Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
  • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
  • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F13/00—Bandages or dressings; Absorbent pads
  • A61F13/02—Adhesive bandages or dressings
  • A61F13/0276—Apparatus or processes for manufacturing adhesive dressings or bandages
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B26—HAND CUTTING TOOLS; CUTTING; SEVERING
  • B26D—CUTTING; DETAILS COMMON TO MACHINES FOR PERFORATING, PUNCHING, CUTTING-OUT, STAMPING-OUT OR SEVERING
  • B26D9/00—Cutting apparatus combined with punching or perforating apparatus or with dissimilar cutting apparatus
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B26—HAND CUTTING TOOLS; CUTTING; SEVERING
  • B26F—PERFORATING; PUNCHING; CUTTING-OUT; STAMPING-OUT; SEVERING BY MEANS OTHER THAN CUTTING
  • B26F1/00—Perforating; Punching; Cutting-out; Stamping-out; Apparatus therefor
  • B26F1/38—Cutting-out; Stamping-out
  • B26F1/384—Cutting-out; Stamping-out using rotating drums
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B26—HAND CUTTING TOOLS; CUTTING; SEVERING
  • B26F—PERFORATING; PUNCHING; CUTTING-OUT; STAMPING-OUT; SEVERING BY MEANS OTHER THAN CUTTING
  • B26F1/00—Perforating; Punching; Cutting-out; Stamping-out; Apparatus therefor
  • B26F1/38—Cutting-out; Stamping-out
  • B26F1/44—Cutters therefor; Dies therefor
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F13/00—Bandages or dressings; Absorbent pads
  • A61F13/02—Adhesive bandages or dressings
  • A61F13/0276—Apparatus or processes for manufacturing adhesive dressings or bandages
  • A61F2013/0296—Apparatus or processes for manufacturing adhesive dressings or bandages for making transdermal patches (chemical processes excluded)
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B26—HAND CUTTING TOOLS; CUTTING; SEVERING
  • B26F—PERFORATING; PUNCHING; CUTTING-OUT; STAMPING-OUT; SEVERING BY MEANS OTHER THAN CUTTING
  • B26F1/00—Perforating; Punching; Cutting-out; Stamping-out; Apparatus therefor
  • B26F1/38—Cutting-out; Stamping-out
  • B26F1/44—Cutters therefor; Dies therefor
  • B26F2001/4472—Cutting edge section features
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B26—HAND CUTTING TOOLS; CUTTING; SEVERING
  • B26F—PERFORATING; PUNCHING; CUTTING-OUT; STAMPING-OUT; SEVERING BY MEANS OTHER THAN CUTTING
  • B26F1/00—Perforating; Punching; Cutting-out; Stamping-out; Apparatus therefor
  • B26F1/38—Cutting-out; Stamping-out
  • B26F1/44—Cutters therefor; Dies therefor
  • B26F2001/4481—Cutters therefor; Dies therefor having special lateral or edge outlines or special surface shapes, e.g. apertures

Definitions

• the present invention relates to the field of manufacture of medical devices for the administration of a drug through the skin of a patient, and more particularly relates to a method and apparatus for the formation of such an article of manufacture having a layered laminate structure comprised of a backing layer, a drug-containing pressure sensitive adhesive layer, and a release layer or liner.
• the structure of the article of manufacture includes a backing to protect the pressure sensitive adhesive from contact with other objects and to prevent loss of the drug. Also included is a release liner which is to be removed from the pressure sensitive adhesive immediately prior to application thereof to the skin of the patient.
• a backing to protect the pressure sensitive adhesive from contact with other objects and to prevent loss of the drug.
• a release liner which is to be removed from the pressure sensitive adhesive immediately prior to application thereof to the skin of the patient.
• This release liner also forms, during processing, the means to carry a pressure sensitive drug-containing adhesive through the manufacturing and cutting operation thereafter.
• a non-releasable or primed backing material is applied over the adhesive.
• the result is a laminate in the form of a web containing an adhesive with a backing on one side and a disposable release liner on the other side.
