according to present invention is gas turbine component or a section/part of a gas turbine component.
[0023] Preferable embodiments of the invention are described in the dependent claims, which disclose for example:
that a subsequent heat treatment step for further adjustment of the microstructure is applied, that the processing parameters to be adjusted are at least one or a combination of laser power, scan velocity, hatch distance, powder shape, powder size distribution, processing atmosphere, that the resulted microstructure and/or porosity of the deposited layers are different, that the resulted microstructure and/or porosity is gradually changing in radial or lateral direction of the article, that the resulted porosity is a closed or opened porosity, that the selectively introduced porosity is used to adjust mass related properties, preferable the eigenfrequency or to counterbalance the effect of additionally added material on an component, that the tailored microstructure comprises in-situ generated second phase particles, preferably hard-phase particles or solid lubricants, that the elements forming the second phase particles, are supplied at least partly by a reactive gas (processing atmosphere) and/or by the SLM metal powder or by the base metal (alloys), that the composition of the reactive gas is actively changed during the SLM process, that Re, Ti, Ni, W, Mo, B are supplied for forming highly lubricous oxides at high temperatures, that elements forming second phase particles are carbide, boride, nitride, oxide or combinations thereof forming elements, such as Al, Si, Zr, Cr, Re, Ti, Ni, W, Mo, Zn, V, that existing holes or channels in the article are filled with a polymeric substance and an inorganic filler material prior to the built-up of SLM layers and the polymeric filler is burnt out during a subsequent heat treatment step, that the method is used for producing of new or repairing of used and damaged turbine components, that the produced article has a locally tailored microstructure (material composition, layers, gradients and/or porosity), that the article comprises at least one part with an open porous structure, that the article comprises an open-porous outer layer and a fully dense inner layer including cooling channels designed for guiding a cooling medium to the open porous outer layer, which cooling channels either end at the interface to the open porous outer layer or partly or fully penetrate the open-porous outer layer, that an open porous surface thermal barrier coating layer is applied onto the open porous outer layer, that the article comprises a complex design structure, but without overhanging areas with an angle of ≧45° or with sharp concave edges, that the article is a turbine blade crown, that the article is a turbine component, on which the section built is either new or an ex-service component.
[0044] The present invention relates to the additive build-up of a turbine blade section out of a gamma-prime precipitation hardened nickel-base superalloy with locally tailored microstructure on an existing turbine blade by the means of selective laser melting (SLM). The direct build-up of material on turbine components (new or reconditioned) using SLM is proposed which has several advantages:
Due to the extremely localized melting and the resulting very fast solidification during SLM, segregation of alloying elements and formation of precipitates is considerably reduced. This results in a decreased sensitivity for cracking compared to conventional build-up welding techniques. In contrast to other state-of-the-art techniques, SLM allows the near-net shape processing of non-castable, difficult to machine or difficult to weld materials such as high Al+Ti containing alloys (e.g. IN738LC). The use of such high temperature strength and oxidation resistant materials significantly improves the properties of the built-up turbine blade section. In build-up welding and additive manufacturing methods, the resulting density in the processed material is strongly dependent on the process parameters. Apart from medical applications, the process parameters are usually optimized for highest density and residual porosity is considered detrimental and therefore unwanted. The possibility to selectively tailor the microstructure and the porosity in the material by locally adjusting process parameters during SLM combined with its increased design freedom however opens new potential in the design of the material properties. One example of benefit could be the reduction of the abrasive effect of the turbine blade crown to reduce honeycomb damages. Another example could be the fabrication of section using process parameters which result open porosity allowing transpiration cooling. Furthermore, structures with graded or layered microstructure can be fabricated in one single fabrication process. This allows for example to produce structures with dense (for strength) and open-porous (for cooling) layers and therefore has the potential to overcome the current drawback of manufacturing transpiration cooling. With a porous structure one can also influence the mass of a manufactured part, which can be used to tune the eigenfrequency or the influence centrifugal forces pulling on the rotor (e.g. in combination with a blade extension for a retrofit upgrade) or influencing the mass in any other specific or general way. In the adding material with different properties of thermal expansion also bi-metallic effects can be built-in. In contrast with casting and conventional repair techniques (e.g. build-up welding), SLM offers a much higher design freedom and allows the production of very complex structures (“complexity for free”) The use of SLM can reduce the amount of process steps, by combination of different repair processes in one single process. An example is the combined replacement of the blade crown and tip in one single process. In case of small volume or individualized coupon repair, costs and lead times can be considerably reduced when the coupon is manufactured by SLM in comparison to casting, as the components are directly fabricated from CAD files and no cast tooling is required. The use of SLM can therefore result in reduced costs and lead times.
[0049] In the present disclosure it is proposed to use SLM for the build-up of turbine component (rotating or static, abradable or abrasive) sections either on new parts or during reconditioning of used components:
using difficult-to-weld, non-castable or difficult to machine materials which could not yet be processed such as high Al+Ti containing alloys (e.g. IN738LC). tailoring the microstructure of the built-up sections by selectively introducing pores as design element to adjust the physical and mechanical properties of the material according to the local needs. exploiting the design freedom of the SLM process to incorporate special features such as pores or channels, e.g. for cooling, into the built-up turbine component section using SLM optimized designs such as rounded inner edges instead of sharp edges to minimize the required support structures. to reduce lead time/through-put time and costs in reconditioning.
BRIEF DESCRIPTION OF THE DRAWINGS
[0055] The present invention is now to be explained more closely by means of different embodiments and with reference to the attached drawings.
[0056] FIG. 1 shows as a first embodiment a blade tip with the blade crown and an opposite arranged abradable (heat shield, SLM generated with tailored porosity);
[0057] FIG. 2 shows the part from FIG. 1 after running in process; FIG. 3 shows a metallographic cut of a IN738LC test specimen treated according to the disclosed method showing a high porosity after SLM;
[0058] FIG. 4 shows a metallographic cut of a IN738LC test specimen treated according to the disclosed method showing a medium porosity after SLM;
[0059] FIGS. 5 , 6 show as two additional embodiments of the invention a cut through a wall, for example a blade tip, with different layers and cooling channels for effussion/transpiration cooling;
[0060] FIG. 7 shows a similar embodiment for a turbine blade with a dense area and an open-porous built-up blade crown;
[0061] FIG. 8 shows an additional embodiment analog to FIG. 7 , but with ribs in the open-porous structure;
[0062] FIG. 9 shows an additional embodiment analog to FIG. 6 , but with ribs in the open-porous structure after production of the blade (short service time of the blade);
[0063] FIG. 10 shows the embodiment according to FIG. 9 after a long service time of the gas turbine with damaged areas 15 ;
[0064] FIG. 11 shows two embodiments of the inventions for a modified turbine blade and a modified compressor blade with a modified cross section of the airfoil;
[0065] FIG. 12 shows details of FIG. 11 and
[0066] FIGS. 13 , 14 show cross sections of the blade according to FIG. 12 at different length of the airfoil 16 ′ as indicated in FIG. 12 .
DETAILED DESCRIPTION
First Embodiment
[0067] The first embodiment of the invention is a build-up of a blade crown 3 of a gas turbine blade tip 1 and heat shield 2 by SLM with selectively adjusted pore structure 4 to reduce wear by the resulting decreased abrasivity. FIG. 1 and FIG. 2 demonstrate this first embodiment of the invention, FIG. 2 shows the optimal sealing even after running in process with minimized damage of the bade tip 1 and the heat shield 2 .
[0068] To get high efficiency, the gas leak between the blade tip 1 and the heat shield 2 must be minimized (see FIG. 1 ). A good sealing is commonly achieved by a grind in process of the turbine blade during heat-up, caused by thermal expansion. Generally, the blade crown 3 is designed as abrasive component, which runs into heat shield 2 designed as abradable. Thermal cycles during service result in a varying distance between the blade tip 1 and the shroud 2 . The blade tip 1 can occasionally touch the shroud 2 and the resulting rubbing damages the blade tip 1 and the head shield 2 . Increasing the gap width would result in higher leaking and lower efficiency and is not desired.
[0069] An optimal design matching of the abradable and the abrasive is required to obtain an effective, long lasting tip sealing. In addition, several other properties such as oxidation resistance need to be considered, which can inhibit optimal abrasive/abradable interaction. Furthermore, limitation in state-of the art fabrication processes also inhibit optimal material selection, especially during reconditioning of gas turbine components.
[0070] An implementation of this invention is the fabrication of a blade crown 3 with increasing porosity towards the blade tip using selective laser melting. The advantage of this set-up is twofold: By using SLM for the build-up process, materials can be applied which cannot be processed by conventional repair methods. Furthermore, the in-situ generation of secondary phase particles allows an optimal tuning of the wear/abrasion behavior between the abrasive and abradable. This can reduce the excessive damage of the abradable during running-in process.
[0071] In another implementation, secondary phase particles are incorporated, which result in a solid-state self-lubrication.
[0072] The porosity can be introduced either as designed structure in the 3D CAD model, which is then reproduced during SLM build up or by adjustment of the process parameter (eg. Laser power, Scan velocity, Hatch distance, Layer thickness) in a way that the resulting structure is not completely dense.
[0073] Two examples for porosity generated by process parameter adjustment according to the disclosed method are shown in FIG. 3 and FIG. 4 for the nickel base superalloy IN738LC.
[0074] FIG. 3 shows a microstructure with high porosity for the following process parameter:
[0075] Scan velocity: 400 mm/s
[0076] Power: 100 W
[0077] Hatch distance: 140 um
[0078] Layer thickness: 30 μm
[0079] FIG. 4 shows a microstructure with medium porosity for the following process parameter:
[0080] Scan velocity: 240 mm/s
[0081] Power: 180 W
[0082] Hatch distance: 110 um
[0083] Layer thickness: 30 μm
[0084] An additional implementation (see FIG. 5 ) incorporates active effusion/transpiration cooling 9 of the built-up section by incorporation of open porosity in the SLM fabricated turbine section by adjusting the process parameters. The open porous section 6 can either stand alone or being built upon a dense structure 5 to increase the mechanical stability. In the second case (see FIG. 5 ), the cooling air is supplied to the open porous section 6 by cooling holes 8 . The dense section 5 can either be already present (e.g. from casting) or be fabricated already incorporating the cooling holes 8 in the same single SLM process together with porous part 6 . This allows the easy preparation of combined effusion/transpiration and/or near wall cooling in one single process step.
[0085] Different types of such channels 8 can be incorporated in the built-up section. The cooling air is finely distributed in the porous layer and homogenously exits the surface resulting in efficient transpiration cooling of the blade surface. The open-porous structure shows a lower thermal conductivity as when dense, which further reduces the thermal loading of the dense structural layer. An open-porous thermal barrier coating can be applied to the open-porous surface layer in order to further decrease the temperature loading without inhibiting transpiration cooling.
[0086] The cooling channels 8 can stop at the interface to the open-porous layer or partly or fully penetrate the open-porous layer. Different types of such channels 8 can be incorporated in the built-up section.
[0087] FIG. 7 shows as an example a part of a repaired turbine blade for an ex-service component. The original blade structure 10 with existing cooling holes 8 is covered with a dense, by means of SLM built-up structure 11 with incorporated cooling holes 8 , 8 ′ which can extend into the SLM built-up open-porous blade crown 3 . The disclosed method avoids the need for letter-box brazing and allows the incorporation of cooling features into the crown with one single process, that means the built up dense structure 11 with incorporated cooling holes/channels 8 , 8 ′ and the built up open-porous blade crown 3 are built in one single SLM process. This is an important advantage.
[0088] In order not to fill existing cooling channels with metal powder, the blade opening can be filled with a polymeric substance and an inorganic filler material which can be burned out after the SLM process in an subsequent heat treatment step. This procedure allows the continuation of existing cooling channels, respectively the connection of a more complex and sophisticated cooling concept (e.g. transpiration cooling) in the built-up section the air supply in the base component.
[0089] The design of the built-up section is optimized for the fabrication with the SLM process and avoids sharp edges or big overhanging areas.
[0090] In combination with the above-described blade crown an abradable counter-part with selectively tailored porosity can be built up with SLM to reduce wear at the blade tip and optimize the blade tip sealing as for example the a fabrication of a heat shield with increasing porosity towards the heat shield surface at the blade tip contact region using SLM. Thereby, the abradability of the heat shield can be selectively increased at the contact region of the blade tip, without decreasing the materials properties at other locations. With an optimized geometric introduction of the porosity, the wear of the blade tip can be reduced without compromising the sealing behavior. (see FIG. 1 and FIG. 2 ).
[0091] In another implementation, porosity can be introduced to decrease heat conductivity and thereby increasing insulation properties of the heat shield.
Second Embodiment
[0092] A second embodiment of the invention is transpiration cooling of the turbine blade by a layered structure fabricated by a single additive manufacturing process (see FIG. 6 ). The inner layer 5 of the blade wall consists of fully dense material with incorporated cooling channels 8 in order to provide mechanical strength and cooling air supply to second, open-porous layer 6 . The air (illustrated with arrows) introduced into the outer, open-porous layer results in transpiration cooling 9 of the outer blade surface resulting in an efficient shielding of the surface from the hot gases. In combination with the reduced thermal conductivity of the porous layer 6 , the thermal loading on the inner structural layer is considerably reduced.
[0093] If required, an additional open-porous ceramic thermal barrier coating 7 can be applied on the porous metal layer 6 in a second process step to provide an additional, also transpiration cooled thermal barrier.
[0094] The cooling channels 8 can stop at the interface to the open-porous layer or partly or fully penetrate the open-porous layer 6 , 7 . Different types of such channels 8 can be incorporated in the built-up section.
[0095] In another embodiment it is also possible to apply an outer dense layer of the base material on the porous metal layer 6 .
Third Embodiment
[0096] This embodiment refers to a separation of porous structures to prevent penetration of hotgas.
[0097] The gas temperature plot along the airfoil illustrates the extend of secondary flows in the hotgas passage. This has an influence on the turbine blade cooling and the material distribution in the blade. Corresponding lines of constant pressure can be shown (not illustrated here). Where such lines are dense the pressure gradients are high. In those areas the open porous structure shall be interrupted by solid ribs 12 which have the effect of a cross-flow barrier to prevent hotgas migration. The ribs 12 separate the suction side 13 from the pressure side 14 . This can be seen in FIG. 8 , which shows a turbine blade tip analog to FIG. 7 .
[0098] Additional implementations are shown in FIG. 9 and FIG. 10 . FIG. 9 is analog to FIG. 6 , but with the arrangement of different ribs 12 as cross-flow barriers in the open-porous metal layer 6 . FIG. 9 shows the component after manufacturing/short service time with an intact surface, FIG. 10 shows the same component after service with damaged areas 15 . Such areas 15 can be oxidation areas or areas of FOD (Foreign Object Damage). The ribs 12 are a barrier in streamwise direction after oxidation and or FOD.
Fourth Embodiment
[0099] A further embodiment of the invention is an airfoil extension with foam-type structures to prevent adding mass.
[0100] FIG. 11 shows in the left part an airfoil 16 , 16 ′ of a turbine blade and in the right part an airfoil 16 , 16 ′ of a compressor blade with the flow path contours of turbine and compressor, before (continuous line for the existing cross section) and after (dotted line for the modified cross section) increase of flow passage. Such flow passage is done to cope with increased massflow. The pull forces on the rotor are limited and a light-weight extension of the airfoil 16 , 16 ′ might be required. 16 is the existing airfoil, 16 ′ the modified airfoil. This can be achieved with porous structures described before and applied with a justified SLM process. Details of FIG. 11 are shown in FIG. 12 , FIG. 13 and FIG. 14 .
[0101] In the left part of FIG. 12 the airfoil 16 is shown with the original length L, in the right part of FIG. 12 the extended airfoil 16 ′ is shown with an extra length EL. A light weight structure core structure 17 compensates the extra length EL. The core structure is here partly embedded with a solid shell structure 18 .
[0102] FIG. 13 and FIG. 14 are two cross sections at different length of the airfoil 16 ′ as indicated in FIG. 12 . FIG. 13 shows the brazed interface 19 , which can be with or without a mechanical interlock between the core 17 and the airfoil 16 . FIG. 14 illustrates the core light-weight structure 17 and the shell structure 18 , which is an additive built-up. There can be 2 pieces with one or more brazed interfaces, the light weight core and coated top layer/layers or the light-weight core and braze sheet and overlay coatings.
[0103] Of course, the present invention is not limited to the described embodiments. It could be used with advantage for producing any three-dimensional article or at least a part of such an article with a wide range of tailored microstructure/porosity/gradients/materials etc. The method is used for producing articles/components or for repairing of already used and damaged articles/components. The articles are preferably made of difficult to weld superalloys or of a non-castable or difficult to machine material and are components or parts of components of turbines, compressors etc. | The invention relates to a method for producing a three-dimensional article or at least a part of such an article made of a gamma prime (γ′) precipitation hardened nickel base superalloy with a high volume fraction (>25%) of gamma-prima phase which is a difficult to weld superalloy, or made of a cobalt base superalloy, or of a non-castable or difficult to machine metal material by means of selective laser melting (SLM), in which the article is produced by melting of layerwise deposited metal powder with a laser beam characterized in that the SLM processing parameters are selectively adjusted to locally tailor the microstructure and/or porosity of the produced article or a part of the article and therefore to optimize desired properties of the finalized article/part of the article. | 1 |
CROSS REFERENCE TO RELATED APPLICATION
[0001] The present application claims priority pursuant to 35 U.S.C. 119(e) to U.S. Provisional Application Ser. No. 61/793,870, filed Mar. 15, 2013.
FIELD OF THE INVENTION
[0002] The present invention is related to laser sintering systems, and more particularly, to laser sintering systems apparatus and methods for improving part quality and reduced disposal of used, unsintered powder.
BACKGROUND OF THE INVENTION
[0003] Laser sintering is one form of additive manufacturing that fabricates three-dimensional objects from digital data. As known in the art, laser sintering heats layers of powder, typically a polymer or a metal, with a laser to cause the powder particles to fuse to one another in predetermined patterns to define the cross-sectional layers of the object being fabricated. Such techniques are disclosed in U.S. Pat. Nos. 4,863,538; 5,155,321; 5,252,264; 5,352,405; 6,815,636; 7,569,174; and 7,807,947, the disclosures of which are incorporated by reference herein in their entirety.
[0004] One problem with laser sintering is laser attenuation during the build process whereby the laser power at the image plane (the surface of the sinterable powder being exposed to the laser beam) changes (typically decreases). Such change in laser power may be due to a number of issues and can lead to parts being different colors from the bottom to the top (along the z-axis) or having different mechanical properties along the z-axis.
[0005] Another problem with laser sintering, particularly with polymers that are heated to near the melting temperature, is that the sinterable powder that is not fused can be reused only a certain number of times before the powder produces parts with undesirable quality (such as “orange peeling” on the surface), coloration, or reduced mechanical properties. The result is that operators of laser sintering machines must dispose of a certain amount of used laser sintering powder to maintain part quality.
BRIEF SUMMARY OF THE INVENTION
[0006] The various embodiments of the present invention address the above needs and achieve other advantages that improve the part quality and reduce the need to dispose of sinterable powder. One embodiment of the present invention includes methods for applying the powder layer to reduce the likelihood of surface features that can lead to reduced part strength or accuracy and that improve the density of the powder in the layer. Certain embodiments use a “two pass” approach (also called “dual APL” (APL=Apply Powder Layer)) to laying down a single layer of powder (with a counter-rotating roller or other powder distributing device) by distributing a layer of powder in a first pass similar to traditional (prior art) applications of a powder layer, but then, unlike the prior art, the roller is moved back in a second pass that distributes residual powder to fill gaps and level the surface of the powder layer. In order to distribute the residual powder from the first pass, a return powder device (such as a piston) is provided on an opposite side of the part bed (the area where the powder is laser sintered) from where the powder is deposited by a hopper. The return powder device is lowered to allow the residual powder to pass beneath the roller and is raised after the roller has passed so that the roller can distribute the residual powder. Any residual powder that remains after the second pass is deposited into a powder return shoot on the side of the part bed. By using the two pass technique, the powder layers have improved uniformity and better densification for more accurate laser sintering.
[0007] Further embodiments of the present invention include a laser power measurement device that is able to measure laser power within the build chamber. Typical laser sintering systems do not include laser power measurement devices (measurements are simply done during service by a serviceperson) or the laser power is measure prior to the laser beam entering the build chamber. The build chamber of a laser sintering system is typically very hot and includes fumes and dust that can adversely affect surfaces. The present invention provides a laser power measurement device that is within the build chamber to determine the laser power delivered to the powder layers in order to adjust or control the scan speed and/or other parameters to ensure that the power being delivered to the sinterable powder is consistent to avoid degradation or other changes in part quality or accuracy. In some embodiments, the laser power measurement device is positioned below the laser window (typically on the ceiling of the build chamber through which the laser enters the build chamber), but above the heaters that heat the sinterable powder (primarily by radiation) so that the device does not block heat delivered to the powder and/or become overheated. By having the laser power measurement device removed as much as possible from the image plane upon which the laser beam is focused, the laser is less focused and the sensing device is better able to withstand the laser without being adversely affected by the laser. In some embodiments, the laser power measurement device comprises a movable mirror that is extended from a position outside the laser scanning area into a position where the laser can be directed to the mirror to direct the laser to the sensing device. Once the measurement has been taken, the mirror can be retracted out of the way of the laser. In some embodiments, the laser power measurements are taken during the application of a new powder layer so that the build time for the part(s) is not increased. In further embodiments, the laser power measurement device is a sensor on a movable (such as rotatable) arm that may be selectively positioned for the laser to project directly onto it.
[0008] Still further embodiments of the present invention include a chute device for the deposition of powder between the roller and part bed with little or no dust being created. The chute device of certain embodiments is a rigid slot below the hopper that extends to near the surface the powder is being deposited to minimize the distance the powder must fall, thus minimizing the amount of dust created. The chute device is rotatable so that it does not interfere with the movement of the roller. The chute is also positioned so that it does not block the laser beam from the part bed. In some embodiments, the chute includes heater elements to preheat the powder to be deposited.
[0009] Other embodiments of the present invention include a roller heater positioned below or proximate the stationary roller position (where the roller is parked during the laser scanning operation) so that the roller surface may be heated to a desired temperature. The roller heater may alternatively comprise a chute heater that pre-heats powder in the chute and also heats the roller surface. The roller may be rotated so that the roller heater evenly heats the surface of the roller to prevent temperature gradients on the roller surface which can lead to undesirable adhesion of powder to some, but not all, surfaces of the roller which results in powder being slung behind the roller which further results in uneven powder surfaces that ultimately result in rough surfaces or other imperfections in the final part.
[0010] Still further embodiments of the present invention include an air scrubber that cleans the air (consisting primarily of nitrogen) within the build chamber. The air is cooled through the scrubber to assist with the removal of airborne contaminants by the filter(s). The exhaust air of the scrubber that is recirculated back into the build chamber is exhausted into a heater bracket that retains the heaters (that heat the powder by radiation and convection) in order to (i) reheat the relatively cool recirculated air and (ii) cool the heater brackets and heaters so that the heaters are not overheated. The heater brackets have exhaust holes along an outwardly facing surface so that the air is circulated back into the chamber in a way that does not create significant turbulence or other undesirable air flow that could adversely affect the laser sintering process. Therefore, the various embodiments of the present invention provide significant improvements to the laser sintering system and process that result in improved part quality and reduced waste material.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0011] Having thus described the invention in general terms, reference will now be made to the accompanying drawings, which are not necessarily drawn to scale and are meant to be illustrative and not limiting, and wherein:
[0012] FIG. 1 is a perspective view of a laser sintering system in accordance with one embodiment of the present invention;
[0013] FIG. 2 is a side cross-sectional view of the laser sintering system of FIG. 1 ;
[0014] FIG. 3A is an enlarged side cross-sectional view of the roller, hopper, chute, roller heater, and other portions of the laser sintering system of FIG. 1 , wherein the chute is in the down position;
[0015] FIG. 3B is an enlarged side cross-sectional view of the roller, hopper, chute, roller heater, and other portions of the laser sintering system of FIG. 1 , wherein the chute is in the up position;
[0016] FIG. 4A is an enlarged perspective view of the hopper and chute of the embodiment of FIG. 1 , wherein the chute is in the down position;
[0017] FIG. 4B is an enlarged perspective view of the hopper and chute of the embodiment of FIG. 1 , wherein the chute is in the up position;
[0018] FIG. 5A is a side cross-sectional view of the upper portion of the laser sintering system of FIG. 1 , showing the laser power measurement device in the retracted position;
[0019] FIG. 5B is a side cross-sectional view of the upper portion of the laser sintering system of FIG. 1 , showing the laser power measurement device in the extended position;
[0020] FIGS. 6A-6C are enlarged perspective views of the laser power measurement device (in the extended position) of a further embodiment of the present invention, wherein the mirror of the laser power measurement device includes a telescoping tube that protrudes into the build chamber through a sealed opening below the laser window (not shown);
[0021] FIG. 7A is an enlarged perspective view of a scrubber of the laser sintering system of FIG. 1 showing the internal passages and filters of the scrubber, as well as the check valve on top and blower motor on the side;
[0022] FIG. 7B is an enlarged side view of the scrubber of FIG. 7A showing the single scrubber inlet and the dual scrubber outlets (each outlet is in fluid communication with one heater bracket);
[0023] FIG. 7C is an enlarged perspective view of the scrubber of FIG. 7A showing the scrubber inlet and scrubber outlets and the heat sink and fan for cooling of the air to be scrubbed (filtered);
[0024] FIG. 8 is an enlarged perspective view of the laser sintering system of FIG. 1 showing the heater brackets (yellow) through which the cooled air from the scrubber outlets is reintroduced into the build chamber in order to heat the air (using the waste heat of the heaters) and to help cool the heaters; also shown is the piping/duct connecting the scrubber inlet to the opening in the build chamber above the heater brackets;
[0025] FIG. 9 is an enlarged perspective view of the laser sintering system of FIG. 1 showing the heaters and heater brackets and the passages on the sides of the heater bracket for the pre-heated air to flow into the build chamber in a direction that does not adversely affect the powder layers; and
[0026] FIG. 10 is an enlarged perspective view of the laser sintering system of FIG. 1 showing the return powder device in the raised position, wherein the return powder device is on an opposite side of the part bed from the hopper and chute.
DETAILED DESCRIPTION OF THE INVENTION
[0027] The present invention now will be described more fully hereinafter with reference to the accompanying drawings, in which some, but not all embodiments of the invention are shown. Indeed, the invention may 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 satisfy applicable legal requirements. Although apparatus and methods for providing improved part quality and reduced powder disposal are described and shown in the accompanying drawings with regard to specific types of laser sintering systems, it is envisioned that the functionality of the various apparatus and methods may be applied to any now known or hereafter devised powder fusing systems in which it is desired to created three dimensional objects (parts) out of powder based upon digital data representing the part to be made. Like numbers refer to like elements throughout.
[0028] With reference to FIGS. 1-10 , laser sintering systems in accordance with embodiments of the present invention are illustrated that include many novel upgrades to prior art laser sintering systems that increase part quality and reduce powder disposal. These inventions not previous known or used in the art provide significant improvement to the part quality by providing consistent energy delivery to the sinterable powder so that the material properties are improved and consistent throughout the part in all directions (x-axis (side to side in the build chamber), y-axis (front to back in the build chamber), and z-axis (bottom to top in the build chamber)). Moreover, the inventions, in particular those relating to the dual APL, provide powder layers of improved density and with no or minimum peaks, valleys, or voids that provide better flow control of laser sintered particles that enables the creation of more accurate, stronger parts and enables powder to be reused (the powder used in a laser sintering build process but not sintered) for many more build processes, thus significantly reducing the need for virgin powder (new/fresh powder that has not undergone a build process) and the need to dispose of used powder. Therefore, the present inventions significantly reduces the costs associated with laser sintering of parts, which makes parts made by laser sintering more affordable, and ultimately results in laser sintering becoming more competitive against parts made by other additive manufacturing techniques, subtractive manufacturing techniques, and other traditional manufacturing techniques.
[0029] The illustrated embodiments are designed for polymer systems that use polyamide powders or PEEK powders or other polymer powders; however, other embodiments of the present invention may be used with further materials such as metals, composites, ceramics, and any other powder materials used to form three-dimensional objects from digital data.
[0030] Turning now to the embodiment of FIG. 1 , the laser sintering system 10 includes a build chamber 12 , a removable part bed cart 14 , and a laser assembly 16 that includes the laser, scanning mirrors and other optics similar to prior art laser sintering systems. The laser sintering system 10 also includes a control panel 18 or other user interface, such as a touch screen computer or tablet, for the operator to control and/or monitor the laser sintering system. FIG. 1 also shows portions of the laser sintering system 10 that are not inside the build chamber 12 , such as the powder hopper 20 , from which powder is supplied to the build chamber, and the scrubber 22 that cleans and recirculates the air (primarily nitrogen) in the build chamber.
[0031] FIG. 2 is a cross-section of the laser sintering system that illustrates additional features of the system, both inside and outside the build chamber 12 . The return powder receptacle 24 receives powder that is not used during the dual APL process. Powder (not shown) deposited into the return powder receptacle 24 can be stored for later use in a subsequent build process or recirculated automatically back to the hopper 20 for use in the same or subsequent build process. FIG. 2 also illustrates components and systems within the build chamber 12 such as the roller 26 , the chute 28 , the image plane 30 where the powder layer is laser sintered (the top layer of the part bed 31 ), and the return powder device 32 (also shown in FIG. 10 ), which in the illustrated embodiment comprises a return powder piston. Further embodiments of the present invention comprise alternative return powder devices that transfer a portion of powder from one side of the powder distribution device to the other side of the powder distribution device in preparation for the second pass of the roller or other powder distributing device. The laser power measurement device 34 is also shown in FIG. 2 and is positioned between (along the z-axis) the laser window 36 and the heaters 38 .
[0032] Certain embodiments of the present invention use the dual APL technique to distribute sinterable powder in layers. Dual APL is the process of moving the roller across the part bed 31 two times for each layer of powder distributed on the part bed. Prior art systems typically used a single pass of the roller or other powder distributing device, such as a doctor blade or a doctor blade like structure that holds powder and deposits powder as it moves across the part bed. Such systems typically have hoppers or supply powder pistons on both sides of the part bed, while other prior art systems have a single hopper but deposit powder for a first layer with a first pass and for a second layer with a second pass (by depositing powder atop the roller assembly (or other powder distributing device) and dislodging the powder on the side of the part bed opposite the hopper). Still other prior art systems use a single pass of the roller or other powder distributing device to apply powder layer in the single pass and then simply return the powder distributing device to its original position without applying a powder layer during the return movement because no powder is provided on the leading edge in the direction of the return. However, as noted below and in the enclosed documents, using the two pass dual APL process that applies powder in both the first and second passes, it has been discovered that the powder density is significantly improved, as well as quality of the surface of the powder layer applied. The density of the powder in the powder layer is important because it has been discovered that the heating and laser sintering of the denser powder is more stable as the fluence (flow) of the temporarily melted material is better controlled during laser sintering. The improved density of the layers provided by dual APL enables used powders to be used for many more build processes because even though the powder quality slightly degrades with each build process it undergoes, the used powder still can create parts with satisfactory part quality (for example, surface quality is smooth compared to prior art techniques where reused powder can lead to rough surfaces such as the well-known “orange peel” if too much powder is used too many times) and satisfactory strength. Therefore, the higher density powder layers provided by the dual APL process significantly reduce the amount of used sinterable powder that must be discarded, thus reducing the costs associated with laser sintering while providing parts of better quality and strength.
[0033] The dual APL technique comprises the following general steps:
1) powder is deposited from the hopper 20 (via chute 28 ) to between the roller 26 and the part bed 31 ; 2) the roller moves across the part bed to distribute the initial layer of powder over the part bed; 3) the return powder device 32 is in a lowered position such that as the roller moves over the return powder device, any powder remaining from the first pass over the part bed is deposited into the gap created by the return powder device, such that the roller moves over the powder above the return powder device; 4) the return powder device raises so that the powder above the return powder device is between the roller and the part bed; 5) the roller moves across the part bed to distribute the remaining powder into any gaps, voids, or other portions missing powder, to level any waves or other raised portions of powder, and to increase the density of the powder layer; and 6) the roller is returned to its home position (show in FIG. 2 ) while the laser scanning step occurs.
[0040] The dual APL is distinguishable from prior art techniques because it comprises two passes of distributing powder, which is not obvious because two passes requires additional time for each layer, which increases the build time, relative to a prior art single pass system, for each part which reduces the throughput of a laser sintering system if all other parameters are kept constant. Additional information relating to the powder density and part strength is provided in the enclosed documentation.
[0041] Turning now to FIGS. 3A-4B , certain embodiments of the present invention comprise a chute 28 positioned between the hopper 20 and the surface between the roller home position (where the roller is positioned during the laser scanning operation) and the part bed so that a new supply of powder can be deposited in front of the roller before the roller's first pass across the part bed. The chute of the illustrated embodiments comprises a slot extending along the y-axis (front to back of the system) that is rotatable about an axis aligned along the y-axis. The chute 28 may be rotated automatically or it may be moved by the motion of the roller, such as by contact with at least one pin 40 positioned on the roller assembly 42 that moves the roller 26 . For example, the roller 26 or other portion of the roller assembly 42 may push the chute from the down position in FIGS. 3A and 4A to the up position in FIGS. 3B and 48 at the beginning of the first pass (first APL) across the part bed, and the pin 40 or other portion of the roller assembly may push the chute back to the down position at the end of the second pass (second APL) across the part bed such that the chute is always in the down position when the roller is in the home position. The chute may be spring loaded or otherwise biased to remain in the up position unless it is held in the down position by the pin 40 or other portion of the roller assembly.
[0042] The chute 28 simply serves as a conduit to deposit powder released from the hopper near the roller in a manner that minimizes dusting or other creation of airborne particles. The illustrated embodiment is a simple slot, but further embodiments of the present invention include alternative chutes that likewise reduce the dusting, spreading, or other undesirable movement of the deposited powder. The chute 28 also comprises a chute heater 44 that pre-heats the powder in the chute so that the deposited powder is closer to the temperature the powder must attain when it is spread on the part bed prior to the melting/fusing of the powder particles by the laser. By pre-heating the powder, the build process time may be reduced. Moreover, the chute heater or other heater in the area may be used to pre-heat the roller. The roller heater, whether it is the chute heater or other heater, of certain embodiments may keep the surface temperature of the roller at a desired level so that the roller distributes the powder in the desired manner. While the roller is in the home position during laser sintering of the powder layers, the roller is slowly rotated (slewed) so that the roller surface is evenly heated. Further embodiments of the present invention include alternative roller heaters to heat the surface of the roller.
[0043] Turning now to the automatic laser calibration of certain embodiments of the present invention, FIGS. 5A-6C illustrate a laser power measurement device that can selectively determine the laser power (and energy) delivered to the layer of sinterable powder. Because the build chamber is hot and includes fumes and gases that may cause surfaces, such as the laser window, to lose transparency, prior art systems have not measured the laser power within the build chamber but have instead measured the laser power prior to (upstream of) the laser beam entering the build chamber or measured the laser power during periodic servicing. Because the transparency of the laser window and the air within the build chamber may change during a single build process, certain embodiments of the present invention measure the laser power within the build chamber periodically during the build to determine changes in the laser power so that the laser can be adjusted/calibrated to ensure that the powder layers are receiving the desired amounts of energy (such as by changing the laser power or changing the scanning speed that the laser beam is moved across the powder layers).
[0044] The laser power measurement device 43 of the illustrated embodiments includes a laser power sensor of a type known in the art and a telescoping mirror 46 that may be selectively positioned in the laser path to reflect the laser beam to the sensor for measurement purposes. As shown in FIG. 5A , the mirror 46 in the retracted position is outside the range of motion of the laser beam so that the laser power measurement device does not block the laser beam from the part bed. As shown in FIG. 5B , the mirror 46 in the extended position is positioned within the range of motion of the laser beam, such as in the center, so that the laser beam may be selectively projected to the sensor within the laser power measurement device 34 . FIGS. 6A-6C illustrate one embodiment of the laser power measurement device 43 in which the mirror 46 is moved by a hollow telescoping shaft that is sealed about its entrance into the build chamber 12 . Further embodiments of the present invention include alternative laser power measurement devices for measuring the power of the laser beam within the build chamber.
[0045] Because the heaters 38 are radiant heaters and it is not necessary or desired that the laser power measurement device be heated and in order to not block the radiated heat from heating the powder layers, the present invention has the laser power measurement device positioned above the heaters near the laser window 36 ; however, further embodiments of the present invention include the laser power measurement device at any location in the build chamber where the laser can be in optical communication with the laser power measurement device.
[0046] The present invention also includes in certain embodiments a scrubber to clean and filter the air within the build chamber. FIGS. 7A-7C illustrate a scrubber 22 in accordance with one embodiment, that includes an initial cooling section 48 and a filtration section 50 . The scrubber 22 includes a scrubber inlet 52 through which air is pulled from the build chamber 12 (such as from above the heaters 38 and below the laser window 36 ) and two scrubber outlets 54 through which air is expelled back to the build chamber (such as into a heater bracket as described below). The cooling section 48 is a serpentine passage or other structure that causes the relatively hot air from the build chamber 12 to be cooled, such as with the use of a heat sink and fan assembly 56 in thermal communication with the passages in the cooling section. The air is cooled to assist in the precipitation of contaminants from the air. The air is then passed through the filter section 50 comprising one or more filters that capture the contaminants from the air passing therethrough. The air is circulated through the scrubber 22 by the blower fan 58 rotated by the blower motor 60 .
[0047] FIGS. 8 and 9 show the pipe or tubing that connects the build chamber to the scrubber inlet 52 , as well as one of the build chamber inlets 62 for the return of the air from the scrubber. The build chamber inlets 62 are in flow communication with the respective heater bracket 64 in the build chamber 12 . The relatively cool air from the scrubber flows into the heater bracket 64 in order to transfer heat from the heater bracket 64 and the heaters 38 , thereby (i) assisting in the cooling of the heaters, which in some embodiments is desirable to increase the operable life of the heaters and/or to increase the performance of the heaters, and (ii) pre-heating returned scrubbed air. The pre-heated air passes out of the array of holes on the side of each heater bracket 64 . The array of holes are sized and positioned to minimize the amount of turbulence or other undesirable air flow within the build chamber (for example, the powder should not be moved by the air in the build chamber).
[0048] The enclosed documentation further describes the apparatus and processes of the present invention, as well as test results produced therefrom. For example, the chart entitled MP Data show the significant improvements in mechanical properties relative to prior art techniques. The columns of the MP Data chart are for “Recycle Runs” where runs 1 through 4 were conducted without adding any new powder to determine the deterioration in part mechanical properties based upon the lack of new/fresh/virgin powder. The Recycle Runs were used to make a plurality of ASTM638 bars for which the mechanical properties of Table 1 were tested for in accordance with industry standard practices known by those of skill in the art. The Recycle Runs included the respective amounts of fresh (previously unused powder), overflow (powder previously used but retrieved from overflow reservoir and not the part cake), and part cake (powder previously used and retrieved from the part cake). The Recycle Runs were conducted with generally consistent build parameters and part parameters, including but not limited to a fill laser power of 60 W, a fill scan count of 1, a fill scan speed of 12 M/sec, an outline laser power of 15 W, an outline fill scan count of 1, a slicer fill scan spacing of 0.2 mm, and a sinter scan of 1. As evidenced by the results for Runs 1, 2, and 4, the decreases in mean density, tensile modulus, and tensile strength are significantly improved compared to prior art laser sintering apparatus and methods. Test data such as provided in the MP Data chart demonstrate that the embodiments of the present invention can be used to reduce the need for virgin powder and the corresponding need to dispose of used powder.
[0000]
TABLE 1
MP Data
Mechanical
Recycle
Recycle
Recycle
Recycle
Recycle
Properties
Run 0
Run 1
Run 2
Run 3
Run 4
Density (LT Front)
0.975
0.971
09.67
(g/cc)
Density (RT Front)
0.973
0.974
0.957
(g/cc)
Density (Middle)
0.973
0.974
0.964
(g/cc)
Density (LT Back)
0.973
0.968
0.964
(g/cc)
Density (RT Back)
0.971
0.974
0.957
(g/cc)
MEAN DENSITY
0.973
0.972
0.962
Tensile Modulus (X)
1911
1925
1798
Tensile Modulus (X)
1887
1948
1771
Tensile Modulus (X)
1878
1938
1845
Tensile Modulus (X)
1939
1917
1801
X MEAN MODULUS
1903.75
1932.00
1803.75
Tensile Modulus (Y)
1962
1855
1904
Tensile Modulus (Y)
2012
1946
1893
Tensile Modulus (Y)
1872
1897
1945
Tensile Modulus (Y)
1873
1861
1794
Y MEAN MODULUS
1929.75
1889.75
1884.00
Tensile Modulus (Z)
1924
2003
1761
Tensile Modulus (Z)
1934
1879
2150
Tensile Modulus (Z)
1938
2003
1863
Tensile Modulus (Z)
1915
1856
1879
Z MEAN MODULUS
1927.75
1935.25
1913.25
Tensile Strength (X)
50.4
49.5
48.9
Tensile Strength (X)
50.3
50.0
47.4
Tensile Strength (X)
49.7
49.7
49.4
Tensile Strength (X)
49.4
48.8
47.8
X MEAN STRENGTH
50.0
49.5
48.4
Tensile Strength (Y)
50.4
48.6
48.6
Tensile Strength (Y)
50.6
50.2
49.4
Tensile Strength (Y)
49.3
50.1
49.0
Tensile Strength (Y)
49.0
48.5
47.7
Y MEAN STRENGTH
49.8
49.4
48.7
Tensile Strength (Z)
49.1
47.7
46.7
Tensile Strength (Z)
49.8
48.2
47.6
Tensile Strength (Z)
50.4
47.0
45.8
Tensile Strength (Z)
48.1
48.1
46.9
Z MEAN STRENGTH
49.4
47.8
46.8
Elongation at Break
18.137%
14.727%
19.061%
(X)
Elongation at Break
18.975%
19.577%
17.212%
(X)
Elongation at Break
15.976%
20.259%
17.724%
(X)
Elongation at Break
14.579%
16.321%
22.901%
(X)
X MEAN EAB
16.917%
17.716%
19.225%
Elongation at Break
14.991%
14.734%
15.401%
(Y)
Elongation at Break
16.680%
16.386%
22.648%
(Y)
Elongation at Break
13.161%
19.850%
24.640%
(Y)
Elongation at Break
17.391%
17.899%
16.648%
(Y)
Y MEAN EAB
15.556%
17.217%
19.834%
Elongation at Break
8.324%
7.075%
8.899%
(Z)
Elongation at Break
8.328%
6.926%
5.981%
(Z)
Elongation at Break
9.280%
5.626%
5.724%
(Z)
Elongation at Break
6.944%
6.297%
7.321%
(Z)
Z MEAN EAB
8.219%
6.482%
6.981%
[0049] The present invention in various embodiments combines the above apparatus and methods to improve the part quality of laser sintered parts and to improve the useful life of unused laser sinterable powders. Thus, the present invention provides significant technical and financial benefits to users of laser sintering systems that were previously unavailable through prior art technologies.
[0050] Many modifications and other embodiments of the invention set forth herein will come to mind to one skilled in the art to which the invention pertains having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the invention is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. It is intended that the present invention cover the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.
[0051] Accordingly, the present invention provides for the production of three-dimensional objects with improved build and support materials. Many modifications and other embodiments of the invention set forth herein will come to mind to one skilled in the art to which the invention pertains having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the invention is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. It is intended that the present invention cover the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.
[0052] The use of the terms “a” and “an” and “the” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any 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”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention. | There is provided improved laser sintering systems that increase the powder density and reduce anomalies of the powder layers that are sintered, that measure the laser power within the build chamber for automatic calibration during a build process, that deposit powder into the build chamber through a chute to minimize dusting, and that scrubs the air and cools the radiant heaters with recirculated scrubbed air. The improvements enable the laser sintering systems to make parts that are of higher and more consistent quality, precision, and strength, while enabling the user of the laser sintering systems to reuse greater proportions of previously used but unsintered powder. | 1 |
FIELD OF THE INVENTION
The present invention relates to a novel process for the manufacture of caustic soda. More particularly, the present invention relates to a causticization process wherein the individual reactants, soda ash and lime, are formed in situ from naturally occurring alkaline mineral feed materials.
BACKGROUND OF THE INVENTION
The manufacture of caustic soda (sodium hydroxide) by treatment of soda ash with lime is well known. This method of producing caustic soda generally is referred to in the art as the "causticization" process and involves reacting either soda ash with quick lime (calcium oxide) or soda ash with slaked lime (calcium hydroxide) to produce aqueous solutions containing 10 to 11 percent by weight of caustic soda. Illustrative of the use of the causticization process to produce caustic soda are the disclosures set forth in U.S. Pat. Nos. 2,979,380 and 4,451,443. For a disclosure of various plant operating designs based upon the use of the causticization process reference is made to Kirk-Othmer Encyclopedia of Technology, Vol. 1, ppgs. 740-748 (1964).
From a reading of the Kirk-Othmer reference cited above, it is clear that most caustic soda manufacturing operations, based upon the use of the causticization process, are associated with larger plant complexes for the manufacture of soda ash. One obvious reason for establishing caustic soda manufacturing operations in such close proximity to these larger plant complexes is the ready availability of the soda ash. Another is that the second reactant utilized in the causticization process; i.e., the lime, also is readily available from such soda ash manufacturing complexes as a co-product.
In contrast to the above, the present invention provides a process which can be operated, totally separated and apart from a soda ash manufacturing operation. More particularly, the present invention provides a process for the manufacture of caustic soda totally independent of a need for a separate source of both soda ash and lime.
SUMMARY OF THE INVENTION
It now has been discovered that caustic soda can be manufactured directly from certain naturally occurring alkaline minerals which eliminates the need for separate sources for the soda ash and lime reactants. In accordance with this discovery the present invention provides a process, which can be operated either batchwise or continuously, wherein a naturally occurring alkaline mineral comprised of sodium and calcium carbonates in combination in a molar ratio of about 1:1, said combination further containing from 2 to 5 moles of water of hydration, is heated at elevated temperatures sufficient to remove the water of hydration therefrom and further to partially decarbonate the mineral by the removal of one mole of carbon dioxide per mole of said mineral undergoing heating. The anhydrous and partially decarbonated intermediate product produced by said heating then is contacted with water to produce a reaction product comprised of a mixture of particulated calcium carbonate suspended in a dilute aqueous caustic soda solution. Finally, this mixture is subjected to separation to recover the desired dilute aqueous caustic soda solution.
DESCRIPTION OF THE DRAWING
The single FIGURE is a diagrammatic illustration of the major process steps of the process of the present invention and of the general flow of the materials therein.
DETAILED DESCRIPTION OF THE INVENTION
Referring to the single FIGURE, a feed stream comprising an alkaline mineral as described hereinabove, and preferably an alkaline mineral selected from the group consisting of pirssonite (Na 2 CO 3 .CaCO 3 .2H 2 O) and gaylussite (Na 2 CO 3 .CaCO 3 .5H 2 O) is introduced into drying/decarbonation zone 12 through line 4 in the form of a particulated solid.
Within drying/decarbonation zone 12 the particulated alkaline mineral is heated to temperatures sufficient to remove any incidental moisture and the water of hydration associated with the alkaline mineral. In addition, the temperatures employed will be sufficiently high to further cause decarbonation of the alkaline mineral. This decarbonation occurs as a result of the calcium carbonate constituent in the alkaline mineral undergoing decomposition to the corresponding oxide; i.e., calcium oxide with simultaneous expulsion of carbon dioxide. Furthermore, as this decarbonation proceeds the original alkaline mineral undergoes phase transformation from a solid material to a melt and back to a solid material. This final solid material which is referred to hereinafter as the "dried and decarbonated alkaline mineral intermediate product" is friable and will readily fracture upon grinding or contact with the water in reaction zone 20. The water and carbon dioxide generated in drying/decarbonation zone 12 as a result of this heating of the alkaline mineral are both removed from drying/decarbonation zone 12 through conduit 8.
Minimum temperatures at which the above disclosed decomposition can be accomplished generally will range from at least about 750° C. to at least about 850° C. As an example of a specific minimum temperature that could be employed within drying/decarbonation zone 12, it has been reported that the calcium carbonate constituent in the alkaline mineral pirssonite will undergo decomposition to its corresponding oxide beginning at about 770° C. (K. V. Tkacher, P. S. Remple and I. I. Strezhneva, Ch. Neorg. Khim, 1968, 13 (12), ppgs. 3179-81) (Chem. Abstracts, pg. 141, Vol. 70, 1969). In general, higher temperatures; i.e., temperatures greater than 850° C. but less than the decomposition temperature of sodium carbonate, will be employed to provide for a practical and more economical utilization of the novel process of this invention. The specific temperature employed as well as the time of retention of the alkaline mineral within drying/decarbonation zone 12 can readily be determined by one of ordinary skill in the art from the guidelines provided hereinabove.
Drying/decarbonation zone 12 can comprise any vessel or apparatus capable of effecting the drying of the alkaline mineral and decomposition of the calcium carbonate constituent therein to its corresponding oxide. Suitable vessels or apparatus for accomplishing these operations may include, for example, the various rotary and vertical type kilns employed in the manufacture of lime from limestone. Regardless of the type of vessel or apparatus employed, means should be provided therein to prevent sticking of the alkaline mineral to the internal surfaces of the vessel or apparatus as the mineral enters into and passes through its molten phase. One such means, for example, can include providing the vessel or apparatus with a bed of previously recovered dried and decarbonated alkaline mineral and introducing the fresh feed of alkaline mineral into the vessel or apparatus and onto this bed. By such means, the alkaline mineral undergoing treatment within the vessel or apparatus substantially will be prevented from contacting and possibly sticking to the internal surfaces of the vessel or apparatus employed as drying/decarbonation zone 12 as the alkaline mineral passes through the aforementioned molten phase.
Drying/decarbonation zone 12 also may comprise one or more of such vessels or apparatus wherein the alkaline material first is dried or dehydrated. in one vessel and then subjected to decarbonation in a second vessel or series of vessels. When a separate vessel is employed to dry the alkaline mineral the drying will be carried out at about the dehydration temperature for the particular alkaline mineral undergoing treatment. Thus, for example, the alkaline mineral pirssonite would be heated within such drying vessel at a temperature of about 190° C. which corresponds to about the dehydration temperature for this particular mineral. However, temperatures ranging from about 150° C. up to temperatures less than about the decomposition temperature of the calcium carbonate constituent in the alkaline mineral undergoing treatment generally can be utilized. Preferably, drying temperatures ranging from about 175° C. to about 300° C. will be employed.
As disclosed hereinabove, the dried and decarbonated alkaline mineral intermediate product exits drying/decarbonation zone 12 through conduit 16 as a friable solid. It is conveyed by conduit 16 to reaction zone 20. The dried and decarbonated intermediate product, which is comprised of sodium carbonate and calcium oxide, is contacted in reaction zone 20 with sufficient water to effect substantial causticization of the sodium carbonate in the intermediate product to the desired caustic soda.
The water required for effecting the causticization of the sodium carbonate in the dried and decarbonated intermediate product is introduced into reaction zone 20 through conduit 24. The quantity of water introduced into reaction zone 20 will be an amount at least equivalent to the theoretical amount required to effect hydration of the calcium oxide in said dried and decarbonated intermediate product. Generally, however, the quantity of water introduced into reaction zone 20 will be an amount in excess of the theoretical amount and sufficient to counteract the loss of water as steam. This steam, which is removed from reaction zone 20 through conduit 28, is generated by the contact of the water with the hot intermediate product as well as by the appreciable heat of hydration which occurs as the water and calcium oxide react to form the calcium hydroxide necessary to the causticization reaction. Therefore, in the practice of the process of the present invention the quantity of water introduced into reaction zone 20 via conduit 24 will be an amount equal to the theoretical amount plus an excess of at least about five percent.
Within reaction zone 20 the mixture of dried and decarbonated intermediate product recovered from drying/decarbonation zone 12 and the water introduced by way of conduit 24 will be maintained in a state or condition of continuous agitation. Such continuous agitation is necessary to provide for intimate contact between the dried and decarbonated intermediate product and the water in order to achieve the desired rate and degree of hydration of the calcium oxide and a causticization of the sodium carbonate constituents. Any vessel or apparatus, or series of two or more vessels or apparatus capable of providing for continuous agitation of the intermediate product and water during the hydration and causticization step can be employed as reaction zone 20. One type vessel which may be particularly useful is that employed in the manufacture of hydrated lime and commonly referred to as a hydrator.
Upon completion of the hydration and causticization in reaction zone 20 the resulting product which is a mixture of particulated solid calcium carbonate suspended in an aqueous solution of caustic soda is removed from reaction zone 20 by conduit 32 and conveyed therein to separation zone 36. Separation zone 36 can be any vessel capable of effecting separation of the suspended calcium carbonate and aqueous caustic soda solution which then are removed from separation zone 36 through conduits 44 and 40, respectively. Examples of vessels which can be employed to separate these materials include any of the known separation devices such as, for example, settling tanks, cyclones, filtration devices such as centrifuges and rotating drums, and the like.
The aqueous caustic soda solutions prepared and recovered in accordance with the process of this invention will contain about 10 to 11 percent by weight of caustic soda. These solutions may be packaged and sold as is or concentrated by known means to provide solutions containing up to 50 percent by weight or more of the caustic soda.
While certain embodiments and details have been shown for the purpose of illustrating this invention, it will be apparent to those skilled in this art that there are changes and modifications that may be made herein without departing from the spirit and scope of the invention as defined in the claims. | There is provided a process for preparing caustic soda solutions from naturally occurring alkaline minerals comprising double salts of sodium carbonate and calcium carbonate. The process comprises heating said naturally occurring alkaline minerals to temperatures sufficient to dehydrate and partially decarbonate said alkaline minerals and provide an intermediate product of a mixture of sodium carbonate and calcium oxide. This intermediate then is contacted with water to effect causticization of the sodium carbonate and provide a recoverable phase comprising an aqueous solution of caustic soda. | 2 |
BACKGROUND
[0001] Progressive optic atrophy associated with excavation of optic nerve head is a hallmark of glaucoma that leads to visual field defects. Although increased intraocular pressure is an obvious risk factor, the mechanisms that lead to the damage of the optic nerve head is still a controversial issue, because glaucomatous optic nerve damage may develop at any level of intraocular pressure. In the past Circulatory or vascular alterations have been considered as a risk factor accounting for the development of glaucomatous optic nerve damage. Fluorescein angiography (FAG) has shown filling defects in the optic disc of eyes with NTG. Color Doppler imaging (CDI) has demonstrated an increase in resistive index (RI) of the ophthalmic arteries in eyes with glaucoma. Laser Doppler analysis showed a decrease in retinal and optic nerve flow in glaucoma patients. Further, measurements of pulsatile ocular blood flow (POBF) showed the POBF to be significantly lower in NTG eyes with or without field loss than in normal subjects.
SUMMARY
[0002] The present invention relates to a method, including the steps of mapping at least a portion of the fundus of the eye by forming a plurality of pixels, estimating the oxygen saturation level at each of the plurality of pixels, superimposing the fundus maps on maps of anatomic borderlines, and comparing portions of the superimposed fundus maps to predetermined fundus maps.
[0003] The present invention also relates to a method, including the steps of mapping at least a portion of the fundus of the eye by forming a plurality of pixels using light from a spectral image system, dividing each light beam from the light that is reflected from the fundus with an interferometer into two coherent beams, recombining the two coherent beams and detecting the interference, measuring the interference as a function of the optical path difference, comparing the intensity of the light to the optical path difference for each of the plurality of pixels, estimating the oxygen saturation level at each of the plurality of pixels, superimposing the fundus maps on maps of anatomic borderlines and comparing portions of the superimposed fundus maps to predetermined fundus maps.
[0004] Additional features and advantages are described herein, and will be apparent from, the following Detailed Description and the figures.
BRIEF DESCRIPTION OF THE FIGURES
[0005] FIG. 1 illustrates a fundus showing seven areas where oxygen saturation (OS) level were measured;
[0006] FIG. 2 illustrates a map of the area of HFA used to calculate the mean of the total deviation (TD);
[0007] FIG. 3 illustrates oxygen saturation image maps;
[0008] FIG. 4 illustrates a comparison of the oxygen saturation levels at the superior, inferior, nasal, superotemporal, inferotemporal juxta-papillary points, and the average of these five points among three groups;
[0009] FIG. 5 illustrates oxygen saturation levels at 5 juxta-papillary points of a high tension subgroup;
[0010] FIG. 6 illustrates correlation between the mean of TD of the 17 points in the upper arcuate area and the oxygen saturation value at the inferotemporal point of the high tension subgroup;
[0011] FIG. 7 illustrates a correlation between MD and the averaged oxygen saturation value at the inferotemporal and the suprerotemporal points of the high tension subgroup; and
[0012] FIG. 8 is a side elevational view in section of a device that creates pressure in the eye positioned adjacent the external surface of the eye.
DETAILED DESCRIPTION
[0013] The present invention relates to a method in which the oxygen saturation (OS) levels in the fundus can be estimated non-invasively at each pixel with about 35 degrees to about 100 degrees (or any other suitable amount) of fundus view. The method can be used on patients with central retinal vein occlusion to evaluate the level of ischemia in the fundus. The oxygen saturation (OS) levels are measured quantitatively in the retina near the optic disc including the area corresponding to the arcuate retinal nerve fiber in eyes with open-angle glaucoma (OAG).
[0014] The oxygen saturation images can be obtained by spectral image (SRI) system. Generally, an SRI system instrument consists of a SD-200 optical head, which uses a Sagnac interferometer mounted on top of a fundus camera (TRC-50IA; Topcon Co., Tokyo, Japan) and a software module consisting of an acquisition and an analysis module; however the SRI system can be any suitable system. Generally, the SRI system allows the measurement of a spectrum in each pixel of the fundus image.
[0015] Preferably, after obtaining complete mydriasis with instillation of 0.5% tropicamide and 0.5% phenylephrine hydrochloride, the fundus is scanned by the camera for about 100 milliseconds to about 6 seconds using light between 480 and 600 nm; however, it is noted that these parameters are merely exemplary and can be any suitable parameters. Every light beam reflected from the fundus can be divided by the Sagnac interferometer into two coherent beams, which can be recombined and the interference detected. The interference can then be measured by a detector as a function of the optical path difference. The intensity versus optical path difference function, called an interferogram, can be Fourier-transformed to achieve the spectral wave, which can be carried out for every pixel of the image.
[0016] To estimate oxygen saturation level from the spectrum in each pixel, the applicability of Beer-Lambert law can be assumed by constructing a mathematical model to describe the measured fundus layers. For example, standard extinction coefficients of oxygenated and deoxygenated hemoglobin ( FIG. 1 a ) and direct response in the system can be substituted by a model based on Beer-Lambert, in which the oxygen saturation and blood column thickness are free parameters. These parameters can be then estimated to obtain the best fit between the model and the actual measured spectrum ( FIG. 1 b ), yielding the oxygen saturation estimate for each pixel of the map. This transformation can be carried out in every pixel to get an image map of the fundus in about 35 degrees to about 100 degrees or any other suitable amount.
[0017] The oxygen saturation maps can then be superimposed on maps of anatomic borderlines by a separate analysis to serve as a guide and as a spatial coordinating system. This can provide geographic maps, and the oxygen saturation pictures with which many physicians are familiar. Acquisition time with a spectral resolution of about 15 nm at about 500 nm can be at about 100 milliseconds to about 6 seconds for a 284×244 pixel image; however, it is noted that these parameters are merely exemplary and can be any suitable parameters. Using this technique and by applying different colors to different oxygen saturation level, red (e.g., about 100%) to purple (e.g., about 40%), the fundus can represent two dimensionally. Coefficient variation of images taken with SRI system can be examined and may be within 5%.
[0018] Using geographic maps, seven different points on the retina can be analyzed, including retinal vessels to compare the values among low tension and high tension subgroups and normal groups or any other suitable groups. If desired, five juxta-papillary points (e.g., superior, superotemporal, inferotemporal, inferior, and nasal point) with approximately 200 μm in diameter, avoiding the visible vessels in the retina, and 200 μm in length along both retinal artery and the vein at 0.75 disc-diameter from the disc margin can be measured. However, it is noted that any number of juxta-papillary points can be measured having any desired and/or suitable dimensions.
[0019] The mean total deviation (TD) of oxygen saturation values can also be calculated at 17 points each in the upper and the lower arcuate area ( FIGS. 2 a and b ), 5 points upper and lower to the blind spot ( FIGS. 2 c and d ), and 4 points temporal to the blind spot related to the optic disc ( FIG. 2 e ). These five regional TD values can correlate the oxygen saturation value at five measurement points respectively. Please note that any number of points each in the upper and the lower arcuate area can be used and in any areas desired.
[0020] Oxygen saturation measurement using a Fourier-transform-based SRI system can show the oxygen saturation level to be significantly lower in OAG eyes compared with normal eyes. In low tension subgroups, decreased oxygen saturation levels in the juxta-papillary area can be evident and can be observed in 3 measurement points (superior, nasal and inferotemporal point) out of five points, while the oxygen saturation level at only inferotemporal point can be significantly low in high tension subgroups.
[0021] Generally, there is no difference between the low tension and the high tensions subgroups by means of several HFA calculations, thus the severity of these two groups' glaucoma can be estimated to be about the same. Nevertheless, there can be a difference in oxygen saturation levels between the two subgroups, although the oxygen saturation level in the retinal artery, vein, and the difference between them in all the groups may be the same. The decreased oxygen saturation level in relationship with the retinal function may be related to development of glaucoma especially in normal tension glaucoma (NTG).
[0022] Patients with NTG have vasospastic episodes, often disc hemorrhages and peripapillary chorioretinal atrophy. In addition, higher endothelin-1 plasma levels in NTG patients than high-tension glaucoma patients have been reported. Decreased OS level in the juxta-papillary area may be present in NTG patients even before the visual field-loss becomes evident.
[0023] In the high tension group, oxygen saturation level can be significantly decreased at the inferotemporal point compared to normal subjects. Among 5 juxta-papillary measurement points, the oxygen saturation levels at inferotemporal, superotemporal, and inferior points were lower than those at nasal point. Averaged oxygen saturation value at inferotemporal and superotemporal points can be significantly correlated with the mean deviation. Additionally, the TD in the upper arcuate area (relating to inferotemporal point), may show good correlation with low oxygen saturation level at corresponding juxta-papillary area with a statistical significance. The decreased oxygen saturation levels at peri-papillary area may have resulted in decreased retinal sensitivity in HVF, in the high tension and in NTG patients.
[0024] Different oxygen saturation levels in the peripapillary area may be observed among low tension, high tension and normal eyes and also altered relation between the oxygen saturation level and HVF analysis in low tension and high tension glaucoma patients. Oxygen saturation measurement can be also a useful method in evaluation and potentially management of OAG patients.
[0025] FIG. 8 illustrates another embodiment in which glaucoma can be detected using a device 20 and method that increases pressure in the eye 10 . The device 20 can increase pressure by creating suction and/or a vacuum at a portion on the eye. For example, the device can be positioned at or near the cornea and/or the sclera or at any other suitable position on the eye. Additionally, if desired, the device can apply pressure to the eye, thus increasing the pressure.
[0026] The device to increase the pressure can be substantially circular with an arcuate inner surface 22 and an outer surface 24 . That is, the surface that is positioned adjacent the cornea and/or sclera can have an arcuate surface or any other suitable surface. The radius of curvature of the arcuate surface can be about the same as the curvature of the eye or have a steeper or shallower radius of curvature of the eye. The device can be formed of any suitable material and be formed from transparent, translucent or opaque material.
[0027] To apply the vacuum, a pump 26 can be attached or coupled to the device use a tube 28 or any other suitable means. The pump through tubing can create suction within the space 30 between the device and the eye, thereby creating a vacuum. This vacuum will increase the pressure in the eye.
[0028] A similarly shaped device can be used to increase the pressure in the eye by applying pressure to the external surface 24 of the device.
[0029] It is noted that any suitable device to increase pressure can be used in this procedure.
[0030] Preferably, the pressure in the eye is gradually raised to between about 1 mm Hg to about 30 mm Hg, and more preferably to between about 3 mm Hg to about 10 mm Hg or to any specific pressure within or without of these ranges or any suitable range therein. For example, the pressure can be raised to 6 mm Hg, if desired or any pressure outside of the above stated range, if suitable. The pressure is maintained at the desired amount for a predetermined time. For example, the pressure can be maintained for about 5 to about 10 seconds or up to about 1 minute, or any other specific suitable time or range of times. Before, during and after the increase in pressure, the oxygen saturation levels are measured and compared and/or contrasted to a normal eye or any other determined amount.
[0031] If desired, the pressure can be reduced and the oxygen saturation levels can be monitored to determine the length of time that is required for the levels to return to normal or substantially normal level. This type of stress test will indicate whether a patient has glaucoma.
[0032] The difference between oxymetry values (i.e., oxygen saturation levels) in sitting vs. laying down position can also be indicative of glaucoma.
EXAMPLES
[0033] The oxygen saturation level of each point was masked as to the subjects' characteristics. Unpaired t-test or non-repeated measures of ANOVA followed by Bonferroni correction or repeated measures of ANOVA followed by Student-Newman-Keuls test was used for statistical evaluation.
[0034] Fifty-six eyes of 56 Japanese OAG patients and 20 eyes of 20 normal Japanese were recruited for the study. Among 56 OAG eyes, 15 eyes (15 patients) constantly showed recorded intraocular pressure (IOP) of ≦15 mmHg and were classified as low-tension (LT) subgroup. The other 41 eyes from 41 patients showed recorded IOP of ≧22 mmHg in multiple readings and were classified as high-tension (HT) subgroup, during more than 6 of months follow-up. The subjects age were 27 to 73 (mean ±SD, 60.5±11.9) years in the LT subgroup, 22 to 78 (55.9±14.8) years in the HT subgroup, and 31 to 79 (52.6±15.7) years in the normal group. The differences in the mean ages among the three groups were not statistically significant (p>0.05, non-repeated measures of ANOVA).
[0035] All patients underwent routine ophthalmic examination previous to this study. There was no obvious change in normal group except for mild senile cataract and refractive error. Patients who had a history of systemic diseases such as systemic hypertension or diabetes mellitus were excluded from this study. Additionally, all LT patients were examined by CT scan or by magnetic resonance images (MRI) that showed normal results. This study was carried out with approval from the review board of the institute and informed written consent was obtained from all the patients. All but two patients had never taken any instillation of medication to lower the IOP, and those who had been taking it were withheld from it for at least 4 weeks before entry in this study. All OAG patients had visual field examination with automatic static perimetry at least twice that showed characteristic glaucoma visual field losses in all. A Humphrey field analysis (HFA) with the program 30-2 SITA (Zeiss Humphrey Instruments, Dublin, Calif., USA) was performed. The oxygen saturation (OS) level in the fundus was measured with Fourier-transform-based spectral retinal image (SRI) system (Retinal Cube; ASI Co. Migdal Hemak, Israel) around noon till 3 o'clock in the afternoon.
Results
[0036] The intraocular Pressure (IOP) of all subjects was measured using a Goldmann applanation tonomer (Haag-Streit, Berne, Switzerland) just before the OS level measurement. It averaged 12.9±1.4 mmHg in the LT subgroup, 20.0±4.1 mmHg in the HT subgroup, and 14.0±2.8 mmHg in the normal group. The differences among the HT subgroup and the other two were statistically significant (p<0.001).
[0037] The average of the mean deviation (MD) of the light intensity was −8.4±6.5 dB in the LT subgroup and −7.7±6.9 dB in the HT subgroup. The mean of total deviation (TD) of 17 points in the upper arcuate and in the lower arcuate area respectively, that of 5 points upper to the blind spot, that of 5 points lower to the blind spot, and that of 4 points temporal to the blind spot was −9.9±9., −7.5±6., −6.5±7., −6.4±8., and −4.7±7. dB in the LT subgroup and −7.9±9.0, −8.6±8. −4.0±6., −4.7±5., and −3.4±6. dB in the HT subgroup, respectively. All of these HFA results showed no significant difference between the two OAG subgroups (unpaired t-test).
[0038] In the normal eyes, OS map demonstrated dominantly yellow to red, with a few green color dots surrounding the optic disc ( FIG. 3 a ) that suggested OS levels of the retina at corresponding area were higher than 80%. In contrast, green and/or blue dots overriding in OS maps of the LT subgroup implied OS levels in the retina to be approximated approximately from 70% to 80% ( FIG. 3 c ). Whereas OS levels in the HT subgroup were more variable than in the LT subgroup, averaged color range lay in the middle of the normal group and the LT subgroup in most of eyes ( FIG. 3 b ). The edge of vessels and rim of the disc were artificially delineated to make them clearer. OS levels in the retina at 5 points in the juxta-papillary retina, as well as in both the retinal artery and vein, were summarized in Table 1 and FIG. 4 .
[0039] OS levels of both the LT and the HT subgroups were significantly lower than those of the normal group at the inferotemporal point and than the averaged OS value of the juxta-papillary five points (p=0.047˜0.001). At the superior and nasal points, OS level of the LT subgroup showed significant decreases as compared with the HT subgroup (p=0.026 and 0.048 respectively) and also those of the normal group (p=0.009 and 0.019 respectively). Except the inferior and the superotemporal points, the OS levels at juxta-papillary area of both HT and LT subgroups were lower than those of normal subjects.
[0040] OS levels in the retinal artery and vein showed no significant differences among these three groups. The value of OS level reduction between artery and vein (artery-vein) also showed no significant inter-group difference (Table 1).
[0041] Differences of OS levels among the 5 juxta-papillary points were then examined. There were no statistically significant differences in the normal group and the LT subgroup. On the other hand, in the HT subgroup, inferior, superotemporal, and inferotemporal points were significantly lower as compared with nasal point (p<0.010, p<0.050, p<0.010, respectively; FIG. 5 ).
[0042] There was a statistically significant correlation between the mean of TD of the 17 points in the upper arcuate area and the OS level of the inferotemporal point (p=0.018, r=0.377; FIG. 6 , table 2) in the HT subgroup. The correlation between MD and the averaged OS value of the inferotemporal and the superotemporal point was also statistically significant (p=0.037, r=0.334; FIG. 7 ). No significant correlation was observed between MD and the averaged OS value of the 5 juxta-papillary points, or between the mean of TD of 17 points in the lower arcuate area and the OS level at the superotemporal point. In the LT subgroup, no such correlation was present (Table 2).
[0000]
TABLE 1
Normal
LT
HT
Superior
88.5 ± 11.1
76.6 ± 10.2
84.4 ± 11.4
Inferior
84.8 ± 9.6
81.5 ± 9.7
82.3 ± 11.0
Nasal
91.8 ± 8.9
77.2 ± 11.0
85.1 ± 14.1
Superotemp.
88.4 ± 11.1
81.7 ± 9.4
81.5 ± 12.1
Inferotemp.
86.3 ± 10.2
73.0 ± 10.9
80.2 ± 12.1
Average
87.6 ± 8.2
77.8 ± 7.6
82.4 ± 9.8
Artery
85.5 ± 14.1
85.5 ± 7.9
85.3 ± 7.7
Vein
68.5 ± 8.0
62.8 ± 8.0
65.2 ± 8.0
Artery-Vein
17.2 ± 11.5
22.8 ± 12.5
20.7 ± 8.0
[0000]
TABLE 2
p
r
Mean of TD of Area a and
HT
0.0179
0.377
Inferotemporal OS
LT
0.6478
0.134
Mean of TD of Area b and
HT
0.6786
0.067
Superotemporal OS
LT
0.9468
0.019
MD and
HT
0.1569
0.225
Average OS
LT
0.6277
0.136
MD and Average of
HT
0.0374
0.334
Inferotemporal and
LT
0.9183
0.030
Superotemporal OS
[0043] It should 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 present subject matter and without diminishing its intended advantages. It is therefore intended that such changes and modifications be covered by the appended claims. | The present invention relates to a method, including the steps of mapping at least a portion of the fundus of the eye by forming a plurality of pixels, estimating the oxygen saturation level at each of the plurality of pixels, superimposing the fundus maps on maps of anatomic borderlines, and comparing portions of the superimposed fundus maps to predetermined fundus maps. | 0 |
This application is a division of applicant's commonly assigned application U.S. application Ser. No. 12/913,968, filed 28 Oct. 2010, and titled Control Logic For Applying Preservative to Agricultural Bales, now U.S. Pat. No. 8,567,311.
FIELD OF THE INVENTION
The present invention relates to machines for forming cylindrical bales of crop material, such as hay, and particularly to an improved control logic using sensed crop moisture for applying a preservative to the crop material as the bale is being formed.
BACKGROUND OF THE INVENTION
In agriculture it is a well known practice to bale crop material using balers that create round or cylindrical bales. It is also a common practice to store such bales outdoors where they are exposed to the elements of rain and snow. Nearly all, round bales stored outside without some form of protection from rain and/or snow will experience mold growth in the outer rind of the bale. The potential benefits of applying mold inhibiting preservatives to hay either during a baling process or to the finished bale are well known and include (a) permitting the hay to be baled and stored at higher moisture contents without spoilage, thus reducing field losses and making the hay making operation less dependent on favorable weather conditions; (b) improved palatability and digestibility; and (c) higher nutrient content. The relative importance of these benefits varies with the crop being treated and the preservative used.
Accordingly, preparations of buffered propionic acid or anhydrous ammonia are sometimes applied to the hay at the time of baling to prevent bacterial and mold growth. Typically, these preparations are applied to the entire bale as it is being formed or injected into the bale after formation. Because of this, there is a desire to apply the preservative only to the portion of the bale having a moisture content requiring preservative application.
Today there are several moisture sensors on the market that measure the moisture of hay as it is being baled. All of these systems use one or more sensors to estimate the average moisture of the hay being harvested. Some of these systems provide a means of applying crop preservative to the hay based on the average moisture level of the incoming crop. The problem with basing the preservative application rates on the average moisture level is that many times the average value appears to be at a suitable moisture level when in fact a significant portion of the crop is at high moisture level that requires a preservative for proper storage. For example, hay normally can be properly stored without applying a preservative at moisture levels less than 20% wet basis (w b ) wherein w b =(weight of water)/(weight of crop material+water). If the incoming crop consisted of 75% of the crop being at 18% w b and 25% of the crop being at 25% w b , the average value=19.25% w b . Based on the average value, one would assume that the crop would not need to be treated with a preservative, when in reality it should have been.
Therefore, basing application rates on average hay moisture values does not allow one to recognize (or identify) that a problem exists and/or the extent of the problem.
Because of this, there is a desire to apply the preservative only to the portion of the bale having a moisture content requiring preservative application and/or applying the preservative at a controlled rate according to the sensed moisture content of incoming crop.
SUMMARY OF THE INVENTION
It is therefore an object of the invention to provide an improved control logic for applying a preservative to a bale as the bale is being formed at a controlled rate and/or only where needed based upon a sensed moisture content in the incoming crop material related to the overall moisture content of the crop material being baled.
This and other objects of the invention are accomplished by a method for applying a preservative to crop material during a baling process wherein a baler comprises a pickup device for picking up crop material from a windrow on the ground, a crop inlet to a baling chamber, at least one moisture sensor, the at least one moisture sensor sensing moisture in incoming crop material across an entire width of the crop inlet, a preservative application system for selectively applying preservative to the crop material as it is being baled and an Electronic Control Unit (ECU) for receiving data from the at least one moisture sensor and for selectively activating the preservative application system, the method comprising the steps of: inputting a high moisture set point in the ECU, the high moisture set point corresponding to a moisture content percentage of crop material entering the baler, below which it is deemed unnecessary to apply preservative; inputting a high moisture set point ratio in the ECU, the high moisture set point ratio corresponding to a percentage of incoming crop material that is above the high moisture set-point at which it is deemed necessary to apply preservative; inputting an application rate/high moisture ratio, the application rate/high moisture ratio corresponding to the rate at which it is deemed necessary to apply preservative to adequately preserve the crop material based upon the percentage of crop material being above the high moisture set-point ratio; commencing a baling process; sensing a moisture content of the incoming crop material; determining whether the sensed moisture content of incoming crop material one of meets and exceeds the high moisture set point; determining whether the sensed moisture content of incoming crop material one of meets and exceeds the high moisture set point ratio; activating the preservative application system to begin the application of preservative when both the high moisture set point and the high moisture set point ratio have been one of met and exceeded; and, adjusting the rate of preservative application to the application rate/high moisture ratio for the high moisture set-point ratio.
The objects of the invention are further accomplished by a method for applying a preservative to crop material during a baling process wherein a baler comprises a pickup device for picking up crop material from a windrow on the ground, a crop inlet to a baling chamber, at least one moisture sensor, the at least one moisture sensor sensing moisture in incoming crop material across an entire width of the crop inlet, a preservative application system for selectively applying preservative to the crop material as it is being baled and an Electronic Control Unit (ECU) for receiving data from the at least one moisture sensor and for selectively activating the preservative application system, the method comprising the steps of: inputting a high moisture set point in the ECU, the high moisture set point corresponding to a moisture content percentage of crop material entering the baler, below which it is deemed unnecessary to apply preservative; inputting a high moisture set point ratio in the ECU, the high moisture set point ratio corresponding to a percentage of incoming crop material that is above the high moisture set-point at which it is deemed necessary to apply preservative; inputting an application rate/high moisture ratio, the application rate/high moisture ratio corresponding to the rate at which it is deemed necessary to apply preservative to adequately preserve the crop material based upon the percentage of crop material being above the high moisture set-point ratio; commencing a baling process; sensing the moisture content of incoming crop material; determining whether the sensed moisture content of incoming crop material one of meets and exceeds the high moisture set point; determining whether the sensed moisture content of incoming crop material one of meets and exceeds the high moisture set point ratio; activating the preservative application system to begin the application of preservative when both the high moisture set point and the high moisture set point ratio have been one of met and exceeded; and, adjusting the rate of preservative application to the application rate/high moisture ratio for the high moisture set-point ratio and the sensed moisture content of the high moisture crop material entering the baling chamber.
Further objects of the invention are accomplished by an improved agricultural baler having a preservative application system and an Electronic Control Unit (ECU) controlling the preservative application system, the improvement comprising: a moisture sensor array sensing the moisture content of crop material entering the baler, the moisture sensor array being in communication with the ECU; the ECU being programmed to control the preservative application system at an application rate based upon a percentage of crop material entering the baler that exceeds a threshold percentage of crop material above a threshold moisture content value.
In general a method and apparatus are provided for applying preservative to agricultural crops during baling. More particularly, a baler has a preservative application system and a crop moisture sensor array. The crop moisture sensor array is in communication with the preservative application system so that the application of preservative to the crop can be controlled in response to a moisture content sensed by the crop moisture sensor array that exceeds both a moisture content threshold value and a threshold value relating to the percentage of crop material having a moisture content above the moisture content threshold value.
To acquaint persons skilled in the art most closely related to the present invention, one preferred embodiment of the invention that illustrates the best mode now contemplated for putting the invention into practice is described herein by and with reference to, the annexed drawings that form a part of the specification. The exemplary embodiment is described in detail without attempting to show all of the various forms and modifications in which the invention might be embodied. As such, the embodiment shown and described herein is illustrative, and as will become apparent to those skilled in the art, can be modified in numerous ways within the spirit and scope of the invention—the invention being measured by the appended claims and not by the details of the specification.
BRIEF DESCRIPTION OF THE DRAWINGS
For a complete understanding of the objects, techniques, and structure of the invention reference should be made to the following detailed description and accompanying drawings, wherein:
FIG. 1 is an elevational view of a round baler employing the apparatus according to the invention;
FIG. 2 is a perspective partially schematic view of a preservative application system according to the invention;
FIG. 3 is a perspective view of a portion of a crop pick-up device for the round baler of FIG. 1 having a moisture sensor array;
FIG. 4 is a flowchart showing the logic of a first embodiment of the method; and,
FIG. 5 is a flowchart showing the logic of another embodiment of the method.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now to FIG. 1 it can be seen that a round baler is generally designated by the numeral 10 . The baler 10 is in many respects conventional in its arrangement and includes a main frame 12 supported on a pair of ground wheels 14 . A draft tongue 16 has a rear end joined to the frame 12 and has a forward end defined by a clevis arrangement 18 adapted for being coupled to a towing vehicle (not shown). A pair of upright side walls 20 are fixed to the main frame 12 and define forward regions of opposite side walls of a baling chamber. Mounted for pivoting vertically about a horizontal pivot arrangement 22 located at an upper rear location of the side walls 20 is a discharge gate 24 including opposite upright side walls 26 , which define opposite sides of a rear region of the baling chamber. A gate cylinder arrangement (not shown) is coupled between the main frame 12 and the opposite side walls 26 of the discharge gate 24 and is selectively operable for moving the discharge gate 24 between a lowered baling position and an opened discharge position. Baler 10 is of a variable size chamber design and thus comprises a plurality of longitudinally extending side-by-side belts 28 supported on a plurality of rollers 30 (only a few of which are shown). A bale forming chamber is defined by the sidewalls 20 , 26 , the rollers 30 and belts 28 .
As mentioned previously, the baler 10 illustrated is a variable chamber design wherein crop is rolled up in a spiral fashion in a nip formed between oppositely moving adjacent loops of belts 28 . The space between adjacent loops of belts 28 grows as the forming bale B grows larger. Accordingly, a belt tensioning device 34 is provided to take up slack in the belts 28 as needed. Thus the position of the tensioning device 34 , at any given time, is an indication of the size of the bale B at that time. A bale diameter sensor 36 in the form of a potentiometer is affixed to the pivot point of the tensioning device 34 and thus provides an electrical signal correlating with bale diameter to an Electronic Control Unit (ECU) 40 . The ECU 40 , via appropriate logic, can then translate the signal into meaningful bale size data that can be communicated to an operator by way of an appropriate display device (not shown). In addition to providing an indication of bale size to the operator, the ECU 40 can be adapted to utilize bale diameter data for other purposes such as triggering a twine or wrapping cycle, opening the discharge gate, initiating bale discharge, or to control the application of preservative to the bale.
In its general operation the baler 10 is drawn through a field by a prime mover (not shown) attached to the tongue 16 . Crop material 42 is fed into a crop inlet 44 of the bale forming chamber from a windrow of crop on the ground by a pickup 46 . In the baler 10 , the crop material 42 is rolled in spiral fashion as described above into the cylindrical bale B. Upon completion, the bale B is wrapped with twine or other appropriate wrapping material and is discharged by actuation of gate cylinders that open gate 24 permitting the completed bale B to be discharged from the baler 10 onto the ground.
With continued reference to FIG. 1 and also now to FIG. 2 it can be seen that the baler 10 further includes a preservative application system 50 that comprises at least one storage container such as holding tank 52 , a transfer device such as a variable speed pump 54 and an applicator device 56 . It will be recognized as the description continues, that various alternative embodiments of the preservative application system are possible. For example the variable speed pump could be a fixed speed pump, or in place of a pump, the system could have a pressurized tank and valve system or a gravity feed and valve system. As illustrated the holding tank 52 and pump 54 are mounted upon a frame 58 above the tongue 16 at the front of the baler 10 . It will, however, be recognized that the tank and pump could be mounted at another location. The applicator device 56 as shown is in the form of an elongated spray bar that generally spans the width of the baling chamber and is mounted just ahead of and above the crop inlet 44 of the baler. It will be recognized that instead of an elongated spray bar, the system could employ other means for applying the preservative such as nozzles having fixed or adjustable spray patterns. The tank 52 is connected to the pump 54 by way of a hose 60 , and the pump 54 is, in turn, connected to the applicator device 56 by a hose 62 . Thus, when the pump 54 is activated, preservative is drawn from the tank 52 via the hose 60 and sent to the applicator device 56 via the hose 62 . Preservative is expelled from the spray bar in a pattern designed to ensure contact with the incoming crop material.
The ECU 40 is connected to and controls the pump 54 by way of appropriate logic to start and stop the pump 54 and/or to control the speed of the pump and therefore the application rate of the preservative. Logic can be programmed in the ECU 40 to start/stop and/or vary the speed of the pump 54 based upon data provided to the ECU 40 from various sensors on the baler as described in more detail below.
The disclosure thus far has described a baler having a preservative application system as is known in the art. The description which follows describes the novel embodiments of the invention. With continuing reference to FIGS. 1 and 2 and also with reference to FIG. 3 , it can be seen that the baler 10 is further provided with an array of moisture sensors 64 that are preferably distributed across the width of the baler ( FIG. 3 ) and preferably below the flow of incoming crop material as indicated by the sensor array 64 A in FIG. 1 . It is also possible to mount the moisture sensor array 64 at other locations on the baler such as above the flow of incoming crop material as it enters the crop inlet as indicated by the sensor array 64 B in FIG. 1 or for example on the draft tongue 16 of the baler so that incoming crop moisture is sensed while the crop is still on the ground as indicated by the sensor array 64 C in FIG. 1 . The possible locations for the moisture sensor array 64 are shown by way of example only. It is contemplated that the sensor array 64 can be located at other locations on the baler 10 that are not specifically shown or described—it only being necessary that the moisture sensors be positioned to monitor moisture content at the time or shortly before crop enters the crop inlet.
The moisture sensor array 64 is preferably comprised of a plurality of sensor elements 66 evenly distributed across the width of the baler 10 . It is contemplated that such sensor elements 66 could be of the conductive, fringe capacitance microwave, transmitted microwave, or Near Infrared (NIR) type, as well as other sensors capable of determining moisture content in the incoming crop material. It is also possible that with certain sensors having the capability of measuring the moisture content of incoming crop material across the baler width, it may not be necessary to provide multiple sensors but instead a single sensor may be adequate. Regardless of the type of moisture sensors employed, the output of the sensor array 64 is communicated to the ECU 40 by way of a wired or wireless connection. The ECU 40 then uses the sensed moisture readings of the sensor array 64 to control the application of preservative as will be described in more detail below.
With reference now to FIG. 4 a preservative application control scheme is set forth in a flowchart generally illustrating the logic used by the ECU to apply preservative. More particularly, FIG. 4 illustrates an embodiment wherein the control logic applies preservative in proportion to the fraction of crop that exceeds a set-point moisture content. Specifically, after the start at 401 an operator inputs a “High Moisture Set-Point” at 402 . This “High Moisture Set-Point” represents a moisture content percentage of crop material entering the baler, below which it is unnecessary to apply preservative. At 403 the operator inputs a “High Moisture Set-Point Ratio” that is above the “High Moisture Set-Point”. The “High Moisture Set-Point Ratio” represents a percentage of incoming crop material that is above the “High Moisture Set-Point” at which it is deemed necessary to apply preservative. Next at 404 the operator inputs an “Application Rate/High Moisture Ratio”. The “Application Rate/High Moisture Ratio” represents the rate at which it is deemed necessary to apply preservative to adequately preserve the crop material based upon the crop material being above the “High Moisture Set-Point Ratio”. At 405 the baling operation is commenced. At 406 the logic queries whether the “High Moisture Set-Point” has been met or exceeded. If the answer is no, then the application system remains off. If at 406 the answer is yes, then at 407 the logic queries whether the “High Moisture Set-Point Ratio” has been met or exceeded. If the answer at 407 is yes, then the pump is turned on at 408 and the application rate is adjusted at 409 according to the “Application Rate/High Moisture Ratio” set at 404 . Next at 410 the logic queries whether the bale has been completed. If the answer at 410 is yes, the pump is turned off at 411 . If the answer at 410 is no, the logic reverts to 406 .
In an alternative embodiment set forth in the flowchart of FIG. 5 the logic used by the ECU to apply preservative is based upon applying preservative to the fraction of the crop that exceeds the set point moisture content and the actual moisture of the crop material that exceeds the set point moisture. This method requires more accurate sensors than the embodiment of FIG. 4 , in that in FIG. 4 it is only necessary to determine the percentage of the crop material exceeding the “High Moisture Set-Point Ratio” wherein the embodiment of FIG. 5 requires a more accurate determination of the actual moisture content of the high moisture material. Specifically, after the start at 501 the operator inputs a “High Moisture Set-Point” at 502 . As in the embodiment of FIG. 4 this “High Moisture Set-Point” represents a moisture content percentage of crop material entering the baler, below which it is unnecessary to apply preservative. At 503 the operator inputs a “High Moisture Set-Point Ratio” that is above the “High Moisture Set-Point”. As in the embodiment of FIG. 4 this “High Moisture Set-Point Ratio” represents a percentage of incoming crop material that is above the “High Moisture Set-Point” at which it is deemed necessary to apply preservative. At 504 the operator inputs an “Application Rate/High Moisture Ratio”. The “Application Rate/High Moisture Ratio”, as in the previous embodiment, represents the rate at which it is deemed necessary to apply preservative to adequately preserve the crop material based upon the crop material being above the “High Moisture Set-Point Ratio”. At 505 the baling operation commences. At 506 the logic queries whether the “High Moisture Set-Point” input at 502 has been met or exceeded. If the answer is no, then the application system remains off. If at 506 the answer is yes then at 507 the logic queries whether the “High Moisture Set-Point Ratio” has been met or exceeded. If the answer at 507 is yes, then the pump is turned on at 508 . At 509 unlike the previous embodiment the application rate is adjusted to not only the “Application Rate/High Moisture Ratio” but also based upon the actual moisture content of the high moisture material entering the baler. This allows for a more accurate and efficient application of preservative based not just upon the fact that material entering the baler is above the “High Moisture Set-Point Ratio”, but also compensates for the actual moisture content of this sensed high moisture material. Next at 510 the logic queries whether the bale has been completed. If the answer at 510 is yes, the pump is turned off at 511 . If the answer at 510 is no, the logic reverts to 506 .
It should now be apparent that the array of moisture sensors allows the variation in moisture levels of the harvested crop to be measured. Rather than averaging the moisture levels to determine the appropriate application rate of the preservative, the application rate is derived based on the fraction of crop that exceeds a critical level for proper storage. For example if 10% of the crop exceeds a critical moisture level, an application rate of X is applied. However, if 20% of the crop exceeds a critical level, an application rate of Y is applied to the crop. Basing the application rate on the fraction of crop that exceeds a critical value (rather than the average moisture value) allows one to identify when a preservative is needed and provides more effective and efficient use of the preservatives.
Having described the preferred embodiments it should now be apparent that alternatives are contemplated wherein the method and apparatus of the invention are utilized with either fixed or variable chamber round balers, as well as a variety of available moisture sensors, and can be utilized with both fluid and dry preservatives provided that appropriate storage, transfer and applicator devices suitable to the preservative are utilized.
Thus it can be seen that the objects of the invention have been satisfied by the structure presented above. While in accordance with the patent statutes, only the best mode and preferred embodiment of the invention has been presented and described in detail, it is not intended to be exhaustive or to limit the invention to the precise form disclosed. Obvious modifications or variations are possible in light of the above teachings. The embodiment was chosen and described to provide the best illustration of the principles of the invention and its practical application to thereby enable one of ordinary skill in the art to utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated. All such modifications and variations are within the scope of the invention as determined by the appended claims when interpreted in accordance with the breadth to which they are fairly and legally entitled. | A method and apparatus are provided for applying preservative to agricultural crops during baling. More particularly, a baler has a preservative application system and a crop moisture sensor array. The crop moisture sensor array is in communication with the preservative application system so that the application of preservative to the crop can be controlled in response to a moisture content sensed by the crop moisture sensor array that exceeds both a moisture content threshold value and a threshold value relating to the percentage of crop material having a moisture content above the moisture content threshold value. | 0 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] 123/118 280/87 041 280/87.42
[0002] 123 198 280/87 042
USA Patents Year Person ″ 430 006 1890 Dorr ″ 2176- 716 1939 Gonleay ″ 3288- 25 1966 Sakwa ″ 6213 484 2001 Robner ″ 1530 165 1925 Flower ″ 4054 296 1977 Sullins ″ 6/ 105 978 2000 ″ 1173 826 1916 Mack ″ 4019 490 1977 Reese
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0003] There is no Federal funding and no companies have any right to inventions.
REFERENCE TO A SEQUENCE LISTING, A TABLE, OR A COMPUTER PROGRAM LISTING COMPACT DISC APPENDIX
[0004] Not Applicable
BACKGROUND OF INVENTION
[0005] The present invention involves skateboard-like board vehicles. The difference between a Truckin Board and a skateboard is a spindled axle with greater ground clearance and a centrally activated brake system that does not impede the ability of a skateboard to tilt and steer, while slowing the wheels on a skateboard. A recoil rope, hand-activated, acts as a handle and a brake-activation mechanism, centrally pulled.
[0006] In the year 1890, U.S. Pat. No. 430-006 shows a wheel with a brake attached to a shoe.
[0007] In 1939, U.S. Pat. No. 2176-716, another shoe with a framed skate, with a sliding mechanism for brake activation.
[0008] In 1966, U.S. Pat. No. 3288-251 shows a real attempt to cause a brake activation while a skate is allowed to tilt to steer. However, it required stepping on a lever to work. This was a far better design than those to follow. Any block or cause of a skateboard to become perpendicular to the ground or wheels, makes tiltability or steering non-existent.
[0009] In 2000 U.S. Pat. No. 6213-484 shows a skateboard with a handle and a foot brake dragging on the wheels; steering or tiltability is diminished by wheels becoming horizontal to the board.
[0010] In April 2002, U.S. Pat. No. 6367-828, a skateboard-like vehicle with a handle and a brake dragging on the ground.
[0011] U.S. Pat. No. 1530-165, a foot pedal skateboard; any foot activation prevents a rider from bracing for a stop with both feet.
[0012] U.S. Pat. No. 4054-296, foot pedal on a skateboard (same USA patent August 2000, U.S. Pat. No. 6105-978), a skateboard using a bent axle to increase ground clearance under an axle.
[0013] Present invention incorporates a new use of a recoil-rope-engine-starting system to a Truckin Board, a skateboard-like vehicle, to activate a brake system and act as a handle that aids in bracing for stops and snaps back into the truck wheel assembly when not in use.
[0014] In 1916, U.S. Pat. No. 1173-826, shows an early recoil-engine starter, and in the year 1977, U.S. Pat. No. 4019-490, a recoil with a brake, preventing a child from starting a small engine. There are no uses of a skateboard using a recoil to activate a brake.
[0015] Present invention uses a recoil rope for two purposes. It activates a brake mechanism within a board-like vehicle and also aids the helm rider when steering and braking. The feet are braced, and the handle aids rider in staying on the board when actually steering and actually braking safely on a skateboard-like vehicle by this novel new design. These and other advantages will become more apparent from the following detailed description of the invention when taken in conjunction with the accompanying exemplary drawings, patenter to include those on document disclosure #522979.
SUMMARY OF INVENTION
[0016] The present invention provides an actual brake system that does not impede steering on recreational board vehicles. The Truckin Board is like the skate board except Truckin Boards use a recoil-rope-pulled brake activation that is centrally pulled and allows the rider to steer while stopping. Additionally, a spindled axle allows greater ground clearance.
[0017] The Truckin Board can be used by standing or lying on an elongated board. Racing can be improved with the brake camber system, Depending upon removal and placement of brake rollers when brakes are applied on one side, when activated steering is aided in downhill racing, Board steers into corners using brake pull on affected wheels. A Truckin Boarder can actually steer left and right while activating brakes to slow or stop a rider safely, as well as adjust steering or change small wheels to large wheels, and brake parts interchange. These and other advantages will become more apparent on a detailed description of the invention when taken in conjunction with the accompanying exemplary drawings.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING
[0018] FIG. 1 Overall view of Truckin Board and rear wheel assembly with recoil.
[0019] FIG. 2 End view of brake adjuster front. Top view of rear brake truck assembly with front and rear view of recoil mechanism.
[0020] FIG. 3 Top view of access holes rear assembly, side view of cutaway shock, 1 .
[0021] FIG. 4 Side, overall view, rear brake mechanism and wheel assembly; cut away of recoil and recoil cog.
[0022] FIG. 5 Top view cable connector adjustment and pulley
[0023] FIG. 6 Side view rear wheel truck assembly with cable route through wheel truck assembly mount.
[0024] FIG. 7 Overall view, exploded of brake lever and brake shoes, with front view of wheel truck assembly with spindles.
[0025] FIG. 8 Exploded view of recoil brake mechanism rear mount for wheel truck assembly.
[0026] FIG. 9 Underside view of friction rollers on long and short brake shoes of elongated brake shoe shapes.
[0027] FIG. 10 . Wheels, showing two sizes and single roller brake.
[0028] FIG. 11 . Underside view of truckin cavity board and recoil spool.
[0029] FIG. 12 . Cutaway view, winged coupling and coupling mount. Cut-away view of front shock with winged coupling on shock mount.
DETAILED DESCRIPTION OF THE INVENTION
[0030] Document Disclosure Program #522979 shows a similar view of FIG. 1 , showing the Truckin Board that differs from a skate board in that Truckin Boards have actual, usable brakes that allow a rider to steer left and right while braking by pulling a brake handle. They have added ground clearance, the ability to alter wheel size, and steering is adjustable, here choosing the smaller diameter wheels and brakes
[0031] If larger wheels are used, FIG. 4 at 7 shows a removable bumper which unscrews from FIG. 6 at 1 .
[0032] A wheel truck assembly front and rear, FIG. 9 at 8 , shows a front brake shoe and 107 , a longer brake shoe for taller wheel 6 . Both types of shoes can be made of high impact plastic or other material.
[0033] Brake shoe FIG. 7 at 81 , interior view, shows an installed friction roller in 81 , inside 80 , a rear brake shoe. These rollers prevent brake lockup as wheel 6 comes in contact with shoe 80 . Both 8 and 80 brake shoes, front and rear friction wheel 81 , will interchange or can be rotated for wear or be removed for other braking characteristics. Shaft screw 82 enters hole 83 , then travels through friction roller 81 in cavity 115 and screws into 84 . There is nothing to prevent riveting or other methods of mounting a friction roller. As roller 81 is eccentrically rotated into wheel 6 , friction roller is binded in cavity 115 within brake shoe where pressure causes 81 friction between wheel 6 and brake 80 , slowing wheel 6 , providing safety in Truckin Board vehicles. All four brake shoes accept friction rollers in a similar way.
[0034] FIG. 8 shows a steel lever 14 with hole 69 on both ends of lever 14 . See FIG. 7 . Brake shoe 80 , FIG. 7 , also has corresponding hole 69 in concave cavity 114 , FIG. 8 , wherein screw 79 , FIG. 7 , fits inside cavity 114 , FIG. 8 . See nut 77 , FIG. 7 . Screw 79 enters lever 14 as shown. A nut 77 screws onto bolt 79 . And a pin 78 enters bore hole 75 in screw 79 . There is nothing to prevent the use of washers to take up space. Brake shoe 80 attaches to lever 14 in the same way, just as does brake shoe at 8 , FIG. 9 , showing the only difference in a number 8 and 80 .
[0035] FIG. 6 at 1 , shows a wheel truck assembly with spindled axles, without brake attached at hole location 87 . Note location of spindled axle 3 to bore hole 87 .
[0036] See FIG. 7 at hole 86 . Both brake shoes attach to lever 14 , attach at slot 85 above axle 3 . See FIG. 4 . Note hole 87 , showing attached brake shoe 8 . FIG. 7, 86 , enters concave cavity in wheel assembly 1 with both brake shoe 8 and 80 mounted in cavity 85 able to move freely back and forth in slot.
[0037] After attaching brake shoes on both wheel truck assemblies front and rear, at 6 , FIG. 10 , wheels with bearings attach to 3 , FIG. 7 , on spindled axles. When mounted, should resemble FIG. 1 upon wheel trundle truck assembly. See rear wheel truck assembly mounted to 24 , FIG. 4 .
[0038] A mount at 16 , FIG. 3 , shows a shock absorber, cut away view of a winged coupling.
[0039] FIG. 12 at 109 shows a nut welded to coupling 108 with 110 , a coupling inside, which is able to rock side to side when mounted on 10 shock mount. Compare FIG. 4 at 10 with FIG. 12 at 16 , showing cut away of winged coupling inside shock 16 . Shock 16 has a cavity for accepting 109 and 108 coupling housing. The winged bottom is V-shaped, allowing movement on shock mount, FIG. 4, 10 . An alternate brake mounting location 116 , peg 129 fits into 130 of shock mount 10 . See side view of 116 for mounting under a traditional shock, for mounting brake shoe 8 or 80 at hole 86 , for a brake alternative, here used as a washer under coupling 108 . Adjustment: with 109 inside 16 shock absorber, nut 11 ( a ) and 11 ( b ) are turned onto bolt 12 , underside of 26 , a front-wheel, truck-assembly mount. 16 and 109 winged coupling, is turned onto bolt 12 .
[0040] At 15 , FIG. 6 , a pivot is placed into coupling 25 , wheel-truck assembly mount 10 , FIG. 4 . See FIG. 12 at 110 , a nut 11 ( c ) turns onto winged coupling 110 on the underside of shock mount 10 . And nut 11 ( a ) and ( b ) is tightened, and nut 11 ( b ) is tightened against 11 ( a ), ( a ) nut acting as a lock nut. With less pressure on shock 16 , coupling 110 is able to shift under shock 16 and create either a looser steering or a firmer ride.
[0041] A slightly different procedure on the rear trundle truck assembly: FIG. 8 at 108 under shock 16 , a washer 59 and nut 11 ( a ) and ( b ) are positioned under a spool 35 that rests under a bearing race 19 . A spring 37 at eye on end of spring attaches to pin 39 inside a drum 36 . Spring 37 with eyes at both ends turns around bolt 12 , FIG. 8 . Spring 37 wound tightly several times around bolt 12 with spring eye 40 attached to spool 35 on top of spool 60 on pin 38 . Carefully, a rope 42 is positioned through bore hole 66 on lever 22 so that cog 43 on rope 42 is behind lever 22 . A rope 42 enters hole 93 in drum and enters 35 , a spool, and is pulled out hole 46 and tied in a knot under spool 35 . Rope 42 is wound around spool 35 . In the opening of 35 under top 60 , a ball 71 is attached to end of rope 42 so that when spring 37 and spool 35 is pushed into cavity 36 , ball 71 prevents rope 42 from being pulled into drum and spool 35 . Bearing 19 race fits under 35 , a spool, on a race, washer 59 , and nut 11 ( a ) tightens spool 35 under drum 36 , lock nut 11 ( b ) tightens to nut 11 ( a ) while shock 16 with coupling 109 is screwed onto bolt 12 .
[0042] Just as the front wheel truck assembly, FIG. 6 at 15 , a pivot placed in coupling 25 , and shock mount 10 shifts onto coupling, FIG. 12 at 110 , and a nut 11 ( c ) attached and tightened into place.
[0043] Returning to lever 22 , at FIG. 8 , mount 23 , a screw 65 enters 64 , a bearing race coupling, that enters lever 22 ; screw 65 , is turned into 23 on the underside of 26 , a rear mounting bracket (allowing lever 22 to move). See side view, FIG. 6 , of 23 . A spring travels from the bottom side of plate 26 to the top side of plate 24 . See FIG. 2 at hole 97 . Compare FIG. 3 at 97 . FIG. 2 at 34 shows dual springs leaving the bottom side and traveling to the top side of mounting top side 24 .
[0044] A pair of bare cables 50 travel through spring 34 , through holes 97 , from the bottom side of plate 24 . See bare cable 50 at FIG. 8 . 52 and 53 , shows top view of a cable connector and a slot 53 which cables turn from backside to frontside and into cable ledge 67 and 68 . With bare cable 50 on ledge 67 and 68 , a spring 34 sets on the ledge and retains cable 50 inside hole 52 and 53 on lever 22 . Bare cable 50 , then traveling through spring 34 , exits a groove 126 , FIG. 2 , and a plastic cable case enclosing cable within sets in a cable connector and exits 96 , a cable connector on one side of a wheel truck assembly, on top of the brake mechanism. Bare cable 50 in the second location travels around a horizontal pulley 49 ; cable then rises over a vertical pulley 32 . Bare cable 50 then travels around pulley and down through opening 47 , exiting the top side of 24 mounting plate.
[0045] FIG. 8 at 114 shows cable exiting under plate 26 . On a cable connector, lever 14 is attached to brakes. Note location 128 showing a spring or lever 14 . See FIG. 7 at 128 , showing a cable connector location and spring retained ledge. Compare FIG. 4 showing 128 side-view of cable connected to lever 14 with a spring on ledges. Cable 50 is attached to brake lever 14 as stated, FIG. 11 . See cable 63 placed in bore hole 117 in board 2 , exiting at 118 in a cavity 122 , in the forward section of board, again a bare cable 50 .
[0046] FIG. 12 at 29 , shows a cable connector and brake adjuster. There is a groove for a cable. See FIG. 5 at 29 and FIG. 2 at 99 . A groove from cable connector pipe to pulley, FIG. 5, 102 , on top of front wheel assembly. Cable 50 travels over pulley 102 , pulley held on top of wheel truck assembly mount with a shaft screw 101 . See FIG. 12 at 100 , cable exiting front mount. Cable, FIG. 4 , attaches to front brake at 14 lever in the same way as the rear section, with a spring over cable 50 on lever at 128 and on 100 , a spring ledge holding cable in place like FIG. 4 at 128 , pulling ball 71 , FIG. 8 , until cog 43 contacts lever 22 . Brakes are pulled downward onto the wheels, though not in adjustment. Both should move freely,
[0047] Removing rope 42 from ball 71 , rope is then fed through cavity 70 , FIG. 11 , exiting 119 in cavity board. Note pulley 72 . See FIG. 8 at 73 , rope 42 extends through pulley mount cavity, then ball 71 loosely tied to rope 42 to prevent rope from being pulled into drum; 73 pulley housing mounted on board 2 , FIG. 11 , turning board over. See pulley 72 . Holding rope 42 downward, pulley 72 , FIG. 8 , is placed over the rope inside cavity 75 and shaft screw axle 74 turns through cavity 75 through pulley 72 and tightens into place.
[0048] FIG. 11 at 123 shows a corner hole. Placing wheel truck assembly inside concave cavity 122 . (See corresponding hole, FIG. 3 at 96 .) Screws are placed in and through wheel truck assemblies and fastened into board in all 8 locations. See FIG. 11 at 118 . This cavity contains FIG. 12 at 29 . These cable connectors inside cavity 122 , all slack is removed in brake system by turning outward front cable connector 29 , then tightening lock nut. This will pick up the brakes off the wheels, both on front and back sections, and removes all play in cables. Pulling the brake ball handle and rope, cog 43 is pulled into lever 22 at 66 , FIG. 8 , a bore hole. As lever 22 begins to be pulled, cable 50 pulls brakes upward toward vertical pulley 102 and 32 , FIG. 5 , where 8 and 80 , the eccentric action of brake shoes are rotated into wheel 6 . For the helm rider or owner, the rope is adjusted where person stands with feet in a braced stance, knees bent in readiness. Cog 43 , FIG. 8 rests upon lever 22 at 66 . With arm held at ready, rope 42 is tied to ball 71 so that either wrist or finger movement will activate the brakes, and when activated, rope acts as a handle behind the rider so that the inertia on the rider is braced by the stance of body coupled to the pressure on brake activation rope. Lessening pressure would remove inertia forces on the body. Ability to steer the board while braking is a new safety claim, eliminating the need at speed to drag foot, balancing on one foot. Riding on one's back on an elongated board downhill racing, typically feet are dragged to aid steering or braking on regular skate boards. Here, if 81 brake rollers are removed on right side brakes (or left), if removed on right, and only the left brakes are pulled, activating those left brakes, the board will steer to the left, aiding in racing, steering, while able to effectively brake and steer.
[0049] This application, when viewed over all, shows a Truckin Board being pieced together. The wheel truck assembly's brake systems attached, then the cables fed through the board, then the wheel truck assemblies bolted to the cavity board. Then the cable and rope adjusted to the rider's stance.
[0050] Nothing in this application should be used to limit the invention, whether a professional skate boarder accomplished in trick riding or racing, or the very young child's toy construction. A wheel truck assembly, traditionally, is made of alloys with a steel axle encased in an alloy material. This is an acceptable method of construction. A young child's board could have a wheel assembly built of high impact plastic with steel spindles or other material, whether the brake shoes or rollers are of high impact plastic or alloys or other durable fracture-resistant material, including but not limited to metal. The purpose of brake rollers, whether they are of plastic, alloy, steel, or other material, is to cause friction and resist brake lock up if desired. Rollers do not roll unless brakes are activated. There is nothing to prevent the non-use of rollers. To cause wheel lock up, the centrally pulled brake lever should be of steel to prevent bending. The recoil system would best be made of steel and alloy type material as it is a part of a wheel truck assembly mount, but it could be of any material. Spring steel springs for spiraling around the post of steel, the spool can be of any type of material but made of a material suitable to the type of use. If strength is needed, the part can be made to the strength necessary for the weight load. A Truckin Board can be of any fiber, including alloy supported or fiber glass or other material typically used in skate boards for carrying a human rider. Wheel truck assemblies are designed to carry a load, including, but not limited to, a human being with brake under foot whenever a brake is necessary. Keep truckin but truck safely. | Truckin Board, a Recreational Board Vehicle with an elongated board, with a front and rear wheel trundle, truck assembly with eccentric friction roller brakes, activated by a spiral spring recoilable rope in a drum, pulling a cog into a lever, activating centrally pulled brakes between the wheels, which allows steering on an adjustable mount. A braking rope aids rider in staying on board while brakes are activated, while able to maintain helm control. Brake activator handle snaps back into board when not in use. | 0 |
RELATED APPLICATIONS
[0001] This application claims the benefit of priority to commonly-owned and copending U.S. Provisional Patent Application Nos. 60/843,113, filed 8 Sep. 2006, and 60/888,243, filed 5 Feb. 2007, each of which is incorporated herein by reference.
BACKGROUND
[0002] 1. Field of the Invention
[0003] The present invention pertains to antimicrobial compositions of the type that may be used to control or destroy pathogenic microorganisms. More particularly, various antimicrobial agents are shown to work with cooperative effects against microorganisms in a wide variety of applications.
[0004] 2. Description of the Related Art
[0005] Antimicrobial compositions are used to reduce the risk of infection. For example, antimicrobials are used to disinfect surfaces in hospitals, lavatories, food preparation facilities, and offices. Other uses include the control of pathogenic organisms on skin, where they may be used to reduce the transmission of disease or infection, e.g., as surgical scrub solutions or hand sanitizers. Antimicrobial compositions may also be used in veterinary applications for the control or prevention of hoof diseases, mastitis (in milk producing animals), or topical infections. Prevention of mastitis is a major goal of the dairy industry, where the disease may result from contact of the bovine or ovine mammary gland with pathogenic microorganisms, usually bacteria but occasionally yeast or fungi.
[0006] Mastitis is the single most costly disease affecting the dairy industry. Annual economic losses due to mastitis approximate $185 per dairy animal. This totals to approximately $1.7 billion annually for the entire United States market. Mastitis is always a potentially serious infection. Severe cases may cause death to the dairy animal. Milder cases are more common, but may have serious consequences, such as long term damage to the animal, loss of milk production for the dairy farmer and an unacceptable increase in veterinary costs.
[0007] To reduce mastitis, commercial teat dips have been developed which are usually administered to the teat by dipping, foaming, or spraying the teat prior to milking as well as after removal of the milking cup. Teat dips applied subsequent to milking may be in the form of lower viscosity dippable or sprayable compositions or in the form of a thick composition, film or barrier that remains on the teat until the next milking, which is generally 8 to 12 hours later.
[0008] Commercially available teat dips may be divided into two primary classifications, namely, non-barrier and barrier dips. The non-barrier teat dips are strictly antimicrobial and are applied to kill microorganisms that are already present in the teat canal or on the surface of the teat skin. By design, the microbiological effect is substantially immediate, targeting the contagious organisms that may be transferred between animals during the pre-milking, milking and post-milking process. The barrier dips may also be antimicrobial and are applied to form a prophylactic film or coating that may prevent microbes from contacting the teat. It is desirable to have an antimicrobial effect that remains active during the inter-milking period.
[0009] Teat dips have used a variety of antimicrobial agents. U.S. Pat. No. 2,739,922 issued to Shelanski describes the use of polymeric N-vinyl pyrrolidone in combination with iodophors. U.S. Pat. No. 3,993,777 issued to Caughman et al. describes the use of halogenated quaternary ammonium compounds. U.S. Fat. No. 4,199,602 issued to Lentsch describes the use of iodophors, chlorine releasing compounds (e.g. alkali hypochlorite), oxidizing compounds (e.g. hydrogen peroxide, peracids), protonated carboxylic acids (e.g. heptanoic, octanoic, nonanoic, decanoic, undecanoic acids), and nitroalkanols. U.S. Pat. No. 4,434,181 issued to Marks, Sr. et al. describes the use of acid anionics (e.g. alkylaryl sulfonic acids), chlorine dioxide (from alkali chlorite), and bisbiguanides such as chiorhexidine.
[0010] Some of the available teat dip agents suffer from serious drawbacks. For example, iodine, hypochlorite, chlorine dioxide, and hypochlorous acid are powerful disinfectants and strong oxidants, but they are also particularly noxious for both humans and animals. Chlorhexidine, for example, has become the focus of regulatory concern. Additionally, the use of overly powerful disinfectants may contribute to the mastitis problem by causing irritation of the teat skin, thus providing an opportunistic site which promotes infection. The Lentsch '602 patent recognizes that iodophors and such chlorine-based biocides as hypochlorite, chlorine dioxide, and hypochlorous acid have achieved the widest commercial acceptance; however, teat dips of the future may have to be iodine-free. Furthermore, the iodine-based and chlorine-based compositions may induce sensitized reactions in cow teats. This issue is of particular importance for barrier type products where the biocide may remain in contact with the skin during the 8-12 hour inter-milking period. On the other hand, less powerful teat dip agents, such as fatty acids and anionic surfactants, are often not broad enough in their antimicrobial spectrum to provide complete germicidal protection.
[0011] From a consumption point of view, it is known that relatively small quantities of iodine and chlorhexidine can result in taste changes of the milk as well as problems in the manufacture of dairy products. Furthermore, milk products must meet food and drug regulations which take into consideration ingestion of residual teat dip agents. There may be concern, for example, about increased iodine consumption because iodine is linked to thyroid function and it is recommended that some populations, such as pregnant women, limit their intake. Also, iodine associates with problems of staining, and some operators/users develop allergic symptoms such as skin irritation and sensitization from iodine-based product use.
[0012] There is a need for compositions that are effective broad spectrum antimicrobials that provide extended germicidal activity and are non-irritating to skin.
SUMMARY
[0013] In embodiments, the invention is an antimicrobial composition comprising an organic acid and an anionic surfactant. In one embodiment the composition is adapted for topical applications on an animal. In other embodiments, the invention is a method of using an antimicrobial composition comprising an organic acid and an anionic surfactant substantially reduces microbial concentrations, which may relate to the treatment or prevention of mastitis. Those skilled in the art will appreciate additional objects and advantages in the detailed description below. All references specifically disclosed in this specification are hereby incorporated by reference.
DETAILED DESCRIPTION
[0014] There will now be shown and described as a particular embodiment, an antimicrobial liquid composition that contains an organic acid mixed with an anionic surfactant. The organic acid, e.g., lactic acid, may be mixed with a carrier that is formulated according to the intended environment of use.
[0015] As used herein, the term “organic acid” means an organic compound that is an acid. The most common examples are the carboxylic acids having an acidity that derives from a carboxyl group —COOH. Other groups may also impart weak acidity, especially hydroxyl (—OH) groups, thiol (—SH) groups, enol groups (—C═C(OH)—), sulfate groups (—OSO 3 H), sulfonate groups (—SO 3 H) and phenols. Preferred organic acids have a carbon number less than twenty, and this number is even more preferably less than ten. The organic acids may be aliphatic, aryl, aromatic, unsubstituted or substituted with functional groups. The substituent(s) may be attached to any position of the carbon chain or carbon ring. The organic acid may, for example, include lactic acid, salicylic acid, tartaric acid, citric acid, glycolic acid, ascorbic acid, maleic acid, succinic acid, mandelic acid, dodecylbenzenesulfonic acid, propionic acid, gluconic acid, malic acid, benzoic acid, aspartic acid, acetic acid, oxalic acid, glutamic acid, adipic acid, hexanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid and combinations thereof. In another aspect, inorganic acids having pK a characteristics approximating those of organic acids may also be used. In one such example, sulfamic acid may be used. Lactic acid is particularly preferred as the organic acid for the disclosed compositions, as will be shown in detail later.
[0016] The compositions reported herein involve the discovery, hitherto unreported, that unexpectedly effective antimicrobial protection can be obtained when an organic acid, e.g., lactic acid, is combined with an anionic surfactant. Sodium Octane Sulfonate (SOS) and Sodium Lauryl Sulphate (SLS) are included in specific embodiments. The selection of these particular ingredients for testing should not, however, is considered a limiting factor because numerous other surfactants could be used which would still fall within the scope of the invention. For example, Sodium Lauryl Ether Sulfate (SLES) has been used in combinations with SOS and/or SLS with success. Further, other anionic surfactants could be used in other embodiments which would fall within the scope of the invention. Some examples of preferred anionic surfactants include but are not limited to alkyl sulfonates, secondary alkane sulfonates, alkyl sulfates, alkyl ether sulfates, aryl sulfonates, aryl sulfates, alkylaryl sulfonates, alkylaryl sulfates and alkyl ether sulfonates. Some examples of such anionic surfactants that are suitable are: alkali lauryl sulfates, alkali dodecylbenzenesulfonates, alkali octane sulfonates, alkali secondary alkane sulfonates, alkali lauryl ether sulfates and ammonium salts thereof.
[0017] Thus, the disclosures of specific embodiments herein should not be interpreted as requiring any particular anionic surfactant.
[0018] In one aspect, an antimicrobial composition contains an antimicrobial agent which is an organic acid, and a second agent which includes one or more anionic surfactants. In an embodiment, the agents are included in a pharmaceutically acceptable carrier, which may, for example, be water.
[0019] The carrier may include one or more additives selected from a buffering agent, an emollient, a humectant, a preservative, a barrier forming agent, a surfactant or wetting agent, a foaming agent, a viscosity control agent, a colorant, an opacifying agent, a skin conditioning agent and any combinations thereof.
[0020] The antimicrobial compositions provide a substantial reduction in Gram positive and Gram negative bacteria, as well other numerous classes of microbes. For particular embodiments, the reduction may be on the order of a three or four log reduction or a substantially complete kill that is greater than a five log (99.999%) reduction. In other embodiments, the kill counts could be higher or lower.
[0021] A broader object of the disclosed instrumentalities is to provide an antimicrobial composition that may be used, for example, according to any purpose for antimicrobial or bactericidal properties. In a particular embodiment, the composition is intended to be used as a teat dip. In other embodiments the composition is intended to be used as a hand sanitizer, a skin cleanser, a surgical scrub, a wound care agent, a disinfectant, a mouthwash, a bath/shower gel, a hard surface sanitizer and the like. Preferred compositions for skin applications have a pH of about 2.0 to about 8.0 and provide a substantial reduction, e.g., greater than a five log reduction (99.999%), in Gram positive and Gram negative bacterial populations. In even more preferred embodiments, the composition could have pH in the range of about 2.5 to 7.5. Further, different uses may prompt different pH targets. For example, compositions adapted for hard surfaces may be provided with lower pH values, such as 2.0 or 1.0.
[0022] Another object is to provide a composition which, when applied, results in a wound healing effect. The composition assists in a faster and qualitatively improved healing of wounds by decreasing the number of microorganisms in the vicinity of the wound. Further, the compositions are non-irritating.
[0023] Methods of preparing compositions may involve dissolving a desired concentration of antimicrobial agents and, optionally, any desired additives in a selected pharmaceutical carrier. The solution is then mixed, for example in a mixer, to form a final antimicrobial composition.
[0024] For some embodiments, the concentrations are those where the percentage of each functional ingredient or mixture of ingredients including antimicrobial agents by total weight of the composition is preferably from about 0.02 to 30% of each antimicrobial agent and 70 to 99.98% of a pharmaceutical carrier and other additives combined; more preferably from about 0.03 to 25% of each antimicrobial agent and from about 75 to 99.97% of a pharmaceutical carrier and other additives combined; and most preferably from about 0.04 to 20% of each antimicrobial agent and from about 80 to 99.96% of a pharmaceutical carrier and other additives combined, and still more preferably from about 0.05 to 15% of each antimicrobial agent and from about 85 to 99.95% of a pharmaceutical carrier and other additives combined.
[0025] As used herein, the term “subject” shall include humans and terrestrial animals. For example, the subject can be a domestic livestock species, a laboratory animal species, a zoo animal, a companion animal or a human. In a particular embodiment, “subject” refers more specifically to any lactating animal. In one embodiment, the subject is a cow.
[0026] The phrase “therapeutically effective amount” is intended to qualify the amount of the topical composition which will achieve the goal of decreased microbial concentration. “Therapeutically effective” may also refer to improvement in disorder severity or the frequency of incidence over no treatment.
[0027] The term “topical” shall refer to any composition which may be applied to the epidermis or other animal portion on which compositions might be applied. Topical shall also refer to compositions used as mouthwashes.
[0028] The term “additive” shall mean any component that is not an antimicrobial agent or a pharmaceutical carrier. A pharmaceutical carrier is generally a bulk solvent used to dilute or solubilize the components of the composition, e.g., water.
[0029] The terms “teat dip” or “teat dipping” shall be interpreted broadly and in accordance with the terminology used in the art of dairy farming. Thus, the composition is not only intended for dipping of the teats but it can, of course, be applied in other ways, such as by spraying or foaming and still fall within the recognized terms teat dip or teat dipping composition or agent.
[0030] As used herein unless otherwise specified, the term “antimicrobial” describes a biocidal effect that may be, for example, an antibacterial, antifungal, antiviral, bacteriostatic, disinfecting, or sanitizing effect.
[0031] As shown in the examples below, combinations of the antimicrobial agents may include an organic acid (e.g., lactic acid) with an anionic surfactant or a mixture of anionic surfactants to make effective biocidal compositions. These antimicrobial ingredients may be formulated using additional antimicrobial agents, barrier-forming agents, foaming agents, viscosity control agents, pH adjusting agents, wetting agents, opacifying agents, skin conditioning agents and carriers to make a wide variety of products.
Additional Antimicrobial Agents
[0032] Traditional antimicrobial agents are the components of a composition that destroy microorganisms or prevent or inhibit their replication. In one aspect, the combined organic acid/anionic surfactant(s) antimicrobial embodiments discussed above may be used to replace or eliminate the need for traditional antimicrobial agents in a wide variety of applications. In another aspect, antimicrobial compositions according to the disclosed embodiments below may be used in combination with these traditional antimicrobial agents, for example, to achieve an effective kill at lower concentrations of traditional antimicrobial agents.
[0033] Traditional antimicrobial agents include iodophors, quaternary ammonium compounds, hypochlorite releasing compounds (e.g. alkali hypochlorite, hypochlorous acid), oxidizing compounds (e.g. peracids and hypochlorite), protonated carboxylic acids (e.g. heptanoic, octanoic, nonanoic, decanoic, undecanoic acids), acid anionics (e.g. alkylaryl sulfonic acids, aryl sulfonic acid, alkyl sulfonic acids, alkylaryl sulfuric acid, aryl sulfuric acid, alkyl sulfuric acid, alkylaryl sulfuric acid), chlorine dioxide from alkali chlorite by an acid activator, and bisbiguanides such as chlorhexidine. Phenolic antimicrobial agents may be chosen from 2,4,4″-trichloro-2′-hydroxydiphenylether, which is known commercially as triclosan and may be purchased from Ciba Specialty Chemicals as IRGASAN™ and IRGASAN DP 300™. Another such antimicrobial agent is 4-chloro-3,5-dimethyl phenol, which is also known as PCMX and is commercially available as NIPACIDE PX and NIPACIDE PX-P. Other traditional germicides include formaldehyde releasing compounds such as glutaraldehyde and 2-bromo-2-nitro-1,3-propanediol (Bronopol), polyhexamethyl biguanide (CAS 32289-58-0), guanidine salts such as polyhexamethylene guanidine hydrochloride (CAS 57028-96-3), polyhexamethylene guanidine hydrophosphate (89697-78-9), and poly[2-(2-ethoxy)-ethoxyethyl]-guanidinium chloride (CAS 374572-91-5) and mixtures thereof.
[0034] In one embodiment, the disclosed germicides may be used in combination with traditional germicides such as copper sulfate, zinc sulfate, sulfamethazine, quaternary ammonium compounds, hydrogen peroxide and/or peracetic acid, for example, to achieve an effective kill at lower concentrations of traditional germicides.
Barrier Forming Agents
[0035] Barrier and film forming agents are those components of a teat dipping composition that remain in contact with the teat between milking cycles. Barrier and film forming agents coat the teat skin and, optionally, the udder. Barrier agents may form a plug at the end of the open teat canal. Typical barrier and film forming agents include thick creams or emollients (made with viscosity control agents), films, polymers, latex and the like. Some nonionic surfactants may help further enhance the barrier properties of a composition, in addition to contributing to surface wetting. Examples of such surfactants may include, without limitation, polyoxyethylene-polyoxypropylene glycol (marketed as Pluronic F108). Another commonly used barrier agent is marketed as Pluronic P105. A latex material that provides an effective covering of the teat is described in U.S. Pat. No. 4,113,854. Suitable barrier forming agents include, for example, latex, arabinoxylanes, glucomannanes, guar gum, johannistree gums, cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, carboxyethyl cellulose, carboxymethyl cellulose, starch, hydroxyethyl starch, gum arabic, curdlan, pullulan, dextran, polysulfonic acid, polyacryl amide, high molecular weight polyacrylate, high molecular weight cross-linked polyacrylate, carbomer, glycerol, sodium alginate, sodium alginate cross-linked with calcium salt, xanthan gum, poly(vinyl alcohol) (PVA) and poly(N-vinylpyrrolidone) (PVP). Preferred embodiments for barrier-forming agents include xanthan gum, carboxymethyl cellulose, sodium alginate, sodium alginate cross-linked with calcium salt, PVA, hydroxyethyl cellulose, PVP, and (2,5-dioxo-4-imidazolidinyl)-urea (Allantoin).
[0036] The compositions those are capable of forming a long-lasting persistent, continuous, uniform barrier film that is based upon modified polysaccharides when applied to the skin. The compositions have particular utility as barrier teat dips that are used prophylactically against mastitis. The barrier film-forming agent includes relatively low molecular weight polysaccharides, for example, as may be derived specifically from hydrolyzed starch.
[0037] The composition may be used for prophylactic treatment of a dairy animal's teats to provide a long lasting persistent protective germicidal barrier film that demonstrates persistence between milkings, and is controllably reproducible to yield a continuous, uniform persistent barrier. This treatment process entails milking the animal, coating the teats with the composition after milking, allowing the composition to dry and so also form a layer of persistent barrier film on the teats. The composition may be applied topically by painting, foaming, dipping or spraying. Furthermore, use of the composition is not limited to use against mastitis, and the composition may be used generally to treat or protect against any infectious skin condition.
[0038] A composition capable of forming a long-lasting, persistent, continuous, uniform barrier film may contain from about 0.1% to about 20% by weight of modified or hydrolyzed polysaccharide material for use as the barrier forming agent. The polysaccharide material has a majority polysaccharide component as starch, modified starch, hydrolyzed starch, a starch derivative, and combinations thereof. The majority polysaccharide components may have overall or average Dextrose Equivalence (DE) value ranging from 2 to 50, and this value more preferably ranges from 3 to 27. In this sense the term “majority polysaccharide component” is used to describe a majority weight percentage of all polysaccharides in the composition, i.e., more than 50% of all polysaccharides in the composition.
Foaming Agents
[0039] A foaming agent may be used in the disclosed antimicrobial compositions. A foaming agent aerates a liquid composition to produce a foam that may increase surface area of the composition and improve contact with the surface to be treated (e.g., an animal hoof). Typically, a foaming agent is in the form of a compressed gas, or a material that will decompose to release gas under certain conditions. Suitable gases include but are not limited to nitrogen, argon, air, carbon dioxide, helium and mixtures thereof. In addition, solid carbon dioxide (dry ice), liquid nitrogen, hydrogen peroxide and other substances that release gas via a change in state or through decomposition are contemplated for use with the present compositions. Typically, a high foaming surfactant such as sodium lauryl sulfate, dodecylbenzene sulfonic acid, sodium alkylaryl polyether sulfate, sodium lauryl ether sulfate, sodium decyl sulfate, cocamine oxide, C 12 -C 14 whole coconut amido betaines can be used to generate a stable foam. The foam is produced when agitation in the form of a compressed gas is mixed with the solution either by bubbling the gas into the solution or spraying the solution or solution-gas mixture through spray equipment. Suitable gases include but are not limited to nitrogen, air, carbon dioxide and mixtures thereof. Foam can also be generated by the mechanical action of animals walking through the composition, or by other mechanical means that mix atmospheric air with the composition. The composition can be applied by having animals walk through an area containing the foam or by having the animal walk through a footbath solution that has foam floating on top of the solution.
[0040] Surfactants are well known for foaming and are widely used as foaming agents in hand soap and manual/hand dishwashing detergents and such surfactants can be used as foaming agents in applications where foaming can boosts the performance and increase contact time of the composition to particular substrates. Examples of such. Suitable anionic surfactants can be chosen from a linear alkyl benzene sulfonic acid, a linear alkyl benzene sulfonate, an alkyl α-sulfomethyl ester, an α-olefin sulfonate, an alcohol ether sulfate, an alkyl sulfate, an alkylsulfo succinate, a dialkylsulfo succinate, and alkali metal, alkaline earth metal, amine and ammonium salts thereof. Specific examples are linear C 10 -C 16 alkyl benzene sulfonic acid, linear C 10 -C 16 alkyl benzene sulfonate or alkali metal, alkaline earth metal, amine and ammonium salt thereof e.g. sodium dodecylbenzene sulfonate, sodium C 14 -C 16 α-olefin sulfonate, sodium methyl α-sulfomethyl ester and disodium methyl α-sulfo fatty acid salt. Suitable nonionic surfactants can be chosen from an alkyl polyglucoside, an alkyl ethoxylated alcohol, an alkyl propoxylated alcohol, an ethoxylatedpropoxylated alcohol, sorbitan, sorbitan ester, an alkanol amide. Specific examples include C 8 -C 16 alkyl polyglucoside with a degree of polymerization ranging from 1 to 3 e.g., C 8 -C 10 alkyl polyglucoside with a degree of polymerization of 1.5 (Glucopon® 200), C 8 -C 16 alkyl polyglucoside with a degree of polymerization of 1.45 (Glucopon® 425), C 12 -C 16 alkyl polyglucoside with a degree of polymerization of 1.6 (Glucopon® 625). Amphoteric surfactants can be chosen from alkyl betaines and alkyl amphoacetates. Suitable betaines include cocoamidopropyl betaine, and suitable amphoacetates include sodium cocoamphoacetate, sodium lauroamphoacetate and sodium cocoamphodiacetate. Alkyl amine oxides based on C12-C14 alkyl chain length feedstock such as those derived from coconut oil, palm kernel oil is also suitable foaming agents.
Viscosity Control Agents
[0041] Viscosity control agents may be added to formulate the antimicrobial compositions according to an intended environment of use. In one example, it is advantageous for some compositions to have an optimized solution viscosity to impart vertical clinging of the product onto a teat. This type of viscous product, especially one having a suitable thixotropic, pseudoplastic or viscoelastic gel strength, minimizes dripping of the product to avoid wastage and is particularly advantageous in teat dip compositions. Teat dip compositions may benefit from a preferred dynamic viscosity ranging from 1 cPs to 3000 cPs. Other applications including hard surface disinfectants have a preferred dynamic viscosity ranging from about 1 cPs to 300 cPs. In another example, the amount of viscosity control agents may be substantially reduced or even eliminated in other compositions, such as surface or floor disinfectants where easy cleanup is desired. An intermediate or medium viscosity composition may be useful in a hand cleaner or personal care product. It is seen from these examples that the antimicrobial compositions may be formulated for a wide variety of applications by altering the amount of viscosity control agents. The viscosity referred to throughout this application is Brookfield viscosity measured in cPs by a Brookfield LV viscometer at ambient temperature (25° C.) with a spindle #2 @ 3 to 30 rpm. In various embodiments, a thickener may be added to achieve a viscosity range of from 50 cPs to 10000 cPs, or from 100 cPs to 4000 cPs.
[0042] Suitable viscosity control agents include hemicellulose, for example arabinoxylanes and glucomannanes; plant gum materials, for example guar gum and johannistree gums; cellulose and derivatives thereof, for example methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose or carboxymethyl cellulose; starch and starch derivatives, for example hydroxyethyl starch or cross linked starch; microbial polysaccharides, for example xanthan gum, sea weed polysaccharides, for example sodium alginate, carrageenan, curdlan, pullulan or dextran, dextran sulfate, whey, gelatin, chitosan, chitosan derivatives, polysulfonic acids and their salts, polyacrylamide, and glycerol. Preferred viscosity controlling agents are, different types of cellulose and derivatives thereof, particularly hydroxyalkyl cellulose, methyl cellulose, and glycerol. High molecular weight (MW>1,000,000) cross-linked polyacrylic acid type thickening agents are the products sold by B.F. Goodrich (now Lubrizol) under their Carbopol® trademark, especially Carbopol® 941, which is the most ion-insensitive of this class of polymers, and Carbopol® 940 and Carbopol®934. The Carbopol® resins, also known as “Carbomer”, are reported in U.S. Pat. No. 5,225,096, and are hydrophilic high molecular weight, cross-linked acrylic acid polymers. Carbopol® 941 has a molecular weight of about 1,250,000, Carbopol® 940 has a molecular weight of approximately 4,000,000, and Carbopol 934 has a molecular weight of approximately 3,000,000. The Carbopol® resins are cross-linked with polyalkenyl polyether, e.g. about 1% of a polyallyl ether of sucrose having an average of about 5.8 allyl groups for each molecule of sucrose. Further detailed information on the Carbopol® resins is available from B.F. Goodrich (Lubrizol), see for example, the B. F. Goodrich catalog GC-67, Carbopol® Water Soluble Resins. Clays and modified clays such as bentonite or laponite can also be used as thickeners. Co-thickeners are often added to improve the stability of the gel matrix, for example, colloidal alumina or silica, fatty acids or their salts may improve gel stability. Typical viscosity control ingredients include xanthan gum, carboxymethyl cellulose, sodium alginate, sodium alginate cross-linked with calcium salt, polysulfonic acids and their salts, polyacrylamide, polyvinyl alcohol (PVA), hydroxyethyl cellulose and polyN-vinylpyrrolidone) (PVP).
Buffering and pH Adjusting Agents
[0043] A composition pH value may be selectively adjusted by the addition of acidic or basic ingredients. Generally, an acidic pH is preferred. Suitable acids for use as pH adjusting agents may include, for example, citric acid, acetic acid, lactic acid, phosphoric acid, phosphorous acid, sulfamic acid, nitric acid, nitrous acid and hydrochloric acid. It will be recognized by those skilled in the art that the organic acid, e.g., lactic acid, selected as the antimicrobial organic acid will also influence pH, and thus, have an adjusting effect as discussed in this paragraph. Mineral acids may be used to drastically lower the pH. The pH may be raised or made more alkaline by addition of an alkaline agent such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, monosodium acid diphosphonate or combinations thereof. Traditional acid buffering agents such as citric acid, lactic acid, phosphoric acid may also be used to maintain a desired pH. The pH value of the composition may be adjusted by the addition of acidic or basic or buffering materials.
[0044] The physical property of pH may be adjusted by acid or base addition, and is broadly preferred in the range of from 2.0 to 8.0 for use in teat dip compositions and other compositions that are intended to contact the skin. In a more preferred sense this range is from 2.0 to 5.0, and a still more preferred range is from 2.5 to 4.5. Hard surface and commercial disinfectants may be provided with lower pH values, such as 2.0 or 1.0.
Wetting Agents
[0045] Wetting agent(s) or surface active agent(s) are also known as surfactants. Typical wetting agents are used to wet the surface of application, reduce surface tension of the surface of application so that the product can penetrate easily on the surface and remove unwanted soil. The wetting agents or surfactants of the composition increase overall detergency of the formula, solubilize or emulsify some of the organic ingredients that otherwise would not dissolve or emulsify, and facilitate penetration of active ingredients deep onto the surface of the intended application surfaces, such as teat skin.
[0046] Suitably effective surfactants used for wetting may include anionic, cationic, nonionic, zwitterionic and amphoteric surfactants. Wetting agents and surfactants used in the inventive applications can be high foaming, low foaming and non foaming type. Suitable anionic surfactants can be chosen from a linear alkyl benzene sulfonic acid, a linear alkyl benzene sulfonate, an alkyl α-sulfomethyl ester, an α-olefin sulfonate, an alcohol ether sulfate, an alkyl sulfate, an alkylsulfo succinate, a dialkylsulfo succinate, and alkali metal, alkaline earth metal, amine and ammonium salts thereof. Specific examples are linear C 10 -C 16 alkyl benzene sulfonic acid, linear C 10 -C 16 alkyl benzene sulfonate or alkali metal, alkaline earth metal, amine and ammonium salt thereof e.g. sodium dodecylbenzene sulfonate, sodium C 14 -C 16 α-olefin sulfonate, sodium methyl α-sulfomethyl ester and disodium methyl α-sulfo fatty acid salt. Suitable nonionic surfactants can be chosen from an alkyl polyglucoside, an alkyl ethoxylated alcohol, an alkyl propoxylated alcohol, an ethoxylatedpropoxylated alcohol, sorbitan, sorbitan ester, an alkanol amide. Specific examples include C 8 -C 16 alkyl polyglucoside with a degree of polymerization ranging from 1 to 3 e.g., C 8 -C 10 alkyl polyglucoside with a degree of polymerization of 1.5 (Glucopon® 200), C 8 -C 16 alkyl polyglucoside with a degree of polymerization of 1.45 (Glucopon® 425), C 12 -C 15 alkyl polyglucoside with a degree of polymerization of 1.6 (Glucopon® 625), and polyethoxylated polyoxypropylene block copolymers (poloxamers) including by way of example the Pluronic® poloxamers commercialized by BASF Chemical Co. Amphoteric surfactants can be chosen from alkyl betaines and alkyl amphoacetates. Suitable betaines include cocoamidopropyl betaine, and suitable amphoacetates include sodium cocoamphoacetate, sodium lauroamphoacetate and sodium cocoamphodiacetate.
[0047] It will be recognizable to those skilled in the art that because at least one surfactant (e.g., an anionic surfactant) is included as a synergistic antimicrobial agent in this composition, that these surfactants would also have an influence on the wetting properties of the mixture.
Opacifying Agents and Dyes
[0048] An opacifying agent or dye is optionally included in the present compositions. For example, color on a teat tells a farmer that a particular cow has been treated. To preclude any problems with possible contamination of milk, it is preferred that only FD&C Certified (food grade) dyes be used. There are many FD&C dyes available which are FD&C Red #40, FD&C Yellow #6, FD&C Yellow #5, FD&C Green #3 and FD&C Blue #1. Dyes used either alone or in combination are preferred. D&C Orange #4 can also be used. Titanium dioxide (TiO 2 ) is widely used as an opacifier and can also be used in combination with various colorants.
Preservatives
[0049] Some known teat dips and hand sanitizers include ethylenediaminetetraacetic acid (EDTA) and/or its alkali salts which can act as a chelating agent to remove metal ions from hard water. The metal ions, if not removed from the composition, serve as reaction sites for enzymes within the bacteria; the metalloenzyme reactions produce energy for bacterial cell replication. Other traditional preservatives are widely used, for example, paraban, methyl paraban, ethyl paraban, glutaraldehyde, etc. Preservatives such as an alcohol can also be added. The alcohol, in embodiments, may be benzyl alcohol, a low molecular weight alcohol having a carbon number less than five, and combinations thereof.
Skin Conditioning Agents
[0050] Skin conditioning agents may also be optionally used in the disclosed compositions. Skin conditioning agents may provide extra protection for human or animal skin prior to or subsequent to being exposed to adverse conditions. For example, skin conditioning agents may include moisturizers, such as glycerin, sorbitol, propylene glycol, D-Panthenol, Poly Ethylene Glycol (PEG) 200-10,000, Poly Ethylene Glycol Esters, Acyl Lactylates, Polyquaternium-7, Glycerol Cocoate/Laurate, PEG-7 Glycerol Cocoate, Stearic Acid, Hydrolyzed Silk Peptide, Silk Protein, Aloe Vera Gel, Guar Hydroxypropyltrimonium Chloride, Alkyl Poly Glucoside/Glyceryl Luarate, shea butter and coco butter; sunscreen agents, such as titanium dioxide, zinc oxide, octyl methoxycinnamate (OMC), 4-methylbenzylidene camphor (4-MBC), oxybenzone and homosalate; and itch-relief or numbing agents, such as aloe vera, calamine, mint, menthol, camphor, antihistamines, corticosteroids, benzocaine and paroxamine HCl.
Pharmaceutical Carriers
[0051] A typical carrier or matrix for an antimicrobial composition is deionized water, although one skilled in the art will readily understand that other solvents or compatible materials other than water may be used to achieve the effective concentrations of germicidal agents. In some embodiments, a composition may contain at least about 60% water and preferably at least about 70% water by weight based on the total weight of the composition. Propylene glycol, glycol ethers and/or alcohols can also be used as a carrier either alone or in combination with water.
Materials and Reagents
[0052] The test bacteria were Eschericia coli (ATCC 11229), which were originally isolated from mastitis infection and obtained on commercial order from Mastitlaboratoriet, SVA, and Staphococcus aureus (ATCC6538 from Microbiologics, St. Cloud, Minn.), which was also isolated from mastitis infection.
Testing of Antimicrobial Activity
[0053] Various standardized test methods are in place for comparatively testing the efficacy of antimicrobial agents. The preferred standard is defined as AOAC Official Method 960.09, as published by the Association of Analytical Chemists (AOAC International) in 2000 (Association of Official Analytical Chemists. 1990 (Official Methods of Analysis, Pages 138-140 in Germicidal and Detergent Sanitizing Action of Disinfectants 960.09, Vol. I. 15 th ed. AOAC, Arlington, Va.). Europeans tend to use other standards for this same purpose, such as the EN1040, EN1656 and EN 14885 test methods. All of these standards are incorporated by reference to the same extent as though fully disclosed herein.
[0054] According to a modified EN1656 dilution neutralization method, freeze dried E. coli (ATCC 11229) and S. aureus (ATCC 6538) were hydrated, grown for four days and transferred. Then bacteria were diluted to form a suspension to have an initial concentration of about 10 8 cfu/mL.
[0055] Freeze-dried pellets of E. coli (ATCC 11229) and S. aureus (ATCC 6538) were hydrated, placed in test tubes containing nutrient agar and incubated at 37° C. for 24 hours. Sterile buffer (0.25 M phosphate adjusted to pH 7.2) was used to dilute and transfer the bacteria to additional nutrient agar tubes, which were incubated for another 24 hours. S. aureus was then diluted with buffer and transferred to nutrient agar in French bottles, and E. coli was diluted and transferred to fresh nutrient agar tubes. Both types of bacteria were incubated at 37° C. for 72 hours. E. coli was then diluted and transferred to nutrient agar in French bottles. Sterile buffer and glass beads were added to the S. aureus French bottles and the solution was vacuum filtered through a #2 filter. The resulting bacterial suspension had a concentration of approximately 10 8 cfu/mL. After 24 hours, the E. coli suspension was collected in the same manner. Sterilized skimmed milk was used as an interfering substance in all testing instead of bovine albumin as in EN 1656 protocol. One mL of milk and 1 mL of bacterial suspension were mixed and left in contact for 2 minutes at 25° C. Eight mL of the solutions described below in Tables 1 and 2 were then added to the mixture and left in contact for 30 seconds at 25° C. One milliliter of the resulting solution was removed and diluted with 9 mL of phosphate buffer at pH 7.2, and then four successive dilutions were made. Samples from each dilution were plated in duplicate and agar was added. One mL of the previous mixture was added to 9 mL of neutralizing solution and then mixed. Three serial dilutions were made of this solution and 1 mL of each solution was dispensed into a Petri dish in duplicate. Also, 0.1 mL of the most dilute solution was dispensed in duplicate. Approximately 15 mL of sterile tryptone glucose extract agar was added to each Petri dish and when solidified, each plate was incubated at 37° C. for 48 hours. This procedure was repeated for all samples to be tested.
[0056] For controls, the 10 8 cfu/mL bacteria suspensions were diluted to concentrations of 10 4 and 10 3 cfu/mL. One milliliter of the 10 4 cfu/mL dilutions and 0.1 mL of the 10 3 cfu/mL dilutions (done in triplicate) were dispensed onto Petri dishes and approximately 15 mL of tryptone glucose extract agar was added. When solidified, the plates were incubated at 37° C. for 48 hours. An average of the plate counts for the triplicate platings of the 10 3 cfu/mL dilution was considered the initial numbers control count.
[0057] The plates with bacterial populations between 25 and 250 were counted and results were expressed as logarithmic reductions according to EN 1656 test method.
Irritation Testing
[0058] As will be seen below, Blood Cell Irritation tests were performed to determine if some particular representative compositions would be mild enough for topical applications. These tests involved separating red blood cells and then exposing them to the compositions. The tests used for the compositions addressed in Tables 1-2 included two measurements made on cow's blood. In the tests, fresh calf blood samples were obtained; 50 mL of sodium citrate buffer (17.03 g trisodium citrate+8.45 g citric acid diluted to 1 L with bacteria-free DI water) was added to every 450 mL of blood and mixed. The blood was then centrifuged to isolate red blood cells (RBC), which were then washed with sodium citrate buffer, and centrifuged several times to remove white cells and plasma, according to a known method. The red blood cells were placed into containers for use in testing the disclosed antimicrobial compositions.
[0059] Red blood cells were treated with water, centrifuged and then, using a UV spectrophotometer, the absorption at 560 nm was measured in order to determine complete cell denaturation (H100). The product to be tested was then diluted in the range of 5000 ppm to 60000 ppm, blood cells were added to these dilutions, centrifuged and the absorption at 560 nm was measured by UV spectrometry. Haemolysis Values (H50) were determined by plotting absorption versus concentration. The H50 value represents the product concentration (expressed in ppm) at which half of the blood cells are denatured.
[0060] Product Haemolysis Values (H50); Product Denaturation Index Values (DI); and Lysis/Denaturation Ratios (LID) were determined for the compositions using known methods. Descriptions of these methods were disclosed by Wolfgang J. W. Pape, Udo Hoppe: In vitro Methods for the Assessment of Primary Local Effects of Topically Applied Preparations, Skin Pharmacol . (1991), 4, 205-212, which is incorporated herein by reference. The haemolysis—or tendency of the red blood cells to rupture when in contact with the test product—was measured by the half-haemolysis value H50. The denaturation of protein caused by the test product was measured by the denaturation index (DI). For DI measurements, a 1000 ppm solution of sodium lauryl sulfate solution was used as a reference. The overall irritation value for a product was determined by the ratio of the H50/DI which is referred to as the lysis/denaturation quotient. The overall irritation score is given by the lysis/denaturation value which is calculated by the equation: L/D=H50 (measured in ppm)/DI (measured in %).
[0061] The H50 score which measures haemolysis alone usually shows a similar irritation correlation to the L/D ratio. The higher the ppm value for H50 the less irritating the product. A crude scale is H50>500 ppm (non-irritant); 120-500 (slight irritant), 30-120 (moderate irritant), 10-30 (irritant), 0-10 (strong irritant).
[0062] The DI score which measures denaturation of protein also shows a correlation to the L/D ratio. A crude scale is DI 0-5% (non-irritant); 5-10% (slight irritant), 10-75% (moderate irritant), 75-100% (irritant), and >100% (strong irritant).
[0063] Although the H50 and DI values may be of use in the interpretation of the results, the LID ratio is the primary value used to determine irritation. This method is best suited to comparing two or more products and determining which product is likely to cause the least irritation to skin and eyes. In terms of indication, an L/D value greater than 100 is an indication that the composition is a non-irritant; levels between 10 and 100 are considered slight irritants; levels between 1 and 10 are considered moderate irritants; levels between 0.1 to 1 are considered irritants; and levels lower than 0.1 are considered strong irritants.
Results
[0064] Historically, combinations of organic acids and surfactants in topical solutions evidenced little antimicrobial efficacy. In some of these instances, the additives interfered with the efficacy. Thus, even when successful kills might be obtained using lactic acid along with a surfactant in an aqueous solution, that effectiveness would diminish when the application required additives (e.g., viscosity control and opacifying agents, barrier forming agents, etc.). This interference made these combinations unsuitable for real-world applications. Especially ones in which some contact with animal skin is intended (e.g., teat-dip topical germicides).
[0065] Through experimentation, it has been discovered that anionic surfactants, and more specifically, certain anionic surfactants, when combined with lactic acid in a particular teat dip composition, provide a synergistic result enabling greater than five-log reductions (99.999%), while still avoiding conventional oxidizers which are more harmful to the animals' skin.
[0066] Shown below are the results of experiments carried out to determine the efficacy of various antimicrobial compositions against E. coli and S. aureus . The antimicrobial agents in the compositions disclosed below in Table 1 are comprised of lactic acid in combination with Sodium Octane Sulfonate (SOS) along with numerous additives which may be included in a product for topical use. One advantage attributable to SOS which is unrelated to efficacy is that it is entirely biodegradable and thus environmentally friendly. So much so, that SOS meets the European Surfactant Detergent Regulation requirements. This makes its inclusion in antimicrobial compositions more readily acceptable than other potential ingredients. Table 1 below shows the use of SOS with lactic acid. Each of the values in the Table is displayed as weight percentages (% w/w).
[0000]
TABLE I
BARRIER TEAT DIP FORMULATIONS WITH LACTIC ACID AND SODIUM OCTANE SULFONATE
Ingredients and Concentration (% w/w): Formulations Sequence
A
B
C
D
E
Water
70.66
71.15
73.65
66.69
70.75
Keltrol RD (Xantan Gum)
0.40
0.40
0.40
0.40
0.40
Maltodextrin (Maltrin M040)
5.00
5.00
5.00
5.00
5.00
Sorbitol 70% (Hexane-1,2,3,4,5,6-Hexaol)
14.29
14.29
Glycerin
10.00
10.00
10.00
Allantoin (2,5-Dioxo-4-Imidazolidinyl) Urea
0.10
0.10
0.10
0.10
0.10
Polyoxyethylene-polyoxypropylene Glycol
0.20
0.20
0.20
0.20
0.20
Lactic Acid 88% USP (L(+)-2-Hydroxypropanoic acid)
4.00
4.00
4.00
4.00
4.00
Bioterge PAS-8S 38% (Sodium Octane Sulfonate
5.30
7.90
5.30
7.90
7.90
Sodium Hydroxide (50%)
0.00
1.20
1.30
1.37
1.60
FD&C Yellow # 5
0.03
0.03
0.03
0.03
0.03
FD&C Blue # 1
0.02
0.02
0.02
0.02
0.02
pH
2.15
3.02
3.53
3.48
3.52
Micro Test: EN 1 656, 30 Seconds contact.@25° C.:
Results are in Log Reduction from Initial Bacteria Count 10 8 cfu/mL
Staphyloccocus aureus
7.0
6.9
5.1
5.9
5.5
Echerichia coli
7.0
7.0
7.0
7.0
7.0
Blood Cell Skin Irritation Test Results:
Product Haemolysis Value (H50) (ppm)
53,000
23400
46000
22,500
22,500
Product Denaturation Index Value (DI) (%)
19.3
9.1
11.2
7.7
11
Lysis/Denaturation Ratio (L/D) (higher better)
2,740.8
2585
4095.1
2,930
2,043
Barrier/Film Quality:
Good
Wet
NA
Good
Good
[0067] It should be recognized that each ingredient's concentration is 100% active unless that ingredient is expressly identified as having a certain percentage of active versus inert ingredients. For example, for the solutions used in Experiments A and D, the emollient sorbitol is disclosed to have a weight percentage of 14.29%. In terms of the active ingredient hexane-1,2,3,4,5,6-hexaol, however, the concentration is shown to be 70%. (See the description in the left margin of Table I). This means that the total hexane-1,2,3,4,5,6-hexaol included in the compositions for experiments A and D is (0.7) times 14.29, or 10.00% in each of compositions A and D. In trials B, C and E, 10.0% glycerin was used instead of sorbitol. Since no concentration percentage is listed in the left-hand margin description for this ingredient, the concentration would be 100%, or 10.0% of the full solution. Similarly, the sodium hydroxide included in trials B-E would only be 50% as shown.
[0068] Partial concentrations of active ingredients are also revealed with respect to the antimicrobial components, lactic acid and anionic surfactant. As can be seen in the chart, the lactic acid ingredient used contains only 88% L (+)-2-hydroxypropanoic acid (the active portion). Thus, although each of trials A-G shows a 4.0% w/w concentration for lactic acid, only (0.88) times 4.0, or 3.52% of L(+)-2-hydroxypropanoic acid is included. With respect to SOS, the only anionic surfactant used in each of experiments A-E, the concentration of actual SOS in the Bioterge PAS-8S product used is 38%. Thus, for the trials which show a weight percentage of 5.3%, the percentage of actual SOS is only 2.0%, and for the rest of the experiments where the percentage is shown as 7.9%, the actual SOS included would be only 3.0%.
[0069] The relatively low percentages of SOS used in experiments A-E have been found to be surprisingly effective from a germicidal standpoint. As can be seen from Table I, the kill numbers for each of the compositions A-E were in excess of five log reductions for both Staphyloccocus aureus as well as Echericia coli . It can also be seen that the SOS and lactic acid are compatible with the additive package, and that neither the glycerin nor sorbitol, nor the thickening agent nor film forming agent, alternatives interfered with efficacy.
[0070] The results shown in Table I show superior kill results. The log reductions for E. coli were a seven log reduction in each instance. For S. aureus , at least five log reductions resulted, which are above industry standards, and in some cases the reductions were as high as seven log (total kill).
[0071] Lactic acid has poor, or marginally effective, germicidal properties against Gram positive and Gram negative bacteria when used as a sole antimicrobial agent. Only a moderate germicidal efficacy of lactic acid has been found, and only at very high concentrations. Typically, less than a three log reduction in S. aureus concentration and a five log reduction in E. coli concentration are attained after 30 seconds contact when 10% lactic acid is used alone. However, some nonionic surfactants in combination with lactic acid have moderate to good germicidal efficacy, but most are skin irritants and are not suitable for topical skin care products. It has now been discovered that an organic acid (e.g., lactic acid) when combined with certain anionic surfactants can provide synergistic kill results—even when included with necessary additives which adapt it for use with topical applications.
[0072] The mildness to the animal's skin is of tremendous benefit when coupled with the outstanding germicidal effectiveness of the lactic acid/anionic surfactant combinations. As already discussed briefly above, traditional germicides that are presently used in skin care products, e.g., topical teat dip applications are often based on iodine, iodophor, chlorine dioxide, or hypochlorite, which are all skin irritants. For this reason, conventional antimicrobials adapted for use on the skin include expensive and formulaically burdensome conditioning agents which are needed in the product to mask the skin irritation. Because the anionic surfactant and lactic acid combination used here is not a skin irritant, skin conditioning and moisturizing agents are at best unnecessary, and at least may be minimized in the product.
[0073] Tests also show that a reasonably high pH value (e.g., 3.0 or above) can be attained without negating the kill properties of the antimicrobial agents. This can be seen in particular with respect to compositions B-E. By maintaining a high pH value, the product is less offensive to the animal's skin.
[0074] The mildness of the product is quantified by the irritation results obtained. Of the compositions listed, only A, B, C, D and E were tested for irritation potential. As can be seen, the values measured for each of Product Haemolysis Value (1-150); Product Denaturation Index Value (DI); and Lysis/Denaturation Ratio (L/D) are within non-irritating ranges. For example, the H50 results for compositions A, B, C, D and E were 22,500 ppm or higher—well above the 500 ppm minimum for classification as a “non-irritant.” Similarly, the DI value for sample A was 19.3 placing it as a moderate irritant may be due to its lower pH of 2.15, 9.1 for B and 7.7 for D placing both in the “slight irritant” category, whereas the DI value for sample C and E was 11.2 and 11, respectively, placing it near the lower range of the “moderate irritant” classification. With respect to L/D ratios, which are the primary value relied on to determine irritability, composition A, produced L/D ratio of 2741, composition B produced 2585, composition C produced 4095 whereas D and E produced ratios of 2930 and 2043, respectively—each over twenty times greater than the minimum threshold of 100 for being classified as a non-irritant. Thus, all of the parameters indicate that the lactic acid/SOS combination is an extremely effective antimicrobial, while being surprisingly mild to the skin.
[0075] The Table I results also reveal that most of the compositions scored well when rated for Barrier/Film Quality. Only compositions A, B, D, and E were evaluated using the testing methods discussed above. Of these, only sample B reflected a “wet” rating, whereas compositions A, D and E all resulted in “good” ratings, meaning that these compositions would perform well in teat dipping and other like topical applications because the composition will form a continuous coating that will remain in contact with the skin.
[0000]
TABLE II
BARRIER TEAT DIP FORMULATIONS WITH LACTIC ACID, SODIUM LAURYL SULFATE AND SODIUM OCTANE SULFONATE
Ingredients and Concentration (% w/w): Formulations Sequence
F
G
H
I
J
K
L
O
P
Water
65.73
67.06
67.73
68.39
66.40
67.39
67.16
68.41
66.51
Keltrol RD (Xantan Gum)
0.40
0.40
0.40
0.40
0.40
0.40
0.40
0.40
0.40
Maltodextrin (Maltrin M040)
5.00
5.00
5.00
5.00
5.00
5.00
5.00
5.00
5.00
Sorbitol 70% (Hexane-1,2,3,4,5,6-Hexaol)
14.29
14.29
14.29
14.29
14.29
14.29
14.29
14.29
14.29
Allantoin (2,5-Dioxo-4-Imidazolidinyl) Urea
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
Polyoxyethylene-polyoxypropylene Glycol
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
Lactic Acid 88% USP (L(+)-2-Hydroxypropanoic acid)
4.00
4.00
4.00
4.00
4.00
4.00
4.00
4.00
4.00
Bioterge PAS -8S 38% (Sodium Octane Sulfonate
5.30
5.30
5.30
5.30
5.30
5.30
5.30
5.00
7.90
Sodium Lauryl Sulfate 30% (Carsonal)
3.33
2.00
1.33
0.67
2.66
1.67
1.67
0.00
0.00
Sodium Hydroxide (50%)
1.60
1.60
1.60
1.60
1.60
1.60
1.60
1.10
1.10
FD&C Yellow # 5
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
FD&C Blue # 1
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
pH
3.52
3.52
3.52
3.52
3.52
3.52
3.55
3.50
3.50
Micro Test: EN 1656, 30 Seconds contact.@25° C.:
Results are in Log Reduction from Initial Bacteria Count 10 8
cfu/mL
Staphyloccocus aureus
7.0
7.0
7.0
7.0
7.0
7.0
5.5
6.5
5.6
Echerichia coli
7.0
7.0
7.0
7.0
7.0
7.0
7.0
5.1
7.0
Blood Cell Skin Irritation Test Results:
Product Haemolysis Value (H50) (ppm)
3500
6300
9200
3800
13000
16400
Product Denaturation Index Value (DI) (%)
9.85
17
11.87
0.00
16.2
Lysis/Denaturation Ratio (L/D) (higher better)
355.39
370.17
774.84
NA
1014
[0076] The compositions provided in Table II include both sodium octane sulfonate (SOS) and sodium lauryl sulfate (SLS) with lactic acid. As shown above, SLS is commercially available product in 30% concentration. Thus, since the values in Table II are expressed in total weight percentages, one must multiply by 0.3 to get the actual SLS content in each of the samples. Doing so, the actual SLS concentrations in composition F would be 1.0%; G would be 0.6%; H would be about 0.4%; I would be 0.2%; J would be 0.8%; and K and L would be 0.5%. The levels of SOS in each case, considering product concentration, are about 2.0% (0.38 times 5.3%).
[0077] Like with the SOS embodiments shown in Table I, the embodiments of SOS blended with SLS that are shown in Table II, are also surprisingly effective from an antimicrobial standpoint. As can be seen from Table II, the germicidal efficacy of each of the compositions F-L resulted in excess of five log reductions for both S. aureus and E. coli . In most cases, the reductions were as high as seven log which is considered total or complete kill.
[0078] Use of SLS in combination with SOS and lactic acid produced synergistic results for kill efficacy much like those observed for combinations of SOS and lactic acid. Unfortunately, SLS is slightly more irritating to the skin than is SOS. However, because SLS is used in all of the trials at low levels (1.0% or less), the observed irritation has been found to be minimal.
[0079] Further, all of the compositions F-L possessed relatively high pH values (e.g., above 3.0) without compromising antimicrobial activity.
[0080] In Table III below, further embodiments are disclosed showing the use of a composition including Lactic Acid and SOS in as it might be used in barrier teat-dip applications.
[0000]
TABLE III
BARRIER TEAT DIP FORMULATIONS WITH LACTIC ACID AND SODIUM OCTANE SULFONATE
Ingredients and Concentration (% w/w): Formulations Sequence
Q
R
S
T
U
Water
64.41
64.21
68.41
68.41
66.71
Keltrol RD (Xantan Gum)
0.40
0.40
0.40
0.40
040
Maltodextrin (Maltrin M040)
5.00
5.00
5.00
5.00
5.00
Sorbitol 70% (Hexane-1,2,3,4,5,6-Hexaol)
14.29
14.29
14.29
14.29
14.29
Allantoin (2,5-Dioxo-4-Imidazolidinyl) Urea
0.10
0.10
0.10
0.10
0.10
Polyoxyethylene-polyoxypropylene Glycol
0.20
0.20
0.65
0.65
0.65
Lactic Acid 88% USP (L(+)-2-Hydroxypropanoic acid)
4.00
4.00
4.00
4.00
4.00
Bioterge PAS-8S 38% (Sodium Octane Sulfonate
5.00
7.20
0.00
0.00
6.70
Sodium Lauryl Sulfate 30% (Carsonal)
5.00
5.00
5.00
0.00
Benzyl Alcohol
1.00
1.00
0.00
Sodium Hydroxide (50%)
1.10
1.30
1.10
1.10
1.10
FD&C Yellow # 5
0.03
0.03
0.03
0.03
0.03
FD&C Blue # 1
0.02
0.02
0.02
0.02
0.02
pH
3.50
3.54
3.50
4.00
3.50
Micro Test: EN 1656, 30 Seconds contact.@25° C.:
Results are in Log Reduction from Initial Bacteria Count 10 8 cfu/mL
Staphylaccocus aureus
6.5
6.5
6.5
6.5
5.10
Echerichia coli
7.1
5.6
7.1
7.1
7.10
Blood Cell Skin Irritation Test Results:
Product Haemolysis Value (H50) (ppm)
1850
3350
1950
2000
Product Denaturation Index Value (DI) (%)
116.5
1.1
1.9
1.3
Lysis/Denaturation Ratio (L/D) (higher better)
16
3045
1013
1538
[0081] Table IV below, shows control experiments conducted using a Lactic Acid composition without the use of an anionic surfactant. As can be seen, without the synergy provided by the Lactic Acid/anionic surfactant combination, there were either minimal or no kills.
[0000]
TABLE IV
BARRIER TEAT DIP FORMULATIONS: CONTROL EXPERIMENTS WITH LACTIC ACID
Ingredients and Concentration (% w/w): Formulations Sequence
V
W
X
Y
Z
Water
94.40
92.15
89.15
86.15
67.51
Keltrol RD (Xantan Gum)
0.40
0.40
0.40
0.40
0.40
Maltodextrin (Maltrin M040)
5.00
Polyvinylpyrrolidone K-30
0.80
0.80
0.80
0.80
Sorbitol 70% (Hexane-1,2,3,4,5,6-Hexaol)
14.29
Allantoin (2,5-Dioxo-4-Imidazolidinyl) Urea
0.10
Polyoxyethylene-polyoxypropylene Glycol
0.20
0.20
0.20
0.20
0.20
Polysorbate 80 (Tween 80)
0.50
0.50
0.50
0.50
0.30
PEG-7-Glyceryl Cocoate (Cetiol HE)
0.50
0.50
0.50
0.50
Sodium Dioctylsulfosuccinate, 75%
0.15
0.15
0.15
0.15
0.15
EO/PO/EO Block Copolymer, Pluronic P105
0.50
0.50
0.50
0.50
Lactic Acid 88% USP (L(+)-2-Hydroxypropanoic acid)
2.00
4.00
6.00
8.00
10.00
Bioterge PAS-8S 38% (Sodium Octane Sulfonate)
Sodium Lauryl Sulfate 30% (Carsonal)
Sodium Hydroxide (50%)
0.75
1.00
2.00
3.00
2.00
FD&C Yellow # 5
0.03
0.03
0.03
0.03
0.03
FD&C Blue # 1
0.02
0.02
0.02
0.02
0.02
pH
3.56
3.52
3.50
3.52
3.50
Micro Test: EN 1656, 30 Seconds contact.@25° C.:
Results are in Log Reduction from Initial Bacteria Count 10 8 cfu/mL
Staphyloccocus aureus
No Kill
No Kill
No Kill
No Kill
2.8
Echerichia coli
No Kill
No Kill
0.9
1.64
5.1
[0082] Table V below shows control experiments where the use of lactic acid alone or the use of an anionic surfactant alone shows reduced kill efficacy versus a composition containing lactic acid in combination with an anionic surfactant. It should be noted that control experiments AA-AC were carried out in the presence of 10% manure or no manure, but similar results are expected when milk is present as the interferent.
[0000]
TABLE V
CONTROL EXPERIMENTS WITH LACTIC ACID, SODIUM
OCTANE SULFONATE AND SODIUM LAURYL SULFATE
AA
AB
AC
Lactic acid (adjusted to
4.0
0
0
100%)
Sodium Lauryl Sulfate
0.0
0
2
(adjusted to 100%)
Sodium Octane Sulfonate
0.0
2.2
0
(adjusted to 100%)
TOTAL (adjusted with
100
100
100
water)
Log Kill S. aureus ,
0
4
0
max kill value 5, 30 sec
(10% manure)
(10% manure)
(0% manure)
Log Kill E. coli ,
0
1
0
max kill value 5, 30 sec
(10% manure)
(10% manure)
(0% manure)
[0083] In Table VI below, further embodiments are disclosed showing the use of a composition including Lactic Acid and SOS in as it might be used in no-barrier teat-dip applications.
[0000]
TABLE VI
NON-BARRIER TEAT DIP FORMULATIONS WITH LACTIC ACID AND SODIUM OCTANE SULFONATE
Ingredients and Concentration (% w/w): Formulations Sequence
A
B
C
D
E
F
G
H
I
Water
75.56
76.05
74.26
70.49
75.55
68.23
68.33
75.55
75.45
Keltrol RD (Xantan Gum)
0.40
0.40
0.40
0.40
0.40
0.40
0.40
0.40
0.40
Sorbitol 70% (Hexane-1,2,3,4,5,6-Hexaol)
14.29
0.00
14.29
14.29
0.00
14.29
14.29
0.00
0.00
Glycerin
0.00
10.00
0.00
0.00
10.00
0.00
0.00
10.00
10.00
Sodium Dioctylsulfosuccinate
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
Polyoxyethylene-polyoxypropylene Glycol
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
Lactic Acid 88% USP (L(+)2-Hydroxypropanoic acid)
4.00
4.00
4.00
4.00
4.00
4.00
4.00
4.00
4.00
Bioterge PAS -8S 38% (Sodium Octane Sulfonate
5.30
7.90
5.30
7.90
7.90
10.83
10.83
7.90
7.90
Sodium Hydroxide (50%)
0.00
1.20
1.30
1.37
1.60
1.80
1.70
1.70
1.80
FD&C Yellow # 5
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
FD&C Blue # 1
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
pH
2.15
3.02
3.54
3.48
3.52
4.00
3.75
3.75
4.00
[0084] In Table VII below, embodiments are disclosed showing the use of a composition including Lactic Acid, SLS, and SOS in as it the composition might be used in non-barrier teat-dip applications.
[0000]
TABLE VII
NON-BARRIER TEAT DIP FORMULATIONS WITH LACTIC ACID,
SODIUM LAURYL SULFATE AND SODIUM OCTANE SULFONATE
Ingredients and Concentration (% w/w): Formulations Sequence
F
G
H
I
J
K
L
Water
70.73
72.06
72.73
73.39
70.40
72.39
86.68
Keltrol RD (Xantan Gum)
0.40
0.40
0.40
0.40
0.40
0.40
0.40
Sorbitol 70% (Hexane-1,2,3,4,5,6-Hexaol)
14.29
14.29
14.29
14.29
14.29
14.29
14.29
Sodium Dioctylsulfosuccinate
0.20
0.20
0.20
0.20
0.20
0.20
0.20
Polyoxyethylene-polyoxypropylene Glycol
0.20
0.20
0.20
0.20
0.20
0.20
0.20
Lactic Acid 88% USP (L(+)-2-Hydroxypropanoic acid)
4.00
4.00
4.00
4.00
4.00
4.00
4.00
Bioterge PAS -8S 38% (Sodium Octane Sulfonate
5.30
5.30
5.30
5.30
5.30
5.30
5.30
Sodium Lauryl Sulfate 30% (Carsonal)
3.33
2.00
1.33
0.67
2.66
1.67
1.67
Sodium Hydroxide (50%)
1.60
1.60
1.60
1.60
1.60
1.60
1.75
FD&C Yellow # 5
0.03
0.03
0.03
0.03
0.03
0.03
0.03
FD&C Blue # 1
0.02
0.02
0.02
0.02
0.02
0.02
0.02
pH
3.52
3.52
3.52
3.52
3.52
3.52
4.00
[0085] Consideration of the above, along with other test data not disclosed herein, reveals that, when presented in a ready-to-use (RTU) product for topical applications, the product components are likely to fall within the ranges set forth in Table VIII below:
[0000]
TABLE VIII
READY TO USE (RTU) FORMULATIONS: RANGES OF
INGREDIENTS (% W/W)
Preferred Range
Broadly
Ingredient:
Preferred
Preferred
More Preferred
Anionic Surfactant(s)
0.01-15
0.01-11.0
0.70-4.0
Sodium Octane Sulfonate (SOS)
0.00-10
0.01-8.0
0.70-3.0
Sodium Lauryl Sulfate (SLS)
0.00-5
0.00-3.0
0.00-1.0
Lactic Acid
0.01-20
2.0-6.0
3.0-5.0
Additives
0.00-99.9
5.0-30.0
15.0-25.0
Carrier (e.g., water)
0.01-99.9
1.0-90.0
1.5-80.0
[0086] Considering the above formulation embodiments along with other test data not disclosed herein, reveals that, when presented in a ready-to-use (RTU) product, where the user would mix the product with some sort of carrier (e.g., water), the product components are likely to fall within the ranges set forth in Table IX below:
[0000]
TABLE IX
CONCENTRATED FORMULATIONS: RANGES OF
INGREDIENTS (% W/W)
Preferred Range
Broadly
Ingredient:
Preferred
Preferred
More Preferred
Anionic Surfactant(s)
0.01-99.9
0.01-30.0
0.70-20.0
Sodium Octane Sulfonate (SOS)
0.00-99.9
0.01-20.0
0.70-15.0
Sodium Lauryl Sulfate (SLS)
0.00-99.9
0.00-10.0
0.00-5.0
Lactic Acid
0.01-99.9
4.0-30.0
6.0-20.0
Additives
0.00-99.9
8.0-50.0
20.0-50.0
Carrier (e.g., water)
0.01-99.9
1.0-70.0
2.0-60.0
[0087] It should be noted in evaluating Tables VIII and IX above that the narrowing of the ranges has been towards a composition adapted for topical applications. In other applications, e.g., surface cleaning, preferably the broad ranges would apply, and the more narrow ranges may not. For example, for some antimicrobial applications no additives would be needed, and the carrier percentages may be much lower than reflected in the “Preferred” and “More Preferred” ranges provided above. Thus, the range charts have been provided as only a depiction of embodiments of the invention, are not intended for any limiting purposes, and thus, should not be interpreted in such a manner.
[0088] Those skilled in the art will appreciate that the foregoing discussion teaches by way of example, and not by limitation. Insubstantial changes may be imposed upon the specific embodiments that are shown and described without departing from the scope and spirit of the invention. | A liquid antimicrobial composition comprising an organic acid and one or more anionic surfactants is disclosed. In one embodiment, the organic acid is lactic acid and the anionic surfactant is sodium octane sulfonate. In a preferred embodiment, the antimicrobial solution is formulated as a teat dip for lactating animals, particularly cows. In other embodiments, the antimicrobial compositions may be used in personal care, hard surface care including hard surface disinfection in households, food processing, hospitals, restaurants, hotels, showers, or topically as hand soaps, surgical scrubs, and hoof disease mitigators. | 0 |
[0001] This application claims priority from German Patent Application No. 200 06 683.8, filed on 11 Apr. 2000, and PCT Application No. PCT/EP01/04205, filed on 11 Apr. 2001, which are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to an air motor, especially for a screw driving device.
BACKGROUND OF THE INVENTION
[0003] An air motor which is installed in a screw driving device (“screwer”) is known in practice. The screwer has a compressed air connection for supplying compressed air to the air inlet of the air motor. The compressed air passes through the air inlet into one of the chambers between motor cylinder and air rotor and acts on one of the lamellae. The air rotor is thereby rotated. A further chamber will then communicate with the air inlet while the chamber already acted upon by compressed air releases the compressed air again via a corresponding air outlet to the environment. Due to the alternating filling and emptying of the chambers with compressed air, and since the lamellae radially protruding outwards from the air rotor are subjected to compressed air, the air rotor and the output shaft connected thereto are rotated on the whole. As a consequence, a corresponding screwing tool is rotated for screwing or unscrewing a screw, or the like.
[0004] The known air motor comprises two chambers opposite each other relative to the air rotor. Such an air motor has a relatively high idling speed and overall performance. The power or rotational speed of such an air motor must be reduced in part by exhaust air throttling measures.
[0005] EP 052162 shows a rotating piston machine with sliding slides for operation with expanding gases, said rotating piston machine. In said rotating piston machine, pressure from gases is directly converted into a rotating movement; the pressure is here to act always exactly in tangential direction relative to the rotary movement. A cover plate has arranged therein openings through which gas enters or exits. The openings are arranged at ends of a drum for permitting the tangential supply of the gases.
[0006] FR 2762879 shows a compressor with a cylindrical rotary body as the rotor. In the rotor, a plurality of lamellae are adjustably supported in corresponding grooves, the lamellae being inclined relative to the radial direction. In corresponding chambers, a fluid is compressed upon rotation of the rotor and discharged to the outside via outlets.
[0007] In the light of EP052162, it is the object of the present invention to improve an air motor of the above-mentioned type in such a way that together with a high efficiency of the motor a more uniform accelerating power, a reduced sound level and less wear are possible together with a reduction of the exhaust air throttling measures.
SUMMARY OF THE INVENTION
[0008] The three-chamber air motor according to the invention yields a lower motor speed and, at the same time, a more uniform accelerating power because of the three chambers. With the same constructional size as in a two-chamber motor, this yields an increase in torque and also a reduced sound level because of a reduced speed. Due to the lower motor speed during screwing, troublesome supply-air and exhaust-air throttling measures are no longer required, in particular in screwers of the nonswitching-off type. At the same time, an oil-free running is more likely due to the lower speed than in the known single-chamber and two-chamber motors. The construction is further simplified in that on outsides of each triangle side at least one air inlet channel and air outlet channel extend in neighboring relationship with each other in the longitudinal direction of the air rotor. It is thus not necessary to form, e.g., corresponding channels in the housing or to provide air inlet or outlet only at ends of the housing.
[0009] The rotational direction of the air rotor is selected in that the rear and/or front rotor cover are rotatable for the alternative supply of air inlet or outlet channel with air relative to the motor cylinder. For instance, the corresponding holes in the rotor cover can be communicated, on the one hand, with the air inlet channels, e.g., for rotations in clockwise direction, or with the air outlet channels to rotate e.g., the air rotor anticlockwise. It is decided through the corresponding assignment of the hole in the rotor cover which ones of said channels serve as air inlet or air outlet.
[0010] To be able to discharge the air from the chambers via the rotor cover, corresponding air outlets may be formed in the front and/or rear rotor cover, said air outlets being connected to air inlet or air outlet channel, depending on the assignment of the corresponding air inlets in the rotor cover. The air outlets are designed as outlet recesses which are open at least towards the rotor cylinder. At least the corresponding air outlet channel communicates with such a recess for the fast discharge of air. Since the outlet recesses extend in partly annular-shaped fashion, the expanded compressed air is already discharged in the area of the corresponding chambers. Such an arrangement of the outlet recesses yields a better expansion ratio than in known air motors and, at the same time, an enhanced performance without the constructional size of the air motor being enlarged.
[0011] To allow a self-centering of the air rotor in a simple way, the inner chamber of the motor cylinder is advantageously provided with the cross-section of an isosceles triangle, the rotational axis of the air rotor being in particular arranged at the point of intersection of the three mid-perpendiculars of the corresponding triangle sides.
[0012] To support the air rotor here in an even better centered way, the triangle sides of the motor cylinder may be convexly curved at least in the area of the respective mid-perpendicular. The curvature is substantially identical with the curvature of the air rotor.
[0013] To be able to guide—upon rotation of the air rotor—the lamellae in a simple way along an inner surface of the motor cylinder with the free ends thereof, such an inner surface of the motor cylinder may be convexly curved preferably at least in the area of the triangle tips. The free ends of the lamellae thereby slide without any difficulty along the inner surface, in particular also in the area of the triangle tips.
[0014] For a simplified manufacture of the motor cylinder and to permit a movement of the air rotor that is as uniform as possible, the inner surface of the motor cylinder may comprise identical radii of curvature in the area of the triangle tips.
[0015] A simple manufacture for air inlet and air outlet channel is possible if e.g., both channels are formed in a channel body of the motor cylinder.
[0016] To accommodate the air motor of the invention in an easy way in a corresponding screwer without any dimensional overdefinition, the outer diameter of the motor cylinder should be located on such a circular line that the whole motor cylinder can be inserted into a screwer with an accommodating means of a correspondingly larger diameter.
[0017] In this context, it must further be considered as an advantage when the diameter of the circular line is also substantially smaller than a diameter of a front and/or rear rotor cover. Said rotor covers close the chambers at front and rear ends positioned in the longitudinal direction of the air rotor and simultaneously serve to support a shaft made mostly integral with the air rotor.
[0018] An advantageous manufacture of the air motor is possible in that the channel bodies extend between the front and rear rotor covers over the whole length of the motor cylinder.
[0019] Air may be supplied to the air inlets, for instance, from a radial direction relative to the motor cylinder. The air may here be supplied between e.g., a rotor cover and the motor cylinder. In a simple embodiment, the rear rotor cover may comprise at least air inlets for the supply of air to the air inlet channels.
[0020] To supply air in the longitudinal direction of motor cylinder and air rotor, respectively, such an air inlet may be designed as a hole passing through the rotor cover.
[0021] The cross section of hole and/or air inlet channel may have different shapes. In the simplest case such a cross section may be circular.
[0022] For discharging air from the corresponding chambers, in particular in radial direction, the outlet recess may be opened radially outwards via an outlet gap.
[0023] To be able to discharge air to the outside not only via the outlet channel, but also at least in part directly from the corresponding chamber, the outlet recess may extend—if connected to an outlet channel at one of its ends—with its other end into an area between triangle tip and channel body.
[0024] The outlet recess can thereby communicate with one of the chambers arranged downstream of the associated outlet channel in the rotational direction of the air rotor—also for the discharge of air into the environment.
[0025] The outlet recess is here sufficiently large if an inner radius of the outlet recess is substantially equal to an outer radius of the air rotor.
[0026] To be able to rapidly supply and discharge, respectively, a sufficient amount of air in the area of air inlet channel and air outlet channel, air inlet channel and air outlet channel may be provided on the inside of the motor cylinder with slits which extend over part of the respective length thereof and are open towards the air rotor and are separated by a sealing web with which the air rotor is in tight contact.
[0027] The air rotor may e.g., comprise four corresponding longitudinal slits and lamellae arranged therein. However, for a uniform acceleration of the air rotor more lamellae and a corresponding number of longitudinal slits are desired, e.g., five, six, seven, eight or more longitudinal slits with corresponding lamellae. For a uniform running of the air motor without a corresponding unbalance, it is further of advantage when the longitudinal slits with the corresponding lamellae are equally spaced apart in circumferential direction.
[0028] To safely subdivide the chambers by the lamellae into a partial chamber to be filled with air and into a partial chamber to be evacuated, a mid-point angle assigned to the length of the outlet recess in circumferential direction may be greater than an angle between two neighboring lamellae.
[0029] To act on the lamellae in a simple way in radial direction to the outside with a force, use is preferably made of even numbers of longitudinal slits and lamellae, a respective pressure spring being possibly arranged between two diametrically opposed lamellae.
[0030] To subject the lamellae at their radially inner ends with compressed air, in addition or as an alternative to the pressure springs, the rear rotor cover may comprise compressed air recesses which are arranged about a central hole and extend concentrically relative to the central hole. Depending on the position of the rear rotor cover relative to the motor cylinder, compressed air is supplied through the compressed air recesses to the longitudinal slits in the air rotor especially in those areas in which the corresponding lamellae in the area of the chambers are pushed out of the air rotor.
[0031] To supply the lamellae with compressed air in a uniform way and in the area of the chambers, the compressed air recesses may be equally spaced apart from one another in the circumferential direction of the central hole and/or opened laterally relative to the central hole. Via the lateral opening relative to the central hole, compressed air can easily be supplied via the central hole to the compressed air recesses.
[0032] To supply compressed air, depending on the orientation of the air inlets in the rear rotor cover, for the right-hand or left-hand rotation of the air rotor, an air distributing means may be arranged for the supply of compressed air to the air inlets of the rear rotor cover at the side thereof that is opposite to the air rotor.
[0033] In a simple embodiment, the air distributing means may be disk-shaped and comprise three air distributing grooves extending from a central air supply hole radially to the outside, i.e. at the side oriented towards the rear rotor cover.
[0034] In accordance with the shape of the air rotor, the air distributing grooves may be arranged in circumferential direction at an equal distance from one another and assigned to a group of air inlets for compressed air actuation, depending on the relative position with respect to the rear rotor cover.
[0035] Instead of a deaerating of the chambers via the air outlets radially to the outside relative to the rear rotor cover, the air outlets may pass through the rear rotor cover for deaerating the chambers in axial direction, in particular when the air motor according to the invention is used in substantially straight tools, in angle screwers, or the like.
[0036] To be able to switch in an easy way between left-hand and right-hand rotation of the air motor, the rear rotor cover may be lockably supported in two positions relative to the motor cylinder for the left-hand and right-hand rotation of the air rotor. It should here be noted that of course instead of a rotation of the rear rotor cover relative to the motor cylinder it is also possible to rotate the front rotor cover and motor cylinder relative to a rear rotor cover which is arranged in a rotationally fixed manner and to switch between left-hand and right-hand rotation of the air rotor in this way.
[0037] In the two aforementioned cases, an adjustment is possible in that a switching knob protrudes radially outwards from the rear rotor cover or from the front rotor cover or from the motor cylinder. It is also possible that the locking operation for fixing the two positions for the left-hand and right-hand rotation of the air rotor takes place by means of the switching knob.
[0038] To accommodate rear and front rotor cover as well as motor cylinder with air rotor in an easy way, the air motor may comprise a motor housing which may comprise an air supply channel communicating with the air supply hole, as well as a rotor hole supporting the output shaft of the air rotor.
[0039] To receive the reaction force of the motor cylinder, a pin may be arranged between front rotor cover and motor cylinder. The reaction moment of the front rotor cover may e.g., be transmitted by a cotter pin, or the like, to the motor housing.
[0040] It should be noted in connection with the air rotor that said rotor in its axial position is defined by the two rotor covers whereas the radial position is solely defined by the air rotor, with a sufficient clearance remaining between motor cylinder and motor housing in that the corresponding diameter of the motor cylinder is smaller than that of the rotor cover.
BRIEF DESCRIPTION OF THE DRAWINGS
[0041] An advantageous embodiment of the present invention shall now be explained in the following in more detail with reference to the figures attached to the drawing, in which:
[0042] [0042]FIG. 1 is a longitudinal section through an air motor according to the invention;
[0043] [0043]FIG. 2 is a top view on a rear rotor cover from the direction of a motor cylinder;
[0044] [0044]FIG. 3 is a view of an air distributing means from the direction of the rear rotor cover;
[0045] [0045]FIG. 4 is a view from the inside on a partly illustrated triangle side of an air rotor in the area of air inlet and air outlet channel;
[0046] [0046]FIG. 5 is a section through FIG. 1 along line V-V for left-hand rotation;
[0047] [0047]FIG. 6 is a section according to FIG. 5 through a motor cylinder; and
[0048] [0048]FIG. 7 is a section through FIG. 1 according to FIG. 5 for right-hand rotation.