• a shaped and precisely sized device is then formed by peripheral cutting through all the layers of the resulting web.
• the disposable release liner can then be removed and a second, scored release liner can be attached to the transdermal drug-containing adhesive.
• the liner can be first scored and assembled with the adhesive and the backing and then the laminate web cut to the desired dimensions.
• the purpose of the multi-step procedure for applying the backing and the release liner to the adhesive containing the drug is to avoid problems encountered when a scored release liner is used in processing. If a completely cut release liner is used prior to coating, the drug-containing adhesive can pass through the release liner at the score causing equipment problems, cracking, separation, heat damage, loss of raw materials, and possible exposure of factory workers to the drug or similar environmental concerns.
• the present invention overcomes the difficulties and disadvantages associated with prior art devices by providing a method and apparatus for simultaneously cutting an assembled transdermal drug delivery device from a web comprising a backing layer, a drug-containing pressure sensitive adhesive and release liner while at the same time scoring the release liner at a position intermediate to the periphery of the transdermal drug delivery device.
• Patent No. 1,963,393 which relates to the cutting of a laminated panel, particularly for a sun visor, to protect automobile drivers.
• the disclosure relates a panel formed of a sheet of thermal plastic material, which has a fabric on one side attached by an adhesive.
• the laminate of the subject transdermal drug delivery device includes one relatively hard surface, i.e., the release liner, a soft or flexible surface, i.e., the backing layer, and a dimensionally unstable inner layer, i.e., the drug- containing pressure sensitive adhesive.
• a further principal object of the invention is to provide a single step method which causes movement of the laminate web from which a transdermal drug delivery device is to be formed, while at the same time forming said device to a predetermined size and shape, while at the same time scoring the layer of said device used as a disposable release liner to a precise degree in a manner which will avoid premature release of the drug-containing adhesive any volatile solvent or the drug itself.
• Another object of the invention is to incorporate the foregoing objectives utilizing a rotary motion capable of continuous, precisely controlled and economical motion that is appropriate for efficient mass production of transdermal drug delivery devices.
• An additional object of the invention is to achieve the aforementioned cutting action along a line disposed between the rotating cylindrical members positively rotating at the same angular speed, resulting in cutting force being asserted in a substantially linear and precise manner, rather than being distributed across the entire periphery and intermediate (or center) in a less precisely controlled manner requiring greater force because all points are substantially simultaneously cut.
• a related object of the invention is to achieve the foregoing objects and advantages with an apparatus and method which avoids stopping and starting that is inherent in apparatus and methods which reciprocate, as is required in our prior invention disclosed in the cross-referenced related applications.
• a collateral object of the invention is to reduce the unit manufacturing cost of transdermal drug delivery devices by utilizing rotating machinery, as opposed to reciprocating machinery, to achieve higher production rates, less maintenance down time, ' and consequent lower maintenance cost such as typically results from replacement of reciprocating machinery with rotating machinery.
• a further object of the invention is to position the cutting edges about the circumference of a cylinder or roller while at the same time sizing the diameter of the cylinder such that a plurality of transdermal drug delivery devices can be cut from a moving laminate web in close packed arrangement and with a repeat length caused by prior sizing of cylinder diameter to minimize waste in the web from which the transdermal drug delivery devices are cut using the inventive apparatus and method.
• This positioning of the cutting edges about the circumference of the cylinder is such as to close pack the positioning to minimize waste of the web between the location of the transdermal drug delivery devices removed therefrom to achieve minimum waste and the greatest possible manufacturing economies.
• an apparatus including a plurality of cylinders in proximity to each other and disposed such that the axis of each is coplanar with the axis of the other.
• Each such cylinder is rotationally mounted in bearing means and supported thereby in a framework that permits the distance or pressure between the axes of the cylinders to be controlled.
• These cutting edges are of two types, generally being of a type to cut and size the laminate web entirely therethrough to form the transdermal drug delivery device from the laminate web, and also of a type used to score simultaneously the release liner without affecting the drug- containing pressure sensitive adhesive adjoining the release liner, nor the backing layer adjoining the drug-containing pressure sensitive adhesive.
• the other cylinder is disposed and positioned in a manner proximal the cutting cylinder. The two cylinders are simultaneously driven to achieve substantially identical surface speed and in such proximity as to just permit the laminate web to pass therethrough as said cylinders rotate on their axes.
• an apparatus comprising a rigid support means having a surface in the form of a first cylinder.
• This support cylinder has an axis and rotatably mounted on that axis is a shaft which, in turn, is mounted in bearing means, said bearing means being disposed within a framework.
• the support cylinder is later referred to as an anvil roller.
• First cutting means are fixedly mounted on a second cylinder having an axis and a shaft coaxial therewith and also being rotatably mounted within bearing means.
• Said bearing means are disposed within a frame such that the axis of the first or support cylinder (anvil roller) and the axis of the cutting cylinder (cutting roller) are coplanar, with at least one pair of said bearing means being controllably movable with respect to a second pair of said bearing means to controllably vary the distance and/or pressure between the axes of the anvil roller and the cutting roller.
• the first cutting means fixedly mounted on a surface of the cutting roller has a cutting edge extending outwardly from a surface of the cutting roller for a first predetermined distance.
• Said cutting edge is configured as a closed loop mounted on and projected above the surface of the cutting roller in a predetermined shape for defining a first region of the cutting roller surface.
• Second cutting means are fixedly mounted on and projected above the surface of the cutting roller within said first region, said second cutting means having a cutting edge extending outwardly from the cutting roller for a second predetermined distance, said second predetermined distance being less than said first predetermined distance, said second cutting means dividing said first region of the cutting cylinder surface to form first and second sub-regions thereof.
• a multilayered laminate web means includes a first layer of release liner, a second layer of a drug-containing pressure sensitive adhesive adhering to said release liner, and a third layer forming a backing adhering to the drug-containing pressure sensitive adhesive layer.
• Said laminate multilayered web is urged first layer first into communication with said first and second cutting means, said first cutting means being arranged to communicate with and penetrate through said first, second and third layers of said multilayered laminate web means, and said second cutting means being arranged to communicate with said first layer release liner only.
• Said urging is through the counter-rotation of the support cylinder and cutting cylinder in proximity to each other.
• a multilayered laminate web is urged between a pair of counter-rotating cylinders rotatably mounted in bearing means in proximity to each other, said multilayered laminate web being urged by said counter- rotation into a gap formed between a support cylinder and a cutting cylinder to achieve a cutting action of said multilayered laminate web along a line between the pair of cylinders and coplanar with the axis of both cylinders, with the method of cutting being established by a first cutting means fixedly mounted and projected on the surface of a cutting cylinder said first cutting means having a cutting edge extending outwardly from the cutting cylinder surface for a first predetermined distance.
• the cutting edge is configured as a closed loop in a predetermined shape for defining a first region projected on the cutting cylinder surface and having a second cutting edge fixedly mounted and projected on the cutting cylinder edge within said first region, said second cutting means having an edge portion extending outwardly from said cutting cylinder edge for a second predetermined distance.
• the second predetermined distance is less than said first predetermined distance, and said second cutting means divides said first region of said support cutting cylinder edge to form first and second sub-regions thereof.
• the laminate multilayered web means is formed of a first layer release liner, a second layer formed of a drug-containing pressure sensitive adhesive adhering to said first layer, and a third layer formed of a backing adhering to said second layer.
• the multilayered laminate web means is urged by the counter-rotation of the cylinders in proximity to each other into communication with first and second cutting means.
• the first cutting means is arranged to communicate with and penetrate through said first, second and third layers of said multilayered laminate web means, and said second cutting means is arranged to communicate with said first layer only.
• Figure 1 is a cross sectional view of a transdermal drug delivery device showing its multilayer laminate structure.
• Figure 2 is a perspective view showing the apparatus of the invention in its simplest form, on which only one cutting section is shown to form a single transdermal device.