DETAILED DESCRIPTION OF THE INVENTION
[0049] [0049]FIG. 1 shows a longitudinal section through an air motor 1 according to the invention. Said motor comprises an output shaft 51 which extends in concentric fashion relative to a rotational axis 16 and is made integral with an air rotor 3 ; see FIG. 5. The air motor 1 is provided in the area of the output shaft 51 with a rear rotor cover 31 and with a front rotor cover 32 spaced apart therefrom in the direction of rotational axis 16 . A motor cylinder 2 is arranged between the two rotor covers. A disk-shaped air distributing means 61 is arranged next to the rear rotor cover 31 . At an end 9 opposite the air distributing means 61 , the rear rotor cover 31 comprises outlet gaps 37 which are outwardly open in radial direction. Said gaps are arranged between the rear rotor cover 31 and the motor cylinder 2 .
[0050] Motor cylinder 2 and rear and front rotor covers 31 , 32 have a substantially circular cross-section.
[0051] Motor cylinder 2 comprises side flanks 52 , 53 extending in the longitudinal direction 4 of said motor cylinder and in the longitudinal direction of air motor 1 , respectively (see also FIG. 5), the flanks extending obliquely radially inwards. The side flanks 52 , 53 separate channel bodies 26 and triangle tips 13 , 14 , 15 ; see also FIG. 6. The triangle tips 13 , 14 , 15 form the corresponding tips of an inner chamber of the motor cylinder 2 having a substantially triangular cross-section.
[0052] The substantially circular cross-section of the motor cylinder 2 follows from channel bodies 26 protruding from corresponding triangle sides 19 , 20 , 21 (see FIGS. 5 and 6) on the outsides 23 thereof, both the triangle tips 13 , 14 , 15 and the channel bodies 26 being rounded on their outer surfaces and extending along a circular line 28 (see FIG. 6). Said circular line 28 has a diameter slightly smaller than the diameter 29 according to FIG. 1.
[0053] In FIG. 1, the front rotor cover 32 is in tight contact with the front end of the motor cylinder 2 .
[0054] An air distributing means 61 is arranged opposite the motor cylinder 2 laterally next to the rear rotor cover 31 . The air distributing means comprises an air supply hole 65 approximately in the center. A stub projecting from the air rotor 3 protrudes in part into said hole. The air supply hole 65 is connected to an air supply channel 66 in the motor housing 64 . At the side of the air distributing means 61 which is oriented towards the rear rotor cover 31 , three air distributing grooves 62 project radially outwards from the air supply hole 65 (see also FIG. 3), the grooves communicating with corresponding air inlets 10 , 11 , depending on the relative rotational position of the rear rotor cover 31 relative to the air distributing means 61 .
[0055] At its side facing the air distributing means 61 , the rear rotor cover 31 comprises a recess which is arranged in concentric fashion relative to the rotational axis 16 and in which a ball bearing 56 is arranged for rotatably supporting the stub of the air rotor 3 . Openings of compressed air recesses 59 which are formed in the side of the rear rotor cover 31 facing away from the air distributing means 61 terminate in the recess. A further embodiment of compressed air recesses 59 of that type is shown in FIG. 2.
[0056] By analogy with the rear rotor cover 31 , the front rotor cover 32 is provided in its side facing away from the air rotor 3 with a recess which is concentrically arranged relative to the rotational axis 16 and in which a ball bearing 55 is also arranged. The output shaft 51 of the air rotor 3 extends through said bearing.
[0057] Rear and front rotor covers, motor cylinder with air rotor and air distributing means 61 are arranged in the motor housing 64 which is bipartite in the illustrated embodiment. A cup-shaped member 68 is provided in its bottom with the air supply channel 66 , and a cover-like member 69 of the motor housing 64 can be screwed onto the free ends of said member 68 .
[0058] The rear rotor cover 31 is connected to a switching knob 63 which is passed from the rear rotor cover radially outwards through the motor housing 64 and can be operated from the outside thereof. The switching knob 63 can be locked in two positions, one position of the rear rotor cover 31 corresponding to a left-hand rotation (see FIG. 5), and the other position to a right-hand rotation (see FIG. 7) of the air rotor 3 .
[0059] For transmitting a reaction moment from the motor cylinder 2 to the front rotor cover 32 , a pin 67 is arranged between said members. A corresponding means for transmitting the reaction moment from the front rotor cover 32 to the motor housing 64 is not shown for the sake of simplicity.
[0060] [0060]FIG. 2 is a view showing an inside of the rear rotor cover 31 from the direction of the motor cylinder 2 according to FIG. 1.
[0061] Various holes 34 are arranged as air inlets 33 in the rotor cover. A total of six holes 34 are provided, of which three drive an air rotor 3 (see FIG. 5) clockwise and anticlockwise, respectively, due to the supply of compressed air and upon a corresponding rotation of the front rotor cover 31 relative to the motor cylinder 2 . Outlet recesses 36 are arranged as air outlets 35 between the holes 34 . The outlet recesses 36 are partly of an annular shape and extend over a length 47 in circumferential direction 48 that corresponds to a mid-point angle 49 . Radially to the outside, outlet recesses 35 communicate via outlet gap 37 (see also FIG. 1) with the surroundings of the air motor 1 .
[0062] An inner radius 41 of the outlet recess 36 corresponds essentially to an outer radius 42 (see FIG. 5) of the air rotor 3 . The diameter 30 of both the rear and front rotor cover 31 , 32 is essentially equal to the diameter 29 of the motor cylinder 2 .
[0063] [0063]FIG. 3 is a front view showing the air distributing means 51 from the direction of the rear rotor cover 31 according to FIG. 1. The air supply hole 65 is arranged in concentric fashion relative to the rotational axis 16 and in the disk-shaped air distributing means 61 , respectively. Three air-distributing grooves 62 extend from said hole in circumferential direction 60 at an equal distance, the grooves 62 being recessed in the visible surface of the air distributing means 61 according to FIG. 3 and laterally opened in the direction of air supply hole 65 (see also FIG. 1).
[0064] [0064]FIG. 4 is a partial view from the inside on the motor cylinder 2 in the area of a channel body 26 . An air inlet channel 24 and an air outlet channel 25 extend within the channel body over the total length thereof. Said channels are arranged in parallel with and spaced apart from each other in the channel body; see also FIGS. 5 and 6. On an inside 43 of the motor cylinder 2 , the two channels 24 , 25 are opened via slits 44 , 45 towards air rotor 3 ; see also FIGS. 5 and 6. The slits 44 , 45 extend approximately centrally relative to the channels 24 , 25 over part of their length.
[0065] [0065]FIG. 5 is a section taken along line V-V of FIG. 1. Identical parts are provided with identical reference numerals and are only mentioned in part.
[0066] [0066]FIG. 5 shows, in particular, the substantially triangular cross-section of the motor cylinder 2 , the triangle being an isosceles triangle with triangle sides 19 , 20 , 21 and corresponding triangle tips 13 , 14 and 15 ; see also FIG. 6. The rotational axis 16 extends through a point of intersection 17 of mid-perpendiculars 18 of the triangle sides 19 , 20 , 21 . In the area of the mid-perpendicular, see FIG. 6, the channel bodies 26 are arranged, each with an air inlet channel 24 and an air outlet channel 25 , on outsides 23 of the triangle sides 19 , 20 , 21 . The channel bodies are opened via their slits 44 , 45 towards air rotor 3 . A sealing web 46 with which the air rotor 3 is in tight contact is respectively arranged between the channels 24 , 25 .
[0067] A chamber 7 , 8 , 9 is formed between air rotor 3 and the corresponding triangle tips 13 , 14 , 15 , respectively. In the area of the triangle tips, an inner surface 22 of the motor cylinder 2 is convexly curved, and the corresponding curvatures have the same radius of curvature in the area of all triangle tips. In the area of the triangle sides 19 , 20 , 21 , the inner surface 22 is convexly curved to a smaller degree, the curvature, in particular in the area of the sealing web 46 , corresponding essentially to the corresponding curvature of the air rotor 3 on the outer circumference thereof.
[0068] In the illustrated relative position of rear rotor cover 31 to motor cylinder 2 , an air inlet 10 (see FIG. 2) is in communication with a corresponding air inlet channel 24 , whereas the remaining air inlets 11 (see FIG. 2 once again) terminate in chambers 7 , 8 , 9 . The air outlet channels 25 are in communication with the outlet recesses 36 as corresponding air outlet 12 ; see FIG. 2. The outlet recesses 36 are here arranged with an end 38 in the area of the opening of the air outlet channel 25 and extend up to their other end 39 in the area of the corresponding chambers 7 , 8 , 9 .
[0069] In the illustrated position of air inlets 10 relative to air inlet channel 24 , the air rotor 3 is rotated clockwise 40 (left-hand rotation). When the rear rotor cover 31 is rotated by about 900 relative to the motor cylinder 2 until the air inlets 11 communicate with the air outlet channels 25 , said air outlet channels serve as air inlet channels while the former air inlet channels 24 communicate with the outlet recesses 36 and serve as air outlet channels. In such a position of the rear rotor cover 31 , the air rotor 3 is rotated counterclockwise (right-hand rotation), i.e. opposite to the rotational direction 40 shown in FIG. 5; see FIG. 7.
[0070] As follows from the above, a connection of the chambers 7 , 8 , 9 is established via the outlet recesses 36 with the outlet gaps 37 and thus with the surroundings of the air motor 1 for discharging compressed air contained in the chambers and supplied via air inlet channels 24 .
[0071] As can in particular be seen in FIG. 5, the outer radius 42 of the air rotor 3 is substantially equal to the inner radius 41 (see FIG. 2) of the outlet recesses 36 . Furthermore, the air rotor 3 comprises eight longitudinal slits 5 in which a corresponding number of lamellae 6 are guided in radial direction. Two neighboring lamellae 5 are each arranged relative to one another at an angle 50 which is smaller than the mid-point angle 49 assigned to the length 47 of the outlet recess 36 ; see FIG. 2.
[0072] Two diametrically opposed lamellae have arranged thereinbetween a pressure spring which acts on the lamellae in radial direction from the outside; see FIG. 7. The distance between two of said diametrically opposed lamellae remains relatively constant because of the inner contour of the motor cylinder 2 , so that the spring lift is relatively small and the spring shows fatigue strength.
[0073] In FIG. 5, as an alternative to the pressure springs 57 according to FIG. 7, the rear rotor cover 31 is formed with the compressed air recesses 59 which, being partly radially inwardly offset with respect to the extended lamellae 6 , are visible in the longitudinal slits 5 . These serve the supply of compressed air into the slits and thus to extend the lamellae.
[0074] The three sealing lines between air rotor 3 and motor cylinder 2 , see the corresponding sealing webs 46 , separate supply air from exhaust air accordingly. A radial air between air rotor and motor cylinder is here as small as possible. A positional definition of the motor cylinder is taken over by the air rotor itself and an outer centering, e.g., in a housing, leads to an overdefinition of the installation position of the motor cylinder due to dimensional tolerances.
[0075] [0075]FIG. 6 shows a section, analogous to FIG. 5, only through the motor cylinder 2 . Reference is made to the description in connection with the preceding figures.
[0076] [0076]FIG. 6 shows, in particular, how mid-perpendiculars 18 of the triangle sides 19 , 20 , 21 intersect at a point 17 corresponding to rotational axis 16 . In particular in the area of the corresponding base points of the mid-perpendiculars 18 , the triangle sides are convexly curved on the inside 22 of the motor cylinder 2 , said curvature corresponding in particular in the area of the corresponding sealing webs 46 to the outer curvature of the air rotor 3 .
[0077] The outer contour or outer surface 27 of the motor cylinder 2 extends in the area of the triangle tips 13 , 14 , 15 and the corresponding channel body 26 in curved fashion along a circular line 28 with diameter 29 ; see FIG. 1.
[0078] [0078]FIG. 7 shows a section, analogous to FIG. 5, for a right-hand rotation of the air rotor 3 . Identical parts are provided with identical reference numerals, and reference is made to the description regarding FIG. 5.
[0079] [0079]FIG. 7 differs from FIG. 5 substantially only by the features that in the longitudinal slits 5 springs 57 are arranged for exerting pressure on the lamellae radially outwards, and that the rear rotor cover 31 is rotated by about 90° relative to the position according to FIG. 5 in anticlockwise direction.
[0080] The function of the three-chamber air motor 1 according to the invention shall now be explained in a few words with reference to the figures.
[0081] In the position according to FIG. 5, compressed air is supplied to the chambers 7 , 8 , 9 via air inlets 10 (see FIG. 2) and, accordingly, air inlet channels 24 with slits 44 . Due to the compressed air acting on the lamellae 6 next to the air inlet channels 24 , the air rotor 3 is rotated in rotational direction 40 ; see FIG. 5.
[0082] Upon rotation of the air rotor 3 , a lamella trailing in the rotational direction finally comes into abutment with the slit 44 and, upon further rotation, is acted upon in rotational direction 40 by the compressed air supplied via the slit. The lamella arranged upstream in rotational direction 40 reaches outlet recess 36 , so that compressed air contained in the corresponding chamber can escape behind said lamella 6 via the outlet recess and the corresponding outlet gap 37 radially to the outside from the air motor 1 ; see FIG. 1.
[0083] By analogy, the compressed air supply and compressed air discharge, respectively, takes place in the other channel bodies 26 .
[0084] When the air inlets 11 (see FIG. 7) are brought into communication with the air outlet channels 25 by rotating the rear rotor cover 31 by about 90° relative to the motor cylinder 2 , the air outlet channel becomes the air inlet channel and the former air inlet channel becomes the air outlet channel communicating with the corresponding outlet recess, the corresponding lamellae being acted upon by compressed air in a direction reverse to the former rotational direction 40 according to FIG. 5.
[0085] Thanks to the three-chamber air motor, there is a lower motor speed than in a two-chamber air motor, so that corresponding exhaust air throttling measures are no longer needed, in particular in screwers of the non-switching-off type. At the same time, the accelerating power is very uniform due to the three chambers and the corresponding number of lamellae, resulting in an increase in torque in comparison with the two-chamber air motor. Since the three-chamber air motor is also running evenly, an oil-free running is quite likely, resulting in an advantageous self-centering of the air rotor with reduced sound level.
[0086] The present invention may, of course, be carried out in other specific ways than those herein set forth without departing from the essential characteristics of the invention. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, and all changes coming within the meaning and equivalency range of the appended claims are intended to be embraced therein. | An air motor, especially for a screwer, comprises an air rotor which is rotatably supported in a motor cylinder and comprises a plurality of longitudinal slits extending in the longitudinal direction of the rotor for radially guiding lamellae, the air rotor and motor cylinder having formed thereinbetween chambers which can be brought into communication with an air inlet and/or an air outlet. To achieve a high efficiency of the motor together with a more uniform accelerating power, a reduced sound level and less wear while the exhaust air throttling measures are reduced at the same time, the motor cylinder comprises an inner chamber of an essentially triangular cross-section, one chamber each being formed between air rotor and a triangle tip. | 1 |
BACKGROUND OF THE INVENTION
This invention relates to packaging container blanks. More particularly it relates to one-piece (i.e., integral) packaging container blanks which are particularly suited for holding products wound around a central core (sometimes referred to hereinafter as roll goods). Such blanks may also be referred to as one-piece folder blanks.
Packaging container blanks as such have been used previously. In general they comprise a section of material (e.g., corrugated paperboard) which may be folded so as to form the top, bottom and sides of a completed container. In the simplest sense only two sides of the package are formed when a previously known blank is folded, the remaining sides being open. Conatainers or packages formed from this type of blank are less sturdy than those wherein all four sides of the container are closed. Additionally, these container blanks, whether providing two or four closed sides when folded, require that some additional means or techniques be employed when centering roll goods on the blank prior to forming the carton therearound. This requirement for additional centering means, of course, reduces the efficiency and adds to the cost of any packaging operation employing such cartons.
Various attempts have been made to strengthen the completed carton while improving the efficiency of the packaging operation at the same time. Thus, for example, centering means which rise from the plane of the blank and are permanently affixed thereto have been previously proposed. However, this approach has not proven entirely satisfactory because the raised centering or positioning means increases the height of the blank, thereby requiring the use of additional space when a plurality of such blanks are stored. Morever, the raised positioning means makes it difficult to provide a stable stack of such blanks.
Other previously used container blanks employ core-locking tabs which fit inside the core of roll goods to be packaged. Such tabs are typically provided as extensions of the closure flaps of the blank. As such they provide no means for easily and accurately locating the roll goods on the blank prior to forming the carton. Additionally they tend to slide toward each other after they have been inserted into the center area of the core, thereby necessitating a locking insert to be placed between them to hold such tabs securely after the package has been made. This reduces the efficiency and increases the cost of the packaging operation. It also adds to the cost of the formed container.
These and other disadvantages of the prior art are overcome by packaging container blanks of the present invention. Such blanks comprise a flat, one-piece construction. Thus, the novel blanks require relatively little storage space per unit and may be easily collected in stable stacks in their unfolded state. Additionally, blanks of the invention may be easily formed into crush-resistant cartons. Moreover, they provide means for quickly and accurately centering roll goods thereon prior to forming the carton.
Containers made from blanks of the invention can be used to package a variety of materials. Representative of these materials are tapes (e.g., masking, cellophane, adhesive, etc.), film adhesives, decorative ribbons, windshield sealers, etc.
SUMMARY OF THE INVENTION
In accordance with the present invention there is provided a packaging container blank comprising a rectangular central section, two outer panels attached to opposite edges of said central section and two flange panels attached to the other opposite edges of said central section;
wherein said central section includes at least one tab hinged on one edge thereof to said central section and lying in the plane of said central section, the remaining edges of said tab being severed from said central section, said tab being adapted to be disposed normal to the plane of said central section at a predetermined height;
wherein each of said outer panels and said flange panels are foldable along the edges of said central section and are further foldable along predetermined lines parallel to the edges of said central section; and
wherein each of said outer and flange panels are adapted to form right angles at the edges of said central section and at said predetermined lines when folded, and wherein the portions of said outer panels and of said flange panels between the edges of said central section and said predetermined lines form the sides of said packaging container upon folding; and wherein a portion of said flange panels are adapted to extend over said folded outer panels.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention is described in more detail hereinafter with reference to the accompanying drawings wherein like reference characters refer to the same parts throughout the several views and in which:
FIG. 1 is a plan view of a preferred embodiment of a packaging container blank according to the present invention.
FIG. 2 is a sectional view of a partially formed container made from the blank of FIG. 1, said view being along the line 2--2 of FIG. 1.
FIG. 3 is a sectional view of a completely formed container made from the blank of FIG. 1, said view being along the line 3--3 of FIG. 1.
FIG. 4 is a perspective, partial cut-away view of a completely formed container made from the blank of FIG. 1.
DETAILED DESCRIPTION OF THE INVENTION
Referring now to FIG. 1, there is shown a preferred embodiment of a blank 10 for a packaging container comprising a rectangular central section 12, two outer panels 14 attached to opposite edges of central section 12 and two flange panels 16 attached to the other opposite edges of central section 12.
Situated within the plane of central section 12 are two tabs 18 which are hingeably fixed to said section along one of their edges at lines 19. The remaining edges of tabs 18 are severed from central section 12 along lines 20.
Tabs 18 are adapted to fold at lines 19 so as to project normal to the plane of central section 12. The foldability of the tabs may be facilitated by scoring or creasing central section 12 along lines 19. Preferably tabs 18 are adaptable to project a predetermined distance A' equal to the interior height of the desired formed container so that portions 14a of outer panels 14, in folded form, rest on tabs 18 as shown in FIGS. 2, 3 and 4. In this configuration tabs 18 provide added structural strength to the formed container and, additionally, provide means by which roll goods may be quickly and accurately aligned on blank 10 prior to forming the completed container. Moreover, they prevent lateral movement of the goods positioned thereon. Consequently, the risk of damage to the roll goods during handling and storage of the completed package is minimized.
While the embodiment set forth in the figures illustrates the use of two tabs, the use of one or more than two is also possible and such use is included within the scope of the invention.
Outer panels 14 and flange panels 16 are foldably attached to the edges of central section at lines 21. Panels 14 and 16 are also foldable along lines 22, which lines are parallel to the edges of central section 12. The foldability of panels 14 and 16 may be improved by scoring or creasing said panels along lines 21 and 22.
Outer panels 14 are adapted so that when folded they may form right angles at lines 21 and 22. It is preferred that edges 15 of the panels abut each other after folding of the panels. When in this configuration, the portion of the panels 14 between lines 21 and 22 defines two opposite sides 24 of the formed carton. Distance A is preferably equal to the distance A' of tabs 18 so that, as discussed above, portions 14a of panels 14 may rest upon tabs 18 in the formed carton.
Flange panels 16 are adapted so that, when folded, they also may form right angles at lines 21 and 22. Additionally, portions 16a of said flange panels extend over portions 14a of the folded outer panels 14 forming flaps thereon as is shown in FIGS. 3 and 4. When so folded, the portions of the flange panels 16 between lines 21 and 22 define the remaining opposite sides 26 of the carton. Distance B is preferably equal to the distance between lines 21 and 22 on panels 14 plus the thickness of one of panels 14.
In a particularly preferred embodiment of the present invention, the width of panels 16 at lines 21 is slightly less than the width of central section 12. However, panels 16 quickly widen out from lines 21 as shown in FIG. 1 so that they are slightly wider than central section 12. This enables panels 16 to substantially completely close the side corners of the formed carton. Additionally, it is preferred that the outer corners of panels 16 be removed as shown in the drawings.
While the embodiment set forth in FIGS. 3 and 4 shows that panels 16 are smaller than panels 14, larger panels are intended to be included within the scope of the present invention.
A number of additional features may be incorporated into the packaging container blank of the invention, if desired. For example, the surface of the blank which is to serve as the interior of the formed carton may have a continous release coating thereon so as to prevent the contents of the carton from sticking to the insides of the carton. Such release coatings are well known and include, for example, silicone-based compositions such as "Sly-Off", commercially available from Dow Corning, and "Bay-cote 470", commercially available from Green Bay Packaging Inc.
Other features that may be included in the blank of the present invention, if desired, are shown in FIG. 1 and include (i) an indexing means 28 comprising, for example, a notch in the edge of the panel 14 for uniformly and accurately positioning a plurality of blanks 10 and (ii) perforations 30 for improving adhesion between panels 14 and 16 when an adhesive is applied therebetween.
As shown in FIG. 1, indexing means 28 is located in one of panels 14 and comprises a triangular notch in the edge of that panel. The location and shape of indexing means 28 is not critical to the present invention, and, accordingly, it may instead be located in any of the other panels and may have any of a variety of useful shapes.
The perforations shown in FIG. 1 comprise a plurality of regularly occurring punctures in panels 16. Preferably they extend into panels 16 without going completely through such panels. While the perforations may be arranged in a variety of configurations, that shown in FIG. 1 is preferred.
Blank 10 may be constructed from any of a variety of known materials. Representative of such materials are corrugated paperboard, chipboard, fiberboard, corrugated polyethylene, expanded polystyrene, etc. A preferred material is corrugated paperboard.
Blank 10 may be manufactured by a variety of techniques. A particularly useful technique comprises die-cutting the blank from a large sheet of the material of construction.
The packaging container blank described in the Figures is but one embodiment of the invention. Other embodiments are also possible, as will be understood by those skilled in the art, and are all included within the scope of the following claims. | A packaging container blank comprising a rectangular central section including at least one tab therein which is hinged on one edge to the central section, the remaining edges of said tab being severed from said central section. Two outer panels are attached to opposite peripheral edges of the central section, and two flange panels are attached to the other opposite edges of the central section. The blank is adapted to be folded into the form of a container. | 1 |
[0001] This application claims priority of U.S. Provisional Application No. 61/783,280 filed with the US Patent and Trademark Office on Mar. 14, 2013, the entire contents of which is herein incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to animal husbandry practices in general and, more specifically, to a method for preventing certain diseases and alleviating symptoms of certain disease states, particularly those resulting from PEDv, resulting in improved health of the animal.
BACKGROUND OF THE INVENTION
[0003] Electrolyzed water including its characteristic ions may be formed by one of several ways. One of the several ways comprises adding a small amount of sodium chloride (NaCl) to pure distilled water, and conducting a current through it across an anode and a cathode. The cathode area attracts the sodium ion and produces basic water, while the anode area attracts the chlorine ion and produces acidic water. In this process, hydrogen gas and hydroxide ions are produced at the cathode, leading to an alkaline solution that consists essentially of sodium hydroxide. At the anode, chloride ions are oxidized to elemental chlorine. If some of this chlorine is allowed to combine with some of the hydroxide ions produced at the cathode, it disassociates into hypochlorous acid, a weak acid and an oxidizing agent. The “acidic electrolyzed water” can be raised in pH by mixing in the desired amount of hydroxide ion solution from the cathode compartment, yielding a solution of sodium hypochlorite NaClO which is the major component of ordinary household laundry bleach. For example, a solution whose pH is 7.3 will contain equal concentrations of hypochlorous acid and hypochlorite ion; reducing the pH will shift the balance toward the acid.
[0004] Because electrolyzed water may have a short shelf life depending on the method by which it is made and several other factors, the widespread use and production of electrolyzed water have been impractical and somewhat unfeasible. Electrolyzed water has been certified for medical use in Japan since the mid-1980s. Most often, it is sold and used in either the basic form or the acidic form.
[0005] The first type of electrolyzed water which was used was the acidic type, which was accepted quickly by the Japanese food industry. It was useful for killing bacteria and parasites in raw fish without compromising its quality. Alkaline water was developed next, and it was used in hospitals to alkalize the body and as an “energy enhancer”.
[0006] Diseases in animal herds have always been problematic for herdsmen. Although diseases and health problems occurred when animals such as swine, cattle, chickens, and horses were reared mostly outdoors, since the advent of confined growth and production of these animals in confinements housing hundreds of animals, the incidence, threat and spread of disease has increased astronomically. The negative effects of disease are magnified by the speed with which contamination can spread both within and between confinements.
[0007] It has long been known that disease often travels via animal to animal contact, perhaps through shared watering or feeding equipment and container or via airborne transfer. It is also theorized—and in some cases known—that air quality in general may affect the overall health, feed to gain ratio, or feed intake of the animals in addition to exacerbating symptoms of certain disease states.
[0008] Some disease examples that plague producers of swine and are related in some way to environmental transmission include the following, several of which include symptoms that may be reduced or contamination that may be mitigated by the uses of electrolyzed water as taught by the current invention:
[0009] Arthritis: Arthritis can cause heavy losses of hogs. The disease may result from a variety of causes including Streptococcus bacteria, erysipelas and injury. It is thought that keeping hogs on damp, cold or rough surfaces may contribute to arthritis. Symptoms include lameness, swollen, hardened joints and stunted growth. Arthritis is treatable with antibiotics if caught in the early stages and there are vaccines for arthritis caused by erysipelas and Streptococcus.
[0010] Bordatella Rhinitis is caused by an infection of the nasal cavity of hogs by Bordatella bronchiseptica, an organism that gets onto open scratches or wounds in the nose or mouth. It can be transmitted from sow to piglet. Symptoms include sneezing and a general failure to thrive. Treatment with antibiotics may be effective. A vaccine is available.
[0011] Circovirus: Porcine Circovirus Disease (PCVD) or Circo is a viral disease that has become a major problem in the United States. Caused by Porcine Circovirus Type 2 (PCV2), not all pigs develop clinical signs of the disease but most swine are infected. Symptoms, duration and mortality can vary by herd. Symptoms can include enlarged lymph nodes, skin rashes, difficulty breathing, jaundice, fever, stomach ulcers and diarrhea. Risks include poor growth, weight loss and weakness with increased chance of mortality between 5 to 14 weeks. There is a vaccine available.
[0012] Clostridium Enteritis: This disease is found among piglets less than a week old and is caused by the bacterium Clostridium perfringens Type C. Symptoms include yellow, pasty diarrhea, weakness and trying to be near a warm place. It is spread through piglet to piglet contact and infected feces of the sow. Treatment with antibiotics is possible, but most survivors will be permanently stunted. Vaccination is available for pregnant sows and gilts prior to farrowing.
[0013] Erysipelas: This very common hog disease is caused by the bacterium Erysipelothrix rhusiopathiae, found in almost every pig farm. Up to half of animals carry it. It is nearly always present in the pig environment and spreads through saliva, feces or urine. It comes on suddenly. It is most often caused by poor hygiene. Treatment is penicillin. A vaccine is available to be given at 3 weeks of age and older.
[0014] Flu: Swine Influenza Virus can be passed by infected pigs, birds or humans. This disease can be dramatic with a rapid onset in 12 to 48 hours. Symptoms include coughing, fever, loss of appetite and pneumonia. Infertility can result in sows and the high fevers can cause abortions. Vaccination is available.
[0015] Greasy Pig Disease: The disease is caused by the bacterium Staphylococcus hyicus which lives normally on the skin without causing disease. This bacterium is normally present on the skin, but in the disease state the bacterium causes dermatitis and oozes greasy fluid. The toxins produced are absorbed and can damage the liver and kidneys. In the sucking piglet disease is usually confined to individual animals, but it can be a major problem in new gilt herds and weaned pigs. Treatment includes antibiotics, disinfecting by washing the infected skin, and disinfecting the confinement and crates after a litter is emptied.
[0016] Ileitis: A common ailment in swine of all ages and especially in pigs that have been recently weaned. Symptoms include inflammation of the small and/or large intestine, diarrhea and stomach distress. Stress is often listed as a cause for this illness. Vaccination through drinking water is available.
[0017] Leptospirosis: Caused by the bacterium Leptospira. Symptoms include loss of condition and reproduction problems. It's difficult to eradicate once started as it spreads by mouth, urine, wallows, feed, water, venereal transmission and contaminated surfaces. Treatment with antibiotics is recommended; there is also a combination vaccine available.
[0018] Mycoplasmal Pneumonia: Symptoms include coughing and difficulty breathing. Caused by bacteria and highly contagious, it can be spread by air, contaminated surfaces, pig to pig, feed and water. Treatment with antibiotics is recommended; vaccination is available.
[0019] PEDv: (Porcine Epidemic Diarrhea Virus): Introduced into the US from elsewhere this virus appeared in multiple, widely distributed sow herds within days, implying a common point-source origin. The virus in the US is 99.4% homologous with that in China in 2012, it has spread to 20 states as of this date, and producers can expect losses of up to 100% of piglets 3 weeks and less of age. Present recommendations for management of infection include fully infecting the herd to accomplish immunity. Infected pigs exhibit symptoms such as watery diarrhea for a week to 10 days before recovering. The incubation time of the disease from contact to symptomatic is thought to be between about 22 and 36 hours; 2-4 days at herd level. Neonatal pigs in a farrowing unit often experience death rate at 100%. In general, the younger the animals the higher the risk of death. In hog production operations, the virus can spread rapidly and cause increase in costs and time to production at best, and, at worst, death rates that can be debilitating for the producer. Almost always, pigs that have suffered PEDv and survived will be sold at measurably lighter weights in order to clear the confinement on schedule, costing the producer thousands of dollars. It is believed that PEDv (and its major symptom) negatively affects feed to gain ratios.
[0020] Porcine Parvovirus: This one is probably the most common cause of infectious infertility in hogs. There are rarely any clinical symptoms except stillbirths, mummified piglets and small litters due to loss of embryos in the womb. Unlike most viral infections, Porcine Parvovirus can live in soil and on surfaces for months. It's resistant to most disinfectants. Once a pig has had it, there is a lifelong immunity. There is no treatment, but vaccine is available.
[0021] PRRS: Porcine Reproductive & Respiratory Syndrome. Production losses can be attributed to reduction in farrowing rate, reduced number of live births/increased stillbirths, poor reproduction in gilts and early farrowing. Symptoms include a reluctance to drink, loss of appetite in sows at farrowing, blueing of the ears, respiratory signs and coughing, no milk and lethargy. This disease first classified in 1991. Vaccine is available.
[0022] Rotavirus: Rotavirus is widespread in almost all pig populations. Symptoms include diarrhea, dehydration, sunken eyes and wasting. Rotavirus is usually caused by poor hygiene, temperature fluctuations and contaminated boots and clothing. Vaccine is available.
[0023] Scours ( E, coli /Clostridium perfringens type C): Scours or baby pig diarrhea is the most common disease among baby pigs. While scours can occur at any age during nursing, there are often two peak periods- before 5 days and between 7 and 14 days. Scours causes severe production losses as well as substantial death losses. Vaccination is available for pregnant sows and gilts prior to farrowing.
[0024] TGE: Transmissible gastroenteritis (TGE) in swine is known to be one of the most significant diarrhea-producing diseases in young pigs. The TGEV is vulnerable to sunlight and various disinfectants such as sodium hypochrolite or iodines. It causes high morbidity/mortality in pigs less than two weeks of age. Many pigs older than three weeks of age will survive but are likely to remain stunted. Anti-biotic treatment is not indicated; vaccine is not typically employed. Good biosecurity and cleaning is recommended.
[0025] About 140 diseases are listed at “www.thepigsite.com” including recommended treatments and preventative measures. In short, there are dozens of diseases and/or conditions that swine might suffer and nearly all of them are exacerbated by confinement growth. Further, there are many that include gastrointestinal symptoms such as diarrhea. Unchecked diarrhea can and does cause death and/or failure to thrive of thousands of hogs every year. By raising hogs in confinements, diseases causing such symptoms can spread through a herd in a matter of only a few days, can result in up to 100% death for neonatal piglets, and cause high rates of death in grow finish operations as well as sows.
[0026] Cattle diseases of interest include, but are not limited to, the following:
[0027] Clostridial diseases caused by bacteria are blackleg, red water, enterotoxemia and tetanus. Sudden death is often the first and only sign of these cattle diseases.
[0028] Respiratory diseases or BRD also known as “shipping disease” or “shipping fever” are the costliest of all cattle diseases, resulting in poor gains and a weakened immune system. Coughing, nasal discharge, fever and difficulty breathing are among the symptoms of these cattle diseases.
[0029] Scours or diarrhea is a common cattle disease that often affects baby calves. Animals that survive this cattle disease often remain weak and perform poorly throughout their lives.
[0030] Although cattle are more often raised outdoors, a number of the aforementioned diseases might be addressed by ingestion through common watering equipment, or by topical treatment of animals, if a substantially whole body treatment regime could be devised. And it would be desirable to reduce infection and transmission that occurs by contamination of water containers, equipment or barn interiors.
[0031] Although vaccine and/or treatment for many of the most common communicable or environment specific diseases of swine, cattle and poultry have been developed, it is not feasible to administer all vaccines to a single animal. The vaccines come with an economic price as well as a cost in labor and effort. They are often not immediately effective and, therefore, may be a wholly unnecessary cost for a herd that is never exposed. More importantly, many common diseases can be prevented through a solid program of good hygiene and animal husbandry, control of flies and biting insects, and selective vaccination when possible and feasible. Some cattle diseases might be addressed by body surface treatment, through watering facilities, or, where barns or other confinement arrangements are employed, good hygiene and animal husbandry may have a positive effect. Many poultry diseases and swine diseases may, likewise, be addressed by hygiene or treatment protocols for the confinement and its atmosphere.
[0032] What was needed was a simple, inexpensive, and effective means to improve air quality in animal confinements and reduce symptoms of respiratory and gastrointestinal diseases. Further, for animals outdoors there was a need for a full body treatment to reduce presence of certain viral or bacterial load on the animal's skin and/or fur for reduction of the rate of transmission and infection.
[0033] A first objective of the present invention was to provide a means to reduce viral or bacterial load on surfaces or in the air;
[0034] A second objective of the present invention was to provide a means to reduce symptoms of respiratory distress or other causes of animal distress associated with disease state or poor air quality;
[0035] A third objective of the present invention was to .provide a simple means to reduce bacterial load for livestock;
[0036] A fourth objective of the present invention was to provide means to administer an anti-viral or anti-bacterial to livestock via respiratory therapy;
[0037] A fifth objective of the present invention was to provide means to reduce virus and bacterial levels on the skin or fur of infected or carrying animals;
[0038] A sixth objective of the present invention was to provide means to reduce dehydration of a diseased animal;
[0039] A seventh objective of the present invention was to provide an oral treatment, easily administered, for the management of the symptoms associated with PEDv or TEG, predominantly watery diarrhea and ensuing dehydration;
[0040] An eighth objective of the present invention was to provide an oral treatment, easily administered, for reducing the days to recovery and to minimize weight loss of an animal infected with PEDv in order to generally preserve life, time to market, and feed to gain ratio;
[0041] A ninth objective of the present invention was to provide a method for reducing risk and recovery time during intentional exposure of a herd to PEDv.
[0042] A tenth objective of the present invention was to provide a method for full herd exposure to reach endemic status and full immunity while at the same time minimizing loss of life, reducing time to recovery, and reducing symptoms and their effects.
SUMMARY OF THE PRESENT INVENTION
[0043] The present invention delivers electrolyzed water, preferably but not necessarily near neutral pH or slightly basic, orally. The invention covers delivery of electrolyzed water, preferably near neutral pH or slightly basic, in liquid form for ingestion, typically administered through drinking water. As a matter of review of information well-known in the art, and not as a point of novelty:
[0044] In pure water electrolysis:
[0045] Cathode (reduction): 2 H 2 O(l)+2e − →H 2 (g)+2 OH − (aq)
[0046] Anode (oxidation): 4 OH − (aq)→O 2 (g)+2 H 2 O(l)+4 e −
[0047] Combining either half reaction pair yields the same overall decomposition of water into oxygen and hydrogen. Overall reaction: 2 H 2 O(l)→2 H 2 (g)+O 2 (g)
[0048] Addition of chlorine to water gives both hydrochloric acid (HCl) and hypochlorous acid (HClO): Cl 2 +H 2 O HClO+HCl
[0049] When chlorine is added to the water for electrolysis in the form of sodium chloride, the sodium salt of hypochlorous acid is formed. NaCl+H 2 O+electricity-->NaOCl+H 2
[0050] This same general reaction occurs for several other salts when present during electrolysis of water.
[0051] When acids are added to aqueous salts of hypochlorous acid (such as sodium hypochlorite in commercial bleach solution), the resultant reaction is driven to the left, and chlorine gas is evolved. Thus, the formation of stable hypochlorite is facilitated by dissolving chlorine gas into basic water solutions, such as sodium hydroxide.
[0052] The oral delivery of electrolyzed water is intended to be used in confinements where animals such as swine and poultry are raised. Further, oral delivery in stables and barns where any animals such as horses, sheep, goats, and other animals are housed may be beneficial to the health of these animals, as well. Finally, oral administration through drinking water facilities, where present for outdoor herds, is also expected to have effect.
[0053] Animals suffering from disease states that cause gastrointestinal or respiratory symptoms, such as but not limited to PEDv or TEG, and to which electrolyzed water at or near pH neutral and slightly basic, for example, pH about 6 to about 9 or pH between about 7 and about 9, is orally administered recover much more effectively and quickly from these illnesses above than animals to which it is not administered. Their symptoms are reduced in severity and duration. Time to recovery is shortened. Feed to gain ratio is generally preserved or at least does not suffer to the degree of that of untreated animals and time to market can be mostly preserved. Yet, immunity comparable to untreated animals is achieved.
[0054] In the present invention, the fluid form of electrolyzed water is administered as drinking water or in certain concentrations in the drinking water for animals suffering the effects of a gastrointestinal disease such as PEDv or TEG. The benefits of ingesting electrolyzed water include improved hydration and lessening of symptoms such as diarrhea; reduction in symptomatic behavior such as lethargy, faster return to normal food intake, and reduction in time to recovery. For some disease states where electrolyzed water is both ingested and inhaled, benefits may be greater. The combined method of administration may show effects that are faster, or more dramatic, or both.
[0055] In another embodiment, the fluid form of electrolyzed water or the misted form may be used as a cleaning and/or rinsing agent on surfaces in the confinement or surfaces otherwise in contact with animals, for the equipment used with animals, and for the clothing worn by animal husbandry practitioners. Where a mist or vapor is administered, surface application is also accomplished, at least to a degree.
[0056] In another embodiment the fluid form or the misted form may be used to disinfect the skin and/or hair and/or feathers and/or fur of the animals to reduce viral or bacterial load thereon, for reducing rate of transmission and infection of the herd or group. Again, where a mist or vapor is administered, it is believed that animals present in the mist will benefit at least from a reduction of viral or bacterial load on the animal's skin, hair or fur. While there is a school of thought that advises infecting the whole herd to create immunity, surface disinfection is equally important, for minimizing transmittal of disease from farm to farm. Trailers, tires, boots, equipment, and vehicles can all be washed or soaked in the electrolyzed water as a means of minimizing or even eliminating viral transmissions.
[0057] In a final embodiment, the fluid form of electrolyzed water is combined with manure in a manure pit either by addition to the pit, or through addition along with the manure to the pit. For diseases primarily transmitted by oral fecal route, removal of manure and decontamination of it via application of electrolyzed water either prior to removal or after, will assist in minimizing transmission.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0058] The present invention comprises application of electrolyzed water for the purpose of killing certain bacteria and viruses and for the purpose of decreasing gastrointestinal symptoms such as diarrhea and for increasing ease of breathing in animals suffering from a respiratory illness and alleviating other symptoms related to animal illness. Specifically in the present invention, electrolyzed water is employed for reducing severity of symptoms associated with PEDv such as diarrhea. The reduction of the severity of diarrhea lessens the degree of dehydration of the animal and lessens the time to recovery. This, in turn, can result in generally maintaining time to market and generally maintaining feed to gain ratio or at least providing an improvement compared to untreated animals. It is widely held that animals that die as a result of PEDv or become so sick as to never fully recover from PEDv do so mostly as a result of dehydration due to prolonged diarrhea. Therefore, alleviating this symptom can drastically improve the outlook for an infected animal, and an infected herd.
EXAMPLE 1
[0059] As a method for alleviating symptoms of PEDv or TEG, electrolyzed water (typically, electrolyzed tap water and/or electrolyzed water where hypochlorous acid, sodium hydroxide, and sodium hypochlorite are present, ideally between about pH 6 and about pH 9, or between about 7.5 and 9, or between about pH 8 and about pH 9) was administered through drinking water. In tests, dilutions of drinking water between about 0.5% electrolyzed water and about 1.5% electrolyzed water in drinking water were provided to pigs in place of drinking water through the normal equipment employed for delivering drinking water.
[0060] Pigs under about 40 pounds were less likely to drink the higher concentrations; pigs above about 40 pounds drank the higher levels of concentrations. Adding more electrolyzed water is not expected to reduce its benefits and higher concentrations may be even more effective. Full strength electrolyzed water is nontoxic. However, it is suspected that certain animals are more sensitive to the taste of the higher concentrations of alkaline water and that it is less palatable to the animals. In order to obtain the benefit of the electrolyzed water, a certain amount of fluid needs to be ingested overall, along with the electrolyzed water. Therefore, where an animal is more sensitive to taste, resulting in less electrolyzed water being ingested, a lower dose may be used.
EXAMPLE 2
[0061] In a first trial, pigs suffering from symptoms of PEDv at about 200 pounds were provided drinking water having about 1.5% electrolyzed water (typically, electrolyzed tap water and/or electrolyzed water where hypochlorous acid, sodium hydroxide, and sodium hypochlorite are present, ideally between about pH 6 and about pH 9, or between about 7.5 and 9, or between about pH 8 and about pH 9). About 48 hours after treatment via drinking water the diarrhea ceased. Within 1 week of beginning treatment, the pigs no longer tested positive for the disease. At 230 pounds these same pigs were again tested, and again all were negative.
EXAMPLE 3
[0062] In a second trial, pigs ranging from about 7 pounds to about 45 pounds were treated after testing positive for PEDv and exhibiting classic symptoms including watery diarrhea and lethargy. These animals were provided drinking water comprising about 0.5% electrolyzed water. Within 48-72 hours the symptoms ceased. Observers noted the pigs also began acting normal rather than lethargic, and ate and drank normally. No deaths were reported in this group, even for the 7 pound young piglets.
EXAMPLE 4
[0063] Drinking water in hog confinement when disease was present was supplemented with electrolyzed water at a rate of 40 gallons/210,000 gallons or about 1 gallon per about 525 gallons. The animals consistently drank more than in the nontreated confinements and symptom reduction was both faster and more pronounced.
EXAMPLE 5
[0064] Cattle suffering from shipping fever were treated by irrigating nostrils with 10 cc's of electrolyzed water on day 1, and 5 cc's per day on days 2-5, and was added to drinking water. The symptoms cleared faster than in untreated animals and the transmission/infection rates were reduced.
EXAMPLE 6
[0065] A 50% electrolyzed water solution was tested. The electrolyzed water was made by neutral electrolysis creating water with a pH of between about 7.5 and about 9. The solution killed E Coli , PRRS virus, Staphylococcus aureus, Salmonella enterica by contact. This solution, or one somewhat stronger or weaker, can be used as an electrolyzed water solution for a pre-soak or as a cleaning agent for barn turn over or crate cleaning, stall cleaning, and other cleaning purposes.
EXAMPLE 7
[0066] Day 1 1st sign of PED appeared on one side of the confinement. Observed 1 pig scour. Started treatment of whole confinement same day. Treatment included replacing normal drinking water with electrolyzed water where hypochlorous acid, sodium hydroxide, and sodium hypochlorite are present, between about pH 8 and about pH 9.
[0067] Day 2 PEDv symptoms appeared in 6 more pens. But symptoms were not severe. Most pigs in pens that are affected still seem to be pretty clean. Roughly drank 8 gallons of treatment/pig. Animals appeared comfortable and not in distress.
[0068] Day 3 Do not see evidence of spread of virus to other pens. Seems that consumption of treated water spiked the first day and then gradually declined. Day 1 water increased 151 gallons. Day 2 dropped back 94 gallons/day. Day 3 dropped another 20 gallons.
[0069] Day 4 PED spread to 3 more pens. Most stools in pens were still solid. Pens that had PED initially (as observed on Day 2) now appear to be getting over the virus. Pigs look exceptionally good for day 3 after PED, No deads, No skinny. May want to consider 50/50 solution; treated barrel was not empty today. 100% solution may be too strong.
[0070] Day 5 Couple more (pens) broke today. Looks as though pens that broke on Day 2 are firming up. First 3-5 pens inside door on south side has gotten worse but everything else looks the same or a little better. Water consumption is going back up the last couple of days. (Total: 1 dead).
[0071] Day 6 about same as Day 5
[0072] Day 7 Looks as though it's almost cleared up. (Total: 1 dead).
[0073] Day 8 Pigs look good. Can't see any signs of PED.
[0074] In short, the treatment of all pigs, infected and uninfected, seemed to reduce both severity of symptoms and the duration of the disease dramatically from the statistical expectations. This experiment did not determine the rate of infection so it cannot be said whether the treatment reduced infection or just reduced the effects and appearance of the symptoms in animals that were infected.
EXAMPLE 8
[0075] Treated Over the Course of Four (4) Days
[0076] Before Treatment: Before treatment the pigs were very inactive and un-responsive to a person being in the pen with them or to their mate, feeding and things of that sort. Pigs laid and acted very sick and weak.
[0077] Treatment; The treatment given to the pigs was a 50/50 mixture of the experimental product (electrolyzed water including hypochlorous acid, sodium hydroxide, and sodium hypochlorite) and normal drinking water which was provided to the pigs ad libitum in a canoe type gruel feeder. Treatment was given to the pigs for approximately 4 days. Water mixed with the experimental product was medicated water that had Pennchlor and Denguard in it. Size of the pigs that were treated varied from 10-20 lbs.
[0078] After Treatment; After the 4 day treatment the pigs seemed much better in the way they acted. They were eating and drinking more and were active and responsive when a person entered the pen with them. They looked as if they had put weight on and just acted healthier in general
EXAMPLE 9
[0079] An infected production facility, which was losing about 50 pigs per day to a PEDv outbreak, reported pigs lethargic and neither eating nor drinking in any measurable amounts. The barn was treated in the evening with a 50/50 solution of electrolyzed water and again at 4:00 am with full concentration. The hogs drank the treated water in quantity; no additional deaths occurred and the barn recovered in a matter of a few days.
EXAMPLE 10
[0080] PEDv broke out in a production facility of 3000 head of hogs. The animals were scheduled to go to market just before Christmas. Became infected with PEDv before Thanksgiving; the producer was instructed to destroy the herd, On Thanksgiving Day the drinking water of the herd was dosed with 70 gallons of electrolyzed water, near neutral pH between about 7.5 and about 9, around 8.5. The symptoms of diarrhea disappeared in 48 hours.
[0081] The present invention has been described with specificity related to the use of electrolyzed water given orally for the relief of symptoms related to disease states; particularly effective with PEDv and other disease states for which diarrhea is a critical symptom. Although TGE may also be so treated, its effect is not quite as dramatic as pigs with TGE are reluctant to drink any water, with or without electrolyzed water diluted in it. Concentration of the electrolyzed water used in drinking water for the present invention may range from about 0.5% to about 100%, more preferably between about 0.5% and about 1.5%, up to about 50%. It is postulated that the lower concentrations are more palatable to the animals, especially the younger ones. The electrolyzed water may also be used as a solution for or pre-soak prior to cleaning surfaces with the expectation that certain important viruses such as PEDv and TGE and/or bacterial will be reduced or eliminated.
[0082] Finally, sanitizing surfaces in animal confinements through the use of foggers, misters, or sprayers where electrolyzed water is present in concentrations preferably above about 20%, and more preferably above about 50%, is within the purview of this invention.
[0083] Based on the data collected relative to the examples provided herein and qualitative data gathered by the inventors related to symptom relief in other animals, other disease states, using other concentrations of the solution, and different dosage regimes, the following claims are made. Although the invention has been described with particularity, one of ordinary skill in the art will be aware that the invention may be accomplished by the use of equivalents relative to steps, order of steps, application, concentrations, timing of dosages, duration of treatment or exposure, means of delivery, and other limitations present in the claims, all of which are within the scope of the invention as disclosed herein. | Pigs infected with PEDv often die due to dehydration caused by diarrhea. Those that survive do not reach market weight as scheduled resulting in costs to the producer. The invention includes providing electrolyzed water either as treatment for infected animals or as a prophylactic against symptom severity in uninfected animals. The electrolyzed water is used as a substitute for or as a solution with regular drinking water. Duration of symptoms for infected pigs is markedly lessened; severity of symptoms is also reduced providing a much higher survival rate. Time to market is less negatively affected for surviving pigs than those untreated, and weight at scheduled time for sale is also less effected translating into positive financial results over those expected for untreated herds. | 0 |
BACKGROUND OF THE INVENTION
The present invention relates to processes and compositions for preserving aqueous systems against the deleterious action of bacteria, fungi and algae.
It is well known that various aqueous systems containing metabolizable components, either in trace or major quantities, are normally susceptible to attack and degradation by microorganisms. Examples of such compositions are cutting oils, cosmetics such as lotions and creams, fuel oil, textile emulsions, latex emulsions and paints, starch-base adhesives, industrial cooling water, emulsion waxes, water used in pulp and paper manufacture (so-called "process" water, e.g., "white water"), and flood water used in secondary oil recovery methods.
A number of problems and limitations have recently faced those in the art who seek to provide effective antimicrobial preservatives for such aqueous systems. These problems involve concerns about worker exposure and environmental impact. Many preservatives are effective because they are toxic to the microorganisms at low concentrations, i.e. concentrations in the order of about 100 parts per million. Human exposure to such preservatives in the part per million range does not normally pose a risk that raises concern. The pure product, however, may pose an unacceptable risk to workers who may be exposed to the pure concentrated material on a daily basis and who must protect themselves from accidental inhalation or accidental exposure to the skin. In the case where the substance is a liquid, its vapor pressure may be of concern, if concentrations in the air could reach levels which could be harmful to workers. If the material is a solid or a powder the inhalation of dust becomes a concern.
One way to keep the concentration of such antimicrobial agents to an acceptable handling level is to use diluents or inert carriers. Such diluents or carriers are also desirable in order to assist in delivering the antimicrobial agents to the medium to be preserved. These diluents must, of course, meet certain criteria. They must be compatible with a particular antimicrobial agent and with the medium in which the antimicrobial agent is to be used. They shouuld not be highly flammable and should not be toxic. Very few diluents can satisfy these criteria at an acceptable price.
More recently, pressures concerning the toxicity of the diluent and its compatability with the environment have served to restrict the number of diluents that are acceptable. It is expected that even fewer diluents or carriers will be acceptable in the future.
There is a need in the industry to find a diluent or a carrier system which meets the following criteria:
(1) The diluent or carrier must be compatible with the antimicrobial agent and should not diminish or destroy the antimicrobial activity.
(2) The final product must have a flash point of greater than 120 degress Fahrenheit in order to avoid dangers due to flammability.
(3) The system must work in the medium for which it is intended.
(4) It should not be on list 1 or list 2 of the Environmental Protection Agency's "Inert Ingredients in Pesticide Products; Policy Statement". (Federal Register, volume 52, number 77, dated April 22, 1987. Lists 1 and 2 cover inert ingredients of toxicological concern and potential toxicological concern, respectively.)
(5) The system must be economically competitive, i.e., it must not be so expensive that the system cannot compete in the market place.
(6) The diluent or carrier should be odorless, or at least have a pleasant odor.
SUMMARY OF THE INVENTION
The invention provides a novel means for the saft handling of β-bromo-β-nitrostyrene which meets the criteria set forth above, and which minimizes human exposure and environmental concerns. The present invention provides a product which comprises β-bromo-β-nitrostyrene absorbed into or encapsulated into a biodegradable and relatively inert, partially hydrolyzed starch such as a maltodextrin or corn syrup solid. Hydrolyzed starches are relatively inert to most antimicrobial agents and usually result in a product with a high flash point, in most cases greater than 200 degrees Fahrenheit. The hydrolyzed starch does not contribute any odor to the final product. It is water soluble and therefore releases the active ingredients in aqueous systems. It is biodegradable and a natural food material, which is not only compatible with eco-systems but actually contributes to them in a positive fashion. The fact that the final product is a solid minimizes worker and user exposure and environmental contamination from spills.
The invention also provides a process for the manufacture of said product. A suitable maltodextrin or corn syrup solid can be mixed with a solution of β-bromo-β-nitrostyrene in the desired proportions. The solvent can then be removed, for example, by vacuum distillation.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Partially hydrolyzed starches containing dextrose, maltose and higher molecular weight saccharides are available from corn starch. The hydrolyzed starch products are usually defined on the basis of their reducing sugar content referred to as the dextrose equivalency (DE). Solid, partially hydrolyzed starches with a dextrose equivalent (DE) of between 1 and 20 are preferred in the practice of the present invention. Partially hydrolyzed starches with a DE of less than 20 are generally classified as maltodextrins and are normally solid compositions of varing particle size and densities. Suitable solid hydrolyzed starches are available under such tradenames as Amaizo Fro-Dex® (American Maize-Products Co.), Maltrin® (Grain Processing Corporation) and Micropor Buds® (A. E. Staley Manufacturing Company). The source of the maltodextrin is not critical to the practice of the present invention. Micropor Buds® 1005, 1015 and 2010, with DE values of 10, 10 and 20, respectively, have been used for purposes of illustrating the present invention but any solid hydrolyzed starch with a DE of between 1-20 may be used. Maltodexrins with a DE value of 5-15 are preferred since they are more readily available and more economical to use.
In preparing the novel systems of the invention, it is preferred to first dissolve the β-bromo-β-nitrostyrene in a non-aqueous solvent. The nature of the solvent is not critical other than that it should be compatible with the antimicrobial agent, should be one which will dissolve the antimicrobial agent and should not react with the partially hydrolyzed starch. Suitable solvents for most applications would be, for example, hydrocarbon solvents such as toluene and the like.
The solution containing the antimicrobial agent and a suitable partially hydrolyzed starch are mixed together in the proper proportions to yield a final product with a correct level of antimicrobial agent. For example, if a final product is desired to have 50% partially hydrolyzed starch and 50% β-bromo-β-nitrostyrene, one could suitably add 100 parts of the partially hydrolyzed starch to 400 parts of a 25% solution of β-bromo-β-nitrostyrene and a suitable solvent, mix for a period of time and then remove the solvent under reduced pressure. The final product is a granular, free-flowing solid. Under most circumstances, one can vary the ratio of the antimicrobial agent to the partially hydrolyzed starch from as little as 0.5% antimicrobial agent and 99.5% partially hydrolyzed starch to as high as 90% antimicrobial agent to 10% partially hydrolyzed starch. It is preferred, however, to use a ratio of from 40-60% β-bromo-β-nitrostyrene to 60-40% partially hydrolyzed starch, since this provides the best free-flowing solid. The most preferred ratios will depend on a number of factors including the use to which the antimicrobial agent is to be applied.
Compositions prepared according to the present invention were found to be stable over time. Analysis of compositions containing 25% and 50% β-bromo-β-nitrostyrene on maltodextrin (DE=10), using standard Ultraviolet Spectroscopic methods, showed no deviation in the composition of the mixtures after 30 days of storage.
The compositions have also been shown to be effective, in general, against a broad spectrum of microorganisms which attack the aqueous systems described herein. Samples of 25% and 50% β-bromo-β-nitrostyrene on maltodextrin were evaluated in agar to obtain a minimum inhibitory concentration range of each sample against a series of bacteria, yeast, and molds. Pure β-bromo-β-nitrostyrene served as a control. The test was designed with small dilution increments so that relatively minor differences in antimicrobial activity could be detected. Results indicate that the activity of the two β-bromo-β-nitrostyrene/maltodextrin samples compared favorably with the control. No significant differences in antimicrobial activity were detected. In the ranges presented in the examples below, no growth occurred at the higher concentration while the lower concentration was non-inhibitory. (Maltodextrin was tested alone and was found to be non-inhibitory against all microorganisms at 100 mcg/ml, the highest concentration of carrier tested.)
The microbial activity of β-bromo-β-nitrostyrene diluted with maltodextrin is identical to an equivalent amount of the pure material, and would therefore be useful as a preservative of aqueous systems as described in U.S. Pat. No. 3,629,465.
ILLUSTRATION OF THE PREFERRED EMBODIMENTS
Example 1: Preparation of Product
To 400 grams of a solution consisting of 100 grams of β-bromo-β-nitrostyrene and 300 grams of toluene, is added 100 grams of a hydrolyzed starch with a DE of 10 available under the tradename Micropor Buds® (grade 1015). The resulting mixture is heated to a temperature of 50° C. The toluene is then removed under reduced pressure (30 mm Hg) at 50° C. to yield a granular solid. Analysis of the granular solid by Ultraviolet Spectroscopic analysis (UV) shows 48-52% β-bromo-β-nitrostyrene. (The range is due to deviations in the test procedure.)
Substitution of Micropor Buds® 1005 or 2010 for the Micropor Buds® 1015 in the above procedure yields the respective product containing 48-52% β-bromo-β-nitrostyrene.
Products containg 25% β-bromo-β-nitrostyrene are prepared using 350 grams of a solution of 50 grams of β-bromo-β-nitrostyrene in 300 grams of toluene in the above procedure. It is well within the skill of one in the art to determine the proper proportions necessary to prepare a product with the desired level of β-bromo-β-nitrostyrene.
Example 2: Microbial Activity
Samples of 25% and 50% β-bromo-β-nitrostyrene on Micropor Buds® grade 1015 were evaluated in agar to obtain a minimum inhibitory concentration range based on BNS concentration of each sample against a series of bacteria, yeast, and molds. Pure β-bromo-β-nitrostyrene served as a control. The test was designed with small dilution increments so that relatively minor differences in antimicrobial activity could be detected.
Results listed in the following tables indicate that the activity of the two samples compared favorably with the control. No significant differences in antimicrobial activity were detected.
Sample Identificaiton:
25 BNS 25% β-bromo-β-nitrostyrene/75% Micropor Buds® #1015
50 BNS 50% β-bromo-β-nitrostyrene/50% Micropor Buds® #1015
Control Pure β-bromo-β-nitrostyrene (m.p. 62°-63° C.)
TABLE I__________________________________________________________________________BACTERIAMinimum Inhibitory Concentration Range in mcg/ml Staphylococcus Escherichia Pseudomonas Proteus BabillusSample aureus coli aeruginosa vulgaris subtilis__________________________________________________________________________25BNS >25 17.5-20.0 12.5-15.0 17.5-20.0 22.5-25.050BNS >25 15.0-17.5 10.0-12.5 15.0-17.5 20.0-22.5Pure BNS >25 15.0-17.5 10.0-12.5 15.0-17.5 20.0-22.5__________________________________________________________________________
TABLE II__________________________________________________________________________YEAST, MOLDSMinmum Inhibitory Concentration Range in mcg/ml Candida Aspergillus Aspergillus Penicillium AureobasidiumSample albicans niger oryzae piscarium pullulans__________________________________________________________________________25BNS 15.0-17.5 7.5-10.0 17.5-20.0 7.5-10.0 2.5-5.050BNS 12.5-15.0 7.5-10.0 15.0-17.5 7.5-10.0 2.5-5.0Pure BNS 12.5-15.0 10.0-12.5 17.5-20.0 7.5-10.0 2.5-5.0__________________________________________________________________________
In the ranges presented, no growth occurred at the higher BNS concentration while the lower BNS concentration was non-inhibitory. Micropor Buds® alone was non-inhibitory against all microorganisms at 100 mcg/ml, the highest concentration of carrier tested.
Example 3: Stability and Compatability
Samples of 25% and 50% β-bromo-β-nitrostyrene on Micropor Buds® grade 1015 were placed in brown sealed bottles and assayed for β-bromo-β-nitrostyrene by standard Ultraviolet Spectroscopic methods over 30 days period.
TA8LE III______________________________________β-bromo-β-nitrostyrene (BNS)/Micropor Buds ® Stability Percent β-bromo-β-nitrostyreneSample Initial 14 days 30 days______________________________________25% BNS 24.7 24.1 24.550% BNS 51.2 51.2 50.6______________________________________ | The use of a novel system for preserving aqueous systems normally subject to spoilage is disclosed. The system comprises the incorporation of β-bromo-β-nitrostyrene onto a solid maltodextrin or corn syrup solid of low to intermediate dextrose equivalency. | 2 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Divisional of U.S. patent application Ser. No. 09/719,153, filed Mar. 16, 2001, which is a 371 of International Patent Application No. PCT/FR99/01375, filed Jun. 10, 1999, and claims priority to French Patent Application No. 98/07276, filed Jun. 10, 1998. The entire contents of these applications are included herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to substrates provided with a photocatalytic coating, and to the process for producing such a coating and to its various applications.
[0004] It relates more particularly to coatings comprising semi-conducting materials based on metal oxide, in particular on titanium oxide, which are capable of initiating radical reactions under the effect of radiation of appropriate wavelength, resulting in the oxidation of organic products. These coatings thus make it possible to confer novel functionalities on the materials which they cover, in particular dirt-repellent, fungicidal, bactericidal, algicidal or odour-controlling properties, optionally in combination with hydrophilic or anti-condensation properties, and the like.
[0005] 2. Discussion of the Background
[0006] Highly diverse substrates have to date been envisaged, in particular construction materials used in the field of construction or vehicles (windows, facing, cladding or roofing materials, and the like) or materials used in purification processes.
[0007] International Patent Applications WO97/10186 and WO97/10185 have thus made known coatings comprising anatase crystallized TiO 2 with photocatalytic properties, coatings obtained from the thermal decomposition of appropriate organometallic precursors and/or from “precrystallized” TiO 2 particles, suited in particular to deposition as a thin layer on glass in order to preserve its optical quality.
[0008] Patent Application EP-A-0,306,301 has also made known the use of photocatalytic TiO 2 on fibrous materials used to purify the air, the deposition of the TiO 2 being carried out by a process of sol-gel type.
SUMMARY OF THE INVENTION
[0009] The aim of the invention is then the improvement of these photocatalytic coatings, being targeted in particular at improving their behaviour on any type of substrate and in particular providing them with better adhesion and better durability, particularly on substrates exhibiting characteristics of surface roughness of porosity.
[0010] The subject-matter of the invention is first of all a substrate comprising a fibrous material which is provided, over at least a portion of its surface and/or within its thickness, with a coating with photocatalytic properties comprising a semi-conducting material with photocatalytic properties of the oxide or sulphide type in combination with a promoter of adhesion to the said fibrous material.
[0011] The semi-conducting material “active” with respect to photocatalysis can be, according to the invention, based on at least partially crystallized metal oxide, for example zinc oxide, tin oxide or tungsten oxide. The preferred example according to the invention relates to titanium oxide at least partially crystallized in anatase form, which is the crystalline phase which confers on TiO 2 its photocatalytic properties. It can also relate to semi-conductors belonging to the family of the sulphides, also at least partially crystallized, such as zinc sulphide or boron sulphide. (In the continuation of the text, for greater simplicity, mention will be made of titanium oxide, it being understood that the information given will be just as valid for the other semi-conducting materials mentioned above).
[0012] The term “fibrous material” is understood to mean, within the meaning of the invention, any material comprising fibres, in particular mineral fibres, more particularly organized fibres made of glass or rock mineral wool, of the type of those used in thermal/sound insulation or to constitute soilless culture substrates. This term “fibrous material” also includes fibres/filaments organized as strands, of the type of the strands used in reinforcement, in particular made of glass.
[0013] These base fibrous materials are subsequently incorporated in a “substrate”, within the meaning of the invention, in various forms: it can relate to felts, mats, webs, “moulds” intended for the insulation of pipes, made of mineral wool, textile strands assembled as fabrics, or non-woven web, made of substrates of paper type, and the like.
[0014] A photocatalytic coating makes it possible to confer highly advantageous novel functionalities on these known substrates. Thus, the felts/mats of mineral wool mainly used in insulation can be treated only superficially, only on one of their faces, for example, or on each of their faces, and can acquire a dirt-repellent/odour-controlling function on at least one of their treated faces (the visible face and/or the hidden face) in false ceiling structures of buildings, in antinoise screens alongside roads or railways, and the like, the condition laid down being that the photocatalytic coating is accessible to a natural or artificial light source. Still in the field of insulation, the “moulds” can also be treated on the inside and/or outside or over their entire thickness, for example, in order to confer on them a dirt-repellent and/or bactericidal or fungicidal function. In the form of mats or of moulds, the substrates treated according to the invention can advantageously be positioned around outlet conduits in any ventilation or air-conditioning system but also by being positioned inside these conduits, these devices being veritable breeding grounds for bacteria, the condition being that it is necessary to provide means for the photocatalytic coating to be exposed to sufficient ultraviolet radiation to be effective: on a visible external face, natural illumination may be sufficient. If not, the substrates have to be combined with artificial illuminating means of the halogen lamp or fluorescent tube type.
[0015] Another application relates to any system for reflecting and/or scattering natural light or light originating from artificial illuminating means, such as lampshades or curtains, when the substrate is, for example, in the web form.
[0016] The other main application, apart from thermal or sound insulation, of the substrates treated according to the invention relates to the filtration or the purification of fluids.
[0017] It can relate to any filter used in the filtration of gases, in particular of air, of paper web or filter paper type, used, for example, in the ventilation/air-conditioning systems for dwellings mentioned above or for industrial premises, vehicles or laboratory rooms with a controlled level of dust, of the “clean” room type.
[0018] The term “filter” covers two notions within the meaning of the invention, both the notion of true filtration, where particles are separated mechanically from the gas carrying them, and the notion of diffuser, in particular of odour-controlling diffuser, where the gas to be treated is not necessarily forced to pass through the photocatalytic substrate, where it can in particular simply be brought into contact with the latter, without retaining the suspended particles.
[0019] Mention may be made of many other applications of the gas “filters” according to the invention: they can also be used to purify any type of industrial gaseous effluent or any atmosphere of a given public place or building (as odour-controlling diffuser in the underground, for example). They can in particular make it possible to reduce the “VOC” (volatile organic compounds) level of a given gas stream or of a given atmosphere.
[0020] The filters, surface-treated or treated throughout their thickness, can become much more effective and much more durable; this is because the treatment according to the invention gives them the ability not only to remove microorganisms but also to decompose organic residues of fatty type, for example, particles which gradually block the filter. With the invention, these filters therefore have a longer lifetime. In addition, they have an odour-controlling function.
[0021] It can also relate to filters for liquids.
[0022] The liquid filters according to the invention have numerous applications: they can be used for the recycling of wastewater or for the recycling of water from systems for the irrigation of soilless culture substrates (for disinfecting the water). They can also fulfill a function of depollution, in particular depollution of soils, or a function of reprocessing/depolluting industrial liquid effluents.
[0023] The advantage of treating all these fibrous substrates according to the present invention has been seen. However, to furnish term with a photocatalytic coating was not, initially, very easy. This was because the question arose of the method of deposition of the coating on a substrate which is generally non-smooth, non-flat and of rough and porous type, as well as the question of the durability of this coating.
[0024] The solution of the invention consisted in adjusting the way in which it was applied to the substrate, namely superficially or throughout its thickness, according to the applications targeted as a function of requirements, and in rendering the anatase TiO 2 of the coating, which is responsible for the photocatalytic performance, integral with the fibrous material via an appropriate adhesion promoter. The latter can thus act as “matrix” for the components of the coating which are “active” with respect to the photocatalysis phenomenon.
[0025] According to a first embodiment of the present invention, the titanium oxide is already at least partially precrystallized in anatase form when it is incorporated in the coating, before being deposited on the substrate. It can be introduced into the coating in the form of crystalline particles in colloidal suspension or in the form of a dry power composed of particles which are optionally more or less agglomerated with one another. This alternative form exhibits the advantage of not imposing a high specific heat treatment on the coating/substrate on which it is deposited (TiO 2 crystallizes in the anatase form generally in the vicinity of 400° C.).
[0026] According to a second embodiment of the present invention which can be combined with the first embodiment, the titanium oxide originates from the thermal decomposition of precursors, in particular of the organometallic or metal halide type, within the coating. The anatase crystallized TiO 2 can thus be manufactured “in situ” in the coating, once applied to the substrate, by providing for an ad hoc heat treatment, which must, however, be compatible with the chosen substrate and the chosen adhesion promoter.
[0027] The adhesion promoter can be single- or multicomponent, and its component or components can be organic, inorganic or organic/inorganic “hybrids”.
[0028] It can thus comprise a silicon-comprising component, in molecular form or in polymeric form, of the silane, silicone or siloxane type, for example. This is because these components exhibit a good affinity with the majority of mineral fibres, glass, rock or even ceramic, affecting the invention. It is even possible, in some cases, to speak of a kind of grafting of the crystallized TiO 2 to the inorganic fibres by this type of component.
[0029] The adhesion promoter can also comprise one or more polymers of organic type. In fact, two scenarios exist: standard organic polymers, for example of the acrylic or phenol-formaldehyde type, or the like, can be chose. In this case, there is a risk of this component being gradually decomposed by photocatalysis by the TiO 2 , at least in the surface regions of the substrate liable to be exposed to ultraviolet radiation. However, the process can in fact prove to be advantageous in some applications, by thus gradually “releasing” active TiO 2 . However, it may be preferable to avoid or slow down as far as possible this decomposition by choosing appropriate polymers, generally fluorinated polymers, which are highly resistant to photocatalytic attacks, for example of the fluorinated acrylic polymer type, of the polytetrafluoroethylene (PTFE), poly (vinylidene fluoride) (PVDF) or tetrafluoroethylene-ethylene copolymer (ETFE) type, and the like.
[0030] One alternative is retaining an adhesion promoter based on organic polymer(s) and thwarting their decomposition by appropriate additives, in particular belonging to the family of the antioxidants (such as the product sold under the name Irganox by the company Ciba) and/or of the ultraviolet absorbers (such as the product sold under the name Tinuvin by the same company) and/or of stabilizers in the form of sterically hindered amines known under the term “hindered amine light stabilizers” or “HALS”.
[0031] The adhesive promoter can also comprise at least one metal oxide of the TiO 2 or SiO 2 type originating from the thermal decomposition of precursors of the silicon-comprising, organometallic or metal halide type within the coating. In this case, the TiO 2 or SiO 2 component is generated in situ in the coating, in particular once applied to the substrate, by an appropriate heat treatment compatible with the substrate. In the case of TiO 2 , it is not, however, necessary to envisage very high temperatures necessary for an anatase crystallization, if only an adhesion promoter function is being sought: it can perfectly well be amorphous or partially crystallized in various crystalline forms, just like SiO 2 . It is thus possible to have a coating of the amorphous metal oxide matrix type which fixes the “active” particles of crystallized photocatalytic oxide.
[0032] The adhesion promoter can also comprise at least one inorganic component chosen from aluminium phosphates and potassium or calcium aluminosilicates.
[0033] One embodiment of the invention consists in that at least one of the two essential components of the coating, namely, on the one hand, the “active” (with regard to photocatalysis) components and, on the other hand, the adhesion promoter, forms part of the binder making possible the intrinsic cohesion of the fibrous material.
[0034] This is because, if the material is glass or rock mineral wool of the insulation type, such as that produced by Isover Saint-Gobain, the latter is in numerous applications provided with a binder generally denoted under the name of size and generally applied in the liquid phase by spraying under the fiberizing devices. The solvent/dispersant is generally aqueous and it evaporates on contact with or in the vicinity of the hot fibres. The agents for sticking the fibres to one another, generally of the resin type, for example phenolic resin, such as urea-phenol-formaldehyde polymers, cure under hot conditions. One possibility then consists in adding the adhesion promoter and the “active” components to the aqueous medium of the size or even in using/adapting the components of the size in order for them to act simultaneously as binder of the fibres to one another and of promoter of fibres/“active” components adhesion.
[0035] For further details on typical sizing compositions and their method of application to fibres, reference may advantageously be made in particular to Patents EP-148,050, EP-246,952, EP-305,249, EP-369,848, EP-403,347, EP-480,778 and EP-512,908. However, it should be noted that, in specific applications, the mineral wool can be devoid of binder, for example that composed of relatively fine fibres used to prepare filter papers, as disclosed, for example, in Patents EP-0,267,092 and EP-0,430,770, or needled felts.
[0036] If the material is instead a fibrous material of reinforcing strands or textile strands type, in particular such as that manufactured by Vetrotex, the cohesiveness of the strands resulting from the assembling of individual filaments under a bushing is generally provided by application of a binder generally denoted under the term of sizing composition. Here again, it is applied in the liquid phase and comprises one or more agents “sticking together” the fibres/filaments. It is therefore possible to choose to add the “active” components and/or the adhesion promoter according to the invention to the liquid medium or to adapt its composition in order to make it act both as interfilament binder and as promoter of strands/“active” components adhesion.
[0037] For further details on sizing compositions, reference may advantageously be made in particular to Patents EP-243,275, EP-394,090, EP-635,462, EP-657,396, EP-657,395, EP-678,485, EP-761,619 and WO-98/18737.
[0038] Mention may also be made of Patent WO-98/51633, relating to the deposition of size in two steps under the fiberizing device, size in addition being capable of polymerizing at room temperature. In this case, it is possible to choose to introduce the material with photocatalytic properties either into the first sizing composition or into the second or into both.
[0039] All these sizes mentioned above are generally applied, using sizing rolls just under the bushing, to the fibrous material still in the form of individual filaments in the course of being gathered together into strands. There also exist binders, intended to ensure the cohesion of mats obtained from a blanket of glass strands, which are ejected onto continuous or non-continuous strands which have already been sized. Mention may be made, by way of example, of Patent WO-97/21861. The photocatalytic material can be incorporated in this binder, which also acts as adhesion promoter.
[0040] The sizes or binders mentioned above are either in the aqueous phase or in the non-aqueous phase. In the latter scenario, a heat treatment is generally no longer necessary to remove the water, the components chosen then being chosen so as to be able to polymerize at room temperature. In this case, the incorporation of materials with photocatalytic properties pre-existing independently of any heat treatment is favoured, such as small crystallized titanium oxide particles.
[0041] As mentioned above, the fibrous material according to the invention can therefore be organized in the web (facing, for example), felt or paper form or in various geometric forms (flat or pleated paper type sheets, for example, panel, hollow cylindrical “mould”, woven or non-woven web, and the like). The fibrous material can also be in bulk, in the form of optionally graded short fibre or flocks.
[0042] The photocatalytic coating of the invention is advantageously applied to the fibrous material so that at least a portion of the “fibres” of the said material (including the notions of fibres, of filaments and of strands) is sheathed with the coating over a thickness of at least 5 nm, in particular over a thickness of the order of 30 to 50 nm.
[0043] This sheathing ensures maximum effectiveness of the coating, its photocatalytic activity increasing as it is distributed over a greater specific surface. The preferred thickness takes into account the most commonly encountered mean size of the anatase TiO 2 crystallites.
[0044] Another subject-matter of the invention is the processes for the manufacture of the substrates defined above.
[0045] According to a first alternative form, the photocatalytic coating is deposited, in the liquid phase, on the production line itself for the fibrous material. The advantage to this alternative form lies in the fact that the still semi-finished fibrous material can be treated an the best use can be made of the temperature which it is at, for example, resulting in a saving in terms of time and of production cost. This, a first embodiment consists in “hot” depositing the coating between the fiberizing devices and the devices for receiving the fibres. The fiberizing devices can consist of glass centrifuging dishes, known as “internal centrifuging devices”, such as ones disclosed, for example, in Patents EP-0,189,534 and EP-0,519,797, making it possible to fiberize mineral wool of glass type, or devices for fiberizing by so-called external centrifuging using a succession of centrifuging wheels, such as ones disclosed, for example, in Patents EP-0,465,310 or EP-0,439,385, making it possible to obtain mineral wool of basalt rock type. It can also relate to devices for fiberizing by mechanical drawing, in order to obtain reinforcing glass strands, by air blowing or by steam blowing, according to processes well known to persons skilled in the art. Use is thus made of the fact that the fibres are still at a relatively high temperature by applying the coating, generally in solution/dispersion, in a solvent, for example an aqueous solvent, which evaporates on contact with or in the vicinity of the fibres. The heat can also make it possible to cure the component or components of the adhesion promoter, if they are of the resin type, or to decompose them thermally, if they are of the silicon-comprising precursor or metallic precursor type mentioned above.
[0046] As mentioned above, the coating in the liquid phase can be applied at the same time as an optional “binder” of the sizing composition type or even form part of it. It may also be preferable to apply it to the fibrous material before or after the said “binder”.
[0047] According to a second embodiment of this first alternative form, the photocatalytic coating, still generally in the liquid phase, can be deposited “after” the receiving devices which collect the fibres/filaments or strands resulting from the fiberizing devices and in particular before or during the post-fiberizing heat treatment of the fibrous material. Thus, for mineral wool of insulation type, the receiving devices are generally composed of a suction conveyor belt which gathers together the mineral wool and passes it into a forming oven. It can be judicious to apply the coating between the two devices (fiberizing/receiving), for example superficially, and to use the heat of the oven to cure or complete the coating, if necessary.
[0048] Likewise, in the field of reinforcing glass, the strands are drawn and wound off in the form of spools or cut up under the bushing, after having been appropriately sized, and then generally dried in heated chambers, before being converted and/or used.
[0049] As mentioned above, it is therefore possible to deposit the photocatalytic coating just under the bushing, in particular concomitantly with the deposition of the size, in which it can be incorporated. It is also possible to deposit it during the stage of finishing the spooled strands into finished products: it can, for example, relate to the conversion operation targeted at manufacturing mats of chopped strands, in a subsequent operation; it is also possible to deposit it on the downstream line, in particular during the conversion of the continuous strands, gathered together as a blanket, into a mat of continuous strands.
[0050] In the last two cases, the photocatalytic coating can be deposited by an ejection system of the adjusted sprayer type, before, during or at the same time as the binder used (or be used in combination with it in the same liquid phase).
[0051] According to a second alternative form, the photocatalytic coating is deposited in the liquid phase on the finished fibrous material, in a subsequent operation. What this involves is instead a “cold” treatment, requiring a post-deposition heat treatment in order to evaporate the solvent and optionally to cure or to complete, to constitute the coating.
[0052] Whatever the alternative form chosen, the coating can be deposited by different techniques. If the coating comprises “active” anatase crystallized TiO 2 powder or particles from the start, it is not necessary for the fibrous substrate to be very hot; temperatures of less than 300° C. and even of less than 200° C. may suffice, indeed even room temperature, and therefore temperatures which are found on production lines for the commonest mineral fibrous materials, temperatures which are in addition compatible with the sizes for these materials, which are generally organic, at least partly. If, on the other hand, it is necessary to generate anatase TiO 2 “in situ”, it is necessary to envisage temperatures of the order of 400° C., instead with fibrous materials devoid of binder in the general sense of the term and in a subsequent operation, for example by a process of sol-gel type.
[0053] In concrete terms, it is possible to choose to impregnate the fibrous material to the core and to use a technique of “dip-coating” type, where the fibrous material is at least partially immersed in a bath comprising the coating in the liquid phase. It is also possible to choose coating or spraying adapted to a surface treatment. The deposition can also be carried out in a fluid which is non-liquid in the usual sense of the term, for example in a hypercritical fluid.
[0054] Another subject-matter of the invention relates to the application of these treated substrates to thermal/sound insulation or facing materials, with a dirt-repellent, fungicidal, antibacterial or odour-controlling function, or to liquid or gas filters of paper type or of felt or mould type.
BRIEF DESCRIPTION OF THE DRAWINGS
[0055] Other advantageous details and characteristics of the invention become apparent from the non-limiting embodiments described below in reference to the following figures:
[0056] FIG. 1 shows a scanning electron microscopy (SEM) photograph of the surface of a fibrous material treated according to an embodiment of the invention;
[0057] FIG. 2 is another SEM photograph showing the surface of the fibrous material shown in FIG. 1 ; and
[0058] FIG. 3 is yet another SEM photograph showing the surface of the fibrous material shown in FIG. 1 .
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0059] All the following examples relate to the deposition of a coating for which the photocatalytic “active” components are made of anatase crystallized TiO 2 . As mentioned above, the invention applies in the same way to semi-conducting “active” components with photocatalytic properties similar to anatase TiO 2 and which can be provided in the same form, in particular zinc oxide, tin oxide and tungsten oxide.
EXAMPLE 1
[0060] a needled felt (dimensions 210×297×5 mm 3 ), composed of glass fibers of insulating type obtained by binder-free internal centrifuging and with a relative density of 55 kg/m 3 , was sprayed with an aqueous TiO 2 solution, sold under the trade name “ToSol” by Saga Ceramics, over its entire thickness.
[0061] This solution containing particles of TiO 2 crystallized in anatase form, probably composed of crystallite agglomerates, these agglomerates having a mean size of the order of 20 to 80 nm. These particles are therefore the “active” components in terms of photocatalysis. The solution also contains an organometallic TiO 2 precursor which will decompose into predominantly amorphous TiO 2 by heat treatment and which will act as adhesion promoter.
[0062] The coating obtained was baked at 200° C. for 2 hours and contains anatase nanocrystals in an amorphous TiO 2 matrix. The yellow colour of the filter thus manufactured testifies to the presence of organic compounds originating from the precursor solution. After exposure to ultraviolet A radiation under a dose of 4 W/m2 for 2 hours, the yellow colour has completely disappeared, which shows complete decomposition of the residual organic pollutants.
EXAMPLE 2
[0063] Glass fibre of insulation type obtained by binder-free internal centrifuging was converted by the papermaking route in pure water. The paper obtained, circular with a diameter of 100 mm and a weight per unit area of 150 g/m2, was subsequently impregnated over its entire thickness by dip-coating it in an alcoholic dispersion containing, by volume, 5% water, 1% tetraethoxysilane (the adhesion promoter) and 1% anatase crystallized TiO 2 particles with a mean diameter of 30 nm (the “active” components). The paper was dried in the open air and then baked in an oven at 450 C for 30 minutes. This filter was subsequently placed over an inlet orifice of a fume cupboard. A control filter, without anatase TiO 2 , was placed over the neighbouring orifice. An ultraviolet A lamp shines on these filters at a dose of 4 W/m2. After the cupboard had been operated for 15 days, the treated filter was still white, whereas the untreated filter was fouled.
EXAMPLE 3
[0064] A composition for the sizing of glass wool of insulation type obtained by internal centrifuging was manufactured by mixing:
[0065] 55 G of resin obtained by condensation of phenol and formaldehyde in an initial formaldehyde/phenol molar ratio of approximately 3.2/1, which condensation is carried out conventionally with a catalyst in the form of sodium hydroxide at 5.5% by weight with respect to the phenol,
[0066] 45 g of urea,
[0067] 3 g of aminopropyltrimethoxysilane,
[0068] 0.3 g of ammonium sulphate,
[0069] 6 g of 30% by volume aqueous ammonia,
[0070] 1200 g of a 25% by weight dispersion in water of anatase crystallized TiO 2 particles, and
[0071] 34 litres of water.
[0072] The TiO 2 particles have a mean diameter of approximately 45 nm. The adhesion promoter for the latter can be regarded as all the other components of the size and very particularly the silane.
[0073] This composition was sprayed via the sizing ring during a fiberizing of the glass wool under the centrifuging dishes. The felt obtained was subsequently passed on the line into an oven at 180° C. for 2 minutes. The felt has a weight per unit area of 560 g/m 2 and a loss on ignition of 1.4% (measurement known to a person skilled in the art, expressed by weight, by heating the felt at a temperature sufficient to remove all the organic compounds). A 1×20×40 mm 3 piece was removed and placed in a vessel with 20 g of an aqueous solution comprising 1 g/l of ethanol and 15 mg/l of hydrogen peroxide. The solution was shone on by a mercury lamp producing 4 W/m 2 of ultraviolet radiation and the concentration of hydrogen peroxide was monitored by colorimetry. Oxidation of ethanol by hydrogen peroxide, catalysed by the anatase TiO 2 irradiated with ultraviolet radiation, is observed.
[0074] The photocatalytic activity of the felt was evaluated by measuring the weight of hydrogen peroxide H 2 O 2 in milligrams which disappears per gram of fibre in the solution and per hour. The result was 4.4 mg H 2 O 2 /g·fibre/hour.
[0075] Samples of 200×300×200 mm3, coming from the same treatment, have been subjected to naturel sun exposure. Gradually the yellow colour, that is characteristic for the resin used, disappeared from the exposed surfaces and to some centimetres in depth. This vanishing clearly indicated a degradation of the phenolic resin used as well as the penetration of the photocatalytic effect inside the material. Similar results were obtained und controlled UVA radiation of 4 W/m 2 for 24 hours.
EXAMPLE 4
[0076] 280 g of glycidoxypropyltrimethoxysilane were added to a sizing composition similar to that of Example 3 (other silane combining with the above to act as adhesion promoter). The felt obtained by fiberizing and sizing with this solution was staved at 180° C. for 2 minutes. The felt has a weight per unit area of 1 kg/m 2 and a loss on ignition of 1.4%. The measurement of the photocatalytic activity, carried out as in Example 3, gave a value of 3 mg H 2 O 2 /g·fibre/hour.
[0077] FIGS. 1, 2 and 3 show, in three different scales, a fibre covered with the photocatalytic coating. FIG. 1 shows more particularly a fibre, at the surface of which is clearly distinguished a sheathing of TiO 2 particles, two successive magnifications being shown in FIGS. 2 and 3 .
[0078] In conclusion, it is found that the coating of the invention exhibits a proven photocatalytic activity on fibres, whatever the implementational alternative forms:
[0079] Example 1 illustrates a deposition “in a subsequent operation”, outside the line for the production of mineral wool, using “precrystallized” TiO 2 particles and an inorganic adhesion promoter manufactured in situ, on a fibrous substrate of felt type.
[0080] Example 2 also illustrates a deposition “in a subsequent operation”, on a fibrous substrate of paper type, with precrystallized TiO 2 particles and a silicon-comprising adhesion promoter.
[0081] Examples 3 and 4 illustrate an in-line hot deposition under the fiberizing devices, which will make possible treatment within the thickness of the fibrous material, with “precrystallized” TiO 2 particles and adhesion promoters of the family of the silanes in combination with the components of a standard size, in the aqueous phase.
[0082] Photocatalytic webs based on mineral fibres were manufactured using a plant which makes it possible to carry out the impregnation of a glass web in a sizing solution, the application Os suction to this web (in order to remove the excess binder) and, finally, its baking in an oven, the entire process being carried out in-line and continuously. The web is unwound on a conveyor belt, conveyed into the sizing bath via an impregnation roller, passes above a negative-pressure tank (suction device) and is finally conveyed by a second conveyor belt into the baking oven.
[0083] Various types of photocatalytic media were synthesized according to this process, in accordance with the following examples:
EXAMPLE 5
A Medium for the Purification of Gases
[0084] An 80 g/m2 glass web was impregnated with an aqueous solution containing 3.1% of Glymo (glycidoxypropyltrimethoxysilane) and 2.9% of titanium dioxide nanoparticles at a rate of 0.2 m/min.
[0085] This web, having been subjected to a suction equivalent to a water column of 35 mm, was subsequently baked at 200° C. for 10 minutes. The resulting loss on ignition is 7%.
[0086] Measurements of effectiveness in the gas phase were then carried out under the following conditions: 150×200 mm 2 of the resulting product were placed in a cylindrical photocatalysis reactor. This reactor is composed of an axial UV-A lamp (365 nm), around which is surrounded, with a spacing of 1 cm, the photocatalytic medium in 3 layers, and of an aluminium jacket. The intensity of the irradiation on the web is 1 mW/cm 2 . The reactor is inserted in a closed circuit, with recirculation, the gas passing through the medium from the inside of the closed cylinder over the web towards the outside.
[0087] The volume of the cell (photocatalysis reactor) is 0.9 l and that of the complete circuit (immobilized volume) is one litre. The experiments consisted in evaluating the photocatalytic decomposition of n-hexane.
[0088] To do this, various amounts of n-hexane (ranging up to 2000 ppm in air) were injected into the circuit, the flow rate of the latter being regulated at 1 l/min. At regular intervals, 50 μl samples of gas were withdrawn in order to measure the concerntration of n-hexane present in the circuit.
[0089] It was shown that the direct decomposition by UV of n-hexane is negligible, just as its absorption by the medium. In constrat, n-hexane is virtually 100% decomposed in less than one hour when it passes through the photocatalytic medium, though under weak UV irradiation.
EXAMPLE 6
A Medium for Liquid Purification
[0090] According to the same process, a 60 g/m glass web was impregnated in an aqueous solution comprising 1 g/l of A1100 silane and 5 g/l of titanium dioxide (sold under the name P25 by Degussa) held in suspension by appropriate means.
[0091] The web was impregnated in-line at 0.6 m/min, the excess binder having been removed under a negative pressure of 90 mm of water column. The product was baked at 300° C. for 30 minutes. Measurements of effectiveness in the liquid phase were then carried out in order to describe this material.
[0092] A circular specimen of web (diameter 100 mm) was placed at mid-height in a 300 ml beaker. The bottom and the edges of the receptacle having been rendered opaque, the beaker is illuminated by a bank of UV-A lamps (365 mm) delivering a power of 3.5 mW/cm2 to the web. An aqueous solution (deionized water) containing 10 mg/l of phenol is poured into the device and is kept stirred magnetically. The decrease in concentration of the phenol is then monitored, samples being withdrawn at regular time intervals, by a UV spectrometer sold by Dr Lange.
[0093] It could be confirmed that virtually 100% of the phenol had disappeared over approximately at most one hour.
[0094] More generally, these last two examples show the advantage of the use of a web formed of photocatalytic mineral fibres, such as those manufactured, in purification operations in a liquid medium as in the gas phase. | A gas guiding device including a conduit configured to pass a gas, and a substrate on the conduit, the substrate including, a fibrous material, and a coating provided at least (i) over a portion of a surface of the fibrous material or (ii) within a volume of the fibrous material, the coating being configured to have photocatalytic properties and having at least a partially crystallized semiconducting material which has photocatalytic properties and which is of the oxide or sulphide type. | 2 |
BACKGROUND OF THE INVENTION
The present invention relates to a device having as main objects:
a) To illuminate the parts of the animal's body to be treated, which usually are in shadow due to the overall illumination of the environment;
b) To provide one or more tonalities of colored light so that the contrast with respect to the color of the animal's fur will allow to perceive even a single hair;
c) To allow the variation of the light intensity of the panel in order to adapt it to the environment's illumination, so that both the time interval required by the operator's eye to perceive the presence of objects (perception rapidity), and the capability of recognizing the smallest details, remain satisfactory (vision's sharpness);
d) To support the weight of the animal and to prevent damage-of the light-emitting panel and/or of the operator or the animal, due to ejection of urine.
In the specific field involving the treatment of animals, in particular cats and dogs, there exist simple tables characterized by a plane onto which the animal is laid as shown in FIG. 1. Said tables may be of fixed or adjustable in height, as shown in FIG. 2. There are tables having a plane with a rectangular shape and tables having a plane with a circular shape, the latter ones generally have a rotatable plane. There do not exist, until now, tables having a plane which consists of a light-emitting panel.
In other industrial fields, as for example hospital's X-ray photography rooms; photographic laboratories and technical design bureaus, there are used light emitting panels in the form of wall panels. The panels may also be horizontal or orientable, they may be supported by tripods, and they have in any case the function of permitting the vision of an X-ray photograph, a slide; a drawing; etc. In any case, said light emitting panels emit white light. Only if they are employed in photographic development laboratories will they emit colored light, in order to avoid to expose the film, in case it has not been already developed.
The primary object Of the present invention is to realize a light-emitting panel with one or more colorings, which is provided with a regulator of light intensity, which also has the function of supporting the animal in order to allow to execute on the same any operation concerned with the care of the animal such as shearing and coiffure, for example. Preventing fatiguing of the operator's eyes, the panel will allow work under perfect visibility conditions and perception of the smallest details as a result of the contrast between the color of the light emitted by the panel and the color of the animal's fur, and as a result of the possibility of adjusting the value of the light intensity of the panel itself.
The panel must also prevent urine which is possibly ejected by the animal, to cause damage to the panel, the operator or the animal itself, and it must be of a type which may be easily cleaned. Furthermore, the tables may comprise other additional features which are not provided by the tables of the art, and precisely including:
one or more drawers which contain the tools for the care of the animal;
a wrapping for the cable of the shearing machine (clipper) and a hook or support for the clipper; and
doors in order to permit the access inside the bodywork.
Said panel may be realized and employed separately, by simply placing it on known tables. Alternatively, it may be incorporated with a supporting structure so as to constitute the supporting plane for the animal.
SUMMARY OF THE INVENTION
According to the present invention the above mentioned objects are attained by means of a device comprising a box-like part provided with a transparent or translucid removable cover, and on whose inside there are one or more light emitting points, which may also have different colors and an adequate electric circuit allowing both to switch on one or the other among the colored light sources, and to adjust their intensity.
In order that the invention be better understood, and in order to show further advantages, two embodiments thereof will now be described with reference to the annexed drawings which are given only for illustrative and non-limitative purposes.
DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a first known table of fixed height;
FIG. 2 is a perspective view of a second known table of adjustable height;
FIG. 3 is a side elevational view of a first preferred embodiment showing the structure of the table;
FIG. 4 is an end elevational view of a first preferred embodiment showing the structure of the table;
FIG. 5 is a side elevational view of the first preferred embodiment including the bodywork, the drawers, the doors and the wrapping for the cable of the clipper;
FIG. 6 is a top plan view of the light emitting panel of a preferred embodiment of the present invention, without a cover;
FIG. 7 is a cross-sectional of the light emitting panel of a preferred embodiment taken along line a--a as shown in FIG. 6;
FIG. 8 is a cross-sectional view of a second preferred embodiment of the light emitting panel taken along line b--b as shown in FIG. 7;
FIG. 9 is a cross-sectional view of a third preferred embodiment of .the light emitting panel taken along line b--b as shown in FIG. 7;
FIG. 10 is a cross-sectional view of a fourth preferred embodiment of the light emitting panel taken along line b--b as shown in FIG. 7;
FIG. 11 is a cross-sectional view of a fifth preferred embodiment of the light emitting panel taken along line b--b as shown in FIG. 7;
FIG. 12 is a top plan view of a light emitting panel of the present invention, showing two circular neon tubes;
FIG. 13 is a top plan view of a light emitting panel of the present invention, showing an arrangement of four circular neon tubes.
FIG. 14 is a top plan view of an embodiment of the light emitting panel of the present invention, which uses electric bulbs and in which a ventilator is provided in order to generate an air flow which is heated by the heat radiated by the electric bulbs and may be used for drying up the animal.
FIG. 15 is a side cross-sectional view of the light emitting panel, taken along line c--c as shown in FIG. 14.
FIG. 16 is a side cross-sectional view of the light emitting panel, taken along line d--d as shown in FIG. 15.
FIG. 17 is a cross-sectional view of a preferred embodiment of the cover of the present invention, including a cover with a luminescent coating.
FIG. 18 is a cross-sectional view of a preferred box-like structure of the present invention, including a microswitch for disconnecting power to the light emitting source when the cover is removed.
FIG. 19 is a partially schematic cross-sectional view of a preferred box-like structure of the present invention, showing a photoelectric cell provided for adjusting an intensity of light emitted from the device in response to an intensity of light in the environment.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the FIGS. 3 to 13 there is shown a first embodiment of the table provided with the light emitting plane of the present invention. In the different figures, the same alphanumeric reference signs indicate the same parts and elements.
Making reference now to the FIGS. 3, 4 and 5, reference number 1 indicates a structure to which there is centrally mounted a linear pneumatic actuator 2 arranged vertically and operated by a manual pump 3 or automatically by means of a central control unit and respective control parts which are not shown. At the end of the rod of the actuator 2, there is assembled a light emitting panel 4 which is shown in FIGS. 6 to 13; therefore, by means of the actuator 2 it is possible to vary the height of the panel 4, with respect to the ground starting from a minimum value h1 until a maximum value h2 (shown in phantom in FIG. 3). In order to render more stable the panel 4, the structure 1 is formed by four tubular uprights 1/a along whose inside there are guided four telescoping columns 4/a which are integral with the light emitting panel 4. The pneumatic actuator 2 may be replaced by a mechanical actuator operated manually or by a motor; alternatively, it may be replaced by equivalent means having the function to lift and lower the light-emitting panel 4.
The structure 1, if it is perimetrically closed by means of panels, will allow the assembling of drawers 5 (shown in FIG. 5), and doors 6 in order to permit the access to the inside, and a wrapping 7 for the cable of the shearing machine 8, or clipper, which can be hooked to an upright 1/a.
The light emitting panel 4 as shown in FIGS. 6 through 13 is made up by a box like part 4/b provided with a cover 9; the latter is formed by a transparent or translucid material, and it is removable with respect to the box-like part 4/b. Said cover 9 may be simply supported or engaged as shown in FIG. 7, or it may be hinged or slipped in or out, for both purposes of allowing a quicker and easier access to the inside, in order to perform maintenance and cleaning operations, and also in order to facilitate cleaning of the cover.
Said cover may be obtained from a plate capable of being deformed by heat and having a sufficiently great thickness in order to resist to the stresses due to the weight and to the movements of the animal which will be placed on it, or it will be supported by small columns or spacers 11, shown in FIGS. 6 and 8.
The light emitting source may consist of linear fluorescent tubes or near neon tubes 10 (shown in FIGS. 6 through 11), or circular tubes 12 (shown in FIGS. 12 and 13, differently arranged. It may also consist of neon tubes with different configurations.
The electric current may be fed in the traditional manner or electronically. The emitted light may be used:
a) in a direct manner (shown in FIGS. 8, 9 and 10), whereby:
in FIGS. 8 and 10 the inner bottom 13 of the panel may be rendered more or less reflective (in FIG. 8 "mirrors" 14 arranged along the edges at an angle of 45° which will improve the luminosity along the periphery of the panel);
in FIG. 9 a plurality of parabolas 15 diffuse and reflect light in a more uniform way;
b) in an indirect manner (shown in FIG. 11), whereby the parabolas 16 direct the light towards the reflecting bottom 13.
Other solutions may consist in coating with a luminescent layer on the inner wall of the closing cover or the box-like inner wall.
In order to obtain colored light, there may exist different solutions:
to use colored tubes 10-12 with known configurations; even those partly of one color and partly of a different color;
to use white light tubes 10-12, and a cover 9 obtained from transparent colored plastic material; and
to use tubes 10-12 emitting white light, a white and transparent cover 9, a colored and transparent plate 17 interposed between the cover and the tubes (shown in FIG. 10), the plate being replaceable in case it is desired to change over to another coloring;
The gradual variation of the light intensity is obtained by known "regulators" which are controlled manually or connected to photoelectric cells which automatically adjust the luminosity of the panel so as to adapt it to the luminosity of the environment.
A second possible embodiment is shown in FIGS. 14, 15 and 16. In this embodiment all what has already been said remains valid except that the light emitting source consists of electric bulbs 18 or halogen lamps (quartz-iodine lamps); i.e. means which produce heat. In this embodiment, to the box-like part 4/b there is assembled a motor-driven ventilator or turbine 19; the air produced by it is heated by the glow lamps or electric bulbs 18; it is collected by the hood 20 onto which a hose is inserted (not shown) which ends into a frusto-conical sleeve collar used as a "phon" in order to dry up and to treat the animal.
In both embodiments there are provided one or more outlets for the insertion of the plug of an electrical shearing machine (clipper) or any other electrical device used by the operators. Obviously, the invention is not limited to the constructive details which have been shown and/or described, but it comprises all those variants and equivalent forms which are realized on the basis of the present inventive concept. We believe that also a table with fixed or adjustable height, provided with an usual non-luminous plane, is also included in the scope of the present invention, provided it comprises drawers, doors, electric outlets, and possibly cable wrappings, even if these additional features are singularly known and within the scope of one skilled in the art, since in our specific field they are new, if taken together, and their common use has never been suggested in the state of the art. The invention may be sold in the following forms:
fixed height table with incorporated light-emitting panel;
table with an adjustable height, comprising an incorporated light-emitting panel;
a single light-emitting panel to be laid on a table of every type whatever;
a table with an usual plane, i.e. non-luminous, which is fixed or adjustable in height, the table comprising drawers, doors, electric outlets and possibly a wrapping for a cable.
Although the present invention has been described with reference to the preferred embodiments, workers skilled in the art will recognize that changes may be made in form and detail without departing from the spirit and scope of the invention. | Table provided with a light emitting plane, for the treatment of pets. The invention includes a light emitting panel formed of a box-like structure, including a light emitting source, a cover for coloring the light; reflecting and diffusing surfaces for reflecting and diffusing the light, a photoelectric device for varying the intensity of the light and a removable cover. The invention also includes a support structure and a device for adjusting a height of the panel. | 0 |
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to Provisional Patent Application No. 60/458,112, filed Mar. 26, 2003, which is herein incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention is generally related to the handling of light bulbs. More specifically, the present invention is related to transporting, storage and disposal of light bulbs.
BACKGROUND
[0003] Light bulbs, such as fluorescent incandescent, halogen, etc., are utilized throughout the world as a means of illuminating an area. Unfortunately, light bulbs do not last forever, creating a need to dispose of the used light bulb and replacing it with a new one. Since light bulbs are generally filled with a gas or harmful metals, disposal of light bulbs can be dangerous and/or environmentally unsafe, if done without care. Shattering a light bulb is unsafe due to flying broken glass and, depending upon the type of light bulb being discarded, it may also potentially be unhealthy due to the exposure to the gas or heavy metal inside the light bulb.
[0004] Accordingly, there has existed a need to provide a safe and easy means for light bulb disposal.
SUMMARY OF THE INVENTION
[0005] The present invention provides apparatus, methods and articles of manufacture for the handling and disposal of glass light bulbs. An object of the present invention is to provide a system for disposing of light bulbs comprising a disposal tube having an open end. In a preferred embodiment the disposal tube is made of puncture resistant material, such as, a heavy plastic. Also in a preferred embodiment the disposal tube further comprises a paper liner for added protection.
[0006] Another object of the present invention provides means within the disposal tube for absorbing metals or gasses that may be released when the light bulb is broken, such as, a strip of sulfur-impregnated carbon paper, a desiccant package of sulfur-impregnated activated carbon granules, or a strip of sulfur chalk.
[0007] Yet another object of the present invention is to provide a method of handling and disposing of glass light bulbs comprising: providing a disposal tube having an open end and further comprising a paper liner with a strip of sulfur-impregnated activated carbon paper, a desiccant package containing sulfur-impregnated activated carbon granules or a strip of sulfur chalk; inserting the bulb into the disposal tube; closing and sealing the open end of the disposal tube; striking the sealed disposal tube with a blunt force object; and disposing the glass from the bulb.
[0008] It is another object of the present invention to provide a method of transporting light bulbs comprising: providing a disposal tube, inserting the light bulb into the disposal tube; sealing the disposal tube for safe transit; and transporting the light bulb in the disposal tube. The tube provides for secure collection of the glass and gasses if the bulb is broken during transit and can also be used for the disposal of the light bulb when the bulb is no longer useable.
[0009] Additional objects, advantages and novel features of the invention will be set forth in part in the description and figures which follow, all of which are intended to be for illustrative purposes only, and not intended in any way to limit the invention, and in part will become apparent to those skilled in the art on examination of the following, or may be learned by practice of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there are shown in the drawings, certain embodiment(s) which are presently preferred. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities shown.
[0011] [0011]FIG. 1 is an illustration of an exemplary disposal tube in accordance with a preferred embodiment of the present invention for long fluorescent tubes.
[0012] [0012]FIG. 2 is an illustration of an exemplary disposal tube in accordance with an alternative embodiment of the present invention with heavy paper liner and a desiccant package containing sulfur-impregnated activated carbon.
[0013] [0013]FIG. 3 is an illustration of an exemplary disposal tube in accordance with an alternative embodiment of the present invention with heavy paper liner and a strip of sulfur-impregnated activated carbon paper.
[0014] [0014]FIG. 4 is an illustration of an exemplary disposal tube in accordance with an alternative embodiment of the present invention with heavy paper liner and a strip of sulfur-impregnated activated carbon paper for a compact fluorescent lamp.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0015] Reference is now made to the accompanying Figures for the purpose of describing, in detail, preferred embodiments of the present invention. Like elements have the same numbers throughout the several views. The detailed description accompanying each Figure is not intended to limit the scope of the claims appended hereto.
[0016] An embodiment of the present invention comprises a disposal tube 10 for placing a light bulb to be disposed of therein. FIG. 1 is an exemplary illustration of disposal tube 10 in accordance with a preferred embodiment of the present system for disposing of or handling one or more light bulbs. For purposes of this disclosure, a fluorescent light bulb will be used for exemplary purposes and should not be considered to limit the application of the present invention. The light bulbs suitable for disposal by the disposal bag of the present invention preferably comprise globes of glass or other breakable materials.
[0017] In addition to the depicted fluorescent bulb, other types of light bulbs including, but are not necessarily limited to, halogen, incandescent, high intensity discharge, etc., may also utilize disposal tube 10 . Accordingly, disposal tube 10 may be sized from less than three inches in length to more than three feet in length to accommodate the available variety of light bulbs, ranging from standard residential light bulbs to light bulbs used in vehicles or large commercial applications.
[0018] Disposal tube 10 may be made of any type of puncture resistant material, including paper, plastic, rubber, and the like, or combinations thereof. In accordance with a preferred embodiment, it is preferable that disposal tube 10 be made of a paper liner 20 within light mil puncture resistant plastic, such as 2 mil plastic. Thus, in the preferred embodiment, the selected puncture resistance plastic and the selected paper liner 20 , together or each alone, is of sufficient thickness not to be pierced by shards of broken glass. At the same time, the material of disposal tube 10 is sufficiently flexible to allow the insertion of one or more light bulbs, and to allow the inserted light bulbs to be shattered by a means external to disposal tube 10 . A one-size fits all disposal tube 10 is preferably used and adjusted for the particular bulb as described below. The length and diameter of disposal tube 10 may alternatively be dependent upon the length and diameter of the light bulb being disposed.
[0019] In a preferred embodiment, disposal tube 10 comprises heavy paper or a heavy paper liner 20 (as shown in FIG. 2) to help absorb the impact during bulb breakage and improve the puncture resistance of the disposal tube.
[0020] In an alternative embodiment, paper liner 20 incorporates a strip of sulfur-impregnated activated carbon paper 30 (as shown in FIG. 3). In another alternative embodiment, a desiccant package 40 containing sulfur-impregnated activated carbon granules (as shown in FIG. 2) is placed inside tube 10 . In yet another embodiment, a strip of sulfur chalk 50 (as shown in FIG. 4) is applied to the inside of paper liner 20 . Alternatively, sulfur is contained within paper liner 20 . The strip of sulfur-impregnated activated carbon paper 30 , desiccant package containing sulfur impregnated activated carbon granules 40 , or sulfur chalk strip 50 allow disposal tube 10 to absorb the mercury included in the fluorescent bulb. In alternative embodiments, one skilled in the art would know of other chemicals that would be suitable and may be used for absorbing the mercury or absorbing other metal or gases that may be used in other light bulbs, or released when the bulbs are broken.
[0021] Disposal tube 10 is formed such that it is cylindrical in shape, having two ends. One end is open 11 and the opposing end 12 is closed (as shown in FIG. 1). Disposal tube 10 may be formed as a seamless bag or sleeve with one open end and one closed end. Alternatively, disposal tube 10 may be produced from one or more sheets of material formed into the cylindrical shape of a bag or sleeve. Closed end 12 prevents the light bulb from passing through disposal tube 10 . Open end 11 of disposal tube 10 is open to permit insertion of the fluorescent bulb, or any bulb to be transported, stored or discarded. Once the bulb has been inserted into tube 10 , open end 11 may be closed and sealed using any means of sealing such an opening, such that no pieces of glass are able to escape from tube 10 when the bulb is shattered. Such closure means include, but are not limited to, twist tie, clasp, clip, clamp, staple, Velcro, drawstrings, tape, pre-applied adhesive strip, pre-applied adhesive strip with a removable protective strip, fold over tabs, and the like. The sides of open end 11 may simply be drawn together or joined in the closure process, or open end 11 of the bag may be folded over one or more time before the closure means is applied, thereby sealing the bag.
[0022] The preferred method for disposing of a fluorescent bulb using disposal tube 10 in accordance with a preferred embodiment is set forth below. A user slides the fluorescent bulb fully into disposal tube 10 (Step 100 ). Open end 11 of disposal tube 10 is then sealed, preferably close to the end of the bulb (Step 101 ). Disposal tube 10 is then preferably placed on the ground and struck with a hammer, mallet or similar blunt force object without danger of injury from broken glass (Step 102 a ). Alternatively, disposal tube 10 may be dropped from a low height onto a hard surface, such as a garage floor or driveway, to avoid danger of injury from broken glass (Step 102 b ). The broken glass inside disposal tube 10 is then discarded (Step 103 ). Disposal tube 10 may be hit in other places to break the bulb into smaller pieces before disposing of disposal tube 10 . In a preferred embodiment, disposal tube 10 is disposed of along with the glass. Therefore, each disposal tube 10 is utilized for a single bulb.
[0023] In an alternative embodiment, disposal tube 10 is reusable, wherein open end 11 is simply closed, but not sealed, after the bulb is inserted, and the broken glass is disposed of in a trash can and disposal tube 10 is reusable for the disposal of other bulbs. In yet another embodiment, disposal tube 10 is used to shatter and dispose of multiple bulbs at one time.
[0024] In still another embodiment, disposal tube 10 is used as packaging material, particularly for the sale or distribution of a new fluorescent bulb, although it may also be applied for handling by the user, such as in the home, office or institution. In this way, shopping for and transporting the new bulb is made safer for the customer in the event that the bulb is broken before the customer is able to install it at home or wherever the bulb will be used. In addition, once the bulb has been safely transported and removed from disposal tube 10 , the disposal tube 10 can then be used for disposal of the old bulb when it is removed or replaced. Until such time as the new bulb is used, it can remain safely in disposal tube 10 during storage, again providing a level of safety if the bulb is broken for any reason while being stored.
[0025] The disclosures of each patent, patent application and publication cited or described in this document are hereby incorporated herein by reference, in their entirety.
[0026] While the foregoing specification has been described with regard to certain preferred embodiments, and many details have been set forth for the purpose of illustration, it will be apparent to those skilled in the art without departing from the spirit and scope of the invention, that the invention may be subject to various modifications and additional embodiments, and that certain of the details described herein can be varied considerably without departing from the basic principles of the invention. Such modifications and additional embodiments are also intended to fall within the scope of the appended claims. | Provided is a system, apparatus and methods of use for the safe and easy handling and disposing of light bulbs. The system provides a disposal tube comprising one or more layers of puncture resistant material and a means for absorbing metals or gasses that may be released when the light bulb is broken, such as by externally striking the disposal tube and the bulb contained therein. The invention also provides a method for using the disposal tube as a means to safely handle and store the light bulbs. | 1 |
FIELD
[0001] The invention generally pertains to the field of construction tools, and more particularly to sander tools having a pivoting handle mechanism, to aid in the sanding of surfaces.
BACKGROUND
[0002] Sanding tools are used to finish surfaces, such as seams between drywall panels where excess drywall compound has been applied, or in smoothing other surfaces perhaps as a preliminary step to further finishing steps such as applying paints, varnishes or adhesives.
[0003] A problem exists, however, when sanding surfaces within a room which contains both wall sections which are easily within reach, as well as surfaces which one cannot easily reach without some sort of assistance. This problem has been previously solved through the use of such items which elevate the user, such as drywall stilts, drywall benches, ladders, and the like. These solutions, because they place the user at an elevated position, place the user at risk of being injured by a fall. In addition, it is cumbersome to lug around this additional equipment and time consuming to set up and change positions using these devices. Other solutions involve the use of separate hand sander devices for the vertical surfaces which are within reach, and then a separate sanding tool having a pole attached for the out-of-reach surfaces, such as ceilings. The problem with this last approach is in having twice the number of tools necessary to finish the surfaces. Not only does the user have to keep track of and carry these extra items to each jobsite, but he or she has to be careful to maintain the same type and grit of sandpaper loaded in each so that the resulting surface finishes match one another.
[0004] The applicants' Sander Tool Apparatus, the subject of U.S. Pat. No. 4,885,876, provides for interchangeable top structures of a sanding tool—one with a handle for sanding surfaces within the user's reach, and one with a universal joint and threaded pole coupler, in addition to a threaded pole, for reaching distally located surfaces.
[0005] The present disclosure discloses a sander tool which solves many of these problems that are associated with existing sander tools. It will be appreciated that the disclosure may disclose more than one invention. The invention(s) is(are) pointed out with particularity in the claims annexed hereto and forming a part hereof.
BRIEF SUMMARY
[0006] The invention(s) generally relate to sander tools suited for sanding planar surfaces.
[0007] A preferred embodiment of a sander tool includes an ergonomically shaped handle which is pivotally connected to a housing which includes a unit base and a unit pedestal. The handle pivots about a first pivotal axis through a wide range of angles to accommodate a variety of comfortable arm, wrist, and hand positions for the sanding of surfaces.
[0008] In one embodiment, the ergonomic handle includes an upper portion, an intermediate portion, and a lower portion. The upper portion is suitable for gripping by the user; the intermediate portion extends downward at both a first and a second end with an open area between the first and second ends to allow for the placement of the user's hand between the upper portion and the lower portion. The lower portion of the handle contains the first pivotal axis, defined by a pair of handle pivot cones, and is pivotally attached to a pivotal handle mounting surface of the housing.
[0009] A preferred embodiment of a sander tool also includes sandpaper retention mechanisms for releasably retaining the sandpaper on the back surface of a unit base.
[0010] In one embodiment, the retention mechanism includes a sandpaper retainer pivotally connected to a housing about a third pivotal axis. In addition, latches, integrally molded with the housing member, are provided for releasably latching the sandpaper retention mechanism in a closed position.
[0011] One advantage of one embodiment of the sander tool is that it saves the user the inconvenience of suffering strained arm, hand, and finger muscles and ligaments which readily occurs with standard hand sanders.
[0012] Another preferred embodiment of a sander tool includes a pivoting pole assembly which additionally allows the user to conveniently sand surfaces which are not within reach by simply attaching a pole to a pivotal pole connector. The pivoting pole is preferably connected to a pivotal pole connector located inside an upper portion of a handle through the use of mating threads, although other suitable fastening methods might be utilized.
[0013] One embodiment relates to a kit assembly including a sander tool with a pivotal pole connector and a pole, whereby the sander tool can be readily converted from a hand sander to a pole sander upon releasable attachment of the pole to the pivotal pole connector. Another embodiment relates to a kit assembly including a sander tool with sheets of sandpaper. Yet another embodiment relates to a kit assembly including a sander tool, a pole, and sheets of sandpaper.
[0014] The above-mentioned advantages of the various embodiments are only representative and illustrative. The invention(s) is (are) pointed out with particularity in the claims annexed hereto and forming a part hereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 is a perspective view of a preferred embodiment of a sander tool.
[0016] FIG. 2 is an exploded view of the embodiment shown in FIG. 1 with a pivoting handle and a pivoting pole connector.
[0017] FIG. 3 is a side view of the embodiment shown in FIG. 1 showing both sandpaper retainers pivoted to an open position so that sandpaper may be loaded on to sandpaper retaining spikes.
[0018] FIG. 4 is a front view of the embodiment shown in FIG. 1 showing the range of motion of the pivoting handle (shown in broken lines).
[0019] FIG. 5 is a perspective view of the embodiment shown in FIG. 1 of a sander tool showing a pole attached to the pivoting pole connector which allows the user to sand out-of-reach surfaces.
[0020] FIG. 6 is a side view of the embodiment shown in FIG. 1 showing the range of motion of the pivoting pole connector (shown in broken lines).
[0021] FIG. 7 is a plan view of the embodiment shown in FIG. 1 .
DETAILED DESCRIPTION
[0022] Referring to the drawings, wherein like reference numerals generally designate identical or corresponding parts throughout the several views, and more particularly to FIGS. 1 and 2 , there is shown a preferred embodiment of a sander tool having many components, designated generally by the numeral 20 .
[0023] The sander tool 20 includes a housing 70 to which a handle 30 is pivotally attached at a first pivotal axis 22 which is located in a longitudinal direction of the sander tool 20 . The housing 70 includes a unit base 40 , which has a substantially planar bottom side, and a unit pedestal 50 which is attached to the top side of the unit base 40 . Preferably, the sander tool is three inches wide and of such a length that a user can cut a standard 9″*11″ piece of sandpaper in thirds and has no waste of the sandpaper. The handle 30 pivots about the first pivotal axis 22 through a wide range of angles to accommodate a variety of comfortable arm, wrist, and hand positions for the sanding of surfaces. In addition, the handle includes an upper portion 74 , an intermediate portion 76 , and a lower portion 78 . The upper portion 74 is suitable for gripping by the user; the intermediate portion 76 extends downward at both a first and a second end with an open area between the first and second ends to allow for the placement of the user's hand between the upper portion 74 and the lower portion 78 . The lower portion 78 of the handle 30 contains the first pivotal axis 22 , defined by a pair of pivotal cones 38 , and is pivotally attached to a pivotal handle mounting surface 52 of the unit pedestal 50 of the housing 70 . As shown in FIG. 2 , the preferred embodiment of the sander tool 20 is made to be conveniently assembled through the use of resilient snap-fit features on the components, and thus does not require screws, and the like in the assembly of the sander tool 20 . Other embodiments, however, may include threaded screws or other fasteners in assembly.
[0024] Embodiments optionally include a foam pad 90 attached to the planar bottom side of the unit base 40 . The foam pad 90 is made from a foam material such as polyethylene or urethane foams, for example, and is preferably at least 1/16″ thick. The foam pad 90 helps accommodate imperfections in the sanding surfaces and may be adhesively mounted to the unit base 40 using common adhesives, or preferably double-sized adhesive tape.
[0025] Sandpaper retention mechanisms are located at each end of the housing 70 , as shown in FIG. 3 (without the sandpaper). In the preferred embodiment, a sandpaper retainer 60 is pivotally connected at a third pivotal axis 26 to each end of the housing 70 . In addition, a resilient latch 64 is integrally molded with the unit base 40 of the housing 70 for releasably latching the sandpaper retainer 60 in a closed position. The latch 64 is outwardly biased for engagement with the sandpaper retainer 60 . Sandpaper retaining spikes 66 are also integrally molded into the unit base 40 , and mating sandpaper retainer bosses (not shown), which secure the sandpaper on the sandpaper retaining spikes 66 , are integrally molded into the sandpaper retainer 60 .
[0026] FIG. 4 shows an angle Ψ (from vertical, as shown) through which the handle 30 may rotate about the first pivotal axis 22 (which has a direction perpendicular to FIG. 4 ), in either direction. In the embodiment shown, the handle may rotate through an angle Ψ of about 60° in either direction from vertical, although other embodiments may include rotation through an angle Ψ of 90° in either direction from vertical. It is preferred that the angle Ψ be through an angle of at least 60° in either direction of vertical; more preferably the angle Ψ may be through an angle of at least 30° in either direction from vertical; most preferably the angle Ψ may be through an angle of at least 20° from vertical.
[0027] Referring now to FIG. 5 , a perspective view of the sander tool 20 with a pole 80 pivotally connected to the handle 30 by a pivotal pole connector 36 . The pivotal pole connector 36 is conveniently recessed within the upper portion 74 of the handle 30 so that its 36 outer surface is flush with the handle 30 so that the pivotal pole connector 36 does not interfere with gripping the handle 30 while using the sanding tool 20 on surfaces in close proximity to the user.
[0028] In order to sand surfaces located at a distance from the user, the user simply rotates the pivotal pole connector 36 upward slightly, attaches the pole 80 , which in the embodiment shown is threaded, to the pivotal pole connector 36 , by, for example, threading the pole into an internally threaded cylindrical receptacle 72 located at either end of the pivotal pole connector 36 . Other embodiments include a pole 80 connected to a sander tool 20 using quick-release connectors, for example, bayonet-type fittings, snap-fit connectors, and the like.
[0029] FIG. 6 shows an angle Φ (from horizontal) through which the pivotal pole connector 36 may rotate about a second pivotal axis 24 in either direction. The second pivotal axis 24 is orthogonal to the first pivotal axis 22 . In the embodiment shown, the pivotal pole connector 36 may rotate through an angle Φ of 30° in either direction from horizontal, although other embodiments may include rotation through an angle Φ of 90° in either direction from horizontal.
[0030] Additionally, a preferred embodiment has a thin wall construction thereby providing a light weight sander. In addition to being light weight, the sander tool includes reinforcement structure such that it is strong and rigid. The components are preferably molded from plastic compounds, although die-casting methods would additionally work using appropriate metal alloys. It will be appreciated that the unit base and unit pedestal structures are designed so that in molding, there is no need for cams, which results in faster molding and a lower mold cost. In addition, the sander tool is preferably held together through the use of snap-fit joints, although other assembly techniques involving such methods as sonic welding and/or the use of fasteners, such as threaded fasteners is contemplated and may be used.
[0031] In addition, level of friction between the bearing surfaces, may be tailored through various mechanisms well known to skilled artisans, so that, for example, the components are free standing. This applies to the components of all three pivotal axes 22 , 24 , and 26 of the pivotal sander 20 in the case where a pole is not attached.
[0032] In one embodiment of the present invention, the sander tool 20 , and the threaded pole 80 might be sold as a kit assembly, thereby effectively providing two sander tools in one kit. The kit may additionally include sheets of sandpaper.
[0033] In use, sandpaper is first secured to the pivotal sander 20 . To secure sandpaper, the latch 64 is depressed, the sandpaper retainer 60 is lifted, as shown in FIG. 3 , and the end of the sandpaper piece is pushed downward so that sandpaper retaining spikes 66 , integrally molded into the unit base 40 , pierce through the sandpaper. Then the sandpaper retainer 60 is pushed back into place, the latch re-engages the sandpaper retainer 60 , and sandpaper retainer bosses (not shown) located on the underside of the sandpaper retainer 60 hold that end of the sandpaper in place. The same procedure is then repeated at the other end of the pivotal sander, and the unit is operational.
[0034] Next, if the user wishes to sand surfaces located within arm's reach, he or she grips the pivotal sander 20 by the upper portion 74 of the handle 30 , with fingers freely extending within the intermediate portion 76 , positions the bottom side of the unit base 40 on the surface to be sanded, and moves the unit back and forth while applying pressure, preferably along the longitudinal (lengthwise) axis of the unit, until the desired surface finish is achieved. Using various grit sizes of sandpaper may be required for efficiently obtaining the desired result, depending upon the particular circumstances.
[0035] Alternately, if the user wishes to sand surfaces located at a distance, he or she threads a threaded pole into the pivotal pole connector 36 of the handle 30 until tight. Next, he or she positions the bottom side of the unit base 40 on the surface to be sanded, and moves the unit back and forth while applying pressure, preferably along the longitudinal (lengthwise) axis of the unit, until the desired surface finish is achieved.
[0036] It should be understood that even though these numerous characteristics and advantages of various embodiments have been set forth in the foregoing description, together with details of the structure and function of the embodiments, the disclosure is illustrative only, and changes may be made in detail, especially in matters of shape, size and arrangement of parts within the principals of the invention(s) claimed in the appended claims to the full extent indicated by the broad general meaning of the terms in which the appended claims are expressed. | Disclosed is a sander tool suited for sanding planar surfaces, and mechanisms enabling the pivoting of an ergonomic handle. Also disclosed is a sander tool having a detachable pole for use in reaching areas located outside the user's normal reach. | 1 |
BACKGROUND OF THE INVENTION
[0001] Virtually all joints have cartilage. Cartilage is important in the body of animals for providing flexibility, compressability under pressure, cushion, tensile strength, ranges and smoothness of movement within joints. Healthy, well developed cartilage is relatively resistant to deterioration over time. Poorly developed cartilage is more susceptible to damage that leads to disease. Examples of joints having cartilage include fingers and toes, neck, knee, hip, shoulder and the like. Animals can suffer from a number of conditions where cartilage is negatively affected thereby bringing about a reduction in the joint's flexibility, compressability and often times resulting in a generalized inflammation of the joint and/or tissue surrounding the joints. Such animal then has significant loss of joint function and experiences pain. Another measure of cartilage health is the quantity of abnormalities visually on the cartilage observed after sacrifice of the animal. The higher the abnormalities, the further the overall joint is weakened which makes it more susceptible to a condition or exacerbates an existing condition. These conditions include arthritis, osteo and rheumatoid, osteochondrosis, degenerative joint disease, synovitis, bacterial purulent arthritis, osteoarthropathia and psoriatica among others. The visualized cartilage abnormalities include lesions in general, erosions, and abnormal growths. Other ways of observing cartilage abnormalities without sacrifice of the animal include MRI, computerized tomography and radiography.
[0002] We have now found a method and composition for reducing the quantity of cartilage abnormalities in those animals in need of said assistance. These animals can already have classical symptoms of the condition(s) or can be susceptible of such condition(s), the latter for example being a large breed dog having hip dysplasia problems which can bring about arthritis or similar conditions. Such assistance can even be given to animals in no apparent immediate need of such assistance but wherein growth of cartilage occurs as in the younger years or approaching an age where such conditions are relatively commonplace, for example “old age”.
[0003] The assistance is provided by the use of certain quantities of a sulfur containing amino acid, such as methionine, and manganese administered in a systemic manner, such as orally, in a food, liquid or dosage unit form. The data in the specification shows that cartilage abnormalities as measured visually are substantially decreased using the invention. The reduction of cartilage abnormalities enhance the joint health and make the joint less susceptible to physical damage and cartilage destruction conditions such as arthritis and other conditions which attack the joint and cartilage.
SUMMARY OF THE INVENTION
[0004] In accordance with the invention, there is a method for decreasing cartilage abnormalities in an animal in need of such decrease which comprises administering to said animal a cartilage abnormality decreasing effective amount of at least one sulfur containing amino acid and manganese.
[0005] Another aspect of the invention is a method for preventing degradation of cartilage tissue in an animal in need of said prevention which comprises administering to said animal a cartilage degradation prevention effective amount of at least one sulfur containing amino acid and manganese.
[0006] An additional aspect of the invention is a composition suitable for systemic administration to an animal comprising a cartilage abnormality decreasing amount of at least one sulfur containing amino acid and manganese in association with a carrier.
[0007] Further, the various modes of action of the sulfur containing amino acid and manganese can bring about each or a combination of the following effects:
(a) enhancing cartilage development in an animal; (b) preventing disease associated with cartilage degradation in an animal; and (c) treating disease associated with cartilage degradation in an animal. All of such above effects can be directed to animals in need thereof.
[0011] There are many other aspects of the invention disclosed throughout this specification.
DETAILED DESCRIPTION OF THE INVENTION
[0012] An animal as used throughout the specification includes human, dog, cat, horse, goat, sheep, swine, cattle, birds including turkeys and chickens, and the like. Preferred are humans, dogs, cats, horses and swine.
[0013] Cartilage affecting conditions wherein cartilage abnormalities are significant are those which are particularly managed by the administration of the sulfur containing amino acid and manganese. Illustrative examples of such conditions include osteoarthritis, rheumatoid arthritis, osteochondrosis, degenerative joint disease, synovitis, bacterial purulent arthritis, osteoarthropathia, and psoriatica.
[0014] The active material(s) of the invention can be administered in any systemic manner.
[0015] The amino acid and manganese can be administered to the animal, preferably one in need of such administration, in any one of many ways, such as oral, parenteral, and the like, although oral is preferred. The amino acid and manganese can be administered in a wet or dry diet, either incorporated therein or on the surface of any diet component, such as, by spraying or precipitation thereon. They can be present in the nutritional diet per se or in a snack, supplement or a treat. They can also be present in the liquid portion of the diet such as water or another fluid. They can be administered as a powder, solid or as a liquid including a gel. If desired they can be orally administered in a pharmaceutical dosage form such as a capsule, tablet, caplet, syringe, and the like. Within the dosage form they can be present as a powder or a liquid such as a gel. Any of the usual pharmaceutical carriers can be employed such as water, glucose, sucrose and the like together with the amino acid and manganese. Although exemplified together, the amino acid and manganese can be administered separately, that is one in a diet and one in a liquid or a unit dose form, for example. Generally, they should be administered at least concomitantly, and preferably in the same carrier. When administered in a food, the sulfur containing amino acid and manganese can be administered as a compound, within the normal food constituents, or a combination of the two.
[0016] With respect to prevention of joint damage from arthritis, particularly osteo, or other noted conditions, a particular target group of pets, especially canines and felines, are those that would be in need of such preventative care as opposed to the general population. For example, pets, particularly large breed canines such as labrador retriever, rottweiler, german shepherd and the like are more susceptible to arthritis as demonstrated by its greater occurence in these pets. Additionally, pets above the age of six (6) years, particularly dogs and cats, have a significantly greater occurrence of arthritis, particularly osteo arthritis. Other examples of pets susceptible to the development of arthritis include horses. The invention can be additionally useful in treating animals especially canines and felines with arthritis, particularly osteo. Although exemplified with arthritis, other cartilage and joint affecting conditions, previously mentioned, are also applicable.
[0017] Various sulfur containing amino acids and their derivatives are applicable in the invention. These include D-methionine, L-methionine, DL-methionine, D-cysteine, L-cysteine, DL-cysteine, D-cystine, L-cystine, DL-cystine, S-adenosylmethionine, betaine, beta-hydroxy analog of methionine, and the like. The sulfur containing amino acid can be provided per se to the animal or can be present naturally in dietary materials such as fish meal, corn gluten meal, poultry meal, casein, manganese methionine (a chelate) and the like.
[0018] The manganese can be supplied to the animal in various forms including manganous sulfate, manganous oxide, manganous dioxide, manganous carbonate, manganous chloride, manganese proteinate, manganese chelate, manganese monoxide, manganese methionine, and the like.
[0019] The quantity of amino acid and manganese which should be employed for bringing about the effect(s) of the invention can vary substantially. All wt % are calculated on a dry matter basis of a daily diet sufficient to satisfy the nutrition needs of the animal. A minimum amount of the amino acid is above about 1.2 wt %, preferably above about 1.5 wt % and more preferably above about 1.8 wt %. The minimum amount of manganese is above about 50 ppm, preferably above about 75 ppm and more preferably above about 100 ppm. For example, a specific amount can be employed in the usual nutrient food ration on a daily basis or the same daily quantity can be provided to the animal in a treat or supplement on a daily basis. Additionally, a combination of these methods or any other dosing means can be employed as long as the effective quantity of sulfur containing amino acid and manganese is provided. Maximum quantities are any amount effective to reduce the quantity of cartilage abnormalities with little (acceptable level) or no toxicity. Examples of such quantities for the amino acid include not more than about 2.6 wt %, 2.3 wt % and 2.0 wt % on the same basis as for the minimums. Examples of such quantities of manganese include not more than about 200 ppm, preferably about 175 ppm and more preferably about 150 ppm on the same basis as the minimums.
[0020] As aforementioned, the amino acid and manganese can be in any food provided to the pet. Examples of such foods are regular diets providing all of the animal's nutrients, treats, supplements and the like. The actives can be provided in liquids or in pharmaceutical dosage forms such as capsules, tablets, pills, liquids or even parenterally administered through syringe. The most important aspect is that the pet be provided an effective amount of actives to reduce the abnormalities. The preferred route of aministration is oral and incorporated with a food. Foods are generally classified in the pet food industry as “wet” or “dry”. A wet food has a relatively high amount of water and is usually present in a can or a container wherein air is substantially or totally excluded. Examples of such foods are “chunk and gravy”, individual solid particles in the presence of a liquid gravy or a loaf type material which generally takes the shape of the receptacle. The dry food is generally a baked or preferably extruded material, the latter then cut into individual shaped portions, usually known as kibbles. The actives are readily incorporated into a wet food through conventional means.
[0021] With respect to pet food such as dog and cat the ranges of protein, fat and carbohydrate for a dog is 15-55 wt %, 5-40 wt %, 10-50 wt % respectively and for a cat is 15-55 wt %, 5-40 wt % and 10-50 wt % respectively.
[0022] Below are examples. These examples are illustrative exemplification of the broad scope of the invention.
[0023] Growing pigs (80 experimental units) were used as test model to determine the effect of methionine and manganese on cartilage abnormalities. The pigs were initially about 35 kg. Each pig was individually housed in 5.2 ft 2 pens with ad libitum access to food and water. The pigs were fed test foods for a period of 60 days to an approximate final weight of about 130 kg.
[0024] At the point of meat fabrication, the distal aspect of the right femur bone was collected and evaluated for gross- and histopathology.
[0025] The distal aspect of the right femor bone was preserved in formaldehyde, and stored at room temperature for gross observation. The joints were evaluated for the total number of lesions present on the joint surface (including clinical lesions, cartilage erosions, and abnormal growth patterns). Gross lesions were confirmed by histopathology characterization. Tissues sections were taken from the ventral weight barring aspects of the medial femoral condyle. Measures were evaluated on 2× and 10× photomicrographs to determine cell counts and to confirm pathological damage of the cartilage into the subchondral bone.
EXAMPLES 1, 2 and 3
[0026]
TABLE 1
Composition of Experimental Foods
Control
Example 1
Example 2
Example 3
Corn
71.00
78.50
71.00
71.00
Soybean meal
18.70
3.35
18.70
18.70
Corn Starch
3.78
3.00
2.52
2.48
Ch White Grease
3.00
1.00
3.00
3.00
Dical
1.97
1.13
1.98
2.03
Limestone
0.62
0.28
0.77
0.74
Salt
0.43
0.31
0.55
0.55
L-lysine
0.15
0.08
0.15
0.15
Vitamin premix
0.10
0.10
0.10
0.10
Choline
0.10
0.10
0.10
0.10
TM premix
0.10
0.10
0.10
0.10
Mn sulfate
0.02
0.02
Tryptophan
0.03
Poultry Meal
12.00
DL-methionine
0.04
1.03
1.03
Total
100
100
100
100
100% DM basis
ME. Kcal/kg
3604
3634
3604
3604
Ca, %
0.86
0.85
0.86
0.86
P, %
0.74
0.74
0.74
0.74
Na, %
0.22
0.22
0.22
0.22
Lys, %
0.97
0.96
0.97
0.97
TSAA, %
0.58
0.60
1.71
1.71
Trp, %
0.20
0.20
0.20
0.20
Thr, %
0.66
0.70
0.66
0.66
Iso, %
0.65
0.65
0.65
0.65
Sulfur, ppm
1664
2229
4147
4238
Manganese, ppm
41.3
107.8
41.2
127.4
[0027]
TABLE 2
Analytical analyses of experimental foods - lot 1
Control
Example 1
Example 2
Example 3
Crude protein
17.32
18.34
16.63
16.93
Fat
7.76
7.58
7.46
7.42
Fiber
2.05
1.73
2.23
2.37
Methionine + Cystine
0.70
0.72
1.51
1.78
Manganese
46.4
81.2
43.4
110.0
[0028]
TABLE 3
Analytical analyses of experimental foods - lot 2
Control
Example 1
Example 2
Example 3
Crude protein
17.38
18.43
19.30
17.94
Fat
6.83
7.89
7.54
7.46
Fiber
2.91
1.82
2.47
2.22
Methionine + Cystine
0.68
0.78
1.61
1.56
Manganese
41.8
96.8
42.2
110.1
[0029]
TABLE 4
Effect of nutrients on cartilage abnormalities
Control
Example 1
Example 2
Example 3
Total lesions
2.38
2.25
1.38
0.88
[0030] As shown by the data, a combination of the sulfur containing amino acid and manganese (manganous ion) are required to statistically reduce the number of visually observed abnormalities (lesions and erosions) abnormalities of the cartilage, see Example 3. Neither examples 1 nor 2 bring about a statistically significant reduction in abnormalities. Example 1 is high in manganese but approximately the same in sulfur containing amino acid as control. Example 2 is high in sulfur containing amino acid but approximately the same in manganese as the control. | A method for decreasing cartilage abnormalities in an animal in need of such decrease which comprises systemically administering to said animal a cartilage abnormality decreasing effective amount of a combination of at least one sulfur containing amino acid and manganese. | 0 |
RELATED APPLICATION
This application is a continuation-in-part of my copending application U.S. Ser. No. 168,349, filed July 11, 1980 (now abandoned).
BACKGROUND OF THE INVENTION
α,2-Toluenedisulfonamide derivatives are useful as agricultural chemicals and in particular as herbicides.
French Pat. No. 1,468,747 discloses the following para-substituted phenylsulfonamides, useful as antidiabetic agents: ##STR1## where R=H, halogen, CF 3 or alkyl.
Logemann et al., Chem. Ab., 53, 18052 g (1959), disclose a number of sulfonamides, including uracil derivatives and those having the formula: ##STR2## wherein R is butyl, phenyl or ##STR3## and R 1 is hydrogen or methyl. When tested for hypoglycemic effect in rats (oral doses of 25 mg/100 g), the compounds in which R is butyl or phenyl were most potent. The others were of low potency or inactive.
Wojciechowski, J. Acta. Polon. Pharm. 19, P. 121-5 (1962) [Chem. Ab., 59 1633 e] describes the synthesis of N-[(2,6-dimethoxypyrimidin-4yl)aminocarbonyl]-4-methylbenzenesulfonamide: ##STR4## Based upon similarity to a known compound, the author predicted hypoglycemic activity for the foregoing compound.
Netherlands Pat. No. 121,788, published Sept. 15, 1966, teaches the preparation of compounds of Formula (i), and their use as general or selective herbicides: ##STR5## wherein
R 1 and R 2 may independently be alkyl of 1-4 carbon atoms; and
R 3 and R 4 may independently be hydrogen, chlorine or alkyl of 1-4 carbon atoms.
Compounds of Formula (ii), and their use as antidiabetic agents, are reported in J. Drug. Res. 6, 123 (1974): ##STR6## wherein R is pyridyl.
The presence of undesired vegetation causes substantial damage to useful crops, especially agricultural products that satisfy man's basic food needs, such as soybeans, wheat and the like. The current population explosion and concomitant world food shortage demand improvements in the efficiency of producing these crops. Prevention or minimizing the loss of a portion of such valuable crops by killing, or inhibiting the growth of undesired vegetation is one way of improving this efficiency.
A wide variety of materials useful for killing, or inhibiting (controlling) the growth of undesired vegetation is available; such materials are commonly referred to as herbicides. The need exists, however, for still more effective herbicides that destroy or retard weeds without causing significant damage to useful crops.
SUMMARY OF THE INVENTION
This invention relates to novel compounds of Formula I and their agriculturally suitable salts, suitable agricultural compositions containing them and their method of use as general herbicides. ##STR7## wherein
L is SO 2 NR 3 R 4 ;
R is H, F, Cl, Br, NO 2 , CF 3 , C 1 -C 3 alkyl or C 1 -C 3 alkoxy;
R 1 is H or C 1 -C 4 alkyl;
R 2 is H or CH 3 ;
R 3 is C 1 -C 4 alkyl or OCH 3 ;
R 4 is C 1 -C 4 alkyl;
R 8 is H, CH 3 or OCH 3 ;
A is ##STR8##
W is O or S;
X is H, Cl, Br, CH 3 , CH 2 CH 3 , C 1 -C 3 alkoxy, CF 3 , SCH 3 or CH 2 OCH 3 ;
Y is CH 3 or OCH 3 ;
Z is N, CH, CCl, CBr, CCN, CCH 3 , CCH 2 CH 3 , CCH 2 CH 2 Cl or CCH 2 CH═CH 2 ;
Y 1 is H, CH 3 , OCH 3 or OCH 2 CH 3 ; and
Q is O or CH 2 ;
and their agriculturally suitable salts; provided that:
(1) when R 3 is OCH 3 , then R 4 is CH 3 ;
(2) the total number of carbon atoms of R 3 and R 4 is five or less; and
(3) when W is S, then R 8 is H. Preferred in increasing order for their higher activity and/or more favorable ease of synthesis.
(1) Compounds of the generic scope wherein Z is N, CH, CCl, CBr or CCH 3 , W is O, and R 8 is H or CH 3 ;
(2) Compounds of Preferred (1) wherein Z is CH or N, X is CH 3 or OCH 3 , and R 1 and R 2 are H;
(3) Compounds of Preferred (2) wherein A is ##STR9## and R and R 8 are H;
(4) Compounds of Preferred (3) wherein R 3 is C 1 -C 3 alkyl or OCH 3 , and R 4 is CH 3 ; and
(5) Compounds of Preferred (4) wherein R 3 is OCH 3 or CH 3 .
Specifically Preferred for highest activity and/or most favorable ease of synthesis are:
2-[(Dimethylamino)sulfonylmethyl]-N-[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]benzenesulfonamide, m.p. 203°-204° C.;
2-[(Dimethylamino)sulfonylmethyl]-N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]benzenesulfonamide, m.p. 171°-176° C.;
2-[(Dimethylamino)sulfonylmethyl]-N-[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]benzenesulfonamide, m.p. 181°-183° C.;
2-[(Dimethylamino)sulfonylmethyl]-N-[(4,6-dimethyl-1,3,5-triazin-2-yl)aminocarbonyl]benzenesulfonamide, m.p. 209°-210° C.;
2-[(Dimethylamino)sulfonylmethyl]-N-[(4,6-dimethoxy-1,3,5-triazin-2-yl)aminocarbonyl]benzenesulfonamide, m.p. 200°-203° C.; and
2-[(Dimethylamino)sulfonylmethyl]-N-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]benzenesulfonamide, m.p. 200°-205° C.
This invention also relates to novel compounds of Formula II which are useful intermediates for the preparation of the herbicidal compounds of Formula I. ##STR10## wherein
L, R, R 1 , and R 2 are as previously defined, and
Z is CH or N.
This invention also relates to novel compounds of Formula III which are useful intermediates for the preparation of the compounds of Formula I. ##STR11## wherein L, R, R 1 and R 2 are as previously defined.
DETAILED DESCRIPTION
Synthesis
The compounds of Formula I, in which W=O, may be prepared as shown in Equation 1 by the reaction of an appropriately substituted benzenesulfonyl isocyanate with an appropriate aminopyrimidine or aminotriazine. ##STR12## wherein
R is H, F, Cl, Br, NO 2 , CF 3 , C 1 -C 3 alkoxy or C 1 -C 3 alkyl;
R 1 is H or C 1 -C 4 alkyl;
R 2 is H or CH 3 ;
R 4 is C 1 -C 4 alkyl;
R 3 is CH 3 O or C 1 -C 4 alkyl; provided that when R 3 is CH 3 O, then R 4 is CH 3 , and provided that the total number of carbon atoms of R 3 and R 4 is five or less;
A is ##STR13##
X is H, Cl, Br, CH 3 , CH 3 CH 2 , C 1 -C 3 alkoxy, CF 3 , CH 3 S or CH 3 OCH 2 ;
Y is CH 3 , CH 3 O or Cl;
Z is N, CH, C-Cl, C-Br, C-CN, C-CH 3 , C--CH 2 CH 3 , C-CH 2 CH 2 Cl or C--CH 2 CH═CH 2 ;
Y 1 is H, CH 3 , CH 3 O or OCH 2 CH 3 ;
and
Q is O or CH 2 .
The reaction of Equation 1 is best carried out in an inert aprotic solvent such as methylene chloride, tetrahydrofuran or acetonitrile at a temperature between 20° and 80°. A catalytic amount of 1,4-diazabicyclo[2,2,2]octane (DABCO) may be used to accelerate the reaction. In cases in which the products are insoluble in the reaction solvent, they may be isolated by simple filtration. When the products are soluble, they may be isolated by evaporation of the solvent and trituration of the residue with solvents such as 1-chlorobutane, ethylether or methanol and filtration.
The benzenesulfonyl isocyanates of Formula III may be prepared as shown below in Equation 2, by phosgenation of the sulfonamides of Formula IV in the presence of butyl isocyanate. The sulfonyl isocyanates of Formula III may also be prepared, as shown in Equation 3, by phosgenation of the butyl ureas of Formula V. ##STR14## wherein R, R 1 , R 2 , R 3 and R 4 are as previously described.
The above reaction is carried out by heating a mixture of the appropriate sulfonamide (IV), an alkyl isocyanate such as butyl isocyanate and a catalytic amount of a tertiary amine such as 1,4-diaza[2,2,2]bicyclooctane (DABCO) in xylene, or other inert solvent of boiling point ≧135° to approximately 135°. Phosgene is then added to the mixture over a 1-6 hour period until an excess of phosgene is present as indicated by a drop in the boiling point to less than 130°. The mixture is cooled and filtered to remove a small amount of insoluble by-products. The solvent and the alkyl isocyanate are distilled off in-vacuo leaving a residue of the crude, sulfonyl isocyanate, III, which can be used without further purification. ##STR15## wherein R, R 1 , R 2 , R 3 and R 4 are as previously described.
The compounds of Formula V are conveniently prepared by stirring a mixture of the sulfonamides, IV, anhydrous potassium carbonate, and n-butyl isocyanate in acetone or methyl ethyl ketone at 25°-80° until all of the isocyanate has reacted. The products are isolated by quenching in dilute mineral acid and recrystallizing the solid product. The compounds V are treated with phosgene and a catalytic amount of DABCO in refluxing xylene or chlorobenzene in a manner analogous to that described in Equation 2.
The sulfonyl isocyanates of Formula III may also be prepared as shown in Equation 4, by the method of Ulrich et al. [J. Org. Chem. 34, 3200 (1969)]. ##STR16##
The synthesis of heterocyclic amine derivatives such as those depicted by Formula VIII has been reviewed in "The Chemistry of Heterocyclic Compounds", a series published by Interscience Publ., New York and London. Aminopyrimidines are described by D. J. Brown in "The Pyrimidines", Vol. XVI of the above series.
The synthesis of the bicyclic pyrimidines of Formula VIII is described in the following references:
Braker, Sheehan, Spitzmiller and Lott, J. Am. Chem. Soc. 69, 3072 (1947).
Mitter and Bhattacharya, Quart. J. Indian. Chem. Soc. 4, 152 (1927).
Shrage and Hitchings, J. Org. Chem. 16, 1153 (1951).
Caldwell, Kornfeld and Donnell, J. Am. Chem. Soc. 63, 2188 (1941).
Fissekis, Myles and Brown, J. Org. Chem. 29, 2670 (1964).
All of the above are herein incorporated by reference.
Compounds of Formula I, in which W=O, can also be prepared by the method described in Equation 5. ##STR17## wherein
R, R 1 , R 2 , R 3 and R 4 are as described previously;
R 12 is methyl;
R 13 is C 1 -C 3 alkyl;
X 2 is Cl or Br;
Y 2 is H, Cl, Br, methyl, ethyl or CF 3 ;
Y 3 is Cl or Br;
Y 4 is methyl, ethyl or CF 3 ; and
E is CH 3 S--.
REACTION STEP (5a)
In Reaction Step (5a), an aromatic sulfonamide of Formula IV is contacted with a heterocyclic isocyanate of Formula VII to yield an N-(haloheterocyclicaminocarbonyl) aromatic sulfonamide of Formula II.
The heterocyclic isocyanates used in Reaction (5a) may be prepared according to methods described in Swiss Pat. No. 579,062, U.S. Pat. No. 3,919,228, U.S. Pat. No. 3,732,223 and Angew Chem. Int. Ed. 10, 402 (1976), the disclosures of which are herein incorporated by reference.
The aromatic sulfonamide and the heterocyclic isocyanate are contacted in the presence of an inert organic solvent, for example, acetonitrile, tetrahydrofuran (THF), toluene, acetone or butanone. Optionally, a catalytic amount of a base, such as 1,4-diazabicyclo[2.2.2]octane (DABCO), potassium carbonate, sodium hydride or potassium tert-butoxide, may be added to the reaction mixture. The quantity of base constituting a catalytic amount would be obvious to one skilled in the art. The reaction mixture is preferably maintained at a temperature of about 25° to 110° C., and the product can generally be recovered by cooling and filtering the reaction mixture. For reasons of efficiency and economy, the preferred solvents are acetonitrile and THF, and the preferred temperature range is about 60° to 85° C.
REACTION STEPS (5b) AND (5c)
In Reaction Steps (5b) and (5c), one or two of the halogen atoms on the heterocyclic ring of the compound of Formula II is displaced by a nucleophilic species. Generally, this may be done by contacting the compound of Formula II either with alkanol, R 12 OH, or with alkoxide, --OR 12 , where R 12 is as defined above.
Thus, in Reaction Step (5b), a compound of Formula II, substituted with one displaceable group, can be contacted with at least one equivalent of alkanol, R 12 OH. This reaction is sluggish, however, and it is preferred to contact the compound of Formula II with at least two equivalents of alkoxide, --OR 12 . The alkoxide can be provided in a number of ways:
(a) The compound of Formula II can be suspended or dissolved in an alkanol solvent, R 12 OH, in the presence of at least two equivalents of alkoxide, --OR 12 . The alkoxide can be added directly as alkali metal or alkaline earth metal alkoxide or can be generated by the addition to the alkanol solvent of at least two equivalents of a base capable of generating alkoxide from the solvent. Suitable bases include, but are not limited to, the alkali and alkaline earth metals, their hydrides and tert-butoxides. For example, when R 12 is methyl, the compound of Formula II could be suspended or dissolved in methanol in the presence of two equivalents of sodium methoxide. Alternatively, two equivalents of sodium hydride could be used in place of the sodium methoxide.
(b) The compound of Formula II can be suspended or dissolved in an inert solvent in the presence of at least two equivalents of alkoxide, --OR 12 . Suitable inert solvents include, but are not limited to, acetonitrile, THF and dimethylformamide. The alkoxide may be added directly as alkali metal or alkaline earth metal alkoxide or may be generated from alkanol and a base as described in (a) above. For example, when R 12 is methyl, the compound of Formula II could be suspended or dissolved in THF in the presence of two equivalents of sodium methoxide. Alternatively, two equivalents each of methanol and sodium hydride could be used instead of sodium methoxide.
For reasons of economy and efficiency, procedure (a) is the more preferred method.
It should be noted that two equivalents of alkoxide are required for Reaction Step (5a) whereas only one equivalent of alkanol is needed for the same process. This difference is due to the reaction which is believed to occur between the alkoxide and the sulfonyl nitrogen of the sulfonamide of Formula VIII. When alkoxide is used, the first equivalent of alkoxide removes a proton from the sulfonyl nitrogen, and it is only the second equivalent which effects displacement of the halogen. As a result, two equivalents of alkoxide are required. The resulting salt must be acidified, e.g., with sulfuric, hydrochloric or acetic acid, to yield a compound of Formula IX. Applicant, of course, does not intend to be bound by the mechanism described above.
In Reaction step (5c) a compound of Formula IXa, substituted with at least one displacement group, is contacted with either one equivalent of alkanol, R 13 OH, or with two equivalents of alkoxide, --OR 13 where R 13 is as described above. The compound of Formula IXa is prepared according to Reaction Step (5b) from a compound of Formula IX where Y 2 is Cl or Br. When alkoxide, --OR 13 is used, it may be provided in either of the methods described above in connection with Reaction Step (5c), and the resulting salt can be acidified to yield a compound of Formula X.
When R 12 =R 13 , Reaction Steps (5b) and (5c) may be combined. Thus, a compound of Formula II may be contacted either with at least two equivalents of alkanol, R 13 OH, or with at least three equivalents of alkoxide, --OR 13 .
When a compound of Formula II contains two displaceable groups, i.e., both X 2 and Y 2 are Cl or Br, certain reaction conditions will favor displacement of only one of the group. These conditions are the use of low temperatures and, when alkoxide is used, the slow addition of the stoichiometric amount of alkoxide or alkoxide-generating base to the medium containing the compound of Formula II.
When alkoxide is used, both Reaction Steps (5b) and (5c) are preferably run at temperatures within the range of about -10° to 80° C., the range of about 0° to 25° C. being more preferred. Reaction Steps (5b) and (5c) are more sluggish when alkanol is used instead of alkoxide, and more drastic conditions are required for the reaction to go to completion. Thus, higher temperatures, up to and including the boiling point of the alkanol itself, are required.
REACTION STEP (5d)
Reaction Step (5d) involves the displacement of the halogen atom in a compound of Formula IIa by a methylthio nucleophile. The starting material, a compound of Formula IIa, is prepared according to Reaction Step (5a), and Y 4 is limited to C 1 -C 2 alkyl and CF 3 .
For this reaction, the compound of Formula IIa is suspended or dissolved in an inert solvent, such as acetonitrile or THF. At least one equivalent of the nucleophilic species and at least two equivalents of a base are then contacted with the starting material. The first equivalent of base is believed to neutralize the sulfonamido proton. The second equivalent of base generates mercaptide ion from the mercaptan. Suitable bases include sodium hydride, sodium methoxide and sodium hydroxide.
Suitable reaction temperatures are within the range of about -10° to 80° C., with a range of about 0° to 25° C. being preferred. The product may be isolated by dilution of the reaction mixture with water, mild acidification and filtration.
The sulfonamides of Formula IV can be prepared by the four step reaction sequence shown in Equation 6. ##STR18## wherein R, R 1 , R 2 , R 3 and R 4 are as defined in Equations 1-5, with the exception that R cannot be NO 2 .
In step 6a, the o-nitrobenzylsulfonyl chlorides of Formula XII, which are well-known in the art, are treated with an amine of Formula XIIa in an inert organic solvent such as methylene chloride, ethyl ether or tetrahydrofuran at 0°-50°. The amine may be taken in excess to act as an acid acceptor; or, alternatively, a tertiary amine such as triethylamine or pyridine may be used as an acid acceptor. The by-product amine hydrochloride is filtered off or washed out of the solvent with water and the product isolated by evaporation of the solvent.
The reduction described in step 6b is accomplished by treating a solution of the compounds of Formula XIII in a solvent such as ethanol, ethyl acetate, or diglyme, in a pressure vessel, with 50-1000 pounds per square inch of hydrogen at 25°-150° in the presence of a hydrogenation catalyst such as 5-10% palladium absorbed on carbon. When the theoretical amount of hydrogen has been absorbed, the solution is cooled and the catalyst is removed by filtration. The product is then isolated by evaporation of the solvent.
In the case where R=NO 2 , the reduction of step 6b an be accomplished using ammonium sulfide or sodium hydrosulfide instead of catalytic hydrogenation. This type of procedure is described in Organic Synthesis Coll. Vol. III, pgs. 242-3, John Wiley and Sons, Inc., New York and London (1955), the disclosure of which is herein incorporated by reference.
The diazotization and coupling with sulfur dioxide, described in step 6c, is accomplished in the following manner. A solution of the aniline of Formula XIV in a mixture of concentrated hydrochloric acid and glacial acetic acid is treated with a solution of sodium nitrite in water at -5° to 0°. After stirring for 10-15 minutes at 0° to insure complete diazotization, this solution is added to a mixture of an excess of sulfur dioxide, and a catalytic amount of cuprous chloride in glacial acetic acid at 0°-5°. The temperature is kept at 0°-5° for 1/4 to 1 hour then raised to 20°-25° and held at that temperature for 2-4 hours. This solution is then poured into a large excess of ice water. The sulfonyl chloride products, XV, can be isolated by filtration or by extraction into a solvent such as ethyl ether or methylene chloride followed by evaporation of the solvent.
The amination described in step 6d is conveniently carried out by treating a solution of the sulfonyl chloride of Formula XV with an excess of anhydrous ammonis in a solvent such as ethyl ether or methylene chloride at 0°-25°. If the product sulfonamide, IV, is insoluble it may be isolated by filtration followed by washing out the salts with water. If the product sulfonamide is soluble in the reaction solution, it may be isolated by filtering off the precipitated ammonium chloride and evaporation of the solvent.
Compounds of Formula I, in which W=O and R 8 =H, can also be prepared by the reaction of an appropriately substituted sulfonamide, IV, with the methyl carbamate of the appropriate aminoheterocycle, XVI, in the presence of an equivalent of trimethylaluminum as shown in Equation 7. ##STR19## wherein R, R 1 , R 2 , R 3 , R 4 and A are as previously defined.
The reaction of Equation 7 is best carried out in an inert solvent such as methylene chloride at 10°-45° and ambient pressure. The preferred mode of addition is to add the trimethylaluminum to a solution or slurry of the sulfonamide, IV, a mildly exothermic reaction occurs accompanied by the evolution of gas. The addition of the heterocyclic carbamate, XVI, is then made and the mixture is stirred at ambient to reflux temperatures for 6 to 48 hours. The addition of aqueous acid such as dilute hydrochloric or acetic acid removes inorganic salts from the product contained in the organic phase. Evaporation of the methylene chloride yields the crude product which can be purified by recrystallization or column chromatography.
As shown in Equation 8, compounds of Formula I, in which W is sulfur and R, R 1 , R 2 , R 3 , R 4 and A are as previously defined and R 8 is H are prepared by reaction of an appropriately substituted sulfonamide, IV, with a heterocyclic isothiocyanate of Formula XVII. ##STR20## The reaction of Equation 8 is best carried out by dissolving or suspending the sulfonamide and isothiocyanate in a polar solvent such as acetone, acetonitrile, ethyl acetate or methyl ethyl ketone, adding an equivalent of a base such as potassium carbonate and stirring the mixture at ambient temperature up to the reflux temperature for one to twenty-four hours. In some cases, the product precipitates from the reaction mixture and can be removed by filtration. The product is stirred in dilute mineral acid, filtered and washed with cold water. If the product does not precipitate from the reaction mixture it can be isolated by evaporation of the solvent, trituration of the residue with dilute mineral acid and filtering off the insoluble product.
The heterocyclic isothiocyanates which are used in the procedure of Equation 8 are prepared, for example, according to the method of Japan Patent Application Pub: Kokai 51-143686, June 5, 1976, or that of W. Abraham and G. Barnikow, Tetrahedron 29, 691-7 (1973).
Agriculturally suitable salts of compounds of Formula I are also useful herbicides and can be prepared in a number of ways known to the art. For example, metal salts can be made by treating compounds of Formula 1 with a solution of an alkali or alkaline earth metal salt having a sufficiently basic anion (e.g. hydroxide, alkoxide, carbonate or hydride) quaternary amine salts can be made by similar techniques. Detailed examples of such techniques are given in U.S. Pat. No. 4,127,405, the disclosure of which is herein incorporated by reference.
The compounds of this invention and their preparation are further illustrated by the following examples wherein temperatures are given in degrees centigrade and all parts are by weight unless otherwise indicated.
EXAMPLE 1
2-Nitrophenylmethyl carbamimidothioate hydrochloride
A solution of 34.3 g of o-nitrobenzyl chloride and 15.2 g of thiourea in 250 ml of #2B alcohol was refluxed for 11/2 hours. The solution was cooled to 60° and 250 ml of 1-chlorobutane added. Further cooling to 20° yielded a precipitate which was filtered, washed with 1-chlorobutane and dried at 65° to give 38.1 g of 2-nitrophenylmethyl carbamimidothioate hydrochloride, m.p. 190°-192°.
NMR (DMSO-d 6 )δ: 4.85 (s, 1.8H, CH 2 ); 7.4-8 (m, 4.2H, 4 aromatics); 9.7 (broad s, 4.0H, 4 NH's).
EXAMPLE 2
N,N-Dimethyl-2-nitrobenzenemethanesulfonamide
To a slurry of 34.7 g of the compound of Example 1 in 350 ml of water was added 20.5 ml of liquid chlorine at 10°-15° over a 45 minute period. After stirring an additional 15 minutes at 10°, the precipitated sulfonyl chloride was filtered off and washed well with water. The wet sulfonyl chloride filter cake was suspended in 200 ml of ether and contacted with 18.0 ml of liquid dimethylamine at 5°-15°. After stirring at room temperature for 11/2 hours, the precipitate was filtered off and washed well with water, then 1-chlorobutane. Oven drying at 60° overnight gave 15.9 g of N,N-dimethyl-2-ntrobenzenemethanesulfonamide, m.p. 129°-132°.
NMR (DMSO-d 6 )δ: 2.7 (s, 6.2H, SO 2 NMe 2 ); 4.8 (s, 1.9H, --CH 2 --); 7.6-8.3 (m, 3.9H, 4 aromatics).
Anal. Calcd. for C 9 H 12 N 2 O 4 S: C, 44.28; H, 4.96; N, 11.47; S, 13.13. Found: C, 44.6; 44.5; H, 4.8; N, 11.4; S, 13.3. 4.7; N, 11.4; S, 13.0.
EXAMPLE 3
N,N-Dimethyl-2-aminobenzenemethanesulfonamide
In a pressure bottle, a mixture of 116 g of the product of Example 2, 1400 ml of 2-methoxyethyl ether and 10 g of 10% palladium on carbon was shaken at 110° under 500 p.s.i. hydrogen until the hydrogen was no longer absorbed. The catalyst was filtered off and the filtrate stripped under reduced pressure to a volume of 200 ml. This residue was poured into 600 ml of ice and the precipitate filtered off and dried to give 84 g of crude product, m.p. 70°-78°. Recrystallization from ˜600 ml of 1-chlorobutane gave 60.6 g of N,N-dimethyl-2-aminobenzenemethanesulfonamide, m.p. 92°-100°.
NMR (DMSO-d 6 )δ: 2.7 (s, 5.8H, SO 2 NMe 2 ); 4.3 (s, 2.1H, CH 2 ); 4.9-5.2 (broad s, 2.0H, NH 2 ); 6.4-7.3 (m, 4.1H, 4 aromatics).
EXAMPLE 4
2-[(Dimethylamino)sulfonylmethyl]benzenesulfonamide
To a solution of 53.5 g of the product of Example 3 in a mixture of 225 ml of concentrated hydrochloric acid and 75 ml of glacial acetic acid was added a solution of 21.4 g of sodium nitrite in 70 ml of water at -5° to 0°. The solution was stirred at 0° for 15 minutes, then poured into a mixture of 6 g of cuprous chloride, 48 ml of liquid sulfur dioxide in 300 ml of glacial acetic acid at 0°-4°. This mixture was stirred at 0° for 1 hour, then at 25° for 2 hours before being poured into 2 liters of ice-water. The precipitate was filtered and washed with water then suspended in 250 ml of ether and treated with 11.0 ml of liquid anhydrous ammonia at 5°-15°. After stirring at 25° for 30 minutes the precipitate was filtered off and washed well with ether then water. Oven drying at 60° gave 40.2 g of 2-[(dimethylamino)sulfonylmethyl]benzenesulfonamide, m.p. 145°-150°.
NMR (DMSO-d 6 )δ: 2.7 (s, 6.0 H, SO 2 NMe 2 ); 4.8 (s, 1.8H, --CH 2 --); 7.2-8.1 (m, 6.2H, 4 aromatics+SO 2 NH 2 ).
EXAMPLE 5
2-[(Dimethylamino)sulfonylmethyl]benzenesulfonyl isocyanate
A solution of 14.0 g of the product of Example 4, 5.0 g of n-butyl isocyanate and 0.1 g of DABCO in 90 ml of mixed xylenes was heated to 136°. To this solution was added 3.6 ml of liquid phosgene over a 2 hour period to maintain the temperature between 125° and 136°. The temperature was kept at 130° for 1/2 hour after the addition. The solution was cooled, and filtered under a nitrogen atmosphere and concentrated at 60°-70° in vacuo to give 16.0 g of crude 2-[(dimethylamino)sulfonylmethyl]benzenesulfonyl isocyanate as a moisture sensitive oil. An infrared peak at 2200 cm -1 confirmed the presence of the --SO 2 NCO group.
EXAMPLE 6
2-[(Dimethylamino)sulfonylmethyl]-N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]benzenesulfonamide
A mixture of 2.6 g of the product of Example 5, 0.9 g of 2-amino-4,6-dimethoxypyrimidine and a few crystals of DABCO in 15 ml of dry acetonitrile was heated at 50°-55° for 1 hour under a nitrogen atmosphere, then stirred overnight at room temperature. The precipitate was filtered off, washed with acetonitrile and dried to give 2.1 g of 2-[(dimethylamino)sulfonylmethyl]-N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]benzenesulfonamide, m.p. 172°-176°.
NMR (DMSO-d 6 )δ: 2.8 (s, 6.3H, SO 2 NMe 2 ); 4.0 (s, 5.6H, Het--OCH 3 's); 5.0 (s, 2.0H, --CH 2 --); 6.1 (s, 0.8H, Het--H); 7.7-8.6 (m, 4.4H, 4 aromatics); 10.8 and 13.2 (broad singlets, NH's).
Anal. Calcd. for C 16 H 21 N 5 O 7 S 2 : C, 41.80; H, 4.61; N, 15.24; S, 13.96. Found: C, 41.8; 42.2 H, 4.6; N, 16.1; S, 14.0. 4.5; N, 16.1; S, 14.3.
Using the procedures and examples described above and choosing the appropriate aminoheterocycle and sulfonyl isocyanate or sulfonamide, the compounds described in Tables I-VI may be prepared.
TABLE I__________________________________________________________________________ ##STR21## m.p.R R.sub.1 R.sub.2 R.sub.4 W R.sub.3 R.sub.8 X Y (°C.)__________________________________________________________________________H H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O 200-203° (d)H H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 200-205° (d)H H H CH.sub.3 O CH.sub.3 H CH.sub.3 CH.sub.3 209-210° (d)H H H CH.sub.3 O CH.sub.3 O H CH.sub.3 O CH.sub.3 OH H H CH.sub.3 O CH.sub.3 CH.sub.2 H CH.sub.3 O CH.sub.3 OH H H CH.sub.3 O CH.sub.3 CH.sub.2 CH.sub.2 H CH.sub.3 O CH.sub.3 OH H H CH.sub.3 O (CH.sub.3).sub.2 CH H CH.sub.3 O CH.sub.3 OH H H CH.sub.3 O CH.sub.3 (CH.sub.2).sub.3 H CH.sub.3 O CH.sub.3 OH H H CH.sub.3 CH.sub.2 O CH.sub.3 CH.sub.2 H CH.sub.3 O CH.sub.3 OH H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 OH H CH.sub.3 CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 OH CH.sub.3 CH.sub.3 CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 OH H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O5-F H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O5-Cl H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O5-Br H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O5-NO.sub.2 H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O5-CF.sub.3 H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O5-CH.sub.3 O H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O5-C.sub.2 H.sub.5 O H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O ##STR22## H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O 5-CH.sub.3 H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O5-C.sub.2 H.sub.5 H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O ##STR23## H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O 3-Cl H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O4-Cl H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O6-Cl H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 OH H H CH.sub.3 O CH.sub.3 H Cl CH.sub.3 OH H H CH.sub.3 O CH.sub.3 H Br CH.sub.3 OH H H CH.sub.3 O CH.sub.3 H CH.sub.3 CH.sub.2 CH.sub.3 OH H H CH.sub.3 O CH.sub.3 H CH.sub.3 CH.sub.2 O CH.sub.3 H H H CH.sub.3 O CH.sub.3 H ##STR24## CH.sub.3 H H H CH.sub.3 O CH.sub.3 H CF.sub.3 CH.sub.3 OH H H CH.sub.3 O CH.sub.3 H CH.sub.3 S CH.sub.3 OH H H CH.sub.3 O CH.sub.3 H CH.sub.3 OCH.sub.2 CH.sub.3H H H CH.sub.3 O CH.sub.3 H CH.sub.3 OCH.sub.2 CH.sub.3 OH H H CH.sub.3 O CH.sub.3 H H CH.sub.3H H H CH.sub.3 O CH.sub.3 H H CH.sub.3 OH H H CH.sub.3 S CH.sub.3 H CH.sub.3 O CH.sub.3 OH C.sub.2 H.sub.5 H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 OH n-C.sub.3 H.sub.7 H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 OH n-C.sub.4 H.sub.9 H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 OH H H CH.sub.3 O CH.sub.3 CH.sub.3 CH.sub.3 O CH.sub.3 OH H H CH.sub.3 O CH.sub.3 CH.sub.3 CH.sub.3 O CH.sub.3H H H CH.sub.3 O CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3H H H CH.sub.3 O CH.sub.3 CH.sub.3 O CH.sub.3 O CH.sub.3 OH H H CH.sub.3 O CH.sub.3 CH.sub.3 O CH.sub.3 CH.sub.3 OH H H CH.sub.3 O CH.sub.3 CH.sub.3 O CH.sub.3 CH.sub.3__________________________________________________________________________
TABLE II__________________________________________________________________________ ##STR25## m.p.R R.sub.1 R.sub.2 R.sub.4 W R.sub.3 R.sub.8 X Y Z (°C.)__________________________________________________________________________H H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O CH 172-176° (d)H H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 CH 181-183° (d)H H H CH.sub.3 O CH.sub.3 H CH.sub.3 CH.sub. 3 CH 203-204° (d)H H H CH.sub.3 O CH.sub.3 O H CH.sub.3 O CH.sub.3 O CHH H H CH.sub.3 O CH.sub.3 CH.sub.2 H CH.sub.3 O CH.sub.3 O CHH H H CH.sub.3 O CH.sub.3 CH.sub.2 CH.sub.2 H CH.sub.3 O CH.sub.3 O CHH H H CH.sub.3 O (CH.sub.3).sub.2 CH H CH.sub.3 O CH.sub.3 O CHH H H CH.sub.3 O CH.sub.3 (CH.sub.2).sub.3 H CH.sub.3 O CH.sub.3 O CHH H H CH.sub.3 CH.sub.2 O CH.sub.3 CH.sub.2 H CH.sub.3 O CH.sub.3 O CHH H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O CHH H CH.sub.3 CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O CHH CH.sub.3 CH.sub.3 CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O CHH H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O CH5-F H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O CH5-Cl H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O CH5-Br H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O CH5-NO.sub.2 H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O CH5-CF.sub.3 H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O CH5-CH.sub.3 O H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O CH5-C.sub.2 H.sub.5 O H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O CH ##STR26## H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O CH 5-CH.sub.3 H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O CH5-C.sub.2 H.sub.5 H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O CH ##STR27## H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O CH 3-Cl H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O CH4-Cl H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O CH6-Cl H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O CHH H H CH.sub.3 O CH.sub.3 H Cl CH.sub.3 O CHH H H CH.sub.3 O CH.sub.3 H Br CH.sub.3 O CHH H H CH.sub.3 O CH.sub.3 H CH.sub.3 CH.sub.2 CH.sub.3 O CHH H H CH.sub.3 O CH.sub.3 H CH.sub.3 CH.sub.2 O CH.sub.3 CH H H H CH.sub.3 O CH.sub.3 H ##STR28## CH.sub.3 CH H H H CH.sub.3 O CH.sub.3 H CF.sub.3 CH.sub.3 O CHH H H CH.sub.3 O CH.sub.3 H CH.sub.3 S CH.sub.3 O CHH H H CH.sub.3 O CH.sub.3 H CH.sub.3 OCH.sub.2 CH.sub.3 CHH H H CH.sub.3 O CH.sub.3 H CH.sub.3 OCH.sub.2 CH.sub.3 O CHH H H CH.sub.3 O CH.sub.3 H H CH.sub.3 CHH H H CH.sub.3 O CH.sub.3 H H CH.sub.3 O CHH H H CH.sub.3 O CH.sub.3 H H CH.sub.3 CClH H H CH.sub.3 O CH.sub.3 H CH.sub.3 CH.sub.3 CCNH H H CH.sub.3 O CH.sub.3 H CH.sub.3 CH.sub.3 CCH.sub.3H H H CH.sub.3 O CH.sub.3 H H CH.sub.3 CCH.sub.3H H H CH.sub.3 O CH.sub.3 H CH.sub.3 CH.sub.3 CCH.sub.2 CH.sub.3H H H CH.sub.3 O CH.sub.3 H H CH.sub.3 CCH.sub.2 CH.sub.3H H H CH.sub.3 O CH.sub.3 H Cl Cl CCH.sub.2 CH.sub.2 ClH H H CH.sub.3 O CH.sub.3 H H CH.sub.3 CCH.sub.2 CH.sub.2 ClH H H CH.sub.3 O CH.sub.3 H CH.sub.3 CH.sub.3 CCH.sub.2 CH.sub.2 ClH H H CH.sub.3 O CH.sub.3 H CH.sub.3 CH.sub.3 CCH.sub.2 CHCH.sub.2H H H CH.sub.3 O CH.sub.3 H H CH.sub.3 CCH.sub.2 CHCH.sub.2H H H CH.sub.3 S CH.sub.3 H CH.sub.3 O CH.sub.3 O CHH C.sub.2 H.sub.5 H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O CHH n-C.sub.3 H.sub.7 H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O CHH n-C.sub.4 H.sub.9 H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.3 O CHH H H CH.sub.3 O CH.sub.3 CH.sub.3 CH.sub.3 O CH.sub.3 O CHH H H CH.sub.3 O CH.sub.3 CH.sub.3 CH.sub.3 O CH.sub.3 CHH H H CH.sub.3 O CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 CHH H H CH.sub.3 O CH.sub.3 CH.sub.3 O CH.sub.3 O CH.sub.3 O CHH H H CH.sub.3 O CH.sub.3 CH.sub.3 O CH.sub.3 O CH.sub.3 CHH H H CH.sub. 3 O CH.sub.3 CH.sub.3 O CH.sub.3 CH.sub.3 CH__________________________________________________________________________
TABLE III__________________________________________________________________________ ##STR29## m.p.R R.sub.1 R.sub.2 R.sub.4 W R.sub.3 R.sub.8 Y' Q (°C.)__________________________________________________________________________H H H CH.sub.3 O CH.sub.3 H C.sub.2 H.sub.5 O OH H H CH.sub.3 O CH.sub.3 H CH.sub.3 O OH H H CH.sub.3 O CH.sub.3 H CH.sub.3 OH H H CH.sub.3 O CH.sub.3 O H CH.sub.3 O OH H H CH.sub.3 O CH.sub.3 CH.sub.2 H CH.sub.3 O OH H H CH.sub.3 O CH.sub.3 CH.sub.2 CH.sub.2 H CH.sub.3 O OH H H CH.sub.3 O (CH.sub.3).sub.2 CH H CH.sub.3 O OH H H CH.sub.3 O CH.sub.3 (CH.sub.2).sub.3 H CH.sub.3 O OH H H CH.sub.3 CH.sub.2 O CH.sub.3 CH.sub.2 H CH.sub.3 O OH H H CH.sub.3 O CH.sub.3 H CH.sub.3 O OH H CH.sub.3 CH.sub.3 O CH.sub.3 H CH.sub.3 O OH CH.sub.3 CH.sub.3 CH.sub.3 O CH.sub.3 H CH.sub.3 O OH H H CH.sub.3 O CH.sub.3 H CH.sub.3 O O5-F H H CH.sub.3 O CH.sub.3 H CH.sub.3 O O5-Cl H H CH.sub.3 O CH.sub.3 H CH.sub.3 O O5-Br H H CH.sub.3 O CH.sub.3 H CH.sub.3 O O5-NO.sub.2 H H CH.sub.3 O CH.sub.3 H CH.sub.3 O O5-CF.sub.3 H H CH.sub.3 O CH.sub.3 H CH.sub.3 O O5-CH.sub.3 O H H CH.sub.3 O CH.sub.3 H CH.sub.3 O O5-C.sub.2 H.sub.5 O H H CH.sub.3 O CH.sub.3 H CH.sub.3 O O ##STR30## H H CH.sub.3 O CH.sub.3 H CH.sub.3 O O 5-CH.sub.3 H H CH.sub.3 O CH.sub.3 H CH.sub.3 O O5-C.sub.2 H.sub.5 H H CH.sub.3 O CH.sub.3 H CH.sub.3 O O ##STR31## H H CH.sub.3 O CH.sub.3 H CH.sub.3 O O 3-Cl H H CH.sub.3 O CH.sub.3 H CH.sub.3 O O4-Cl H H CH.sub.3 O CH.sub.3 H CH.sub.3 O O5-Cl H H CH.sub.3 O CH.sub.3 H CH.sub.3 O OH H H CH.sub. 3 S CH.sub.3 H CH.sub.3 O OH H H CH.sub.3 O CH.sub.3 H H OH H H CH.sub.3 O CH.sub.3 CH.sub.2 H CH.sub.3 OH H H CH.sub.3 O CH.sub.3 H H CH.sub.2H H H CH.sub.3 O CH.sub.3 H C.sub.2 H.sub.5 O CH.sub.2H H H CH.sub.3 O CH.sub.3 H CH.sub.3 CH.sub.2H H H CH.sub.3 O CH.sub.3 H CH.sub.3 O CH.sub.2H H H CH.sub.3 O CH.sub.3 CH.sub.2 H CH.sub.3 O CH.sub.2H C.sub.2 H.sub.5 H CH.sub.3 O CH.sub.3 H CH.sub.3 O OH n-C.sub.3 H.sub.7 H CH.sub.3 O CH.sub.3 H CH.sub.3 O OH n-C.sub.4 H.sub.9 H CH.sub.3 O CH.sub.3 H CH.sub.3 O OH CH.sub.3 H CH.sub.3 O CH.sub.3 CH.sub.3 CH.sub.3 O OH H H CH.sub.3 O CH.sub.3 CH.sub.3 CH.sub.3 OH H H CH.sub.3 O CH.sub.3 CH.sub.3 C.sub.2 H.sub.5 O OH H H CH.sub.3 O CH.sub.3 CH.sub.3 O CH.sub.3 O CH.sub.2H H H CH.sub.3 O CH.sub.3 CH.sub.3 O CH.sub.3 CH.sub.2H H H CH.sub.3 O CH.sub.3 CH.sub.3 O C.sub.2 H.sub.5 O CH.sub.2__________________________________________________________________________
TABLE IV______________________________________ ##STR32## R R.sub.1 R.sub.2 R.sub.3 R.sub.4 W R.sub.8 Y'______________________________________H H H CH.sub.3 CH.sub.3 O H CH.sub.3H H H CH.sub.3 O CH.sub.3 O H CH.sub.3H H H C.sub.2 H.sub.5 CH.sub.3 O H CH.sub.3H H H n-C.sub.4 H.sub.9 CH.sub.3 O H CH.sub.3H H H CH.sub.3 CH.sub.3 O H CH.sub.3 OH H H CH.sub.3 CH.sub.3 O H C.sub.2 H.sub.5 OH H H CH.sub.3 CH.sub.3 O H HH H H CH.sub.3 CH.sub.3 S H CH.sub.3 OH CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 O H CH.sub.3 OH CH.sub.3 H CH.sub.3 CH.sub.3 O H CH.sub.3 OH n-C.sub.4 H.sub.9 H CH.sub.3 CH.sub.3 O H CH.sub.3 OH H H CH.sub.3 CH.sub.3 O H CH.sub.3 O3-Cl H H CH.sub.3 CH.sub.3 O H CH.sub.3 O4-Cl H H CH.sub.3 CH.sub.3 O H CH.sub.3 O5-Cl H H CH.sub.3 CH.sub.3 O H CH.sub.3 O6-Cl H H CH.sub.3 CH.sub.3 O H CH.sub.3 OH H H CH.sub.3 CH.sub.3 O CH.sub.3 CH.sub.3H H H CH.sub.3 CH.sub.3 O CH.sub.3 CH.sub.3 OH H H CH.sub.3 CH.sub.3 O CH.sub.3 O CH.sub.3H H H CH.sub.3 CH.sub.3 O CH.sub.3 O CH.sub.3 O______________________________________
TABLE V______________________________________ ##STR33## R R.sub.1 R.sub.2 R.sub.3 R.sub.4 Z______________________________________H H H CH.sub.3 CH.sub.3 CHH H H CH.sub.3 O CH.sub.3 CHH H H C.sub.2 H.sub.5 CH.sub.3 CHH H H n-C.sub.4 H.sub.9 CH.sub.3 CHH H H i-C.sub.3 H.sub.7 CH.sub.3 CHH H H C.sub.2 H.sub.5 C.sub.2 H.sub.5 CHH CH.sub.3 H CH.sub.3 CH.sub.3 CHH C.sub.2 H.sub.5 H CH.sub.3 CH.sub.3 CHH n-C.sub.4 H.sub.9 H CH.sub.3 CH.sub.3 CHH CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 CH3-Cl H H CH.sub.3 CH.sub.3 CH4-Cl H H CH.sub.3 CH.sub.3 CH5-Cl H H CH.sub.3 CH.sub.3 CH6-Cl H H CH.sub.3 CH.sub.3 CHH H H CH.sub.3 CH.sub.3 NH H H CH.sub.3 O CH.sub.3 NH H H C.sub.2 H.sub.5 CH.sub.3 NH H H n-C.sub.4 H.sub.9 CH.sub.3 NH H H i-C.sub.3 H.sub.7 CH.sub.3 NH H H C.sub.2 H.sub.5 C.sub.2 H.sub.5 NH CH.sub.3 H CH.sub.3 CH.sub.3 NH C.sub.2 H.sub.5 H CH.sub.3 CH.sub.3 NH n-C.sub.4 H.sub.9 H CH.sub.3 CH.sub.3 NH CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 N3-Cl H H CH.sub.3 CH.sub.3 N4-Cl H H CH.sub.3 CH.sub.3 N5-Cl H H CH.sub.3 CH.sub.3 N6-Cl H H CH.sub.3 CH.sub.3 N______________________________________
TABLE VI______________________________________ ##STR34## R R.sub.1 R.sub.2 R.sub.3 R.sub.4______________________________________H H H CH.sub.3 CH.sub.3H H H CH.sub.3 O CH.sub.3H H H C.sub.2 H.sub.5 CH.sub.3H H H i-C.sub.3 H.sub.7 CH.sub.3H H H n-C.sub.4 H.sub.9 CH.sub.3H CH.sub.3 H CH.sub.3 CH.sub.3H C.sub.2 H.sub.5 H CH.sub.3 CH.sub.3H n-C.sub.4 H.sub.9 H CH.sub.3 CH.sub.3H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.33-Cl H H CH.sub.3 CH.sub.34-Cl H H CH.sub.3 CH.sub.35-Cl H H CH.sub.3 CH.sub.36-Cl H H CH.sub.3 CH.sub.35-F H H CH.sub.3 CH.sub.35-Br H H CH.sub.3 CH.sub.35-NO.sub.2 H H CH.sub.3 CH.sub.35-CF.sub.3 H H CH.sub.3 CH.sub.35-CH.sub.3 O H H CH.sub.3 CH.sub.35-CH.sub.3 H H CH.sub.3 CH.sub.35-i-C.sub.3 H.sub.7 O H H CH.sub.3 CH.sub.35-i-C.sub.3 H.sub.7 H H CH.sub.3 CH.sub.3______________________________________
FORMULATIONS
Useful formulations of the compounds of Formula I can be prepared in conventional ways. They include dusts, granules, pellets, solutions, suspensions, emulsions, wettable powders, emulsifiable concentrates and the like. Many of these may be applied directly. Sprayable formulations can be extended in suitable media and used at spray volumes of from a few liters to several hundred liters per hectare. High strength compositions are primarily used as intermediates for further formulation. The formulations, broadly, contain about 0.1% to 99% by weight of active ingredient(s) and at least one of (a) about 0.1% to 20% surfactant(s) and (b) about 1% to 99.9% solid or liquid diluent(s). More specifically, they will contain these ingredients in the following approximate proportions:
TABLE VII______________________________________ Active* Ingredient Diluent(s) Surfactant(s)______________________________________Wettable Powders 20-90 0-74 1-10Oil Suspensions,Emulsions, Solu-tions (includingEmulsifiableConcentrates 3-50 40-95 0-15Aqueous Suspensions 10-50 40-84 1-20Dusts 1-25 70-99 0-5Granules andPellets 0.1-95 5-99.9 0-15High StrengthCompositions 90-99 0-10 0-2______________________________________ *Active ingredient plus at least one of a surfactant or a diluent equals 100 weight percent.
Lower or higher levels of active ingredient can, of course, be present depending on the intended use and the physical properties of the compound. Higher ratios of surfactant to active ingredient are sometimes desirable, and are achieved by incorporation into the formulation or by tank mixing.
Typical solid diluents are described in Watkins, et al., "Handbook of Insecticide Dust Diluents and Carriers", 2nd Ed., Dorland Books, Caldwell, N.J. The more absorptive diluents are preferred for wettable powders and the denser ones for dusts. Typical liquid diluents and solvents are described in Marsden, "Solvents Guide", 2nd Ed., Interscience, New York, 1950. Solubility under 0.1% is preferred for suspension concentrates; solution concentrates are preferably stable against separation at 0° C. "McCutcheon's Detergents and Emulsifiers Annual", MC Publishing Corp., Ridgewood, N.J., as well as Sisely and Wood, "Encyclopedia of Surface Active Agents", Chemical Publishing Co., Inc., New York 1964, list surfactants and recommended uses. All formulations can contain minor amounts of additives to reduce foam, caking, corrosion, microbiological growth, etc.