• Figure 3 is a perspective view of a cutting roller showing a close packed arrangement of cutting sections over substantially the entire surface of the roller and also showing pressure journals, drive gear, and shaft ends.
• Figure 4 is a perspective view of a stack in which the pair of rollers shown in figure 2 are centrally disposed between a lower rubber covered nip roller, and an upper pressure roller.
• Figure 5 is a broken slightly enlarged view showing cutting sections at the top side and bottom of the cutting roller.
• Figure 6 is an alternative embodiment of half of figure 5 which employs a field of resilient material around the cutting sections to discharge the transdermal devices and scrap from the cutting roller after the transdermal device formation has occurred.
• Figure 7 is a greatly enlarged broken cross sectional view taken along the line 7-7 of figure 5 and showing the detail of the construction of a cutting section.
• Figure 8 shows the flow path of a laminate web through the invention. Conventional unwinding, scrap disposal, and proprietary transdermal device pick-up and packaging equipment are shown only generally since they are not a part of the present invention.
• FIG. 1 is a cross section view of the laminate multilayer transdermal drug delivery device 10 and also the web material from which it is formed by the present invention.
• the laminate web or transdermal device 10 is comprised of a release liner 12, a drug-containing pressure sensitive adhesive layer 14, and a backing layer 16.
• Figure 2 shows the essence of the invention in perspective view with a cutting roller 18 which rotates on axis 20 and an anvil roller 22 which rotates on axis 24.
• cutting roller 18 may, for example, rotate on axis 20 counter-clockwise and then anvil roller 22 will rotate on axis 24 clockwise. They will preferably be driven together positively so as to operate with the same surface speed.
• a cutting section 30 having a peripheral cutting edge 32 and a center cutting edge 34.
• Figure 3 illustrates a preferred embodiment of a cutting roller such as 18, except that this cutting roller 36 has the maximum number of cutting sections 30 disposed on its face in a close packed arrangement so as to minimize the losses resulting from scrap.
• All of the material in web 10 from which the transdermal devices are cut disposed between cutting sections 30 and 30' as shown at 38 constitutes scrap, which scrap necessarily includes not only backing material, release liner, and pressure sensitive adhesive, but also the drug for which the transdermal device formed by the present invention is to be used, which drug may be expensive.
• the preferred embodiment of the cutting roller show in figure 3 is to minimize scrap.
• the cutting roller of figure 3 is also shown with pressure journals 40 and 42. The purpose of these journals will be illustrated in the following figure.
• FIG. 4 illustrates in perspective view the apparatus of the present invention through which the inventive method is practiced. Shown therein is a base 50 on which are mounted drive side frame 52 and operator side frame 54. Vertical columns 56 of drive side frame 52 and 58 of operator side frame 54 all contain precision machined interior surfaces 60 for slidable engagement of bearing blocks 62, 64, 66, and 68.
• Anvil roller bearing blocks 70 and 72 are not slidable.
• Drive side frame 52 and operator side frame 54 both contain a top 72 centrally perforated by a threaded hole 74 through which is disposed a threaded pressure applicator 76 which is rotated for that purpose using knurled knob 78.
• pressure roller 80 Rotationally disposed between bearing block 68 and bearing blo ' ck 62 and 68, is pressure roller 80 which contains symmetrically at both ends, a pressure journal 82 having a precision machined circumference 84.
• Disposed between bearing blocks 64 and 66 is cutting roller 86 on which can be seen pressure journal 42 and spur gear 48. Also shown are a plurality of cutting sections 30.
• Frame 52 retains lips 88 which ride over the inside surfaces of vertical columns 56 thereby restraining bearing blocks within drive side frame 52 notwithstanding their vertical movement. These lips 88 are also found in symmetrical form on bearing blocks 62 and 64 in the internal sides of operator's side frame 54. The pattern is symmetrical with that shown for the drive side and need not, therefore, be separately shown.
• Another aspect of the relationship between pressure roller 80 and cutting roller 86 is the existence of an optional strain gauge 90 as shown between bearing block 62 and bearing block 64 on the operator's side.
• a companion strain gauge is also employed on the drive side in symmetrical form, and strain gauges 90 cooperate with conventional electronic equipment to permit reproducibility of the pressure applied to cutting roller 86 by pressure roller 80.
• Anvil roller 92 Rotationally supported between bearing blocks 70 and 72 is anvil roller 92 which cooperates with the cutting edges of cutting sections 30 to size and form the transdermal drug delivery devices.
• Anvil roller 92 includes, on the drive end, spur gear 94 which interconnects with cutting roller spur gear 48 to achieve a positive drive between anvil roller 92 and cutting roller 86. It is anvil roller 92 which is preferably driven by mechanical means connected to its drive shaft that penetrates bearing block 72, but the drive means is conventional and not shown.
• anvil roller 92 The entire circumference of anvil roller 92 is preferably precision machined, but this is particularly important at the ends because of contact with pressure journal 42 on the drive side and a symmetrical pressure journal 40 not visible in figure 4, but readily seen in figure 3. Pressure journals 42 and 40 establish a precise minimum spacing between anvil roller 92 and the cutting edges of cutting sections 30 on the surface of cutting roller 86.
• the bottom roller in this stack is a rubber covered nip roller 96 which is not driven, except by contact with or pressure communicated from anvil roller 92. It is brought into contact by an adjusting mechanism which may optionally be eccentric 96, which is symmetrically provided at both the operator's side frame 54 as illustrated in figure 4, and also at drive side frame 52.
• the combination of anvil roller 92 and rubber nip roller 96 feed the laminate layered web of figure 1 into the previously described combination to achieve the inventive method using the inventive apparatus.
• FIG 5 a broken front elevation view of cutting roller 86 is shown in a slightly enlarged view with cutting sections 30 at the top and bottom of the roller and also on the side facing the viewer.
• cutting sections 30 are comprised of a peripheral cutting edge 32 and an intermediate or center cutting edge 34.
• Peripheral cutting edge 32 is shown to wrap around the circumference of the roller in this figure.
• peripheral cutting edge 32 is intended to cut entirely through release layer 12, drug-containing pressure sensitive layer 14, and backing layer 16 as illustrated in figure 1, while center cutting edge 34 is intended to score release liner 12 without entering drug-containing pressure sensitive adhesive layer 14 or backing layer 16.
• the present invention represents several improvements over similar technology that is the subject of our prior application Serial No. 407,874, now U. S. Patent No. 5,032,207, which employed similar dimensional technology in a planar, reciprocating, total cut at one time, separately fed technique.
• the present inventive method and apparatus achieved cutting essentially along a line representing the closest point between the cutting edges of cutting sections 30 of cutting roller 86 as seen in figure 4 and the surface of anvil roller 92.
• cutting roller 86 translates by rotation of cutting roller 86 past the aforedescribed line
• cutting takes place progressively around the circumference of a given transdermal drug delivery device as the same translates through the closest proximity between the anvil roller and the cutting roller.
• this motion also feeds the web at precisely the right speed to achieve a quality cut with maximum efficiency.
• the same also results in a continuous rotary motion thereby eliminating reciprocating motion which is inefficient, maintenance prone, slow, and less subject to uniformity.
• Figure 6 shows an alternative embodiment to that shown in the previous figures in which the cutting- sections 30 are surrounded by a layer of highly resilient material, such as a foam rubber 98.
• Foam rubber 98 will be seen not only to surround the peripheral cutting edge 32, but is disposed on either side of center cutting edge 34 as shown at 100.
• the resilient material 98 and 100 is intended to achieve rapid discharge of the cut transdermal devices from cutting roller 86 as well as the scrap left after cutting as shown at 38 in this figure, and in figure 2.
• Figure 7 is a greatly enlarged cross sectional view of cutting section 30 taken along the line 7-7 of figure 5. It shows that, contrary to the disclosure of our parent application Serial No. 407,874, now U.S. Patent No. 5,032,207 the peripheral cutting edge 32 is in the form of an inverted V. That is also the configuration of center cutting edge 34 as illustrated in figures 5 and 6. The difference in height between peripheral cutting edge 34 and center cutting edge 32, which has a shorter dimension is clearly shown by the great enlargement of figure 7.