The methods of making such compositions are well known. Solutions are prepared by simply mixing the ingredients. Fine solid compositions are made by blending and, usually, grinding as in a hammer or fluid energy mill. Suspensions are prepared by wet milling (see, for example, Littler, U.S. Pat. No. 3,060,084). Granules and pellets may be made by spraying the active material upon preformed granular carriers or by agglomeration techniques. See J. E. Browning, "Agglomeration", Chemical Engineering, Dec. 4, 1967, pp. 147ff and "Perry's Chemical Engineer's Handbook", 5th Ed., McGraw-Hill, New York, 1973, pp. 8-57ff.
For further information regarding the art of formulation, see for example:
H. M. Loux, U.S. Pat. No. 3,235,361, Feb. 15, 1966, Col. 6, line 16 through Col. 7, line 19 and Examples 10 through 41.
R. W. Luckenbaugh, U.S. Pat. No. 3,309,192, Mar. 14, 1967, Col. 5, line 43 through Col. 1, line 62 and Examples 8, 12, 15, 39, 41, 52, 53, 58, 132, 138-140, 162-164, 166, 167 and 169-182.
H. Gysin and E. Knusli, U.S. Pat. No. 2,891,855, June 23, 1959, Col. 5, line 66 through Col. 5, line 17 and Examples 1-4.
G. C. Klingman, "Weed Control as a Science", John Wiley & Sons, Inc., New York, 1961, pp. 81-96.
J. D. Fryer and S. A. Evans, "Weed Control Handbook", 5th Ed., Blackwell Scientific Publications, Oxford, 1968, pp. 101-103.
In the following examples all parts are by weight unless otherwise indicated.
EXAMPLE 7
______________________________________Wettable Powder______________________________________2-[(Dimethylamino)sulfonylmethyl]-N--[4,6-dimethyl-pyrimidin-2-yl)aminocarbonyl]benzene-sulfonamide 80% sodium alkylnaphthalenesulfonate 2% sodium ligninsulfonate 2% synthetic amorphous silica 3% kaolinite 13%______________________________________
The ingredients are blended, hammer-milled until all the solids are essentially under 50 microns and then reblended.
EXAMPLE 8
______________________________________Wettable Powder______________________________________2-[(Dimethylamino)sulfonylmethyl]-N--[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]-benzenesulfonamide 50% sodium alkylnaphthalenesulfonate 2% low viscosity methyl cellulose 2%diatomaceous earth 46%______________________________________
The ingredients are blended, coarsely hammer-milled and then air-milled to produce particles of active essentially all below 10 microns in diameter. The product is reblended before packaging.
EXAMPLE 9
______________________________________Granule______________________________________wettable powder of Example 8 5%attapulgite granules 95%(U.S.S. 20-40 mesh; 0.84-0.42 mm)______________________________________
A slurry of wettable powder containing ≈25% solids is sprayed on the surface of attapulgite granules in a double-cone blender. The granules are dried and packaged.
EXAMPLE 10
______________________________________Extruded Pellet______________________________________2-[(Dimethylamino)sulfonylmethyl]-N--[(4,6-dimethoxy-pyrimidin-2-yl)aminocarbonyl]-ben-zenesulfonamide 25% anhydrous sodium sulfate 10% crude calcium ligninsulfonate 5%sodium alkylnaphthalenesulfonate 1% calcium/magnesium bentonite 59%______________________________________
The ingredients are blended, harmmed-milled and then moistened with about 12% water. The mixture is extruded as cylinders about 3 mm diameter which are cut to produce pellets about 3 mm long. These may be used directly after drying, or the dried pellets may be crushed to pass a U.S.S. No. 20 sieve (0.84 mm openings). The granules held on a U.S.S. No. 40 sieve (0.42 mm openings) may be packaged for use and the fines recycled.
EXAMPLE 11
______________________________________Oil Suspension______________________________________2-[(Dimethylamino)sulfonylmethyl]-N--[(4,6-dimethyl-1,3,5-triazin-2-yl)aminocarbonyl]-benzenesulfonamide 25% polyoxyethylene sorbitol hexaoleate 5% highly aliphatic hydrocarbon oil 70%______________________________________
The ingredients are ground together in a sand mill until the solid particles have been reduced to under about 5 microns. The resulting thick suspension may be applied directly, but preferably after being extended with oils or emulsified in water.
EXAMPLE 12
______________________________________Wettable Powder______________________________________2-[(Dimethylamino)sulfonylmethyl]-N--[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]-benzenesulfonamide 20% sodium alkylnaphthalenesulfonate 4% sodium ligninsulfonate 4% low viscosity methyl cellulose 3%attapulgite 69%______________________________________
The ingredients are thoroughly blended. After grinding in a hammer-mill to produce particles essentially all below 100 microns, the material is reblended and sifted through a U.S.S. No. 50 sieve (0.3 mm opening) and packaged.
EXAMPLE 13
______________________________________Low Strength Granule______________________________________2-[(Dimethylamino)sulfonylmethyl]-N--[(4,6-dimethoxy-1,3,5-triazin-2-yl)aminocarbonyl]-benzenesulfonamide 1% N,N--dimethylformamide 9% attapulgite granules 90% (U.S.S. 20-40 sieve)______________________________________
The active ingredient is dissolved in the solvent and the solution is sprayed upon dedusted granules in a double cone blender. After spraying of the solution has been completed, the blender is allowed to run for a short period and then the granules are packaged.
EXAMPLE 14
______________________________________Aqueous Suspension______________________________________2-[(Dimethylamino)sulfonylmethyl]-N--[(4,6-dimethyl-pyrimidin-2-yl)aminocarbonyl]benzene-sulfonamide 40% polyacrylic acid thickener 0.3% dodecylphenol polyethylene glycolether 0.5% disodium phosphate 1% monosodium phosphate 0.5% polyvinyl alcohol 1.0% Water 56.7%______________________________________
The ingredients are blended and ground together in a sand mill to produce particles essentially all under 5 microns in size.
EXAMPLE 15
______________________________________Solution______________________________________2-[(Dimethylamino)sulfonylmethyl]-N--[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]-benzenesulfonamide, sodium salt 5%water 95%______________________________________
The salt is added directly to the water with stirring to produce the solution, which may then be packaged for use.
EXAMPLE 16
______________________________________Low Strength Granule______________________________________2-[(Dimethylamino)sulfonylmethyl]-N--[(4,6-dimethoxy-pyrimidin-2-yl)aminocarbonyl]benzene-sulfonamide 0.1%attapulgite granules 99.9%(U.S.S. 20-40 mesh)______________________________________
The active ingredient is dissolved in a solvent and the solution is sprayed upon dedusted granules in a double cone blender. After spraying of the solution has been completed, the material is warmed to evaporate the solvent. The material is allowed to cool and then packaged.
EXAMPLE 17
______________________________________Granule______________________________________2-[(Dimethylamino)sulfonylmethyl]-N--[(4,6-dimethyl-1,3,5-triazin-2-yl)aminocarbonyl]benzene-sulfonamide 80%wetting agent 1%crude ligninsulfonate salt (containing5-20% of the natural sugars) 10%attapulgite clay 9%______________________________________
The ingredients are blended and milled to pass through a 100 mesh screen. This material is then added to a fluid bed granulator, the air flow is adjusted to gently fluidize the material, and a fine spray of water is sprayed onto the fluidized material. The fluidization and spraying are continued until granules of the desired size range are made. The spraying is stopped, but fluidization is continued, optionally with heat, until the water constant is reduced to the desired level, generally less than 1%. The material is then discharged, screened to the desired size range, generally 14-100 mesh (1410-149 microns), and packaged for use.
EXAMPLE 18
______________________________________High Strength Concentrate______________________________________2-[(Dimethylamino)sulfonylmethyl]-N--[(4,6-dimethoxy-1,3,5-triazin-2-yl)aminocarbonyl]benzene-sulfonamide 99%silica aerogel 0.5%synthetic amorphous silica 0.5%______________________________________
The ingredients are blended and ground in a hammer-mill to produce a material essentially all passing a U.S.S. No. 50 screen (0.3 mm opening). The concentrate may be formulated further if necessary.
EXAMPLE 19
______________________________________Wettable Powder______________________________________2-[(Dimethylamino)sulfonylmethyl]-N--[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]-benzenesulfonamide 90%dioctyl sodium sulfosuccinate 0.1%synthetic fine silica 9.9%______________________________________
The ingredients are blended and ground in a hammer-mill to produce particules essentially all below 100 microns. The material is sifted through a U.S.S. No. 50 screen and then packaged.
EXAMPLE 20
______________________________________Wettable Powder______________________________________2-[(Dimethylamino)sulfonylmethyl]-N--[(4,6-dimethyl-pyrimidin-2-yl)aminocarbonyl]benzene-sulfonamide 40%sodium ligninsulfonate 20%montmorillonite clay 40%______________________________________
The ingredients are thoroughly blended, coarsely hammer-milled and then air-milled to produce particles essentially all below 10 microns in size. The material is reblended and then packaged.
EXAMPLE 21
______________________________________Oil Suspension______________________________________2-[(Dimethylamino)sulfonylmethyl]-N--[(4,6-dimethoxy-pyrimidin-2-yl)aminocarbonyl]benzene-sulfonamide 35%blend of polyalcohol carboxylicesters and oil soluble petroleumsulfonates 6%xylene 59%______________________________________
The ingredients are combined and ground together in a sand mill to produce particles essentially all below 5 microns. The product can be used directly, extended with oils, or emulsified in water.
EXAMPLE 22
______________________________________Dust______________________________________2-[(Dimethylamino)sulfonylmethyl]-N--[(4,6-dimethyl-pyrimidin-2-yl)aminocarbonyl]benzene-sulfonamide 10%attapulgite 10%Pyrophyllite 80%______________________________________
The active ingredient is blended with attapulgite and then passed through a hammer mill to produce particles substantially all below 200 microns. The ground concentrate is then blended with powdered pyrophyllite until homogeneous.
UTILITY
The compounds of the present invention are active herbicides. They have utility for broadspectrum pre- and/or post-emergence weed control in areas where complete control of all vegetation is desired, such as around fuel storage tanks, ammunition depots, industrial storage areas, oil well sites, drive-in theaters, around billboards, highway and railroad structures. By properly selecting rate and time of application. Some compounds of this invention may be used to modify plant growth beneficially, and also selectively control weeds in crops such as wheat and barley.
The precise amount of the compound of Formula I to be used in any given situation will vary according to the particular end result desired, the amount of foliage present, the weeds to be controlled, the crop species involved, the soil type, the formulation and mode of application, weather conditions, etc. Since so many variables play a role, it is not possible to state a rate of application suitable for all situations. Broadly speaking, the compounds of this invention are used at levels of about 0.05 to 20 kg/ha with a preferred range of 0.1 to 10 kg/ha. In general, the higher rates of application from within this range will be selected for adverse conditions or where extended persistence in soil is desired.
The compounds of Formula I may be combined with other herbicides and are particularly useful in combination with 3-(3,4-dichlorophenyl)-1,1-dimethylurea (diuron); the triazines such as 2-chloro-4-(ethylamino)-6-(isopropylamino)-s-triazine (atrazine); the uracils such as 5-bromo-3-sec-butyl-6-methyluracil (bromacil); N-(phosphonomethyl)glycine (glyphosate); 3-cyclohexyl-1-methyl-6-dimethylamino-s-triazine-2,4(1H,3H)-dione (hexazinone); N,N-dimethyl-2,2-diphenylacetamide (diphenamide); 2,4-dichlorophenoxyacetic acid (2,4-d) (and closely related compounds); 4-chloro-2-butynyl-3-chlorophenylcarbamate (barban); S-(2,3-dichloroallyl)diisopropylthiocarbamate (diallate); S-(2,3,3-trichloroallyl)diisopropylthiocarbamate (triallate); 1,2-dimethyl-3,5-diphenyl-1H-pyrazolium methyl sulfate (difenzoquat methyl sulfate); methyl 2-[4-(2,4-dichlorophenoxy)phenoxy]propanoate (diclofop methyl); 4-amino-6-tertbutyl-3-(methylthio)-1,2,4-triazin-5(4H)one (metribuzin); 3-(3,4-dichlorophenyl)-1-methoxy-1-methylurea (linuron); 3-isopropyl-1H-2,1,3-benzothiodiazin-4(3H)-one-2,2-dioxide (bentazon); α,α,α-trifluoro-2,6-dinitro-N,N-dipropyl-p-toluidine (trifluralin); 1,1'-dimethyl-4,4'-bipyridinium ion (paraquat); monosodium methanearsonate (MSMA); 2-chloro-2',6'-diethyl (methoxymethyl)acetanilide (alachlor); 1,1-dimethyl-3-(α,α,α-trifluoro-m-tolyl)-urea (fluometuron); and 5-[2-chloro-4-(trifluoromethyl)phenoxy]2-nitrobenzoic acid, methyl ester (acifluorfen-methyl).
The activity of these compounds was discovered in greenhouse tests. The test procedure is described and the data obtained are shown below.
TEST A
Seeds of crabgrass (Digitaria spp.), barnyardgrass (Echinochloa crusgalli), wild oats (Avena fatua), cassia (Cassia tora), morningglory (Ipomoea sp.), cocklebur (Xanthium spp.), sorghum, corn, soybean, rice, wheat and nutsedge tubers (Cyperus rotundus) were planted in a growth medium and treated pre-emergence with the chemicals dissolved in a non-phytotoxic solvent solution of the compounds of Table A. At the same time, cotton having five leaves (including cotyledonary ones), bush beans with the third trifoliate leaf expanding, crabgrass, barnyardgrass and wild oats with two leaves, cassia with three leaves (including cotyledonary ones), morningglory and cocklebur with four leaves (including the cotyledonary ones), sorghum and corn with four leaves, soybean with two cotyledonary leaves, rice with three leaves, wheat with one leaf, and nutsedge with three to five leaves were sprayed with a non-phytotoxic solvent solution of the compounds of Table A. Other containers of the above mentioned weeds and crops were treated pre- or post-emergence with the same non-phytotoxic solvent so as to provide a solvent control. A set of untreated control plants was also included for comparison. Pre-emergence and post-emergence treated plants and controls were maintained in a greenhouse for sixteen days, then all treated plants were compared with their respective controls and rated visually for response to treatment utilizing the following rating system:
0=no effect;
10=maximum effect;
C=chlorosis or necrosis;
E=emergence inhibition;
G=growth retardation;
H=formative effects;
X=axillary stimulation; and
6Y=abscised buds or flowers.
The data obtained are summarized in Table A. ##STR35##
TABLE A__________________________________________________________________________ Com- pound Compound 1 Compound 2 Compound 3 Compound 4 Compound 6Rate kg/ha 0.1 2 0.1 2 0.1 2 0.1 2 0.1 2 2__________________________________________________________________________POST-EMERGENCEBush bean 5C,9G, 4C,9G, 1C,4G, 4S,9G,6Y 5C,9G,6Y 5C,9G,6Y 2C,5G,6Y 3C,7G,6Y 3G 2C,9G 0 6Y 6Y 6YCotton 5C,9G 5C,8G 1C 5C,8G 3C,3H,7G 5C,7G 3C,3H 3C,4H 1C 2C,1H 0Morningglory 4C,9H 5C,9G 2C,5G 3C,6G 3C,8H 6C,9G 2C,4H 3C,4G 1C,9H 2C 0Cocklebur 3C,9G 4C,9G 0 1C 3C,9H 4C,9G 1C 1C 1C 1C 0Cassia 3C,7H 3C,6G 1C 1C 3C 3C,5G 1C 1C 0 2G 0Nutsedge 1C,9G 1C,9G 0 1C,5G 2C,6G 3C,8G 2G 0 0 1C,5G 0Crabgrass 1C,3G 8G 0 0 0 2C,5G 0 0 0 0 0Barnyardgrass 3C,9H 9C 0 0 1C,6H 4C,9H 0 1C 0 0 0Wild Oats 0 0 0 0 0 1C,6G 0 0 0 0 0Wheat 0 0 0 0 0 3G 0 0 0 0 0Corn 2C,7H 5U,9C 0 0 2C,5H 2C,9H 0 1C,4G 0 0 0Soybean 3C,9G 4C,9G 1C,1H 2C,4G 2C,8G,5X 2C,8G 1C,3G 1C,4G 1C 0 0Rice 1C,5G 8G 0 2G 1C,2G 3C,7G 0 2G 0 0 0Sorghum 5C,9G 9C 0 1C,2G 3C,9H 3C,9G 0 2C,4G 1C 1C,3G 0PRE-EMERGENCEMorningglory 2C,5H 9G 0 3C,6G 3C,5H 9G 1C 4C,9G 1C 3C,8G 0Cocklebur 1C,3H 9H 0 6G 9H 9H 0 2C 0 9H 0Cassia 6C 3C,8G 0 2C 3C,3H 2C,8G 2C 2C 0 2C 0Nutsedge 10E 10E 0 3G 2C,6G 10E 1C 8G 0 5G 4GCrabgrass 1C 2C,8G 0 0 2C 2C,8G 2G 4G 0 2C 5GBarnyardgrass 3C,8H 5C,9H 0 1C,2G 2C,6H 5C,9H 1C 6G 0 2C,6G 1C,3GWild Oats 1C 3C,7G 0 3G 2C,6G 4C,8G 0 4G 0 4G 0Wheat 1C 4G 0 4G 2C 1C,7G 2G 0 2G 2G 0Corn 2C,9H 9H 0 3C,9H 3C,8H 9G 1C,6G 9G,2C 1C 2C,8H 2C,4GSoybean 3C,5H 9H 0 2C,3G 3C,6H 9H 1C 1H,1C 1C 1H 1HRice 2C,6G 10E 0 3G 3C,7G 9H 1C,4G 2C 2C 5C 1CSorghum 2C,9G 5C,9H 0 3C,8G 5C,8H 4C,9H 1C,3G 9G,3C 2C 3C,7G 2C,5G__________________________________________________________________________ | The compounds are of the class of N-[(substituted pyrimidin-2-yl)aminocarbonyl]-2-(sulfonylmethyl)benzenesulfonamides, useful as preemergent or postemergent herbicides or plant growth regulants. | 2 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention generally relates to a self-adjusting apparatus for use in cleaning surfaces of endless belt conveyor belt apparatuses, and the like.
2. Description of the Prior Art
When bulk material such as coal, coke, sinter, stone, ore, and the like are transported on endless belt conveyor belts, oftentimes some of the materials do not drop off the discharge end of the conveyor belt. Such materials, which may be of a moist or putty-like consistency, stick to the conveyor belt, with a substantial portion of the materials shaking off the belt as the belt returns to the tail-end section of the conveyor apparatus. The materials so shaken off may build up on the floor below the conveyor belt apparatus, to such an extent that the materials may surround components of the apparatus, such as for example the return and training idlers of the conveyor belt, thereby detraining the belt and damaging the components of the conveyor apparatus. Such build-up of materials around the conveyor belt apparatus requires clean-up of the area, replacement of damaged return and training idlers, belts, end pulleys, snub pulleys, and other components of the conveyor belt.
Many different types of conveyor belt cleaning devices have been used in the past in an attempt to deal with the material carried back from the discharge end of the conveyor belt. For example, brushes have been positioned past the discharge end point and in contact with the conveyor belt to brush material from the belt. However, the material has the tendency to build up and compact and cake between the bristles of the brushes thereby rendering the brushing action ineffective.
Streams of compressed air have also been used to clean conveyor belts. However, the cost of generating such compressed air is quite high and the use of compressed air frequently creates turbulence which results in a dusty environment around the conveyor belt apparatus.
Likewise, single scrapers or scrapers with multiple hard blades have been used in an attempt to clean conveyor belts. Generally, these scrapers are mounted behind the head pulley; however, hard scrapers currently in use in the industry often damage or destroy the conveyor belt and do not clean properly the belt. Other scrapers utilized to clean conveyor belts include blades made from soft, flexible material, with the blades mounted on the head pulley. Such scrapers are quite inefficient and frequently result in damage to the conveyor belt when grit and other small particles lodge between the flexible scraper and the conveyor belt thereby causing a "sandpaper" effect when the conveyor belt is operated.
As is well known in the art, when the conveyor belt leaves the discharge end pulley, it begins to change shape from a straight-line cross section to a concave cross section having intermittent wave action. This occurs until the conveyor belt reaches the snub pulley or the first return idler, at which point the belt, because it is supported on the snub pulley or the first return idler, again achieves a straight-line cross section. Thus, when the conveyor belt is not supported, a cross section of the belt would take a concave shape having an intermittent wave action.
Even though it has been recognized that the unsupported conveyor belt takes a concaved shape, most conveyor belt cleaning devices in the prior art are installed behind the head pulley in the area where the belt is unsupported. These devices, which have either single or multiple scraping blades having a straight-line cross section, are rigidly mounted or, in some instances, mounted by springs. Because of the concave shape of the conveyor belt at such locations, frequently the scraping blades do not fully contact the conveyor belt across its width. Rather, the ends of such blades make contact with the belt, while the center portion of the blades do not. In such instances, material adhering to the conveyor belt is not cleaned off in the area near the center of the cleaning blades; this has a further disadvantage because as the material travels through the void between the conveyor belt and the center portion of the cleaning blade, the center portion is worn faster than the ends thereof. This causes the ends of the blades to become sharpened by wear and cut grooves into the face of the belt. It is for this reason that cleaning blades utilized in such cleaning apparatus are replaced very frequently.
In a further effort to avoid the conveyor belt damage noted above, some prior art devices have cleaning blades constructed in an arcuate shape. Such devices assume that the curved blade will match the shape of the conveyor belt as the belt passes thereacross. However, because these devices are installed at a location where the conveyor belt is unsupported, the belt may not assume the exact curvature of the blade. Thus, cleaning devices having such blades have the disadvantage similar to that discussed above with respect to straight blades; that is, the edges of the curved blades, because they do not touch the belt, are worn excessively by the material being carried back by the conveyor belt. This results in the center portion of the blades becoming sharp and destroying the belt as described above, while the material sticking to the conveyor in the area underlying the edges of the blade remains on the belt and is not removed.
The prior art has also recognized that the better location for a cleaning apparatus is on the head pulley. At this position, the flexible conveyor belt is still wrapped on the pulley and is supported by that pulley. This results in a belt which is flat and does not have the concaved or wavey attributes associated with an unsupported belt. In addition, at this location a flat cleaning blade could make flush contact with the surface of the belt. As a further advantage, the cleaning blade at this location is directly above the main discharge end chute such that the material scraped off the conveyor belt would fall with the bulk material being unloaded.
However, prior art cleaning devices which are positioned at the location where the conveyor belt is wrapped and supported by the head pulley are comprised of a single or double flexible bar, such as rubber or urethane, supported by a continuous steel bar. This apparatus is pressed against the surface of the conveyor belt and is pivotably supported by levers mounted parallel to the conveyor belt. The flexible bar cleaning apparatus is forced into the face of the conveyor belt by means of counterweights or springs. Such devices provide several disadvantages. First, the flexible conveyor belt itself often exhibits uneveniness due to uneven wear; that is, the center of the conveyor belt wears faster due to the fact that generally more material travels on the center of the belt than along the outer edges. Because of this, constant pressure of the cleaning bar cannot be achieved across the width of the conveyor belt so the cleaning efficiency is reduced. In addition, contaminants not detachable by the cleaning bar or a slight out of roundness of the head pulley will cause the cleaning bar to bounce from the surface of the belt thereby causing the cleaning bar to miss portions of the belt.
In order to counteract the above problems, prior art devices have increased the contact forces associated with the cleaning bar such that the cleaning bars are firmly held in contact with the conveyor belt. In order to do so, the cleaning bars must be made of a soft, flexible material because a hard material, such as, for example, steel or tungsten carbide, will damage the surface of the conveyor belt at increased contact pressures. It has been found, however, that when such soft, flexible materials are used as cleaning bars, small particles of the material removed from the surface of the conveyor belt will be imbedded in the face of such cleaning bars. This results in such cleaning bars acting with a sandpaper effect on the surface of the conveyor belt thereby damaging the belt.
The novel apparatus of the present invention overcomes the foregoing deficiencies noted in the prior art by providing an apparatus which cleans the surface of conveyor belts and removes therefrom material that is not discharged from the discharge end of the conveyor belt. The present invention accomplishes this result in a manner which minimizes damage to the surface of the conveyor belt. Accordingly, it is an object of the present invention to provide an apparatus for cleaning conveyor belts which does not have the inherent deficiencies of the prior art.
It is yet another object of the present invention to provide a cleaning apparatus which includes one or more blade tips positioned in contact with the surface of the conveyor belt at a location where the conveyor belt is in contact with the head, or other, pulleys of the conveyor belt system, thereby allowing material to be removed from the conveyor belt in an efficient manner.
It is yet a further object of the present invention to provide a cleaning apparatus which is self-adjusting in that the blade tips move in response to deformities of the head, or other, pulleys and the conveyor belt surface and in that the blade tips remain in contact with the belt surface as the tips wear during use.
These and other objects and avantages of the present invention will become apparent to those skilled in the art with reference to the foregoing, the attached drawings, and the description of the invention which hereinafter follows.
SUMMARY OF THE INVENTION
The present invention provides a self-adjusting cleaning apparatus for use in cleaning the surface of conveyor belts and the like. The apparatus comprises a blade support having a blade tip attached thereto; the blade support is attached to a curvilinear arm. The curvilinear arm is connected to a suspension unit holder which is mated with a plug removably engaged to a shaft. Each end of the shaft is rotatably and torsionally supported on an arm support which is threadably engaged on a threaded spindle. The spindle is attached to supports adapted to be connected to stationary structures associated with the conveyor belt. Adjustment of the cleaning apparatus may be made by rotating the shaft around its longitudinal axis and translating the arm support along the threaded spindle. The self-adjusting feature of the present invention results from the torsion action associated with both the curvilinear arm and the arm support.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a partial cross-section of a portion of a conveyor belt apparatus showing the cleaning apparatus of the present invention associated therewith.
FIG. 2 is a view of FIG. 1 taken along the lines A--A showing the cleaning apparatus of the present invention.
FIG. 3A is a top view of the U-shaped bracket associated with the arm support.
FIG. 3B is a side view of the U-shaped bracket shown in FIG. 3A.
FIG. 3C is a top view of the housing of the arm support.
FIG. 3D is a side view of the housing shown in FIG. 3C.
FIG. 4 depicts the shaft utilized in the present invention.
FIG. 5 is a cross-section of the shaft, shown in FIG. 4, depicting the reinforcing bar and a plug positioned within a void in a bar attached to the shaft.
FIG. 6 is a cross-section of the suspension unit which is engageable on the plug shown in FIG. 5.
FIG. 7 is a top view of the blade arm utilized in the present invention.
FIG. 7A is a cross-section of the blade arm taken along the lines A--A of FIG. 7.
FIG. 7B is a cross-section of the blade arm taken along the lines B--B of FIG. 7.
FIG. 7C is a cross-section of the blade arm taken along the lines C--C of FIG. 7.
FIG. 8 is a side view of the blade arm shown in FIG. 7.
FIG. 9 is a side view of the blade showing the blade tip connected thereto.
FIG. 10 depicts two blade arms attached to the shaft at one end and at the other end thereof attached to the blade.
FIG. 11 shows the housing depicted in FIGS. 3C and 3D mated to the U-shaped bracket depicted in FIGS. 3A and 3B.
DESCRIPTION OF THE PREFERRED EMBODIMENT
As noted, the present invention relates to a self-adjusting cleaning apparatus used to clean conveyor belts, and the like. With respect to conveyor belts, as depicted in FIG. 1, the conveyor belt apparatus (not a part of this invention) is generally shown by reference numeral 10. The conveyor belt apparatus 10 is comprised of a head pulley 12, a snub pulley 14, and an endless flexible belt 16. The flexible belt 16 travels in the direction of the arrows shown on FIG. 1 by virtue of rotation imparted on the head pulley 12 and the snub pulley 14 through motors (not shown) which are conventional in the conveyor belt art. Idler rollers and other components of the conveyor belt apparatus 10 are not shown in FIG. 1. Material carried on the belt 16 is discharged at the discharge end generally shown by reference numeral 11.
The self-adjusting cleaning apparatus 18 of the present invention shown in FIG. 1 is also depicted in FIG. 2 (taken along the lines A--A of FIG. 1). As there shown, the cleaning apparatus 18 comprises a shaft 20 engageably attached at each end thereof to end units 22. A portion of the end units 22 may be enclosed with a rubber boot 15 (shown in dashed lines in FIG. 1) for protection from materials falling from the belt 16 during the cleaning operation. Also engageably attached to the shaft 20, by means hereinafter described, is at least one blade 24.
The end units 22 include a threaded spindle 26 with one end thereof attached to a spindle support 28. The spindle support 28 is adapted to be attached to a stationary structure such as a side wall of or an angle iron associated with the conveyor belt 10 so that the cleaning apparatus 18 can be held in position adjacent the flexible belt 16. An arm support 30 is positioned on the threaded spindle 26 and held thereon with threaded adjustment lugs 32 having sleeves 33 associated therewith (see FIG. 11). Thus, the arm support 30 is translatable along the longitudinal axis of the spindle 26 through the adjustment of the threaded adjustment lugs 32.
The arm support 30 is shown in detail in FIGS. 3A through 3D. As depicted in FIG. 3A, the arm support 30 comprises, as one component, a generally U-shaped bracket 34 having attached, as by welding, a stop 36 to the inner surface thereof along the closed portion of the U-shaped bracket 34. A shaft support 38 is attached to the outer surface of the U-shaped bracket 34. The arms 40 of the U-shaped bracket 34 are provided, at the ends thereof, with holes 42a, 42b 42c, and 42d. These holes, as shown in FIG. 3B (which is a side view of FIG. 3A) are off-set from the vertical and horizontal axes of the arms 40. That is, the center line of the holes 42a and 42c (shown by the dashed line at reference numeral 15) are off-set from the vertical axis of the arm 40 (shown by the dashed line at reference numeral 17) and the center line of the holes 42b and 42d (shown by the dashed line at reference numeral 19) are off-set from the horizontal axes of the arms 40 (shown by the dashed line at reference numeral 21). It has been determined that the angular off-set of these holes from the respective horizontal and vertical axes of the arms 40 can be from about 1° to about 20°, with about 15° being preferred.
As also shown in FIG. 3B, the shaft support 38 is provided with a void 44 for receipt of the shaft 20. In addition, the shaft support 38 includes at least one threaded hole 46 for the receipt of a set screw (not shown) which is used to hold the shaft 20 in position when the shaft 20 is inserted into the void 44 of the shaft support 38. Preferably, the shaft support 38 includes a plurality of threaded holes 46 to ensure that the shaft 20 is securely held within the shaft support 38.
The arm support 30 also includes, as another component, a housing 48 (see FIGS. 3C and 3D). The housing 48 comprises a generally tubular member 50 sized for receipt of the threaded spindle 26 therein. The tubular member 50 is attached to a plate 52 and L-shaped brackets 54 through bolts (not shown) inserted through holes 56, 58, and 60.
Positioned between the L-shaped brackets 54, and attached thereto as by welding, is a torsion unit 62. The torsion unit 62 advantageously may be of the type sold by Lovejoy, Inc., Unit No. DR-A, type 45×80. This unit 62 comprises a chamber 64 having a square-shaped central void 66 therein. A square-shaped member 68 having rounded corners 70 is positioned in the central void 66 and is adapted such that a diagonal dimension of the square-shaped member 68 is less than horizontal dimension of the central void 66. When positioned in the void 66, the diagonal axes of the square-shaped member 68 lie along the vertical and horizontal axes of the chamber 64. Also positioned within the void 66 are a plurality of torsion members 72, depicted in FIG. 3B as 72a, 72b, 72c, and 72d. These members are advantageously constructed from a hard rubber-like material having resiliency associated therewith. It should be appreciated that the torsion unit 62 acts in a combined spring-damper-bearing fashion due to the resiliency of the torsion members 72 when the square-shaped member 68 is rotated about its longitudinal axis. The square-shaped member 68 is also provided with a plurality of holes positioned along the diagonal axes thereof (shown as reference numerals 74a, 74b, 74c, and 74d) for purposes hereinafter described.
In order to form the arm support 30, the housing 48 is mated with the U-shaped bracket 34. This is done by aligning the holes 74a, 74b, 74c, and 74d, of the square-shaped member 68, with, respectively, the holes 42a, 42b, 42c, and 42d found in the arms 40 of the U-shaped bracket 34 and positioning set screws, bolts, and the like (not shown) therethrough. Upon such positioning, the tubular member 50 will be off-set from the vertical by an angle equivalent to that discussed above with respect to the holes 42a, 42b, 42c, and 42d. This is shown in FIG. 11.
The tubular member 50 is also provided with a set screw holder 76, which includes a void 78 for receipt of a set screw 150 (see FIG. 11). The stop 36 of the U-shaped bracket 34 is advantageously positioned such that upon turning of the set screw in the void 78, the set screw 150 will contact the stop 36. As will be explained hereinafter, when the arm support 30 is secured to the shaft 20, turning the set screw 150 onto the stop 36 will cause the square-shaped member 68 to rotate about its longitudinal axis due to the resiliency associated with torsion members 72a, 72b, 72c, and 72d. Thus, when the arm support 30 is positioned on the spindle 26 and the adjustment lugs 32 are tightened to hold the arm support 30 firmly, turning the set screw 150 will cause the U-shaped bracket 34 to be rotated about the longitudinal axis of the square-shaped member 68.
Referring now to FIG. 4, the shaft 20 is shown. The shaft 20 includes a reinforcing bar 80 welded along one surface thereof to reinforce the shaft 20 and on the opposing surface thereof a square-shaped bar 82 is welded thereto (see FIG. 5). The shaft 20 may be a pipe to decrease the overall weight of the cleaning apparatus 18. The bar 82 is provided with a plurality of spaced-apart holes 85 for receipt of a plurality of spaced-apart plugs 86. The bottom portion 88 of the plugs 86 is sized to provide a tight fit in the holes 85.
Positioned on each plug 86 is a suspension unit holder 90 (see FIG. 6). The suspension unit holder 90 is provided with a void 92 adapted to receive the plug 86. Communicating with the void 92 is a threaded screw hole 94 for receipt of a set screw (not shown) to hold the suspension unit holder 90 tightly on the plug 86. The suspension unit holder 90 includes a top portion 96 thereof containing a square-shaped void 98 therein. A square-shaped bar 112 having rounded corners 114 is positioned in the void 98 and is adapted such that a diagonal dimension of the square-shaped bar 112 is less than horizontal dimension of the void 98. When positioned in the void 98, the diagonal axes of the square-shaped bar 112 lie along the vertical and horizontal axes of the void 98. Also positioned within the void 98 are a plurality of torsion members 116, depicted in FIG. 6 as 116a, 116b, 116c, and 116d. These members are advantageously constructed from a hard rubber-like material having resiliency associated therewith. It should be appreciated that the suspension unit 90 acts in a combined spring-damper-bearing fashion due to the resiliency of the torsion members 116 when the square-shaped bar 112 is rotated about its longitudinal axis. The ends of the bar 112 extend beyond the outside dimension of the suspension unit holder 90 for purposes described subsequently.
A blade arm 100 (see FIG. 7) is attached to the suspension unit holder 90. As shown in FIG. 8, the blade arm 100 is curvilinear in shape and is constructed of a stainless steel or other metallic material. Although the blade arm 100 is an integral unit, cross-sections thereof show that it may comprise different geometric shapes. For example, FIG. 7A is a cross-section of the blade arm 100 taken along the lines A--A of FIG. 7 and shows that the cross-section is substantially rectangular. FIG. 7B, which is a cross-section taken along the lines B--B of FIG. 7, shows that the cross-section at this location is elliptical in shape. FIG. 7C, which is a cross-section taken along the lines C--C of FIG. 7, shows that the cross-section of the blade arm 100 is substantially an irregular pentagon in shape at this location.
It has been determined that the shape of the blade arm 100 provides significant advantages to the present invention. The shape as depicted in FIG. 7, and the cross-sections relating thereto, allows material which is cleaned from the conveyor belt to flow around the blade arm 100, thereby decreasing the likelihood of undesired build-up of material in the area of the blade arm 100.
The blade arm 100 has attached to it at one end thereof a bolt 102 for receipt of the blade 24 (see FIG. 9). The blade 24 includes a hole 106 adapted to mate with the bolt 102 and a blade tip 108 which may be made from tungsten carbide or a ceramic material heat bonded to blade tip support 110. The blade 24 is attached to the blade arm 100 by a nut, or the like (not shown). Alternatively, the blade 24 can include a plurality of holes 106 as shown in FIG. 10 if it desired to utilize wider blades. In this situation, each of the holes 106 would be positioned on identical blade arms 100. In other words, if the blade was wide enough to require support at two locations, the blade 24 would be attached to two adjacent blade arms 100.
The end of the blade arm 100 opposite the bolt 102 is provided with an attachment member 120. The attachment number 120 includes a void 122 adapted to receive that portion of the bar 112 extending beyond the outside dimension of suspension unit holder 90. The attachment member 120 also includes a threaded screw hole 124 for receipt of a set screw (not shown) used to tighten the member 120 on the bar 112 and firmly hold the blade arm 100 thereon. For example, as shown in FIG. 10, two blade arms 100 are attached to the bar 112 passing through the suspension unit holder 90. At the opposite end thereof, the blade 24, provided with two holes 106, is attached to the blade arms 100 by nuts 104.
As will be appreciated, the number of blades 24 of the cleaning apparatus 18 is a function of the width of the flexible belt 16 to be cleaned and the width of the blades. Through experimention, it has been determined that blade widths of from about 4 to about 6 inches work particularly well for conveyor belts having flexible belt widths of about 16 to about 120 inches. However, it should be noted that the width of the blades may vary from that given above, it only being necessary to ensure that the blades are not so wide as to give rise to the problems noted in the prior art.
Prior to operation, the cleaning apparatus 18 is adjusted such that the blade tip 108 rides slightly against the belt 16 of the conveyor belt 10, preferably at a location where the belt 16 makes contact with the head pulley 12 or any other pulley or roller associated with the conveyor belt 10, it only being necessary to assure that the blade tip 108 contacts the surface of the belt 16 at a location where the belt 16 is supported by such pulleys, rollers, etc. In addition, for maximum efficiency of cleaning, it is preferred that the blade tip 108 contact the surface of the belt 16 at an obtuse angle, with such angle being measured between a line tangent to the surface of the belt and the blade tip 108. This is accomplished by tightening the set screw 150 passing through hole 78 to cause the U-shaped bracket 34 to be rotated about the longitudinal axis of the square-shaped member 68. In addition, the shaft 20 is rotated about its longitudinal axis until the blade tip 108 is in close proximity to the flexible belt 16. Then, the set screws positioned in the holes 46 are tightened to secure the shaft 20. The set screw 150 passing through the hole 78 is then released so that the U-shaped bracket 34 rotates counterclockwise under influence of the torsion unit 62 until the blade tip 108 makes contact with the flexible belt 16. Proper location of the blade tip 108 for efficient cleaning of the belt 16 is achieved when the blade tip 108 contacts the belt 16 rearward of a line drawn between the center of the head pulley 12 (or other pulleys or rollers) and the center of the square-shaped bar 112.
During operation of the conveyor belt 10, the belt 16 may have a tendency to vibrate across its width, such as due to imperfections in the head pulley 12. Such vibration will cause varying forces to be applied to the blade tips 108. Accordingly, the cleaning apparatus 18 of the present invention allows each blade tip 108 to be independently movable with respect to the remaining blade tips 108. This occurs through rotation of the blade arms 100 about the longitudinal axis of the square-shaped bar 112 positioned within the suspension unit 90 (as depicted with reference to the arc identified by the letter "x" in FIG. 1) and by further rotation of the U-shaped bracket 34 about the longitudinal axis of the square-shaped member 68 positioned within the torsion unit 62 (as depicted with reference to the arc identified by the letter "y" in FIG. 1). | The present invention relates to a self-adjusting apparatus for use in cleaning the surface of endless belt conveyor belt apparatuses and the like. The apparatus is characterized by a blade tip which is positioned to contact the surface of the conveyor belt at a location where the conveyor belt is in contact with a head pulley, snub pulley, idler roller, or the like. The blade tip is attached to a rotatable and translatable support structure. The support structure comprises a plurality of tortion units which permit the blade tip to move in response to deformations of the surface of the conveyor belt during the operation of the conveyor belt. | 1 |
BACKGROUND of the INVENTION
1. Field of the Invention
A subject-matter of the present invention is the use of specific alkylpolyglycosides as emulsifying agents for the preparation of oil-in-water emulsions comprising inorganic fillers or pigments.
The invention finds application in particular in the cosmetics and pharmaceutical field.
2. Related Art
The formulation of fillers and pigments, in particular of inorganic fillers and pigments, in an emulsion is complex. This is because the presence of fillers or pigments introduces electrical charges into the emulsion which disrupt this emulsion. The latter is difficult to stabilize, often forcing the formulator to use a complex emulsifying system, one or more stabilizers for the aqueous phase, or a dispersing surfactant, to prevent reagglomeration of the fillers over time.
In the case of antisun emulsions, this reagglomeration of the fillers results in a low or unstable UV protecttion factor which decreases over time. In the case of makeup emulsions, reagglomeration of the fillers can also occur, resulting in poor homogeneity of the color in the emulsion itself or when it is applied to the skin. In both these cases, the reagglomeration of the fillers, if it is significant, detrimentally affects the texture of the emulsion, which, instead of appearing smooth and glossy, becomes dull and granular.
To overcome these difficulties, recourse is often had:
either to complex emulsifying systems, which are generally based on fatty chains with a length of 16 and 18 carbon atoms (saturated, unsaturated or branched); or to complex manufacturing processes; for example, inorganic filters with a UV-inhibiting role are very often predispersed in the oil phase or in the water phase.
The problem to be solved thus consists in having available oil-in-water emulsions, comprising inorganic fillers or pigments, which are easy to prepare and which are stable over time, that is to say in which the pigments or fillers do not reagglomerate.
It has now been discovered unexpectedly, and this is the basis of the invention, that an emulsifier based on an alkylpolyglycoside structure with a length of alkyl chain having from 6 to 12 carbon atoms makes it possible to readily formulate oil-in-water (hereinafter “O/W”) emulsions comprising inorganic fillers and/or pigments. This result is all the more surprising since short-chain surfactants are not supposed to exhibit good emulsifying properties. These emulsions exhibit an excellent dispersion of the fillers without it being necessary to add coemulsifier or dispersant and without it being useful either to apply specific manufacturing processes as described above. The dispersion obtained with the emulsifier according to the invention is furthermore stable over time, that is to say that, surprisingly, the emulsifier makes it possible, by itself alone, to prevent the reagglomeration of the fillers and/or pigments, including in fluid emulsions such as milks.
SUMMARY OF THE INVENTION
Thus, according to a first aspect, a subject matter of the invention is alkylpolyglycosides represented by the following formulae (Ia) or (Ib):
HO—R—O(X) r (Ia)
(X) s —OR—O—(X) t (Ib)
in which:
X represents the residue of a C 5 or C 6 sugar, preferably the glucose or xylose residue; R represents an alkylene or alkylidene group having from 6 to 12 carbon atoms; r, s and t represent the mean degree of polymerization of each sugar residue. They are greater than 1 and less than or equal to 5, and more particularly less than or equal to 2.5.
DESCRIPTION OF PREFERRED EMBODIMENTS
One aspect of the invention is alkylpolyglycosides represented by the following formulae (Ia) or (Ib):
HO—R—O(X) r (Ia)
(X) s —OR—O—(X) t (Ib)
in which:
X represents the residue of a C 5 or C 6 sugar, preferably the glucose or xylose residue;
R represents an alkylene or alkylidene group having from 6 to 12 carbon atoms;
r, s, and t represent the mean degree of polymerization of each sugar residue. They are greater than 1 and less than or equal to 5, and more particularly less than or equal to 2.5.
When X represents the xylose residue, r, s and t are more particularly between 1.005 and 1.5.
When X represents the glucose residue, r, s and t are more particularly between 1.05 and 2.
The compounds of formula (Ia) or (Ib) in accordance with the present invention can be prepared by reaction of a reducing sugar and of an alkanediol having from 6 to 12 carbon atoms, preferably hexanediol, octanediol, decanediol or dodecanediol, in desired predetermined proportions.
This reaction results either in the products resulting from the acetalization of one of the two hydroxyl groups of the diol (compounds (Ia)), or in the products resulting from the acetalization of both hydroxyl groups of the diol (compounds (Ib)), or in the mixture of the compounds (Ia) and (Ib).
On an industrial scale, these compounds will preferably be prepared according to one of the two routes conventionally used for the synthesis of alkylpolyglycosides, for example by reaction, in an acidic medium, between the alkanediol having from 6 to 12 carbon atoms and a reducing sugar, such as glucose or xylose.
Such synthetic routes are well known to a person skilled in the art.
If appropriate, this synthesis can be supplemented by neutralization, filtration or decoloration operations or operations for the partial distillation or extraction of the excess diol.
According to a second aspect of the present invention, a subject matter of the latter is a concentrate (C), characterized in that it consists essentially of:
from 30% to 100% by weight of a mixture (M) of at least one compound of formula (IIIa)
R 1 —O(X 1 ) p1 (IIIa)
in which
R 1 represents a linear or branched alkyl radical comprising from 6 to 12 carbon atoms, X 1 represents the xylose residue, p 1 , which represents the mean degree of polymerization of the xylose residue, is a decimal number of greater than 1 and less than or equal to 2.5, and of at least one compound of formula (IIIb)
R 2 —O(G) n (IIIb)
in which
R 2 represents a linear or branched alkyl radical comprising from 6 to 12 carbon atoms, G represents the glucose residue, n, which represents the mean degree of polymerization of the xylose residue, is a decimal number of greater than 1 and less than or equal to 2.5, and
from 0% to 70% by weight of a topically acceptable solvent.
In the concentrate (C) as defined above, the mixture (M) of compounds of formula (IIIa) and of formula (IIIb) is composed essentially:
of 20% to 99% by weight of at least one compound of formula (IIIa), and of 1% to 80% by weight of at least one compound of formula (IIIb).
Examples of topically acceptable solvents are water, alcohols, such as ethanol, propanol or isopropanol, glycols, such as propylene glycol, butylene glycol or hexylene glycol, or water/alcohol or water/glycol mixtures.
According to preferred aspects of the present invention, the concentrate (C) as defined above exhibits one or another or some following specific characteristics:
the concentrate (C) does not comprise solvent; the concentrate (C) is an aqueous solution of the mixture (M); the mixture (M) consists essentially of:
from 20% to 30% by weight of at least one compound of the formula (IIIa) and
from 70% to 80% by weight of at least one compound of formula (IIIb);
in the formula (IIIa), p is ≧1.005 and ≦1.5; in the formula (IIIb), n is ≧1.05 and ≦2.
According to a third aspect, a subject matter of the invention is the use of at least one alkylpolyglycoside of formula (Ia) or (Ib) as emulsifying agent for the preparation of oil-in-water emulsions comprising inorganic fillers and/or pigments.
According to a fourth aspect, a subject matter of the invention is the use of at least one alkylpolyglycoside of general formula (II):
R—O(X) p (II)
in which:
R represents a linear or branched alkyl radical having from 6 to 11 carbon atoms; X represents the residue of a C 5 or C 6 sugar, preferably the glucose or xylose residue; and p, which represents the mean degree of polymerization of the sugar residue, is a decimal number of greater than 1 and less than or equal to 5, and more particularly of less than or equal to 2.5,
as emulsifying agent for the preparation of oil-in-water emulsions comprising inorganic fillers and/or pigments.
In the formula R—O—(X) p , the R—O— group is bonded to X via the anomeric carbon of the sugar residue, so as to form an acetal functional group.
When X represents the xylose residue, p is more particularly between 1.005 and 1.5.
When X represents the glucose residue, p is more particularly between 1.05 and 2.
The compound of formula R—O—(X) p can be prepared according to methods well known to a person skilled in the art.
The alkylpolyglycosides in the concentrate (C) in accordance with the invention make it possible to prepare oil-in-water (O/W) emulsions comprising inorganic fillers and/or pigments.
They advantageously represent from 0.2 to 10% by weight, preferably from 0.5 to 5% by weight, of the O/W emulsion.
The inorganic fillers and/or pigments can be lamellar or spherical and without specific limitation with respect to the particle size. Mention may in particular be made, as examples of inorganic fillers and pigments, of titanium dioxide; zinc oxide; iron oxide (black, red or yellow); iron titanate; carbon black; chromium oxide; chromium hydroxide; zirconium oxide; cerium oxide; cobalt titanate; ultramarine; Prussian blue; titanium oxide-coated mica; bismuth oxychloride; pearl essence; talc; aluminum powder; copper powder; gold powder; mica; sericite; boron nitride; photochromic pigments; or interferential pigments. These fillers may have been subjected to a surface treatment or may be encapsulated, such as, for example, in nylon matrices or polymers.
These fillers and pigments generally represent from 0.5 to 40% by weight, preferably from 2 to 25% by weight, of the O/W emulsion.
The O/W emulsion also comprises from 1 to 50% by weight, preferably from 5 to 35% by weight and more preferably from 5 to 25% by weight of a fatty phase composed of one or more oils and/or of one or more waxes.
The oil is advantageously chosen from the following oils:
oils of vegetable origin, such as sweet almond oil, coconut oil, castor oil, jojoba oil, olive oil, rapeseed oil, peanut oil, sunflower oil, wheat germ oil, corn germ oil, soybean oil, cottonseed oil, alfalfa oil, poppy oil, pumpkinseed oil, evening primrose oil, millet oil, barley oil, rye oil, safflower oil, candlenut oil, passionflower oil, hazelnut oil, palm oil, karite butter, apricot kernel oil, calophyllum oil, sisymbrium oil, avocado oil or calendula oil; vegetable oils and their methyl esters which are ethoxylated; oils of animal origin, such as squalene or squalane; mineral oils, such as liquid paraffin, liquid petrolatum and isoparaffins; synthetic oils, in particular fatty acid esters, such as butyl myristate, propyl myristate, cetyl myristate, isopropyl palmitate, butyl stearate, hexadecyl stearate, isopropyl stearate, octyl stearate, isocetyl stearate, dodecyl oleate, hexyl laurate, propylene glycol dicaprylate, esters derived from lanolic acid, such as isopropyl lanolate or isocetyl lanolate, or fatty acid monoglycerides, diglycerides and triglycerides, such as glyceryl triheptanoate, alkyl benzoates, poly-α-olefins, polyolefins, such as polyisobutene, synthetic isoalkanes, such as isohexadecane or isododecane, perfluorinated oils and silicone oils.
This oil can also be chosen from fatty acids, fatty alcohols, waxes of natural or synthetic origin and more generally still any fatty substance of vegetable, animal or synthetic origin.
The wax is advantageously chosen from fatty substances which are solid at ambient temperature, such as, for example, beeswax; carnauba wax; candelilla wax; ouricury wax; Japan wax; cork fiber or sugarcane wax; paraffin waxes; lignite waxes; microcrystalline waxes; lanolin wax; ozokerite; polyethylene wax; hydrogenated oils; silicone waxes; vegetable waxes; fatty alcohols and fatty acids which are solid at ambient temperature; or glycerides which are solid at ambient temperature.
The O/W emulsion in accordance with the invention can also comprise up to 10% by weight, for example from 0.1 to 10% by weight, of a stabilizing system.
The stabilizing system can be composed of one or more compounds chosen from magnesium silicate; aluminum silicate; sodium silicate; xanthan gum; acacia gum; locust bean gum; scleroglucan gum; gellan gum; alginates; cellulose and cellulose derivatives; clays; starches and starch derivatives; carbomer; acrylic acid polymers and copolymers; acryloyldimethyl taurate polymers and copolymers; polyvinylpyrrolidone; acrylamide polymers and copolymers; or polyurethanes.
The O/W emulsion can also comprise up to 30% by weight of one or more additives generally used in cosmetics and chosen from:
coemulsifiers, such as, for example, fatty acids and fatty acid soaps; ethoxylated fatty acids; fatty acid esters; ethoxylated fatty acid esters, including polysorbates; polyglycerol esters; sucrose esters; alkylpolyglycosides with a chain length of greater than 12 carbon atoms; ethoxylated fatty alcohols; sulfated fatty alcohols; or phosphated fatty alcohols; preservatives generally used in cosmetics; fragrances or other additives with a scenting function (such as, in particular, essential oils and essential waxes); cosmetic active principles; cosolvents, such as, for example, glycerol; sorbitol; PEG; monopropylene glycol; butylene glycol; isoprene glycol; 2-methyl-1,3-propanediol; ethanol; or hexylene glycol; inorganic or organic bases, such as, for example, sodium hydroxide; potassium hydroxide; ammonia; triethanolamine; tetrahydroxypropylethylenediamine; trishydroxyaminomethane; or aminomethylpropanol; acids, in particular lactic acid, citric acid, acetic acid or tartaric acid.
Thus, according to a fifth aspect, a subject matter of the present invention is an oil-in-water emulsion comprising at least one alkylpolyglycoside corresponding in particular to the formula (Ia), (Ib) or (II), and pigments and/or fillers.
According to a sixth aspect of the present invention, a subject matter of the latter is an oil-in-water emulsion comprising from 0.5% to 10% by weight and more particularly from 1% to 5% by weight of the concentrate (C) as defined above, and inorganic pigments and/or fillers.
The O/W emulsion in accordance with the invention can be prepared by processes known to a person skilled in the art, such as, for example, a process which comprises the following stages:
a 1 ) The aqueous phase comprising the fillers is milled using, for example, a bead mill or a device with a rotor-stator turbine mixer of Silverson type. This aqueous phase is subsequently heated to a temperature of 70 to 85° C. b 1 ) At the same time, the fatty phase, comprising the emulsifier and the oils, is heated to an identical temperature of 70 to 85° C. c 1 ) The compositions according to the invention are introduced without distinction into the fatty phase or the aqueous phase. d 1 ) The two phases are subsequently mixed and emulsified using, for example, a rotor-stator emulsifying device (for example, a laboratory mixer of Silverson type). After emulsifying for a few minutes, the emulsion is cooled with moderate stirring.
Another example of the process for the preparation of the O/W emulsion comprises the following stages:
a 2 ) The aqueous phase is heated to 70-85° C. b 2 ) The fatty phase, comprising the fillers, emulsifier and the oils, is heated to an identical temperature of 70 to 85° C. c 2 ) The compositions according to the invention are introduced without distinction into the fatty phase or the aqueous phase. d 2 ) The two phases are subsequently mixed and emulsified using, for example, a rotor-stator emulsifying device (Silverson laboratory mixer). After emulsifying for a few minutes, the emulsion is cooled with moderate stirring.
It is also possible, provided all the constituents of the emulsion are liquid at ambient temperature, to prepare said emulsion by a process devoid of heating.
According to a final aspect of the present invention, a subject matter of the latter is a process for the preparation of a cosmetic or pharmaceutical oil-in-water emulsion for topical use, characterized in that between 0.2% and 10% by weight and more particularly between 0.5% and 5% by weight of a concentrate (C) as defined above is mixed with the other constituents of said composition.
EXAMPLES
The invention is illustrated by the nonlimiting examples below. In these examples, the emulsions prepared are monitored:
by monitoring using a microscope with a magnification of 40. by visual (macroscopic) monitoring of the stability of the emulsions with checking after 3 months of the appearance of the emulsions in the flask: smooth or granular appearance, glossy or matt appearance, monitoring of phenomena of phase separation, of release of pigments at the surface of the emulsion or of stratification of the pigments with a nonuniform visual effect. The optimum criteria are a glossy, perfectly smooth and homogeneous emulsion without phase separation or release or stratification of the pigments and fillers. The grading is as follows: +if all the criteria are satisfactory, +/−if at least one of the criteria is unsatisfactory, 0 if none of the criteria is satisfactory. by monitoring of the texture with the preparation, on a Plexiglas® sheet, of films calibrated to 120 μm and checking for the absence of agglomerates of fillers and pigments. The grading is as follows: + in the absence of specks 3 months after the manufacture of the emulsion, +/− in the presence of a few specks, 0 in the presence of numerous specks.
In the case of the emulsions comprising fillers with the role of protecting from UV radiation, the protection factor is evaluated according to the method described below:
The protection factor is evaluated in vitro by measuring the absorbing power with respect to UV-B and UV-A radiation after spreading a film of emulsion over a support which models the skin surface.
The emulsion is spread in a calibrated way (2 mg/cm 2 ) over a prehydrated collagen matrix sold under the name Vitroskin® by IMS. After drying the film for a period of 15 minutes, the coated support is subjected to exposure to UV radiation using a Labsphere® spectrophotometer. The sun protection coefficient is calculated by the software of the device according to the Diffey formula from the transmission of the UV radiation over the whole spectrum between 280 and 400 nm.
In view of the role of UV-A radiation in the onset of skin cancers, the relative importance of the protection with respect to UV-A radiation is calculated by producing the ratio of the area under the absorbance curve in the UV-A spectrum to the area under the absorbance curve in the UV-B spectrum. A UV-A/UV-B ratio of >0.6 is recommended for effective protection with respect to UV-A radiation.
Example 1
Preparation of an Alkylpolyxyloside of Formula (I)
908.4 g of 1,10-decanediol, sold by Cognis under the name Speziol® C10/2, are gradually introduced into a two liter glass reactor. The reactor is brought to a temperature of 90° C., so as to effectively melt the 1,10-decanediol, stirring is started and 390.0 g of xylose are dispersed in the presence of a catalytic amount of sulfuric acid. After two hours at 80° C./85° C. under vacuum and neutralization with sodium hydroxide, the product exhibits the following analytical characteristics:
Appearance (visual): off-white solid Color of a molten product (NFT 20 030): 1 vcs pH of a 5% dispersion (NFT 73 206): 7.8 Water content: 0.47% Acid number (NFT 60 204): 0.25 Hydroxyl number: 689 Residual 1,10-decanediol: 37.3%
Example 2
Preparation of an Alkylpolyxyloside of Formula (I)
The procedure of example 1 is repeated but 500.6 g of 1,10-decanediol being reacted with 430 g of xylose to result in a product exhibiting the following analytical characteristics:
Appearance (visual): black solid pH of a 5% dispersion (NFT 73 206): 7.8 Water content: 2.0% Acid number (NFT 60 204): 4.9 Hydroxyl number: 726 Residual 1,10-decanediol: 9.0%
Example 3
Preparation of O/W Emulsions Intended for UV Protection
O/W emulsions are prepared which comprise the following ingredients:
A
Emulsifier
02.50%
C 12 –C 15 Alkyl benzoate
20.00%
Titanium oxide (20 nm/dimethicone coating)
10.00%
B
Cyclomethicone
05.00%
Glycerol
07.00%
C
Tetrasodium EDTA
00.20%
Water
q.s. for 100%
Carbomer ®
00.05%
Tromethamine
q.s. pH > 7
Magnesium silicate/Aluminum silicate
01.00%
Xanthan gum
00.15%
D
DL-α-Tocopherol
00.05%
Preservatives
q.s.
The Carbomer®, the magnesium silicate/aluminum silicate and the xanthan gum are dispersed in the aqueous phase. The aqueous phase is heated to 70-85° C. and then the EDTA and the tromethamine are added.
The fatty phase, comprising the titanium oxide, the emulsifier and the C 12 -C 15 alkyl benzoate, is heated to an identical temperature of 70 to 85° C. The cyclomethicone and the glycerol are added to this hot fatty phase.
The two phases are subsequently mixed and emulsified using a rotor-stator emulsifying device (Silverson laboratory mixer). After emulsifying for a few minutes, the emulsion is cooled with moderate stirring.
The tocopherol and the preservatives are added at the end of cooling with moderate stirring.
The results are presented in table 1.
TABLE 1
Microscopic
Texture
Brookfield
appearance
of the
viscosity
Stability
of the
Emulsifier
emulsion
(mPa · s)
at AT
emulsion
Decylglucoside
Smooth
9500
>3 months
Fine and
(p = 1.45)
milk
homogeneous
Decylglucoside
Smooth
7000
>3 months
Fine and
(p = 1.9)
milk
homogeneous
Example 1
Smooth
9000
>3 months
Fine and
milk
homogeneous
Ethylhexyl-
Smooth
10 500
>3 months
Fine and
glucoside
milk
homogeneous
(p = 1.45)
Comparative Example 1
The procedure of example 3 is repeated by using alkylpolyglucoside-based emulsifiers having a chain with 4 and 12 carbon atoms and ethoxylated emulsifiers. The results are presented in table 2.
TABLE 2
Microscopic
Texture of
Brookfield
appearance
the
viscosity
Stability
of the
Emulsifier
emulsion
(mPa · s)
at AT
emulsion
Cetearyl-
Granular
43 000
>3 months
agglomerates
glucoside
cream
(p = 1.25)
Dodecyl-
Granular
7000
<7 days
agglomerates
glucoside
milk
(p = 1.43)
Butyl-
Non-
—
—
—
glucoside
emulsifying
(p = 1.45)
Laureth-7
Granular
15 000
<3 months
agglomerates
Deceth-4
Granular
8000
<7 days
agglomerates
milk
Deceth-5
Granular
11 000
<7 days
agglomerates
cream
Deceth-3
Non-
—
—
—
emulsifying
It is not possible with butylglucoside to obtain an emulsion and dodecylglucoside results in emulsions which are less stable than those obtained with the alkylglucosides according to the invention. Cetearyl-glucoside and dodecylglucoside give agglomerates. The ethoxylated nonionic surfactants are less effective than the alkylpolyglycosides according to the invention.
Example 4
Stability Over Time of the Dispersion of Pigments and of the Protection Factor of O/W Emulsions
An emulsion is prepared which comprises the following ingredients:
A
Emulsifier
2.50%
Diisopropyl adipate
25.00%
Titanium oxide (20 nm/dimethicone coating)
10.00%
Zinc oxide (50 nm)
02.00%
B
Cyclomethicone
03.00%
Glycerol
07.00%
C
Tetrasodium EDTA
00.20%
Water
q.s. for 100%
Carbomer ®
00.05%
Tromethamine
q.s. pH > 7
Magnesium silicate/Aluminum silicate
01.00%
Xanthan gum
00.15%
D
DL-α-Tocopherol
00.05%
Preservatives
q.s.
The Carbomer®, the magnesium silicate/aluminum silicate and the xanthan gum are dispersed in the aqueous phase. The aqueous phase is heated to 70-85° C. and then the EDTA and the tromethamine are added.
The fatty phase, comprising the titanium oxide and the zinc oxide, the emulsifier and the oil, is heated to an identical temperature of 70 to 85° C. The cyclomethicone and the glycerol are added to this hot fatty phase.
The two phases are subsequently mixed and emulsified using a rotor-stator emulsifying device (Silverson laboratory mixer). After emulsifying for a few minutes, the emulsion is cooled with moderate stirring.
The tocopherol and the preservatives are added at the end of cooling with moderate stirring.
The results are presented in table 3.
TABLE 3
(PEG 100
stearate + glycerol
stearate) 1.7% +
DEA cetyl
Dodecyl-
Decylglucoside
phosphate 0.8%
glucoside
Emulsifier
(invention)
(comparative)
(comparative)
Texture of the
Smooth milk
Granular milk
Granular milk
emulsion
>1 year
at 1 month
at 1 day
Microscopic
Fine and
Onset of
Onset of
appearance
homogeneous
agglomerates
agglomerates
dispersion
beyond 15 days
at 1 day
>1 year
Stability
AT
>1 year
>1 year
<1 month
40° C.
>6 months
<3 months
<1 month
50° C.
>1 month
<15 days
<1 month
Protection
factor
7 days
14
15
8
1 month
16
8
—
1 year
15
5
—
UV-A/UV-B
Ratio
7 days
0.9
0.9
0.55
1 year
0.9
0.6
—
Decylglucoside, the emulsifier according to the invention, makes it possible, in contrast to the comparative emulsifiers, to retain a fine and homogeneous dispersion of the fillers during the storage with consequently a visual texture which remains perfectly smooth over time and a stable protection factor, both in the UV-B spectrum and in the UV-A spectrum, as is illustrated by the value of the factor and that of the UV-A/UV-B ratio.
Example 5
Preparation of an O/W Emulsion without Heating
An emulsion is prepared which comprises the following ingredients:
A
Emulsifier
03.00%
Caprylic/capric triglycerides
20.00%
Zinc oxide
05.00%
Glycerol
05.00%
C
Tetrasodium EDTA
00.10%
Water
q.s. for 100%
Sepigel ® 305
01.50%
Tromethamine
q.s. pH > 7
Magnesium silicate/Aluminum silicate
01.00%
Xanthan gum
00.15%
D
DL-α-Tocopherol
00.05%
Preservatives
q.s.
The Sepigel® 305 (polyacrylamide and C 11 -C 13 isoparaffin and laureth-7; sold by Seppic), the magnesium silicate/aluminum silicate and the xanthan gum are dispersed in the aqueous phase. The EDTA and the tromethamine are added to the aqueous phase.
The fatty phase is produced by simple mixing of the constituents without heating.
The two phases are subsequently mixed and emulsified using a rotor-stator emulsifying device (Silverson laboratory mixer). The tocopherol and the preservatives are added with moderate stirring.
The results are presented in table 4.
TABLE 4
Emulsifier
Decylglucoside
Octylxyloside
Texture of the
Smooth milk
Smooth milk
emulsion
Microscopic
Fine and
Fine and
appearance
homogeneous
homogeneous
dispersion
dispersion
Stability
AT
>1 month
>1 month
40° C.
>1 month
>1 month
50° C.
>1 month
>1 month
Protection factor
1 month
9
6
1 year
8.5
6
Example 6
Preparation of Emulsions Intended for Makeup
A
Emulsifier
2.50%
Isononyl isononanoate
08.00%
Diisopropyl dimer dilinoleate
08.00%
B
Cyclomethicone
04.00%
Sepigel ® 305
01.50%
C
Water
q.s. for 100%
Micropearl ® M305
02.00%
(crosslinked methyl methacrylate polymer)
Tetrasodium EDTA
00.50%
D
Pigment paste
Butylene glycol
04.00%
Polyethylene glycol 400
04.00%
Titanium dioxide, E171
07.00%
Talc, Luzenac 000C
02.00%
Yellow iron oxide,
00.80%
Sicovit yellow 10 E172
Red iron oxide, Sicovit red 30 E172
00.30%
Black iron oxide, Sicovit black
00.05%
Water
20.00%
NaOH
q.s. for pH > 8
E
Preservatives
q.s.
Fragrance
00.20%
The pigment paste is milled beforehand on a bead mill.
The water is heated to 70-75° C. and then the Micropearl®, the EDTA and the pigment paste are added to the hot aqueous phase.
The fatty phase, comprising the emulsifier and the oils, is heated to a temperature of 70 to 75° C. The cyclomethicone and the Sepigel® 305 are added to this hot fatty phase.
The two phases are subsequently mixed and emulsified using a rotor-stator emulsifying device (Silverson laboratory mixer). After emulsifying for a few minutes, the emulsion is cooled with moderate stirring.
The preservatives and the fragrance are added at the end of cooling with moderate stirring.
The results are presented in table 5.
TABLE 5
Sodium stearate
Cetearyl-
1.7% + Steareth-10
Decylglucoside
glucoside
0.8%
Emulsifier
(invention)
(comparative)
(comparative)
Visual
+
+/−
+/−
appearance
after 3 months
Texture after
+
+/−
0
3 months
Rendering of
the color on
application
(Minolta CR300
chromameter)
after 3 months
Parameter L
68.3 (±0.7)
70.1 (±0.4)
73.4 (±0.6)
Parameter a
2.3 (±0.6)
18.2 (±2.3)
16.5 (±2.7)
Parameter b
30 (±0.9)
23.7 (±1.5)
20.2 (±2.8)
The fineness of the dispersion of the fillers is reflected by an improvement in the spreading over the skin, by uniform color and by a better rendering of the color on the skin: decrease in the whiteness (parameter L) and an enhancement in the colored parameters a (red hue) and b (blue hue). The non-uniformity in the color with the comparative examples is clearly apparent with regard to the standard deviation values for a and b, which are higher than in the example according to the invention.
Example 7
Preparation of O/W Emulsions Intended for Makeup
A
Isononyl isononanoate
08.00%
Triisostearyl citrate
08.00%
Simulgel ® NS
04.00%
B
Water
q.s. for 100%
Tetrasodium EDTA
00.05%
Emulsifier
0.8%
C
Pigment paste
Butylene glycol
04.00%
Polyethylene glycol 400
04.00%
Titanium dioxide, E171
05.00%
Yellow iron oxide,
00.80%
Sicovit yellow 10 E172
Red iron oxide, Sicovit red 30 E172
00.30%
Black iron oxide, Sicovit black
00.05%
Water
20.00%
NaOH
q.s. for pH > 8
D
Preservatives
q.s.
Fragrance
00.20%
The pigment paste is milled beforehand on a bead mill.
The Simulgel® NS (sodium acryloyldimethyl taurate/hydroxyethyl acrylate copolymer and squalane and polysorbate 80; sold by Seppic) is mixed with the oils. The aqueous phase B is added to phase A to form the cream gel. The pigment paste (phase C) and subsequently phase D are then added directly to the cream gel with moderate stirring.
The results are presented in table 6.
TABLE 6
Decylglucoside
Laureth-7
Emulsifier
(invention)
(comparative)
Visual appearance
+
0
after 3 months
Texture after
+
0
3 months
It will be understood that many additional changes in the details, materials, steps and arrangement of parts, which have been herein described in order to explain the nature of the invention, may be made by those skilled in the art within the principle and scope of the invention as expressed in the appended claims. Thus, the present invention is not intended to be limited to the specific embodiments in the examples given above. | A composition and process of preparation of emulsifier agents based on an alkylpolyglycoside structure with a length of alkyl chain having from 6 to 12 carbon atoms to be used. The resulting emulsions exhibit an excellent dispersion of the fillers and/or pigments without it being necessary to add coemulsifier or dispersant. The emulsifier makes it possible, by itself alone, to prevent the reagglomeration of the fillers and/or pigments. | 2 |
TECHNICAL FIELD
The present invention generally relates to systems and methods for purging super heated air contained within a passenger compartment of an automobile.
BACKGROUND
The air contained within the interior of a vehicle absorbs the sun's radiated emissions and depending on the external environment can become extremely hot after a vehicle has been exposed to the sunlight for an extended period of time. Typically, the vehicle passenger must ventilate the passenger compartment by lowering the vehicle windows. While this manual method of purging the super heated air works to remove the air from the interior of the vehicle, unfortunately, the vehicle occupant is also subjected to the super heated air. Consequently, depending on how long the vehicle has been exposed to sunlight the cool down time or “time to comfort” might be significant causing the vehicle occupant to be subjected to a very uncomfortable environment.
While this and other prior art systems and methods for controlling the build up of super heated air within vehicle interiors achieve their intended purpose other problems still exist. For example, ventilating super heated air through vehicle sunroofs and windows leaves the vehicle vulnerable to theft, as well as water damage in rainy conditions, and dirt in dusty conditions. Generally, prior art solutions are inflexible and only eliminate the super heated air at fixed times and for fixed time periods.
Therefore, what is needed is a new and improved system and method for controlling the build up of super heated air within an interior compartment of a vehicle. Such a new and improved system and method should ventilate the super heated air only as required to provide a comfortable environment for vehicle occupants.
SUMMARY
In accordance with an aspect of the invention a ventilation system for purging air contained within a vehicle interior is provided. The ventilation system includes a blower, a first vent, a second vent, at least one interior temperature sensor, at least one external temperature sensor, a humidity sensor, a motion sensor for windy days and dusty areas, a sunload sensor and a control module. The blower is a conventional vehicle air conditioning blower and is located within the vehicle interior for creating a pressure differential between the interior and exterior of the vehicle. The first vent expels air from the vehicle interior and the second vent draws external air into the vehicle interior. The at least one interior sensor is located within the vehicle interior for determining an interior condition of the vehicle. The at least one external sensor determines an external condition of environment external to the vehicle interior. Finally, the control module is in communication with the blower, first and second vents, interior and exterior sensors for monitoring the internal and exterior sensors and comparing the sensor outputs to predefined thresholds for actuating the blower, first and second vents to exhaust the air contained within the interior of the vehicle and draw in ambient air.
In accordance with another aspect of the invention a method for ventilating hot air contained with a vehicle interior is provided. The method includes creating a pressure differential between the interior and exterior of the vehicle using a bi-directional blower, expelling air from the vehicle interior using a first vent, drawing external air into the vehicle using a second vent, determining an interior condition of the vehicle using at least one interior sensor located within the vehicle interior, determining an external condition of the environment external to the vehicle using at least one external sensor, and finally, communicating with the blower, first and second vents, interior and exterior sensors to monitor the internal and exterior sensors and to compare the sensor outputs to predefined thresholds to actuate the blower, first and second vents to exhaust the air contained within the interior of the vehicle and draw in ambient air, using a control module.
Further objects, features and advantages of the invention will become apparent from consideration of the following description and the appended claims when taken in connection with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic diagram of a system for controlling the build up of super heated air within a vehicle's interior, in accordance with the present invention;
FIG. 2 is a block diagram illustrating a control module for use with the system of the present invention;
FIGS. 3 a-d are flow diagrams illustrating a method for controlling build up of super heated air within a vehicle interior, in accordance with the present invention;
FIG. 4 is a flow diagram illustrating a method for carrying out a High Cabin Pressure Strategy, in accordance with the present invention; and
FIG. 5 is a flow diagram illustrating a method for carrying out a Low Cabin Pressure Strategy, in accordance with the present invention.
DETAILED DESCRIPTION
The following description of the preferred embodiment is merely exemplary in nature, and is in no way intended to limit the invention or its application or uses.
Shown in FIG. 1 is a vehicle 10 that includes a cabin air purge system (CAPS) 12 for evacuating super heated air trapped within the passenger compartment 14 of vehicle 10 . Cabin air purge system 12 , includes a passenger compartment temperature sensor 16 , a passenger compartment humidity sensor 18 , a motion sensor 20 , a bi-directional blower motor 22 , defrost vents 24 , fresh air intake vent 26 , ambient temperature sensor 28 , ambient humidity sensor 30 , and a cabin air purge control module 32 . Passenger compartment temperature sensor 16 and passenger compartment humidity sensor 18 are placed within the passenger compartment of vehicle 10 for measuring the temperature and humidity of the passenger compartment, respectively. Motion sensor 20 also located within the passenger compartment may be used in conjunction with the other sensors to detect wind direction. Blower motor 22 is capable of running in a forward direction to draw fresh air into the fresh air intake vent 26 and distributing the air into the passenger compartment through the panel/floor vents 24 . Blower motor 22 also may be operated in reverse to draw cabin air into the defroster vents 24 and expel the air out of the passenger compartment through fresh air intake vent 26 .
With continuing reference to FIG. 1, ambient temperature sensor 28 and ambient humidity sensor 30 are illustrated, in accordance with the present invention. Ambient temperature sensor 28 and ambient humidity sensor 30 are placed outside of the passenger compartment. Temperature sensor 28 measures the ambient air temperature while humidity sensor 30 measures the ambient air humidity.
Control module 32 , is shown in greater detail in FIG. 2 . Control module 32 is operatively configured to receive sensor signals from the sensors described above. As will be described in greater detail below, control module 32 broadcasts control signals to actuate various vehicle components such as windows 34 , the mode doors (not shown) of the vehicles climate control system, and blower motor 22 to carry out the cabin air purge strategy of the present invention. Other vehicle components may also be actuated by control module 32 to aid in carrying out the control strategy. For example, a vehicle sunroof may also be used to purge cabin air or draw in ambient air.
Control module 32 is preferably located within the passenger compartment and has a plurality of sensor input ports 50 for receiving various sensor signals. It will be apparent to one of ordinary skill in the art that additional input ports and/or output ports may be utilized for communicating with additional sensors and vehicle components. Accordingly, a plurality of actuator ports 52 are provided on control module 32 for actuating various vehicle components 54 .
Vehicle components 54 may include blower motor 22 , mode door (not shown) and windows 34 . Of course, other motor vehicle components and systems may also be actuated by control module 32 for enhancing the operation of cabin air purge system 12 . Additionally, for each of the vehicle components 54 actuated by control module 32 , feedback input ports 56 are provided in control module 32 for receiving feedback signals from the vehicle components. For example, a blower motor feedback signal allows control module 32 to determine the direction of the blower motor, as well as, the rotational speed of the motor. Similarly, a mode door feedback signal is received by control module 32 for determining mode door status, such as open or closed. A window feedback signal is also provided, for enabling control module 32 to determine the window status (open or closed).
With continuing reference to FIG. 2, battery power 58 , ignition 60 , and ground 62 connections are illustrated, in accordance with the present invention. Battery power connection 58 provides a battery voltage signal to control module 32 to allow monitoring of the battery voltage to insure the system does not degrade the battery voltage to an unacceptable level. For example, the present invention may prevent the continued operation of the cabin air purge system to insure the vehicle's engine will start. The unacceptable battery voltage level is, of course, temperature dependent. Additionally, an adaptive learning strategy is incorporated to optimize battery performance. Ignition connection 60 provides the input that triggers control module 32 to operate. Ground connection 62 provides the required electrical ground for control module 32 , typically, ground 62 is at or near the voltage level of the negative battery terminal.
Reference is now made to FIGS. 3 a - 3 d , wherein a cabin air purge strategy (CAPS) or methodology is illustrated, in accordance with the present invention. The cabin air purge strategy is initiated, at block 100 . At block 102 , an ignition switch is checked. If the ignition switch is “OFF” then a read CAPS sensors routine is initiated, at block 97 . The CAPS sensors that are read are, for example, the sensors described above. At block 106 a cabin pressure equalization strategy is initiated. The cabin pressure equalization strategy cracks open the windows (if they are shut) when the ignition is turned “OFF” and any car door is opened. Further, the windows are then shut after all the car doors are closed. Thus, door closing efforts are reduce and the vehicle has a higher quality feel. However, If the ignition switch is not “OFF”, then a last ignition state flag is set to “ON”, as represented by block 105 . The last ignition state is determined, at block 103 . If the last ignition state is “ON” then the last ignition state flag is set to “OFF”, as represented by block 107 . This path is only executed once upon the transition from ignition “ON” to ignition “OFF”.
At block 101 , a CAPS user switch is checked. If the CAPS user switch is “on” then the system checks whether the windows are closed, at block 104 . However, if the CAPS user switch is “OFF” then the system determines the whether a CAPS enable flag has been set to “TRUE”, at block 113 .
A block 104 , the system determines whether the windows are closed. If the windows are determined to be closed then the “CAPS enabled flag” is set to “TRUE”, as represented by 109 and an “ignition off time” variable is set to “getTime( )”, at block 111 . This function gets the current time and stores it in the variable “ignition off time”. Thus, as illustrated above, CAPS is only activated if the ignition transitions from “on” to “off” and the CAPS user switch is “on” and the windows are closed at the time of the ignition transition. A CAPS enabled flag is checked, at block 113 . If the CAPS enabled flag is “TRUE” then a CAPS entry ignition off time is set equal to a calculated adaptive CAPS entry ignition off time, as represented by block 99 . However, if CAPS enabled flag is not set to “True” then a cabin pressure equalization strategy complete flag is set equal to “True”, as represented by block 159 .
The cabin air purge strategy also determines how long the ignition has been “off”, as represented by block 108 . This “ignition off-time” determination is calibratable and is selected based on the environmental conditions the vehicle will be primarily exposed to. Further this “ignition off time” is determined via an adaptive learning algorithm. For example, if the vehicle is primarily operated in an extremely hot environment, the ignition “off time” may be adjusted to a low value in order to activate the cabin air purge strategy more often. Thus, if the getTime( ) minus the ignition “off time” is not greater than the preset ignition “off time” (or CAPS_entry_IGW_off_time) the cabin air purge strategy is restarts. However, if the ignition “off time” is greater than the preset ignition “off time”, then the cabin air purge strategy continues at block 115 where a daylight hysteresis flag is checked. Thus, the present invention does not enable CAPS unless the vehicle has been off for a minimum amount of time. For example, preferably CAPS is not activated when a user goes to a gas station to re-fuel the vehicle.
If the daylight hysteresis flag is “on” as it would be during a first cycling of the cabin air purge strategy then a CAPS_Validdaylight variable is set to a high value, as represented by block 117 . However, if the daylight hysteresis flag is “off”, then the CAPS_Validdaylight variable is set to a low value, as represented by block 119 . At block 121 , the daylight, as measured at block 97 is compared to the CAPS_Validdaylight variable. If the current daylight is not greater than the CAPS_Validdaylight variable, then the daylight hysteresis flag is set to “off”, as represented by block 125 and the cabin air purge strategy is terminated. However, if the current daylight is greater than the CAPS_Validdaylight variable, then the daylight hysteresis flag is set to “on”, as represented by block 123 . Thus, CAPS is aborted if it is dark outside (i.e. night time), since it is unlikely the temperature of the vehicle's interior will be elevated due to radiated heat from the sun. This strategy also lessens wear and tear on the battery and other mechanical actuators.
Continuing at block 127 , the strategy checks the in car hysteresis flag. If the in car hysteresis flag is “on” as it would be during a first cycling of the cabin air purge strategy then a CAPS_ValidinCarTemp variable is set to a high value, as represented by block 129 . However, if the in car hysteresis flag is “off”, then a CAPS_ValidinCarTemp variable is set to a low value, as represented by block 131 . At block 133 , the in car temperature, as measured during the block 97 is compared to the CAPS_ValidinCarTemp variable. If the current in car temperature is not greater than the CAPS_ValidinCarTemp variable the in car hysteresis flag is set to “on”, as represented by block 137 and the cabin air purge strategy is restarted. However, if the ambient temperature is greater than the ambient temperature variable, then the ambient hysteresis flag is set to “off”, as represented by block 120 . Thus, if an in-car temperature is low then CAPS is aborted.
At block 110 it is determined whether the algorithm will be using a “low” or “high” temperature constant when determining whether or not to execute the cabin air purge strategy. Upon entering this algorithm the first time the hysteresis flag is set to “on” which means that the ambient temperature must be higher than the “hi” temperature constant, block 112 , to continue with the cabin air purge strategy, block 116 . This means that the strategy will never be executed unless the ambient temperature has exceeded this “hi” temperature constant, block 118 . Assuming that the ambient temperature has exceeded the “hi” temperature constant, block 116 , the ambient hysteresis flag is set to “off”, block 120 . This means that the next time the algorithm executes, block 110 , the temperature constant which is compared against the ambient temperature, is the “low” temperature constant, block 114 . Therefore, even when the ambient temperature falls below the ambient temperature “hi” constant the cabin air purge strategy will continue to function based on the ambient temperature sensor input until it falls below the “low” constant. In which case, the ambient hysteresis flag is set to “on”, block 118 and the strategy is disabled till the ambient temperature sensor rises above the “hi” temperature constant. This insures that the system is not cycled rapidly because of an ambient temperature sensor that is fluctuating by several degrees. This protects the system from wear and tear, and provides for more efficient operation. The method or control strategy of the present invention uses hysteresis and hysteresis flags throughout for this purpose.
Continuing at block 127 , the strategy checks an InCar hysteresis flag. If the InCar hysteresis flag is “on” as it would be during a first cycling of the cabin air purge strategy then an CAPS_InCar variable is set to a high value, as represented by block 129 . However, if the InCar hysteresis flag is “off”, then the CAPS_InCar variable is set to a low value, as represented by block 131 . At block 133 , the InCar temperature, as measured during the cabin pressure equalization strategy of block 106 , is compared to the CAPS_ValidInCar temperature. If the current InCar temperature is not greater than the CAPS_ValidInCar temperature the InCar hysteresis flag is set to “on”, as represented by block 137 and the cabin pressure equalization strategy complete flag is set equal to “True”, as represented by block 159 . However, if the InCar temperature is greater than the CAPS_ValidInCar temperature variable, then the InCar hysteresis flag is set to “off”, as represented by block 135 .
At block 139 , an ambient temperature is subtracted from the in car temperature and the result is compared to an Incar_ambient_delta variable. If the result is greater than the Incar_ambient_delta variable then the cabin pressure equalization strategy complete flag is set equal to “True”, as represented by block 159 . Thus, if the absolute value of the difference between the in car temperature and the ambient air temperature is greater than the calibratable value “in car_ambient delta” CAPS is aborted. This may result from a malfunctioning sensor, or the vehicle recently running with the heater on in cold weather, or the AC running in hot weather. However, if the result is less than the Incar_ambient_delta variable then the in car temperature is compared to the ambient temperature at block 141 . If the in car temperature is less than the ambient temperature then the cabin pressure equalization strategy complete flag is set equal to “True”, as represented by block 159 . However, if the in car temperature is greater than the ambient temperature then a calculate adaptive CAPS battery voltage parameter routine is executed, at block 143 . This routine calculates an “AdaptiveCAPS_BatteryVoltage low” and an “AdaptiveCAPS_BatteryVoltage High” parameters. Thus, if the vehicle's interior is cooler than the outside air temperature, CAPS is aborted. This may occur, for example, if it is a sunny day and the vehicle is parked in the shade and the AC has been running for a significant period of time.
At block 122 a voltage hysteresis flag is checked to determine whether the flag is “on”. If the flag is “on”, then a voltage variable is set to a high voltage, as represented by block 124 . However, if the voltage hysteresis flag is “off”, then the voltage variable is set to a low voltage level, as represented by block 126 . The system voltage as measured during the cabin pressure equalization strategy of block 106 , is compared to the voltage variable, as represented by block 128 . If the system voltage is not greater than the voltage variable, the voltage hysteresis flag is set to “on”, as represented by block 130 and the cabin air purge strategy is terminated. However, if the system voltage is greater than the voltage variable then the voltage hysteresis flag is set to “off”, as represented by block 132 . Thus, the system verifies that the battery has enough voltage to operate CAPS and allow the vehicle to be started.
A humidity hysteresis flag is checked, at block 134 . If the humidity hysteresis flag is “on”, then a humidity variable is set to a low humidity level, as represented by block 136 . However, if the humidity hysteresis flag is set to “off”, then the humidity variable is set to a high humidity level, as represented by block 138 . At block 140 , the humidity read during the cabin pressure equalization strategy of block 106 is compared to the humidity variable. If the current humidity is greater than the humidity variable, then the humidity hysteresis flag is set to “on”, as represented by block 142 . However, if the humidity is less than the humidity variable, the humidity hysteresis flag is set to “off”, as represented by block 144 . Thus, if it is very humid the humidity hysteresis flag will be set to “on”.
At block 146 , a sunload load hysteresis flag is checked to determine whether it is “on”. If the sunload hysteresis flag is “on”, then a sunload variable is set to a high sunload value, as represented by block 148 . However, if the sunload hysteresis flag is set to “off”, then the sunload variable is set to a low sunload value, as represented by block 150 . At block 152 , the actual measured sunload measured during the cabin pressure equalization strategy routine of block 106 is compared to the value of the sunload variable. If the sunload is not greater than the sunload variable, then the sunload hysteresis flag is set to “on”, as represented by block 154 . However, if the sunload is greater than the sunload variable, the sunload hysteresis flag is set to “off”, as represented by block 156 . Thus, if it is very cloudy the sunload hysteresis flag will be set to “on”.
At block 158 , the sunload hysteresis flag and the humidity hysteresis flag are checked. If the sunload hysteresis flag and the humidity hysteresis flag are set to “on” then the cabin pressure equalization strategy complete flag is set equal to “True”, as represented by block 159 . At block 172 , a CAPS_Close Window( ) routine is executed to close the vehicle's windows. Thus, if it is cloudy and humid (high chance of rain) then CAPS is aborted. Moreover, this strategy uses feedback current from the window motors to determine if anything is blocking the window's path. If the window's path is being blocked the window opens and tries to closes several times. If the window's path is still blocked the window will remain open.
At block 173 , a CAPS_StopActuators( ) routine is initiated. This routine stops the operation of the climate control motor and mode doors. Various system variable are then reset at block 170 before the strategy returns to the beginning, as represented by block 168 .
However, if either the sunload hysteresis flag or the humidity hysteresis flag are set to “off”, then a HCPS_LCPS_StartDelay time is subtracted from a gettime( ) variable and the result is compared to a HCPS_LCPS_Delay_Time constant, at block 157 . If the result is greater than or equal to the HCPS_LCPS_Delay_Time constant a high pressure cabin strategy flag is checked, at block 160 . This allows for a time delay between the High Cabin Pressure Strategy (HCPS) and Low Cabin Pressure Strategy (LCPS), so that the system is not running the blower continuously till the battery is drained.
If the high pressure cabin strategy flag is “off”, then a low pressure cabin strategy flag is checked, at block 162 . However, if the high pressure cabin strategy flag is set to “on”, then the high pressure cabin strategy routine is initiated, as represented by block 163 , and thereafter the strategy returns to the beginning of the process, as represented by block 168 . Upon initial entry into this algorithm the high pressure cabin strategy flag is “on” which will initiate the execution of the high pressure cabin strategy. The high pressure cabin strategy incorporates a series of timers and logic that set the high pressure cabin strategy flag to “off” and turns “on” the low pressure cabin strategy flag.
Accordingly, at block 166 a low pressure cabin strategy routine is initiated if the low cabin pressure strategy flag is on, as determined at block 162 . Thereafter, the strategy returns to the beginning of the process, as represented by block 168 . However, if the low cabin pressure strategy flag is off then the strategy returns to the beginning of the process, as represented by block 168 . Likewise, the low pressure cabin strategy also incorporates a series of timers and logic that turns “off” the low pressure cabin strategy flag and turns “on” the high pressure cabin strategy flag. This enables a mutually exclusive cycling of the low pressure cabin strategy and the high pressure cabin strategy.
The high cabin pressure strategy is illustrated in flow chart form in FIG. 4 . In operation, the high cabin pressure strategy is initiated at block 200 . At block 202 , the climate control mode doors are set to panel/floor. The climate control blower direction is set to normal and the blower is set to maximum speed, as represented by 204 . At block 206 , a startHCPS_Time is subtracted from the gettime( ) and the result is compared to HCPS_Window_Open_Time variable. Here the system determines whether the windows have been open long enough. HCPS_Window_Open_Time must be greater than HCPS_Window_Closed_Time for the strategy to function properly. If the result is not greater than HCPS_Window_Open_Time the result is compared to HCPS_Window_Closed_Time variable to determine if the windows have been closed long enough, as represented by block 208 . However, if the result is greater than HCPS_Window_Open_Time variable then a CAPS_CloseWindow routine is activated, at block 210 . At block 212 , the high cabin pressure strategy flag is set to “off”. At block 214 , the low cabin pressure strategy flag is set to “on”. At block 216 , a start_LCPS_Time variable is set equal to the getTime( ) variable and then terminates at return block 218 . Thus, the HCPS is completed, the windows are closed and setup for LCPS.
However, if at block 208 , the result of startHCPS_Time subtracted from gettime( ) is greater than HCPS_Window_Closed_Time variable then a MotionSensorSelectCAPS_ActiveWindows( ) routine and a CAPS_OpenWindow( ) routines are activated, at blocks 219 and 220 . The MotionSensorSelectCAPS_ActiveWindows( ) routine determines wind direction and which windows should be opened. Thereafter, the strategy returns to the starting point, as represented by block 218 . However, if at block 208 , the result of startHCPS_Time subtracted from gettime( ) is less than HCPS_Window_Closed_Time variable then the strategy terminates at return block 218 .
Thus, in operation the high cabin pressure strategy forces outside air into the vehicle via panel and floor vents, for example, by running the blower in the normal forward direction while the windows are closed. This will cause the hotter air to rise within the vehicle interior and create a positive pressure within the vehicle interior, so that when the windows are opened the hot air is forced out.
A low cabin pressure strategy is illustrated in flow chart form in FIG. 5 . In operation, the low cabin pressure strategy is initiated, at block 300 . At block 302 , the climate control mode doors are set to panel/defrost. The climate control blower direction is set to reverse and the blower is set to maximum speed, as represented by 304 . At block 306 , the start_LCPS_Time is subtracted from the gettime( ) and the result is compared to an LCPS_Window_Open_Time variable. Here the system determines whether the windows have been open long enough. LCPS_Window_Open_Time must be greater than LCPS_Window_Closed_Time for the strategy to function properly. If the result is not greater than LCPS_Window_Open_Time variable the result is compared to LCPS_Window_Closed_Time variable to determine if the windows have been closed long enough, as represented by block 308 . However, if the result is greater than LCPS_Window_Open_Time variable then a CAPS_CloseWindow routine is activated, at block 310 . At block 312 , the high cabin pressure strategy flag is set to “on”. At block 314 , the low cabin pressure strategy flag is set to “off”. At block 316 , a start_HCPS_Time variable is set equal to the getTime( ) variable and then terminates at return block 318 . Thus, the LCPS is completed, the windows are closed and setup for HCPS.
If at block 308 , the result of start_LCPS_Time subtracted from gettime( ) is greater than LCPS_Window_Closed_Time variable then a MotionSensorSelectCAPS_Active-Windows( ) and a CAPS_OpenWindow( ) routines are activated, at blocks 319 and 320 . The MotionSensorSelectCAPS_ActiveWindows( ) routine determines wind direction and which windows should be opened. Thereafter, the strategy returns to the starting point, as represented by block 318 . However, if at block 308 , the result of start_LCPS_Time subtracted from gettime( ) is less than LCPS_Window_Closed_Time variable then the strategy terminates at return block 318 .
Thus, in operation the low cabin pressure strategy expels hot air out of the vehicle via the panel and defrost vents, by running the blower in the reverse direction while the vehicle's windows are closed. The panel and defrost vents are used since the hotter air will rise within the vehicle interior. This creates a negative pressure within the interior of the vehicle, so that when the windows are opened fresh cool air rushes into the vehicle through the windows replacing the hot interior air.
Upon system reset or initialization key CAPS variables are initialized. For example, InCarHysteresisFlag is set to “on”, VoltageHysteresisFlag is set to “on”, HumidityHysteresisFlag is set to “on”, SunloadHysteresisFlag is set to “on”, and the DaylightHysteresisFlag is set to “on”. Additionally, the CAPS_enabledFlag is set to “false”, the LowCabinPressureStrategyFlag is set equal to the Low_CPS_Flag, the HighCabinPressureStrategyFlag is set equal to the High_CPS_Flag and the CabinPressureEqualizationStrategyCompleteFlag is set equal to “False”. These calibration constants are stored in non-volatile RAM, such as EEPROM, and if both are set to off, the CAPS strategy will be disabled. This allows the manufacturing plant flexibility in deciding which vehicles have the CAPS strategy activated.
The foregoing discussion discloses and describes a preferred embodiment of the invention. One skilled in the art will readily recognize from such discussion, and from the accompanying drawings and claims, that changes and modifications can be made to the invention without departing from the true spirit and fair scope of the invention as defined in the following claims. | A ventilation system for purging air contained with a vehicle interior is disclosed. The ventilation system includes a blower, a first vent, a second vent, at least one interior temperature sensor, at least one external temperature sensor, a motion sensor for windy days and dusty areas, a humidity sensor, a sunload sensor and a control module. The blower is a conventional vehicle air conditioning blower and is located within the vehicle interior for creating a pressure differential between the interior and exterior of the vehicle. The first vent expels air from the vehicle interior and the second vent draws external air into the vehicle interior. The at least one interior sensor is located within the vehicle interior for determining an interior condition of the vehicle. The at least one external sensor determines an external condition of environment external to the vehicle interior. Finally, the control module is in communication with the blower, first and second vents, interior and exterior sensors for monitoring the internal and exterior sensors and comparing the sensor outputs to predefined thresholds for actuating the blower, first and second vents to exhaust the air contained within the interior of the vehicle and draw in ambient air. | 1 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a room temperature curable organopolysiloxane composition which cures easily in the presence of moisture in air to become a rubber-like elastic material, and more particularly to a room temperature curable organopolysiloxane composition having excellent mildewproofing properties.
2. Description of the Prior Art
Heretofore, room temperature curable organopolysiloxane compositions which cure easily in the presence of moisture to form a rubber-like elastic material have been used for a wide range of applications such as adhesive, coating material, electrically insulating sealing material, constructional sealing material, etc. This type of compositions, however, have the disadvantage that in a long-term use thereof, the appearance of their cured products is damaged due to propagation of fungi deposited on the surface thereof.
In order to prevent the deposition and propagation of fungi, a number of methods have been known for controlling the propagation of fungi by adding a mildewproofing agent to the compositions of the above type. For example, there have been known a method by addition of 2,3,5,6-tetrachloro-4-methylsulfonylpyridine (Japanese Pre-examination Patent Publication (KOKAI) No. 51-106158 (1976)), a method by addition of 2-(4-thiazolyl)benzimidazole (Japanese Pre-examination Patent Publication (KOKAI) No. 54-127960 (1979)), a method by addition of an N-substituted benzimidazolyl carbamate derivative (Japanese Pre-examination Patent Publication (KOKAI) No. 56-38348 (1981)), a method by addition of a germicide having the following general formula:
R--Ph--SO.sub.2 --C(R').sub.2 --I
wherein R is a hydrogen atom, a halogen atom or an alkyl group of from 1 to 4 carbon atoms, and R' is a hydrogen atom, an iodine atom or an alkyl group of from 1 to 4 carbon atoms (Japanese Pre-examination Patent Publication (KOKAI) No. 56-127658 (1981)), a method by addition of triorganotin compound (Japanese Pre-examination Patent Publication (KOKAI) Nos. 56-133150 (1981) and 57-96044 (1982)), a method by addition of benzimidazolyl alkyl carbamate (Japanese Pre-examination Patent Publication (KOKAI) No. 60-18693 (1985)), a method by addition of tetraalkylthiuram disulfide (Japanese Pre-examination Patent Publication (KOKAI) No. 60-115660 (1985)), and so on.
However, the conventional methods are limited in the kind of fungi whose propagation can be prevented. In addition, according to the conventional methods it has been difficult to maintain the mildewproofing effect for a long time.
SUMMARY OF THE INVENTION
It is accordingly an object of the present invention to provide a room temperature curable organopolysiloxane composition effective in inhibiting for a long time the propagation of extensive fungi, and a cured product of the same.
According to the present invention, there is provided a room temperature curable organopolysiloxane composition comprising:
(a) a diorganopolysiloxane having the following general formula (1): ##STR1## wherein R 1 may be the same or different and each are a substituted or unsubstituted monovalent hydrocarbon group of from 1 to 10 carbon atoms, and n is a positive integer,
(b) an organosilicon compound having at least two hydrolyzable groups in its molecule, and
(c) a compound having at least one carbon-bonded hydroxyimino group in its molecule.
Namely, it is a dominant characteristic of the composition of the present invention to incorporate the hydroxyimino group-containing compound of the component (c) as an agent for inhibiting propagation of fungi, whereby deposition or propagation of fungi on the surface of a cured product of the composition can be inhibited effectively and for a long time, the inhibitive effect being on various kinds of fungi.
DETAILED DESCRIPTION OF THE INVENTION
(a) Diorganopolysiloxane
In the composition according to the present invention, a diorganopolysiloxane having the above general formula (1): ##STR2## wherein R 1 and n are as defined above, is used as a base polymer.
In the above general formula (1), the monovalent hydrocarbon groups R 1 each have from 1 to 10, preferably from 1 to 8, carbon atoms. Typical examples of R 1 include alkyl groups such as methyl, ethyl, propyl, butyl, hexyl, etc.; aryl groups such as phenyl, tolyl, etc.; alkenyl groups such as vinyl, allyl, butenyl, hexenyl, etc.; cycloalkyl groups such as cyclohexyl, etc.; aralkyl groups such as benzyl, 2-phenylethyl, etc.; and groups derived from these groups by substituting a part or all of the carbon-bonded hydrogen atoms with a halogen atom, cyano group or the like, the derived groups including, for example, chloromethyl, trifluoropropyl, cyanoethyl, and so on.
In the general formula (1) above, n is a number corresponding to the polymerization degree. From the viewpoint of viscosity, workability and the like, n is preferably an integer in the range from 50 to 2,000.
Such diorganopolysiloxanes of the component (a) include, for example, those diorganopolysiloxanes which have any of the following chemical formulas:
H--O--(SiMe.sub.2 O).sub.p --H ,
H--O--(SiMe.sub.2 O).sub.p --(SiPh.sub.2 O).sub.q --H ,
H--O--(SiMe.sub.2 O).sub.p --[Si(Me)(C.sub.2 H.sub.4 CF.sub.3)O].sub.q --H , and
H--O--(SiMe.sub.2 O).sub.p --[Si(Me)(CH═CH.sub.2)O].sub.q --H ,
wherein in the formulas Me is a methyl group, Ph is a phenyl group, and p and q are each a positive integer, with p+q being an integer corresponding to n.
(b) organosilicon compound having hydrolyzable group
The organosilicon compound of the component (b) must have at least two hydrolyzable groups, and incorporation of such component ensures room-temperature cure of the composition of the present invention in the presence of moisture or water content.
The hydrolyzable groups include, for example, alkoxyl groups such as methoxyl, ethoxyl, propoxyl, butoxyl, methoxyethoxyl, ethoxyethoxyl, etc.; alkenyloxyl groups such as propenoxyl, isopropenoxyl, isobutenyloxyl, 1-ethyl-2-methylvinyloxyl, etc.; ketoxime groups such as dimethyl ketoxime, methyl ethyl ketoxime, diethyl ketoxime, cyclopentanoxime, and cyclohexanoxime groups; acyloxyl groups such as acetoxyl, propionyloxyl, butyroyloxyl, benzoyloxyl, etc.; amino groups such as N-methylamino, N-ethylamino, N-propylamino, N-butylamino, N,N-diethylamino, and cyclohexylamino groups; amide groups such as N-acetylacetamide, N-ethylacetamide, and N-methylbenzamide groups; aminoxyl groups such as N,N-dimethylaminoxyl, N,N-diethylaminoxyl, etc.; isocyanate group; α-silyl ester groups; halogen atoms such as chlorine; and so on. Where the organosilicon compound of the component (b) has a chlorine or other halogen atom as a hydrolyzable group, much care should be given to the danger from evolution of the strongly corrosive and toxic halogen halide gas upon hydrolysis reaction of the compound.
In the organosilicon compound of the component (b), other groups than the silicon-bonded hydrolyzable group are preferably substituted or unsubstituted monovalent hydrocarbon groups similar to R 1 in the component (a). Such monovalent hydrocarbon groups are preferably alkyl groups of from 1 to 8 carbon atoms, alkenyl groups of from 2 to 10 carbon atoms, phenyl group and the like, from the viewpoint of ease of synthesis.
Typical examples of the organosilicon compound of the formula (b) having hydrolyzable groups include alkoxysilanes such as methyltrimethoxysilane, vinyltrimethoxysilane, phenyltrimethoxysilane, methyltriethoxysilane, tetramethoxysilane, tetraethoxysilane, tetrapropoxysilane, 3-chloropropyltrimethoxysilane, etc.; alkenyloxysilanes such as methyltriisopropenyloxysilane, vinyltriisopropenyloxysilane, phenyltriisopropenyloxysilane, etc.; ketoximesilanes having an oxime group of the formula: --O--N═CR 2 where each R is a monovalent hydrocarbon group provided that the two R groups may form together a divalent hydrocarbon group to form a ring, such as methyltris(methyl ethyl ketoxime)silane, vinyltris(methyl ethyl ketoxime)silane, phenyltris(methyl ethyl ketoxime)silane, methyltris(dimethyl ketoxime)silane, tetrakis(methyl ethyl ketoxime)silane, etc.; acetoxysilanes such as methyltriacetoxysilane, vinyltriacetoxysilane, phenyltriacetoxysilane, tetraacetoxysilane, etc.; aminosilanes such as methyltris(N-butylamino)silane, vinyltris(N-hexylamino)silane, phenyltris(N,N-diethylamino)silane, etc.; amidosilanes such as methyltris(N-methylacetamido)silane, vinyltris(N-ethylacetamido)silane, etc.; aminoxysilanes such as methyltris(N,N-diethylaminoxy)silane, vinyltris(N,N-diethylaminoxy)silane, etc.; and partially hydrolyzed products of these organosilicon compounds. These may be used singly or in combination of two or more.
The component (b) is used preferably in an amount of from 0.2 to 30 parts by weight, more preferably from 0.5 to 20 parts by weight, per 100 parts by weight of the diorganopolysiloxane of the component (a). If the amount of the component (b) is excessively small, the resulting composition cannot cure satisfactorily. It the amount is excessively large, on the other hand, the cured product obtained will be hard and brittle, such properties being deleterious to performance as a sealing material.
(c) Compound having hydroxyimino group
The compound of the component (c) is a compound having at least one carbon-bonded hydroxyimino group (HO--N═C) in its molecule. Such compounds are represented by oxime compounds. The hydroxyimino group-containing compounds have strong antifungal properties against most fungi. By incorporating such a compound in a composition, according to the present invention, it is possible to inhibit effectively and for a very long time the propagation of any of a variety of fungi.
In the present invention, suitable examples of the hydroxyimino group-containing compound include the oxime compounds having respectively the following general formulas (2) to (6): ##STR3## wherein in the formulas R 2 , R 3 , R 7 and R 8 are each a hydrogen atom or a substituted or unsubstituted monovalent hydrocarbon group of from 1 to 10 carbon atoms, provided that R 2 and R 3 may be the same or different from each other, and R 7 and R 8 may be the same or different from each other; R 4 , R 5 and R 6 are each an unsubstituted or substituted divalent hydrocarbon groups of from 2 to 10 carbon atoms, provided that R 5 and R 6 may be the same or different from each other. These compounds may be used either singly or in combination of two or more.
In the above general formulas, the monovalent hydrocarbon groups R 2 , R 3 , R 7 and R 8 include, for example, alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.; aryl groups such as phenyl, tolyl, etc.; alkenyl groups such as vinyl, allyl, etc.; cycloalkyl groups such as cyclohexyl, etc.; aralkyl groups such as benzyl, β-phenylethyl, etc.; and groups derived from these groups by substituting some or all of the hydrogen atoms with a halogen atom, cyano group or the like, the derived groups including, for example, chloromethyl, trifluoropropyl, cyanoethyl and so on.
In the above general formulas, besides, the divalent hydrocarbon groups R 4 , R 5 and R 6 include, for example, alkylene groups such as ethylene, propylene, tetramethylene, pentamethylene, hexamethylene, methylethylene, methylpropylene, etc.; and groups derived from these groups by substituting some or all of the hydrogen atoms with a halogen atom, cyano group or the like, the derived groups including, for example, tetrafluoroethylene group and so on.
Among the above-mentioned oxime compounds, the following compounds: ##STR4## wherein in the formulas Me is a methyl group, Et is an ethyl group, and Ph is a phenyl group, are particularly preferred for use in the present invention.
The amount of the component (c) is preferably from 0.1 to 20 parts by weight, more preferably from 0.25 to 5 parts by weight, per 100 parts by weight of the component (a). If the amount of the component (c) is excessively small, the resulting composition is insufficient in antifungal properties, whereas excessively large amounts lead to unsatisfactory cure of the resulting composition, thereby degrading the performance as a sealing material.
CONDENSATION CATALYST
Generally, a comparatively long time is needed to cure a condensation curable type organopolysiloxane composition such as the composition according to the present invention. Where the curing time is to be shortened, a condensation catalyst is normally used. The condensation catalyst for use in the present invention may be any one of those conventionally used. The usable condensation catalysts include, for example, organic tin compounds such as dibutyltin methoxide, dibutyltin diacetate, dibutyltin dioctoate, dibutyltin dilaurate, dimethyltin dimethoxide, dimethyltin diacetate, etc.; organic titanium compounds such as tetrapropyl titanate, tetrabutyl titanate, tetra-2-ethylhexyl titanate, dimethoxytitanium diacetylacetonate, etc.; amine compounds such as hexylamine, 3-aminopropyltrimethoxysilane, tetramethylguanidylpropyltrimethoxysilane, etc.; and salts thereof. These catalysts may be used either singly or in combination of two or more.
The condensation catalyst is generally used preferably in an amount of up to 10 parts by weight, more preferably from 0 to 5 parts by weight, per 100 parts by weight of the above component (a). Use of an excessively large amount of the condensation catalyst leads to unsatisfactory cure of the resulting composition, thereby impairing the performance as a sealing material.
OTHER COMPOUNDING INGREDIENTS
If necessary, the composition of the present invention may further comprise various compounding ingredients, for example, filler, pigments, dyes, adhesive agent, thixotropy improver, rust preventive, other mildewproofing agents than the component (c), flame retardant, etc.
EXAMPLES
The present invention will now be further illustrated by the following examples, in which "parts" means "parts by weight".
Example 1
A universal mixer was charged with 100 parts of α,ω-dihydroxydimethylpolysiloxane having a viscosity of 20,000 cSt, 2.0 parts of cyclohexanone oxime, 2.0 parts of anatase-type titanium oxide, and 10 parts of fumed silica whose surfaces had been treated with dimethyldichlorosilane. The contents of the mixer were mixed with each other to form a base compound. The base compound thus prepared was admixed with 5.0 parts of methyltriacetoxysilane at room temperature under a reduced pressure, to obtain an organopolysiloxane composition.
The composition was formed into a 2-mm thick sheet, and cured under the conditions of 20° C. and 55% RH for 7 days, to yield a cured product.
The cured product was cut into a 3-cm diameter disc, which was treated in running water for one week in order to remove the by-products arising from cure. The disc thus treated was used as a specimen for a fungus resistance test according to JIS-Z-2911, which was carried out as follows. First, a petri dish with a diameter of 9 cm was filled with potato dextrose agar, on which the specimen was placed in a central area. Next, a suspension containing spores of the fungi Aspergillus niger, Penicillium citrinum, Rhizopus nigricans, Cladosporium herbarum and Chaetomium globusum was sprayed uniformly onto the specimen, and the petri dish was closed with a cover.
After the petri dish was left to stand in a thermo-hygrostat adjusted to a temperature of 28° C. and a relative humidity of 98% for 56 days, the specimen was examined. No germination of fungi was observed on the specimen.
Example 2
An organopolysiloxane composition was prepared and a cured product thereof was obtained, in the same manner as in Example 1 except that 1.2 parts of dimethylglyoxime was used in place of 2.0 parts of cyclohexanone oxime which was used in Example 1. The cured product thus obtained was subjected to a fungus resistance test in the same manner as in Example 1. Again, no germination of fungi was observed.
Comparative Example 1
A composition was obtained in the same manner as in Example 1, except that cyclohexanone oxime was not compounded. When the composition thus obtained was subjected to a fungus resistance test in the same manner as in Example 1, propagation of fungi was observed over substantially the entire surfaces of the specimen.
Example 3
A universal mixer was charged with 100 parts of a,ω-dihydroxydimethylpolysiloxane having a viscosity of 20,000 cSt at 25° C., 1.5 parts of cyclohexanedione dioxime, 0.1 parts of dibutyltin dimethoxide, and 100 parts of calcium carbonate whose surfaces had been treated with a fatty soap having an average particle diameter of 0.04 μm. The contents of the mixer were mixed with each other to prepare a base compound. The base compound thus obtained was admixed with 6.0 parts of vinyltrimethoxysilane at room temperature under a reduced pressure, to obtain a desired composition.
The composition thus obtained was processed in the same manner as in Example 1 to yield a cured product. Using the cured product, a fungus resistance test was carried out in the same manner as in Example 1. No germination of fungi was observed.
Example 4
A cured product was obtained in the same manner as in Example 3, except that 2.0 parts of benzophenone oxime was used in place of cyclohexanedione oxime and that 9.0 parts of 2-butanoximesilane was used in place of vinyltrimethoxysilane. The cured product thus obtained was subjected to a fungus resistance test in the same manner as in Example 1. Again, no germination of fungi was observed.
Comparative Example 2
A cured product was obtained in the same manner as in Example 3, except that cyclohexanedione dioxime was not compounded. When the cured product thus obtained was subjected to a fungus resistance test in the same manner as in Example 1, propagation of fungi was observed on about 2/3 of the entire surfaces of the specimen.
Comparative Example 3
A cured product was obtained in the same manner as in Example 4, except that benzophenone oxime was not compounded. The cured product thus obtained was subjected to a fungus resistance test in the same manner as in Example 1. Propagation of fungi was recognized on about 2/3 of the entire surfaces of the specimen. | A condensation curable organopolysiloxane composition, capable of curing in the presence of moisture in air to become a rubber-like elastic material, comprising a compound having at least one carbon-bonded hydroxyimino group in its molecule. The composition is capable of inhibiting effectively, and for a long time, the propagation of any of a variety of fungi on the surface of a cured product of the composition. | 2 |
CROSS-REFERENCE TO RELATED APPLICATION
[0001] The present application is a continuation of International Application No. PCT/KR2012/008995 filed on Oct. 30, 2012, which claims priority to Korean Application No. 10-2011-0112746 filed on Nov. 1, 2011, which applications are incorporated herein by reference.
TECHNICAL FIELD
[0002] The present invention relates to an apparatus for adhering a soft slab and a covering material which is used to manufacture a leather seat for vehicles or the like.
BACKGROUND ART
[0003] Seats for vehicles include a frame provided in a seat, a cushion coupled to the frame, and a covering which covers the cushion. Not only seats for vehicles, but general seats also include a frame, a cushion and a covering which covers the cushion.
[0004] Such a covering may directly cover a cushion in such a way that a covering material is manufactured using synthetic leather or natural leather and then merely sewn to the cushion. Recently, particularly, with regard to vehicles or the like, a technique by which a covering for use in covering a vehicle seat is manufactured by coupling synthetic leather or natural leather to a slab made of soft sponge or the like is widely used.
[0005] Basically, this is to improve seating comfort. In other words, this technique aims to provide predetermined elasticity and flexibility to even a covering which covers a cushion that typically has elasticity and flexibility, thus improving seating comfort, and enhancing the durability of the covering by virtue of increased shock absorption performance of the covering itself.
[0006] Such a covering includes a soft slab and a covering material disposed on the slab. The covering material may be coupled to the slab by only sewing the perimeter of the covering material to the slab. Alternatively, the covering material may adhere to the surface of the slab with the entirety of the covering material in close contact with the slab.
[0007] In the case of the covering material coupled to a slab by sewing, such covering materials are stretched over time by repeated seating. Because of this, the covering material may form creases and detach from the slab which it covers. To avoid these problems, a technique by which the entirety of the covering material is adhered to the soft slab while being in close contact with the soft slab has recently used.
[0008] However, in this technique, only synthetic leather, that is, only a covering material that can be manufactured in any shape and form, can be used. Because natural leather is not uniform in its original shape, it is fundamentally impossible to manufacture a roll of natural leather, so that natural leather has not been used in the technique by which the entity of the covering material is adhered to the soft slab.
[0009] Therefore, a technique for manufacturing a seat covering is required, which can effectively adhere natural leather to a soft slab and reliably fix the natural leather in a place and bring the natural leather into close contact with the soft slab without creasing during a process of adhering the natural leather to the slab, even if the natural leather has an unevenly cut shape rather than being supplied in a predetermined width from a roll, whereby the marketability of the product can be markedly improved.
[0010] The foregoing is intended merely to aid in the understanding of the background of the present invention, and is not intended to mean that the present invention falls within the purview of the related art that is already known to those skilled in the art.
SUMMARY
[0011] Accordingly, the present invention has been made keeping in mind the above problems occurring in the prior art, and an object of the present invention is to provide an apparatus for adhering a soft slab and a covering material together which is used to manufacture a seat covering and can effectively adhere a covering material including natural leather to a soft slab and, particularly, reliably fix a covering material in place and bring the covering material into close contact with the soft slab without creasing during a process of adhering the natural leather to the slab, whereby the marketability of the seat covering can be markedly enhanced.
[0012] In order to accomplish the above object, the present invention provides an apparatus for adhering a soft slab and a covering material together, including: a moving unit comprising a plurality of rollers and moving the soft slab; a conveyor unit comprising a belt configured to allow air to pass through upper and lower surfaces thereof, and a drive unit provided to move the belt, the conveyor unit transferring the covering material placed on the upper surface of the belt towards an adhesive surface of the soft slab; and an air suction unit provided below the lower surface of the belt, the air suction unit sucking air such that the covering material comes into close contact with the upper surface of the belt whereby the covering material adheres to the adhesive surface of the soft slab without creasing.
[0013] The apparatus may further include a heating unit heating the adhesive surface of the soft slab that is moved by the moving unit, wherein the conveyor unit may transfer the covering material towards the adhesive surface that has been heated.
[0014] The apparatus may include an adhesive applying unit applying an adhesive to the adhesive surface of the soft slab that is moved by the moving unit, wherein the conveyor unit may transfer the covering material towards the adhesive surface to which the adhesive has been applied.
[0015] The soft slab may be made of sponge, and the covering material may be made of natural leather.
[0016] The moving unit may include a feed roll and a collecting roll respectively disposed at both sides of the apparatus, and a guide roller 160 provided between the feed roll and the collecting roll, the guide roller guiding the adhesive surface of the soft slab to a position adjacent to the covering material placed on the upper surface of the belt of the conveyor unit to enable the covering material to adhere to the adhesive surface of the soft slab.
[0017] The moving unit may further include a compression roller provided between the collecting roll and the guide roller, the compression roller compressing the soft slab to which the covering material has adhered.
[0018] A plurality of vent holes may be formed in the belt of the conveyor unit to enable air to pass through the upper and lower surfaces of the belt.
[0019] The belt of the conveyor unit may be made of porous material to enable air to pass through the upper and lower surfaces of the belt.
[0020] The drive unit of the conveyor unit may transfer the belt in a direction equal to a direction in which the soft slab is transferred, whereby the covering material placed on the belt is transferred in the direction equal to the direction in which the soft slab is transferred, and then adheres to the adhesive surface of the soft slab.
[0021] The drive unit may comprise drive units respectively provided at front and rear positions, the drive units circulating the belt, and the air suction unit may be installed between the drive units below the lower surface of the belt, the air suction unit sucking air from the upper surface of the belt towards the lower surface thereof.
[0022] The apparatus may further include a covering jig including a covering seating depression having a shape equal to a shape of the covering material, wherein the covering material may be seated into the covering seating depression, and the covering jig may be placed on the upper surface of the belt of the conveyor unit and transferred towards the adhesive surface of the soft slab.
[0023] The covering jig may be configured such that air can pass through upper and lower surfaces thereof, whereby the covering materials in the covering seating depression is brought into close contact with the covering jig by the air suction unit so that the covering material can adhere to the adhesive surface of the soft slab without creasing.
[0024] In an apparatus for adhering a soft slab and a covering material together according to the present invention, even when the covering material is made of natural leather, the covering material can be transferred while being evenly spread and then attached to the soft slab without creasing. Therefore, the apparatus according to the present invention makes it possible to manufacture a seat covering that has improved marketability.
[0025] Furthermore, in the present invention, an automated process is used, so that even if natural leather which is irregular in shape is used as the covering material, the number of processes can be markedly reduced. Particularly, the apparatus can reduce the steps required to spread natural leather covering materials and fix the covering material in place to attach the covering materials to the soft slab, thereby greatly improving productivity.
BRIEF DESCRIPTION OF DRAWINGS
[0026] FIG. 1 is a view illustrating an apparatus for adhering a soft slab and a covering material together according to a first embodiment of the present invention;
[0027] FIG. 2 is a view illustrating an apparatus for adhering a soft slab and a covering material together according to a second embodiment of the present invention;
[0028] FIG. 3 is a view illustrating an apparatus for adhering a soft slab and a covering material together according to a third embodiment of the present invention;
[0029] FIG. 4 is a view illustrating a covering jig used in the apparatus for adhering a soft slab and a covering material together according to the present invention; and
[0030] FIG. 5 is a view showing natural leather sheets seated in the covering jig of FIG. 4 .
DETAILED DESCRIPTION
[0031] Hereinafter, an apparatus for adhering a soft slab and a covering material according to predetermined embodiments of the present invention will be described in detail with reference to the attached drawings.
[0032] FIG. 1 is a view illustrating an apparatus for adhering a soft slab and a covering material together according to a first embodiment of the present invention. The apparatus for adhering the soft slab and the covering material together according to the present invention includes: a moving unit 100 which includes a plurality of rollers and moves the soft slab S; a conveyor unit 500 which includes a belt 520 configured to allow air to pass through upper and lower surfaces thereof, and a drive unit 540 provided to move the belt 520 , and which is configured to transfer the covering material placed on the upper surface of the belt 520 towards an adhesive surface of the soft slab; and an air suction unit 700 which is provided below the lower surface of the belt 520 so as to suck air such that the covering material comes into close contact with the upper surface of the belt 520 whereby the covering material can adhere to the adhesive surface of the soft slab S without creasing.
[0033] The apparatus may further include a heating unit 300 which heats the adhesive surface of the soft slab S that is moved by the moving unit 100 . In this case, the apparatus is configured in such a way that the conveyor unit 500 transfers the covering material to the adhesive surface of the soft slab S that has been heated by the heating unit 300 . Alternatively, the apparatus may further include an adhesive applying unit 300 which applies adhesive to the adhesive surface of the soft slab S that is moved by the moving unit 100 . In this case, the apparatus is configured in such a way that the conveyor unit 500 transfers the covering material to the adhesive surface of the soft slab S to which adhesive has been applied.
[0034] Although the covering material may be adhered to the soft slab by means of adhesive applied to the adhesive surface of the soft slab, in this embodiment, the apparatus and method of adhering the covering material to the soft slab in such a way that the adhesive surface of the soft slab is heated and then the covering material adheres to the heated adhesive surface of the soft slab will be described in detail.
[0035] In an embodiment, the soft slab S is made of sponge, and the covering material L is made of natural leather. As stated above, the soft slab S functions to cover a seat for vehicles. Particularly, the soft slab S covers a cushion of the seat to provide a double shock absorption structure to the seat and enhance the durability of the seat. The covering material L functions as a finishing material and is thermally fused to the adhesive surface of the soft slab such that the covering material L can be tautly maintained for a long period of time without creasing. Particularly, with regard to a natural leather product which is irregular in shape, form and flatness, the present invention is effective in maintaining the quality of the product constant.
[0036] The reason for this is that because of irregularity in shape of natural leather, it is very difficult to adhere it to the soft slab S without creasing. In the present invention, the covering material L made of natural leather is transferred while being brought into close contact with the belt by means of the air suction unit 700 and then attached to the melted adhesive surface of the soft slab S with close contact with the soft slab S. Therefore, the covering material L can be thermally fused to the soft slab S while maintaining flatness. Thereby, a clean product can be produced without creases on the surface of the product. In the case of typical synthetic leather, because it is provided from a roll in the same manner of that of the slab, it can be reliably attached to the slab without creasing by only a simple transferring and adhering processes. However, with regard to natural leather, it is difficult to evenly adhere it to the slab via a simple transferring and adhering processes without creasing. Thus, additional handwork and correction work has been required in the conventional technique.
[0037] On the other hand, in the present invention, because the air suction unit 700 enhances the degree to which the covering material made of natural leather comes into close contact with the slab, even if a worker only places the covering material on the belt 520 , the covering material made of natural leather can be transferred with close contact with the belt and attached to the slab without creases. Therefore, the completeness of the product and the productivity can be markedly enhanced, compared to the manual work.
[0038] The moving unit 100 includes a feed roll 120 and a collecting roll 140 which are disposed at both sides of the apparatus, and a guide roller 160 which is provided between the feed roll 120 and the collecting roll 140 and guides the adhesive surface of the soft slab S to a position adjacent to the covering material placed on the upper surface of the belt 520 of the conveyor unit so that the covering material can adhere to the adhesive surface of the soft slab S.
[0039] The soft slab S is provided in a form of roll. In this embodiment, the soft slab S is unwound from the feed roll 120 and is wound around the collecting roll 140 after the covering material adheres to the soft slab S. Disposed between the feed roll 120 and the collecting roll 140 , the guide roller 160 guides the soft slab S towards the covering material L so that the covering material can adhere to the melted adhesive surface of the soft slab S. Preferably, the guide roller 160 , along with a rear drive roller of the conveyor unit 500 which moves the covering material, compresses the soft slab S to which the covering material has been attached. That is, the covering material is attached to the soft slab S by the guide roller 160 and the rear drive roller of the conveyor unit 500 and, simultaneously, the soft slab S and the covering material are compressed together by them.
[0040] Furthermore, the moving unit 100 may further include a compression roller 180 which is provided between the collecting roll 140 and the guide roller 160 to compress the soft slab S to which the covering material has been attached.
[0041] The compression roller 180 may comprise a pair of compression rollers 180 which compress the upper and lower surfaces of the soft slab S at the same time. In this case, the soft slab S can be double-compressed whereby the covering material and the soft slab S can be more reliably coupled to each other.
[0042] Meanwhile, a plurality of vent holes are formed in the belt 520 of the conveyor unit 500 so that air can pass through the upper and lower surfaces of the belt 520 . Through the vent holes, the covering material L can be brought close contact with the belt 520 by the air suction unit 700 which is provided below the lower surface of the belt 520 . By virtue of this construction, even if a worker only places the covering material L on the belt 520 , as the belt 520 is transferred, the covering material L is smoothly spread on the belt 520 and brought into close contact with the belt 520 while passing through the air suction unit 700 . In this state, the covering material adheres to the soft slab S. Therefore, it becomes possible for the covering material to adhere to the soft slab S without creasing. Furthermore, the belt 520 of the conveyor unit 500 may be made of porous material so that air can more reliably pass through the upper and lower surfaces of the belt 520 .
[0043] The drive unit 540 of the conveyor unit 500 transfers the belt 520 in the same direction as a direction in which the soft slab S is transferred, whereby the covering material that is placed on the belt 520 can be transferred in the same direction as that of the soft slab S and then adheres to the adhesive surface of the soft slab S.
[0044] The drive unit 540 comprises two drive units which are respectively provided in front and rear ends of the conveyor unit and circulate the belt 520 . The air suction unit 700 is disposed between the two drive units 540 below the lower surface of the belt 520 so as to suck air from the upper surface of the belt 520 towards the lower surface thereof.
[0045] FIG. 2 is a view illustrating an apparatus for adhering a soft slab and a covering material together according to a second embodiment of the present invention. FIG. 4 is a view illustrating a covering jig used in the apparatus for adhering the soft slab and the covering material together according to the present invention. FIG. 5 is a view showing natural leather sheets seated in the covering jig of FIG. 4 . The apparatus for adhering the soft slab and the covering material together according to the second embodiment further includes the covering jig 800 which has in an upper surface thereof covering seating depressions 840 having the same shapes of corresponding covering materials L. The covering jig 800 is placed on the belt 520 of the conveyor unit 500 and moved towards the adhesive surface of the soft slab S with the covering materials L seated into the covering seating depressions 840 .
[0046] The covering jig 800 includes a jig body 820 which has a predetermined thickness, and the covering seating depressions 840 which are formed in the jig body 820 and have predetermined depths. The covering seating depressions 840 have shapes corresponding to those of various covering materials L. Particularly, the covering jig 800 is placed on the belt 520 with the covering materials L seated in the corresponding covering seating depressions 840 , and the covering materials L are attached to the adhesive surface of the soft slab S while the covering jig 800 is transferred by the belt 520 . After the covering materials L have been attached to the soft slab S, the covering jig 800 may be returned and reused.
[0047] The covering jig 800 is configured such that air can pass through upper and lower surfaces of the covering jig 800 . Thus, the covering materials L in the covering seating depression 840 can be brought into close contact with the covering jig 800 by the air suction unit 700 whereby the covering materials L can adhere to the adhesive surface of the soft slab S without creasing.
[0048] That is, the present invention is configured such that air can pass through not only the covering jig 800 but also the belt 520 . Thus, the covering materials L can be brought into close contact with the covering jig 800 by the air suction unit 700 , whereby the covering materials L can be transferred while being evenly spread and can be attached to the adhesive surface of the soft slab S without creasing.
[0049] FIG. 3 is a view illustrating an apparatus for adhering a soft slab and a covering material together according to a third embodiment of the present invention. In this embodiment, a coating roll 900 is disposed below the lower surface of the soft slab S. Unwound from the coating roll 900 , a coating material B is attached to the adhesive surface of the soft slab S. The covering material L is adhered between the slab S and the coating material B. The coating material B may be used as a film for protecting the covering material L or, alternatively, as a packing material. Furthermore, although the coating material B is supplied from the separate coating roll 900 , the coating material B along with the slab S is wound around the collecting roll 140 for the slab S. Furthermore, as shown in the drawing, the covering material L and the slab S may adhere to each other in such a way that after the covering materials L have been seated into the covering jig 800 , the covering materials L and the covering jig 800 adhere to the soft slab 5 , and later the coating material B and the covering jig 800 are removed together from the soft slab S.
[0050] As described above, in an apparatus for adhering a soft slab and a covering material together according to the present invention, even if a covering material is made of natural leather which has various shapes and forms, it can be transferred while being evenly spread and then attached to the slab. Therefore, a natural leather seat covering that has improved marketability can be produced without creases as if it were synthetic leather.
[0051] Furthermore, an automated process is used, so that even if natural leather which is irregular in shape is used as the covering material, the number of processes can be markedly reduced. Particularly, the apparatus can reduce the steps required to spread natural leather covering materials and fix each covering material in place to attach the covering materials to the soft slab, thereby contributing greatly to improvement in productivity.
[0052] Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims. | The present invention relates to an apparatus for adhering a soft slab and a covering material together. The apparatus for adhering the soft slab and the covering material together includes: a moving unit consisting of a plurality of rollers for moving the soft slab; a conveyor unit including a belt configured such that air passes through the top and bottom surface thereof, and a driving unit for driving the belt, the conveyor unit being intended for transferring a covering material seated on the top surface of the belt toward an adhesive surface of the soft slab; and an air suction unit provided at the bottom surface of the belt so as to suction air such that the covering material is tightly attached onto the top surface of the belt, thereby attaching the covering material onto the adhesive surface of the soft slab without generating pleats. | 1 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority under 35 USC §119(e) of U.S. Provisional Application Nos. 61/269,975, filed Jul. 1, 2009, and 61/205,235, filed Jan. 20, 2009, the entireties of which are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The field of the invention is directed to methods for reprogramming somatic cells to a less differentiated status. In particular, the field of the invention is directed to methods for reprogramming amnion epithelial cells (AEC), including amnion-derived cells (ADC) and Amnion-derived Multipotent Progenitor cells (AMP cells), to a less differentiated status. The field is further directed to compositions comprising reprogrammed AEC, ADC and AMP cells, and uses thereof.
DESCRIPTION OF RELATED ART
[0003] Yamanaka, S. (Philos Trans R Soc Lond B Biol Sci 2008 363(1500):2079-87) reviews molecular mechanisms of and known methods of inducing pluripotency in somatic cells.
[0004] Yamanaka, S. (Cell Prolif 2008 Suppl 1:51-6) describes induction of pluripotent stem cells from mouse fibroblasts by four transcription factors.
[0005] Okita, K., et al., (Science 2008 322(5903)949-53, Epub 2008 Oct. 9) describe generation of mouse induced pluripotent stem cells with out viral vectors.
[0006] Park, I. H., et al., (Nature 451:141-6, 2008) describe reprogramming of human somatic cells to pluripotency with defined factors.
[0007] Yu, J., et al., (Science 318:1917-20, 2007) describe induced pluripotent stem cell lines derived from human somatic cells.
[0008] Takahashi, K., et al., (Nat Protoc 2007 2(12):3081-9) describe induction of pluripotent stem cells from fibroblast cultures.
[0009] Oliveri, R. S. (Regen Med 2007 2(5):795-816) reviews epigenetic dedifferentiation of somatic cells into pluripotency.
[0010] Alberio, R., et al., (Reproduction 2006 132(5):709-20) reviews reprogramming somatic cells into stem cells.
[0011] U.S. Publication No. 20080280362, published Nov. 13, 2008, describes methods for reprogramming somatic cells.
BACKGROUND OF THE INVENTION
[0012] The differentiation status of cells is a continuous spectrum, with the terminally differentiated state at one end and de-differentiated state (the pluripotent state) at the other end. Reprogramming encompasses any movement of the differentiation status of a cell along the spectrum toward a less-differentiated state. For example, reprogramming includes reversing a multipotent cell back to a pluripotent cell or reversing a terminally differentiated cell back to either a multipotent cell or a pluripotent cell.
[0013] Much research is directed to developing methods for reprogramming cells to a less differentiated status. Such methods include but are not limited to viral-induced reprogramming through the introduction of pluripotency genes into cells via viral vectors, contacting cells with chemical agents (i.e. demethylating agents) that alter chromatin structure and consequently differentiation status, nuclear transfer methodologies, and contacting cells with unique media and matrix combinations that effect dedifferentiation. Most of the methods described thus far have been successful to at least some degree in most cells tested, although some, for example viral-induced dedifferentiation and reprogramming, do have associated risks such as teratoma formation which make the clinical application of these reprogrammed cells not feasible at this time.
SUMMARY OF THE INVENTION
[0014] The invention is directed to methods for reprogramming somatic cells to a less differentiated status. In particular, the field of the invention is directed to methods for reprogramming amnion epithelial cells (AEC), including amnion-derived cells (ADC) and Amnion-derived Multipotent Progenitor cells (AMP cells), to a less differentiated status. In accordance with the methods of the invention, the AEC, ADC and/or AMP cells, are contacted with a candidate agent capable of effecting reprogramming of the cells to a less differentiated status. Dedifferentiated cells are then selected and assessed for pluripotency characteristics (i.e., teratoma formation, embryoid body formation, expression of pluripotent cell markers, lack of expression of differentiation markers, etc.). The presence of at least a subset of pluripotency characteristics in the cells indicates that the agent is capable of reprogramming the cells to a less differentiated status. The invention is further directed to compositions comprising the reprogrammed cells, as well as uses of the reprogrammed cells. Once reprogrammed, the cells are termed AEC R , ADC R and AMP R cells. AEC R , ADC R and AMP R cells can be treated with various differentiation media, agents, condition, etc., to induce them to differentiate down any cellular pathway. For example, the AEC R , ADC R and/or AMP R can be exposed to conditions known to effect neural differentiation, pancreatic differentiation, hematopoietic differentiation, and the like. The advantage of using AEC, ADC and/or AMP cells is that the cells are obtained from a non-controversial source, the normally discarded placenta, and therefore do not possess the assorted ethical, religious or political issues that are associated with ES cells. In addition, AEC, ADC and/or AMP cells may already express one or more pluripotency genes (i.e. Oct4), which may aid in the dedifferentiation of these cells.
[0015] Accordingly, a first aspect of the invention is a method of reprogramming amnion epithelial cells to a less differentiated state comprising contacting the cells with an agent capable of effecting such reprogramming. In one embodiment the amnion epithelial cells are amnion-derived cells or AMP cells. In another embodiment the amnion epithelial cells are human amnion epithelial cells. In still another embodiment the agent is a pluripotency gene. And in a specific embodiment the pluripotency gene is Oct4, Sox2, Klf4, c-Myc, nanog, Lin28, or Stella. Other specific embodiments are ones in which the pluripotency gene is one of Oct4, Sox2, Klf4, c-Myc, nanog, Lin28, or Stella; the pluripotency gene is two of Oct4, Sox2, Klf4, c-Myc, nanog, Lin28, or Stella; the pluripotency gene is three of Oct4, Sox2, Klf4, nanog, Lin28, Stella or c-Myc; the pluripotency gene is four of Oct4, Sox2, Klf4, c-Myc, nanog, Lin28, or Stella; the pluripotency gene is five of Oct4, Sox2, Klf4, c-Myc, nanog, Lin28, or Stella; the pluripotency gene is six of Oct4, Sox2, Klf4, c-Myc, nanog, Lin28, or Stella; or the pluripotency gene is all of Oct4, Sox2, Klf4, c-Myc, nanog, Lin28, or Stella.
[0016] In another embodiment, the pluripotency gene is delivered to the amnion epithelial cell by retrovirus-mediated transfection, lentivirus-mediated transfection, adenovirus-mediated DNA transfection or non-viral-mediated DNA transfection. In still another embodiment the agent is a demethylating agent or a deacetylation agent. In a specific embodiment the demethylating agent is a 5-aza-cytidine or 5-azadeoxycytidine. In another specific embodiment the deacetylation agent is trichostatin A, trapoxin B, depsipeptides, benzamides, electrophilic ketones, phenylbutyrate or valproic acid. In another embodiment the less differentiated state is totipotency or pluripotency.
[0017] A second aspect of the invention is a dedifferentiated cell made by the method of the first aspect.
[0018] A third aspect of the invention is a method of treating a disease or disorder in a subject in need thereof comprising transplanting the dedifferentiated cell of the second aspect into the subject.
[0019] A fourth aspect of the invention is a composition comprising AEC R , ADC R or AMP R cells, or a combination thereof, wherein the cells exhibit pluripotency characteristics. In one embodiment the pluripotency characteristic is expression of one or more ES cell markers. In a specific embodiment the ES cell markers are Oct4, SSEA1, SSEA3, SSEA4, elevated Alkaline Phosphatase levels, nestin, AC133, Tcf4 or Cdx1. In still another embodiment the pluripotency characteristic is expression of pluripotency genes. And in a particular embodiment the pluripotency genes are one or more of Oct4, Sox2, Klf4, m-Myc, nanog, Lin28, or Stella. In yet another embodiment the pluripotency characteristic is the ability to differentiate into any cell type in body. And in another embodiment the pluripotency characteristic is the ability to form embryoid bodies. In still another embodiment the pluripotency characteristic is having the capacity for self-renewal.
[0020] A fifth aspect of the invention is a composition comprising AEC R , ADC R or AMP R cells wherein the cells are capable of forming any cell type which arises from the endoderm. In particular embodiments, the cell type which arises from the endoderm is a stomach cell, colon cell, liver cell, pancreas cell, urinary bladder cell, lining of the urethra cell, epithelial parts of the trachea cell, lung cell, pharynx cell, thyroid cell, parathyroid cell, or intestinal cell.
[0021] A sixth aspect of the invention is a composition comprising AEC R , ADC R or AMP R cells wherein the cells are capable of forming any cell type which arises from the mesoderm. In particular embodiments, the cell type which arises from the mesoderm is a skeletal muscle cell, skeletal cell, dermal cell, connective tissue cell, urogenital system cell, heart cell, blood cell, lymph cells, or spleen cell.
[0022] A seventh aspect of the invention is a composition comprising AEC R , ADC R or AMP R cells wherein the cells are capable of forming any cell type which arises from the ectoderm. In particular embodiments, the cell type which arises from the ectoderm is a central nervous system cell, lens cell, cranial and sensory nerve cell, motor nerve cell, ganglion cell, pigment cell, head connective tissue cell, epidermal cell, hair cell, or mammary gland cell.
Definitions
[0023] As defined herein “isolated” refers to material removed from its original environment and is thus altered “by the hand of man” from its natural state.
[0024] As defined herein, a “gene” is the segment of DNA involved in producing a polypeptide chain; it includes regions preceding and following the coding region, as well as intervening sequences (introns) between individual coding segments (exons).
[0025] As used herein, the term “marker” means any molecule characteristic of a cell or in some cases of a specific cell type.
[0026] As used herein, the term “protein marker” means any protein molecule characteristic of a cell or in some cases of a specific cell type. Protein markers may be located on the cell membrane, may be intracellular or may be secreted from the cell.
[0027] As used herein, “enriched” means to selectively concentrate or to increase the amount of one or more materials by elimination of the unwanted materials or selection and separation of desirable materials from a mixture (i.e. separate cells with specific cell markers from a heterogeneous cell population in which not all cells in the population express the marker).
[0028] As used herein, the term “substantially purified” means a population of cells substantially homogeneous for a particular marker or combination of markers. By substantially homogeneous is meant at least 90%, and preferably 95% homogeneous for a particular marker or combination of markers.
[0029] The term “placenta” as used herein means both preterm and term placenta.
[0030] As used herein, the term “totipotent stem cells” shall have the following meaning In mammals, totipotent cells have the potential to become any cell type in the adult body; any cell type(s) of the extraembryonic membranes (e.g., placenta). Totipotent cells are the fertilized egg and approximately the first 4 cells produced by its cleavage.
[0031] As used herein, the term “pluripotent stem cells” shall have the following meaning Pluripotent stem cells are true stem cells with the potential to make any differentiated cell in the body, but cannot contribute to making the components of the extraembryonic membranes which are derived from the trophoblast. The amnion develops from the epiblast, not the trophoblast. Three types of pluripotent stem cells have been confirmed to date: Embryonic Stem (ES) Cells (may also be totipotent in primates), Embryonic Germ (EG) Cells, and Embryonic Carcinoma (EC) Cells. These EC cells can be isolated from teratocarcinomas, a tumor that occasionally occurs in the gonad of a fetus. Unlike the other two, they are usually aneuploid.
[0032] As used herein, the term “multipotent stem cells” are true stem cells but can only differentiate into a limited number of types. For example, the bone marrow contains multipotent stem cells that give rise to all the cells of the blood but may not be able to differentiate into other cells types.
[0033] The term “self-renewal” as used herein means a cell or population of cells having the ability to go through numerous cycles of cell division while maintaining the undifferentiated state.
[0034] The term “somatic cells”, as used herein, also includes adult stem cells. An adult stem cell is a cell that is capable of giving rise to all cell types of a particular tissue. Exemplary adult stem cells include hematopoietic stem cells, neural stem cells, and mesenchymal stem cells.
[0035] The term “pluripotency gene”, as used herein, refers to a gene that is associated with pluripotency. The expression of a pluripotency gene is typically restricted to pluripotent stem cells, and is crucial for the functional identity of pluripotent stem cells.
[0036] As used herein, the term “extraembryonic tissue” means tissue located outside the embryonic body which is involved with the embryo's protection, nutrition, waste removal, etc. Extraembryonic tissue is discarded at birth. Extraembryonic tissue includes but is not limited to the amnion, chorion (trophoblast and extraembryonic mesoderm including umbilical cord and vessels), yolk sac, allantois and amniotic fluid (including all components contained therein). Extraembryonic tissue and cells derived therefrom have the same genotype as the developing embryo.
[0037] As used herein, the term “extraembryonic cytokine secreting cells” or “ECS cells” means a population of cells derived from the extraembryonic tissue which have the characteristics of secreting a unique combination of physiologically relevant cytokines in a physiologically relevant temporal manner into the extracellular space or into surrounding culture media and which have not been cultured in the presence of any non-human animal-derived components, making them and cell products derived from them suitable for human clinical use. In one embodiment, the ECS cells secrete at least one cytokine selected from VEGF, angiogenin, PDGF and TGFβ32 and at least one MMP inhibitor selected from TIMP-1 and TIMP-2. In another embodiment, the ECS cells secrete more than one cytokine selected from VEGF, angiogenin, PDGF and TGFβ32 and more than one MMP inhibitor selected from TIMP-1 and TIMP-2. In a preferred embodiment, the ECS cells secrete the cytokines VEGF, angiogenin, PDGF and TGFβ2 and the MMP inhibitors TIMP-1 and TIMP-2. The physiological range of the cytokine or cytokines in the unique combination is as follows: ˜5-16 ng/mL for VEGF, ˜3.5-4.5 ng/mL for angiogenin, ˜100-165 pg/mL for PDGF, ˜2.5-2.7 ng/mL for TGFβ2, ˜0.68 μg mL for TIMP-1 and ˜1.04 μg/mL for TIMP-2. ECS cells may be selected from populations of cells and compositions described in this application and in US2003/0235563, US2004/0161419, US2005/0124003, U.S. Provisional Application Nos. 60/666,949, 60/699,257, 60/742,067, 60/813,759, U.S. application Ser. No. 11/333,849, U.S. application Ser. No. 11/392,892, PCTUS06/011392, US2006/0078993, PCT/US00/40052, U.S. Pat. No. 7,045,148, US2004/0048372, and US2003/0032179, the contents of which are incorporated herein by reference in their entirety.
[0038] As used herein, the term “Amnion-derived Multipotent Progenitor cell” or “AMP cell” means a specific population of ECS cells that are epithelial cells derived from the amnion. In addition to the characteristics described above for ECS cells, AMP cells have the following characteristics. They have not been cultured in the presence of any non-human animal-derived components, making them and cell products derived from them suitable for human clinical use. They grow without feeder layers, do not express the protein telomerase and are non-tumorigenic. AMP cells do not express the hematopoietic cell markers CD34 and CD45 protein. The absence of CD34 and CD45 positive cells in this population indicates the isolates are not contaminated with hematopoietic stem cells such as umbilical cord blood or embryonic fibroblasts. Virtually 100% of the cells react with antibodies to low molecular weight cytokeratins, confirming their epithelial nature. Freshly isolated amnion epithelial cells, from which AMP cells are derived, will not react with antibodies to the stem/progenitor cell markers c-kit (CD 117) and Thy-1 (CD90). AMP cells will not react with antibodies to the stem/progenitor cell markers c-kit (CD117). Several procedures used to obtain cells from full term or pre-term placenta are known in the art (see, for example, US 2004/0110287; Anker et al., 2005, Stem Cells 22:1338-1345; Ramkumar et al., 1995, Am. J. Ob. Gyn. 172:493-500). However, the methods used herein provide improved compositions and populations of cells. AMP cells have previously been described as “amnion-derived cells” (see U.S. Provisional Application Nos. 60/666,949, 60/699,257, 60/742,067, U.S. Provisional Application Nos. 60/813,759, U.S. application Ser. No. 11/333,849, U.S. application Ser. No. 11/392,892, and PCTUS06/011392, each of which is incorporated herein in its entirety).
[0039] By the term “animal-free” when referring to compositions, growth conditions, culture media, etc. described herein, is meant that no non-human animal-derived components, such as animal-derived serum, protein, carbohydrate, lipid, nucleic acid, vitamin, co-enzyme, etc., are used in the preparation, growth, culturing, expansion, or formulation of the composition or process. Only human-derived components may be used in the preparation, growth, culturing, expansion, or formulation of the composition or process.
[0040] By the term “expanded”, in reference to cell compositions, means that the cell population constitutes a significantly higher concentration of cells than is obtained using previous methods. For example, the level of cells per gram of amniotic tissue in expanded compositions of AMP cells is at least 50 and up to 150 fold higher than the number of cells in the primary culture after 5 passages, as compared to about a 20 fold increase in such cells using previous methods. In another example, the level of cells per gram of amniotic tissue in expanded compositions of AMP cells is at least 30 and up to 100 fold higher than the number of cells in the primary culture after 3 passages. Accordingly, an “expanded” population has at least a 2 fold, and up to a 10 fold, improvement in cell numbers per gram of amniotic tissue over previous methods. The term “expanded” is meant to cover only those situations in which a person has intervened to elevate the number of the cells.
[0041] As used herein, the term “passage” means a cell culture technique in which cells growing in culture that have attained confluence or are close to confluence in a tissue culture vessel are removed from the vessel, diluted with fresh culture media (i.e. diluted 1:5) and placed into a new tissue culture vessel to allow for their continued growth and viability. For example, cells isolated from the amnion are referred to as primary cells. Such cells are expanded in culture by being grown in the growth medium described herein. When such primary cells are subcultured, each round of subculturing is referred to as a passage. As used herein, “primary culture” means the freshly isolated cell population.
[0042] As used herein, the terms “a” or “an” means one or more; at least one.
[0043] “Treatment,” “treat,” or “treating,” as used herein covers any treatment of a disease or condition of a mammal, particularly a human, and includes: (a) preventing the disease or condition from occurring in a subject which may be predisposed to the disease or condition but has not yet been diagnosed as having it; (b) inhibiting the disease or condition, i.e., arresting its development; (c) relieving and or ameliorating the disease or condition, i.e., causing regression of the disease or condition; or (d) curing the disease or condition, i.e., stopping its development or progression. The population of subjects treated by the methods of the invention includes subjects suffering from the undesirable condition or disease, as well as subjects at risk for development of the condition or disease.
DETAILED DESCRIPTION
[0044] In accordance with the present invention there may be employed conventional molecular biology, microbiology, and recombinant DNA techniques within the skill of the art. Such techniques are explained fully in the literature. See, e.g., Sambrook et al, 2001, “Molecular Cloning: A Laboratory Manual”; Ausubel, ed., 2007, “Current Protocols in Molecular Biology” Volumes I-IV; Celis, ed., 2005, “Cell Biology: A Laboratory Handbook” Volumes I-III; Coligan, ed., 2007, “Current Protocols in Immunology”; Gait ed., 1984, “Oligonucleotide Synthesis”; Hames & Higgins eds., 1991, “Nucleic Acid Hybridization”; Hames & Higgins, eds., 1985, “Transcription And Translation: A Practical Approach”; Freshney, ed., 2006, “Animal Cell Culture” 2 nd Ed.; IRL Press, 1986, “Immobilized Cells And Enzymes”; Perbal, 1984, “A Practical Guide To Molecular Cloning.”
[0045] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.
[0046] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described.
[0047] It must be noted that as used herein and in the appended claims, the singular forms “a,” “and” and “the” include plural references unless the context clearly dictates otherwise.
[0048] Obtaining and Culturing of Cells
[0049] Various methods for isolating cells from the amnion of the placenta, which may then be used to obtain AEC, ADC and AMP cells and subsequently produce the dedifferentiated and reprogrammed cells of the instant invention, are described in the art (see, for example, US2003/0235563, US2004/0161419, US2005/0124003, U.S. Provisional Application Nos. 60/666,949, 60/699,257, 60/742,067, 60/813,759, U.S. application Ser. No. 11/333,849, U.S. application Ser. No. 11/392,892, PCTUS06/011392, US2006/0078993, PCT/US00/40052, U.S. Pat. No. 7,045,148, US2004/0048372, and US2003/0032179).
[0050] In particular, AMP cell compositions are prepared using the steps of a) recovery of the amnion from the placenta, b) dissociation of the cells from the amniotic membrane, c) culturing of the cells in a basal medium with the addition of a naturally derived or recombinantly produced human protein; d) selecting AMP cells from the cell culture, and optionally e) further proliferation of the cells, optionally using additional additives and/or growth factors. Details are contained in US Publication No. 2006-0222634-A1, which is incorporated herein by reference.
[0051] AMP cells are cultured as follows: The AMP cells are cultured in a basal medium. Such medium includes, but is not limited to, Epilife (Cascade Biologicals), Opti-pro, VP-SFM, IMDM, Advanced DMEM, K/O DMEM, 293 SFM II (all made by Gibco; Invitrogen), HPGM, Pro 293S-CDM, Pro 293A-CDM, UltraMDCK, (all made by Cambrex), Stemline I and Stemline II (both made by Sigma-Aldrich), DMEM, DMEM/F-12, Ham's F12, M199, and other comparable basal media. Such media may either contain human protein or be supplemented with human protein. As used herein a “human protein” is one that is produced naturally or one that is produced using recombinant technology. “Human protein” also is meant to include a human fluid or derivative or preparation thereof, such as human serum or amniotic fluid, which contains human protein. Details on this procedure are contained in US Publication No. 2006-0222634-A1, which is incorporated herein by reference.
[0052] In a most preferred embodiment, the cells are cultured using a system that is free of animal products to avoid xeno-contamination. In this embodiment, the culture medium is IMDM, Stemline I or II, Opti-pro, or DMEM, with human albumin added up to concentrations of 10%. The invention further contemplates the use of any of the above basal media wherein animal-derived proteins are replaced with recombinant human proteins and animal-derived serum, such as BSA, is replaced with human albumin. In preferred embodiments, the media is serum-free in addition to being animal-free. Details on this procedure are contained in US Publication No. 2006-0222634-A1, which is incorporated herein by reference.
[0053] In alternative embodiments, where the use of non-human serum is not precluded, such as for in vitro uses, the culture medium may be supplemented with serum derived from mammals other than humans, in ranges of up to 40%.
[0054] Genes and DNA Constructs
[0055] In accordance with the present invention, AEC, ADC and/or AMP cells may be genetically manipulated such that they comprise one or more pluripotency gene(s) (i.e., Oct4, Sox2, Klf4, c-Myc, nanog, Lin28, or Stella) linked to DNA encoding a selectable marker in such a manner that the expression of the selectable marker substantially matches the expression of the pluripotency gene. In one embodiment, the AEC, ADC and/or AMP cells comprise a first pluripotency gene linked to DNA encoding a first selectable marker in such a manner that the expression of the first selectable marker substantially matches the expression of the first pluripotency gene. The AEC, ADC and/or AMP cells may also be engineered to comprise any number of pluripotency genes, each respectively linked to a distinct selectable marker. The AEC, ADC and/or AMP cells may also be engineered to have one or more pluripotency gene expressed as a transgene under an inducible promoter. In a preferred embodiment, the AEC, ADC and/or AMP cells are genetically manipulated to comprise the Oct4, Sox2, Klf4, and c-Myc pluripotency genes.
[0056] The selectable marker may be linked to an appropriate pluripotency gene such that the expression of the selectable marker substantially matches the expression of the pluripotency gene i.e., the selectable marker and the pluripotency gene are co-expressed, although it is not necessary that their relative expression levels be the same or even similar. It is only necessary that the AEC, ADC and/or AMP cells in which a pluripotency gene is activated will also express the selectable marker at a level sufficient to confer a selectable phenotype on the reprogrammed cells. Skilled artisans are familiar with selectable markers commonly used in genetic engineering strategies.
[0057] The DNA encoding a selectable marker may be inserted downstream from the end of the open reading frame (ORF) encoding the desired pluripotency gene, anywhere between the last nucleotide of the ORF and the first nucleotide of the polyadenylation site. An internal ribosome entry site (IRES) may be placed in front of the DNA encoding the selectable marker. Alternatively, the DNA encoding a selectable marker may be inserted anywhere within the ORF of the desired pluripotency gene, downstream of the promoter, with a termination signal. An internal ribosome entry site (IRES) may be placed in front of the DNA encoding the selectable marker. Skilled molecular biologists recognize that many other suitable constructs are possible and all are contemplated by the methods of the invention.
[0058] Methods for Reprogramming AEC, ADC and/or AMP Cells
[0059] In general, the methods for reprogramming AEC, ADC and/or AMP cells comprise treating the cells with an agent capable of effecting dedifferentiation and reprogramming. Such treatment may involve contacting the cells with an agent which alters chromatin structure (i.e., a demethylating agent), or may involve transfecting the cells with one or more pluripotency gene(s) (as described above), or both. The above two treatments may be concurrent or sequential. Reprogrammed AEC, ADC and AMP cells (termed AEC R , ADC R and AMP R cells) are identified by selecting for cells that express the appropriate selectable marker. In addition, AEC R , ADC R and/or AMP R cells are assessed for the presence of pluripotency characteristics. The presence of pluripotency characteristics indicates that the AEC, ADC and/or AMP cells have been reprogrammed to a pluripotent status.
[0060] The term “pluripotency characteristics”, as used herein, refers to many characteristics associated with pluripotency, including but not limited to, for example, the ability to differentiate into all types of cells and having a gene expression pattern distinct for a pluripotent cell, including for example expression of pluripotency genes (i.e., Oct4, Sox2, Klf4, c-Myc, nanog, Lin28, or Stella), expression of other ES cell markers (i.e., SSEA-1, SSEA-3, SSEA-4, elevated Alkaline Phosphatase levels, nestin, AC133, Tcf4 or Cdx1), lack of expression of differentiation markers, in some instances teratoma formation, embryoid body formation (i.e., aggregates of cells derived from embryonic stem cells), etc. Self-renewing capacity, marked by induction of telomerase activity, is another pluripotency characteristic that can be assessed. Functional assays of the AEC R , ADC R and/or AMP R cells may be performed by introducing the cells into blastocysts and determining whether the cells are capable of forming some cell types, wherein they are multipotent; if the AEC R , ADC R and/or AMP R cells are capable of forming all cell types of the body including germ cells, they are pluripotent.
[0061] AEC, ADC and/or AMP cells may be reprogrammed to gain a complete set of the pluripotency characteristics. Alternatively, AEC, ADC and/or AMP cells may be reprogrammed to gain only a subset of the pluripotency characteristics.
[0062] Expression of an exogenous pluripotency gene may occur in several ways. In one embodiment, the exogenously introduced pluripotency gene may be expressed from a chromosomal locus different from the endogenous chromosomal locus of the pluripotency gene. Such chromosomal locus may be a locus with open chromatin structure and contain a gene dispensable for the cell. An exemplary chromosomal locus is the human ROSA 26 locus (see, for example, Irion, et al., Nature Biotechnology 25, 1477-1482 (2007)). The exogenously introduced pluripotency gene may be expressed from an inducible promoter such that their expression can be regulated as desired. The term “inducible promoter”, as used herein, refers to a promoter that, in the absence of an inducer (such as a chemical and/or biological agent), does not direct expression, or directs low levels of expression of an operably linked gene (including cDNA), and, in response to an inducer, its ability to direct expression is enhanced. Skilled artisans are familiar with inducible promoters and their application.
[0063] In an alternative embodiment, the exogenously introduced pluripotency gene may be transiently transfected into AEC, ADC and/or AMP cells, either individually or as part of a cDNA expression library, such library prepared from pluripotent cells. The cDNA library is prepared by conventional techniques familiar to skilled artisans.
[0064] Several agents may be used in the methods which may cause chromatin to take on a more open structure, which is more permissive for gene expression. For example, DNA methylation and histone acetylation are two known events that alter chromatin toward a more closed structure. Loss of methylation by genetic deletion of the DNA methylation enzyme Dnmt1 in fibroblasts results in reactivation of endogenous Oct4 gene. See J. Biol. Chem. 277: 34521-30, 2002; and Bergman and Mostoslaysky, Biol. Chem. 1990. Thus, DNA methylation inhibitors and histone deacetylation inhibitors are two classes of agents that may be used in the methods of the invention. Exemplary demethylation agents include 5-aza-cytidine or 5-azadeoxycytidine and deacetylation agents include trichostatin A, trapoxin B, depsipeptides, benzamides, electrophilic ketones, phenylbutyrate or valproic acid.
EXAMPLES
[0065] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions of the invention, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.
Example 1
Preparation of AMP Cell Compositions
[0066] Recovery of AMP cells—Amnion epithelial cells were dissociated from starting amniotic membrane using the dissociation agent PXXIII. The average weight range of an amnion was 18-27 g. The number of cells recovered per g of amnion was about 10-15×10 6 for dissociation with PXXIII.
[0067] Method of selecting AMP cells: Amnion epithelial cells were isolated from the amnion and frozen in liquid nitrogen. Once thawed, the cells were plated and after ˜2-3 days in culture non-adherent cells were removed and the adherent cells were kept. The adherent cells represent about 30% of the plated cells. This attachment to plastic tissue culture vessel is the selection method used to obtain the desired population of AMP cells. Adherent and non-adherent cells appear to have a similar cell surface marker expression profiles but the adherent AMP cells have greater viability and are the desired population of cells. Selected AMP cells were cultured until they reached ˜120,000-300,000 cells/cm 2 . At this point, the cultures were confluent. Suitable cell cultures will reach this number of cells between ˜5-14 days. Attaining this criterion is an indicator of the proliferative potential of the AMP cells and cells that do not achieve this criterion are not selected for further analysis and use. Once the AMP cells reach ˜120,000-300,000 cells/cm 2 , they were collected and cryopreserved. This collection time point is called p 0 .
Example 2
DNA Constructs for Introducing Pluripotency Genes into Cells
[0068] DNA constructs containing pluripotency genes are constructed. The constructs may be transfection plasmids or they may be viral vectors.
[0069] The DNA constructs may contain one pluripotency gene (i.e., any of one Oct4, Sox2, Klf4, c-Myc, nanog, Lin28, or Stella) or they may contain one, two, three, four, five, six or seven pluripotency genes. Many combinations of the different pluripotency genes is also contemplated. For example, a DNA construct may contain Oct4 and Sox2; Klf4 and Stella; Oct4, Sox2 and Klf4, etc. A preferred DNA construct contains Oct4, Sox2, Klf4, and c-Myc. Any and all combinations of pluripotency genes in DNA constructs are contemplated by the invention.
[0070] To construct the DNA constructs, the cDNAs for the pluripotency genes can be obtained from various sources. For example, the cDNAs may be purchased from GeneCopoeia, Inc., 18520 Amaranth Drive, Germantown, Md., 20874 (www.genecopoeia.com) using the following product IDs: Oct4 Product ID T2820; Sox2 Product ID T2547; Klf4 Product ID Q0453; nanog Product ID W2005; Stella Product ID Y4255. c-Myc can be obtained from OriGene Technologies, Inc., 6 Taft Court, Suite 100, Rockville, Md., 20850 (www.origene.com) catalog # SC107923.
[0071] Viral vectors can be obtained from several sources as well. For example, lentiviral packaging kits can be obtained from GeneCopoeia, Inc., 18520 Amaranth Drive, Germantown, Md., 20874 (www.genecopoeia.com), Product No. PLv-PK-01. Retroviral packaging kits can be obtained from Fischer Scientific, Inc., 2000 Park Lane Drive, Pittsburgh, Pa. 15275, Catalog No. 6160 or 6161. Adenoviral expression kits can be obtained from Invitrogen, Inc., Carlsbad, Calif. 92008 (www.invitrogen.com) SKU #K4930-00.
[0072] Skilled artisans are familiar with standard molecular biology protocols for the construction of DNA constructs. Any standard methodology for the introduction of DNA into cells is suitable for use in the methods of the invention, including calcium phosphate precipitation, lipofection, electroporation, infection with viral vectors, etc.
Example 3
Culture Method for Producing Pluripotent Cells or Maintaining Pluripotency of Cells
[0073] Specific culture methods are suitable for producing pluripotent cells. For example, the method described by Brons, et al (Nature 2007, 448:191-195) or the method described by Tesar et al (Nature 2007, 448:196-199) is suitable for producing pluripotent cells or for maintaining pluripotency of cells. Cells suitable for use in such methods include the AEC R , ADC R and/or AMP R cells described herein, or other reprogrammed or induced pluripotent cells known to skilled artisans, for examples, those described by Yamanaka, S. (Philos Trans R Soc Lond B Biol Sci 2008 363(1500):2079-87); Yamanaka, S. (Cell Prolif 2008 Suppl 1:51-6), Okita, K., et al., (Science 2008 322(5903)949-53, Epub 2008 Oct 9); Park, I. H., et al., (Nature 451:141-6, 2008), Yu, J., et al., (Science 318:1917-20, 2007); Takahashi, K., et al., (Nat Protoc 2007 2(12):3081-9); Oliveri, R. S. (Regen Med 2007 2(5):795-816); Alberio, R., et al., (Reproduction 2006 132(5):709-20); and U.S. Publication No. 20080280362, each of which is incorporated herein by reference. Naturally occurring pluripotent cells such as ES cells and cells derived from a pre-implantation embryo, are also suitable for use in the methods.
Example 4
Analyzing Cells for Pluripotency
[0074] Any number of assays and analyses are used to assess the pluripotency of the AEC R , ADC R and/or AMP R cells. For example, RT-PCR is performed to detect expression of pluripotency genes (i.e., Oct4, Sox2, Klf4, c-Myc, nanog, Lin28, or Stella). FACS is performed to detect the expression of cell surface markers (i.e., SSEA-1, SSEA-3, SSEA-4). AEC R , ADC R and/or AMP R cells are injected into SCID mice to look for teratoma formation. The AEC R , ADC R and/or AMP R cells are cultured to detect embryoid body formation. Self-renewing capacity, marked by induction of telomerase activity, is assessed by RT-PCR. Functional assays of the AEC R , ADC R and/or AMP R cells is performed by introducing the cells into blastocysts and determining whether the cells are capable of forming some cell types.
Example 5
Uses of Reprogrammed Cells
[0075] AEC R , ADC R and AMP R cells are treated with various differentiation media, agents, conditions, etc., to induce them to differentiate down any cellular pathway. For example, the AEC R , ADC R and/or AMP R are exposed to conditions known to effect differentiation of cells arising from all three primary germ layers, the endoderm, mesoderm and ectoderm. The endoderm forms the stomach, the colon, the liver, the pancreas, the urinary bladder, the lining of the urethra, the epithelial parts of trachea, the lungs, the pharynx, the thyroid, the parathyroid, and the intestines. The mesoderm forms: skeletal muscle, the skeleton, the dermis of skin, connective tissue, the urogenital system, the heart, blood (lymph cells), and the spleen. The ectoderm forms: the central nervous system, the lens of the eye, cranial and sensory, the ganglia and nerves, pigment cells, head connective tissues, the epidermis, hair, and mammary glands.
[0076] Such differentiated cells are then used to treat various conditions, for example, diabetes, heart disease, nervous system disease, etc.
[0077] The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. Any equivalent embodiments are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.
[0078] Throughout the specification various publications have been referred to. It is intended that each publication be incorporated by reference in its entirety into this specification. | The invention is directed to methods for reprogramming somatic cells to a less differentiated state. In particular, the invention is directed to methods for reprogramming amnion epithelial cells (AEC) including amnion-derived cells (ADC) and Amnion-derived Multipotent Progenitor cells (AMP cells) to a less differentiated state. The invention is further directed to compositions comprising reprogrammed AEC, ADC and AMP cells, and uses thereof. | 2 |
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent Application Ser. No. 61/110,822, filed Nov. 3, 2008, the disclosure of which is incorporated herein by reference.
FIELD
[0002] The present application relates to equipment for, and methods of, performing surgeries. In particular, the present application relates to implantable devices for decompressing, fusing, and stabilizing the spine and methods and equipment for implanting such devices during spinal surgery.
BACKGROUND
[0003] Prior art surgical procedures on the spine are substantially invasive. Even procedures currently marketed as “minimally-invasive” typically require incisions that are several inches long. Because smaller incisions and less invasive procedures would result in shorter hospitalizations and faster patient recovery, a procedure that is truly minimally invasive (or “micro-invasive”) is desirable. It is estimated that using the equipment and procedures set forth herein could shorten typical post-operative hospital stays from three to five days to one day for spinal stabilization and spinal fusion procedures.
[0004] Nevertheless, the prior art minimally-invasive spinal procedures have increased in popularity over the course of the past decade. Compared to the open techniques that came before them, these prior art minimally-invasive procedures allow patients to experience shorter hospital stays, faster post-operative recoveries, and an earlier return to work. These procedures were initially limited to simple decompressive procedures. Over the past few years, however, surgeons have begun to expand the applications of these systems to include spinal stabilization and spinal fusion procedures.
[0005] FIG. 1 shows two generic vertebrae 100 , and FIG. 2 shows a top view of FIG. 1 . The front (or “anterior”) portion of the vertebra 100 is the body 102 . The bodies 102 of adjacent vertebrae 100 are typically separated by an intervertebral disk 154 . Posteriorly, the body 102 is joined by a left pedicle 104 and right pedicle 106 to the lamina 108 . The lamina 108 joins a spinous process 114 that generally serves for muscle and ligamentous attachments. Transverse processes 110 and 112 project laterally from the junction of the respective pedicle 104 , 106 and the lamina 108 and also serve for muscle and ligamentous attachments. A supraspinous ligament attaches the spinous processes 114 of adjacent vertebrae 100 to provide stability to the spinal column.
[0006] The lamina 108 , pedicles 104 , 106 , and body 102 surround a passageway known as the vertebral foramen 116 . The vertebra 100 also has articular processes 118 that extend above and below the vertebra 100 to interact with adjacent vertebra 100 ; these interactions are known as facet joints.
[0007] While the parts of vertebrae 100 shown in FIG. 1 and FIG. 2 are common to most vertebrae 100 of the spinal column, details of anatomy differ with position of the vertebra 100 in the spinal column. For example, the vertebral body 102 is wider at lower levels of the spinal column, such as the lumbar region, than in vertebrae of the cervical spine; this provides greater weight-bearing capability at the lower levels. The body 102 of each vertebra is located anterior to the lamina 108 and spinous process 114 . The spinal cord—or for lumbar vertebrae 100 its caudal extension, the cauda equina—passes through the vertebral foramen 116 . Also found within the vertebral foramen 116 exiting the spinal cord are dorsal and ventral roots, arteries, veins, and a posterior longitudinal ligament 120 that attaches each vertebra 100 to its adjacent vertebrae 100 . In addition, there is an anterior longitudinal ligament 122 that attaches each vertebra 100 to its adjacent vertebrae 100 . Motor and sensory nerves exit the spinal canal together at a space between pedicles 106 , 104 of adjacent vertebrae 100 known as intervertebral or neural foramina.
[0008] As a subject ages, or suffers injury, various disease processes may narrow, or impinge on, the spinal canal defined by successive vertebral foramens 116 such that less space is available for the spinal cord, nerve roots, and other tissues. Among these disease processes may be bulging or rupture of an intervertebral disk 154 that impinges on the spinal canal, tumors, abscesses, ligamentous hypertrophy, spondylolisthesis, ossification of the posterior longitudinal ligament, bone spur formation, etc. Whenever the spinal canal, defined by successive vertebral foramina 116 , is effectively narrowed by a disease process impinging on the spinal cord, cauda equina, or nerve root, function may be impaired. This may result in symptoms of numbness, weakness, ataxia, impotence, incontinence, pain, and even paralysis. In some subjects, it is necessary to surgically decompress the neural elements to prevent further damage and provide relief of symptoms. Surgical decompression often requires a laminectomy to provide additional room for the spinal canal, which involves cutting through the lamina 108 on both sides of the spinous process 114 and subsequently removing this segment.
[0009] Further, damage to (including fractures) or diseases (including arthritis) of the vertebral body 102 , the facet joints 118 between vertebrae 100 , or the intervertebral disks 154 between adjacent vertebral bodies 102 may require surgical intervention. And in some patients, vertebral bodies 102 may be anteriorly displaced in relation to each other. This may result from fractures or diseases of the facet joints 118 , or from defects in the pars interarticularis, and is known as spondylolisthesis.
[0010] A known surgical stabilization technique is spinal fusion with instrumentation; this has traditionally been done using an open surgical technique where the spinal column is approached from the front through the abdomen to gain access to the vertebral body 102 , and/or from the back. In this surgery, an intervertebral disk 154 between two vertebrae 100 is often removed and replaced with an implant that is typically made of bone, metal, or another appropriate substance. This type of surgery is known as an interbody fusion. The implant provides the necessary matrix to allow bone growth and healing to fuse the adjacent vertebrae 100 . Posterolateral fusions can also be performed between the transverse processes 110 and 112 of adjacent vertebrae. Other repairs to the vertebral body 102 may also be done.
[0011] After the matrix for fusion has been established (i.e. via posterolateral and/or interbody fusion), instrumentation is often utilized to stabilize the spinal column and promote fusion (arthrodesis) by preventing micromotion of the instrumented adjacent vertebra 100 . Several different forms of instrumentation have been developed in the past. However, biomechanical studies have proven that pedicle screws provide the most effective form of lumbar spinal instrumentation with the highest pull-out strength. Pedicle screws are placed from a posterior approach at the junction of the transverse process 110 , 112 and facet 118 . These screws are then passed through the pedicle 104 , 106 into the vertebral body 102 . The pedicle screws of adjacent vertebral bodies 102 are then attached to rods, and this construct provides stabilization to the fused segment by preventing micromotion.
[0012] Conventional open surgical techniques typically utilize larger incisions, as direct visualization of the vertebral structures is required, and occasionally require both anterior and posterior approaches to the spine. Prior art minimally-invasive techniques, as noted above, typically utilize incisions that are several inches long, which results in hospitalizations and recoveries that are marginally better than comparable open surgical techniques. Micro-invasive systems and methods, such as those set forth herein, may result in shorter hospitalizations, faster post-operative recoveries, less narcotic dependence, and earlier return to work than both open and prior art minimally-invasive techniques.
SUMMARY
[0013] Systems for use in performing spinal surgery are provided herein. In one embodiment, a system includes at least two threaded caps and at least two screw assemblies. Each assembly includes a cannulated and threaded screw having upper and lower ends, a polyaxial head permanently fixed to the screw upper end in a ball-and-socket engagement, and an extension portion fixed to the head wherein movement of the extension portion causes the head to move in concert. Each head has a receiving area for engaging a rod and a threaded area for receiving one of the caps after the rod is engaged in the receiving area such that the rod is sandwiched by the polyaxial head and the cap. Each extension portion has: (a) two arms spaced apart such that the arms are on opposite sides of the polyaxial head receiving area; and (b) at least one point of weakness such that forcing the arms away from one another causes the extension portion to divide at the point of weakness and separate the extension portion from the head.
[0014] In another embodiment, a system includes for use in performing spinal surgery includes a rod, at least two threaded caps, and at least two screw assemblies. Each screw assembly includes a cannulated and threaded screw having upper and lower ends, a polyaxial head permanently fixed to the screw upper end in a ball-and-socket engagement, and an extension portion attached to the polyaxial head wherein movement of the extension portion causes the polyaxial head to move in concert. Each polyaxial head has a receiving area for engaging the rod and a threaded area for receiving one of the caps after the rod is engaged in the receiving area such that the rod is sandwiched by the polyaxial head and the cap. Each extension portion has: (a) first and second arms configured to pass the rod therebetween and guide the rod to the polyaxial head receiving area; and (b) at least one point of weakness such that forcing the arms away from one another causes the extension portion to divide at the point of weakness and separate the extension portion from the polyaxial head.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 is a posterior view of a pair of generic vertebrae.
[0016] FIG. 2 is a top view of one of the generic vertebra from FIG. 1 .
[0017] FIG. 3 is an oblique view of the posterolateral spinal column.
[0018] FIG. 4 shows a port, according to an embodiment, placed over a facet joint from FIG. 3 .
[0019] FIG. 5 a is a perspective view of the port of FIG. 4 .
[0020] FIG. 5 b is a side view of the port of FIG. 5 a.
[0021] FIG. 5 c is another perspective view of the port of FIG. 5 a.
[0022] FIG. 6 is an illustration of a view through the port of FIG. 4 , showing retraction of a descending nerve root.
[0023] FIG. 7 illustrates placement of an interbody fusion device between adjacent vertebrae through the port of FIG. 4 .
[0024] FIG. 8 illustrates placement of K-wires within pedicles of adjacent vertebrae.
[0025] FIG. 9 illustrates percutaneous placement of a screw assembly, according to an embodiment.
[0026] FIG. 10 is a front view of the screw assembly of FIG. 9 .
[0027] FIG. 11 is a perspective view of the screw assembly of FIG. 10 .
[0028] FIG. 12 is a sectional view of a pedicle screw from the screw assembly of FIG. 10 .
[0029] FIG. 13 is a perspective view of a polyaxial head from the screw assembly of FIG. 10 .
[0030] FIG. 14 is a sectional view of the polyaxial head of FIG. 13 .
[0031] FIG. 15 is front view of the pedicle screw and the polyaxial head of FIG. 10 .
[0032] FIG. 16 is perspective view of the pedicle screw and the polyaxial head of FIG. 15 .
[0033] FIG. 17 is a perspective view of the extension portion from the screw assembly of FIG. 10 .
[0034] FIG. 18 is a partial view of the extension portion of FIG. 17 .
[0035] FIG. 19 a is perspective view of a screwdriver, according to an embodiment, in use with the screw assembly of FIG. 10 .
[0036] FIG. 19 b is another perspective view of the screwdriver and the screw assembly of FIG. 19 a.
[0037] FIG. 19 c is a partial view taken from FIG. 19 b.
[0038] FIG. 20 illustrates placement of two screw assemblies of FIG. 10 within pedicles of adjacent vertebrae.
[0039] FIG. 21 illustrates a measurement device in use with the two screw assemblies of FIG. 20 .
[0040] FIG. 22 is a perspective view of a rod insertion tool, according to an embodiment.
[0041] FIG. 23 is a sectional view of the rod insertion tool of FIG. 22 .
[0042] FIG. 24 is another sectional view of the rod insertion tool of FIG. 22 .
[0043] FIG. 25 is a detailed sectional view of the rod insertion tool of FIG. 22 .
[0044] FIG. 26 is a partial view of the rod insertion tool of FIG. 22 .
[0045] FIG. 27 is another detailed sectional view of the rod insertion tool of FIG. 22 .
[0046] FIG. 28 is a perspective view of a rotating end and an attachment device from the rod insertion tool of FIG. 22 .
[0047] FIG. 29 is a perspective view of a deformable crown of the attachment device of FIG. 28 .
[0048] FIG. 30 is an end view of the deformable crown of FIG. 29 .
[0049] FIG. 31 is a side view of the deformable crown of FIG. 29 .
[0050] FIG. 32 is a perspective view of an actuator of the attachment device of FIG. 28 .
[0051] FIG. 33 is a side view of the actuator of FIG. 32 .
[0052] FIG. 34 is an end view of a rod, according to an embodiment.
[0053] FIG. 35 is a side view of the rod of FIG. 34 .
[0054] FIG. 36 is a perspective view of a cap, according to an embodiment.
[0055] FIG. 37 is a sectional view showing the screw assembly of FIG. 10 in use with the rod of FIG. 35 and the cap of FIG. 36 .
[0056] FIG. 38 is a perspective view showing two screw assemblies of FIG. 10 in use with the rod of FIG. 35 and two caps of FIG. 36 .
[0057] FIG. 39 illustrates a compressor device, according to an embodiment, in use with the two screw assemblies of FIG. 10 .
[0058] FIG. 40 is a front view of the compressor device of FIG. 39 .
[0059] FIG. 41 is a perspective view of the compressor device of FIG. 40 .
[0060] FIG. 42 is another perspective view of the compressor device of FIG. 40 .
[0061] FIG. 43 a is a perspective view of a salvage tool, according to an embodiment, with its extensions at an open alignment.
[0062] FIG. 43 b is a perspective view of the salvage tool of FIG. 43 a , with its extensions at a closed alignment.
[0063] FIG. 44 is a side view of the salvage tool of FIG. 43 b.
[0064] FIG. 45 is a front view of the salvage tool of FIG. 44 .
[0065] FIG. 46 is a perspective view of the extensions of the salvage tool of FIG. 44 .
[0066] FIG. 47 illustrates placement of three screw assemblies of FIG. 10 for a two level procedure.
[0067] FIG. 48 is a top view of an alignment tool, according to an embodiment.
[0068] FIG. 49 is a perspective view of the alignment tool of FIG. 48 .
[0069] FIG. 50 a is a perspective view of one receiving member of the alignment tool of FIG. 48 .
[0070] FIG. 50 b is another perspective view of the receiving member of FIG. 50 a.
[0071] FIG. 51 is a top view of the receiving member of FIG. 50 a.
[0072] FIG. 52 is a sectional view of the receiving member of FIG. 50 a.
[0073] FIG. 53 a is a perspective view of another receiving member of the alignment tool of FIG. 48 .
[0074] FIG. 53 b is another perspective view of the receiving member of FIG. 53 a.
[0075] FIG. 54 is a top view of the receiving member of FIG. 53 a.
[0076] FIG. 55 is a sectional view of the receiving member of FIG. 53 a.
[0077] FIG. 56 is a perspective view of the three screw assemblies of FIG. 47 , in use with the alignment tool of FIG. 48 , the rod of FIG. 35 , and caps of FIG. 36 ; it should be appreciated that the rod would never be placed as shown until after all of the screw assemblies are received in bone, and that the caps would not be set in place until after the rod is positioned in all three screw assemblies.
[0078] FIG. 57 is a flowchart summarizing various surgical procedures set forth herein.
DETAILED DESCRIPTION
[0079] The equipment and methods set forth herein may allow spine surgeons to perform posterior lumbar decompressions (e.g., laminectomies, microdiscectomies, facetectomies, and lumbar interbody fusions) in addition to posterior pedicle screw instrumentation through a small, single incision. Notably, the disclosed equipment and methods may allow spine surgeons to perform a decompressive laminectomy from a posterior approach through smaller incisions than possible with prior art systems.
[0080] A minimally invasive fusion procedure (and equipment used) according to one embodiment is shown and described with reference to FIGS. 1 through 46 of the accompanying drawings. As set forth above, FIGS. 1 and 2 show generic vertebrae 100 . FIG. 3 similarly shows generic vertebrae 100 . In FIG. 4 , with the aid of fluoroscopy, a port 200 has been placed percutaneously through the patient's skin at a facet joint 118 . The incision location is shown in FIG. 1 at line 152 .
[0081] The port 200 is shown in detail in FIGS. 5 a through 5 c . Unlike prior art ports, which are tubular and have upper and lower ends that are generally perpendicular to the sidewall, the port 200 has a lower end 202 that is not perpendicular to sidewall 204 . Though various angles may be appropriate, an angle between twenty and forty degrees to the horizon, and preferably an angle of approximately thirty degrees, may be most desirable. This angled configuration may allow the lower end 202 of the port 200 to be simultaneously positioned along the facet 118 and adjacent lamina 108 of the vertebrae 100 . This distinguishes the port 200 from prior art by allowing the surgeon to perform a facetectomy/microdiscectomy concomitant to performing a laminectomy through the same approach for spinal decompression.
[0082] In addition, the port 200 includes a lip (sometimes referred to herein as “rim”) 208 at an upper end 206 . The rim 208 provides an advantage over the prior art in that a nerve root retractor 180 (shown in FIG. 6 holding nerve roots 182 out of the way) and/or other equipment may be attached to the rim 208 , allowing hands-free operation of the attached equipment. And, as shown in FIGS. 5 a through 5 c , an engagable portion 209 may extend upwardly from the lip 208 . Though not shown in the drawings, an arm may attach to the engagable portion 209 and secure the port 200 to the bed to stabilize the port 200 . It should be understood that other engagable configurations may additionally, or alternately, be used.
[0083] While various materials and configurations would be appropriate for the port 200 , in one currently preferred embodiment, the port 200 is constructed of titanium, the sidewall 204 has a wall thickness of about one millimeter, and the rim 208 has an outer diameter that is about four millimeters greater than the inner diameter. The inner diameter of the port 200 may vary in increments (e.g., two millimeter increments, from 16 to 26 millimeters inner diameter), allowing for use in different patients with different pathology. Accordingly, multiple ports 200 may be present to allow the appropriately-sized port 200 to be selected for a given procedure. In some embodiments, the port 200 may contain a radiopaque ring at the tip for visualization by intraoperative fluoroscopy, while the port itself is radiolucent; the surgeon may thus determine exactly where the port 200 is docked in the patient by imaging this radiopaque ring.
[0084] Returning now to FIG. 4 , after the port 200 is secured in place, the facet joint 118 and lamina 108 may be resected using conventional tools and a microscope. Once the lamina 108 is removed, the contra lateral lamina may be removed as well by under-cutting the spinous process. Removal of the lamina 108 allows the spinal cord to be decompressed centrally, and removal of the facet 118 and intervertebral disc 154 allows the nerve root to be decompressed.
[0085] After the necessary portions are removed, adjacent vertebrae 100 are fused together by a spinal fusion device 190 ( FIG. 7 ), which is well known in the art, and may include such devices as a bony implant, a PEEK (polyether keytone) implant, bone morphogenic protein, a titanium cage, et cetera. The fusion device 190 is attached to an insertion tool 192 placed in the port 200 and wedged into the disc space using fluoroscopy. Once the fusion device 190 is appropriately positioned, hemostasis is obtained and the port 200 is removed.
[0086] As time passes, bone growth will result in spinal fusion as the spinal fusion device 190 is incorporated into the end plates of the bodies 102 of adjacent vertebrae 100 , fusing both vertebrae 100 into a single bony unit. Stabilization, which in this case involves placement of pedicle screw instrumentation, significantly improves arthrodesis rates and provides stability in patients with instability, such as may result from fractures or spondylolisthesis.
[0087] Pedicle screw instrumentation begins with placement of standard Jamshidi needles (not shown) into adjacent pedicles 104 (or pedicles 106 ) with use of intraoperative fluoroscopy. This is done through the patient's skin, as the port 200 has been removed. Bone penetrating, stainless steel, “K-wires” 193 ( FIG. 8 ) are then passed through the Jamshidi needles into the pedicles 104 (or the pedicles 106 ) of each vertebra 100 and are advanced into the vertebral bodies 102 of the vertebrae 100 above and below the interbody fusion device 190 . Though the patient's skin is not shown in the accompanying drawings, it should be understood that the K-wires 193 stick out through the skin percutaneously.
[0088] Next, a pedicle screw assembly 400 is inserted over each K-wire 193 and advanced into the pedicle 104 (or the pedicle 106 ) and into the vertebral body 102 . FIG. 9 shows one screw assembly 400 in place, and the screw assembly 400 is shown in detail in FIGS. 10 through 18 . A screwdriver 500 for use in placing the screw assembly 400 is shown in FIGS. 19 a through 19 c and described below.
[0089] The screw assembly 400 includes a pedicle screw 410 , a screw head 420 , and an extension portion 430 . The pedicle screw 410 ( FIG. 12 ) has an upper end 412 , a lower end 414 , and a cannulated core 416 that extends between the ends 412 , 414 and allows the screw 410 to be inserted over (and guided by) the K-wire 193 . The upper end 412 is configured to be driven by the screwdriver 500 , and may take a variety of shapes (e.g., hexagonal cavity 413 , an octagonal cavity, etc.).
[0090] The screw head 420 (which may also be referred to herein as a “polyaxial head”) is specifically shown in FIGS. 13 and 14 and is permanently fixed to the upper end 412 of the screw 410 through a ball-and-socket joint (see FIGS. 15, 16 , and 37 , though the structure that prevents the screw 410 from separating from the screw head 420 is not shown in the drawings). The ball-and-socket joint allows 360 degree rotation along the axis of the screw 410 and additionally allows the screw head 420 to pivot relative to the screw 410 . The screw head 420 defines a receiving area 421 and may include structure 424 for coupling the screw head 420 to the extension portion 430 .