• the peripheral cutting edge 32 generally has a circumference of from 3 to 40 mm and preferably from 7.9 to 17.7 mm depending on the surface areas appropriate for delivery of the drug. It has a radius of 0.48 to 6.4 mm, and preferably 1.3 to 2.8 mm, again depending on the appropriate radius for the drug to be delivered, as is known to those skilled in the art.
• peripheral cutting edge 32 is sized, in cooperation with the thickness of the web shown in figure 1 to pass completely through the web, thus cutting through the release liner 12, drug- containing pressure sensitive adhesive layer 14, and backing material 16.
• center cutting edge 34 scores the release liner 12 and does not penetrate drug-containing pressure sensitive adhesive layer 14 or backing liner 16.
• 32 is preferably from 100 to 1,500 microns in height from the base surface of cutting roller 86, and more preferably 900 to 1,000 microns, and even more preferably 930 to 950 microns, although obviously the height of the cutting edge is dependent on the thickness of the web.
• center cutting edge 34 is preferably 100 to 1,500 microns, and more preferably 850 to 950 microns, and even more preferably 925 to 945 microns, although again the height is totally dependent on the thickness of the release liner. For example, with a web of 10 microns in thickness where the release liner is 6 microns in thickness, cutting edge 32 would be 937 microns in height, which center cutting edge 34 would be 935 microns in height. That is, center cutting edge 34 has to extend sufficiently into the release liner to cause a score, but not sufficiently to cut the drug-containing pressure sensitive adhesive layer.
• FIG 8 a schematic is shown of the web path by which the inventive method and apparatus operates.
• a quantity or stock of a laminate multilayer web as shown in figure 1, preferably in rolled form, is provided to the inventive apparatus and method and unwound using conventional technology as shown at 102.
• the web 10 enters the stack of rollers beneath a lower rubber cover nip roller 96 whose speed is derived by contact with or pressure transmitted from anvil roller 92.
• the rotational speed and diameter of rubber covered roller 96 sets the web 10 speed into exact conformity with a continuous rotary motion cutting that occurs thereafter. That is, the speed of web 10 is achieved by contact with rubber covered nip roller 96, in contact and combination with the speed of anvil roller 92.
• Web 10 then travels from between the nip formed by rubber covered nip roller 96 and anvil roller 92 around to the top of anvil roller 92 to enter into the cutting method and apparatus as occurs between cutting roller 86 and anvil roller 92 as hereinabove described.
• the web 10 is now comprised of scrap material surrounding each of the cutting sections 30 and the transdermal devices which maintain momentarily their position within web 10.
• Web 10 then travels across a transfer plate 104, which is perforated to prevent the buildup of adhesion or static electricity.
• the transdermal drug delivery devices are then removed from the web and packaged for storage, shipment, sale, and use, using equipment generally described for that purpose at 106. The same is not shown, described, or claimed in the present application as not constituting part of the present invention although it is proprietary.
• the remainder of web 10 constituting scrap is then continuously fed to waste disposal 108, of conventional means.

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• Engineering & Computer Science (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Mechanical Engineering (AREA)
• Forests & Forestry (AREA)
• Dermatology (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Vascular Medicine (AREA)
• Heart & Thoracic Surgery (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Biomedical Technology (AREA)
• Manufacturing & Machinery (AREA)
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• 1992
  • 1992-04-24 EP EP92912870A patent/EP0592481A1/de not_active Withdrawn
  • 1992-04-24 SG SG1996009225A patent/SG43349A1/en unknown
  • 1992-04-24 WO PCT/US1992/003326 patent/WO1992019451A1/en not_active Application Discontinuation
  • 1992-04-24 CA CA002109099A patent/CA2109099C/en not_active Expired - Lifetime
  • 1992-04-24 AU AU20040/92A patent/AU2004092A/en not_active Abandoned

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