[0091] The extension portion 430 is attached to the screw head 420 and includes at least two arms 432 to allow percutaenous placement of the screw 410 over the K-wire 193 and to allow percutaneous manipulation of the polyaxial head 420 while inserting a rod 700 and a cap screw 900 , which are discussed below. An important development over the prior art concerns the extension portion 430 and the manner in which the extension portion 430 is coupled to the pedicle screw 410 . As detailed in FIG. 18 , the extension portion 430 may have at least one point of weakness or “defect” 433 , allowing the extension portion 430 to be broken apart and separated from the head 420 when no longer needed. As best shown in FIG. 37 , a catch 439 may interact with a cavity 425 in the head 420 (also shown in FIGS. 13 and 14 ) and a passage 435 (also shown in FIG. 17 ) in the extension portion 430 to temporarily couple the extension portion 430 to the screw head 420 (i.e., before the extension portion 430 is broken at the defect 433 ). While other means for fastening the screw head 420 to the extension portion 430 may also be used (e.g., a protrusion extending from the head 420 or the extension portion 430 interacting with a cavity in the extension portion 430 or the head 420 , etc.), the catch 439 may allow the screw head 420 to be coupled to the extension portion 430 without further weakening the defect 433 .
[0092] Attention is now directed to the screwdriver 500 , shown in FIGS. 19 a through 19 c . The screwdriver 500 includes a shaft 510 having an end 512 complementary to the upper end 412 of the screw 410 for driving the screw 410 , and the shaft 510 is hollow to allow the K-wire 193 to pass therethrough. In addition, a guide 520 is fixedly coupled to the shaft 510 (e.g., through welding, a set screw, or any other appropriate method/device) such that the guide 520 and shaft 510 rotate together. The guide 520 has passageways 522 configured to allow the arms 432 to pass through, temporarily securing the screwdriver 500 to the screw assembly 400 . By securing the screwdriver 500 to the screw assembly 400 (i.e., to the arms 432 ), the screwdriver/percutaneous pedicle screw complex is more rigid, which may be desirable. To increase rigidity and prevent migration of the guide 520 along the arms 432 , a set screw, complementary latching structure, and/or other fastening devices may be included to temporarily lock the guide 520 to the screw assembly 400 . Though not shown, a handle may be coupled to the shaft 510 above the guide 520 .
[0093] Once the screws 410 are in place in the pedicles 104 (or the pedicles 106 ), the screwdriver 500 and the K-wires 193 may be removed ( FIG. 20 ). At this point in the procedure, the only devices extending through the patient's skin may be the extension arms 432 for each screw assembly 400 . Because of their attachment to the screw heads 420 , movement of the extension arms 432 may rotate the screw heads 420 three hundred and sixty degrees and also tilt the screw heads 420 .
[0094] The desired rod 700 length is then selected. The rod length may be selected in various ways, such as by inspecting intraoperative fluoroscopic images or using a measurement device 600 ( FIG. 21 ), for example. The measurement device 600 has two arms 610 operatively coupled together (e.g., by a pivot 612 , a sliding mechanism, etc.), and a calibrated scale 614 is attached to one arm 610 such that the other arm 610 lines up with markings along the scale 614 . The arms 610 of the measurement device 600 are passed through the skin of the patient along the extension portions 430 such that each arm 610 contacts one of the heads 420 of the two screw assemblies 400 . A desired rod length is determined using the calibrated scale 614 , and the appropriate length rod 700 is selected. The rod 700 is typically curved to allow reconstruction of the normal curvature of the lumbar spine; this curvature is known as lordosis. However, in some cases, the surgeon may select a straight rod 700 . The scale 614 may add a predetermined distance (e.g., 10 mm) to the measured distance, and the ends of the arms 610 may be configured like ends of the rod 700 ; for example, each arm end may extend 5 mm (or another appropriate distance) outward from a respective screw head 420 .
[0095] After the appropriate length rod 700 is selected, it is positioned using a percutaneous rod insertion tool 800 such that it is received in the receiving area 421 of the two screw heads 420 . The rod insertion tool 800 is shown in detail in FIGS. 22 through 33 . FIG. 22 shows the rod insertion tool 800 secured to the rod 700 . As shown, the rod insertion tool 800 includes an elongate housing 810 having upper and lower ends 812 a , 812 b . The lower end 812 b is shown having a smaller diameter than the upper end 812 a ; this allows the lower end 812 b to function inside the patient's body as needed, and also allows the surgeon to easily maneuver the upper end 812 a . The rod insertion tool 800 also includes a rotating end 820 , a control system for the rotating end 820 , an attachment device 840 , and a control system for the attachment device 840 .
[0096] The rotating end 820 and the control system for the rotating end 820 are shown in FIGS. 23 through 27 . The rotating end 820 is shown in detail in FIG. 27 and includes an attachment side 822 which rotates from a first position facing generally the same direction as the central axis of the housing 810 ( FIG. 26 ) to a second position facing generally perpendicular to a central axis of the housing 810 ( FIG. 27 ). When the rod 700 is coupled to the attachment device 840 , the rod 700 extends generally parallel to the housing axis when the rotating end 820 is at the first position, and extends generally perpendicular to the housing axis when the rotating end 820 is at the second position ( FIGS. 22 through 24 ). The rotating end 820 is pivotably coupled to the housing 810 at pivot point 824 .
[0097] The control system for the rotating end 820 includes a thumbwheel 832 ( FIGS. 22 through 25 ) and an internal plunger 834 ( FIGS. 23 through 26 ). The thumbwheel 832 and the internal plunger 834 are configured with complementary structure such that rotation of the thumbwheel 832 causes the internal plunger 834 to become higher or lower relative to the housing 810 . While various structures may be acceptably used to achieve this motion, one example is complementary threads, such that the thumbwheel 832 acts as a stationary nut and the plunger 834 acts as a linearly-moving screw. In such a configuration, only a portion of the plunger 834 needs to be threaded (i.e., the portion interacting with the thumbwheel 832 as the attachment side 822 moves between the first and second positions). To keep the plunger 834 from rotating (instead of moving linearly), the plunger 834 may interact with the housing 810 away from the threaded portion. For example, protrusions 836 ( FIG. 25 ) on the plunger 834 may interact with rails or slots (not shown) in the housing 810 . As shown in the drawings, the plunger 834 may include an internal channel 835 .
[0098] To translate the linear movement of the plunger 834 into rotational movement of the rotating end 820 , a link 838 may be pivotably coupled to the plunger 834 and the rotating end 820 , as shown in FIGS. 26 and 27 . When the plunger 834 is raised, the attachment side 822 may rotate about the pivot point 824 to the first position ( FIG. 26 ), and when the plunger 834 is lowered, the attachment side 822 may rotate about the pivot point 824 to the second position ( FIG. 27 ).
[0099] Turning now to the attachment device 840 and the control system for the attachment device 840 , attention is directed specifically to FIGS. 22 and 28 through 33 . The attachment device 840 includes a protrusion 842 ( FIG. 28 ) for aligning the rod 700 , a deformable crown 844 ( FIGS. 28 through 31 ), and an actuator 852 ( FIGS. 28, 32 , and 33 ). The deformable crown 844 is naturally at a cylindrical configuration, as shown in FIGS. 28 through 31 , and includes a plurality of expansion channels 846 . While various materials and configurations may of course be acceptable, an exemplary crown 844 is constructed of a resilient material such as titanium, has an outer diameter 844 a of approximately 0.12 inches, an inner diameter 844 b of approximately 0.10 inches, a height 844 c of approximately 0.216 inches, a channel depth 844 d of approximately 0.16 inches, and a channel width 844 e of approximately 0.02 inches.
[0100] The actuator 852 ( FIGS. 28, 32 , and 33 ) has a first portion 854 that is generally cylindrical and a second portion 856 that is generally conical, and the actuator 852 sits inside the crown 844 ( FIG. 28 ). The actuator 852 may be configured such that the cylindrical portion 854 does not deform the crown 844 , and the conical portion 856 causes the crown 844 to expand. While various materials and configurations may of course be acceptable, an exemplary actuator 852 is constructed of the same material as the crown 844 , has an outer diameter 852 a for the cylindrical portion 854 of approximately 0.09 inches, has a maximum diameter 852 b for the conical portion 856 of approximately 0.11 inches, has an overall length 852 c of approximately 0.2 inches, and has a length 852 d for the conical portion 856 of approximately 0.12 inches.
[0101] The control system for the attachment device 840 includes a screw 862 ( FIG. 22 ) and an internal cable (not shown). The internal cable extends from the screw 862 (which alternately may be a thumbwheel similar to thumbwheel 832 , or may be any other device for causing linear movement of the internal cable) to the actuator 852 (e.g., to cavity 853 ) and passes through the internal channel 835 of the plunger 834 . When the screw 862 is utilized to increase tension on the internal cable, the internal cable pulls the actuator 852 inward, causing the crown 844 to expand; when the screw 862 is utilized to reduce tension (or impart a pushing force upon) the internal cable, the internal cable pushes (or allows the actuator 852 to move) outward, allowing the crown 844 to contract ( FIG. 28 ). The internal cable may be any appropriate structure capable of providing sufficient pulling and pushing forces, as described above and understood by one of skill in the art. An exemplary internal cable is constructed of 7×49 stainless steel with an outer diameter of approximately 0.044 inches.
[0102] In use, then, the rod 700 is selected, and is aligned such that the protrusion 842 mates with cavity 712 at one end 710 of the rod 700 ( FIGS. 34 and 35 ), and the crown 844 and actuator 852 are inserted in cavity 714 of the rod 700 ( FIG. 34 ) such that the crown 844 is generally cylindrical. The screw 862 is then used to increase tension on the internal cable, causing the actuator conical portion 856 to deform the crown 844 . With the crown 844 deformed, the crown 844 exerts force on the rod 700 , in effect locking the rod 700 to the attachment device 840 .
[0103] Using the rod insertion tool 800 , the rod 700 is inserted through the patient's skin (i.e., inside an extension portion 430 ) such that the rod 700 is generally aligned with the center axis of the shell 820 . Once the rod 700 is inserted, the thumbwheel 832 is rotated, causing the internal plunger 834 to lower and the rotating end 820 (and the attached rod 700 ) to rotate. After the rod 700 is received in the receiving areas 421 of the two screw heads 420 , the screw 862 is used to provide a pushing force (or release tension) on the internal cable, allowing the actuator conical portion 856 to exit the crown 844 and the crown 844 to return to the cylindrical configuration. With the crown 844 at the cylindrical configuration, the attachment device 840 may be separated from the rod 700 and the rod insertion tool 800 may be removed.
[0104] Turning to FIGS. 36 through 38 , once the rod 700 is in place in the receiving areas 421 of the two screw heads 420 , a cap 900 is fixed to a threaded portion of each of the screw heads 420 . The caps 900 may be placed using the screwdriver 500 or another tool (e.g., a simple screwdriver having an appropriate driving mechanism), and the caps 900 lock the rod 700 in place by exerting force on the rod 700 .
[0105] If compression is desired, one of the caps 900 is set in place and tightened, and the other cap 900 is set in place but not yet tightened. Before the second cap 900 is tightened, a compressor device 1000 is fitted onto the arms 432 of each extension portion 430 ( FIG. 39 ). Pressure is then applied from the compressor device 1000 to the arms 432 to provide compressive stress across the instrumentation construct to improve interbody fusion device surface area contact with the adjacent vertebral body endplates, thus increasing the probability of successful fusion of the vertebrae during healing and minimizing post-operative interbody graft migration. While compressive forces are applied, the second cap 900 is tightened, securing the rod 700 in a compressed position. The extension portions 430 of adjacent screw assemblies 400 may overlap slightly during compression; this is possible because the extension portions 430 of adjacent screw assemblies 400 are thin and low profile, which allows more effective compression.
[0106] The compressor device 1000 is shown in detail in FIGS. 40 through 42 and has a pivot 1002 , two arms 1004 , and a notched indicator 1006 attached to one arm 1004 . Each arm 1004 has an attachment portion 1005 ( FIGS. 41 and 42 ) configured for attachment to the extension portions 430 of the screw assemblies 400 . A tooth 1008 coupled to the second arm 1004 can be advanced along the notched indicator 1006 in the manner of a ratchet to set and maintain a desired level of compression. More particularly, the notched indicator 1006 has a toothed side that engages the tooth 1008 on the second arm 1004 to maintain a compressed state. Compression is maintained until the tooth 1008 is released from the indicator 1006 to permit removal of the compressor device 1000 from the extension portions 430 after the second cap 900 is tightened.
[0107] After the rod 700 is in place and both caps 900 are tightened, the extension portions 430 may be removed from the pedicle screws 410 and the screw heads 420 by simply pulling the arms 432 away from one another, causing the extension portions 430 to fail at the defects 433 , which are best shown in FIG. 18 . In an exemplary embodiment, approximately a 30° angle between the arms 432 is required to separate the extension portions 430 from the pedicle screws 410 and the screw heads 420 ; this of course can be altered (e.g., by altering the design of the defects 433 ), however. Once the extension portions 430 are removed, the fascia and skin may be closed, and the procedure may be concluded.
[0108] In prior art percutaneous pedicle screw systems, early release of the percutaneous screw extensions is a significant problem. This typically requires complete removal of the pedicle screw, and a larger diameter pedicle screw/extension complex is then assembled and re-inserted into the pedicle over a new K-wire. This requires extensive operative time, and can be a major source of patient morbidity. Salvage tool 1500 (shown in FIGS. 43 a through 46 ) effectively reconstructs the extension portion 430 in the event that the extension portion 430 is released prematurely; this avoids the need for pedicle screw removal and replacement. To be clear, salvage tool 1500 is currently not intended to be used in every surgery, or even routinely, but is instead a device which may be used if necessary.
[0109] The salvage tool 1500 contains two extensions 1510 that are manufactured to the same dimensions and configurations as the original extension portion 430 . Salvage tool 1500 also contains a trigger 1522 along a handle 1520 . By pulling the trigger 1522 , the two extension arms 1510 are brought from an open alignment ( FIG. 43 a ) into a closed (parallel) alignment ( FIGS. 43 b and 45 ). This may be accomplished, for example, through linkage coupled to at least one of the extensions 1510 and operable by the trigger 1522 to rotate the extension 1510 to the closed alignment when the trigger 1522 is pressed. Various other mechanical systems may alternately be used to rotate at least one of the extensions 1510 upon pressing the trigger 1522 , as will be clear to one skilled in the art.
[0110] The extension(s) 1510 may be biased to the open alignment (e.g., by one or more spring), and a lock 1530 may be employed to maintain the extension(s) 1510 at the closed alignment for a period of time. The lock 1530 shown in FIGS. 44 and 45 is simply a catch that is rotatable about the handle 1520 to maintain the trigger 1522 at the pressed configuration until released. Again, various other mechanical devices may alternately be used to lock the extension(s) 1510 at the closed alignment, as will be clear to one skilled in the art.
[0111] To use the salvage tool 1500 (e.g., in the event of premature separation of extension portions 430 from pedicle screw 410 ), the extensions 1510 are inserted adjacent the screw head 420 . The trigger 1522 is then pulled, bringing the extensions 1510 to the closed alignment along the screw head 420 , and the lock 1530 may be employed. As shown in FIG. 46 , a ledge (or “wall”) 1511 may be located at the distal end 1510 a of each extension 1510 to extend along the lower side of the screw head 420 when the extensions 1510 are in place. The extension portions 430 are thus reconstructed, allowing the operation to continue (e.g., the rod 700 may be positioned and/or secured) without having to convert to an open procedure or remove and replace the pedicle screw 410 .
[0112] While the procedure set forth above includes only two screw assemblies 400 , multilevel procedures may also be performed using the equipment and techniques set forth above. As an example, a two level minimally invasive procedure according to one embodiment is shown and described with reference to the above description and FIGS. 1 through 46 of the accompanying drawings, and additionally with reference to FIGS. 47 through 56 of the accompanying drawings.
[0113] For a two level procedure, the steps set forth above to fuse vertebrae 100 (i.e., the steps utilizing the port 200 ) are repeated on an additional adjacent vertebra 100 such that the additional vertebra 100 is similarly fused. This situation is shown schematically in FIG. 47 .
[0114] For a multilevel fusion, screw assemblies 400 are first fixed to the upper and lower vertebrae 100 a , 100 b ( FIG. 47 ) in the same manner as described above (i.e., starting with placement of Jamshidi needles and ending with removal of the screwdriver 500 and the K-wires 193 after the screws 410 are in place in the pedicles 104 or 106 ). Next, an alignment tool 1600 is attached to the extension portion 430 of the fixed screw assemblies 400 .
[0115] The alignment tool 1600 is shown in FIGS. 48 through 56 and includes opposed rails 1610 (identified individually as 1610 a and 1610 b ) and a plurality of receiving members 1620 . In some embodiments, at least one of the receiving members 1620 is permanently coupled to at least one of the rails 1610 such that it may or may not be movable along the rail 1610 but cannot be separated from the rail 1610 . In other embodiments, all of the receiving members 1620 are removably coupled to the rails 1610 .
[0116] Each receiving member 1620 is configured to receive a respective extension portion 430 . In some embodiments, as shown in FIGS. 48 through 56 , the receiving members 1620 for use at the ends 1600 a of the alignment tool 1600 each have first and second holes 1622 a , 1622 b configured to receive the arms 432 of respective extension portions 430 (these receiving members 1620 are identified individually as 1620 a ), while receiving members 1620 for use in a middle region 1600 b of the alignment tool 1600 each have a single hole 1624 for receiving the arms 432 of respective extension portions 430 (these receiving members 1620 are identified individually as 1620 b ). The holes 1624 may be rectangular, as shown in FIGS. 48 and 49 , or may be circular, as shown in FIGS. 53 a through 56 , or may be any other appropriate shape. A circular shape may be desirable for allowing easier rotation of the extension portion 430 inside the hole 1624 . While only one receiving member 1620 b is shown in the drawings, it should be appreciated that additional receiving members 1620 b may be required for procedures requiring placement of four or more pedicle screws 410 .
[0117] If a receiving member 1620 is movable along the rails 1610 , a locking device is preferably included to restrict the receiving member 1620 from moving from a desired location along the rail 1610 a . For example a set screw 1632 ( FIGS. 50 a and 50 b ) operable by the user may extend through hole 1634 in the receiving device 1620 to interact with the rail 1610 a passing through hole 1636 in the receiving device 1620 , effectively locking the receiving member 1620 to the rail 1610 a . While a specific embodiment of a locking device is shown in the accompanying drawings, one skilled in the art will appreciate that other locking devices and configurations may alternately, or additionally, be used.
[0118] Additionally, a locking device is preferably included to restrict the receiving member 1620 from moving from a desired location along the arms 432 of a respective extension portion 430 . For example, a set screw 1642 ( FIGS. 50 a and 50 b ) operable by the user may extend through hole 1644 in the receiving device 1620 to interact with the rail 1610 b passing through hole 1646 in the receiving device 1620 . Because pressure on the rail 1610 b from set screw 1640 causes the rail 1610 b to exert pressure on the arm 432 (which passes through hole 1622 b for receiving members 1620 a , and which passes through hole 1624 for receiving members 1620 b ), this effectively locks the receiving member 1620 to both the rail 1610 b and the arm 432 . While a specific embodiment of a locking device is shown in the accompanying drawings, one skilled in the art will appreciate that other locking devices and configurations may alternately, or additionally, be used.
[0119] In use, then, the extension portions 430 of the upper and lower screw assemblies 400 are coupled to respective receiving members 1620 (e.g., receiving members 1620 a ), which may require adjusting the receiving members 1620 along the rails 1610 , as set forth above. Once in place, the locking devices are used to fix the receiving members 1620 to the rails 1610 and also to fix the receiving members 1620 to the extension portions 430 . At this point, intraoperative fluoroscopy may be utilized. The unlocked receiving member 1620 (e.g., receiving member 1620 b ), and specifically the hole 1624 , is aligned with the pedicle 106 (or the pedicle 108 ) and fixed to the rails 1610 , as set forth above.
[0120] Next, the remaining screw assembly 400 is fixed to the remaining vertebra 100 in the same manner as described above and used for the prior two screw assemblies 400 (i.e., starting with placement of a Jamshidi needle and ending with removal of the screwdriver 500 and the K-wire 193 after the screw 410 is in place in the pedicle 104 or 106 ), though the Jamshidi needle, the K-wire 193 , and the screw assembly 400 are all inserted through the hole 1624 . By using the alignment tool 1600 (e.g., by working through the hole 1624 ), all of the screw heads 420 will be aligned to receive the rod 700 . This is generally shown in FIG. 56 , though it should be appreciated that the rod 700 would never be in place before all of the screw assemblies 400 are in place, and that the caps 900 would not be set in place until after the rod 700 is positioned in all three receiving areas 421 .
[0121] The rod 700 is selected as set forth above. Next, using the rod insertion tool 800 , the rod 700 is positioned through the extension portion 430 of the upper screw assembly 400 or the lower screw assembly 400 , and rotated, as set forth above, such that the rod 700 is positioned in all three receiving areas 421 of the screw heads 420 . Caps 900 are then set in place as described above, and only one cap 900 (e.g., the cap 900 in the middle) is tightened. Once the caps 900 are set in place, the alignment tool 1600 may be released from the extension portions 430 and set aside.
[0122] If compression is desired, the compressor device 1000 may be used generally as set forth above. The upper or lower screw assembly 400 is first compressed with the central screw assembly 400 and locked into place by tightening the appropriate cap 900 , and then the other screw assembly 400 is compressed with the central screw assembly 400 and locked into place by tightening the remaining cap 900 . To conclude the procedure, the extension portions 430 may be removed from the pedicle screws 410 and the screw heads 420 as set forth above, and the fascia and skin may be closed.
[0123] A summary of the procedures described above is illustrated in the flowchart of FIG. 57 . Procedure 2000 begins with an incision 2002 for a posterior approach to the patient's spine. The port 200 is then inserted through the skin incision until it is flush with the facet 118 . The decompression is then performed at step 2004 through the port 200 , which includes a facetectomy and microdiscectomy. If a laminectomy is needed (see step 2005 ), it is performed at step 2006 through the port 200 , and then the procedure 2000 continues to step 2008 ; if a laminectomy is not needed, the procedure 2000 continues from step 2004 to step 2008 .
[0124] At step 2008 , the nerve root is gently retracted medially with a nerve root retractor 180 that may be attached to the port 200 . The discectomy is then completed at step 2010 , and the interbody fusion device 190 is inserted through the port 200 into the intervertebral space between the vertebral bodies 102 to elicit arthrodesis. The port 200 is then removed, and the procedure 2000 continues to step 2012 .
[0125] At step 2012 , K-wires 193 are inserted into the pedicles 104 (or 106 ) of the vertebrae using Jamshidi needles, and cannulated pedicle screws 410 (of screw assemblies 400 ) are inserted percutaneously over the K-wires 193 into the upper and lower vertebrae 100 of the spinal segment to be stabilized.
[0126] If a multilevel fusion is performed (see step 2014 ), the alignment tool 1600 is placed over the percutaneous extensions 430 of the screw assemblies 400 and then the intervening pedicle screw(s) 410 is/are inserted through the alignment tool 1600 at step 2016 . This guarantees alignment of the middle pedicle screw(s) 410 within the construct, thereby facilitating rod placement, and the procedure 2000 continues to step 2018 . If more than two vertebrae are not involved, the procedure 2000 moves from step 2012 to step 2018 .
[0127] If an extension portion 430 of a screw assembly 400 is accidentally released prematurely (see step 2018 ), the salvage tool 1500 is used at step 2020 to grip the screw head 420 , allowing completion of the procedure 2000 without replacing the pedicle screw assembly 400 ; the procedure 2000 then continues to step 2022 . If the extension portion 430 is not released prematurely, the procedure 2000 moves from step 2018 to step 2022 .
[0128] At step 2022 , the appropriate rod length is measured (e.g., from intraoperative fluoroscopic images or using the measurement device 600 ), and the procedure 2000 continues to step 2024 .
[0129] At step 2024 , the rod 700 having the appropriate length is selected and inserted into the rod insertion tool 800 . The rod insertion tool 800 is then used to insert the rod 700 between the percutaneous screw extensions 430 of the most caudad or cephalad pedicle screw assembly 400 within the construct. Next, the rod 700 is rotated into position within the receiving areas 421 of the polyaxial heads 420 , and the caps 900 are set in place. One cap 900 is tightened, securing the rod 700 in place.
[0130] The procedure 2000 then moves to step 2026 , where different paths are taken depending on whether compression is desired. If so, the procedure 2000 continues to step 2028 ; if not, the procedure 2000 continues to step 2030 .
[0131] At step 2028 , the compressor device 1000 is fitted onto the extension portions 430 and adjusted to provide the amount of compression that is desired. The untightened caps 900 are tightened while compression is applied to maintain the instrumentation construct in the compressed position, and the compressor device 1000 is set aside. The procedure 2000 then moves to step 2032 .
[0132] At step 2030 , the untightened caps 900 are fully tightened to finish securing the rod 700 in place, and the procedure 2000 continues to step 2032 .
[0133] At step 2032 , the extension portions 430 are removed, and the incision is closed at step 2034 to end the procedure 2000 .
[0134] It should be understood that the matter contained in the above description and/or shown in the accompanying drawings should be interpreted as illustrative and not in a limiting sense. Those skilled in the art appreciate that variations from the specified embodiments disclosed above are contemplated herein. Certain features and subcombinations are of utility and may be employed without reference to other features and subcombinations and are contemplated within the scope of the claims. Further, various steps set forth herein may be carried out in orders that differ from those set forth herein without departing from the scope of the present methods. The description should not be restricted to the above embodiments, but should be measured by the following claims. | Spinal surgery systems are provided. In one embodiment, a system includes threaded caps and screw assemblies. Each assembly includes a cannulated and threaded screw having upper and lower ends, a polyaxial head permanently fixed to the screw upper end in a ball-and-socket engagement, and an extension portion fixed to the head wherein extension portion movement causes the head to move in concert. Each head has a receiving area for engaging a rod and a threaded area for receiving one of the caps after the rod is engaged in the receiving area. Each extension portion has: (a) two arms spaced apart such that the arms are on opposite sides of the polyaxial head receiving area; and (b) at least one point of weakness such that forcing the arms away from one another causes the extension portion to divide at the point of weakness and separate the extension portion from the head. | 0 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation of pending International patent application PCT/NL2005/000629 filed on Aug. 31, 2005 which designates the United States and claims priority from The Netherlands Patent Application No. 1026933 filed on Aug. 31, 2004, the content of which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates in general to a method and device for loosening a sticking connection, for example a threaded connection, and in particular to the loosening of glow plugs in the cylinder head of an engine.
BACKGROUND OF THE INVENTION
[0003] A device for loosening a threaded connection provided with a vibration/impact mechanism and an impact cap is known from U.S. Pat. No. 3,861,250. The vibration/impact mechanism comprises an impact plunger driven by compressed air which is an impact piece/connection piece and the impact cap exerts vibrations on the thread without exerting a torque on it.
[0004] It is generally known to persons skilled in the art of automotive and engine technology that glow plugs are difficult to remove from the cylinder head of an engine. This is due to a number of factors such as corrosion occurring between the thread of the glow plug and the thread of the cylinder head, carbon deposits between the cylinder head and the glow plug and the ‘eating away’ of the various metals, such as aluminum and steel. In this way the plug can stick very fast and there is a risk of it breaking during removal. Similar phenomena occur in atomisers, in particular of diesel engines, which are generally assembled with a clamp connections or adjustable fittings and which can also only be removed with difficulty due to corrosion and/or deposits.
[0005] The usual way of removing a glow plug from an engine is to warm up the engine, or to drive until it is warm if the glow plugs are still intact, leave them to glow by way of a separate cable for 4-5 minutes in order to burn them clean. Penetrating oil or an equivalent multifunctional oil is then applied to the thread after which the glow plug is carefully unscrewed using the correct tool. Here, the fitter must always ensure that a maximum torque which has been predetermined by the manufacturer, for example 40 Nm, is not exceeded as otherwise the glow plug can break off. The thread can also be damaged through the application of less than the maximum torque, depending on the extent of the corrosion and/or carbon depositing.
[0006] If the glow plug causes damage during disassembly and/or unexpectedly breaks, as is often the case, it has to be drilled out, after which the cylinder head has to be rethreaded. Drilling out the glow plugs and providing a new thread is a very time-consuming and risky operation. In many cases the cylinder head of the engine has to be dismantled and replaced itself, with all the additional costs involved.
[0007] U.S. Pat. No. 4,807,349 describes a device for loosening a threaded connection which is provided with a manually operated key and a vibration/impact mechanism. The vibration/impact mechanism exerts vibrations on the threaded connection without exerting a torque thereon. At the same time the threaded connection can be unscrewed with the key. In this device the vibration/impact mechanism acts on an impact plunger driven by a riveting machine. There is also no impact cap in this device.
[0008] German examined and published application (“Auslegeschrift”) 1 067 739 discloses a device for loosening a threaded connection is in which a plug key is specified as an application. The device is a manually operated key and comprises an impact mechanism. A hammer hits an impact mechanism whereby the force of the hammer is converted into a moment on the threaded connection (the “impact nut principle”).
[0009] U.S. Pat. No. 6,681,663 discloses a hand tool for loosening a threaded connection in which a vibration mechanism is included in the hand grip with which vibrations can be exerted on the thread without exerting a moment thereon. The threaded connection can then be unscrewed with the key.
[0010] Pneumatic turning/impact equipment is also known in accordance with the state of the art. For example, reference is made to U.S. Pat. Nos. 4,243,108 and 4,836,296.
[0011] Although much attention is paid in the literature to the problem of loosening sticking connections, and in particular threaded connections, until now none of the cited solutions has proven adequate in practice to routinely replace glow plugs of car engines etc. with a high success rate (i.e. without the plug breaking during assembly). There is therefore a need for further improvements to devices for loosening sticking connections, especially threaded connections and more particularly glow plugs, which are able to overcome the above problem or at least minimize it further. The criterion here is the percentage of plugs broken during removal from an engine block (or cylinder block as the case may be) by trained personnel decreasing or preferably considerably decreasing.
[0012] Surprisingly, it has now been found that this aim can be achieved by subjecting the sticking connection to axial vibrations, whereby at the same time a preferably controlled measurable couple is exerted on the connection to loosen it.
SUMMARY OF THE INVENTION
[0013] Accordingly, the present invention provides a device for loosening a sticking connection which comprises a mechanism for generating vibrations in an axial direction as well as means of transmitting the vibrations to the sticking connection, wherein the device also comprises means of exerting a couple on the connection to be loosened.
[0014] Preferably, the axial vibrations are generated pneumatically or hydraulically.
[0015] Preferably, the means comprise a torque key or torsion rod for exerting a moment, with the couple preferably being adjustable.
[0016] In a further preferred embodiment for the sake of simplicity the torque key or torsion rod is detachably connected to the mechanism for generating vibrations in an axial direction. This can be achieved, for example, by equipping the housing in which an impact/vibration mechanism is preferably arranged with a device on or in which an external torque key can be arranged. The means of transmitting the vibrations to the threaded connection preferably also comprise a connection piece with which a vibration mechanism/impact mechanism of the device can be connected to the object to be removed from the threaded connection or to the thread itself. The device normally comprises an impact plunger driven by compressed air or hydraulically, which via an impact piece—connection piece and an impact cap exerts vibrations on the thread without exerting a moment. The vibration mechanism/impact mechanism also preferably comprises a very finely adjustable reduction valve with which the impact force frequency for the correct vibration energy can be set.
[0017] The device in accordance with the invention is primarily suited to loosening sticking threaded connections and in particular to the loosening and removal of glow plugs from an engine block in which glow plugs are mounted. The device is also suitable for loosening clamped or fitted connections and in particular for the loosening and removal of atomisers from a (diesel) engine block in which these atomisers are assembled. Thereby, in a suitable manner, use can be made of a suitable adapter or tool with which the atomiser, etc., is on the one hand firmly attached and which on the other hand is connected to the device in accordance with the invention in such a way that vibrations generated by the device in accordance with the invention are specifically transmitted to the atomiser etc. During or after the vibration process a couple is exerted on the sticking connection which in this case can also be an axial force in order to loosen the connection, as an atomiser generally has a thread. A suitable adapter is, for example, a variant of the apparatus shown in DE 20 2004 009 755 U1 whereby an additional device is applied in order to connect this apparatus with the device in accordance with the invention (see FIGS. 8 and 9 of the present application).
[0018] The device in accordance with the invention is also suitable for loosening fuse pins etc, usually using a standard adaptor, for example a ⅜ inch connection.
[0019] The invention also relates to a method of loosening a sticking connection, which comprises subjecting the sticking connection to pneumatically generated axial vibrations with a couple also being exerted on the sticking connection in order to loosen it.
[0020] Preferably, this couple can be read-off or is pre-adjustable. The couple is preferably also manually exerted on the sticking connection.
[0021] In principle, in a preferred embodiment of the invention the device operates as follows. By way of a known pneumatically operated vibration mechanism/impact mechanism the device generates axial vibrations, which are transmitted via an impact piece/connection piece to the object to be removed, typically, for example (the cover) of a glow plug, whereby the corrosion and the carbon deposits between the thread of the glow plug and the thread of the cylinder head are vibrated loose. In this way the friction between the two threads should be reduced to a greater or lesser degree. If the threaded connection is vibrated sufficiently loose, the glow plug can be unscrewed with a small couple during vibration and thus be removed complete from the cylinder head with less vibration energy. It is clear that the loosening process will depend on the extent to which the threaded connection is stuck and thus on the degree of corrosion and, in the case of glow plugs, of carbon deposits. The same principles apply if the connection to be loosened is not a threaded connection but a clamped or shaft connection.
[0022] The working duration is not particularly critical and normally takes from one minute to several minutes, depending on the degree of corrosion and/or carbon depositing and the frequency of the axial vibration mechanism. Preferably, prior to and/or during vibration penetrating oil or an equivalent is applied to the corroded connection. In a preferred embodiment of the device, the impact/vibration frequency can be adjusted. A suitable setting has, for example, a frequency in the range of around 3000-8000 vibrations/minute, preferably around 4000-6000 vibrations/minute, and most preferably around 5000 vibrations/minute. This corresponds to a pressure of the order of 5-10 bar. The couple that is manually exerted on the object to be loosened generally is critical, and certainly is so in the case of glow plugs. As a rule the limits indicated by the manufacturer should not be exceeded. If, after a few minutes of operation, the object still cannot be loosened, it should be repeated until the object can eventually be unscrewed.
[0023] If the glow plug still does not come loose, it is possible to unscrew the supply pin in the shaft of the plug and to tap a thread into the shaft (preferably a left-handed thread) and to apply a threaded rod or bolt with the aid of which better vibration can be transmitted to the sticking part of the glow plug, and generally at the same time reinforcing of the thread and casing can be brought about.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] The invention will now be illustrated further by the following examples which are not to be construed as limiting scope of the invention in any respect and with reference to the accompanying drawings, in which:
[0025] FIG. 1 is a perspective view of a device in accordance with the invention in a preferred embodiment complete with a torque key;
[0026] FIG. 2 is a partial enlargement of the panel of the torque key indicator shown in FIG. 1 ;
[0027] FIG. 3 is another perspective view of a device in accordance with the invention without a torque key or torsion rod;
[0028] FIG. 4 is a top view of a device in accordance with FIG. 1 or FIG. 3 ;
[0029] FIG. 5 is a schematic cross-section of the device in accordance with the invention taken on the line A-A in FIG. 3 ;
[0030] FIG. 6 is a schematic cross-section of the device in accordance with the invention taken on the line B-B in FIG. 4 ;
[0031] FIG. 7 is a schematic perspective view of another device in accordance with the invention in its various components;
[0032] FIG. 8 is a schematic perspective view of an embodiment of the device in accordance with the invention with an adapter suitable for vibrating loose and removing atomisers; and
[0033] FIG. 9 is a schematic cross-section of the device and adapter in accordance with FIG. 8 .
DETAILED DESCRIPTION OF THE INVENTION
[0034] It should be noted that for the sake of clarity in the various figures the same reference numbers are used as far as possible for the same or equivalent components.
[0035] With reference to FIG. 1 a device in accordance with the invention is shown which comprises three principal components:
[0036] A. A section with a conventional pneumatic vibration mechanism, which mainly comprises the following components: a casing 1 , in which the vibration mechanism is essentially located, including a cover, and a head 2 which is connected to the casing by way of bolts 4 , with a compressed air connection 3 , an air regulating valve 5 and a torque key 8 being mounted on the head 2 . In place of a pneumatic vibration mechanism another vibrating mechanism with equivalent operation can be used, such as an electric or hydraulic vibration mechanism. Such variants are known to persons skilled in the art.
[0037] B. A torque key 8 , in this embodiment an indicator moment key with a reader panel 16 , which is shown partially enlarged in FIG. 2 . Instead of an indicator torque key an adjustable torque key or torsion rod can be used, but the illustrated form of embodiment is preferred at present. The torque key or torsion rod 8 is usually detachably connected to the head 2 , as shown for example in FIG. 4 or FIG. 7 .
[0038] C. An impact cap 9 , usually hexagonal, which is connected via a vibration rod 14 to the vibration mechanism in casing 1 , whereby the vibration rod is locked with the locking pins 15 . Via the vibration rod 14 the axial vibrations generated by the vibration mechanism are transmitted to the impact cap 9 and thereby to the sticking connection to be loosened.
[0039] With reference to FIG. 3 a device according to the invention in shown which is essentially identical to the device in FIG. 1 but without a torque key or torsion rod and in another perspective. FIG. 3 thus shows a device comprising a casing 1 , which mainly contains a vibration device, a head 2 , with a compressed air connection 3 and an air 5 regulating valve 5 . An impact cap 9 is attached to the vibration mechanism via a vibration rod 14 which is locked to the casing 1 at 15 . In the casing 1 there are also openings 24 for venting the return chamber of the vibration mechanism, the operation of which will be described in further detail below.
[0040] With reference to FIG. 4 the head 2 of a device in accordance with the 10 invention is shown from the top, where 3 is again the connection of the compressed air line and 5 an air regulating valve. The head is fixed to the casing with the bolts 4 . The head in this embodiment is also provided with a precision-fit flange 17 or a thread for accommodating a torque key or torsion rod.
[0041] With reference to FIG. 5 and FIG. 6 two different longitudinal sections of the 15 same device in accordance with the invention are shown. Using these the operation of a conventional type of vibration mechanism that can be advantageously used in the device will now be described. The vibration mechanism is mainly located in the casing 1 and is bounded at one end of the casing by the head 2 and at the other end by the vibration rod 14 . The vibration mechanism comprises a cylinder 18 in which a plunger 11 is moved back 20 and forth. It will be clear to a person skilled in the art that on the one hand it fits tightly to the internal wall of the cylinder and other hand it must be able to move easily in the cylinder. The plunger 11 divides the cylinder 18 into two chambers which hereinafter are referred to as the pressure chamber and the return chamber. The pressure chambers is close to the edge of the head 2 , while the return chamber is bounded by the vibration rod 25 14 at the end that is removed from the plunger 11 .
[0042] The operation of the vibration mechanism is based on the rapid to and fro movement of the plunger 11 . Compressed air is fed via the inlet 3 into the head 2 and there passes through the air regulating valve 17 via a supply channel. The air is then fed via the valve 10 with the change-over valve 21 into the pressure chamber as a result of 30 which the plunger 11 is moved in the direction of the vibration rod 14 giving the vibrating rod an impulse. By way of the described movement of the plunger 11 in the cylinder 18 an opening 23 in the cylinder wall is made free through which the air flows through the casing to the outside and the pressure in the pressure chamber is released. In this way the change-over valve 21 closes too as a result of which the compressed air now flows into 35 the return chamber via air channel 20 and pushes the plunger 11 due to its adapted shape back in the direction of the head 2 . Through this movement the opening in 23 in the cylinder wall is closed and an opening 22 in the cylinder wall is opened through which the air flows out through the opening(s) 24 via an air channel and the pressure in the return chamber is released. At the same time the change-over valve 21 opens again as a result of which the compressed air flows into the pressure chamber and the process described above begins again. The plunger 11 is thus rapidly moved to and fro and this generates a vibration of the vibration rod 14 , which is passed on to any impact cap 9 mounted thereon. The air channel 20 (see FIG. 6 ) thus has the function of controlling the change-over valve 21 . It will be clear to a person skilled in the art that the vibration mechanism is controlled by the pressure from the supplied compressed air which in the first instance is externally determined and then finely regulated by the regulating valve 5 . The fastening of the impact cap on the vibration rod can be any type of conventional fastening which is known to a person skilled in the art, such as a clamping spring or other locking device. The vibration rod 14 is fastened in a moveable manner to the casing 1 by means of a locking device 15 , for example locking pins. Preferably a buffer ring 19 is arranged around the vibration rod close to the end that limits the cylinder 18 and closely fitting the inner edge of the casing 1 . The buffer ring 19 serves both to counteract leakage of air from the pressurized system which promotes good operation of the vibration mechanism, as well as to absorb the pulses produced by the vibration mechanism so that more vibration energy remains in the vibration rod and does not enter the machine as negative energy. Preferably the buffer ring is made of a durable elastic plastic or rubber. Preferably the locking pins 15 are made of a hard plastic.
[0043] Modifications of the vibration mechanisms are also envisaged, but the application of these does not differ from the described principle.
[0044] With reference to FIG. 7 another form of embodiment of the device in accordance with the invention is shown. The casing 1 , including protection is here shown in an axial downward embodiment, but in the operating condition this is attached to the head 2 . In the head 2 the holes for the supply of compressed air 3 and the bolts 4 are visible. The air regulating valve 5 is locked by an external lock nut 6 in this embodiment. In other forms of embodiment locking normally takes place by means of an O-ring (not shown) or in another way which is known to a person skilled in the art. In place of a vibration rod an impact pin 7 is used in this embodiment, which together with the connection piece 12 and the locking nut 13 has an identical function to the vibration rod in the previously described embodiments. The valve 10 and the cylinder 18 with the impact plunger 11 are also shown and also have identical functions as described. A torque key 8 in this case of an adjustable click type and an impact cap 9 usually of a hexagonal design are also shown.
[0045] With reference to FIG. 8 and FIG. 9 another form of embodiment of the invention is shown, comprising a device in accordance with the invention as well as an adapter 5 suitable for vibrating loose and removing an atomiser 25 which is inserted in a cylinder head 32 . The device does not essentially differ from the previously described forms of embodiment except that the vibration rod 14 is designed with a angled end, normally at an angle of 45° with regard to the longitudinal direction of the rod, which by means of suitable adapter is preferably directly brought into contact with an atomiser 25 or a tension spindle 10 28 for an atomiser. The tension spindle 28 shown here is derived from a conventional type and comprises a support cylinder 26 , a bearing ring 30 , a support plate 31 and a tightening nut 29 . Preferably the support plate comprises an angle correction whereby there is a greater chance that the atomiser can be drilled loose and removed under the applicable circumstances. This type of tension spindle is known to a person skilled in the 15 art and will not be described further. The new element in this adapter is the guide bush 27 for the also used vibration rod 31 , whereby the device according to the invention can exert effective axial vibration on the atomiser. As an atomiser does not generally have a thread it is in this case not necessary to apply a (manual) radial force on the atomiser in order to loosen it, as described above, but the atomiser can be loosened and removed by axial 20 force as well as by tightening the nut 29 .
[0046] The material of which the device according to the invention is manufactured is preferably high-quality steel for the ‘heavy’ parts which generate and/or transmit the vibrations, such as the vibration rod 14 or the impact pin 7 , the impact plunger 11 , the extension piece 12 , the impact cap 9 and generally also the torque key 8 , and lightweight 25 metal, such as aluminum for the casing 1 and the head 2 . Where necessary or required the head 2 is reinforced. For a person skilled in the art the choice of material and any variations thereof will not present any problem.
[0047] The shown torque keys or torsion rod form part of the device according to the invention but are not generally integrally connected to the head of the vibration device. 30 However, such a form of embodiment is envisaged in the scope of this invention. The torque key can also be provided at another place, for example on the casing 1 with the vibration/impact mechanism or between the casing 1 and the object to be removed, in the same way as described in U.S. Pat. No. 4,807,349. A form of embodiment is also envisaged in which no manual, but a mechanical or electrical couple is exerted.
[0048] In place of the impact cap shown as component C, which is mainly of use when loosening and removing glow plugs, any other connection piece can be applied between the vibration mechanism and the object to be removed. This component can also form an integral unit with, for example, the impact piece-connection piece 12 .
[0049] For a person skilled in the art it will be clear that modifications and adaptations to the device described in this application can be made without deviating from the essence of the invention. Such modifications and adaptations, some of which are set out above, are therefore included in this invention. | A method and device are provided for loosening a sticking connection, in particular a glow plug in the cylinder head of an engine. The device comprises a mechanism for generating vibrations in an axial direction, preferably pneumatically, hydraulically or electrically, as well as means of transmitting the axial vibrations to the sticking connection, wherein the device also comprises means of exerting a couple, preferably read off or pre-adjustable, to the connection to be loosened. In the method, the sticking connection is subjected to preferably pneumatically, hydraulically or electrically generated axial vibrations, wherein a couple is also exerted on the sticking connection, preferably manually and pre-adjusted, in order to loosen it. | 1 |
FIELD OF THE INVENTION
The invention relates to devices and methods for storing and dispensing cuvettes for use in an automated clinical sample analyzer.
BACKGROUND OF THE INVENTION
Automatic clinical sample analyzers are common in hospitals and research institutions for analyzing large quantities of samples. For example, environmental specimens, such as water, or patient specimens, such as blood, urine or other biological samples, can be tested using automated sample analyzers to determine concentrations of contaminants or analytes, for example.
Automated sample analyzers have a variety of component systems that work in concert to manipulate patient samples. For example, an automated sample analyzer may have one or more reagent dispensing components, sample holder dispensing components, sample and reagent probes, washing stations, detecting mechanisms, and automated arms, carousels, or conveyors for moving samples from one station to another.
Automated sample analyzers reduce time taken to perform assays on the samples, improve output, and reduce human error and contamination, thereby providing cost effective sample analysis. However, despite the automated functioning of such analyzers, operator intervention is often required if a component malfunctions, or if consumables, such as reagents and sample holders, need replacing. Therefore, there is a need in the art for an automated sample analyzer that reduces the need for operator intervention, thereby further improving efficiency, accuracy of testing, and throughput.
SUMMARY OF THE INVENTION
The invention is related to an apparatus and methods for dispensing sample holders for use in an automated clinical sample analyzer. In one aspect, the invention is directed to a device for separating a sample holder from a stack of sample holders. The device includes a support member for receiving a stack of at least two sample holders and at least one releasing member, preferably two releasing members. The support member is positioned to introduce at least one of the sample holders in the stack of sample holders between a first releasing member and a second releasing member. The first and second releasing members each include a helical thread. The first releasing member is operatively connected to a first rotator capable of rotation in a clockwise direction. The second releasing member is operatively connected to a second rotator capable of rotation in a counter-clockwise direction. The first and second rotators rotate the first and second releasing member thereby releasing one of the at least two sample holders from the stack of sample holders. In a further embodiment, the first rotator is further capable of rotation in a counter-clockwise direction while the second rotator is further capable of rotation in a clockwise direction. The rotator may comprise an oscillating motor in one embodiment.
According to the invention, in one embodiment, the releasing members are threaded. For example, in one embodiment, the first releasing member has a right hand oriented helical thread and the second releasing member has a left hand oriented helical thread. In one embodiment, the pitch of the right-hand helical thread is the same as the pitch of the left hand helical thread. Alternatively, the pitch of one helical thread differs from the pitch of another helical thread. The pitch is in the range of about 6.9°-7.3° in one embodiment, while in another embodiment, the pitch is in the range of about 9.2°-9.6°. In a further embodiment, the pitch is about 9.4°, while in another embodiment, the pitch is about 7.1°.
In yet another embodiment, the first releasing member has a right hand oriented helical thread and a left hand oriented helical thread. The second releasing member also has a right hand oriented helical thread and a left hand oriented helical thread. According to one embodiment, the pitch of the right hand helical thread of the first releasing member differs from the pitch of the left hand helical thread of the first releasing member. For example, the pitch of the right hand helical thread is in the range of about 6.9°-7.3° while the pitch of the left hand helical thread is in the range of about 9.2°-9.6°. In a further embodiment, the pitch of the right hand helical thread is about 7.1° while the pitch of the left hand helical thread is about 9.4°.
In a further embodiment, the first releasing member is substantially cylindrical and has the same diameter as the second releasing member. In another embodiment, the diameter of the first releasing member is different than the diameter of the second releasing member. In yet another embodiment, the releasing member is tapered with the widest portion at the top, or alternatively, the widest portion is at the bottom.
The device according to the invention also includes a sample holder receiver, according to one embodiment of the invention. For example, the sample holder receiver receives the sample holder following separation of the first sample holder from the second sample holder.
In another embodiment, the support member for receiving a stack of at least two sample holders is a tube, while in another embodiment, the support member comprises at least two walls, each wall having a C-shaped cross-section.
The device, according to one embodiment, further comprises a rotating module, for example, a wheel, disc, or cylinder, having a plurality of openings for supporting stacks of sample holders. In one embodiment, each of the plurality of openings is positioned equidistant from the center of the carousel and equidistant from each other. In yet another embodiment, the plurality of openings are positioned around the circumference of the rotating carousel.
According to another aspect, the invention includes a method for separating a sample holder from a stack of sample holders. The method includes positioning a stack of at least two sample holders adjacent a first releasing member comprising a helical thread, rotating the first releasing member in a first direction, engaging said sample holder; disengaging the first sample holder from the stack of sample holders; rotating the first releasing member in a second direction; and releasing the sample holder from the stack of sample holders.
In a further embodiment, the method includes positioning the stack of sample holders adjacent a second releasing member. The releasing member, for example, includes a helical thread. In one embodiment, the first releasing member has a right hand oriented helical thread, and the second releasing member has a left hand oriented helical thread. In a further embodiment, the first releasing member also includes a left hand oriented helical thread, while the second releasing member also includes a right hand oriented helical thread.
In one embodiment, the method includes rotating said second releasing member in a second direction while performing the step of rotating said first releasing member in a first direction. In another embodiment, the method includes rotating said second releasing member in a first direction while performing the step of rotating said first releasing member in a second direction. In one embodiment, the first direction is a clockwise direction and the second direction is a counter-clockwise direction. In another embodiment, the step of releasing the sample holder from the first releasing member while simultaneously releasing the sample holder from the second releasing member.
DESCRIPTION OF THE DRAWINGS
FIG. 1 is a top plan view of an automated sample analyzer having a cuvette dispensing station, according to an illustrative embodiment of the invention.
FIG. 2 is a perspective view of a cuvette for holding a sample and for dispensing from a cuvette dispensing station, according to an illustrative embodiment of the invention.
FIG. 3A is a plan view of a cuvette dispenser of an automated sample analyzer including a cuvette loading module on the top portion to receive stacks of cuvettes, according to an illustrative embodiment of the invention.
FIG. 3B is a perspective view of the cuvette dispenser of an automated sample analyzer as shown in FIG. 3A , with the cuvette loading module removed to reveal an engagement piece for engaging and rotating the cuvette loading module, according to one illustrative embodiment of the invention.
FIG. 4 is a perspective view of a cuvette dispenser of an automated sample analyzer including several sensors for activating movement of cuvettes through the cuvette dispenser, according to one illustrative embodiment of the invention.
FIG. 5A is a cross-sectional view of a cuvette loading module housing a stack of cuvettes prior to the cuvettes being released into the cuvette dispense chute for distribution, according to one illustrative embodiment of the invention.
FIG. 5B is a cross-sectional view of a cuvette dispenser including the cross-sectional view of the cuvette loading module of FIG. 5A , wherein the stack of cuvettes shown in FIG. 5A has been released into the cuvette dispense chute, according to one illustrative embodiment of the invention.
FIG. 5C is a cross-sectional view of the cuvette dispenser shown in FIG. 5B , wherein a cuvette from the stack of cuvettes has been released from the cuvette release members to the cuvette transfer position, according to one illustrative embodiment of the invention.
FIGS. 6A-C are successive perspective views of a releasing member, according to one embodiment of the invention, as it rotates in a clockwise direction.
FIGS. 7A-C are successive perspective views of a releasing member, according to one embodiment of the invention, as it rotates in a counter-clockwise direction.
FIGS. 8A-C are perspective views of cuvette release members for releasing a cuvette from a stack of cuvettes in the cuvette dispense chute, wherein the cuvette release members are threaded and rotate to engage the cuvette to remove it from the stack and dispense it at the cuvette transfer position according to an illustrative embodiment of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Automated sample analyzers are used for detecting a substance, such as a contaminant or an analyte, in a sample. For example, a sample may be an environmental sample such as a soil or water sample, or the sample may be from a human or animal patient, such as a blood or urine sample. An automated sample analyzer can analyze a sample according to a predetermined protocol that may include, for example, providing a sample holder, providing a sample, adding reagents, aspirating the sample, and detecting the contents of a sample.
The invention, as described herein, discloses a cuvette dispenser for use with an automated sample analyzer. A cuvette dispenser, according to the invention, dispenses sample holders in a manner that reduces operator intervention with the dispenser. According to the invention, after an operator loads the cuvette dispenser with sample holders, the cuvette dispenser manages the task of distributing individual sample holders to the automated sample analyzer as needed, which reduces the need for operator intervention. Furthermore, the cuvette dispense mechanism is designed to reduce malfunction, thereby improving the efficiency of the cuvette dispenser and the automated sample analyzer.
Automated Sample Analyzer
FIG. 1 is a top view of an automated sample analyzer having a cuvette loading station, according to an illustrative embodiment of the invention. According to one illustrative embodiment of the invention, the automated sample analyzer 11 has a cuvette dispensing station 10 positioned adjacent a cuvette transport carousel 1 . The cuvette dispensing station 10 dispenses empty cuvettes 12 (not shown) for retrieval by a cuvette transfer arm 14 (not shown), which transfers cuvettes 12 from the cuvette dispensing station 10 to the cuvette transport carousel 1 .
An exemplary sample cuvette 12 according to the invention is shown in FIG. 2 . According to one embodiment, the cuvette 12 is a container that has two side walls 56 and two end walls 58 . In a further embodiment, cuvette 12 has a lip or flange 50 extending around the opening 51 of the cuvette 12 . For example, the lip 50 protrudes at approximately 90° from the side walls 56 in one embodiment, while in another embodiment, the lip 50 protrudes at approximately 90° from the end walls 58 . Alternatively, the lip 50 extends around the perimeter of the opening 51 .
With continued reference to FIG. 2 , in a further embodiment, the cuvette 12 has a projection 52 on a side wall 56 for engaging a groove, hole or recess 54 in another cuvette 12 . In yet another embodiment, the cuvette 12 has a first projection 52 on a first side wall 56 and a second projection 52 on a second side wall 56 . In another embodiment, the cuvette 12 has a groove, hole or recess 54 on a side wall 56 for being engaged by a projection 52 from another cuvette 12 . In yet another embodiment, the cuvette 12 has a first recess 54 on a first side wall 56 and a second recess 54 on a second side wall 56 . For example, when a first cuvette 12 is inserted into a second cuvette 12 , the first projection 52 of the first cuvette engages a groove 54 on a first side wall 56 of the second cuvette 12 and a second projection 52 on the first cuvette 12 engages a groove 54 on a second side wall 56 of the second cuvette 12 to releasably secure the first cuvette 12 to the second cuvette 12 to form a stack of cuvettes 120 .
As used herein, a stack of cuvettes 120 means at least two cuvettes 12 that are releasably joined to one another. Releasably joined means that the earth's gravitational forces alone are not sufficient to separate a bottom cuvette 12 from a top cuvette 12 when the two cuvettes are joined, but that the addition of an external force to separate the bottom cuvette, i.e., the first cuvette, from the top cuvette, i.e., the second cuvette is necessary. The number of cuvettes in a stack may be 2-500, preferably 10, 20, 25, 30, 50, or 100, for example.
In another embodiment, the cuvette 12 has a projection 52 on the end wall 58 , while in a further embodiment, the cuvette 12 has a groove, hole or recess 54 on the end wall 58 . In a different embodiment, the cuvette 12 has a first projection 52 and first recess 54 on a first end wall 58 and a second projection 52 and a second recess 54 on a second end wall 58 .
Referring again to FIG. 1 , the cuvette transport carousel 1 has a series of slots 2 for receiving a cuvette 12 . According to one embodiment of the invention, the cuvette transport carousel 1 rotates in both the clockwise and counter clockwise directions in order to position cuvettes 12 held in the slots 2 at different stations adjacent to the cuvette transport carousel 1 in the automated sample analyzer. For example, in one embodiment, cuvette transport carousel 1 rotates to position a cuvette 12 near the sample pipette robot 5 so that the sample pipette robot 5 can dispense a sample from a sample carousel (not shown) into the cuvette 12 .
In another embodiment, the cuvette transport carousel 1 rotates to position a cuvette 12 at a reagent dispensing station 7 . At the reagent dispensing station, according to one embodiment of the invention, one or more reagents (not shown), such as buffers or magnetic particles having antigens or antibodies bound thereto, for example, are dispensed into the sample cuvettes 12 by one or more reagent pipettes (not shown).
In a further embodiment, the cuvette transport carousel 1 rotates to position a cuvette 12 at a magnetic particle washing station 4 . Cuvettes 12 are removed from the cuvette transport carousel 1 wherein the magnetic beads added to the cuvette 12 at the reagent dispense station 7 are washed according to methods described in the concurrently filed U.S. patent application entitled “Magnetic Particle Washing Station” Ser. No. 11/704,138.
In yet another embodiment, the cuvette transport carousel 1 rotates to position the cuvette 12 near an analysis station 6 . For example, in one embodiment according to the invention, the analysis station is a luminometer 6 . The cuvettes 12 are removed from the cuvette transport carousel 1 and positioned inside the luminometer 6 one at a time. In one embodiment, the luminometer 6 provides a sealed environment free from outside light for performing chemiluminescent assays which measure, for example, target molecules in the sample.
Cuvette Dispenser
FIG. 3A is a perspective view of a cuvette dispenser of an automated sample analyzer, including a cuvette loading module for receiving stacks of cuvettes, according to an illustrative embodiment of the invention, while FIG. 3B is a perspective view of the cuvette dispenser of an automated sample analyzer as shown in FIG. 3A , but with the cuvette loading module removed to reveal an engagement piece for engaging and rotating the cuvette loading module according to one illustrative embodiment of the invention.
As shown in FIGS. 3A-B , according to one embodiment, the cuvette dispenser 10 includes a cuvette loading module 14 , a cuvette dispense chute 20 , one or more cuvette release members 30 , 32 , and a cuvette transfer position 36 . The cuvette loading module 14 has a plurality of slots 16 for holding stacks of cuvettes 120 . The cuvette dispense chute 20 receives stacks of cuvettes 120 from the cuvette loading module 14 and provides them to the one or more cuvette release members 30 , 32 . Cuvette release members 30 , 32 separate individual cuvettes 12 from the stack of cuvettes 120 , depositing individual cuvettes 12 one at a time to the cuvette transfer position 36 .
According to one embodiment of the invention, the cuvette loading module is positioned above the cuvette dispense chute 20 and the cuvette release members 30 , 32 . In one embodiment, the cuvette loading module 14 is circular, for example, a wheel, disc, or cylinder. In a further embodiment, the cuvette loading module 14 has a plurality of vertically oriented slots 16 extending from the top 13 of the module 14 to the bottom 24 of the module 14 for receiving stacks of cuvettes 120 . The module 14 has, for example, 15 , 20 , or 25 slots 16 . Each slot 16 includes two side walls 18 . The side walls 18 of the slot 16 abut a rear wall 21 . According to one embodiment of the invention, each slot 16 is spaced an equal distance from the center of the circular module 14 . In a further embodiment, each slot 16 is equally distributed around the perimeter of the module 14 .
In a further embodiment of the cuvette loading module 14 , each side wall 18 has a lip 17 for securing the stack of cuvettes 120 . In another embodiment, between lip 17 of the first side wall and lip 17 of the second side wall 18 , there is a gap 23 . The gap 23 allows an operator to see whether or not a slot 16 is empty or filled with cuvettes 12 , thus improving ease of operation. In a further embodiment, rear wall 21 includes a window 19 for allowing a sensor (not shown) to detect the presence or absence of a cuvette 12 .
According to one embodiment, the cuvette loading module 14 rotates about a central axis. The module 14 sits on a base plate 360 and engages a central pin 34 . The pin 34 is operatively connected to a motor (not shown), for example, by an axle or shaft. The pin 34 rotates causing the module 14 to rotate to position a stack of cuvettes 120 above a cuvette shutter 22 . In one embodiment, while the module 14 rotates, the base plate 360 remains stationary. In a further embodiment, the base plate 360 supports the base of the cuvette stack 120 .
FIG. 4 is a perspective view of a cuvette dispenser of an automated sample analyzer showing several sensors for activating movement of cuvettes through the cuvette dispenser, according to one illustrative embodiment of the invention. In one embodiment, a cuvette stack sensor 400 is fixed to the base plate 360 . According to another embodiment of the invention, the cuvette stack sensor 400 detects the presence or absence of a stack of cuvettes 120 in the slots 16 . For example, in one embodiment, the cuvette stack sensor 400 detects the presence or absence of a cuvette stack 120 via the window 19 in the rear wall 21 of the slot 16 . For example, if a cuvette is not detected in the slot 16 , the sensor 400 detects the absence of the cuvette stack 120 and the cuvette loading module 14 rotates to position a stack of cuvettes 120 over the cuvette shutter 22 .
FIG. 5A is a cross-sectional view of a cuvette loading module housing a stack of cuvettes prior to the cuvettes being released into the cuvette dispense chute for distribution, according to one illustrative embodiment of the invention. Once the cuvette stack 120 is positioned over the cuvette shutter 22 , as shown in FIG. 5A , the cuvette stack sensor 400 detects a cuvette, activating the cuvette shutter 22 to open. In one embodiment, the cuvette shutter 22 pivots in the plane of the base plate 360 to open and close over a cuvette chute 20 , described below in greater detail. In another embodiment, the cuvette shutter 22 pivots in a plane not parallel to the base plate 360 . For example, the cuvette shutter 22 , in one embodiment, is a door that opens from a plane parallel to the base plate 360 to a plane that is substantially perpendicular to the base plate 360 .
FIG. 5B is a cross-sectional view of the cuvette dispenser. The stack of cuvettes shown in FIG. 5A has been released into a cuvette dispense chute, according to one illustrative embodiment of the invention. Once the cuvette shutter 22 opens, the cuvette stack 120 drops from the cuvette loading module 14 into cuvette dispense chute 20 , for example. At this point, the cuvette 12 at the bottom of the stack rests on a first cuvette release member 30 and a second cuvette release member 32 , while the remaining cuvettes are supported by the chute 20 .
According to one embodiment of the invention, the chute 20 is a tube, for example, a rectangular tube, a square tube or a cylindrical tube, sized and shaped to receive a plurality of cuvettes 12 , e.g., a stack of cuvettes 120 . In a further embodiment, the tube 20 is open on the front portion 60 , while in another embodiment, the tube is closed over the front portion 60 . In another embodiment, the chute 20 includes a first parallel wall 28 and a second parallel wall 29 to support cuvettes 12 , thereby permitting visibility of the cuvettes 12 in the chute. For example, in one embodiment, the cuvette dispense chute 20 is a pair of parallel walls, each shaped in cross-section like a square bracket ([ ]) providing a hollow passage between the walls to support a stack of cuvettes 120 .
Referring again to FIG. 4 , once the stack of cuvettes 120 is present in the cuvette dispense chute 20 , a cuvette dispense sensor 56 , positioned for example, at the base of the cuvette dispense chute 20 , detects the presence of the cuvette stack 120 , according to one embodiment of the invention. Upon detecting the presence of a cuvette stack 120 , the first cuvette release member 30 and second cuvette release member 32 rotate to release a cuvette 12 from the cuvette stack 120 . The cuvette dispense chute 20 supports the cuvettes 12 until they are removed from the stack 120 by the first cuvette release member 30 and second cuvette release member 32 .
FIGS. 6A-C and FIGS. 7A-C are perspective views of a first cuvette release member and a second cuvette release member respectively. As shown in FIGS. 6A-C and FIGS. 7A-C , the first cuvette release member 30 and the second cuvette release member 32 are cylindrical in shape. In one embodiment, the first cuvette release member 30 has the same diameter as the second cuvette release member 32 . In another embodiment, the first cuvette release member 30 has a diameter that is different from the diameter of the second cuvette release member 32 (not shown). In an alternate embodiment, however, the first cuvette release member 30 and the second cuvette release member 32 are tapered (not shown). For example, in one embodiment, the widest part of the tapered first cuvette release member 30 is the bottom of the cuvette release member 30 , while in another embodiment, the widest part of the tapered cuvette release member 30 is the top of the cuvette release member 30 .
With continued reference to FIGS. 6A-C and FIGS. 7A-C , according to one embodiment of the invention, the cuvette release members 30 , 32 are threaded, for example, like the windings on a screw. According to one embodiment, the first cuvette release member 30 has a helical thread 31 that is in a first orientation while the second cuvette release member 32 has a helical thread in a second orientation 33 . For example, in one embodiment, the first cuvette release member 30 has a right hand oriented helical thread 31 disposed on the cuvette release member 30 , while the second cuvette release member 32 has a left hand oriented helical thread 33 disposed on the cuvette release member 32 . In a further embodiment, the first cuvette release member 30 has a right hand oriented thread 1135 as well as a left hand oriented helical thread 1131 disposed on the cuvette release member 30 . In a further embodiment, the second cuvette release member 32 has a left hand oriented helical thread 1136 as well as a right hand oriented helical thread 1132 disposed on the cuvette release member 32 .
In an alternate embodiment, the first cuvette release member 30 has a helical thread 31 that is in the same orientation as the helical thread 33 of the second cuvette release member 32 . For example, the first cuvette release member 30 and the second cuvette release member 32 each have a helical thread 31 , 33 with a right hand orientation, while in another embodiment, the first cuvette release member 30 and the second cuvette release member 32 each have a helical thread 31 , 33 with a left hand orientation. In one embodiment, a cuvette release member 30 , 32 has only one thread, while in another embodiment, a cuvette release member 30 , 32 has two or more threads.
With continued reference to FIGS. 6A-C and FIGS. 7A-C , in a further embodiment, the first cuvette release member 30 has a thread 1131 of a first orientation at the top end 131 . The orientation of the thread 1131 reverses direction on the cuvette release member 30 to become a thread of a second orientation 1135 . The thread 1131 reverses direction at a reversal point 1133 which is about 5-45% along the length of the axis of the cuvette release member 30 , the axis running from the top end 131 of the cuvette release member 30 to the bottom end 231 of the cuvette release member. Preferably the thread 1131 reverses direction at a reversal point 1133 which is about 10-35%, about 15-30%, or more preferably at a point about 25% along the length of the axis of the cuvette release member 30 . For example, in one embodiment, the first cuvette release member 30 has a left hand oriented thread 1131 originating from or near the top portion 131 of the first cuvette release member 30 . In one embodiment, after making approximately a full turn (360 degrees) around the cuvette release member 30 , the left hand orientation 1131 of the thread is reversed to a right hand orientation 1135 at a point 1133 .
In a further embodiment, the second cuvette release member 32 has a thread 1132 of a first orientation at the top end 132 . The orientation of the thread 1132 reverses direction on the cuvette release member 32 to become a thread of a second orientation 1136 . The thread reverses direction at a reversal point 1134 which is about 5-45% along the length of the axis of the cuvette release member 32 , the axis running from the top end 132 of the cuvette release member 32 to the bottom end 232 of the cuvette release member. Preferably the thread 1132 reverses direction at a reversal point 1134 which is about 10-35%, about 15-30%, or more preferably at a point about 25% along the length of the axis of the cuvette release member 32 . For example, in one embodiment, the first cuvette release member 32 has a right hand oriented thread 1132 originating from or near the top portion 132 of the first cuvette release member 32 . In one embodiment, after making approximately a full turn (360 degrees) around the cuvette release member 32 , the right hand orientation of the thread 1132 is reversed to a left hand orientation 1136 at a reversal point 1134 .
With continued reference to FIGS. 6A-C and FIGS. 7A-C , in a further embodiment, the pitch of the helical thread 31 of the first cuvette release member 30 is the same as the pitch of the helical thread 33 of the second cuvette release member 32 . In a further embodiment, the pitch of the helical threads 31 , 33 on the first and second cuvette release members 30 , 32 is between about 6° and 10°, and in a further embodiment, the pitch is about 7°.
With reference to FIGS. 6A-C , in a further embodiment, the first cuvette release member 30 has a first portion of a helical thread in a first orientation 1131 having a first pitch and a second portion of the helical thread in a second orientation 1135 having a second pitch. The first portion of the helical thread 1131 , after making approximately a full turn (360 degrees) around the cuvette release member 30 , reverses orientation at a reversal point 1133 and a second portion of the helical thread 1135 having a second pitch continues turning around the cuvette release member from the reversal point 1133 . For example, the second portion 1135 makes one, two, three, or four full turns around the cuvette release member 30 . In one embodiment, the first pitch is between about 9.2° and 9.6° and the second pitch is between about 6.9° and 7.3°. In a further embodiment, the first pitch is about 9.4° and the second pitch is about 7.1°.
With reference to FIGS. 7A-C , in another embodiment, the second cuvette release member 32 has a first portion of a helical thread in a first orientation 1132 having a first pitch and a second portion of the helical thread in a second orientation 1136 having a second pitch. The first portion of the helical thread 1132 , after making approximately a full turn (360 degrees) around the cuvette release member 30 , reverses orientation at a reversal point 1134 and a second portion of the helical thread 1136 having a second pitch continues turning around the cuvette release member from the reversal point 1134 . For example, the second portion 1136 makes one, two, three, or four turns around the cuvette release member 30 . In one embodiment, the first pitch is between about 9.2° and 9.6° and the second pitch is between about 6.9° and 7.3°. In a further embodiment, the first pitch is about 9.4° and the second pitch is about 7.1°.
As used herein, the pitch of a helical thread 31 , 33 means the angle formed between the helical thread and a plane that intersects the helical thread 31 , 33 , the plane being perpendicular to the longitudinal axis of the cuvette release member 30 , 32 .
As shown in FIGS. 3A-3B , the first cuvette release member 30 and the second cuvette release member 32 rotate in an axis parallel to the axis of the cuvette stack 120 , according to one embodiment of the invention. In another embodiment, first cuvette release member 30 and the second cuvette release member 32 rotate around an axis perpendicular to the cuvette stack 120 .
Referring again to FIGS. 3A-B , cuvette release members 30 , 32 are each connected to a rotating member 42 . For example, in one embodiment, an exemplary rotating member is a gear wheel 42 as shown in FIGS. 3A-B . The gear wheel 42 is operatively connected to a motor (not shown), for example, an oscillating motor, capable of effecting the rotation of the gear wheels 42 , and thereby the rotation of the cuvette release member 30 . For example, in one embodiment, the first cuvette release member 30 is connected to a first rotating member 42 by axle 46 and the second cuvette release member 32 is connected to a second rotating member 44 by axle 48 .
The first rotating member 42 and the second rotating member 44 , in one embodiment, are each capable of rotating in both the clockwise or counter-clockwise direction to effect the rotation of the first cuvette release member 30 and the second cuvette release member 32 , respectively. For example, in one embodiment, the first cuvette release member 30 and the second cuvette release member 32 each rotate in the same direction, for example, clockwise, or alternatively, counter-clockwise.
In yet another embodiment, the first cuvette release member 30 rotates in a direction opposite from the second cuvette release member 32 . For example, the first cuvette release member 30 rotates in a clockwise direction while the second cuvette release member 32 rotates in a counter-clockwise direction. Alternately, in another embodiment, the first cuvette release member 30 rotates in a counter-clockwise direction while the second cuvette release member 32 rotates in a clockwise direction.
In an even further embodiment, the first cuvette release member 30 rotates in a first direction, e.g., clockwise, for a first period of time, while the second cuvette release member 32 rotates in a second direction, e.g., counter-clockwise, for a first period of time, after which the first cuvette release member 30 reverses to rotate in a second direction for a second period of time and the second cuvette release member 32 simultaneously reverses to rotate in a first direction for a second period of time.
FIGS. 8A-C are perspective views of cuvette release members for releasing a cuvette from a stack of cuvettes in the cuvette dispense chute. The exemplary first cuvette release member 30 and second cuvette release member 32 are threaded and rotate to engage the cuvette 12 to remove it from the stack 120 . Once the cuvette 12 has traveled fully through the cuvette release member 30 , 32 , the cuvette 12 is dispensed at the cuvette transfer position 36 according to an illustrative embodiment of the invention. As discussed above, once the cuvette shutter 22 opens, a stack of cuvettes 12 moves downward until the bottom cuvette 12 in the cuvette stack 120 comes to rest on the first cuvette release member 30 and the second cuvette release member 32 , according to one embodiment of the invention. The cuvette dispense sensor 58 detects the presence of the cuvettes 12 , e.g., the bottom cuvette 12 , and the first cuvette release member 30 and the second cuvette release member 32 begin to rotate to release the cuvette 12 from the stack 120 .
As shown in FIG. 8A , according to one embodiment of the method of the invention, the first cuvette release member 30 and the second cuvette release member 32 , described above with respect to FIGS. 6A-C and FIGS. 7A-C , rotate to engage the lip 50 of the cuvette 12 to effect the cuvette's 12 separation from the stack of cuvettes 120 . Alternately, in one embodiment, the first cuvette release member 30 rotates while the second cuvette release member 32 is stationary; when the first cuvette release member 30 stops rotating, the second cuvette release member 32 rotates. In yet another embodiment, the first cuvette release member 30 rotates simultaneously with the second cuvette release member 32 .
In a further embodiment, the first cuvette release member 30 rotates in a first direction, e.g., clockwise, while the second cuvette release member rotates in a second direction, e.g., counter-clockwise, in order to engage the lip 50 of the cuvette 12 and to separate it from the stack 120 . In yet another embodiment, the first cuvette release member 30 rotates in a first direction, e.g., clockwise, both to engage the lip 50 of the cuvette 12 and to release the cuvette 12 into the cuvette transfer position 36 , while the second cuvette release member 32 rotates in a second direction, e.g., counter-clockwise, both to engage the lip 50 of the cuvette 12 and to release the cuvette 12 into the cuvette transfer position 36 . In a further embodiment, the first cuvette release member 30 rotates in a first direction e.g., clockwise, while the second cuvette release member rotates in a second direction, e.g., counter-clockwise, in order to engage the lip 50 of the cuvette 12 and to separate it from the stack 120 ; the first cuvette release member 30 and the second cuvette release member 32 then each reverse their direction of rotation in order to release the cuvette 12 into the cuvette transfer position 36 .
With continued reference to FIG. 8 A., according to one embodiment of the invention, the first cuvette release member 30 has a helical thread 31 having a first portion of a first orientation (e.g., left-handed) 1131 beginning at the top portion 131 of the first cuvette release member 30 . The second cuvette release member 32 also has a helical thread 33 having a first portion of a second orientation (e.g., right handed) 1132 beginning at the top portion 132 of the second cuvette release member 32 . The first cuvette release member 30 rotates in a first direction (e.g., clockwise) and the left cuvette release member 32 rotates in a second direction (e.g., counter-clockwise) to engage the cuvette 12 and to release it from the stack 120 .
According to one embodiment, once the cuvette 12 is released from the stack 120 , the rotation of the first cuvette release member 30 and the second cuvette release member 32 is reversed. In one embodiment, the rotation of the first cuvette release member 30 and the second cuvette release member 32 is reversed when the cuvette 12 engages a reversal point 1133 between the first-orientation (e.g., left handed) helical thread portion 1131 and the second-orientation thread (e.g., right handed) portion 1135 on the first cuvette release member 30 , and the reversal point 1134 between the second-orientation (e.g., right handed) thread portion 132 and the first orientation (e.g., left handed) thread portion 1136 on the second cuvette release member 32 . At that point, for example, the first cuvette release member 30 changes direction to rotate in a second direction (e.g., counter-clockwise) and the second cuvette release member 32 changes direction to rotate in a first direction (e.g., clockwise). The change in rotation prevents a second cuvette 12 from being dispensed prior to the first cuvette 12 being delivered to the cuvette transfer position 36 .
As shown in FIG. 8B , the helical threads 31 of the first cuvette release member 30 and the helical threads 33 of the second cuvette release member 32 continue to engage the lip 50 of the cuvette 12 after the cuvette 12 releases from the stack of cuvettes 120 and while the cuvette 12 moves in a downward direction via the cuvette release members 30 , 32 toward the cuvette transfer position 36 . In one embodiment, the first cuvette release member 30 and the second cuvette release member 32 engage the lips 50 of the side walls 56 of the cuvette 12 , while in another embodiment, the first cuvette release member 30 and the second cuvette release member 32 engage the lips 50 of the end walls 58 of the cuvette 12 .
With continued reference to FIG. 8A , according to a further embodiment, the force exerted on the cuvette 12 by the helical threads 31 of the first cuvette release member 30 and the helical threads 33 of the second cuvette release member 32 causes the projections 52 on cuvette 12 to disengage from the stack of cuvettes 120 . For example, in one embodiment, the downward force exerted by the rotating first orientation (e.g., left hand) helical thread portion 1131 of the first cuvette release member 30 and the second orientation (e.g., right hand) helical thread portion 1132 of the second cuvette release member 32 causes the recesses 54 on the walls of the cuvette 12 to disengage from the projections 52 on the adjacent cuvette 12 in the stack 120 .
With reference to both FIGS. 8A and 8B , as the first rotating member 30 and the second rotating member 32 continue to rotate, the cuvette 12 moves along the helical thread 31 of the first rotating member 30 and the helical thread 33 of the second rotating member 32 in a downward direction, as indicated by the directional arrow in FIG. 8A . For example, in one embodiment, once the cuvette 12 is released from the stack 120 , the first cuvette release member 30 and the second cuvette release member 32 reverse rotational direction to further facilitate the cuvette traveling in a downward direction.
With continued reference to FIGS. 8A and 8B , in one embodiment, the first cuvette release member 30 has a helical thread 31 having a top portion 1131 and a bottom portion 1135 . The top portion 1131 has a first orientation (e.g., left hand) and the bottom portion 1135 has a second orientation (e.g., right hand). The first orientation reverses to the second orientation at reversal point 1133 . The second cuvette release member 32 also has a helical thread 33 having a top portion 1132 and a bottom portion 1136 . The top portion 1132 has a first orientation (e.g., right hand) and the bottom portion 1136 has a second orientation (e.g., left hand). The first orientation reverses to the second orientation at reversal point 1134 . When the rotational direction of the first cuvette release member 30 and the second cuvette release member 32 reverses, the cuvette 12 , in one embodiment, then travels along the bottom portion 1135 of the first cuvette release member 30 helical thread 31 and the bottom portion 1136 of the second cuvette release member 32 helical thread 33 in a downward direction toward the cuvette transfer position 36 .
FIG. 5C is a cross-sectional view of the cuvette dispenser shown in FIG. 5B , while FIG. 8C shows a perspective view of the cuvette dispenser. A cuvette from the stack of cuvettes has been released from the exemplary cuvette release members to the cuvette transfer position, according to one illustrative embodiment of the invention. According to one embodiment of the invention, the cuvette transfer position 36 is located directly below and between the first cuvette release member 30 and the second cuvette release member 32 . As shown in FIG. 3A , the cuvette release members 30 , 32 rest on a platform 38 . In one embodiment, the cuvette transfer position 36 includes a first projection 39 and a second projection 40 from the platform 38 . A space 37 separates the first projection 39 from the second projection 40 . For example, the space 37 receives the body of the cuvette 12 , while the lips 50 of the cuvette 12 rest on the first projection 39 and the second projection 40 according to one embodiment of the invention.
Referring again to FIG. 4 , once the cuvette 12 is positioned in the cuvette transfer position 36 , a cuvette transfer sensor 48 detects the presence of the cuvette 12 , and stops the first cuvette release member 30 and the second cuvette release member 32 from rotating. This prevents another cuvette 12 from occupying the cuvette transfer position 36 , until the cuvette 12 currently occupying the cuvette transfer position 36 is removed. In a further embodiment, once a cuvette 12 is present at the cuvette transfer position 36 , the cuvette transfer sensor 48 signals to a robotic arm (not shown), for example, to remove the cuvette 12 from the transfer position 36 and to place it on the cuvette transport carousel 1 .
According to one embodiment of the invention, once the cuvette 12 is removed from the cuvette transfer position 36 , the cuvette transfer sensor 48 detects the absence of a cuvette 12 , signaling the first cuvette release member 30 and the second cuvette release member 32 to rotate and provide another cuvette 12 to the cuvette transfer position 36 . Once the stack of cuvettes 120 in the cuvette dispense chute 20 has been dispensed, the cuvette dispense sensor 56 detects the absence of cuvettes 12 , causing the cuvette loading module 14 to rotate until the cuvette stack sensor 400 detects a stack of cuvettes 120 , at which point the process of dispensing cuvettes 12 proceeds as previously discussed.
In another aspect, the invention is a method for automatically loading a plurality of cuvettes 12 onto a conveyor, such as a rotating cuvette carousel 1 , in an automated clinical sample analyzer. For example, in one embodiment, an operator first loads stacks of cuvettes 120 into the slots 16 of the cuvette loading module 14 . The module 14 rotates until the cuvette stack sensor 400 detects the presence of a stack of cuvettes 120 over the cuvette shutter 22 .
Once a stack of cuvettes 120 is positioned over the cuvette shutter 22 , the cuvette shutter 22 opens and the stack of cuvettes 120 falls into the cuvette chute 20 , with the bottom cuvette 12 of the stack 120 resting on the first cuvette releasing member 30 and the second cuvette releasing member 32 . Cuvette dispense sensor 56 detects the presence of the cuvette stack 120 and causes the first cuvette release member 30 and the second cuvette release member 32 to rotate to engage and release a cuvette 12 from the stack 120 , and to deliver the cuvette to the cuvette transfer position 36 .
In one embodiment, the first cuvette release member 30 rotates in a first direction, e.g., clockwise, while the second cuvette release member 32 rotates in a second direction, e.g., counter-clockwise to engage the cuvette 12 ; the first cuvette release member 30 then switches direction to rotate in a second direction while the second cuvette release member 32 switches direction to rotate in a first direction to release cuvette 12 to the cuvette transfer position 36 . In another embodiment, the first cuvette release member 30 rotates in a first direction, e.g., clockwise, both to engage the cuvette 12 and to release the cuvette 12 at the cuvette transfer position 36 , while the second cuvette release member 32 rotates in a second direction, e.g., counter-clockwise, both to engage the cuvette 12 and to release cuvette 12 at the cuvette transfer position 36 .
Once the cuvette 12 rests in the cuvette transfer position 36 , cuvette transfer sensor 58 signals to a robotic arm (not shown), for example, to remove the cuvette 12 from the transfer position 36 and to place it in a slot 2 of the cuvette transport carousel 1 .
Variations, modifications, and other implementations of what is described herein will occur to those of ordinary skill in the art without departing from the spirit and the scope of the invention as claimed. Accordingly, the invention is not to be defined by the preceding illustrative description but instead by the spirit and scope of the following claims. | An apparatus and methods for dispensing sample holders for use in an automated sample analyzer is disclosed herein. The apparatus for dispensing sample holders includes a rotating carousel for housing stack of sample holders. Stacks of sample holders from the rotating carousel are fed into a chute where sample holders contact a set of rotating members having helical threads thereon. The helically threaded rotating members engage the sample containers and separate each sample holder from the remaining sample holders in the stack by rotation of the helically threaded rotating members. The sample holder can then be transferred for use in an automated sample analyzer. | 1 |
FIELD OF THE INVENTION
This invention relates to couplings which include filters to remove contaminants. The preferred embodiment of the invention is for use in connection with gases. However, other embodiments could accommodate liquids.
BACKGROUND OF THE INVENTION
It has become necessary in certain areas of the United States to switch from gasoline powered vehicles to either propane or natural gas powered vehicles. For instance, some portions of southern California are so heavily plagued by smog that alternative fuels are being strongly pursued to reduce the air pollution.
U.S. Pat. No. 5,323,812 to Wilcox issued Jun. 28, 1994 is directed toward a pressure locked coupling for use with propane and natural gas. The coupling of the '812 patent securely couples the source of the gas to the vehicle. The present invention adds filters to the coupler and the nipple. The filters can be in both the coupler and the nipple, the coupler only or the nipple only.
OBJECTS OF THE PRESENT INVENTION
It is an object of the present invention to provide a coupling for use with gas delivery systems which removes contaminants from the gas stream. The present invention insures the delivery and transfer of clean gas.
It is a further object of the present invention to provide a coupling having filters in the coupler and the nipple, the coupler only or the nipple only.
It is a further object of the present invention to provide a coupling having filters which are easily removable and easily interchangeable. This is accomplished by positioning the filters at the inlets of the coupler and the nipple. In the coupler the filter is maintained in place by means of a first shoulder which resides on the first wall means of the coupler and a snap ring. In the nipple the filter is maintained in place by a second shoulder on the second wall means of the nipple body and an O-ring.
It is a further object of the present invention to provide a coupling having a high contaminant capacity filter therein.
It is a further object of the present invention to provide a coupler filter and a nipple filter oriented such that the direction of the flow of the gas in said coupler and said nipple urges said filters to engage respective shoulders on first and second wall means within the coupler and the nipple respectively.
It is a further object of the present invention to provide a coupler and a nipple each having a 40 to 250 micron high strength stainless steel filter located therein. The 40 to 250 micron filters have pore sizes in the range of 40 to 250 microns.
BRIEF DESCRIPTION OF THE DRAWINGS
The structure, operation and advantage of the preferred embodiment of the invention will become further apparent upon consideration of the following description taken in conjunction with the accompanying drawings, wherein:
FIG. 1 is a half-sectional view of the coupler disengaged. FIG. 1 illustrates the coupler filter residing in the first end portion of the coupler. FIG. 1 also illustrates an arrangement of the pressure-locking structure of U.S. Pat. No. 5,323,812 to Wilcox issued Jun. 28, 1994. FIG. 1 shows the coupler filter secured by a first shoulder on the first wall means of the coupler and a snap ring.
FIG. 2 is half-sectional view of the nipple disengaged.
FIG. 3 is simply an enlarged half-sectional view of the portion of FIG. 1 illustrating in detail the portion of the coupler which shows the coupler filter best. FIG. 3 illustrates the coupler filter secured in place by a first shoulder on the first wall means of the coupler and a snap ring.
FIG. 4 is simply an enlarged half-sectional view of the nipple member showing the portion of the nipple member which has the nipple filter located therein.
DETAILED DESCRIPTION OF THE INVENTION
The coupling with filters includes a coupler 15 and a nipple 66. The coupler 15 and nipple 66 are sometimes referred to herein as coupler halfs. The coupler 15 is described first immediately below followed by the description of the nipple. The coupler includes an adaptor 1, a coupler valve 12, a retainer 3, a sliding sleeve 4, a body 2, a locking sleeve 5, a cylindrical block 5', a bumper 8, first locking balls 6, second locking balls 7, a first wall means 101, a first shoulder 103 located on the first wall means 101, a snap ring 104, a first recess 105, and a coupler filter 106. The coupler 15 has a first end portion 16 and a second end portion 17.
Body 2 has first 35 and second 36 ball housings located therein. First ball housings 35 are tapered conical bores. Second ball housings 36 are cylindrical bores. Additionally there are a plurality of first 6 and second 7 balls residing in the first 35 and second 36 housings of the body 2. First and second balls 6 and 7 are sometimes referred to hereinafter as first and second ball detents. See, FIG. 1. The first end portion 16 of the coupler is sometimes referred to herein as the first inlet. Body 2 includes a third spring shoulder 22.
First balls 6 or first ball detents 6 have a first portion 95 and a second portion 96. Second balls 7 or second ball detents 7 have a first portion 98 and a second portion 99. FIG. 1 illustrates the coupler disengaged. Balls 6 are restrained by the second ball housings 35 due to their tapered conical shape. Ball housings 35 prevent balls 6 from becoming free of the coupler. Sliding sleeve 4 restrains balls 7 during disengagement of the coupler and the nipple.
The sliding sleeve 4 is generally cylindrically shaped and has a face 20 which engages the nipple during coupling. The sliding sleeve includes a second spring shoulder 28. Retainer 3 has a first shoulder 23, a face 26 and a second shoulder 24. Coupler valve 12 has first 42 and second 41 end portions, respectively, ports 39, a valve seat 72, and a shoulder 43. Thread means 14 affix the body to the adaptor 1.
Locking sleeve 5 is generally cylindrically shaped. Locking sleeve 5 includes a fourth spring shoulder 32. The locking sleeve 5 is affixed to bumper 8 by means of circumferential ridges 51 residing on the exterior of said locking sleeve 5. Bumper 8 facilitates easy uncoupling of the coupler and the nipple. Circumferential block 5'supports locking sleeve 5 and bumper 8. Block 5'is also affixed to bumper 8 by means of circumferential ridges 52.
The adaptor 1 has a first spring shoulder 45 located thereon. A sliding sleeve spring 18 is disposed between the first shoulder 23 of the retainer and the second spring shoulder 28 of the sliding sleeve. A locking sleeve spring 38 is disposed between the third spring shoulder 22 of the body 2 and the fourth spring shoulder 32 of the locking sleeve 5. A coupler valve spring 13 is disposed between the first spring shoulder 45 of the adaptor and the shoulder 43 of the coupler valve 12.
FIG. 1 illustrates the coupler not engaged with the nipple 66. When the coupling is disengaged, coupler valve 12 seats against retainer 3 to prevent flow therethrough. Specifically, valve seat 72 mates with a corresponding surface on the retainer 3 and O-ring seal 47 seals port 39 to prohibit flow. Coupler valve spring 13 urges coupler valve 12 toward the second end portion 17 of the coupler to the closed position. The movement of the coupler valve 12 toward the second end portion of the coupler is limited by retainer 3.
The pressure source (not shown) is connected to adaptor 1. The pressure source resides upstream of the coupler. Passageway 40 is therefore under the source pressure, if any. FIG. 1 indicates the condition of the coupling with no or very little pressure applied to the coupler.
When uncoupled, sliding sleeve spring 18 urges the sliding sleeve toward the second end portion 17 of the coupler. The sliding sleeve engages and supports second balls 7. While uncoupled, first balls 6 have room to move freely in tapered ball housing 35 to the extent permitted by locking sleeve 5.
The first wall means 101 of the coupler defines a first fluid passage through the coupler. The first wall means includes a first shoulder 103 and a first recess 105. See FIG. 3. A coupler filter 106 resides within the first fluid passageway 40 as shown in FIG. 1. The coupler filter 106 includes a first lip 109. The first lip 109 of the coupler filter engages the first shoulder 103 of the first wall means 101. A snap ring 104 is employed to retain the coupler filter in position. The snap ring 104 resides in the first recess 105. The coupler filter of the preferred embodiment is made from high strength stainless steel.
The coupler filter of the preferred embodiment employs 17-4 ph (precipitating hardening) or 15-5 ph high strength stainless steel. The coupler filter is typically in the 40 to 250 micron range. The 40 to 250 micron filters have pore sizes in the range of 40 to 250 microns. This means that a 40 micron filter will allow particles smaller than 40 microns to pass therethrough but will not permit particles 40 microns or larger to pass therethrough. It will be noted from FIG. 1 that the coupler filter is larger than the nipple filter 120 which will be discussed hereinbelow. The coupler filter has a high contaminant capacity.
It will be observed by those skilled in the art that different size filters outside of the 40 to 250 micron range are usable in the coupling of the present invention. The 40 to 250 micron filters have pore sizes in the range of 40 to 250 microns.It will also be observed by those skilled in the art that the coupler filter could assume various dimensions and shapes and still function. The coupler filter of the preferred embodiment of the present invention is generally conically shaped. The coupler filter has an interior 110 and an exterior 111. The coupler filter of the preferred embodiment is oriented such that the flow direction (FIG. 1) is in the direction from first end portion 16 to the second end portion 17 of the coupler.
The flow of gas in this direction acts in furtherance of the engagement of the first lip 109 of the coupler filter 106 against the first shoulder 103 of the coupler formed on the first wall means 101 of the coupler. Positioning of the coupler filter 106 at the inlet to the coupler enables any contaminants which may be in the gas stream to be filtered out of the gas stream prior to entering the coupler valve and its seating surfaces. FIG. 3 is an enlarged portion of the first end portion 16 of the coupler. It is this first end portion which houses the coupler filter. It will be observed that the coupler filter is very easily removed and replaced when dirty. The snap ring 104 holds the first lip 109 of the coupler filter 106 in engagement with the first shoulder 103 of the first wall means of the coupler. The snap ring 104 resides in recess 105 in the first wall means 101 of the coupler. It is therefore a simple matter to remove the snap ring 104 and retract the coupler filter for replacement or cleaning. The coupler filter is removed by hand or with a tool adapted to engage the interior of the nipple filter. The snap ring 104 in the preferred embodiment is constructed of metal. However, other materials such as plastic could be used for the snap ring. The description of the nipple follows.
The nipple 66 includes a nipple body 9, a check valve 11, a valve seat 78, a check valve guide 10, a check valve spring 62, a check valve guide clip 57, a second wall means 56, a second shoulder 123 located on the second wall means 56, an O-ring 126, a second recess 125 and a nipple filter 120. The nipple body 9 is generally cylindrically shaped and is adapted for insertion into the coupler 15. The nipple body has first 53 and second 54 end portions. The second end portion 54 is sometimes referred to herein as the second inlet. The second end portion of the nipple includes a face 55, conjugate to face 20 of the sliding sleeve 4.
Nipple body 9 includes an exterior surface 67. The exterior surface 67 of the nipple 9 has a circumferential locking notch 59. Circumferential locking notch 59 includes first 60, second 61 and third 80 walls. The nipple body 9 further includes second wall means 56 on the interior thereof defining a second fluid passageway 40'.
Check valve 11 includes a face 81 and an annular recess 64. Check valve spring 62 is disposed between check valve guide 10 and check valve 11 and urges check valve 11 into a closed position where it is in engagement with valve seat 78. This occurs when the nipple is not engaged with the coupler or while engaged when there is insufficient pressure on the face 81 of the check valve. Nipple member 9 has second wall means 56 therethrough. O-ring seal 63 resides in annular recess 64. O-ring seal 63 seals against valve seat 78 insuring that no flow of gas or fluid will leak to the environment from a receiver of the gas when the nipple is not engaged with the coupler. The receiver (not shown) resides downstream of the nipple. The O-ring seals employed in the present invention are preferably elastomeric seals. However, those skilled in the art may substitute other seals without deviating from the intent of the subject invention.
The nipple includes a nipple filter 120. The nipple filter has a first end portion 121 and a second end portion 122. Interior second wall means 56 of nipple 9 includes a second shoulder 123 on said second wall means 56 and a second recess 125 in said second wall means 56. The nipple filter additionally has a second lip 124.
The nipple filter 120 is generally conically shaped. However, it will be understood by those skilled in the art that the nipple filter 120 need not necessarily be conically shaped but could assume any one of a number of possible shapes. The nipple filter 120 is manufactured from the same materials as the coupler filter 106. The nipple further includes an O-ring for securing the nipple filter in place. It will be observed (FIGS. 2 and 4) that recess 125 is larger than O-ring 126 providing some space for movement of said O-ring 126. When the coupler and nipple are engaged the second end portion 41 of the coupler valve 12 urges O-ring 126 against nipple filter 120. O-ring 126 serves a dual purpose as a seal for the coupling when engaged and as a means for securing the nipple filter in place.
FIG. 4 is an enlarged portion of the second end portion 54 of the nipple. The second end portion 122 of the nipple filter does not engage the face 81 of the check valve. There is a gap 83 between the face 81 of the check valve and the nipple filter 120. The second lip 124 of the nipple filter engages the second shoulder 123 of the second wall means 56 of the nipple body. The O-ring 126 is used to secure the nipple filter 120 in place. The O-ring is an elastomeric O-ring in the preferred embodiment.
The nipple filter is easily removed. The O-ring 126 is easily extracted from the second end portion 54 of the nipple 9. The nipple filter 120 is then simply removed by hand or with a tool adapted to engage the interior of the nipple filter. The nipple filter is oriented such that the flow is from the second end portion to the first end portion of the nipple, or put another way, from the left to the right when viewing FIG. 2. The nipple filter has an interior 127 and an exterior 128.
It should be understood that the present invention is such that it may be practiced by using or employing a filter in both the coupler and the nipple, the coupler only or the nipple only. The invention will work satisfactorily using any of the aforesaid combinations. It should also be understood that many different materials may be used for the coupler and nipple filters. It is further understood that many different configurations of the coupler and the nipple filter may be used.
It will be thus seen that a coupling for accomplishing the objectives of the invention has been provided. The objectives are to permit the clean transportation of a fluid medium such as a gas. This coupling includes a coupler female part and a nipple male part movable between coupled and uncoupled positions. The first and second walls define fluid passages through the coupler and the nipple. The coupler has first ball detents 6 which act between the coupler and the circumferential notch 59 of the nipple to hold the same together when the parts are in a coupled position.
When the adaptor 1 is connected to a pressure source a force is exerted on the coupler filter tending to secure the first lip of the coupler filter against the first shoulder 103 of the coupler. Additionally this pressure also exerts a force on the nipple filter securing the nipple filter against the second shoulder 123 of the nipple body formed on the wall means 56 of the nipple.
The retainer 3 is provided as part of the coupler and it is movable back and forth between locked and unlocked positions. The retainer functions to urge the ball type detents to firmly lock in position to prevent separation of the coupler and nipple. As seen, the so-called first ball detents 6 are carried in the openings 35 of the coupler and the circumferential locking notch 59 is provided in the nipple which receives one portion 95 of the first ball detents 6. The locking sleeve 5 is movable axially and surrounds the second portions 96 of the first ball detents.
The sliding sleeve 4 is axially movable and is positioned between the retainer and the nipple in the coupled condition of the coupling (not shown). The second ball detents 7 are carried in the coupler and have first 98 and second portions 99.
The sliding sleeve 4 in a first position engages the first portion 98 of the second ball detents to hold the second portions 99 of the second ball detents in engagement with the locking sleeve 5 to hold the locking sleeve 5 in a first position. See, FIG. 1 illustrating the coupler not engaged with the nipple.
The sliding sleeve in its second position (coupler and nipple engaged) permits radial inward movement of the second balls 7 which in turn permits movement of the locking sleeve to its second position (not shown). Movement of the retainer to the locked position (not shown) causes the retainer to engage the sliding sleeve which exerts a locking force on the first ball detents to hold them into engagement with the locking sleeve 5' and the circumferential notch 59 of the nipple to hold the coupler and nipple firmly and reliably together.
The coupler valve 12 and the check valve 11 are provided respectively in the coupler and the nipple and each are movable between an open and a closed position. The coupler valve spring 13 and check valve spring 62 are provided which normally urge the coupler valve 12 and the check valve 11 to the closed positions. See FIGS. 1 and 2. The coupler valve 12 in the coupler is opened by engagement with the nipple when the parts are coupled. The fluid pressure in the coupling when engaged causes the check valve member 11 in the nipple to move to the open position (not shown). The protective bumper 8 surrounds the coupler and particularly the locking sleeve 5 and the supporting block 5' with which it is connected and with which it moves axially. The bumper member 8 is preferably made of a synthetic resinous material. The bumper protects the end of the coupler.
While the invention has been described in combination with embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art in light of the foregoing description. Accordingly, it is intended to embrace all of such alternatives, modifications and variations that fall within the spirit and the scope of the appended claims. | A coupling is provided having filters in the coupler and/or the nipple members. The coupler filter resides in the inlet to the coupler and the nipple filter resides in the inlet to the nipple member. The coupler and the nipple filters are easily replace due to their locations and the means employment to secure them in place. The coupler and the nipple filters are strength stainless steel filters having pores in the range of to 250 microns. | 1 |
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of U.S. Ser. No. 384,790, filed June 4, 1982, now abandoned.
This invention relates to solid soaps of the class referred to as milled soaps.
PRIOR ART
In FERRARA et al; U.S. Pat. Nos. 3,814,698 and 3,941,712, there are described novel techniques for producing milled soaps containing high levels of emollients and bath oil mixtures. The emollients and bath oils consist of mixtures containing at least one water immiscible product such as mineral oil or a water immiscible bath oil ester such as isopropyl myristate. The novel processes described therein differ from the usual methods of milled soap manufacture in that the bath oils and emollients, either singly or in combination are added and mixed into the hot liquid saponification mixture before it is cooled, solidified and dried rather than by milling these in. After drying, the soap chips or flakes are placed in an amalgamator where the soaps are mixed with suitable pigments, preservatives, and fragrances prior to milling and plodding. They are then extruded in the form of rods, bars or other shapes. A cutting machine reduces the extruded soap to pieces of lengths and weights to accommodate the dies used to mold and imprint the bars.
While the novel technology of the FERRARA et al patents make possible a wide latitude in the amounts and types of bath oils and emollients which can be incorporated in the soaps, these soaps must be pliable yet firm enough to withstand the mechanical handling as the soap passes through the succession of steps from milling and plodding, on through the final wrapping. If soap bars are too sticky or too soft, they must be handled at lower rates of processing with attendant disadvantage. Generally difficultly processable soaps can be run at acceptable speeds by a number of techniques well-known to those versed in the art.
Thus, incidence of softness or stickiness may be overcome by resorting to lubricants like brine solutions, water solutions of sodium lactate, glycerine, alcohols like ethanol and isopropanol. These lubricants or mould release agents are applied in various ways to the machinery parts coming in contact with the soap. The use of chilled dies, with the chilling produced by refrigerants passing through the internal cavity of a die is another way of offsetting soap stickiness. Refrigeration stiffens the soap surface areas by the rapid formation of a crystal lattice at the chilled surfaces. Non-stick materials, such as polytetrafluoro ethylene, polytrifluorochloro ethylene, silicone polymers and the like, may be coated on the dies to achieve the release effects. These steps are well-known to those versed in the art. Additionally, manufacturers can improve the surface stiffness of soaps by adjusting the amounts of salt, more particularly sodium chloride, added to the soap while it is still in the hot liquid phase.
Manufacturers of soap can also manipulate, within limits, the process of soap drying. Thus by producing a soap with a moisture level of 5-6%, as opposed to the usual 9-12% level, the soaps display an extra degree of firmness. This is a costly solution to the problem especially if the drying capacity available is inadequate to remove this extra water.
When producing milled soaps having large quantities of water immiscible bath oils and/or emollients incorporated therein for the purpose of providing an exceptionally fine feel with residual emollient effects, it has been found that the soap so produced is particularly difficult to work on a given production line at expected speeds. Even the known production speed up techniques set forth above do not seem to be capable of achieving adequate production rates where at least about 10 weight percent emollients or the like have been incorporated with the hot liquid saponification mixture prior to cooling, etc.
Thus, it is a principal object of this invention to provide a milled soap containing at least about 10 weight percent water immiscible emollients which is easily processed on conventional soap making machinery at good production speeds and substantially no adverse effects.
In the United States Patents of FERRARA et al, referred to above, the production of soaps with high levels of bath oils and emollients is given particular emphasis. One reason for this emphasis is the growing awareness among users of skin care products that certain water insoluble or immiscible emollients and bath oils do in fact help maintain healthy skin conditions. Claims for such soaps include words like "nurtures", "nourishes", "revitalizes" and even "eliminates wrinkles". These soaps are also characterized as "moisturizing". Another objective of this invention is to produce a soap having the capacity to offer such beneficial aspects. Referring to the art of the FERRARA et al patents, the soap products of those inventions have in fact demonstrated benefits to users thereof.
It is however, an object to provide such a desirable emollient soap product which is easily processible and has a perceptibly superior feel relative to lower, or non-emollient soaps.
There are certain generally recognized criteria associated with the perception that a soap is beneficial. For example, when the soap is used, it should leave the skin with a feeling of softness and appear as contributing to a lubricated effect in a pleasing manner. It must also be gentle, mild, and demonstrate desirable cleansing effects. It should lather well. With these targets in mind, researchers have generated a wide range of products and promises. Among these new ideas one finds soaps containing proteins derived from hydrolyzed collagen, and products with cationic properties. Molecules of both categories are supposed to give rise to substantivity, another style of defining lubricity. These special effects are not easily measured even with the aid of modern analytical devices such as scanning electro micrographs.
The true measure of skin benefits to be derived from an emollient soap can only be established through continued use, over a period of time; a week, a month, and even longer in some cases. Soaps with oils and emollients made by the art of FERRARA et al give rise to a lower incidence of chapped hands during winter when cold and low humidity are generally experienced. The increase in substantivity may also be shown through a longer period of fragrance retention as opposed to the usual soaps. These attributes are subjective, interpreted by each subject user in his or her own way. To break through the challenge of perception, this invention has another objective; which is to make a product which is instantly perceived to be "different", that is different in a beneficial way.
BRIEF STATEMENT OF THE INVENTION
In accord with and fulfilling these objects, one significant aspect of this invention is to further enhance high emollient content milled soaps by incorporating therein at least one additive in sufficient quantity and form to increase the slipperiness of the soap bar in order to improve its processibility as well as its user perceived feel. This is accomplished by incorporating one or more slip agents into the milled soap, preferrably incorporating such agent into the saponification mixture along with the water immiscible emollients as set forth in the above cited FERRARA et al patents.
It is important to note that the slip agents are preadmixed with the bath oil emollient before incorporating such into the saponification mixture and that the slip agents and the emollient are substantially unreactive with respect to each other. One way of determining this unreactivity is to mix the bath oil and the slip agent together, preferably at ambient temperature conditions, and observe that the viscosity of this mixture does not appreciably change, e.g., increase, with time. Particularly, the viscosity of this mixture does not substantially change over a period of at least about one hour.
One particular aspect of this invention is the bath oil-slip agent physical mixture itself which has advantageous and unexpected utility according to this invention in being able to incorporate slip agent ethylene oxide polymers into soap compositions without forming the disadvantageous stringers which existed when these polymers were incorporated without admixture with non-reactive bath oil. In a further preferred embodiment of this invention, the slip agent ethylene oxide polymers are preferably maintained in a substantially dry condition until admixture within the bath oil emollient. Thereafter contact with water, for example in the saponification bath, is permitted.
DETAILED DESCRIPTION OF THE INVENTION
Slip agents are known class of materials which may be water soluble or insoluble. Exemplary of such materials are poly alkylene oxides--e.g., ethylene oxide and/or propylene oxide homo and/or copolymers having molecular weights of about 100,000 to more than 5,000,000. Such materials have been used in cleansing compositions in the past since they are non-ionic surfactants and therefore capable of assisting in dirt solubilization and floatation. See for example, U.S. Pat. No. 3,248,333, O'Roark wherein Polyox WSR-205-an ethylene oxidepolyether having a molecular weight of about 600,000--was incorporated in a soap in a proportion of about 0.3125%. Note, however, that the composition of this patent is a synthetic detergent and not a soap and that this polyether was added to the composition in the amalgamator, not into the liquid saponification mixture as required by the instant invention for reasons which will become readily apparent from the examples and further discussion below.
Other known slip agents include vinyl polymers having carboxyl side groups which are sometimes known in the trade as Carbopol resins. Such slip agents and many other similarly equivalent materials are widely known and do not per se constitute this invention. Nor does the pure incorporation of slip agents in cleansing bars constitute this invention.
This invention does, however, constitute in part solid cleansing compositions, soaps or syndets, which have incorporated therein a high proportion of bath oil and/or emollient and a slip agent both having been incorporated into a hot liquid precursor of the solid product well prior to solidification, amalgamation milling, plodding and extruding. In the case of soaps, this addition is to the hot, liquid saponification mixture. Thus, to reiterate, there are at least two aspects of this invention: the cleansing product preferably soap containing both high proportions of water immiscible bath oil/emollients and sufficient slip agent to give an immediate added slippery feel to the milled bar thereof; and the method of incorporating such slip agent into the solid milled cleansing product along with the bath oil/emollients and sufficient slip agent to give an immediate added slippery feel to the milled bar thereof; and the method of incorporating such slip agent into the solid milled cleansing product along with the bath oil/emollient into a hot liquid precursor of the solid product prior to amalgamation, etc.
The following examples will demonstrate certain facets of this invention.
EXAMPLE 1
In this Example 1, we took a quantity of soap chips made according to the FERRARA et al technology. These chips contained 10.7% moisture and approximately 12% added emollient, calculated on the soap solids, which had been added at the stage where it was still hot (88° C.-90° C.) and liquid. The emollient was a mixture of mineral oil, glyceryl monostearate, a coconut-oil fatty acid ester of sodium isethionate, and a coco-betaine. The soap chips were fed to an amalgamator, and there was added 0.40% ethylene oxide polyether of about 5,000,000 molecular weight, 0.20% titanium dioxide, and 1.25% fragrance. After thorough mixing, the soap was conventionally processed through a plodder equipped at the outlet with a fine screen. The fine "spaghetti" soap product was then milled 3 times until the flakes showed uniform dispersion of the TiO 2 pigment. At this point the flakes were transferred to a plodder-extruder unit, and formed in the bars which in cross section measured 1"×2". The soap bar was cut into 4" lengths and fed into a press.
On aging overnight at room temperature, the soap bars were tested for residual feel and slipperiness. It was then apparent that the bars thus made were not only slippery but were quite slimey. In fact the slime formation was sufficient to cause the development of soap strings or strands as the hands are parted; one hand holding the soap as the other hand was withdrawn. The soap stands were strong enough to be stretched as much as 2-3 inches before breaking apart. Even continued use of the bar, to simulate a "wearing-down" of the bar, did not materially effect a change in the development of the soap strands. The "strands" were not unlike one experiences with stretching candy like "taffy", or from trying to pull apart hot toasted marshmallows. While these effects were quite extraordinary, and certain to create the perception of a different soap, the end result was considered too messy to be of practical value.
An interesting observation derived from this experiment is that the bars showed practically no tendency to be sticky when being shaped in the dies. The bars were easily separated from the stainless steel dies, and were sufficiently firm to take a sharp imprint. This experiment produced evidence that although these bars processed well, the product was not acceptable because it was too slimey and produced soap residue stringers.
EXAMPLE 2
In this example, we took 12 bars of the product of EXAMPLE 1, and placed these on edge on a circular tray, inside a 5 quart stainless steel pressure cooker. The soap tray was supported about 11/2" from the bottom of the cooker. The bottom was covered with about 3/4" of water. The cooker was brought to steam pressure of 15 pounds per square inch and held at this pressure for 45 minutes. After this interval, the cooker was de-pressurized and opened. The 12 bars of soap had darkened slightly from exposure to the steam. They were soft enough to yield a gel-like layer where the soaps contacted the supporting tray. When the soaps were cooled to room temperature, these were separated from the tray with a spatula, and re-pressed to the same shape as when installed in the cooker.
When the pressure cooked soap bars constituting this example were tested, it was found that the soaps no longer developed the stringiness evidenced in Example 1. There was no slimey feel, only a nice silky or soft feel which is characteristic of substantivity. The result of this example suggests that these soap bars in whatever form caused by the steam, were now quite good items.
The soaps of Example 2 were not sticky and separating cleanly from the stainless surfaces of the die and die frame.
EXAMPLE 3
In this Example the same ingredients in the same proportions were used as in Example 1 except that the ethylene oxide polyether was "dissolved" in mineral oil and added to a hot saponification mixture of the soap being used.
The soaps of Example 3 show the suitability of pre-mixing the slip agent in a water immiscible oil like mineral oil prior to its being added to the hot liquid soap. The soap products produced as this Example 3 have a noticeable degree of slip-feel, lather extremely well, yield a soft, lubricated feel superior to that of soaps made without slip agent. The soaps are hard with a nice shiney finish. One of the surprising benefits from incorporating the slip agent by this technique is the absence of stickiness.
A large batch, made on a plant scale, approximately 2000 lbs. of soap solids, passed through chill rolls and soap dryer with comparative ease. Viscosity changed very little with the introduction of the slip agent in the manner described herein.
EXAMPLE 4
Having shown by way of Example 3, a method by which slip agent could be uniformly distributed within a soap by adding it as a dispersion in mineral oil, there remained the possibility of adding a portion of the slip agent by this route, and some by milling. This possibility might, if successful, provide a method of fine tuning the use of slip agents at higher levels. With this objective in mind, it was decided to include 0.27% of the same ethyleneoxide polyether in the same manner as Example 3, in the hot oil liquid soap, and when the soap chips produced by chilling and drying were obtained, to mill in an additional 0.13% of this same polyether following the milling steps of Example 1.
The product of this Example proved to be slimey and stringy very similar to the product produced in Example 1. Thus it can be concluded that not only is the incorporation of slip agent through milling not effective to produce the desired effects, but that it is actually detrimental and at least in these proportions overrode the beneficial effects produced by incorporating slip agent into the hot liquid precurser.
EXAMPLE 5
The literature on the slip agents exemplified above suggests that ethylene oxide polymers, being polyethers, hydrogen bond strongly with water. This fact accounts for their unusual thickening power which increase as the molecular weights increase to 5,000,000. This hydrogen bonding property also accounts for the formation of strong association complexes between this resin and highly polyunsaturated oils like a refined corn oil. With this thought in mind, we explored the addition of polyether to a hot liquid saponification mixture using corn oil as the dispersing agent.
When dispersions were made, adding the same polyether as in Example 1 to corn oil at a level of 0.80% based on soap solids, the mixtures showed a tendency to thicken with time. The thickening stopped after approximately 18 hours at which time, it was evident the polyether was in solution. This indicated the formation of a new association compound of corn oil with the polyethylene oxide.
When the polyether was introduced to the hot liquid saponification mixture using corn oil as a carrier, the end product, was not equal to Example 3 in lather and residual feel, even though the proportions of corn oil and polyether were maintained at the same level. On the other hand, the tendency for the bars to show any sticky quality was even less than Example 3.
Thus it appears that a different soap product has been created having superior slip but lower lather and residual oil feel.
The 5 examples set forth herein clearly establish the unique slip-agent effect of polyalkylene oxide polyether resins, when incorporated in a hot liquid soap with emollients and bath oils. The slippery characteristic is an easily perceived property. Less readily apparent, though of singular importance is the lubricating feel, and skin softening effect which is enhanced by incorporating such polyether slip agents. And, of particular significance to a producer of commercial soaps made in todays' modern, high speed processing equipment, the soaps so formulated have substantially eliminated any sticky aspects created with soaps having very high levels of oils and emollients.
In the manufacture of soaps using tallows, coconut oil and similar sources of fatty acids, the proportions of tallow and coconut oil (there are the principal sources of todays' commercial fatty acids) can be varied over a wide range, without compromising the benefits attributed to the soaps of this invention in their most preferred form.
While the maximum and minimum levels of slip agent may vary widely the investigations thus far suggest a minimum of about 0.20%; and a maximum tolerance of 1.0%. There is nothing to suggest usage of higher than 0.80% or 1.0% can deliver properties superior to those shown herein for 0.40%. However, this invention is in no way limited to such proportions, they being merely preferred.
U.S. Pat. Nos. 3,814,698 and 3,941,712 are hereby incorporated in their entirety by reference. | A hard, solid, milled cleaning material having improved slippery feel comprising a normally solid cleansing material and incorporated therein at least about 10% bath oil/emollient which was incorporated into a hot liquid precursor of said normally solid cleansing material and sufficient slip agent to improve the processability of said material and to improve the slippery feel thereof but insufficient to cause said material to be slimey, said proportion being about 0.2% to at least about 1% by weight. | 2 |
CROSS REFERENCE TO RELATED APPLICATION
This application is a National Stage of International Application No. PCT/CH2007/000446 filed Sep. 12, 2007, claiming priority based on Switzerland Patent Application No. 2006-001485, filed Sep. 18, 2006 and 2007-000212, filed Feb. 8, 2007, the contents of all of which are incorporated herein by reference in their entirety.
TECHNICAL FIELD
The present invention relates to a contrast agent for postmortem angiography in particular for the examination of animal or human corpses or components thereof, e.g. of extremities or organs. The contrast agent therein contains an essentially oil-based, non-polar contrast component, as it is used for X-ray examinations, wherein the contrast component has a contrast component viscosity in the range of 30-100 mPas. The invention further relates to angiographic methods in which such a contrast agent is used at least during certain time intervals.
BACKGROUND ART
Angiography is the visualization of blood vessels by use of X-rays. For this purpose, a contrast agent, i.e. a substance, which is barely permeable for X-rays, is injected into the blood vessel. The radiographic image then shows the vessel's inner cavity filled with contrast agent. The resulting image is called angiogram. In medical language, the long word angiography is often shortened by the word angio. Computer tomography can also be used for angiography.
Computer tomography, of which the short form is CT, is the computer-assisted analysis of a number of radiographic images of an object, taken from different directions, in order to produce a three-dimensional image (voxel data). This is an imaging method.
The techniques currently used for image-producing vessel examination can be divided into three groups of methods: On the one hand casting techniques are available, on the other hand contrast agents exist, which are able to penetrate capillaries. A general overview of all techniques of postmortem angiography can be found in “Postmortem Angiography—A Review of Former and Current Methods” (S. Grabherr et al, AJR 2006 in press).
Casting Techniques:
For the casting techniques, for example methylmethacrylate (for example MERCOX® (methyl metharcrylate monomer solution (acrylic resin mixture)) or MICROFIL® (silicone rubber injection compounds), are used. These substances are injected, immediately after their mixing, after the vessels have been rinsed. After their hardening the tissue is macerated, which takes 2-4 weeks. What is then left over is the cast of the vessels, which can be analyzed by the naked eye, with the aid of a microscope or electron microscope, or also by radiographic techniques (see Djonov et al., Anal Embryo 2000; 202 :347-357). Disadvantages of this method are the tedious manufacture of these preparations, the long time necessary for maceration and nonetheless the high risk of damaging the preparations by maceration and the subsequent handling, during which small parts of the preparation can easily break off.
Liquid Contrast Agents:
Most of the liquid contrast agents are not suitable for microangiographies. Water-based mixtures have the property to very quickly exit the vessel by penetrating the vessel's wall (so-called extravasation), which leads to diffuse contours of the represented vessels. Furthermore, their contrast is not high enough to clearly represent small vessels, such as capillaries.
Oily contrast agents have the property to remain intravasal without penetrating the vessel's wall (normally no extravasation). This leads to a clearly contoured image of the vessels. However, capillaries cannot be penetrated due to possible occlusions of the so-called capillaries [hair vessels].
Corpuscular contrast agents can be used for microangiography if small corpuscular particles are used. The most common corpuscular agent is MICROPAQUE® (barium sulfate-containing x-ray contrast agent). However, in its use in combination with micro-CT-devices, the problem of precipitation of the dissolved particles was described, which leads to artifacts (M. Marxen et al., Med Phys 2004, 31:305-313). Marxen clearly describes in his paper the necessity and the lack of a suitable contrast agent for microangiography using micro-CT.
SUMMARY OF THE INVENTION
An object of the invention thus is to provide an improved contrast agent for image-producing methods of the above mentioned type. It especially thus concerns the improvement of a contrast agent for angiography, for example for the examination of animal or human corpses or components thereof, e.g. of extremities (which may still be attached to the body), containing an essentially non-polar (in other words hardly or not miscible with water), that means usually oil-based contrast component for X-ray examinations. Therein, the contrast component in this type has a relatively high viscosity, typically in the range of 30-100 mPas.
The problem of such non-polar, oily contrast components is the fact, that they have a high viscosity. This high viscosity has the consequence that the contrast component cannot arbitrarily penetrate into capillaries and accordingly is also not able to completely represent the vascular system. In addition, it can lead to a real occlusion of capillaries and sections. The advantage of the essentially non-existent extravasation can thereby be reversed in numerous applications.
Surprisingly, it was determined, that such contrast components can be used very advantageously in a mixture. Therein, the mixture is characterized in that the contrast component is present in a mixture with at least one further non-polar component, of which the viscosity is lower or at the most equal to the viscosity of the contrast component. The admixing of this further non-polar component is used, on the one hand, in order to adjust the viscosity to the desired value, for example to the value of blood. On the other hand, it is used, in order to serve as a carrier for the contrast component, without changing the properties thereof concerning extravasation. This was especially unexpected with respect to the fact that the positive properties concerning extravasation can be maintained while nevertheless allowing the viscosity of the entire mixture to be adjusted to an optimal value, and that an excellent contrast is possible despite the dilution of the contrast component.
Preferably, the contrast agent is essentially free from water, meaning that it is not present as an emulsion. In other words, the mixture according to the invention preferably is a mixture, which only consists of non-polar components, wherein these components preferably can be essentially arbitrarily mixed among each other.
A first preferred embodiment is characterized in that the further non-polar component is an essentially saturated, branched, unbranched, or cyclic hydrocarbon, or a mixture of such hydrocarbons. Preferably, the further non-polar component is an alkane (preferably n-alkane, iso-alkane) or a mixture of alkanes, with a number of carbon atoms in the range of 5-45, especially preferably in the range of 12-30.
For example, it is possible to admix a non-polar component with a comparably low viscosity, such as for example an alkane with 12-18, preferably with 14-16 carbon atoms, or a mixture of such alkanes, wherein it preferably is an n-alkane or a mixture of such n-alkanes.
Therein, tetradecane or hexadecane are especially preferred, however, systems like cyclohexane or mixtures such as for example petroleum or even petroleum ether can also be used. Preferred systems have a melting point above 0° C. and/or a boiling point of at least 200° C.
Another preferred embodiment is characterized in that the further non-polar component is a component with a rather higher viscosity (but still at most equally high to that of the contrast component), such as for example an alkane, especially an n-alkane or also an iso-alkane, with 20-30 carbon atoms. Preferred is e.g. paraffine oil, especially paraffinum perliquidum. However, the non-polar component having a rather higher viscosity can also be a vegetable oil, such as for example a methylated rape oil or similar vegetable oils.
An additional preferred embodiment is characterized in that the contrast component has a viscosity in the range of 30-80 mPas. Thus, the contrast component for angiography preferably can be a iodine-based or sulphur-based radiographic contrast agent, especially preferably an iodized or brominated component or especially oil, for example a propyliodon, a fatty acid ethyl ester of iodized poppy-seed oil (e.g. LIPIODOL®), or iodipin, wherein it especially preferably is LIPIODOL® ultrafluid.
An especially preferred embodiment of the mixture is characterized in that the further non-polar component has a viscosity which is lower than the viscosity of the contrast component. The further non-polar component thus preferably has a viscosity in the range of 0.2-80 mPas, preferably in the range of 2-60 mPas.
As already mentioned, it is possible to admix a non-polar component with a comparatively low viscosity, thus preferably with a viscosity in the range of 1-10 mPas, preferably in the range of 2-4 mPas. Alternatively or especially preferably additionally (e.g. as a ternary or even multinary mixture), it is possible to admix a non-polar component with a rather higher viscosity (still lower than the viscosity of the contrast component), such as for example with a viscosity in the range of 25-80 mPas, wherein, as already mentioned, paraffinum perliquidum is especially preferred.
Therefore, for example a binary mixture of LIPIODOL® (ethyl esters of iodized fatty acids of poppy seed oil) ultrafluide, and tetradecane or hexadecane, or a binary mixture of LIPIODOL® ultrafluide and paraffinum perliquidum, or a ternary mixture of LIPIODOL® ultrafluide, tetradecane or hexadecane, and paraffinum perliquidum, is especially preferred.
Preferably, the contrast agent therein is characterized in that the volume ratio of contrast component to further non-polar component is in the range of 1:1 to 1:10, preferably in the range of 1:2-1:8, especially preferably in the range of 1:4-1:6.
For the angio-injection method and the angio-perfusion method, this is preferably the range for the volume ratio of a contrast component to a further non-polar component which has a rather higher viscosity (for example 25-80 mPas, see specifications above, corresponds e.g. to an alkane, especially an n-alkane or also an iso-alkane, with 20-30 carbon atoms, such as e.g. paraffine oil, especially preferably paraffinum perliquidum). The volume ratio of contrast component (or of contrast component already in a mixture with a further non-polar component of a rather high viscosity) to a further non-polar component with a comparatively low viscosity (for example in the range of 1-10 mPas, see specifications above, corresponds for example to an alkane with 12-18, preferably with 14-16 carbon atoms, or a mixture of such alkanes, especially preferably an n-alkane or a mixture of such n-alkanes, such as e.g. especially tetradecane or hexadecane) is best adjusted under consideration of the desired viscosity for the angio-injection method and the angio-perfusion method, resulting for example in ratios (contrast component: non-polar component with a comparably low viscosity) in the range of 20:1-100:1 or preferably 30:1-70:1.
For the so called angio-injection method preferably a ternary mixture is used, wherein the contrast component (e.g. LIPIODOL®) and a further non-polar component with a rather higher viscosity (e.g. paraffinum perliquidum, virtually as carrier) are used in a ratio in the range of 1:5, and subsequently the component with a comparatively low viscosity (e.g. hexadecane and/or tetradecane) e.g. in a ratio of 50:1 is used to adjust the viscosity of the entire mixture again depending on the radiographic contrast (radio-opacity) and the desired flow property.
Especially for microangio, mixtures of contrast component and non-polar component with a comparatively low viscosity (e.g. tetradecane or hexadecane) are used in a ratio of 1:4 or 1:6, wherein the quantity of the non-polar component is adjusted via the desired radio-opacity and the depth of penetration into small capillaries.
Furthermore, the present invention concerns a method for the dynamic angiographic examination of animal or human corpses or organs, or components, e.g. of extremities, thereof. The method is preferably characterized in that a contrast agent, e.g. as described above, is introduced into the vascular system and that subsequently or synchronously a radiograph is taken by the aid of x-rays, in particular a CT-image.
Furthermore, the present invention concerns a virtually dynamic method for the angiographic examination of animal or human corpses or organs, or components, e.g. of extremities thereof. This method is characterized in that first, a further non-polar component, as described above (or one or more polar components, such as e.g. water and/or polyethylene glycol) is essentially continuously introduced into the vascular system and circulated therein, and that during a time span of this non-polar component, a contrast component, as characterized above (or during the circulation of a polar component, one or more polar contrast components, such as e.g. on the basis of iopentole, methylglucamine ioxithalamate, iodixanole, iohexole, or similar), is added, wherein subsequently, synchronously or section-wise, radiographic images are taken by the aid of x-rays, especially a CT-image (so-called dynamic angiography, for example first arterial imaging, then parenchymal imaging, and then venous imaging, wherein paraffinum perliquidum, possibly in mixture with a decane (the term decane is to be subsequently understood as tetradecane and/or hexadecane) is used as a carrier, and a batch of contrast component is introduced). Generally, it is also possible, by the way, to colour the further component(s), such that e.g. a red colouring of the paraffinum perliquidum with sudan-red is possible.
The contrast agent for use in this method according to a first preferred embodiment thus can be a non-polar mixture, as described in detail above. However, it can also be an essentially polar mixture, which is preferably of an aqueous basis, and for which then a water-soluble contrast component or a contrast component which is emulsifiable in water is used. For the adjustment of the viscosity of such a mixture as a contrast agent, polar components having a high viscosity can be added. Such components can for example be polyols, such as e.g. long-chained sugars or long-chained glycols, such as e.g. polyethylene glycole (e.g. PEG 200 of Schärer und Schläpfer A G, Rothrist, C H). As a contrast component, e.g. Imagopaque 300 (iopentole, Amersham Health) then can be used. Here too, the desired viscosity of the contrast agent can then be adjusted by the additional polar component or its fraction in water, respectively. Typically, a viscosity of the contrast agent in the range of 0.5-60 mPas, especially preferably in the range of 0.1-50 mPas, especially preferably in the range of 20-45 or 30-40 mPas, is set for the applications according to the invention. In this case, the mixture thus preferably consists of an essentially polar contrast component (or a contrast component which is emulsifiable in water) and a further polar component, wherein this further polar component can either be present alone, if the desired viscosity can already be achieved thereby, or, however, as a mixture. If the further polar component is present as a mixture, preferably a system is used, in which a first further polar component with a low viscosity, preferably water, is used in combination with a second further polar component with a high viscosity, preferably a polyol. Thereby, the ratio between the first further polar component and the second further polar component can be used to adjust the viscosity of the contrast agent. This adjustment can preferably be carried out dynamically, which means that it is possible, just as for the application of the non-polar system described in detail above, to adjust the viscosity differently, by change of ratio of these two components, during the course of conducting the analysis, and thereby to visualize different areas of the vascular system during the course of the analysis.
Furthermore, the present invention concerns the use of a contrast agent, as described above, for the angiographic examination of animal- or human corpses or organs, or components, e.g. of extremities thereof.
According to another embodiment, a method is suggested, which is characterized in that a contrast agent, preferably in the form of a mixture, as the one described above, is introduced into the blood vessels in a non-pulsing manner. All measurements on the living body must be circulated in a pulsing manner, which is only not necessary on a corpse and opens essential additional analytical possibilities. Preferably, the contrast agent is introduced into the blood vessels under essentially constant pressure, or under a pressure varying temporally with a substantially lower or substantially higher rate than the naturally possible heart rate. Thus preferably, the circulation medium is not introduced in a volume-controlled, but in a pressure-controlled manner.
A further large analytical additional asset, which is not available from the natural analyses, is the possibility to circulate the contrast agent in the vascular system in the process at least section-wise against the natural flow direction of the blood. Possibly in combination with said pressure-control and the variation of further parameters which cannot be varied as much on the living body, incredible additional analytical possibilities are also established. Generally, additionally the difference of contrast agent introduced into the circulatory system and contrast agent exiting the circulatory system, concerning volume, pressure, temperature and/or component concentration, can be registered, and taken into account, preferably in a quantitative way, in the analysis. Thereby, for example the blood loss through an opening in the circulatory system can be quantitatively determined.
Generally, it is possible, in addition or alternatively, to vary the contrast agent during the introduction into the circulatory system in at least one of the following parameters, during and/or before the measurement, especially preferably depending on the image data obtained: temperature, mixing ratio, pressure. Prior to the introduction of contrast agent, the circulatory system can be rinsed, especially preferably by using a non-polar component or a (physiological) NaCl- or lactate-solution.
Furthermore, the present invention concerns a device for carrying out a method as described above. This device is preferably characterized in that means for pump-driven introduction of contrast agent into the circulatory system are provided, as well as means for the recording and quantitative registration of contrast agent exiting the circulatory system after circulation.
Alternatively or in addition, the device can be characterized in that a unit is provided, with which, prior to the introduction of the contrast agent into the circulatory system, the contrast agent is either admixed in an automated way in a desired ratio of contrast agent and one or more further non-polar (or polar) component(s), possibly in a temporally dependent fashion, and prepared for the introduction, and/or the contrast agent is adjusted in its temperature.
Further preferred embodiments of the present invention are described in the dependent claims.
SHORT DESCRIPTION OF THE FIGURES
The invention shall subsequently be further explained using some examples in connection with the drawings, wherein are shown:
FIG. 1 : a post-mortem micro-CT-scan of a mouse, with a representation of the large vessels;
FIG. 2 : a better overview of the large vessels of the entire body after removal of the ribs and front legs at the work station (virtual scalpel);
FIG. 3 : a visualization of the smaller vessel-branches by changing the windowing at the work station;
FIG. 4 : a representation of the heart and the liver vessels after virtual editing of the data of a partial body scan of a mouse;
FIG. 5 : a representation of the main branches of the kidney vessels after virtually cutting the organ out of a partial body scan;
FIG. 6 : a high-resolution scan of a lung assay of a mouse with 3D-representation of smallest vessels;
FIG. 7 : a better view of the main branches of the lung vessels of an image according to FIG. 6 with the same data set by changing the windowing;
FIG. 8 : different representation possibilities of a kidney from the data set of a high-resolution single organ scan;
FIG. 9 : shows the angio-injection method on a human corpse, wherein in a) the access of the contrast agent via re A. carotis communis is shown, and b)-d) show different views of the CT-images on the head of the examination object;
FIG. 10 : shows the angio-injection method on the single organ (human kidney), wherein in a) the access of the contrast agent via A. renalis is shown, and b)-d) show different views of the CT-images of the scan of the kidney;
FIG. 11 : shows the angio-injection method on the lower extremity of a human corpse, wherein the access is opened via A. femoralis superficialis, and different representations of the leg are shown;
FIG. 12 : shows a schematic representation of the angio-perfusion method; and
FIG. 13 : shows CT-images of a corpse, which suffered from PAOD (Peripheral Arterial Occlusive Disease), wherein in a) and b) the generally very poor perfusion in the area of the lower leg can be recognized, in c) the lower area of the lower leg with PAOD, and in d)-f) the corresponding specific localization of an occlusion.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The suggested contrast agent can be used, for example, for microscopical vessel research (so-called microangio), but also for the angio-injection method or for the angio-perfusion method.
The preferred mixtures for these three methods are as follows:
Microangio: LIPIODOL®+decane (hexadecane or tetradecane), for example at a ratio of 1:4; Angio-injection method: LIPIODOL®+paraffinum perliquidum+possibly decane, for example at a ratio of 1:5 and decane until the desired viscosity is reached; Angio-perfusion method: Perfusion with paraffinum perliquidum, possibly supplemented by decane according to the desired viscosity, bolus injection of LIPIODOL® into the existing and continuing circulation.
After we have successfully used oily perfusates and contrast agents on animal cadavers and human corpses within the scope of the development of a minimally invasive, postmortem angiography, an unexpectedly advantageous new mixture for the use of a postmortem angiography using micro-CT was developed on this basis. In contrast to our previously used oily liquid, this new mixture does not lead to micro-embodies of the capillary system (S. Grabherr at al, A.IR 2006 in press) but to the penetration and thereby to the representation of this area of the vascular system.
Components:
1. LIPIODOL® ultrafluide . (Guerbert, France) [0056]
2. Tetradecane (Tetradecane olefine free, Fluka, Switzerland) or hexadecane (Hexadecane, Fluka, Switzerland)
The composition of these components can be varied. The oily contrast agent Lipiodol Ultrafluide® provides for a high contrast (about 2000 HU), while the decane serves as a diluent which allows the penetration of capillaries. The more decane is used, the lower the viscosity becomes, and the smaller the vessels which can be visualized.
As mixtures already successfully used, a ratio of LIPIODOL®:decane of 1:4 and 1:6 are advisable.
Advantages of the new contrast agent (essentially for all the three methods mentioned above):
Practical ways of handling: one of the probably most essential advantages of this contrast agent mixture is the easy handling. A simple injection into the vascular area to be visualized is enough.
Durability of the assays: Because the oily contrast agent remains intravasal, the assays can be stored for several days after injection and only then examined.
Transportability of the assays: The long durability of the assays allows the transport between laboratories (e.g. injection in Berne, examination and analysis in the USA).
Repeated examination possibilities: Multiple scans and analyses of an assay are possible, which is essential in the case of ambiguous findings.
3D-reconstruction with “zoom-in” and virtual assay editing: With the help of the examination with micro-CT, besides the two-dimensional reconstruction, also a three-dimensional reconstruction of the data is possible. By zoom-in and virtual cutting of the assays, arbitrary areas can be enlarged, cut out and represented, without destroying the assays.
Quantification: Special software already existing e.g. for the measurement of bone density for micro-CT-applications, can very easily be adapted for the quantification of the high-contrast vessels.
Selective, caliber-dependent representability: Depending on the mixing ratio, different vessel sections can be represented according to their caliber. It is thus possible to selectively visualize only large supply vessels or also capillaries.
Possibility of dynamic angiography: In case of a corresponding injection technique, a precise determination of the arterial, venous and capillary phase is made possible, in analogy to clinical angiography.
Possibility of repeated injection: When carrying out a dynamic angiography, a rinsing-out of the contrast agent from the vascular system is possible due to a lack of loss of contrast agent to the surrounding tissue, which enables a repeated injection without a falsification of the results by remainders of the previous injection. This is important, if ambiguous findings appear in a phase of dynamic angiography.
Possibility for further examinations: The examined organs can be embedded and additionally be examined morphologically (paraffin embedding and examination by electron microscopical section examination). This is important if the 3 D-structure correlates with the tissue morphology and shall be compared.
EXPERIMENTAL PART
Microangiography (Microangio)
For this method, a mixture of LIPIODOL® and decane was injected as contrast agent (KM) into the vascular system of a dead mouse, followed by the performance of a micro-CT with a device of the type “Siemens Micro-CT-Scanner”.
Preliminary Test to Evaluate the KM in the “Live Scanner”:
Scan KM (LIPIODOL®: decane=1:4) in 0.8 mm Venflon (butterfly needle/permanent venous catheter [Verweilkanule]): KM is clearly visible.
Mouse 1:
KM (LIPIODOL®: decane=1:4) from below into the V. cava inf.; scan of the anterior/upper part of the body only.
Mouse 2:
KM (LIPIODOL®: decane=1:6) from below into the V. cava inf.; no scan of the complete mouse; organ removal for isolated organ scans:
heart liver kidney head
Mouse 3:
KM (LIPIODOL®: decane=1:6) from below into the V. cava inf.; injection KM (LIPIODOL® decane=1:6) into right V. saphena; 3 scans for whole body representation.
Mouse 4:
Injection KM (LIPIODOL®: decane=1:6) into left ventricle; scan of anterior part of body only.
Mouse 5:
Injection KM (LIPIODOL®: decane=1:6) aorta (small amount) and V. cava inf.; 2 scans (head and thorax).
Mouse 6:
Injection KM (LIPIODOL®: decane=1:6) from below into the V. cava inf.; 2 scans (head and thorax).
Mouse 7:
Injection KM (LIPIODOL®: decane=1:5) into V. porta; Organ removal for single scans:
liver lobes (upper, incl. gall bladder) heart right and left kidney.
Different reconstructions from the data set of the micro-CT scans mentioned above are shown in FIG. 1-8 . From the figures, is can be seen that the contrast agent on the one hand allows a high resolution, and on the other hand an excellent penetration, even into smallest vascular systems.
Angio-Injection Method:
Herein, a manual injection of iodine-containing contrast agent LIPIODOL® was carried out in assays of corpses fixated by formalin for 2 years, whose vessels were occluded with fixated blood.
Preparation with a dilution series of KM, wherein LIPIODOL®: paraffin oil (each time as paraffinum perliquidum) 1:1, 1:5, 1:10, and 1:20 were examined. The following angiographies were performed with 1:5, because this showed the best compromise of viscosity, contrast effect and vessel penetration for the aspired visualization.
Mixing of the contrast agent: LIPIODOL®: paraffin oil=1:5. Per 500 ml of this mixture, additionally about 10 ml of decane. After injection of the contrast agent mixture, multi slice-CT with data reconstruction as MIP and VRT.
FIGS. 9-11 show the thus obtained images from the angio-injecting method on the one hand, of the head area ( FIG. 9 ), of a kidney ( FIG. 10 ) and of a leg ( FIG. 11 ), wherein it can be recognized how the used contrast agent allows an excellent contrast and despite the previously stored blood clots, an excellent penetration into the blood vessels, without any substantial extravasation being recognizable.
3. Angio-Perfusion Method:
Angio-experiment on the human corpse, body: anatomy-corpse after Till-fixation, injuries already present (state after operation on left knee and an open tibia fracture on the right)
Method (see schematic representation in FIG. 12 ):
Cannulation in the right groin (A. femoralis, V. femoralis). Perfusion with the aid of a heart-lung machine (perfusate: paraffin oil+decane at a ratio of about 500 ml : 10 ml). Perfusion speed 5-10 ml per kg bodyweight / min. See a) in FIG. 12 . Addition of the contrast agent Lipiodol® (40 ml) into the perfusate (injection into the tube that leads to the artery, within a time span of a few seconds (bolus injection). See b) in FIG. 12 .
CT-scans. See c) in FIG. 12 .
Result: Successful perfusion (filling of the varices on the legs, filling of the A. Carotis); contrast in the CT.
The results of the perfusion can be recognized in FIGS. 13 a - f . The examined corpse suffered from PAOD (Peripherial Arterial Occlusive Disease) prior to death, while FIGS. 13 a ) and b) show the generally very poor perfusion in the region of the lower leg, FIG. 13 c ) shows the lower area of the lower leg with PAOD, and the Figures d)-f) show the according specific localization of an occlusion.
Contrast agent can either be injected as a bolus or added in higher quantity, wherein for dynamic angiography, a bolus should be introduced within a time-span as short as possible. Longer tubes of the heart-lung-machine are advantageous for a whole body scan, in order to compensate for the movement of the CT-table (typ. about 3 m).
Summary:
The new contrast agent allows a reliable, fast and repeated examination and representation of 2D and 3D vessel architecture of laboratory animals (e.g. microangiography with micro-CT), as well as postmortem on the human and animal corpse (angio-injection method). Furthermore, it allows dynamic imaging and quantification of the “blood loss” by the use of the angio-perfusion method. Practical handling, quantification possibilities, and exact representation of different vascular parts will establish this method as a standard examination in the evaluation of genetically manipulated laboratory animals, pharmacological and toxicological studies and of genetically engineered products. This new visualization and quantification method shall replace the old, reliable, however very time-consuming and highly specific techniques and pave the way for a comprehensive, simple, practical and uncomplicated application.
Below, the machine concept of the post-mortem angiography shall be described with the aid of a modified heart-lung-machine. The machine concept is based on two angiography methods, which can optionally be carried out in a stationary (in a forensic department) or mobile manner. The design of the heart-lung-machine is concipated this way, such that stationary as well as mobile postmortem angiographies can be carried out. As a basic device of such a heart-lung-machine, for example the device distributed by Maquet, or Jostra, respectively, can be used. With the name Jostra HL 20 MECC CONSOLE.
Components of the machine concept: the machine concept of the modified heart-lung-machine contains six basic components (machine scaffold, power supply, drive unit, control unit, computer unit as well as expendable material), which will each be described below.
Machine scaffold: The machine scaffold consists of two base plates (lower, upper), four steel tubes, as well as two rear transverse bracings for stabilization purposes. On the lower steel base plate, a drive rack is integrated. The drive rack with four wheels can be arrested and is rotatable around the longitudinal axis.
Power supply: Principally, the modified heart-lung machine is supplied with power via an external source. Usually, the machine is supplied with 220V or 110V. The power converter contains batteries, which ensure a line current-independent operation of 120 minutes (maximal capacity).
Drive unit: the drive unit consists of a double-V-belt-driven roller pump or peristaltic pump. The roller pump is connected with the power converter via a plug connection. For the mobile model, said additional battery unit is provided. This way, only the pump alone can be operated, which allows an additional field of application (Single Shot Angiography) without a computer unit, and also a static angiography-process. For the dynamic angiography, the roller pump is connected with the control- and computer unit. This connection allows a form of angiography, which can be carried out in a pressure- as well as in a volume-controlled manner (see below). Furthermore, it is possible, to provide means (e.g. flow-through heater etc.), by which the circulation medium is heated or cooled prior to and/or after the circulation. The roller pump provides the possibility of occlusive adjustment, in order to ensure a pressure-controlled postmortem perfusion.
Furthermore, optionally, a unit can be provided, which automatically mixes the contrast agent introduced into the corpse from starting materials, as described above (contrast component, further apolar component(s), etc.) in a controlled manner. This mixing can of course also be carried out in a time-dependent and process-dependent fashion, in order to allow a real dynamic process management concerning the contrast agent composition. The control of this mixing unit can be carried out by the control unit discussed below.
Control unit/user module: In order to answer the defined questions (quantity, occlusion, etc.), the pump contains at least four possible settings ( 3/16-, ¼-, ⅜- and ½-inch), via which by the aid of the determinants, number of revolutions, and tube diameter, the searched-for volumina can be calculated and graphically represented (whole body perfusions or selective organ perfusions). The integrated pressure control additionally allows directed conclusions about occlusion rates of defined vessel parts. Furthermore, the roller pump can also be operated in the so-called It. or ml/min mode, which additionally allows defined conclusions about volume losses.
Control unit: The control unit consists of a screen-like user module, as well as electric modules, which are fastened to the upper base plate. The user module of the control unit serves for the power line- and battery control and the activation of the pressure- and volume modes.
The electric modules are connected with the computer unit. The electric modules contain a pressure registration and a volume registration. The pressure registration consists of four independent pressure measurement units, which can be set to every defined pressure limit and therefore allow all pressure perfusions and allow the recognition of the smallest pressure gradients (bleeding, occlusion). The volume registration consists of an ultrasound measurement, which on the one hand registers the application of the contrast agent and on the other hand the efflux of the contrast agent. In addition, the ultrasound measurement can be connected with the venous reservoir, thereby enabling a dynamic, continuous perfusion, as the liquid is determined and quantified via the ultrasound detection (see perfusion concept).
The computer unit comprises a user module and primarily serves for data registration purposes (pressure sensors, ultrasound and pump functions of the roller pump), which are detected by the aid of a memory card and can be subsequently visualized in defined programs. This process can be carried out during or after the postmortem perfusion, or it can be printed out as a hand protocol. On the memory card and/or the computer unit, different types of process management can be automatically pre-determined, that means that on the memory card and/or the computer unit, software can be stored, which automatically controls the process management, possibly after the setting of several parameters by the user.
Furthermore, the possibility exists to directly control and refine the postmortem perfusion by the aid of empirically collected data. In addition, the postmortem perfusion can be automated on empirically validated data and ultimately standardized (see validation concept).
Expendable material: The expendable material comprises, among others, two different plastic tube types (silicone, polyethylene), and a hard shell reserve, as well as two types of cannula (venous, arterial), and different connectors (the canulla sizes and the corresponding canulla types are dependent on the corresponding perfusion method). The tube type of silicone is used as a drive tube for the roller pump and corresponds essentially to the length of the roller pump circumference. The drive tube dimensions are variable and have an external diameter of between 3/16-½-inches (whole body- or selective organ perfusion). The remaining tube connections consist of polyethylene and have an external diameter of ¼-inch. The expendable material is arranged as in a conventional perfusion. The polyethylene tube is connected as a so-called venous inlet with the reservoir via the venous cannula and a connector. Parallel, an additional tube is connected with the venous cannula via a Y-connector. This tube serves for discarding the primary postmortem perfusate (coagulated blood). The outlet of the reservoir is connected with the silicone tube, which itself is guided into the roller pump and thereby empties the reservoir during operation. From the pump outlet, the silicone tube is connected via a connector with an additional polyethylene tube and connected with the arterial cannula via a connector having a Luer-Lock (contrast agent inlet). The perfusate is guided into the reservoir with a special fill line.
Perfusion Concept, Static Clinical Angiography Vs. Postmortem Dynamic Perfusion Angiography:
Static clinical angiography: Today, different angiography methods are used clinically. The most prevalent are arteriography, phlebography, coronary angiography, as well as varicography. The aim therein is to obtain an angiogram, which represents the filled inner cavity of a vessel and by which different diagnostic conclusions can be made with respect to different vascular diseases (KHK, carotis stenoses, PAVK, vessel deformations, thromboses, varices, vessel injuries).
In clinical angiography, the contrast agent is injected into the vascular system with a catheter. The cardiovascular system therein works as a “motor” for the distribution of the contrast agent. The imaging is thus only possible during the corresponding circulation time and leads to an antegrade representation in arteriography or in coronary angiography (i.e. measurement exclusively in the direction of the natural blood flow). Also in phlebo- or varicography, the contrast agent is introduced into the venous vascular system during the corresponding circulation time, and the sequence of images is taken in the antegrade (normal) blood flow. The angiography methods described above thus are static methods, which do not result in any quantitative flow data, and only the occlusion rate of single vessels can be indicated in %.
Dynamic postmortem angiography: In the real dynamic postmortem angiography, the “motor”, thus the cardio-vascular system, is replaced by a roller pump. By loss or replacement of the natural heart activity, the vascular system can be filled and represented in an antegrade or, for the first time, also retrograde manner (against the normal blood flow). Vascular pathologies therefore can be looked at and represented from the “front” or from the “rear”. This has relevant character, as for example a coronary thrombus, which is interpreted as a subtotal stenosis in the antegrade imaging, can be rinsed out and visualized in a retrograde manner. In addition, a severe vascular injury can even be quantified via a double cannulation (arterial-venous): Therein, a defined quantity of a defined contrast agent is introduced via the arterial cannula, and collected again via a venous cannula, wherein the difference between the inflow and outflow results in the quantity of blood loss, which can be calculated from the determinants of number of revolutions of the pump, tube diameter and time.
Most substantial differences between the two methods: Principally, all conventional angiography methods can also be carried out by the postmortem perfusion. The fundamentally different possibilities of the two methods, however, allow a new dimension of vessel imaging. For the first time, a constriction of an artery for example can also be viewed and represented distal from the stenosis, which is impossible in the static perfusion on the living body.
A second essential point is the “motor” of the postmortem perfusion. This can be linked and operated via a computer. The circulation of the contrast agent thus can be influenced almost arbitrarily, which of course is not possible on the living body. This for example allows, after a defined validation phase and the comparison of empirically-evaluated data from heart surgery, a punctual control of the pump and thus enables an exact quantification of the stenosis- or bleeding rates. The pressure gradients over the used arterial and venous cannulas of the healthy vessel with a defined quantity of volume, which was applied over the roller pump, are deemed to be empirically-evaluated data. The data thus obtained are deemed to be “norm values” and are confronted with the data obtained from the postmortem perfusion. The pressure differences are then used for the exact control of the roller pump.
Furthermore, it shall be stressed that, contrary to the measurements on the living body, not only the circulation of the contrast agent or of the entire circulation agent, respectively, can be adjusted almost arbitrarily in the sense of a desired measurement, but also other parameters. For example, the circulation rate or the circulation pressure, respectively, can also be adjusted depending on the measurement, or the progress of the measurement, respectively, such that for example in a batch-wise introduction of contrast agent a reduction of speed or a reduction of pressure, respectively, can be effected in that moment, in which the analysis device registers the entrance of the contrast agent into the area mainly examined. It is possible to make measurements at a constant pressure (that means, not in the naturally pulsed manner of flow), and thereby, for example to obtain exact data for the conditions at a maximal blood pressure and at minimal blood pressure of the circulation. Furthermore, it is, however, also possible, for example, to allow the circulation agent and the contrast agent contained therein to circulate at different temperatures. Thereby, e.g. the viscosity, but also the streaming behavior, etc. can be influenced.
This results, in summary, among others, in the following differences:
Clinical angiography:
Postmortem angiography:
Antegrade perfusion
retrograde perfusion
inconstant (heart, pulsed, flow-
constant (pump, pressure-
controlled)
controlled)
static (circulation time)
dynamic
inflow method
in- and outflow method
qualitative method
quantitative method | A contrast agent for angiography is disclosed, in particular, for examining animal or human bodies or components thereof such as members or organs thereof, comprising an essentially oil-based apolar contrast component for X-ray examinations, the contrast component having a contrast component viscosity in the range of 30-100 mPas. The contrast agent is characterised in that the contrast component is present in a mixture with at least one further apolar component, the viscosity of which is less than or at most equal to the contrast component viscosity. Methods for angiography examination are also disclosed, in which such a contrast agent or also a polar contrast agent are used at least periodically and applications of such contrast agents. | 0 |
This application is a continuation, of application Ser. No. 07/487,198, filed Mar. 1, 1990, now abandoned.
The invention relates to a unit to dispense wiping materials stored in roll form or folded in Z form and delivered in the form of concertina-folded strips.
The object of the invention relates to means to dispense wiping materials of such material as paper, cotton wool, non-woven or other types.
CROSS-REFERENCES TO RELATED APPLICATIONS
The present invention is an improvement of the invention disclosed in copending application Ser. No. 07/224,408 filed: Jul. 26, 1988 now U.S. Pat. No: 5,013,291 and the division thereof Ser. No. 07/641,723 filed: Jan. 15, 1991 now U.S. Pat. No. 5,147,279. These applications claim priority of French patent applications 8805939 and 8807823. The subject matter of said U.S. patent applications and said French patent applications are incorporated in their entireties by reference.
BACKGROUND OF THE INVENTION
According to the application Nos. 8805939 and 8807823, the applicant of which is also the holder, a unit was proposed to automatically dispense lengths of wiping materials loaded in the unit in the form of a roll and delivered in the form of concerntina-folded strips so as to be very resistant to the manual pulling force on the part projecting from the end when the user has wet hands. The said folded strip, due to components suitably positioned between a return and forming means of the unrolled strip and the driving and cutting devices, goes back to its original or practically original form naturally in order to offer a sufficient wiping surface.
Despite everything, with certain types of materials, sudden or reckless pulling on the projecting strip, may tear the material before the cut which risks jamming the unit.
SUMMARY OF THE INVENTION
In order to overcome this and according to a first characteristic of the invention, the unit is fitted with a dampening device whose active part is arranged so as to have an effect over the tension of the strip between the storage point of the roll and the return and forming means, and automatically form, after every dispensing operation of the folded strip, by pulling the projecting part and by rotating the roll of material, a loop of unrolled material which is taken up when the next strip is pulled thus avoiding any undue tearing of the delivered material by sudden pulling. According to another characteristic, the dampening device is made up of a bow hinged on the fixed walls of the unit and elastically returned against the roll support, the transversal part of the said bow having a return means for the unrolled strip facilitating the sliding and forming of the loop when the projecting strip is pulled manually. Another characteristic is found in the fact that in order to check the size of the loop formed by the dampening device in a more precise manner, the rotation of the roll of material is slowed down on its support. With this in mind and according to another characteristic, the roll support, which is fixed to part of the unit hinged on the fixing part with a working surface, is made up of two side end pieces which can be inserted into the mandrel of the roll by a sideways movement with respect to two bolts fixed to the walls of the hinged part, against coil springs suitably calibrated in order to brake the roll accordingly.
For this type of unit, comprising on the part hinged to the fixing part, some return and forming means for the strip unrolled from its support, it was also desired to improve the sliding and forming of the said strip before it passed between the folding components arranged in a complementary manner on the said fixed and hinged parts.
With this in mind and according to another characteristic, the top face of the hinged part which takes the return means in its middle part, has, either side of the said means, a shape in the arc of a circle extending laterally and towards the bottom with a slope substantially up to the middle part, the top face being profiled in a convex manner at least at the level of the slopes in order to improve the sliding of the strip thus guided and formed.
In order to improve the loading and passage of the strip between the folding, driving and cutting means, a special arrangement of extended folding projections made in a complementary manner on the fixed and hinged parts of the unit has been provided. With this in mind and according to other characteristics, the said projections are fixed so as to be adjusted in height with respect to their support, in order to be constantly as close as possible to drive means, or are interchangeable in order to adapt their position with respect to the diameter of the pairs of toothed drive wheels, or self-orientating in order to facilitate the passage of the strip of material, or are made of a flexible, deformable material in a solid or alveolar form.
It was also desired to use materials stored in Z-form with this unit. In this case, it is necessary to provide a means of storage for the pile instead of the roll support and dampening device. With this in mind, several solutions can be envisaged within the scope of the invention.
For example and according to other characteristics, the casing of the unit housing both the fixed and hinged parts, is designed either directly or in a built up manner in order to take and guide the pile or a swivelling and interchangeable container is fixed to the side walls of the hinged part, or the packaging of the pile is provided to be housed between the casing the hinged part.
These characteristics and others will be made apparent from the following description.
BRIEF DESCRIPTION OF THE DRAWINGS
In order to clarify the object of the invention, however, without limiting it, the accompanying drawings have been provided, in which:
FIG. 1 is a side, sectional view illustrating a unit fitted with a dampening device according to the invention shown in solid lines in the idle position after loading and dashes in the loop forming position.
FIG. 2 is a partial front view illustrating the arrangement of the top face of the hinged part of the unit.
FIG. 3 is a section illustrating the braked rotating assembly of the roll of material.
FIG. 4 is a perspective view illustrating a casing fitted with receiving and guiding means for a pile of Z-type folded material.
FIG. 5 is a partial section illustrating a receiving and guiding container for a pile of Z-type folded material.
FIG. 6 is a schematic section showing the pile of material folded in Z-form in the unit.
DETAILED DESCRIPTION OF THE INVENTION
The object of the invention will become more apparent from the following non limitating description when considered in conjunction with the accompanying drawings.
The unit illustrated in FIG. 1 is of the type corresponding to that of applications 8805939 and 8807823, i.e. it is mainly formed of a lose part (A) having end walls to be fixed to any surface, a paper carrying means part (B) hinged at the bottom end with respect to part (A) and a casing (C) also hinged to part (A), for example, on the same axes (M).
The bottom part of part (A) is designed to take the driving and cutting device (D) for the folded material which is preferably assembled in the form of an interchangeable cassette, especially to offer different lengths of cut material. Close to the top end of part (A), there are extended projections (E) spaced and converging towards one another at the bottom part, whereas similar projections (G) are made in the same way on part (B) to provide concertina type folding of the unrolled strip passing between these interpenetrating projections. The top end of part (B) has a return component for the strip which can be made up of an idle barrel shaped shaft (H) to centre and preform the unrolled strip. At the bottom end, the part (B) is cut out at the centre to allow a roller (J) to pass facilitating the sliding of the folded strip inserted between toothed wheels (K) to feed and rotate the strip.
According to one of the characteristics of the invention, the top face (1) of part (B), is in the shape of an arc of a circle (1a) on either side of the return component (H), extending laterally and towards the bottom with a slope (1b) substantially up to the level of the component (H) thus making up a guide for the unrolled strip. In order for it to be easier for the said strip to slide, the profile of the said top face has a convex cross section at least the level of the slopes. According to another important characteristic, the unit is fitted with a shock absorber (N) preventing any undue tearing of the wiping material due to sudden manual pulling.
For this purpose, a bow (2) hinged by its side legs (2a) on the end walls of part (A) is provided, preferably on the bolts (M). The transversal leg (2b) has at least in the middle part, a rotary shaft (3) to return the strip unrolled from its storage roll (R) in the loading direction indicated. This shaft may be cylindrical or barrel shaped like component (H). The bow is urged by two springs (4) fixed to the side walls (B1) of part (B) in order to keep it applied against the mounting bolts of the roll of material.
Therefore, as shown in FIG. 1, after the roll has been loaded, when the folded strip projecting from the unit is pulled, the bow (2), under the effect of the pulling, swivels towards the rear by an angle proportional to the pulling force. After the strip has been cut, cancelling the pull on the strip, the bow, returned by its springs, goes back to the front abutting position and its shaft (3) pulls on the material forcing the roll (R) to turn in the unrolling direction. By sliding due to the pulling speed, the strip is unrolled a bit more and a loop appears between the shaft (3) and shaft (H). At the time of the new pulling action, the loop thus formed, is reduced when the bow is moved to the rear again, the roll (R) is rotated and when the bow returns, a new loop is formed. This way, even when there is a sudden pull on the projecting strip, there is no excessive tension at the roll of material and therefore no undue tearing of the strip.
In order to check the formation of the dampening loop more precisely, it is anticipated for the roll of material to be mounted in a braked manner. For example, as illustrated in FIG. 3, the two side walls (B1) have a bolt (5) on which a shouldered end piece (6) can slide and turn in order to mount and centre the mandrel (R1) of the roll. A coil spring (7) suitably calibrated, is placed between the wall (B1) and shoulder of the end piece to brake the unrolling action of the roll and enable the said roll to be quickly and easily mounted, by a thrust on the end pieces.
Folding, driving and cutting tests made with the unit according to the previous applications, have brought up some problems. In particular, when drive means (K) of different diameters (interchangeable cassettes) have been fitted or the distance between the projections (E and G) and the said means (K) is varied, this can be harmful to the satisfactory operation, particularly for the loading, folding and driving.
For this purpose, different ways of making the projections (E and G) have been planned. For example, they cab be fixed so as to be easily interchangeable in order for them to be constantly arranged as close to the drive means as possible. All the projections except the end ones, can be fixed in a self-orientating manner with limited oscillation to make it easier for the material to pass. They can also be made out of a flexible, deformable material and in solid or alveolar form.
As indicated in the foreword, with this type of unit, it is possible to use strips of material folded in Z-form. In this case, the pile of said material must be supported and guided upstream from the return and forming components arranged instead of the roll support and bow which is no longer required as the strip folded in Z-form acts as a tension dampener. In order to overcome this problem of storing the pile, several solutions can be envisaged.
For example, as illustrated in FIG. 4, the casing (C) can either directly or in a built up manner, have side guides (C1) and possible internal supports (C2) for the pile (P) which is arranged horizontally by tipping towards the front of the casing. According to FIG. 5, a container (8) is hinged on the bolts (M) to also take by forward tipping, the pile (P) on a bottom (8a) and against a front wall (8b).
In FIG. 6, a packaging (9) containing the pile of material folded in Z-form is provided to be housed between the casing (C) and hinged part (B). The advantages are made clearly apparent from the description, the following is highlighted in particular: the reliability of the unit the dampening device of which enables all types of wiping materials to be dispensed without any risk of tearing before the cutting operation provided. | The unit to dispense wiping materials stored in roll or Z-folded form and delivered in the form of concertina-folded strips is outstanding in that it is fitted with a dampening device (N) the active part of which is arranged so as to periodically have an effect on the tension of the strip between the storage point of the roll and the return and forming means (H) and automatically form, after every dispensing operation of a folded strip by pulling the projecting strip and rotating the roll of material, a loop (b) of unrolled material which is taken up when the next strip is pulled thus preventing any undue tearing of the material. | 0 |
CROSS REFERENCE TO RELATED APPLICATIONS
This Application is a continuation application of U.S. patent application Ser. No. 14/148,374 filed Jan. 6, 2014, entitled “Convection Recirculating Fryer for Cooking Foods,” by David R. Highnote, pending, which is a continuation application and claims the benefit of and priority under 35 U.S.C. §120 to U.S. patent application Ser. No. 12/435,722 filed May 5, 2009, entitled “Convection Recirculating Fryer for Cooking Foods,” by David R. Highnote, now patented as U.S. Pat. No. 8,646,382 issued Feb. 11, 2014, which is hereby incorporated by reference herein as if set forth herein in its entirety.
TECHNICAL FIELD
The present invention is generally related to a convection frying apparatus for cooking foods within a recirculating bath of cooking liquid.
BACKGROUND OF THE INVENTION
Although there are many ways to prepare food for consumption, one common method of preparing foods is to cook the food by frying. Additionally, one method of frying food is to “deep fry” the food by placing the uncooked food in a quantity of-cooking liquid, in most deep frying situations, the cooking liquid typically comprises a cooking oil, such as vegetable oil or animal fat. The food product is immersed in the cooking oil. The cooking oil is typically at a high temperature, such as above 350 degrees Fahrenheit.
Devices for deep frying are common in commercial food preparation environments. They are also becoming increasingly common in the home environment. Although a commercial frying apparatus and a home frying apparatus may he constructed on different scales, these two types of fryers have some of the same basic features.
The primary feature of a typical fryer, whether commercial or residential, is a cooking tank housing the heated bath of cooking oil The cooking tank is usually designed so that it may receive a metal basket into the tank. Food is placed in the metal basket and lowered into the cooking oil so that the food is at least partially submersed in the oil.
A heating device is typically used to maintain the oil in the tank at a substantially constant temperature. This heating device usually comprises a gas burner placed below the tank.
The typical fryers used in commercial and residential sailings do not remove the oil from the tank during operation. The cooking oil simply remains in the tank and the temperature of the oil is regulated by heating the oil while the oil remains in the tank. In contrast a recirculating fryer removes oil from the tank, adjusts the heat energy in the oil, and then returns the oil to the tank.
There have been previous attempts to develop a commercial recirculating fryer. However, these recirculating fryer designs have all suffered from a number of limitations. For example, some recirculating fryer designs exhibited problems with leaking seals in the pump. The pump seals became worn with use and began to leak. Other designs, while not necessarily having a problem with leaking seals, experienced failure of the pump bearings. This was usually a result of the arrangement of the pump. In general, the prior recirculating fryers were far too expensive to maintain in order to be feasible for commercial use.
Thus, a heretofore unaddressed need exists in the industry to develop a convection recirculating fryer that is efficient, cost-effective, and having reasonable maintenance costs.
BRIEF DESCRIPTION OF THE DRAWINGS
Many aspects of the invention can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the present invention. Moreover, in the drawings, like reference numerals designate corresponding parts throughout the several views.
FIG. 1 is a side view of the convection recirculating fryer.
FIG. 1A is section view of the gas injectors of the convection recirculating fryer of FIG. 1 .
FIG. 2A is a top view of the convection recirculating fryer of FIG. 1
FIG. 2 B is a front view of the convection recirculating fryer of FIG. 1
FIG. 3 is cut away view of the magnetic pump of the convection recirculating fryer of FIG. 1 .
FIG. 4 is a cut away side view of a magnetic pump to be used in the convection recirculating fryer of FIG. 1 .
FIG. 5 is an exploded part view of a magnetic pump used in the convection recirculating fryer of FIG. 1 .
DETAILED DESCRIPTION
A convection recirculating fryer of one exemplary embodiment comprises, generally, a fryer housing forming a tank, and encasing a pump and a heat exchanger. Although all of these elements are not required by the invention disclosed herein, these three elements are the basic components of an exemplary embodiment of a convection recirculating fryer.
PARTS LIST
10.
Convection fryer
11.
Free standing housing
13.
Fry tank
16.
Oil inlet orifice
17.
Oil outlet orifice
18.
Filter screen
19.
Bottom of tank
20.
Oil dispersement pipe
21.
Magnetic pump
22.
Pump inlet line
26.
Motor
27.
Motor casing
28.
Motor shaft
29.
Driving magnet assembly
31.
Impeller housing
32.
Driven magnet
34.
Impeller
35.
Pump housing
46.
Hot oil supply line
50.
Blower
52.
Fuel injector tube
54.
Glow plug with flame sensor
56.
A-D Fuel injectors
58.
Gas manifold
60.
Perforated burner sleeve
62.
Control
64.
Ceramic pump shaft
66.
Magnet
67.
Seal
68.
Filter pump
An exemplary embodiment of a convection recirculating fryer 10 is depicted in FIG. 1 . FIG. 1 is not to scale and is merely presented to provide a general understanding of the components of the convection recirculating fryer 10 . The arrangement of the components of the convection recirculating fryer 10 , as discussed below, is only one exemplary arrangement.
FIG. 1 depicts the convection recirculating fryer 10 having a housing 11 . The housing 11 of the fryer 10 can be comprised of a metal material. The housing 11 of the preferred embodiment 10 is a free-standing housing 11 . FIG. 2A is a top view of the convection recirculating fryer 10 . Alternatively, the housing 11 of the convection recirculating fryer 10 could comprise a smaller, counter-top model such as for home use. The principles of the invention described herein are not changed by scaling the fryer 10 up or down in size.
The fryer 10 also has a fry tank 13 . See FIG. 1 . The fry tank 13 of the preferred embodiment 10 is adapted to receive and hold cooking liquid (not depicted), such as cooking oil (e.g. animal fat shortening, vegetable-oil, or the like). The tank 13 of the preferred embodiment 10 has an open top, an oil inlet orifice 10 and an oil outlet orifice 17 . Basically, the preferred tank 13 resembles a deep tub, or retangularly-cubic bucket
The tank 13 is also preferably designed to receive a basket (not depicted). The basket typically houses a food product to be cooked in the cooking liquid. Other implementations of placing food to be cooked in the cooking liquid are, of course, possible. The present invention is not limited to any particular method and apparatus for exposing food products to a cooking liquid.
The tank 13 of the preferred convection recirculating fryer 10 may also comprise a filter apparatus 18 , as depicted in FIG. 3 . As depicted in FIG. 3 , the filter apparatus is a screen 18 positioned along the bottom 19 of the tank 13 . This apparatus maybe of any appropriate type; however, the preferred filtering apparatus is an active filtering device that pulls cooking liquid into the apparatus 18 , removes foreign matter, and then deposits the cooking liquid back into the main compartment of the tank 13 . The preferred filtering apparatus 18 is comprised of a frame that supports the filter material or “filter sock,” and a gear pump. The filter sock is placed over the frame; which has a pipe connection at a bottom portion. The gear pump draws the cooking liquid from the tank 13 , through the filter sock, through an oil dispersement pipe 20 , a filter pump 68 , and back into the tank 13 . Contaminants in the cooking liquid are deposited on the filter sock where they become imbedded and remain there.
The fryer 10 also employs a passive filter (not depicted) at the oil outlet orifice 17 of the tank 13 . The convection recirculating fryer 10 includes a magnetic pump 21 that draws cooking liquid from the tank 13 . For this reason, a passive filtering apparatus could include a screen-type assembly releasably mounted in the cooking tank 13 , and substantially covering the oil outlet orifice 17 of the cooking tank 13 , for prohibiting larger foreign matter from entering into the magnetic pump 21 and disturbing beat exchanger 41 .
As noted above, the tank 13 has an oil outlet orifice 17 . This orifice 17 is preferably near a lower portion of the tank 13 . This orifice 17 of the tank 13 is connected to pump inlet line 22 . This inlet line 22 is designed to carry the cooking liquid to an inlet of the pump 21 .
The magnetic pump 21 is depicted in FIG. 4 . The magnetic pump 21 comprises a motor 26 in a motor casing 27 . A motor shaft 28 to be driven by the motor 26 protrudes from the motor casing 27 and is attached to a driving magnet assembly 29 comprising a driving magnet. The driving magnet assembly 29 of the preferred embodiment is cylindrical in shape. A magnet such as the driving magnet 29 can be manufactured from a Samarium Cobalt material which will withstand the high temperature of the cooking oil,
Inside the cylindrical driving magnet assembly 29 , with a plurality of magnets 66 , is an impeller magnet housing, or casing 31 . The impeller magnet housing 31 of the magnetic pump 21 is hermetically sealed so that any fluid in the impeller magnet housing 31 will not escape to an area exterior to the impeller magnet housing 31 .
Inside the impeller magnet housing 31 is a driving magnet 32 and an impeller 34 . As depicted, the driven magnet 32 and the impeller 34 may be a single unit, in an alternative embodiment, the impeller 34 and the driven magnet 32 may be separate elements connected by a shaft. As is understood by one with ordinary skill in the art, the impeller 34 is the actual device that moves fluid through the magnetic pump 21 .
The impeller magnet housing 31 is preferably connected to a pump housing 35 . The pump housing 35 , in combination with the impeller magnet housing 31 , encases the impeller 34 . The pump housing 35 has a pump inlet 36 and a pump outlet 37 . The cooking liquid is drawn from the tank 13 , though the pump inlet line 22 , into pump inlet 36 and into the pump housing 35 by the action of the impeller 34 . The impeller 34 also, through its motion, ejects the cooking liquid from the pump housing 35 of the magnetic pump 21 . The cooking liquid is ejected though the pump outlet 37 and into pump outlet line 38 .
It is essential that the shaft 64 of the pump about which the impeller 34 turns be constructed of ceramic material to withstand the heat of the oil. A seal 67 prevents the leakage of oil from the pump.
The preferred motor 26 of the magnetic pump 21 has approximately 1.0 horsepower and will perform at approximately 3450 revolutions per minute. Of course, the motor 26 may be sized differently depending on the particular design of the convection reciprocating fryer 10 . One having ordinary skill in the art will readily be able to size the motor 26 for a particular fryer.
FIG. 5 depicts an exploded part diagram of the magnetic pump to be used with the present preferred embodiment. FIG. 5 depicts that pump 21 comprises a motor 26 and a housing 27 , a driving magnet assembly 29 , an impeller magnet housing 31 , an impeller 34 , with driven magnets 32 and a pump housing 35 . Of course, this is only one possible magnetic pump that may be used with the present invention.
As depicted in FIG. 2A , the magnetic pump 21 is preferably situated vertically within the fryer housing 11 in order to minimize the possibility of a steam look in the pump, which would prevent the circulation of the oil through the fryer. Although preferred in the exemplary embodiment 10 , the pump is not required to be situated vertically. Also, the pump outlet 37 of the pump housing 35 is connected by the pump outlet line 38 to a heat exchanger 41 .
The preferred heat exchanger 41 comprises a series of tubing (not depicted) with a heat source near, or even within, the tubing. In the preferred embodiment 10 , the heat exchanger 41 comprises a cylindrical heat exchanger as is conventionally known in the art. The heat exchanger has a heat exchanger exhaust 42 . The heat exchanger exhaust 42 of the heat exchanger 41 is in fluid communication with the pump outlet 37 of the pump 21 via the pump outlet line 38 .
The heating element of the heat exchanger 41 preferably comprises a burner positioned along the axis of the heat exchanger 41 . The heating element could be electric or gas powered, for example. It is preferred that the heating element, comprise an LP or natural gas powered burner. The heating element, of course, could also be equipped with a blower 50 in order to more evenly distribute heat throughout the heat exchanger 41 .
Gas can be distributed through a gas manifold 58 as shown in FIG. 1A to a number of fuel injectors 56 A-D to a fuel injector tube 52 . Several fuel injectors are preferred for the even burning of the gas. It has been found that four injectors are preferred. The gas is ignited by a glow plug with a flame sensor 54 to make sure the gas is turned off if it does not ignite in a specified time. The flame extends from the fuel injector tube 52 into the heat exchanger 41 through a perforated burner sleeve 60 . The convection recirculating fryer 10 is controlled by a controller 60 .
The heat exchanger 41 is designed such that the cooking oil travels through heat exchanger tubing within the heat exchanger 41 . The internal heat exchanger tubing is configured to permit the passage of the cooking oil back and forth across the burner within the heat exchanger. The internal tubing also includes fins for facilitating the absorption of heat from the burner.
The heated cooking oil is ejected from the heat exchanger 41 at the hot oil supply line 46 . Preferably, the cooking oil is moved from the heat exchanger 41 at a constant predetermined temperature (which is usually around 350 degrees Fahrenheit). A control system (not depleted) operates in conjunction with a temperature sensor (not depicted) mounted on the outside of the hot oil supply line 46 to ensure that the cooking oil outlet from the heat exchanger 41 remains at the predetermined temperature. Obviously, if the temperature of the cooking oil drops below the target value, or range, the heating element is instructed by the control system to emit more heat energy into the cooking oil. Conversely, if the temperature of the cooking oil increases above the target value, or range, the heating element is caused to emit less heat energy.
The hot oil supply line 46 of the heat exchanger 41 is connected to the oil inlet orifice 16 of the tank 13 . Thus, the cooking oil completes its journey from the tank 13 , to the pump 21 , to heat exchanger 41 , and back, to the tank 13 . As noted above, the magnetic pump 21 of the fryer 10 is the device that actually causes the cooking oil to flow from the tank 13 , to the pump 21 , to heat exchanger 41 , and back to the tank 13 . The appropriate rate of flow of the oil can be determined by one of ordinary skill in the art and is not important to the present invention.
It should be emphasized that the above-described embodiments of the present invention, particularly, any “preferred” embodiments, are merely possible examples of implementations, merely set forth for a clear understanding of the principles of the invention. Many variations and modifications may be made to the above-described embodiment(s), 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 this disclosure. | A convection recirculating food product fryer with a fry tank with and inlet tube connected to a heat exchanger and an outlet connected to a magnetic pump with an outlet tube to the heat exchanger, the pump having a driving magnet assembly housing an impeller and a driven magnet, with a ceramic shaft extending through the impeller about which the impeller rotates when pumping oil; an electric motor magnetically coupled to the magnetic pump; a burner to heat the oil in the heat exchanger; a controller to control the ignition and running of the burner. | 0 |
BACKGROUND OF THE INVENTION
This invention relates to a primer for PCR and also to a method for deciding a base sequence thereof. More particularly, the invention relates to a PCR primer suitable for the adenylation in the course of PCR using a termostable DNA polymerase having terminal transferase activity and also to a method for deciding the sequence of such a PCR primer.
For the detection of DNA or RNA, it is usual to detect after amplification of a sequence of DNA or RNA obtained from a specimen. For this purpose, PCR amplification is usually performed. In order to detect a PCR-amplified DNA fragment, the DNA fragment is subjected to radioisotopic labeling or is labeled with chemical emission or fluorescence, followed by detection of the labeled DNA fragment after separation of a sample such as by gel electrophoresis. Recently, terminal fluorescence labeling by a synthetic DNA and fluorescence labeling by intercalator capable of intercalation with DNA fragments is enabled and has now been in frequent use. When using an intercalating fluorphore, a DNA fragment subjected to electrophoresis with an agarose gel is labeled with an intercalator, such as ethidium bromide, acridine orange or the like, and detected.
For the measurement of a more accurate fragment length, a terminal fluorescence-labeled DNA fragment is subjected to electrophoresis with a polyacyrlamide gel and detected. For a process requiring the measurement of an accurate fragment length, mention is made of RT-PCR (Reverse Transcriptase-PCR, J. Stenman et al.; “Accurate determination of relative messenger RNA levels by RT-PCR” Nature Biotechnology, 1999, 17, 720-722), FDD (Fluorescent Differential Display, T. Ito et al.; “Fluorescent differential display: arbitrarily primed RT-PCR finger printing on an automated DNA sequencer” FEBS Letters, 1994, 351, 231-236), ATAC-PCR (K. Kato; “Adaptor-tagged competitive-PCR: a novel method for measuring relative gene expression” Nucleic Acids Research, 1997, 25, 4694-4696), SSCP (M. Orita et al.; “Detection of polymorphisms of human DNA by gel electrophoresis as single-Strand conformation polymorphisms” Proc. Natl. Acad. Sci. USA, 1989, 86, 2766-2770) and the like. In these methods, an amplified product is analyzed with a fluorescent-type DNA sequencer after PCR.
SUMMARY OF THE INVENTION
The currently proposed amplification and detection of a DNA fragment based on PCR and electrophoresis has been introduced hereinabove, with many problems undesirably involved in practical applications. More particularly, adenylation to a DNA fragment by the DNA polymerase takes place in the course of PCR, and thus, two peaks are detected based on an adenylated fragment and a non-adenylated fragment, respectively. The probability of the occurrence of the adenylation varies depending on the type of sample DNA and the PCR conditions. This makes it difficult to obtain a peak area of a target DNA fragment due to the splitting of peak.
In SSCP analyses for diagnostic purposes, a peak area is determined for quantitative analysis, enabling one to detect LOH (Loss of Heterozygosity) that will not be judged by a conventional method (K. Sugano et al.; “Sensitive Detection of Loss of Heterozygosity in the TP53 Gene in Pancreatic Adenocarcinoma by Fluorescence-Based Single-Strand Conformation Polymorphism Analysis Using Blunt-End DNA Fragments” Genes, Chomosomes and Cancer, 1996, 15, 157-164, Sensitive Detection of Loss of Heterozygosity in the TP53 Gene in Pancreatic Adenocarcinoma by Fluorescence-Based Singled Strand Conformation Polymorphism Analysis Using Blunt-End DNA Fragments). However, for highly accurate diagnosis, it is necessary to suppress a rate of a peak area of non-adenylated products to peak area of adenylated products to a level within 10%.
To prevent the peak splitting, two procedures are considered including removal of added adenine or positive adenylation caused to occur to 100%. With the method of removal of the added adenine, exnzymatic treatment has to be performed for the removal after PCR (F. Ginot et al.; “Correction of some genotyping errors in automated fluorescent microsatellite analysis by enzymatic removal of one base overhangs” Nucleic Acids Research, 1996, 24, 540-541). On the other hand, in order to cause the adenylation to positively occur, it is necessary to control a concentration of Mg 2+ ions in a reaction solution and to change reaction conditions. Nevertheless, a difficulty is now involved in stably obtaining an adenylated PCR product. Moreover, although there is a report stating that the efficiency of adenylation changes depending on the sequence in the vicinity of 5′ terminus of a template DNA fragment (V. L. Magnuson et al.; “Substrate Nucleotide-Determined Non-Templated Addition of Adenine by Taq DNA Polymerase: Implications for PCR-Based Genotyping and Cloning” Biotechniques, 1996, 21, 700-709), the sequence is not general, with no decision method of the sequence being proposed.
The method of changing the efficiency of adenylation depending on the sequence at 5′ terminus of a template DNA is called reverse primer tailing (M. J. Brownstein et al.; “Modulation of Non-Templated Nucleotide Addition by Taq DNA Polymerase: Primer Modifications that Facilitate Genotyping” Biotechniques, 1996, 20, 1004-1010).
An object of the invention is to design, in reverse primer tailing, a sequence that causes adenylation to generally occur in a high efficiency against any type of PCR primer capable of amplifying a target DNA fragment, thereby providing a primer sequence that can amplify a DNA fragment capable of being simply analyzed by electrophoresis.
To achieve the above object, a PCR primer having an anchor sequence wherein a sequence is designed to cause adenylation to occur in a high efficiency at 5′ terminus of a reverse primer is used according to the invention. The term “anchor sequence” used herein means a sequence which is positioned at the 5′ terminus of a primer sequence that is complementary with a target gene and which is not complementary with a target DNA sequence. The anchor sequence does not hybridize with a target sequence in the first cycle of PCR, but hybridizes only when complementary strand synthesis proceeds at an opposite strand. Accordingly, the anchor sequence hybridizes in the second and subsequent cycles of the PCR, and the resulting amplified fragment becomes one that has a target sequence and an anchor sequence. The anchor sequence can be designed irrespective of a target DNA sequence, so that it is possible to select a sequence capable of causing adenylation to occur in a high efficiency. It is known that the adenylation of PCR is such that the efficiency of adenylation differs depending on the type of base species at the 5′ terminus, and the efficiency of the adenylation is decided by approximately 5 bases at the 5′ terminus.
In the practice of the invention, four types of primers having anchor sequences wherein only one base at the 5′-terminus among the anchor sequences each made of two to five bases is changed are provided to perform PCR. The results of the PCR are such that the efficiencies of adenylation of the four types of anchor sequences are measured, followed by screening an anchor sequence that is more likely to undergo adenylation. Next, a sequence, in which the adenylation is most likely to occur at the first base of the anchor sequence from the 5′ terminus, is decided, followed by synthesis of four types of primers wherein the second base from the 5′ terminus of the anchor sequence is changed. Like the case of the first base, PCR is performed and a base species with which adenylation is likely to occur at the sequence of the second base from the 5′ terminus is decided. The above procedure is repeated to decide an anchor sequence made of 2 to 5 bases with which adenylation is liable to occur.
PCR is performed using a primer having such an anchor sequence which has been decided by the above procedure and with which adenylation is likely to occur. As a result, an amplified product wherein adenylation has occurred is preferentially obtained. If the ratio of a non-adenylated, amplified product to an adenylated, amplified product is 10% or below, this is usable for diagnosis requiring quantitative analysis.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic view showing PCR using a PCR primer having an anchor sequence according to the invention, an embodiment of the resulting product, and the evaluation of the PCR primer having an anchor sequence with a labeled fluorescence intensity after electrophoresis of the product;
FIG. 2A is an electropherogram of an amplified product in PCR using an anchor sequence-free reverse primer, and
FIG. 2B is an electropherogram of an amplified product in PCR using a reverse primers having an anchor sequence;
FIGS. 3A to 3 D are, respectively, flow charts showing the concept of a screening method of anchor sequences that facilitate adenylation according to the invention;
FIGS. 4A to 4 D are, respectively, electropherograms particularly showing the results of electrophoresis of PCR products obtained by using PCR reverse primers having four types of anchor sequences;
FIG. 5 is a graph showing, for comparison, the results of the efficiency of adenylation of (S A /(S A +S)) based on the results of electrophoresis of the PCR products obtained by using PCR reverse primers having four types of anchor sequences;
FIGS. 6A to 6 D are, respectively, flow charts of deciding a second base from the 5′ terminus of each anchor sequence subsequent to FIGS. 3A to 3 D;
FIGS. 7A to 7 D are, respectively, electropherograms showing the results of electrophoresis of PCR products obtained by using PCR reverse primers having four types of anchor sequences;
FIG. 8 is a graph showing, for comparison, the results of the efficiency of adenylation of (S A /(S A +S)) based on the results of electrophoresis of the PCR products obtained by using PCR reverse primers having four types of anchor sequences;
FIGS. 9A to 9 D are, respectively, flow charts of deciding a third base from the 5′ terminus of each anchor sequence subsequent to FIGS. 6A to 6 D;
FIGS. 10A to 10 D are, respectively, electropherograms obtained by electrophoresis of amplified products wherein PCR is carried out by use of PCR reverse primers having four types of anchor sequences;
FIG. 11 is a graph showing, for comparison, the efficiency of adenylation of the amplified products wherein PCR is carried out by using PCR reverse primers having four types of anchor sequences;
FIGS. 12A and 12B are, respectively, a schematic view showing a PCR reverse primer structure having an anchor sequence decided in the example of the invention;
FIGS. 13A and 13B, respectively, show an instance of evaluating the influence of adenylation in SSCP wherein FIG. 13A is an electropherogram showing the results of analysis of an amplified product in PCR using an anchor sequence-free reverse primer and FIG. 13B is an electropherogram showing the results of analysis of an amplified product in PCR using a reverse primers having an anchor sequence.
FIG. 14A is an electropherogram in case where a target DNA is subjected to PCR using a fluorescence-labeled PCR forward primer group and an anchor sequence-free PCR reverse primer group, and
FIG. 14B is an electropherogram in case where a target DNA is subjected to PCR using a fluorescence-labeled PCR forward primer group and a reverse primer having an anchor sequence; and
FIG. 15 is a flowchart showing an example of software for simply designing a base sequence of a PCR primer having an anchor sequence.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention is described by way of examples.
EXAMPLE 1
FIG. 1 is a schematic view showing PCR using a PCR primer having an anchor sequence according to the invention, an embodiment of the resulting product, and the evaluation of the PCR primer having an anchor sequence with a labeled fluorescence intensity after electrophoresis of the product. Reference numeral 1 indicates sample DNA. Reference numeral 2 indicates a forward primer for PCR and reference numeral 4 indicates a reverse primer for PCR. When the sample DNA 1 is denatured into two single strands 1 - 1 and 1 - 2 , the respective primers, respectively, have a base length of 12 to 20 bases which are complementary to two single strands. The forward primer 2 is labeled with a fluorphore F at the 5′ terminus thereof. The anchor sequence 3 is connected at the 5′ terminus of the reverse primer 4 . It will be noted that the anchor sequence 3 has a base length of 2 to 5 bases and is one which is not complementary to the target DNA sequence. Accordingly, the base length of the reverse primer 4 containing the anchor sequence 3 corresponds to 14 to 25 bases.
Such primers as set out above are provided, and when PCR is performed using a thermostable DNA polymerase having terminal transferase activity, the primers 2 , 4 are, respectively, elongated as shown by arrows. As stated hereinbefore, in the second and subsequent cycles of PCR, an amplified fragment becomes one that has a target sequence and an anchor sequence, and this fragment serves as target DNA, thereby permitting the elongation reaction of the forward primer 2 to occur. At this stage, there are amplified a fragment 5 , which has not undergone adenylation at the 3′ terminus of the resulting PCR product, and a fragment 6 , which has undergone adenylation at the 3′ terminus. The added adenine is indicated as A enclosed with a circle in the figure.
The thus obtained PCR product is analyzed by electrophoresis, revealing that as shown in electropherogram 9 , a peak 8 derived from the adenylated fragment 6 and a peak 7 derived from the non-adenylated fragment 5 are detected. In the electropherogram, the horizontal axis indicates a base length wherein the base lengths of the peak 8 and the peak 7 differ only by one base of adenine resulting from the absence or presence of added adenine. For better understanding of the figure, the respective peaks are shown as kept away from each other.
If the 5′ terminus of the anchor sequence 3 is converted to a base that facilitates the adenylation, it becomes possible that the peak 8 derived from the adenylated fragment 6 is made significantly greater than the peak 7 derived from the non-adenylated fragment 5 , thus improving the accuracy of the analysis.
In Example 1, cDNA was prepared from RNA extracted from a wild strain of budding yeast and used as sample DNA 1 . As PCR forward primer 2 , a primer for forward PCR that has (sequence 1) and is labeled with fluorphore HEX at the 5′ terminus thereof was used.
Sequence 1
5′-HEX-agaaagagggc tccaatttct c-3′
On the other hand, a PCR primer having (sequence 2) at a moiety that is complementary relative to the sample DNA was used among the PCR reverse primers 4 .
Sequence 2
5′-gtgagcaata cacaaaattg ta-3′
When PCR of the sample DNA 1 derived from the wild strain of germinated yeast was carried out by use of the above primer pair, a PCR product having a length of 187 bp is amplified. PCR was performed such that using Ex-Taq polymerase (Takarashuzo K. K.), 25 cycles, each consisting of 94° C. and 30 seconds, 60° C. and 60 seconds and 72° C. and 30 seconds, were repeated, followed by keeping the conditions of 72° C. and 2 minutes. The resulting PCR product was subjected to electrophoretic analysis using a 3.5% polyacrylamide gel. The resultant electrophoretic data were corrected with respect to the base line according to a software attached to the electrophoresis device used, thereby making an electropherogram.
FIG. 2A is an electropherogram 10 of an amplified product in PCR using an anchor sequence-free reverse primer, and FIG. 2B is an electropherogram 13 showing an amplified product in PCR using a reverse primer having an anchor sequence. With the electropherogram of FIG. 2A, as will be apparent from the comparison between the peak 11 of the adenylated fragment 6 and the peak 12 of the non-adenylated fragment 5 , the peak 11 is smaller than the peak 12 . The ratio of the peaks is approximately at 1:4. On the other hand, with the electropherogram 13 of FIG. 2B, the comparison between the peak 11 of the adenylated fragment 6 and the peak 12 of the non-adenylated fragment 5 reveals that the peak 11 is predominantly greater than the peak 12 . More particularly, it will be seen that in the PCR of this example, while adenylation is promoted by the reverse primer having the anchor sequence, the non-adenylated fragment 5 is suppressed to a level of 10% or below of the adenylated fragment 6 .
FIGS. 3A to 3 D are, respectively, a flow chart showing the concept of a screening method of anchor sequences that facilitate adenylation according to the invention. As illustrated with respect to FIG. 1, there are provided sample DNA 1 , and PCR forward primer 2 and PCR reverse primer 4 , both for carrying out PCR using DNA 1 , converted to single strands, as templates, respectively. In order to amplify a target DNA fragment, the PCR forward primer 2 has such a sequence as to be complementary to a target sequence and is labeled with fluorphore F. The PCR reverse primer 4 is composed of a sequence 4 complementary to a target sequence and anchor sequences 3 - 1 , 3 - 2 , 3 - 3 or 3 - 4 , which are not complementary to the target sequence and are made of four bases.
Attention should be paid to the 5′ terminii of the anchor sequences 3 - 1 , 3 - 2 , 3 - 3 and 3 - 4 , from which it will be apparent that four types of bases such as A, C, G and T are, respectively, at 5′ terminus. It is to be noted that the base sequence of NNN means 64 (=4×4×4) base sequences consisting of all combinations of A, C, G and T. The sequences 3 - 1 , 3 - 2 , 3 - 3 and 3 - 4 are mixtures of 64 oligonucletides, and, in practice, can be handled as four types of oligonucletides made of A, C, G and T bases at the 5′ terminus. In FIG. 3A, PCR is performed, like FIG. 1, by means of a PCR reverse primer wherein A is attached to at the 5′ terminus of the anchor sequence 3 - 1 . As a result, a non-adenylated DNA fragment 5 and an adenylated DNA fragment 6 are obtained. Thus, as shown in electropherogram 9 , the area of a peak 7 derived from the non-adenylated, amplified DNA fragment 5 , and the area of a peak 8 derived from the adenylated, amplified DNA fragment 6 can be discriminated from each other and detected. One of 64 oligonucletides may have such a sequence as to be complementary to the target DNA fragment, and the other 63 oligonucletides are non-complementary, so that it may be possible to substantially deal with these oligonucletides as a non-complementary anchor sequence. Hence, the peak area of peak 7 and 8 are calculated as an oligonucletide that has an anchor sequence having base A at the terminus thereof. Likewise, in FIGS. 3B to 3 D, the area of the peak 7 derived from the non-adenylated, amplified DNA fragment 5 and the area of the peak 8 derived from the adenylated, amplified DNA fragment 6 can be discriminated from each other and detected.
The area S of the peak 7 derived from the non-adenylated, amplified DNA fragment 5 and the area S A of the peak 8 derived from the adenylated, amplified DNA fragment 6 are obtained, and the efficiency of adenylation of (S A /(S A +S) ) is calculated from the ratio between the peak areas. The base at the 5′ terminus of the PCR reverse primer, which gives the highest efficiency of adenylation is adopted as an anchor sequence.
In FIGS. 4A to 4 D, specific examples of the results of electrophoresis of PCR products obtained by using PCR reverse primers having four anchor sequences 3 - 1 , 3 - 2 , 3 - 3 and 3 - 4 are shown as electropherograms 41 , 42 , 43 and 44 , respectively. From each electropherogram, the area S A of a peak derived from the adenylated, amplified DNA fragment 6 and the area S of a peak derived from the non-adenylated, amplified DNA fragment 5 are decided, from which the adenylation efficiency of (S A /(S A +S) ) is calculated for the respective primer reverse primers, with the results shown in FIG. 5 as graph 45 for comparison. In the graph, the anchor sequence (c) yields the highest adenylation efficiency and this sequence was selected. The anchor sequence (c) had base G, so that G was adopted as a base at the 5′ terminus of the anchor sequence.
As stated hereinabove, anchor primers wherein four types of bases were used as a base at the 5′ terminus of the anchor sequence were used, of which an anchor sequence exhibiting the best effect was firstly selected. Secondly, while using the thus selected base at the 5′ terminus of the anchor sequence, anchor primers wherein four types of bases are applied to as a base at the second from the 5′ terminus are used, and an anchor sequence having the best effect is selected from among the four anchor sequences. When the above procedure is repeated for screening, for example, the bases of all the anchor sequences 3 made of four bases can be decided.
FIGS. 6A to 6 D show flow charts of deciding the second base from the 5′ terminal of the anchor sequences subsequent to FIGS. 3A to 3 D. Initially, PCR reverse primers having anchor sequences 3 - 5 , 3 - 6 , 3 - 7 and 3 - 8 wherein the base at the 5′ terminus is decided as G are provided. N in the base sequences of the anchor sequences 3 - 5 , 3 - 6 , 3 - 7 and 3 - 8 of the PCR reverse primers consists of a mixed base of A, C, G and T. Accordingly, the base sequences of NN of the anchor sequences 3 - 5 , 3 - 6 , 3 - 7 and 3 - 8 of the PCR reverse primers in FIGS. 6A to 6 D are made of 16 (4×4) base sequences composed of all the combinations of A, C, G and T. The target DNA is amplified by the combinations of the PCR reverse primers having the four anchor sequences 3 - 5 , 3 - 6 , 3 - 7 and 3 - 8 and the fluorescence-labeled PCR forward primer 2 . The thus amplified DNA fragments are each analyzed by gel electrophoresis, from which the peak areas of the non-adenylated DNA fragment 5 and the adenylated DNA fragment 6 are decided, of which an anchor sequence having the best effect is selected as second base species from the 5′ terminus.
In FIGS. 7A to 7 D, the specific examples of the results of electrophoresis of the PCR products obtained by use of the PCR reverse primers having the four anchor sequences 3 - 5 , 3 - 6 , 3 - 7 and 3 - 8 are shown as electropherograms 80 , 81 , 82 and 83 , respectively. The peak area S A derived from the adenylated, amplified DNA fragment 6 and the peak area S derived from the non-adenylated, amplified DNA fragment 5 are, respectively, decided from each electropherogram, and the adenylation efficiency of (S A /(S A +S) ) is calculated for the respective primer reverse primers, with the results shown in FIG. 8 as graph 84 for comparison. From the FIG. 8, it will be seen that the anchor sequence (c) gives the best efficiency of adenylation and thus, this sequence (c) is selected. Since the anchor sequence (c) has base G, G is adopted as a second base from the 5′ terminus of the anchor sequence. More particularly, evidence is given that the bases up to the second from the 5′ terminus of the anchor sequence should favorably be GG.
It will be noted that in FIG. 8, the anchor sequences (a) and (d) other than the anchor sequence (b) whose effect is lowest were also checked, with the following results being obtained. The efficiencies of adenylation of both (a) and (d) in FIG. 8 are substantially equal to that of (c) in FIG. 8 . (d) was not adopted because in the electropherogram 83 shown in FIG. 7D, the peak derived from the non-adenylated, amplified product 5 and the peak derived from the adenylated, amplified product 6 were detected as being separate from each. With respect to (a), the peak of electropherogram 80 shown in FIG. 7A is such that the peak derived from the non-adenylated, amplified product 5 and the peak derived from the adenylated, amplified product 6 are recognized as the same as one peak and this sequence was adopted. The base of the anchor sequence (a) is A, which was adopted as the second base from the 5′ terminus of the anchor sequence. That is, it is shown that the bases up to the second base from the 5′ terminus of the anchor sequence should favorably be GA.
As a result, it is shown in this example that the anchor sequence is favorably such that the bases up the second from the 5′ terminus may be GG or GA.
In FIGS. 9A to 9 D, there are shown flow charts showing the decision of a third base from the 5′ terminus subsequent to FIGS. 6A to 6 D. In this instance, the case where the bases up to the second from the 5′ terminus of the anchor sequence are decided as GG is described, and if GA is adopted, it is sufficient to read GG for GA. Initially, PCR reverse primers having anchor sequences 3 - 9 , 3 - 10 , 3 - 11 and 3 - 12 which individually have two bases of GG from the 5′ terminus are provided. N in the base sequences of the anchor sequences 3 - 9 , 3 - 10 , 3 - 11 and 3 - 12 of the PCR reverse primers consists of a base sequence of four bases of A, C, G and T. Accordingly, PCR reverse primers having anchor sequences 3 - 9 , 3 - 10 , 3 - 11 and 3 - 12 and the base sequence of N are four types of bases of A, C, G and T. The target DNA is amplified by PCR through combinations of the PCR reverse primers having the thus provided four anchor sequences 3 - 9 , 3 - 10 , 3 - 11 and 3 - 12 and a fluorescence-labeled PCR forward primer 2 . The amplified DNA fragment is analyzed by gel electrophoresis, and the peak areas of the non-adenylated DNA fragment 5 and the adenylated DNA fragment 6 , from which an anchor sequence having the best effect is selected as third base species from the 5′ terminus.
FIGS. 10A to 10 D, respectively, show electropherograms obtained by electrophoresis of amplified products, which are obtained by PCR using the PCR reverse primers having the four anchor sequences 3 - 9 , 3 - 10 , 3 - 11 and 3 - 12 . The adenylation efficiency of each PCR reverse primer is obtained from the respective electropherograms.
FIG. 11 is a graph 90 showing, for comparison, the adenylation efficiencies of the amplified products subjected to PCR by use of PCR reverse primers having four anchor sequences 3 - 9 , 3 - 10 , 3 - 11 and 3 - 12 . Like the foregoing instances, an anchor having the best effect is selected as a base species at the third base from the 5′ terminus. With Example 1, the results of the screening for the third base reveal that no significant difference is found in the efficiency of adenylation and that only adenylated fragments were detected for all the PCR reverse primers having such anchor sequences as mentioned above. Accordingly, the selection of the third base is unnecessary.
In this way, an anchor sequence which enables the efficiency of adenylation to be set at a required value by proper selection of bases of up to the second from the 5′ terminus is decided in this example. Accordingly, it is not always necessary that the anchor sequence be composed of 4 bases. More particularly, it will be seen that the anchor sequence of Example 1 may be one which has a GA or GG sequence at the 5′ terminus. In general, when screening is effect for five or more bases, the difference in the efficiency of adenylation becomes small. In this sense, it is sufficient for practical applications that the length of an anchor sequence corresponds to approximately 5 bases.
FIGS. 12A and 12B schematically show PCR reverse primer structures having such anchor sequences as decided in this example, respectively. A PCR reverse primer 91 having the anchor sequence is constituted of a sequence part 95 hybridized with target DNA and a anchor sequence 94 which is adjacent to the 5′ terminus of the sequence 95 and is non-complementary to the target DNA. The two bases at the 5′ terminus of the anchor sequence is in a GA base sequence or GG base sequence.
When the anchor sequence is made of three bases, the anchor sequences are possible at 4×4=64 in total. In Example 1, an anchor sequence that ensures a high efficiency of adenylation can be decided by three cycles of screening among 64 sequences. The base sequence of the PCR reverse primer is, in turn, decided such that the thus decided anchor sequence is positioned at the 5′ terminus of a sequence that is complementary to the target DNA. PCR using the primer having such an anchor sequence as to ensure a high efficiency of adenylation as in this example is carried out, and according to an analytical method of detecting an amplified product by electrophoresis, only the peak of an adenylated, amplified product can be detected, thereby obtaining the results of analysis of high resolution.
EXAMPLE 2
The method of the invention is applicable to SSCP. In the same manner as illustrated with reference to FIGS. 3A-3D to 11 , target DNA is subjected to PCR amplification using a PCR forward primer labeled with flurophore and PCR reverse primer having an anchor sequence wherein a combination of bases capable of causing a high efficiency of adenylation are arranged at the 5′ terminus. As a result of the PCR, an adenylated fragment and a non-adenylated fragment were, respectively, amplified. After heat denaturing and cooling on ice of the resultant PCR product, it is subjected to electrophoresis using an SSCP electrophoretic gel made of 6% polyacrylamide gel containing 10% glycerol. A 1×TBE buffer containing 10% of glycerol is used as an electrophoretic buffer.
FIGS. 13A and 13B are, respectively, an instance of evaluating the influence of the adenylation on SSCP and correspond to FIGS. 2A to 2 B. FIG. 13A shows an electropherogram 140 obtained as the results of analysis of the amplified product in PCR using an anchor sequence-free reverse primer, and FIG. 13B shows an electropherogram 141 obtained as the results of analysis of the amplified product in PCR using a reverse primer having an anchor sequence. In the electropherogram 140 of FIG. 13A, a peak 142 derived from an adenylated fragment amplified from paternal DNA, a peak 143 derived from a non-adenylated fragment amplified from paternal DNA, a peak 144 derived from an adenylated fragment amplified from a maternal DNA, and a peak 145 derived from a non-adenylated fragment amplified from maternal DNA are detected. In the electropherogram 140 , the ratio between the non-adenylated fragment and the adenylated fragment is at 3:1, thus, the adenylated fragment being mixed at 10% or over. On the other hand, in the electropherogram 140 of FIG. 13B, a peak 142 derived from the adenylated fragment amplified from paternal DNA and a peak 144 derived from the adenylated fragment amplified from maternal DNA are detected. As will be seen from the figure, little non-adenylated fragment is detected in the electropherogram 141 .
As will be appreciated from FIGS. 13A and 13B, when the adenylation is promoted by the reverse primer having an anchor sequence, the PCR product can be one wherein a non-adenylated fragment is removed from a mixture of a non-adenylated fragment and an adenylated fragment. As a result, diagnosis with SSCP can be made more accurately.
EXAMPLE 3
The method of the invention can be applicable to multiplex PCR. In the same manner as in Example 1, target DNA is subjected to PCR amplification by use of a fluorescence-labeled PCR forward primer and a reverse primer having an anchor sequence. In Example 1, the procedure is illustrated on the assumption that one target DNA is amplified through one reaction tube. In multiplex PCR, a plurality of target DNA's are simultaneously amplified by in reaction tube, and the resulting PCR products are electrophoretically separated and simultaneously detected. The anchor sequence may be one which should satisfy the requirement that the sequence is not complementary to target DNA, and can be design irrespective of the sequence of the target DNA, so that the same anchor sequence is usable against all the PCR reverse primers.
FIG. 14A is a view showing an electropherogram 150 of the case where target DNA is subjected to PCR by use of a group of fluorescence-labeled PCR forward primers and a group of anchor sequence-free PCR reverse primers and the resultant PCR products are electrophoretically analyzed. FIG. 14B is a view showing an electropherogram 151 of the case where target DNA is subjected to PCR by use of a group of fluorescence-labeled PCR forward primers and a group of reverse primer having an anchor sequence and the resultant PCR products are electrophoretically analyzed. As shown in FIG. 14A, where multiplex PCR is performed without use of an anchor sequence promoting the adenylation efficiency, the peaks of the electropherogram 150 are closed to one another and quantitative analyses thereof may be difficult in some cases. However, as shown in FIG. 14B, when multiplex PCR is performed by use of the PCR primers that, respectively, have an anchor sequence facilitating the adenylation efficiency, the peaks are kept more distant from one another as seen in the electropherogram 151 . This enables one to carry out a high degree of multiplexing. In Example 3, because any peak derived from a non-adenylated fragment is not detected, a high degree of multiplexing becomes possible.
Example of a Software For Deciding an Anchor Sequence
At a stage of deciding a primer sequence by use of PCR, the use of a software capable of simply designing a base sequence of a PCR primer having an anchor sequence is beneficial.
FIG. 15 shows an example of a flow chart of a soft ware designed therefor. In step 101 , a PCR reverse primer with an anchor sequence to a PCR reverse primer n with an anchor sequence are each subjected to PCR in the same manner as illustrated with reference to FIGS. 3A-3D to 11 . In step 102 , the efficiency of adenylation is calculated from each of the products of PCR carried out in the step 101 with respect to the PCR reverse primers having the respective anchor sequences. In step 103 , the efficiencies of adenylation are compared with one another from the results of the step 102 to judge and select a PCR reverse primer having an anchor sequence capable of giving a higher adenylation efficiency. In step 104 , an anchor sequence capable of giving a high efficiency of adenylation is stored in a file from result of step 103 . Attention should be paid here to the fact that in step 103 , although a PCR reverse primer with an anchor sequence capable of giving a higher efficiency of adenylation is selected, this soft wafer is intended to select an anchor sequence for application to arbitrary target DNA and the anchor sequence alone is cut off from the PCR reverse primer having the selected anchor sequence and stored in the file.
Those steps up to the step 104 are a so-called preparatory stage of this soft ware, and the process of deciding a PCR primer for target DNA includes step 105 onward.
In step 111 , a sequence of target DNA is introduced. In step 112 , an amplification region of the target DNA is decided. In step 113 , base sequences of a PCR forward primer and a PCR reverse primer, which, respectively, correspond to the sequences of amplification region of target DNA are so designed appropriate Tm value and not to form either an interprimer or intraprimer secondary structure. Next, in step 114 , one of anchor sequences stored in the file prepared beforehand (i.e. a candidate for anchor sequence) is retrieved and joined at the 5′ terminus of the PCR reverse primer designed in the step 113 to temporarily decide an anchor sequence-bearing PCR reverse primer. In step 115 , it is evaluated whether or not the PCR reverse primer that is so designed as not to form a secondary structure has the secondary structure formed in the step 113 as a result of the addition of the anchor sequence. If a secondary structure or a dimer of the primer is formed, a candidate for another anchor sequence is selected and a PCR reverse primer having the selected anchor sequence is temporarily decided. If any secondary structure is not formed, the temporarily decided primer in the step 117 is decided as a reverse primer having an anchor sequence.
In the step 115 , when anchor sequences are judged as ones that form a secondary structure 32 times or over, i.e. when the step 116 is judged as Yes, the procedure is returned to the step 112 wherein the amplification region of the target DNA is decided again, followed by repeating the above-stated procedure to decide a reverse primer having an anchor sequence-bearing PCR reverse primer. It will be noted that in this example, the anchor sequence is checked 16 times with respect to all the anchor sequences of two bases subsequent to GA at the 5′ terminus and the anchor sequence is also checked 16 times with respect to all the anchor sequences of two bases subsequent to GG at the 5′ terminus. If a secondary structure is formed in all of these checks, the procedure is returned to step 112 .
As will be apparent from the above, if the software is used, an anchor sequence capable of giving a high efficiency of adenylation can be simply decided from among a plurality of anchor sequences. Additionally, an anchor sequence that gives a high efficiency of adenylation can be stored in a file, and can be selected as a candidate for an anchor sequence against a variety of primers. To check whether or not an anchor sequence-added primer has a secondary structure formed therein enables one to simply design a PCR primer having an anchor sequence and decide a base sequence. If information of a target DNA sequence and an approximate base length of an amplified product is obtained from a user, design service of a PCR primer having an anchor sequence is possible.
Others
In the above-stated examples, the addition of an anchor sequence to a PCR reverse primer on the assumption that a PCR forward primer is labeled with a fluorophore has been illustrated. Needless to say, the invention is also applicable to the case where a PCR reverse primer is subjected to fluorescence labeling. In this case, an anchor sequence is added merely to the 5′ terminus of the PCR forward primer.
Moreover, an anchor sequence may be, respectively, attached to both a PCR forward primer and a PCR reverse primer.
In PCR of a target DNA sequence, anchor sequence-added primer enables adenylation at the terminus of a DNA fragment at a high efficiency, resulting in the analysis of high resolution.
2
1
21
DNA
Artificial Sequence
forward DNA primer which is used in PCR and
hybridizes with DNA fragment originated from yeast gene.
1
agaagagggc tccaatttct c 21
2
22
DNA
Artificial Sequence
base sequence of a part of reverse DNA primer
which is used in PCR and the base sequence of a part of
reverse DNA primer hybridizes with DNA fragment
originated from yeast gene.
2
gtgagcaata cacaaaattg ta 22
Free text of a sequence table:
(1) Description of other related information relating to the sequence of sequence No. 1.
A forward primer for amplifying yeast gene (YGR281W)
(2) Description of other related information concerning the sequence of Sequence No. 2.
A sequence complementary to yeast gene (YGR281W) of a reverse primer for amplifying the yeast gene (YGR281W). | Adenylation of a DNA fragment with a DNA polymerase occurs in the course of PCR, and thus two peaks are detected. To prevent the peak splitting, it is necessary to raise efficiency of adenylation a single peak to occur without changing reaction conditions. To this end, four types of PCR primers which, respectively, have an anchor sequence at 5′ terminus so that any of A, C, G or T is attached to at the 5′ terminus of the anchor sequence, and PCR is carried out by use of the respective primers to determine efficiencies of adenylation. Subsequently, an anchor sequence that is more likely to undergo adenylation is screened to decide an anchor sequence more likely undergo adenylation, followed by PCR by use of a primer having the decided anchor sequence. | 2 |
BACKGROUND OF THE INVENTION
[0001] The present invention relates to a solid-state light source comprising a solid-state emitter designed for emitting light energy, preferably having an LED, a luminescent light conversion medium, made from glass or glass ceramics, for converting emitted light energy to light energy of a different frequency spectrum, and having a coupling medium for decoupling the light energy to an ambient medium, such as air.
[0002] In order to improve the efficiency of light sources in lighting engineering one has tried to replace conventional incandescent light sources or fluorescent light sources by solid-state light sources. Solid-state light sources in the form of LEDs produce light in a very narrow spectral band, while white light is required for illumination purposes. Commercially available white LEDs use a III nitride emitter for stimulating a luminescent material (down conversion) that emits a secondary wavelength in a lower wavelength band. One known solution uses a blue InGaN/GaN LED for stimulating YAG:CE, a broadband yellow luminescent material. With these LEDs, which have been converted using a luminescent material, a given proportion of the emitted blue light passes the luminescent layer covering the LED chip so that the overall spectrum obtained assumes a color very close to white light. Due to the absence of any spectral portions in the blue/green band and in the red wavelength band, the resulting color is not satisfactory in most of the cases.
[0003] Another solution consists in the use of a solid-state emitter, emitting in the UV or the near UV range, which is coupled to a full-color luminescent system. It is thereby possible to realize white light sources that are satisfactory in terms of color (compare Phys. Stud. Sol. (a) 192 No. 2, 237-245 (2002, M. R. Krames et al.: High-Power III-Nitride Emitters for Solid-State Lighting”).
[0004] The luminescent particles are embedded in this case in epoxy resin and are applied onto the solid-state emitter as a luminescent layer.
[0005] Embedding the luminescent materials used in epoxy resin leads, however, to certain disadvantages with the before-mentioned luminescent systems that serve for converting the light emitted by the LEDs to a desired spectral range, especially for producing white light. The granulates used lead to scattering losses. A non-homogeneous distribution of the granulate on the solid-state emitter may lead to variable color perception as a function of angle. In addition, epoxy resins are instable over time in many respects, especially with respect to their optical and mechanical properties. And as a rule, thermal stability and stability to short-wave radiation in the blue or the UV spectral band is also unsatisfactory. Moreover, production of such conversion layers is complex and expensive.
[0006] US 2003/0025449 A1 discloses an LED according to the preamble of Claim 1 , where the light emitted by an LED chip passes a cavity which is filled with a UV-stable optical medium having a refractive index of 1.4 to 1.5, and then reaches a cap, which consists of luminescent glass, for converting the emitted light to a longer-wave spectral band. In an alternative embodiment, the cavity surrounding the chip is filled with an optical coupling medium in the form of a luminescent material designed in such a way that the entire emission spectrum appears to be white. The cap 18 in this case has optical properties and may be an optic Fresnel lens, a bifocal lens, a plano-convex or a plano-concave lens, for example.
[0007] Another solid-state light source according to the preamble of Claim 1 has been known from DE 103 11 820 A1.
[0008] The light emitted by the LED is converted in this case to longer-wave light via a luminescent glass body consisting of a base glass with a rare earth doping. The rare earth doping may take a proportion of up to 30 % by weight. It preferably consists of Eu 2 O 3 or CeO 2 . The base glass may be a borosilicate glass, an alkaline earth borosilicate glass, an alumino-borosilicate glass, a lead-silicate glass (optical flint), a soda-lime glass (crown glass), an alkali-alkaline earth silicate glass, a lanthanide borate glass or a barium oxide silicate glass. Especially preferred as a base glass is a fluoro-phosphate glass.
[0009] Although a significant improvement has been achieved according to the two last-mentioned documents, in that the use of glass or glass ceramics as a luminescent conversion material leads to improved homogeneity and long-term stability, the known systems still have disadvantages. In particular, reflection losses at the interfaces between the different components of the system are relatively high.
SUMMARY OF THE INVENTION
[0010] It is a first object of the present invention to provide an improved solid-state light source in which reflection losses are kept as low as possible.
[0011] It is a second object of the present invention to provide an improved solid-state light source which exhibits a simple structure with long-term stability.
[0012] It is a third object of the present invention to provide an improved solid-state light source having a good conversion efficiency for downconverting light emitted from a solid-state light source within the blue or UV range, preferably to generate white light.
[0013] These and other objects of the invention are achieved with a solid-state light source of the type described at the outset by selecting the light conversion medium so as to have a refractive index n cs determined as a function of the refractive index n HL of the solid-state emitter, in the range of 0.7·(n HL 2 ) 1/3 to 1.3·(n HL 2 ) 1/3 , preferably in the range of 0.8·(n HL 2 ) 1/3 to 1.2·(n HL 2 ) 1/3 , most preferably in the range of 0.9·(n HL 2 ) 1/3 to 1.1·(n HL 2 ) 1/3 .
[0014] The object of the invention is thus perfectly achieved.
[0015] With a refractive index of the conversion medium selected in this way refraction losses are minimized at the transition of the light energy from the solid-state emitter to the light conversion medium. The efficiency of the solid-state light source is, thus, clearly increased.
[0016] According to a preferred further development of the invention, the coupling medium is a glass, a glass ceramics material or a plastic material.
[0017] The coupling medium may in this case be configured as a lens so as to achieve bundled light emission from the solid-state light source.
[0018] According to a preferred further development of the invention, the coupling medium has a refractive index n oo , selected as a function of the refractive index n HL of the solid-state emitter, in the range of 0.7·(n HL ) 1/3 to 1.3·(n HL ) 1/3 , preferably in the range of 0.8·(n HL ) 1/3 to 1.2·(n HL ) 1/3 , most preferably in the range of 0.9·(n HL ) 1/3 to 1.1·(n HL ) 1/3 .
[0019] In this way, both the refractive index of the light conversion medium and the refractive index of the coupling medium are aligned to the refractive index of the solid-state emitter. This permits especially high luminous efficiency to be achieved because reflection losses are avoided.
[0020] In principle, it is imaginable for the light conversion medium and the coupling medium to be identical. As a rule, however, a separate coupling medium is used in order to achieve suitable light control.
[0021] According to a preferred further development of the invention, the light conversion medium is designed for conversion of light energy in the blue band or in the UV band to white light.
[0022] This provides the advantage that LEDs emitting in the blue and in the UV band (for example in the band of 350 to 480 nm) may be used to produce white light.
[0023] According to a further embodiment of the invention, the light conversion medium has a coefficient of thermal expansion adapted to the coefficient of thermal expansion of the substrate of the solid-state emitter.
[0024] The coefficient of thermal expansion of the light conversion medium is at least equal to 2.5·10 −6 /K. Preferably, that coefficient is adapted to the coefficient of thermal expansion of the material making up the solid-state emitter, which is (in 10 −6 /K):
InN 3.8/2.9 GaN 3.17/5.59 GaP 4.65 AlN 5.27/4.15 Al 2 O 3 5.6/5.0
[0025] Where two values are stated above, these relate to the coefficient of thermal expansion for anisotropic materials.
[0026] Stresses that may occur due to temperature differences between the solid-state emitter or the substrate on which the latter is applied and the light conversion medium are thus avoided.
[0027] According to another embodiment of the invention, the light conversion medium comprises an optically transparent base material doped with at least one rare-earth metal, especially with Ce, Eu, Tb, Tm or Sm, of a fluorescent or luminescent kind.
[0028] According to a further embodiment of the invention, the base material used is a lanthanum phosphate glass, a fluoro-phosphate glass, a fluor crown glass, a lanthanum glass, a glass ceramics material produced therefrom, a lithium-aluminosilicate glass ceramics material or a glass ceramics material containing high quantities of yttrium.
[0029] According to a preferred further development of the invention, the base material is additionally doped with a material that supports stronger absorption at the stimulation wavelength. Especially preferred as such dopant is bismuth or another non-ferrous metal such as Mn, Ni, CO or chromium.
[0030] Given the fact that rare earths have a small absorption band, clearly wider absorption in the UV band can be achieved in this way if doping is effected using a d-orbital metal.
[0031] The proportion of the additional doping with bismuth or non-ferrous metals may amount to approximately 3 to 100 ppm in this case.
[0032] According to a further embodiment of the invention, the base material is a lanthanum phosphate glass containing 30 to 90% by weight P 2 O 5 , preferably 50 to 80% by weight, most preferably 60 to 75% by weight P 2 0 5 , as well refining agents in usual quantities.
[0033] According to a further embodiment of the invention, the base material used is a lanthanum phosphate glass containing 1 to 30% by weight La 2 O 3 , preferably 5 to 20% by weight, most preferably 8 to 17% by weight La 2 O 3 .
[0034] According to a further embodiment of the invention, the base material may further contain 1 to 20% by weight Al 2 O 3 , for example 5 to 15% by weight Al 2 O 3 .
[0035] According to a further embodiment of the invention, the base material contains 1 to 20% by weight R 2 O, where R is at least one element selected from the group of alkaline metals.
[0036] According to a further development of that embodiment, the base material contains 1 to 20% by weight K 2 O, preferably 5 to 15% by weight K 2 O.
[0037] According to a further embodiment of the invention, the base material may be a fluorophosphate glass containing 5 to 40% by weight P 2 O 5 and a proportion of fluoride of 60 to 95% by weight.
[0038] According to a further embodiment of the invention, the base material is an optical glass containing 0.5 to 2% by weight La 2 O 3 , 10 to 20% by weight B 2 O 3 , 5 to 25% by weight SiO 2 , 10 to 30% by weight SrO, 2 to 10% by weight CaO, 10 to 20% by weight BaO, 0.5 to 3% by weight Li 2 O, 1 to 5% by weight MgO and 20 to 50% by weight F as well as refining agents in usual quantities.
[0039] According to a further development of the invention, the base material is an optical glass containing 30 to 60% by weight La 2 O 3 , 30 to 50% by weight B 2 0 3 , 1 to 5% by weight SiO 2 , 1 to 15% by weight ZnO, 2 to 10% by weight CaO as well as refining agents in usual quantities.
[0040] Such compositions of the light conversion medium permit highly stable light conversion media to be obtained with their refractive indices, depending on the selected composition, lying in the desired range as a function of the refractive index of the solid-state emitter.
[0041] According to a further embodiment of the invention, the outer surface of the coupling medium is provided with a structure, the elements of such structure having a size of between 50 nm and 2000 nm.
[0042] Preferably, diffractive optical elements are provided for this purpose on the outer surface of the coupling medium.
[0043] This has the effect to minimize reflection losses at the transition from the coupling medium to the surrounding medium.
[0044] According to a further embodiment of the invention, the solid-state light source comprises a base material of glass or glass ceramics containing at least the components SiO 2 , Al 2 O 3 and Y 2 O 3 , the ratio by weight between Y 2 O 3 and the total weight of SiO 2 , Al 2 O 3 and Y 2 O 3 being at least 0.2, preferably at least 0.3, most preferably at least 0.4.
[0045] Preferably, the maximum weight ratio between SiO 2 and the total weight of SiO 2 , Al 2 O 3 and Y 2 O 3 does not exceed 0.5 in this case.
[0046] Preferably, the maximum weight ratio between Al 2 O 3 and the total weight of SiO 2 , Al 2 O 3 and Y 2 O 3 does not exceed 0.6, more preferably 0.55 in this case.
[0047] Such compositions, when subjected to a suitable thermal treatment, allow the separation of crystal phases that may serve as host phases for rare earths.
[0048] Suited as composition for the base material are in this case (in % by weight on an oxide basis):
SiO 2 10-40 Al 2 O 3 10-40 Y 2 O 3 20-70 B 2 O 3 0-15 rare earths 0.5-15.
[0049] It is understood that the features of the invention mentioned above and those yet to be explained below can be used not only in the respective combination indicated, but also in other combinations or in isolation, without leaving the scope of the invention.
BRIEF DESCRIPTION OF THE FIGURES
[0050] Further features and advantages of the invention will become apparent from the description that follows of a preferred embodiment of the invention, with reference to the drawing. In the drawings:
[0051] FIG. 1 shows a diagrammatic representation of a solid-state light source according to the invention.
DESCRIPTION OF PREFERRED EMBODIMENTS
[0052] FIG. 1 shows a diagrammatic representation of a solid-state light source according to the invention, indicated generally by reference numeral 10 . The solid-state light source 10 comprises a solid-state emitter (chip) 12 , supported on the base of a housing 16 . The solid-state emitter 12 is enclosed in a light conversion medium 18 , which may be a luminescent glass or a luminescent glass ceramics material. The light conversion medium 18 is provided for this purpose with a recess conforming with the shape of the solid-state emitter 12 so that the light conversion medium can be positioned on the solid-state emitter 12 . Alternatively, the solid-state emitter 12 may be directly enclosed by the housing on both sides in which case the light conversion medium is placed on the surface of the solid-state emitter only in the form of a thin plate. In any case, the inside of the housing 16 preferably is reflective in order to improve the emission of light. Above the light conversion medium 18 there is provided a coupling medium 20 , which is designed as a light guide and the upper surface of which may be formed as a convex lens, for example.
[0053] According to the invention, the refractive indices of the light conversion medium 18 and the coupling medium 20 are now adapted to the refractive index of the solid-state emitter 12 . To this end, the light conversion medium 18 is given a refractive index n cs selected as a function of the refractive index n HL of the solid-state emitter, preferably on the basis of the following formula:
n cs = 3 √{square root over (n 2 HL )}.
[0054] Further, the coupling medium preferably has a refractive index n 00 selected on the basis of the following formula:
3 √{square root over (n HL )}.
[0055] It has been found that by adapting the refractive indices for the light conversion medium and the coupling medium in this way, as a function of the refractive index of the substrate of the solid-state emitter, it is possible to minimize refraction losses.
[0056] Examples of refractive indices for solid-state materials (at 632 nm) are:
n=3.35 for GaP n=2.20 (o) and 2.29 (e) for GaN n=2.13 (o) and 2.20 (e) for AlN n=2.09 for InN,
where (o) is the ordinary and (e) is the extraordinary ray for non-cubic, double-refractive crystal phases. At shorter wavelengths (for example 460 nm or 410 nm), as used for solid-state light-emitting diodes, the refractive index is even higher.
[0061] An example of a substrate material on which the solid-state materials of the solid-state emitters have been deposited, is corundum (Al 2 O 3 ) which has a refractive index of 1.76.
[0062] In case GaN, for example, is used as a solid-state emitter, the reflection losses can be minimized by a light conversion medium having a refractive index of between approximately 1.6 and 1.9. At the same time, the refractive index of the coupling medium is selected to be between approximately 1.15 and 1.4 in this case.
[0063] If, in contrast, the solid-state emitter consists of GaP, for example, the light conversion medium used preferably should have a refractive index approximately in a range of between 1.85 and 2.2, while the refractive index used for the coupling medium should be selected to be between approximately 1.35 and 1.5.
[0064] If, however, InP is used as a solid-state emitter, then the light conversion medium should be selected to have a refractive index greater than approximately 2.1 and smaller than approximately 2.4. The material selected for the coupling medium should in this case have a refractive index of between approximately 1.4 and 1.6.
[0065] The light conversion medium 18 is a material made from glass or glass ceramics, bulk doped with a rare earth metal, especially Ce, Eu, Tb, Tm or Sm, that is fluorescent or luminescent. That material is particularly well suited for converting light emitted by blue LEDs or LEDs emitting in the UV range to white light.
[0066] Further, the coefficient of thermal expansion of the light conversion medium is preferably adapted to the coefficient of thermal expansion of the solid-state emitter in this case, which preferably is at least 2.5·10 −6 /K. Further, the coefficient of thermal expansion of the coupling medium may be similarly adapted to the coefficient of thermal expansion of the light conversion medium connected with it, and may preferably be at least 2.5·10 −6 /K.
[0067] In addition to the rare earth doping a supplementary dopant, for example Mn, Ni, Co, Cr and/or Bi, is preferably used in order to achieve higher absorption at the stimulation wavelength.
[0068] In order to render production especially easy, the coupling medium 20 may also consist of a polymer as a polymer permits the desired adaptation of the refractive index to the refractive index of the solid-state emitter to be achieved without difficulty. This then allows an especially simple and low cost production process to be realized.
[0069] Even though the coupling medium is made from glass or glass ceramics, the material used preferably is selected to melt at low temperatures in order to permit the coupling medium to be directly pressed to the desired shape.
[0070] Preferably, the outer surface of the coupling medium 20 is additionally provided with diffractive optical elements, for example in the form of microlenses, having a diameter of between 50 nm and 2000 nm, in order to support effective coupling-out of the light.
EXAMPLE 1
[0071] Compositions of different lanthanum phosphate glass types that are single-doped with Cr 2 O 3 or multiple-doped with rare earth ions, are summarized in Table 1:
TABLE 1 OXIDE wt.-% wt.-% wt.-% wt.-% wt.-% Sample A B C D E Al 2 O 3 8.498 8.774 8.857 8.498 8.498 P 2 O 5 68.378 70.593 71.267 68.378 68.378 K 2 O 9.316 6.328 6.388 9.316 9.316 La 2 O 3 13.808 14.256 10.669 13.808 13.808 Ce 2 O 3 0.126 0.13 1.21 Eu 2 O 3 1.24 1.23 Tb 2 O 3 2.693 2.63 2.62 Cr 2 O 3 0.050 Tm 2 O 3 1.02
EXAMPLE 2
[0072] The fluorophosphate glass types used have a P 2 O 5 content of 5 to 40% by weight and a fluoride content of 60 to 96% by weight. The glass is doped with rare earths to between approximately 0.5 and 15% by weight.
EXAMPLE 3
[0073] A lithium aluminum glass ceramics material (LAS ceramics) is doped with rare earths. The material used may especially consist of an LAS glass ceramics material marketed by Schott under the trade marks Ceran®, CLEARTRANS® or ROBAX®.
EXAMPLE 4
[0074] A glass with a high lanthanum content is molten which has a refractive index of over 1.7. The glass has the following composition (in % by weight on an oxide basis):
SiO 2 4.3 B 2 O 3 34.3 Al 2 O 3 0.4 ZrO 2 5.4 La 2 O 3 41.0 CaO 1.6 ZnO 6.0 CdO 6.4 Li 2 O 0.3 As 2 O 3 0.3.
[0075] The lanthanum oxide may be replaced in this case in part by oxides of the rare earths.
EXAMPLE 5
[0076] A glass containing the following components (in % by weight on an oxide basis) is molten:
SiO 2 23.64 B 2 O 3 6.36 Al 2 O 3 20.91 Y 2 O 3 46.36 Eu 2 O 3 2.73.
[0077] The glass obtained is molten and homogenized in a platinum crucible at a temperature of approximately 1550 to 1600° C. After the material has cooled down to room temperature, a clear transparent glass is obtained.
[0078] When stimulated with UV light (λ=240 to 400 nm) the glass shines in a bright orange color both in its glassy and in its ceramized condition.
[0079] The glass can be ceramized by a suitable temperature treatment during which process crystal phases can be separated that serve as host phases for rare earth ions.
[0080] The material is also especially well suited as light conversion medium.
[0081] Therefore, what is claimed, is: | The invention describes a solid-state light source comprising a solid-state emitter designed for emitting light energy, which preferably has an LED, a luminescent light conversion medium, made from glass or glass ceramics, for converting emitted light energy to light energy of a different frequency spectrum, and a coupling medium for decoupling the light energy to an ambient medium, such as air, the light conversion medium having a refractive index n cs , selected as a function of the refractive index n HL of the solid-state emitter in the range of 0.7·(n HL 2 ) 1/3 to 1.3·(n HL 2 ) 1/3 . | 2 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent application Ser. No. 14/196,418 filed on 4 Mar. 2014, which is a continuation of U.S. patent application Ser. No. 13/463,471 filed on 3 May 2012 (now U.S. Pat. No. 8,702,412 issued on 22 Apr. 2014), which is a continuation-in-part of U.S. patent application Ser. No. 13/005,212 filed on 12 Jan. 2011 (now U.S. Pat. No. 8,512,023 issued on 20 Aug. 2013), the disclosure of each of which is incorporated herein, in its entirety, by this reference.
BACKGROUND
[0002] Injection molding processes have relatively widespread use and may be employed to produce a wide variety of parts. For instance, injection molded parts may range from only a few millimeters in size to parts that are several meters wide. Injection molding also may be used produce components that have various geometries, complexity of which may vary from simple to highly intricate in detail. Furthermore, injection molding processes may produce parts from various materials, including but not limited to thermoplastic polymers, aluminum alloys, zinc alloys, etc.
[0003] Oftentimes, molds used to manufacture injection molded parts (i.e., injection molds) may be relatively expensive. Consequently, injection molding is most commonly used to manufacture parts in large quantities. This may allow the cost of the injection mold to be amortized over thousands or even hundreds of thousands of molded parts.
[0004] Typical molds are constructed from metallic materials, such as steel, aluminum, brass, copper, etc. Usability of the mold may vary based on the materials used therein. For example, use of softer and/or less wear-resistant metals, which may exhibit increased wear in an injection mold, may lead to unusable parts produced by the mold. Ordinarily, material wear results from “cycling” the mold—i.e., closing the mold, injecting molten molding material, opening the mold, and/or ejecting or removing the parts. The rate and/or amount of wear may depend on the part geometry, molding material used in the process, frequency and number of cycles, and other factors present during the operation of the mold.
[0005] Additionally, an injection mold may include certain components that may exhibit more wear than other components, due to the nature of the operation of the mold. Thus, in some instances, a typical mold may require repair or replacement where increased wear may lead to failure of such components.
SUMMARY
[0006] Various embodiments of the invention are directed to injection mold assemblies and components that comprise a superhard material, as well as injection molding system that may utilize such injection mold assemblies and components. Superhard materials may be arranged and formed in any number of sizes and configurations. In some embodiments, superhard materials may be available in limited sizes. Hence, multiple segments may be used to enable forming desired surface sizes and configurations, notwithstanding possible limitations in the size of available superhard materials. Superhard materials also may be located along all or portion of one or more surfaces of the injection mold component, to form one or more wear-resistant surface, which may provide increased resistance to wear for such surfaces of the injection mold component.
[0007] According to one embodiment, an injection mold component for use in an injection mold includes a substrate and a superhard material bonded to the substrate that forms a wear-resistant surface. The wear-resistant surface is moveable within the injection mold, and/or the wear-resistant surface defines at least a portion of a conduit for communicating a molding material flows into the injection mold.
[0008] According to another embodiment, an injection mold assembly includes a first mold plate, a second mold plate, and one or more molding elements located on one or more of the first or second mold plates. The injection mold assembly also includes an injection mold component located on at least one of the first mold plate, on the second mold plate, or on the molding element. The injection mold component includes a superhard material forming at least a portion of a surface of the injection mold component, wherein the superhard material is bonded to a substrate.
[0009] According to yet another embodiment, an injection molding system includes an injection molding machine and an injection mold operably coupled to the injection molding machine. The injection mold includes a stationary portion, a moving portion, and one or more molding elements located on the stationary and/or on the moving portions. The injection mold also includes an injection mold component located on the stationary portion and/or on the moving portion. The injection mold component includes a superhard material forming a wear-resistant surface on the injection mold component. The superhard material is bonded to a substrate. The injection molding machine is configured to move the moving portion. The injection molding machine is also configured to inject molding material into the injection mold via a conduit at least partially defined by the wear-resistant surface of the injection mold component; or the wear-resistant surface is moveable within the injection mold.
[0010] Features from any of the disclosed embodiments may be used in combination with one another, without limitation. In addition, other features and advantages of the present disclosure will become apparent to those of ordinary skill in the art through consideration of the following detailed description and the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] The drawings illustrate several embodiments of the invention, wherein identical reference numerals refer to identical or similar elements or features in different views or embodiments shown in the drawings.
[0012] FIG. 1 is a schematic cross-sectional view of an injection molding machine and an injection mold, which may utilize any of the injection mold components disclosed herein;
[0013] FIG. 2 is a cross-sectional view of an injection mold in accordance with one embodiment of the invention;
[0014] FIG. 3A is a cross-sectional view of sprue bushing of an injection mold in accordance with one embodiment of the invention;
[0015] FIG. 3B is a cross-sectional view of a sprue bushing of an injection mold in accordance with another embodiment of the invention;
[0016] FIG. 3C is a cross-sectional view of a sprue bushing of an injection mold in accordance with yet another embodiment of the invention;
[0017] FIG. 3D is a cross-sectional view of a hot runner system and various hot tips in accordance with one embodiment of the invention;
[0018] FIG. 3E is a cross-sectional view of a gate insert of an injection mold in accordance with one embodiment of the invention;
[0019] FIG. 4A is a cross-sectional view of a locating ring of an injection mold in accordance with one embodiment of the invention;
[0020] FIG. 4B is a cross-sectional view of a locating ring of an injection mold in accordance with another embodiment of the invention;
[0021] FIG. 5A is a cross-sectional view of an ejector sleeve of an injection mold in accordance with one embodiment of the invention;
[0022] FIG. 5B is a cross-sectional view of an ejector sleeve of an injection mold in accordance with another embodiment of the invention;
[0023] FIG. 5C is a cross-sectional view of an ejector sleeve of an injection mold in accordance with yet another embodiment of the invention;
[0024] FIG. 5D is a cross-sectional view of a different embodiment of an ejector sleeve of an injection mold in accordance with one embodiment of the invention;
[0025] FIG. 5E is a cross-sectional view of yet another embodiment of an ejector sleeve of an injection mold in accordance with one embodiment of the invention;
[0026] FIG. 6A is a cross-sectional view of an undercut relief system of an injection mold in accordance with one embodiment of the invention;
[0027] FIG. 6B is a cross-sectional view of the undercut relief system of FIG. 6A taken along line 6 B- 6 B thereof;
[0028] FIG. 6C is a cross-sectional view of an undercut relief system of an injection mold in accordance with another embodiment of the invention;
[0029] FIG. 6D is a cross-sectional view of an undercut relief system of an injection mold in accordance with yet another embodiment of the invention;
[0030] FIG. 6E is a cross-sectional view of an undercut relief system of an injection mold in accordance with another embodiment of the invention;
[0031] FIG. 6F is an isometric view of an undercut relief system of an injection mold in accordance with yet another embodiment of the invention;
[0032] FIG. 6G is an isometric view of an undercut relief system of an injection mold in accordance with yet another embodiment of the invention;
[0033] FIG. 7A is a cross-sectional view of a slide retainer in accordance with one embodiment of the invention;
[0034] FIG. 7B is a cross-sectional view of a slide retainer in accordance with another embodiment of the invention;
[0035] FIG. 8A is an isometric view of a rectangular two-plate interlock pair in an open position in accordance with one embodiment of this invention;
[0036] FIG. 8B is an isometric view of a rectangular two-plate interlock pair in a closed position in accordance with another embodiment of this invention;
[0037] FIG. 8C is a side view of a three-plate interlock pair in an open position in accordance with one embodiment of this invention;
[0038] FIG. 8D is a side view of a three-plate interlock pair in a partially closed position in accordance with another embodiment of this invention;
[0039] FIG. 8E is an isometric view of a tapered interlock pair in accordance with one embodiment of this invention;
[0040] FIG. 8F is a side view of a tapered interlock pair in a closed position in accordance with another embodiment of this invention;
[0041] FIG. 8G is an isometric view of a cylindrical tapered interlock pair in accordance with one embodiment of this invention; and
[0042] FIG. 8H is a cross-sectional view of a cylindrical tapered interlock pair in a closed position in accordance with another embodiment of this invention.
DETAILED DESCRIPTION
[0043] Various embodiments of the invention are directed to injection mold assemblies and components that comprise a superhard material, as well as injection molding system that may utilize such injection mold assemblies and components. Superhard materials may be arranged and formed in any number of sizes and configurations. In some embodiments, superhard materials may be available in limited sizes. Hence, multiple segments may be used to enable forming desired surface sizes and configurations, notwithstanding possible limitations in the size of available superhard materials. Superhard materials also may be located along all or portion of one or more surfaces of the injection mold component, to form one or more wear-resistant surface, which may provide increased resistance to wear for such surfaces of the injection mold component.
[0044] There are numerous types of injection molding machines and techniques available for manufacturing injection molded parts. In particular, the injection molding machine may inject, for example, molten thermoplastics, thermosets, elastomers, aluminum alloys, and zinc alloys into an injection mold, to manufacture various parts from such materials or combinations thereof. Additionally, the injection molding machine may inject thermoplastics, thermosets, elastomers, or combinations thereof that incorporate metallic powder, thereby producing a “green” part, which may allow the manufacturer to make metal parts by removing the polymer material from the “green part” and sintering the metallic powder. FIG. 1 illustrates an injection molding system 100 , which may include an injection molding machine 110 and an injection mold 120 (shown in a closed position). Although the particular configuration or operation of the injection molding machine 110 may vary in some regards with respect to other available machines or processes, the injection molding machine 110 may be a typical machine used for manufacturing injection molded parts.
[0045] The injection molding machine 110 may include a front platen 111 and a back platen 112 . The back platen 112 may move with respect to the front platen 111 , which may cause the injection mold 120 to open. In particular, the injection mold 120 may have a stationary portion 121 and a moving portion 122 , which may define a parting line 123 (i.e., the line (or one or more planes) along which the injection mold 120 splits to open). The stationary portion 121 of the injection mold 120 may be secured to the front platen 111 and the moving portion 122 may be secured to the back platen 112 . Accordingly, movement of the back platen 112 in a direction away from the front platen 111 may cause the moving portion 122 of the injection mold 120 to move away from the stationary portion 121 , thereby opening the injection mold 120 along the parting line 123 . Similarly, movement of the back platen 112 toward the front platen 111 may cause the injection mold 120 to close.
[0046] The injection molding machine 110 also may include a material hopper 113 and an injection system 114 , which may supply molten molding material into the injection mold 120 . More particularly, molding material (e.g., plastic pellets) may be added into the material hopper 113 and fed into the injection system 114 . In one embodiment, the injection system 114 may include a screw 115 that may rotate within a barrel. Optionally, one or more heaters 116 may surround the barrel to heat and/or at least partially or completely melt the molding material.
[0047] The melted molding material may be conveyed by the screw 115 , which may be a reciprocating screw, toward the injection mold 120 . The molten molding material may be injected into the injection mold 120 through an injection nozzle 117 . It should be noted that other configurations of the injection molding machine 110 may be used to manufacture molded parts. For instance, the injection system 114 may include a plunger, which may replace or may be incorporated into the screw 115 , and which may inject the molten molding material into the injection mold 120 .
[0048] Once the injection mold 120 is in a fully closed position (as shown in FIG. 1 ), molten molding material may be injected into the injection mold 120 . More specifically, the molten material may fill a molding volume 131 within the injection mold 120 . Subsequently, as shown in FIG. 2 , the molten molding material may cool and at least partially solidify to form a part corresponding to the molding volume 131 . When the molten molding material forming the part has cooled to a desired temperature, the injection mold 120 may be opened, by moving the back platen 112 away from the front platen 111 (as described above), and the part may be ejected or removed from the injection mold 120 .
[0049] To produce the part, the injection mold 120 may incorporate various molding elements, which may have necessary shapes and sizes to form a part 130 . For example, as illustrated in FIG. 2 , the injection mold 120 may include one or more molding elements 140 , such as molding elements 140 a , 140 b , 140 c (which may include a cavity, a core, a core pin, core inserts, etc.) that assemble to define the molding volume 131 . A “molding element” refers to any portion of the injection mold 120 that forms at least a portion of the part 130 (i.e., portion(s) of the injection mold 120 that define the molding volume 131 ). Thus, to produce multiple parts in a single cycle, the injection mold 120 may include multiple sets of molding elements 140 , which may be substantially identical (to produce the same parts) or may vary, for production of different parts in the single cycle. A “set of molding elements” refers to the molding elements 140 that, when combined, form or define the molding volume 131 (see FIG. 1 ), which may accept molten material and form the part 130 .
[0050] As described above, the injection mold 120 may be secured in the injection molding machine 110 . More specifically, the injection mold 120 may be secured to the front platen 111 and back platen 112 . For instance, the nonmoving portion 121 of the injection mold 120 may have one or more clamping grooves that may accommodate clamps for securing the nonmoving portion 121 to the front platen 111 of the injection molding machine 110 . For example, the nonmoving portion 121 may include one or more plates, such as a first plate 121 a and a top clamping plate 121 b , which may form such clamping grooves. The nonmoving portion 121 also may include an overhang that may accommodate clamps, bolt holes that may accept bolts for securing the nonmoving portion 121 to the front platen 111 , and/or other features that may be used to secure the nonmoving portion 121 to the front platen 111 , which should be appreciated by those skilled in the art.
[0051] The nonmoving portion 121 also may include a sprue bushing 150 , which may channel the molten molding material into the injection mold 120 . For example, the injection nozzle 117 may have a spherical tip which may contact a sphere of the same or similar radius on the sprue bushing 150 . Subsequently, the molten molding material may flow from the injection system 114 of the injection molding machine 110 , through the injection nozzle 117 , through the sprue bushing 150 , and into the injection mold 120 . In some instances, the nonmoving portion 121 also may include a locating ring 160 , which may aid in aligning the injection mold 120 and/or the sprue bushing 150 with the injection molding machine 110 as well as with the injection nozzle 117 .
[0052] The moving portion 122 of the injection mold 120 may be connected to the back platen 112 of the injection molding machine 110 . Similar to the nonmoving portion 121 , the moving portion 122 may incorporate a clamping groove or other features that may allow the manufacturer to connect the moving portion 122 of the injection mold 120 to the back platen 112 of the injection molding machine 110 . Furthermore, the moving portion 122 may include a second plate 122 a that may secure or incorporate the molding element 140 b . The moving portion 122 of the injection mold 120 also may include a support plate 122 b , which may provide support to the second plate 122 a and additional rigidity to the injection mold 120 .
[0053] Additionally, the moving portion 122 and the nonmoving portion 121 of the injection mold 120 may include leader pins and corresponding bushings (not shown), which may aid in aligning the moving portion 122 and the nonmoving portion 121 during the opening and closing of the injection mold 120 . In some embodiments, it may be desirable to provide additional alignment mechanisms, to further align the moving and the nonmoving portions 122 , 121 of the injection mold 120 as well as to prevent undesirable movement of the nonmoving and moving portions 121 , 122 during injection of the molding material. For example, as further described below, the injection mold 120 may include interlock pairs 280 , which may comprise male and corresponding female interlock portions. Furthermore, clearance between the male and the corresponding female interlock portions may be substantially smaller than the clearance between the leader pins and corresponding bushings. For instance, the clearance between the male and female interlocks may be in the range of 0.0002 inch to 0.0005 inch per side.
[0054] The injection mold 120 also may incorporate an ejection mechanism, which may eject the part 130 after the part 130 has cooled down to a desired temperature. In particular, the ejection mechanism may include an ejector housing 122 c and ejector plates 122 d . For example, the ejector plates 122 d may connect to an ejection system of the injection molding machine 110 , which may move the ejector plates 122 d toward the front platen 111 . The ejector plates 122 d , in turn, may secure one or more ejector pins 170 , which may move together with the ejector plates 122 d and eject the part 130 out of the injection mold 120 .
[0055] In some embodiments, as further described below, the injection mold 120 also may incorporate one or more ejector sleeves, such as ejector sleeves 220 a , 220 b . More particularly, the ejector sleeve 220 a may guide the ejector pin 170 through the molding element 140 b . Hence, a portion (e.g., a top surface) of the ejector sleeve 220 a may contact the part 130 and may at least in part form the molding volume 131 .
[0056] In at least one embodiment, a core pin 140 c may be secured in the ejector housing 122 c . The core pin 140 c may at least in part define the molding volume 131 (e.g., the core pin 140 c may form a hole in the part 130 ). The ejector sleeve 122 b may provide additional uniformity during ejection of the part 130 . More specifically, the ejector plates 122 d also may secure one or more ejector sleeves, such as the ejector sleeve 122 b , which may slide about the core pin 140 b , thereby aiding in ejection of the part 130 .
[0057] It should be appreciated that the injection mold 120 may include all, some, and/or additional molding elements, plates, and/or devices described herein. For instance, the injection mold 120 may have no ejector housing or ejector plates, and the manufacturer may choose to remove the parts with a robotic arm (or manually) to avoid ejector pin marks on the parts. Additionally or alternatively, the injection mold 120 may also include additional plates and/or devices, not described herein, which may be necessary for operation. For example, in lieu of ejector pins, the manufacturer may choose to use a stripper plate (where applicable), which may strip the part 130 from the molding element 140 b . Thus, it should be noted that components described herein may be used in the injection mold 120 of any configuration or design.
[0058] In some instances, the part 130 may include undercuts or undercutting portions, which may need to be relieved before the part 130 may be ejected from the injection mold 120 . In particular, one or more slides or lifters may be used to relieve undercuts and allow the part 130 to be ejected, as described in more detail below. A slide may move substantially orthogonally with respect to the undercut, thereby removing at least a portion of the molding element 140 away from the part 130 . A lifter may move in a direction of ejection (i.e., toward the front platen 111 ) and orthogonally to the undercut—thus, ejecting the part while relieving the undercut.
[0059] In at least one embodiment, one or more surfaces of one or more components comprising the injection mold 120 may include one or more layers of superhard material. More particularly, one or more layers of superhard material may form one or more wear-resistant surfaces on the injection mold components. An “injection mold component” refers to any component and/or element comprising an injection mold. Also, as used herein, the term “superhard,” or the phrase “superhard material,” refers to any material having a hardness that is at least equal to the hardness of tungsten carbide. Furthermore, element numbers denoted with letters “sm” identify superhard material in particular embodiments. It should be noted that so denoted superhard material may be any superhard material disclosed herein. Similarly, element numbers denoted with letters “wr” identify wear-resistant surface that may be formed by one or more layers of superhard material on a particular injection mold component.
[0060] In some embodiments, one or more substrates may be bonded to the injection mold components. The substrates may be a cobalt-cemented tungsten carbide substrate or other carbide substrate. Additionally, the layer of superhard material forming the wear-resistant surface may be natural diamond, polycrystalline diamond, polycrystalline cubic boron nitride, silicon carbide, diamond grains bonded together with silicon carbide, or any combination of the preceding materials. Furthermore, the superhard material may be thermally-stable diamond in which a catalyst material (e.g., iron, nickel, cobalt, or alloys thereof) has been at least partially depleted from a surface or volume of the polycrystalline diamond using, for example, a leaching process. A cemented carbide substrate (e.g., cobalt cemented, nickel cemented, cemented using alloys of cobalt, or cemented using alloys of nickel) may comprise any suitable carbide, such as tungsten carbide, tantalum carbide, vanadium carbide, niobium carbide, chromium carbide, titanium carbide, or combinations of the foregoing carbides.
[0061] In at least one embodiment, the superhard material includes one or more polycrystalline diamond compacts (PDCs). For instance, the substrate may comprise cobalt-cemented tungsten carbide and the layer of superhard material may include polycrystalline diamond. Such structures may be fabricated by subjecting diamond particles, placed on or proximate to a cobalt-cemented tungsten carbide substrate, to a high-pressure/high-temperature (HPHT) sintering process. The diamond particles with the cobalt-cemented tungsten carbide substrate may be HPHT sintered at a temperature of at least about 1000° Celsius (e.g., about 1100° C. to about 1600° C.) and a pressure of at least about 4 GPa (e.g., about 5 GPa to about 9 GPa) for a time sufficient to consolidate and form a coherent mass of bonded diamond grains. In such a process, the cobalt from the cobalt-cemented tungsten carbide substrate sweeps into interstitial regions between the diamond particles to catalyze growth of diamond between the diamond particles. More particularly, following HPHT processing, the superhard material may comprise a matrix of diamond grains that are bonded with each other via diamond-to-diamond bonding (e.g., sp 3 bonding), and the interstitial regions between the diamond grains may be at least partially occupied by cobalt or another catalyst, thereby creating a network of diamond grains with interposed cobalt or other catalyst, otherwise known as polycrystalline diamond (PCD).
[0062] In some embodiments, the catalyst used for forming the PCD superhard material may be a metal-solvent catalyst, such as cobalt, nickel, iron, or alloys thereof. A thermal stability of such PCD superhard material may be improved by leaching the metal-solvent catalyst from of the PCD. Leaching may be performed in a suitable acid, such as aqua regia, nitric acid, hydrofluoric acid, or combination thereof, so that the leach PCD superhard material is substantially free of metal-solvent catalyst. Furthermore, the PCD superhard material may be entirely or partially. Generally, a maximum leach depth may be greater than 250 μm. For example, the maximum leach depth may be greater than 300 μm to about 425 μm, greater than 350 μm to about 400 μm, greater than 350 μm to about 375 μm, about 375 μm to about 400 μm, or about 500 μm to about 650 μm.
[0063] The superhard material comprising the PCD also may allow operation of various components of the injection mold without lubricants. Thus, incorporating superhard material into injection mold components can avoid contamination of molded parts with lubricants, which, otherwise, may be required for proper operation of the injection mold in order to preserve the life of the injection mold components. In other words, incorporating PCD superhard material into the injection mold components may replace lubricants and may maintain the life and usefulness of the injection mold components. Lubricant-free operation may be particularly advantageous in molding medical products and/or components thereof (as well as other clean products and components), which may have more rigorous requirements of environment cleanliness than other molded products.
[0064] In one or more embodiments, the substrate may be omitted, and the injection mold components may include one or more layers of superhard materials such as cemented tungsten carbide or polycrystalline diamond. Also, the layer of superhard material (e.g., diamond) may be deposited, using chemical vapor deposition (CVD), physical vapor deposition, plasma-assisted chemical vapor deposition, or other deposition techniques. Example methods for depositing a superhard material are described in U.S. Pat. No. 7,134,868, the disclosure of which is incorporated by reference herein in its entirety.
[0065] The layer of superhard material may exhibit a substantially uniform thickness (i.e., with substantially uniform thickness) or a non-uniform thickness. Additionally or alternatively, the layer of superhard material may be continuous/contiguous or may be interrupted or formed from multiple segments. Furthermore, in some embodiments, a thickness of the layer of superhard material that forms a wear-resistant surface may be in the range of about 0.010 inches to about 0.200 inches. Additionally or alternatively, the thickness of the layer of superhard material may be in the range from about 0.020 inches to about 0.120 inches, about 0.040 inches to about 0.100 inches, and about 0.060 inches to about 0.090 inches. Moreover, the thickness of the superhard layer may be greater than about 0.200 inches.
[0066] In some embodiments, the superhard material may form more than one wear-resistant surface on a particular injection mold component. For example, as further described below, the superhard material may form two wear-resistant surfaces disposed at approximately 90° with respect to each other. Similarly, the superhard material may have one or more bonding surfaces. Furthermore, the boding surfaces also may be continuous or interrupted; for example, an entire surface of the superhard material may be bonded to the substrate or only a portion thereof. Hence, the superhard material may have more than one thickness measurements, depending on the number of bonding surfaces—e.g., the superhard material that has two bonding surfaces, and which forms two wear-resistant surfaces, may have two or more thickness measurements that correspond to the thicknesses between the respective bonding surfaces and a point on each of the wear-resistant surfaces.
[0067] The wear-resistant surface, formed by the superhard material, may have a reduced amount of wear from operation of the injection mold 120 , as compared to a surface that is not formed from superhard material. In some embodiments, the wear-resistant surface may at least in part for a surface of an injection mold component that contacts the molten molding material injected into the injection mold 120 . For example, such injection mold component may be the sprue bushing 150 , as illustrated in FIGS. 3A-3C . The sprue bushing 150 may include a through-hole 151 , defined by inner wear-resistant surface 151 wr , which may allow the molten molding material to be injected from the injection molding machine 110 into the injection mold 120 . The sprue bushing 150 also may have a minor diameter 152 , a major diameter 153 , and a shoulder 154 , which may be formed between the minor and major diameters 152 , 153 . One or more of the minor diameter 152 , the major diameter 153 , or the shoulder 154 may assist with locating the sprue bushing 150 in the injection mold 120 .
[0068] The sprue bushing 150 also may include a seal-off 155 , which may have a substantially hemispherical shape. Hence, the injection nozzle 117 of the injection molding machine 110 may press against the seal-off 155 , to create a sealed pathway for the molten molding material, from the injection system 114 into the injection mold 120 . As the material passes through the through-hole 151 of the sprue bushing 150 , the wear-resistant surface 151 wr may provide an improved durability and wear resistance to the molten molding material, as compared to other materials. Similarly, repeated contact between the seal-off 155 and the injection nozzle 117 may wear or damage the surface of the seal-off 155 .
[0069] In one or more embodiments, the surface that defines the through-hole 151 may be at least partially formed by a wear-resistant surface 151 wr . In particular, a superhard material 150 sm may form the wear-resistant surface 151 wr . Furthermore, the wear-resistant surface 151 wr may span or cover only a portion of the through-hole 151 ( FIG. 3A ). In some embodiments, the superhard material 150 sm that forms the wear-resistant surface 151 wr may be disposed on an insert, which may be press-fitted into the sprue bushing 150 . Alternatively, the superhard material 150 sm may be bonded to the sprue bushing 150 directly or through the substrate, as described above.
[0070] In at least one embodiment, the wear-resistant surface 151 wr may span or cover the entire through-hole 151 ( FIGS. 3B and 3C ). Thus, in some embodiments, the wear-resistant surface 151 wr may reduce wear (resulting from flow of molten molding material through the through-hole 151 ) on part of the through-hole 151 of the sprue bushing 150 ( FIG. 3A ). Alternatively, in other embodiments, the wear-resistant surface 151 wr may reduce such wear along the entire surface of the through-hole 151 ( FIGS. 3B and 3C ).
[0071] Additionally or alternatively, the sprue bushing 150 also may have a wear-resistant surface 155 wr disposed along the seal-off 155 . The wear-resistant surface 155 wr may reduce the amount of wear associated with repeated contacts of the injection nozzle 117 with the seal-off 155 . Accordingly, the wear-resistant surface 155 wr may extend life of the sprue bushing 150 . In some embodiments, at least a portion of the injection nozzle 117 may comprise superhard material.
[0072] The wear-resistant surface 155 wr may cover the entire seal-off 155 . In other embodiments, the wear-resistant surface 155 wr may cover only a portion of the seal-off 155 . Moreover, the same superhard material 150 sm that may form the wear-resistant surface 151 wr may also form the wear-resistant surface wear-resistant surface 155 wr . Alternatively, different separate bodies of superhard material may form the wear-resistant surfaces 151 wr and 155 wr . Also, as described above, the superhard material 150 sm may have varied and varying thicknesses. Furthermore, the superhard material 150 sm also may cover a top of the sprue bushing 150 ; in other words, the superhard material 150 sm may extend to the major diameter 153 of the sprue bushing 150 ( FIG. 3C ).
[0073] In some embodiments, as illustrated in FIG. 3D , in lieu of or in addition to a sprue bushing, the manufacturer may use a hot runner system 180 , which may include a runner manifold 190 and one or more tip inserts 200 . The molten molding material may enter the hot runner system 180 through the sprue bushing. In some embodiments, the sprue bushing may incorporate one or more heating elements and may also include one or more wear-resistant surfaces, as described above. Alternatively, the injection nozzle 117 may seal off against the runner manifold 190 of the hot runner system 180 . Accordingly, the molten molding material from the injection molding machine 110 may directly enter the runner manifold 190 of the hot runner system 180 through the injection nozzle 117 . Generally, one or more embodiments may include one or more of the injection nozzles 117 , runner manifolds 190 , and tips inserts 200 comprising a superhard material. More particularly, any surface (or a portion thereof) of the injection nozzle injection nozzles 117 , runner manifolds 190 , and tips inserts 200 that contacts molten molding material may comprise a superhard material.
[0074] The hot runner system 180 may have one or more heater elements (not shown), which may help maintain the molding material in at least partially molten state within the hot runner system 180 . Similarly, the tip inserts 200 also may include heating elements 201 that may keep the molding material in at least partially molten state within the tip inserts 200 . The tip inserts 200 also may include an opening 202 , which may allow the molten molding material to flow into the molding volume 131 ( FIG. 1 ). In other words, the opening 202 may provide a channel for the molten molding material to flow from the runner manifold 190 of the hot runner system 180 into the molding volume 131 , defined by one or more molding elements 140 ( FIG. 1 ).
[0075] In some embodiments, the opening 202 may be at least partially defined by a wear-resistant surface 202 wr . As described above, a superhard material 200 sm may form the wear-resistant surface 202 wr . Furthermore, the wear-resistant surface 202 wr may span an entire length of the opening 202 or may only partially cover the surface of the opening 202 . For example, the wear-resistant surface 202 wr may be disposed proximate to a connection point between the tip insert 200 and runner manifold 190 (i.e., proximate to the point where the molten molding material from the runner manifold 190 enters the tip insert 200 ). Alternatively, the wear-resistant surface 202 wr may be disposed proximate a material exit point of the tip inserts 200 (i.e., proximate to the point where the material exits the tip insert 200 and enters the molding elements 140 .
[0076] Additionally, in at least one embodiment, the tip inserts 200 also may have an outer portion 203 that includes one or more wear-resistant surfaces 203 wr . For instance, the wear-resistant surface 203 wr may be disposed proximate to an end (i.e., to the exit point) of the tip insert 200 . Moreover, the superhard material 200 sm that forms the wear-resistant surface 202 wr also may form the wear-resistant surfaces 203 wr . As described above, the superhard material 200 sm that forms the wear-resistant surface 202 wr and/or wear-resistant surfaces 203 wr may be bonded to a substrate that is bonded to the tip inserts 200 , may be deposited onto a surface of the tip inserts 200 , and/or may form part of an insert that is bonded or mechanically secured to one or more of the tip inserts 200 .
[0077] In some instances, the part 130 ( FIG. 2 ) molded in the injection mold 120 may be direct-gated—i.e., a runner or the sprue bushing 150 may provide a direct pathway for the molten molding material into the molding volume 131 . Alternatively, the molding elements 140 may incorporate a tunnel gate 210 , illustrated in FIG. 3E . Hence, a runner 212 may connect with the tunnel gate 210 and channel the molding material into the molding volume 131 ( FIG. 1 ). As described above, flow of the molten molding material may wear the surfaces of the 210 and/or runner 212 . Furthermore, as the injection mold 120 opens and/or as the part 130 is ejected from the molding element 140 a or molding element 140 b , the molding material in the tunnel gate 210 may be sheared off by an edge 211 of the tunnel gate 210 . Thus, repetitive shearing of the molding material by the edge 211 of the tunnel gate 210 may wear, dull, and/or damage the edge 211 , which may result in subnormal damage to the final part 130 .
[0078] In at least one embodiment, the surface of the tunnel gate 210 may include a wear-resistant surface 210 wr , which may be formed by a superhard material 210 sm . The wear-resistant surface 210 wr may cover the entire surface of the tunnel gate 210 or only a portion thereof. In some embodiments, the edge 211 of the tunnel gate 210 also may comprise superhard material. Moreover, the superhard material 210 sm material that forms the wear-resistant surface 210 wr , also may form the edge 211 of the tunnel gate 210 .
[0079] Similar to the above-described superhard material, the superhard material 210 sm forming the wear-resistant surface 210 wr and/or the edge 211 of the tunnel gate 210 may be bonded to a substrate that is bonded to the injection mold component (e.g., to an injection mold plate and/or to one of the molding elements 140 ). The superhard material 210 sm also may be bonded directly to the injection mold component. Alternatively, the tunnel gate 210 , at least partially, may be formed by a gate insert. Accordingly, the gate insert may incorporate the superhard material. In particular, the gate insert may comprise a substrate to which a superhard material may be bonded; the gate insert also may comprise steel or other metallic material to which the substrate with the superhard material 210 sm may be bonded; or the gate insert may comprise steel or other metallic material and a bonded superhard material 210 sm.
[0080] In one or more embodiments, the injection mold 120 may include injection mold components that have surfaces in contact with other injection mold components (e.g., sliding surfaces that incorporate one or more wear-resistant surface formed by superhard material). For example, as illustrated in FIGS. 4A and 4B , the locating ring 160 ( FIG. 2 ) may include a locating inside diameter 161 that may fit over the major diameter 153 of the sprue bushing 150 . Accordingly, the locating ring 160 may be aligned with the sprue bushing 150 . Hence, the locating ring 160 may be used to align the injection mold 120 within the injection molding machine 110 , such that the injection nozzle 117 of the injection molding machine 110 may substantially align with the sprue bushing 150 .
[0081] In particular, in one embodiment, the locating ring 160 may have an outside diameter 163 that may fit into an opening of substantially the same diameter in the front platen 111 of the injection molding machine 110 . Thus, a peripheral surface 162 of the locating ring 160 may contact the surface (or a portion thereof) of the corresponding opening in the front platen 111 of the injection molding machine 110 . In some embodiments, the surface defining the peripheral surface 162 may be formed as or may incorporate a wear-resistant surface 163 wr , which may be formed by superhard material 160 sm . Accordingly, the wear-resistant surface 163 wr may have less wear and or deterioration from repeated contact with the corresponding opening in the front platen 111 (as compared with a steel surface forming the outside diameter 163 ).
[0082] Additionally, the surface of the locating inside diameter 161 of the locating ring 160 may contact the surface of the sprue bushing 150 that defines the major diameter 153 . In some embodiments, the surface of the locating inside diameter 161 may be formed as or may incorporate a wear-resistant surface 161 wr , which may be formed by one or more layers of superhard material 160 sm . Accordingly, the wear-resistant surface 161 wr may exhibit reduced wear or deterioration. It should be noted that the same superhard material 160 sm may form the wear-resistant surface 161 wr and wear-resistant surface 163 wr.
[0083] In some instances, a surface of an injection mold component (sliding surface) may have relative sliding motion in contact with a surface of another injection mold component (stationary surface). In other words, the surface of a first injection mold component may slide in contact with the surface of a second injection mold component (one or both surfaces may be moving during such sliding motion). For example, as described above, the ejector pins 170 may be moved by the ejector plates 122 d toward the front platen 111 of the injection molding machine 110 , thereby ejecting the part 130 out of the injection mold 120 . As the ejector pins 170 move, the outside surface of the ejector pins 170 (e.g., surface of the outside diameter of the ejector pins 170 ) may slide or contact with the surface of corresponding openings in the molding elements 140 (e.g., in the molding element 140 b ).
[0084] The contact between the opening and the ejector pins 170 may wear the ejector pins 170 and/or the openings in the molding elements 140 . Such wear may result in flashing—i.e., molten molding material flowing between the surfaces of the ejector pins 170 and the corresponding openings in the molding elements 140 . For instance, as illustrated in FIGS. 2 , 5 A- 5 E, the molding elements 140 may incorporate an ejector sleeve 220 (e.g., ejector sleeves 220 a , 220 b shown in FIG. 2 ), which may have one or more wear-resistant surfaces or surface segments. Such ejector sleeve 220 may be secured in one or more of the molding elements 140 (e.g., in the molding element 140 b ) and may, in part, form one or more surfaces of the molding elements 140 that at least in part defines the molding volume 131 ( FIG. 1 ).
[0085] The ejector pins 170 may pass through an opening 221 of the ejector sleeve 220 and eject the part 130 . Alternatively, the ejector sleeve 220 may be secured to the ejector plates 122 d and the opening 221 may fit around a core pin (e.g., the core pin may be secured in the ejector housing 122 c ). Accordingly, in some embodiments, such ejector sleeve 220 also may, at least in part, move toward the front platen 111 of the injection molding machine 110 to eject the part 130 . In additional or alternative embodiments, the ejector pin 170 also may include a superhard material 170 sm . For example, a tip of the ejector pin 170 may incorporate superhard material 170 sm , which may form a wear-resistant surface 170 wr.
[0086] In one or more embodiments, the opening 221 may include a fitted portion 222 and a relieved portion 223 . The fitted portion 222 may have a close fit with the ejector pins 170 or with the core pin, as applicable. For instance, the ejector pin 170 may be a cylindrical pin. Hence, the opening 221 may have a substantially cylindrical shape. Furthermore, ejector sleeve 220 may have a clearance between the internal diameter of the opening 221 and the outside diameter of the ejector pin 170 in the range of about 0.01 mm to about 0.15 mm. The relieve portion 223 of the opening 221 may have a clearance that is greater than 0.15 mm between the internal diameter of the opening 221 and the outside diameter of the ejector pin 170 .
[0087] Whether stationary with respect to the ejector pins 170 (e.g., secured to the molding element 140 b ) or movable with respect to a core pin (e.g., secured in the ejector plates 122 d ), the ejector sleeve 220 may include a wear-resistant surface 221 wr , which may be formed by a superhard material 220 sm . The wear-resistant surface 221 wr may extend along and cover the entire fitted portion 222 or a part of the fitted portion 222 of the opening 221 . The wear-resistant surface 221 wr also may cover the entire relieved portion 223 or a part of the relieved portion 223 of the opening 221 .
[0088] Furthermore, the superhard material 220 sm that forms the wear-resistant surface 221 wr may have various thicknesses, as described above. For example, the superhard material 220 sm may have a thickness that is less than the distance from the wear-resistant surface 221 wr to an outer dimension of the ejector sleeve 220 (e.g., a thickness defined between the inside diameter of the opening 221 and an outside diameter 225 of the ejector sleeve 220 ). The superhard material 220 sm may be bonded to the ejector sleeve 220 in the same manner as described above in connection with other injection mold components.
[0089] Additionally, as described above, a portion of the ejector sleeve 220 may form part of one or more molding elements 140 . In particular, a front face 224 of the ejector sleeve 220 may form part of the molding element 140 b , which may contact at least a portion of the part 130 ( FIG. 2 ). Thus, the front face 224 may experience wear caused by the flow of molten molding material in contact with the front face 224 . Accordingly, the ejector sleeve 220 also may include a wear-resistant surface 224 wr . The same superhard material 220 sm that may form the wear-resistant surface 221 wr , also may form the wear-resistant surface 224 wr . The wear-resistant surface 224 wr may cover all or a portion of the front face 224 of the ejector sleeve 220 and/or ejector pin 170 .
[0090] Additionally, as described above, thickness of the superhard material 220 sm may vary, at least in part, based on the direction of the measurement. For instance, the thickness of the same superhard material 220 sm may be measured from the wear-resistant surface 221 wr as well as from wear-resistant surface 224 wr . Moreover, thickness of the superhard material 220 sm may be measured only from one of the wear-resistant surfaces 221 wr , 224 wr . More specifically, thickness of the superhard material 220 sm (as measured from the wear-resistant surface 224 wr ) may be such as to cover part of the fitted portion 222 of the opening 221 ( FIG. 5B ). Alternatively, thickness of the superhard material 220 sm may be such as to cover all of the fitted portion 222 and part of the relieved portion 223 of the opening 221 ( FIG. 5E ).
[0091] As described above, the ejector sleeve 220 , such as the ejector sleeve 220 b ( FIG. 2 ) may move with respect to the core pin. In addition to contact that may occur between the ejector sleeve 220 and the core pin, the outside diameter 225 of the ejector sleeve 220 also may slide in contact with one or more molding elements 140 (e.g., within an opening of the molding element 140 b ). Accordingly, the surface formed by the outside diameter 225 of the ejector sleeve 220 may experience wear associated with such sliding. In at least one embodiment, a wear-resistant surface 225 wr , which may cover all or part of the surface formed by the outside diameter 225 of the ejector sleeve 220 , may reduce such wear ( FIGS. 5B and 5E ). Furthermore, the wear-resistant surface 225 wr may be formed by the same body superhard material 220 sm that may form the wear-resistant surface 221 wr and/or wear-resistant surface 224 wr.
[0092] As described above, in some instances, the molding elements 140 may form or may have undercutting portions, such that the undercut must be relieved in order to eject the part 130 from the injection mold 120 . For example, as illustrated in FIGS. 6A-6G , the injection mold 120 may include an undercut relief system 230 . In at least one embodiment, the undercut relief system 230 may include a slide body 240 and a heel lock 250 . The slide body 240 may secure one or more of the molding elements 140 (e.g., a core 140 d ).
[0093] The core 140 d may form an undercutting portion of the part 130 . For example, the core 140 d may form a hole or a ledge in the part 130 . Before ejecting the part 130 , the slide body 240 may move the core 140 d out of the formed hole, thereby allowing the part 130 to be ejected. While the injection mold 120 is in the closed position, an angular portion 251 of the heel lock 250 may contact a corresponding angular portion 241 of the slide body 240 , which may aid in maintaining the slide body 240 in a desired position.
[0094] Accordingly, to relieve or release the undercutting portion, such as the core 140 d , when the injection mold 120 opens, an angle pin 260 may force the slide body 240 to move away from the part 130 (before the part 130 is ejected from the injection mold 120 ). More specifically, as the injection mold 120 opens, the moving portion 122 (which may include the second plate 122 a and the support plate 122 b ) move away from the nonmoving portion 121 (which may include the first plate 121 a and the top clamping plate 121 b ). The part 130 and the slide body 240 may remain on the moving portion 122 ; the slide body 240 may be restricted from movement away from the moving portion 122 by one or more gibs (not shown; see FIG. 6B-6G ), which may guide the slide body 240 . The slide body 240 also may have a single degree of freedom of motion, to slide away from the part 130 (e.g., along the second plate 122 a ). Thus, as the slide body 240 moves away from the nonmoving portion 121 , which secures the angle pin 260 . Hence, as the slide body 240 moves with respect to the angle pin 260 , the slide body 240 is forced to slide away from the part 130 .
[0095] In at least one embodiment, the angular portion 241 of the slide body 240 may have a wear-resistant surface that covers the entire or a part of the angular portion 241 . For example, a superhard material 240 sm , as described above, may form all or part of the surface of the angular portion 241 . Accordingly, the surface of the angular portion 241 may have reduced wear (compared with another material, such as steel) from contact with the angular portion 251 .
[0096] Additionally or alternatively, the heel lock 250 also may incorporate a superhard material 250 sm , which may form a wear-resistant surface on at least a part of the surface of the angular portion 251 . In some embodiments, the wear-resistant surface of the angular portion 251 may have a lower hardness than the wear-resistant surface of the angular portion 241 . Alternatively, the wear-resistant surface of the angular portion 251 may have substantially the same or higher hardness than the wear-resistant surface of the angular portion 241 .
[0097] Furthermore, the angular portion 241 of the slide body 240 or the angular portion 251 of the heel lock 250 may at least partially incorporate a wearing surface. As used herein, the term “wearing” surface refers to a surface that comprises a material that is softer than the superhard material of the wear-resistant surface that is in contact with the wearing surface. Suitable materials for the wearing surface include steel, brass, bronze, copper alloys, aluminum alloys, polytetrafluoroethylene (PTFA), combinations thereof, or other suitable material. Accordingly, the wearing surface may aid in reducing the amount of wear experienced by the wear-resistant surface. For example, the wearing surface may comprise material that is softer than the superhard material that comprises the wear-resistant surface. Thus, a softer wearing surface may absorb more energy generated by friction at an interface between the wear-resistant surface and a contacting surface (e.g., the wearing surface) than by a harder contacting surface. In some embodiments, the wearing surface also may have a reduced coefficient of friction (as compare to other suitable materials). To illustrate, the angular portion 241 of the slide body 240 may include a wear-resistant surface comprising superhard material (as described above), and the angular portion 251 may have a wearing surface, which may wear more quickly or easily than the wear-resistant surface of the angular portion 241 , and which may increase the life of the wear-resistant surface of the angular portion 241 .
[0098] In some embodiments, the wearing surface may be removable and replaceable. For example, the wearing surface may comprise an insert that incorporates material that is softer than the wear-resistant surface that contacts the wearing surface. Hence, once the wearing surface has worn beyond an acceptable level, the insert comprising the wearing surface may be removed and replaced.
[0099] Furthermore, as the slide body 240 moves toward and away from the part 130 (or the molding elements 140 that at least in part form the part 130 ), the slide body 240 may be guided by one or more gibs 280 ( FIGS. 6B-6G ). One should note that, as described above in connection with FIG. 6A , the cross-sectional view in FIG. 6A shows a cross-section that does not pass through the gibs 280 ; by contrast, cross-sectional views shown in FIGS. 6B-6E show a cross-section that is orthogonal to the cross-section shown in FIG. 6A , and which passes through the gibs 280 . In particular, the gibs 280 may have one or more surfaces that may prevent the slide body 240 from lifting off from a surface upon which the slide body 240 slides (e.g., a slide surface 290 ). For instance, the gibs 280 may have one or more retaining surfaces 281 (see FIG. 6F ), which may restrict lifting off of the slide body 240 . The slide body 240 also may have one or more shoulder surfaces 243 , which may interface (or interfere) with the retaining surfaces 281 of the gibs 280 .
[0100] Additionally or alternatively, the gibs 280 may have one or more surfaces that may control the direction of movement of the slide body 240 , and which may limit deviation of the slide body 240 from such direction. In particular, the gibs 280 may have one or more side surfaces 282 , 283 , which may contact with one or more side surfaces 244 , 245 of the slide body 240 . Accordingly, the side surfaces 244 , 245 of the slide body 240 may move in sliding contact with the side surfaces 282 , 283 of the gibs 280 , thereby guiding the slide body 240 along a desired path.
[0101] In one or more embodiments, one or more of the side surfaces 244 , 245 may incorporate wear-resistant surfaces, which may cover the portion of side surfaces 244 , 245 positioned within the gib 280 s (e.g., FIG. 6D ). It should be noted that FIG. 6D illustrates different examples of wear-resistant surfaces on the slide body 240 and on the gibs 280 , which are shown differently on the left and the right sides of an assembly of the slide body 240 and gibs 280 . The wear-resistant surfaces also may cover only a portion of one or more of the side surfaces 244 , 245 (e.g., FIGS. 6B , 6 C, and 6 E). Accordingly, the side surfaces 244 , 245 that incorporate, at least in part, the wear-resistant surfaces may experience reduced wear from the sliding in contact with the side surfaces 282 and/or 283 (as compared with a different material, such as steel). As described above, the wear-resistant surfaces incorporated into the side surfaces 244 , 245 may be formed by a superhard material 240 sm , which may be bonded to the slide body 240 through a substrate, directly, or may form part of an insert secured to the slide body 240 .
[0102] Additionally or alternatively, the one or more of the side surfaces 282 , 283 also may incorporate one or more wear-resistant surfaces, which may cover the side surfaces 282 , 283 entirely or partially. In some embodiments, the wear-resistant surfaces formed on or incorporated into the side surfaces 282 , 283 may have substantially the same hardness as the wear-resistant surface formed on or incorporated into the side surfaces 244 , 245 . In other embodiments, the wear-resistant surfaces formed as or incorporated into the side surfaces 282 , 283 may be softer than the wear-resistant surface formed as or incorporated into the side surfaces 244 , 245 . Furthermore, the wear-resistant surfaces formed on or incorporated into the side surfaces 282 , 283 also may be harder than the wear-resistant surface formed on or incorporated into the side surfaces 244 , 245 .
[0103] Moreover, the one or more wear-resistant surfaces that form one or more of the side surfaces 244 , 245 or the side surfaces 282 , 283 , may be continuous or interrupted, as illustrated in FIGS. 6B-6G . For instance, as the gibs 280 may have multiple wear-resistant surfaces 281 wr and/or side surfaces 282 wr , 283 wr that may at least partially form the retaining surfaces 281 and/or side surfaces 282 , 283 . In one or more embodiments, the wear-resistant surfaces 281 wr , 282 wr , 283 wr , or combinations thereof may comprise discrete surface segments, formed by multiple discrete layers or bodies of superhard material. Alternatively, the wear-resistant surfaces 281 wr , 282 wr , 283 wr , or combinations thereof may be formed by a single layer or body of superhard material that has variable thickness to form raised portions, forming the wear-resistant surfaces 281 wr , 282 wr , and/or 283 wr.
[0104] In one or more embodiments, one or more of the side surfaces 282 , 283 of the gibs 280 may incorporate or may be formed as wearing surfaces, which have a substantially lower hardness than the wear-resistant surfaces. Thus, one or more of the side surfaces 244 , 245 that may be formed as or incorporate wear-resistant surfaces may experience further reduced wear. Alternatively, the side surfaces 244 , 245 of the slide body 240 may be formed as or may incorporate wearing surfaces, which may come into contact with wear-resistant surfaces formed as or incorporated into the side surfaces 282 , 283 .
[0105] Additionally or alternatively, the slide body 240 may have a bottom sliding surface 246 , which may slide in contact or across a top surface 291 of a slide plate 290 . The slide plate 290 may be incorporated into or secured to a plate comprising the nonmoving portion 121 or moving portion 122 of the injection mold 120 . The slide plate 290 also may be incorporated into or secured to one or more of the molding elements 140 .
[0106] The bottom sliding surface 246 of the slide body 240 may be formed as or may incorporate a wear-resistant surface 246 wr . Similar to the wear-resistant surfaces described above, the wear-resistant surface 246 wr may be formed from a single body or multiple bodies or layers of superhard material. Moreover, the bottom sliding surface 246 may be continuous or interrupted, and the wear-resistant surface 246 wr may cover the entire bottom sliding surface 246 or only a part of the bottom sliding surface 246 of the slide body 240 ( FIGS. 6B-6E ).
[0107] The top surface 291 of the slide plate 290 also may incorporate or may be formed as a wear-resistant surface (formed by a superhard material 290 sm ). In at least one embodiment, a wear-resistant surface 291 wr may be incorporated into or may at least partially form the top surface 291 of the slide plate 290 . For example, the wear-resistant surface 291 wr may cover the entire or only a portion of the top surface 291 . For example, the wear-resistant surface 291 wr may comprise discrete surface segments ( FIG. 6G ). Alternatively, the wear-resistant surface 291 wr may comprise a unitary on continuous surface, which may be substantially level or may have raised and/or lowered portions therein.
[0108] To move the slide body 240 , in some embodiments, the injection mold 120 may include the angle pin 260 , which may pull the slide body 240 away from the part 130 as the injection mold 120 opens ( FIG. 6A ). More specifically, the angle pin 260 , which may remain stationary while the moving portion 122 moves away from the nonmoving portion 121 , may guide the slide body 240 away from the part 130 , as the moving portion 122 (including the slide body 240 ) moves away from the nonmoving portion 121 . Alternatively, other mechanisms may be used to move the slide body 240 away from the part 130 . For instance, the slide body 240 may be moved by a cylinder (e.g., a hydraulic cylinder). Thus, as shown in FIG. 6A , the slide body 240 may have the opening 242 , which may accommodate the angle pin 260 therein.
[0109] In at least one embodiment, the surface of the opening 242 and/or of the angle pin 260 may include a wear-resistant surface. For example, the wear-resistant surface may cover the entire or a part of the surface of the opening 242 in the slide body 240 . The wear-resistant surface of the opening 242 may reduce the amount of wear experienced by the opening 242 from repeated entry, exit, and/or sliding movement of the angle pin 260 against the surface of the opening 242 of the slide body 240 . The wear-resistant surface of the opening 242 may be formed by a superhard material 240 sm , which may be bonded to a substrate (such substrate may in turn be bonded to the slide body 240 ), to the slide body 240 directly, or may comprise an insert that is secured to the slide body 240 .
[0110] Additionally, the undercut relief system 230 also may include a slide retainer 270 , which may secure the slide body 240 (e.g., when the injection mold 120 is in the open position). For example, as illustrated in FIGS. 7A and 7B , the slide retainer 270 may include a slide plate 271 , and a retention ball 272 and a spring 274 (i.e., a spring-loaded retention ball 272 ). As the slide body 240 moves away from the part 130 (or the corresponding molding elements 140 forming at least a portion of the part 130 ), the slide plate 271 moves past the spring loaded retention ball 272 . Once the spring loaded retention ball 272 reaches a detent 275 on the slide plate 271 , the retention ball 272 may maintain the slide plate 271 (and consequently the slide body 240 ) in a fixed position.
[0111] In some instances, movement of the retention ball 272 across (and in contact with) a bottom surface of the slide plate 271 may wear the bottom surface 273 of the slide plate 271 . In at least one embodiment, the bottom surface 273 of the slide plate 271 may include or may be formed by a wear-resistant surface formed by superhard material 270 sm . Furthermore, the wear-resistant surface may cover (or form) the entire or only a part of the bottom surface 273 of the slide plate 271 , as shown in FIG. 7A . Also, superhard material 270 sm , which may form one or more wear-resistant surfaces, may be continuous across the entire bottom surface 273 of the slide plate 271 or may be interrupted. Moreover, as shown in FIG. 7B , superhard material 270 sm may comprise an insert, which may be secured to the slide body 240 (e.g., with mechanical fasteners such as screws or using bonding techniques, such as welding, brazing, etc.). In some embodiments, the insert may comprise the superhard material 270 sm bonded to a substrate ( FIG. 7B ). Alternatively, the entire insert may comprise superhard material—i.e., the superhard material 270 sm may be an insert secured to the slide body 240 .
[0112] As described above, the injection mold 120 may include one or more interlock pairs 280 ( FIG. 2 ). For example, as illustrated in FIGS. 8A and 8B , the injection mold may include one or more rectangular two-plate interlock pairs 280 a or interlock pairs having another suitable shape. More particularly, the rectangular single side interlock pair 280 a comprise a male interlock 281 a and a female interlock 282 a . The male interlock 281 a may have a protrusion 283 a , which may enter and substantially align with a recess 284 a within the female interlock 282 a . The protrusion 283 a and/or the recess 284 a may respectively incorporate superhard material 283 sm , 284 sm . Accordingly, the protrusion and 283 a and the recess 284 a also may include wear resistant surfaces 283 wr , 284 wr , respectively.
[0113] As described above, the interlock pair, such as the rectangular single side interlock pair 280 a may include small clearance on each side, between the protrusion and the recess of the respective male and female interlock portions. For instance, such clearance may be in one of the following ranges 0.0002 inches to 0.0005 inches 0.0005 inches to 0.001 inches, and 0.001 inches to 0.005 inches. Thus, as the injection mold closes, sides of the protrusion and the recess may slide in contact one with the other. In particular, the wear-resistant surface 283 wr may slide in contact with the wear-resistant surface 284 wr , as the protrusion 283 a enters the recess 284 a.
[0114] In one or more embodiments, superhard material 283 sm and 284 sm may form the wear-resistant surfaces 283 wr , 284 wr that may define the entire surface of the protrusion and the recess (as shown in FIGS. 8A and 8B ) or portions thereof. Additionally or alternatively, the superhard material 283 sm may form wear-resistant surfaces 283 wr only on the sides of the protrusion 283 a , as shown in FIG. 8A . Similarly, the superhard material 284 sm may form wear-resistant surface 284 wr only on the sides of the recess 284 .
[0115] In additional or alternative embodiments, the superhard material 283 sm , 284 sm , may form the entire protrusion 283 and recess 284 , as shown in FIG. 8B . Thus, the superhard material 283 sm , 284 sm may form other wear-resistant surfaces, in addition to the side surfaces of the protrusion 283 and the recess 284 . For instance, the part material 284 sm may form a bottom wear-resistant surface 284 wr of the recess 284 . Furthermore, as described above, superhard material 283 sm , 284 sm may comprise one or more inserts, which may be secured within the male interlock 281 a and/or the female interlock 282 a.
[0116] In at least one embodiment, the injection mold may include a three-plate interlock pair 280 b , as shown in FIGS. 8C and 8D , which may align three plates of the injection mold. Accordingly, the three-plate interlock pair 280 b may include a male interlock 281 b , which may enter into two opposing female interlocks 282 b . More specifically, the male interlock 281 b may include two opposing protrusions 283 b , which may enter into recesses 284 b of the female interlocks 282 b . Similar, as described above in connection with the rectangular two-plate interlock pairs 280 a ( FIGS. 8A and 8B ), the three-plate interlock pair 280 b may incorporate superhard material 283 sm , 284 sm , which may form wear-resistant surfaces 283 wr , 284 wr of the protrusions 283 and recesses 284 , respectively.
[0117] Thus, the superhard material 283 sm , 284 sm may form wear-resistant surfaces 283 wr , 284 wr only on the respective sides of the protrusions 283 and recesses 284 that contact one another ( FIG. 8C ). Additionally or alternatively, the superhard material 283 sm , 284 sm also may form wear-resistant surfaces 283 wr , 284 wr on other sides and/or portions of the male and female interlocks 281 , 282 . For instance, as shown in FIG. 8D , the superhard material 283 sm , 284 sm may form the entire protrusion 283 and/or recess 284 , respectively.
[0118] The injection mold also may include tapered interlocks. For instance, as shown in FIGS. 8E and 8F , the injection mold may incorporate one or more tapered interlock pairs 280 c . More specifically, the tapered interlock pair 280 c may comprise a male interlock 281 c and a corresponding female interlock 282 c . The male interlock 281 c may include a tapered protrusion 283 c that may enter a corresponding tapered recess 284 c in the female interlock. In one or more embodiments, the tapered interlock pair 280 c may include superhard material 283 sm , 284 sm , which may form wear-resistant surfaces 283 wr , 284 wr . Additionally, the superhard material 283 sm , 284 sm may form only the surfaces 283 wr , 284 wr of the respective protrusion 283 c and recess 284 c that may contact one another when the tapered interlock pair 280 c closes, as described above (see also FIG. 8E ). The superhard material 283 sm , 284 sm also may form the protrusion 283 c and/or the recess 284 c ( FIG. 8F ).
[0119] In further embodiments, the tapered interlock pair may be a cylindrical tapered interlock pair 280 d , as shown in FIGS. 8G and 8H . Similarly, the cylindrical tapered interlock pair 280 d may comprise a male and female interlocks 281 d , 282 d , which may have a corresponding protrusion 283 d and recess 284 d . Also, the protrusion 283 and recess 284 may include superhard material 283 sm , 284 sm , respectively, which may form wear-resistant surfaces 283 wr , 284 wr . As described above, the wear-resistant surfaces 283 wr , 284 wr may form only the one or more surfaces of the respective protrusion and recess 283 , 284 that may contact one another when the cylindrical tapered interlock pair 280 d closes ( FIG. 8G ). Additionally or alternatively, the superhard material 283 sm , 284 sm may form the respective protrusion and/or recess 283 , 284 ( FIG. 8H ).
[0120] While various aspects and embodiments have been disclosed herein, other aspects and embodiments are contemplated. The various aspects and embodiments disclosed herein are for purposes of illustration and are not intended to be limiting. Additionally, the words “including,” “having,” and variants thereof (e.g., “includes” and “has”) as used herein, including the claims, shall be open ended and have the same meaning as the word “comprising” and variants thereof (e.g., “comprise” and “comprises”). | Embodiments of the invention relate to injection mold components, assemblies, and molding system that include superhard materials. Such injection mold components, assemblies, and systems may decrease wear of certain injection mold components, which may result in improved productivity of the injection mold and molding systems that utilize such components. | 1 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to an apparatus and method for manufacturing an anisotropic formed body having anisotropy to exhibit in specific directions within a matrix various properties, such as electrical conductivity, heat conductivity, expansion coefficient, light transmittance, magnetism, hardness, elasticity, water absorption, dielectric constant, gas permeability, piezoelectric characteristics, and vibration absorption. In particular, the present invention relates to an apparatus and method for manufacturing an anisotropic formed body in which anisotropy is imparted by utilizing a magnetic field.
2. Description of the Related Art
As an example of an anisotropic formed body as mentioned above, an anisotropic conductive device is known. For example, an anisotropic conductive connector for electrical connection of a microphone and a printed circuit board contained in a mobile phone is known. As an example of such an anisotropic conductive connector, there is known a formed body composed of a disc-shaped main body portion with a continuous conductive portion formed therein. The main body portion uses electrically insulating silicone rubber as a matrix. Conductive, magnetic fine particles are oriented in a specific direction to form the continuous conductive portion. This formed body is generally obtained as follows: A mold with conductive fine particles arranged therein is filled with liquid silicone rubber, and the conductive fine particles are oriented by a parallel magnetic field generated by permanent magnets embedded in the upper and lower portions of the mold so as to be opposed to each other. Then, the silicone rubber is crosslinked.
As a prior-art technical document disclosing a technique in which an anisotropic formed body is formed by utilizing the parallel magnetic field of such permanent magnets, the applicant of the present invention has referred to the following patent document.
However, in the method of forming an anisotropic formed body by utilizing the magnetic field of permanent magnets, there are limitations regarding the intensity of the magnetic field that can be generated. Thus, the functional fine particles allowing orientation and exhibiting properties such as conductivity are restricted to ferromagnetic materials such as nickel or iron. With paramagnetic materials, such as aluminum, platinum, palladium, titanium, and manganese, and diamagnetic materials, such as gold, silver, copper, metal oxide, metal nitride, metal carbide, metal hydroxide, carbon, organicpolymer, protein, and DNA, it is difficult to effect orientation so as to attain the intended anisotropy. Further, due to its weak magnetic force and unevenness in magnetic field generated by its surface irregularities, it is rather difficult for a permanent magnet to generate a uniform parallel magnetic field in a large space. Thus, it is very difficult to produce an anisotropic formed body exhibiting an anisotropy which is parallel and of a uniform interval within a large area.
SUMMARY OF THE INVENTION
In view of the above problem in the prior art, it is an object of the present invention to provide an anisotropic formed body allowing use of a wider variety of materials as the functional fine particles and realizing an anisotropy which is parallel and of a uniform interval within a large area.
To achieve the above object, the present invention basically adopts a technical concept according to which a superconducting magnet device generates a uniform and parallel magnetic field in which magnetic lines of force are arranged at equal intervals so as to be parallel to each other and a mold is placed in this uniform and parallel magnetic field to orient the functional fine particles therein. This helps to realize a uniform and parallel orientation along the magnetic lines of force constituting the uniform and parallel magnetic field even with functional fine particles that are difficult to orient by conventional permanent magnets, thus making it possible to use a wider variety of materials for the functional fine particles. Thus, it is possible to obtain an anisotropic formed body that can be used as a functional material exhibiting, uniformly and in parallel, various properties inherent in the functional fine particles, such as electrical conductivity, heat conductivity, expansivity, light transmittance, magnetism, hardness, elasticity, water absorption, dielectric constant, gas permeability, piezoelectric characteristics, and vibration absorption, and to use the anisotropic formed body in various technical fields.
As an apparatus for manufacturing an anisotropic formed body providing the action and effect based on the above technical concept, the present invention provides an apparatus for manufacturing an anisotropic formed body in which functional, magnetic fine particles are oriented in a specific direction within a matrix and in which anisotropy is given to properties attributable to the functional fine particles. The apparatus includes a super conducting magnet device that has a cylindrical super conducting coil and generates a uniform and parallel magnetic field in which magnetic lines of force at equal intervals and parallel to each other extend through a mold arranged in a barrel axis of the superconducting coil.
Further, the present invention provides a method for manufacturing an anisotropic formed body, in which a superconducting magnet device applies a uniform and parallel magnetic field with magnetic lines of force at equal intervals and parallel to each other to a mold, in which a matrix is filled with a liquid molding material containing functional, magnetic fine particles, to orient the functional fine particles in a direction of the magnetic lines of force which subsequently harden in the liquid molding material.
In the above-described manufacturing apparatus of the present invention, the cylindrical superconducting coil is composed of an upper superconducting coil and a lower superconducting coil vertically spaced apart from each other, and a gap between the coils constitutes a transfer opening for the mold. By thus using the gap between the coils as the transfer opening for the mold, it is possible to advantageously utilize the portion usually constituting a dead space of a split type superconducting magnet device equipped with upper and lower superconducting coils, thereby rationally simplifying the construction of the device. Thus, there is no need to separately form a transfer opening or to provide a transfer mechanism leading to a separate transfer opening.
The above-described manufacturing apparatus of the present invention may be equipped with a heating device for heating in the mold the liquid molding material with functional fine particles contained in the matrix. In this arrangement, it is possible to further soften through heating a synthetic resin material, such as a thermoplastic resin or a thermosetting resin, natural rubber, synthetic rubber, or an elastomer material, such as thermoplastic elastomer, so that the orientation of functional fine particles by the uniform and parallel magnetic field is facilitated. Further, in the case of using natural rubber or synthetic rubber, it is possible to crosslink the molding material.
The above-described manufacturing apparatus of the present invention may be equipped with a drive device for driving at least one of the mold and the heating device in the barrel axis direction of the superconducting coil. In this drive device, the mold and the heating device are driven in the barrel axis direction of the superconducting coil, so that it is possible to significantly utilize the internal space of the superconducting coil, making it possible to rationally simplify the construction of the device.
The above-described manufacturing apparatus of the present invention may be equipped with an injection molding device using an injection mold as the mold. Further, the manufacturing apparatus of the present invention may be equipped with a photo-setting molding device using a photo-setting mold as the mold. This makes it possible to obtain anisotropic formed bodies of various configurations and materials in which functional fine particles are oriented by a uniform parallel magnetic field.
In the above-described manufacturing apparatus of the present invention, the superconducting magnet device is equipped with a heat insulating portion. Thus, the cooling of the superconducting coil is not hindered by the heat due to the heat generating mechanism such as the heating device or the injection molding device.
Incidentally, as stated above, the functional, magnetic fine particles to be contained in the matrix are endowed with anisotropy with respect to properties, such as electrical conductivity, heat conductivity, expansion coefficient, light transmittance, magnetism, hardness, elasticity, water absorption, dielectric constant, gas permeability, piezoelectric characteristics, and vibration absorption. Specific examples of the functional fine particles include nickel, iron, cobalt, aluminum, platinum, palladium, titanium, manganese, gold, silver, copper, metal oxide, metal nitride, metal carbide, metal hydroxide, a carbon material, such as carbon fiber, graphite, or carbon nanotube, organic polymer, protein, and DNA. Examples of conductive functional fine particles include magnetic conductors, such as nickel, iron, or cobalt, or an alloy using these as main components, conductor particles consisting of copper, aluminum, gold, or silver plated with a magnetic conductor, magnetic conductor particles plated with a conductor as mentioned above, and carbon materials, such as carbon fiber, graphite, or carbon nanotube. Further, examples of functional fine particles with heat conductivity include, in addition to the above-mentioned carbon materials, metal oxide, metal nitride, metal carbide, and metal hydroxide. According to the present invention, to orient these functional fine particles by a superconducting magnet device, a uniform parallel magnetic field with a magnetic flux density of 1 to 10 T is generated. Generally speaking, it is difficult to obtain a high magnetic field of 1 T or more by using permanent magnets. Regarding the above-mentioned functional fine particles, it is possible to achieve the requisite and sufficient anisotropic orientation with a magnetic flux density of 1 to 10 T. Further, in this case, it is possible to achieve the requisite cooling of the superconducting coil by using a refrigerator cooling system that can achieve a forced-flow cooling or a conduction cooling, and an immersion cooling system, which involves immersion in a large amount of liquid helium, is not required. Thus, a superconducting magnet device of a simpler device construction suffices. In the present invention, this high magnetic field generated by the superconducting magnet device is a uniform parallel magnetic field having a diameter of 300 to 1000 mm. Thus, it is possible to obtain an anisotropic formed body and exhibiting anisotropy with respect to properties, such as electrical conductivity, heat conductivity, expansion coefficient, light transmittance, magnetism, hardness, elasticity, water absorption, dielectric constant, gas permeability, piezoelectric characteristics, and vibration absorption within a large area.
The present invention is not restricted to what has been described above. The objectives, advantages, features, and usages of the invention will be further clarified by the following description given with reference to the accompanying drawings. It should be understood that all appropriate modifications made without departing from the gist of this invention are within the scope of this invention.
BRIEF DESCRIPTION OF THE DRAWINGS
In the accompanying drawings:
FIG. 1 is a schematic sectional view of an anisotropic formed body manufacturing apparatus according to an embodiment of the present invention;
FIG. 2 is a schematic plan view taken along the line 2 - 2 of FIG. 1 ;
FIG. 3 is a schematic explanatory view of a uniform parallel magnetic field generated by a superconducting coil provided in the manufacturing apparatus of FIG. 1 ;
FIG. 4 is a schematic sectional view of an anisotropic formed body manufacturing apparatus according to another embodiment of the present invention; and
FIG. 5 is a schematic sectional view of an anisotropic formed body manufacturing apparatus according to still another embodiment of the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
An embodiment of the present invention will now be described with reference to the drawings.
An anisotropic formed body manufacturing apparatus 1 according to this embodiment has an upper superconducting coil 2 a and a lower superconducting coil 2 b , which are respectively accommodated in hollow and annular sealed containers 3 a and 3 b that are substantially evacuated. These sealed containers 3 a and 3 b are respectively accommodated in an upper casing 4 a and a lower casing 4 b , which are hollow and annular in configuration. The upper casing 4 a is secured to an upper frame 5 a , and the lower casing 4 b is secured to a lower frame 5 b . Between the upper casing 4 a and the lower casing 4 b , there is provided a spacer 6 , and the upper casing 4 a mounted to the upper frame 5 a are supported by the spacer 6 .
The split type superconducting coils 2 a and 2 b composed of upper and lower portions are formed into an annular configuration using, e.g., NbTi. For improved productivity, ones with a large diameter are desirable. Thus, the coils have an inner diameter of at least 200 mm or more, and more preferably, an inner diameter of 300 mm or more. These superconducting coils 2 a and 2 b generate a uniform and parallel magnetic field in which the magnetic lines of force are at equal intervals and parallel to each other. The magnetic flux density thereof is at least 1 to 10 T. Further, the difference in magnetic flux density in the transverse direction of the uniform and parallel magnetic field is within a range of ±1%. Further, the diameter of the uniform and parallel magnetic field is 300 to 1000 mm. An example of the specific construction of the superconducting coils 2 a and 2 b , generating such a uniform and parallel magnetic field, is disclosed in JP2001-264402A invented by Kiyoshi et al. filed on Mar. 17, 2000 in Japan, and it is possible to realize the superconducting coils based on this example. The teachings described in this patent application are hereby incorporated by reference. Refrigerators 7 a and 7 b are respectively mounted to the superconducting coils 2 a and 2 b . The refrigerators are supplied with refrigerants provided from a pressure feeding device (not shown) to cool the superconducting coils 2 a and 2 b . That is, the superconducting coils 2 a and 2 b of this embodiment are cooled by using a refrigerator which can achieve a forced-flow cooling or a conduction cooling.
Between the upper superconducting coil 2 a and the lower superconducting coil 2 b , and more specifically, between the upper casing 4 a and the lower casing 4 b (slidable receiving plate 12 ), there is formed, by means of the spacer 6 , a gap d whose height is larger than that of a mold described below. In the manufacturing apparatus 1 of this embodiment, this gap d is utilized as a “transfer opening” for the mold.
Between the outer side surfaces of the sealed containers 3 a and 3 b and the inner side surfaces of the casings 4 a and 4 b , there are mounted heat insulating materials 8 a and 8 b consisting of glass wool, hard urethane, or the like to insulate the sealed containers 3 a and 3 b from heat generated by heating devices 9 a and 9 b.
The superconducting magnet device of this embodiment is constructed as described above.
Next, the heating devices of this embodiment will be described. The upper heating device 9 a is mounted to the lower end of a column 10 extending vertically downwards through the cylindrical interior of the upper casing 4 a , and is adapted to heat the mold 11 from above. The lower heating device 9 b is mounted to the upper end of a slide 12 , which extends through the cylindrical interior of the lower casing 4 b and serves as a “drive device” driven by a hydraulic cylinder, an electric motor, or the like. The lower heating device 9 b is adapted to heat the mold 11 from below. Thus, the lower heating device 9 b is vertically movable, and capable of moving toward and away from the upper heating device 9 a . The lower heating device 9 b is upwardly displaced with the mold 11 placed thereon to thereby bring the mold 11 into contact with the upper heating device 9 a . To thus place the mold 11 on the lower heating device 9 b , the mold 11 is brought from outside the manufacturing apparatus 1 onto an annular, disc-like slidable receiving plate 13 mounted to the upper surface of the lower casing 4 b , and the mold is caused to slide thereon to be placed on the lower heating device 9 b.
Next, an anisotropic formed body manufacturing method according to an embodiment, using the above manufacturing apparatus 1 , will be described. In this embodiment, the anisotropic formed body to be obtained is a sheet-like anisotropic conductive connector. This anisotropic conductive connector uses silicone rubber as the matrix and nickel particles as the functional fine particles.
First, the mold 11 is previously filled with a liquid molding material composed of liquid silicone rubber containing nickel particles. More specifically, the mold 11 is composed of upper and lower mold portions, and the cavity to form the outer contour of the anisotropic conductive connector, formed in the lower mold portion 11 b , is filled with the liquid molding material. The upper mold portion 11 a is used as a lid for closing the lower mold portion 11 b.
Next, as shown in FIG. 2 , this mold 11 is pushed by a transfer device 14 a composed of a straight feeder or the like provided in the manufacturing apparatus 1 , and is transferred to the interior of the manufacturing apparatus 1 . During this transfer, the mold 11 is caused to slide on the slide recipient plate 13 through a transfer plate 15 a . The height of the lower heating device 9 b is previously adjusted by the vertically movable slide 12 such that its upper surface is substantially flush with the upper surface of the slide recipient surface 13 (See FIG. 1 ). When the mold 11 has been placed at a predetermined position on the lower heating device 9 b , the transfer device 14 a retreats, and the lower heating device 9 b is caused to ascend by the slide 12 until the mold 11 comes into contact with the upper heating device 9 a.
Then, the mold 11 is heated for a predetermined period of time while being sandwiched between the upper heating device 9 a and the lower heating device 9 b , and the liquid silicone rubber is further softened. In the meantime, the upper superconducting coil 2 a and the lower superconducting coil 2 b form a uniform and parallel magnetic field 16 , in which, as shown in FIG. 3 , the magnetic lines of force 16 a are at equal intervals and are parallel to each other in a planar direction. As a result, in the mold 11 , the nickel particles constituting the functional fine particles are easily oriented in the vertical direction along the uniform and parallel magnetic field 16 within the liquid silicone rubber further softened by being heated by the heating devices 9 a and 9 b , whereby an anisotropic conductive portion is formed. Thereafter, heating is performed at still higher temperature to crosslink the liquid silicone rubber, thereby fixing the orientation of the nickel particles in the anisotropic conductive portion. After the completion of this molding process, the lower heating device 9 b is lowered by the slide 12 until its upper surface becomes substantially flush with the upper surface of the slide recipient plate 13 . Then, as shown in FIG. 2 , the mold 11 is pulled by a transfer device 14 b composed of a straight feeder or the like provided in the manufacturing apparatus 1 , and is brought to the exterior of the manufacturing apparatus 1 by means of a transfer plate 15 b.
In the anisotropic conductive connector obtained by the above forming method, it is possible to form the anisotropic conductive portion in which the nickel particles are oriented with precision and in a fine pitch. Further, it is possible to form such a conductive portion in a large area. Thus, the connector can be used for connection, for example, between a liquid crystal display and a printed circuit board.
Instead of the mold 11 used in the above embodiment, it is possible to adopt a mold with a ferromagnetic substance embedded therein so that magnetic lines of force may be formed at desired positions in the mold. By thus realizing a magnetic circuit design in the mold, it is possible to make the intervals of the magnetic lines of force in the uniform and parallel magnetic field partially different.
While in the above embodiment a single mold 11 is supplied to the manufacturing apparatus 1 , it is also possible to supply the manufacturing apparatus 1 with a plurality of molds 11 stacked together or arranged in a planar direction, performing simultaneous molding with a plurality of molds.
While in the above embodiment silicone rubber is used as the matrix and nickel particles as the functional fine particles, these allow modifications according to the anisotropic formed body to be obtained. With such modifications, the period of time and temperature for the heating by the heating devices 9 a and 9 b are appropriately changed.
While in the above embodiment the superconducting coils 2 a and 2 b are cooled by the cooling system using the refrigerators 7 a and 7 b to thereby realize the manufacturing apparatus 1 in a generally simple construction, it is also possible to adopt the immersion cooling system if such simplification in apparatus construction is not desired.
While in the above embodiment the heat insulating portion has the heat insulating materials 8 a and 8 b , it is also possible to provide a water cooling pipe for heat insulation.
Instead of the manufacturing apparatus 1 of the above embodiment, it is also possible, for example, to adopt manufacturing apparatuses as shown in FIGS. 4 and 5 . In the manufacturing apparatus 1 shown in FIG. 4 , an injection molding device is provided. This injection molding device is equipped with a cylinder 20 , a screw 21 , a drive source 22 for driving the screw 21 composed of an injection cylinder and a hydraulic motor or the like, a heater 23 , a bracket 24 accommodating the drive source 22 , a hopper 25 , an injection mold 26 , etc. The bracket 24 is fixed to the upper frame 5 a through the intermediation of an angle member 27 , whereby the entire injection molding device is secured in position. The opening and closing of the mold 26 is effected through the vertical movement of the slide 12 , and the releasing of the anisotropic formed body is effected by an adsorption nozzle or the like (not shown). Thus, also with the anisotropic formed body manufacturing apparatus 1 shown in FIG. 4 , it is possible to obtain, through injection molding, an anisotropic formed body in which the functional fine particles are oriented so as to be at equal intervals and parallel to each other by a uniform and parallel magnetic field generated by the upper superconducting coil 2 a and the lower superconducting coil 2 b . In the manufacturing apparatus 1 shown in FIG. 5 , a photo-setting molding device is provided inside the upper casing 4 a and the lower casing 4 b . The photo-setting molding device is equipped with a photo-setting mold 30 formed of a transparent material such as acrylic resin or glass, and a light source device 31 using ultraviolet laser or the like. Reference numerals 32 and 33 indicate support members on which the photo-setting mold 31 is to be placed. Thus, also with the anisotropic formed body manufacturing apparatus 1 shown in FIG. 5 , it is possible to obtain, through photo-setting molding, an anisotropic formed body in which the functional fine particles are oriented so as to be at equal intervals and parallel to each other by a uniform and parallel magnetic field generated by the upper superconducting coil 2 a and the lower superconducting coil 2 b.
While in the above embodiment a split type superconducting coil composed of the upper superconducting coil 2 a and the lower superconducting coil 2 b are used as an example, it is also possible to use a unitary superconducting coil.
According to the apparatus and method for manufacturing an anisotropic formed body of the present invention, a uniform and parallel magnetic field, which can not be generated by permanent magnets, is used to orient functional fine particles at equal intervals and parallel to each other, which is difficult to effect with permanent magnets, whereby it is possible to obtain various anisotropic formed bodies exhibiting, uniformly and in parallel, various properties, such as electrical conductivity, heat conductivity, expansion coefficient, light transmittance, magnetism, hardness, elasticity, water absorption, dielectric constant, gas permeability, piezoelectric characteristics, and vibration absorption. The anisotropic formed bodies thus obtained can be used in a variety of technical fields. | An apparatus for manufacturing an anisotropic formed body in which functional, magnetic fine particles are oriented in a specific direction within a matrix and in which anisotropy is given to properties attributable to the functional fine particles. The apparatus allows use of a wide variety of materials as the functional fine particles and realizes an anisotropy which is parallel and of a uniform interval within a large area. Further, a method for manufacturing an anisotropic formed body, includes applying, by using a superconducting magnet device, a uniform and parallel magnetic field with magnetic lines of force at equal intervals and parallel to each other, to a mold in which the matrix is filled with a liquid molding material containing functional, magnetic fine particles, to orient the functional fine particles in a direction of the magnetic lines of force, whereby the liquid molding material subsequently hardens. | 1 |
The invention relates to novel thiadiazole compounds, to their use as cardiotonic agents, and to a method for producing S-methyl-N-(chloromethanesulfonyl)isothiourea, which is used as an intermediate in the preparation of the novel thiadiazole compounds of the invention.
The thiadiazole compounds of the invention are inhibitors of cyclic nucleotide phosphodiesterase. Inhibition of this enzyme is associated with increased contractility of heart muscle; therefore these compounds can be used as cardiotonic agents. Inhibition of phosphodiesterase is also associated with a decrease in platelet aggregation; therefore, the thiadiazole compounds of the invention may also be useful as antithrombotic agents. The compounds of the invention also show activity in the inhibition of calcium dependent smooth muscle contraction, and therefore may also be useful as broncho dilators.
BRIEF SUMMARY OF THE INVENTION
The novel thiadiazole compounds of the invention are 1H-1,2,4-thiadiazolo[3,4-b]quinazolin-5-one-2,2-dioxides, as represented by Structural Formula I, shown in FIG. 1. The compounds of the invention can be produced by reacting an isatoic anhydride (Structural Formula III) with S-methyl-N-(chloromethanesulfonyl)isothiourea (II), in accordance with the reaction sequence shown in FIG. 2. An improved process for preparing S-methyl-N-(chloromethanesulfonyl)-isothiourea comprises reacting S-methylisothiourea sulfate with chloromethanesulfonyl chloride in the presence of a base such as an alkali metal carbonate, in a two phase reaction mixture comprising water and an organic solvent such as methylene chloride or other organic solvent that is substantially immiscible with water.
THE PRIOR ART
The thiadiazoloquinazolinone ring system has not been previously reported. There exists a 1973 French patent (No. 2,145,005) that discloses fused 1,2,4-thiadiazoline-1,1-dioxides as a general class; this patent also discloses a synthesis of S-methyl-N-(chloromethanesulfonyl)isothiourea by a single-solvent method which applicants herein have been unable to duplicate. The same authors have published a related paper: A. Etienne al., Bull. Chem. Soc. Fr., 7-8, Pt. 2, 1580-1584 (1974).
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a structural formula that represents the novel thiadiazole compounds of the invention; and
FIG. 2 shows a reaction sequence that can be used to prepare the compounds of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Referring to the reaction sequence shown as FIG. 2, the reaction of an isatoic anhydride (III) with the known chloromethanesulfonyl isothiourea (II), in an appropriate solvent such as acetonitrile or dioxane and in the presence of a proton acceptor such as sidium hydride, a tertiary amine, or other base, provides the compounds of the invention (I). In both Formulas I and III, each R substituent individually represents halogen, hydroxyl, lower alkyl (i. e., C 1 to C 6 alkyl), OR 1 (wherein R 1 represents lower alkyl, optionally substituted by R 2 R 3 N--CO--, wherein R 2 and R 3 individually represent lower alkyl or cycloalkyl), nitro, amino (optionally substituted by R 1 , wherein R 1 is as described above), or R 1 S(O) x (wherein R 1 is as described above, and x=0,1, or 2), and represents a number having a value of from 0 to 4, and n preferably from 0 to 2.
The thiadiazole compounds of the invention can be produced from an isatoic anhydride of Formula III via the general reaction shown in FIG. 2, so long as the group or groups represented by the R variable in Formulas I and III are not chemically reactive under the conditions of the reaction. Examples 2-8, below, illustrate representative reaction conditions that can be used to produce the thiadiazole compounds of the invention from the corresponding isatoic anhydride.
Many of the isatoic anhydrides that are used as starting reactants in the synthesis of the compounds of the invention are known compounds. Isatoic anhydrides can be produced by the procedures described by G. Coppola et al. in J. Het. Chem., 22, 193 (1985) and G. Coppola, Synthesis, 505 (1980).
The isatoic anhydride is reacted with (II) in approximately equimolar proportions, in a suitable reaction medium in the presence of an acid acceptor such as a tertiary amine or alkali metal hydride. The reaction is preferably carried out under an inert atmosphere such as nitrogen or argon. The reaction is carried out at a temperature and for a period of time sufficient to produce the desired compound. Usually, it is most convenient to carry out the reaction under atmospheric reflux conditions for a period of time within the range of from about 1 to about 24 hours. The reaction temperature will usually be from about 50° C. to about 120° C. Upon the completion of the reaction, the reaction mixture is cooled and the desired product is recovered by standard procedures. For example, the cooled reaction mixture may be poured into an aqueous acid such as citric, acetic, or hydrochloric acid, which will precipitate the desired product compound. The compound may then be recovered by filtration and may be purified by recrystallization from a suitable solvent. The examples, below, illustrate representative reaction conditions that have been found to be effective in producing the compounds of the invention.
The invention also provides an improved process for the synthesis of (II) in which S-methylisothiourea (as the salt of an inorganic acid) is sulfonylated by chloromethanesulfonyl chloride in a two-phase system in the presence of an inorganic base, water, and an organic solvent such as methylene chloride that is substantially immiscible with water.
The compounds of this invention have shown activity as inhibitors of cyclic nucleotide phosphodiesterase, and thus are potentially useful as cardiotonic agents. Inhibitors of cyclic nucleotide phosphodiesterase frequently act to inhibit platelet aggregation. Therefore, the compounds of this invention may also have utility as antithrombotic agents.
EXAMPLE 1
Preparation of S-methyl-N-(chloromethanesulfonyl)isothiourea (II).
Water (250 ml) is added with stirring to a slurry of S-methylisothiourea sulfate (77.3 g, 0.556 mol) and sodium carbonate (273 g, 2.58 mol) in methylene chloride (1100 ml). Chloromethanesulfonyl chloride (85% pure, 94.8 g, 0.542 mol) is then added slowly with stirring at such a rate as to maintain gentle reflux of the solvent. The mixture is then stirred at room temperature for 16 hr, and the organic solution is decanted from the inorganic residue. The residue is washed with additional methylene chloride (500 ml), and the combined organic solutions are dried with magnesium sulfate, filtered, and concentrated to leave crude II as a yellow oil (99.5 g, 90%). This crude material is adequate for preparing the thiadiazole compounds of the invention (e.g., see Example 4, below). Purification by chromatography on silica gel (2.5% ethyl ether in methylene chloride as eluant) provides the title compound as a colorless solid, mp 60°-62° C. (72 g, 65%).
In the preparation of II, the preferred solvent is methylene chloride, as is illustrated in the foregoing Example. It may be replaced by other organic solvents in which water is less than about 2% soluble, such as chloroform, diethyl ether, benzene, or toluene. Solvents in which water is more soluble, such as ethyl acetate, are less satisfactory. The preferred inorganic base for use in this process is sodium carbonate. Satisfactory substitutes are, for instance, sodium bicarbonate, potassium carbonate, and potassium bicarbonate. The reaction temperature is most conveniently the boiling point of methylene chloride, but may be varied between about 0° C. to about 60° C. The reaction is essentially complete within one hour, and longer reaction times do not affect the yield. The proportion of added water may be varied. In the foregoing Example, 200 to 400 ml could be used. The proportion of organic solvent has been chosen for convenience, and it is anticipated that the volume can be reduced.
EXAMPLE 2
Preparation of Thiadiazoles (I)
7-Nitro-1H-1,2,4-thiadiazolo[3,4-b]quinazolin-5-one-2,2-dioxide.
To a stirred solution of 5-nitroisatoic anhydride (1.04 g, 5.0 mmol) and S-methyl-N-(chloromethanesulfonyl)isothiourea (1.04 g, 5.0 mmol) in acetonitrile (10 ml) under nitrogen is added 4-(N,N-dimethylamino)-pyridine (0.61 g, 5.0 mmol). The solution is refluxed for 16 hr, cooled, and poured into 10% aqueous citric acid. The resulting solid is collected by filtration and recrystallized twice from isopropanol/DMF, then from DMSO, to provide the title compound as a light yellow solid, mp >300° C. (225 mg, 16%).
EXAMPLE 3
7,8-Dimethoxy-1H-1,2,4-thiadiazolo[3,4-b]quinazolin-5-one-2,2-dioxide.
To a stirred slurry of 4,5-dimethoxyisatoic anhydride (4.46 g, 20 mmol) and S-methyl-N-(chloromethanesulfonyl)isothiourea (4.06 g, 20 mmol) in dioxane (30 ml) is added 1,5-diazabicyclo[4.3.0]non-5-ene (2.5 ml). The mixture is refluxed for 4 hr under nitrogen, then cooled and poured into 0.3N aqueous hydrochloric acid. The precipitate is collected by filtration and recrystallized from DMSO to provide the title compound as a light yellow solid, mp >300° C. (445 mg, 7.5%).
EXAMPLE 4
6,7-Dimethoxy-1H-1,2,4-thiadiazolo[3,4-b]quinazolin-5-one-2,2-dioxide.
To a stirred solution of 5,6-dimethoxyisatoic anhydride (8.93 g, 40 mmol) and S-methyl-N-(chloromethanesulfonyl)isothiourea (90% pure, 9.73 g, 44 mmol) in N-methyl-2-pyrrolidinone (50 ml) under nitrogen is added sodium hydride (1.65 g of 60% dispersion in oil, 41 mmol). After 15 min at room temperature, the mixture is stirred at 80° C. for 18 hr, then cooled and poured into 0.5N aqueous hydrochloric acid (150 ml). The precipitate is collected by filtration, and washed with water, then with ether. Recrystallization from DMF containing 5% water provides the title compound as a tan solid, mp >300° C. (2.55 g, 21%).
EXAMPLE 5
7,8-Dichloro-1H-1,2,4-thiadiazolo[3,4-b]quinazolin-5-one-2,2-dioxide.
To a stirred slurry of 4,5-dichloroisatoic anhydride (11.54 g, 50 mmol) in N-methyl-2-pyrrolidinone (50 ml) under nitrogen is added sodium hydride (2.05 g of 60% oil dispersion, 52 mmol). The mixture is stirred for 30 min at room temperature, and to the resulting solution is added S-methyl-N-(chloromethanesulfonyl)-isothiourea (11.0 g, 55 mmol). The mixture is stirred under nitrogen at 80° C. for 18 hr, then worked up as in Example 4 above. Recrystallization from DMF provides the title compound as a white solid, mp >300° C. (4.69 g, 31%).
EXAMPLE 6
7-Chloro-1H-1,2,4-thiadiazolo[3,4-b]quinazolin-5-one-2,2-dioxide.
To a stirred slurry of 5-chloroisatoic anhydride (5.93 g, 30 mmol) and S-methyl-N-(chloromethanesulfonyl)isothiourea (6.08 g, 30 mmol) in dioxane (50 ml) is added 4-(N,N-dimethylamino)pyridine (3.67 g, 30 mmol). The mixture is refluxed under nitrogen for 24 hr, then worked up as in Example 4 above. Recrystallization from DMF provides the title compound as a white solid, mp >300° C. (1.24 g, 15%).
EXAMPLE 7
8-Chloro-1H-1,2,4-thiadiazolo[3,4-b]quinazolin-5-one-2,2-dioxide.
To a stirred slurry of 4-chloroisatoic anhydride (4.95 g, 25 mmol) and S-methyl-N-(chloromethanesulfonyl)isothiourea (5.07 g, 25 mmol) in acetonitrile (25 ml) under nitrogen is added 4-(N,N-dimethylamino)pyridine (3.97 g, 33 mmol). The mixture is refluxed under nitrogen for 24 hr, concentrated, then worked up as in Example 4 above. The resulting gummy solid is triturated with hot ethanol, then recrystallized from DMF to provide the title compound as a white solid, mp >300° C. (1.65 g, 24%)
EXAMPLE 8
1H-1,2,4-Thiadiazolo[3,4-b]quinazolin-5-one-2,2-dioxide.
To a stirred slurry of isatoic anhydride (3.10 g, 19 mmol) and S-methyl-N-(chloromethanesulfonyl)isothiourea (3.85 g, 19 mmol) in acetonitrile (30 ml) under nitrogen is added 4-(N,N-dimethylamino)pyridine (2.32 g, 19 mmol). The mixture is refluxed under nitrogen for 16 hr, concentrated, then worked up as in Example 4 above. Recrystallization from DMF provided the title compound as a white solid, mp >300° C. (1.32 g, 29%).
EXAMPLE 9
7-(N-Cyclohexyl-N-methyl-4-amino-4-oxobutyloxy)-1H-1,2,4-thiadiazolo[3,4-b]quinazolin-5-one-2,2-dioxide.
To a stirred solution of 5-hydroxy-2-nitrobenzaldehyde (29.8 g, 0.178 mol) and ethyl 4-bromobutyrate (26.8 ml, 0.187 mol) in DMF under nitrogen is added potassium carbonate (25.1 g, 0.182 mol). The mixture is heated to 90° C. and stirred at this temperature for 2 hr, then poured into 1500 ml ice water. The mixture is extracted with ethyl ether (5×300 ml), and the ether extracts are washed with water and dried over magnesium sulfate, filtered, and concentrated to provide 45.7 g (91%) 5-(4-ethoxy-4-oxobutoxy)-2-nitrobenzaldehyde as a yellow oil. This material is dissolved in ethanol (350 ml), and potassium hydroxide (11.3 g) in water (180 ml) is added. The mixture is stirred at room temperature for 3 hr then partially evaporated to remove the ethanol. The aqueous solution is washed with ethyl ether and then acidified with 6N HCl (50 ml). The mixture is then extracted with chloroform and the organic solution dried with magnesium sulfate, filtered, and concentrated to a volume of 100 ml. Addition of hexane precipitates a yellow solid, which is collected by filtration to provide 5-(3-carboxypropyloxy)-2-nitrobenzaldehyde, mp 112°-114° C. (37.2 g, 91%).
This material is suspended in 200 ml benzene, and oxalyl chloride (32 ml, 0.366 mol) is added. The resulting mixture is stirred under nitrogen and heated to reflux for 5 min, then cooled to room temperature and stirred for 1 hr. The resulting solution is evaporated to leave the acid chloride as a brown oil. This is dissolved in tetrahydrofuran (50 ml), and added dropwise to a stirred solution of N-methyl cyclohexylamine (50 ml) in tetrahydrofuran (100 ml) kept at 5°-10° C. After 2 hr, the mixture is concentrated, and the residue dissolved in ethyl acetate and washed three times with 1N HCl, once with water, and once with 1N NaOH. The organic solution is then dried with magnesium sulfate, filtered, and concentrated to provide a brown oil. Trituration with diethyl ether (300 ml) provides 43.5 g (85%) 5-(N-cyclohexyl-N-methyl-4-amino-4-oxobutyloxy)-2-nitrobenzaldehyde as a tan solid, mp 98°-100° C.
This material (17.4 g, 0.05 mol) is added to a slurry of silver(I) oxide (5.91 g, 0.026 mol) in 53 ml 1N NaOH, and the mixture stirred for 6 hr at 60° C., then cooled and filtered through Celite. The filtrate is washed with ethyl ether, then brought to pH 1.0 with conc. HCl. The mixture is then extracted with methylene chloride (4×200 ml), and the organic extracts are dried with magnesium sulfate, filtered, and concentrated to provide a brown gum. Chromatography on silica gel with 45:45:9:1 methylene chloride:dichloroethane:isopropanol:acetic acid provides 5-(N-cyclohexyl-N-methyl-4-amino-4-oxobutyloxy)-2-nitrobenzoic acid (11.5 g, 63%) as a non-crystalline foam after solvent removal. Hydrogenation of the above acid (10.7 g, 29.4 mmol) in ethanol (100 ml) over 10% Pd/Carbon under 50 psi hydrogen for 2 hr provides, after filtration and solvent removal, 9.75 g (99%) 5-(N-cyclohexyl-N-methyl-4-amino-4-oxobutyloxy)-2-aminobenzoic acid as a yellow foam. This material is refluxed with ethyl chloroformate (11 ml) under nitrogen for 18 hr. The solution is cooled, and acetyl chloride (40 ml) is added dropwise with stirring. This mixture is refluxed for 6 hr, then cooled. The resulting precipitate is collected by filtration, and washed with carbon tetrachloride, providing 5-(N-cyclohexyl-N-methyl-4-amino-4-oxobutyloxy)isatoic anhydride (4.73 g, 45%) as a grey solid, mp 222°-224° C.
The above isatoic anhydride (3.60 g, 10 mmol) is converted by the method of Example 4 (above) to the title compound, obtained after chromatography on silica gel (4% isopropanol in methylene chloride as eluant) as a colorless solid, mp >330° C. (0.69 g, 16%).
BIOLOGICAL ACTIVITY
The compound of Example 9 has an IC 50 of 13 μM versus cyclic nucleotide phosphodiesterase fraction III. When this compound was administered to a dog intravenously at 1.9 mg/kg, cardiac force increased 37%.
Biological Assay Tests
Procedure I
Cyclic Nucleotide Phosphodiesterase Assay
Literature Reference:
Thompson, W. J., Terasaki, W. L., Epstein, P. M. and Strada, S. J. Assay of Cyclic Nucleotide Phosphodiesterase and Resolution of Multiple Molecular Forms of the Enzyme. In Advances in Cyclic Nucleotide Research, ed. by G. Brooker, P. Greengard, and G. A. Robioson Vol. 10 (1979), pp. 69-92.
Test Object:
Heart, Lung, and Other Tissues
Procedures:
This assay measures the ability of compounds to inhibit cyclic nucleotide phosphodiesterase. This enzyme converts either cyclic AMP or cyclic GMP to the noncyclized AMP or GMP, respectively. Compounds are tested at various concentrations in the presence of cyclic AMP (0.10-1.0 μM containing 0.2 μCi 3 H-cyclic AMP), enzyme, and 0.05M Tris-Cl buffer (pH 7.4, containing 5 mM MgCl 2 ). After a specified time, the reaction is stopped by heating to 100° C. for 1 min. After cooling, 0.10 ml of a solution containing snake venom (1 mg/ml) is added and the reaction is allowed to proceed for 30 min. Termination of this reaction is accomplished by the addition of 1.0 ml of 33% Dowex slurry to separate the product from unconverted substrate. An aliquot is removed from the supernatant and quantitated by liquid scintillation spectrometry.
Analysis:
Data is presented as the IC 50 which is the concentration (μM) of compound required to inhibit 50% of the cyclic nucleotide phosphodiesterase activity.
Procedure II
INHIBITION OF CALCIUM DEPENDENT SMOOTH MUSCLE CONTRACTION
Literature References:
Farley, J. M. and Miles, P. R. The Sources of Calcium for Acetylcholine-Induced Contractions of Dog Tracheal Smooth Muscle. J. Pharmacol. Exp. Ther. 207: 340-346,l 1978.
Test Object:
Canines, guinea pigs and rabbits
Procedure:
Trachea from dogs killed by excess KCl injection are stored overnight at 4° C. in oxygenated Krebs-Henseleit buffer. Tracheal rings, one cartilage segment wide (5-10 mm), are cut starting from the bronchial end. After cutting the cartilage, the trachealis muscle tissue is suspended in oxygenated Krebs-Henseleit buffer at 37° C. in a 25 ml tissue bath. After a 60 minutes equilibration period, the tissues are challenged with 10 μM carbachol. After 5 minutes the tissues are rinsed and allowed to rest 50 minutes. The tissues are then challenged with 50 mM KCl and, after 30 minutes, the contractions are quantitated. The tissues are then rinsed and reequilibrated for 50 minutes. Test compounds are then added for 10 minutes, and the tissue is rechallenged with 50 mM KCl. After 30 minutes, the contraction is recorded and used to determine the % inhibition of control.
Analysis:
The percent inhibition of smooth muscle contraction is calculated from response data before and after drug treatment. ##EQU1##
Procedure III
Acute In Vivo Cardiotonic Evaluation
Literature Reference:
Cardiotonic Activity of Amrinone-Win 40680. Alousi, A. A., Farah, A. I., Lester, G. Y. and Opalka, C. J. Circ. Res. 45:666, 1979.
Test Object:
Dog
Procedure:
Adult mongrel dogs are anesthetized with sodium pentobarbital and artifically respired. Arterial pressure is recorded via a femoral artery and the pressure pulse is used to trigger a cardiotachometer for heart rate. Left ventricular pressure is measured with a Millar catheter and dP/dt is derived. Cardiac output is determined by measuring ascending aortic blood flow with an electromagnetic flow probe and myocardial contractile force is measured with a Walton Brodie strain gauge sutured to the right ventricle. Lead II EKG is also recorded.
A standard dose of dopamine or dobutamine is administered to assess myocardial responsiveness.
Test compounds are administered by i.v. infusion or bolus administration and the effects on cardiovascular parameters are determined.
Analysis:
Dose related effects of the test compound on blood pressure, heart rate, dP/dt max. (dp/dt represents the rate at which blood pressure rises), cardiac force, and cardiac output are compared to pretreatment control values, expressed as a % change and rated for activity. Statistical evaluations are made using the appropriate parametric test against a vehicle control.
The compounds of Examples 2-9 were subjected to various combinations of the foregoing biological assay procedures. The results are as follows:
______________________________________ Procedure I II III IC.sub.50 % inhibition % Change CFExample No. (μM) (dose μM) (dose mpk)______________________________________2 -- 9% (10) --3 35 13% (2) 8% (1.9)4 -- 43% (2) 22% (1.9)5 -- 11% (2) --6 70 18% (10) --7 150 31% (10) --8 150 20% (10) --9 13 -- 37% (1.9)______________________________________
In interpreting the results tabulated above, Procedure I gives the concentration of drug that inhibits the enzyme by 50%, Procedure II indicates potential utility as a broncho-dilator, as revealed by inhibition of muscle contractility at the given dose, and Procedure III indicates enzyme inhibition in the tissue, as revealed by an increase in cardiac force (CF). | 1H-1,2,4-thiadiazolo[3,4-b]quinazolin-5-one-2,2-dioxides are disclosed. These compounds are useful as caridotonic agents. A preferred compound is 7-(n-cyclohexyl-N-methyl-4-amino-4-oxobutyloxy)-1H-1,2,4-thiadiazolo[3,4-b]quinazolin-5-one-2,2-dioxide. | 2 |
BACKGROUND OF THE INVENTION
The present invention relates to an automatic transfer apparatus for loading and unloading a push car into and from an elevator.
For conveying a push car from one story of a building to another, it has been a common practice to load an elevator with a push car and unload it by hand. Inefficiency is caused and hard labor is attendant upon this work. Furthermore, the work is attended with danger.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide an automatic transfer apparatus which makes automatic the work of horizontally loading an elevator with a push car and unloading it.
In accordance with the present invention, there is provided an automatic transfer apparatus for loading and unloading a push car into and out an elevator, comprising: a guide means fixedly mounted on the floor of the elevator; a carriage mounted in the guide means so as to be movable while guided by the guide means; a first conveyor means provided in the guide means for moving the carriage along the guide means; a drive means for driving the first conveyor means; a second conveyor means provided on the carriage and having an endless travelling member for conveying a push car into and out of the elevator; a drive means for driving the second conveyor means; and a plurality of pairs of pins secured to the endless travelling member and adapted to engage pins provided on the push car.
With the above-described object in view and as will become apparent from the following detailed description, the present invention will be more clearly understood in connection with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a vertical sectional front view of an automatic transfer apparatus in accordance with the present invention;
FIG. 2 is a horizontal sectional view thereof;
FIG. 3 is a vertical sectional side view thereof;
FIG. 4 is an enlarged horizontal sectional view of a pair of pins provided on an endless chain; and
FIGS. 5 to 8 are front views illustrating the operation of the transfer apparatus.
DETAILED DESCRIPTION OF THE INVENTION
Referring now to the drawings, an elevator 1 has a guide member 2 fixedly mounted thereon. A carriage 3 mounted in the guide member 2 is adapted to move in a horizontal direction along side walls of the guide member 2.
Both ends of a chain 4 extending in the direction in which the carriage 3 moves are secured to both ends of the guide member 2. The chain 4 passes around a pair of idler rollers 6 and engages with a sprocket wheel 5 provided in the mid portion of the carriage 3. The carriage moves in either direction by a predetermined stroke when a motor M 1 (FIGS. 1 and 2) for driving the sprocket wheel 5 is energized.
The travel of the carriage 3, which can be set by controlling the motor M 1 by means of limit switches, ranges from the position where the full length of the carriage 3 is disposed in the guide member 2 (FIG. 5) to the position where one of the idler rollers 6 reaches one end of the chain 4 so that nearly half the length of the carriage 3 projects from one end of the guide member 2 (FIG. 6).
A pair of endless chains 8 are disposed along both sides of the carriage 3. Each of the endless chains 8 engages with a pair of sprocket wheels 7 provided at both ends of the carriage 3. One of the sprocket wheels 7 is driven by a motor M 2 so as to cause the endless chain 8 to travel in either direction.
Two pairs of pins are secured to each endless chain 8, each pair being made up of a pin 9 and a pin 10. The pins on one endless chain 8 are arranged in alignment with the pins on the other endless chain 8.
Referring now to FIGS. 3 and 4, holders 11 are secured to each endless chain 8. The pins 9 and 10 are mounted on the holders 11 so as to pivot around shafts 12 and horizontally project transversely of the endless chains 8. Each shaft 12 extends through a cam 13 which forms an integral part of the pin 9 or 10 as shown in FIG. 4. The arrangement of the cam 13 on the holder 11 allows the pivotal movement of each pin from a first position where the pin extends normal to the direction of travel of the endless chain 8 to a second position in which the pin tilts toward the other pin. By the provision of a spring 14 positioned about the shaft 12, each pin is urged toward the first position.
A suitable space is left between the pins 9 and 10 in the direction of travel of the endless chain 8. As shown in FIG. 1, the space between two pairs of pins is sufficiently large that two pairs of pins will be disposed at both ends of the upper run of the endless chain 8.
Referring now again to FIGS. 5 to 8, a push car 15 to be carried by the transfer apparatus according to the present invention is adapted to straddle over the transfer apparatus. Wheels 16 are provided at the four corners of the under surface of the push car 15. A pair of downward pins 17 are secured to both sides of the front part of its under surface, and another pair of downward pins 17 are secured to its rear part. Either pair of downward pins 17 are adapted to be engaged between the pins 9 and 10.
The endless chains 8 are shielded with a cover 18 on the carriage 3 with only the pins 9 and 10 projecting transversely from both sides.
In operation, when the elevator 1 is to ascend or descend, the full length of the carriage 3 is disposed in the guide member 2 as shown in FIG. 5.
For conveying the push car 15 from one story of a building to another, it is brought to a standby position near the elevator on a floor 19 as shown in FIG. 5.
When the motor M 1 is started, the carriage 3 moves toward the push car 15 as shown in FIG. 6 to such a position that its leading end is under the push car 15. Then the motor M 1 stops.
When the motor M 2 is started thereafter, the endless chains 8 and hence the pins 9 and 10 run in a clockwise direction in FIG. 6. During this running, a pair of pins 17 secured to the under surface of the push car 15 get caught between the first two pairs of pins 9 and 10, so that the push car will be pulled toward the elevator.
In FIG. 4, the pin 9 disposed in front in relation to the travel direction of the endless chain 8 is adapted to be pivotable backwardly. Consequently, when the pin 9 strikes against the pin 17, the former lets the latter go past. On the contrary, the pin 10 disposed to the rear cannot pivot backwardly but catches the pin 17 so as to draw the push car 15 toward the elevator 1.
The motor M 2 is deenergized when two pairs of pins 9 and 10 come to the ends of the upper run of each endless chain 8 as shown in FIG. 1. Then the motor M 1 is restarted in the reverse direction so as to restore the carriage 3 to its original position on the guide member 2, carrying the push car 15. Then the motor M 1 stops.
Now the push car 15 is in position on the elevator 1 as shown in FIG. 7, and is ready to be conveyed to another story of the building. When the push car 15 is in this condition, two pairs of the pins 17 secured to the front and the rear parts of the under surface of the push car 15 are engaged between the pins 9 and 10.
The motors M 1 and M 2 are controlled in like manner when the push car 15 is delivered off of the elevator 1 to a floor 19. The push car 15 moves together with the carriage 3 as shown in FIG. 8, and is pushed out of the elevator 1 to such a position that the pins 17 secured to the rear part of the under surface of the push car 15 get clear of the pins 9, 10. Then, in preparation for the next operation, the carriage 3 is restored to its original position on the guide member 2 by restarting the motor M 1 in the reverse direction.
Thus the transfer apparatus according to the present invention serves to improve efficiency by making automatic the work of horizontally loading the elevator 1 with a push car and unloading it from the elevator. The present invention has another advantage that a push car can be moved on and off the elevator in either direction. | An automatic transfer apparatus for loading and unloading a push car into and from an elevator is provided. It includes a guide member, a carriage mounted in the guide member, a conveyor for moving the carriage toward the push car, and another conveyor for pulling the push car into and out of the elevator. Firstly the carriage moves toward the push car, pulls it to mount it just on itself, and moves back to its original position to carry it onto the elevator. | 1 |
[0001] The present invention relates to the control of sea lice, for example Lepeophtheirus salmonis, Caligus elongatus and Caligus rogercresseyi, infestations in fish farming, which includes the application of the neonicotinoid clothianidin to the fish.
[0002] The basis of sea lice control in commercial salmonid farming is largely still a treatment with chemicals such as organophosphates, synthetic pyrethroids, chitin synthesis inhibitors, hydrogen peroxide or macrocyclic lactones such as emamectin benzoate. Developing resistance by sea lice against said commercial products presents a big threat to the fish industry; on the one hand higher doses of the compounds might be employed which accelerates the issue of resistance development and moreover has the potential to create environmental toxicology issues. On the other hand there is a desperate search for new chemicals and treatment schedules thereof.
[0003] EP0590425 discloses very broadly a method of combatting fish parasites by administering an agonist or antagonist of the nicotinergic acetylcholine receptors to the fish. The document discloses a number of those agonists or antagonists specifically, but is silent about clothianidin. In addition, no details about the application of said class of compounds, such as the amount being necessary to control fish parasites, are available, and no in vivo data are disclosed. The only working example concerns the in vitro activity of imidacloprid against sea lice in a sea water bath containing 1 ppm or 100 ppm of the active ingredient.
[0004] Clothianidin is a known insecticide which is used in plant protection and in the treatment of seeds. However, no application in the veterinary field has been reported until now.
[0005] Surprisingly, it has now been found that clothianidin is extremely efficient in eliminating sea lice infestations while being tolerated very well by the fish and being environmentally safe.
[0006] The present invention therefore provides a method for reducing or eliminating sea lice in a fish population, which comprises treating the fish with clothianidin or a veterinary acceptable salt thereof at a concentration of from 3 to 300 mg clothianidin per kg of fish biomass.
DETAILED DESCRIPTION
[0007] Clothianidin, (E)-1-(2-Chlor-1,3-thiazol-5-ylmethyl)-3-methyl-2-nitroguanidin, CAS No. 210880-92-5 (formerly 205510-53-8), has the chemical formula
[0000]
[0000] and may be applied in free form or in form of a veterinary acceptable salt. The above-given formula shows the molecule with trans-configuration of the nitro group relative to the thiazolylmethylamino moiety. However, the term clothianidin is also meant to encompass products which are mixtures of trans- and cis-isomer. It is preferred to apply a commercially available clothianidin product that either consists of the pure trans-isomer or is a mixture of trans-isomer with a small portion of cis isomer, for example 0% (w/w) cis isomer.
[0008] In accordance with this invention clothianidin is excellently suited for use in the control of fish-parasitic crustaceans. These include the Family Caligidae with representative genus Dissonus, Caligus (i.e. C. curtus, C. elongatus, C. clemensi, C. rogercresseyii ), and Lepeophtheirus (i.e. L. salmonis ); Families Cecropidae, Dichelesthiidae, Lernaeopodidae with representative genus Salmincola; Families Pandaridae, Pennellidae with representative genus Lernaeocera and Pennella; and Family Sphyriidae; Family Lernaeidae with representative genus Lernaea; Families Bomolochidae, Chondracanthidae, Ergasilidae and Philichthyidae; Family Argulidae with representative genus Argulus (i.e. A. foliaceus ).
[0009] The fish include food fish, breeding fish, aquarium, pond, river, reservoir fish of all ages occurring in freshwater, sea water and brackish water. For example, bass, bream, carp, catfish, char, chub, cichlid, cod, eel, flounder, gourami, grayling, grouper, halibut, mullet, plaice, pompano, roach, rudd, salmon, sole, tilapia, trout, tuna, whitefish, yellowtail.
[0010] Clothianidin is particularly suitable for treating salmon. The term “salmon” within the scope of this invention will be understood as comprising all representatives of the family Salmonidae, especially of the subfamily salmoninae, and preferably, the Atlantic salmon ( Salmo salar ), rainbow trout ( Oncorhynchus mykiss ), brown or sea trout ( S. trutta ), the Pacific salmon, Cherry salmon or seema ( O. masou ), Taiwanese salmon ( O. masou formosanum ), chinook salmon or King salmon ( O. tshawytscha ), chum salmon or Calico salmon ( O. keta ), coho salmon or silver salmon ( O. kisutch ), pink salmon ( O. gorbuscha ), Sockeye salmon or Red salmon ( O. nerka ), artificially propagated species, such as Salmo clarkii, and Salvelinus species such as Brook trout ( S. fontinalis ).
[0011] Preferred objects of the present invention are the Atlantic and Pacific salmon and the sea trout including trout species, which are farmed at sea but not traditionally called “sea trout”.
[0012] The fish may be treated orally, e.g. via their feed. Moreover, the active ingredient may be applied by bath treatment, for example in a “medicinal bath” wherein the fish are placed and where they are kept for a period of time (minutes to several hours), for example, when being transferred from one breeding basin to another. It is also possible to treat the biotope of the fish temporarily or continuously, e.g the net cages, entire ponds, aquaria, tanks or basins in which the fish are kept. According to still a further embodiment, the fish are treated parenterally, for example by injection.
[0013] The active substance is administered in formulations which are adjusted to the specific application. A formulation for oral administration is, for example, a powder, granulate, solution, emulsifiable concentrate or suspension concentrate, in particular a medicated fish feed as described below. Formulations for bath application or for treating the biotope are powders, granulates, solutions, emulsions or suspensions, tablets or the active substance itself. The user may use these formulations in diluted or undiluted form. Suitable injectable formulations are either powders, pellets or granules which are reconstituted in a suitable solvent before use, or are ready-to-use solutions, suspensions including nanosuspensions, or the like.
[0014] Clothianidin is preferably applied via an in-feed treatment, for example, in form of a medicated fish feed. Fish feed is typically present in the form of granules or pellets; common ingredients of said pellets or granules are, for example, fishmeal, fish oil, vegetable proteins, saccharides, such as typical mono- or disaccharides, polysaccharides, such as mannans glucans or alginates, and/or other typical excipients such as pigments, vitamins, minerals, binders and the like. A clothianidin-medicated fish feed may be prepared by incorporating a suitable amount of clothianidin or a salt thereof into the fish feed product. The clothianidin may be incorporated into the feed mixture prior to pelleting. However, it is preferred to coat the pellets or granules with clothianidin. For example, commercially available fish pellets or granules are coated with a pre-mix containing the clothianidin and one or more suitable excipients such as a starch, fumed silica (Aerosil®), microcrystalline cellulose, lactose or the like. In addition, a typical preservative may be present. The concentration of clothianidin in the pre-mix may be chosen within a broad range; for example, a clothianidin concentration of from 0.001 to 10% w/w, preferably from 0.05 to 5% w/w and in particular from 0.15 to 2.5% w/w, based in each case on the entire weight of the pre-mix, has proven as valuable. The feed pellets may be coated with the pre-mix by a dry-coating method. To this end the pre-mix is mixed with the pellets so that it is uniformly distributed onto the pellets; preferably, fish oil or vegetable oil is then added to the mixture to coat the medicated pellets. In an alternative, the pre-mix is first mixed with fish or vegetable oil, which is then mixed with the pellets to disperse it onto them, and additional fish or vegetable oil is added to the coated pellets and mixed until the pellets are thoroughly coated. According to still another embodiment, the pre-mix is first dispersed in some fish or vegetable oil, said dispersion is then sprayed onto the pellets to disperse it onto them under a vacuum coating system and mixed until the pellets are thoroughly coated.
[0015] Following the addition of the active ingredient to the fish feed, the pellets or granules comprise, for example, from 0.0005 to 5% (w/w), preferably from 0.001 to 2.5% (w/w), and in particular from 0.0025 to 1.25% (w/w) clothianidin, based on the entire weight of the fish feed.
[0016] A preferred in-feed treatment according to the invention comprises feeding clothianidin or a veterinary acceptable salt thereof to a fish population at a daily dose of 0.5 to 30 mg clothianidin per kg of fish biomass for a time period of 3 to 14 days, and wherein the overall amount of clothianidin applied during said time period is from 3 to 300 per kg of fish biomass.
[0017] According to this embodiment, the overall time period for the treatment against sea lice is, for example, from 3 to 14 days, preferably from 5 to 14 days, more preferably from 5 to 10 days and in particular for 7 days (1 week). During the overall treatment time, the feeding of the clothianidin is performed, for example, daily or every second day, and in particular daily.
[0018] The overall amount of clothianidin applied during the treatment is preferably from 5 to 175 mg per kg of fish biomass, more preferably from 5 to 140 mg per kg of fish biomass, even more preferably from 7 to 105 mg/kg fish biomass, and especially from 7 to 70 mg/kg fish biomass.
[0019] According to one preferred embodiment of the invention the clothianidin is administered daily, for a period of time of 3 to 14 days, preferably of 5 to 14 days, more preferably of 5 to 10 days and in particular of 7 days (1 week), wherein the daily dose is from 0.5 to 25 mg/kg fish biomass, preferably from 0.75 to 20 mg/kg fish biomass, more preferably from 1 to 15 mg/kg fish biomass, and in particular preferably from 1 to 10 mg/kg fish biomass. One particularly preferred treatment comprises administering clothianidin for 7 consecutive days with a daily dose of 0.75 to 20 mg clothianidin/kg fish biomass, (total amount of 5.25 to 140 mg/kg fish biomass) in particular 1 to 15 mg clothianidin/kg fish biomass (total amount 7 to 105 mg/kg fish biomass). A further particularly preferred treatment comprises administering clothianidin for 7 consecutive days with a daily dose of 0.75 to 15 mg clothianidin/kg fish biomass (total amount 5.25 to 105 mg/kg fish biomass), especially 1 to 10 mg clothianidin/kg fish biomass (total amount 7 to 70 mg/kg fish biomass), and in particular 5 to 10 mg clothianidin/kg fish biomass (total amount 35 to 70 mg/kg fish biomass).
[0020] According to a further embodiment of the invention clothianidin is administered once every second day, for a period of time preferably of 5 to 13 days, more preferably of 5 to 9 days, and in particular of 7 days. A particular treatment comprises treating the fish for a time period of 7 days, administering the feed comprising the clothianidin on days 1, 3, 5 and 7 and withholding any food the day prior to the treatment and on days 2, 4 and 6 of the treatment period. The concentration of clothianidin is adjusted to ensure that the same average dose per kg of fish biomass is administered over the entire treatment period than in a daily treatment. Concerning the overall amount of clothianidin applied during this pulsed treatment, the above given ranges including the preferences apply.
[0021] As an example, concerning a 7-day treatment with clothianidin applied on days 1, 3, 5 and 7, the clothianidin dose on each of said days is, for example, from 1.3 to 35 mg/kg fish biomass (total amount from 5.2 to 140 mg/kg fish biomass), preferably from 1.3 to 26 mg/kg fish biomass (total amount from 5.2 to 104 mg/kg fish biomass), even more preferably from 1.75 to 17.5 mg/kg fish biomass (total amount from 7 to 70 mg/kg fish biomass), and in particular from 8.75 to 17.5 mg/kg fish biomass (total amount from 35 to 70 mg/kg fish biomass).
[0022] When applying clothianidin to the fish according to the present invention, the fish will absorb the clothianidin and provide the therapeutic effect, i.e. the reduction or preferably complete elimination of sea lice, quickly.
[0023] In addition, the compound is safe both from a toxicological and environmental perspective, as its half-life in animals and in the environment is in each case short. Accordingly, the withdrawal period is short, the fish may be harvested and enter the human food chain soon following the last clothianidin treatment.
[0024] Clothianidin may in general be applied at any stage of the fish development as curative treatment in order to reduce or eliminate sea lice infestations of fish. In case of salmons, treatments take place advantageously whilst the fish are at sea.
[0025] According to one embodiment of the invention, a curative treatment with clothianidin as described above is carried out during the months with high sea water temperature and high sea lice pressure. Moreover, it is preferred to use clothianidin in cases, where a sea lice infestation of fish has to be cleared rapidly. According to a further embodiment of the invention, fish, in particular salmons, are treated with clothianidin at a late stage of the fish development; for example, the adult fish are cleared from sea lice shortly before being harvested.
[0026] A curative treatment of the fish with clothianidin also may be used in combination with a previous protective treatment with another sea lice control agent in order to efficaciously control sea lice infestations of the fish. Suitable protective sea lice controlling agents are, for example, benzoylurea compounds, in particular lufenuron or hexaflumuron, avermectins, for example emamectin benzoate, or organophosphates, for example dichlorvos. A suitable combination treatment of clothianidin and a further protective sea lice-controlling agent as mentioned above, in particular lufenuron or hexaflumuron, may be performed, for example, by treating the fish, in particular salmon, initially with said other sea lice-controlling agent, and thereafter, for example 1 week to 3 month or more, preferably 3 to 5 months or more, more preferably 6 months or more and in particular 8 to 12 months after the end of the treatment with said protective sea lice-controlling agent, performing a treatment with clothianidin as described above. According to a preferred embodiment of this combination treatment, the first treatment is an in-feed treatment with hexaflumuron or in particular lufenuron, or with another active ingredient with long lasting protection against sea lice such as emamectin benzoate, which takes place at the end of the fresh water phase of salmon evolution or at the beginning of their sea water phase.
[0027] Clothianidin is preferably not used in combination with another compound being used in the curative treatment of sea lice infestations, such a compound of formula
[0000]
[0000] known from WO2011/157733, wherein the variables are defined as described therein.
[0028] The treatment according to the present invention may in certain cases be improved by the use of clothianidin in combination with other agents, for example a vaccine component including immune enhancing agents; or a feed ingredient containing immune modifying agents.
[0029] The following Examples further illustrate the invention.
EXAMPLE 1
[0030] In-feed treatment of sea lice infested salmon with 5 different neonicotinoids (a) Method: Atlantic salmon (estimated mean weight 50-100 g) were batch weighed and allocated to a single 2 m diameter challenge tank. Fish were challenged with sea lice (L. salmonis) copepodids. Within one week of the successful lice challenge, fish were randomly allocated from the 2 m challenge tank to 1 m diameter treatment tanks so that each tank contained thirty fish.
[0031] Fish were maintained until lice developed to adult stages. This was monitored by periodic examination of fish from the control tank. There were five test compounds acetamiprid (A), clothianidin (B), imidacloprid (C), nitenpyram (D) plus a control (E), each compound was tested at three doses. Experimental diets were prepared by top dressing feed pellets with the powder formulation and sealing with fish oil. Once lice had developed to adult stages, fish in all tanks received an in-feed treatment according to the relevant group for a period of seven days. Uneaten feed was collected daily to estimate the mean dose achieved in each group. Fish were examined for lice ten days following the end of the treatment period.
(b) Results
[0032] (b1) Feed Consumption
[0033] Ten grams of feed fortified with premix and fish oil were weighed and contained 133 pellets as a comparative guide for conversion to dry weight. The estimated % of nominal dose received was assessed as shown in Table 1 below. A high level of uneaten pellets may indicate a negative effect on appetite and/or low palatability of the medicated feed.
[0000]
TABLE 1
Dose achieved in treatment groups based on uneaten feed
% of target dose
% of target
% of target
Compound
achieved
dose achieved
dose achieved
Nominal dose
10
5
1
[mg/kg/day]
Control
106
106
106
Acetamiprid
38
62
98
Clothianidin
97
98
99
Imidacloprid
33
77
100
Nitenpyram
92
96
108
[0034] The Table above reveals that acetamiprid and imidacloprid are unsuited for an in-feed treatment of salmon, as the food-uptake at medium and higher concentrations of added active ingredient in the food is reduced to an unacceptable level.
[0000] (b2) Efficacy Results on Salmons Infected with Sea Lice
[0035] Following the 7day treatment period, the mean sea lice count in the control group was 7±3 adult sea lice meaning the total of adult males, adult non-ovigerous females and adult ovigerous females. The overall reduction of sea lice achieved with the different active ingredients is shown in Table 2.
[0000]
TABLE 2
Reduction of total
Reduction of total
Reduction of total
Compound
sea lice [%]
sea lice [%]
sea lice [%]
Dose
10
5
1
[mg/kg/day]
Control
0
0
0
Acetamiprid
85
64
53
Clothianidin
99
98
90
Imidacloprid
81
94
91
Nitenpyram
89
89
48
[0036] The Tables above reveal that clothianidin is the only compound showing an sea lice reduction efficacy of 90% or higher at all three selected concentrations. In addition, clothianidin was shown to be the only active ingredient which provided full sea lice elimination while not affecting the feed uptake. | The present invention concerns the use of clothianidin for controlling sea lice in a fish population, which comprises feeding clothianid to the fish population according to a specific regime as outlined in the specification and claims. The process is especially suited for the treatment of salmon and provides prolonged effective protection against sea lice at sea. | 0 |
This is a continuation of application Ser. No. 723,217, filed Apr. 15, 1985.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention lies in the field of sulfonating acyloxy benzene esters with sulfur trioxide.
2. Prior Art
Knaggs and Nussbaum U.S. Pat. No. 3,169,142 taught a continuous process for sulfation and sulfonation of liquid organic compounds with sulfur trioxide, by contacting a liquid film of an organic compound with a gaseous mixture of sulfur trioxide and inert gas. The resulting product was commonly then neutralized with aqueous base, particularly when making sulfonates having utility as surfactants.
It was appreciated in practicing this process that a small (up to 1.5 weight percent) increase in desired sulfonic acid yield could be obtained in the sulfonation of an alkyl benzene to produce directly the corresponding intermediate sulfonic acid, such as, for example, dodecylbenzene sulfonic acid, by allowing a short holding period to occur between sulfonation and neutralization. This holding period produced such a yield increase because of the reaction of residual quantities of SO 3 , present with unreacted alkyl benzene starting feed. No rearrangement is involved.
Esters, such as methyl esters and fatty acid glycerides, are mentioned among many other compounds, in Knaggs and Nussbaum U.S. Pat. No. 3,169,142 as feedstocks for sulfonation (see col. 3, lines 24-30). In ester sulfonation, the SO 3 apparently preliminarily forms an adduct with the carboxyl group. This adduct can be and preferably is rearrangeable to produce sulfonic acid intermediate products before neutralization. In the case of fatty acid methyl esters, the rearrangement is characteristically endothermic, and alpha sulfonated products result. So far as is now known, no class of esters was previously known whose SO 3 adduct would or could rearrange to produce a ring substituted sulfonic acid.
The practice of the Knaggs and Nussbaum U.S. Pat. No. 3,169,142 process with ester and other previously employed organic feedstocks characteristically produces side reactions in addition to a main or primary reaction. Thus, it is not easy, and sometimes not even possible, to produce directly by this process high yields of relatively pure sulfated or sulfonated product species, such as is desired and even necessary for many individual and commercial purposes. Terminal purification procedures are sometimes necessary in order to obtain sulfonated products of a desired purity. Such purification procedures are undesired since they add to the cost of making a product.
Recently, it has been proposed to use acyloxy benzene sulfonate compounds, of the class wherein the acyl group is derived from a fatty acid, in commercial detergent formulations. Large-scale usage appears to require a synthetic route for making such compounds which is inexpensive and capable of producing a relatively high purity product in high yield.
The indicated Knaggs and Nussbaum process would at first appear to offer promise as a potentially inexpensive synthetic route for making these compounds by sulfonating the corresponding phenyl ester. So far as is now known, no one has previously prepared acyloxy benzene sulfonate by direct synthesis with SO 3 from acyloxy benzene. However, when one attempts to practice such U.S. Pat. No. 3,169,142 patent teachings of Knaggs and Nussbaum to sulfonate an acyloxy benzene, various formidable unexpected problems arise, some of which appear never heretofore to have been experienced in SO 3 sulfonation of organic compounds, especially esters. These problems result in yields of acyloxy benzene sulfonates that are so low as not to be of apparent commercial practicality or feasibility. Further, the desired product is accompanied by significant quantities of unwanted by-products, for example, sulfones and phenolic materials, which detract even further from the commercial value or practicality of using such so-produced acyloxy benzene sulfonates in surfactant formulations.
One of the yield-reducing problems which can arise when sulfonating is the occurrence of degradation which is undesired and which results from the reactivity of the sulfur trioxide with acyloxy benzene. Degradation not only reduces the yield of the desired acyloxy benzene sulfonate, but also produces by-products which adversely affect desired product characteristics, such as color and shelf-life stability.
Moreover, if one attempts to follow prior art teachings as regards use of a heated digestion zone between sulfonation and neutralization, then both side reactions and degradation problems are compounded and yields of acyloxy benzene sulfonate go down. Thus, the sulfonation process taught by the Knaggs and Nussbaum U.S. Pat. No. 3,169,142 is not suitable for directly making acyloxy benzene sulfonates of commercially acceptable quality and purity. At the least, it appears that with this process some sort of a special terminal "clean-up" step would be needed to produce a light color product with a content of acyloxy benzene sulfonate above about 70 weight percent (total product solids weight basis). However, such "clean-up" step would only undesirably add to the cost of making the final product.
Apart from the foregoing considerations with regard to sulfonation, the prior art has heretofore appreciated that the conditions employed in neutralization of an organosulfonic acid ester can affect yields of the resulting desired product salt. For example, unless the temperature and the pH at which neutralization is accomplished with a material such a sulfonic acid of an aliphatic carboxylic acid ester are controlled, such as, for example, an alpha sulfo methyl fatty acid ester, one can wind up with a neutralized product which is substantially hydrolyzed. In the case of neutralizing acyloxy benzene sulfonate acid, control of neutralization using special conditions is necessary in order to avoid hydrolysis of this acid.
Thus, the prior art does not provide any sulfonation process which permits one to produce acyloxy benzene sulfonates in high yield and in high purity.
BRIEF SUMMARY OF THE INVENTION
There has now been unexpectedly discovered a new and very useful process for making acyloxy benzene sulfonates of high purity and in high yields utilizing a direct sulfonation of acyloxy benzene with sulfur trioxide (SO 3 ), a controlled digestion procedure, and then a following special neutralization procedure for the intermediately produced acyloxy benzene sulfonic acid to produce a salt thereof.
The use of a temperature controlled digestion step appears to be novel in the sulfonation art.
The sulfonation step results in the production of a new and unusual class of adducts of SO 3 with acyloxy benzene. These adducts can be used, in accordance with the process of this invention, to produce acyloxy benzene sulfonic acid as taught herein.
This process results in the direct production (without any intervening purification step) of a new and very useful class of compositions which comprise mainly neutralized acyloxy benzene sulfonate salt in combination with minor amounts of certain organic impurities. These compositions can be produced as aqueous solutions or in the form of dried solids. These compositions are characterized by being substantially colorless and by having excellent storage characteristics. Thus, the impurities do not interfere with characteristics of the acyloxybenzene sulfonate or with the ability to use such in surfactant and detergent formulations.
This process overcomes the above-described difficulties experienced, for example, when one attempts to utilize the Knaggs and Nussbaum process of U.S. Pat. No. 3,169,142 for sulfonating acyloxy benzene to produce acyloxy benzene sulfonates in high yield and with high purity.
In the present sulfonation procedure, substantially pure acyloxy benzene is contacted with SO 3 under special conditions which (a) moderate the ensuing addition reaction, (b) maximize production of preferably a 1:1 molar adduct of SO 3 with acyloxy benzene, and (c) minimize production of unwanted by-products, (d) minimize formation of colored impurities, and (e) control any rearrangement during sulfonation of the adduct-containing reaction product.
Surprisingly and unexpectedly, an SO 3 acyloxy benzene adduct intermediate formed by SO 3 contacting, even when produced in an impure form, such as might be produced generally by following prior art sulfonation teachings, displays a remarkable tendency to rearrange with great exothermiscity. The rearrangement can result in a ring substituted sulfonic acid. Such an exothermic rearrangement of an SO 3 adduct has never previously been reported, so far as is now known. For example, if an SO 3 -acyloxy benzene adduct is formed at room temperature, then within about 30 seconds of its formation, the reaction mass will have risen to a temperature which is characteristically over about 100° C. The uncontrolled combination after adduct formation of rapid rearrangement with associated evolution of substantial heat results in a rearranged product of poor color which contains excessive amounts of unwanted by-products along with the corresponding acyloxy benzene sulfonic acid derivative.
In accordance with one primary aspect of the present invention, a process is provided for controlling the formation of an SO 3 acyloxy benzene adduct and for controlling the rearrangement of such adduct in a digestion procedure so that yields of an acyloxy benzene sulfonic acid derivative preferably in excess of about 80 weight percent, and more preferably above about 87%, are routinely obtainable from the intermediate SO 3 -acyloxy benzene adduct. To achieve such controls, the present invention provides a set of sulfonation and digestion conditions which are conducted at controlled temperatures which are novel in the ester sulfonation art. Further, to achieve such controls, the sulfonation step is practiced under special conditions which minimize color formation, by-product formation and adduct degradation during the sulfonation process.
The high purity acyloxy benzene sulfonic acid derivative, once formed by the practice of the process steps of the present invention, is relatively stable even at ambient conditions. In commercial practice, however, the sulfonic acid intermediate is converted (neutralized) under aqueous liquid phase conditions into a salt, especially a salt of a cation selected from the group consisting of alkali metals, alkaline earth metals, and ammonium. Sodium is presently a most preferred cation.
Thus, after digestion, the resulting acyloxy benzene sulfonic acid is preferably neutralized. To minimize ester hydrolysis and to avoid loss in yield of the desired acyloxybenzene sulfonate salt product, neutralization is preferably carried out by contacting the acyloxy benzene sulfonic acid with an inorganic hydroxide whose cation is selected from the group consisting of alkali metals, alkaline earth metals, ammonium, and mixtures thereof (preferably sodium) under aqueous liquid phase conditions. Preferably, the inorganic hydroxide is preliminarily dissolved in water to provide an aqueous solution. For example, such a solution can contain from about 5 to 50 weight percent of dissolved inorganic hydroxide.
The resulting neutralized acyloxy benzene sulfonate salt then either is used as such in solution form, or is dried to produce a powder (the latter being presently preferred). Drying can be carried out by any convenient procedure, but spray drying is presently preferred. The acyloxy benzene sulfonate salt product is typically directly formulatable without any clean-up or purification step with other components, as desired, to produce synthetic detergent compositions, surfactant blends, and the like.
Various objects, aims, purposes, features, advantages, variations, alterations, modifications, and the like, will become apparent to those skilled in the art from the teachings of the present specification taken with the appended claims.
DETAILED DESCRIPTION
Acyloxy Benzene
An acyloxy benzene starting material employed in the practice of the process of the present invention is preferably substantially pure, that is, a starting acyloxy benzene is at least about 98 weight percent pure. Typically and preferably the impurities when and if present in combination therewith comprise phenol, fatty acid, ketone phenol, or the like. Most preferably, a starting acyloxy benzene is at least about 99 weight percent pure.
Various synthetic methods are available in the prior art for producing acyloxy benzene; see, for example, JAOCS 32, p. 170.
In general, such a starting material employed in the practice of the present invention comprises at least one acyloxy benzene of the following formula: ##STR1## where R is a saturated aliphatic group containing from about 2 to 19 carbon atoms inclusive.
Presently preferred acyloxy benzene compounds of formula (1) above are characterized by those wherein R is a saturated aliphatic group containing 7, 8, or 9 carbon atoms each, that is, phenyl octanoate, phenyl nonanoate, phenyl isononanoate, and/or phenyl decanoate. Straight or branched chain alkyl radicals can preferably be used.
Sulfonation
In general, sulfonation of acyloxy benzene with SO 3 in accordance with the teachings of the present invention is conducted by contacting liquid or gaseous (or mixture thereof) SO 3 with at least one acyloxy benzene starting material (as described above) which is in a liquid phase. The contacting is carried out at an average temperature below about 50° C. and preferably below about 30° C.
In order to obtain the high-purity yields of a product acyloxy benzene sulfonate salt as desired by the practice of the present invention, it is necessary to control the temperature of the sulfonation reaction mass so as to make this temperature as low as practical. In general, such average temperature should be lower than about 50° C. and preferably below about 30° C. Thus, it is presently preferred to utilize an average contacting temperature for SO 3 and acyloxybenzene which ranges from about -30° to +50° C. and more preferably from about -10° to +30° C. Such temperatures (a) maximize the yield of the desired SO 3 -acyloxy benzene adduct, and (b) minimize the occurrence of (1) color formation, (2) by-product formation, and (3) adduct degradation during residency of a reaction mass in a sulfonation reaction zone.
In the sulfonation reaction zone, the initial mole ratio of SO 3 to acyloxy benzene can range from about 0.9 to 1.1, and preferably from about 0.95 to 1.05.
Also, in the sulfonation zone, a diluent (gaseous, or preferably liquid, or mixture thereof) can be present. The presence of a diluent is presently preferred, because such permits an improved capacity to regulate the temperature in the sulfonation reaction zone. The adduct forming reaction is itself apparently exothermic, and it is desirable to avoid heat build-up on a localized basis during sulfonation.
Heat exchange capacity located in functional association with the sulfonation reaction zone is desirable in order to remove heat of reaction, and use of such is preferred in practicing this invention for temperature control and maintenance in this raction zone.
Various combinations of contacting conditions can be employed for any given sulfonation as shown by the following examples of sulfonation techniques:
(A) Falling Film. One may employ the falling film sulfonation apparatus described in Knaggs and Nussbaum U.S. Pat. No. 3,169,142. Here, a falling liquid film is mainly comprised of acyloxy benzene, while a gas phase is provided by a gaseous composition comprised of a mixture of sulfur trioxide and substantially inert gas wherein a proportion within the range of from about 5:1 to 50:1 of inert gas to sulfur trioxide by volume is employed. The inert gas can be as described in the Knaggs and Nussbaum U.S. Pat. No. 3,169,142 patent (see column 3, lines 45 through 52 thereof), or otherwise, if desired. The confining reaction zone formed by the heat exchange surface upon which the falling film is supported and confined is preferably exteriorly jacketed so that a heat exchange fluid can be circulated in heat exchange relationship thereto so that the average temperature of the reaction zone is maintained below about 50° C. and preferably below about 30° C. Similarly, and preferably, the temperatures of the liquid feed and of the gaseous feed are likewise regulatable and also the temperature of the liquid effluent can be monitored.
(B) Batch. The acyloxy benzene is preliminarily dissolved in a solvent such as a low boiling liquid diluent which preferably boils below about 10° C. although higher boiling such diluents can be used. One presently preferred such diluent comprises liquid sulfur dioxide. Preferably a reactant such as sulfur trioxide is then admixed with (dissolved in) the resulting solution and a contacting as desired is achieved between the starting acyloxy benzene and the sulfur trioxide. Acyloxy benzene is soluble in SO 2 and in other lower boiling liquid diluents. Mixing of reactants in such a liquid diluent is preferred during such contacting to avoid localized oversulfonation. Because SO 2 boils at atmospheric pressure at about -10° C., it is necessary to maintain the reaction or contacting zone under pressurized conditions during sulfonation when SO 2 is used as a liquid diluent. For reasons of practicality, as well as for reasons of maximizing production of the desired adduct, it is presently here most preferred to maintain the reaction zone at a temperature below about 15° C. Liquid phase conditions can be maintained at such temperatures by employing pressures in the range of from about 5 to 20 pounds per square inch gauge.
Although sulfur dioxide in liquid form is a preferred diluent or solvent for use in liquid phase sulfonation of acyloxy benzene, other low boiling liquid diluents or solvents may be employed, such as a perfluorinated hydrocarbon (e.g., a member of the "Freon" family), ethylene dichloride, methylene chloride, carbon tetrachloride, heptane, and the like. Such a solvent, when used for liquid phase sulfonation, should preferably boil below the indicated preferred upper digestion temperature employed in the practice of the present invention. In general, it is preferred to remove such a solvent before the subsequent digestion step is completed by boiling, venting, or the like.
Batch sulfonation techniques suitable for use in the practice of this invention include:
(1) Acyloxy benzene dissolved in a solvent and addition of liquid SO 3 thereto;
(2) Acyloxy benzene dissolved in a solvent and addition of gaseous SO 3 thereto;
(3) Each of acyloxy benzene and SO 3 separately dissolved in a solvent and the resulting solutions admixed together;
and the like.
In summary, the general conditions employed for sulfonation are shown in the following Table I:
TABLE I______________________________________SULFONATION CONDITIONS Value RangeCondition Preferred More Preferred______________________________________Contacting Temperature about -20 to 50° C. about -10 to +30° C.Combined Mole Ratio of about 0.9 to 1.1 about 1SO.sub.3 to Acyloxy BenzeneRatio of Solvent: Ester about 0.1 to 3.0 about 0.5 to 1.0wt:wt______________________________________
During sulfonation, the mole ratio of SO 3 to acyloxy benzene can vary, but preferably is maintained within the ranges of indicated, the localized instantaneous mole ratio being dependant upon the particular technique being employed and other related factors. For one example, in a falling film sulfonation, which is continuous, the mole ratio of SO 3 to acyloxy benzene preferably ranges from about 0.9 to 1.1. For one example, in a batch sulfonation, this ratio can range from an initial value of 0 to a maximum value (as at the end of a sulfonation) of about 1.1.
A product of such a sulfonation is presently impossible to analyze directly by conventional techniques because of its reactivity, and so its exact composition in any given instance is presently unknown; however, best available evidence indicates that such product is an adduct of SO 3 and acyloxy benzene.
Digestion
Evidently, during sulfonation, acyloxy benzene forms an adduct with SO 3 at the ester carbonyl group. In the prior art, SO 3 adducts tend to form when aliphatic carboxylic acid esters are sulfonated with SO 3 , but such prior art adducts have vastly different characteristics. However, after formation, this present adduct unexpectedly appears to spontaneously rearrange even at low temperatures. Investigation has led to the present discovery that at average temperatures below about 75° C., such rearrangements can be caused to take place in a controlled manner.
The rate of adduct rearrangement is roughly proportional to the temperature. With increasing temperatures over about 75° C., the rate and frequency of side reactions appears to increase while at temperatures below about 15° C., the rate of rearrangement tends to become impractically long for commercial purposes. At temperatures in the high end of the range of about 15° to 75° C., control of the rearranging mass appears to be difficult to maintain, especially in early stages of digestion. In general, the average temperature of digestion is controlled below about 75° C. in order to minimize occurrence of localized overheating. Digestion times longer than about 4 hours or less than about 0.1 hour appear to be impractical commercially, especially when using conventional apparatus, such as a heat exchanger or the like, for the digestion zone.
For example, in the case of phenyl octanoate, the SO 3 adduct requires about 4 hours to digest completely at about 35° C. whereas at about 55° C., digestion is completed in about 15 minutes (about 0.25 hr). The time for substantially complete rearrangement to occur is generally inversely proportional to the temperature of the adduct/sulfonic acid mixture within the ranges taught herein.
It is apparently possible to chill, and then interveningly to store, an SO 3 -acyloxy benzene adduct reaction product from sulfonation by using a storage temperature which is typically in the range from about -10° to -20° C. Even such a chilled product will apparently rearrange very slowly with the rate of rearrangement at any given time being influenced by the temperature. However, it is generally presently preferred in the practice of this invention to transfer an adduct effluent from a sulfonation reaction zone directly and immediately into a digestion or stripping zone without intervening storage or holding.
Preferably, during digestion, the acyloxy benzene sulfonic acid being produced is maintained in a liquid form.
By maintaining the digestion temperature within the above-indicated temperature range, the rearrangement of a SO 3 -acyloxy benzene adduct takes place with a maximum production of the desired acyloxy benzene sulfonic acid and with a minimum production of other products. Also, with digestion in such a temperature range, color formation, adduct degradation, and by-product formation are minimized.
In a mixture of adduct and acyloxy benzene sulfonic acid formed from adduct, further digestion (and rearrangement) takes place under liquid phase conditions at a temperature below the solidification or melting point temperature of the sulfonic acid. Solidification of such sulfonic acid evidently tends not to occur until the acyloxy benzene sulfonic acid level reaches a critical value which appears to be dependent on structure of the final product in any given case. For example, straight chain acyloxybenzne sulfonic acid levels may reach concentration levels of about 75 to 80% before such an acid solidification occurs.
In one preferred mode of practicing digestion in accord with the present invention, a starting acyloxy benzene is sulfonated as described above under batch conditions in the presence of the low boiling liquid diluent (preferably comprised of SO 2 ), and digestion is them immediately initiated thereafter. During digestion, the low boiling liquid diluent is evaporated preferably by using reduced pressures.
The rate of evaporation effectively and inherently regulates the digestion temperature. As such diluent evaporates, it cools the rearranging mass. This is particularly effective in regulating in the most critical early of digestion when the possibilities for unwanted by-product formation appear to be greatest.
Reduced pressures may be employed if desired to accomplish such evaporation and temperature control. The temperature of the reaction product during such evaporation can conveniently range from about -10° to +15° C.
After such diluent has been effectively completely removed, then the digestion of the reaction mass can be continued at a temperature initially approximating that achieved in the reaction mass at the end of diluent removal, or at a higher temperature, if desired. The temperature employed can be influenced by the equipment being used for digestion. Preferably in this operation, the rearranging reaction product is maintained at a temperature ranging from about 10° to 75° C. for a time sufficient to cause substantially complete rearrangement of the reaction product, thereby to produce a maximum yield of acyloxy benzene sulfonic acid. The total time for digestion (including time for diluent removal and subsequent temperature control) should preferably be within the time periods above indicated.
As indicated, during digestion, in addition to the above-indicated desired rearrangement into acyloxy benzene sulfonic acid, by-products are possible. For example, reaction can take place so as to result in the production of a fatty acid and sulfonated phenol. (Alternatively, for another example, acyloxy benzene can rearrange under conditions of a so-called Fries Rearrangement to cause the ester group to rearrange into a ketone phenol, and such a ketone phenol can further react with a fatty acid by-product to produce various esters.) The number and variety of ultimate rearrangement products which can occur is substantial, and the by-product mixtures achievable are complex in nature. However, carrying out intermediate adduct rearrangements under the digestion conditions herein provided generally maximizes production of acyloxy benzene sulfonic acid and minimizes production of other materials. Thus, examples of by-products produced when controlled digestion is practiced as taught herein may include: unreacted starting acyloxybenzene ester, ketone phenol, ketone ester, sulfones, and the like, but additional and alternative other by-products may be present. The exact quantities of these individual by-products which are present in a given rearranged product of controlled digestion are not now known. These by-products seem generally to be relatively stable materials which do not in themselves appear to affect the stability of the desired sulfonic acid produced.
In general, the intermediate sulfonic acid product produced by the digestion procedures of the present invention is a composition which characteristically comprises on a 100 weight percent total composition basis:
(a) from about 80 to 92 weight percent of acyloxy benzene sulfonic acid, and
(b) from about 8 to 20 weight percent of by-products.
The product of the digestion is thus a composition which contains a higher content of acyloxy benzene sulfonic acid than can be obtained by sulfonation alone (without a controlled digestion step) even using the same starting material and identical sulfonation conditions, as the Examples illustrate below. Optimizing of process conditions in any given instance apparently can produce significant differences in such comparative yields, as those skilled in the art will readily appreciate. Such increases in yields are believed to be surprising and unexpected. No other techniques or means for so increasing yields of acyloxy benzene sulfonic acid directly utilizing only SO 3 sulfonation and digestion is now known.
The purity of an acyloxybenzene sulfonic acid composition produced by utilizing such digestion can range as above indicated. However, contents of acid above about 93 to 95 weight percent (the exact upper limit not now being known) appear to be not capable of achievement even by the superior process steps of this invention for reasons not now altogether clear, but which are theorized to be associated with the tendency for the intermediate product of the sulfonation step (sometimes termed herein the adduct) to rearrange even under the controlled digestion condition herein employed with only the inherent production of some by-products. By-product production cannot be completely avoided, it is theorized.
In addition to such yield increases, the product of the digestion is a composition which has a lower associated color that can be obtained by sulfonation alone (without a controlled digestion step) even using the same starting material and identical sulfonation conditions, as the Examples illustrate below. As in the case of yields, optimizing of process conditions in any given instance apparently can result in significant color improvements over the prior art as those skilled in the art will readily appreciate. Such improvements in color are believed to be surprising and unexpected. No other technique or means for so increasing color of acyloxybenzene sulfonic acid directly utilizing only SO 3 sulfonation and digestion is now known.
The color of a product sulfonic acid largely determines the color of a neutralized and dehydrated final product (see the following description pertaining to these further processing steps). However, for measurement purposes, the color of a neutralized and dehydrated final product is measured. For present purposes, APHA color value (where the sample evaluated is measured as a 10% aqueous solution) is used. For commercial acceptability, the color of a final neutralized and dehydrated product should be below about 150 APHA, and preferably below about 100.
Such low color values cannot be achieved or even approached by using only prior art sulfonation without digestion. For instance, the prior art sulfonation procedure shown in Example 1 below produces a product neutralized acid having an APHA color value in the range from about 250 to 400; yet, when this same procedure is utilized with controlled digestion as shown in Examples 2-4 below, the APHA color value is only about 150. Also, when the procedure of Examples 5 and 6 below is employed, the APHA color value is only about 50 to 60 which value is not more than about 1/5 the value achieved by the prior art sulfonation procedure. Thus, a dramatic improvement in color is provided by the practice of the present invention. Largely because of such color considerations, the combination of batch sulfonation with subsequent digestion as taught herein represents a presently preferred embodiment of this invention.
Neutralization
The desired intermediate product sulfonic acid produced by the foregoing digestion procedures can, if desired, as indicated above, be stored before being further processed. However, in the preferred practice of this invention, such intermediate acid product is promptly (after its formation) admixed with a preformed aqueous solution of a base whose cation selection from the group consisting of alkali metals, alkaline earth metals, and ammonium as indicated above with sodium being presently preferred. Preferably neutralization is accomplished at a temperature below about 15° C. and more preferably below about 5° C. under aqueous liquid phase conditions.
Neutralization in accord with the present invention can be carried out batchwise or continuously. If carried out batchwise, it is preferred preliminarily to dissolve the acyloxybenzene sulfonic acid in water preferably under liquid phase conditions at a temperature as near to 0° C. as practical to minimize hydrolysis of such sulfonic acid ester in water. Preferably, the resulting sulfonic acid aqueous solution contains from about 3 to 30 weight percent on a total solution weight basis of such acid with the balance being water. Thereafter, the aqueous base solution is admixed therewith under liquid phase conditions preferably in approximately an equimolar amount relative to the acyloxy benzene sulfonic acid and preferably at a temperature below about 10° C. Preferably the final pH of the resulting mixture ranges from about 5 to 6.
If neutralization is carried out continuously, it is preferred to bring together continuously the aqueous base solution with such sulfonic acid ester (preferably freshly digested) in a mixing zone or chamber. The mixing takes place rapidly under liquid phase conditions preferably at a temperature ranging from about 0° to 35° C. These continuous mixing conditions minimize hydrolysis of such sulfonic acid ester. The respective quantities of such base solution and such sulfonic acid ester as fed to the mixing zone are continuously regulated so as to maintain the pH of the resulting mixture issuing from the mixing zone in the range from about 4 to 7 and preferably from about 5 to 6.
In general, the product produced by the neutralization procedures above characterized appears to be an aqueous solution or slurry that has an APHA color which is less than about 150 and which comprises on a 100 weight percent total composition basis:
(a) from about 10 to 40 weight percent of an acyloxy benzene sulfonate salt,
(b) from about 1.0 to 12.0 weight percent of by-products, and
(c) from about 48 to 89 weight percent water.
In such salt, the cation is selected from the group consisting of alkali metals, alkaline earth metals, and ammonium. The acyl group is as defined above. The by-products remain substantially unchanged as now understood.
The by-products present in the salt appear to be substantially identical in type and composition to the by-products above described as being present in a product of controlled digestion produced by the teachings of this invention.
Thus, for example, one presently preferred process of this invention permits production of an acyloxy benzene sulfonate salt which has an APHA color that is less than about 100. Such preferred process comprising the steps of sequentially:
(A) contacting SO 3 with at least one acyloxybenzene of the formula: ##STR2## where R is a saturated aliphatic group containing from about 2 to 19 carbon atoms inclusive under liquid phase conditions in the presence of a substantially inert liquid which boils below about 10° C. to produce a reaction product wherein the combined mole ratio of SO 3 to acyloxybenzene ranges from about 0.9 to 1.1,
(B) evaporating said inert liquid from said reaction product at a rate sufficient to maintain said reaction product at a temperature in the range from about -10° to 15° C.,
(C) maintaining said resulting reaction product at a temperature in the range from about 10° to 75° C. until said reaction product has been substantially completely rearranged, thereby to produce acyloxybenzene sulfonic acid, and
(D) continuously admixing a stream of said acid with a stream of dilute aqueous base solution under liquid phase conditions at a temperature below about 35° C. while maintaining the pH of the resulting mixed solution in the range from about 4 to 7.
Dehydration
The neutralized product, as above characterized and produced by the foregoing neutralization procedures, may either be in an aqueous slurry or aqueous solution form. It may be used as such. It can also be dehydrated or substantially completely dried to produce a solid product (usually and preferably in a particulate form). When dried, the solid product produced is comprised mainly of acyloxy benzene sulfonate salts as the foregoing product compositional description indicates. It is presently preferred to convert such an aqueous neutralized product into a salt in solid, particulate form by drying. For example, a neutralized slurry can be drum dried or spray dried (the latter being presently preferred).
In general, a dried product is a storable solid which comprises on a 100 weight percent total composition basis:
(a) from about 80 to 94 weight percent of an acyloxybenzene sulfonate salt, and
(b) from about 6 to 20 weight percent of by-products.
In such salt, the cation is selected from the group consisting of alkali metals, alkaline earth metals, and ammonium. The acyl group is as above defined. The by-products remain substantially unchanged as now understood.
A presently preferred such dried product comprises on a total composition basis from about 85 to 94 weight percent of said acyloxybenzene sulfonate salt, and from about 6 to 15 weight percent of such by-products.
A presently preferred spray drying process comprises spraying such a starting aqueous solution or slurry composition into a drying chamber in the initial form of droplets while simultaneously impinging against said droplets in said chamber an inert gas stream maintained at a temperature ranging from about 100° to 175° C. and thereafter collecting the dried particular composition so resulting.
EMBODIMENTS
The present invention is further illustrated by reference to the following examples. Those skilled in the art will appreciate that other and further embodiments are obvious and within the spirit and scope of this invention from the teachings of these present examples taken with the accompanying specification.
EXAMPLE 1
(Prior Art)
Using a Knaggs/Nussbaum-type falling film sulfonation apparatus as described in the aforementioned Knaggs and Nussbaum U.S. Pat. No. 3,169,142, sulfonation of phenyl octanoate (whose composition is shown in Table VII below) carried out under the following conditions:
SO 3 /Air-5% (vol/vol)
Jacket temperature-8° C.
Irrigation rate-8.4
The term "irrigation rate" has reference to the feed rate in pounds/hr. of the phenyl octanoate per circumferential inch (circumference of tube).
The reaction product from the reactor is collected and the temperature change thereof with respect to time is recorded at measured intervals. The samples are collected and analyzed to determine the percent of octanoyloxy benzene sulfonic acid present in the product composition (on a dry weight basis). The results are shown in Table VIII below:
TABLE VII______________________________________Composition of Phenyl Octanoate(100 Weight Percent Basis)______________________________________Phenol 0.34%Octanoic Acid 0.44%Phenyl Octanoate 98.9%Phenyl Decanoate 0.34%______________________________________
TABLE VIII______________________________________Yield of Octanoyloxy Benzene Sulfonic AcidWithout Controlled Digestion Temperature Active Location andTime °C. wt. % Comments______________________________________ 0 sec. 49 34.1 At reactor outlet20 sec. 104 75.9 Stirred in beaker40 sec. 98 78.5 Stirred in beaker60 sec. -- 77.8 Stirred in beaker90 sec. -- 77.5 Stirred in beaker______________________________________
The percent actives is determined by hyamine-mixed indicator titration.
For reasons of accurate measurement, calculation of yields is here based upon the non-neutralized acid rather than on a neutralized salt prepared therefrom. However, some samples of sulfo phenyl octanoate described in Table VIII are dissolved in ice water and neutralized by addition of 10% aqueous NaOH to pH-5.5. For each sample, the active sodium sulfo phenyl octanoate produced is shown in Table IX.
TABLE IX______________________________________Salt Yield Temperature ActivesTime °C. %______________________________________ 0 sec. 49 --20 sec. 104 77.440 sec. 98 --60 sec. -- 81.490 sec. -- 80.0______________________________________
It is estimated that these neutralized acid (salt) products have an APHA color of about 275-400 measured as a 10% solids solution in water. This measurement is described in ASTM test procedure number D2108-71.
Thus, in this example, no digestion zone is employed and the effluent from the sulfonation reactor is allowed to experience temperature changes with no effort being made to control exotherm or to cool the reaction product. Hence this procedure is comparable to teachings contained in the aforedescribed Knaggs and Nussbaum U.S. patent.
EXAMPLES 2-4
The sulfonation procedure of Example 1 is repeated with the same phenyl octanoate. Here, however, the effluent from the reactor is immediately charged from the reaction zone into the tube of a shell and tube heat exchanger via an in line continuously operating transfer pump. An in line mixer is positioned in the feed line between the pump and the heat exchanger. Temperature measurements are made at various locations along the transfer lines and along the tube of the heat exchanger. Also, samples are concurrently collected from various locations as follows:
(a) at reactor outlet,
(b) before the pump,
(c) after the pump,
(d) after the mixer, and
(e) after the heat exchanger
Samples are then analyzed to determine the weight percent of acyloxy benzene sulfonic acid recovered. This procedure is repeated three times. The results are recorded in Table X below:
TABLE X______________________________________Yield of Octanoyloxy Benzene Sulfonic AcidWith Controlled Digestion Temper- Ac- ature tivesTime °C. Wt. % Location______________________________________Run I 0 sec. 39 At reactor outlet(Ex. 2) 3 sec. 50 36.5 Before pump 5 sec. 70 63.4 After pump 15 sec. 71 81.3 Before heat exchanger 165 sec. 41 82.3 After heat exchangerRun II 0 sec. 47 At reactor outlet(Ex. 3) 3 sec. 76 51.3 Before pump 5 sec. 80 72.4 After pump 15 sec. 72 82.8 Before heat exchanger 165 sec. 43 82.3 After heat exchangerRun III 0 sec. 44-45 -- At reactor outlet(Ex. 4) 3 sec. 95 58.0 Before pump 5 sec. 90 74.7 After pump 15 sec. 79 75.3 Before heat exchanger 165 sec. 42 83.3 After heat exchanger______________________________________
The results shown in Table X demonstrates that, by the use of the described digestion step, approximately a 5 to 6% increase in yield of octanoyloxy benzene sulfonate is achieved.
Table X also illustrates that when the digestion temperature is allowed to rise above about 75° C., digestion is not permitted to proceed to completion within the 3 to 5 second time frame experienced.
A few of these digested acid products are neutralized at 0° C. and analyzed by the procedure described in Example 1 to obtain information concerning the effect of neutralization on yield. The results are shown in Table XI below:
TABLE XI______________________________________Salt Yield Actives Time %______________________________________Run I 0 sec. --(Ex. 2) 3 sec. -- 5 sec. -- 15 sec. 85.5 165 sec. 82.8Run II 0 sec. --(Ex. 2) 3 sec. -- 5 sec. -- 15 sec. 78.4 165 sec. 77.9Run III 0 sec. --(Ex. 3) 3 sec. -- 5 sec. -- 15 sec. -- 165 sec. --______________________________________
These neutralization results indicate the propriety of using the sulfonic acid as the basis for yield calculation since differences exist between the yield of acid and the yield of salt directly derived therefrom. The exact cause of such differences is unknown, but available evidence indicates that some hydrolysis occurs by this neutralization procedure. Comparison of the yields of salts here produced to the yields of salt produced in Example 1 does not appear to be proper because of the procedural differences involved, especially the temperature of neutralization.
The color of a 10 weight percent solids solution in water of the so neutralized acid is found by APHA analyses to be about 150. This color appears to be properly comparable to the color achieved in the product of Example 1.
EXAMPLE 5
110 grams (0.5 moles) of the same phenyl octanoate is placed in a 500 ml flask fitted with a dry ice-acetone condenser, a stirrer, and a gas inlet tube. Gaseous SO 2 is passed into the flask to accomplish batch sulfonation. As the gas passes up the condenser, it liquifies and drops into the flask. Addition is stopped when about 200 mls of liquid SO 2 have been added. The reflux temperature ranges from about 0° to -5° C. Good stirring is maintained.
While continuing a slow flow of gaseous SO 2 , 41.5 grams (0.52 mole) SO 3 is vaporized in about one hour, under the liquid level, as a co-current stream, to complete sulfonation.
Thereafter, to initiate controlled digestion, the flask is connected to a vacuum source and immersed in a 55° C. water bath and the SO 2 is continuously evaporated over a time of about 45 minutes. During the period of SO 2 evaporation, some digestion under controlled conditions occurs. Digestion temperature is regulated by the temperature of the evaporating SO 2 . Foaming is avoided by adjusting the vacuum level. Following removal of SO 2 , digestion is continued at 55° C. for fifteen to thirty minutes until rearrangement is completed.
The sulfo phenyl octanoate actives thus obtained has the following analysis:
Acidity-3.30 ME/G
Actives-89.0%
Thereafter, the resulting (rearranged) sulfonic acid is slowly added to 1000 mls cold water (0°-5° C.) so that the temperature does not rise above about 10° C. Then, the product resulting is neutralized at 0°-5° C. with added 10% NaOH until the pH reaches about 5.0-6.0. At 0°-5° C. in cold water, the acid is stable for about 4 hours. The neutralized acid is substantially more stable even at room temperatures.
The resulting solution can be either spray dried or drum dried to produce a white powder. For example, spray drying in a laboratory sized BUCHI 190 mini spray dryer is accomplished under the following conditions:
Slurry concentration 15% solids
Slurry flow rate 3-4 cc/min.
Air flow: 45 M 3 /min.
Air temperature in: 130° C.
Air temperature out: 90° C.
This spray dried product is a white powder having neutralized acid (salt) actives of 89.1%.
The color of a 10 weight percent solids solution in water is found by APHA analysis to be 50. This color appears to be properly comparable to the color achieved in the products of Example 1 and of Examples 2-4.
EXAMPLE 6
Following the procedure of Example 5, 117 grams (0.5 mole) of phenyl pelargonate (whose composition is shown in Table XII below) is treated with 41.8 grams (0.52 mole) SO 3 ). The resulting degassed and digested sulfo phenyl pelargonate had the following analysis:
Acidity-3.16 ME/G.
Actives-89%
Neutralization and spray drying as in Example 5 produced a white powder with 90.7% activies. The APHA color is 60 (10% solids).
TABLE XII______________________________________Composition of Phenyl Nonanonate(100 weight percent basis)______________________________________phenol 0.37%2-methyl phenyl octanoate 2.59%phenyl nonanonate 96.57%______________________________________
Similar results to those achieved in the procedures of Examples 2-4 and Examples 5 and 6 are found to occur when:
(A) the acyloxy benzene starting material has an acyl group which contains 10 or 12 carbon atoms,
(B) the acyloxy benzene starting material is a mixture of different acyloxy benzene compounds wherein the acyl group is comprised of 8, 9, 10, 11, and 12 carbon saturated aliphatic chains.
Lower yields when such a mixed acyloxybenzene starting material is employed are not observed compared to yields obtained with such single acyloxybenzene starting materials. Also, changes in process conditions when such a mixed acyloxybenzene starting material is employed are not needed over those employed for such pure starting materials in order to obtain such comparable yields.
As the molecular weight of a starting acyloxybenzene increases, a slightly higher digestion temperature is presently preferred compared to the digestion temperature employed for a lower molecular weight such starting material.
As is apparent from the foregoing specification, the invention is susceptible of being embodied with various alterations and modifications which may differ particularly from those that have been described in the preceding specification and description. For this reason, it is to be fully understood that all of the foregoing is intended to be merely illustrative and is not to be construed or interpreted as being restrictive or otherwise limiting of the present invention, excepting as it is set forth and defined in the hereto-appended claims. | A process is provided for making acyloxy benzene sulfonates by the steps of sulfonating with SO 3 , digesting the sulfonation adduct, and neutralizing. The sulfonation adduct can spontaneously rearrange. Unless the rearrangement is controlled as taught in the sulfonating and digesting steps, product yields of acyloxy benzene sulfonate drop to unusable levels and the color of the product is poor and the content of by-products is excessive in the product. | 2 |
[0001] This application is a divisional application of U.S. patent application Ser. No. 14/219,073 filed Mar. 19, 2014 which claims priority to U.S. provisional application Ser. No. 61/805,583 filed on Mar. 27, 2013.
BACKGROUND OF INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to the destruction of cancer and bacteria cells and other harmful cells at various locations within the human body by generating an electrical current between two electrodes such that the current passes through the portion of the body in which bacteria or other harmful cells reside.
[0004] 2. Description of Related Art
[0005] The ability to kill bacteria, cancer cells, fungus and mold spores by utilizing an electrolytic cell has been known for many years. Utilizing an anode and a cathode in a container of water and supplying an AC or DC current to the anode and cathode, the cells between the electrodes have been destroyed. The prevailing wisdom says that the current upsets the osmotic balance of the bacteria cell and causes the cell to either implode or explode. This destruction has been verified by many studies that are readily available to the public. See for example, U.S. Pat. No. 5,948,733 to Yoshida et al issued Sep. 7, 1999 and “Pretreatment Capabilities and Benefits of Electrocoagulation” by Michael Mickley, Boulder Colo., December 2004.
[0006] Additionally, Patent Publication No. 2009/0117513A1, published May 7, 2009 discloses that low direct current between two electrodes positioned on opposite sides of teeth gums in the human mouth is effective to kill bacteria as well as viruses and fungus. Similarly, U.S. Pat. No. 7,837,719 to Brogan et al issued Nov. 23, 2010, discloses that toenail fungus can be destroyed by placing one or both feet in a container filled with a solution and passing a low current over and around the toes and nails. The current is created by electrodes positioned within the container.
[0007] With respect to cancer cells, studies have shown that low current flow between electrodes implanted within the body is effective in treating cancer cells. See for examples, U.S. Pat. No. 6,366,808 to Schroeppel et al, issued Apr. 2, 2002 and U.S. Pat. No. 7,079,890 to Aker et al, issued Jul. 18, 2006.
[0008] These prior art medical devices utilize very low current levels and are only effective to destroy surface bacteria and or viruses but are not effective to penetrate deeper into human tissue to kill bacteria and or viruses located beneath the surface or skin level without implantation.
BRIEF SUMMARY OF THE INVENTION
[0009] The present invention is the destruction of bacteria molds or cancer cells below the surface level of the human body by creating an electric current between two electrodes which are positioned externally between the areas of the body to be treated. The electric current is confined between the two electrodes and thus does not injure other areas of the body.
[0010] Tests have been done using beef hamburger meat over an inch thick and applying a DC current across the meat with a given amount of bacteria throughout the entire thickness of the meat. After analysis, it was proven that the bacteria in the middle of the meat were destroyed without changing the temperature of the meat. This test was conducted several times to arrive at the best power settings to assure the destruction of the bacteria at a given thickness. More voltage is required to penetrate a thicker sample of meat than that of a thinner piece. It was found that the required amps would be fairly constant but more voltage would be required to achieve the amps in thicker samples of meat.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)
[0011] FIG. 1 is a schematic view of an embodiment of an apparatus suitable for carrying out an embodiment of the invention.
[0012] FIG. 2 is a schematic view of an embodiment of the invention suitable for treating foot disorders.
[0013] FIG. 3 is a schematic view of a second embodiment according to the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0014] FIG. 1 is a schematic view of device suitable for carrying out an embodiment of the invention. A pair of electrodes 11 and 12 are connected to the opposite poles of a power source 14 which may be a variable power output source. The power source is preferable a DC power source. The electrodes can be made of any known material suitable for electrodes such as stainless steel, but preferably are constructed as a base plate made of titanium with a ruthenium or other noble coatings. The size and shape of the electrodes will depend upon the area of the body to be treated and could include curved surfaces and plates that have been curved for positioning around a finger, arm or leg for example.
[0015] Electrodes 11 and 12 are positioned exteriorly on either side of the area of the body to be treated as figuratively illustrated at 13 . Power source can then be activated and the power adjusted in order to provide an effective amount of current to pass through body mass 13 so as to destroy the bacteria in the area to be treated.
[0016] In an alternative arrangement shown in FIG. 3 , non-rigid electrodes 31 and 32 could be a wire mesh or any porous substance arrangement 35 and 36 in a protective bag, cloth or other suitable material 33 and 34 . The electrodes can be saturated with a brine solution of water to facilitate the transfer of the electricity from the electrode to the area of the body 37 being treated. The wire mesh or porous material can be stainless steel or other suitable conductive material but using a noble electrode made of titanium with a ruthenium coating is preferred. In either arrangement, a layer of water between the electrodes or a cloth wrap or sponge will protect the body from making contact with the electrodes.
[0017] FIG. 2 illustrates an embodiment of an apparatus for treating feet. In this embodiment three elongated electrodes 21 , 22 and 23 are positioned within a container. Electrodes 21 , 22 and 23 are long enough to cover the entire foot length and high enough to cover the foot up to about ankle height. The patient's feet are positioned between the plate electrodes as shown at 26 and 27 . Plates 21 and 23 are connected to one pole of the power sources via lead 24 and electrode 22 is connected to the opposite pole by lead 25 . In operation a conductive solution is placed in the container and the patient's feet are positioned at 26 and 27 . The power source is energized and can be adjusted so that an effective amount of current flows between the electrodes to destroy bacteria and or fungus below the toe nails.
[0018] The range of current for the foot bath type of device is from 0.5 amps to 6 amps. Higher current will be utilized to penetrate deeper to treat diseases under the skin.
[0019] In the case of wire mesh pads and the embodiment of FIG. 1 , the range will range from 0.05 amps up to 6 amps depending on the thickness of the extremity being treated. The voltage will vary depending on the conductivity of the extremity which will determine how many volts will be required to push the required amps through the extremity.
Example 1
[0020] Treatment of abscessed tooth utilizing dc current to kill the associated bacteria which caused great pain due to the infection in the root of the tooth. Pain is the most common system of needing a root canal. The paining from this condition is fairly specific. If the tooth is still alive, it will become extremely sensitive to hot or cold water. This pain can continue day and night and an abscess will form when the pulp of the tooth dies and a pus pocket forms around the end of the root. The pus accumulates in an area of dead nerve tissue that is infected with bacteria. Although antibiotics can help the bacteria from spreading to other surrounding teeth and gums, a root canal will be required to clean out all the dead tissue and bacteria inside the pulp inside the root canal.
[0021] The root canal cannot be performed while there is still an infection in the tooth due to bacteria. Antibiotics must be taken for up to 10 days before the infection is cleared and before the root canal can be performed. During these 10 days the pain will continue day and night until antibiotics can destroy the bacteria and lesson the pain. This pain can continue for days until controlled.
[0022] Two patients who were diagnosed with an abscessed tooth both of which had tremendous pain were treated with a bacteria treatment device according to the invention which includes a positive and negative electrode which are inserted in the mouth and placed on either side of the infected tooth. The positive electrode was placed on one side and the negative placed on the opposite side. This placement is to assure that dc current can pass through the entire tooth and gum area of the selected tooth. The electrodes are made of titanium plates with ruthenium coating or other similar noble metal and are covered with a sponge type material for comfort wetted with a saline solution to enhance current flow to the tooth and gums.
[0023] Both patients were subjected to 0.1 and 0.4 of an amp with voltage being varied as to the thickness of the gums. This treatment was held for approximately 3 minutes but more or less may be required. The goal was to destroy the bacteria thus relieving the pain quickly in lieu of waiting days for the pain to subside. Some patients cannot take the strong pain medication due to other health issues and must face the pain until the antibiotics clear the infection. This procedure can also shorten the time which a root canal can be accomplished when a dental x-ray confirms the infection is gone.
[0024] Both patients noted that the pain was diminished right away and all pain relieved within a couple of hours. Both patients eventually had the root canals done at their convenience.
Example 2
[0025] A 50 year old patient was referred to a podiatrist with a fungal growth on his toes. The doctor noted a visible fungal growth on the patient's feet and a biopsy was taken. The pathology report which was received in the doctors off was as follows:
Diagnosis: Nail plate and attached superficial nail bed, right hallux, biopsy showed PAS reaction demonstrates probably dermatophytes. Moderate fungal growth is observed. Onychomycosis, sub fungal pattern. Treatment: The patient was treated using an anode and cathode device which is placed over each toe with one electrode on the top of the toe and the other electrode on the bottom of the toe. This arrangement allows the direct current when applied to flow through the toe to destroy the fungus. The toes were treated utilizing voltages ranging from 9 volts to 32 volts depending on the size of the toe. Time of treatment was approximately 5 minutes per toe. A post treatment biopsy was taken by the attending doctor. Post treatment biopsy results: A PAS reaction and GMS stain fail to demonstrate fungal elements. It was shown that treatment of this fungus using DC current with specific applied voltages was very successful. All treatment was conducted under a doctor's care in the doctor's office.
Example 3
[0031] Infected acne or boils can occur when a hair follicle becomes plugged with oil or dirt and then becomes infected with bacteria. In most cases these areas are just under the skin and are easily treated with spaced electrodes as disclosed herein.
[0032] Patient with infected acne on facial cheek: The patient had a very painful rising on his left cheek that was very red and stood out on his face.
[0033] The patient was given a device which resembles a large clothes pin where one surface is a stainless positive electrode and the opposite surface was stainless negative electrode. The electrodes were connected to a DC current power supply capable of supplying 0.1 to 0.9 amps with varied voltage. The patient was able to clamp the two electrodes over the infected area and then gradually increase voltage/amps until the amount of current becomes uncomfortable then the power is dialed back to a level that could be tolerated. The power was left on for approximately 60 seconds.
[0034] Results: By the end of the day the pain had subsided and the soreness was better. By the next morning, the area was no longer swollen and the soreness was totally gone. Two days later, there was no sign of the infected area. The DC current had penetrated under the skin and destroyed the bacteria allowing a healing process to begin.
[0035] Although the present invention has been described with respect to specific details, it is not intended that such details should be regarded as limitations on the scope of the invention, except to the extent that they are included in the accompanying claims. | Bacteria, cancer cells, fungus and other harmful cells located beneath the surface of a mammal body can be effectively destroyed by passing an electrical current through the area to be treated. Electrodes are positioned on either side of the area to be treated, for example, gums, fingers, arms, legs, feet and torso, and an electric current is caused to flow between the electrodes and through the area to be treated. The electric current will destroy the bacteria, cancer cells, fungus or other harmful cells. | 0 |
FIELD OF THE INVENTION
[0001] This invention relates to the treatment of tinnitus and related common auditory dysfunctions such as hyperacusis, auditory hallucinations, misophonia, phonophobia and central auditory processing disorders.
BACKGROUND OF THE INVENTION
Tinnitus
[0002] Tinnitus is the phantom sensation of hearing in the absence of external sounds. Two main types can be identified: (1) objective tinnitus, which is caused by sounds generated somewhere in the body; (2) subjective tinnitus, which is the perception of meaningless sounds without any physical sound being present. Objective tinnitus is rare and is caused by a sound in the body, such as turbulent flow of blood or muscle contractions in the head. Such tinnitus can be heard by an observer in contrast to subjective tinnitus, which can only be heard by the individual who has the tinnitus. Subjective tinnitus is the most prevalent type of tinnitus. Tinnitus sounds can take a variety of forms such as buzzing, ringing, whistling, hissing or a range of other sounds. For some people it can even sound like music or singing. It can be a benign sound or it can prevent its sufferers from sleep or the ability to do intellectual work. All degrees of subjective tinnitus occur in between these extremes. Tinnitus is also related to other symptoms, such as hyperacusis, auditory hallucinations, misophonia, phonophobia and central auditory processing disorders. Affective disorders, such as anxiety and depression, often accompany severe tinnitus and that form of tinnitus can lead to suicide. Tinnitus is most likely related to altered neuronal activity which leads to plastic changes in the central auditory pathway derived from a distorted input. However, the mechanisms underlying the different forms of tinnitus remain incompletely understood.
[0003] Tinnitus often occurs as a result of dysfunction of the hearing system, such as from noise exposure, presbyacusis or from administration of specific pharmacologic agents. It can also be caused as the result of ear or head injuries, some diseases of the ear, ear infections and emotional stress. Perhaps the most common source of chronic tinnitus is exposure to loud sound. The noise causes permanent damage to the sound-sensitive cells of the cochlea, a spiral shaped organ in the inner ear. Carpenters, pilots, soldiers, rock musicians, street repair-workers are among those people whose jobs put them at risk. But also recreational use of sound, like MP3 players at maximal volume can produce damage. In addition, a long list of drugs can induce tinnitus. In some cases the causative agent remains unknown. One in 10 adults have clinically significant tinnitus (regular prolonged spontaneous tinnitus lasting 5 minutes or more), and for 1 in 100 adults tinnitus severely affects their ability to lead a normal life. Estimates indicate that 13 million people in western Europe and the USA currently seek medical advice for their tinnitus. Over 4 million prescriptions are written each year for tinnitus relief but these are all for off-label drugs from a wide variety of therapeutic classes and most are associated with considerable side effects. Despite the significant unmet clinical need for a safe and effective drug targeting tinnitus relief, there is currently no FDA-approved drug on the market that targets tinnitus.
[0004] Tinnitus can be associated with common auditory dysfunctions such as hyperacusis, distortion of sounds, misophonia, phonophobia and central auditory processing disorders. An extremely rare condition called “exploding head syndrome” has sometimes been called “explosive tinnitus”; however exploding head syndrome is not encompassed within the normal meaning of tinnitus or associated common auditory dysfunctions, and the present invention does not cover the treatment of exploding head syndrome.
[0005] There are several therapeutic approaches to alleviate tinnitus, however, they have limited results and most patients are left unsatisfied. This includes: 1. counselling which can help the patient to cope with his tinnitus; 2. if tinnitus is accompanied by hearing loss, a hearing aid can help with tinnitus management; 3. sound therapy, also known as sound enrichment; 4. Tinnitus Retraining Therapy, a combination of counseling and sound therapy; 5. cognitive-behavioral therapy; 6. repetitive transcranial magnetic stimulation; 7. epidural cortical stimulation with implantable electrodes and 8. a series of off-label drugs like antidepressants, anxiolytics, anesthetics, anticonvulsants, analgesics, antiarrythmics, herbal medicines, anticoagulants, sedative-hypnotics, antihistaminergic compounds, antipsychotics, antioxidants, vasodilators, among others.
[0006] Specifically, the following proposals have been made in the patent literature, but have not been proven for widespread use:
[0007] U.S. Pat. No. 4,735,968 discloses a method of treating tinnitus with aminoxyacetic acid (ADAA) administered orally. U.S. Pat. No. 4,954,486 proposed treating tinnitus symptoms with furosemide. U.S. Pat. No. 5,668,117 proposed treatment of tinnitus with a carbonyl trapping agent in combination with antidepressants or antianxiety medications; anti-convulsants; lidocaine; aminooxyacetic acid; praxilene; aniracetam; piracetam; 13-cisretionic acid; and 13-trans-retinoic acid. U.S. Pat. No. 5,716,961 discloses the treatment of tinnitus using specific neuroprotective agents. U.S. Pat. No. 5,863,927 proposed to treat tinnitus with dextromethorphan in combination with a debrisoquin hydroxylase inhibitor. U.S. Pat. No. 6,358,540 disclosed the treatment of tinnitus with an herbal composition. U.S. Pat. Nos. 6,656,172 and 6,969,383 proposed treatment of tinnitus using a catheter to infuse a therapeutic agent for example an agent comprising a local anesthetic such as lidocaine, or a GABA agonist. U.S. Pat. No. 6,713,490 discloses a compound which is (R)-6[2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidibyl]-1-hydroxyethyl]-3,4-dihydro-2(1H)-quinolinone inter alia for the treatment of tinnitus. U.S. Pat. No. 6,770,661 disclosed various aryl substituted pyridines inter alia as antitinnitus agent.
[0008] Cyclobenzaprine
[0009] Cyclobenzaprine is a skeletal muscle relaxant. The exact mechanism of action for cyclobenzaprine is unknown. Current research appears to indicate that cyclobenzaprine acts on the locus coeruleus where it results in increased norepinephrine release, potentially through the gamma fibers which innervate and inhibit the alpha motor neurons in the ventral horn of the spinal cord. Decreased firing of the alpha motor neuron results in decreased muscular tone. Cyclobenzaprine is a muscle relaxant acting primarily on the central nervous system. It is structurally similar to Amitriptyline, differing by only one double bond. Cyclobenzaprine is typically prescribed to relieve pain and muscle spasms. Typically, muscle spasms occur in an injury to stabilize the affected body part and prevent further damage. Whereas this is beneficial in acute injury, muscle spasm frequently persists over time, becomes dysfunctional and can increase the pain level. It is believed that by decreasing muscular spasm, pain is diminished. A common application would be that of a whiplash injury in a car accident. Cyclobenzaprine has also been studied in the treatment of fibromyalgia. In a study of 120 fibromyalgia patients, those receiving Cyclobenzaprine (10 to 40 mg) over a 12 week period had significantly improved quality of sleep and pain score. Interestingly, there was also a reduction in the total number of tender points and muscle tightness. It is also prescribed off-label as a sleeping-aid.
[0010] U.S. Pat. No. 7,387,793 proposes an extended release form of cyclobenzaprine for treating muscle spasm associated with painful musculoskeletal conditions.
[0011] Cyclobenzaprine has been proposed in U.S. Pat. No. 6,632,843 and patent application US 2006/06178511 for the treatment of bruxism by topical administration as a cream onto the skin overlying accessible muscles of mastication. Possible accessory alleviation of the other symptoms including tinnitus was also mentioned
[0012] GB Patent Specification 1 334 326 proposes a composition having skeletal muscle relaxant activity comprising cyclobenzaprine and aspirin, which is intended to reduce the side effects of aspirin when administered in recommended dosages, such side effects including provoking epigastric distress, nausea, vomiting and tinnitus and more important, gastric erosion, exacerbation of peptic ulcer symptoms, perforation and hemorrhage.
[0013] Despite many suggestions for tinnitus treatment discussed above, there remains a need for an effective treatment of tinnitus that could be widely accepted.
[0014] As-yet unpublished PCT patent application PCT/IB2010/051373, filed 30 Mar. 2010, relates to cyclobenzaprine for use in the treatment of tinnitus and related auditory dysfunctions by oral administration or by parenteral administration through intramuscular, intravenous, subcutaneous or intrathecal injection or infusion, and presents data demonstrating the efficacy of cyclobenzaprine for these treatments. This unpublished PCT patent application mentions the use of extended release cyclobenzaprine for tinnitus by once-a-day administration but does not provide any details thereupon, neither of the means for providing extended release, nor any other details.
[0015] Background Art on Extended-Release Drug Formulations
[0016] Considerable efforts have been devoted to developing matrix tablet-based and multi-particulate capsule-based drug delivery systems for oral applications, in order to make therapeutic agents available at a constant rate at or near the absorption site. The resulting delayed absorption of therapeutic agents generally results in desired plasma concentrations leading to maximum efficacy and minimum toxic side effects.
[0017] U.S. Pat. No. 4,839,177 concerns a system for the controlled-rate release of active substances consisting of a core comprising an active substance and (a) a polymeric material having a high degree of swelling on contact with water and a gellable polymeric material and/or (b) a single polymeric material having both swelling and gelling properties, and a support platform of a water insoluble polymeric material applied to the core.
[0018] U.S. Pat. No. 4,851,228 discloses a multi-particulate osmotic pump for the controlled release of a pharmaceutically active agent, consisting essentially of a core containing an active agent and a rate-controlling water-insoluble wall comprising a semi-permeable polymer and at least one pH insensitive pore-forming additive dispersed throughout the wall.
[0019] U.S. Pat. No. 4,590,062 discloses a compressed product containing an active agent produced by dry blending with a matrix combination of a hydrophobic polymer such as ethylcellulose, and a wax, fatty acid, neutral lipid or combination thereof.
[0020] U.S. Pat. No. 4,996,047 is directed to an oral pharmaceutical composition in unit dosage form of ion-exchange resin particles having a pharmacologically active drug bound thereto, wherein the drug-resin complex particles are coated with a water-impermeable diffusion barrier to provide controlled release of the active drug.
[0021] U.S. Pat. No. 5,120,548 discloses a controlled-release drug delivery device comprising a polymer composition which swells upon exposure to an aqueous environment, a plurality of controlled-release swelling modulators, at least one active agent and a water insoluble polymer or a microporous wall surrounding the composition.
[0022] U.S. Pat. No. 5,350,584 discloses a process for the production of microcrystalline cellulose-free multiparticulates comprising a medicament and a charged resin, producing spheronized beads that can be used in controlled-release dosage forms.
[0023] U.S. Pat. No. 5,366,738 describes a drug delivery device for controlled release of an active agent, including a compressed core with an active agent and a polymer that forms gelatinous microscopic particles upon hydration and a water insoluble, water impermeable polymeric coating comprising a polymer and plasticizer that surrounds and adheres to the core.
[0024] U.S. Pat. No. 5,582,838 discloses a drug delivery device for the controlled release of a beneficial agent, including a compressed core having at least two layers. At least one layer is a mixture of a beneficial agent and a polymer that forms microscopic polymer gel beads upon hydration and at least one outer layer comprises a polymer that forms microscopic polymer gel beads upon hydration. A water-insoluble, water-impermeable coating is applied to the core. The coating has apertures exposing between about 5-75% of the core surface.
[0025] U.S. Pat. No. 5,874,418 discloses a pharmaceutical composition comprising a carrier and a mixture of a sulfoalkyl ether-cyclodextrin and a therapeutic agent. Delayed, sustained or controlled release formulations are described wherein the pharmaceutical core is coated with a film coating comprising a film forming agent and a pore forming agent.
[0026] U.S. Pat. No. 5,882,682 relates to a drug delivery process involving: preparing a uniform mixture of a polymer that forms gelatinous microscopic particles upon hydration, the beneficial agent and other excipients; compressing the mixture into cores; coating the cores with a water-insoluble, water-impermeable polymeric coating including a polymer and a plasticizer; and forming apertures through the coating.
[0027] U.S. Pat. No. 5,952,451 relates to a process for preparing high molecular weight poly(phosphoester) compositions comprising a biologically active substance, useful in prolonged released drug delivery systems.
[0028] A multi-layered osmotic device described in U.S. Pat. No. 6,004,582 comprises a compressed core including a first active agent and an osmotic agent. A semi-permeable membrane having a preformed passageway therein surrounds the core, wherein the membrane is permeable to a fluid and is substantially impermeable to the first active agent. This membrane preferably consists essentially of cellulose acetate and poly(ethylene glycol). The external coat can include poly(vinylpyrrolidone) and poly(ethylene glycol) and further materials such as HPMC, ethylcellulose, hydroxylethylcellulose, CMC, dimethylaminoethyl methacrylate-methacrylic acid ester copolymer, ethyl acrylate-methyl methacrylate copolymer, and combinations thereof.
[0029] As mentioned above, U.S. Pat. No. 7,387,793 proposes an extended release form of cyclobenzaprine for treating muscle spasm associated with painful musculoskeletal conditions, wherein the extended-release is produced by beads comprising the cyclobenzaprine coated with a water-insoluble polymer possibly in combination with a water-soluble polymer.
[0030] WO 99/30671 describes an oral delivery vehicle including an aspected particle comprising a pharmaceutically active component and excipients and a coating to provide sustained drug delivery to the particle.
[0031] WO 98/53802 describes a multi-layered osmotic device capable of delivering a first active agent in an outer lamina to one use environment and a second active agent in the core to another use environment. An erodible polymer coat between an internal semi permeable membrane and a second active agent-containing external coat comprises poly(vinylpyrrolidone)-vinyl acetate) copolymer. The active agent in the core is delivered through a pore containing an erodible plug.
[0032] WO 98/18610 relates to particles containing an active agent, which provide controlled release of the active ingredient without substantial destruction of the matrix material. A release-rate controlling component is incorporated in a matrix to control the rate-release of the encapsulant. A hydrophobic component or a high water binding capacity component may be used for extending the release time. Release properties may also be controlled by precoating the encapsulant and/or coating the particles with a film-forming component.
[0033] WO 98/06439 relates to a composition comprising a biologically active agent encapsulated in a matrix comprising a polyether ester copolymer, such as polyethylene glycol terephthalate/polybutylene-terephthalate copolymer, that protects the active agent from degradation and facilitates the drug delivery.
SUMMARY OF THE INVENTION
[0034] One aspect of the invention provides an extended-release dosage form of cyclobenzaprine for use in the treatment of tinnitus and related auditory dysfunctions by once-a-day oral administration, wherein the dosage form is a tablet or capsule comprising cyclobenzaprine as active agent in an amount from 10-80 mg, preferably from 10-60 mg, 10-50 mg, or 15-45 mg, the active agent being associated with a polymer coating or matrix that comprises a water-insoluble polymer, the polymer coating or matrix providing the dosage form with an extended release of the active agent over at least 12 hours and preferably over at least 16 hours when the dosage form is administered to a patient.
[0035] As explained below, this combines the efficacy of cyclobenzaprine for treating tinnitus and related auditory dysfunctions with an improvement in the desired relatively uniform plasma concentrations leading to maximum efficacy while reducing side effects and minimizing intersubject variability.
[0036] Providing the dosage form with an extended release of the active agent over at least 12 hours when the dosage form is administered to a patient means that usually from 60-85% of the total active agent is released gradually over 12 hours, under standard conditions. In particular, in most cases the polymer coating or matrix provides the dosage form with the following dissolution profile when measured in a USP type II apparatus at 50 rpm, at a temperature of 37 degrees C.:
no more than about 40% of the total active agent is released in 2 hours; from about 40-65% of the total active agent is released after 4 hours; from about 60-85% of the total active agent is released after 8 hours; and from about 75-85% of the total active agent is released after 12 hours.
[0041] After 16 hours, typically more than 85% of the total active agent will be released.
[0042] The water insoluble polymer is usually selected from ethers of cellulose, esters of cellulose, cellulose acetate, ethyl cellulose, polyvinyl acetate, neutral copolymers based on ethylacrylate and methylmethacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, pH-insensitive ammonio methacrylic acid copolymers, and mixtures thereof.
[0043] The polymer coating or matrix may further comprise a water-insoluble polymer for example selected from methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyethylene glycol polyvinylpyrrolidone and mixtures thereof.
[0044] The polymer coating or matrix can further comprise a plasticizer, in particular selected from triacetin, tributyl citrate, tri-ethyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, castor oil, acetylated mono- and di-glycerides and mixtures thereof.
[0045] The extended-release dosage forms described herein can comprise a polymer coating on core particles comprising the active agent, wherein the water-insoluble polymer in the polymer coating corresponds for example to 7% to 12% of the weight of the dosage form. The core particles may be formed by the active agent alone or coated on an inert particle core in particular a sugar sphere or an acidic or alkaline buffer crystal.
[0046] The particles may be formed by granulating and dry milling and/or by extrusion and spheronization of the active agent, then applying a polymer coating.
[0047] The dosage form can alternatively be formed into capsules containing extended-release coated particles as described above, or a mixture of extended-release coated particles and “immediate release” particles of the uncoated active agent, and/or a mixture of extended-release coated particles having different coatings providing different release times.
[0048] Instead of including coated particles, the dosage form may comprise the active agent cyclobenzaprine associated with a polymer matrix as described in several of the prior art disclosures summarized above.
[0049] The active agent can be included in the dosage form as cyclobenzaprine or as pharmaceutically acceptable salts and derivatives thereof, in particular as cyclobenzaprine hydrochloride.
[0050] The extended-release dosage form can be used for a long-term treatment of tinnitus and related auditory dysfunctions extending over 2 weeks or more, preferably 8 weeks or more.
[0051] Another aspect of the invention is a method of treating tinnitus and related auditory disorders in a mammal, comprising once-a-day orally administering to a mammal in need of such treatment, an extended-release dosage form of cyclobenzaprine, wherein the dosage form is a tablet or capsule comprising cyclobenzaprine as active agent in an amount from 10-80 mg, preferably from 10-60 mg, the active agent being associated with a polymer coating or matrix that comprises a water-insoluble polymer, the polymer coating or matrix providing the dosage form with an extended release of the active agent over at least 12 hours and preferably over at least 16 hours when the dosage form is administered to a patient. This method is in particular applicable to a subject having been previously diagnosed with and possibly also treated for tinnitus.
[0052] As shown by the tests reported below, which are taken over from the above-mentioned PCT patent application PCT/IB2010/051373, cyclobenzaprine has a positive effect on tinnitus severity and on tinnitus loudness in the tested subjects, it is safe to administer and though common side effects (like constipation and dry mouth) may be experienced, it is tolerated well by most subjects. Similar results are expected for associated auditory dysfunctions. Generally, according to the invention, the described extended release form of cyclobenzaprine is effective for the treatment of an auditory dysfunction selected from tinnitus, hyperacusis, auditory hallucinations, misophonia, phonophobia and central auditory processing disorders.
[0053] General Aspects of Extended-Release Cyclobenzaprine for Treating Tinnitus
[0054] For many chronic conditions such as chronic pain, management guidelines recommend the use of long-acting, extended-release formulations. Guidelines for pharmacological treatment of tinnitus however have not been established, although tinnitus is a chronic condition. As such, the goal of pharmacological therapy for tinnitus is to provide sustained relief. The use of long-acting, extended-release formulations for tinnitus is desirable because they provide prolonged, more consistent plasma concentrations of drug compared with short-acting agents, thus minimizing fluctuations that could contribute to end-of-dose breakthrough tinnitus. In this regard, a randomized, open-label, two-period crossover, single-centre study, has demonstrated that single-dose pharmacokinetics of once-daily cyclobenzaprine extended release 30 mg versus cyclobenzaprine immediate release 10 mg three times daily in healthy young adults, provides a controlled release of cyclobenzaprine with sustained plasma concentrations, in contrast to the fluctuating profile of cyclobenzaprine immediate release with comparable systemic exposures.
[0055] Better Efficacy and Fewer Side Effects
[0056] With cyclobenzaprine extended release a more stable plasma concentration can be achieved. In general, in chronic diseases, less fluctuations in the plasma concentrations result in better efficacy. This is well known for the treatment of chronic pain, where analgesics are most efficient when they are administered in a way which results in a very stable plasma concentration, e.g. by transdermal application.
[0057] For example, side effects of tricyclic drugs depend more on changes in the plasma concentration and on peak concentration than on the mean concentration over time. So every drug administration regime which results in more stable plasma concentrations and fewer fluctuations will produce less side effects. In the case of cyclobenzaprine, constipation, which is the main complaint and the main reason for dropouts from therapy, could be diminished.
[0058] Control of Tinnitus Overnight
[0059] The patient with tinnitus is burdened by decreased quality of life, decreased sleep, interference with social relationships, diminished cognitive functions, interference with activities of daily living, decreased productivity, and increased anxiety and depression. Tinnitus can disrupt sleep, and poor sleep can lower the tinnitus threshold, which may contribute to increased tinnitus. Thus, effective management of tinnitus is complicated by the presence of additional conditions that occur frequently together with tinnitus, in particular sleep disturbances. The most frequent sleep complaints include delayed onset of sleep, frequent awakenings, decreased sleep duration, daytime fatigue, and non-restorative sleep. Because greater tinnitus annoyance has been associated with decreased sleep satisfaction, less total sleep time, delayed onset of sleep, and more awakenings due to tinnitus, effective tinnitus control should improve sleep in patients with tinnitus and vice versa. Thus, an important goal of tinnitus pharmacotherapy is to provide sustained relief; therefore, regular administration of immediate release formulations is required to ensure that the next dose of medication is given before the effects of the previous dose have dissipated. Extended release formulations in general provide more consistent and improved nighttime control, without the need to take another dose of medication during the night, and less clock-watching by patients. All these aspects are expected to improve tinnitus-related sleep disturbances.
[0060] Compliance
[0061] In order to achieve sufficient stable plasma concentrations with short-acting (immediate release) cyclobenzaprine, the drug has to be taken at least three times daily. In contrast, a once daily regimen suffices for the extended release formulation of cyclobenzaprine. Consequently, tinnitus patients would benefit enormously from an extended-release formulation, which can be administered once daily. Among the factors which are most important for long term efficiency is treatment adherence and compliance. For long-term compliance of drug intake the administration regime is of utmost importance. The patient compliance for a once-daily administration is much higher than for a treatment regimen which requires drug intake three times a day.
SUMMARY OF ADVANTAGES
[0062] Extended release formulations provide better around-the-clock efficacy, result in fewer changes in drug plasma concentrations when compared with short-acting formulations, provide maximal tolerability, and have minimal long term adverse events with prolonged use.
[0063] The total dosage needed for achieving symptom control is lower, the side effects which depend on peak concentrations and on concentration changes are fewer and less pronounced. At equal concentrations, extended release cyclobenzaprine is more efficient.
[0064] In addition, extended release formulations should provide better nighttime tinnitus control with less need for nighttime dosing, improving sleep. Finally, compliance and long-term adherence are better, resulting in better long-term efficiency.
BRIEF DESCRIPTION OF THE DRAWINGS
[0065] FIG. 1 is a graph of the Global Improvement Scale of the tested subjects.
[0066] FIG. 2-6 are graphs showing the audiogram of different subjects; the progression of Minimum Masking Levels (MML) during the tests; and the progression of Tinnitus Handicap Inventory (THI) and Tinnitus Impairment Questionnaire (TBF12) during the tests.
DETAILED DESCRIPTION
[0067] As described in U.S. Pat. No. 7,387,793, the contents whereof are incorporated herein by way of reference, the dosage form of the present invention may include particles with an active core that comprises an inert particle or an acidic or alkaline buffer crystal, which is coated with a active-agent-containing film-forming formulation, preferably a water-soluble film-forming composition to form a water-soluble/dispersible particle.
[0068] The amount of active agent in the core will depend on the required dose, and usually varies from about 5 to 60 weight %. Generally, the polymeric coating on the active core will be from about 4 to 20% based on the weight of the coated particle, depending on the type of release profile required and/or the polymers and coating solvents chosen. In one embodiment, the inactive core may be a sugar sphere or a buffer crystal or an encapsulated buffer crystal such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid which alters the microenvironment of the active agent to facilitate its release.
[0069] Instead of coating the active agent on an inert core, alternatively the active agent may be prepared by granulating and milling and/or by extrusion and spheronization of a polymer composition containing the active substance.
[0070] The active-agent-containing particle may be coated with an extended release coating comprising a water insoluble polymer or a combination of a water insoluble polymer and a water soluble polymer to provide extended release beads. In certain embodiments, the water insoluble polymer and the water soluble polymer may be present at a weight ratio of from 100/0 to 65/35, more particularly from about 95/5 to 70/30, and still more particularly at a ratio of from about 85/15 to 75/25. The extended release coating is applied in an amount necessary to provide the desired release profile and typically comprises from about 1% to 15%, more particularly from about 7% to 12%, by weight of the coated beads.
[0071] The invention also contemplates a modified release dosage form including a mixture of two bead populations. One method of manufacturing such a mixture includes the steps of: 1. preparing a drug-containing core by coating an inert particle such as a non-pareil seed, an acidic buffer crystal or an alkaline buffer crystal with the active agent and a polymeric binder or by granulation and milling or by extrusion/spheronization to form an immediate-release bead; 2. coating the immediate-release bead with a plasticized water-insoluble polymer alone such as ethylcellulose or in combination with a water soluble polymer such as hydroxypropylmethylcellulose to form an extended release bead; 3. filling into hard gelatin capsules extended-release beads alone or in combination with immediate-release beads at a ratio to produce modified release capsules providing the desired release profile.
[0072] An aqueous or a pharmaceutically acceptable solvent medium may be used for preparing active-agent-containing core particles. The type of film-forming binder that is used to bind the drug to the inert sugar sphere is not critical but usually water soluble, alcohol soluble or acetone/water soluble binders are used. Binders such as polyvinylpyrrolidone (PVP), polyethylene oxide, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), polysaccharides such as dextran, corn starch may be used at concentrations for example from about 0.5 to 5 weight %. The active agent may be present in this coating formulation in the solution form or may be dispersed at a solid content up to about 35 weight % depending on the viscosity of the coating formulation.
[0073] In certain embodiments, the active substance, optionally a binder such as PVP, a dissolution rate controlling polymer (if used), and optionally other pharmaceutically acceptable excipients are blended together in a planetary mixer or a high shear granulator such as from Aeromatic-Fielder (GSA Pharma Systems AG) and granulated by adding/spraying a granulating fluid such as water or alcohol. The wet mass can be extruded and spheronized to produce spherical particles (beads) using an extruder/marumerizer. In these embodiments, the drug load could be as high as 90% by weight based on the total weight of the extruded/spheronized core.
[0074] Cyclobenzaprine hydrochloride is normally used as active agent.
[0075] Representative examples of water insoluble polymers useful in the extended-release coating include ethylcellulose powder or an aqueous dispersion (such as AQUACOAT™. ECD-30), cellulose acetate, polyvinyl acetate (Kollicoat SR#30D from BASF), neutral copolymers based on ethyl acrylate and methylmethacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups such as Eudragit NE, RS and RS30D, RL or RL30D and the like. Representative examples of water soluble polymers include low molecular weight hydroxypropyl methylcellulose (HPMC), methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyethylene glycol (PEG of molecular weight>3000) and mixtures thereof. The extended release coating will typically be applied at a thickness ranging from about 1 weight % up to 15 weight % depending on the solubility of the active in water and the solvent or latex suspension-based coating formulation used.
[0076] The coating compositions used in forming the membranes are usually plasticized. Representative examples of plasticizers include triacetin, tributyl citrate, triethyl citrate, acetyl tri-n-butyl citrate diethyl phthalate, polyethylene glycol, polypropylene glycol, castor oil, dibutyl sebacate, acetylated monoglycerides and the like or mixtures thereof. The plasticizer may comprise about 3 to 30 wt. % and typically about 10 to 25 wt. % based on the polymer. The type of plasticizer and its content depends on the polymer or polymers, and the nature of the coating system (e.g., aqueous or solvent-based, solution or dispersion-based and the total solids).
[0077] In general, it is desirable to prime the surface of the particle before applying an extended release membrane coating or to separate the different membrane layers by applying a thin hydroxypropyl methylcellulose (HPMC)(OPADRY™ Clear) film. While HPMC is typically used, other primers such as hydroxypropylcellulose (HPC) can also be used.
[0078] The membrane coatings can be applied to the core using any of the coating techniques commonly used in the pharmaceutical industry, particularly fluid bed coating.
[0079] The present invention is applied to multi-dose forms, i.e., active agent products in the form of multi-particulate dosage forms (pellets, beads, granules or mini-tablets) or in other forms suitable for oral administration. As used herein, these terms refer interchangeably to multi-particulate dosage forms.
[0080] The invention will further be described by way of example in the tests reported below for tinnitus.
DESCRIPTION AND RESULTS OF TRIAL TESTS
[0081] From February to November 2008, 30 subjects were screened and 15 recruited to this trial. The sample counted on 7 males and 8 females with an age range from 36 to 71 years, mean age 54.6 years (Std=11.3 years).
[0082] Medication
[0083] The selected subjects received Cyclobenzaprine tablets, in the amounts described below. In the initial tests as reported in PCT/IB2010/051373 tablets were administered three times daily. However short-term tests using 15 mg and 30 mg extended-release cyclobenzaprine available under the trademark Amrix give equally encouraging results in terms of tinnitus treatment. From theoretical considerations and from the data provided in U.S. Pat. No. 7,387,793, extended-release cyclobenzaprine is expected to provide the same tinnitus-treating effect combined with an improvement in the desired relatively uniform plasma concentrations leading to maximum efficacy while reducing side effects and minimizing intersubject variability.
[0084] Table 1a shows the cyclobenzaprine dosage 3 times/day and Table 1b shows the proposed cyclobenzaprine dosage with extended-release cyclobenzaprine 1 time/day.
[0000]
TABLE 1a
Cyclobenzaprine dosage
Baseline-
Week
Week
Week
Week
Week
Week
week 2
2-4
4-8
8-12
12-13
13-14
14-16
Concentration
15
22.5
30
30
22 5
15
0
mg/day
[0000]
TABLE 1b
Extended-release cyclobenzaprine proposed dosage
Baseline-
Week
Week
Week
Week
week 3
4-8
8-12
13-14
14-16
Concentration
15
30
30
15
0
mg/day
[0085] Results
[0086] Four selected outcome variables were used in this preliminary analysis: Global improvement (GI), Tinnitus Handicap Inventory (THI) and Tinnitus Impairment Questionnaire (TBF 12) questionnaires and Minimum Masking Levels (MML). The changes on the outcome variables were obtained by subtracting week 12's scores from the screening scores. The presence of a negative result means a decrease on values. On Subject number 6 the final scores correspond to week 8 (last observation carried forward analysis). Subject 3 had an intermittent tinnitus which interfered on the psychoacoustic examination.
[0000]
TABLE 2
Changes on outcome variables ordered by
Global Improvement (GI) classification.
Changes on
Subject
MML
number
GI
THI
TBF 12
Right
Left
2
1
−14
−2
−5
−8
3
1
−30
6
Not possible to measure but noticed
change on intensity and less episodes
during the day
8
2
−48
−11
−11
−17
4
2
−8
−3
−25
−12
10
2
−14
−2
−8
−9
14
2
−10
−10
2
0
11
2
−28
−5
−5
1
13
2
−40
−7
1
−8
9
3
−14
−1
−7
−7
5
3
−42
−4
0
−4
6
3
−38
−4
Trial suspended because of side effects
15
4
−36
−6
Didn't return for measurements
7
4
−32
−3
9
−7
12
4
−28
−6
3
8
1
4
0
−3
14
3
[0087] In Table 2 the changes on outcome variables are listed by Global Improvement (GI) classification, as follows: GI 1=much better; 2=better; 3=slightly better; 4=no change; 5=slightly worse; 6=worse; 7=much worse; THI: Tinnitus Handicap Inventory, TBF 12: Tinnitus Impairment Questionnaire; MML: minimal masking levels, measured in dB HL (Hearing Level).
[0088] Four different criteria were established to determine whether a subject responded or not to treatment (see Table 3). The prevalence of positive results to Cyclobenzaprine will reflect on how rigid the outcome criteria are selected.
[0000]
TABLE 3
Criteria and prevalence of Cyclobenzaprine treatment results.
Non
Responders
responders
Responders
Criteria
% and n
% and n
(subject #)
Criteria 1
73.3%
26.7%
2, 3, 4, 5, 6, 8, 9,
Improvement on GI
11
4
10, 11, 13 and 14
Criteria 2
73.3%
26.4%
2, 3, 4, 5, 6, 8, 9,
Criteria 1 + decrease on
11
4
10, 11, 13 and 14
THI
Criteria 3
66.6%
33.3%
2, 4, 5, 6, 8, 9,
Criteria 2 + decrease on
10
5
10, 11, 13 and 14
TBF 12
Criteria 4
53.3%
46.7%
2, 4, 5, 8, 9, 10,
Criteria 3 + decrease on
8
7
11 and 13
MML
[0089] Using the less conservative criteria, Criteria 1, based on subjects score to Global Improvement, (GI) 11 subjects (73.3%) referred that tinnitus improved with medication and 4 (26.7%) didn't notice any change. Different degrees of changes in GI perception are described on FIG. 1 . As can be seen, 8 subjects were Better or Much Better; and 11 subjects were Slightly Better, Better or Much Better.
[0090] FIGS. 2-6 show by way of example results for subjects 4, 8, 9, 10 and 11 that responded to all of the Criteria 1-4. The progressive reduction of the Minimum Masking Levels (MML) in all of these subjects is particularly striking. Using Criteria 4, the most conservative approach to select responders, only subjects that reported improvement on GI and demonstrated decrease on THI, TBF 12 and MML were included (see Table 2). Based on these criteria the rate of improvement was 53.3%.
[0091] General Data on Subjects and Tinnitus Characteristics
[0092] Some of the data collected on this trial are listed on Tables 4 to 7, so one can have an idea about the bibliographical data, tinnitus characteristics and other variables collected on Case History Questionnaire. Tinnitus psychoacoustic measurements, audiograms as well as time line graphs for selected subjects showing THI and TB12 during different moments at the trial are presented in FIGS. 2 to 6 .
[0000]
TABLE 4
Case History Questionnaire Data of the 15 subjects
Time of
Gradual/
Subject
Family
onset
sudden
number
Gender
Age
history
Etiology
Hearing
(months)
onset
Pulse
1
M
62
Y
Other
Asymmetric
180
Gradual
N
NSHL*
2
M
43
N
Other
Unilateral
10
Gradual
N
NSHL Left
3
F
57
Y
Other
Unilateral
180
Sudden
YES, ≠
NSHL Right
heart
4
M
70
Y
Noise
Asymmetric
72
Gradual
N
NSHL
5
F
61
N
Stress
Asymmetric
60
Gradual
Y, Like
NSHL
heart
6
F
36
Y
Ear
Normal
8
Gradual
Y, Like
Infection
heart
7
M
60
N
Noise
Symmetric
504
Gradual
N
NSHL
8
F
71
N
Other
Symmetric
336
Gradual
N
NSHL
9
F
57
Y
Other
Asymmetric
336
Gradual
N
NSHL
10
F
69
N
Other
Symmetric
216
Gradual
N
NSHL
11
F
43
N
Hearing
Symmetric
24
Sudden
N
Loss
NSHL
12
F
56
N
Hearing
Asymmetric
144
Gradual
N
loss
NSHL
13
M
40
N
Noise
Symmetric
216
Gradual
Y
NSHL
14
M
45
N
Noise
Asymmetric
288
Gradual
N
NSHL
15
M
49
N
Barotrauma
Unilateral
8
Gradual
N
NSHL Left
*NSHL = neurosensory hearing loss
[0000]
TABLE 5
Tinnitus description from Case History Questionnaire
Subject
Constant/
Changes On
Intensity
number
Location
intermittent
intensity
0-100
Quality
Pitch
1
BOTH EARS
Constant
Y
30
Crickets
High
2
LEFT EAR
Intermittent
Y
50
Wheezing
High
3
RIGHT EAR
Intermittent
Y
70
Crickets
Medium
4
BOTH EARS
Constant
Y
30
Crickets
High
5
BOTH EARS,
Constant
Y
70
Wheezing
Very High
WORST LEFT
6
BOTH EARS,
Constant
Y
50
Wheezing/
High
WORST LEFT
crickets
7
BOTH EARS
Constant
Y
70
Wheezing
Medium
8
LEFT EAR
Constant
N
60
Wheezing
Medium
9
BOTH EARS
Constant
Y
80
Tonal
High
10
BOTH, WORST
Constant
N
90
Wheezing
High
RIGHT
11
BOTH,
Constant
N
80
Other
High
WORST RIGHT
12
LEFT EAR
Intermittent
Y
70
Wheezing
Very High
13
BOTH EARS,
Constant
N
50
Wheezing
Medium
WORST LEFT
14
BOTH,
Constant
N
60
Other
Very High
WORST RIGHT
15
LEFT EAR
Constant
N
70
Crickets
High
[0000]
TABLE 6
Associated Symptoms/Somatic modulation
Subject
TMJ*
Neck
Other
Somatic
#
Headache
Vertigo
Dysfunction
Pain
Pain
modulation
1
N
N
N
Y
Y
N
2
N
N
N
Y
Y
N
3
N
N
N
Y
N
N
4
Y
Y
N
Y
Y
Y
5
N
N
N
Y
Y
N
6
Y
Y
Y
Y
Y
Y
7
Y
Y
Y
Y
Y
N
8
N
N
Y
Y
Y
N
9
Y
Y
Y
N
Y
N
10
N
N
N
N
Y
N
11
Y
Y
Y
Y
Y
N
12
Y
N
N
N
N
Y
13
Y
Y
N
Y
N
N
14
N
N
Y
Y
N
Y
15
N
N
Y
Y
Y
Y
*Temporomandibular Joint Dysfunction
[0000]
TABLE 7
Tinnitus Psychoacoustic characteristics collected at screening and at week 12
(“12 W”)
MML Right Ear
MML Left Ear
Residual
Pitch (kHz)
(dB HL)
(dB HL)
Inhibition
Subject #
Screening
12 W
Screening
12 W
Screening
12 W
Screening
12 W
1
2
3
38
52
42
45
Complete
No
2
Broad Band
Broad Band
50
45
70
62
Complete
Complete
3
—
6
—
—
—
—
—
—
4
8
4
63
38
50
38
Complete
Partial
5
4
4
53
53
49
45
Complete
Complete
6
Broad Band
—
15
.
24
.
No
—
7
2
2
35
44
44
37
Partial
Partial
8
6
Broadband
55
44
59
42
Partial
Complete
9
4
6 AND 1
66
59
70
63
Complete
Complete
10
8
Broadband
50
42
50
41
Complete
Complete
11
8
4
56
51
57
56
Partial
Partial
12
Broadband
Broadband
40
43
37
45
Complete
Complete
+2K
+2K
13
8
8
15
16
25
17
Complete
Complete
14
4
4
35
37
34
34
Partial
Partial
15
6
40
.
57
.
Complete
—
[0093] Changes on tinnitus pitch were an unexpected effect of the tests, probably indicating that this medication induced a change on neural firing pattern. It was observed in 5 out of 15 subjects.
[0094] The time of tinnitus onset was not a predictive variable to positive outcome; subjects suffering for 28 years had positive results as well as subjects who had it for 8 months.
[0095] All publications, patent applications, patents, and other documents cited herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting in any way. | The invention provides an extended-release dosage form of cyclobenzaprine for use in the treatment of tinnitus and related auditory dysfunctions by once-a-day oral administration, wherein the dosage form is a tablet or capsule comprising cyclobenzaprine as active agent in an amount from 10-80 mg, preferably from 10-60 mg. The active agent is associated with a polymer coating or matrix that comprises a water-insoluble polymer, the polymer coating or matrix providing the dosage form with an extended release of the active agent over at least 12 hours and preferably over at least 16 hours when the dosage form is administered to a patient. | 0 |
The present invention relates to pumps, and in particular, to small sized high capacity piezoelectric fluid pumps. This invention was made with Government support under contract DAAH01-01-C-R046 awarded by DARPA. The Government has certain rights in this invention.
BACKGROUND OF THE INVENTION
Conventional fluid pumps are well known. Although conventional fluid pumps are readily available in both low and high capacity designs, a common feature is that they have many moving parts that create noise and vibration. Also, there are reliability and lifetime limitations due to normal wear phenomena. Furthermore, because conventional pumps have multiple parts, they tend to be large, heavy and expensive.
Micropumps, also known as miniature pumps, are pumps that are fabricated on a microchip utilizing micromachining processes. For small capacity requirements, micropumps provide improved reliability with fewer parts. For example, micropumps utilizing electroactive transducers have emerged for biomedical and metering applications where small pressures and flow rates are required and where conventional pumps are somewhat impractical. The typical capacity of a micropump may be in the range of a few nano liters per second to a few micro liters per second. Since the total fluid power output of these devices is very small, efficiency is not highly important and is generally low. The relatively low efficiency of the micropump makes massive parallel arraying of many micropumps unattractive as a way of competing with larger conventional pumps. Scaling up the size and pressure of such electroactively driven devices does not improve the efficiency and is difficult due to on-chip fabrication techniques. This class of pump is therefore not able to compete directly with larger conventional pump designs for large fluid output.
Micro Electro Mechanical System (MEMS) microvalve arrays are known and are utilized to achieve precision fluid flow control. In a microvalve array, multiple diaphragms cover multiple ports to restrict and control fluid flow. In some designs, heaters can be activated to warm and expand a closed fluid volume that in turn moves diaphragms to close and open the individual ports to achieve a desired flow. This arrangement permits precise flow rate control but is slow to respond due to thermal conduction to and from the closed fluid volume. Other activation methods, such as piezoelectric activation, can provide faster opening and closing of the ports.
What is needed is a compact, high capacity pump that has minimal moving parts, is able to handle a relatively large fluid output, and has improved operating efficiency and reliability as well as reduced weight, size and cost.
SUMMARY OF THE INVENTION
The present invention provides a compact, high capacity pump for pumping fluid. A first one-way valve is between an inlet port and the pump's fluid chamber. A second one-way valve is between the pump's fluid chamber and an outlet port. A diaphragm separates a piezoelectric stack from the fluid chamber. A power source provides power to the piezoelectric stack causing it to expand and contract. The expansion and contraction of the piezoelectric stack causes fluid to be pumped from the inlet port to the fluid chamber through the first one-way valve and causes fluid to be pumped from the fluid chamber to the outlet port through the second one-way valve. In one preferred embodiment, both one-way valves are disc valves. In another preferred embodiment both one-way valves are MEMS valves.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a first preferred embodiment of the present invention.
FIG. 1A shows a preferred passive disc.
FIGS. 2A-3B illustrate the operation of the first preferred embodiment.
FIG. 4A shows a second preferred embodiment of the present invention.
FIGS. 4B-4I illustrate the operation of the second preferred embodiment.
FIGS. 5A-5F show a third preferred embodiment of the present invention.
FIGS. 6A-6C show a fourth preferred embodiment of the present invention.
FIG. 7 is a graph of Output Pressure/E Field vs Frequency.
FIG. 8 presents an example of a utilization of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
FIGS. 1-3B disclose a first preferred embodiment of the present invention. As shown in FIG. 1 , AC power source 1 provides power to piezoelectric stack 4 of piezoelectric fluid pump 5 . In the preferred embodiment, pump 5 is approximately 3 inches tall, 1.5 inches diameter and weights approximately 200 grams. Frequency modulator 2 and amplitude modulator 3 are connected in series as shown and can be adjusted to vary the frequency and amplitude of the signal reaching piezoelectric stack 4 . Diaphragm 6 is bonded to the top of stack 4 and separates stack 4 from fluid chamber 7 . Inlet 1-way passive disc valve 10 controls the flow of fluid through inlet port 8 into fluid chamber 7 . Likewise, outlet 1-way passive disc valve 11 controls the flow of fluid leaving fluid chamber 7 through outlet port 9 .
Preferred Passive Disc Valve
FIG. 1A shows a top view of a preferred passive 1-way disc valves 10 (part no. J378062) and 11 (part no. J378067), both available from Kinetic Ceramics, Inc. with offices in Hayward, Calif. Passive 1-way disc valves are preferably fabricated from metal and are approximately 0.02 inches thick
Operation of the First Preferred Embodiment
As voltage is applied to stack 4 via AC power source 1 , stack 4 will expand and contract in response to the AC signal, causing diaphragm 6 to bend up and down in a piston-like fashion.
FIG. 2B shows a plot from t=0−½ T of the sine wave of the AC signal generated by AC power source 1 . From t=0−½ T, stack 4 has contracted (i.e., decreased in length), see FIG. 2A . This has caused diaphragm to bend downward, thereby expanding the size of fluid chamber 7 . The expanding of the size of fluid chamber 7 causes a corresponding drop in pressure inside fluid chamber 7 . When the pressure inside fluid chamber 7 becomes less than the pressure inside fluid inlet port 8 , 1-way passive disc valve 10 will open permitting the flow of fluid into fluid chamber 7 . When the pressure inside fluid chamber 7 becomes less than the pressure inside fluid outlet port 9 , 1-way passive disc valve 11 will close preventing a back flow of fluid from outlet port 9 into fluid chamber 7 .
From t=½ T−T (see FIG. 3B ), stack 4 has expanded (i.e., increased in length), as shown in FIG. 3A . This has caused diaphragm to bend upward, thereby decreasing the size of fluid chamber 7 . The decreasing of the size of fluid chamber 7 causes a corresponding increase in pressure inside fluid chamber 7 . When the pressure inside fluid chamber 7 becomes greater than the pressure inside fluid outlet port 9 , 1-way passive disc valve 11 will open permitting the flow of fluid into fluid chamber 7 . When the pressure inside fluid chamber 7 becomes greater than the pressure inside fluid inlet port 8 , 1-way passive disc valve 10 will close preventing a back flow of fluid from fluid chamber 7 into inlet port 8 .
In this fashion, piezoelectric fluid pump 5 will continue to pump fluid from inlet port 8 to outlet port 9 until AC power source 1 is removed.
Applicant built and tested a prototype of the first preferred embodiment and achieved an output power of approximately 0.1 horsepower. In comparison it is estimated that a conventional pump capable of operating at the same or similar capacity would have many more parts and would weigh 2 to 4 Kg.
Second Preferred Embodiment
A second preferred embodiment is disclosed by reference to FIGS. 4A-4E . In the second preferred embodiment, 1-way active disc valves 15 and 16 have replaced 1-way passive disc valves 10 and 11 of the first preferred embodiment. 1-way active disc valves 15 and 16 are electrically connected to AC power sources 12 and 13 as to open and close based on electrical signals.
Preferred Active Disc Valves
FIG. 4F shows a top view of active disc valve 15 and FIG. 4G shows a perspective ¼ cutout section of active disc valve 15 . Piezoelectric actuator 15 a is bonded to the top of metal disc valve 15 b . Piezoelecrtric actuator 15 a utilizes the d 31 piezoelectric mode of operation (d 31 describes the strain perpendicular to the polarization vector of the ceramics).
Operation of Active Disc Valves
FIGS. 4H and 4I illustrate the operation of the preferred active disc valve. In FIG. 4H no electricity has been applied to the piezoelectric actuator 15 a and metal disc valve 15 b is sealing flow inlet port 8 . In FIG. 4I , electricity has been applied to piezoelectric actuator and it has contracted causing metal disc valve 15 b to bend thereby breaking the seal over inlet port 8 . Fluid can now flow through the valve.
Operation of the Second Preferred Embodiment
In FIG. 4A , t=0 (FIG. 4 E 1 ) and the voltage output of AC power source 1 is at a maximum. 1-way active disc valve 16 is closing in response to power source 12 and 1-way active disc valve 15 is opening in response to power source 13 .
In FIG. 4B , 0<t<½ T (FIG. 4 E 1 ) and the voltage output of AC power source 1 is a negative going sine function. Voltage from AC power source 1 has caused stack 4 to contract bending diaphragm 6 downward resulting in a pressure drop in fluid chamber 7 . Pressure sensor 19 has sensed a decrease in pressure inside pumping chamber 7 and has sent a signal to microprocessor 18 . Microprocessor 18 has sent a control signal to power sources 12 and 13 causing them to transmit control voltages to 1-way active disc valves 16 and 15 , respectively. The positive voltage from AC power source 13 (FIG. 4 D 2 ) has caused 1-way active disc valve 15 to open and the negative voltage from power source 12 (FIG. 4 D 1 ) has caused 1-way active disc valve 16 to remain closed. Fluid from inlet port 8 has entered pumping chamber 7 .
In FIG. 4C , ½ T<t<T, the voltage output of AC power source 1 is a positive going sine function (FIG. 4 E 1 ), causing stack 4 to expand bending diaphragm 6 upward and resulting in a pressure increase in fluid chamber 7 . Pressure sensor 19 has sensed a an increase in pressure inside pumping chamber 7 and has sent a signal to microprocessor 18 . Microprocessor 18 has sent control signals to power sources 12 and 13 causing them to transmit control voltages to 1-way active disc valves 16 and 15 , respectively. The negative voltage from AC power source 13 has caused 1-way active. disc valve 15 to close and the positive voltage from AC power source 12 has caused 1-way active disc valve 16 to open. Fluid from pumping chamber 7 has entered outlet port 9 .
At time t=T (FIG. 4 E 1 ), the voltage output of AC power source 1 is again at a maximum and stack 4 is at a fully expanded condition, as shown in FIG. 4A . 1-way active disc valve 15 is opening in response to power source 13 and 1-way active disc valve 16 is closing in response to power source 12 preventing fluid from flowing back to fluid chamber 7 through 1-way active disc valve 16 . In this fashion, piezoelectric fluid pump 5 will continue to pump fluid from inlet port 8 to outlet port 9 until AC power sources 1 , 12 , and 13 are removed.
In this fashion, piezoelectric fluid pump 5 will continue to pump fluid from inlet port 8 to outlet port 9 until AC power source 1 is removed.
Due to the fast response of the piezoelectric active disc valve, the pump actuator can be cycled faster than it could with the passive disc valve. This will allow for more pump strokes per second and an increase in pump output.
Third Preferred Embodiment
MEMS Valves
A third preferred embodiment is disclosed by reference to FIGS. 5A-5F . The third preferred embodiment utilizes two passive MEMS valve arrays.
In the third preferred embodiment, pump 30 is similar to pump 5 shown in FIG. 1 , with an exception being that disc valves 10 and 11 of pump 5 have been replaced with I-way passive microvalve arrays 31 and 32 , as shown in FIG. 5A . Preferably, microvalve arrays 31 and 32 are two micromachined MEMS valves.
FIG. 5B shows an enlarged side view of microvalve array 31 . Microvalve array 31 is fabricated from silicon, silicone nitride or nickel and includes an array of fluid flow ports 31 a approximately 200 microns in diameter. The array of fluid flow ports 31 a is covered by diaphragm layer 31 b . FIG. 5C shows an enlarged top view of a cutout portion of microvalve array 31 . Microvalve array 31 has a plurality of diaphragms 31 c covering each fluid flow port 31 a.
Operation of a Microvalve Array
Microvalve arrays 31 and 32 function in a fashion similar to passive disc valves 10 and 11 . In FIG. 5E , the pressure pressing downward on diaphragm 31 c is greater than the pressure of fluid inside fluid flow port 31 a . Therefore, diaphragm 31 c seals fluid flow port 31 a . Conversely, in FIG. 5F , the pressure pressing downward on diaphragm 31 c is less than the pressure of fluid inside fluid flow port 31 a . Therefore, diaphragm 31 c is forced open and fluid flows through fluid flow port 31 a.
Applying this principle to the third preferred embodiment, when the pressure inside fluid chamber 7 becomes less than the pressure inside fluid inlet port 8 , individual valves within the multitude of microvalves in microvalve array 31 will open permitting the flow of fluid into fluid chamber 7 . When the pressure inside fluid chamber 7 becomes less than the pressure inside fluid outlet port 9 , the individual valves within the multitude of micro valves in the microvalve array 32 will close preventing a back flow of fluid from outlet port 9 into fluid chamber 7 .
Likewise, when the pressure inside fluid chamber 7 becomes greater than the pressure inside fluid outlet port 9 , the individual valves within the multitude of micro valves in microvalve array 32 will open permitting the flow of fluid into outlet port 9 . When the pressure inside fluid chamber 7 becomes greater than the pressure inside fluid inlet port 8 , the individual valves within the multitude of micro valves in microvalve array 31 will close preventing a back flow of fluid from fluid chamber 7 into inlet port 8 .
Due to its small size and low inertia, the microvalve array can respond quickly to pressure changes. Therefore, pump output is increased because it can cycle faster than it could with a more massive valve
Fourth Preferred Embodiment
Active MEMS Valve Operation
A fourth preferred embodiment is similar to the second preferred embodiment described above in reference to FIGS. 4A-4E , with the exception that active disc valves 15 and 16 ( FIG. 4A ) are replaced with active microvalve arrays 41 and 42 ( FIG. 6A ).
FIG. 6B shows an enlarged side view of microvalve array 41 . Microvalve array 41 is fabricated from silicon and includes an array of “Y” shaped fluid flow ports 41 a approximately 200 microns in diameter. Preferably, microvalve array 42 is identical to microvalve array 41 . Below the junction of each “Y” are heaters 41 b . Heaters 41 b for microvalve array 41 are electrically connected to power source 51 and heaters 41 b for microvalve array 42 are electrically connected to power source 52 . Pressure sensor 19 senses the pressure inside fluid chamber 7 and sends a corresponding signal to microprocessor 18 . Microprocessor 18 is configured to send control signals to power sources 51 and 52 .
Operation of an Active Microvalve Array
Microvalve arrays 41 and 42 function in a fashion similar to active disc valves 15 and 16 . For example, in FIG. 6B active microvalve array 41 is open. Fluid is able to flow freely through fluid flow ports 41 a . In FIG. 6C , microvalve array 41 is closed. Power source 51 has sent voltage to heaters 41 b of microvalve array 41 . Heaters 41 b have heated the adjacent fluid causing a phase change to a vapor phase and the formation of high pressure bubbles 41 c . High pressure bubbles 41 c block fluid flow ports 41 a for a short time closing microvalve array 41 . The lack of mass or inertia due to there being no valve diaphragm permits very fast response which enables the valves to open and close at high a frequency beyond 100 kHz.
Applying this principle to the third preferred embodiment, when piezoelectric stack 4 contracts and the pressure inside fluid chamber 7 becomes less than the pressure inside fluid inlet port 8 , pressure sensor 19 will send a corresponding signal to microprocessor 18 . Microprocessor 18 will then send a control signal to power sources 51 and 52 . Consequently, individual valves within the multitude of microvalves in microvalve array 41 will open permitting the flow of fluid into fluid chamber 7 ( FIG. 6B ). Also, individual valves within the multitude of micro valves in the microvalve array 42 will close ( FIG. 6C ) preventing a back flow of fluid from outlet port 9 into fluid chamber 7 .
Likewise, when piezoelectric stack 4 expands and the pressure inside fluid chamber 7 becomes greater than the pressure inside fluid outlet port 9 , pressure sensor 19 will send a corresponding signal to microprocessor 18 . Microprocessor 18 will then send control signals to power sources 51 and 52 . Consequently, the individual valves within the multitude of micro valves in microvalve array 42 will open permitting the flow of fluid into outlet port 9 . Also, the individual valves within the multitude of micro valves in microvalve array 41 will close preventing a back flow of fluid from fluid chamber 7 into inlet port 8 .
Due to its ability to anticipate the need to open and close, the active microvalve array can respond very quickly. Hence, the pump can cycle faster and pump output is increased.
Fifth Preferred Embodiment
Resonant Operation
The fifth preferred embodiment recognizes that at certain frequencies generated by AC source 1 , stack 4 will resonate. As stack 4 resonates, the amount of electrical energy required to displace stack 4 by a given amount will decrease. Therefore, the efficiency of the piezoelectric pump will be increased.
Any electromechanical spring/mass system (including piezoelectric stack 4 ) will resonate at certain frequencies. The “primary” or “first harmonic” frequency is the preferred frequency. In the fifth preferred embodiment, AC power source 1 sends an electrical drive signal to the piezoelectric stack 4 at or near the primary resonant frequency. That frequency is calculated by using the mass and modulus of elasticity for the piezoelectric stack: f=sqrt(k/m) where m is the mass of the resonant system and k is the spring rate (derived from the modulus of elasticity). When in resonance, the amplitude of the motion will increase by a factor of 4 or 5. Thus for a given pump stoke, the drive voltage and electrical input power can be reduced by a similar factor.
For example, FIG. 7 shows a graph of output pressure versus frequency for two pump configurations: A pump having a piezoelectric stack with a length of 3.2 inches, and a pump having a piezoelectric stack with a length of 0.8 inches. As can be seen by the graph, when the pump is operated so that the piezoelectric stack resonates, it is possible to achieve approximately a 300% increase in efficiency.
Utilization of the Present Invention
The present invention can be utilized for a variety of purposes. One preferred purpose is illustrated in FIG. 8 . In FIG. 8 , pump 5 is utilized to pump hydraulic fluid to hydraulic actuators 91 - 99 . The hydraulic actuators are utilized for the primary flight control system for a remotely piloted vehicle. In the preferred embodiment shown in FIG. 8 , piezoelectric pump 5 pumps hydraulic fluid to hydraulic actuators 91 - 99 at a flow rate of up to 60 cc/second. The high hydraulic power output permits fast aircraft control surface adjustments. The combination of high power and light weight materials permits fast aircraft maneuvering that would otherwise not be feasible.
Although the above-preferred embodiments have been described with specificity, persons skilled in this art will recognize that many changes to the specific embodiments disclosed above could be made without departing from the spirit of the invention. Therefore, the attached claims and their legal equivalents should determine the scope of the invention. | A compact, high capacity pump for pumping fluid. A first one-way valve is between an inlet port and the pump's fluid chamber. A second one-way valve is between the pump's fluid chamber and an outlet port. A diaphragm separates a piezoelectric stack from the fluid chamber. A power source provides power to the piezoelectric stack causing it to expand and contract. The expansion and contraction of the piezoelectric stack causes fluid to be pumped from the inlet port to the fluid chamber through the first one-way valve and causes fluid to be pumped from the fluid chamber to the outlet port through the second one-way valve. In one preferred embodiment, both one-way valves are disc valves. In another preferred embodiment both one-way valves are MEMS valves. | 0 |
TECHNICAL FIELD
[0001] This invention relates to method of making footwear.
BACKGROUND
[0002] A variety of constructions for making footwear are used by the footwear industry. For the most part, each footwear construction has characteristics that make it particularly well-suited for efficient manufacturing and ease of production. Typically, in an effort to improve the comfort, durability, and the aesthetic appeal of the footwear, a number of different assembly methods can be used.
SUMMARY
[0003] In a general aspect of the invention, a method for making footwear includes providing a finished platform having a peripheral side region; providing an outsole unit; and providing an upper attached to the peripheral side region of the finished platform. The finished platform includes an insole; a sock lining unit having a peripheral portion for seaming and stitching, the sock lining unit attached to an upper surface of the insole; and a wrapper covering the peripheral side region of the finished platform, the wrapper seamed or stitched to the peripheral portion of the sock lining unit.
[0004] In embodiments of the invention, one or more of the following features may also be included. The insole of the finished platform includes a foam insole cover adhesively attached to the upper surface of the insole, a fiber tuck, and a steel shank. The finished platform is molded for heel height for a heel positioned in a heel portion of the underside region of the finished platform.
[0005] In certain embodiments, the wrapper forms a bottom cover having an outsole region marked for attachment of the outsole unit and a shank area for joining the bottom cover. The outsole region marked for attachment is positioned in the forepart of the bottom cover and the outsole unit is cemented and stitched to the outsole region marked for attachment. The bottom cover is seamed or stitched in the shank area of the bottom cover, and the bottom cover is further attached adhesively to the peripheral side region of the finished platform. The bottom cover is made of the same material as the upper.
[0006] As yet another feature, the upper is hand-sewn around the entire periphery of the finished platform with Opanka stitch series against the peripheral side region of the finished platform, thereby joining the upper to the finished platform.
[0007] Additionally, the sock lining unit comprises a sock forepart and a skeleton sock backpart, both adhesively attached to the foam insole cover. The sock lining unit further comprises a sock lining pad placed over a heel portion of the finished platform, covering the skeleton sock backpart.
[0008] According to another aspect of the invention, the insole is made of molded rubber material. The insole has an insole cavity in the upper surface for attaching the sock lining unit. And a foam insole cover is placed in the insole cavity and adhesively attached to the insole cavity.
[0009] In certain embodiments, the wrapper is a strip made from a same material as the upper, and the wrapper is attached to the sock lining unit by Opanka stitch series. The wrapper stitched to the sock lining forms an opening for the placement of the insole, and the wrapper is adhesively fixed to a side and a bottom periphery region of the insole.
[0010] As yet another feature, the upper is marked for hand-sewing with Opanka stitch series for placement of awl, and the upper is pre-punched with dots for hand-sewing. The upper is hand-sewed to the sock lining unit by Opanka stitch series simultaneously stitching the finished platform to the sock lining.
[0011] In certain embodiments, the finished platform has a plurality of cavities in the underside region for reducing the weight of the platform and giving it elasticity.
[0012] In embodiments of the invention, the outsole unit is made of molded rubber and has a cavity to accommodate the finished platform and a shank cavity to fix a steel shank cavity therein.
[0013] Additionally, a sole cement is applied to a bottom surface of the finished platform and an upper surface of the outsole unit for adhesively attaching the finished platform to the outsole unit.
[0014] According to yet another aspect of the invention, a method for making footwear includes attaching an insole to a sock lining unit having a peripheral portion for seaming and stitching; providing and securing a wrapper covering an underside region of the insole; attaching the finished platform to an outsole unit; and, securing an upper to the peripheral side region of the finished platform. Moreover, the wrapper is seamed to the peripheral portion of the sock lining unit. The wrapper attached to the insole forms a finished platform which has a peripheral side region.
[0015] Embodiments may have one or more of the following advantages.
[0016] A method for making footwear using the present invention provides the benefit of having a finished platform which can readily receive an upper. This permits simple and economical attachment of the upper to a finished platform.
[0017] In other words, in the process for completing the shoe, the advantage lies in providing a method of making footwear which reduces the need for complicated machinery or highly skilled workers. Given a finished platform to which an upper can be quickly attached to, the process efficiently streamlines production and manufacturing of shoes. This eliminates the need for working with various components which may delay production for the completed shoes. Thus, the method makes a simple and cost-favorable production possible.
[0018] Another advantage is that the process of sewing the upper to a finished platform gives added resilience and resistance to all the components of the shoe, protecting them from deterioration and leading to prolonged life of the shoe. With prolonged wearing, the finished platform is less prone to deformation due to its resilience and strength.
[0019] In addition, this method of making footwear inherently enhances the overall appearance of the footwear by permitting genuine hand-sewn seams, all around the periphery of the shoe. Another advantage of this shoe is enhanced comfort provided by the cushioned layers of the finished platform, significantly reducing foot and leg muscle fatigue, as well as the fashionable style resulting from these functional components.
[0020] Thus, the upper is enhanced by hand-sewn seams all around the periphery of the shoe, giving it a finished, aesthetically superior quality. The pre-engineered apertures used for creating the hand-sewn seams ensure accuracy of seaming and wrapping locations as required for improved fitting qualities.
[0021] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.
DESCRIPTION OF DRAWINGS
[0022] [0022]FIG. 1 is a schematic side view of a footwear.
[0023] [0023]FIG. 2 is a pictorial exploded view of the components of the footwear of FIG. 1.
[0024] [0024]FIG. 3 is a bottom view of the footwear of FIG. 1.
[0025] [0025]FIG. 4 is a perspective view of the footwear of FIG. 1.
[0026] [0026]FIG. 5 is a perspective view of another embodiment.
[0027] [0027]FIG. 6 is a pictorial exploded view of the components of the footwear of FIG. 5.
[0028] [0028]FIG. 7 is a bottom view of the footwear of FIG. 5.
DETAILED DESCRIPTION
[0029] Referring now to the figures in which identical elements are numbered identically throughout, a description of the embodiments of the present invention will now be provided.
[0030] Referring to FIG. 1, a sandal-type shoe 10 includes a shoe upper 12 , an outsole unit 50 , an insole 40 , and a sock lining unit 30 .
[0031] Shoe upper 12 has a vamp that can have various types of designs and constructions. The shoe upper 12 is shown stitched to a finished platform 20 , forming the internal spacing where the wearer's foot is inserted (not shown). The upper 12 may include an opening for the toes. The shoe upper 12 is preferably made of leather and may also include an inner liner sewed to the inner surface of upper 12 which can be fabricated of materials (e.g., soft leather) selected to provide comfort to the wearer during walking. Prior to attachment to other components of the shoe 10 , the shoe at this stage, includes a sewed upper with bottom portions of the upper 12 open for attachment with a finished platform 20 .
[0032] Shoe upper 12 is similar to conventional sandal-type uppers with a side portion 13 of the upper 12 shaped to accommodate pre-punched holes around its periphery for hand-sewing. These pre-punched holes (not shown) are used, as will be described below, for attachment to a finished platform 20 in the construction of the completed shoe 10 .
[0033] Shoe upper 12 is designed such that the lower perimeter of the upper 12 will fit within the contoured perimeter of the insole 40 . The term ‘lower perimeter’ refers to the edge of the upper 12 that contacts the insole 40 in the finished platform 20 .
[0034] Outsole unit 50 is formed of molded polyurethane. In other embodiments, the outsole unit can be produced of a plastic material, for example, from a vinyl polymer, polyolefin, polystyrene, or a rubber. The outsole unit 50 provides a flexible and durable structure which resists wear. Outsole unit 50 includes a bottom walking surface 52 and an opposed surface 54 opposite to the walking surface 52 . In this embodiment, outsole unit 50 includes a separate heel portion 18 . The outsole unit 50 is preferably designed to provide the silhouette and support for the shoe 10 , which is aesthetically desirable and comfortable for the wearer.
[0035] In the present embodiment, the outsole unit 50 is secured to an outsole region 21 with heel 18 separately formed on the bottom walking surface 52 . The outsole unit 50 of the present invention has a desired thickness across its length.
[0036] The heel 18 , illustrated in FIGS. 1, 3, and 4 is attached to the insole 40 . The heel 18 includes a support base 19 to provide additional heel support, lift, and non-skidability for the wearer. Notches 17 formed on the walking surface of the support base 19 assist by providing cavities to enhance the non-skid features of the heel 18 .
[0037] Referring to FIG. 2, the insole 40 and sock lining unit 30 are described.
[0038] The insole 40 is a padded structure designed to provide cushioning and support to a wearer's foot. The insole 40 includes several layers: a molded insole 44 , a steel shank 60 , a fiber tuck 43 , and a foam insole cover 42 . Each of these layers may be used for alignment with the other layer components. The insole 40 also includes a peripheral insole region 47 and an underside region 49 for attachment to a wrapper 22 , described further below.
[0039] The molded insole 44 is formed of a rigid fiber material and is covered by a metal reinforcement steel shank 60 which is embedded within the insole 40 . The molded insole 40 extends generally from a heel portion 62 of the shoe 10 to the edge of the toe portion 61 of the shoe 10 and provides the structural rigidity to the heel portion 62 of the shoe where it is most needed. Moreover, the molded insole 44 supports the heel 18 , which is attached to the outsole unit 50 .
[0040] The insole 40 includes a foam insole cover 42 which is made of a foam cushion material with a covering of leather of suitable man-made material, in the form of a sock lining unit 30 . The foam insole cover 42 is about 3 mm in thickness. The foam insole cover 42 is cushy and covers the molded insole 44 and the steel shank 60 and is bound tightly to the molded insole 44 by an adhesive glue. Preferably, the foam insole cover 42 is shaped in conformity with the molded insole 44 , and is spaced from the stitches by about ½ inch about its periphery. When the various components of the shoe 10 are stitched together, the foam insole cover 42 is held securely at its edges by the gluing.
[0041] As constructed, the foam insole cover 42 provides enhanced wearing comfort of the shoe 10 . At the same time, it is protected from wear and from being damaged while inserting or removing the foot. Depending upon the compressability of the foam, the shoe may provide different configuration and shapes, as a softer foam is used and pressed differently in different portions of the shoe 10 .
[0042] In this embodiment, the sock lining unit 30 includes two components, a sock lining pad 32 and an inside layer made from a sock lining forepart 33 connected to a skeleton sock backpart 34 . The sock lining forepart 33 and the skeleton sock backpart 34 is formed of a polyester material and covered by the sock lining pad 32 made, e.g., of pigskin leather. As the shoe 10 is assembled, the sock lining unit 30 has an opening 37 formed by the skeleton sock backpart 34 . The opening 37 allows heel 18 to be securely attached to the insole 40 by either nails or other attachment means. In this embodiment, nails (not shown) are driven through an inner section 45 of the finished platform 20 and anchored into the fiber tuck 43 . The opening 37 is then covered by the sock lining pad 32 so that the pad 32 is in direct contact with and covers the foam insole cover 42 . Consequently, opening 37 allows more efficient cutting of the assembly materials such as those shown in FIG. 2 and the access to the inner section 45 of the finished platform 20 of the heel 18 is facilitated. The sock lining pad 32 is made of the same material as the upper 12 and wrapper 22 , thus giving a uniform, aesthetically pleasing look to the finished platform 20 . Although leather is the preferred material, different materials may be used. Additional padding layers may be added to the socklining unit 30 , as necessary or as desired.
[0043] In some embodiments, the sock lining unit 30 may be decoratively quilted to provide an aesthetically pleasing look to the interior surface of the shoe 10 . Moreover, the sock lining unit 30 includes a peripheral portion 35 for attaching to the upper 12 and the wrapper 22 described further below. This peripheral portion 35 becomes the peripheral side region 25 of the completed finished platform 20 .
[0044] Referring to FIG. 3, the underside portion 54 of the assembled shoe 10 is illustrated. The walking surface 52 has the outsole unit 50 which includes a recessed channel 51 that the contact surface of the shoe 10 . The recessed channel 51 forms a notch 41 on the outsole unit 50 . Similarly, a recessed channel 53 on the heel 18 form a notch 17 . In essence, the recessed channels 51 and 53 protect the outsole unit 50 and the heel 18 , respectively, by ensuring that the contact between the ground and these components are minimized and the shoe can be worn for prolonged duration.
[0045] The walking surface 52 further includes a wrapper 22 preferably made of the same material as the upper 12 . The qualities of the material, such as leather, should be tear resistant, or high quality stitched-in textile made of strong fiber material. The wrapper 22 includes a center seam 70 having stitches 72 on a first side 74 and a second side 76 of the center seam 70 . As will be described in greater detail below, the wrapper 22 functions as a bottom cover 80 for the finished platform 20 , which is secured to the underside region 49 of the insole 40 . The bottom cover 80 covers the underside region 49 thereby forming the underside portion 54 of the shoe 10 . Specifically, the center seam 70 serves to secure the wrapper 22 to the insole 40 of the shoe 10 . FIG. 4 provides a perspective view better illustrating the stitches 72 on the first side 74 of the center seam 70 and the other components of the underside portion 54 of shoe 10 . It can be seen that the bottom cover 80 has a shank area 23 for joining the bottom cover 23 .
[0046] The construction method of this embodiment will now be described in conjunction with the figures.
[0047] In preparation for constructing shoe 10 , the upper 12 is cut, stitched and finished. The various components of the insole 40 are adhesively secured together. Namely, the molded insole 44 is adhesively combined with the steel shank 60 and the fiber tuck 43 in a compact fashion, securely attaching all surfaces of the these components to form a tight, well-formed insole 40 . The molded insole 40 can be molded to different shapes depending on a desired heel height.
[0048] The bottom cover 80 will be marked for outsole location, and thereafter folded at the center seam 70 to be seamed and stitched. The bottom cover 23 is seamed and stitched in the shank area 23 by stitches 72 . The outsole unit 50 is then cemented and joined by stitches 59 securely attaching the outsole unit 50 to the leather bottom cover 80 .
[0049] The bottom cover 80 is placed adhesively against the underside region 49 of the insole 40 , ensuring proper alignment with the insole 40 . Excess material from the bottom cover 80 is marked and trimmed so that the peripheral insole region 47 is covered adequately by the bottom cover 80 . The bottom cover 80 also serves as a “wrapping strip” in a manner that permits the strip to be wrapped, or sidelasted, onto the insole 40 . The fitting qualities are engineered into the attachment of the bottom cover 80 “wrapping strip” to the peripheral sides of the insole 40 and are dependent upon accurate stitching of this “wrapping strip” to the peripheral insole region 47 of the insole 40 .
[0050] Finally, the finished platform 20 is constructed by attaching the sock forepart 33 and the skeleton sock backpart 34 of the sock lining unit 30 to the insole 40 . The sock forepart 33 and the skeleton sock backpart 34 are adhesively placed onto the foam insole cover 42 . The sock lining pad 32 may be adhesively placed over the opening 37 of the insole 40 either at this point of the construction process or after the finished platform has been secured to the outsole unit 50 . Because shoe 10 can be made more comfortable by providing as many layers of cushion or foam inserts as desired, sock lining pad 32 is inserted into the finished platform 20 so as to be disposed between the finished platform and the foot of the wearer. So that the sock lining pad 32 does not dislodge, tear or bend when inserting or removing the foot from the shoe, adhesive gluing or other secure means for attachment must be accurately performed.
[0051] To form the shoe 10 , the upper 12 is now hand-sewn using pre-punched holes in the upper 12 and the peripheral portion 35 of the sock lining unit 30 thereby attaching it to the finished platform 20 . The stitching used is an Opanka stitch series. In certain embodiments, the stitching or seaming is done by passing a thread or other suitable means through pre-punched holes, forming a criss-cross stitch pattern. The stitching continues along the entire peripheral side region 25 of the finished platform, joining the upper 12 to the sock lining unit 30 and the wrapper 22 . The joining of these components by stitching creates a one-piece “cavity”, the internal spacing of the shoe 10 , which is comfortable on the foot.
[0052] The heel 18 is secured and nailed to the heel region 62 of the insole 40 covered with the bottom cover 80 . Finally, the sock lining pad 32 can be inserted now or before forming the finished platform 20 , over into internal spacing of the shoe 10 created by the upper 12 within which the wearer's foot is to be inserted. The completed shoe is shown in FIGS. 1 and 4.
[0053] In a further embodiment as shown in FIGS. 5 - 7 , a finished platform 20 is provided which does not have a bottom cover 80 . As illustrated in FIG. 5, the shoe 10 includes a shoe upper 12 , an outsole unit 50 , an insole 40 , and a sock lining unit 30 .
[0054] The shoe upper 12 , preferably made from leather, may have a vamp of various types and styles such as closed toe or open toe designs. The shoe upper 12 is attached to the insole 40 , forming what will be the internal spacing of the shoe. Shoe upper 12 may also include an inner liner sewed to the inner surface of upper 12 which can be fabricated of materials (e.g., soft leather) selected to provide comfort to the wearer during walking, in the same manner as described in connection with the previous embodiment.
[0055] Shoe upper 12 is similar to conventional sandal-type uppers with a side portion 13 of the upper shaped to accommodate pre-punched holes around its periphery for hand-sewing. These pre-punched holes (not shown) are used, as will be shown later, for attachment to a finished platform 20 in the construction of the shoe 10 .
[0056] Outsole unit 50 is formed of molded polyurethane. Outsole unit 50 includes a bottom walking surface 52 and an opposed surface 54 opposite to the walking surface 52 which attaches to the insole 40 . The outsole unit 50 provides a flexible and durable structure which resists wear.
[0057] In this embodiment, the outsole unit 50 may be formed by a one-piece molded outsole integrated with a heel 18 , thereby simplifying the manufacturing process of the shoe. The outsole unit has a desired thickness across its length and includes an integrally molded, upstanding sidewall 57 extending around its periphery.
[0058] The opposed surface 54 of the outsole unit 50 is provided with an outsole cavity 55 and the open cells 56 for bonding with the underside region 49 of the insole 40 , and an additional cavity 71 to accommodate the steel shank 60 (not shown). In general, this means that the outsole unit 50 in the form of the outsole cavity 55 and the open cells 56 provides sufficient structural integrity to support the wearer's weight without being crushed, while providing a reduced amount of material compared with a completely filled supporting outsole unit structure.
[0059] The outsole cavity 55 has a depth ranging from about 2 mm to about 4 mm. The outsole cavity 55 is slightly larger than the size of the insole 40 to provide a peripheral fit for adhesively securing and bonding the insole 40 to the opposed surface 54 of outsole cavity 55 .
[0060] The heel 18 includes a support base 19 to provide additional heel support, lift, and non-skidability for the wearer, in the same manner as described in connection with the previous embodiment.
[0061] Referring to FIG. 6, the insole 40 and sock lining unit 30 are described.
[0062] The insole 40 for this embodiment has a simplified construction. It includes a molded insole 44 and a foam insole cover 42 of about 3 mm in thickness. Each of these layers may be used for alignment with the other layer. The insole 40 may also include a platform in lieu of the molded insole 44 . The molded insole 44 is then covered with foam insole cover 42 . The insole 40 also includes a peripheral insole region 47 and an underside region 49 for attachment to the outsole unit 50 and the wrapper 22 .
[0063] The molded insole 44 is formed of a flexible rubber material, extending generally from the heel portion 62 of the shoe 10 to the edge of the toe portion 61 and the molded insole 44 provides a flexible structure for the shoe 10 .
[0064] The insole 40 further includes a foam insole cover 42 made of a foam cushion material with a covering of leather of suitable man-made material, in the form of the sock lining unit 30 . The molded insole 44 includes a cavity 63 to accommodate the foam insole cover 42 . The foam insole cover 42 is cushy and covers the molded insole 44 . Preferably, the foam insole cover 42 is approximately ⅜″ thick and is attached securely within the cavity 63 of the molded insole 44 by gluing. Depending upon the compressability of the foam insole cover 42 , the shoe 10 may provide different configuration and shapes, as a softer foam is used and pressed differently in different portion of the shoe 10 .
[0065] In this embodiment, the sock lining unit 30 includes only one component, a sock lining 32 . The sock lining 32 may be made from one piece of any suitable material or it can be made from composite parts. The sock lining 32 may be decoratively quilted to provide an aesthetically pleasing look to the interior surface of the shoe. The sock lining 32 , as well as the upper 12 , may be provided with corresponding or matching surface ornamentation in order to impart to these components a coordinated appearance or stitching pattern.
[0066] Moreover, the sock lining unit 30 includes a peripheral portion 35 for attaching to the upper 12 and the wrapper 22 , described further below. This peripheral portion 35 becomes the peripheral side region 25 of the completed finished platform 20 .
[0067] Referring to FIG. 7, the underside portion 49 of the insole 40 is illustrated. The underside region 49 includes a strip of the wrapper 22 folded over the underside portion 49 and seamed or adhesively glued to the peripheral edge 47 of the underside portion 49 . The strip of wrapper 22 is preferably made of the same material as the upper 12 such as leather, but any suitable material for the strip is appropriate. As desired, the wrapper 22 may be a connecting endless ring-like strip, especially in an embodiment such as that shown in FIGS. 5 - 7 rather than a strip of wrap with a finite length.
[0068] The underside region 49 of the insole 40 further includes cavities 48 having a honeycomb construction. These cavities reduce the weight and provide added elasticity to the finished platform 20 .
[0069] A construction method for making this embodiment will now be described in conjunction with FIGS. 5 - 7 .
[0070] In preparation for constructing shoe 10 , the upper 12 is prepared as usual. The upper 12 may also include an opening for the toes as in the previous embodiment. The upper 12 is marked with pre-punched holes (not shown) for hand-sewing with Opanka stitch series of dots for placement of awl. The components of the insole 40 are adhesively secured together. Namely, the molded insole 44 is adhesively combined with the foam insole cover 42 , securely attaching them to form a tight, well-formed insole 40 . The molded insole 40 may also be formed to different shapes depending on the desired heel height. In this embodiment, the stitching is done by passing a thread through the pre-punched holes, forming a criss-cross stitch pattern.
[0071] The sock lining 32 of the sock lining unit 30 is thereafter cut in order to be placed above the foam insole cover 42 . The peripheral portion 35 of the sockining unit 30 is marked with a series of dots for placement of awl or pre-punched holes may be formed for eventual hand-sewing in Opanka stitch series.
[0072] Foam insole cover 42 is attached adhesively onto the cavity 57 of the insole 40 . Wrapper 22 is seamed with the peripheral portion 35 of the sock lining 32 , along the entire periphery of the sock lining 32 . In other words, the stitching continues along the entire peripheral side region 25 of the finished platform. This is achieved by forming a closing seam (not shown) joining the wrapper 22 to the sock lining unit 30 by placing the components to be seamed face to face and stitching close to the edge, which then results in a hidden seam. The closing seams can be performed by a sewing machine.
[0073] Consequently, a cavity is formed by joining the sock lining unit 30 and the wrap 22 for placement of the insole 40 . The insole 40 is placed within the cavity, with the wrapper 22 adhesively fixed to the side 63 and peripheral edge 47 of the underside portion 49 .
[0074] In other words, the wrapper 22 extends downwardly from the point of its attachment at the side of the insole 40 and is lasted into the underside region 49 of the insole 40 . Thus, the peripheral edge 47 of the wrap 22 terminates at a point before covering the honeycomb cavity 48 . In effect, this enables manufacture of the finished platform 20 with a minimum quantity of leather and thereby reduces the material cost of the shoe.
[0075] Moreover, the strip of wrap 22 becomes almost like an extension of the sock lining unit 30 in that it serves to anchor and hold the finished platform 20 together.
[0076] Once so bonded to the insole 40 , the wrap 22 is sealed securely against the penetration of moisture and is guarded against scruffing and side blows imparted to the shoe 10 .
[0077] Next, the peripheral edge 47 of the wrap 22 (FIG. 7) may be roughed in order to remove the leather finish of the wrapper 22 and to allow sole cement to penetrate the wrapper leather. The finished platform 20 is now completed for this embodiment.
[0078] The upper 12 is now attached to the finished platform 20 , by hand-sewing the upper 12 using pre-punched holes, to the peripheral portion 35 of the sock lining unit 30 and attaching the upper 12 to the finished platform 20 with Opanka stitch series.
[0079] To complete the shoe 10 , sole cement is applied to the honeycomb cavities 48 in the underside region 49 of the insole 40 . For secure and tight bonding, sole cement is also applied in the outsole cavity 55 , including the additional cavity 71 to accommodate the steel shank 60 . This additional sole cement ensures adequate bonding of the insole 40 into the cavity 55 of the outsole unit 50 . For this purpose, a last (not shown) is then inserted into the resulting one-piece finished platform 20 and the outsole unit 10 is pressed to form the secure bond. The lasting is accomplished by slipping a last into the internal spacing where the wearer's foot is inserted. The last is used as leverage so that the outsole unit 50 can be pressed to the finished platform 20 thus completing the construction of the shoe 10 .
[0080] Although the invention, preferably relates to casual sandals, other fields of application are entirely within the scope of the invention, especially in the broad sector of footwear manufacturing. Thus, a number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims. | A method for making footwear using a finished platform. The method includes providing a finished platform having a peripheral side region; providing an outsole unit; and providing an upper attached to the peripheral side region of the finished platform. The finished platform includes an insole, a sock lining unit, having a peripheral portion for seaming and stitching, which is attached to an upper surface of the insole, and a wrapper covering the peripheral side region of the finished platform, the wrapper seamed to the peripheral portion of the sock lining unit. The present method provides the advantage of having a finished platform which can readily receive an upper. This allows a simple and economical attachment of the upper to a finished platform, efficiently streamlining manufacturing and production of completed shoes, making a simple and cost-favorable shoe production possible. | 0 |
RELATED APPLICATIONS
The present application is a divisional application of U.S. application Ser. No. 11/578,159 filed Oct. 10, 2006 now abandoned, which is a 371 of PCT/SE2005/000596 filed Apr. 22, 2005.
FIELD OF THE INVENTION
The present invention relates to new anthracycline derivatives and their use in cancer therapy and cancer diagnosis.
BACKGROUND
Doxorubicin (C 27 H 29 NO 11 ; MW: 543.53), abbreviated as DOX, also known among other names as adriamycin, or adriablastine is an antibiotic and antineoplastic agent of the anthracycline family (see structure below). DOX was originally isolated from the aquatic bacterium Streptomyces peucetius var. coesius and since the early 1970s, anthracyclines, in particular doxorubicin and daunorubicin, and alkylating agents (cyclophosphamide, melphalan, etc.) are the most versatile and most frequently used chemotherapeutic agents in the clinic today [1]. Anthracyclines are amphipathic molecules consisting of a hydrophobic aglycone heterocycle with a quinone-hydrochinone functional group and a hydrophilic aminosugar moiety [2, 3].
Chemical Structure of Daunorubicin and Doxorubicin
Doxorubicin is used extensively in the treatment of bone and soft tissue sarcomas and carcinomas of the lung, breast, thyroid, bladder, ovary, testis, head, and neck [1, 4]. Doxorubicin is also used against leukemias and lymphomas but daunorubicin is the primarily treatment against acute leukemias. The overall response rates for doxorubicin is 45% for thyroid cancer, 41% for lymphomas, 33% for bladder carcinomas, 26% for sarcomas, 25% for ovarian carcinomas, 24% for leukemias [5].
Doxorubicin has multiple mechanisms of action but the main anti-tumour activity of doxorubicin and other anthracyclines stems from their ability to intercalate with DNA resulting in blockade of DNA-, RNA- and protein-synthesis. Anthracyclines also inhibit topoisomerase II and impair DNA repair [1, 5]. Because of their quinone-hydroquinone functional group, anthracyclines are thought to be involved in the generation of free radicals leading to DNA damage [2]. Anthracyclines bind specifically to cardiolipin, a phospholipid found in high concentrations in cardiac mitochondria and membranes of malignant cells, which may explain cardiotoxic side effects of doxorubicin [1]. Anthracyclines have narrow therapeutic indices, i.e. the administered dose has to be within narrow limits, since the drug has no effect if the dosage is too small and severe side effects can result if the dosage is too large. The acute dose-limiting toxicity of doxorubicin is bone-marrow suppression, leukopenia, and stomatitis occurring in 80% of treated patients. Other side effects include alopecia (100%), nausea and vomiting (20-55%), cardiac toxicity, i.e. supraventricular arrhythmias, heart block, ventricular tachycardia and even congestive heart failure in 1-10% of patients.
Previously, anthracycline derivatives have been disclosed by e.g. Pribe (2003) Chemico-Biological Interactions 145:349-358, U.S. Pat. No. 4,948,880, U.S. Pat. No. 6,673,907, and WO00/56267. These derivatives have cytotoxic effect in cancer treatment.
Radionuclide therapy has a relatively small but important role in cancer therapy and is currently gaining increasing attention. Radionuclide therapy implements nuclear radiation to eradicate malignant cells. The radiation can be generated by stable nuclides e.g. 10 B and 157 Gd following neutron activation or by radioactive nuclides. The most commonly used therapeutic radionuclide especially against thyroid cancer is the intermediate-range (800 μm) β-emitter, 131 I, but administration of 131 I causes considerable radiation damage in healthy tissue [6]. However, due to these side effects the therapeutic potential of short-range, low-energy Auger electron emitters, such as 125 I, is getting progressively wider recognition. In order for it to be effective in anticancer treatment, 125 I has to be delivered directly and selectively into tumour cell nuclei since 125 I is not toxic unless it is within a few nanometers from the DNA [7]. 125 I therapy thus requires a method of specific nuclear delivery, which has previously been achieved using 125 I-labelled nucleosides, oligonucleotides, steroid hormones and growth factors but a need for improvement has been recognized [7].
Murali D. and DeJesus. O, Bioorganic & Medicinal Chemistry letters 8 (1998) 3419-3422, describes a radiolabelled daunorubicin derivative having improved cytotoxic properties compared to doxorubicin. No results are presented in the article, and no continuation of this work has been published.
Targeted drug delivery via liposomes minimizes the dose-limiting side effects of conventional cancer chemotherapy such as bone marrow suppression, mucositis, cardiac-, neuro-, and nephro-toxicity [1] by encapsulating the cytotoxic agent into membrane bound vesicles (liposomes) and coupling tumour-specific antibodies to the liposome membrane (targeted liposomes). Targeted liposomes in the blood are actively and selectively taken up by tumour cells overexpressing the targeted surface marker. However, despite some progress, this strategy has so far not resulted in a major improvement in chemotherapy [8]. Thus, there is a great need for more potent therapeutic agents and treatment strategies.
SUMMARY OF THE INVENTION
The present invention relates to diagnostic and therapeutic agents possessing DNA-intercalating properties and to which nuclides can be coupled. The present invention further relates to drug delivery systems for these diagnostic or therapeutic agents and therapeutic and diagnostic methods using said agents or drug delivery systems. The present invention is intended for cancer diagnostics and therapy. The aim of the present invention is to deliver a nuclide specifically into tumour cell nuclei and thus to combine the benefits of radionuclide therapy, chemotherapy, and targeted liposomal drug delivery in a single two-step targeting approach that minimizes cytotoxic side effects in healthy tissue. Thus, the present invention provides a new therapeutic strategy with novel drugs, which are potentially more potent than previously known chemotherapeutic drugs.
Anthracyclines are potent anticancer drugs by themselves. In the present application, the inventors have synthesized amino-benzyl derivatives of daunorubicin (drug precursors), which have similar cytotoxicity profiles as the commercially successful anthracyclines doxorubicin and daunorubicin. When the present inventors iodinated the drug precursors with 125 I, they obtained radiotherapeutic agents being more effective against cultured tumor cells, To protect healthy tissue and to deliver the radionuclide selectively into malignant cancer cells, the 125 I-coupled daunorubicin derivatives can be encapsulated into targeted liposomes, which serve as specific drug delivery vehicles for tumor cells.
The results of the experiments described herein confirm that the therapeutic agents according to the present invention can successfully be encapsulated into targeted liposomes, and that the drugs are well retained under the experimental preparation and assay conditions. After incubation with tumour cells, the above-mentioned agents reach and bind to the cell nucleus with a similar affinity as that of doxorubicin. When bound to DNA, the radiotherapeutic agent causes DNA fragmentation, leading to a tumour cell growth inhibition of several orders of magnitudes higher than that caused by doxorubicin and daunorubicin, two of the most successful chemotherapeutic agents in the clinic today.
None of the drugs precursors or radiotherapeutic drugs according to the present invention have previously been described in the prior art.
According to one aspect of the invention, there is provided anthracycline derivatives that serve as precursor molecules for the radiotherapeutic agents, and which will henceforth be referred to as drug precursors. The drug precursors intercalate with DNA and possess cytostatic properties. The drug precursors can thus be used in cell- or tissue-targeted cancer therapy by themselves. The anthracycline derivatives (drug precursors) are disclosed herein.
According to a further aspect of the invention, there is provided radiotherapeutic drugs that can be used in cell- or tissue-targeted radiotherapy. The radiotherapeutic agents are generated from their precursors by linking the drug precursors to a nuclide or a chemical group containing a nuclide. Such a nuclide may be a radioactive nuclide, a stable nuclide, or a nuclide that can be activated by exposure to neutrons or photons, e.g. 10 B (as part of a boron-rich cage-compound derivative such as the closo-carboranes o-, m- or p-C 2 H 12 B 10 ) and will henceforth be referred to as nuclides. The radiotherapeutic drugs are disclosed herein.
According to a still further aspect of the invention, the radiotherapeutic drug may also be used as an imaging tool for cancer diagnostics. The use as an imaging tool is disclosed herein.
According to a still further aspect of the invention, the drug precursor or radiotherapy drug may also be used as a DNA targeting agent, i.e. as a DNA-interacting agent as disclosed herein.
According to a still further aspect of the invention, there is also provided drug delivery systems. Said system preferably comprises a carrier capable of encapsulating the drug precursors or radiotherapeutic drugs (possessing DNA-interacting properties) and guide drugs specifically or preferentially to the targeted cell population. Consequently, cell- and tissue-damaging effects will affect preferentially targeted cells and tissues. Such drug delivery systems may involve single- or multiple-step targeting strategies. The DNA-intercalating properties of the drug precursors are the basis of the DNA-targeting step that directs their cytotoxic effects to the nucleus or, when the nuclide is coupled to the drug precursor, localizes the radioactivity emitted from the nuclide to the cell nucleus. This targeting step, which will henceforth be referred to as the DNA-targeting step, thus dramatically increases the therapeutic effect of the radiotherapeutic drugs and reduces damage to healthy cells and tissues.
To differentiate between malignant and healthy tissue, the radiotherapeutic drugs are directed towards cancer cells or tissues using a drug delivery system that exhibits a tumour-cell specific targeting agent at its surface as a cell-targeting step in a two-step targeting strategy, which will henceforth be referred to as the cell-targeting step. The drug carrier is capable of enclosing or binding the radiotherapy drug and directing its transport after systemic administration to and preferably across membranes of targeted cells. The cytotoxic and/or radiotoxic effect of the radiotherapeutic drugs will consequently be localized to the targeted cell population. The drug delivery system is disclosed herein.
According to a still further aspect of the invention, there is also provided a method of diagnosing or treating cancer, comprising administering said drug delivery systems including the precursor drug or radiotherapeutic drug to a patient in need thereof. In addition to its use as a treatment against solid tumours, the invention is also envisioned as a treatment against metastasizing tumour cells in systemic circulation after removal of the primary tumour. The treatment could be particularly beneficial against disseminated breast cancer, but also against disseminated ovarian, prostate and colorectal cancers.
Said therapeutic methods may also be used in combination with subsequent tumour radiation when the location of the tumour is known. Local radiotherapy can be achieved by using stable nuclides and activation by external irradiation with neutrons or photons.
The invention could also be an effective treatment against multi-drug resistant (MDR) tumours overexpressing P-glycoprotein (PGP), a membrane-bound efflux pump for xenobiotics. The radiotherapeutic drugs would in this case target and radiodamage P-glycoprotein, which is known to bind to anthracyclines. The therapeutic methods are disclosed herein.
DESCRIPTION OF THE DRAWINGS
FIG. 1 : Retention of doxorubicin in buffer or medium and Compound 1 in buffer at a temperature of 37° C.
FIG. 2 : Cryo-transmission microscopy image of liposomes loaded with Compound 1. The spheres represent liposomes and the spots inside the liposomes represent crystalline Compound 1.
FIG. 3 : Autoradiography of 125 I-Compound 1 after 1 h of incubation at 37° C. with tumour cells.
FIG. 4 : Binding of 125 I-Compound 1 to free DNA after 2.5 h incubation on ice.
FIG. 5 : DNA fragmentation after 125 I-Compound 1-binding in an agarose gel loaded with plugs containing U-343MGaCl2:6 glioma cell DNA. In the figure, a) represents molecular weight marker ( Scizosaccharomyces pombe , Megabase DNA standard), b) DNA incubated with 125 I-Compound 1, c) DNA incubated with 125 I-Compound 1 and excess of doxorubicin, and d) controls with DNA incubated without 125 I-Compound 1.
FIG. 6 : Growth curves of tumour cells treated with 0.5 ng/ml of doxorubicin, daunorubicin, Compound 1, or 125 I-Compound 1.
DETAILED DESCRIPTION OF THE INVENTION
Drug derivatives described herein are intended for use as cancer therapeutics in the form of drug precursors or coupled to a nuclide as potent radiotherapeutic anti-cancer drugs or diagnostic imaging tools.
Their usefulness might however be compromised by their indiscriminate cytotoxicity to healthy tissue. This problem will be minimized by encapsulating drugs into liposomes, or alternative drug carriers, and selectively targeting the tumour cells by attaching tumour-specific targeting agents to the surface of liposomes or alternative drug carriers. Thus, the drug precursors or radiotherapeutic drugs are intended for use in combination with a two-step targeted drug delivery system as disclosed in U.S. Pat. No. 6,562,316. Such a drug delivery system comprises a carrier coupled to cell-targeting agent(s) to direct the drug delivery system in the cell-targeting step specifically to the targeted cell population or tissue. In the DNA-targeting step, encapsulated nuclides will be directed to the cell nucleus by their link to a molecule with DNA intercalating properties. The herein described drug precursors or radiotherapeutic drugs will serve as such DNA-targeting agents possessing DNA-intercalating properties.
The described two-step targeting system will minimize the cytotoxicity of nuclides, the drug precursors or radiotherapeutic drugs in healthy tissue. A further advantage of the two-step targeting system is that it has the potential for treatment of metastasized and/or multi-drug resistant tumour cells.
The drug carrier might be a molecule, an aggregate, or a particle able to bind or enclose pharmaceutically active agents, i.e. drug precursors or radiotherapeutic drugs. Liposomes are currently the preferred drug carriers, but polymeric drug carriers such as micro-gels, or lipid/polymer composite particles may be equally or better suited for certain applications.
The targeting agents for the cell-targeting step of the two-step targeting strategy bind selectively and with high affinity to the tumour cells. Ideally, tumour-specific targets are molecules that exist exclusively on tumour cell surfaces. However, a general tumour-specific cell marker that is present in all cancer cells but absent in normal cells has yet to be found and the similarities between the tumour cells and normal cells are by far outnumbered by their differences. There are, however a number of cell surface markers overexpressed specifically in certain tumour cells. EGF (epidermal growth factor) receptors are, for example, overexpressed in tumour cells of the brain, bladder, breast, and lung as compared to normal cells. EGF receptors in tumours can thus be targeted to attain high selectivity for EGF-conjugated radionuclides or stable nuclides. Monoclonal antibodies against target tumour cells have also been demonstrated to be effective for tumour-targeting.
The agent for the cell-targeting step is thus preferably chosen from a group comprising ligands, antibodies, or antibody fragments, and may also comprise epidermal growth factor (EGF) or a molecule that binds to a tumour-specific mutated EGF receptor.
The liposomal drug delivery system, the first-step targeting agent, and their respective preparations are described in the above-mentioned U.S. Pat. No. 6,562,316. The preparation of polymeric carriers or lipid/polymer carriers are not disclosed in present patent, but the person skilled in the art will easily obtain relevant preparation protocols from the literature.
Drug Precursors (DNA-Targeting Agent)
Anthracycline derivatives (drug precursors) used as DNA-targeting agents should possess DNA-interacting properties or electrostatic binding properties. DNA-intercalators are particularly suitable as DNA-targeting agents since intercalation of the molecule with DNA results by itself in therapeutic activity.
The general formula (I) of anthracycline derivatives according to the present invention is the following:
wherein:
R is either a double-bound oxygen atom, a hydroxyl group in both stereoisomeric forms, or
R 1 is either CH 3 , CH 2 OH,
R 2 is a Y—Ar—Z group, wherein:
Y is either a spacer molecule, such as —(CH 2 ) n — or a polyethylene glycol chain having the formula —(CH 2 CH 2 O) n —, where n is 1-8; Ar is a conventional monocyclic aromatic group or stable aromatic boron cage compound, where the conventional aromatic residues comprise a substituent (such as a hydrogen atom) capable of being directly radiolabelled using electrophilic aromatic substitution or an activating group (e.g. a trialkylstannyl group such as a trimethylstannyl or tributylstannyl group), which can be exchanged for a radionuclide or which comprises a halogen (e.g. Br or I) such that the aromatic residue can undergo halogen-halogen exchange reactions; and Z is optionally a chemical group that increases the hydrophilicity, such as a sugar group;
and salts thereof.
Examples of salts are salts like hydrochloride, hydrobromide, formates and other carboxylates.
The conventional monocyclic aromatic group is preferably a phenyl or pyridine group, and the stable aromatic boron cage compound is preferably a stable closo-carborane, such as C 2 H 12 B 10 .
The present invention relates to stereoisomeric mixtures of said drug precursors (on which the radiotherapeutic drugs are based), as well as to the separate stereoisomers.
The agent for the DNA-targeting step must:
possess high affinity for the nuclear DNA,
possess properties that permit efficient loading into the carrier,
show minimal leakage (or release) at physiological pH and ionic strength when enclosed in (or bound to) the carrier,
possess properties that, following release from the carrier, enables the agent to reach and bind to nuclear DNA.
The drug precursors and radiotherapeutic drug according to the present invention exhibit these features.
Specific examples of the drug precursors are given below:
Synthesis of the Drug Precursors
The synthesis of the drug precursors follows standard procedures and can be performed by any person skilled in the art. The synthesis of the drug precursors is not part of the intended scope of protection.
Radiotherapeutic Drugs
When using the radiotherapeutic drugs according to the present invention, i.e. the drug precursors coupled to a nuclide, large amounts of nuclides will be delivered to the tumour cells and these nuclides will reach and bind to the nuclear DNA. Each radioactive decay will result in nuclear DNA damage. Thus, the radiotherapeutic drugs will be more potent than their drug precursors at the same concentration. The amount of DNA damage will be at least ten times higher when the radioactive nuclide is localized inside the cell nucleus as compared to the situation when the radioactive nuclide is outside the cell nucleus. Delivery of large amounts of radioactive nuclides to tumour cells may therefore expand the range of treatment from palliative to curative. If conventional cellular one-step (without the DNA-intercalation) targeting strategies are used only palliative treatments appear possible.
Every radionuclide has a distinct set of properties such as half-life, and type of emitted radiation. The invention allows to selectively choose the appropriate nuclide for the specific type of cancer or the specific clinical problem. The physical half-life of the chosen radionuclide has to be matched with the biological half-life of the drug precursor. It is therefore important that the emission characteristics of the radionuclide match the size and location of the particular tumour. High-energy beta emitters, such as 90 Y, may be suitable for the treatment of large tumours. Other nuclides, such as 131 I, emit low-energy beta particles and possess consequently a shorter range of radiation, which make them more suitable for smaller tumours or even single tumour cells. Auger electron emitters, such as 125 I and 123 I, emit particles that travel only about 1-2 μm and hence have to be located inside the cancer cell nucleus to cause DNA damage. The ranges of alpha particle emitters are typically between 50 and 70 μm and cause local deposition of a large amount of energy.
Radiohalogens have a wide range of physical half-lives and types of emitted radiation, which widens their range of application. The beta emitter, 131 I is one of the most commonly used radionuclides in nuclide therapy. Positron emitting radiohalogens, such as 18 F, 76 Br, and 124 I, can be used for diagnostic purposes in positron emission tomography (PET). They allow for radiation dosimetry of tissues and for monitoring changes of tumour volume via PET scans.
The radiohalogen 211 At has a relatively short half-life (7.2 hours) and decays by α-particle emission. It is extremely cytotoxic and could therefore be an effective therapeutic agent if delivered specifically to the targeted cell population.
Auger electron emitters kill cells effectively when incorporated in the cell nucleus. 125 I (half-life 60 days), 123 I (half-life, 13.2 hours), and 77 Br (half-life 56 hours) decay by electron capture followed by emission of Auger electrons. The radiotherapeutic drugs discussed in the present patent application are especially well suited for coupling to 125 I. 125 I is relatively inexpensive, widely commercially available, and its relatively long half-life is appropriate for in vitro applications. 123 I might also be an attractive candidate for therapeutic use because of its short physical half-life and especially since it also emits γ-radiation in addition to Auger electrons, which allows for imaging.
Radionuclides with a short radiation range, 125 I (Auger radiation) and 211 At (alpha-particles) generate high local ionization densities and seem at present to be best suited for targeting single cells and will cause minimal damage to surrounding healthy cells or tissues.
Radiotherapeutic drugs may include stable nuclides, which can be activated by neutrons or photons. The stable nuclide 10 B is not cytotoxic. However, if a 10 B-enriched compound is selectively localized in tumour cells, cells can then externally be irradiated with non-toxic low-energy neutrons. These neutrons are captured by 10 B atoms generating excited-state 11 B atoms, which instantaneously disintegrates into two highly cytotoxic particles, α-particles and 7 Li 3+ ions. The range of these ions in tissue is approximately 9 and 5 μm, respectively, which is close to one cell diameter. 157 Gd can also be subjected to neutron activation. Other alternatives are stable iodine or bromine isotopes, which can be activated by photons. In addition, these isotopes can be combined with long-range β-emitting radionuclides, i.e. 131 I, 32 P, 67 Cu, 90 Y or 189 Re producing cross-fire radiation suited for larger tumour cell aggregates. These neutron- or photon-activated nuclides can for example be stabilized using closed carboranes, i.e. boron rich cage-compounds such as the closo-carboranes o-, m- or p-C 2 H 12 B 10 .
The radioactive nuclide in the radiotherapeutic drugs described in the present patent application is preferably 123-125 I, 131 I, 18 F, 76-77 Br, 211 A, 90 Y, 32 P, 67 Cu, or 189 Re, and 125 I is particularly preferred, and the stable nuclide is preferably 10 B and 157 Gd.
Radiolabeling of the Drug Precursors
All drug precursors for radioiodination contain an aromatic residue and are labeled with 125 I using conventional methods such as the chloramine-T method. Radiolabeling was performed either by direct electrophilic substitution of an aromatic ring or by replacement of an activating group, such as a trialkylstannyl, e.g. a trimethylstannyl or tributylstannyl group, in the aromatic ring. These methods follow standard procedures and can be performed by any person skilled in the art.
EXAMPLES
To test if the drug precursors or radiotherapeutic drugs according to the present invention could be used in a drug delivery system, the following experiments were performed.
Example 1
Drug Retention in Liposomes
Preparation of Liposomes
Liposomes were composed of 1,2-distearoyl-sn-glycero-3-phosphatidyl-choline (DSPC), cholesterol, 1,2-distearoyl-sn-glycero-3-phosphatidyl-ethanolamine-N-[methoxy (poly-ethyleneglycol)-2000 (DSPE-PEG 2000 ) at a molar ratio of 57:40:3. Liposomes were prepared by the lipid film hydration method [9]. Briefly, cholesterol and lipids were dissolved in chloroform. The solvent was evaporated under a gentle stream of nitrogen gas and the lipid film was dried under vacuum overnight. The lipid film was hydrated with 300 mM citrate buffer (pH 4) for 1 h with intermediate vortex mixing at a lipid concentration of 20 mM at a temperature of 60° C. Liposomes were repetitively frozen in liquid nitrogen and thawed at a temperature of 60° C. five times before extrusion. Liposomes were extruded ten times through two stacked polycarbonate membranes filters (Whatman Inc. Nucleopore, Newton, Mass.) with a pore size of 100 nm at a room temperature using an Avanti Mini-extruder (Avanti Polar Lipids Inc., Alabaster, Ala.).
Drug Encapsulation
Compound 1 (3′-N-(4-hydroxy-3-iodobenzyl)-13-(R/S)-dihydrodaunorubicin, stereoisomeric mixture) and Compound 2 (3′-N-(4-Hydroxy-3-iodobenzyl)daunorubicin), structures are shown below, or doxorubicin (Sigma Aldrich, St. Louis, Mo., USA) were encapsulated into liposomes using the pH-gradient driven loading protocol by Mayer et al. The pH gradient across the liposome membrane was generated by exchanging the extravesicular 300 mM citrate buffer (pH 4) with 20 mM N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid] (HEPES) buffered 150 mM saline (HBS) (pH 7.5) on a Sephadex G-50 column. Doxorubicin was dissolved in HBS at a concentration of 1 mM. Compound 1 was dissolved at a concentration of 0.5 mM in 10% (wt/vol) sucrose solution. Compound 2 did not dissolve completely at a concentration of 0.5 mM in 10% (wt/vol) sucrose solution but dissolved when liposomes were added and drug was encapsulated into liposomes. A preheated drug solution was added to the liposomes at a 0.2 drug-to-lipid molar ratio. The mixture was incubated for 15 min at a temperature of 60° C. with intermittent mixing using a Vortex-apparatus resulting in 100% drug encapsulation.
Chemical Structures of Compounds 1 and 2
Attachment of the Targeting Ligand Trastuzumab to Drug-Loaded Liposomes
a) Conjugation of 125 I-Trastuzumab to DSPE-PEG 3400
The N-hydroxysuccinimidyl ester of 1,2-distearoyl-sn-glycero-3-phosphatidyl-ethanolamine-N-[methoxy (polyethyleneglycol)-3400 (NHS-DSPE-PEG 3400 ) was hydrated with 125 I-trastuzumab solution at molar ratio of 0.1:6 at a temperature of 60° C. for 5 min Radiolabeled trastuzumab was used to trace liposomes. The concentration of NHS-DSPE-PEG 3400 was at approximately 0.2 mM. The mixture was incubated for 1 h at room temperature with stirring. Unbound trastuzumab was removed from 125 I-trastuzumab-DSPE-PEG 3400 by gel filtration on a Sephacryl S-300 column with HBS (pH 7.4).
b) Transfer of 125 I-trastuzumab-DSPE-PEG 3400 to Liposomes
125 I-trastuzumab-DSPE-PEG 3400 was mixed with drug-loaded liposomes at a 1:33 molar ratio and a temperature of 60° C. for 1 h. Unincorporated 125 I-trastuzumab-DSPE-PEG 3400 was removed from liposomes by gel filtration on a Sepharose CL-4B column with HBS (pH 7.4).
Determination of Drug Retention
Liposomes were incubated at temperatures of 37° C. or 60° C. At selected time intervals, aliquots were withdrawn in triplicate and non-encapsulated drug was removed on a Sephadex G-50 mini-column with HBS (pH 7.5) in a centrifugal field of 680 g for 2 min The volume of the eluent was adjusted to 1 ml with HBS and 1 ml of 1% Triton X-100 solution was added. Samples were heated to a temperature of 90° C. and cooled down to room temperature. The fluorescence intensity of samples was determined at an excitation wavelength of 468 nm and an emission wavelength of 589 nm. The percentage of encapsulated drug after incubation was determined relative to the amount of encapsulated drug before incubation.
Cryogenic Transmission Electron Microscopy (Cryo-TEM) of the Loaded Lioposomes
In brief, liposome samples were transferred on to a copper grid coated with a perforated polymer film in a custom-build environmental chamber at controlled temperature (25° C.) and humidity conditions to minimize water evaporation. Excess sample was removed by aspiration onto a filter paper. Thin (10-500 nm) sample films were vitrified by submersion in liquid ethane at a temperature of −165° C. and transferred under nitrogen atmosphere at a temperature of −165° C. into a Zeiss EM 920 A transmission electron microscope (Carl Zeiss Inc., Oberkochen, Germany). Samples were exposed to an electron density of 5-15 e − /Å 2 and images were taken in zero-loss bright field mode with an acceleration voltage of 80 kV.
Results and Discussion
Approximately 80% of doxorubicin and more than 90% of Compound 1 remained encapsulated in liposomes when incubated in medium at a temperature of 37° C. for 24 h ( FIG. 1 ). These results show that under the described conditions for liposome preparation and cell culture, doxorubicin and Compound 1 will not be significantly released from liposomes.
The cryo-TEM image of liposomes containing 125 I-trastuzumab-DSPE-PEG 3400 and loaded with Compound 1 ( FIG. 2 ) confirms that Compound 1 is in a crystalline state inside the liposomes.
Example 2
DNA-Binding
Example 2a
Cell Culture
Human cultured tumour cells overexpressing were grown as monolayer cultures using Ham's F-10 medium (Biochrom AG, Berlin, Germany) containing 10% fetal calf serum, glutamine (2 mM), streptomycin (100 μg/ml), and penicillin (100 IU/ml) at a temperature of 37° C. in a humidified 5% CO 2 incubator.
DNA-Binding
Cultured human tumour A431 cells (squamous carcinoma) were grown on glass slides, cooled to a temperature of 4° C., and washed with phosphate buffer. Cells were inactivated in methanol for 15 minutes at a temperature of −20° C. and then quickly washed at a temperature of 4° C. with phosphate buffer. Cells were thereafter permealised by acetone treatment for 10 seconds at a temperature of 4° C. After drying cells were incubated with 125 I-Compound 1 at room temperature for one hour, washed, and analyzed for radioactivity using a gamma counter (1480 Wallac Wizard, Perkin Elmer, Wellesley, Mass., USA). In addition, cells were inspected by fluorescence microscopy.
Results and Discussion
When cultured permealised human tumour A431 cells (squamous carcinoma) were incubated with 125 I-Compound 1 at room temperature for one hour, the specific radioactivity of Compound 1 bound to cells was determined at 21.2±3.7×10 3 cpm/10 5 cells after background subtraction. Binding could be blocked by using excess of doxorubicin.
Fluorescence microscopy revealed that Compound 1 was bound to the cell nucleus and not located inside the cytoplasm. Fluorescence microscopy experiments were repeated with similar results using human bladder cancer T24 and human glioma U343 cells.
Example 2b
Agarose Plugs
InCert agarose (BioWhittaker Molecular Applications, Rockland, Me.) was dissolved in serum free medium to a final concentration of 1%. 1 ml agarose solution was mixed with 1.5×10 6 U-343 cells and 20 μl plugs were cast in plastic moulds and cooled for 30 min at a temperature of 4° C. Plugs were submerged in lysis buffer (1 mg/ml Proteinase K, 2% Sarcosyl in 10 ml 0.5 M Na 3 -EDTA, pH 8.0) at a temperature of 50° C. over night to obtain pure DNA. After lysis, the plugs were washed twice with 0.5 M Na 3 -EDTA to remove cell debris. Plugs were stored at a temperature of 4° C. in 0.5 M Na 3 -EDTA. Plugs without DNA served as controls. Agarose plugs were incubated in duplicates for 3 h on ice with 600 μl solution containing 125 I-Compound 1. Control plugs contained excess amounts of doxorubicin at a concentration of 3×10 −5 M. The final concentration of 125 I-Compound 1 was 4×10 −7 M (in dH 2 O). After incubation and thorough rinsing on ice the radioactivity remaining in plugs was determined using the gamma counter.
Autoradiography
SKBR-3 cultured breast cancer cells were incubated with 125 I-Compound 1 for 1 h at a temperature of 37° C. at a concentration of 0.1 μg/ml culture media (0.3 kBq/ng). After incubation the cells were washed 6 times with serum free media and detached with 1 ml of trypsin/EDTA (0.25%/0.02% in PBS, Biochrome, Berlin, Germany) for 10 minutes. Cells were re-suspended with 14 ml culture media and transferred to centrifuge tubes. Cells were centrifuged for 5 min at 1200 rpm to get a cell pellet. The cell pellets were fixed with formalin buffer (0.01 M phosphate buffered formaldehyde (4%), Histolab Products AB, Göteborg, Sweden) for one week in 4° C. Thereafter pellets were dehydrated by following procedure: 2×15 min 70% EtOH, 30 min 90% EtOH, 2×15 min 95% EtOH, 2×15 min 99% EtOH and 3×20 min Historesin infiltration solution (Leica Instruments Gmbh, Heidelberg, Germany). After embedding in Historesin with activator over night 4 μm sections of the pellets were cut and transferred to slides. Slides were dipped into Kodak NTB photo emulsion (Eastman Kodak Company, Rochester, N.Y., USA) in darkness and dried before storage in 4° C. for 3 days. The slides were developed using Kodak D19 solution for 3 min, thereafter transferred to 0.1% acetic acid for 10 sec and fixed using Kodak fixer for 5 min, all in darkness. After extensive washing with water, cell nuclei were stained with Mayer Hematoxylin (Histolab Products AB, Göteborg, Sweden) for 3 min Before mounting with Pertex (Histolab Products AB, Göteborg, Sweden) slides were washed with water for 5 min and let to dry in air. Cells were inspected in microscope and images were captured of representative cells.
Results and Discussion
Binding of Compound 1 to the cell nucleus could be confirmed by the autoradiography of 125 I-Compound 1 ( FIG. 3 ) since the staining pattern of 125 I is co-localized with the Hematoxylin-stained cell nuclei.
When agarose plugs containing U-343 cellular DNA were incubated for 3 h on ice with 125 I-Compound 1 solution, 125 I-Compound 1 accumulated in the agarose plugs. Accumulation and thus binding of 125 I-Compound 1 to DNA could be blocked by excess amounts of doxorubicin. Results confirm the affinity of Compound 1 to DNA. The fact that binding of 125 I-Compound 1 to DNA could be displaced by doxorubicin ( FIG. 4 ) suggests that both Compound 1 and doxorubicin occupy the same DNA binding sites.
Example 2c
Pulsed-Field Gel Electrophoresis (PFGE)
To investigate the efficiency of 125 I-Compound 1 to induce DNA damage, the induction of double strand breaks (dsb) was analyzed on pulsed-field gel electrophoresis (PFGE, Pharmacia Biotech, Uppsala, Sweden). Agarose-plugs were incubated with 125 I-Compound 1 as described above. After washing, plugs were maintained at a temperature of 4° C. for 8 days. Plugs were then loaded in a 0.8% (w/v) agarose gel (Seakem Gold agarose powder, Cambrex Bio Science Rockland Inc., Rockland, Me., USA). DNA-fragmentation was analyzed for 45 h pulse field gel electrophoresis at 2 V/cm according to the following protocol: 10 min pulses (i.e. the field is pulsed every 10 minutes) for 3 h, 20 min pulses for 5 h 20 min, 30 min pulses for 8 h, 40 min pulses for 9 h 20 min and 1 h pulses for 20 h. After the gel was run it was stained with ethidium bromide (0.5 μg/ml) for 8 h then destained in dH 2 O over night. As molecular weight marker, a Scizosaccharomyces pombe , Megabase DNA standard (Cambrex Bio Science Rockland Inc., Rockland, Me., USA) was used. Each lane was cut in 2 blocks, corresponding to DNA fragments having a size being equal to or less than 5.7 Mbp and equal to or greater than 5.7 Mbp, respectively. Each block was put in a vial and the radioactivity was measured in the previously mentioned automated gamma counter. The fraction of DNA smaller than 5.7 Mbp was determined and then used for the calculations with the Blöcher-formula:
F <k =1− e −rk/n (1 +rk/n ( Int J Rad Biol 57, 7-12, 1990)
F <k is the fraction of DNA smaller than k base pairs, r is the average number of dsb/chromosome and n is the total number of base pairs in one chromosome of mean size. k=In this assay 5.7 Mbp was used; n=130 Mbp for the average human chromosome.
To obtain the number of double-strand breaks (r) the formula has to be solved numerically.
Results and Discussion
The number of double-strand breaks (dsb) following incubation of 125 I-Compound 1 with glioma cell DNA ( FIG. 5 ) was determined at approximately 0.4 dsb/decay. Thus, when coupled to Compound 1, 125 I is positioned close enough to DNA to cause DNA fragmentation, since 125 I not bound to DNA would not lead to DNA fragmentation. As a comparison, the use of 125 I-labeled DNA-precursor molecules, which results in direct incorporation of the nuclide into the DNA strand, gives a dsb value of approximately 1 dsb/decay. The difference in dsb values is relatively little, which indicates that the nuclide must have come within a very short distance from the DNA (in order for the radiation to have that effect) and that DNA-intercalation has occurred.
Example 2d
Type 1 calf thymus DNA sodium salt (Sigma-Aldrich Co., St Louis, M.O., USA) was hydrated in BPES buffer (6 mM Na 2 HPO 4 , 2 mM NaH 2 PO 4 , 1 mM EDTA, 185 mM NaCl, pH 7) at a concentration of approximately 2 mg/ml and sonicated at approximately 8 μA in a MSE Soniprep 150 ultrasonic disintegrator (Integrated Services TCP Inc., Palisades Park, N.J., USA) for 30 min in a water bath on ice. The sample was then dialyzed for 48 h against BPES using Slide-A-Lyzer® dialysis cassettes (10,000 MWCO) (Pierce, Rockford, Ill., USA). The final DNA concentration was determined spectrophotometrically on a HP8453 spectrophotometer (Hewlett-Packard Company Houston Tex., USA) at a wavelength of 260 nm using an extinction coefficient of 12,824 M (bp) −1 cm −1 .
Fluorescence titration experiments were performed on a SPEX 1680 Fluorolog spectrofluorometer (SPEX Industries Inc., Edison, N.J., USA) at room temperature with λ ex =480 nm (slid width 2.5 mm) and λ em =592 nm (slid width 2.5 mm). The initial free drug concentration was 1 μM. The concentration of free drug (C f (M)) was calculated by determining the fluorescence intensity ratio of investigated compounds in the absence (I 0 ) and presence of DNA (I) according to:
C f =C T ( I/I 0 −P )/(1 −P ) ( Biopolymers 6, 1225-1235, 1968)
where C T (M) is the initial drug concentration, and P is the ratio between the observed quantum yield of fluorescence intensity of the fully bound drug (I min ) and that of the free drug (P=I min /I 0 ). The concentration of bound drug was calculated by the difference between C T and C f . Binding constants (K i ) and exclusion parameters (n) were calculated by plotting r/C f versus r (Scatchard plot), where r is the number of moles of bound drug per mol DNA base pairs. Theoretical curves for the neighbor exclusion model were calculated by using the algorithm:
r/C f =K i (1 −nr )[(1 −nr )/[1−( n− 1) r]] n−1 ( J. Mol. Biol. 86, 469-489, 1974)
where K i (M −1 ) is the intrinsic binding constant and n (base pairs) is the exclusion parameter. The parameters K i and n were varied to generate theoretical curves that closest fitted the experimental data.
Table 1 (below) shows binding constants (K i ) and exclusion parameters (n) of daunorubicin, doxorubicin, Compound 1 and Compound 2 to calf thymus DNA (CT DNA). Values in parentheses indicate the standard error of mean values (SEM) (n=3). a =p<0.05 versus daunorubicin. b =p<0.05 versus Compound 2. Differences between the mean values were tested by one way analysis of variance followed by the Student Newman-Keuls test.
Literature Values
Daunorubicin K i : 0.7×10 6 M −1 ±0.07, n: 3.5 base pairs±0.35 (Chaires, et al. (1982) Biochemistry 21, 3933-3940). Doxorubicin 3.3×10 6 M −1 , n: 3.8 base pairs (Messori et al. (2001) Bioorg. Med. Chem. 9, 1815-1825).
TABLE 1 Binding constants and exclusion parameters of doxorubicin, daunorubicin, Compound 1, and Compound 2. K i n Drug (Ki × 10 6 M −1 ) (base pairs) Daunorubicin 0.7 3.6 (0.05) (0.17) Doxorubicin 3.2 a 3.9 (0.64) (0.23) Compound 1 3.3 a 3.4 (0.11) (0.21) Compound 2 3.0 a 3.7 (0.65) (0.31)
Results and Discussion
The similarity of CT DNA binding constants and exclusion parameters of Compound 1 and Compound 2 to those of doxorubicin, confirms that the derivatisation of daunorubicin did not cause loss of DNA-binding properties (Table 1). On the contrary, the binding constants of Compound 1, and Compound 2 were higher than that of the parent compound, daunorubicin?.
Example 3
Toxicity
Growth curves 125 I-Compound 1, Compound 1, doxorubicin, or daunorubicin were dissolved in culture media to a concentration of 0.5 ng/ml. The specific activity of 125 I-Compound 1 was 100 kBq/ng. SKBR-3 cells were incubated with drug in 60 mm plastic Petri dishes as triplicates, for 2.5 h. Control-cells were incubated with ordinary culture medium. After incubation, the medium was removed from all dishes and cells were washed six times with serum-free medium. Cells were detached from dishes by adding 0.5 ml of trypsin/EDTA for 10 min at a temperature of 37° C. After re-suspension in 1 ml of culture media cells were counted using a coulter counter (Z2 Coulter Counter, Beckman Coulter) and sub-cultivated to 10 5 cells to generate growth curves. Growth curves were corrected for loss of cells at each sub-cultivation.
Results and Discussion
Growth curves of cultured SKBR-3 cell monolayers revealed that the cytotoxic effect of 125 I-Compound 1 at a concentration of as little as 0.5 ng/ml was greater by several orders of magnitudes as compared to that after incubation with Compound 1, doxorubicin, or daunorubicin ( FIG. 6 ). Neither of the latter compounds had any significant cytotoxic effect. Hence, the cytotoxic effect displayed by 125 I-Compound 1 is solely caused by the nuclide 125 I attached to Compound 1.
REFERENCES
[1] B. A. Chabner, C. E. Meyers (1982) in Cancer: Principles and practice of oncology (DeVita Jr. V. T., S. Hellman and S. A. Rosenberg, eds.), pp. 156-197, J. B. Lippincott Company, Philadelphia, Toronto.
[2]H. G. Keizer, H. M. Pinedo, G. J. Schuurhuis, H. Joenje, Doxorubicin (adriamycin): A critical review of free radical-dependent mechanisms of cytotoxicity, Pharmaceutics and Therapeutics 47 (1990) 219-231.
[3] J. Bouma, J. H. Beijnen, A. Butt, W. J. M. Underberg, Anthracycline antitumour agents, Pharmaceutisch Weekblad Scientific Edition 8 (1986) 109-133.
[4] C. P. Association, Compendium of pharmaceuticals and specialities, Vol. 13, CK Productions Toronto, 1995.
[5] R. H. Blum, S. K. Carter, Adriamycin. A new anticancer drug with significant clinical activity, Ann Intern Med 80 (1974) 249-59.
[6] M. N. Gaze, The current status of targeted radiotherapy in clinical practice, Phys Med Biol 41 (1996) 1895-903.
[7] J. A. O'Donoghue, T. E. Wheldon, Targeted radiotherapy using auger electron emitters, Phys Med Biol 41 (1996) 1973-92.
[8] S. Kim, Liposomes as carriers of cancer chemotherapy. Current status and future prospects, Drugs 46 (1993) 618-38.
[9] (M. J. Hope, M. B. Bally, G. Webb, and P. R. Cullis (1985) Biochim Biophys. Acta 812: 55-65). | Anthracycline derivatives are suitable for use in cancer therapy and diagnosis. These anthracycline derivatives can be radiolabelled and used as an imaging agent in cancer diagnosis. The radiolabelled anthracycline derivatives can also be used together with a drug delivery system, in particular including a two-step targeting strategy, for treating solid and disseminated tumors. These drug delivery system can advantageously be used for treatment and diagnosis of breast cancer. | 0 |
This application is a continuation of application Ser. No. 114,220, filed on Oct. 28, 1987, which is hereby incorporated by reference is abandoned.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to athletic equipment and in particular athletic supporters.
2. Art Background
The avowed purpose for athletic supporters is the support of the genitals and scrotum during athletic endeavors or during less strenuous activities. The supporters generally include a waistband, a downward and then rearward projecting pouch appended to the front of the waistband to support the scrotum and genitals and a pair of straps extending from the bottom of the pouch to separated positions on the waistband. Supporters are made in a few discrete sizes. However this concept of a few sizes fitting all is often unsatisfactory. Even if a generically sized supporter fits when new, lending some of the desired support, washings and use soon take their toll.
Attempts to extend the usefulness of supporters have often involved improvement of the materials, e.g., elastic materials. Some other approaches involve mechanical expedients. For example, U.S. Pat. No. 3,547,117, issued Dec. 15, 1970, describes an adjustable waistband having a fastener, e.g., a Velcro ® fastener, to reduce or enlarge the circumference of the waistband. This adjustability does not significantly improve the support provided. An alternate approach to increased convenience (U.S. Pat. No. 4,141,357, issued Feb. 27, 1979) employs, as shown in FIG. 1, a pouch, 1, with no straps at the bottom of the pouch but having two adjustable straps, 3 and 4, attached to opposing ends at the top of the pouch and adapted to attach to the waistband of a separate garment, e.g., a bathing suit. Lack of straps at the bottom of the pouch significantly decreases support.
Attempts to compensate for the varying degrees of support required for different activities for the variety of human configurations and for the ranges of use have not been entirely successful.
SUMMARY OF THE INVENTION
Significant support for a wide variety of physiques and activities as well as compensation for the effects of wear is possible with the inventive supporter configuration. In particular a configuration is used that includes: (1) a waistband, (2) a pouch attachable to the waistband in the front, (3) means for attaching the pouch to the waistband, and (4) holding members extending from the bottom portion of the pouch to the waistband. The means for attachment should satisfy certain criteria. The attachment means should provide for attachment and detachment from a plurality of positions extending in a direction from the bottom of the waistband to the top. The attachment at each such position should be such that (1) the pouch should advantageously not substantially distort downwardly due to the forces exerted upon attachment by contact with the wearer's body and such that (2) the waistband should not substantially pucker due to the forces upon attachment exerted by contact with the body.
For example, excellent support for a wide variety of body configurations is achieved by employing a hook and loop attachment means such as Velcro®. In one specific embodiment one portion of the attachment means, e.g., the hooks, is arrayed substantially completely across the top of the pouch and the other portion of the attachment means, e.g., the loops, is arrayed across the waistband (37 in FIG. 2) width and extends along the circumference of the waistband a distance substantially corresponding to the dimension of the pouch occupied by the attachment means, e.g., the hooks. In this embodiment the support afforded is adjusted by pulling the top of the pouch upwardly and attaching it at a comfortable position on the waistband. The resulting support and comfort is substantially maintained because the pouch does not sag attachment is all across the top of the pouch) and the waistband does not pucker (the force generated by the desired support is distributed over a relatively substantial portion of the waistband).
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is illustrative of embodiments outside the invention, and FIGS. 2 and 3 are illustrative of embodiments of the invention and of the manner in which the inventive athletic supporter provides comfort and adjustable support.
DETAILED DESCRIPTION
The inventive athletic supporters are characterized by their comfort and adjustable support. These attributes are obtained by employing (1) a waistband, 37 in FIGS. 2 and 3, (2) a pouch, 35, (3) an appropriate means for attaching the upper portion of the pouch to the front portion of the waistband, and (4) holding members, 33, that extend from and provide support for the bottom portion of the pouch while extending to the waistband. (The different elements of the athletic supporter need not be discrete. It is possible, for example, to form the waistband and holding members from one piece of cloth, e.g., a structure that resembles an underwear brief.)
The expedient employed to provide the means for attachment is not critical, but it is desirable that attachment and detachment be relatively convenient. Expedients such as a plurality of snaps, a plurality of hooks with eyes, and/or Velcro® are suitable. However, the expedient should be configured so that certain criteria are satisfied. The attachment should provide a plurality of positions for attachment extending in a direction from the bottom, 36, of the waistband, i.e., the edge closest to the toes when the athletic supporter is worn, to the top. (The waistband need not be a constant width. For example, a larger range of adjustment is possible if the waistband is wider where the pouch is attached.) For example, snaps are provided in rows, e.g., rows 21, 22, 23, and 24 in FIG. 2 parallel to the bottom edge of the waistband, with a plurality of rows stacked in an upward direction. Each row corresponds to an attachment position for the pouch. In another embodiment, a Velcro® patch 30 in FIG. 3 (either the hooks or the loops) extends along the waistband and also extends in the direction from bottom to top of the waistband. (Directions and locations such as upward, downward, bottom and top as used in this disclosure are those that apply when the athletic supporter is being worn and the wearer is standing on his feet.) In all embodiments, irrespective of the expedient utilized for attachment, a plurality of positions for attachment on the waistband and/or pouch is provided. (A position of waistband (pouch) attachment is a curve defining the lower boundary for the points of waistband (pouch) attachment.)
To obtain the entire benefit of comfort and adjustability it is desirable that the attachment means satisfy more than the requirement of multi-position attachment. The pouch should attach to the waistband so that upon pouch attachment the forces produced due to contact of the athletic supporter with the body (1) do not induce substantial puckering of the waistband and (2) do not produce a downward distortion of the imaginary curve connecting the uppermost points of the pouch before attachment that are no higher than the position of ultimate pouch attachment. Puckering in this context is a loss of contact of the waistband with the body in localized regions. Also in the context of the disclosure a point of attachment is a point (1) on the pouch and waistband of direct attachment, or (2) the point on the pouch (point of pouch attachment) and point on the waistband (point of waistband attachment) to which an intervening member connecting the two attaches.
The embodiments of FIG. 2 and FIG. 3 satisfy these conditions. In FIG. 2 the snaps in a given row, for example 21, are sufficiently closely spaced so that substantial downward distortion of the pouch does not occur. Additionally, because the forces of contact with the body are spread over a relatively long region of the waistband (region 40 denoted by bracket) substantial puckering of the waistband is avoided.
Similarly, in the embodiments of FIG. 3, the forces are spread over the bracketed region 44 to avoid puckering and since the pouch is supported across its width substantial deformation is also avoided. (It is possible to attach the pouch to the waistband in a direction that is not parallel to the edge of the waistband.)
In contrast, for the athletic supporter shown in FIG. 1, as the adjustment is made forces are applied at points 10 and 11. Since the forces are not distributed there is a tendency for the waistband to pucker as the buckles, 14, are tightened to provide adjustment. Additionally the top of the pouch is supported only in the corners and thus sags in the middle. If more force is applied at the corners to remove the sag, this force is transferred to the waistband and contributes to puckering.
The use of, for example, a limited number of contact points, e.g., snaps, however is not to be totally precluded. Exemplary of the possibilities is the use of snaps on the pouch with stiffening members along the pouch and waistband. The stiffening member prevents sagging of the pouch and distributes forces to preclude puckering. Indeed, when Velcro® is employed the fabric backing, when present, provides stiffening that contributes to the prevention of puckering.
The materials used for the pouch, means for attaching the pouch to the..waistband, and the waistband itself are not critical. Typically, materials such as stretchable cloth are used. The attaching members are generally sewn to the pouch and waistband. However, other means for connection are acceptable such as the use of Velcro® that also provides adjustment. Additionally, it is possible for provision to be made for a hard cup or foam cushion such as used in contact sports. Adjustment such as where the support members attach to the waistband yields additional comfort especially when a hard cup is employed. The upward adjustment of the pouch puts tension on the supporting members. This tension is relieved by a concomitant adjustment of the supporting members such as at 45 in FIG. 3. | An athletic supporter provides enhanced support and comfort by employing an attachment means between the pouch and waistband. This attachment means provides a plurality of position for attachment that allows the support to be adjusted to the situation. | 0 |
FIELD OF THE INVENTION
The present invention generally relates to a method and apparatus for continuously and non-invasively monitoring intracranial pressure, and more specifically relates to an improved method and apparatus for continuously determining intracranial pressure using ultrasonic measurements of the velocity of blood flow through an eye artery.
BACKGROUND OF THE INVENTION
This invention is an extension and improvement of our previously invented method and apparatus U.S. Pat. No. 5,951,477 (the '477 patent) for single or single repeatable absolute intracranial pressure (ICP) value measurement and diagnosing of brain pathologies based on such measurements. This document is incorporated by reference in the present application.
The '477 patent teaches an apparatus and method for deriving an indication of intracranial pressure in a non-invasive manner using an ultrasonic Doppler measuring technique that is applied to the eye artery. In one aspect, this is achieved by a chamber which can apply a slight pressure to the eye and an ultrasonic apparatus which can simultaneously measure the internal and external blood flows in the eye artery. Signals representative of these velocity measurements, V I and V E are then compared and their difference, ΔV, is used to control the pressure in the chamber. When the pressure in the chamber causes ΔV to approach a desired minimum value, that pressure becomes an indication of the intracranial pressure.
One disadvantage of the method and apparatus taught in the 477' patent is that it is impossible to continuously and non-invasively monitor the absolute ICP value. Continuous monitoring of absolute ICP value is one of the aims of the US and EU traumatic brain injury management guidelines.
Therefore, one objective of the present invention is the continuous non-invasive monitoring of absolute ICP value. To achieve this objective, we non-invasively determine an absolute intracranial pressure value Po i in i-th measurement cycle using the method and apparatus taught in the '477 patent. This non-invasive measurement of Po i is then used as a single autocalibration procedure for the non-invasive ICP monitor during i-th time interval of ICP monitoring, and becomes the initial value of the absolute ICP scale for the next continuous absolute ICP monitoring cycle, Po (i+1) . After the time of continuous ICP monitoring during (i+1)-th time interval, the next single autocalibration procedure is performed and new value PO (i+2) is identified. That value is used as the initial value of the absolute ICP scale for the next continuous absolute ICP monitoring cycle. This process is repeated for the desired number of monitoring cycles.
When several Po i data points are collected, a conversion factor Ω can be determined as a function of pulsatility indexes for a wider interval of absolute ICP values. Stability of the conversion factor dictates whether the time interval of continuous ICP monitoring should be decreased, or increased. If the conversion factor Ω is stable, the continuous absolute ICP monitoring time interval can be increased. If the conversion factor and the pathophysiological conditions of the patient are changing, the continuous absolute ICP monitoring time interval must be decreased.
Advantages of the present invention are that the absolute ICP monitoring is continuous and the external pressure Pe is used only for autocalibration of the system “individual patient—non-invasive ICP meter”. In the '477 patent, it was necessary to apply external pressure Pe to the eye for the entire sampling period of discrete absolute ICP monitoring. Thus, the added value of the invention is the possibility to obtain important information about absolute ICP value non-invasively and continuously between two single absolute ICP measurements which are used for the system's autocalibration.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide a non-invasive method and apparatus for continuous absolute ICP monitoring.
In order to overcome the deficiencies of the prior art and to achieve at least some of the objects and advantages listed, an embodiment of the apparatus for continuously obtaining an indication of intracranial pressure comprises a device for measuring the pulsatility index of blood flow in the intracranial portion of an eye artery (P.I.(int)) and generating an internal pulsatility index signal representative thereof, and measuring the pulsatility index of blood flow in the extracranial portion of an eye artery (P.I.(ext)) and generating an external pulsatility index signal representative thereof; a device for applying an external pressure against an eye, measuring the external pressure applied against the eye, and generating an external pressure signal representative of the measured external pressure; and a processor for receiving the external pressure signal, the internal pulsatility index signal, and the external pulsatility index signal and calculating a conversion factor (Ω) therefrom for converting said internal pulsatility index signal and said external pulsatility index signal into an indication of continuous absolute intracranial pressure.
The device for continuously measuring the pulsatility index of blood flow in the intracranial portion of an eye artery and measuring the pulsatility index of blood flow in the extracranial portion of an eye artery may be provided as an ultrasonic Doppler device.
Conversion factor (Ω) may be calculated as the value of the measured external pressure which causes the ratio of the external pulsatility index (P.I.(ext)) to the internal pulsatility index (P.I.(int)) to become equal to one (1). Additionally, the indication of continuous absolute intracranial pressure (ICP) may be calculated from the formula ICP=Ω(P.I.(ext)/P.I.(int)) and it may be calculated for at least on sampling period. The processor may also calculate a value of said conversion factor (Ω) for each of the at least one sampling periods.
The processor provided in one embodiment may also determine whether the conversion factor is stable by comparing the value of the conversion factor for each of the at least one sampling periods. The conversion factor is stable if there is an insubstantial change in the value of the conversion factor for each of the at least one sampling periods. If the conversion factor is stable, the length of each of the at least one sampling periods may be increased. If the conversion factor is not stable, the length of each of the at least one sampling periods may be decreased.
An embodiment of a method for continuously obtaining an indication of absolute intracranial pressure is also provided. The method may comprise the steps of: A) measure the pulsatility index of blood flow in the intracranial portion of an eye artery (P.I.(int)); B) measure the pulsatility index of blood flow in the extracranial portion of an eye artery (P.I.(ext)); C) apply an external pressure against an eye and measure said external pressure applied against the eye; D) calculate a ratio of P.I.(ext) to P.I.(int); E) calculate a conversion factor to convert the ratio of P.I.(ext) to P.I.(int) into intracranial pressure, wherein said conversion factor is equal to the external pressure measured which causes said ratio of P.I.(ext) to P.I.(int) to become equal one (1); and F) repeat steps A, B, and D and determine intracranial pressure (ICP) by applying said conversion factor to the calculated ratio of P.I.(ext) to P.I.(int).
The method may also comprise the steps of: G) periodically repeat steps A-E; and I) repeat step F. In another embodiment, the method of claim further comprises the step of: J) determine whether the conversion factor is stable by comparing the value of the conversion factor calculated in steps E and G. In yet another embodiment, the method further comprises the step of: K) determine that the conversion factor is stable if there is an insubstantial change in the value of the conversion factor calculated in steps E and G.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a time chart of non-invasive absolute ICP continuous monitoring device.
FIG. 2 is a structural diagram of the apparatus for non-invasive absolute ICP continuous monitoring.
FIG. 3 is an algorithm of the apparatus for non-invasive absolute ICP continuous monitoring.
DETAILED DESCRIPTION OF THE INVENTION
We have found that with the apparatus in accordance with the present invention, the absolute value of intracranial pressure can be monitored continuously and non-invasively.
As shown in FIG. 1 , the present invention involves an apparatus for non-invasively determining an absolute intracranial pressure value Po i in i-th measurement cycle. Using the method and apparatus taught in the '477 patent, the intracranial pressure value Po i is determined by applying an extracranial pressure P e to the eye over some time interval, for example 200 seconds. During that interval, P e is increased step-by-step from 0 mmHg to 25.0 mmHg, at 5.0 mmHg increments, until the ratio of extracranial to intracranial pulsatility indexes P.I.(ext)/P.I.(int) of blood flow in the intracranial and extracranial segments of the eye artery (ophthalmic artery) becomes equal to 1.0.
Pulsatility index PI is defined by the ratio (Vsyst−Vdiast)/Vmean, where Vsyst the systolic blood flow velocity value, Vdiast is the diastolic blood flow velocity value, and Vmean is the mean value of blood flow. Blood flow velocities are measured by a two-depth transcranial Doppler (TCD) device in both the intracranial and extracranial segment of the eye artery. Thus, both pulsatility indexes P.I.(int) in the intracranial segment and P.I.(ext) in the extracranial segment of eye artery are defined using results of Vsyst, Vdiast and Vmean measurement.
The non-invasive measurement of Po i is used as a single autocalibration procedure for the non-invasive ICP monitor during i-th time interval of ICP monitoring. The value of Po i also becomes the initial value of the absolute ICP scale for the first continuous absolute ICP monitoring cycle, PO (i+1) .
Continuous monitoring of absolute ICP data begins from Po (i+1) (e.g., Po i =10 mmHg in FIG. 1 ). ICP is continuously and non-invasively monitored using the ratio of the pulsatility indexes, i.e., P.I.(ext)/P.I.(int). Once the ratio is known, we can calculate ICP=Ω(P.I.(ext)/P.I.(int)), where Ω is a conversion factor for converting pulsatility indexes into absolute non-invasive ICP values. Conversion factor Ω is individual to each patient and depends on the physiological state of the patient, i.e., arterial blood pressure, cerebrospinal compliance, etc.
After the time of continuous ICP monitoring during (i+1)-th measurement cycle (e.g., 1 hour in FIG. 1 ), the next single autocalibration procedure—non-invasive measurement of absolute ICP PO (i+2) —is performed and new value PO (i+2) is identified. That value is used as the initial value of the absolute ICP scale for the next continuous absolute ICP monitoring cycle. This process is repeated for the desired number of monitoring cycles.
When several Po i data points are collected, values of conversion factor Ω can be determined as a function of ICP for a wider interval of absolute ICP values. Stability of the conversion factor as a function of time can also be checked. The conversion factor is stable if there is in an insubstantial change in its value over time. If the conversion factor Ω is stable, the continuous absolute ICP monitoring time interval can be increased. If the conversion factor and the pathophysiological conditions of the patient are changing, the continuous absolute ICP monitoring time interval must be decreased. In practice, a single absolute ICP non-invasive measurement time for the system's calibration is much shorter than the fifteen (15) minute continuous non-invasive absolute ICP monitoring time.
With reference to FIG. 2 , an apparatus 20 is shown to practice the continuous measurement of the intracranial pressure as described above. The apparatus is mountable to the head of a person so that an eye engaging inflatable device 22 can apply a slight pressure against the eye lid 23 . Suitable braces and positioning bands 24 , 26 are used to hold the device 22 in place. The device 22 is formed of a suitable soft material such as rubber or other polymer film to form an inflatable chamber 28 . Chamber 28 is approximately annular in shape so as to enable an ultrasonic transducer 30 to be mounted against an inner flexible membrane 32 and enable a pressurization of the chamber by a pump 34 .
The inner membrane conforms to the shape of the eye 35 as illustrated and in such manner enables the pressure from the inflation of chamber 28 to provide a slight pressurization of the tissues surrounding the eye and thus the eye socket. This results in a pressurization of the eye artery 36 , which originates from inside the cranium 40 and passes through the optic nerve canal 42 to the eye 35 .
The ultrasonic transducer 30 has a central axis 44 , which can be aligned by adjusting the position of the transducer inside its mounting to device 22 . This alignment allows one to adjust the angle of axis 44 so as to direct its ultrasonic acoustic pulses at both interior and exterior portions 46 , 48 of the eye artery 36 at the same angle. With such alignment, Doppler measurements of the blood flow velocities in these different portions 46 , 48 can be made without the introduction of errors from the use of different angles of axis 44 with respect to portions 46 and 48 . Hence, a reliable measurement of the intracranial and extracranial pulsatility indexes, P.I.(int) and P.I.(ext) respectively, can be determined.
The ultrasonic transducer 30 has its input line 50 coupled to an acoustic pulse transmitter 52 . The transducer 30 also acts as a sonic receiver so that its input line 50 is connected to a gate 54 . A gate input 56 is connected to the transmitter 52 to protect a receiver 58 from the high transmitter output pulses during pulsing of the transducer 30 . The receiver 58 produces an output signal on line 60 representative of the acoustic echoes from the blood flow in the eye artery OA and caused by the ultrasonic pulses from the transmitter 52 .
A depth control network 62 is provided to enable the apparatus 20 to select that portion of received echoes representative of either the internal or external, cranium, eye artery, blood velocities. The network 62 produces an internal selection signal on line 64 and an external selection signal on line 66 . The internal selection signal is applied to an AND gate 67 to enable the echoes related to the blood flow inside the cranium to be selected for further processing. Similarly, the external signal is applied to an AND gate 68 to select the echoes related to the blood flow in the eye artery external of the cranium. The network 62 operates as a range gating system with which acoustic returns of different depths can be selected and analyzed for their Doppler frequency shift relative to the transmitter frequency f c .
The internal and external selection signals are generated in sequence in a manner as is well known by a control 70 activated after each transmitter pulse by the signal on line 56 . The outputs from AND gates 67 , 68 are coupled through an OR gate 72 to a sampler frequency counter 74 . This samples the received echo signals and produces sample signals, such as the signal frequency, f I , in the pulse representative of blood velocity inside the cranium, the signal frequency, f E , inside the echo pulse from the eye artery external of the cranium, and the frequency, f C , in the transmitted pulse. The sampled frequency signals are stored at 76 in a suitable memory and at 78 the shifts in the frequencies from the frequency of the transmitted pulse, such as f C −f I and f C −f E , are determined. A suitable microprocessor can be used to implement these functions.
The frequency shifts can be determined for each transmitter pulse and resulting echo. Each frequency shift is representative of the blood velocity in the eye artery and the values can be so stored to provide an indication of the internal blood velocity, V I , and external blood velocity, V E , at 78 . The velocity difference value ΔV at 80 can then be displayed and the display is used to determine the intracranial pressure.
The difference values ΔV are used to determine the intracranial pressure Po i . This is done by increasing the pressure inside the inflatable device 22 to a level where ratio of the intracranial and extracranial pulsatility indexes (which depend on the value of ΔV) becomes equal to one. The Po i measurement can be made by manually increasing the pressure inside the device 22 until the visual indications of the measured pulsatility indexes P.I.(int) and P.I.(ext), or the frequency shifts, appear the same or with an automatic control such as 82 .
Alternatively an automatic control 82 can be implemented, for example, by first testing at 84 whether the value of ΔV is below a minimum value such as ΔV min . If not, then at 86 a value for the pump pressure is incremented and its value applied to pump 34 to cause it to increase the pressure P e inside the inflatable device 22 . A pressure transducer 90 senses the pressure inside the chamber 28 .
When the test at 84 shows positive, the value P e is stored at 92 as an indication of the intracranial pressure, Po i . This can be displayed at 94 and suitably recorded.
In the operation of apparatus 20 , it desirable that an initial alignment mode be undertaken to assure that the transmitter pulses from the transducer 30 are properly directed at both the internal and external portions 46 and 48 of the eye artery 36 . This involves adjustments in the angle φ between the axis 44 of the ultrasonic transducer 30 and the alignment axis 96 of the eye artery passage 42 .
A controller 97 of continuous ICP monitoring is added to the structural diagram of previously invented method and apparatus of the '477 patent. The additional controller 97 is connected with clock 98 and increment pump 86 . The controller 97 manages i-th measurement cycles, performs pressure P e increments of the pump 34 , calculates the ratio of pulsatility indexes P.I.(ext)/P.I.(int), compares it with the predetermined 1.0 value, and calibrates the non-invasive ICP monitoring display 94 by the output signal 99 .
With reference to FIG. 3 , a routine 100 for making such alignment is illustrated. Thus at 102 the apparatus 20 is initialized and at 104 operative contact between the acoustic transmitter 30 and the eye cavity is established by observing return echoes on a display. At 106 the depth of the operative probe depth R E , see FIG. 1 , is entered by the probe depth control block 70 (See FIG. 1 ). Typical initial values of R E are approximately between 40 mm and 50 mm.
At 108 the spatial angle φ of the transducer axis 44 is changed to find the velocity signal associated with the extracranial eye artery portion 48 . This is found by observing the shape of the blood velocity pulsation curve of the extracranial part 48 of the eye artery 44 , (see FIG. 5 ). The spatial angle, φ 1 , which yields the maximum Doppler signal level, is selected at 110 and noted.
At 112 , the initial value of the internal probe depth R I is entered by the control block 70 . The typical values of R I are approximately between 52 mm and 65 mm.
At 114 the spatial angle φ 2 is determined for the alignment of the transducer 30 yielding the maximum Doppler signal pulsation from the internal portion 46 of the eye artery 36 . The operating orientation of the transducer 30 is the selected at 116 by aligning the axis 44 of the transducer 30 along the middle between the angles φ 1 and φ 2 .
Then at 118 the probe depth control 70 is actuated so that the blood velocities, within the internal and external eye artery portions 46 , 48 , are sequentially measured. The depths of external and internal optic nerve canal's entrances are determined by increasing R E from the values between those selected at 106 and the values selected at 112 while observing the blood velocity pulsation of FIG. 5 . The blood velocity pulses have smaller amplitudes inside the optic nerve canal.
Then at step 120 the depths R 1 and R 2 of respectively the external and internal optic nerve canal entrances are determined. This is done by observing a decrease in the amplitudes of the blood velocity pulses, as shown in FIG. 5 , and typical for measurements made inside the optic nerve canal in comparison with the amplitudes of blood velocity pulses from outside the optic nerve canal.
After that, at step 122 the final value of R E and R I are set using the criteria R E <R 1 and R I >R 2 . Once the position of the ultrasonic transducer is determined and set a measurement of the internal and external blood velocities can be made as described above. A determination of the intracranial pressure Po i is obtained when the pulsatility index measurements are the same.
As shown in FIG. 3 , periodical autocalibration and continuous ICP monitoring procedures 125 are also added to the algorithm of non-invasive absolute ICP continuous monitoring apparatus.
It should be understood that the foregoing is illustrative and not limiting, and that obvious modifications may be made by those skilled in the art without departing from the spirit of the invention. Accordingly, reference should be made primarily to the accompanying claims, rather than the foregoing specification, to determine the scope of the invention. | A method and apparatus for continuously measuring the absolute intracranial pressure in a non-invasive manner is described by using an ultrasonic Doppler device which detects the pulsatility indexes of the blood flow inside the eye artery for both intracranial and extracranial eye artery portions. The eye in which the blood flow is monitored is subjected to a small pressure, sufficient to equalize the pulsatility index measurements of the internal and external portions of the eye artery. The pressure at which such equalization occurs is used as a reference for autocalibration of the apparatus so that continuous absolute intracranial pressure measurements may be taken over a particular sampling period. | 0 |
This application is a continuation of application Ser. No. 08/580,042, filed Dec. 20, 1995, now abandoned which is a continuation of application Ser. No. 08/224,837 filed Apr. 8, 1994, Entitled: CONTROL OF PHOTOREFRACTIVE KERATECTOMY, now abandoned.
BACKGROUND
This invention relates to improvements in photorefractive keratectomy (PRK).
In PRK, corneal tissue is removed in a controlled fashion to shape the surface of the cornea of a patient's eye to treat, e.g., myopia, hyperopia, presbyopia or astigmatism
The cornea comprises transparent avascular tissue that forms the anterior portion of the eye. The cornea functions as both a protective membrane and a "window" through which light passes as it proceeds to the retina. The transparency of the cornea is due to its uniform structure, avascularity, and deturgescence, which is the state of relative hydration of the corneal tissue.
A major proportion of the refractive power of the eye is determined by the curvature of the anterior surface of the cornea, so that changing the shape of the cornea offers a way to significantly reduce a refractive problem in the eye.
Various techniques have been proposed for shaping the cornea of a patient's eye. Some techniques include removing the epithelium, and then shaping the underlying Bowman's and stroma layers. In PRK, photoablation is employed using e.g., ultraviolet radiation from an excimer laser, e.g., at 193 nm wavelength, or infrared laser radiation that has a wavelength in the range of about 2.9 to 3.2 μm.
In one technique, described in Marshall et al., U.S. Pat. No. 4,941,093 (assigned to Summit Technology Inc.), the shape and size of the area of the corneal surface which is irradiated by laser radiation is selected and controlled so that some areas of the corneal surface become more eroded than others and a desired corneal shape is achieved.
Another technique, described in Muller, U.S. Pat. No. 4,856,513 (assigned to Summit Technology Inc.), uses a laser and an erodible mask. The mask, with a predefined profile of resistance to erosion by laser radiation, is disposed between the laser and the corneal surface. A portion of the laser radiation is absorbed by the mask, while another portion is transmitted to the corneal surface in accordance with the mask profile, thereby enabling the selective photoablation of the corneal surface into a desired shape.
There are circumstances in which it is desired to accomplish the PRK treatment with the ablated zone larger than 5 mm in diameter. With such zones, under usual operating conditions it has been observed that the final surface achieved by the ablation process differs from the expected shape. Surface irregularity and significant refractive error have been observed post-operatively in the corneal topographies of some patients treated for PRK. These irregularities may lead to visual disturbances such as diplopia, blurred vision, and loss of Best Corrected Visual Acuity (i.e., the vision obtained with the best possible lens correction).
The PRK procedure has achieved a clinically accepted level. However the possibility of achieving even better results with larger ablation zones has been somewhat elusive. The present invention provides a new insight into conditions that can occur in PRK and provides techniques that address these conditions to enable enhanced predictability, stability, and safety of the procedure to be achieved.
SUMMARY OF THE INVENTION
In performing a photorefractive keratectomy procedure employing pulses of photoablative radiation to selectively ablate corneal tissue of a patient's eye to produce a desired refractive correction in the corneal tissue, particularly when ablating areas larger than about 5.5 mm in diameter, we have realized that improved results can be achieved by controlling the effect of ocular fluid at the corneal surface so as to reduce the disturbance of this fluid on the ablation process while maintaining hydration of the tissue. The ocular fluid to which we refer is the physiological fluid produced naturally by the eye, which contains various proteins and solutes, and which tends to accumulate in regions subjected to photoablation. As the ablation proceeds, solid residues of the preceding ablative process also enter the fluid. The reference to the fluid being "at the corneal surface" refers to liquid on the surface and fluid present among the initial molecules that form the surface structure. By "controlling", we refer to systematic selection or adjustment of parameters of the treatment conditions in a way that takes into account the detrimental effect accumulated ocular fluid can have upon the result of the procedure relative to the correction that is desired, and the need not to dehydrate the remaining corneal tissue.
In addition to recognizing the importance of this controlling step, we have also conceived various approaches for accomplishing the step, some of which can be accomplished by simple adjustment or selection of parameters without affecting the complexity of the procedure or its cost.
In the case of wide-area ablation, in which a pulsed beam of ablative energy of variable controlled diameter is centered on the eye, it is often desired to maintain the fluence of the beam constant from pulse to pulse. We have realized that selection of the repetition rate of the optical pulse may be employed for controlling the ocular fluid effect. By employing a rate sufficiently high, in excess of 10 Hz, intrapulse fluid accumulation can be reduced at the surface to be ablated such that the aggregate disturbing effect does not result in a dioptic variation greater than a prescribed amount, for instance 1/4 Diopter. Preferably the effective pulse rate is selected in the range between about 12 to 100 Hz, depending upon other parameters being employed.
In other wide-area ablation systems, the fluence of the pulses may also be selected for the purpose of controlling the effect of intrapulse fluid accumulation without dehydration of the corneal tissue. We have realized that selecting higher beam fluence levels, within a practical operating range, reduces the sensitivity of each beam pulse to intrapulse fluid accumulation. Here, advantage is taken of a saturation trend, i.e., the increase of the amount of material ablated, as the fluence increases, occurs at a rate that has a decreasing value.
In other systems, the repetition rate and fluence levels employed can both be selected based on their effect in respect of the ocular fluid problem. In sophisticated systems employing control by a computer program the values of these parameters may be varied on a case-by-case basis for controlling the effect of ocular fluid accumulation, while avoiding corneal tissue dehydration.
We have also realized that the sensitivity of the ablative process to the effects of ocular fluid accumulation is dependent upon the depth of the tissue being removed. This dependency can be understood from the following considerations. Refractive error of a procedure is typically desired to be held within a prescribed absolute tolerance, or "precision" such as 1/4 Diopter. On the other hand, the disturbance caused by a given value of intrapulse accumulation of ocular fluid is cumulative, increasing for a given site with the number of pulses that are incident on the site. Furthermore, we have observed that the rate of accumulation of ocular fluid at a site increases with the depth of tissue removed. Likewise the amount of ablative residue in the fluid may increase with the depth of tissue removed. It is realized that if more ocular fluid or fluid with higher, absorptive values exists in some areas than in other areas in the ablation zone, non-uniform ablation will occur with pulses that overlap those areas. Thus the sensitivity of the ablative process to the ocular fluid problem is realized to be dependent upon the depth of tissue removal.
We have further realized it is significant that the depth of tissue removed, for a given Diopter correction, varies as a power function with the diameter of the ablation zone. The degree of disturbance of the ablation attributable to accumulated ocular fluid and the degree of required control on the effects of ocular fluid likewise are found in general to be related to a power function of the diameter of the ablation zone.
According to the invention, based on observations conducted employing beam pulses of 180 mJ cm -2 of excimer laser pulses of 193 nm wavelength, the method and system for applying beam pulses of photoablative radiation are preferably selected so that at any given site of incidence of the beam pulses in the ablation zone, the average rate (Rep Rate, expressed in Hz) at which the beam pulses are provided, the effective average fluence (F, expressed in mJ cm -2 ) of the beam pulses, and the average diameter (φ, expressed in mm) of the ablation zone, have the general relationship:
Rep Rate≧C×φ.sup.2 /ln(F),
where C is between 15 and 20.
Also because the depth of tissue varies with the Diopter value of the correction to be effected in the patient's cornea, for improved control, the system parameters can be selected to take this factor into account as well. Because it is desirable that the precision of the correction be maintained at an absolute value over the range of dioptric corrections, e.g., within 1/4 Diopter, and because small localized variations in tissue depth may have a large effect upon the local refractive value, we have realized that the size of the correction in Diopter has greater than a linear effect on the degree of control needed in respect of the ocular fluid problem According to this realization, the invention also features a method and system in which the beam pulses are selected so that, at any given site of incidence of the beam pulses in the ablation zone, the average rate (Rep Rate, expressed in Hz) at which the beam pulses are provided, the effective average fluence (F, expressed in mJ cm -2 ) of the beam pulses, the average diameter (φ, expressed in mm) of the ablation zone, and the dioptric power (D, expressed in Diopter) at the location of maximum correction to be effected in the patient's cornea, maintain the general relationship:
(φ.sup.2 ×D.sup.2)/(ln(F)×Rep Rate)≦C',
where C' is about 15. This is based on observations made employing beam pulses of 180 mJ cm -2 of excimer pulses of 193 nm wavelength, at a 6 mm diameter ablation zone, for a 5 Diopter correction at 20 Hz pulse rate.
Other techniques to control the effects of accumulating ocular fluid can be used in conjunction with the technique just described or can constitute effective control by themselves.
An evaporative effect provided uniformly can be employed to remove intrapulse accumulation of ocular fluid.
In one case, the invention features a double pulse system Immediately preceding the main pulse at ablating energy level (e.g. fluence between about 100 to 250 mJ cm -2 in the case of pulses of 193 nm wavelength in a wide area ablation system), a precursor evaporative pulse of the same wavelength of carefully controlled energy is introduced at fluence below the ablative threshold, e.g., of 50 mJ cm -2 . The effect of the precursor pulse is to produce evaporation of accumulated ocular fluid. In order to obtain evaporation without dehydrating the corneal tissue, the parameters of the precursor beam are selected to limit the depth of the energy deposition.
In another case, a separate source of irradiation is employed which may operate continuously, intermittently, or in pulses at desired times. In one preferred embodiment, a CO 2 laser is employed to produce radiation at a wavelength that is highly absorbed by water. The stream of pulses of evaporative energy may advantageously be coordinated to avoid overlap of the incident pulses of evaporative and ablative wavelengths and to optimize the state of reduction of fluid accumulation without tissue dehydration at the time of incidence of the ablative pulse upon a given site.
According to another aspect of the invention, the ambient humidity at the locus of the eye is maintained at a well controlled level below saturation during the procedure to accelerate evaporation of ocular fluid that tends to accumulate This may include maintaining the room at low humidity or special provisions localized to the region of the eye, such as a gentle, general distribution of gas, at appropriate humidity to cause evaporation of accumulated ocular fluid, via a series of outlets uniformly distributed about the eye.
According to another aspect of the invention, controlling the effect that can be caused by the accumulation of ocular fluid involves reducing the tendency of the body to present such fluid at the ablative site. This can be effected by systemic or local administration of a drug that is effective to retard the fluid accumulation. Such treatment may be supplemented with control of the general thermal condition of the eye, as by cooling prior to treatment, in manner that retards flow of the ocular fluid to the ablation site.
It will be understood that the degree of control to be employed with respect to any parameter during wide area ablation for controlling the effect of ocular fluid is not to be determined in isolation, but rather out of consideration of the values of other parameters that are employed. Suffice it to say that effective wide area ablation, with ablating zones in excess of about 5.5 mm, up to about 10 mm, and in particular including the range of 6.0 mm to 8.0 mm, can be performed following the present teachings. Specifically, the present invention contributes to solving the problem of "islands" of excess tissue that have been observed as a result of operation of some ablative systems.
In certain broader aspects, the invention equally is relevant to scanning ablative systems in which the ablative beam is narrow in one or both dimensions relative to the dimension of the ablative zone, or is smaller in area than the ablation zone, and in which such beam is displaced laterally from pulse to pulse. In such systems, the intrapulse accumulation of ocular fluid relates to the period between which pulses are incident at the same point, which is typically at a much lower rate than the pulse rate of the originating laser, due to the distribution of the pulses between many different points in the ablative zone.
The considerations above apply with even greater force in respect of such scanning systems, while the nature of such systems permit control of additional parameters.
According to the invention, in such systems higher fluence levels can be selected because the opportunity for thermal build up can be reduced by judicious distribution of the pulses. Also, because of the smaller beam size, it is feasible to operate at lower controlled fluence levels. The range of practical fluence levels for scanning-type systems lies between about 80 and 500 mJ cm -2 . Likewise the repetition rate of the laser itself may be very high when scanning techniques are employed, while the local effective pulse rate of any site of incidence of the beam may be maintained over a wide range depending upon the selected fluence, but still must be sufficiently frequent, e.g., above 10 Hz, to control the effect of the ocular fluid.
It will be understood that scanning systems enable further degrees of freedom in operation and provide abilities to more readily control the effect of the ocular fluid than are provided by control of the average repetition rate and average fluence of the beam. In a scanning system, one can easily change the size of the spot. Changing the size of the spot while keeping the same total energy in the beam is an easy way to change the fluence from pulse to pulse in a very dramatic way. The repetition rate with which the system fires the pulses can likewise be very different than the repetition rate for a wide area ablation system, and can be varied. Furthermore, a given site in the ablation zone in a scanning system can be revisited by the pulses of the laser on a selected basis. Each of these variables may be implemented according to an appropriate algorithm which addresses the issues of controlling the ocular fluid. For example, according to the invention an algorithm is provided which starts to cut deeper areas, and re-visits the places which are to be deeply ablated more frequently than the places which are to be shallow-ablated The shallow-ablated regions can tolerate lower repetition rate and a resultant greater disturbance by ocular fluid per pulse, because of a lesser aggregative effect on the dioptric error. Thus the scanning system provides further degrees of freedom to employ algorithmic control by revisiting places of deeper removal with higher frequency. Such a system automatically compensates and thus distinguishes other algorithms that can be used to treat essentially the entire area over the duration of the procedure.
In certain further respects, scanning systems have a greater need to comply to the principles established above. Because the ablation occurs in a distribution of small spots or lines there is the additional possibility of lateral transport of material under the dynamic conditions of scanning and a more detrimental effect can occur if ocular fluid is permitted to accumulate. In the case of certain scanning systems, to avoid this effect, the inventors conceive it to be advantageous for each successive firing of the laser to be directed to a relatively distant, virgin place at which any accumulated fluid has not been recently dynamically disturbed by the previous firing.
These illustrate just some of the greater possibilities which scanning systems offer for controlling the effects of ocular fluid at the corneal surface.
While the physiology of the eye and its mechanisms are not fully understood at a detailed level, certain observations that lead to further insight into the present invention can be mentioned.
Ocular fluid present in the native cornea that is responsible for maintaining proper hydration of the eye may appear on the surface of the cornea within the boundaries of the treatment zone. Though this fluid is water-based, it contains substantial quantities of proteins and various solutes necessary for proper corneal function. As the corneal lamellae are ablated, ocular fluid may flow out of the stroma and tend to accumulate non-uniformly on the exposed ablated surface. During the course of the ablation treatment, the concentration in the ocular fluid of solid residues of the preceding ablative action can increase. The possibility of redeposit on the corneal surface of fluid cast into space by the ablation process is also possible. Although pure water may have little effect on the ablative beam, the biomaterial present in the fluid can have strong absorption characteristics for the photoablating laser energy used in PRK, and the absorptive character of the fluid can increase as the concentration of ablative residue increases.
It is realized that accumulated ocular fluid, particularly if it covers the tissue to be ablated, can cause the incoming photoablating laser energy to be partially absorbed before reaching the underlying stromal tissue, thereby reducing the fluence available to ablate the corneal tissue and disturbing the rate of ablation. On the other hand, if the stromal tissue is not so completely wetted by the ocular fluid, the ablation can proceed in a manner much less affected by the ocular fluid.
Non-uniform accumulations of ocular fluid over the surface being ablated are therefore believed to be detrimental to the photo-ablative process. The step of controlling the effects of accumulated ocular fluid without dehydrating the tissue solves this problem and enables use of ablative zones larger than 5 cm with improved effect.
Other features and advantages of the invention will become apparent from the following description and from the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a side elevational view of a patient undergoing photoablative shaping of corneal tissue.
FIG. 1A is a schematic diagram illustrating the relationship between optical components inside the laser source housing and the optical support assembly shown in FIG. 1.
FIGS. 2-2D are elevational schematic views of a patient's cornea at successive times during a conventional PRK procedure.
FIGS. 3-3B are elevational schematic views of a patient's cornea at successive times during a PRK procedure according to the invention.
FIG. 4 is a schematic side view of a system employing precursor evaporative pulses preceding ablative pulses during PRK.
FIGS. 4A-4F illustrate steps of use of pulses of the precursor beam of subablation energy preceding ablation pulses.
FIGS. 5-5D are elevational schematic views of a patient's cornea at successive times during a PRK procedure according to the invention in which an ocular fluid drying beam is employed.
FIG. 6 is an elevational schematic view of a PRK system employing evaporative illumination for controlling accumulated fluid effects.
FIGS. 7 and 7A are top schematic views of a patient's cornea onto which are projected scannable beam pulses having a circular beam projection and a long, narrow beam projection, respectively.
FIG. 8 is a flow diagram of a method for performing PRK according to the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring to FIG. 1, a patient 10, lying on an operating bed 12 with his head restrained between two side supports 14, is shown undergoing photoablative shaping of the cornea in a PRK procedure in accordance with the invention.
An optical support assembly 16 supports beam delivery optics that transmit photoablative radiation from, e.g., a laser source inside housing 18 to beam delivery optics 20. During the cornea shaping procedure, the patient's eye may be observed using a surgical microscope 22.
As shown in FIG. 1A, the laser source housing 18 includes a laser 24 (e.g., an EXCIMED™ ArF excimer laser (193 nm) available from Summit Technology, Inc. of Watertown, Mass. U.S.A.; other lasers may also be used such as HF, pulsed CO 2 , infrared lasers at wavelengths of about 2.6-3.2 μm, Er:YSGG and Er:YAG lasers) that is controlled by a laser emission repetition rate controller 26, and powered by a power supply 28. A laser beam attenuator 30 is employed to control the fluence of the laser pulses delivered from laser 24.
A controller 32 (e.g., a commercially available microprocessor-based computer) choreographs the PRK procedure based upon the parameters of zone size (34) and Diopter correction (36) which are selected by the PRK surgeon based upon the needs of patient 10. As described in detail below, based upon the input information, controller 32 optimizes the average pulse rate and the average pulse fluence for beam pulses 38 that are delivered to the patient's cornea.
A feedback device 40, such as a profilometer or keratometer (e.g., a PHOTOKERATOSCOPE™ manufactured by Sun Contact Lens Company of Kyoto, Japan, or a CORNEASCOPE™ manufactured by International Diagnostic Instruments Limited, Broken Arrow, Okla. U.S.A.), sends signals to the controller via a feedback path 42, for precise control of the laser during the photoablation procedure.
Beam-shaping optics 44 provide a beam of a desired shape and dimension to an optical delivery system housed within optical support assembly 16. The beam-shaping optics may not always be necessary, should the laser output beam be directly usable. However, with most lasers it will normally be desirable to perform some initial shaping of the beam. For example, some types of laser systems produce beams with rectangular cross-sections (e.g., excimer lasers) and it will normally be preferable to form the beams into beams with square or circular cross-sections.
As mentioned above, it has been discovered that under certain conventional PRK conditions, detrimental phenomena may occur that can affect the accuracy and predictability of PRK procedures.
Referring to FIGS. 2-2D, under conventional PRK conditions the pulse rate and fluence levels of the photoablative beam pulses are not optimized, and the resulting accumulation of fluid in the treatment zone can detrimentally affect the outcome of the PRK procedure.
FIG. 2 shows an initial beam pulse 46 and the resulting depth of the removed corneal tissue in an ablation zone 48. As shown schematically in FIG. 2A, if the time between pulses is not short on the time-scale of corneal fluid perfusion, which has been experimentally observed to be on the order of about 1 second, ocular fluid 50 from the patient's eye can accumulate in ablation zone 48.
Referring to FIG. 2B, ocular fluid 50 can detrimentally affect the ablation uniformity of a subsequent laser beam pulse 52, which is incident upon ablation zone 54, which includes ablation zone 48, by non-uniformly altering the fluence that ultimately reaches the corneal surface as a result of the radiation absorption characteristics of the ocular fluid. Accordingly, a non-uniform corneal surface feature, in the shape of a bump 56, is created in ablation zone 54 by pulse 52. Subsequently, additional fluid 58 can accumulate in ablation zone 54, thereby causing additional non-uniform corneal surface features to be created As shown in FIG. 3D, the final corneal shape resulting from PRK under such conditions can be rough with final surface features 60 having dimensions on the order of 1-10 μm.
It is to be appreciated that the drawings presented herein are shown schematically for ease of visualization, and that in actual PRK procedures the sharp, cliff-like features shown in these drawings would not be present, and instead smooth transition regions would be present between the different ablation zones.
Assuming the corneal fluids have an absorption coefficient in the range of 3000-5000 cm -1 , for low pulse rates, enough ocular fluid could accumulate between successive beam pulses to cause attenuation in the laser beam of about 5% in the region of fluid accumulation. Non-uniform accumulation of such fluid in the treatment zone would cause a difference in the corneal tissue removal rate of 0.01-0.02 μm/pulse, relative to the removal rate expected for un-attenuated fluence levels, resulting in a cumulative error effect.
In conventional PRK practiced by Summit Technology Inc., in the past, for zone sizes of about 5 mm, beam pulse fluence levels of about 180 mJ/cm 2 , and repetition rates of about 10 Hz, no significant non-uniformities in ablation have been observed for up to 5 Diopters of ablation. However, as the zone diameter is increased beyond about 5.5 mm (e.g., between about 6 and 10 mm) the inventors have discovered the importance of addressing the effects of fluid accumulation which if permitted to occur during PRK might cause non-uniform ablation resulting in an error in the final corneal shape which may degrade to some extent the final visual outcome. For instance, in treating a zone size of 6 mm, with 5 Diopter myopic correction, using a fluence level of about 180 mJ cm -2 , it was discovered that shifting the effective pulse rate of the laser to 20 Hz, surprisingly produced a significantly improved result in achieving the desired correction and without hazing that would be attributable to dehydration of the corneal tissue.
Following such observations, the inventors have provided a number of approaches for controlling the effects of ocular fluid accumulation in the patient's cornea in a manner substantially preventing the ocular fluid in the ablation area from affecting the photoablation of the patient's cornea during the PRK procedure, while preserving hydration of the corneal tissue.
Referring to FIGS. 3-3B, according to the invention, the beam pulse rate is optimally selected, within a practical operating range, to minimize the detrimental effects of fluid accumulation in the treatment zone.
As shown in FIG. 3, an initial beam pulse 62 removes a substantially known depth of corneal tissue in an ablation zone 64 in a patient's cornea 66. Referring to FIG. 3A, a subsequent beam pulse 68 is incident upon cornea 66, in an ablation zone 70 that includes initial ablation zone 64, in a time before a substantial amount of ocular fluid could accumulate in zone 64. Thus, beam pulse 68 is capable of uniformly ablating a substantially predetermined depth into cornea 66. As shown in FIG. 3B, the shape of the corneal surface resulting from PRK performed according to the invention is substantially smooth in the treatment zone size with a diameter between about 6 and 10 mm.
Particularly for wide-area ablation procedures, the beam pulse fluence levels are preferably fixed within a fluence range of about 100 to 250 mJ cm -2 . A more preferred range under present operating conditions is 170 to 190 mJ cm -2 . In the presently most preferred embodiments, the beam fluence is about 180 mJ cm -2 . In these procedures, only the repetition pulse rate is optimally selected so that detrimental intrapulse fluid accumulation is substantially avoided. Preferably, the beam pulse repetition rate is controlled by a control switch operating at an effective average repetition rate between about 12 to 100 Hz.
As mentioned above, the effective average rate (Rep Rate, expressed in Hz) at which the beam pulses are provided to a specific site, the effective average fluence (F, expressed in mJ cm -2 ) of the beam pulses, and the average diameter (φ, expressed in mm) of the ablation zone, have the general relationship:
Rep Rate≧C×φ.sup.2 /ln(F)
where C is between 1.5 and 2.
In certain preferred embodiments, the fluence level of each beam pulse 62, 68 is also optimally selected, within a practical range, to minimize the above-mentioned fluid accumulation effect.
Suitable irradiation intensities (i.e., fluence value) are selected based upon the wavelength of the laser radiation and the nature of the irradiated surface. For any given wavelength of laser radiation applied to the corneal layers, there is typically a threshold value of energy density below which significant ablation does not occur. Above this threshold density, there will be a range of energy density over which increasing energy densities provide increasing depths of ablation, until a saturation point is reached, above which no significant increase in ablation rate occurs.
Typically, under conventional PRK conditions, the laser system is used to provide an ideal fluence level at the corneal surface that is slightly less than the saturation value. For example, when ablating the cornea with radiation having a wavelength of 193 nm, using wide area ablation techniques, it is preferable to provide pulses of radiation that have ideal energy densities. Typically, a single pulse with this fluence level will ablate a depth of corneal tissue in the range of about 0.1 to 0.3 μm.
However, according to the invention, for a given radiation wavelength, fluence values greater than the ideal value are used to reduce the sensitivity of each pulse to fluid that may accumulate in the ablation zone. The fluence level is preferably selected so that the amount of fluid that accumulates in the ablation zone between successive pulses absorbs an amount of beam fluence equal to the additional fluence above the ideal value. This selection is based, in part, upon a desire not to unnecessarily heat the corneal surface. According to this scheme, the additional fluence does not cause significant additional ablation in the corneal regions in which fluid has not accumulated, and instead only serves, in effect, to remove accumulated ocular fluid from the ablation zone without dehydration of the tissue.
For wide area ablation, fluence up to about 250 mJ cm -2 may be employed In scanning systems with smaller beam size, fluence of a pulse can start as low as about 80 mJ cm -2 , but may be increased significantly with an upper limit as high as about 500 mJ cm -2 , depending on other parameters, for controlling the effect of accumulated fluid.
Because the sensitivity of the procedure varies as a power function with the Diopter value of the correction to be effected in the patient's cornea, for improved control, the system parameters can be selected to take this factor into account as well.
According to this realization, the beam pulses are selected so that, at any given site of incidence of the beam pulses in the ablation zone, the average rate (Rep Rate, expressed in Hz) at which the beam pulses are provided, the effective average fluence (F, expressed in mJ cm -2 ) of the beam pulses, the average diameter (φ, expressed in mm) of the ablation zone, and the dioptric power (D, expressed in Diopter) at the location of maximum correction to be effected in the patient's cornea at the location of the maximum correction, maintain the general relationship:
(φ.sup.2 ×D.sup.2)/(ln(F)×Rep Rate)≦C,
where C is about 15.
In certain other embodiments, the excess fluid that accumulates in the ablation area is substantially evaporated during the during PRK by applying non-photoablative beam pulses to the corneal surface.
Referring to FIG. 4, in one embodiment according to this scheme, the fluence level of the actual photoablative beam pulses 72 (e.g., from an excimer laser) are preceded by precursor pulses 74 below the intensity level required for corneal photoablation. The intensity of the precursor pulses is maintained sufficiently high to substantially evaporate excess fluid that may accumulate so that the ablating pulses are substantially unaffected by accumulated ocular fluid. FIGS. 4A through 4F illustrate various stages of this procedure
Alternatively, as shown in FIGS. 5-5D, pulses of infra-red radiation 80, 84 (e.g., from a pulsed CO 2 laser) of a wavelength selected to correspond with a peak in the wavelength-absorption profile of water can be employed to substantially evaporate the excess water accumulation in the ablation area during the PRK procedure. The amount of infrared radiation acting on a given volume at the surface, determined by wavelength, fluence, pulse duration and pulse rate, is selected to enhance evaporation of the ocular fluid. The wavelength of this radiation is selected to limit the absorption depth, for instance, to less than 100μ. For this purpose, a wavelength of about 10μ or 294μ or another wavelength corresponding to strong resonant absorption of water is selected. The infra-red beam cross-section is preferably shaped to substantially correspond to the ablation area, although in other embodiments restricting the beam to those regions tending to accumulate the most ocular fluid (central region in case of myopic correction; annular region in case of hyperopic correction) is employed. The pulses of infrared radiation 80, 84 are preferably delivered in a sequence that alternates with the incidence of the photoablative beam pulses 82, 86 on the surface of the ablation area. Alternatively, infrared pulses can be delivered to the treatment zone at twice the rate of the photoablative pulses, as shown in the drawings. As shown in FIG. 5D, the shape of the resulting surface is substantially smooth using this technique.
In an alternative embodiment, shown in FIG. 6, the effect of ocular fluid across the ablation area can be controlled by controlled application of evaporative energy to the anterior surface of a patient's cornea 88 by using a source 90 of illumination 92 having a sufficient intensity and a wavelength selected to be preferentially absorbed by the anterior 100 μm of corneal tissue. The power intensity of illumination 92 is preferably selected to be about 10 mJ cm -2 , or greater. As shown, source 90 preferably has an aperture, not shown, through which beam pulses 96 of photoablative radiation passes. Illumination 92 is preferentially delivered only to the treatment zone on the corneal surface to avoid unnecessary heating of the patient's eye.
Referring to FIGS. 7 and 7A, in two embodiments according to the invention, the projection of the photoablating radiation onto corneal treatment zones 98, 100, are selected, at least in one dimension, to be substantially less than the average diameter of the respective zones.
Referring to FIG. 7, a circular projection 102 of a beam pulse is incident upon surface 98. The location of the projection of each successive beam pulse is scanned across the treatment zone, as shown in phantom, until the corneal surface is shaped in the desired manner.
Referring FIG. 7A, a long, narrow projection 104 is incident upon corneal surface 100. The long dimension of projection 104 is preferably shorter than the average diameter of treatment zone 100. Projection 104 is scanned across treatment zone 104 in the direction indicated by double-headed arrow 106, until the corneal surface is properly shaped. The intensity profile across projection 104 is preferably modified in a manner enabling the desired shaping of the treatment zone.
Using the beam projections shown in FIGS. 7 and 7A, computer algorithms, as indicated above, can be employed to particular advantage. In one instance, the regions of the deeper tissue removal can be revisited more frequently to limit the intrapulse fluid accumulation to a higher degree than that employed in more shallow regions, thus to provide a more uniform removal of the tissue during the ablative process according to the prescribed correction. Similarly, the controller can alternate the locations of the site of incidence of successive pulses so that dynamic disturbances do not affect succeeding pulses.
Referring to FIG. 8, in an exemplary method of performing PRK according to the invention, a surgeon enters into controller 32, a desired photoablative beam pulse fluence range (110), a desired treatment zone size (112), and a desired Diopter of corneal correction (114) for a given patient. A computer program running within controller 32 computes an optimal beam pulse rate and beam fluence, within the specified range (116). Controller 32 also computes the required number of pulses to achieve the desired Diopter refractive correction in the patient (118) on a conservative basis that avoids over correction. The controller outputs the computed repetition pulse rate to the laser emission repetition rate controller 26 and the computed fluence level to laser beam attenuator 30 (120). Laser source 24 then delivers the required number of pulses to the patient's cornea. Feedback device 40 measures the shape of the corneal surface and relays this information to the controller (124). If the shape is within the desired correction (126), the procedure terminates (128). However, if further correction is required, the controller recomputes the required number of pulses to achieve the desired Diopter refractive correction (118).
In certain embodiments, drugs can be topically applied to the cornea to regulate and reduce the release of corneal fluids so as to control the uniformity of corneal hydration during PRK. Preferred ocular fluid-controlling drugs include phenol-barbital and carbonic-anhydrase inhibitors such as acetazolamide which has an inhibiting effect on fluid proliferation.
It should be noted that further preferred embodiments employ selected combinations of the above-described schemes, depending upon the parameters of the system, in order to avoid non-uniform material removal problems. The combinations are selected to achieve more predictable and accurate results.
The further features described in an application entitled Improvements in Photo-Refractive Keratectomy, filed contemporaneously herewith, and assigned to Summit Technology Inc. to whom the present invention is assigned, the contents of which are hereby incorporated by reference, can also be combined with useful effect with the features taught here. | A method and system are described for performing photorefractive keratectomy procedure employing pulses of photoablative radiation to selectively ablate corneal tissue of a patient's eye in an ablation zone on the anterior corneal surface to produce a desired refractive correction in the corneal tissue. The method and system employ control of the effect of ocular fluid at the corneal surface so as to reduce the disturbance of such fluid on the desired ablation process while maintaining hydration of the corneal tissue. Controlling the average repetition rate of the radiation pulses applied to the corneal surface so as to reduce intrapulse fluid accumulation at the corneal surface without dehydrating the corneal tissue, selecting an increased fluence level of the pulse applied to the corneal surface to reduce the effect of fluid accumulation at the corneal surface, and applying evaporative energy to the site of incidence of a pulse of an ablative beam prior to incidence of said pulse at said site are shown as ways to effect this control. Application of the new method and system to wide area ablation techniques and to scanning techniques are described Reduction of irregularities when ablating large areas, e.g., grater than 5.5 cm is made possible in either case. | 0 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention generally relates to an aquatic device for use in an aquatic environment.
2. Description of the Prior Art
Swimming appliances with extended fins for propelling a swimmer faster and more efficiently through the water have existed for years. For example, U.S. Pat. No. 1,745,280 discloses a devise having a fin or blade attached to the bottom of each foot. The device cooperates with the movement of the feet up and down in the water to propel the swimmer, similar to the function of a fish's tail.
U.S. Pat. No. 2,094,532 discloses a swimmer's appliance or shoe that employs a blade or fin coupled to a sole piece. A coiled spring and flexible cords cooperate to control the movement of the blade as the water pressure on the blade fluctuates during swimming. For this particular swimmer's appliance, the water pressure on the blade increases as the swimmer moves his or her foot forward through the water.
More recently, swimming appliances have been developed, not with the goal of making the swimmer go faster in the water, but with the goal of providing rehabilitative resistance when a wearer of the device moves in the water. U.S. Pat. No. 6,540,647 discloses a platform, a foot restraint attached to the platform, a first side wing pivotally attached to the platform, a second side wing pivotally attached to the platform opposite of the first side wing, a first end wing pivotally attached to the platform between the first side wing and the second side wing, and a second end wing opposite of the first end wing. During downward movement within the water, the wings are extended outwardly to create an increased surface area, which increases the resistance to the downward movement. During upward movement within water, the water pressure collapses the wings to make the device more hydrodynamic and thus reduce the resistance to the upward movement. The described device is a water rehabilitation device that mimics the up and down resistance of a stair-stepper machine without the bodily impacts and forces.
At least one drawback of the aforementioned appliances is that they only provide a training or rehabilitative benefit to the person as long as the person is either swimming or moving their legs directly up and directly down (i.e., stair stepping) in the water. This restricted range of motion limits the types of training and/or rehabilitative activities that can be done in the water. Consequently, it would be desirable to provide a training and/or rehabilitative device that could be used in combination with or as an alternative to other types of swimming appliances while providing a variety of new and different ways to train and/or do rehabilitative therapy in the water.
BRIEF SUMMARY OF THE INVENTION
The embodiments described herein are generally directed to an aquatic device that can be used in an aquatic environment for a variety of purposes, for example for physical therapy, rehabilitation, and/or exercise. The aquatic device permits a person to simulate, replicate, or mimic a walking or running gait cycle in the aquatic environment, reducing the stress/strain associated with walking or running on the ground. The aquatic device is adaptable and modifiable to have varying shapes, designs, sizes, resistance levels, and/or other aspects.
In one aspect, an aquatic device includes a foot-receiving member having a foot compartment and a leading edge surface, the foot compartment positioned aft of the leading edge surface; a first surface positioned proximate to at least a portion of the leading edge surface; a fin member having an upper surface, a lower surface, and a trailing edge surface, the fin member rotationally coupled to and extending from the foot-receiving member; and a second surface positioned proximate to at least a portion of the trailing edge surface, wherein the trailing edge surface of the fin member is contiguous with the leading surface of the foot-receiving member when a first force acting on the bottom surface of the fin member exceeds a first counterforce acting on the top surface of the fin member, and wherein the second surface of the fin member is contiguous with the first surface of the foot-receiving member when a second force acting on the top surface of the fin member exceeds a second counterforce acting on the bottom surface of the fin member.
In another aspect, an aquatic device includes a foot-receiving member having a foot compartment and a leading edge surface, the foot compartment positioned aft of the leading edge surface; a first surface positioned proximate to at least a portion of the leading edge surface; a fin member having a trailing edge surface, the fin member rotationally coupled to and extending from the foot-receiving member, the fin member movable between an extended position and a folded position; and a second surface positioned proximate to at least a portion of the trailing edge surface, wherein the trailing edge surface of the fin member is contiguous with the leading edge surface of the foot-receiving member when the fin member is in the extended position, and wherein the second surface of the fin member is contiguous with the first surface of the foot-receiving member when the fin member is in the folded position.
In yet another aspect, a method for simulating a gait in an aquatic environment includes moving an aquatic device downward through the aquatic environment, the aquatic device having a foot-receiving member rotationally coupled to a fin member, wherein moving the aquatic device downward urges a trailing edge surface of the fin member against a leading edge surface of the foot-receiving member; and moving the aquatic device upward through the aquatic environment wherein a first surface, which is positioned adjacent to and at a first angle relative to the leading surface of the foot-receiving member, is urged against a second surface, which is positioned adjacent to and at a second angle relative to the trailing edge surface of the fin member.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
In the drawings, identical reference numbers identify similar elements or acts. The sizes and relative positions of elements in the drawings are not necessarily drawn to scale. For example, the shapes of various elements and angles are not drawn to scale, and some of these elements are arbitrarily enlarged and positioned to improve drawing legibility. Further, the particular shapes of the elements as drawn, are not intended to convey any information regarding the actual shape of the particular elements, and have been solely selected for ease of recognition in the drawings.
FIG. 1 is a top, right, isometric view of an aquatic device having sidewalls and in an extended position, according to the illustrated embodiment.
FIG. 2 is a bottom isometric view of the aquatic device of FIG. 1 showing a hinge mechanism.
FIG. 3 is a side, elevational expanded view of the respective angles of a first surface and a second surface of the aquatic device of FIG. 1 relative to hinge rotation centerline, according to another illustrated embodiment.
FIG. 4 is a top, right, isometric view of the aquatic device of FIG. 1 in a folded position, according to the illustrated embodiment.
FIG. 5 is a side, elevational view of an aquatic device in an extended position without sidewalls, according to another illustrated embodiment.
FIG. 6 is a side, elevational view of an aquatic device in an extended position without sidewalls and with an elastic hinge, according to another illustrated embodiment.
FIG. 7A is a schematic view of an aquatic device moving through a stance phase in an aquatic environment, according to one illustrated embodiment.
FIG. 7B is a schematic view of the aquatic device of FIG. 7A transitioning from a stance phase to a swing phase.
FIG. 7C is a schematic view of the aquatic device of FIG. 7A moving through a swing phase.
DETAILED DESCRIPTION OF THE INVENTION
In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the invention. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures associated with aquatic fins and methods of using the same have not been shown or described in detail to avoid unnecessarily obscuring the description.
Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is as “including, but not limited to.”
Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
The headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.
This description generally relates to an aquatic device that can be used in an aquatic environment for a variety of purposes, for example physical therapy, rehabilitation, and/or exercise. In one embodiment, the aquatic device permits a person to run in the water to strengthen muscles while reducing impact on joints, which may be part of a therapeutic or rehabilitative regimen after an injury, particularly in the foot, leg, knee, pelvic, and/or back region. In another embodiment, the aquatic device can benefit persons training for a sport, exercising to loose weight, or wanting to improve their overall fitness.
Biomechanics of Human Gait Cycle and Possible Advantages of Aquatic Device
Before describing the embodiments of the invention, a brief discussion of the biomechanics of a human gait cycle is provided. The normal human gait cycle is composed of a stance phase and a swing phase. In general, the stance phase comprises initial contact (heel strike), loading, mid stance, terminal stance, and pre-swing (ending in toe-off). The swing phase comprises an initial, mid, and terminal swing.
It is understood that the majority of energy transfer associated with walking or running occurs during the stance phase, in particular during initial contact and loading. During this time, the kinetic and/or gravitational (inertial) energy of the person is converted to heat, noise, and/or strain energy upon impact of the foot or feet with the ground or other medium. The strain energy is absorbed by a combination of the person's body (e.g., muscles and joints) and the ground or other medium.
In an aquatic environment when compared to an air environment, an additional amount of loading and/or resistance is imparted to the body during both the stance phase and the swing phase. The additional loading occurs because the drag (i.e., resistance to motion) from the water, for example, is much greater than the drag or resistance from the air. Further, the amount of energy transferred to the body during the stance phase is decreased in the aquatic environment primarily because the buoyancy effect of the water counteracts gravity.
It is understood and appreciated that a person moving their bare foot or feet through the water would encounter much less resistance than if their foot or feet were contained in some type of fin device. These fin devices are typically configured to enhance a kicking stroke of a swimmer, thus allowing the swimmer to achieve a more efficient and powerful stroke when trying to accelerate through the water. With these types of fin devices, however, the resistance is generally equal when flexing or extending the leg, which is in contrast to resistance or loading cycle when walking or running on ground.
Accordingly, one possible advantage of the aquatic devices and methods described and claimed herein is that a person may substantially replicate or mimic a walking and/or running gait cycle in an aquatic environment, e.g., a swimming pool, lake, etc. In addition, the aquatic devices and methods may provide many of the benefits associated with running, to include strengthening the muscles in a similar manner, while reducing wear and tear on the body, specifically on the joints. Alternatively or additionally, the aquatic device may help people to lose weight and minimize injury by permitting the user of the device to achieve a good cardiovascular workout while reducing the amount of stress/strain in the muscles, joints, and/or other tissue. Yet another advantage of the aquatic device permits persons with bad (i.e., injured, deteriorated, arthritic, etc.) joints or with recently repaired joints (e.g., joints that have been surgically repaired, such as anterior cruciate ligament (ACL) reconstruction) to strengthen the muscles associated with walking and/or running in a low impact, aquatic environment. For recently repaired joints, for example, the aquatic device may further help the person to accelerate the range of motion, flexibility, and the overall healing process of the joint.
The Aquatic Device
FIG. 1 shows an aquatic device 100 having a foot-receiving member 102 , a fin member 104 , a first surface 106 , and a second surface 108 , according to one illustrated embodiment. The foot-receiving member 102 includes a foot compartment 110 and at least a leading edge surface 112 . A portion 111 of the foot-receiving member 102 may operate as a fin, thus increasing the surface area of the foot-receiving member 102 . The fin member 104 includes an upper surface 114 , a lower surface 116 , and at least a trailing edge surface 118 . The foot-receiving member 102 is rotationally coupled to the fin member 104 such that the fin member 104 is moveable between a first or extended position, which is shown in FIG. 1 , and a second or folded position, which is shown in FIG. 4 .
The foot-receiving member 102 and the fin member 104 may be made of similar or different kinds of rubber or plastic materials. In one embodiment, the foot-receiving member 102 is made from a soft, pliable, and possibly stretchable material to allow a person to comfortably insert their foot and yet remain snug while being worn. The fin member 104 may be made from a stiff rubber and/or hard plastic material so that the fin member 104 does not bend under applied and repetitive loading.
Both the foot-receiving member 102 and the fin member 104 may include attached or integrally molded reinforcing stiffening members 113 a , 113 b (i.e., illustrated as sidewalls) to increase the overall strength and/or stiffness of the foot-receiving member 102 and/or the fin member 104 . In the illustrated embodiment, the first surface 106 may include a portion of the lower surface 115 of the foot-receiving member 102 and a portion of the sidewall 113 a . In a similar manner, the second surface 108 may include a portion of the lower surface 116 of the fin member 104 and a portion of the sidewall 113 b.
The sidewalls 113 a , 113 b located on the foot-receiving member 102 and on the fin member 104 , respectively, can increase the bending strength and/or stiffness of these components. The thickness and height of the sidewalls 113 a , 113 b are two parameters, for example, that can be selected and/or modified to increase or decrease the flexibility and/or strength of the fin member 104 . As will be described in greater detail below, the foot-receiving member 102 and/or the fin member 104 can vary in thickness along the length. In one embodiment, the thickest portion of the foot-receiving member 102 is near the leading edge surface 112 , and the thickest portion of the fin member 104 is near the trailing edge surface 118 . The overall surface area of the aquatic device 100 and particularly the surface area of the fin member 104 may primarily provide the desired resistance in the aquatic environment.
FIG. 2 shows the aquatic device 100 having a hinge mechanism 120 , according to one illustrated embodiment. The hinge mechanism 120 , as illustrated, operates similar to a common door hinge with a first plate 122 attached to the foot-receiving member 102 and a second plate 124 attached to the fin member 104 . The first plate 122 and the second plate 124 rotate about a pin 126 , thus allowing the fin member 104 to rotate relative to the foot-receiving member 102 . The pin 126 and the plates 122 , 124 can be made from materials similar to those described above or can be made from other materials, such as from metals like aluminum or corrosion resistant steel, commonly referred to as CRES.
In this illustrated embodiment and depending on the thickness of the first plate 122 , the first surface 106 may include the surface of the first plate 122 and the corresponding surface 128 of the sidewalls 113 a . Likewise and depending on the thickness of the second plate 124 , the second surface 108 may include the surface of the second plate 124 and the corresponding surface 130 of the sidewalls 113 b.
FIG. 3 shows that an angle 132 of the first surface 106 can be in the range of about 45 to 85 degrees from the leading edge surface 112 of the foot-receiving member 102 and an angle 134 of the second surface 108 can have equal and opposite proportions, e.g., range from about 45 to 85 degrees from the trailing edge surface 118 of the fin member 104 . In one exemplary embodiment, the angles 132 , 134 are each 45-degrees, respectively; therefore the fin member 104 is positioned at approximately a 90-degree angle when in the folded position, which occurs during the swing phase of the gait. As is further shown, the first and second plates 122 , 124 of the hinge mechanism 120 may be recessed in the foot-receiving member 102 and the fin member 104 , respectively.
FIG. 4 shows the aquatic device 100 in the folded position. Specifically, the fin member 104 is rotated downward and relative to the foot-receiving member 102 . The foot-receiving member 102 includes a first wedge section 136 proximate the hinge mechanism 120 and the fin member 104 includes a second wedge section 138 proximate the hinge mechanism 120 . The wedge sections 136 , 138 can be molded and/or integrally formed with the foot-receiving member 102 and the fin member 104 , respectively. The wedge sections 136 , 138 provide the aquatic device 100 with increased strength and stability near the hinge mechanism 120 . In addition, the wedge sections 136 , 138 each include contact surfaces 140 , 142 to transfer load from the fin member 104 directly to the foot-receiving member 102 via compression when the aquatic device 100 is in an extended position. In addition, the surfaces 140 , 142 may comprise a relatively thick part or the thickest part of the foot-receiving member 102 and the fin member 104 , respectively and also be positioned approximately over a center of rotation and/or hinge centerline of the pin 126 . As will be described in greater detail below regarding the operation of the aquatic device 100 , it is understood that the fin member 104 will be forced upward, placing the hinge mechanism 120 in compression and the wedge sections 136 , 138 in compression, when the person is stepping forward and downward during the stance phase of walking or running in the aquatic environment.
The wedge sections 136 , 138 will typically be structurally identical or substantially similar. For purposes of brevity, only the wedge section 138 of the fin member 104 will be described in detail. The wedge section 138 of the fin member 104 , for example, can be an increased thickness portion of the fin member 104 . The fin member 104 can vary in thickness with the thickest portion near the hinge mechanism 120 .
FIG. 5 shows an alternate embodiment of an aquatic device 200 , without the sidewalls 113 a , 113 b , and having a foot-receiving member 202 , a fin member 204 , and a hinge mechanism 206 . In the illustrated embodiment, a first plate 208 of the hinge mechanism 206 extends widthwise from one side of the foot-receiving member 202 to the other. Accordingly, a first surface 210 of the aquatic device 200 is the same as the surface of the first plate 208 . Similarly, a second plate 212 extends widthwise from one side of the fin member 204 to the other. Thus, a second surface 214 of the aquatic device 200 is the same as the surface of the second plate 212 .
FIG. 6 shows another embodiment of an aquatic device 300 without sidewalls and including a foot-receiving member 302 and a fin member 304 . The foot-receiving member 302 is rotationally coupled to the fin member 304 through an elastic hinge 306 . The elastic hinge 306 can be made from rubber, plastic, or other equivalent materials as long as permits the fin member 304 to repetitively rotate, under load, relative to the foot-receiving member 302 . The elastic hinge 306 can be bonded, molded, or fastened to the foot-receiving and fin members 302 , 304 , respectively. A first surface 308 of the aquatic device 300 comprises the exposed surface of the portion 310 of the elastic hinge 306 that is coupled to the foot-receiving member 302 . A second surface 312 of the aquatic device 300 comprises the exposed surface of the portion 314 of the elastic hinge 306 that is coupled to the fin member 304 . Additionally or alternatively, an optional or alternate elastic hinge 316 may be positioned on the surfaces 318 , 320 of the foot-receiving member 302 and the fin member 304 , respectively.
Operation of the Aquatic Device
FIGS. 7A-7C schematically show an aquatic environment 400 where the water 402 , for example, acts on an aquatic device 404 as a person 406 exercises their walking or running gait. It is understood and appreciated that the following description, in combination with FIGS. 7A-7C , involves assumptions and simplifications regarding physics, fluid dynamics, and other disciplines. Thus, the following description is provided to demonstrate the operation of the aquatic device 404 as it may be used in one type of aquatic environment 400 , such as a pool.
FIG. 7A shows the commencement of the stance phase. The person 406 begins moving their leg forward and downward through the water 402 , wherein the arrow 408 indicates this movement. The water 402 resists this movement, which is indicated by the plurality of vertical and horizontal force vectors 410 . The force of the water 410 resisting the person's movement (i.e., drag) acts to move the fin member 412 of the aquatic device 404 into the extended position.
FIG. 7B shows the person 406 in a transition period between reaching the end of the stance phase and beginning the swing phase of their gait. In one embodiment and during at least a brief moment in time, the person's weight 414 and the water pressure 416 acting on the aquatic device 404 may be reacted by the bottom surface 418 of the aquatic environment 400 if the water level permits the person to contact the bottom surface 418 during their gait movement. In another embodiment, the aquatic device 404 permits the person to run and/or walk in the aquatic environment 400 's when the level of the water is greater than the height of the person. Thus, the aquatic device 404 permits to the person to run and/or walk in the aquatic environment 400 without ever touching the bottom surface 418 .
FIG. 7C shows the person 406 actively moving 408 through the swing phase of their gait. The water 402 again resists this movement, as indicated by the plurality of vertical and horizontal force vectors 420 . In the illustrated embodiment, however, the resistance of the water is decreased because the fin member 412 of the aquatic device 404 is forced into the folded position. Hence, there is less surface area of the aquatic device 404 for the person 406 to urge through the water 404 . The fin member 412 remains in the folded position and the resistance remains low through the swing phase and/or until the person's leg 406 reaches its maximal level of extension. This level can vary depending on the person's physical capabilities or desires. As the person 406 transitions back to the beginning of the stance phase, the fin member 412 is forced back into the extended position ( FIG. 7A ) and greater resistance is applied to the aquatic device 404 because of the substantially greater surface area (commonly referred as “drag area”) resisting the movement of the person 406 . The aforementioned operation may be repeated numerous times and at varying rates for a variety of purposes, such as rehabilitation, therapy, exercise, and/or some other purpose.
The amount of resistance the person 406 experiences may be varied. For example the amount of resistance can be directly related to the effort (speed, leg extension, etc.) of the person. Additionally or alternatively, removing and installing different sized fin members 412 may vary the amount of resistance. In one embodiment, the hinge mechanism 422 can be quickly and easily detached from the fin member 412 , which permits a different sized fin member 412 to be quickly re-installed.
All of the above U.S. patents or patent applications referred to in this specification and/or listed in the Application Data Sheet are incorporated herein by reference, in their entirety.
From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims. | An aquatic device is usable in an aquatic environment for a variety of purposes, such as physical therapy, rehabilitation, and/or exercise. The aquatic device permits a person to simulate a walking or running gait cycle in the aquatic environment, reducing the stress/strain associated with walking or running on the ground. An aquatic device includes a foot-receiving member rotationally coupled to a fin member. The fin member, when in an extended position, provides increased resistance as the person attempts to walk or run in the aquatic environment. During a walking or running gait, the fin member moves into a folded position, thus reducing the resistance of the water on the aquatic device. The aquatic device is adaptable and modifiable to have varying shapes, designs, sizes, resistance levels, and/or other aspects. | 0 |
CROSS-REFERENCE TO RELATED APPLICATION(S)
[0001] This application claims the benefit of U.S. Provisional Patent Application Ser. No. 61/875,896, filed Sep. 10, 2013, the entirety of which is hereby incorporated herein by reference.
STATEMENT OF GOVERNMENT INTEREST
[0002] This invention was made with government support under agreement No. DMR-1215034, awarded by the National Science Foundation. The government has certain rights in the invention.
BACKGROUND OF THE INVENTION
[0003] 1. Field of the Invention
[0004] The present invention relates to nanocrystal growth and, more specifically, to a method of generating nanocrystal frame structures.
[0005] 2. Description of the Related Art
[0006] Manipulating the morphology, structure and composition of noble-metal nanocrystals offers a powerful means to tailor and improve their properties for a myriad of applications, such as catalysis, plasmonics, and biomedicine. In particular, bimetallic (and trimetallic) nanocrystals have drawn interest owning to their abundant variations in compositions and spatial distributions. Compared to monometallic nanocrystals, the electronic coupling between the two constituent metals of a bimetallic nanocrystal can dramatically improve their catalytic performance or even initiate new features. For example, the oxygen reduction reaction activity catalyzed by Pt 3 Ni {111} surface holds a 90-fold gain over the state-of-art Pt/C electrocatalyst. Moreover, the localized surface plasmon resonance peaks of Au—Ag nanocages can be tuned in a wide-range by adjusting the ratio of Au:Ag. These advances demonstrated the significance of rational design of bimetallic nanocrystals with new structures and highlighted properties to fit a specific application.
[0007] Therefore, there is a need for methods of controlling the morphology of bimetallic nanocrystals.
SUMMARY OF THE INVENTION
[0008] The disadvantages of the prior art are overcome by the present invention which, in one aspect, is a method of generating a nanocrystal with a core-frame structure, in which a seed crystal, including a first substance, is exposed to a capping agent. The seed nanocrystal has a plurality of first portions that each has a first characteristic and a plurality of second portions that each has a second characteristic, different from the first characteristic. The capping agent has a tendency to adsorb to portions having the first characteristic and has a tendency not to adsorb to portions having the second characteristic. As a result, a selectively capped seed nanocrystal is generated. The selectively capped seed nanocrystal is exposed to a second substance that has a tendency to nucleate on the plurality of second portions and that does not have a tendency to nucleate on portions that have adsorbed the capping agent, thereby generating a frame structure from the plurality of second portions of the seed nanocrystal.
[0009] In another aspect, the invention is a method of generating a cubic frame structure, in which a plurality of Pd (palladium) nanocrystals having a cubic shape is exposed to a solution including Br − (bromide) ions for a time sufficient so that the Br − ions are adsorbed to a {100} family of crystal facets on the Pd nanocrystals so as to form selectively capped nanocrystals. A solution including a salt precursor to Rh (rhodium) is added to the selectively capped nanocrystals at a rate that causes Rh atoms derived from the precursor to nucleate from edges and corners of the Pd nanocrystals so as to generate a core-frame structure affixed to the edges and corners of the Pd nanocrystals. Pd is then etched from the core-frame nanocrystals so as to leave a plurality of cubic Rh frame structures.
[0010] In yet another aspect, the invention is a method of generating a cuboctahedral core-frame structure, in which a plurality of Pd nanocrystals having a cuboctahedral shape is exposed to a solution including Br − ions for a sufficient time so that the Br − ions are adsorbed to a {100} family of crystal facets on the Pd nanocrystals so as to form selectively capped nanocrystals. A solution including a salt precursor to Rh is added to the selectively capped nanocrystals at a rate that causes Rh atoms to nucleate from a {111} family of crystal facets on the Pd nanocrystals so as to generate a frame structure affixed to the {111} family of crystal facets of the Pd nanocrystals.
[0011] These and other aspects of the invention will become apparent from the following description of the preferred embodiments taken in conjunction with the following drawings. As would be obvious to one skilled in the art, many variations and modifications of the invention may be effected without departing from the spirit and scope of the novel concepts of the disclosure.
BRIEF DESCRIPTION OF THE FIGURES OF THE DRAWINGS
[0012] FIGS. 1A-1D are a series of perspective view schematic diagrams showing development of a cubic frame structure.
[0013] FIGS. 2A-2C are a series of plan view schematic diagrams showing development of a cubic frame structure.
[0014] FIGS. 3A-3D are a series of perspective view schematic diagrams showing development of a cuboctahedral core-frame structure.
[0015] FIG. 4 is a flow chart demonstrating one method of making a frame structure.
[0016] FIG. 5 is a micrograph of a plurality of cubic frame structures made in accordance with one embodiment of a method disclosed herein.
[0017] FIG. 6 is a micrograph of a plurality of cuboctahedral frame structures made in accordance with one embodiment of a method disclosed herein.
DETAILED DESCRIPTION OF THE INVENTION
[0018] A preferred embodiment of the invention is now described in detail. Referring to the drawings, like numbers indicate like parts throughout the views. Unless otherwise specifically indicated in the disclosure that follows, the drawings are not necessarily drawn to scale. As used in the description herein and throughout the claims, the following terms take the meanings explicitly associated herein, unless the context clearly dictates otherwise: the meaning of “a,” “an,” and “the” includes plural reference, the meaning of “in” includes “in” and “on.”
[0019] A Rh frame structure 118 can be generated by adsorbing a capping agent, such as a solution including bromide ions (Br − ) 110 to the {100} facets of at least one Pd seed nanocrystal 100 , leaving the edges 112 and corners 113 uncapped, as shown in FIG. 1A and FIG. 2A . The nanocrystal 110 is then exposed to a solution that includes a Rh precursor 114 , as shown in FIG. 1B . As a result, Rh atoms derived from the precursor will nucleate on the edges 112 and corners 113 , thereby forming frame structure 116 around the Pd nanocrystal 100 , as shown in FIG. 1C and FIG. 2B . The combined nanocrystal 100 and frame structure 116 is referred to as a “core-frame structure” 118 . Pd can be etched from the core-frame structure 118 to leave a void 120 surrounded by the frame structure 116 , as shown in FIG. 1D and FIG. 2C .
[0020] In one embodiment, as shown in FIGS. 3A-3B , a cuboctahedral Pd crystal 200 with six {100} facets 202 and eight {111} facets 204 can be exposed to a capping agent so that the capping agent 214 adheres to the {100} facets 202 . The capped crystal is then exposed to a Rh precursor, which results in Rh nucleation 216 on the {111} facets 204 . In one embodiment, if the Rh precursor is applied at a first rate and a relatively low temperature (e.g., Rh precursor applied at 4.0 mL/hour and 140° C.), then the nucleation will form islands of Rh on the exposed facets. In another embodiment, if the Rh precursor is applied at a second rate and a at a relatively high temperature (e.g., Rh precursor applied at 1.0 mL/hour and 180° C.), then the nucleation will demonstrated layered growth to form pyramids 218 extending from the exposed facets.
[0021] In one embodiment, as shown in FIG. 4 , the {100} facets of Pd nanocubes are prepared by reducing Na 2 PdCl 4 with L-ascorbic acid (AA) in an aqueous solution containing bromide ions 300 . A Pd-Rh core-frame structure is grown from the corners and edges of the nanocubes 302 by exposing them to a salt precursor to Rh that includes Na 3 RhCl 6 at a rate and temperature for an amount of time that will result in a desired core-frame structure morphology. Pd is selectively etched from the core-frame structure so as to leave a Rh frame structure 304 .
[0022] A cubic frame structure is shown in FIG. 5 and a cuboctahedral frame structure is shown in FIG. 6 .
[0023] In one experimental embodiment, Pd—Rh bimetallic nanocrystals were made from cuboctahedral Pd seed nanocrystals. For investigating the site-selective overgrowth of the secondary metal atoms, a seed with more than one type of crystallographic facets was used, as such a seed crystal allows one to clarify the role of different crystallographic facets. Well-defined cuboctahedral Pd nanocrystals, which are enclosed by eight {111} facets and six {100} facets, were chosen as the seeds to conduct the overgrowth of Rh. Pd—Rh nanocrystals were obtained after the addition of 6.0 mL of Na 3 RhCl 6 solution in ethylene glycol (EG) (2.5 mg/mL) with a syringe pump at 4.0 mL/h into a reaction solution, containing KBr as the capping agent, L-ascorbic acid (AA) as the reductant, and cuboctahedral Pd nanocrystals as the seeds. As a result, multi-pods were anchored on all the {111} surface of the cuboctahedral Pd seeds, giving the cuboctahedral Pd-Rh nanocrystals a partially rough appearance. No Rh atoms nucleated on {100} surfaces of the cuboctahedral Pd seeds. The main surface of the Rh portion was parallel to the {200} plane, indicating the surface of the protruding Rh multi-pods were dominated by {100} surface. The exposure of Rh{100} surface could be attributed to the presence of Br − ions in the reaction solution, as Br − ions are specific capping agents for Rh(100) surface. The orientation of the overgrown Rh portions were identical with the Pd cuboctahedral seeds. The results confirmed the successful spatially-controlled overgrowth of Rh on the {111} surfaces of the cuboctahedral Pd nanocrystals and the preservation of Pd{100} surfaces.
[0024] Also monitored was the growth process of these cuboctahedral Pd—Rh nanocrystals when increasing amounts of Na 3 RhCl 6 solution in EG were added into the reaction solution. Aliquots of the reaction solution were taken out at various stages. When a relatively small amount of Na 3 RhCl 6 (1.0 mL, 2.5 mg/L) was introduced into the reaction solution in the presence of KBr, some salient islands emerged at the {111} surfaces while the {100} surfaces remained smooth. This observation demonstrated that the generated Rh atoms selectively deposited and nucleated on Pd{111} surfaces at the early stage of the growth process. With the increasing addition of Na 3 RhCl 6 , the number of salient islands on each (111) facet was increased. Subsequently, the Rh salient islands continuously grew up, and finally formed multi-pods on each of the Pd (111) surfaces. During the entire overgrowth process, the Pd{100} surfaces preserved smooth, resulting in a spatially-controlled overgrowth of Rh atoms on Pd{111} surfaces. The slow adding rate of Na 3 RhCl 6 was an important factor to avoid the self-nucleation of the newly generated Rh atoms and enable the Rh atoms to nucleate and grow on the Pd seeds. In this condition, as the concentration of the generated Rh atoms was much higher from the beginning, most of them preferentially self-nucleated and the following Rh atoms tended to grow on the small Rh seeds forming a large number of Rh nanocrystals. As a result, very few Rh atoms overgrew on the cuboctahedral Pd seeds. If the Na 3 RhCl 6 solution was added at a slower rate (1.0 mL/h), the concentration of the generated Rh atoms was even lower. At the initial stage, there would be fewer nucleation sites on each of the Pd{111} surface. The continuous growth of Rh was also slowed down. As a result, the number of the Rh pods on each of the Pd{111} surface was decreased, giving the final cuboctahedral Pd—Rh nanocrystals a relative smooth appearance.
[0025] To further investigate the effect of different shapes of the Pd polyhedral seeds, octahedral Pd nanocrystals and cubic Pd nanocrystals were used as the seeds to conduct the synthesis of Pd—Rh bimetallic nanocrystals in the presence of KBr. For the octahedral Pd seeds, the surface was enclosed by eight Pd{111} facets with small portion of {100} facets on the slight truncated vertexes. After adding 6.0 mL of Na 3 RhCl 6 solution (2.5 mg/mL), all the Pd{111} surfaces were covered by a dense array of Rh salient pods, indicating the nucleation and deposition of the generated Rh atoms on the entire Pd {111} surfaces. It was found that the small {100} surfaces at the vertexes were still kept smooth. A number of Rh salient islands emerged on all the Pd { 111 } surfaces, confirming the nucleation and then overgrowth process. Compared to octahedral-Pd nanocrystals, cubic Pd nanocrystals were enclosed by six {100} surfaces with slight truncation at the corners and edges. The products turned to be Pd—Rh core-frame nanocubes with concave side faces. This core-frame concave structure was generated by a selective-deposition of Rh atoms only on the truncated corner and edge sites of the cubic Pd seeds.
[0026] The overgrowth of Rh atoms on Pd {100} surfaces with the three different Pd polyhedrons as the seeds (cuboctahedral, octahedral, and cubic nanocrystals) were all debarred in the presence of KBr. Similar spatially-controlled Pd—Rh bimetallic nanocrystals could also be obtained when KBr was substituted by an equimolar amount of NaBr. This site-selective overgrowth of Rh atoms may be attributed to the blocking effect of Br − ions by capping the Pd {100} facets. The addition of Bf ions can promote the formation of Pd {100} facets by the capping effect. The cubic Pd seeds used in the overgrowth of Rh were also synthesized with the capping of Bf ions. And the cuboctahedral and octahedral Pd nanocrystals were obtained from a secondary growth of the preformed Br − -capped cubic Pd nanocrystals in an aqueous solution without the addition of extra Br − ions.
[0027] The surface capping agents of metallic nanocrystals could affect their secondary growth or reactions. For example, the galvanic replacement reactions involved cubic metal templates could be precluded from starting at {100} surfaces by the protection of {100} with surface specific capping agents, such as PVP or hexadecylamine. For further illuminating the blocking effect of Br − ions by capping on Pd {100} surface, a set of experiments was conducted to synthesize Pd—Rh bimetallic nanocrystals using the three different polyhedral Pd seeds, respectively, without the addition of KBr. During the reaction, the original layer of Br − that capped on Pd {100} could dynamically drop out as the relative high temperature (140° C.), leading to the weakening or disappearance of blocking effect. Without the addition of extra KBr, both the {100} and {111} surfaces of the cuboctahedral Pd seeds were covered by a dense layer of Rh multi-pods. As a result, the integral morphology of the Pd—Rh bimetallic nanocrystals from cuboctahedral Pd nanocrystals was identical to that from the octahedral Pd seeds. In the absence of capping agent, the shape of these Rh multi-pods was irregular. When cubic Pd nanocrystals was applied as the seeds in the absence of KBr, beside on the corners and edges, Rh multi-pods also anchored on the side Pd{100} surfaces. This morphological transition illuminated the blocking effect of Br − ions by capping on Pd{100} surface during the aforementioned spatially-controlled overgrowth of Rh on Pd polyhedral seeds.
[0028] The premise of this spatially-controlled synthesis of Pd—Rh bimetallic nanocrystals was the slow kinetics of generation of Rh atoms. As the reduction of Na 3 RhC 16 under this synthetic condition was extremely fast, the generation of Rh atoms could be completely manipulated by the injection rate of Na 3 RhCl 6 solution. The Na 3 RhCl 6 solution was added slowly (4 mL/h, 2.5 mg/mL) into the reacting system with a syringe pump. Once the Na 3 RhCl 6 was added into the reaction solution, it was immediately reduced into Rh atoms, which then deposited on the Pd seeds. Therefore, the concentration of the newly generated Rh atoms was kept extremely low in the reaction solution, which could effectively avoid the self-nucleation and provide the Rh atoms the opportunity to nucleate and deposit on the surface of the Pd seeds and thus achieve the spatially-selective overgrowth.
[0029] All the exposed Pd{100} facets were capped and preserved by Br − ions during the overgrowth process. The generated Rh atoms were caused to nucleate and deposit on the bare area, for example, {111} facets and truncated corners/edges. In a seed-mediate overgrowth for bimetallic nanocrystals, the difference of the bond dissociation energies between the two involved metal elements could largely affect their heterogeneous nucleation and growth modes. For example, Pd—Pt dendritic core-shell nanostructures could be obtained when Pt was reduced by a relative strong reducing agent and deposited on preformed Pd seeds because the bond dissociation energy of Pt—Pt bond (307 kJ/mol) is much higher than that of Pt—Pd (191 kJ/mol) and Pd—Pd bonds (136 kJ/mol). The heterogeneous nucleation and growth of Pt atoms on Pd surface was assigned to the island growth mode. The nucleation and growth of Rh on the substrate of Pd seeds also followed this island growth mode because of the relative high bond dissociation energy of Rh—Rh (285 kJ/mol) and the large surface free energies of Rh. When cuboctahedral Pd nanocrystals were applied as the seeds, because the Pd{100} surfaces were blocked by the capping Br − ions, the generated Rh atoms were preferentially nucleated on Pd{111} surfaces with multi-sites forming salient Rh islands. And then the adding Rh atoms preferentially deposited and grew on these Rh islands as the strong Rh—Rh interaction, leaving Pd {100} surfaces uncovered. When octahedral Pd nanocrystals enclosed only by {111} facets were used as the seeds, the Rh atoms would nucleate and deposit on the entire surface. However, the generated Rh atoms could only deposit at the truncated corner and edge sites on the cubic Pd seeds, whose {100} facets were covered by Br − ions. The migration of initially deposited Rh atoms was involved to minimize the surface free energy as the corner and edge sites are much higher in energy. The surface migration let to the formation of Rh faces with smooth surfaces.
[0030] Rh frames from Pd—Rh Bimetallic nanocrystals were generated through selective etching. One of the advantages from the spatial composition-separation of a hybrid bimetallic nanocrystal is the difference in reactivity between the two metal components. For instance, Rh possesses much higher oxidative corrosion resistance than Pd. The Pd cubic core could be selectively removed from the Pd—Rh core-frame nanocrystal to generate a cubic frame consisting of pure Rh. This selective-etching was conducted in an aqueous solution based on the oxidation etchant of Fe 3+ /Br − pair. The structure of Pd—Rh bimetallic nanocrystals apparently determined the final structure of Rh nanoframes. The Rh nanoframes from cuboctahedral Pd—Rh nanocrystals, octahedral-Pd—Rh nanocrystals and cubic Pd—Rh nanocrystals are referred to herein as cuboctahedral Rh NFs, octahedral Rh NFs and Cub-Rh NFs, respectively. For the cuboctahedral Rh NFs, as no Rh grew on the {100} facets of the Pd cores, large caves emerged at the region of bare Pd{100} facets after the dissolution of Pd cores. For the octahedral Rh NFs, all the frame walls consisted of a dense array of Rh pods without apparent holes on the surface, taking an integral octahedral nanocage structure. As the entire {100} surfaces of Pd cores were exposed in cubic Pd—Rh nanocrystals, the cubic Rh NFs resulted in a cubic skeleton frame structure with great open degree after the removal of Pd cores. These Rh frame structures may have great potential in catalytic applications owning to their large surface area and unique hollow/open structures.
[0031] Spatially-controlled synthesis of Pd-Rh nanocrystals was achieved through a site-selective overgrowth of Rh atoms on polyhedral Pd seeds. Three types of Pd polyhedrons, including Pd cuboctahedrons, Pd octahedrons and Pd cubes, have been applied as the seeds to illuminate the effects of the seed shapes and the capping agents. Under the kinetic control and the presence of Br − ions, Rh atoms selectively nucleated and deposited on the {111} facets of cuboctahedral Pd and octahedral Pd seeds, or only at the corner and edge sites of cubic Pd seeds. This selective overgrowth of Rh on Pd seeds followed an island growth mode owing to the relative high bond dissociation energy of Rh—Rh and large surface free energies of Rh. This mechanistic study confirmed the slow addition of Na 3 RhCl 6 solution can efficiently avoid the self-nucleation of the generated Rh atoms, offering them the opportunity to deposition on Pd seeds. More importantly, XPS studies indicated that the Br − ions specifically capped on Pd(100) surface, which could play as an obstacle preventing the deposition of Rh atoms on the {100} facets of the Pd seeds. At the end, we selectively removed the Pd cores from the three types of Pd—Rh bimetallic nanocrystals with different elemental spatial-distribution, generating three corresponding Rh frames with different open structures. Our study provides a rational platform for the design of bimetallic nanocrystals with hetero-nanostructures through seed-mediated approaches.
[0032] In the experimental embodiments, the following chemicals and materials were used. Ethylene glycol (EG, lot no. K43B24) was purchased from J. T. Baker. Sodium Pd(II) tetrachloride (Na 2 PdCl 4 , 99.998%), sodium Rh (III) hexachloride (Na 3 RhCl 6 ), poly(vinyl pyrrolidone) (PVP, MW≈55,000), L-ascorbic acid (AA), potassium bromide (KBr), formaldehyde (HCHO, 37 wt. % in H2O), hydrochloric acid (HCl, 37%), and iron(III) chloride (97%) were all obtained from Sigma-Aldrich and used as received. All aqueous solutions were prepared using deionized (DI) water with a resistivity of 18.2 MΩ·cm.
[0033] The following procedure was employed in the synthesis of 18-nm Pd nanocubes. The 18-nm Pd nanocubes used as the seeds were synthesized by adding a Na 2 PdCl 4 solution into an aqueous solution containing PVP, AA and KBr. Typically, 105 mg of PVP, 60 mg of AA, 600 mg of KBr, and 8.0 mL of DI water were mixed in a vial and preheated at 80° C. in an oil bath under magnetic stirring for 10 min. Subsequently, 57 mg of Na 2 PdCl 4 was dissolved in 3.0 mL of DI water and then injected into the preheated solution with a pipette. The mixture of reagents was capped, and maintained at 80° C. for 3 h. The product was collected by centrifugations, washed three times with water to remove excess PVP and inorganic ions, and then re-dispersed in 11 mL of solvent (EG or DI water).
[0034] The following procedure was employed in the synthesis of Pd cuboctahedrons and octahedrons. The Pd cuboctahedrons and octahedrons were synthesized through a seed-mediated approach as our previous report. In a standard procedure, 8.0 mL of an aqueous solution containing 105 mg of PVP, 100 μL of HCHO, and 0.3 mL of an aqueous suspension (1.8 mg/mL in concentration) of 18-nm Pd nanocubes was preheated at 60° C. for 5 min under magnetic stirring in a capped vial. Then, 3.0 mL of aqueous Na 2 PdCl 4 solution was injected into the mixture through a pipette. The weight amounts of Na 2 PdCl 4 for obtaining cuboctahedrons and octahedrons were 8.7 mg and 29.0 mg, respectively. The reaction was maintained at 60° C. for 3 h. The products were collected by centrifugation, washed two times with water, and then re-dispersed in 1.0 mL of EG.
[0035] The following procedure was employed in the synthesis of spatially-controlled Pd—Rh bimetallic nanocrystals. The spatially-controlled synthesis of Pd—Rh bimetallic nanocrystals was conducted by introducing Na 3 RhCl 6 solution (in EG) into the reaction system which contained the polyhedral Pd seeds. Typically, 52.8 mg of L-ascorbic acid, 54 mg of KBr, 1.0 mL of polyhedral Pd seeds (e.g., cuboctahedrons, octahedrons, and nanocubes) in EG, and 6.0 mL of EG were mixed together in a 50 mL three-neck flask. The mixture was preheated at 110° C. for 2 h under magnetic stirring, and then ramped to 140° C. Meanwhile, 15 mg of Na 3 RhCl 6 and 133 mg of PVP were separately dissolved in 6 mL of EG. Then, both of the EG solutions were pumped into the preheated mixture under 140° C. at the same rate of 4.0 mL/h. The reaction took additional 10 min after the pumping. The product was collected by centrifugation, washed two times with ethanol and then three times with water, and then re-dispersed in 5 mL of DI water.
[0036] The following procedure was employed in the synthesis of Rh frames. Chemical etching was conducted towards the three Pd—Rh bimetallic nanocrystals in an acidic aqueous solution to prepare Rh frames. Typically, 300 mg of KBr, 50 mg of PVP, 50 mg of FeCl 3 , 0.3 mL of HCl (37%), 5.7 mL of DI water, and 2.0 mL of the aqueous dispersion of the as-prepared Pd—Rh bimetallic nanocrystals were mixed together in a 50-mL flask. Then, the mixture was heated at 100° C. in an oil bath under magnetic stirring. After 48 h, the products were collected by centrifugation, washed two times with ethanol and three times with water, and then re-dispersed in DI water.
[0037] These methods represent a new approach to the syntheses of core-frame nanocrystals and their further conversion into frame-like nanostructures. Two types of metals can be presented on the surface of such a core-frame nanocrystal in a spatially well-defined pattern. The products can be important to a variety of catalytic applications, especially for catalytic converters used in automobiles, petroleum refinery, and pharmaceutical industry.
[0038] The technology based on the site-selected deposition of one metal on the surface a seed made of the same or a different metal. It involves a capping agent that can selectively adsorb onto a specific type of facets on the surface of a seed and thus block these facets from receiving additional atoms from the solution during the growth process. In addition, the surface diffusion of adatoms should be suppressed to help confine the atoms to the originally deposited sites.
[0039] This involves selective deposition of Rh atoms onto the corners and edges of Pd nanocubes (i.e., the seeds). In such a synthesis, Br − ions (as well as other halide ions such as iodide) were found to play an important role in selectively blocking the {100} side faces on a Pd nanocube. As such, only the corner and edge sites on the surface of a Pd nanocube can receive new atoms from the reaction solution. When a salt precursor to Rh was slowly injected into the reaction solution through a syringe pump, the deposition of Rh atoms could be tightly confined only to the corners and edges of the Pd nanocubes, generating Pd—Rh core-frame nanocubes with concave side faces. The same approach can also be extended to other platinum group metals, including Pt (platinum), Ir (iridium), and Pd (palladium).
[0040] As one of the many applications, the core-frame structure may offer a new approach to increasing the shape stability and thus catalytic activities of noble-metal nanocrystals at elevated temperatures. It was found that the Pd—Rh core-frame nanocubes could be maintained with a cubic shape up to a much higher temperature as compared with Pd nanocubes. Therefore, the Pd—Rh core-frame nanocubes are anticipated to exhibit improved catalytic durability in a catalytic reaction at a high temperature.
[0041] This technology can also be extended to a variety of Pd seeds with other types of polyhedral shapes. When Pd cuboctahedrons were used as the seeds to conduct the growth, the nucleation and deposition of Rh atoms was confined solely to the {111} facets of a Pd seed, because the {100} facets were selectively capped by a layer of chemisorbed Br − or I − ions. When the synthesis was conducted at a relative low temperature, the deposition of Rh atoms would follow an island growth mode due to the high Rh—Rh interatomic binding energy. The surface diffusion of deposited Rh atoms can be facilitated by increasing the reaction temperature. Under this condition, the deposition of Rh on the Pd{ 111 } facets was switched to a layered growth mode. A variety of other types of polyhedral Pd seeds that contained Pd{111} and Pd{100} facets in different proportions on the surface were also applied to the synthesis. A series of Pd-Rh bimetallic nanocrystals with distinctive elemental distributions on the surface were obtained. The Pd cores can be removed via selective chemical etching to generate Rh frames with different types and degrees of porosity.
[0042] The above described embodiments, while including the preferred embodiment and the best mode of the invention known to the inventor at the time of filing, are given as illustrative examples only. It will be readily appreciated that many deviations may be made from the specific embodiments disclosed in this specification without departing from the spirit and scope of the invention. Accordingly, the scope of the invention is to be determined by the claims below rather than being limited to the specifically described embodiments above. | In a method of generating a nanocrystal with a core-frame structure, a seed crystal, including a first substance, is exposed to a capping agent. The seed nanocrystal has a plurality of first portions that each has a first characteristic and a plurality of second portions that each has a second characteristic, different from the first characteristic. The capping agent has a tendency to adsorb to portions having the first characteristic and has a tendency not to adsorb to portions having the second characteristic. As a result, a selectively capped seed nanocrystal is generated. The selectively capped seed nanocrystal is exposed to a second substance that has a tendency to nucleate on the plurality of second portions and that does not have a tendency to nucleate on portions that have adsorbed the capping agent, thereby generating a frame structure from the plurality of second portions of the seed nanocrystal. | 2 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates generally to alloys which are characterized by high temperature strength characteristics, and more particularly to alloys of the Co-Cr-C type.
2. Description of the Prior Art
Unidirectional solidification of lamellar eutectic alloys is know in the art, as indicated in Kraft U.S. Pat. No. 3,124,452, or Giessereiforschung 24 (1972) pp. 45-53, for instance. That technique refers to a process in which the alloy is partially melted to form a liquid-solid interface or solidification front. The interface is caused to be moved in a unidirectional fashion as the alloy is cooled through an appropriate temperature. In this way the crystallites of each phase grow or form normal to the solidification front parallel to the direction in which the solidification front moves relative to and through the alloy. The conditions of unidirectional solidification can be determined by the following equation in which the ratio of temperature gradient G and growth rate v is determined by ##EQU1## wherein m is the slope of the liquidus line in the usual temperature phase diagram at the point determined by the melt composition, D is the diffusion coefficient of the liquid atoms, Δ c is the compositional deviation of the melt composition from eutectic composition and K i C i is a constant governed by the impurity concentration C i . Fulfillment of this condition serves to prevent the formation of dendrites or cell boundaries.
The melt is convectionless with no thermal fluctuations at the interface, in order to prevent the formation of growth bands or other growth defects.
This technique has been applied to Co-Cr-C alloys in the prior art. For instance, Thompson, U.S. Pat. No. 3,564,940, and German publication 1,928,258 report an alloy of the composition 35-45% wt Cr, 2.2-2.6% wt C and 52.4-62.8% wt Co. The Co-Cr-C alloys of the Thompson patent are aligned polyphase structures which solidify according to the monovariant eutectic structure: at a fixed pressure these compositions are monovariant thermodynamically and involve, in ternary systems for example, the three phase equilibrium between the melt and two solids over a temperature and composition range and not, as in the binary or pseudo-binary systems, at a fixed temperature and composition. Those compositions are located on a eutectic trough.
However, the alloys reported in Thompson are generally characterized by unsatisfactory strength characteristics, particularly time-dependent creep strength, and, therefore, the range of application of such alloys is limited. Although that prior patent indicates that its composition had a contemplated utility in the formation of gas turbine blades, in practice, those alloys have not been found to be sufficiently satisfactory.
Efforts had thus been made to improve the strength properties of this system of alloys, without success. For instance, methods are known in the present field of the art for improving the high temperature strength characteristics, but not without sacrifice of other properties, such as corrosion resistance.
Lemkey et al U.S. Pat. No. 3,552,953, discloses another Co-Cr-C alloy of the composition 45.2 - 49.2% wt Co, 49 - 53% wt Cr and about 1.87% wt C which is unidirectionally solidified such that a carbide of the formula Cr 23 C 6 is dispersed in a skeletal distribution in the matrix phase. This type of alloy, however, is quite different from the alloy of the present invention.
A need continues to exist for a technique of improving the high temperature strength characteristics of Co-Cr-C alloys, without sacrifice of other desirable properties of the alloy, particularly without sacrifice of corrosion resistance.
SUMMARY OF THE INVENTION
Accordingly, it is one object of this invention to provide a Co-Cr-C alloy which is characterized by excellent high-temperature strength properties without sacrifice of such other alloy properties as corrosion resistance.
This and other objects of this invention as will hereinafter become more readily understood by the following description, have been attained by providing an anisotropic body comprising an at least partially monovariant ternary eutectic alloy of Co, Cr and C, the eutectic part of the alloy comprising a matrix phase consisting substantially of Co containing at least Cr in a solid solution and a dispersed phase consisting substantially of a carbide of the formula Cr 7 -x -y Co x Me y C 3 wherein x is a number capable of values from 0 to 2 and y is a number capable of values from 0 to 4, and wherein Me is an additional element contained in the matrix and/or dispersed phase, the dispersed phase consisting essentially of a plurality of high strength carbide fibers oriented in substantial alignment, and embedded in the matrix phase, the improvement which comprises the additional element Me being selected from the group consisting of manganese, aluminum, yttrium, boron, one or more rare earths and mixtures thereof, wherein said additional element Me is present in an amount of from 0.1 to 15% by weight based on the total weight of the composition.
One or more additional elements selected from the group consisting of Mn, Al, Y, B or a rare earth is used to replace Co and/or Cr in quantities of 0.1 to 15% wt.
BRIEF DESCRIPTION OF THE DRAWINGS
A more complete appreciation of the invention and many of the attendant advantages thereof will be readily attained as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawing, the sole FIGURE of which is a phase diagram showing the compositional range with which the present invention is principally concerned.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the alloy of this invention, the matrix is composed predominantly of Co and Cr, and possibly some carbon, generally in the well-known crystallographic form of γ Co solid solution, while the fibrous dispersed carbide phase is predominantly of the type Cr 7 C 3 which is the chromium carbide appearing purely in the binary Cr-C marginal system of the present basic ternary Cr-Co-C system and having the same crystallographic structure as the carbide Cr 7 -x -y Co x Me y C 3 in the preferred compositional ranges of the present invention. Essential to this invention is the use of certain other metals or elements which are added into the composition, either appearing in the matrix and/or in the carbide phase in quantities from 0.1% wt to 15% wt based on the total weight of the alloy.
Suitably such additional elements are Mn, Fe, Al, Y, B or the rare earths, particularly La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu, or mixtures thereof.
The preparation of the alloy body of this invention is by directional casting techniques as described by Thompson, supra, Kraft, supra, or Giessereiforschung, supra.
The microstructure of the body according to the present invention will show a carbide phase in fibrous or fibrillar form embedded in a matrix. The aspect ratio i.e. the ratio of the length to the diameter of the fibres preferably is greater than or equal to 50, and the fibers will predominantly have a thickness of about 0.1 to 3 μ. Up to 49% of the fibers, however, may have a thickness dimension and/or length to thickness ratio (aspect) other than as above indicated.
The fibers embedded in the matrix may have a length of at least 0.1 mm up to the length of the casting, although lengths of from 1 mm up to the length of the casting are preferred.
It is also significant that the carbides which are embedded into the matrix are directionally oriented in an essentially, mutually parallel configuration. This is achieved by directionally solidifying the melt by the technique mentioned supra as known per se.
The composition of the carbide will have essentially the formula:
Cr.sub.7.sub.-x.sub.-y Co.sub.x Me.sub.y C.sub.3
wherein x and y are numbers which may assume values from 0 to 2 respectively from 0 to 4.
The carbide fibers may have substituted therein a quantity of an additional element or a mixture of elements mentioned supra.
The alloys of the present invention and their properties will be understood in detail more readily in the light of the following description with reference to a selected part of the primary crystallization phase diagram of the ternary Cr-Co-C system as represented schematically in the enclosed drawing.
Considering the following remarks it has to be kept in mind that the pure ternary Cr-Co-C system as partly represented in the drawing is merely the basic alloy to be used with the specific additional alloy elements according to the present invention. Generally speaking, it can be said that the characteristic phase limits of the said basic phase diagram, and particularly the primary crystallization phase limits appearing in the liquidus surface of the three-dimensinal phase diagram, as well as the corresponding solidification phase reactions basically maintain their typical form and position in the ternary Cr-Co-C diagram when the additional elements of the present invention are incorporated into the alloy, particularly in replacement of Cr and/or Co. For this reason it is justified to explain and characterize the basic alloy part of the complete alloys according to the present invention by useful and sufficient approximation in the said basic ternary diagram.
Turning now to the enclosed diagram, this representation has to be understood as a section of the complete ternary diagram including the Co corner of the diagram. Accordingly, the Cr and C content in weight percentage have been marked along the ordinate and abscissa, respectively, starting from the Co corner.
In the diagram there are different primary crystallization regions well-know per se, mainly the solid solution regions G and C which are of no interest in the present connection, further the chromium-richer carbide region Cr 23 -x Co x C 6 which is at most of minor interest in so far as this chromium-richer carbide for certain marginal compositions may exist in minor amounts in the dispersed phase besides the main carbide dispersed phase Cr 7 -x Co x C 3 , the letter being the primary crystallization phase area of main interest for the present invention, and finally the solid solution primary crystallization region γCo being also of interest for the present invention.
All the lines between the different primary crystallization regions except the line p, which represents a peritectic trough, indicate eutectic troughs well-known in the art, for instance from the Thompson and Lemky specifications supra. Of substantial interest for the present invention is the eutectic trough e which extends from above trough a first nonvariant eutectic point E T1 and a second nonvariant eutectic point S 2 defined as the triple point between the three regions Cr 23 -x Co x C 6 , Cr 7 -x Co x C 3 and γCo, to a third nonvariant eutectic point E T2 defined as the triple point between Cr 7 -x Co x C 3 , γCo and C. In this connection it may be of interest that it was not agreed to before the latest inquiries that the eutectic reaction in the Co-Cr-C system really does occur in a compositional point where the peritectic trough p joins the eutectic trough e.
Now going further into details, compositions in the nearer or farther vicinity of the section of the eutectic trough e between the eutectic points S 2 and E T2 are of major interest as basic alloys for the present invention. In this connection it has to be kept in mind that all the compositions being exactly on this section of the eutectic trough e lead to simultaneous solidification of γCo and Cr 7 -x Co x C 3 resulting in the well-known very fine grained eutectic structure, while any compositional deviation from the eutectic trough leads to primary crystallization of γCo on the one side and of Cr 7 -x Co x C 3 on the other side.
The carbide phase solidifies in a fibrous or similar crystal structure for alloy compositions exactly in the eutectic trough as well as on the carbide side thereof, i.e. in the Cr 7 -x Co x C 3 area, thus rendering structures in principle useful for the present invention. However, the amount of carbide solidified as a part of the eutectic, that means simultaneous with, and dispersed in the matrix phase has a very much finer crystal structure with a smaller fiber diameter compared with the amount of carbide which, due to an alloy composition on the carbide side of the eutectic trough has solidified from the melt by primary crystallization before the remaining melt attains the eutectic composition. Therefore, alloy compositions in the eutectic trough or quite near to it on the carbide side are the preferred ones for the present invention, while, in practice, considerable deviations into the carbide primary crystallization area are tolerable and even useful as well. To a certain extent, the primary carbide fibers with their greater diameter contribute favorably to the high mechanical strength of the alloy, while the specific additional alloy elements of the present invention are preserving the useful properties which might be otherwise affected by the coarser carbide fiber structure. This holds true particularly for corrosion resistance, creep strength, and other important properties of alloys of the present invention.
Compositional deviations from the eutectic trough into the solid solution region, i.e. generally into the γCo primary crystallization region are accompanied by formation of dendrites which is usually undesired and tolerable only to minor degrees.
Therefore, summarizing it can be stated that the best mode of operation of the present invention uses basic alloys with compositions on the eutectic trough e between the non-variant eutectic points S 2 and E T2 including compositions deviating slightly from the correct eutectic one, while compositional ranges still useful comprise comparatively small deviations from the eutectic trough into the Co solid solution primary crystallization region on the one hand and considerably greater deviations into the carbide primary crystallization region on the other hand.
Occurence of the Cr 23 -x Co x C 6 carbide in the dispersed phase within the eutectic part of the alloy should generally be avoided because of the brittle character of this carbide. However, small amounts of this carbide besides the Cr 7 -x Co x C 3 carbide occurring in the vicinity of the peritectic trough P may be tolerable.
By the way, suffice to remark that the foregoing explanation mentioned the carbide formula Cr 7 -x Co x C 3 with reference to the basic alloy, i.e. without additional elements Me and y = 0.
Now turning further to the details of the best mode of operation of the present invention, most favourable results have been obtained by combining the above-mentioned additional elements with basic alloy compositions within a region of the basic ternary Cr-Co-C diagram defined by the following corner compositions:I. Co-Me = 53.1 % Cr-Me = 44.7 % C = 2.2 %II. 50.25 47 2.75III. 67.15 30 2.85IV. 62.5 34 3.5
This compositional region with the corner points I to IV has been pointed out by shading in the enclosed drawing.
Of particular interest for the present invention are basic alloys with compositions on the line s b in the diagram. This line represents a pseudo-binary cut within the present ternary system, this pseudo-binary cut behaving like a binary eutectic with γCo and Cr 7 -x Co x C 3 as the partner of a eutectic reaction represented by the section of the said line s b with the eutectic trough e.
As to the diagram it should be kept in mind that the phase boundary lines are a schematic representation which in one or the other section eventually could and will be amended in view of future research and measurements. Nevertheless, the diagram is held to be fully sufficient in explaining and identifying the basic alloys for use with the present invention.
As stated supra the eutectic alloy for use with the present invention preferably consists of γCo as the matrix phase and Cr 7 -x Co x C 3 as the dispersed phase, and it is an important aspect of the present invention that the additional elements will be incorporated in the matrix and/or the dispersed phase during solidification.
In detail the effects of the additional elements are the following ones:
Boron is a desirable substituent to be added to the composition, either in the carbide or in the matrix, because it can improve interstitial hardening. Boron also acts to refine the grain and the phase boundaries.
Through accumulation in the grain boundaries a general consolidation is attained which has a favorable effect on the time dependent creep strength. Particularly good results are attained when the boron is present in amounts of 0.005% to 0.5% wt. Beyond 0.5%, the strength of the composition tends to be reduced due to a coarsening of the fiber structure. Mn and/or Al may also be added to improve strength properties, although larger quantities of Mn or Al would be needed, as compared with the smaller quantity of boron which will provide similar effects.
Yttrium may be added for the same purpose, however, it achieves this effect indirectly, by increasing oxidation resistance.
A combination of metals such as boron and aluminum have proven to be quite effective. In this instance, the boron should be present in amounts of 0.001 to 0.006% and aluminum from 1 to 3%. To this can also be added yttrium in amounts of 0.1 to 0.8%.
These alloys will become partly dissolved in the matrix and partially in the carbide, interstitially as well as substitutionally, to enhance hardening. The effect of the additive metals also seems to be an enhancement in corrosion resistance, particularly when aluminum or yttrium are used.
Manganese may also be used as an alloying metal to increase the strength of the carbide fibers, since it goes extensively into solution in the carbide so as to cause a solution hardening effect. Manganese can be used in amounts of up to 10% wt. Above 10% wt, the fiber structure is adversely affected.
Aluminum, on the other hand, will tend to smooth the fiber morphology and thereby increase the strength of the fiber by creating a morphology having fewer stress points. In larger amounts, the aluminum tends to enhance the corrosion resistance of the composition. Quantities of 0.1 to 3% appear to be optimal, since about 3% the structure of the fiber becomes undesirably altered.
Yttrium, or the rare earths, particularly Cerum-Mischmetal, act mainly to stabilize the passivation layer on the surface of the casting, and thereby provides added protection for compositions intended for use in highly corrosive environments. These metals thus have an indirect effect on the time dependent strength. Good results are attainable when these metals are used in amounts of 0.1 to 2.5% wt. Beyond about 2.5% the fiber structure, as well as the casting properties, change disadvantageously.
Having generally described the invention, a more complete understanding can be obtained by reference to certain specific examples, which are included for purposes of illustration only and are not intended to be limiting unless otherwise specified.
EXAMPLE
The values in the following tables were obtained with specimens of composition given in the tables and produced as follows:
TABLE 1__________________________________________________________________________Tensile Strength at 1000°CAlloyingmetal% by wt Co Cr C Mn B Al Y (MN/m.sup.2)__________________________________________________________________________Basic Alloy 56.9 40.7 2.4 -- -- -- -- 480Example 1 45 46.8 3.5 4.7 -- -- -- 610Example 2 40 46.8 3.5 9.7 -- -- -- 630Example 3 56.8 40.7 2.4 -- 0.1 -- -- 590Example 4 54.9 40.7 2.4 -- -- 1 0.5* 620__________________________________________________________________________ *0.5% Ce-Misch Metal added
TABLE 2__________________________________________________________________________Temperature-Dependent CreepStrength at 1000°C and150 MN/m.sup.2 Load (Stress) RuptureAlloying timemetals Co Cr C Mn B Al Y (hours)__________________________________________________________________________Basic alloy 56.9 40.7 2.4 -- -- -- -- 100Example 1 55.9 39.7 2.4 -- -- -- 2 270Example 2 56.795 40.7 2.4 -- 0.005 0.1 -- 135Example 3 56.9 39.348 2.25 -- 0.002 1.5 -- 135Example 4 56.9 38.7 2.4 -- -- 2 -- 160__________________________________________________________________________
The indicated ingredients were melted after weighing, in an alumina crucible and brought into the desired mold, e.g. rod-shaped mold, by a vacuum drawing method. Directional solidification proceeded in an inert gaseous atmosphere with solidification velocities of about 7 cm/hr and temperature gradients around 100°K/cm. After this, the specimens were brought into the desired shape (here rods of 5mm diameter and 60 mm length) by free cutting machining. By the indicated method, the fibers are directed parallel to the rod axis. As the tables show, the increase in tensile strength and time-dependent creep strength at high temperatures compared to the basic alloys is considerable. It can be understood by reference to the tables that improvement in the tensile strength by as much as 30% is obtained by the presence of Mn and Al in the composition. The usable life of the compositions is improved by as much as 100%, of. Table 2.
Table 2 shows the especially favorable effect on useable life when yttrium is present. This effect is believed to be a result of the observation that corrosion resistance of the material is increased and a reduction in the specimen rod's cross-section resulting from oxidation is obtained.
Having now fully described the invention, it will be apparent to one of ordinary skill in the art that many changes and modifications can be made thereto without departing from the spirit or scope of the invention as set forth herein. | In a cast anisotropic body comprising an at least partially monovariant ternary eutectic alloy of Co, Cr and C, the eutectic part of the alloy comprising a matrix phase consisting substantially of Co containing at least Cr in a solid solution and a dispersed phase consisting substantially of a carbide of the formula Cr 7 -x -y Co x Me y C 3 wherein x is a number capable of values from 0 to 2 and y is a number capable of values from 0 to 4, and wherein Me is an additional element contained in the matrix and/or dispersed phase, the dispersed phase consisting essentially of a plurality of high strength carbide fibers oriented in substantial alignment, and embedded in the matrix phase, the improvement which comprises the additional element Me being selected from the group consisting of manganese, aluminum, yttrium, boron, one or more rare earths and mixtures thereof, wherein said additional element Me is present in an amount of from 0.1 to 15% by weight based on the total weight of the composition. | 2 |
BACKGROUND OF THE INVENTION
In general, this invention concerns a vacuum cleaner having a hanging feature, and in particular concerns a vacuum cleaner combining a relatively compact, lightweight construction together with a keyhole feature for hanging storage of the vacuum cleaner during periods of non-use.
Heretofore, larger scale vacuum cleaners have typically been constructed in either permanent upright or canister-type embodiments. In general, such vacuum cleaners can be characterized as relatively bulky and/or of relatively greater weight. Due to their weight and size, it is generally not practical for such upright and canister-style cleaners to be supported off the floor in a hanging position during periods of non-use thereof.
In relatively recent times, with the introduction of improved materials and motors, the size and weight of vacuum cleaners have been reduced while effectively maintaining adequate levels of vacuum power. However, generally no provisions have been made for such new generation of vacuum cleaners in an upright or convertible upright construction to be particularly adapted for hanging support thereof.
More recently, a vacuum cleaner has become known which is convertible between upright and hand-held configurations, though not particularly adapted for hanging support. See for example U.S. Pat. Nos. 4,660,246 (Duncan et al.); 4,662,026 (Sumerau et al.); and 4,670,937 (Sumerau et al), all of which patents are commonly assigned with the present application. The disclosures of such patents are incorporated herein by reference, particularly with respect to the operational details (e.g. vacuum sources, etc.) and convertible features thereof.
SUMMARY OF THE INVENTION
The present invention recognizes and addresses the general prior lack of hanging features or arrangements for vacuum cleaners, particularly concerning upright or convertible upright styles (i.e., vacuum cleaners other than relatively small scale, battery-operated hard-held units). Accordingly, it is one general object of the present invention to provide an improved vacuum cleaner which is particularly adapted for convenient and relatively compact hanging storage thereof during periods of non-use.
It is a more particular object of the present invention to provide such an improved vacuum cleaner for integral storage in a space-saving configuration of both itself and its associated power cord. It is a still further particular object to provide such a vacuum cleaner which is adapted to hang substantially flush against a planar support surface, such as a wall, preferably from a support member such as a nail or screw mounted on such wall.
It is yet another object of the present invention to provide such an improved vacuum cleaner for hanging storage which is of relatively lightweight construction, while possessing operational and functional features of vacuum cleaners having upright and/or convertible upright-type constructions.
Different features and characteristics of the present invention may be embodied in various combinations for providing a vacuum cleaner constructed in accordance with the present invention. One exemplary such embodiment generally includes a vacuum cleaner having a head portion incorporating a vacuum nozzle; a body portion incorporating a collecting bag, the body portion being operatively and pivotably associated with the head portion, and upon selected pivoting thereof further defining together with the head portion a generally planar lower surface; cord storage means, received on the generally planar lower surface, for storing a coiled power cord for such vacuum cleaner in a storage plane generally parallel to and immediately adjacent to such generally planar lower surface; and vacuum cleaner hanging means, substantially facing such planar lower surface, and adapted for supporting the vacuum cleaner on an external support member mounted on a wall or similar planar support surface; with the vacuum cleaner planar lower surface substantially facing towards such planar support surface, and with the vacuum cleaner power cord stored on the cord storage means so as not to interfere with operation of the hanging means.
Another exemplary embodiment of the present invention concerns a vacuum cleaner adapted for hanging storage thereof during periods of non-use, such vacuum cleaner comprising a main chassis, including a lower side thereof defining a first substantially planar surface, at least one vacuum nozzle directed towards such chassis lower side, at least one exhaust port located generally towards the rear of such chassis, and at least one vacuum channel operatively interconnecting the vacuum nozzle with the exhaust port. The embodiment also includes a body compartment adapted for supporting a dirt collection bag having an input orifice operatively interconnected with the chassis exhaust port, such body compartment having generally opposing ends, one of which is pivotably attached to the chassis rear, and the other of which is generally adjacent the bag input orifice, such body compartment further having a lower side thereof defining a second planar surface, with a trough formed substantially centrally in such body compartment lower side and running longitudinally therealong. Such embodiment further includes flexible tubing means, received substantially within the body compartment lower side trough, for operatively interconnecting the chassis exhaust port with the bag input orifice; suction means for transporting dirt and dust from generally adjacent the vacuum nozzle to the dirt collection bag, via the vacuum channel, the exhaust port, the tubing means, and the bag input orifice; and a power cord for selectively interconnecting the suction means with input power from a source such as a wall socket. Still further included are cord wrapping means, including two respective pairs of elements with each such pair generally associated with respective opposing ends of the bag compartment and relatively adjacent the lower side trough thereof for defining a third substantially planar surface which is parallel to and slightly spaced from the second planar surface, the cord wrapping means being further adapted for coiled receipt of the power cord therearound, generally in a plane within an area defined between such slightly spaced second and third planar surfaces; and tubing cover means, situated across one end of the body compartment lower side trough, for covering the interconnection between the tubing means and the bag input orifice, the cover means further being situated between a pair of the cord wrapping means elements, and defining centrally relative the vacuum cleaner a support opening adapted for receipt of a support member therein; whereby, with the body compartment pivotably situated relative the main chassis such that their respective lower side planar surfaces are substantially in co-planar alignment, the vacuum cleaner may be stored during periods of non-use by hanging the support opening thereof on a support member, with the power cord wrapped about the cord wrapping means so as to generally not disturb the substantially planar nature of the planar surfaces so that the vacuum cleaner may be positioned substantially flush against a surface, such as a wall, from which the support member protrudes.
Various further alternative features, such as particular integral keyhole members, and reinforcement thereof, may be provided in further embodiments in accordance with the present invention. Moreover, those of ordinary skill in the art will recognize various modifications and variations to different features and characteristics of the present invention, all of which are intended to come within the spirit and scope of the present invention by virtue of present reference thereto. Such modifications include, but are not limited to, substitution of various functional equivalents for particular features and characteristics illustrated or discussed, or the reversal of illustrated characteristics.
Additionally, general concepts and principles of the present invention may be applied to particular vacuum cleaner constructions or styles differing from the exemplary construction illustrated in the accompanying drawings. The selection and incorporation of various present features into given alternative constructions is considered to fall within the skill of those of ordinary skill in the art, without further particular discussion or explanation herewith.
BRIEF DESCRIPTION OF THE DRAWINGS
A full and enabling disclosure of the present invention, including the best mode thereof, is set forth more particularly in the remainder of the present specification, which includes reference to the accompanying drawings, in which:
FIG. 1 illustrates a perspective view of an exemplary embodiment in accordance with the present invention, during hanging storage thereof; and
FIGS. 2 and 3 illustrate side and rear elevational views, respectively, of the exemplary embodiment of present FIG. 1.
Repeat use of like reference characters throughout the specification and accompanying drawings is intended to represent same or analogous features or elements of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
As indicated above, principles and features of the present invention may be applied to vacuum cleaners of various alternative constructions. However the presently preferred exemplary embodiment of the present invention is illustrated as generally incorporated into a convertible upright/hand-held construction, as disclosed in relative detail in the above-mentioned three United States patents (all of which disclosure is incorporated herewith). Hence, repeat explanation of some details not particularly concerning present features, such as those concerning the vacuum operation or convertibility of such exemplary embodiment, are omitted from this specification.
FIG. 1 illustrates a vacuum cleaner 10 generally of the convertible type mentioned above, and constructed in accordance with the present invention for hanging storage. The vacuum cleaner is particularly constructed for providing a generally planar lower surface 12, and hanging means associated therewith (not illustrated in FIG. 1). In general vacuum cleaner 10 comprises relatively lightweight materials, preferably so as to have a total weight of no more than about ten pounds (though higher weights could be accommodated if desired in connection with particular alternative constructions). Such lightweight feature contributes to the advantageous hanging feature of vacuum cleaner 10, which is more particularly achieved with the hanging means and overall configuration thereof, including the power cord storage discussed more particularly below with reference to FIGS. 2 and 3.
Though a vacuum cleaner constructed in accordance with the present invention may be stored on various alternative support members virtually without limitation, storage adjacent a generally planar surface such as wall 14 of closet 16 is preferred. A support member such as a nail or screw may be mounted relative wall 14, such as in a beam 18 thereof. Vacuum cleaner 10 may then be hung from such support member so as to lie substantially flush adjacent planar support surface 14, either slightly spaced therefrom (as particularly illustrated in present FIG. 1) or directly flush thereagainst (as may be understood by those of ordinary skill in the art).
Of course, planar support surface 14 need not be strictly vertical, but may instead comprise an angled support wall as sometimes found in upstairs closets over staircases or in other circumstances. In such instance, vacuum cleaner 10 could be supported on the angled support wall, substantially at the angle thereof, with the hanging feature discussed below securing the vacuum cleaner to such wall.
Referring to present FIGS. 2 and 3, side and rear elevational views, respectively, of the exemplary vacuum cleaner 10 of present FIG. 1 are illustrated. Vacuum cleaner 10 generally includes a head portion or main chassis 20 which has a vacuum nozzle 22 incorporated on a lower side 24 thereof. As illustrated, lower side 24 comprises a first substantially planar surface.
Vacuum cleaner 10 also includes a body portion or compartment 26 which receives therein a dust or dirt collection bag (not shown) having an input orifice, as well known by those of ordinary skill in the art. Body compartment 26 also has a lower side 28, which forms a second substantially planar surface, and which may be disposed in relatively co-planar alignment with lower surface 24 as illustrated. In general, head portion 20 and body portion 26 may be pivotably attached with respect to each other generally about an axis 30, as more particularly discussed in the above-mentioned U.S. Patents. Relative pivoting permits the achievement of co-planar alignment for surfaces 24 and 28 as illustrated, or upright operation as discussed in such patents.
Pivotable and extendable handle means 32 are further provided in accordance with the present exemplary embodiment, all for cooperation with the pivotable feature concerning axis 30 for converting vacuum cleaner 10 from a hand-held configuration (illustrated in the present Figures) to an upright configuration (illustrated in the above-mentioned incorporated U.S. patents). In general, the selection of position of handle means 32 does not for present purposes affect the functionality of the hanging arrangement of the present invention. In other words, the pivoted position of handle means 32 about the general pivot point 34 thereof does not affect hanging features associated with generally planar lower surface 12 of vacuum cleaner 10 since handle means 32 is situated on a side of vacuum cleaner 10 opposite lower side 12 thereof.
Furthermore, handle means 32 may alternatively be provided as either a permanently extended member or a permanently hand-held positioned member, all without substantially affecting the generally planar lower surface and related hanging features of the present invention.
Lower surface 12 includes a centrally located trough 36 extending along a longitudinal axis of body portion 26. Flexible tubing means 38 are generally received within trough 36, for operatively interconnecting an exhaust port 40 of chassis 20 with an input orifice of a dirt collection bag (not illustrated) located beneath tubing cover means 42 comprising a generally planar member situated across one end of trough 36. Though tubing 38 may occasionally protrude from trough 36 (as represented in present FIG. 2), it is adequately flexible to be pushed fully into trough 36, and out of the way for hanging, by the weight of vacuum cleaner 10 should the cleaner be supported directly flush on a support surface.
A vacuum channel (not illustrated) interconnects exhaust port 40 with vacuum nozzle 22. Also, suction means, as well known to those of ordinary skill in the art, may be provided in vacuum cleaner 10 for transporting dirt and dust from generally adjacert vacuum nozzle 22 to the dirt collection bag within body compartment 26, via such vacuum channel, exhaust port 40, flexible tubing means 38 and the bag input orifice located beneath tubing cover means 42. Examples of vacuum channels, suction means, and other such detailed aspects of vacuuming operations are more fully explained in the above-identified U.S. patents.
A support opening or hanging means 44 is defined in tubing cover means 42, preferably along the central axis of vacuum cleaner 10 for balanced hanging thereof (as illustrated in present FIG. 1). Hanging means 44 may assume various constructions, but preferably comprises a keyhole feature with reinforcement 46 about the periphery thereof. Cover means 42 may be injection molded (or alternatively formed) with the reinforced keyhole integrally formed therein. As better illustrated in FIG. 2, reinforced keyhole 44 is adapted to receive and engage the head 48 of an external support member such as a nail or screw mounted on a support surface such as a wall or beam 50.
As well understood by those of ordinary skill in the art, a power cord 52 is usually provided for supplying power to a suction means located within vacuum cleaner 10. Just as handle means 32 are preferably configured for avoiding interference with lower planar surface 12 and the related hanging features thereof, power cord wrapping or storage means are provided for accommodating power cord 52 also without interfering with hanging features of the present invention A power cord wrapping or storage means is provided in the presently illustrated exemplary embodiment by respective pairs of wing-like structures 54-60, which are provided generally on the lower surface of vacuum cleaner 10.
More particularly, respective pairs of elements 54-60 are preferably integrally formed with vacuum cleaner 10 (such as with injection molding or the like) so as to project slightly rearwardly and axially outwardly from the centrally formed trough 36 thereof. The winglike elements thus preferably form or define a third substantially planar surface 62 which is generally parallel to and slightly spaced from second substantially planar surface 28. The planar area thus formed between the slightly spaced planes of second planar surface 28 and third planar surface 62 forms an area within which power cord 52 may be coiled or wrapped about elements 54-60 without substantially altering the generally planar nature of lower surface 12 of vacuum cleaner 10. In general, the cord is kept within such planar area by wrapping successive coils of the cord outwardly one on top of each other, as better illustrated in present FIG. 3. As also represented by present Figure, the length of cord 52 is preferably selected so that plug head 64 thereof is received relatively near the middle (i.e. side) of the wrapped cord 52, rather than near wing-like elements 54-60, to further prevent interference with hanging operations.
Also, the surface of the generally planar member comprising tubing cover means 42 is slightly recessed from third planar surface 62 so that it also falls between second and third planar surfaces 28 and 62, respectively. Hence, the preferably slightly raised reinforcement structure 46 of hanging means 44 is not affected in its interaction with a planar support surface by the storage of power cord 52 on the present cord storage or wrapping means.
While various modifications and variations may be practiced, the foregoing exemplary embodiment represents one construction in accordance with the present invention which enables convenient, spacesaving hanging storage of a relatively lightweight, convertible vacuum cleaner providing either hand-held or upright service. The description set forth by the foregoing specification is intended as words of example and description only, and not words of limitation with respect to the present invention, which is more particularly defined below in the appended claims. | A vacuum cleaner of relatively compact and lightweight construction provides a generally planar lower surface having a reinforced keyhole integrally associated therewith for hanging the vacuum cleaner preferably on a planar support surface, such as a wall, during periods of non-use of the vacuum cleaner. | 0 |
FIELD OF THE INVENTION
The present invention relates to vibrating conveyors, and more particularly, to a vibratory conveyor of the flat stroke design, capable of conveying in both the forward and reverse flow direction.
BACKGROUND OF THE INVENTION
Two-way flat stroke vibratory conveyors or feeders have substantial applications in a variety of fields. One typical application is in foundry operations wherein, for example, foundry castings may be delivered to a conveyor energized to feed the castings to one end or the other, depending upon where it is desired to locate the castings. Another typical application is in the bulk operations of granular materials wherein, for example, sugar, sand, stone, flour, cement, and various other chemical compounds may be delivered to one end or the other in the same way. Additionally, the conveyors may also move combinations of these object, granular and powder materials.
A conventional two-way flat stroke conveyor made according to the prior-art will typically include a motor powered drive system that includes four drive shafts having pairs of eccentric counterweight wheels connected via an elaborate belt connection. This drive is coupled to an elongated bed with an upwardly facing, generally horizontal conveying or feeding surface terminating at opposite ends. In operation the two sets of eccentric counterweight wheels are driven such that the wheels in each set rotate in opposite direction and the two sets are 90° out of phase relative to one another. When the motor powers the drives, a cyclic vibratory force is produced and the output displacement is transferred to the bed to create material flow. If one were to plot the sum of the stroke versus stroke angle of the sets of eccentric counterweight wheels, the result would be a skewed or biased sine wave in the direction of material flow. By reversing the rotation of the system, the skewed sine wave is reversed and the material flow is reversed.
This prior art conveyor poses a number of problems, the greatest of which is the complexity of the drive on what is essentially a brute force system. In other words, as the drive consists of four shafts with pairs of eccentric counterweight wheels, and the wheels, bearings and shafts must be large to transfer the forces, the result is a complex belt drive system with great maintenance and alignment difficulties.
U.S. Pat. No. 5,934,446 to Thomson (incorporated herein by reference) attempts to address these problems with a vibratory conveyor that includes a generally horizontal, elongated conveying surface connected to a base by generally vertically arranged, resilient slats. A drive is mounted to the surface and includes two rotary eccentric shafts coupled in series and set 90° out of phase for vibrating the surface in a generally horizontal direction by imparting a cyclic vibrating force in the form of a skewed sine wave. In other words, the drive, through the connecting drive slats, imparts a horizontal force to the trough, causing it to vibrate in the horizontal direction.
Essentially, the conveyor in the Thomson patent is tuned, through the reactor slats, to approximately 7% above the primary shaft rpm. This design, as such, takes advantage of the sub-resonant natural frequency and reduces the forces to the drive bearings as well as reducing the motor size requirements as compared to the prior art. In other words, the primary horizontal eccentric force and stroke is amplified and the lessor secondary eccentric wheel force is transmitted in a brute force manner, resulting in a smaller skewing stroke component. However, the disadvantage of the Thomson patent remains its drive complexity and space limitation with respect to both manufacture and maintenance costs.
Accordingly, it is a general object of the present invention to provide a new and improved flat stroke bi-directional conveyor.
Another general object of the present invention is to overcome those deficiencies of the flat stroke conveyors of the prior art.
It is a more specific object of the present invention to provide an improved flat stroke bi-directional conveyor which utilizes the skewed sine wave principle to transfer force to the conveying bed.
It is another object of the present invention to provide an improved conveyor which utilizes less and smaller component parts, as compared to current practice, thereby greatly reducing manufacture and maintenance costs.
SUMMARY OF THE INVENTION
The invention is generally directed to a bi-directional vibratory conveyor having a trough with an upper conveying surface for transferring energy to convey material along the surface. The drive assembly includes a drive shaft with a primary counterweight and a driven sheave, a motor shaft with a secondary counterweight and a driver sheave, a timing belt connecting the sheaves and a motor having a reversible output connected to the motor shaft for causing a direction of rotation that produces both horizontal and vertical energy components.
BRIEF DESCRIPTION OF THE DRAWINGS
The features of the present invention which are believed to be novel, are set forth with particularity in the appended claims. The invention, together with the further objects and advantages thereof, may best be understood by reference to the following description taken in conjunction with the accompanying drawings, in the several figures of which like reference numerals identifying like elements, and in which:
FIG. 1 is a side elevation view of a flat stroke bi-directional conveyor made according to the principles of the present invention with certain parts omitted for clarity purposes.
FIG. 2 is a cross-sectional top plan view of the bi-directional conveyor made according to the principles of the present invention taken along lines 2 — 2 of FIG. 1 .
FIG. 3 is a cross-sectional frontal view of the bi-directional conveyor made according to the principles of the present invention taken along lines 3 — 3 of FIG. 1 .
FIG. 4 is a cross-sectional rear view of the bi-directional conveyor made according to the principles of the present invention taken along lines 4 — 4 of FIG. 1 .
FIG. 5 is a cross-sectional rear view of the bi-directional conveyor made according to the principles of the present invention taken along lines 5 — 5 of FIG. 1 .
FIG. 6 is a graph plotting stroke versus stroke angle of the primary and secondary counterweights as well as the combined sum of the two frequencies showing the skewed sinusoidal stroke.
FIG. 7 is a graph of the combined sum of the two frequencies of FIG. 6 when the motor rotation is reversed.
FIG. 8 is a depiction of the eccentric counterweight wheel positions every 90° of counter-clockwise rotation of the secondary wheels.
FIG. 9 is a depiction of the eccentric counterweight wheel positions every 90° of clockwise rotation of the secondary wheels.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
An exemplary embodiment of a flat stroke bi-directional conveyor or feeder is illustrated in the drawings and will be described herein as a conveyor, it is understood that the terms conveyor and feeder are synonymous for purposes of the present application. Referring now to the drawings, and particularly to FIG. 1 , a conveyor 10 constructed in accordance with the invention is seen to basically include a base 12 , which may be mounted on the underlying terrain as, for example, the floor of a building, a table structure or the like. Supported about the base 12 is a generally horizontal, elongated, trough 14 having opposed ends 16 and 18 , as well as an upper conveying surface 20 . The trough 14 is supported about the base 12 by a series of vertically arrayed, vertical resiliency members 22 , for example a rocker leg and coil spring combination, or, preferably vertical leaf spring slats of conventional construction that are secured to both the underside of the trough 14 and to the base 12 at spaced locations via fabricated structural brackets 24 and fabricated brackets 26 respectively.
The drive assembly, FIG. 2 , consists of a structural drive fabricated horizontal rectangular box 28 and is preferably opened at the top and bottom. Two flange bearings 30 are mounted on each longitudinal side holding a lateral drive shaft 32 which in turn supports two primary eccentric counterweights 34 . A preferably totally enclosed and non-ventilated heavy duty reversible shaker motor 36 is bolted at one end of the drive box 28 so that the motor shaft 38 is lateral and horizontal to the elongated trough 14 . Two secondary eccentric counterweights 40 are mounted on the motor shaft 38 . The two primary eccentric counterweights 32 are driven by a synchronous timing belt 42 and driver and driven sprocket system are respectively longitudinally aligned whereby the driver sheave 44 is mounted on the motor shaft 38 and the driven sheave 46 is mounted on the primary drive shaft 32 . The drive assembly is attached to the trough 14 with a horizontal resiliency member 48 , preferably a leaf spring slat connected to the drive at the opposite end of the drive motor 36 and attached to a trough drive bracket 50 that is in turn connected to the trough 14 . Lastly, a spring 52 is connected to the bottom side of the drive and at the opposite end to the base 12 .
Thus far, FIGS. 1 and 2 have been shown and described to give the overall look and general structure of the principle components of the present invention. Turning now to the cross-sectional views of FIGS. 3-5 , the functional aspects of the principle components of the present invention are shown and described. Referring to FIG. 3 , the front of the drive assembly is shown with respect to its position above the base 12 and beneath the trough 14 as supported by the spring 52 . Within the drive box 28 is the shaker motor 36 which drives motor shaft 38 . The two secondary eccentric counterweights 40 rotate about the shaft 38 upon the motor 36 generating rotational power to the shaft 38 . Also, coupled to and rotating with the motor shaft 38 is the driver sheave 44 . The driver sheave 44 in turn rotates the driven sheave 46 through timing belt 42 . In the preferred embodiment, the driven sheave 46 is preferably twice the diameter of the driver sheave 44 , thereby causing the primary eccentric counterweights 34 to rotate at half the speed of the secondary eccentric counterweights 40 . Although, multiple combinations may provide the desired results, these speeds of rotation are preferably 300 r.p.m. and 600 r.p.m. respectively.
Referring now to FIG. 4 , the rear of the drive assembly is shown with respect to its positions above the base 12 and beneath the trough 14 as supported by the spring 52 . The previously discussed rotation of the driven sheave 46 in turn rotates the lateral drive shaft 32 , which is supported within the drive box 28 by flange bearings 30 , thereby causing the two primary eccentric counterweights 34 to rotate about the drive shaft 32 . The primary eccentric counterweights 34 and the secondary eccentric counterweights 40 are timed so that the primary eccentric counterweights 34 are horizontal when the secondary eccentric counterweights 40 are vertical i.e. lag the primary eccentric counterweights by 90°. The spring 52 illustrated in FIGS. 1-4 as being connected to the bottom side of the drive assembly and the opposite end connected to the base 12 serves a dual purpose. First, the spring 52 is sized to isolate and help support the drive assembly from the base 12 and accordingly nearly eliminates the vertically induced forces transmitted to the ground. In other words, the forces of the wheels not in line with the trough stroke (infra) are absorbed via this spring. Second, the spring 52 supports the drive assembly weight in order to relieve pre-loading the horizontal leaf spring slat 48 .
Finally, FIG. 5 illustrates the coupling of the base 12 and the trough 14 through the leaf spring slats 22 that are connected thereto by fabricated structural brackets 24 and fabricated brackets 26 respectively. These leaf spring slats 22 are sized so that the total spring rate sets the single mass natural frequency of the elongated trough 14 mass at preferably about seven percent (7%) over the primary running frequency. Furthermore, the leaf spring slats 22 are positioned vertically with respect to the base 12 and trough 14 so that the direction of the vibratory motion is horizontal and parallel to the elongated trough 14 .
With the general structure and function of the component parts shown and described with respect to FIGS. 1-5 , FIGS. 6-9 are now discussed as they relate to the general operation of the present invention. During operation and when the motor 36 is turned on to rotate the motor shaft 38 in a counter-clockwise manner, the secondary eccentric counterweights 40 and the primary eccentric counterweights 34 transfer energy through the horizontal leaf spring slat 48 , the trough drive bracket 50 , and ultimately the trough 14 in the form of a modified sinusoidal skewed stroke pattern as shown in FIG. 6 . This stroke pattern has been termed a “skewed sine wave” in that the slope of one side of each wave is shallower than the slope of the other side of the wave. Thus, if the stroke pattern illustrated by FIG. 6 is being applied to the components in the manner illustrated in FIGS. 1-5 , movement of the trough 14 to the right, that is toward the end 18 , will be relatively slow while the return movement toward the other end 16 will be relatively fast. In this case, conveying will be to the right because the slow movement to the right will allow the material being conveyed to frictionally engage and be advanced in that direction by the conveying surface 20 of the trough 14 . On the other hand, the fact that the return is so rapid, and the fact that the material still contains momentum energy from the rightward stroke will result in little or no reverse movement during the return stroke. The net result will be conveying of the material to the right.
When the operation is as in FIG. 7 , the opposite will occur. By reversing the motor rotation, the sinusoidal skewed stroke is biased to the left and the material flow is reversed to the left. As above, but stated differently, the stroke is skewed, now to the left, so that the trough movement to the left takes approximately twice the time which results in a low enough acceleration force, to promote material conveyance during the portion of the cycle as the return movement to the right does. The result is a biased impulse to the left causing material on the trough to be conveyed to the left.
As shown and described, it is the transfer of energy of the counterweights to the trough that produces the material flow. The present invention provides this forward material flow because the eccentric counterweight wheels are aligned such that the secondary wheels lag the primary wheels by 90° when the primary wheels are in line with the line of action of the trough stroke. The 90° offset fixed eccentric counterweight wheels are further capable of producing reverse material flow because the offset run in the opposite direction changes from a lagging profile to a leading profile resulting in reversing the skewed sinusoidal stroke.
This lagging/leading 90° offset is best illustrated with respect to FIGS. 8 and 9 respectively. FIG. 8 shows a step-wise representation 54 of the relative positions of the primary 34 and secondary 40 eccentric counterweights for every 90° counter-clockwise rotation 56 of the secondary eccentric counterweights 40 . The phase illustration 58 to the right of the nine-step series 54 shows the positions of the wheels where the maximum strokes occur when the material flow is from left to right. Similarly, FIG. 9 shows a step wise representation 60 of the relative positions of the primary 34 and secondary 40 eccentric counterweights for every 90° clockwise rotation 62 of the secondary eccentric counterweights 40 . The phase illustration 64 to the right of the nine-step series 60 shows the positions of the wheels where the maximum strokes occur when the material flow is from right to left.
From the foregoing, it will be appreciated that a flat stroke bi-directional vibratory conveyor made according to the invention produces a number of advantages over the prior art apparatus. For one, wheel sizes are greatly reduced without loss of stroke force. More particularly, the present invention utilizes a 2:1 frequency ratio and a 1:3 eccentric force ratio that results in the wheel sizes to be [(2×2)×1]:[1×3] or a 4:3 ratio for wheel size. Furthermore, the size of the wheels are even smaller because the present invention's lower frequency stroke is amplified by the sub-resonant tuned frequency of the trough, thereby further reducing the 4:3 ratio to around 1.75:3 ratio. In other words, by adapting the motor to the secondary frequency, motor eccentric counterweight wheels are small, and further, the primary eccentric counterweight wheels are minimized because of the sub-resonant tuning of the conveyor.
By way of example, assume that the conveyor trough natural frequency is set to be around 7% above the primary frequency. So, if the primary frequency is 300 rpm then the trough frequency is set to 320 rpm. The combined result is that the primary running frequency of 300 rpm is amplified as a sub-resonant natural frequency single mass conveyor system. The primary and secondary counterweight wheels have approximately the same brute force stroke. Because the primary natural frequency is close to the primary running speed, the trough stroke amplifies by a factor of about three times the brute force stroke.
It will therefore be appreciated that a flat-stroke bi-directional conveyor made according to the principles of the present invention provides considerable advancements over the aforementioned deficiencies of the prior art.
While a particular embodiment of the invention has been shown and described, it will be obvious to those skilled in the art that changes and modifications may be made therein without departing from the invention in its broader aspects, and, therefore, the aim in the appended claims is to cover all such changes and modifications as fall within the true sprit and scope of the invention. | A flat stroke bi-directional conveyor for conveying object, granular and powder material. The unit utilizes the skewed sine wave trough stroke principle using primary eccentric counterweights wheels driven by a motor running at the secondary speed and equipped with the secondary eccentric counterweight wheels. The forces not in line with the trough stroke are absorbed with an isolation spring mounted between the drive assembly and the base. | 1 |
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional Application No. 62/018,789 filed on Jun. 30, 2014. The above identified patent application is herein incorporated by reference in its entirety to provide continuity of disclosure.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to an air conditioning device for vehicles. More specifically, the present invention pertains to a portable air conditioning device that utilizes a thermoelectric cooling module to circulate cool air or heated air within the interior of a vehicle to increase comfort to the vehicle passengers. The present air conditioning device may be used with existing vehicles having no air conditioner or heating unit or to replace an inoperable air conditioner or heating unit.
[0004] Vehicle air conditioning systems cool the occupants of a vehicle in hot weather, and have come into wide and popular use throughout the automobile industry. Most air conditioning systems are installed into vehicles during the manufacturing process. These systems use an engine-mounted compressor, driven off of the crankshaft of the engine via a drive belt, with an evaporator in the trunk of a vehicle to deliver cold air through the rear parcel shelf and overhead vents. In this way, vehicle air conditioning systems move heat from inside of a vehicle to the outdoors. Conventional air conditioning systems, however, decrease the fuel efficiency of a vehicle because these systems use energy supplied by the alternator, which comes from the engine that uses the fuel. The air conditioning systems cannot function properly when the vehicle is not running because the belt that engages the compressor, which is used to compress the coolant, will only run with the engine started.
[0005] Additionally, diagnosing and repairing vehicle air conditioning systems can be very complicated. If a vehicle air conditioning system is not fixed, however, passengers can be subjected to excessive heat, which may be potentially dangerous during hot weather. Nonetheless, it is impracticable and expensive to install an air conditioning system in existing vehicles. More specifically, installing a new air conditioning system to an existing vehicle requires a user to modify the structure of the vehicle. It is recognized that portable cooling units may be used as a means of cooling the interior of a vehicle. It is submitted, however, that existing portable cooling units are bulky and lack the means to secure the cooling unit to the inside of a vehicle, and further lack means to effectively ventilate cool and hot air.
[0006] 2. Description of the Prior Art
[0007] Devices have been disclosed in the prior art that relate to air conditioning systems for vehicles, and further to those emphasizing portability of the system. These include devices that have been patented and published in patent application publications. Some of these patents describe air conditioners that are built into vehicles during the manufacturing process. Others describe portable air conditioner devices that utilize air vents disposed on the housing of the air conditioner. These devices, however, are not specifically designed to be used with existing vehicles and lack a flexible air duct system to facilitate the direction of the air flow within the interior of a vehicle. The following is a list of devices deemed most relevant to the present disclosure, which are herein described for the purposes of highlighting and differentiating the unique aspects of the present invention, and further highlighting the drawbacks existing in the prior art.
[0008] For example, U.S. Pat. No. 8,418,477 to Klein and U.S. Pat. No. 6,662,572 to Howard disclose solar-thermoelectric air-conditioning units that comprises a solar photovoltaic panel that is positioned in a window or another exterior portion of a vehicle to provide current to a thermoelectric assembly, which pumps excess heat out of the interior of the vehicle. Additionally, the solar photovoltaic panel blocks a portion of sun rays from entering the vehicle. Klein, however, does not disclose an air conditioning unit that comprises thermoelectric cooling module that includes aluminum plates.
[0009] U.S. Pat. No. 3,187,043 to Zoleta, U.S. Pat. No. 3,138,934 to Roane, and U.S. Pat. No. 7,866,164 to Rice disclose automobile air conditioning systems that comprises thermoelectric devices. Zoleta discloses a Seebeck generator that is operated via an engine exhaust. The generator supplies electrical current to a Peltier unit that is located in a vehicle cabin for removing heat from the same. Roane discloses finned aluminum plates and a fan for generating an air flow. Rice discloses a housing with an elongated vent for allowing air to exit therethrough. While the foregoing devices disclose thermoelectric devices, these devices do not disclose a housing that is in fluid communication with an air duct system.
[0010] Finally, U.S. Pat. No. 4,823,554 to Trachtenberg discloses a vehicle thermoelectric cooling and heating food and drink appliance that comprises Peltier elements. The design and intent of the Trachtenberg devices, however, differ from the present invention in that Trachtenberg discloses a device for keeping food and beverage items cool. Thus, Trachtenberg is inoperable to cool the inside of a vehicle cabin. In contrast, the present invention comprises an air conditioning device for cooling or heating the inside of a vehicle cabin.
[0011] These prior art devices have several known drawbacks. The present invention is adapted to provide air conditioning system for vehicles without an existing air conditioning system or for vehicles without an operable air conditioning system. The present invention does not require structural modification to the vehicle, and offers the flexibility of being able to be moved as necessary. The present invention helps to cool the interior of a vehicle to provide a comfort to the passengers. The housing is designed to be compact so that it may be placed in the interior of a vehicle, while the strap secures the device in place. Additionally, the air duct hoses can be easily maneuvered to direct air flow to the driver and the passenger.
[0012] It is therefore submitted that the present invention substantially diverges in design elements from the prior art, which overcomes the disadvantages of the prior art devices, and consequently it is clear that there is a need in the art for an improvement to existing air conditioning systems for vehicles. In this regard the instant invention substantially fulfills these needs.
SUMMARY OF THE INVENTION
[0013] In view of the foregoing disadvantages inherent in the known types of air conditioning systems for vehicles now present in the prior art, the present invention provides a new improvement to a portable air conditioning device for vehicles wherein the same can be utilized for cooling or heating the interior of a vehicle.
[0014] It is therefore an object of the present invention to provide a new and improved portable air conditioning device for vehicles that has all of the advantages of the prior art and none of the disadvantages.
[0015] It is another object of the present invention to provide a new and improved portable air conditioning device for vehicles having an air duct system that includes one or more flexible air duct hoses with adjustable vents to control the direction of the air flow to the occupants of a vehicle.
[0016] Another object of the present invention is to provide a new and improved portable air conditioning device for vehicles having a fan with a fan speed control switch that is adapted to control the amount of air flow to the occupants of a vehicle.
[0017] Yet another object of the present invention is to provide a new and improved portable air conditioning device for vehicles that is compact in design for use with new or existing vehicles without modifying the structure of the vehicles.
[0018] Still yet another object of the present invention is to provide a new and improved portable air conditioning device for vehicles that is externally powered via a retractable power supply adapter or a retractable outlet plug.
[0019] Still yet another object of the present invention is to provide a new and improved portable air conditioning device for vehicles that utilizes a thermoelectric cooling module.
[0020] Still yet another object of the present invention is to provide a new and improved portable air conditioning device for vehicles that includes a strap system to secure the device to the interior of a vehicle.
[0021] Other objects, features and advantages of the present invention will become apparent from the following detailed description taken in conjunction with the accompanying drawings.
BRIEF DESCRIPTIONS OF THE DRAWINGS
[0022] Although the characteristic features of this invention will be particularly pointed out in the claims, the invention itself and in manner in which it may be made and used may be better understood after a review of the following description, taken in connection with the accompanying drawings wherein like numeral annotations are provided throughout.
[0023] FIG. 1 shows a perspective view of an embodiment of the present invention.
[0024] FIG. 2 shows a perspective view of another embodiment of the present invention.
[0025] FIG. 3 shows a cross sectional view of the present invention.
[0026] FIG. 4 shows a view of the present invention as placed inside of a vehicle.
DETAILED DESCRIPTION OF THE INVENTION
[0027] Reference is made herein to the attached drawings. Like reference numerals are used throughout the drawings to depict like or similar elements of the portable air conditioning device for vehicles. For the purposes of presenting a brief and clear description of the present invention, the preferred embodiment will be discussed as used for heating or cooling the interior of a vehicle. The figures are intended for representative purposes only and should not be considered to be limiting in any respect.
[0028] Referring now to FIGS. 1 and 2 , there are shown perspective views of various embodiments of the present invention. The present invention is a vehicle air conditioning unit 11 that uses a thermoelectric cooling module to exchange heat, and that can be used as a heating or cooling device as desired by the user. The present air conditioning unit 11 comprises a housing 28 that is composed of rigid material such as durable plastic or thin metal. The housing 28 preferably comprises a rectangular prism shape having a top side 13 , a bottom side, a front side 14 , a back side, a first lateral side 25 , and a second lateral side 15 , forming an interior volume adapted to enclose various components of the air conditioner therein. The top side 13 of the housing 28 comprises one or more outlet ports, wherein each port is connected to an air duct hose 17 so that the air duct hose 17 is in fluid communication with the interior volume of the housing 28 . In the illustrated embodiment, the top side 13 comprises two outlet ports so that the device comprises two air duct hoses 17 , wherein one air duct hose can be used to direct heated or cooled air towards the driver and another air duct hose can be used to direct heating or cooled air towards the front passenger. However, the air duct hoses 17 may be used to direct heated or cooled air to any part of the vehicle where air flow is desired.
[0029] Each air duct hose 17 may be manufactured from one or more plastic materials and may have a flexible, accordion-like structural configuration to facilitate movement thereof. The air duct hose 17 comprises a first end 26 and a second end 19 , wherein the first end 26 is connected to the outlet port disposed on the top side 13 of the housing 28 . The perimeter of the first end 26 is sealed around the outlet port to prevent air leakage. The second end 19 of the air duct hose 17 comprises an adjustable air vent 20 that enables a user to control the direction and the amount of the air flow. Additionally, the air duct hose 17 comprises a closed loop strap 18 having hook and loop fasteners thereon. The strap 18 may be used to secure the second end 19 of the air duct hose 17 to a desired location inside of the vehicle.
[0030] The front side 14 of the housing 28 comprises a fan speed control switch. In the exemplary embodiments, the front side 14 includes a speed control switch 12 for a two-speed fan disposed within the interior volume of the housing 28 . More specifically, the exemplary embodiments comprise an off mode, a low speed setting, and a high speed setting. The housing 28 further comprises a control for allowing the user to switch between heating and cooling modes, so that the device can be used to heat or cool the interior of the vehicle as desired by the user. Additionally in some embodiments, the present invention comprises a digital display to show the temperature of the interior of the vehicle in which the air conditioning device is placed.
[0031] The first lateral side 25 comprises a recessed portion that is adapted to store retractable power adapters and/or cables 24 , 25 therein. More specifically, the device may include a standard outlet plug 23 and a retractable 12-Volt power supply adapter 24 . Each of the standard outlet plug 23 and the power supply adapter 24 are electrically connected to the various air conditioner components disposed inside of the housing 28 . It is contemplated that each of the standard outlet plug 23 and the power supply adapter 24 is retractable.
[0032] Optionally, the second lateral side 15 comprises an exhaust port. The exhaust port is connected to an exhaust hose 16 so that the exhaust hose 16 is in fluid communication with the interior volume of the housing 28 . Similar to the air duct hose 17 , the exhaust hose 16 may be manufactured from one or more plastic materials and may have a flexible, accordion-like structural configuration to facilitate movement thereof. The exhaust hose 16 comprises a first end 27 and a second end 29 , wherein the first end 27 is connected to the exhaust port disposed on the second lateral side 15 of the housing 28 . The perimeter of the first end 27 is sealed around the exhaust port to prevent any air leakage therefrom.
[0033] The second end 29 of the exhaust hose 16 comprises a tip 21 that is flat in structural configuration, so that it may be held or wedged between the window and the vehicle door frame. In this way, the tip 21 can release hot air produced from the interior of the housing 28 to the outdoors. Additionally, the second end 29 of the exhaust hose 16 comprises one or more suction cups 22 attached thereto. The suction cups 22 may be attached to the exhaust hose 16 via a strap or the like. The suction cups 22 help to secure the second end 29 of the exhaust hose 16 to the window and prevent the exhaust hose 16 from slipping or falling down. Optionally, the exhaust hose 16 may include a warning indicator to alert the user of the heated air that is blown from the tip 21 .
[0034] The housing 28 may further comprise a strap system so as to secure the present invention to a back of a vehicle seat. The strap system comprises a first strap 30 and a second strap 31 . The straps 30 , 31 may be composed of durable material such as nylon, polyester, polypropylene, leather, or other suitable material. The first strap 30 comprises a proximal end that is attached to the back side of the housing 28 , and a free distal end 32 . Similarly, the second strap 31 comprises a proximal end 36 that is attached to the front side 14 of the housing 28 , and a free distal end 33 . The proximal ends of the straps 30 , 31 may be attached to the front side 14 and the back side of the housing 28 via a fastener 37 such as a screw. The distal end 32 of the first strap 30 may comprise a buckle 34 , which can engage one of the apertures 35 disposed near the distal end 33 of the second strap 31 , as shown in FIG. 1 . Alternatively, the distal end 32 of the first strap 30 may comprise hook fasteners 38 , which can engage loop fasteners 39 disposed on the distal end 33 of the second strap 31 , as shown in FIG. 2 .
[0035] Referring now to FIG. 3 , there is shown a cross sectional view of the air conditioning unit of the present invention. The housing 28 of the air conditioning unit 11 comprises an outer layer 45 and an inner layer 46 . The outer layer 45 comprises ceramic heat insulation and the inner layer 46 comprises a thermoelectric cooling module adapted to produce heated or cooled air, wherein the thermoelectric cooling module spans the entire surface area of the inner layer 46 . Preferably, the outer layer 45 is substantially coextensive with the inner layer 46 . Additionally, the outer layer 45 and the inner layer 46 form a channel 51 in the interior volume of the housing 28 . The channel 51 provides access to the outlet port 48 disposed on the top side of the housing 28 and to the inlet port 47 disposed on the bottom side of the housing 28 .
[0036] The thermoelectric cooling module of the inner layer 46 comprises a cool side, a hot side, and a plurality of metal conductors and thermoelectric N, P elements therebetween. The cool side and the hot side comprise ceramic plates. The cool side faces the interior of the housing 28 and the hot side faces the outer layer 45 of the housing 28 . Thus, heat is absorbed from the cool side in the interior of the housing 28 , then transmitted to the hot side. The cool side comprises a plurality of aluminum plates 50 perpendicularly attached thereto. As such, the aluminum plate protrudes toward the interior of the housing 28 . In the illustrated embodiment, the aluminum plates 50 are rectangular in shape and are separated at regular intervals so as to cool the air in a uniform manner. Each aluminum plate comprises a plurality of apertures thereon to allow air to pass therethrough. Because the aluminum plates have good thermal conductance to provide heat transfer with minimal resistance, the aluminum plates 50 increase the efficiency of the device by facilitating in cooling or heating the air within the channel 51 .
[0037] The inlet port 47 comprises a two-speed fan 43 therein. The fan speed may be determined via the fan speed control switch disposed on the exterior of the housing 28 . The fan 43 is adapted to force the heated or cooled air through the channel 51 and exit through the outlet ports 48 . In some embodiments, the inlet port 47 may further comprise an air filter to eliminate any debris before the air is directed toward the outlet port 48 connected to the air duct hose 17 . The filter may be in a form of pleated fibrous materials which removes solid particulates such as dust, pollen, mold, and bacteria from the air.
[0038] The heat generated from the energy spent to cool the air may be released through the exhaust port connected to the exhaust pipe. Alternatively, the heat may be released through the inlet port 47 or cooled within the interior of the housing as the heat travels through the channel 51 . Accordingly, some embodiments of the present invention may not comprise an exhaust port. Any condensation or moisture formed within the interior of the housing may be released through an opening disposed on the bottom side of the housing, wherein the opening may be closed or opened via a plug 44 .
[0039] It is contemplated that the present invention may be powered externally via a vehicle battery or a solar panel connected thereto. Accordingly, the housing 28 comprises a plurality of power cords and plugs 23 , 24 , wherein the power cords and plugs 23 , 24 are in electrically connected to the thermoelectric cooling module and the fan 43 . In other embodiments, however, the present invention may be powered internally via a battery.
[0040] Referring now to FIG. 4 , there is shown a view of the present invention as placed inside of a vehicle. The device is placed inside of a vehicle, such as the area behind the front seat of the vehicle, or the area behind the center console. The housing 28 may be secured to the front seat 40 or to the center console, and remain secured thereto via straps 31 . The outlet ports direct air through the air duct hoses which can be disposed in the front of the vehicle so as to provide heated or cooled air to the driver and passenger. The tip 21 of the exhaust hose 16 may be extended toward the window 42 , and wedged between the window 42 and the vehicle door frame 41 . The tip 21 of the exhaust hose 16 should face outward to direct hot air produced from the device to the outdoors. Additionally, the suction cups 22 may be placed on the window 42 to prevent the exhaust hose 16 from falling off of its place. Releasing hot air to the outdoors increases the efficiency of the present invention by maintaining cool temperature inside of the vehicle.
[0041] It is therefore submitted that the instant invention has been shown and described in what is considered to be the most practical and preferred embodiments. It is recognized, however, that departures may be made within the scope of the invention and that obvious modifications will occur to a person skilled in the art. With respect to the above description then, it is to be realized that the optimum dimensional relationships for the parts of the invention, to include variations in size, materials, shape, form, function and manner of operation, assembly and use, are deemed readily apparent and obvious to one skilled in the art, and all equivalent relationships to those illustrated in the drawings and described in the specification are intended to be encompassed by the present invention.
[0042] Therefore, the foregoing is considered as illustrative only of the principles of the invention. Further, since numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the invention to the exact construction and operation shown and described, and accordingly, all suitable modifications and equivalents may be resorted to, falling within the scope of the invention. | Disclosed is a portable air conditioning device for vehicles. The device includes a plurality of air duct hoses and an exhaust hose that is connected to a housing member that encloses a thermoelectric cooling module capable of producing heated or cooled air, and a fan with a fan speed control switch. The air duct hoses supply cool air to the interior of a vehicle while the exhaust hose releases heat to the outdoors. The device may be internally powered via a battery or externally powered via a power adaptor or outlet. The device may be conveniently placed inside of a vehicle and secured in place via a strap system disposed thereon. In this way, the device may be ideally used with existing vehicles lacking an operable air conditioning and/or heating system. Additionally, the device may be used to supplement an operable air conditioning system for a vehicle. | 1 |
CROSS REFERENCE TO RELATED APPLICATION
This application is a continuation of U.S. patent application Ser. No. 14/222,510, filed on
Mar. 21, 2014, which is a continuation of U.S. patent application Ser. No. 13/954,974, filed on Jul. 30, 2013, now U.S. Pat. No. 8,709,494, which is a continuation of U.S. patent application Ser. No. 13/569,095, filed on Aug. 7, 2012, now U.S. Pat. No. 8,597,687, which is a continuation of U.S. patent application Ser. No. 11/840,728, filed on Aug. 17, 2007, now U.S. Pat. No. 8,372,437, which claims the benefit under 35 U.S.C. §119 (e) of U.S. provisional patent application No. 60/838,467, entitled “Method and System for Preserving Amnion Tissue For Later Transplant,” filed Aug. 17, 2006. The contents of these applications are incorporated herein by reference in their entireties.
FIELD OF THE INVENTION
The present invention relates generally to tissue allografts and, in particular, to placental membrane tissue grafts (amnion and chorion) and methods of preparing, preserving, and medical uses for the same.
BACKGROUND OF THE INVENTION
Human placental membrane (e.g. amniotic membrane or tissue) has been used for various types of reconstructive surgical procedures since the early 1900s. The membrane serves as a substrate material, more commonly referred to as a biological dressing or patch graft. Such membrane has also been used widely for ophthalmic procedures in the United States and in countries in the southern hemisphere. Typically, such membrane is either frozen or dried for preservation and storage until needed for surgery.
Such placental tissue is typically harvested after an elective Cesarean surgery. The placenta has two primary layers of tissue including amniotic membrane and chorion. The amniotic membrane is a non-vascular tissue that is the innermost layer of the placenta, and consists of a single layer, which is attached to a basement membrane.
Histological evaluation indicates that the membrane layers of the amniotic membrane consist of epithelium cells, thin reticular fibers (basement membrane), a thick compact layer, and fibroblast layer. The fibrous layer of amnion (i.e., the basement membrane) contains cell anchoring collagen types IV, V, and VII. The chorion is also considered as part of the fetal membrane; however, the amniotic layer and chorion layer are separate and separable entities.
Amniotic membrane and chorion tissue provide unique grafting characteristics when used for surgical procedures, including providing a matrix for cellular migration/proliferation, providing a natural biological barrier, are non-immunogenic, promote increased self-healing, are susceptible of being fixed in place using different techniques including fibrin glue or suturing. And, such grafts, when properly prepared, can be stored at room temperature for extended periods of time, without need for refrigeration or freezing, until needed for a surgical procedure.
Known clinical procedures or applications for such amnion grafts include Schnciderian Membrane repair (i.e. sinus lift), guided tissue regeneration (GTR), general wound care, and primary closure membrane. Known clinical procedures or applications for such chorion grafts include biological would dressing.
A detailed look at the history and procedure for harvesting and using “live” amniotic tissue for surgical procedures and a method for harvesting and freezing amniotic tissue grafts for ophthalmic procedures is described in U.S. Pat. No. 6,152,142 issued to Tscng, which is incorporated herein by reference in its entirety.
There is a need for improved procedures for harvesting, processing, and preparing amnion and/or chorion tissue for later surgical grafting procedures.
There is a need for improved procedures for processing and preparing multiple layers of amnion and/or chorion tissue for later surgical grafting procedures.
There is a need for preparing and storing such tissue such that the stroma and basement sides of the tissue are easily and quickly identifiable by a surgeon when using such tissue in a surgical procedure.
For these and many other reasons, there is a general need for a method for preparing placenta membrane tissue grafts for medical use, and that includes the steps of obtaining a placenta from a subject, cleaning the placenta, separating the chorion from the amniotic membrane, disinfecting the chorion and/or amniotic membrane, mounting a selected layer of either the chorion or the amniotic membrane onto a drying fixture, dehydrating the selected layer on the drying fixture, and cutting the selected layer into a plurality of tissue grafts. There is an additional need for a drying fixture that includes grooves or raised edges that define the outer contours of each desired tissue graft and that make cutting of the grafts more accurate and easy. There is a further need for a drying fixture that includes raised or indented logos, textures, designs, or text that emboss the middle area of the tissue grafts during dehydration and that enables an end user to be bale to distinguish the top surface from the bottom surface of the graft, which is often necessary to know prior to using such grafts in a medical application or surgical procedure. Such logos, textures, designs, or text can be used for informational purposes or they can, additionally and advantageously, be used for marketing or advertising purposes. There is a need for grafts that are comprised of single layers of amnion or chorion, multiple layers of amnion or chorion, or multiple layers of a combination of amnion and chorion.
The present invention meets one or more of the above-referenced needs as described herein in greater detail.
SUMMARY OF THE INVENTION
One embodiment of the present invention is directed to one or more methods of preparing placenta membrane tissue grafts, comprising the steps of obtaining a placenta from a subject, wherein the placenta includes an amniotic membrane layer and a chorion tissue layer, cleaning the placenta in a solution, separating the chorion tissue layer from the amniotic membrane layer, mounting a selected layer of either the chorion tissue layer or the amniotic membrane layer onto a surface of the drying fixture, dehydrating the selected layer on the drying fixture, and thereafter, cutting the selected layer into a plurality of placenta membrane tissue grafts. The placenta membrane tissue grafts can be either amniotic membrane tissue grafts or chorion tissue grafts. Since amniotic membrane has a stromal side and an opposite, basement side, when dehydrating an amniotic membrane layer, such layer is mounted onto the drying fixture with the basement side facing down and stromal side facing up.
Preferably, the drying fixture includes a texture or design adapted to emboss such texture or design into the placenta membrane tissue grafts during the step of dehydration wherein the texture or design embossed into the placenta membrane tissue enable a user to identify a top and bottom surface of the placenta membrane tissue.
Preferably, the placenta is cleaned in a hypertonic solution wherein the hypertonic solution comprises NaCl concentration in a range of from about 30 % to about 10 %.
In some embodiments, the method further comprises the step of, after separation of the chorion tissue layer from the amniotic membrane layer, soaking the selected layer in an antibiotic solution. Optionally, the method then also includes the step of rinsing the selected layer to remove the antibiotic solution.
In some embodiments, the method further includes the step of, after separation of the chorion tissue layer from the amniotic membrane layer, physically cleaning the selected layer to remove blood clots and other contaminates.
In other features, the step of dehydrating the selected layer further comprises placing the drying fixture in a breathable bag and heating the bag for a predetermined period of time. Preferably, the bag is heated at a temperature of between 35 degrees and 50 degrees Celcius and the predetermined period of time is between 30 and 120 minutes, wherein 45 degrees Celcius and 45 minutes of time in a non-vacuum over or incubator for a single layer of tissue generally seems ideal.
In one arrangement, the surface of the drying fixture has a plurality of grooves that defines the outer contours of each of the plurality of placenta membrane tissue grafts and wherein the step of cutting comprises cutting the selected layer along the grooves.
In another arrangement, the surface of the drying fixture has a plurality of raised edges that define the outer contours of each of the plurality of placenta membrane tissue grafts and wherein the step of cutting comprises rolling a roller across the top of the selected layer and pressing the selected layer against the raised edges.
In another feature, the method further comprises the step of mounting one or more additional layers of chorion tissue or amniotic layer onto the surface of the drying fixture prior to the step of dehydration to create a plurality of laminated placenta membrane tissue grafts having a thickness and strength greater than a single layer of placenta membrane tissue grafts.
In a further feature, each of the plurality of placenta membrane tissue grafts is rehydrated prior to use of the respective graft for a medical procedure.
In yet further features, the present invention includes tissue grafts processed and prepared according to any of the methods described herein.
In another embodiment, the present invention is directed to a tissue graft that comprises a dehydrated, placenta tissue having a top and bottom surface and an outer contour sized and shaped for use in a suitable medical procedure, wherein a texture or design is embossed within the dehydrated, placenta tissue and wherein the embossment distinguishes the top from the bottom surface of the placenta tissue; and wherein the dehydrated, placenta tissue graft is usable in the suitable medical procedure after being rehydrated. In a feature of this embodiment, the dehydrated, placenta tissue comprises either an amniotic membrane layer or a chorion tissue layer. In yet another feature, the dehydrated, placenta tissue comprises two or more layers of amniotic membrane and chorion tissue, wherein the two or more layers include a plurality of amniotic membrane, a plurality of chorion tissue, or a plurality of amniotic membrane and chorion tissue.
These and other aspects of the present invention will become apparent from the following description of the preferred embodiment taken in conjunction with the following drawings, although variations and modifications therein may be affected without departing from the spirit and scope of the novel concepts of the disclosure.
BRIEF DESCRIPTION OF THE DRAWINGS
Further features and benefits of the present invention will be apparent from a detailed description of preferred embodiments thereof taken in conjunction with the following drawings, wherein similar elements are referred to with similar reference numbers, and wherein:
FIG. 1 is a high level flow chart of the primary steps performed in a preferred embodiment of the present invention;
FIG. 2 is an exemplary tissue check-in form used with the preferred embodiment of the present invention;
FIG. 3 is an exemplary raw tissue assessment form used with the preferred embodiment of the present invention;
FIG. 4 is an exemplary dehydration process form used with the preferred embodiment of the present invention;
FIG. 5 is a perspective view of an exemplary drying fixture for use with a preferred embodiment of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention is more particularly described in the following examples and embodiments that are intended as illustrative only since numerous modifications and variations therein will be apparent to those skilled in the art. Various embodiments of the invention arc now described in greater detail. As used in the description herein and throughout the claims that follow, the meaning of “a”, “an”, and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein and throughout the claims that follow, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise. Moreover, titles or subtitles may be used in the specification for the convenience of a reader, which are not intended to influence the scope of the present invention. Additionally, some terms used in this specification are more specifically defined below.
Without intent to limit the scope of the invention, exemplary instruments, apparatus, methods and their related results according to the embodiments of the present invention are given below. Note that titles or subtitles may be used in the discussion of exemplary embodiments of the present invention for convenience of a reader, which in no way should limit the scope of the invention. Moreover, certain theories are proposed and disclosed herein; however, in no way they, whether they are right or wrong, should limit the scope of the invention so long as the invention is practiced according to the invention without regard for any particular theory or scheme of action.
Overview of the Process
Turning first to FIG. 1 , a high level overview 100 of the steps undertaken to harvest, process, and prepare placental material for later use as an allograft is disclosed. More detailed descriptions and discussion regarding each individual step will follow. At a high level, initially, the placenta tissue is collected from a consenting patient following an elective Cesarean surgery (step 110 ). The material is preserved and transported in conventional tissue preservation manner to a suitable processing location or facility for check-in and evaluation (step 120 ). Gross processing, handling, and separation of the tissue layers then takes place (step 130 ). Acceptable tissue is then decontaminated (step 140 ), dehydrated (step 150 ), cut and packaged (step 160 ), and released (step 170 ) to the market for use by surgeons and other medical professionals in appropriate surgical procedures and for wound care.
Initial Tissue Collection (Step 110 )
The recovery of placenta tissue originates in a hospital, where it is collected during a Cesarean section birth. The donor, referring to the mother who is about to give birth, voluntarily submits to a comprehensive screening process designed to provide the safest tissue possible for transplantation. The screening process preferably tests for antibodies to the human immunodeficiency virus type 1 and type 2 (anti-HIV-1 and anti-HIV-2), hepatitis B surface antigens (HBsAg), antibodies to the hepatitis C virus (anti-HCV), antibodies to the human T-lymphotropic virus type I and type II (anti-HTLV-I and anti HTLV II), CMV, and syphilis, using conventional serological tests. The above list of tests is exemplary only, as more, fewer, or different tests may be desired or necessary over time or based upon the intended use of the grafts, as will be appreciated by those skilled in the art.
Based upon a review of the donor's information and screening test results, the donor will either be deemed acceptable or not. In addition, at the time of delivery, cultures arc taken to determine the presence of, for example, Clostridium or Streptococcus. If the donor's information, screening tests, and the delivery cultures are all negative (i.e., do not indicate any risks or indicate acceptable level of risk), the donor is approved and the tissue specimen is designated as initially eligible for further processing and evaluation.
Human placentas that meet the above selection criteria arc preferably bagged in a saline solution in a sterile shipment bag and stored in a container of wet ice for shipment to a processing location or laboratory for further processing.
If the placenta tissue is collected prior to the completion or obtaining of results from the screening tests and delivery cultures, such tissue is labeled and kept in quarantine. The tissue is approved for further processing only after the required screening assessments and delivery cultures, which declare the tissue safe for handling and use, are satisfied.
Material Check-in and Evaluation (Step 120 )
Upon arrival at the processing center or laboratory, the shipment is opened and verified that the sterile shipment bag/container is still sealed and intact, that ice or other coolant is present and that the contents are cool, that the appropriate donor paperwork is present, and that the donor number on the paperwork matches the number on the sterile shipment bag containing the tissue. The sterile shipment bag containing the tissue is then stored in a refrigerator until ready for further processing. All appropriate forms, including a tissue check-in form, such as that shown in FIG. 2 , are completed and chain of custody and handling logs (not shown) arc also completed.
Gross Tissue Processing (Step 130 )
When the tissue is ready to be processed further, the sterile supplies necessary for processing the placenta tissue further arc assembled in a staging area in a controlled environment and are prepared for introduction into a critical environment. If the critical environment is a manufacturing hood, the sterile supplies are opened and placed into the hood using conventional sterile technique. If the critical environment is a clean room, the sterile supplies are opened and placed on a cart covered by a sterile drape. All the work surfaces are covered by a piece of sterile drape using conventional sterile techniques, and the sterile supplies and the processing equipments are placed on to the sterile drape, again using conventional sterile technique.
Processing equipment is decontaminated according to conventional and industry-approved decontamination procedures and then introduced into the critical environment. The equipment is strategically placed within the critical environment to minimize the chance for the equipment to come in proximity to or is inadvertently contaminated by the tissue specimen.
Next, the placenta is removed from the sterile shipment bag and transferred aseptically to a sterile processing basin within the controlled environment. The sterile basin contains , preferably, 18 % NaCl- hypertonic saline) solution that is at room or near room temperature. The placenta is gently massaged to help separate blood clots and to allow the placenta tissue to reach room temperature, which will make the separation of the amnion and chorion layers from each other, as discussed hereinafter, easier. After having warmed up to the ambient temperature (after about 10-30 minutes), the placenta is then removed from the sterile processing basin and laid flat on a processing tray with the amniotic membrane layer facing down for inspection.
The placenta tissue is examined and the results of the examination are documented on a “Raw Tissue Assessment Form” similar to that shown in FIG. 3 . The placenta tissue is examined for discoloration, debris or other contamination, odor, and signs of damage. The size of the tissue is also noted. A determination is made, at this point, as to whether the tissue is acceptable for further processing.
Next, if the placenta tissue is deemed acceptable for further processing, the amnion and chorion layers of the placenta tissue are then carefully separated. The materials and equipments used in this procedure include the processing tray, 18% saline solution, sterile 4×4 sponges, and two sterile Nalgcne jars. The placenta tissue is then closely examined to find an area (typically a corner) in which the amniotic membrane layer can be separated from the chorion layer. The amniotic membrane appears as a thin, opaque layer on the chorion.
With the placenta tissue in the processing tray with the amniotic membrane layer facing down, the chorion layer is gently lifted off the amniotic membrane layer in a slow, continuous motion, using care to prevent tearing of the amniotic membrane. If a tear starts, it is generally advisable to restart the separation process from a different location to minimize tearing of either layer of tissue. If the chorion layer is not needed, it may be gently scrubbed away from the amniotic membrane layer with one of the sterile 4×4 sponges by gently scrubbing the chorion in one direction. A new, sterile 4×4 sponge can be used whenever the prior sponge becomes too moist or laden with the chorion tissue. If the chorion is to be retained, then the separation process continues by hand, without the use of the sponges, being careful not to tear either the amnion layer or the chorion layer.
Care is then taken to remove blood clots and other extraneous tissue from each layer of tissue until the amniotic membrane tissue and the chorion are clean and ready for further processing. More specifically, the amnion and chorion tissues are placed on the processing tray and blood clots are carefully removed using a blunt instrument, a finger, or a sterile non-particulating gauze, by gently rubbing the blood until it is free from the stromal tissue of the amnion and from the trophoblast tissue of the chorion. The stromal layer of the amnion is the side of the amniotic membrane that faces the mother. In contrast, the basement membrane layer is the side of the amnion that faces the baby.
Using a blunt instrument, a cell scraper or sterile gauze, any residual debris or contamination is also removed. This step must be done with adequate care, again, so as not to tear the amnion or chorion tissues. The cleaning of the amnion is complete once the amnion tissue is smooth and opaque-white in appearance. If the amnion tissue is cleaned too much, the opaque layer can be removed. Any areas of the amnion cleaned too aggressively and appear clear will be unacceptable and will ultimately be discarded.
Chemical Decontamination (Step 140 )
The amniotic membrane tissue is then placed into a sterile Nalgene jar for the next step of chemical decontamination. If the chorion is to be recovered and processed further, it too is placed in its own sterile Nalgene jar for the next step of chemical decontamination. If the chorion is not to be kept or used further, it can be discarded in an appropriate biohazard container.
Next, each Nalgene jar is aseptically filled with 18% saline solution and sealed (or closed with a top. The jar is then placed on a rocker platform and agitated for between 30 and 90 minutes, which further cleans the tissue of contaminants.
If the rocker platform was not in the critical environment (e.g., the manufacturing hood), the Nalgene jar is returned to the critical/sterile environment and opened. Using sterile forceps, the tissue is gently removed from the Nalgene jar containing the 18% hypertonic saline solution and placed into an empty Nalgene jar. This empty Nalgene jar with the tissue is then aseptically filled with a pre-mixed antibiotic solution. Preferably, the premixed antibiotic solution is comprised of a cocktail of antibiotics, such as Streptomycin Sulfate and Gentamicin Sulfate. Other antibiotics, such as Polymixin B Sulfate and Bacitracin, or similar antibiotics now available or available in the future, are also suitable. Additionally, it is preferred that the antibiotic solution be at room temperature when added so that it does not change the temperature of or otherwise damage the tissue. This jar or container containing the tissue and antibiotics is then sealed or closed and placed on a rocker platform and agitated for, preferably, between 60 and 90 minutes. Such rocking or agitation of the tissue within the antibiotic solution further cleans the tissue of contaminants and bacteria.
Again, if the rocker platform was not in the critical environment (e.g., the manufacturing hood), the jar or container containing the tissue and antibiotics is then returned to the criticaUsterile environment and opened. Using sterile forceps, the tissue is gently removed from the jar or container and placed in a sterile basin containing sterile water or normal saline (0.9% saline solution). The tissue is allowed to soak in place in the sterile water/normal saline solution for at least 10 to 15 minutes. The tissue may be slightly agitated to facilitate removal of the antibiotic solution and any other contaminants from the tissue. After at least 10 to 15 minutes, the tissue is ready to be dehydrated and processed further.
Dehydration (Step 150 )
Next, the now-rinsed tissue (whether it be the amniotic membrane or chorion tissue) is ready to be dehydrated. The amniotic membrane is laid, stromal side down, on a suitable drying fixture. The stromal side of the amniotic membrane is the “tackier” of the two sides of the amniotic membrane. A sterile, cotton tipped applicator may be used to determine which side of the amniotic tissue is tackier and, hence, the stromal side.
The drying fixture is preferably sized to be large enough to receive the tissue, fully, in laid out, flat fashion. The drying fixture is preferably made of Teflon or of Delrin, is the brand name for an acetal resin engineering plastic invented and sold by DuPont and which is also available commercially from Werner Machines, Inc. in Marietta, Ga. Any other suitable material that is heat and cut resistant, capable of being formed into an appropriate shape to receive wet tissue and to hold and maintain textured designs, logos, or text can also be used for the drying fixture. The tissue must be placed on the drying fixture so that it completely covers as many “product spaces” (as explained hereinafter) as possible.
In one embodiment, similar to that shown in FIG. 5 , the receiving surface of the drying fixture 500 has grooves 505 that define the product spaces 510 , which are the desired outer contours of the tissue after it is cut and of a size and shape that is desired for the applicable surgical procedure in which the tissue will be used. For example, the drying fixture can be laid out so that the grooves arc in a grid arrangement. The grids on a single drying fixture may be the same uniform size or may include multiple sizes that are designed for different surgical applications. Nevertheless, any size and shape arrangement can be used for the drying fixture, as will be appreciated by those skilled in the art. In another embodiment, instead of having grooves to define the product spaces, the drying fixture has raised ridges or blades.
Within the “empty” space between the grooves or ridges, the drying fixture preferably includes a slightly raised or indented texture in the form of text, logo, name, or similar design 520 . This textured text, logo, name, or design can be customized or private labeled depending upon the company that will be selling the graft or depending upon the desired attributes requested by the end user (e.g., surgeon). When dried, the tissue will mold itself around the raised texture or into the indented texture—essentially providing a label within the tissue itself. Preferably, such texture/label can be read or viewed on the tissue in only one orientation so that, after drying and cutting, an end user (typically, a surgeon) of the dried tissue will be able to tell the stromal side from the basement side of the dried tissue. The reason this is desired is because, during a surgical procedure, it is desirable to place the allograft in place, with basement side down or adjacent the native tissue of the patient receiving the allograft. FIG. 5 illustrates a variety of marks, logos, and text 520 that can be included within the empty spaces 510 of the drying fixture 500 . Typically, a single drying fixture will include the same design or text within all of the empty spaces; however, FIG. 5 shows, for illustrative purposes, a wide variety of designs that can be included on such drying fixtures to emboss each graft.
In a preferred embodiment, only one layer of tissue is placed on the drying fixture. In alternate embodiments, multiple layers of tissue are placed on the same drying fixture to create a laminate-type allograft material that is thicker and stronger than a single layer of allograft material. The actual number of layers will depend upon the surgical need and procedure with which the allograft is designed to be used.
Once the tissue(s) is placed on the drying fixture, the drying fixture is placed in a sterile Tyvex (or similar, breathable, heat-resistant, and sealable material) dehydration bag and scaled. Such breathable dehydration bag prevents the tissue from drying too quickly. If multiple drying fixtures are being processed simultaneously, each drying fixture is either placed in its own Tyvex bag or, alternatively, placed into a suitable mounting frame that is designed to hold multiple drying frames thereon and the entire frame is then placed into a larger, single sterile Tyvex dehydration bag and sealed.
The Tyvcx dehydration bag containing the one or more drying fixtures is then placed into a non-vacuum oven or incubator that has been preheated to approximately 35 to 50 degrees Celcius. The Tyvex bag remains in the oven for between 30 and 120 minutes, although approximately 45 minutes at a temperature of approximately 45 degrees Celcius appears to be ideal to dry the tissue sufficiently but without over-drying or burning the tissue. The specific temperature and time for any specific oven will need to be calibrated and adjusted based on other factors including altitude, size of the oven, accuracy of the oven temperature, material used for the drying fixture, number of drying fixtures being dried simultaneously, whether a single or multiple frames of drying fixtures are dried simultaneously, and the like.
An appropriate Dehydration recordation form, similar to that shown in FIG. 4 , is completed at the end of the dehydration process.
Cutting & Packaging (Step 160 )
Once the tissue has been adequately dehydrated, the tissue is then ready to be cut into specific product sizes and appropriately packages for storage and later surgical use. First, the Tyvex bag containing the dehydrated tissue is placed back into the sterile/critical environment, The number of grafts to be produced is estimated based on the size and shape of the tissue on the drying fixture(s). An appropriate number of pouches, one for each allograft, are then also introduced into the sterile/critical environment. The drying fixture(s) are then removed from the Tyvex bag.
If the drying fixture has grooves, then the following procedure is followed for cutting the tissue into product sizes. Preferably, if the drying fixture is configured in a grid pattern, a #20 or similar straight or rolling blade is used to cut along each groove line in parallel. Then, all lines in the perpendicular direction are cut.
If the drying fixture has raised edges or blades, then the following procedure is followed for cutting the tissue into product sizes. Preferably, a sterile roller is used to roll across the drying fixture. Sufficient pressure must be applied so that the dehydrated tissue is cut along all of the raised blades or edges of the drying fixture.
After cutting, each separate piece or tissue graft is placed in a respective “inner” pouch. The inner pouch, which preferably has a clear side and an opaque side, should be oriented clear side facing up. The tissue graft is placed in the “inner” pouch so that the texture in the form of text, logo, name, or similar design is facing out through the clear side of the inner pouch and is visible outside of the inner pouch. This process is repeated for each separate graft.
Each tissue graft is then given a final inspection to confirm that there are no tears or holes, that the product size (as cut) is within approximately 1 millimeter (plus or minus) of the specified size for that particular graft, that there are no noticeable blemishes or discoloration of the tissue, and that the textured logo or wording is readable and viewable through the “inner” pouch.
To the extent possible, oxygen is removed from the inner pouch before it is sealed. The inner pouch can be sealed in any suitable manner; however, a heat seal has shown to be effective. Next, each inner pouch is separately packaged in an “outer” pouch for further protection, storage, and shipment.
It should be noted that the above process does not require freezing of the tissue to kill unwanted cells, to decontaminate the tissue, or otherwise to preserve the tissue. The dehydrated allografts are designed to be stored and shipped at room or ambient temperature, without need for refrigeration or freezing.
Product Release (Step 170 )
Before the product is ready for shipment and release to the end user, a final inspection is made of both the inner and outer pouches. This final inspection ensure that the allograft contained therein matches the product specifications (size, shape, tissue type, tissue thickness (# of layers), design logo, etc.) identified on the packaging label Each package is inspected for holes, broken seals, burns, tears, contamination, or other physical defects. Each allograft is also inspected to confirm uniformity of appearance, including the absence of spots or discoloration.
Appropriate labeling and chain of custody is observed throughout all of the above processes, in accordance with accepted industry standards and practice. Appropriate clean room and sterile working conditions are maintained and used, to the extent possible, throughout the above processes.
Overview of Clinical Applications
In practice, it has been determined that the above allograft materials can be stored in room temperature conditions safely for at least five (5) years.
When ready for use, such allografts are re-hydrated by soaking them in BSS (buffered saline solution), 0.9% saline solution, or sterile water for 30-90 seconds.
Amnion membrane has the following properties and has been shown to be suitable for the following surgical procedures and indications: Guided Tissue Regeneration (GTR), Schneiderian Membrane repair, primary closure, and general wound care.
Laminated amnion membrane has the following properties and has been shown to be suitable for the following surgical procedures and indications: GTR, Reconstructive, General Wound Care, Neurological, ENT.
Chorion tissue grafts have the following properties and have been shown to be suitable for the following surgical procedures and indications: Biological Dressing or Covering.
Laminated chorion tissue grafts have the following properties and have been shown to be suitable for the following surgical procedures and indications: GTR, Reconstructive, General Wound Care, Neurological, ENT.
Laminated amnion and chorion combined tissue grafts have the following properties and have been shown to be suitable for the following surgical procedures and indications: Advanced Ocular Defects, Reconstructive, General Wound Care, Biological Dressing.
Although the above processes have been described specifically in association with amnion membrane and chorion recovered from placenta tissue, it should be understood that the above techniques and procedures arc susceptible and usable for many other types of human and animal tissues. In addition, although the above procedures and tissues have been described for use with allograft tissues, such procedures and techniques are likewise suitable and usable for xenograft and isograft applications.
In view of the foregoing detailed description of preferred embodiments of the present invention, it readily will be understood by those persons skilled in the art that the present invention is susceptible to broad utility and application. While various aspects have been described in the context of screen shots, additional aspects, features, and methodologies of the present invention will be readily discernable therefrom. Many embodiments and adaptations of the present invention other than those herein described, as well as many variations, modifications, and equivalent arrangements and methodologies, will be apparent from or reasonably suggested by the present invention and the foregoing description thereof, without departing from the substance or scope of the present invention. Furthermore, any sequence(s) and/or temporal order of steps of various processes described and claimed herein are those considered to be the best mode contemplated for carrying out the present invention. It should also be understood that, although steps of various processes may be shown and described as being in a preferred sequence or temporal order, the steps of any such processes are not limited to being carried out in any particular sequence or order, absent a specific indication of such to achieve a particular intended result. In most cases, the steps of such processes may be carried out in various different sequences and orders, while still falling within the scope of the present inventions. In addition, some steps may be carried out simultaneously. Accordingly, while the present invention has been described herein in detail in relation to preferred embodiments, it is to be understood that this disclosure is only illustrative and exemplary of the present invention and is made merely for purposes of providing a full and enabling disclosure of the invention. The foregoing disclosure is not intended nor is to be construed to limit the present invention or otherwise to exclude any such other embodiments, adaptations, variations, modifications and equivalent arrangements, the present invention being limited only by the claims appended hereto and the equivalents thereof. | A method for preparing placenta membrane tissue grafts for medical use, includes obtaining a placenta from a subject, cleaning the placenta, separating the chorion tissue from the amniotic membrane, mounting a selected layer of either the chorion tissue or the amniotic membrane onto a drying fixture, dehydrating the selected layer on the drying fixture, and cutting the selected layer into a plurality of tissue grafts. Preferably, the drying fixture includes grooves or raised edges that define the outer contours of each desired tissue graft, after they are cut, and further includes raised or indented logos that emboss the middle area of the tissue grafts during dehydration and that enables an end user to distinguish the top from the bottom side of the graft. The grafts are comprised of single layers of amnion or chorion, multiple layers of amnion or chorion, or multiple layers of a combination of amnion and chorion. | 0 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to signature handling equipment which supplies signatures in an on-edge orientation one at a time to bindery equipment. The invention particularly cooperates with a hopper loader apparatus which transfers and separates individual signatures of sheet materials from a vertically aligned, stack of such signatures. The separated, individual signatures may then be subjected to bindery operations such as stapling or stitching.
2. Description of the Related Art
It is usual in the graphic arts that sheet materials such as newspapers, books, printed cartons and the like emerge from a printing operation in a serial stream of partially overlapping signatures in shingled form. Such a stream of signatures is collected on a conveyor and moved to a stacker for aligning. The stacker receives the sheets in a serial mode from the conveyor and forms an aligned stack for removal and transportation. While large numbers of signatures can be conveniently handled in stack form, some operations on the signatures can only be performed individually. These include such bindery operations as stitching and stapling, among others. It therefore becomes necessary to separate individual signatures from a stack for individual treatment. A signature feed assembly is commonly used to feed signatures one at a time from a hopper onto a conveyor. One known assembly for feeding signatures one at a time onto a conveyor is disclosed in U.S. Pat. No. 4,180,255. Known signature supply assemblies have previously been used to supply signatures to a hopper in a signature feed assembly. Known signature supply assemblies or hopper loaders are disclosed in U.S. Pat. Nos. 3,674,258 and 3,945,633. The signature supply assemblies disclosed in the aforementioned patents supply signatures to a hopper in a generally horizontal orientation. Although hopper loaders are known in the art to supply a stream of generally horizontally positioned signatures, upstanding on-edge vertical signatures are generally required for feeding the signatures one at a time for processing by many stitcher lines.
Signature supply assemblies for supplying signatures in a vertical, an on-edge orientation are disclosed in U.S. Pat. Nos. 4,177,982 and 4,436,297. The complicated nature of the construction and mode of operation of known on-edge signature supply assemblies increases the probability of a jam or other malfunction during operation of the signature supply assemblies. In addition, the more complicated the construction of the signature supply assembly, the greater will be the cost of construction. The present invention seeks to simplify hopper loader construction cost.
It has been a problem in the art to reliably provide an efficient and effective means of separating a stack into its individual signatures for presentation to such bindery equipment. Prior art hopper loaders do not run reliably with a large range of signature sizes. The paper stock may range from heavyweight to lightweight and from a few pages per signature to many pages per signature. This difference in paper weight and/or pagination has required the operator to perform many adjustments to make the machine ready for a production run.
In addition, prior art hopper loaders for bindery equipment must be relatively fixed in position. That is, due to its complexity and the need to critically place the hopper loader in correct position adjacent to the bindery equipment, the hopper loader has not been mobile. That is, one cannot easily move the prior hopper loaders from one piece of bindery equipment to another. The present invention seeks to enhance hopper loader mobility. In the past, a stacked pile of printed signatures has been moved on a horizontal conveyor to an upwardly moving conveyor where both conveyors travel at the same speed. Such an operation has many disadvantages since the stack does not reliably separate into evenly spaced overlapping individual signatures. This unevenness inevitably leads to down stream signature jams and misfeeds requiring considerable operator attention. U.S. Pat. No. 4,180,259 discloses a system for varying the drop of sheets into a hopper. Signatures are fed in a shingled stream and dropped one-by-one into a hopper, which then feeds a gathering chain. Signatures are stripped from a stack and are passed around a complex series of rollers and a large drum ultimately to a pocket. U.S. Pat. No. 5,374,050 discloses a conveyor wherein a stream of signatures is moved upwardly to a pocket having a jogger for the stacked stream of signatures. Difficulties in operating vertical loaders such as disclosed in these prior patents arise in that a large quantity of signatures cannot be loaded in the loader without interfering with the feeding of signature at the supply station, and the loaders cannot handle very short and very long signatures without substantial changes in the feeding mechanism. Further, the signatures are subjected to a constant riffling, sliding and jostling action that results in damage to the folds on the signatures when they move between conveyor belts. U.S. Pat. No. 4,973,038 also discloses a signature handling apparatus, however, this disclosure uses a horizontal feed conveyor which requires a stack pusher. The signatures tend to slide down a second ramp conveyor and hence require a retainer wedge. The present invention operates in the absence of such a pusher.
The present invention provides a vertical loader which avoids or reduces problems encountered in the prior art. The present invention pertains to an apparatus for separating individual signatures which are substantially vertically aligned on a folded edge from a stack of signatures and then feeding them into a pocket from which they are fed by a feed mechanism to bindery equipment. Individual signatures flow reliably, one-by-one out of the pocket to bindery equipment. The simplified equipment is economical, mobile, and signature size changeovers are easy to accomplish.
These and other features, advantages and improvements will be in part discussed and in part apparent to one skilled in the art upon a consideration of the detailed description of the preferred embodiment and the accompanying drawings.
SUMMARY OF THE INVENTION
The invention provides an apparatus for forming a generally vertically oriented stack of on-edge signatures from a horizontally oriented stack of signatures which comprises:
an accumulating hopper for collecting a horizontally oriented stack of signatures; a vacuum conveyor comprising a horizontally oriented vacuum source positioned at a lowermost level of the accumulating hopper and a conveyor belt having a plurality of holes therethrough, the conveyor belt having a horizontal portion which is in juxtaposition with the horizontally oriented vacuum source such that the vacuum source draws air through the conveyor belt holes for pulling a stream of lowermost signatures from a horizontally oriented stack of signatures from the accumulating hopper and forming a shingled stream of signatures against the conveyor belt; the horizontal portion of the conveyor belt leading to a downwardly extending portion of the conveyor belt which downwardly extending portion leads away from the vacuum source and the accumulating hopper toward a top surface of a receiving surface; a guide adjacent and parallel to the downwardly extending portion of the conveyor belt, which guide exerts a pressure normal to a top surface of the conveyor belt; the conveyor belt and the guide being positioned to retain a shingled stream of signatures therebetween and being adapted for depositing an edge of each signature of the stream of signatures onto a top surface of a receiving surface.
The invention also provides a method for forming a generally vertically oriented stack of on-edge signatures from a horizontally oriented stack of signatures which comprises:
I. providing an apparatus for forming a generally vertically oriented stack of on-edge signatures from a horizontally oriented stack of signatures which comprises: an accumulating hopper for collecting a horizontally oriented stack of signatures; a vacuum conveyor comprising a horizontally oriented vacuum source positioned at a lowermost level of the accumulating hopper and a conveyor belt having a plurality of holes therethrough, the conveyor belt having a horizontal portion which is in juxtaposition with the horizontally oriented vacuum source such that the vacuum source draws air through the conveyor belt holes for pulling a stream of lowermost signatures from a horizontally oriented stack of signatures from the accumulating hopper and forming a shingled stream of signatures against the conveyor belt; the horizontal portion of the conveyor belt leading to a downwardly extending portion of the conveyor belt which downwardly extending portion leads away from the vacuum source and the accumulating hopper toward a top surface of a receiving surface; a guide adjacent and parallel to the downwardly extending portion of the conveyor belt, which guide exerts a pressure normal to a top surface of the conveyor belt; the conveyor belt and the guide being positioned to retain a shingled stream of signatures therebetween and being adapted for depositing an edge of each signature of the stream of signatures onto a top surface of a receiving surface; II. collecting a horizontally oriented stack of signatures in the accumulating hopper; III. forming a shingled stream of said signatures against the conveyor belt by pulling a stream of lowermost signatures from the horizontally oriented stack of signatures in the accumulating hopper by the vacuum conveyor; IV. leading the shingled stream of signatures away from the accumulating hopper and from the horizontally oriented vacuum source to the downwardly extending portion of the conveyor belt toward the top surface of a receiving surface while pressing the shingled stream of signatures between the guide and the conveyor belt, and depositing an edge of each signature of the stream of signatures onto a top surface of the receiving surface.
The invention further provides a machine for forming a generally vertically oriented stack of on-edge signatures which comprises:
I. an apparatus for forming a generally vertically oriented stack of on-edge signatures from a horizontally oriented stack of signatures which comprises: an accumulating hopper for collecting a horizontally oriented stack of signatures; a vacuum conveyor comprising a horizontally oriented vacuum source positioned at a lowermost level of the accumulating hopper and a conveyor belt having a plurality of holes therethrough, the conveyor belt having a horizontal portion which is in juxtaposition with the horizontally oriented vacuum source such that the vacuum source draws air through the conveyor belt holes for pulling a stream of lowermost signatures from a horizontally oriented stack of signatures from the accumulating hopper and forming a shingled stream of signatures against the conveyor belt; the horizontal portion of the conveyor belt leading to a downwardly extending portion of the conveyor belt which downwardly extending portion leads away from the vacuum source and the accumulating hopper toward a top surface of a receiving surface; a guide adjacent and parallel to the downwardly extending portion of the conveyor belt, which guide exerts a pressure normal to a top surface of the conveyor belt; the conveyor belt and the guide being positioned to retain a shingled stream of signatures therebetween and being adapted for depositing an edge of each signature of the stream of signatures onto a top surface of a receiving surface; and II. a hopper-loader which deposits a stream of signatures into the accumulating hopper.
In one embodiment the above described hopper loader comprises
a) a chassis; b) a first continuous, downwardly inclined planar conveyor mounted on the chassis; said first conveyor being capable of moving a parallelepiped shaped stack of vertically aligned signatures to a second conveyor and depositing a separated, shingled stream of the signatures onto the second conveyor; and c) a single, continuous, second conveyor mounted on the chassis and aligned with an end of the first conveyor; the second conveyor comprising a plurality of driven belts which travel over each of an upwardly inclined planar ramp segment, an arched transition segment, and a planar exit segment; the arched transition segment comprising either a belt slide or a plurality of serially arranged rollers.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a side view of the hopper loader according to the invention.
FIG. 2 shows a side view of a hopper loader according to the invention and further showing the movement path of signatures.
FIG. 3 shows a side view of the right side of the planar exit segment of the second conveyor showing signature pushers and a signature jogger.
FIG. 4 shows a view of the front of the planar exit segment of the second conveyor showing signature pushers and a signature jogger.
FIG. 5 shows an apparatus for forming a generally vertically oriented stack of on-edge signatures from a horizontally oriented stack of signatures according to the invention. The apparatus is attached to an exit end of a hopper loader.
FIG. 6 shows the top view of the stripper gate and nip roller assembly for varying signature thicknesses.
FIG. 7 shows the formation of a horizontally oriented stack of signatures ready for passage through the adjustable stripper gate and shows an adjustable stripper gate for varying signature thicknesses.
FIG. 8 shows a front elevation of the apparatus according to the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring to the drawings, FIGS. 1 and 2 show a hopper loader 10 according to the invention. It comprises a framework 12 which is movable by wheels 14 . It has a first, downwardly inclined, planar conveyor 16 which preferably comprises a plurality of conveyor belts. In the preferred embodiment the belts are sturdy enough to move a relatively heavy stack of sheet signatures 18 . As shown, the signatures are substantially vertically aligned and are in the form of a parallelepiped shaped stack. It is an important feature of the invention that the conveyor 16 be downwardly inclined. In the preferred embodiment, conveyor 16 has a downward decline measured from the horizontal of from about 100 to about 20°. This downward decline provides a gravity assist in the feeding of individual signatures from conveyor 16 to second upwardly inclined, planar conveyor section 20 . In the preferred embodiment, the belts of the first conveyor are flat top chain belts and the second conveyor comprises a plurality of driven belts such that the belts of the first conveyor are aligned and interdigitated with the belts of the second conveyor.
The second conveyor 20 is capable of separating individual signatures from the stack on the first conveyor at an entry end of the second conveyor. Signatures fall over into an evenly overlapping shingled stream and travel up the second ramp conveyor as shown. In the preferred embodiment, the second conveyor has an upward incline measured from the horizontal of from about 25° to about 35°. An important feature of the invention is that an angle is formed between the first, downwardly inclined, planar conveyor and the second, upwardly inclined, planar conveyor which is from about 125° to about 145°. In addition, it is also important that the belts of the second conveyor belts travel at a speed which is faster than the belt speed of the first conveyor. In the preferred embodiment, the belt speed of the first conveyor ranges from about 1.1 feet/minute to about 7.1 feet per minute.
In the preferred embodiment, the belt speed of the second conveyor ranges from about 5.9 feet/minute to about 38.5 feet per minute. Most preferably the speed ratio of the second conveyor to the first conveyor is from about 3:1 to about 9:1. This combination of downward sloping first conveyor, upward sloping second conveyor, included angle of from about 125° to about 145° and speed differential gives a smooth, even transition from a stack of signatures to a thick shingled stream of even overlapping individual signatures.
The hopper loader configuration according to the invention, allows processing of a wide variety of sizes of signatures from thick multipage books to thin signatures having a very few pages. In the preferred embodiment, the signatures are supported down the first conveyor by a side guide 22 .
As shown in FIG. 2 , the stream of individual signatures travels up the incline of second conveyor in overlapping shingles fashion. The second conveyor comprises several integral, sequential segments, namely an upwardly inclined planar ramp segment 24 , an arched transition segment 26 , and a planar exit segment 28 . The belts of the second conveyor move up ramp segment 24 and around the arched transition segment 26 . The arched transition segment 26 comprises either a curved sheet metal slide over which the belts slide or a plurality of serially arranged rollers, such as 30 . Preferably the arched transition segment comprises from about two to about five rollers. The arched transition segment has a radius of curvature sufficiently large such that a signature moved by the second conveyor has a greater tendency to follow a path of the arched transition segment than to be propelled tangent to the upwardly inclined planar ramp segment. Preferably the arched transition segment has an effective radius of curvature of at least about 10 inches and more preferably from about 10 inches to about 15 inches.
The arched transition segment 26 progresses to planar exit segment 28 . Preferably the planar exit segment of the second conveyor has a downward decline of from about 5° to about 20° measured from the horizontal. As shown in FIGS. 3 and 4 the planar exit segment of the second conveyor showing preferably has a plurality of reciprocating signature pushers such as L-shaped signature pushers 32 positioned between the belts 37 , which push the signatures in a forward direction. Optionally, but preferably the planar exit segment of the second conveyor has a signature jogger 34 , which aligns the signatures via jogger paddles 36 for exit from the second conveyor. The exit segment 28 preferably has a horizontal or declining upper segment 38 terminating at a belt turnaround roller 40 , which meets a substantially horizontal belt return segment 42 . Preferably the turnaround roller has a diameter of about 3 inches or less. Preferably the angle between the upper segment and the return segment is in the range of about 10° or less. This gives a needle-nosed configuration which greatly assists in the precision placement of exiting signatures to subsequent processing equipment.
The movement of the first and second conveyors is accomplished by suitable drive means including motors, pulleys, belts and rollers shown generally at 44 . It is understood that the provision of such suitable drive means is well within the ability of those skilled in the art.
In the preferred embodiment, the drive of the first conveyor and the second conveyor are controlled by a sensor 46 such as a photoelectric cell which is responsive to the presence or absence of a signature at a position.
FIGS. 5 , 7 and 8 show an apparatus 100 for forming a generally vertically oriented stack of on-edge signatures from a horizontally oriented stack of signatures according to the invention. It has an accumulating hopper 102 for collecting a horizontally oriented stack of signatures 104 . Hopper 102 receives a shingled stream of signatures 106 from a cooperating hopper loader 10 . Hopper loaders 10 are well known in the art. As shingled stream 106 is supplied from hopper loader 10 to accumulating hopper 102 the signatures are formed into an aligned stack 104 by backstop 108 , opposing paddles 36 of a jogger 34 and signature pushers, or end tappers 32 . The stack 104 is formed on a vacuum conveyor. The size of the stack 104 may be controlled by sensing the height of the stack via photoelectric cell type controller 105 which controls the delivery of signatures from hopper loader 10 . In one embodiment, the height of the stack in the accumulating hopper is limited to about 3 inches or less, preferably from about 1.5 to about 3 inches. The vacuum conveyor has a horizontally oriented portion comprising a vacuum conveyor belt 110 having a plurality of holes therethrough, and a vacuum source or plenum 112 which draws air through the vacuum conveyor belt holes and pulls a stream of lowermost signatures from the stack 104 and forms a downwardly directed shingled stream of the signatures against the belt 110 a downwardly extending portion of the vacuum conveyor. This downwardly directed shingled stream is formed by passing the lowermost signature under a stripper gate 114 . As best seen in FIG. 6 , stripper gate 114 comprises a bar 116 whose height is adjustable for varying signature thicknesses. On either side of bar 116 are downwardly directed air jets 118 which aid the separation of adjacent signatures. The separated signatures then pass under nip roller 120 which presses the lowermost signature against the vacuum belt and draws the lowermost signature away from the succeeding signature. In one embodiment, the position of the nip roller 120 is automatically adjustable or floatable by arms 121 to accommodate different signature stream thicknesses. After the lowermost signature passes under nip roller 120 , it is directed toward a downwardly extending portion of the vacuum conveyor which leads signatures away from the accumulating hopper 102 toward a top surface of a receiving surface such as an indexing conveyor 122 via a guide section 124 .
Guide section 124 is positioned parallel to the downwardly extending portion of the vacuum conveyor, and guide exerts a pressure normal to the top surface of the vacuum conveyor belt. Guide section 124 is shown to comprise a belt 126 which passes around a series of rollers 128 which are supported in a suitable frame 130 .
The shingled stream of signatures is trapped between the vacuum conveyor belt and the belt 126 until the signatures are released from between the belts and deposited one by one into a substantially vertical stack onto receiving surface 122 which is preferably an indexing conveyor. In a preferred embodiment, the apparatus 100 also comprises a pair of bowing bars 132 behind rollers 128 , which serve to slightly bend, or bow, the signatures as they are transported from the guide section onto receiving surface 122 . This assists in assuring a neatly aligned vertical stack of signatures 134 on the receiving surface 122 . In one embodiment, the combination of belt 126 , rollers 128 , frame 130 , bowing bars 132 are adapted to pivot upwardly around point 136 to provide manual access to vertical stack 126 or receiving surface 122 . This also allows an operator to optionally manually place a vertical stack 126 on receiving surface 122 . In a one embodiment, attached to a lowermost part of the apparatus 100 are side vibrators 138 which jog the signatures as they drop onto the indexing surface 122 , as well as a limit switch 140 to control the size of growing stack 134 by limiting the number of signatures delivered to the receiving surface. In use, signatures from stack 126 are removed one by one by a suitable device 142 such as bindery equipment for individually removing a stream of signatures on edge from the top surface of the receiving surface 122 .
While the present invention has been particularly shown and described with reference to preferred embodiments, it will be readily appreciated by those of ordinary skill in the art that various changes and modifications may be made without departing from the spirit and scope of the invention. It is intended that the claims be interpreted to cover the disclosed embodiment, those alternatives which have been discussed above and all equivalents thereto. | Vertical pocket feeder signature handling equipment which supplies signatures in an on-edge orientation one at a time to bindery equipment. The vertical pocket feeder particularly cooperates with a hopper loader apparatus which transfers and separates individual signatures of sheet materials from a vertically aligned, stack of such signatures. The separated, individual signatures may then be subjected to bindery operations such as stapling or stitching. | 1 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a divisional application of co-pending U.S. patent application Ser. No. 10/156,723 filed May 28, 2002, which claims priority to German Application No. 201 19 410.4 filed on Nov. 28, 2001 and German Application No. 201 08 701.4 filed on May 25, 2001 under 35 U.S.C. § 119(a). The disclosures of all three applications are hereby incorporated by reference.
FIELD
[0002] The invention concerns a vehicle seat having a headrest detachably fastenable to a seatback, and having an integrated display screen device for which the headrest has a receiving space.
BACKGROUND OF THE DISCLOSURE
[0003] In order to offer passengers in a motor vehicle the ability to work or to entertain or inform themselves, it is known to install a display screen device in the region of the headrest of the seatback of a vehicle seat. The display screen device can be, for example, a TV receiver, a video device, or a computer.
[0004] Known vehicle seats that fulfill this purpose are described in German Utility Model Applications DE 295 18 369 U1 and DE 296 00 783 U1, and in U.S. Pat. No. 5,529,265. Utility Model DE 296 00 783 U1, for example, discloses a headrest for motor vehicles in which entertainment-sector devices can be integrated into a cavity. The vehicle seat having the headrest described is one of the type described initially.
[0005] In the case of the headrest for vehicle seats known from Utility Model DE 295 18 369 U1, there is arranged on the back side of the headrest a display screen that is integrated into a shaped element, removable from the headrest, having a space that is intended for reception of the headrest.
[0006] U.S. Pat. No. 5,529,265 describes a vehicle seat in which the integrated display screen device is mounted pivotably in a receiving space of the headrest, although the headrest is not fastened detachably to the seatback of the seat but rather forms a physical unit therewith.
[0007] It is the object of the invention to configure a vehicle seat having an integrated display screen device of the kind described initially, using means of simple design, so as to improve its ease of assembly while ensuring maximum comfort and a high level of safety for the vehicle's passengers.
[0008] The teachings hereinbelow extend to those embodiments which fall within the scope of the appended claims, regardless of whether they accomplish one or more of the above-mentioned needs.
SUMMARY OF EXEMPLARY EMBODIMENTS
[0009] This object is achieved by way of a vehicle seat of the kind cited initially in which in the assembled state, the display screen device is fastened in the receiving space positively and/or nonpositively between the headrest and the seatback.
[0010] The vehicle seat is thus, advantageously, very easy to assemble as a result of a modular construction of the headrest, display screen device, and seatback. The positive and/or nonpositive join, which in particular can be a clamped join, can be made sufficiently secure and, if necessary, can be reinforced in additionally securing fashion without thereby negatively affecting the ease of assembly.
[0011] This object is furthermore achieved by a vehicle seat of the kind described initially in which at least the display screen of the display screen device is pivotable about an axis extending in the transverse direction of the seat in the upper region of the seatback, and alternatively or additionally is rotatable about a (further) center axis extending in the transverse direction of the seat. The establishment of specific display screen positions thereby made possible allows the safety standard to be raised, and the comfort of the vehicle seat according to the present invention to be improved.
[0012] In motor vehicles, the headrest of a vehicle seat is generally guided in vertically displaceable fashion with two retaining rods in guide sleeves that are joined to the frame of the seatback of the vehicle seat. In a preferred embodiment of the invention, for detachable fastening of the display screen device an integral combination of the two guide sleeves, constituted by a bridge and serving as support part for the display screen device, can comprise a receiving opening which is configured in such a way that it can receive a commercially available plug connector for an electrical connection. The contacts of the plug connector can be allocated to supply lines necessary for operation of the display screen device. The entire cable bundle of the connector lines can thus advantageously, in a manner invisible to the passengers, be routed within the seatback and guided to the corresponding supply devices. The necessary electrical connection is then created simultaneously with placement of the display screen device onto the support part.
[0013] The display screen, which preferably can be embodied using LCD technology, can advantageously be arranged on an (in particular, flat) bottom part (console) that additionally comprises passthrough holes for passage of the retaining rods of the headrest. The result is to achieve an additional positive immobilization of the display screen device, which thus cannot be removed from its retaining apparatus without removing the headrest.
[0014] The receiving space of the headrest for the display screen device can advantageously be configured as a recess that is open on two sides (at the bottom and in the viewing direction of the viewer of the display screen device) and completely surrounds the display screen device, thus also yielding comprehensive impact protection for the passengers sitting in front of the display screen device. Sufficient passenger protection can be guaranteed even if the headrest must be adjusted vertically for purposes of adaptation.
[0015] Further advantageous embodiments of the invention are contained in the dependent claims and the following specific description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] The invention will be explained in more detail with reference to two exemplary embodiments depicted in the appended drawings, in which:
[0017] [0017]FIG. 1 is an exploded depiction, in perspective, of a first embodiment of a vehicle seat according to an exemplary embodiment;
[0018] [0018]FIG. 2 is a schematic side view of a portion of a second embodiment of a vehicle seat according to an exemplary embodiment;
[0019] [0019]FIGS. 3 and 4 depict, in perspective and in two different positions, the second embodiment of a vehicle seat according to an exemplary embodiment;
[0020] [0020]FIG. 5 is an exploded depiction, in perspective, of a display screen device of the second embodiment of a vehicle seat according to an exemplary embodiment.
[0021] In the various Figures of the drawings, identical parts are always labeled with the same reference characters so that as a rule, they are each also described only once.
DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS
[0022] As is apparent firstly from the graphic depiction in FIG. 1 for the first embodiment but also from FIG. 3 for the second embodiment, a vehicle seat according to the present invention comprises a headrest 1 that is detachably fastenable to a seatback 20 (depicted in FIGS. 3 and 4). For that purpose, retaining rods 2 are fastened in known fashion to the underside of headrest 1 .
[0023] Headrest 1 comprises a receiving space 3 for a display screen device 4 integrated into the vehicle seat according to the present invention. Upon assembly, this display screen device 4 can be fastened in clamping fashion (nonpositively) in receiving space 3 between headrest 1 and seatback 20 . Receiving space 3 is advantageously constituted by a recess in headrest 1 that, in the assembled state, positively surrounds display screen device 4 and is open at the front (toward a viewer of display screen 4 ) and at the bottom (toward seatback 20 ).
[0024] In the embodiment depicted in FIG. 1, seatback 20 has associated with it a support part 5 , arranged in an upper part of seatback 20 , for display screen device 4 . Fastening sleeves 6 for joining seatback 20 to headrest 1 , through which retaining rods 2 of headrest 1 pass in the assembled state, are arranged in known fashion in seatback 20 . Fastening sleeves 6 are joined in bridge fashion to one another by way of support part 5 for display screen device 4 , or are configured integrally with support part 5 . Support part 5 with sleeves 6 can advantageously be arranged in a depression of seatback 20 in such a way that it terminates flush with the upper side of seatback 20 , e.g. with an upholstered surface of the back, or projects slightly thereabove.
[0025] Display screen device 4 comprises a flat bottom part 7 on which display screen 8 is arranged projecting vertically upward. The latter can, in known fashion, be surrounded by a housing 9 in which a suitable keypad 10 for operation of display screen device 4 is located. In an advantageous embodiment, display screen 8 can be a flat display screen, in particular an LCD screen.
[0026] For creation of an optimum nonpositive (clamping) connection of display screen device 4 between headrest 1 and seatback 20 of the seat according to the present invention, it is advantageous in this context if the base outline of bottom part 7 is larger than the base outline of display screen 8 (including the base outline of its housing 9 ), and preferably surrounds said base outline. It is additionally advantageous in this context if the base outline of bottom part 7 corresponds approximately to the base outline of support part 5 in the upper part of the seatback, and approximately to the base outline of a bottom surface 11 of headrest 1 . As a result of this base outline configuration, headrest 1 is advantageously supported on bottom part 7 , and bottom part 7 on support part 5 , over a large area, contributing to optimum clamping.
[0027] In a particularly advantageous embodiment of the invention, as already mentioned, passthrough openings 12 for retaining rods 2 of headrest 1 can be arranged in bottom part 7 , so that passage of retaining rods 2 through said openings 12 results in additional positive immobilization of display screen device 4 . As a result, the clamping connection described above is additionally reinforced and reliability is increased, since display screen 4 can no longer be taken out of the vehicle seat without removing headrest 1 .
[0028] With regard to the electrical connection or, for example, also the antenna connection of display screen device 4 , a plug connector part 14 connected to connector lines 13 , for electrical connection to a corresponding plug part (not depicted) of display screen 4 arranged in particular in the base of display screen device 4 , can be integrated into support part 5 for display screen device 4 . Connector lines 13 of plug connector part 14 can preferably be routed inside seatback 20 .
[0029] The second embodiment of a vehicle seat according to the present invention illustrated by FIGS. 2 through 5 differs from the first embodiment especially in that at least display screen 8 of display screen device 4 is pivotable about an axis X-X extending in the transverse direction of the seat in the upper region of seatback 20 .
[0030] Provision can be made in particular for display screen 8 to be pivotable backward, i.e. usually opposite to direction of travel F if the seat is installed correspondingly in the motor vehicle, upon application of a first torque. This is indicated by the arrow labeled M 1 in FIG. 2. Torque M 1 that is depicted is a resiliently acting return torque which counteracts the pivoting motion and brings the display screen back into its original position. Its magnitude can be small. This kind of pivotability of display screen 8 makes it possible, when headrest 1 has been removed, to bring seatback 20 of the motor vehicle seat according to the present invention into a horizontal position by folding it forward, while preventing display screen 8 from being damaged if it collides in the process with, for example, the dashboard or sun visor.
[0031] Provision can furthermore be made for display screen 8 to be pivotable up to 90 degrees forward, i.e. usually in direction of travel F, upon application of a second torque. This is indicated by the arrow labeled M 2 in FIG. 2, which symbolizes the resistance to this pivoting motion. When the corresponding torque, which can be eight to ten times the magnitude of the first torque, is exceeded, the display screen folds down into a stable position. This pivotability of display screen 8 represents a misuse prevention feature. The deflecting pivoting of display screen 8 , and optionally of further parts joined to it, in response to a large mechanical load prevents display screen 8 or other parts of display screen device 4 from breaking, for example if a passenger inadvertently leans on display screen 8 while exiting. The pivoted position assumed by display screen 8 with headrest 1 removed, which could also be called the “misuse position,” is depicted in FIG. 4.
[0032] Lastly, provision can be made for display screen 8 to be slightly pivotable (less than 90 degrees) in direction of travel F, in particular upon application of a third torque in the context of the abrupt action of large acceleration forces, such as those that occur in the context of a rear-end impact on the vehicle. This is indicated by the arrow labeled M 3 in FIG. 2, which illustrates a damping resistance torque opposite to the pivoting. The corresponding torque can preferably be greater than first torque M 1 (e.g. twice as great), but less than second torque M 2 , as indicated by the differing sizes and thicknesses of the arrows in FIG. 2. This represents a safety feature in a crash situation.
[0033] In order to determine the motion sequence upon pivoting of display screen 8 , in particular the forces or torques M 1 , M 2 , M 3 that initiate and inhibit the pivoting motion, a device that preferably comprises at least one spring member and one damper member can be integrated into display screen device 4 . In FIG. 5, for example, a spring 21 is provided as the spring member and a damper 22 as the damper member, located in the assembled state in corresponding associated housing parts, i.e. a spring housing part 23 and damper housing part 24 . Spring 21 applies return torque M 1 , while damper 22 counteracts any pivoting of display screen 8 , for example in the event of a crash, while applying torque M 3 . Spring housing part 23 and damper housing part 24 constitute, together with a further housing part 25 that provides cable guidance, a frame part (not further labeled as a whole) for display screen 8 which is fastened via a base part 26 to an adapter 27 for connection to an upper part of seatback 20 . The adapter could also, like part 5 depicted in FIG. 1, be referred to as the support part for display screen device 4 .
[0034] Corresponding to the flat bottom part 7 of the first embodiment of the invention shown in FIG. 1, FIG. 5 shown the two bottom segments 7 a, 7 b, of which one ( 7 b ) comprises passthrough openings 12 for retaining rods 2 of headrest 1 . In the assembled state, bottom segments 7 a, 7 b surround base part 26 joined to adapter 27 , and conceal adapter 27 .
[0035] The aforementioned axis X-X extending in the transverse direction of the seat in the upper region of seatback 20 , about which display screen 8 of display screen 4 is pivotable, is depicted in FIG. 5 as being offset because of the exploded depiction. In the installed state it extends in a straight line, beginning at a lower end of housing part 25 for cable guidance, continuing through base part 26 and damper 22 , and ending in damper housing part. 24 .
[0036] In the installed state, spring housing part 23 is arranged parallel to pivot axis X-X; spring 21 arranged therein can preferably be embodied as a leaf spring and can engage into base part 26 .
[0037] [0037]FIG. 5 furthermore shows that advantageously, at least one cover part, but preferably (as depicted) a front (in terms of direction of travel F) cover part 28 b and a rear cover part 28 a, can be fastenable to display screen 8 of display screen device 4 . Cover parts 28 a, 28 b are configured in the manner of half shells so they can surround display screen 8 . Rear cover part 28 a comprises a window 29 through which display screen 8 is visible. Front cover part 28 b does not possess a window, but instead protectively covers the back panel of the display screen in the installed state.
[0038] In the installed state, display screen 8 is arranged between the two cover parts 28 a, 28 b and held, together with said parts, in a preferably multi-part frame that corresponds to housing 9 of the first embodiment of the invention depicted in FIG. 1. This frame (not further labeled as a whole) encompasses a front (in terms of direction of travel F) frame part 30 b and a rear frame part 30 a.
[0039] A further special aspect of the second embodiment of the vehicle seat according to the present invention is the fact that display screen 8 (including its two cover parts 28 a, 28 b ) is mounted rotatably about a further center axis Y-Y that extends in the transverse direction of the seat and, in particular, is contained in the frame. This makes it possible, before display screen 8 is optionally pivoted forward once headrest 1 has been removed, to bring display screen 8 with cover parts 28 a, 28 b into a protected position in which the originally front (windowless) cover part 28 a faces away from direction of travel F and—after display screen 8 (inclusive of frame parts 30 a, 30 b ) has been pivoted approximately 90 degrees—upward. This non-use position of display screen device 4 is depicted in FIG. 4.
[0040] The non-use position of display screen device 4 can be established even if there is no intention to fold down seatback 20 . For example, starting from the use position depicted in FIG. 3, firstly headrest 1 can be removed, then display screen 8 with the two cover parts 28 a, 28 b can be rotated 180 degrees about center axis Y-Y extending in the transverse direction of the seat, and then the headrest can be put back in place, thus resulting once again in a position similar to that in FIG. 3, except that display screen 8 is protected by front cover part 28 b.
[0041] The mounting of display screen 8 in frame parts 30 a, 30 b, which permits a rotation of up to 180 degrees, also advantageously makes it possible, in the use position of display screen device 4 depicted in FIG. 3, to perform an individual adaptation of display screen 8 to the needs of a viewer in the context of a smaller rotation angle, by the fact that an optimum viewing angle can be steplessly set by way of a corresponding rotation. To ensure that display screen 8 does not independently rotate forward or backward away from that angle during vehicle operation, a brake mechanism 31 can be provided for locking, as shown in FIG. 5.
[0042] In contrast to display screen 8 and its cover parts 28 a, 28 b, spring housing part 23 , damper housing part 24 , and housing part 25 that serves for cable guidance—which also (as already mentioned) constitute a frame part—are immovably (nonrotatably) joined to, in particular interposed between, front frame part 30 b and rear frame part 30 a. The manner in which assembly, for example fastening with screws 32 , can be accomplished is illustrated in FIG. 5 by the unlabeled dot-dash lines.
[0043] The invention is not limited to the exemplary embodiments depicted, but instead also encompasses all embodiments of identical function within the meaning of the invention. In particular, for example, the conformation and dimensioning of the parts described may deviate from the embodiments depicted. Or, for example, the upper and lower sides of bottom part 7 , headrest 1 , and support part 5 , depicted respectively as being flat, can be equipped with contours that correspond positively to one another, thereby preventing any mutual relative motion of said parts.
[0044] One skilled in the art may moreover provide further features for the technical configuration of a vehicle seat according to the present invention without leaving the context of the invention. For example, it is possible for an infrared remote control also to be provided for display screen device 4 , as illustrated by infrared window 33 depicted in FIG. 5.
[0045] Instead of the bearing point of brake mechanism 31 depicted in FIG. 5, provision can also be made that display screen 8 could be mounted laterally (to the right and left of braking mechanism 31 that is depicted) in its frame by way of ball joints located in particular in rear cover part 28 , and thus could be adapted to different viewing directions; in the context of a pivoting motion about a vertical axis also made possible thereby, one or the other of the two ball joints would need in each case to be snapped out.
[0046] In addition, the invention is not limited to the combination of features defined in the independent claims, but instead can also be defined by any other combination of specific features of all the globally disclosed individual features. This means that in principle, practically any individual feature of the independent claims can be omitted or replaced by at least one individual feature disclosed elsewhere in the Application. In this respect, claim 1 is to be understood as merely a first attempt to state an invention, and independent inventive significance is also assigned, as stated, to Claims 15 and 24.
[0047] Priority application 201 19 410.4, filed Nov. 28, 2001, including the specification, drawings, claims and abstract, is incorporated herein by reference in its entirety.
[0048] Priority application 201 08 701.4, filed May 25, 2001, including the specification, drawings, claims and abstract, is incorporated herein by reference in its entirety.
LIST OF REFERENCE CHARACTERS
[0049] [0049] 1 Headrest
[0050] [0050] 2 Retaining rod of 1
[0051] [0051] 3 Receiving space of 1 for 4
[0052] [0052] 4 Display screen device
[0053] [0053] 5 Support part for 4
[0054] [0054] 6 Fastening sleeves for 2
[0055] [0055] 7 Bottom part of 4
[0056] [0056] 7 a, 7 b Bottom segments
[0057] [0057] 8 Display screen of 4
[0058] [0058] 9 Housing of 4
[0059] [0059] 10 Keypad of 4
[0060] [0060] 11 Bottom surface of 1
[0061] [0061] 12 Passthrough openings for 2 in 7 , 7 b
[0062] [0062] 13 Connector line
[0063] [0063] 14 Plug connector part in 5
[0064] [0064] 20 Seatback
[0065] [0065] 21 Spring
[0066] [0066] 22 Damper
[0067] [0067] 23 Spring housing part
[0068] [0068] 24 Damper housing part
[0069] [0069] 25 Housing part for cable guidance
[0070] [0070] 26 Base part
[0071] [0071] 27 Adapter
[0072] [0072] 28 a Rear cover part for 8
[0073] [0073] 28 b Front cover part for 8
[0074] [0074] 29 Window in 28 a
[0075] [0075] 30 a Rear frame part
[0076] [0076] 30 b Front frame part
[0077] [0077] 31 Brake mechanism
[0078] [0078] 32 Screws
[0079] F Direction of travel
[0080] M 1 Torque
[0081] M 2 Torque
[0082] M 3 Torque
[0083] X-X Pivot axis for 8
[0084] Y-Y Rotation axis for 8
[0085] While the exemplary embodiments illustrated in the FIGS. and described above are presently preferred, it should be understood that these embodiments are offered by way of example only. Accordingly, the present invention is not limited to a particular embodiment, but extends to various modifications that nevertheless fall within the scope of the appended claims. | An entertainment system for a vehicle has a display configured such that it may be pivoted with respect to a seat. The display may be configured to be pivoted in either a forward direction or a direction opposite the forward direction. The display may be configured to face both the forward direction of travel and a different direction. The display may also be configured to be pivoted in a direction by generating a first torque, and pivoted father in that direction by generating a second torque of greater force than the first torque. This may be accomplished by using a damper and a spring. The system may include a braking mechanism, may include a frame where the display is visible through a first side and protected by a second side, and may be pivotable along more than one axis. | 1 |
FIELD OF THE INVENTION
[0001] The present invention relates to a food recipes for nourishing, maintaining and cultivating a variety of stem cells and a method for manufacturing the same, and more specially relates to the food recipes for proliferation, activation, repairing, nourishing of the stem cells and a method for manufacturing the same.
BACKGROUND OF THE INVENTION
[0002] The various pharmaceutical factories in the current world are doing a lot of efforts to induce stem cells to convert into the tissues or cells as desires, and it thus leads this as one of the most attracting major subject for all institutes in stem cell research Area in the world. The United Stated has conducted many researches that combines food which has stimulating single stem cell. The resveratrol attracts more attention especially after Dr. SeLuzi Nujo of France in 1991 found that there are resveratrol in the red wine, and then Dr. Pezzuto, University of Illinois, declared resveratrol is effective of inhibiting the three main stages of initiation, promotion and progression of the tumor. In the following study, people found that resveratrol have some inhibitory effects on 29 kinds of cancer/tumor. They also found if resveratrol is used along with the chemotherapy and radiotherapy, the curative effect is double than any single use. In past two years, people's newest study has found that resveratrol surprisingly could uniquely inhibit the cancer stem cells. From 2000, people found that resveratrol used in the animal experiment could prolong the 30-75% of life of nematodes, drosophila, African Carp (a most short-lived fish) and mouse by starting the animal longevity gene called Sirtuin. The resveratrol also is amazing to make the aging skin younger. Over 3000 research literatures in the world declares the resveratrol could improve people in functions of antioxidation, antibiosis, anti-virus, eliminating toxin, anti-inflammatory, anti-obesity, adjusting the immune function, prevention of cardiovascular disease, protecting the central nervous system, improving the eye sight, reducing the high blood pressure, high cholesterol and high blood sugar. It also could activate the estrogenic hormone, has bipartite regulatory effects to delay and relieve the female climacteric syndrome, and prevents/treats the osteoporosis and arthritis. The study found that the resveratrol could process a lot of chemical binding reactions and impact a lot of specifically major gene, as shown in FIG. 1 and FIG. 2 .
[0003] There exists a problem, called molecular dissolution after taken, for an application of resveratrol. The resveratrol, with a molecular formula C 14 H 12 O 3 , a molecular weight 228.25, a melting point 256-257° C. and a sublimation point 261° C., is a colorless needle-shaped crystal which is hardly soluble (slightly soluble) in water, but soluble in ethyl ether, chloroform, methanol, ethanol, acetone, acetic ether and other organic solvents with strong nonpolarity. The resveratrol is hardly absorbed if being swallowed with water, but is well absorbed with red wine, because of alcohol content in red wine, and it thus solves the mystery of French Paradox.
[0004] There are called cis & trans structures and its transformation. The resveratrol is with its extraordinary effect only if it is in a trans-resveratrol structure but is with not any effect in the cis-resveratrol structure. Natural resveratrol mainly exists in trans-resveratrol structure, and it turns into the cis-resveratrol structure under UV irradiation. Resveratrol exists in 72 plants and can be synthesized chemically. Resveratrol extracted from natural plant is generally the mixture of cis & trans structures, whose proportion varies by different plants. However, cis-resveratrol as the parent compound of 1,2-viniferins has never been examined in grape extracts.
[0005] The so-called problem of high absorption rate and low bioavailability is explained as follows. If the resveratol is taken orally, it generates a very special phenomenon different from general compounds, which brings a great challenge for its application as a drug. According to the results obtained from pharmacokinetics studies, whether to be taken orally or injected, the resveratrol will be absorbed by human body rapidly (within 10 min) and enter the circulation (blood) system. After that, the concentration of resveratrol in blood rises greatly to reach its peak in about 1 to 2 hours and declines greatly after that. In about 4 hours, resveratrol can't be detected in the blood, and after 4 hours, about 77% resveratrol is detected in the urine. This regrettable phenomenon is called as “high absorption rate and low bioavailability”
[0006] Another problem called problem of storage and processing is that during processed or after made into food, resveratrol shall be provented from exposure to the air to against oxidization. Trans-resveratrol will degrade seriously after preserved under a low temperature of 4° C. over 1 year, so it can't be preserved in ice overstepping the time limit.
[0007] The so-called absorption route of resveratol is that there are two functional routes after resveratrol being taken orally and entering human body. The functional routes includes: a sirt1-dependent route, taking effect through activating sirt1 gene and whose effect is closely linked with sirt1 gene; and a sirt1-independent route, taking effect without stimulating sirt1 gene.
[0008] As discovered in the latest studies, if low-dose resveratrol is taken orally, it will take the sirt1-dependent route, which will activate sirt1 gene and then release sirt1 protein to change, including enhance or weaken, the functions of P53, FOXO, NF κ B and other genes. On the other hand, if high-dose resveratrol is taken orally, it will take the sirt1-independent route, the functions of which are not concerned with sirt1. It is a wrong cognition of general people that a higher dose generates better effect.
[0009] Thus, it is an issue regarding how to appropriately use dose of resveratrol.
SUMMARY OF THE INVENTION
[0010] Therefore, the object of the present invention provides a food recipes for nourishing, maintaining and cultivating a variety of stem cells and a method for manufacturing the same, based on the consideration that the proliferation and activation of the stem cells according to the above mentioned drug test report, also indicating that it is only allowed to activate normal stem cells at the present time and the cancer stem cells may also be activated after activation of the normal stem cells. Meanwhile, there are also some restrictions and difficulties of the main ingredient resveratrol in application.
[0011] The food recipes for nourishing, maintaining and cultivating a variety of stem cells and a method for manufacturing the same of the present invention is advantageous as follows.
[0012] (I) Based on the basic theories of the compound foods and the test results for all food combination materials, the present invention is enabled to effect for nourishment, maintenance of hematopoietic stem cells, mesenchymal stem cells, neural stem cells, retinal stem cells, skin stem cells, endothelial progenitor stem cells and cochlea stem cells and to inhibit the cancer stem cells.
[0013] (II) The secondary ingredients of the present the present invention are composed of agonist of peroxisome proliferator activated receptor (PPARs) and the food materials such as quercetin, catechin and β-glucan, etc. The conjunctive use of one of the element with resveratrol has an additive plus effect than a single element used. The natural extracts containing these elements are applied without interacting with each other to perform its best effect. The present invention is applied together with cyanidin, carotenol and other food materials, based on the principle of “prevention of interactions but performance of the cooperative functions”, which is another characteristic of the present invention.
[0014] (III) The constituent parts of the present the present invention, including the vitamin, linseed oil powder and beer yeast (containing yeast β-1,3/1,6 glucan) is applied since their cooperative effect if combined, and the other constituent parts are proved to be effect directly or indirectly in animal experiment, in-vitro experiment and in-vivo experiment for stem cell proliferation, activation, repair, moistening and adjustment. Ingredient molecule in the present invention is selected from varied plants with function of nourishment, maintenance and decay for varied in-vivo stem cells but not only aiming at a single stem cell, since it is beneficial to nourish and maintain the varied in-vivo stem cells even though there is only one or two kinds of in-vivo stem cells which is senescent, deteriorative and decreased.
[0015] (IV) Constituent parts of the present invention are non-carcinogens. On the contrary, there are documents of the research results prove these constituent parts is effect in cancer prevention, anticancer and cancer therapy. Especially, they are good for the stem cell proliferation, activation, repair, moistening and adjustment but is not helpful or even inhibits for the cancer stem cells.
[0016] (V) Resveratrol, the main constituent of the present invention, is a molecule in natural food which has effects on 29 cancers/tumors as discovered by many animal experiments. With regard to its anticancer mechanisms, the most advantageous mechanism is that it can treat the cancer stem cell CD133 molecule, interfere the signal pathway to phosphatidylinositol-3-kinase (PI3K), inhibit the signal pathway of mammalian target of rapamycin (mTOR), slow down the growth of cancer stem cell and inhibit the proliferation of cancer stem cell. Resveratrol can also inhibit the transcription of cancer hTERT gene (telomerase reverse transcriptase), thus to decrease the hTERT mRNA. There is a position for the combination of NF κ B and AP-1 at the startup of hTERT to decrease the activity of hTERT and inhibit the growth of cancer stem cells without destroying the normal stem cells. Resveratrol is the inhibitor of cancer bodyguard NF κ B, inhibits the tumor angiogenesis, promotes the in-vitro differentiation of GBM (glioblastoma multiforme) stem cell with positive CD133 to decrease its ability to form tumors in the experimented animal body, and inhibits the Interleukin-8 (IL-8) expression of cancer stem cell. The main constituent of the present invention is the natural product discovered with the most effective capability to treat the cancer stem cells.
[0017] (VI) The constituent of the present invention including ginseng, matrimony vine, herba rhodiolae, radices rehmanniae, ganoderma lucidum, gordyceps sinensis, brown algae, green algae, mushroom, and agaricus blazei murill (ABM), beer yeast (β-1,3/1,6 glucan) the present invention are all polysaccharide containing sugar chain, which is used for treating the cancer cells with excellent effect in these 20 years in Japan, since the sugar chain can generate the phenomenon of carbohydrate antigens on the surface of the cancer cells, in which a cell without carbohydrate antigen is a normal cell free of cancer. Low-molecule agaricus blazei murill (LMPAB) can down regulate the expression of RNA and mRNA of hTERT, decrease the activity of telomerase and inhibit the growth of tumor stem cell. In addition, the root of red-rooted salvia, catechin and resveratrol are called as the NF κ B inhibitor of cancer bodyguard, which will slow down the growth of cancer stem cell without affecting the growth and survival of normal stem cells. Triterpenes of bitter gourd can block the signal pathway by the cancer cell to the core thus to inhibit the proliferation of the cancer stem cells.
[0018] (VII) Food formula provided by the present invention for nourishment, maintenance of varied stem cells is extracted from purely natural ingredients, which is edible for human body without side effect.
[0019] (VIII) The present invention solves the restrictions and difficulties of resveratrol in application, changes the disadvantages into advantages, and furthermore enables resveratrol to have addition-multiplication effect via the cooperative effect and exerts a biological.
[0020] The solutions the present invention solve the conventional restrictions and difficulties of resveratrol in application as follows.
[0021] 1. Solutions to the problem of molecular dissolution after being taken. (1) Embed resveratrol molecule by Hydroxypropyl-β-Cyclodextrin (HP-β-CD) to improve its solubility. Indicates in studies, the hardly soluble drugs embedded by HP-β-CD not only increases the solubility but also advances the bioavailability and stability thereof as well. After test, using HP-β-CD to embed the resveratrol is proved extremely good by the determination of the inclusion rate.
[0022] (2) The other extracts in the constituents containing resveratrol such as (ripe) polygonum multiflorum extracts, pseudo-ginseng extracts, root of red-rooted salvia extracts and blueberry extracts shall be included, or otherwise the resveratrol shall be taken with red wine, wine, deep-sea fish oil or vegetative ω3, which can also solve the problems of solubility and stability.
[0023] 2. Solutions to the problem of cis & trans structures and transformation of resveratrol. Trans-resveratrol is very instable and will transform into cis-resveratrol under the UV irradiation. After its aqueous solution (pH1-7) kept in dark place for 28 day, 4.7% of the trans-resveratrol will transform into cis-resveratrol. Low water solubility and poor stability under UV irradiation restrict the all-purpose application. Therefore, HP-β-CD is used to embed the resveratrol into inclusion compound. Under the irradiation of UV analyzer (136 μw/cm 2 ) in experiment, if compared with the unembedded resveratrol, the isomerization of the embedded trans-resveratrol slows down and the unembedded resveratrol quickens up isomerization. Moreover, the food formula packaged by capsule solves the problems of oxidization misgivings and stability.
[0024] 3. Solutions to the problem of high absorption rate and low bioavailability of resveratrol. If taken orally, high absorption rate and low bioavailability problem will occur in resveratrol, which is a very special phenomenon distinct from general compounds. This brings a great challenge for its drug application. Discovered from the studies, the co-existence of trans-resveratrol with some antioxidants will prolong the residence time of resveratrol in human body. Thus the present invention selects the antioxidant food materials having that kind of ingenious relationship with resveratrol, such as cyanidin and procyanidin which prolong the residence time of trans-resveratrol in human body. Moreover, in the discover of biologists and physicians, the co-existence of trans-resveratrol and a certain substance can enhance greatly the effect of trans-resveratrol as indicated in guidance file of National Institutes of Health (USA) which explains clearly that joint use of trans-resveratrol and the antioxidant such as cyanidin, indole or green tea catechin generates cooperative effect. Reported by a periodical of Nature in November, 2006 and Cell in December 2006 respectively, the resveratrol could reduce the acetylation reaction of PGC-1α ferment, enhance the active effect of PGC-1α and combine with PPARs active agent to present an addition-multiplication activation effect of PPAR molecule. Experiment by clinical group of National Health Research Institutes, Taiwan also confirms that resveratrol has effect of transformation coenzyme similar to RXR and is able to activate PPAR molecule. Explained clearly in the papers published in 2007, the joint use of trans-resveratrol and the antioxidant quercetin had cooperative effect. Papers of joint study by Professor Walter Wichgar in University of Louisville (USA) and Professor Flogny of innovation research institute (Czechoslovakia) explains that the joint use of trans-resveratrol and glucan has cooperative effect. It can prolong the half-life period of resveratrol in human body, increase the area under the curve, promote the maximum blood concentration of resveratrol, reduce its clearance rate, enhance the bioavailability and exert the pharmacological action of resveratrol, by applying, for example, the blueberry extracts rich in cyanidin and procyanidin, apple extracts rich in quercetin, green tea extracts rich in catechin, beer yeast β glucan rich in β-1,3/1,6 glucan; (ripe) polygonum multiflorum extracts, grape skin or polygonum cuspidatum root extracts, pseudo-ginseng extracts and blueberry extracts rich in resveratrol and containing PPARs active agent; momordica charantia extracts, soybean extracts, the root of kudzu vine extracts, herba rhodiolae extracts, liquorice extracts, ginseng extracts, brown alga extracts, green alga extracts, rhizoma dioscoreae extracts rich in PPARs active agent; and with the multiphasic liposomes.
[0025] 4. Solutions to the problem of processing and storage of resveratrol. Although the chemically synthesized resveratrol is inexhaustible in supply, its effect is much poor than that extracted from natural products, which is effective without side effect. The optimal solution for powders and capsules is to apply naturally resveratrol prepared and processed as raw material to prevent from being exposed in the and sunlight after manufactured as raw material or as products, not stored under a condition of 4 over 1 year to prevent from serious degeneration and embedded with HP-β-CD.
[0026] 5. Solutions to the problem of absorption route of resveratrol. There are two absorption routes after resveratrol taken orally: sirt1-dependent route and sirt1-independent route, wherein low-dose resveratrol will take the sirt1-dependent route, which is closely linked with human activity, and high-dose resveratrol in condition of major diseases or cancer will take the sirt1-independent route. General food formula selects a low dose about 80-150 mg. Oral taking is the most common path, since it is convenient in use and acceptable by the masses. However, unsatisfactorily, Oral taking generally is not as significant effective in human body as in animal experiment if it doesn't cooperate with the cooperative substance. In oral taking path, the dose of drugs reaching the target infected cells is hard to be controlled accurately since the drug has to pass through intestines and stomach digestive system, first pass metabolism and blood circulation system, thus to make the drug dose too much or too little and fail to achieve the desired effect. Low dose of 80-150 mg in the present invention mainly takes the sirt1-dependent route. If required by the eaters' body, the dose can be increased to take the sirt1-independent route suitable to different persons. Taking sodium alginate as the carrier, the resveratrol embedded into inclusion by HP-β-CD as capsule in slow-release technology can prolong the residence time of formula in body and achieve the target controlled release effect.
[0027] 6. Solutions to the problem of using dose of resveratrol. According to an animal experiment for 28 consecutive days with a dose of 30-3000 mg, it is considered that a dose within 2000 mg is safe and has no side effect for the safety in heredity or deformity for pregnant mice and fetus mice experiment. However, what dose is effective for human body? As regard to this problem, some scientists suggest to convert based on the amount in animal experiment to the amount in human body (in unit of body weight). While, some suggest to apply the dose-dependent type according to the animal experiment of related symptoms. Dr. Xi Zhao-Wilson points out that until now studies on the human body can't determine the optimum dose of resveratrol, and suggests taking in high-quality resveratrol from daily food for a good health. Ward Daean considers that, although the optimum dose of resveratrol in human body is not determined, the reasonable dose of human body is significant within the following scope: 1-10 mg/day for prevention and anti-aging and 10-100 mg/day for curing. It is recommended that a higher dose is used for supplementary control of all cancers.
[0028] Professor Sinclair in Harvard University (USA) estimates that an adult with a body weight of 60 kg shall take in 1344 mg trans-resveratrol each day to achieve the same effect of longevity and anti-aging effect as in the mice experiment. However, since Mr. Sinclair involves a complicated business operation, his estimation is accused of lots of queries from the academic world immediately. In the year 2007-2009, research papers about dose required for human body provides some applicable data for all experiments, wherein 80-150 mg is the mainstream dose obtained the most support. This formula takes 80-150 mg as the effective dose and set 1500 mg as the upper limit of the safe dose in consideration of the safety.
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] The structure and the technical means applied by the present invention for achieving the above and other objects can be best understood by referring to the following detailed description of the preferred embodiments and the accompanying drawings.
[0030] The FIG. 1 is a block diagram that resveratrol can make many chemical reactions to combine the reactive molecules.
[0031] The FIG. 2 is a block diagram that the present invention shall be influenced by resveratrol.
[0032] The FIG. 3 shows the orientation of FIG. 3A , 3 B, 3 C and 3 D which are block diagrams showing that the present invention proven in animals testing and human testing can nourish, maintain and repair the stem cells.
[0033] The FIG. 4 is flow diagram of manufacturing method of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0034] The detailed description of the invention which follows is made with reference to the drawings and in terms of a preferred embodiment of the invention. The detailed description is not intended to limit the scope of the present invention, and the only limitations intended are those embodied in the claims hereto.
Embodiment 1
[0035] Composition of food recipes for nourishment, maintenance and cultivation of varied stem cells. In a preferred embodiment, food recipes for nourishment, maintenance and cultication of varied stem cells is in form of powder. Each unit of ingredient is composed of 80-150 mg grape skin or polygonum cuspidatum root extracts, 30-60 mg ginseng extracts, 45-90 mg pseudo-ginseng extracts, 50-95 mg matrimony vine extracts, 45-90 mg the root of kudzu vine extracts, 35-70 mg ligusticum wallichii extracts, 35-65 mg the root of kudzu vine, 40-80 mg herba rhodiolae extracts, 25-50 mg brown alga extracts, 25-45 mg green alga extracts, 25-45 mg apple extracts, 20-35 mg pot marigold extracts, 20-40 mg green tea extracts, 20-35 mg glossy ganoderma extracts, 20-35 mg blueberry extracts, 10-30 mg cordyceps sinensis extracts, 10-30 mg broomrape extracts, 10-30 mg leek seed extracts, 10-40 mg beer yeast (yeast β-1,3/1,6 glucan), 5-20 mg (ripe) polygonum multiflorum extracts, 5-20 mg liquorice extracts, 5-20 mg agaricus blazei murill extracts, 5-20 mg rhizoma dioscoreae extracts, momordica charantia extracts, 5-20 mg soybean extracts, 5-20 mg mushroom extracts, 5-20 mg linseed oil powder and 5-10 mg vitamin. The ingredient can also includes spice, fruit juice powder and HP-β-CD, which can enhance its palatability, promote the food solubility, increase the UV stability and improve the food bioavailability.
[0036] The detailed description of the invention in the follows is made with reference to the drawings and in terms of a preferred embodiment of the invention. The detailed description is not intended to limit the scope of the present invention, and the only limitations intended are those embodied in the claims hereto. The food recipes comprises grape skin or polygonum cuspidatum root extracts, pseudo-ginseng extracts, (ripe) polygonum multiflorum extracts, the root of red-rooted salvia extracts and blueberry extracts are rich in resveratrol, which contains the molecule for chemical binding reaction to affect the gene acting on human body and achieve the effect of varied stem cells proliferation, activation, repair, nourishment and adjustment. The root of red-rooted salvia extracts and blueberry extracts contain both resveratrol and PPARs active agent. The ginseng extracts, herba rhodiolae extracts, momordica charantia extracts, soybean extracts, rhizoma dioscoreae extracts and liquorice extracts are rich in PPARs; liquorice extracts are rich in PPARs active agent and puerarin; brown algae extracts are rich in PPARs active agent, puerarin and sodium alginate; green algae extracts are rich in PPARs active agent, phycocyanin and DHA. PPARs is a kind of transcriptional factor depending on ligand activation and belongs to the nuclear hormone receptor family. It includes three isomers, i.e. PPARα, PPARβ/δ and PPARγ, which will bind with retinoids to form heterodimers and activate after binding with the ligand (PPARs active agent), thus to bind in the PPAR response area on the upper stream of the start point of target gene transcription and activate the target gene for transcription. In addition to that the composite molecule with PPARs active agent is able to wake up and activate the functions of cells, the PPARβ/PPARγ may participate in the regulation on proliferation and differentiation of neural stem cells. PPARγ can enable the mesenchymal stem cells to differentiate into fat cells, shorten the differentiation process and promote the differentiation efficiency. Stem cell proliferation, activation and repair by resveratrol are achieved through PPARs sometimes. Stem cell proliferation, activation and repair by resveratrol can also be achieved through puerarin, fucoidan, sodium alginate and phycocyanin, for example that the ligusticum wallichii extracts contain ferulic acid and ligustrazine, green tea extracts contain catechin, apple extracts contain quercetin, leek seed extracts contain ethylamine sulfonic acid, matrimony vine extracts, glossy ganoderma extracts, cordyceps sinensis extracts, agaricus blazei murill extracts, mushroom extracts and β-glucan contain polysaccharide, wherein any of catechin, quercetin and β-glucan if activated with resveratrol will have an additional plus effect. Sodium ferulate can accelerate the hemopoietic stem cell to repair the damaged kidney, ligustrazine has a certain mobilization effect on the hemopoietic stem cell, which can improve the microenvironment of bone marrow and promote the hemopoietic reconstitution of bone marrow. Sodium ferulate can induce the mesenchymal stem cells to differentiate to the nerve cells and has the function of nerve protection and neurogenesis enhancement. Ligustrazine can enhance the proliferation of mesenchymal stem cells, induce the mesenchymal stem cells to differentiate into neuron-like cells, promote the proliferation of neural stem cell at the subventricular zone (SVZ) induced by focal cerebral ischemia, promote the proliferation of endogenous neural stem cell in dentate gyrus of hippocampus of ischemia-reperfusion injury rats. Both ferulic acid and ligustrazine can significantly accelerate the regeneration and prolongation of axon in retinal ganglial cells. Catechin can accelerate the proliferation and differentiation of hemopoietic stem cell and hemopoietic progenitor cell, which can accelerate the growth of human hair follicle and promote the proliferation of human dermal papilla cells through affecting the cell cycle. Quercetin can accelerate the proliferation and osteogenic differentiation of mesenchymal stem cells, promote the bone fracture healing and prevent against osteoporosis. Meanwhile, quercetin can promote the proliferation of human retinal pigment epithelial cell (RPE), inhibit the damage of oxidative stress to RPE and prevent against apoptosis. Ethylamine sulfonic acid can promote the proliferation of neural stem cell after focal cerebral ischemia and prevent against apoptosis in neuronal cells due to hematencephalon, which has a certain protection function on nerve cells. Ethylamine sulfonic acid can induce the cell differentiation of mesenchymal stem cells to photoreceptor cell or rhodopsin. Lycium barbarum polysaccharide can accelerate the proliferation of hematopoietic stem cells from bone marrow and promote the granulocyte differentiation of colony forming unit of granulocyte and macrophage (CFU-GM). In addition, Lycium barbarum polysaccharide can also delay the differentiation of mesenchymal stem cells to endothelial ancestry and induce the mesenchymal stem cells to transform into neuron-like cells. Lycium chinense is rich in zeaxanthin, which is the optimum nutrient for eye macular. Meanwhile, lycium chinense can protect the retinal ganglion cells, photoreceptor cell and neural stem cell. Ganodema lucidum polysaccharide F3 can promote the proliferation of hemopoietic stem cell and enhance human immunity. Spores of ganoderma lucidum can promote proliferation of the cellula adhesiae in damaged spinal cord central canal. Part of the proliferated cells can differentiate into neural stem cells, neuron-like cells, oligodendrocytes and astrocyte-like cells. Lycium barbarum polysaccharide has the neuroprotective function to the hippocampus neuron cell damage induced by β amyloid protein (Alzheimer's disease). Spores of ganoderma lucidum have the recovery function to retinal photoreceptor cells damage. Cordyceps sinensis can promote the proliferation of hemopoietic stem cell, accelerate the differentiation of sclerocyte and bone histogenesis of the mesenchymal stem cells, reduce the gene expression of osteoclast differentiation factor and induce the committed differentiation of neural stem cells. Agaricus blazei murill (ABM) polysaccharide can promote the proliferation of hemopoietic stem cell and hemopoietic progenitor cell, etc. The food formula for nourishment, maintenance and culture of varied stem cells can be powdery, granule or liquid type. The unit can be a capsule, a tablet, a pastille, a packing bag or a packing bottle. Daily dose can be 1-6 units. Moreover, an excipient or carrier acceptable in pharmaceuticals can be included and selected from the group composed of flavoring agent, sweetener, preservative, chelating agent, penetrating agent, lubricant, tablet adjuvant, colorant, moisturizing agent, binder as well as the medicine compatible carrier.
Embodiment 2
[0037] Manufacturing method of food formula for nourishment, maintenance and cultivation of varied stem cells. Please refer to FIG. 4 of the manufacturing method of food recipes for nourishment, maintenance and culture of varied stem cells, including:
[0000] S1, adding appropriate amount of water into Hydroxy C-beta-cyclodextrin (HP-β-CD) and brown algae extracts (sodium alginate), then dissolving them completely by a magnetic stirring device;
S2, taking appropriate amount of resveratrol from grape skins/polygonum cuspidatum root extracts, dissolving following extracts by using appropriate amount of anhydrous alcohol, the extract comprising pseudo-ginseng extracts, cooked polygonum multiflorum extracts, salvia miltiorrhiza bunge extracts, blueberry extracts, balsam pear extracts, soybean extracts, ginseng extracts, rhodiola rosea extracts, chinese yam extracts, liquorice extracts, puerarin extracts, brown algae extracts, green algae extracts, ligusticum chuanxiong hort extracts, green tea extracts, apple extracts, leek seed extracts, matrimony vine extracts, pot marigold extracts, ganoderma spp extracts, cordyceps sinensis extracts, agaricus blazei extracts, cistanche extracts, mushroom extracts, beer yeast (β-1,3/1,6 glucan), flaxseed oil powder extracts and vitamin, the dissolved extract being slowly dropped and added into the water solution containing cyclodextrin and sodium alginate, continuing to stir for a period of time, resting these extracts for a period of time, and then filtering out impurities;
S3, acquiring a mixed solution by combining S1 with S2 to obtain a filtrate, the filtrate transferred into a petri dish, and storing into refrigerator overnight;
S4, taking out the mixed solution, which is frozen, from the refrigerator in the next day, drying it by using spray drying or vacuum drying for 12 hours to make them as trituration of loose bulk materials so that the food recipes in form of powder of inclusion complex is obtained;
S5, using an excipient to make the powdered food recipes into type of capsule, tablet, ingot and aluminum foil bag, wherein each of the capsule type, the tablet type, the ingot type and the aluminum foil bag type.
[0038] Percentages of all ingredients in this food recipes are as follows:
[0039] 1. Resveratrol is in weight of about 42% of grape skin or polygonum cuspidatum root, pseudo-ginseng extracts, (ripe) polygonum multiflorum extracts, the root of red-rooted salvia extracts and blueberry extracts.
[0040] 2. PPARs agonist is in weight of about 28% of ginseng extracts, the root of kudzu vine extracts, herba rhodiolae extracts, brown algae extracts, green algae extracts, soybean extracts, rhizoma dioscoreae extracts and liquorice extracts.
[0041] 3. Catechin is in weight of 90% of green tea extracts.
[0042] 4. Quercetin is in weight of 80% of apple extracts.
[0043] 5. Polysaccharide (glucoprotein) is in weight of 20% of ginseng extracts, matrimony vine extracts, herba rhodiolae extracts, radices rehmanniae extracts, glossy ganoderma extracts, cordyceps sinensis extracts, mushroom extracts, ABM extracts, beer yeast (β-1,3/1,6 glucan).
[0044] 6. Ginsenosides is in weight of 30% of ginseng extracts.
[0045] 7. Panax notoginseng saponins take up 30% of panax notoginseng extracts.
[0046] 8. Phylloxanthine is in weight of 80% of pot marigold extracts.
[0047] 9. Zeaxanthin is in weight of 25% of matrimony vine extracts.
[0048] 10. Tanshinone, danshensu and protocatechuic acid take up 27% of root of red-rooted salvia extracts.
[0049] 11. Ligustrazine and sodium ferulate take up 60% and 30% respectively of the ligusticum wallichii extracts.
[0050] 12. Puerarin is in weight of 70% of root of kudzu vine extracts.
[0051] 13. Medicinal serum is in weight of 60% of (ripe) polygonum multiflorum extracts and cistanche extracts.
[0052] 14. Rhodioside is in weight of 30% of the herba rhodiolae extracts.
[0053] 15. Ganoderma lucidum spores take up 30% of ganoderma lucidum extracts.
[0054] 16. Fucoidan and sodium alginate take up 40% respectively of brown alga extracts.
[0055] 17. Phycocyanin is in weight of 10% of green alga extracts.
[0056] 18. Ethylamine sulfonic acid is in weight of 70% of leek seed extracts.
[0057] 19. DHA is in weight of 80% of linseed oil powder extracts and 5% of green alga extracts.
[0058] The present invention includes the procedure to add an excipient to make the powdery food recipes into capsule, tablet, pastille and packing bag. The prepared mixed solution can also include spice and juice powder. The unit can be a capsule, a tablet, a pastille, a packing bag or a packing bottle. Daily dose can be 1-6 units.
Embodiment 3
[0059] Regarding ingredients in the food recipes of the present invention. This embodiment is applied to use in single stem cell proliferation, activation, repair, moistening and adjustment. As discovered by the present invention, some ingredients have the function of nourishment, maintenance and cultivation of varied stem cells, which can be developed into a mixture for nourishment, maintenance and cultivation of varied stem cells as well as cancer stem cells inhibition. Its functions have been proved by the previous experiment report. FIG. 3 shows the orientation of FIG. 3A , 3 B, 3 C and 3 D which show the name thereof, effective molecules and functions of normal stem cells for proliferation, activation, repair, moistening and adjustment in these ingredients and the fact that cancer stem cell inhibited.
Embodiment 4
[0060] The food recipes with its function of inhibition of cancer stem cells. In 2003, Michael Clarke of Stanford University (USA) and Hilla Singh in Toronto's Hospital for Sick Children (Canada) discovered tumor stem cells in leukaemia, breast cancer and brain tumour. After that, the scientists discovered the tumor stem cells and isolated the carcinogenic cells with the characteristics of stem cells different cancer tissues, e.g. lung cancer, liver cancer, oral cancer, ovarian cancer, prostate cancer, colorectal cancer, pancreatic cancer, melanoma, head and neck cancer. Surface antigens such as CD44 + and CD24 − usually adhere on the surface of the cancer cells. In 2004, Dirks and other research teams in Toronto University confirmed that once the surface of human neural stem cell shows the CD133 + glycoprotein surface antigen, new tumors will be developed out. As the research developed, special surface antigens possessed by many cancer cells have been specified gradually. Generally, there is no surface antigen on the surface of normal cells, but there are special surface antigens discovered on the surface of tens of tumors (see Table 1).
[0000]
TABLE 1
Special surface antigen identified in human cancer stem cells
Special surface
Type
antigens
References
Acute myeloid
CD123 + , CD44 + ,
Proc. Natl. Acad.
leukemia
CLL-1 + , CD25 + , CD32 + ,
Sci. 2001
CD96 + , and CD47 +
breast cancer
CD44 + , CD24 − /low
Proc. Natl. Acad.
Sci. 100: 3983, 2003.
brain tumour
CD133 +
Nature 432:
396, 2004.
melanomas
CD20 +
Cancer Res.
65: 9328, 2005.
prostate cancer
CD44 + , α2β1 +hi ,
Cancer Res.
CD133 +
65: 10946, 2005.
multiple myeloma
CD138 −
Blood 103:
2332, 2004.
Head and neck
CD44 +
Head Neck. 34: 894,
squamous cell
2012.
carcinoma
colon cancer
CD133 +
Nature
445: 106, 2007.
colon cancer
CD44 + , EpCam + , CD166 +
Proc. Natl. Acad.
Sci. 104: 10158,
2007.
Pancreatic Cancer
CD44 + CD24 + ESA +
Cancer Res.
67: 1030, 2007.
Epithelial Ovarian
CD44 +
Cancer Res.
Cancer
65: 3025, 2005.
[0061] With regard to the studies on cancer stem cells in Taiwan, in June 2008, the VGHtpe-YangMing Team consisted of the presenter in Stem Cell Laboratory of Taipei Veterans General Hospital and Shih-Hwa Chiou in Institute of Clinical Medicine, National Yang Ming University discovered that the cancer stem cells showed a lot of anti-apoptosis protein and embryonic stem cell regulation proteins. If these specific gene or proteins can be inhibited, the drug resistance and radioresistance of cancer stem cells will disappear, thus the cancer stem cells can be eliminated, and the cancer can be cured once and for all. On Aug. 13, 2008, Yu, Alice Lin-Tsing, the Distinguished Research Fellow and Deputy Director of Genomics Research Center, Academia Sinica and Yu, John, the Distinguished Research Fellow of Institute of Cellular and Organismic Biology, Academia Sinica found out a hexasaccharide (Fucα 1→2Galβ1→3GalNAc β1→3Galα 1→4Galβ1→4Glcβ1) named as Globo H on the surface of breast cancer stem cell, which was seldom expressed in healthy cells. Gb5, which is occurred frequently in embryonic stem cells, was detected in 77.5% breast cancer cells and detected in 62.5% general stem cells. Consequently concluded from the studies, these two glycomolecule existing on the surface of breast cancer cells can be treated as the target to find the antibody drugs or food for breast cancer curing once and for all.
[0062] A major breakthrough appeared in the cancer medicine of VGHtpe-YangMing Team of Taiwan on Aug. 6, 2011, Professor Hsei-Wei Wang explained that cancer stem cell was one of the few leading causes with high malignancy, able to escape the chemical therapy and radiotherapy and result in cancer recurrence and metastasis. Discovered by the research team, the stubborn survival of cancer stem cells was related to that the epithelial-mesenchymal transition factor snail was able to activate the inflammatory cytokines IL8. Neutralizing antibody of IL8 (IL8 inhibition) applied in animal experiment could inhibit the cancer stem cells by 2/3. Professor Shih-Hwa Chiou explained that if the cancer stem cell tissue was compared to a crime syndicate, IL-8 was just the leading assistant of snail. Relevant drugs are developed and screened to inhibit IL-8 directly and achieve the effect of symptom retard.
[0063] Some studies indicate that even though we can't detect the activity of telomerase in normal body cells but can detect it in the highly-divided cells such as the stem cell and more than 80% cancer cells. Thus, it will be an optimum anticancer method to reduce the activity of cancer cell telomerase but not damage the normal stem cells. The activity of telomerase is mostly depended on the expresson level of hTERT gene (telomerase reverse transcriptase). NF κ B and AP-1 can regulate the transcription of hTERT (i.e. the promoter of hTERT) positively. Discovered in recent studies, inhibition of hTERT gene expression will lead to cell death caused by the reduction of activity of non-telomerase. This is because that hTERT will affect the cell survival via p53 or PARP upon analysis. Thus besides reducing the activity of telomerase, inhibition of hTERT gene expression will also lead to cell death directly.
[0064] Carbohydrate chemistry and molecular glycobiology is one of another key issue for R & D team of Academia Sinica, Taiwan and become a significant results for them. The president Wong, Chi-Huey is good at carbohydrate technology and becomes the internal authority due to more than 30 years' studies on sugar chain (glycoprotein). Ganoderma lucidum polysaccharide is a very useful material recommended by him. Substances containing sugar chain (e.g. glossy ganoderma, β glucan and ABM, etc) are suggested by experts of Taiwan and world, for treats the carbohydrate antigens. Cells without the carbohydrate antigens are normal cells, that is, these cells without cancer cells.
[0065] People gradually learn some molecular characteristics of the cancer stem cells, such as surface molecule markers, drug resistance, radioresistance and signal channel of tumor stem cells. In 2008, Mei-Chuan Tang and Dr. Yeu Su in Institute of Biopharmaceutical Science, National Yang-Ming University published the New Dawn for Cancer Curing in Science Development. They found out the inhibition and annihilation methods against varieties of tumor stem cells and explained that selectively inhibiting the growth of and even annihilating the tumor stem cells are a possible task. In the paper, they pointed out that it would not bring bad impact on the growth and survival of normal stem cells but have the effect of inhibition and annihilation of the cancer stem cells to adopt the transcriptional factor NF κ B and phosphatidylinositol 3-kinase (PI3K), mammalian target of rapamycin mTOR, bone morphogenetic protein and other strategies. In the progress to find out what ingredient has all or part of these effects, as proved by the history, the ingredients in the present invention are not cancerigenic factors. On the contrary, they have the effects of cancer prevention, anticancer and cancer curing. The main ingredients resveratrol, PPARs active agent, ginsenosides, root of red-rooted salvia, panax notoginseng saponins, soybean isoflavone, catechin and polysaccharide have crucial inhibition effect on the cancer cells.
[0066] (I) Nuclear transcription factor NF κ B is the bodyguard of cancer, which can activate the signal transcription channel and has important effects on immune response, inflammation, cell proliferation, cell differentiation, apoptosis and canceration. NF κ B is the main controllable factor for anti-apoptosis, which can activate the survived gene and express the survived protein. In 2008, Iyori discovered that, resveratrol could inhibit the activation of NF κ B, subunit phosphorylation of NF κ B P65, nuclear translocation and transcription of NF κ B-dependent report gene as well as block up NF κ B activation induced by phorbol ester, lipopolysaccharide, H 2 O 2 and ceramide, etc. Moreover, resveratrol could inhibit both NF κ B activation and NF κ B-related gene expression, which exerted functions through inhibiting I κ B kinase of NF κ B so as to block NF κ B activation and NF κ B-dependent gene expression. Resveratrol, catechin, root of red-rooted salvia and dioscin are all the inhibitors of NF κ B.
[0067] (II) The anti-tumor effect of resveratrol that was found by She QB in 2002 is closely associated with the signal transduction pathways of interference phosphatidylinositol-3-kinase (PI3K). In JB6 epidermal cells planted by using the mouse, the resveratrol and its derivatives can inhibit the conversion of tumour cells through blocking the PI3K-Akt activity transmitted by epidermal growth factors. In 2004, Pozo-Guisado E in research on human breast cancer cells found that resveratrol could impact the PI3K signal pathways related to the estrogen hormone receptor a so as to block the cells survival and proliferation, but and the process is not associated with the function of estrogen hormone receptor a.
[0068] Yu-Jhen Cheng, China Medical University, Graduate Institute of Cancer Biology (Taiwan), makes the related research on the cells metastasis of lung cancer inhibited by resveratrol in the FOXC2 (forkhead box C2) in 2009, and this conclusion shows the resveratrol could decrease the activity of PI3K/Akt-FOXC2 through using activation of Serine/Threonine and Dephosphorylation, so as to obtain inhibiting the purpose of metastasis of lung cancer cells.
[0069] In 2010, Huang Linyu in the Center of Molecular Biology (CMB), Medical College of Shantou University investigates that resveratrol inhibits EGF-induced invasion of human lung adenocarcinoma A549 cells, and this conclusion showed that 20 μM resveratrol inhibit A549 cells' invansion possibly through the suppression of the phosphorylation of ERK1/2 and PI3K-Akt signalling pathways, subsequently exerting effect on matrix metalloproteinases 2 (MMP-2).
[0070] In 2010, Ye Cuilin et al. researched on the mechanism of resveratrol anti-breast cancer in the Department of Traditional Chinese Medicine of the Sixth People's Hospital Affiliated of Shanghai Jiao-Tong University, and they confirmed that resveratrol could inhibit breast cancer initiation, promotion and progression. The resveratrol might be associated with anti-inflammatory effects, restraining the activity of cytochrome enzyme P450, adjusting the levels of estrogen hormone in the initiation stage. Resveratrol might be associated with the anti-inflammatory, inhibition mechanism of cyclooxygenase-2 (COX2) and peroxidase in the promotion stage. Resveratrol might be associated with interfering the signal pathways of phosphoinositide 3-kinase (PI3K), inducing the differentitatin and apoptosis of tumor cells, inhibiting the tumor cells proliferation mechanism in the progression stage. Other mechanisms of the resveratrol against breast cancer include inhibiting angiogenesis, survivin, and the activity of BCRP/ABCG2 multidrug resistance proteins of breast cancer.
[0071] (III) In 2010, Gurusamy firstly found that low doses of resveratrol may enhance the effects of killing the cancer cells of anti-cancer drugs through inhibiting the signal pathways of target protein mTOR of rapamycin, impacting the Akt signal transduction.
[0072] (IV) In 2008, SHAO Hua-yi who works Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical Collage investigates that advance of bone morphogenetic protein-2 (BMP2) and osteoporosis drugs. This experimental results show that the resveratrol might improve the activities of alkaline phosphatase, increase mineralization, and enhance the levels of type I procollagen, osteocalcin and BMP-2. SHAO Hua-yi also speculated that resveratrol might affect the synthesis and expression of BMP-2 so as to impact the activity of alkaline phosphate and osteocalcin.
[0073] In 2009, Kawei researched on to the proliferation and differentiation of rat mesenchymal stem cells affected by quercetin in Jinan University (Guangzhou City, Guangdong). This conclusion shows that quercetin might promote the proliferation and differentiation of mesenchymal stem cells of bone marrow. The differentiation mesenchymal stem cells that the quercetin could increase the expression of BMP2 mRNA.
[0074] The above contents coincided with the phenomenon of Transcription Factor NF κ B and phosphatidylinositol 3-kinase (PI3K) message transmission to abnormal activation within cancer stem cells, opinion that use the current NF κ B and PI3K inhibitor to slow its growth, opinion that inhibit the target protein mTOR of mammalian rapamycin in the phosphatidylinositol to increase the anti-cancer drugs killing cancer cells; In addition, the above contents also coincided with the Bone Morphogenetic Protein (BMP) found by scientist could promote the differentiation in vitro of GBM (glioblastoma multiforme) stem cells of CD133 positive, opinion that could decrease forming the tumour in the body of experimental animals.
[0075] (V) In 2008, Li Tan made the research on the Resveratrol Anti-hepatoma Bel-7402 and Regulation of Tumor-bearing Mice L-8 Secretion Mechanism in the Department of Immunology, Medical College of Chinese People's Armed Police Force (Tianjin, China). This conclusion indicates that the resveratrol could inhibit the tumor-bearing mice L-8 generation and inhibit the content of Mrna and protein, this conclusion also considered that the resveratrol in the outside of inside of body could exert the effective anti-hepatoma biology activity and immune regulation function.
[0076] In November 2008, Ma Yongyong made the research on the effects of resveratrol on expression and secretion of IL-8 and VEGF of Lymphoma Raji cells in The First Affiliated Hospital of Wenzhou Medical College. This conclusion indicates that the resveratrol could inhibit the proliferation of lymphoma Raji cells and IL-8 mRNA expression of lymphoma Raji cells in vitro. This research indicated that resveratrol could inhibit the endothelial cell proliferation to form new blood vessels through inhibiting IL-8, so as to inhibit the tumor growth and metastasis, and provided the theoretical basis for the clinical application of resveratrol.
[0077] In 2009, WU Xiao-jie investigate the effects of resveratrol and rutin on the secretion of interleukin-6 (IL-6) and interleukin-8 (IL-8) from human mononuclear cells (MNCs) and polymorphonuclear cells (PMNCs) following the stimulation with lipopolysaccharide (LPS) or peptidoglycan (PGN) in Institute of Antibiotics, Huashan Hospital, Fudan University in Shanghai. This conclusion indicated that the resveratrol and rutin may exert different inhibitory effects on the cytokine secretion of human MNCs and PMNCs.
[0078] The above contents coincided with Hsei-Wei Wang point of view in VGHtpe-YangMing team in 2011, the point of view is to inhibit the cancer stem cells through inhibiting the IL-8 so as to slow the symptom.
[0079] (VI) In 2009, Li Tan, who worked in the Department of Immunology, Medical College of Chinese People's Armed Police Force (Tianjin, China), made the research on Resveratrol to induce apoptosis of leukaemia cells in Acta Academiae Medicine CPAPF. The conclusion from an existing study indicated that:
1 The resveratrol can induce the apoptosis of tumor cells through regulating the cells cycle. 2. The resveratrol can facilitate the apoptosis of tumor cells through inducing the p53 expression. 3. The resveratrol can induce the apoptosis of tumor cells through Bcl-2 family. 4. The resveratrol can induce the apoptosis of tumor cells by mitochondrial pathway. 5. The resveratrol can induce the apoptosis of tumor cells through Fas-FasL signal.
[0085] In 2009, LI Yong-jun made the research on the Expression Impact of Resveratrol to Esophageal Cancer Cell Apoptosis Related Gene, Survivin and Bax in the Department of Laboratory, the Second Hospital of Hebei Medical University (Shijiazhuang, China). This conclusion indicates that the resveratrol could induce the esophageal cancer cell apoptosis, its mechanism may be related to the expression of survivin and Bax.
[0086] Survivin is an apoptosis inhibition protein which can widely express the human tumors, and it has various functions such as inhibition of cells apoptosis, involving in cells cycle regulation and promotion of blood vessel formation.
[0087] 2011, YANG Kai who worked in the Department of Respiratory Medicine of First People's Hospital in Huaihua City, Hunan Province, made the research on the inhibitory effect of resveratrol on growth of Lewis lung cancer cells in mice and possible mechanism. This conclusion indicates that resveratrol has an effect of inhibiting the growth of Lewis lung carcinoma in mice, while its mechanism may be related to inhibiting the expression of MIF protein and inducing the apoptosis of cancer. MIF is a unique cell factor that can promote the occurrence of malignant tumors, and it can directly effect the fragmentation of normal cells and induce the malignant transformation of cancer genes, it can also inhibit the function of cancer gene P53, and promote angiogenesis, occurrence and development of tumors through adjusting the immunological reaction.
[0088] In May 2011, Li Yan who worked in the First Hospital Affiliated of China Medical University made the relevant research on the Impact of resveratrol to MDA-MB-231 cell apoptosis of breast cancer induced by TRAIL. This conclusion indicated that combination application between tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and resveratrol could inhibit the MDA-MB-231 cell proliferation and reduce its apoptosis. In addition, the effects whose resveratrol enhanced the TRAIL to induce the cell apoptosis are achieved by promoting the expression of caspase-8 and caspase-3.
[0089] TRAIL is a cell factor that may induce the apoptosis through combining with relevant receptors to induce the apoptosis in the target cells. It can selectively kill the cancer cells, but no obvious damages to normal tissue.
[0090] In October 2011, Zhang Zhiliu who worked in the Gynecology department of Ancillary Hospital of Qingdao University Medical College made the research on the Resveratrol Inhibiting the Proliferation of Hela Cells and Its Mechanism. This conclusion indicated that the resveratrol has obvious inhibition effects on the vitro growth of cervical cancer Hela cells, and its mechanism may be related to the expression of inhibiting p-e1F4E and p-4E-BP1, inducing the activation of caspase-3 to increase the apoptosis of Hela cells.
[0091] In 2011, Yang Zheng who worked in the Stomatology Department of First Affiliated Hospital in Liaoning Medical College made the research on the Impacts and Its Mechanism of resveratrol to Proliferation and Apoptosis of Human's Oral Squamous Cell Carcinoma KB Cells. This conclusion indicated that resveratrol could inhibit the proliferation of KB cells, retard S phase to induce the apoptosis of cells. At the same time, survivin, caspase-3 and Smac gene involved in the role of resveratrol to induce the apoptosis of KB cells.
[0092] The above contents accord with the opinions of Shih-Hwa Chiou, which are to inhibit the anti-apoptotic protein of cancer stem cells to eliminate the drug resistance and radioresistance of cancer stem cells in order to completely annihilate it.
[0093] (VII) In 2004, Lin Hai who worked in the Jilin University made the research on the Experiment of Anti-tumor Effect of Resveratrol. This conclusion indicates that the resveratrol could decrease the telomerase activity in K562 cells to exert the anti-tumor effects, and take on the dose-response relationship. Lin Hai firstly considered that the resveratrol could affect the telomerase activity in tumor cells.
[0094] In 2004, Jia Xudong who worked in the Nutrition and Food Safety Institution of Chinese Center for Disease Control and Prevention made the research on the Effects of Tea Polyphenols/Tea Pigments to HepG2 Telomerase Activity of Human Hepatoma Cell Line. This conclusion indicates that the tea polyphenols and tea pigments could markedly inhibit the telomerase activity in HepG2 Cells, and the telomerase activity might be a useful biomarker in the cancer chemoprevention study.
[0095] In 2006, ZHENG Guo-hua, who worked in the Fujian University of Traditional Chinese Medicine, research on inhibitory action and its mechanism of garlic oil combined with resveratrol on human gastric cancer cell. This conclusion indicates that the combined medication of garlic oil and resveratrol could not only inhibit the proliferation of gastric cancer cells but also have the synchronizing action. Its mechanism might be associated with the gene expression of reverse transcriptase hTERT, which could inhibit the gastric cancer cells Bcl-2, c-myc and human telomerase.
[0096] In 2008, Zhang Dong-dong who worked in the Basic Medical College of Jiamusi University made the research on the Mechanism of Resveratrol Inhibiting Gastric Cancer BGC823 Cells proliferation. This conclusion indicates that after resveratrol acted on BGC823, with the extension of the time, the telomerase activity should be declined. The results indicates that the cancer cells inhibited by resveratrol drug might be associated with telomerase activity. The results analyzed by experimentation indicates that the resveratrol could inhibit the proliferation effects of human gastric cancer BGC823 cells planted by out of human body, it might be associated with cancer cells that were arrested cell cycle at S phase and activated by telomerase.
[0097] In January 2010, WANG Xiao-yan who worked in Department of Gastroenterology, the Affiliated Hospital of Jiangsu University, explored the effect of resveratrol on promoter and human telomerase reverse transcriptase (hTERT) expression of human colorectal cancer cells. This conclusion indicates that the expression of mRNA and protein of cells treated with resveratrol were down-regulated in dose- and time-dependent manner. Resveratrol may suppress telomerase activity through inhibiting expression of hTERT promoter of colorectal cancer cells.
[0098] In 2010, SHEN Rong, worked in the Affiliated Hospital of Jiangsu University, explored the effect and mechanism of resveratrol on human laryngealcarcinoma cell proliferation. This conclusion indicates that the resveratrol may suppress human laryngeal cancer Hep-2 cell proliferation through inhibiting the telomerase activity and hTERT protein expression.
[0099] In 2008, NIU Ying-cai, who worked in the Institute of Medical Sciences, Qiqihaer Medical College, explored the effect of a low molecular weight polysaccharides isolated from Agaricus Blazei Murill (LMPB) on Telomerase-RNA mRNA expression in Bel-7402 hepatocellular carcinoma (HCC) cells. This conclusion indicates that the low molecular weight polysaccharides from Agaricus Blazei Murill (LMPB) could decrease the expression of telomerase-RNA mRNA, so as to reduce the telomerase activity and inhibit the growth of cancer cells.
[0100] In 2009, LIU found that telomerase activity in the Leukemia K562 Cells was very high. When using PPARs active agent to act on K562 Cells, LIU found that PPARs active agent could activate PPARγ and reduce the telomerase activity in K562 cells. Using PPARs active agent to act on K562 Cells for 72 hours, LIU found that telomerase activity in K562 Cells closed to zero.
[0101] The researchers found that they have a variety of mechanism on inhibiting the cancer generation through research on Resveratrol, PPARs activity agent, Catechin and Agaricus Blazei Polysaccharide. In particular, they had not only transcription effects which could inhibit the Cancer cells hTERT (Telomerase transcriptase) gene, so as to cause hTERT mRNA to descend, but also the combination location of NF κ B and AP-1 on hTERT promoter, and they would not harm the telomerase in the normal stem cells.
[0102] (VIII) In 2007, LUD found that part of PPARγ receptor activity agents could activate PPARγ inhibition β-catenin protein expression, so as to effect β-catenin signal transduction pathways. At the same time, LUD found that PPARγ could cause apoptosis and growth inhibition of CD133 + brain tumor stem cells.
[0103] (IX) In 2011, Su Zhiyun, who worked in the Neurosurgery of Lanzhou General Hospital, Lanzhou Military Region, investigate the effect of resveratrol of glioma cell line U87 and cancer stem cells (CSCs). This conclusion indicates that the resveratrol could induce apoptosis of the malignant glioma cell line U87 and cancer stem cells (CSCs).
[0104] (X) In 2012, Shih-Hwa Chiou who worked in the Medical Research and Education Department of Taipei Veterans General Hospital made the research on the isolation and cultivation technology of cancer stem cells, and treatment platforms of enhancing the radiosensitivity by resveratrol. This conclusion indicates that the polyphenol compound resveratrol could inhibit the self-renewal capacity of cancer stem cells after selecting a variety of substances. The high concentration of resveratrol could also enhance the radiosensitivity through using mice bearing tumor in experiment, so as to enhance 30%-50% of radiotherapy, and one-third of cancer stem cells survival. Mice's survival period could be extended from two months to four months, so mice's survival period has doubled.
[0105] The above contents are the new example for natural ingredients, which can inhibit the cancer/tumor stem cells. The present invention will combine it into a new formula to achieve the anticipated effects.
[0106] The above content is only example. Any spirit and scope that did not separate the intention, which is modified and changed, shall contain in the attached application patent scope.
[0107] The above description should be considered as only the discussion of the preferred embodiments of the present invention. However, a person skilled in the art may make various modifications to the present invention. Those modifications still fall within the spirit and scope defined by the appended claims.
[0108] The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations within the spirit and scope of the invention. | A food recipes for nourishing, maintaining and cultivating a variety of stem cells, each unit of the food recipes includes grape skin/polygonum cuspidatum root extracts; pseudo-ginseng extracts; cooked polygonum multiflorum thunb extracts; salvia miltiorrhiza bunge extracts; blueberry extracts; bitter melon extracts; soybean extracts; ginseng extracts; rhodiola extracts; yam extracts; licorice extracts; kudzu extracts; brown algae extracts; green algae extracts; szechuan lovage rhizome extracts, Green tea extracts; apple extracts; leek seed extracts; wolfberry extracts; marigold extracts; ganoderma lucidum extracts; caterpillar fungus extracts; agaricus blazei extracts; cistanche deserticola extracts; mushroom extracts; beer yeast; flaxseed oil powder; and vitamin. | 2 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
This application relates to games and more particularly to action games in which the players try to avoid a disaster.
2. Background Art
Games which combine some element of chance and skill to avoid, or at least postpone, the occurrence of disastrous events are old in the art. Examples of such games are PICK UP STICKS, TIP IT, and DON'T COOK YOUR GOOSE, the latter two being shown in U.S. Pat. Nos. 3,402,929 and 3,656,746, respectively. There remains, however, a need for such entertaining games.
SUMMARY OF THE INVENTION
The present invention is concerned with providing a game that involves the elements of chance selection, some physical skill and the inevitable occurrence of a disastrous conclusion in an entertaining manner. This and other objects and advantages of the invention are achieved in a game including a plurality of various types of simulated clothing articles, a chance device for determining a number and type of article and a receptacle latched against a bias which will eventually be triggered by the placement of articles within the receptacle. Compatible with the simulated clothing, the receptacle is a simulated, substantially enclosed washing machine, the sides of which are latched against a bias urging them open. Insertion of the simulated clothing articles through an opening in the top of the washing machine urges the bottom down about a base mounted column. Above, but near the bottom of their lower edges, the sides are mounted on the bottom for outward pivotal movement and latched closed adjacent their upper edges by the top, downward movement of the bottom will eventually disengage the latch and the bias will open all of the sides simultaneously and disgorge the simulated chance device, players determine how many of what type of simulated clothing article they must put in the washing machine during a turn. If the player successfully inserts all of the laundry in the machine without it exploding, points are awarded the player. Once the machine does explode the round of play ends and all players other than the one causing the disaster will receive additional points.
BRIEF DESCRIPTION OF THE DRAWINGS
For a better understanding of the present invention reference may be had to the accompanying drawings in which:
FIG. 1 is a perspective view of a game embodying the present invention;
FIG. 2 is an enlarged scale, sectional view taken generally along line 2--2 of FIG. 1;
FIG. 3 is a sectional view like that of FIG. 2, but showing the receptacle with its sides open;
FIG. 4 is a sectional view taken generally along line 4--4 of FIG. 2;
FIG. 5 is a reduced scale perspective view of the inside of one of the sidewalls;
FIG. 6 is an enlarged scale view of the chance device; and
FIG. 7 is a top plan view of a score sheet usable with the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now to the drawings in which like parts are designated by like reference numerals throughout the several views, FIG. 1 shows a game 10 with a pile of simulated articles of clothing 12, such as socks 13, underwear 14, shorts 15, shirts 16, and pants 17. Particularly, since the simulated clothing articles may be made by die cutting them out of a variety of inexpensive materials, such as cloth, thin flexible plastic, or even paper, a large number of such articles may be included with the game. For example, ten of each different type of simulated clothing could be provided for a total of fifty articles. In addition to cost, the choice of material is only limited by the requirements that the articles can be deformed and later returned to an approximation of their original shape. It is not necessary in this invention that the articles have the property of returning to substantially their identical original shape on their own. Moreover, since the articles are to represent simulated clothing about to be washed, it is not detrimental that after a number of uses in which the articles are deformed and then returned to an approximation of their original shape, they become wrinkled. The fact that some of the articles such as the pants 17 are significantly larger than, for example, the socks 13 becomes part of the play of the game.
A receptacle 20 styled to simulate a washing machine is provided for player insertion of the simulated clothing articles. Receptacle 20 includes a substantially flat base 22, with a generally disposed upright post 23 onto which is secured an upright column 24. Received for up and down movement about the column is a square bottom wall 26, which includes an inner, generally, upright sleeve 27 that conforms in shape, but is slightly larger than the outer dimensions of column 24. About its outer peripheral edge, bottom wall 26 has a generally upwardly extending peripheral flange 28. Inside each corner of flange 28 is a mounting block 30 that extends above the flange. Each block has a bore 32 in each of its inwardly facing sides at substantially the same height above the top of flange 28.
As illustrated, washing machine receptacle 20 has four identical sides 34. Near the lower edge of each side, a pair of coaxial stubshafts 36 extend out from the lateral edges. Each stubshaft 36 is journaled in a respective bore 32 in one of the mounting blocks. Accordingly, each side is mounted for up and down movement with bottom wall 26 and also for pivotal movement from a generally upright position through approximately ninety degrees to an outer open position as illustrated in FIG. 3. Substantially at the center of the bottom edge, a hook 38 extends in from the inner face of sidewall 34. A single elastic band 40 is attached to each of the four hooks 38 to bias the bottom of all four of the sides inwardly and urge each of the sides to pivot about their coaxial stubshaft 36 into the open position illustrated in FIG. 3. Intermediate their upper and lower edges, each sidewall 34 has an inwardly directed trapezoidal shelf 42, below which is a bracing member 43.
Atop column 24, a top wall 44 is mounted by means of a generally centrally disposed plug 45. Depending from the periphery of top wall 44 is a skirt 46. Like bottom wall 26, top wall 44 is square and the inner dimension from one side of depending skirt 46 to the other is approximately equal to the inner dimension from one side to the other of upstanding outer flange 28. When bottom wall, carrying sidewalls 34 manually compressed together against the bias of band 40, is moved up and under top 44, the upper edges of each of the sidewalls bear against the inner faces of depending skirt 46. The combination of the frictional engagement between sleeve 28 and column 24, together with the frictional engagement of the abutting portions of the upper parts of each of the sidewalls with depending skirt 46 is sufficient to maintain the bottom wall in its upward raised position spaced from the base, as shown in FIG. 2 and maintain the sides of the receptacle closed. However, insertion of enough of the articles 12 exerting a downward force on shelves 42 will eventually force the bottom wall down toward the base and move sidewalls 34 out of engagement with depending skirt 46, permitting the bias of the band 40 to pivot open the sidewalls 34 and throw or explode out the simulated articles of clothing. Because of the higher position of shelves 42, articles resting upon it are thrown out more vigorously and further than if the articles where stuffed all the way down to the bottom of the receptacle.
Top wall 44 is provided with three openings 50 for insertion of the articles. It is possible, to cause an explosion with less than a full load of simulated clothing articles, if enough of the articles are concentrated within one area to cause sufficient downward movement of bottom wall 26. Accordingly, since receptacle 20 is substantially enclosed except for the three openings 50, players have to pay attention to what openings the opposing players have used for the insertion of their articles. To insure that a player has properly inserted the articles all the way into the receptacle 20, a lid 52 is provided. The lid fits flush with the upper surface of top wall 44. Hinges 54 along one edge provide for opening and closing of the lid and a latch 56 is provided at the edge opposite the hinges.
In order to determine what articles of clothing a player must put into receptacle 20 during a turn, a spinner 60 is provided. As illustrated in FIG. 1, the spinner may be mounted on one wall of the receptacle. Each article of clothing is depicted in a radial division of the spinner plate 62 and further radial subdivisions indicate a number "1", "2" and "3" for each type of article. In addition, there is a radial division reading "NO LAUNDRY TODAY--ADD 2 POUNDS" and another radial portion reading "HEAVY LOAD--ADD 1 PIECE--SPIN AGAIN". Mounted for rotation on plate 62 is a pointer 63. A score card 65, as illustrated in FIG. 7, is provided for playing a number of rounds, each round being designated by a day of the week.
After designating an order of play, one player is conveniently appointed as the scorekeeper. At the onset, the washing machine receptacle is set by manually compressing the sides 34 against the bias of the band 40 and moving the sides and bottom up to the top, until the upper edges of the sides engage the insides of peripheral skirt 46. Play begins with the starting player's use of the spinner. If the pointer stops in one of the simulated clothing divisions, the player then lifts the lid of the washing machine and inserts the designated number of the type of article into an opening 50 of the player3 s choice. Of course, a larger size article such as pants 17 is more likely to trip the release of sidewalls 34, particularly as washing machine 20 becomes full. Provided the washing machine does not explode, the player receives one point for each article added. Should the pointer stop in the "NO LAUNDRY TODAY" division, the player receives two free points and passes the spinner. When the pointer lands in the "HEAVY LOAD" division, the player must insert one article of the player's own choice into the receptacle and then spin again. Once a particular type of article is used up, if the pointer lands in the division of that type, the player gets the number of points indicated as if the player had successfully inserted the number of articles. At the end of every turn a player completes without the washing machine exploding, the score keeper adds the points to the player's score. However, when a player, while putting articles into one of the openings, or closing of the lid, causes the washing machine to explode, the round of play ends and every other player receives five points. At the end of five rounds or "days" of doing dirty laundry, the player with the highest point total wins the game.
While a particular embodiment of the present invention has been shown and described, it will be apparent to those skilled in the art that changes and modifications may be made. It is intended in the appended claims to cover all such changes and modifications as fall within the true spirit and scope of the present invention. | A game involving the insertion of simulated articles of dirty clothing into a washing machine receptacle, the sides of which are biased to explode open. The number and type of articles to be inserted during a turn is determined by a spinner. Insertion of the articles through an opening in the top wall of an otherwise substantially enclosed receptacle, eventually effects downward movement of the bottom to which the sidewalls are pivotably mounted. Once the bottom and sidewalls move down enough to disengage the upper edges of the sidewalls, the sides of the washing machine receptacle spring outwardly, spewing out the laundry. | 0 |
BACKGROUND OF THE INVENTION
[0001] The present invention generally relates to an automatic safe disposable blood sampling device for medical use, more particularly, to a casing self-locking type of automatic safe blood sampling device, in which a press button of which is locked by engagement thereof with the casing of the blood sampling device after a lancet needle of the blood sampling device is launched so that the blood sample device is brought into a self-locking state and can not be reused.
[0002] Various types of medical blood sampling device are known, there is a tendency to develop a “mini” type automatic blood sampling device which is safe and disposable once the lancet needle is launched. In order to make it disposable, this kind of blood sampling device is provided with a disposable self-locking mechanism which achieves self-locking effect immediately after a lancet needle of the blood sampling device is launched, thus causing the catch-launching mechanism failure. Therefore, the potential safety hazards involved in the previous blood sampling device are thoroughly eliminated.
[0003] Presently, there are two types of self-locking mechanism. The first type of self-locking mechanism employs a structure in which the lancet needle is engaged with a casing, that is, the lancet needle and the casing each are provided with a special structure, the engagement of the lancet needle with the casing achieves a self-locking effect after the lancet needle of the blood sampling device is launched. For example, the Chinese Utility Model No. CN2486104Y filed on Jul. 30, 2001 and granted to the applicant of the present application on Apr. 17, 2002 discloses an automatic safe disposable blood sampling device having a new type catch-launching mechanism, in the blood sampling device of the above Chinese Utility Model No. CN2486104Y, an elastic arm C is slantwise provided on the lancet needle and a stopping notch is provided in the casing of the blood sampling device. After the lancet needle of blood sampling device is launched, the elastic arm C is retracted together with the lancet needle so as to fall into the stopping notch to be self-locked therewith.
[0004] The second type of self-locking mechanism is a lancet needle self-locking structure, that is, the self-locking mechanism is completely provided on the lancet needle, and achieves a self-locking effect after the lancet needle of the blood sampling device is launched. For example, the Chinese Patent Application No. 200420025752.5 filed on Mar. 25, 2004 by the same applicant as that of the present application discloses an automatic safe disposable blood sampling device of lancet needle self-locking type. In the blood sampling device, and an elastic arm is provided on a side portion of the lancet needle. A self-locking hook is provided on an end of the elastic arm, and the elastic arm is inwardly bent upon application of an external force when the lancet needle of the blood sampling device is launched by pressing. Consequently, and the end is forced across the hook so as to be caught by the self-locking hook, thus achieving the self-locking effect. The above two types of self-locking mechanisms have disadvantageous in their structures, features and effects respectively.
BRIEF SUMMARY OF THE INVENTION
[0005] An object of the present invention is to provide a novel casing self-locking type of automatic safe blood sampling device based on “one-off launching and not reusable” principle, in the casing self-locking type of automatic safe blood sampling device of the present invention, a self-locking mechanism is completely formed by structures on a casing. This self-locking mechanism is of the third type, that is, the casing self-locking type.
[0006] In order to achieve the above object, there is provided a casing self-locking type of automatic safe blood sampling device, comprising: a casing formed with a launching chamber therein, the launching chamber being provided with a lancet needle-exiting hole at a front end thereof; a lancet needle arranged inside the launching chamber; a spring; a launching mechanism composed of the spring and a catch-launching mechanism; a press-launching mechanism provided on the casing; and a self-locking mechanism composed of barbs provided on the press-launching mechanism and self-locking hooks or self-locking notches provided on the casing corresponding to the barbs, the self-locking hooks or self-locking notches being located on paths along which the barbs are advanced, respectively.
[0007] The related contents and variations of the above technical scheme are explained as follows:
1. In the above technical scheme, the self-locking mechanism has two types, i.e. the side-pressing type and the end-pressing type. 2. With regard to the side-pressing type of self-locking mechanism, the press-launching mechanism is embodied as an press button for launching provided on a side of the blood sampling device, the press button is mounted on a side of a casing or formed by a first elastic arm extended integrally from the side of the casing, barbs are provided on the press button, and self-locking hooks or self-locking notches are provided on the casing corresponding to the barbs. 3. With regard to the end-pressing type of self-locking mechanism, the press-launching mechanism is embodied as a sliding sleeve provided at an end of the blood sampling device, the sliding sleeve as a part of the casing of the blood sampling device is slideably connected to another part of the casing, barbs are provided on the sliding sleeve, and self-locking hooks or self-locking notches are provided on provided on the another part of the casing corresponding to the barbs respectively.
[0011] The operation of the blood sampling device according to the present invention is described as follows.
[0012] When being pressed, the press-launching mechanism triggers the catch-launching mechanism, so that the lancet needle is disengaged from the casing, the spring pushes the lancet needle so as to launch the lancet needle. As the same time, because of movement of the press-launching mechanism, the barbs pass across the self-locking hooks or self-locking notches during the forward movement thereof. Therefore, during retraction, the barbs are locked with the self-locking hooks or self-locking notches and thereby can not return to their primed states, thereby the catch-launching mechanism is caused to be failure and can not be reused.
[0013] By comparison to the prior art, the blood sampling device has the following advantages.
1. The self-locking mechanism of the blood sampling device according to the present invention is novel, the self-locking function is achieved by changing structure of the casing, so that the blood sampling device is simple in structure and can be operated reliably. 2. The operation of the self-locking mechanism is performed in the following orders: the self-locking mechanism firstly enters into its self-locking state, and then enters into launching state. However, the conventional self-locking mechanism using engagement of the lancet needle with the casing is firstly launched, and then enters into its self-locking state. Therefore, the blood sampling device according to the present invention can reflect the design philosophy of one-off launching and not reusable”. 3. In comparison to the conventional self-locking mechanism, the self-locking mechanism of the present invention is novel, simple in structure. 4. The blood sampling device according to the present invention is easy to use and simple to operate. 5. After use, the lancet needle is retracted into the casing automatically and will be not exposed to outside, thus ensuring safety of the used blood sampling device.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1 is a structural sectional view of the blood sampling device according to the first embodiment of the present invention, showing an assembled state before use;
[0020] FIG. 2 is a structural sectional view of the blood sampling device according to the first embodiment of the present invention, showing that the lancet needle is pushed into a self-locked state;
[0021] FIG. 3 is a structural sectional view of the blood sampling device according to the first embodiment of the present invention, showing that the blood sampling device is in a state to be launched with a lancet needle cap being removed;
[0022] FIG. 4 is a structural sectional view of the blood sampling device according to the first embodiment of the present invention, showing that the blood sampling device is in a launching state;
[0023] FIG. 5 is a structural sectional view of the blood sampling device according to the first embodiment of the present invention, showing a state after use;
[0024] FIG. 6 is a partial sectional view of a self-locking mechanism of the blood sampling device according to the first embodiment of the present invention, showing a state before the lancet needle is locked;
[0025] FIG. 7 is a sectional view taken along line B-B in FIG. 6 ;
[0026] FIG. 8 is a partial sectional view of a self-locking mechanism of the blood sampling device according to the first embodiment of the present invention, showing that the blood sampling device is in a state to be launched;
[0027] FIG. 9 is a sectional view taken along line A-A in FIG. 8 ; and
[0028] FIG. 10 is a structural schematic view of the blood sampling device according to the second embodiment of the present invention.
[0029] In the above drawings, the reference numerals denote the following members respectively: 1 : case; 2 : lancet needle; 2 - 1 : first locking section; 2 - 2 : second locking section; 3 : spring; 4 : launching chamber; 5 : lancet needle-exiting hole; 6 : elongated lancet needle cap; 7 : boss; 8 : lancet needle tip; 9 : catching plate; 10 : catching groove; 11 : protruding ring; 12 : second elastic arm; 13 : first elastic arm; 13 - 1 : intermediate section of the first elastic arm; 13 - 2 : extension section of the first elastic arm; 13 - 3 : leg; 14 : blocking notch; 15 : barb; 16 : self-locking hook; 17 : sliding sleeve; 18 : bevel; 19 : elastic catching member; 20 : outer sleeve.
DETAILED DESCRIPTION OF THE INVENTION
[0030] Embodiments of the present invention will be described in detail with reference to the accompanying drawings.
The First Embodiment
[0031] As shown in FIG. 1 to FIG. 5 , there is illustrated a side-pressing and casing self-locking type of automatic safe disposable blood sampling device, comprising a casing 1 , a lancet needle 2 , an elongated lancet needle cap 6 and a spring 3 .
[0032] The casing 1 comprises an upper part and a lower part which are connected into an integral structure by using holes and pins provided on contacting surfaces thereof respectively. A launching chamber 4 is formed inside the casing 1 , and the lancet needle 2 and the spring 3 are arranged in the launching chamber 4 . The spring 3 is located behind the lancet needle 2 wherein the head of the spring 3 is caught in a catching groove 10 , and the tail of the spring 3 is caught on the catching plate 9 , thus forming an elastic sliding structure in a launching direction. A lancet needle-exiting hole 5 is provided at one end of the casing 1 in a direction consistent with the launching chamber direction. A cylindrical boss 7 is provided at the head of the lancet needle 2 , and a lancet needle tip 8 is extended centrally out of the boss 7 . Further, a protruding ring 11 is provided circumferentially on the boss 7 . An elongated lancet needle cap 6 has a rod structure and is provided with a deep hole in a front portion thereof and a tail wing at a rear end thereof. The front portion of the elongated lancet needle cap 6 passes through the lancet needle-exiting hole 5 so as to fit over the boss 7 , and the elongated lancet needle cap 6 can be prevented from retracting accidentally from the boss 7 through engagement of the protruding ring 11 with the deep hole.
[0033] A catch-launching mechanism and a self-locking mechanism are provided between the lancet needle 2 and a side of the casing 1 along a compression path of the spring 3 .
[0034] As shown FIGS. 6 to 9 , the catch-launching mechanism comprises a second elastic arm 12 extended from a side of the casing 1 , a first elastic arm 13 extended from another side of the casing 1 , and a blocking notch 14 provided in the lancet needle 2 . The second elastic arm 12 and the blocking notch 14 are located at a bottom side of the casing 1 in FIGS. 1 to 5 , and the second elastic arm 12 is inclined towards to the inside of the launching chamber 4 . A cantilever end of the second elastic arm 12 is engaged with the blocking notch 14 so as to form a locking structure. The first elastic arm 13 serving as an press button is located at an upper side of the casing 1 in FIG. 1 , and an intermediate section 13 - 1 of the first elastic arm 13 serving as a pressing portion is protruded from the upper side of the casing 1 in FIG. 1 . An extension section 13 - 2 of the first elastic arm 13 has an inversed U-shape, and the lancet needle 12 is located between two legs 13 - 3 of the inversed U-shape extension section 13 - 2 while two legs 13 - 3 extend into holes provided on the casing 1 and pass across the launching chamber 4 respectively. Distal ends of the two legs 13 - 3 contact or are close to the cantilever end of the second elastic arm 12 .
[0035] The self-locking mechanism comprises barbs 15 provided respectively on two outer sides of the inversed U-shape extension section 13 - 2 , and self-locking hooks 16 provided at positions corresponding to the barbs 15 on the inner wall of the casing 1 . The self-locking hooks 16 are located on paths along which the barbs 15 are advanced. In order to protect the self-locking mechanism in a state in which the lancet needle 2 of the blood sampling device is not launched, the lancet needle 2 is provided with a first locking section 2 - 1 and a second locking section 2 - 2 . Prior to be locked, the position of the second locking section 2 - 2 corresponds to that of the inversed U-shape extension section 13 - 2 as shown in FIG. 1 , and the bottom side of the second locking section 2 - 2 has the same inclination and inclined direction as that of the second elastic arm 12 . The cross section of the second locking section 2 - 2 has substantially the same width from top to bottom, and widths of gaps formed between the two sides of the second locking section 2 - 2 and the inner walls of the casing 1 are smaller than that of the two legs 13 - 3 of the inversed U-shape extension section 13 - 2 . Therefore, at this time, the inversed U-shape extension section 13 - 2 of the first elastic arm 13 can not move downwards. As a result, the barbs 15 on the inversed U-shape extension section 13 - 2 can not engage with the self-locking hooks 16 on the casing 1 so as to lock with each other respectively, as shown in FIG. 7 . When the lancet needle 2 is pushed towards to the rear side (right side in FIG. 1 ) of the casing 1 , the first locking section 2 - 1 of the lancet needle 2 is moved rearwards so that the position of the first locking section 2 - 1 is brought to gradually come close to the position of the inversed U-shape extension section 13 - 2 of the first elastic arm 13 . The width of the cross-section of the first locking section 2 - 1 is decreased gradually from top to bottom, and the widths of gaps formed between two sides of the first locking section 2 - 1 and the inner walls of the casing 1 are equal to or larger than that of the two legs 13 - 3 of the inversed U-shape extension section 13 - 2 respectively. Therefore, the inversed U-shape extension section 13 - 2 can be moved downwards so that the barbs 15 can be moved downwards along with the inversed U-shape extension section 13 - 2 so as to be engaged and locked with the self-locking hooks 16 on the casing 1 . Before the cantilever end of the second elastic arm 12 is caught by the blocking notch, since the second locking section 2 - 2 has a larger width in the transverse direction of the cross-section thereof (the cross-section of the second locking section 2 - 2 has a rectangle shape in the embodiment, as shown in FIG. 7 ), the inversed U-shape extension section 13 - 2 of the first elastic arm 13 can not pass through the gaps formed between the inversed U-shape extension section 13 - 2 and inner walls of the casing 1 even if pressing the inversed U-shape extension section 13 - 2 , thus achieving the self-locking mechanism. The lancet needle 2 is brought into a locking state by pushing the elongated lancet needle cap 6 , at this time, the first locking section 2 - 1 of the lancet needle 2 corresponds to the inversed U-shape extension section 13 - 2 , since the transverse width of the cross-section of the first locking section 2 - 1 is decreased from top to bottom (the cross-section of the first locking section 2 - 1 has a tapered shape in this embodiment, as shown in FIG. 9 ), the widths of the gaps increase, so that two legs 13 - 3 of the inversed U-shape extension section 13 - 2 of the first elastic arm 13 can be inserted into the gaps formed between the inversed U-shape extension section 13 - 2 and inner walls of the casing 1 by pressing the inversed U-shape extension section 13 - 2 , contact with and act on the cantilever end of the second elastic arm 12 at last, thus causing the cantilever end of the second elastic arm 12 to disengage from the blocking notch 14 .
The Second Embodiment
[0036] As shown in FIG. 10 , there is illustrated an end-pressing and casing self-locking type of automatic safe disposable blood sampling device, comprising a casing, a lancet needle 2 , an elongated lancet needle cap 6 and a spring 3 . The casing comprises a sliding sleeve 17 and an outer sleeve 20 , and an elastic catching member 19 is provided at a side of the lancet needle 2 . When the elongated lancet needle cap 6 is pushed, the lancet needle 2 presses the spring 3 . While the elastic catching member 19 is caught at an end of the sliding sleeve 17 , thus achieving locking. The self-locking mechanism comprises a barb 15 and a self-locking hook 16 , and the barb 15 is provided on the sliding sleeve 17 while the self-locking hook 16 is provided on the outer sleeve 20 .
[0037] In operation, the elongated lancet needle cap 6 is first pulled out, then the outer sleeve 20 is held by hand of a user. Thereafter, the lancet needle-exiting hole in the casing is directed at a region of a human body to be blood-sampled and the blood sampling device is pressed. At the same time, the sliding sleeve 17 is moved by an external force towards a closed end (right end in FIG. 10 ) of the outer sleeve 20 (rightward in the FIG. 10 ) inside an inner chamber formed inside the outer sleeve 20 . The bevel 18 forces the elastic catching member 19 to disengage from the sliding sleeve 17 , and the spring 3 pushes the lancet needle 2 along a guide groove (not shown) to launch the lancet needle 2 . Then a lancet needle tip of the lancet needle 2 is ejected out of the lancet needle-exiting hole so as to puncture the region of a human body to be blood-sampled. At the same time, since the sliding sleeve 17 is slid towards the closed end of the outer sleeve 20 inside inner chamber of the outer sleeve 20 , the barb 15 is engaged and locked with the self-locking hook 16 . Therefore, the sliding sleeve 17 can not further slide inside the inner chamber of the outer sleeve 20 , thus causing the blood sampling device to fail.
[0038] While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those ordinary skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt to a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto. | An automatic safe disposable blood sampling device includes a casing with a launching chamber formed therein. The launching chamber has a lancet needle-exiting hole at a front end thereof; a lancet needle arranged inside the launching chamber; a spring; a launching mechanism composed of the spring and a catch-launching mechanism; a press-launching mechanism provided on the casing; and a self-locking mechanism composed of barbs provided on the press-launching mechanism and self-locking hooks or notches provided on the casing which engage corresponding barbs. When pressed, the press-launching mechanism triggers the catch-launching mechanism, to disengage the lancet needle from the casing. The spring pushes the lancet needle so as to launch the lancet needle. During forward movement of the press-launching mechanism, the barbs pass across the self-locking hooks or notches. In the process of retraction, the barbs are locked with the self-locking hooks or notches and cannot return to their initial states. | 0 |
BACKGROUND OF THE INVENTION
This is a division of application Ser. No. 598,484, filed July 23, 1975, now U.S. Pat. No. 4,027,058.
The present invention relates generally to a method for forming and shaping metal, plastic, paper, fiberboard, paperboard, or the like, sheets or webs in the assembly and construction of a novel product, consisting of or comprising an expanded triangularly celled structure useful per se as a packing material or, when combined with one or more face sheets, useful in the makeup of packages and containers for enclosing articles of commerce, or useful as rigid structural panels in the assembly of various structures, or in the construction of buildings or manufacture of vehicles or parts thereof.
At present, one generally accepted method of joining flat webs of, e.g., paperboard or fiberboard material, to produce a panel product having a thickness dimension greater than that of the material employed in its makeup, is the assembly of so-called corrugated board stock fabricated, for example, from coarse fiber kraft material referred to in the trade as liner board, and a center medium material. This known product comprises a laminate of two outer liner sheets bounding a fluted center medium member which is corrugated by passage through meshing or gear-like cylinders with subsequent "take-up" of some 50% of the length of the medium in the formation of convolutions therein. Adhesive is applied to the apex of each convolution of the center medium to attach the planar outer sheets thereto thus producing a panel configuration. This known product exhibits rigidity in a direction parallel to the corrugations or convolutions and is generally weak in a direction at right angles to these convolutions.
There is a broad similarity between the present invention and the production of such corrugated board stock in that the present invention also contemplates that two outer liner sheets can be attached to opposite sides of a center medium sheet after the center sheet has passed between forming cylinders. In the present invention, however, the center medium is not corrugated and, instead, is shaped by special forming cylinders to define an array of triangular, alternately displaced forms, the planes of the triangles serving to provide areas for adhesive attachment of the center medium to the outer liner sheets, and the sides of each triangle being folded generally perpendicular to the planes of the liner sheets, thus providing a displacement, or spacing, between the alternate triangular forms so that their planes alternately face opposite sides of the center medium.
Like corrugated media, the preparation of the center medium employed in the present invention is accomplished by use of gear-like forming cylinders but the cylinder peripheries are provided with dual-opposed helical tooth arrangements each of which is broken into a series of triangular elements engaging complementarily shaped recesses in the opposite cylinder. Unlike the known corrugating procedure, the method and apparatus of the present effects intermittent cutting of the web being formed in a plurality of parallel lines oriented longitudinal to the web direction. The cuts are displaced from line to line, thus permitting folding of the triangular sides of each element without lateral take-up in the web. The take-up entirely in the longitudinal direction of web extension or travel.
A second known method for joining flat sheets employs a cellular configuration between sheets fabricated by a variety of procedures to form so-called "honeycomb" shapes, the side planes of which are perpendicular to said sheets. The "honeycomb" edges are attached to the boundary sheets by bonding means. The product of the present invention is also broadly similar to honeycomb in that the triangular side fold of each element or cell provides ribs which are generally perpendicular to the outer sheet, panel or web, to form cellular enclosures. However, unlike honeycomb, the base line of each triangular form in the present invention is cut, to relieve the web laterally and to provide one open side, thus permitting the passage of gas or fluid through and between these cellular members throughout the structure. Moreover, unlike honeycomb, the forming apparatus and process of the present invention permits high speed forming and assembly of the novel product of the present invention in virtually all materials, employing bonding or mechanical means for connection of the formed center medium to one or more outer boundary sheets.
The principal industrial advantage of the present invention lies in the simplicity of the process with which the product is achieved. A combination of web handling apparatus may be employed, for example, in which three webs pass from unwind rolls through draw rolls or delivery apparatus with one web passing through the nip of a pair of forming cylinders having the dual opposed helical-triangular forms described earlier, operative to cut and fold the web constituting the center member of the final product, followed by passage of the formed web to adhesive applicators which apply adhesive to the flat triangular planes formed on each side of the formed mechanism, followed by laminating steps introducing two planar outer webs to opposite sides of the center member with required heating or cooling to bond or set the adhesive agent used.
The novel forming cylinders used in the present invention can be mounted in existing corrugated machinery in place of the conventional corrugating cylinders customarily used in such machinery. Operational speeds of the resulting equipment are better than those of existing corrugating equipment however, because of the larger areas afforded for connecting of the outer liner sheets to the center medium. Moreover, unlike conventional corrugating apparatus, the forming cylinders of the present invention permit repair without need for replacement of an entire cylinder or even demounting the cylinder for this purpose.
It has been found that the cutting and folding procedures employed in the present invention exhibit substantial improvements over techniques utilized heretofore in conjunction with distensible materials that are formed by application of heat and/or pressure. Such distensible materials lend themselves to embossing, vacuum forming, and other procedures involved in the cutting of a web, e.g. like those described in Koski U.S. Pat. No. 3,703,432 issued Nov. 21, 1972, where embossing and cutting wheels or cylinders are utilized which depend upon the utilization of heat, and which effect a change of gauge in the material since the formed shape is created by drawing material from the adjoining areas.
In the production of the formed panel of the present invention, the gauge of the material is maintained substantially constant since the material is merely folded, and since the folds are accommodated in such a way that a uniform take-up occurs only in the longitudinal direction of the web. To achieve such folding, a triangular form must be employed in which the sides extend along straight lines. Similarly, the several triangular forms must be identical and must dispose base lines oppositely and alternately to gather the web uniformly across the web width. In addition, the cutting and folding procedures employed in the present invention minimize the space or intervals between the base line cuts. The space between adjacent cuts should be approximately one-twelfth the length of a given cut and preferably never more than 15% or less than 5% of said length. The radius of the nose or apex of the triangular form in the plane, as well as in the perpendicular relationship, must have a diameter equivalent to this spacing. With such proportioning, the hazard of puncturing the web or causing it to distort objectionably is substantially reduced. The end result is quite different from that effected in the aforementioned Koski patent since the triangular form contemplated therein is not self-accommodating, and folding of the Koski triangular form, even with the cut relief in the sheet, is not possible without deforming, distending or stretching the material. In the present invention, the cuts employed open the sheet and make possible the gathering of the material by the accommodation of the folding in alternating planes so that the thickness of the combination thus achieved is a function of the shared fold dimension of each triangle side.
The base line cuts in the present invention can be other than a straight line without disturbing the folding characteristics of the folded side of the triangular shape, or its formation. A curved cut, or one of "u" shape can, if desired, be employed, e.g., as an auxiliary means for connecting cover sheets or webs to the folded center panel.
It is accordingly an object of this invention to produce a board or panel having a central medium of novel configuration exhibiting isotropic rigidity and strength, with respect to its plane.
It is a further object to provide such a novel medium or panel having a configuration adapted to receive additions of reinforcement within the openings of the medium for the purpose of enhancing column strength and improving the flat crush properties of the medium.
It is also an object to provide a novel panel having a center medium which is reinforced by discs or washers enclosed within the confines of the dual triangular cells of the novel medium, to improve column strength and the flat crush properties of the overall panel.
It is also an object of this invention to provide an apparatus and process capable of achieving high speed production of board or panels of novel configuration fabricated from any of a variety of materials and in any of various different gauges, all by employing generally the same machine configuration.
It is a further object to apply the process of the present invention in conjunction with known spiral winding techniques, in the production of individual packaging forms such as tubs, buckets, barrels and rectangular and square configurations fabricated of a novel medium.
Another object of this invention is the provision of a technique which, through the introduction of process variations achieves a variation in the triangular cell form size of the novel medium with respect to lateral web direction, to provide web crescents or arc forms adaptable to the making of tapered tubs, buckets, cups and other nested configurations.
It is another object to provide a novel forming apparatus capable of axial adjustment in a longitudinal direction of one or both cylinders employed in the invention, so that the triangular base line of each tooth component engages its adjoining member in controlled shear relationship to that member. A related object is to provide an apparatus wherein the shear adjustment is openable to provide for displacement of material rather than cutting thereof when a web of flexible plastic material is being formed, thereby to cause the material to flow under pressure so as to provide a membrane, or a closed cell form in the formed medium.
It is a further object of this invention to employ various side fold dimensions of the triangular components of the formed center member so a variation is spacing between panels and a variety of widths or gauges can be achieved without changing the center spacing of the triangular forms utilized.
It is another object of this invention to provide added strength in the combination by reducing the number of triangular components per unit area in said center panel, or, conversely, to increase the gauge substantially by enlarging the size and decreasing the number of triangular components provided per unit area.
A further object of this invention is to provide an apparatus that simultaneously cuts and folds a component in the plane of the web as it passes between two forming cylinders, thus permitting a gathering or take-up of the web in its longitudinal direction, while providing relief in the lateral direction, thus accomplishing diagonal and generally perpendicular folds which are alternately placed in relation to the direction of web travel.
It is another object of this invention to control the interval or spacing between longitudinal cuts in the novel medium, to permit expansion of the sheet by a folding of the triangular forms produced without tearing or overtly distorting the uncut areas of the sheet. A further object is to use contoured surfaces on the periphery of forming cylinders which are arranged to cut and fold a web in novel fashion thereby to produce lateral variations in gauge in a given web as it passes through the forming cylinders.
It is a further object of this invention to produce a novel product that lends itself to connection by overlapping and the telescoping of triangular forms within one another to produce a seam in a cylindrical product fabricated from the formed medium of the present invention.
It is a further object to be able to produce a cylindrical product, fabricated from the formed medium of the present invention, which will wind on a 45° mandrel, as in spiral winding, or which will wind, as is normal, in line with the longitudinal direction of web travel.
It is a further object of this invention to provide a novel process and product wherein a web is provided with parallel cuts longitudinally of the web, and wherein the web material is folded along the cuts while alternating the fold direction, to produce a series of angular truss-like forms in which the longitudinal apexes of the resultant forms connect the formed members to the planes of one or more outer panels associated therewith.
SUMMARY OF THE INVENTION
The objects of the present invention are achieved by converting three or more flat fiber, metal or plastic sheets or webs into a combination panel, the panel having a flat, tapered or contoured gauge and a dimensional thickness generally greater than the combined thicknesses of the sheets employed. The panel is formed by the cutting and folding of a center sheet member into triangular adjoining shapes, alternately disposed in parallel rows, each of which is cut open along its base line while leaving a short connecting portion of the center sheet to sustain the continuity of the web, followed by laminating steps in which a pair of planar outer sheets are affixed to opposite sides of the formed center sheet.
The fold, or change from the plane position, in each triangular formation of the center panel has generally perpendicular sides, but tends to slope in keeping with the draft characteristics of the triangular tooth components of a pair of forming cylinders that cooperate with one another to produce this shape. In the preferred form of the invention, the sides of the triangle formations are shared to effectively produce 45° alignment with respect to web direction. The bases of each triangular formation align in a plurality of rows extending longitudinal to the direction of the web. The base line cuts along this line set boundaries with respect to triangle height. The pattern of the triangular formations provides alternate planes which are in parallel relationship to one another, but displaced on opposite sides of the median line of the center sheet member so these alternate planes face in opposite directions to establish the gauge perimeters of the final panel. The arrangement of the triangular side angles can be varied to form equilateral or isosceles triangles with bases of consequent varied length and resulting variation in the angle of side alignment disposed across the web.
The formed center sheet member is combined with two outer sheets by the utilization of bonding means and laminating techniques common to the art. An additional cylinder, having a surface configuration like the pair of cylinders used to form the center member, can be engaged with the previously formed center member at one side of the center member to provide back-up for the application of a first planar outer panel so that full pressure can be applied during this first lamination step. At a following station, the combined center medium and first outer panel can be introduced to the second outer panel by passage between two plain cylinders under minimum pressure. Unlike corrugated materials, the compression strength exhibited in the formed center sheet permits, under most circumstances, a laminating function in which the two outer sheets are joined to the center member simultaneously without need for internal support.
Unlike corrugated materials, the product of the present invention can be varied substantially by a change in the tooth configurations of the cylinders employed to form the center member. The gauge of the first panel, as noted earlier, is a function of the tooth engagement, or the triangular elements telescoping into one another, at the nip of the forming cylinders. If the side slope taper of the teeth is continued so that the tooth height is increased, the panel gauge is increased proportionately. However it is important to note that there is no change in the longitudinal take-up of the web with such an increase in tooth height. The material taken from the web to produce the thickness of the formed center medium is taken from the plateau of plane area of each triangle, and this area can actually be diminished to a point, thus forming the shape of a half-pyramid, if carried to the extreme. The fact that longitudinal web take-up is unchanged by this variation in thickness of the center medium makes possible the production of a product which is contoured or tapered in the lateral direction. This can be done by varying the height of the triangular components on a profile line parallel to the axis of the forming cylinder. In similar fashion a panel of tapered configuration or form can be achieved by variation in the triangle height, as well as the cylinder engagement, along the same profile line.
The forming apparatus used in the present invention comprises two forming cylinders of special design and shape that differ from prior art structures. These forming cylinders comprise surface areas studded with discrete trangular shapes disposed around the cylinder periphery in a dual-opposed helical tooth array, dimensionally arranged so each element engages another in a fashion analogous to gear teeth. A portion of each triangular element, more particularly its base line, is placed on one cylinder to engage the inverted identical portion of a form on the opposite cylinder so that shear occurs when these two portions engage. As a result, as a web or sheet passes through the nip or engagement of the forming cylinders, a series of intermittent longitudinal cuts are formed in the webs as each triangular element engages its mating element in the opposing cylinder. These longitudinal openings in the web are on parallel lines that relieve the material laterally while permitting formation of an angular fold with alternating opposite angles, thereby to form the two sides of each triangular formation in the web. The triangular pattern produced in the web defines a generally square grid configuration, disposed with sides angularly aligned, forming bisecting ribs generally perpendicular to the plane of the outer sheets.
The specific apparatus form of the cylinders can be produced in a variety of ways. Each discrete triangular die element may be made as an individual component and anchored in suitable openings on the face of a plane cylinder. A second practical system for the production of such cylinders is to investment cast steel segments or saddles which are mounted on the cylinder periphery in adjoining relation to one another.
A third technique is to utilize bar elements, produced from extremely hard materials such as tool steel, which are mounted on the cylinder periphery by use of appropriate pins and/or fasteners. Unlike the discrete tooth component mounting procedures or those associated with the segment technique, mentioned above, this third procedure provides a reasonably sized member which serves better for replacement resulting from breakage or use damage. This latter form also lends itself to forging procedures, and machining steps can be minimized prior to cylinder mounting and the subsequent grinding stage of manufacture.
Beyond the specific apparatus variations in the production of triangular forms, and the mounting of such dies on the periphery of the cylinder, there is the possibility, described earlier, of variation in the triangular dimensions to alter the configuration and/or dimensions of the product being produced. Each triangular tooth form can be shallow or deep depending upon the desired gauge of the product. An increase in gauge, however, diminishes the planar areas, available on opposite sides of the center member, for attachment to the outer sheet members and weakens the product formed if the panel gauge is increased to excess. For example, with 3/8 inch circumferential spacing of triangular forms, the optimum panel gauge ranges from one-eighth of an inch to three-eights of an inch. If greater flat crush and column strength is desired, the center spacing can be halved or quartered and the triangular forms reduced in size. For larger forms and heavier gauges, the center distances can be increased, thereby providing for a proportional increase in the gauge of the combination.
Another variation provides a different product form. In this procedure, the two die cylinders employed are conical or tapered in form but identical in die arrangement to one another, and the two tapered cylinders are mounted for rotation on angularly placed axial shafts so that their engagement or nip provides a common line of connection. The discrete triangular die forms or shapes on the cylinder peripheries vary in size with respect to each increment of diameter so that the same number of elements are provided in each circumferential grouping or ring. In this way, the gauge of the web generated is the same across the cylinder width. Take-up, or gathering effect longitudinally, is a function of the size of the triangular form area and is independent of tooth height. The resulting product takes the form of an arc and curves to a point of overlap and terminus with respect to a given cylinder diameter and taper. Thus, each such form will require individual cylindrical shapes suited to achieve a given dimension. The purpose of such an apparatus is to produce cups, tubs, buckets, or barrels suitable for nesting. The medium sheet produced with this procedure must, of necessity, have connection to at least one outer element to effectively provide the required enclosure of the cellular form. Such buckets or tubs will require a disc form for bottoms and a folding procedure to form edges.
In all of the foregoing description, it has been contemplated that three sheets or webs are used in the formation of a panel. It will be understood by those skilled in the art, however, that the single medium configuration, i.e., the formed "center" member per se, has utilization as a packing material, or can be applied in a variety of applications to satisfy various product requirements. It will also be understood that the medium sheet formed with the triangular-cellular shapes can be bonded to only a single flat outer sheet for use in product areas where so-called "single face" corrugated is presently employed. Where situations demand spiral winding, such winding procedures dictate mandrel winding of a plain sheet followed by application of the single face form for production of tubes or larger barrel configurations.
Beyond the variations set forth in process and apparatus to vary product form, an additional configuration having extreme column and flat crush strength can be achieved by the addition of a reinforcing component within the cell openings of the formed center member. In this embodiment of the invention, a secondary feeder apparatus is provided which functions, immediately after the formation of the triangular web configuration, to introduce discs, rings, or washers equivalent in thickness to the inner gauge dimension of the formed web, through the upward facing opening at one side of the sheet so that these added components are forced into the space provided by the triangular forms that, in their dual adjoinment, actually constitute a square open area. After forcing these components into place, the formed combination is rolled between two rollers to reduce the gauge slightly and clamp these added components in place. The introduction into the structure of a disc or ring-shaped supporting member provides a strength equivalent to that of solid materials.
The use of rings or washer-like components provides a lightweight structure and serves effectively in metal applications. In paper or fiber applications of the invention, discs of "hardboard" or "cylinder board" also function effectively. Foamed plastic, plaster, gypsum and other products can also be introduced in a wet state into the triangular cell openings, for reinforcement or other purposes, if required in specific applications.
If the present invention is practiced with certain plastics or distensible materials that lend themselves to stretching and strain under pressure, a product variation can be achieved by adjustment of the "shearing" portions of the dies used in the forming apparatus. The product produced when such materials are employed, and when the apparatus is so adjusted, varies from that described previously in that the base line "cut" of the triangular form is not actually produced. By adjustment of the shear engagement between the cylinders, an opening can be provided in the space between the triangle base line cutting surfaces to minimize interference between these planes of engagement, so that a stretched membrane is produced across what is normally the cut or open area of the product described previously. This modification is desirable in certain cushioning and packaging applications where plastic products are employed and is also effective where a closed product is required. An example of a material that lends itself to this type of treatment is polypropylene. By utilizing low heat in the order of 175° F on the forming cylinders, stock 0.020 inch thick can be drawn across a 0.125 inch opening with a gauge reduction to 0.006 inch thus providing a web which completely closes the area that is normally open in the earlier described embodiments of the invention.
From the foregoing, it can be seen that substantial variations are possible in the products and apparatus of the present invention. Other configurations will be readily apparent to those familiar with the art.
BRIEF DESCRIPTION OF THE DRAWINGS
The foregoing objects, advantages, construction and operation of the present invention will become more readily apparent from the following description and accompanying drawings in which:
FIG. 1 is a plan view of a structural medium constructed in accordance with the present invention;
FIG. 2 is an enlarged perspective view of a portion of the structure shown in FIG. 1;
FIG. 3 is a perspective view illustrating how the structure of FIG. 2 may be combined with imperforate cover sheets;
FIG. 4 is a view similar to FIG. 3 showing how the medium of the present invention may be utilized in conjunction with partially perforated, tab-defining cover sheets;
FIG. 5 is a cross-sectional view illustrating a multi-layer product employing media of the type shown in FIG. 1;
FIGS. 6A and 6B show to different cylindrical products, respectively, fabricated from the medium of the present invention;
FIG. 7 is a view similar to FIG. 3 showing how a product constructed in accordance with the present invention may be reinforced;
FIG. 8 is a detail view of a portion of FIG. 7 showing one form of reinforcement element which may be employed;
FIG. 9A is a schematic plan view of a medium constructed in accordance with the present invention employing triangular forms of varying altitude to produce a web having a lateral cross section of varied shape;
FIG. 9B is a perspective view of a product which is fabricated utilizing the medium of FIG. 9A;
FIGS. 10A and 10B are cross sectional views of two different products having varying gauges constructed by use of media fabricated in accordance with the present invention;
FIG. 11 is a partial schematic view of a pair of forming cylinders adapted to cut and fold a web to produce the medium of the present invention;
FIG. 12 is a perspective view of two bars having integral triangular dies, such as may be employed in the apparatus of FIG. 11;
FIG. 13 is a schematic illustration of a portion of one of the dies shown in FIGS. 11 and 12, depicting possible variations in configuration of the die;
FIG. 14 is a schematic perspective view showing how tapered forming cylinders, employing triangular dies of varying size, may be used in the production of a curved medium of the type shown in FIG. 9A; and
FIG. 15 is a schematic view of an apparatus which may be employed in the high speed production of products of the type shown, for example, in FIG. 3.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring initially to FIGS. 1 and 2, it will be seen that the structural medium of the present invention comprises a sheet 10, fabricated of a material such as metal, plastic, paper or fiber, having a deformed surface defining an array of closely adjacent projections 11 and intervening depressions 12 each of which comprises an integral portion of the sheet 10 and each of which has a triangular shape in a direction parallel to the plane of said sheet. The structure illustrated is essentially symmetrical in that, when the sheet is reversed through 180° the regions depicted as projections 11 become "depressions" when viewed from the opposite side of the sheet, and the illustrated depressions 12 similarly become "projections" when viewed from said opposite side of the sheet. The terms "projections" and "depressions" are therefore interchangeable in dependence upon the side of the sheet which is being utilized as a reference.
The edges of each triangular depression 12 are bounded by the edges of three adjacent triangular projections which are disposed in surrounding relation to said depression, e.g., as depicted in FIG. 1, depression 12a is bounded by the edges of the three projections 11a, 11b, and 11c. Moreover, as best shown in FIG. 2, the sheet of material adjacent at least two edges of each triangular projection 11 is folded so as to extend continuously from said two edges in a direction transverse to the plane of the sheet (essentially orthogonal, but slighlty inclined) to define transverse side walls 13, 14 which merge into the corresponding edges of the adjacent triangular depression 12 and which are accordingly shared by each projection 11 and an adjacent depression 12. The third side of each projection 11, however, does not include such a shared side wall and, instead, is freely spaced from the underlying corresponding edge of an adjacent depression 12 by an intervening slot 15. These slots 15, as will become apparent from the subsequent description, are produced by shearing the sheet 10 to produce a plurality of aligned, spaced cuts disposed longitudinally with respect to the web direction to achieve lateral relief in the sheet so that the side walls 13 and 14 can be folded into their desired configuration without tearing the sheet of distorting its gauge.
The unslit portion (designated a in FIG. 2) between the adjacent ends of the cuts or slits (designated b in FIG. 2) in each row of slits preferably has a length in the range of substantially 5% to 15% of the length of each slit b to minimize the space between the cuts while retaining the integrity of the sheet. The intervals or spaces a between the relief cuts b must be proportioned to the size of the parallel triangular spaces of projections 11 and depressions 12 and to the length of the relief cuts b. Each uncut interval a must approximate the horizontal radius c (see FIGS. 2 and 13) at the apex of the triangular form, as well as the radius d (see FIG. 13) in the perpendicular plane of the same apex point. Additional radii are important to assure appropriate relief of the material and minimization of friction during the folding of the shared sides 13, 14, these additional radii being designated e in FIG. 2 and being located at the junction of each triangular face of a projection 11 and the adjacent transverse side walls of shared sides 13, 14. The radius of the nose of each triangular projection 11, at points below the radius designated c at the extreme apex point of the triangular face of a projection 11, is of approximately the same dimension as the radius designated e.
As shown in FIGS. 1 and 2, the triangular projections 11 and depressions 12 are each of equilateral form although, as will be appreciated by those skilled in the art, the principles of the present invention can be employed in conjunction with triangular forms of different shape. When the equilateral form is employed, the triangular top surfaces of the several projections 11 cooperate with the triangular bottom surfaces of the adjacent depressions 12 to produce square cellular forms which are separated from one another by intervening upstanding ribs (comprising aligned transverse side walls 13 and aligned transverse side walls 14 respectively as best shown in FIG. 2) that are disposed along intersecting lines 16,17 (see FIG. 1). This array of upstanding, intersecting ribs achieves a grid-like reinforcement of the overall structure.
The triangular planar top surfaces of the several projections 11 are, in the embodiment of the invention shown in FIG. 2, disposed in generally coplanar relation to one another and cooperate to define a first discontinuous surface comprising one side of the structural medium. Similarly, the triangular planar bottom surfaces of the several triangular depressions 12 are also substantially coplanar with one another and define a second discontinuous surface comprising the other side of the structural medium. The distance between these two opposing discontinuous surfaces comprises the gauge of the formed medium, and this gauge may be a constant throughout the medium when the discontinuous surfaces are parallel to one another, or (as will be discussed subsequently in reference to FIGS. 10A and 10B) the gauge may vary along the length of the medium when the discontinuous opposing surfaces of the medium are disposed in planes which are curved and/or in planes which diverge away or converge toward one another. The opposing discontinuous planar surfaces may, moreover, be associated with one or more imperforate or perforate cover sheets which are adhesively or mechanically attached thereto to produce a structure which has even greater strength and/or a continuous outer surface, as may be necessary in certain applications.
FIG. 3 shows an arrangement of this latter type wherein the opposing discontinuous surfaces of the formed medium have a pair of imperforate cover sheets 18 and 19 affixed thereto, e.g., by use of an adhesive applied to the outer triangular surfaces of each depression 11 and each depression 12.
In an alternative form of the invention shown in FIG. 4, the cover sheets 20 and 21 are each partially perforated at 22 (in the fashion described in my prior U.S. Pat. No. 3,846,218, only a limited number of such partial perforations being depicted for purposes of simplicity) to define tabs 23 which may be bent out of the plane of each cover sheet into the region between said cover sheets in adjacent overlying relation to the aforementioned side walls 13, 14 of the intervening center medium. The tabs 23 associated with cover sheet 20 are, as shown in FIG. 4, located adjacent the outer sides of the several transverse walls 13, 14, whereas the tabs 23 associated with cover sheet 21 are disposed adjacent the inner surfaces of said walls 13, 14; and said tabs may be adhesively or mechanically attached to the facing surfaces of transverse walls 13, 14 to produce an overall structure of the type shown in FIG. 4 which is not only reinforced by the addition of the cover sheet but which is also of ventilating configuration in that air may readily pass through the entire structure via the several partial perforations 22 and the gaps between the several triangular projections and depressions of the center medium.
Various combinations of the structures shown in FIGS. 3 and 4 are, of course, possible. For example, only a single cover sheet, of either perforated or imperforate form, may be utilized. Alternatively, a pair of cover sheets may be employed, one of which is imperforate in the fashion shown in FIG. 3, and the other of which is partially perforated in accordance with FIG. 4. When one or more partially perforated sheets of the type shown in FIG. 4 are employed, moreover, the partially perforated sheet may be attached to the adjacent formed medium at the tabs alone, or it may also be attached to the center medium by additional adhesive or mechanical bonding between the cover sheet and the underlying triangular faces of the projections 11 and depressions 12.
A still further variation is shown in FIG. 5 wherein a multi-layer structure is produced comprising two media layers 25, 26 constructed with accordance with FIGS. 1 and 2, which are separated from one another by an intervening central sheet 27 and which are bounded on their outermost sides by cover sheets 28 and 29. The several sheets 27, 28, 29 may be perforate and/or imperforate in accordance with the preceding discussion, and the strength characteristics of the multi-layered structure may be varied by varying the disposition of the projections and depressions in one medium 25 relative to the projections and depressions in the other medium 26. Moreover while a two-layer structure has been shown in FIG. 5, it will be appreciated that three or more layers can be provided in analogous fashion in dependence upon the ultimate application of the structure.
The medium shown in FIGS. 1 and 2 may be bent into cylindrical form when a product of that shape is desired, and the overlapping ends of such a cylindrically-shaped medium may have their corresponding projections and depressions nested within one another and affixed together to maintain the structure in its cylindrical configuration. The cylindrical form can assume the arrangement shown in FIG. 6A in which the several relief cuts and the resulting slots 15 of the medium are disposed along lines which are parallel to the axis of the cylinder so that the rib lines 16, 17 (FIG. 1) are disposed on 45° intersecting lines 16a, 17a with respect to the cylinder axis. Alternatively, as shown in FIG. 6B, the medium may be so wrapped that the several relief cuts and the resulting slots 15 in the medium are disposed along lines which are diagonal to the cylinder axis to place the rib lines 16, 17 in directions which are aligned with and at right angles to the cylinder axis, respectively.
In those applications where the medium alone does not exhibit sufficient strength, and where the strength is not sufficiently increased by the addition of cover sheets thereto, further reinforcement can be effected by inserting a reinforcing material or a reinforcing component into some or all of the cells, as discussed earlier. Where such reinforcing elements are employed, the elements may take the form of discs, rings, washers or the like. One such arrangement is shown in FIGS. 7 and 8 wherein a product of the general type shown in FIG. 3 has its column and flat crush strength increased by insertion of ring-shaped elements 30 into the pocket areas formed between the alternately disposed triangular surfaces of the several projections and depressions in the formed medium. Each ring 30 extends through one of the aforementioned slots 15 and includes a portion which underlies the top triangular surface of a projection 11 and a further portion which overlies the upwardly facing bottom surface of an adjacent depression 12. The edge surfaces of the ring 30 may be inclined to comform to the corresponding inclinations of the intervening side walls 13, 14 described previously. After the several rings 30 have been forced into place via the aforementioned slots 15, they may be clamped in position by pressing the various transverse side walls 13, 14 into closely confirming engagement with the outer edge of the adjacent ring 30. The introduction of such disc or ring-shaped structures give the overall medium a strength equivalent to that of a solid material.
The several rings 30 may have an annular configuration as shown in FIG. 7, or they may be solid; and they can be fabricated of various materials. Instead of providing such rings, other reinforcing materials such as foam plastic, plaster, gypsum, etc., can be employed to fill some or all of the cell openings if required in the specific application.
In the medium shown in FIG. 1 the various triangular projections and depressions are all of the size, and the several projections and depressions are disposed along a plurality of essentially parallel rows each of which is occupied by alternately inverted triangular projections and depressions which are disposed directly adjacent one another. As a result, the several rows of projections and depressions are parallel to one another with the distance between each adjacent pair of rows corresponding to the altitudes of the triangular projections and depressions, the several slots 15 are disposed along lines which are parallel to one another, the several transverse sidewalls 13 are disposed along further lines which are similarly parallel to one another, and the several transverse sidewalls 14 are disposed along still further lines which are parallel with one another. In accordance with variations of the invention, however, the triangular projections and depressions which are disposed adjacent one another in one such pair of rows may have a size different from the triangular projections and depressions between another pair of rows so that the spacing between various different rows differs from one another and the various slots 15, the various sidewalls 13, and the various sidewalls 14 are disposed along respective lines which are not straight but, instead, exhibit a desired curvature. In short, by appropriately varying the sizes of the various triangular projections and depressions throughout the medium, it is readily possible to produce any desired change in the shape of the medium and, by varying the heights of the transverse sidewalls 13, 14 throughout the medium it is also possible to achieve any desired variation in the gauge (or external surface configuration) of the medium. These aspects of the invention are shown in FIGS. 9 and 10.
FIG. 9A shows a variant form of medium (which can be fabricated by an apparatus of the type to be described hereinafter in reference to FIG. 14) wherein the alternating triangular projections and depressions in row 31 are all of the same height but have a greater height than those in an adjacent row 32, with the heights of the said alternating projections and depressions decreasing successively in further adjacent rows 33, 34, 35, and 36. By reason of this variation in the sizes of the several projections and depressions, from row to row, the overall medium was curved edges 37 and 38 due to the disproportionate gathering of the web material between said edges 37 and 38. The resultant medium can be provided with cover sheets, e.g., of the general type described in reference to FIG. 3, and is useful in the production of tapered cylindrical products of the general type shown in FIG. 9B.
In the arrangements of FIGS. 10A and 10B the heights of the various transverse sidewalls 13, 14 are varied (in accordance with considerations to be discussed hereinafter in reference to FIG. 13), in a predetermined manner to provide a desired variation in the gauge of the final product. In the arrangement of FIG. 10A, the variation is such that the outer surfaces of the product are each curved as at 40 and 41. In the arrangement of FIG. 10B, the outer surfaces 42 and 43 are each flat, but said surfaces 42 and 43 are variably spaced from one another to provide the product of tapered cross section. Combinations of the arrangements shown in FIG. 10A and 10B may, of course, be provided, i.e., by appropriate control of the heights of the sidewalls 13 and 14 in the medium one boundary surface of the final product may be curved while the other is flat, and the spacing between said surfaces may be varied as desired or necessary.
The structural medium of the present invention is formed, in general, by slotting the planar web of material to provide a plurality of spaced aligned slits along each of a plurality of parallel rows, the unslit portion of the web between adjacent ends of the slits in each row having a length in the range of 5% to 15% of the length of each slit in that row (for the reasons previously discussed) and the unslit portions of the web in each row being positioned opposite slit portions of the web (preferably opposite the mid-point of said slit portions) in the adjacent rows. The portions of the web located along the several slits are depressed away from the plane of the web into a plane parallel to the plane of the web while additional portions of the material are simultaneously folded into planes disposed transverse to the plane of the web along pairs of lines which extend respectively from opposing ends of each slit in each row in converging relation to one another toward an unslit portion of the web in an adjacent row. By thus slitting and folding the web, the surface of the web is deformed into an array of closely adjacent triangular projections and depressions which are disposed in alternately inverted relation to one another between adjacent pairs of said rows, and from row to row, without altering the actual gauge of the web material.
The sequence of steps described above can be effected by use of hand tools or various mechanisms. The steps can be achieved in high production fashion, by use of a dual-cylinder cutting and folding apparatus of the type shown in FIG. 11.
In the arrangement of FIG. 11 a pair of forming cylinders 50, 51 are mounted for rotation, in opposing directions and in surface-to-surface engagement with one another, on a pair of parallel axes 52, 53. The surface of each cylinder supports a plurality of triangular die elements which completely cover each cylinder surface (only a very few such die elements are shown for each cylinder in FIG. 11, to simplify the drawing) with the die elements carried by one cylinder being oriented in a direction opposite to the die elements carried by the other cylinder, and with the die elements on one cylinder being so positioned relative to the die elements on the other cylinder that, as said cylinders rotate in opposing directions, each die element on one cylinder periodically enters and then leaves the triangular space defined between a cluster of three adjacent die elements on the other cylinder. A web of material which is fed through the cylinders at their nip 54 is accordingly formed in the manner shown in FIGS. 1 and 2 as the cylinders 50, 51 rotate.
More particularly, referring to both FIGS. 11 and 12, the surface of each cylinder carries a plurality of elongated bars 55 which are oriented in a direction parallel to the rotational axis of the cylinder and which have a length substantially equal to the axial length of the cylinder surface. Each bar element is mounted in position on its associated cylinder surface by means of screws 56 and pins 57 which accurately align the bar elements on a given cylinder relative to one another, align the bar elements on one cylinder relative to those on the other, and permit any given bar element to be readily removed and replaced as a unit if necessary, e.g., due to breakage of a die element. Each bar 55 is machined on one surface thereof to provide as an integral part of the bar, a plurality of axially spaced, similarly oriented, triangular die elements 58. As best shown in FIGS. 12 and 13, each such triangular die element 58 has a flat triangular top surface 58a which is disposed in a plane parallel to the axis of its associated cylinder, and three side walls which extend respectively from the edges of said triangular top surface 58a toward the periphery of the forming cylinder. One of the die side walls 58b extends in a plane which is substantially orthogonal to the axis of the cylinder, and the other two die side walls 58c and 58d extend from the associated edges of surface 58a in inclined planes which are nonorthogonal to the axis of the forming cylinder and which diverge from one another toward the periphery of the forming cylinder. The substantially orthogonal edge 58b of each die on each forming cylinder cooperates, at the nip of the contra-rotating forming cylinders 50, 51, with another such substantially orthogonal die surface on a complementary die located on the other forming cylinder, to shear the web which is passing through the nip of the cylinder, thereby to produce a cut in said web having a length corresponding to the length of the die surface 58b; and the inclined die surfaces 58c and 58d act to fold portions of the web extending from the opposing ends of each such cut into the transverse side walls 13, 14 described previously.
As best shown in FIG. 12, the several bars 55 on each forming cylinder are so positioned relative to one another that the triangular dies on one bar are positioned in staggered relation to the triangular dies on a directly adjacent bar. The shearing surfaces 58b of the die on each bar are oriented in a direction at right angles to the axis of the associated forming cylinder (i.e., they are oriented in the longitudinal direction of web travel through the nip of the forming cylinders) and, due to the staggered configuration of the dies on adjacent bars, the shearing surfaces 58b of dies on alternate ones of said bars are in alignment with one another.
The dies on the several bars on each cylinder are disposed in closely adjacent relation to one another in a plurality of circular rows which extend about the axis of the associated forming cylinder, and the adjacent apices of the dies in adjacent ones of said rows are spaced from one another by a distance in the range of 5% to 15% of the length of the shear surface 58b of each die. Moreover, the nose of each die (i.e., the apex opposite to shear surface 58b) is located adjacent to, but substantially similarly spaced from, the space between the aligned shear surfaces 58b of the dies in the adjacent rows so that the dies are clustered in groups of three to define a substantially triangular space therebetween, e.g., see the cluster of dies A, B, C and the intervening space D in FIG. 12. It will be appreciated that the triangular space D is oriented in a direction opposite to the orientation of the dies which define that space, and each space D is accordingly oriented in the same direction as one of the triangular dies on the other forming cylinder so that, as the forming cylinders 50, 51 rotate, each die on one forming cylinder enters the triangular space between a cluster of three dies on the other forming cylinder at the nip of the cylinder, to cause shear engagement between the complementary surfaces 58b of dies on the two different cylinders while the inclined surfaces 58c, 58d fold the web material, in the fashion described previously, into the triangular space D. By reason of the various dimensional considerations discussed earlier, this folding is accomplished without tearing the web, and causes a longitudinal take-up of the web without any lateral take-up thereof.
By slight axial displacement of the positions of the dies on one forming cylinder relative to those on the other forming cylinder, the shearing action accomplished between the cooperating faces 58b of corresponding dies in the two cylinders can be changed into a drawing action when the web being formed is fabricated of appropriate plastic material, to produce a stretched, comparatively thin membrane across the region between the cooperating die surfaces 58b, rather than actually cutting the web in this region. The modified product thus produced has value in certain applications where it is desirable to utilize a formed medium which has a completely continuous surface uninterrupted by cuts or perforations therein.
A further aspect of the invention, useful for example in the formation of products of the types described in reference to FIGS. 10A and 10B, is illustrated in FIG. 13. If the sides 58b, 58c, 58d of the basic die element 58 were to be extended upwards relative to bar 55, they would intersect at an apex 60, and the die would have a half-pyramid shape. If a die of this shape were then reduced in height to the level designated by the line I--I, the upper surface of the die would have a triangular shape similar to surface 58a, but of smaller size. Such a die would, when used in the fashion described previously, produce a projection or depression in the web material having a triangular face of smaller size, and transverse side walls of greater height. If the height of the half-pyramid die is reduced to the levels designated II--II through IV--IV, each such reduction in height of the die would correspondingly increase the size of the triangular face of the deformed web while decreasing the height of the transverse side walls formed therein. By appropriate selection and patterning of the heights of the various dies in the forming cylinders, therefore, projections and depressions of varying different heights can be produced, to permit the fabrication of a final product having any desired external gauge, or any desired variation in external gauge. It will be appreciated that when the height of the side walls is increased, by a related increase in the height of the forming die, the material which is used to provide an increase in height of the transverse side walls 13, 14 is taken from the triangular lateral face of the formed projection or depression in the web, and the dimensional variation in the web projection or depression is accordingly accomplished without any change in the longitudinal take-up of the web.
FIG. 14 schematically illustrates a different type of forming cylinder arrangement which can be employed to produce the product shown in FIG. 9A. In this modified arrangement, the forming cylinders 65, 66 are each of conical configuration and are mounted for rotation on mutually inclined axes to accommodate the taper of the cylinders thereby to produce a parallel relationship between the cylinders at their nip 67. As a result, the nip provides a vertical plane through which a web 68 may pass. The surfaces of the two cylinders 65, 66 carry triangular dies of the general type described in reference to FIGS. 11-13, but the sizes of the various dies are graduated to provide smaller dies adjacent the smaller ends of the two cylinders which progressively increase in size for dies disposed closer to the larger ends of the two conical cylinders. The dies on one cylinder are inverted in orientation relative to those on the other cylinder, to cooperate with one another so as to achieve the shearing and folding functions described earlier.
As the web 68 passes through the nip 67 of the conical forming cylinders 65, 66, a product of the type shown in FIG. 9A is produced. The web is cut and folded to generate a product having a curvature, caused by variations in the folding function, which is directly proportional to the number of triangular dies which are disposed along a given web length. At the smaller ends of the forming cylinders, more folds are provided along the edge 68a of the web than are provided at its opposite edge 68b. The curved product which is produced as a result is useful in the fabrication of components having a conical form, e.g., tubs, cups, or buckets having a tapered cylindrical shape.
FIG. 15 is a schematic three-dimensional illustration of an apparatus which can be employed in the high speed production of a product of the type shown in FIG. 3. The web material which is to be deformed into the medium of the present invention is taken from a supply roll 70 and fed by means of draw rolls 71 through a pair of forming cylinders 72 of the type described in reference to FIG. 11. The deformed medium then passes a glue applicator 73 which applies adhesive to the lateral triangular faces on one side of the formed medium. A web of cover sheet material is taken from a further supply roll 74 by means of draw rolls 75 and is fed through a pair of rolls 76, 77 into contact with the adhesive bearing side of the formed medium for lamination therewith.
Roll 76, which is used during the laminating step, can be smooth-surfaced and works in conjunction with the planar surface of the web taken from roll 74. Roll 77, however, which is disposed adjacent the deformed surface of the center medium, may have a surface configuration corresponding to that of one of the forming cylinders of FIG. 11 so that the triangular projections and depressions on the surface of roll 77 provide a back-up function permitting full pressure to be applied across the web width without distorting the projections and depressions in the center web.
Immediately following the lamination of cover material 74 onto the formed center web, the laminate passes a further glue applicator 78 which applies adhesive to the opposite side of the laminate. The other cover sheet material, taken from a further supply roll 79 by means of draw rolls 80, is laminated to the opposite side of the product under pressure supplied by smooth rolls 81. The final panel then passes through a cutter 82 which severs a desired length 83 of the finished product and stacks the severed lengths as at 84.
While I have thus described preferred embodiments of the present invention, many variations will be apparent to those skilled in the art. It must therefore be understood that the foregoing description is intended to be illustrative only and not limitative of the present invention, and all such variations and modifications as are in accord with the principles described are meant to fall within the scope of the appended claims. | Metal, fiber or plastic panels are fabricated by the attachment of planar imperforate and/or partially perforated outer sheets to a specially formed center member comprising a web or sheet having a deformed surface defining an array of adjacent triangular projections and depressions. The center member is produced by the longitudinal cutting and folding of the web as it passes between two forming cylinders which mesh with one another, the cylinder peripheries carrying complementary arrays of spaced triangular-shaped tooth elements having their base lines aligned in the opposing cylinders, to shear and thereby relieve the passing web laterally so as to produce intermittent parallel cuts and angular folds in the web while gathering the web longitudinally thereby to form triangular, flat-topped cells in the center member. Instead of using two outer sheets, the formed center member can be used per se, e.g., as a packing medium, or it can be combined with only one outer sheet to form a single-face product. | 1 |
REFERENCE TO RELATED APPLICATION
[0001] This application is the national stage application under 35 USC 371 of International Application No. PCT/JP2011/066772, filed Jul. 15, 2011, the entire contents of which are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The invention relates to a rotary workhead for machine tools which process workpieces with tensile or compressive force applied on the workpieces.
BACKGROUND OF THE INVENTION
[0003] Conventionally, in order to produce curved surfaces on workpieces, machine tools having a plurality of feed axes are used. When a thin and fragile workpiece, such as turbine blades for steam or gas turbines is processed, it is necessary to prevent deformation of the workpiece due to machining force and vibrations generated from the contact between the tool and the workpiece.
[0004] Patent Document 1 describes a method and an apparatus for machining turbine blades. In the invention of Patent Document 1, one end of a workpiece is secured to a fixture and the other end is supported by a center piece of a tail stock. A tension member of the tailstock is engaged with a stepped part of the end of a turbine blade, and axially moved by a hydraulic cylinder, which is provided in the tail stock, in order to apply a tensile force to the turbine blade whereby the turbine blade is processed under the condition that the apparent rigidity of the turbine blade is increased.
[0005] In a machine tool for a turbine blade disclosed in Patent Document 2, one end of a turbine blade is secured by a main chuck, and the other end is held by a pressure chuck provided in a sub-chuck head. Compressive force is applied to the turbine blade by pressing the end of the turbine blade with the pressure chuck whereby the turbine blade is processed under the condition that the apparent rigidity of the turbine blade is increased.
[0006] Patent Document 1: Japanese Unexamined Patent Publication No. S57-15609
[0007] Patent Document 2: Japanese Unexamined Patent Publication No. H10-76437
SUMMARY OF THE INVENTION
[0008] In the invention of Patent Document 1, the hydraulic cylinder for axially moving the tension member is provided in the tailstock, resulting in complex configuration. In addition, a special tail stock, incorporated with a hydraulic cylinder, must be produced, resulting in remarkably increased cost.
[0009] Further, similar to the invention of Patent Document 1, in the invention of Patent Document 2, a pressing mechanism is incorporated in the sub-chuck head, resulting in complex configuration and increase in the production cost.
[0010] The invention is directed to solve the problems in the prior art, and the objective of the invention is to provide a rotary workhead device for a machine tool, which processes a workpiece under tensile or compressive force applied, improved to have a simple configuration whereby the production cost is reduced.
[0011] According to the invention, there is provided a rotary workhead device, disposed on a table of a machine tool, for rotatably mounting a workpiece to be processed, including a base plate adapted to be secured to the table of the machine tool, two opposing rotary workheads disposed on the base plate so as to align the respective rotational axes with each other, guide means for allowing at least one of the rotary workheads to reciprocally move in the direction of the rotational axes; and biasing means for biasing one of the rotary workheads in the direction away from or toward the other of the rotary workheads, wherein a tensile or compressive force is applied to the workpiece secured at its ends between the two rotary workheads.
[0012] According to this feature, a workpiece can be processed while tensile or compressive force is applied to the workpiece whereby the rigidity of the workpiece is apparently increased. Therefore, even a thin and low rigidity workpiece, such as a turbine blade, can be successfully processed because the bending is very small and vibrations are not generated.
[0013] It is not necessary to form a hydraulic cylinder in a tailstock, as described in patent document 1, because the means for biasing one of the two rotary workheads in the direction away from or toward the other rotary workhead can be disposed outside of the movable rotary workheads. This avoids the necessity of a hydraulic cylinder formed in a narrow space of the tailstock whereby the configuration is simplified and the cost can be reduced.
[0014] Further, commercial products can be used as the rotary workheads, which remarkably reduces production cost. This is further advantageous for users, because a special operation is not required. Further, when a problem occurs, it can be quickly fixed by replacing the broken rotary workhead with a commercial product, and therefore the downtime of the machine tool can be reduced.
[0015] According to the invention, the biasing means includes a fluid pressure operated cylinder provided between one of the rotary workheads and the base plate, and a pressure control device for varying the fluid pressure supplied to the fluid pressure operated cylinder.
[0016] According to this feature, suitable tensile or compressive force can be applied depending on the dimension and material of the workpiece by varying the fluid pressure supplied to the fluid pressure operated cylinder with the pressure control device.
[0017] Further, according to the invention, the guide means includes a lever device for allowing manual operation of the reciprocal movement of one of the rotary workheads when a biasing force of the biasing means is not applied.
[0018] In the invention, when a workpiece is mounted to the rotary workhead device, it is necessary to reciprocally move the rotary workhead along the guide means depending on the length of the workpiece or the shapes of the fixtures. According to the feature, this operation can be carried out with the lever device, when the biasing means does not apply the biasing force to one of the rotary workheads.
[0019] According to the invention, the guide means includes a brake device for clamping the reciprocal movement of one of the rotary workheads.
[0020] According to this feature, the brake device clamps the reciprocal movement of one of the rotary workheads, after a biasing force is applied to a rotary workhead. The biasing force is kept applied to the one of the rotary workheads if the biasing means is deactivated.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] FIG. 1 is a front view of a machine tool with a rotary workhead device according to an embodiment of the invention.
[0022] FIG. 2 is a side view of the machine tool of FIG. 1 .
[0023] FIG. 3 is a plan view of the rotary workhead device.
[0024] FIG. 4 is an end view of the rotary workhead device in the direction of arrow lines IV-IV in FIG. 3 .
[0025] FIG. 5 is a plan view similar to FIG. 3 a rotary workhead device according to a second embodiment.
[0026] FIG. 6 is an illustration of an alternative embodiment of the fixtures.
DETAILED DESCRIPTION OF THE INVENTION
[0027] With reference to FIGS. 1-4 , an embodiment of the rotary workhead device according to the present invention will be described below. FIG. 1 is a front view of a machine tool with a rotary workhead device according to an embodiment of the invention, FIG. 2 is a side view of the machine tool of FIG. 1 , FIG. 3 is a plan view of the rotary workhead device and FIG. 4 is an end view of the rotary workhead device in the direction of arrow lines IV-IV in FIG. 3 .
[0028] With reference to FIG. 1 , a machine tool 100 , provided with a rotary workhead device 10 according the embodiment of the invention, is a horizontal machine tool comprising a bed 102 adapted to be secured to a factory floor, a column 104 mounted to the top face of a rear part of the bed 102 for moving in the left-right direction (X-axis direction) by an X-axis feed mechanism, a spindle head 106 mounted to the front surface of the column 104 for moving in the vertical direction (Y-axis direction) by a Y-axis feed mechanism and a saddle 110 mounted to the top face of a front part of the bed 102 for moving in the front-rear direction (Z-axis direction) by a Z-axis feed mechanism. A spindle 108 is supported by the spindled head 106 for rotation about a rotational axis extending in the front-rear direction. A tool T is attached to the end of the spindle 108 . A rotary table 112 is rotatably supported by the saddle 110 for angular range of ± 180 degrees about a vertical axis (B-axis).
[0029] The X-axis feed mechanism may include a pair of X-axis guide rails 102 a horizontally extending in the left-right direction in the top face of the bed 102 , guide blocks (not shown) mounted to a bottom face of the column 104 for sliding along the X-axis guide rails, an X-axis ball screw (not shown) extending in the X-axis direction in the bed 102 , a nut (not shown) mounted to the lower end portion of the column 104 so as to engage the X-axis ball screw and a servomotor, connected to an end of the X-axis ball screw, for driving the X-axis ball screw.
[0030] Similarly, the Y-axis feed mechanism may include a pair of Y-axis guide rails (not shown) vertically extending in the column 104 , guide blocks (not shown) mounted to the spindle head 106 for sliding along the Y-axis guide rails, a Y-axis ball screw (not shown) extending in the Y-axis direction in the column 104 a nut (not shown) mounted in the spindle head 106 so as to engage the Y-axis ball screw and a servomotor, connected to an end of the Y-axis ball screw, for driving the Y-axis ball screw.
[0031] Similarly, the Z-axis feed mechanism may include a pair of Z-axis guide rails 102 b horizontally extending in the top face of the bed 102 perpendicularly to the X-axis guide rails 102 a, guide blocks (not shown) mounted to a bottom face of the saddle 110 for sliding along the Z-axis guide rails, an Z-axis ball screw (not shown) extending in the Z-axis direction in the bed 102 , a nut (not shown) mounted to a bottom face of the saddle 110 so as to engage the Z-axis ball screw and a servomotor, connected to an end of the Z-axis ball screw, for driving the Z-axis ball screw.
[0032] The machine tool 100 further comprises a pallet changer 120 mounted to the front end of the bed 102 and a pallet stocker 114 disposed in front of the pallet changer 120 . In this embodiment, the machine tool 100 , including the pallet changer 120 and the pallet stocker 114 , is enclosed by a splash guard 116 . The pallet changer 120 comprises a changing arm 124 which can rotate about and vertically move along a vertical axis O, and a revolving door 122 which can rotate about and vertically move along the axis O together with the changing arm 124 . The revolving door 122 divides the space within the splash guard 116 into a machining chamber 126 between the revolving door 122 and the column 104 and a preparation chamber 128 , where the pallet stocker 114 is disposed, in front of the revolving door 122 . A front door 116 a , provided in a front panel of the splash guard 116 , allows an operator to access the preparation chamber 128 .
[0033] In this embodiment, a workpiece W is mounted to the rotary workhead device 10 and processed with the tool T. The rotary workhead device 10 comprises a base plate 12 forming a pallet, stationary and movable rotary workheads 14 and 16 mounted to the top face of the base place 12 at either end thereof. Direct drive servomotors (not shown) are respectively provided in the stationary and movable rotary workheads 14 and 16 for rotation about a horizontal rotational axis (A-axis). Face plates 14 a and 16 a are secure to the respective shafts of the servomotors. The face plates 14 a and 16 a are provided with fixtures 14 b and 16 b for fixing a workpiece W. The stationary rotary workhead 14 is secure to the top face of the base plate 12 at one end thereof with a spacer 18 having a suitable thickness allowing the axes of the servomotors of the stationary and movable rotary workheads 14 and 16 to coincide with each other whereby a horizontal rotational feed axis, i.e., A-axis is formed. The movable rotary work head 16 is mounted to the top face of the base plate 12 at the opposite end for liner motion by guide rails, which extend parallel to the common rotational axis (A-axis) of the stationary and movable rotary workheads 14 and 16 and the servomotors, and slider 22 mounted to a bottom face of the movable workhead 16 for sliding along the guide rails 20 .
[0034] Accordingly, the machine tool 100 is a machine tool having five feed axes of three orthogonal liner feed axes, i.e., X-axis, Y-axis and Z-axis, and two rotational feed axes, i.e., A-axis and B-axis.
[0035] The rotary workhead device 10 further comprises, in order to displace the movable rotary workhead 14 along the guide rails 20 , lever 32 , cam 34 attached to the end of the lever 32 and a cam follower 38 mounted to the slider 22 so as to engage the cam 34 . The lever 32 is mounted the base plate 12 for rotation about a vertical axis 32 a. In the embodiment of FIG. 3 , by rotating the lever 32 in the counter clockwise direction, the movable rotary workhead 16 moves (to the right in FIG. 3 ) away from the stationary rotary workhead 14 .
[0036] The rotary workhead device 10 further comprises a hydraulic cylinder 42 for biasing the movable rotary workhead 14 in the direction away from the stationary workhead 14 and a pressure plate 43 attached to the slider so that a piston 42 a of the hydraulic cylinder 42 can abut thereagainst, a hydraulic pressure source 44 for supplying hydraulic pressure to the hydraulic cylinder 42 and an on-off valve 46 for controlling the on and off of the hydraulic pressure supply to the hydraulic cylinder 42 . The hydraulic pressure source 44 may include for example a reservoir (not shown) for accumulating the working oil, a pump for supplying the working oil to the hydraulic cylinder 42 . The hydraulic cylinder 42 is preferably a one-way cylinder which works effectively in the extending direction of the piston 42 a.
[0037] The rotary workhead device 10 is further provided with a seating sensor 50 . The seating sensor 50 may comprise for example a sensor block 52 attached to the base plate 12 , a pneumatic port 54 formed in the sensor block 52 so as to face the end of the slider 22 and a pressure sensor (not shown), fluidly communicating with the pneumatic port 54 , for detecting the pressure in the pneumatic port 54 . When the end of the slider 22 contacts the sensor block 52 , the port 54 is closed by the end of the slider 22 whereby the pressure sensor detects the increase in the pressure in the pneumatic port 54 . When a workpiece is mounted between the fixers 14 b and 16 b, the end of the slider 22 does not contact the sensor block 52 . However, if the pressure sensor detects an increase in the pressure in the pneumatic port 54 , it means that the end of the slider contacts the sensor block 52 . This may be judged that the tension applied to the workpiece W and may trigger a warning.
[0038] In order to supply electric power to the servomotors of the stationary and movable rotary workheads respectively, and to supply the working oil to the hydraulic cylinder 42 , the machine tool 100 comprises a cable and conduit assembly 36 and a central relay 118 for connecting the cable and conduit assembly 36 to an electric source (not shown) and the hydraulic pressure source 44 . The cable and conduit assembly 26 is connected to the servomotors and the hydraulic cylinder 42 through the relay 24 provided on the movable rotary workhead 16 .
[0039] The functional operation of this embodiment will be described below.
[0040] When a machining operation in the machining chamber 126 is completed, a machine controller (not shown) of the machine tool sends a pallet changing command to the pallet changer 120 . This moves the changing arm 124 upwardly along with the revolving door 122 along the axis O whereby either end of the changing arm 124 engage the rotary workhead device 10 , to which the processed workpiece W is mounted in the machining chamber 126 , and the rotary workhead device 10 ′, to which a non-processed workpiece is mounted in the preparation chamber 128 , so as to simultaneously lift them from the rotary table 112 and the pallet stocker 114 , respectively. Further, the pallet changer 120 rotates the changing arm 124 over 180 degrees about the vertical axis O together with revolving door 122 , whereby the processed workpiece W and the non-processed workpiece, respectively attached to the rotary workhead devices 10 and 10 ′, are replaced with each other. After the rotation of the changing arm 124 over 180 degrees, the pallet changer 120 lowers the changing arm 124 with the revolving door 122 , whereby the rotary workhead device 10 ′, to which the non-processed workpiece is mounted, and the rotary workhead device 10 , to which the processed workpiece W is mounted, are respectively placed onto the rotary table 112 and the pallet stocker 114 .
[0041] When a workpiece W is processed in the machining chamber 126 of the machine tool 100 , an operator of the machine tool 100 can open the front door to access the preparation chamber 128 in order to remove a processed workpiece from and to mount a new and non-processed workpiece to the rotary workhead device 10 . For this purpose, the operator closes the on-off valve 46 to block the hydraulic pressure applied to the hydraulic cylinder 42 from the hydraulic pressure source 44 . Then, the workpiece W is removed from the rotary workhead device 10 by loosening the fixtures 14 b and 16 b, e.g., chucks.
[0042] Thereafter, a new and non-processed workpiece is mounted to the fixtures 14 b and 16 b. At that time, the lever 32 can be rotated in clockwise or counter-clockwise direction to move the movable rotary workhead 16 along the guide rails 20 so as to adjust the distance between the movable and stationary rotary workheads 16 and 14 to the length of the non-processed workpiece. An operator can directly hold and move the movable rotary workhead device, even if the lever 32 is not provided. However, the provision of the lever 32 allows fine adjustment of the positioning of the movable rotary workhead device 16 , and facilitates the mounting operation of a workpiece W. After a non-processed workpiece is secured to the fixers 14 b and 16 b, the on-off valve 46 is opened so as to apply the hydraulic pressure to the hydraulic cylinder 42 from the hydraulic pressure source 44 , whereby the piston 42 a of the hydraulic cylinder 42 abuts the pressure plate 43 so that the movable rotary workhead 16 is biased in the direction away from the stationary rotary workhead 14 , resulting in application of tension in the workpiece.
[0043] Now, with reference to FIG. 5 , a second embodiment of the invention will be described below. FIG. 5 is a plan view, similar to FIG. 3 , of a rotary workhead device according to the second embodiment.
[0044] The rotary workhead device 50 according to the second embodiment can be mounted, similar to the rotary workhead device 10 according to the first embodiment, to the machine tool 100 , and has generally the same configuration. Accordingly, only the configurations different from the rotary workhead device 10 according to the first embodiment will be described below to avoid redundant explanations.
[0045] A hydraulic cylinder 62 is mounted to a base plate 12 of the rotary workhead device 50 , and is oriented so that a piston 62 a extends and retracts in the direction of an axis A. The piston 62 a is secured to a slider 22 of a movable rotary workhead 16 . The movable rotary workhead 16 can reciprocally move in the direction of axis A along with the piston 62 a. The hydraulic cylinder 62 is fluidly connected to a hydraulic pressure source 64 through a pressure control valve 66 and a directional control valve 68 . The directional control valve 68 may be a three-position directional control valve having a first position for extending the piston 62 a, a second position for retracting the piston 62 a and a third neutral position, at which the movable rotary workhead 16 can be manually moved along guide rails 20 . Although this embodiment is not provided with a lever device similar to the lever 32 of FIG. 3 , a lever may be provided. The pressure control valve 66 is an element for adjusting the hydraulic pressure from the hydraulic pressure source 64 to the hydraulic cylinder 62 according to requirements of machining processes, and may be switched between a plurality of positions for different tensile or compressive forces, for example 0 kg, 35 kg, 70 kg and 100 kg applied to the a workpiece to be processed, or may continuously adjust the tensile or compressive force.
[0046] Further, air brakes 72 are provided in a bottom face of the movable rotary workhead 16 . A pneumatic pressure source 74 is fluidly connected to the air brakes 72 through an on-off valve 76 . The air brakes 72 insert wedge shaped members between the slider 22 and the guide rails 20 by the pneumatic pressure from the pneumatic pressure source 74 so as to clamp the slider relative to the guide rails 20 .
[0047] Further, when a workpiece is applied a compressive force, the fixers 14 b and 16 may be replaced with centering couplings 14 c and 16 c, as shown in FIG. 6 , having features complementary to the end shapes of the workpiece W.
[0048] The functional operation of the second embodiment will be described below.
[0049] Similar to the first embodiment, when a workpiece W is processed in the machining chamber 126 of the machine tool 100 , an operator of the machine tool 100 can open the front door to access the preparation chamber 128 in order to remove a processed workpiece from and to mount a new and non-processed workpiece to the rotary workhead device. For this purpose, the operator closes the on-off valve 76 to block the pneumatic pressure applied to the air brakes 72 from the pneumatic pressure source 74 so that the air brakes are unclamped. This allows the rotary workhead 16 to be manually moved along the guide rails 20 . Then, the workpiece W is removed from the rotary workhead device by loosening the fixtures 14 b and 16 b, e.g., chucks.
[0050] Thereafter, a new and non-processed workpiece is mounted to the fixtures 14 b and 16 b. At that time, an operator can manually move the movable rotary workhead 16 along the guide rails 20 so as to adjust the distance between the movable and stationary rotary workheads 16 and 14 to the length of the non-processed workpiece.
[0051] After a non-processed workpiece is secured to the fixers 14 b and 16 b, the directional control valve 68 is moved to one of the first and second positions so as to apply tensile or compressive force to the non-processed workpiece. Then, the on-off valve 76 is opened in order to clamp the slider to the guide rails 20 by the air brake 72 . This allows the non-processed workpiece to be applied with tensile or compressive force even if the directional control valve 68 is moved to the neutral position and the hydraulic pressure to the hydraulic cylinder 62 is blocked. Accordingly, the air brake 72 allows the supply of the hydraulic pressure to the hydraulic cylinder 62 to be blocked, and thus contributes to energy saving.
[0052] According the above-described first and second embodiments, a workpiece can be processed by controlling the three orthogonal liner feed axes, i.e., X-axis, Y-axis and Z-axis, and the two rotational feed axes, i.e., A-axis and B-axis with tensile or compressive force applied to the workpiece so as to increase apparently the rigidity of the workpiece. Therefore, even a thin and low rigidity workpiece, such as a turbine blade, can be successfully processed because the bending is very small and vibrations are not generated.
[0053] Further, according to the above-described first and second embodiments, it is not necessary to form a hydraulic cylinder in a tailstock, as described in patent document 1 , because the hydraulic cylinder 42 , providing means for biasing the movable rotary workhead 16 in the direction away from the stationary rotary workhead 14 , or the hydraulic cylinder 62 , providing means for biasing the movable rotary workhead 16 in the direction away from or toward the stationary rotary workhead 14 , can be disposed outside of the movable rotary workhead 16 . This avoids the necessity of a hydraulic cylinder formed in a narrow space of the movable rotary workhead 16 whereby the configuration is simplified and the cost is reduced.
[0054] Further, rotary workheads available in the market can be used as the stationary and movable rotary workheads 14 and 16 , which remarkably reduces the production cost. If commercial products are used for the stationary and movable rotary workheads 14 and 16 , it is advantageous for users, because a special operation is not required. Further, when a problem occurs, it can be quickly fixed by replacing the broken rotary workhead with a commercial product, and therefore the downtime of the machine tool 100 is reduced.
[0055] Furthermore, according to the first and second embodiment, during the process of the workpiece W, a workpiece for the next process can be prepared, and therefore, the total processing time can be reduced compared with the invention of patent document 2.
[0056] Furthermore, by using the centering couplings 14 c and 16 c as the fixtures, when a workpiece is remounted to the rotary workhead device 50 after the workpiece has been once removed, the workpiece can be placed precisely in the previous position before the removal. | The rotary workhead device, which is loaded on the table of a machine tool and onto which a workpiece to be machined is rotatably mounted, is equipped with: a base plate that is attached to the table of the machine tool; two rotary workheads that are provided on the base plate and disposed so that the axes of rotation coincide and the workpiece-fixing parts face each other; a guide means that is provided so as to be capable of moving at least one of the rotary workheads back and forth in the direction of the rotation axes; and an impelling means for impelling the one rotary workhead in a direction that separates or brings together the two rotary workheads. The rotary workhead device applies a tensile force or a compressive force on a workpiece, the respective ends of which are fixed between the two rotary workheads. | 1 |
CROSS REFERENCE TO RELATED APPLICATIONS
Provisional patent application 60/645,679 filed Jan. 21, 2005
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
N/A
BACKGROUND OF THE INVENTION
This invention relates to aerosol dispensing containers incorporating a bag holding a product to be dispensed and a propellant chamber formed between the bag and container sidewall, and more particularly, to an improved grommet or fill valve (sometimes also referred to as an umbrella valve or seal valve) by which a propellant is introduced into the container and retained therein until all the product in the container is dispensed. Alternately, the container may employ a piston on one side of which is the product to be dispensed and on the other side of which is the propellant chamber. Again, the improved fill valve allows a propellant to be introduced into the chamber and retained therein until all the product is dispensed.
Certain types of aerosol containers include a collapsible bag or pouch disposed within the container. The bag or pouch is filled with a fluent material dispensed by the container. A propellant chamber is formed between the bag and container sidewall. At the base of the container, on a domed bottom surface thereof, an opening is formed and a fill valve is seated in this opening. During manufacture, after the bag or pouch is seated in the container and a dispensing valve attached to the top of the container, a propellant is injected into the container. For a 7 ounce container, 10-12 grams of a propellant such as butane is injected. To inject the propellant, the fill valve is unseated so propellant can flow into the chamber around the valve. The fill valve has a stem which fits through the opening, an inner sealing element formed on one end of the stem, and a “bowtie” section formed on the outer end of the stem. Opposed longitudinally extending grooves extend from the bowtie section along the side of the stem. During filling, a nozzle presses against the bowtie section of the valve and pushes the valve a sufficient distance inwardly that the butane can flow through the grooves into the chamber. In addition, pressure of the butane causes the valve to flex upwardly to create a larger opening for the gas to enter the container. When the nozzle is withdrawn, the pressure in the chamber now forces the inner sealing element of the fill valve against the inner surface of the container bottom, sealing the container. An example of this type of aerosol container is shown in co-assigned U.S. Pat. No. 5,915,595.
A second type container utilizes a piston disposed in the container with the product to be dispensed being on an outlet valve side of the piston, and the other side of the piston partially forming a propellant chamber in which the butane is injected. The propellant is introduced into the container through a fill valve fitted in the base of the container in the same manner as described above.
Many of the bag-in-can modalities and all piston cans require a bottom gassing, after which the entry hole in the can base for the injection of the gas must be hermetically plugged. A variety of grommets have been developed. Those include U.S. Pat. No. 4,658,979 by Mietz et al. (Hereinafter “Mietz”). Mietz discloses a basic umbrella-shaped grommet used for a pressurized dispensing container. The grommet includes umbrella sealing means located within the container, shoulder means located outside of the container, and stem means joining the umbrella sealing means and the shoulder means. U.S. Pat. No. 6,729,362 by Scheindel (Hereinafter “Scheindel”). Scheindel also discloses a grommet for a pressurized dispensing container. The grommet is characterized by a resilient neck portion which is extended during the injection of propellant so that a passageway for the propellant is formed around the neck. After the charging is completed, the neck contracts creating a tight sealing between the grommet and the container bottom. The grommet may be thermoset molded using buna-N or neoprene or other known material. The grommet may be injection molded.
There are number of problems with the currently used grommets, however, both with respect to their design and manufacture. Although a number of attempts have been made, existing types of grommets do not properly seal, allowing propellant to leak out of the container subsequent to filling. Propellant leakage dramatically reduces the usefulness of a container to dispense product, and if enough propellant leaks out, the result is a “dead” container. A “dead” container is one on which, when the outlet valve is actuated, little or no product is dispensed. It will be understood that there is usually a significant time between when a container is filled and it is used. During this period when the container is being packaged, shipped, warehoused, sits on a shelf in a store, and finally purchased, any loss of propellant, however small, will affect the final usefulness of the can. It has been estimated that even a small leak can result in the loss of as much as 1 gm. of propellant a year.
Other, related problems occur during manufacture of the fill valve. Heretofore, fill valves have been made using a compression molding process which has been found to result in poor sealing because of poor cross-linking of the molded material during the manufacturing process, and compression setting. Cross-linking is the formation of chemical links between molecular chains in polymers. Compression set is a property of grommets that adversely affects their sealing capability. The result has been that even if a fill valve properly seals after filling; over time, propellant can still escape from the container because of poor compression set.
In addition to these factors, another factor causing poor sealing is the cryogenic process used to remove flash produced on a grommet during compression molding. After the molding process is completed, the fill valves are frozen and any extraneous material (the flash) is knocked or broken off the part. However, the freezing process can result in large and/or microscopic cracks being created in the grommet and these cracks become leakage paths for propellant to escape from the container.
It will be appreciated by those skilled in the art, that release of the propellant to the atmosphere adds to our environmental problems, regardless of how the propellant escapes. In addition, one “band aid” fix to loss of propellant is to inject more propellant into the container during filling than is otherwise needed, so even if some propellant escapes there is still sufficient propellant that product is adequately dispensed from the container. Further, manufacturers, fillers, or suppliers of the containers often have to replace “dead” containers adding to their warranty costs.
Another problem with previous fill valves has been that molded into each fill valve is indicia identifying the particular mold and mold cavity in which the fill valve is formed. This, of course, is to assist in trouble shooting if valves are found to be defective. Currently, this indicia is in the form of raised alphanumeric characters on one surface of the fill valve. It has been found that after manufacture, when the fill valves are placed on a conveyor which moves them to a container assembly station, the raised characters often cause the valves to not move smoothly along the conveyor, but rather more haphazardly. This can require additional manpower to insure that the fill valves do properly get to the assembly station and are properly oriented for insertion into the bottom of a container.
BRIEF SUMMARY OF THE INVENTION
The present invention is directed to an improved fill valve for use in an aerosol container to provide a better sealing capability. The fill valve is made using a flashless injection molding process rather than the compression molding process previously used. As part of this process, both the mold cavity and molding material are heated to elevated temperatures and this significantly improves the cross-linking which occurs during the molding process. Further, a section of the backside of the sealing area of the fill valve now has a recessed portion that improves flexing of the seal after propellant is injected into the container, thereby creating a more responsive seal. Information about the fill valve is now engraved on an out-of-the-way surface of the valve so to facilitate conveying of the valve during manufacture of a container.
This improved fill valve has a number of advantages over previous valves. One is a fill valve with more consistent dimensional and operational characteristics than previous fill valves. Importantly, the improved fill valve provides a more capable seal, and a valve less prone to the formation of leak paths through the valve. This significantly reduces the possibility of propellant leakage from a container, even containers with long shelf lives. This, in turn, reduces warranty returns and the associated costs of replacing a non-functioning or “dead” container. Additionally, because of the improved sealing capability, the reduction in leakage reduces pollution. It may also be possible to reduce the amount of propellant injected into a container during filling because, with less leakage, more propellant will remain in the container.
The elimination of unnecessary raised lettering also now makes it easier to handle and move significant volumes of fill valves during fabrication of a container.
Other objects and features will be in part apparent and in part pointed out hereinafter.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
The objects of the invention are achieved as set forth in the illustrative embodiments shown in the drawings which form a part of the specification.
FIGS. 1A and 1B are simplified representations of aerosol container using an improved fill valve of the present invention;
FIG. 2 is a perspective view of the fill valve;
FIG. 3A is plan view of one end of the fill valve and FIG. 3B is a sectional view of the valve taken along lines 3 B- 3 B in FIG. 3A ; and,
FIG. 4 is plan view of the opposite end of the fill valve.
Corresponding reference characters indicate corresponding parts throughout the several views of the drawings.
DETAILED DESCRIPTION OF INVENTION
The following detailed description illustrates the invention by way of example and not by way of limitation. This description will clearly enable one skilled in the art to make and use the invention, and describes several embodiments, adaptations, variations, alternatives and uses of the invention, including what I presently believe is the best mode of carrying out the invention. As various changes could be made in the above constructions without departing from the scope of the invention, it is intended that all matter contained in the above description or shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense.
Referring to FIG. 1A , an aerosol container 10 comprises a cylindrically shaped body 12 , a bottom, dome shaped end piece 14 , and an upper cap/valve assembly 16 . A product bag 18 is disposed in the container for dispensing a fluent product, and for this purpose, the container is filled with a propellant material, under pressure. End piece 14 has a central opening or aperture 20 formed in it, and a grommet or fill valve 22 of the present invention is seated in this opening to seal it. A propellant chamber 24 is formed in the lower end of the container and a propellant such as butane is injected into the container through valve 22 to pressurize this chamber during a filling operation.
In FIG. 1B , an aerosol container 30 comprises a cylindrically shaped body 32 , a bottom, dome shaped end piece 34 , and an upper cap/valve assembly 36 . A piston 38 is disposed in the container for dispensing the product, and again, the container is pressurized with a propellant material during a fill operation. End piece 34 has an aperture 40 formed in it and grommet or fill valve 22 is seated in this opening to seal it. A propellant chamber 44 is formed in the lower end of the container and the propellant is injected into the container through valve 22 to pressurize chamber 44 .
As shown in FIG. 2 , fill valve or grommet 22 comprises a unitary valve molded of a suitable elastomeric material in a multi-cavity mold. The valve is shown to have a first section 22 a , referred to as the “backend” of the valve, a central shaft section 22 b , and a head or “bowtie” section 22 c . Section 22 a is the greatest diameter portion of the valve. During fabrication of the container, the fill valve is pushed through opening 20 or 40 in the respective container 10 or 30 , from the inside of the container, using an appropriate tool. The “bowtie” section of the valve then projects through the respective opening to the outside of the container. The length of shaft 22 b is slightly greater than the thickness of the dome end of the container, so there is a slight play in the valve when first installed and before the container is pressurized with propellant.
A circumferential seal 46 is formed by the shoulder or rim portion of section 22 a which contacts or abuts against the inner face of the bottom 14 or 34 of container 10 or 30 . As noted, when the fill valve is first installed in the un-pressurized container, it fits loosely in place. However, after the container is filled with a propellant, the internal container pressure forces section 22 a of the fill valve tightly against the inner face of the container bottom. Seal 46 is now tightly pressed against this bottom wall surface of the container preventing leakage of propellant from the container.
On the other end 22 c of the fill valve, opposed grooves 48 a , 48 b are formed. The grooves extend longitudinally of section 22 c and into central shaft section 22 b of the fill valve. The grooves taper along the length of this section of the fill valve so that they terminate at the transition between this section and backend section 22 a of the valve. Section 22 c tapers outwardly from the outer end of the section to the abrupt transition between this portion of the fill valve and the section 22 b . A circumferential shoulder 50 is formed at the inner end of section 22 c where the transition occurs. During a container fill operation, a nozzle (not shown) is pressed against the outer end of section 22 c of the fill valve, forcing shoulder 50 against the outer face of the container bottom 14 or 34 . This action moves section 22 a of the valve away from opening 20 or 40 in the container. The grooves 48 a , 48 b formed in the fill valve now allow flow of propellant through opening 20 or 40 , into the propellant chamber 24 or 44 . When the nozzle is removed, the internal pressure in the container forces shoulder 46 of the valve to seal opening 20 or 40 as previously discussed.
The improved grommet or fill valve 22 of the present invention has a number of advantages of previous valves. One significant improvement is a better compression set from an increased cross-link density formed during the molding process and an improved elastomeric formulation. In the flashless injection molding process by which fill valves 22 are manufactured, the mold is maintained at a temperature necessary to cross-link the elastomer. The temperature of the elastomer injected into the mold to form the fill valves is at a temperature well above room temperature at the time of injection. In the fill valve of the present invention, the fact the mold and molding compound are heated to relatively high temperatures enhances the cross-linking process and substantially reduces the creation of leak paths. A particular advantage of the process by which the grommets are now made is that cryogenic deflashing of the fill valve is now unnecessary. Eliminating this manufacturing step prevents formation of cracks in the fill valve which could provide leakage paths for the propellant from the container in which the fill valve is installed
As shown in FIGS. 3A and 3B , an annular ring 52 is formed inwardly of the peripheral rim of section 22 a . Progressing further inwardly toward the center of the valve, an annular raised section 54 is formed. Inwardly of the raised section 54 is formed a section 56 which is stepped-down or recessed from the raised section 54 by approximately 0.007″. The recessed section 56 provides a number of advantages to fill valve 22 over previous valves.
First, it provides an area by which the elastomer injected into a mold cavity can be readily injected without the gate for the cavity getting in the way of the flow of compound into the cavity.
Second, the recess reduces the amount of friction present during the feeding of the product on an assembly line.
Third, the undercut reduces the amount of material required to make the fill valve and results in a valve which is more flexible than previous fill valves. This makes the valve easier to handle and also helps it provide a better seal when a container is pressurized with propellant.
At the center of the recessed section 56 is a depression or recess 58 . This recess 58 is designed to receive the end of a tool (not shown) used to insert fill valve 22 in the opening 20 or 40 in an aerosol container during fabrication of the container. The valve is inserted by pushing against section 22 a so to force the outer, smaller diameter end 22 c of the fill valve through the opening 20 or 40 .
Finally, previous fill valves had raised characters formed on the section 54 of the backside of the valve. As previously noted, this often complicated movement of the fill valves on a conveyor or inserting them into a container. Now, as shown in FIGS. 3A and 3B , the section 56 within annular ring 52 has pertinent information about the fill valve engraved on it. Specifically, this information identifies the mold and mold cavity in which the valve was formed. Such information is useful in analyzing productions problems which might occur so a mold or section of a mold which needs to be repaired or replaced is readily identified. Importantly, since this information is recorded in an out-of-the-way location but accessible location, this type of lettering is no longer required and the now “clean” surface of the backside of the fill valve makes it easier to handle the valve.
In view of the above, it will be seen that the several objects and advantages of the present invention have been achieved and other advantageous results have been obtained. | The present invention is directed to an improvement for a fill valve ( 22 ) for an aerosol container ( 10, 30 ) to provide better sealing capability. The fill valve is made using a flashless injection molding process in which both the mold cavity and molding material are heated to elevated temperatures to significantly improve cross-linking which occurs during the molding process. A backside ( 22 a ) of the fill valve now has a recessed portion ( 56 ) to facilitate ejection of the valve from a mold so leak paths are not created due to the forces applied to the valve during its extraction from the mold. The recessed portion reduces the amount of material required to make the fill valve and makes the fill valve flexible to aid in providing a good seal against leakage of a propellant from the container after filling. | 1 |
Subsets and Splits