Classifications

• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
  • C08J5/00—Manufacture of articles or shaped materials containing macromolecular substances
  • C08J5/18—Manufacture of films or sheets
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B42/00—Surgical gloves; Finger-stalls specially adapted for surgery; Devices for handling or treatment thereof
• • 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
  • A61F6/00—Contraceptive devices; Pessaries; Applicators therefor
  • A61F6/02—Contraceptive devices; Pessaries; Applicators therefor for use by males
  • A61F6/04—Condoms, sheaths or the like, e.g. combined with devices protecting against contagion
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/04—Macromolecular materials
  • A61L31/043—Proteins; Polypeptides; Degradation products thereof
  • A61L31/044—Collagen
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
  • B01D71/06—Organic material
  • B01D71/74—Natural macromolecular material or derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
  • C08L89/00—Compositions of proteins; Compositions of derivatives thereof
  • C08L89/04—Products derived from waste materials, e.g. horn, hoof or hair
  • C08L89/06—Products derived from waste materials, e.g. horn, hoof or hair derived from leather or skin, e.g. gelatin
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
  • C08J2389/00—Characterised by the use of proteins; Derivatives thereof
  • C08J2389/04—Products derived from waste materials, e.g. horn, hoof or hair
  • C08J2389/06—Products derived from waste materials, e.g. horn, hoof or hair derived from leather or skin

Definitions

• the present invention relates to a collagen gel and to a process for obtaining it, to film articles made therefrom and to a process for making said articles. More particularly, the present invention relates to an improved homogeneous collagen gel, which can be used in the manufac ⁇ ture of collagen film articles of improved thinness and smoothness, superior strength, and superior homogeneity, to a process for obtaining the improved gel, and to film articles made therefrom and possessing the above-described superior properties.
• Articles encompassed by the present invention include but are not limited to condoms, vaginal diaphragms, surgical gloves, films, permeable membranes, tubing, etc.
• Ceca are naturally thin membranes resulting in articles of rather satisfactory strength and, in contrast with natural and synthetic elastomers, increased sensiti ⁇ vity and gas permeability. However, ceca are limited in quantity and expensive to prepare. In addition, ceca have
• OMPI c ⁇ , WIPO , v an unpleasant appearance as they cannot be freed of "veins", i.e., surface irregularities remaining after removal of fatty or muscle tissue.
• Collagen gels of the prior art were Theologically non-homogeneous and contaminated with ligamentous particles. Very thin, smooth films with uniform strength were diffi ⁇ cult to prepare from these gels and were unsuitable for many of the above mentioned uses.
• Miyata discloses a collagen condom made prefer ⁇ ably from the achilles tendon of young animals. Unfor- 5 tunately, achilles tendon is not commercially available as it is usually left on the animal carcass through the meat retail stage. In addition, the collagen treatment dis ⁇ closed by Miyata results in a collagen film that is not sufficiently strong and cannot be * economically used in 0 large scale production of condoms or other film articles.
• a method of making collagen gel suitable for use in the manufacture of thin collagen film articles having superior mechanical properties comprising: (a) providing clean frozen animal tendon containing at least 30% collagen and free of ligamentous tissue;
• Another aspect of the present invention relates to a gel made by the above method.
• Yet another aspect of the present invention relates to a method for making film using the above gel, said method comprising:
• tanning said film in a tanning solution containing 0.05 - 1.0% based on weight of an aldehyde selected from the group consisting of formaldehyde, glutaraldehyde and glyoxal, for about 30 sec. to 5 min.;
• the film can be formed by adding starch to the gel in an amount up to about 100% by weight based on the colllagen solids, forming the film as above, drying at 65-95*C for a time sufficient for crosslinking to take place, washing the film as above with or without tanning and removing the film from the substrate.
• a further aspect of the present invention relates to a collagen film article made by using the above film-making method.
• BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a schematic diagram of a erocess for making collagen gel from tendon material.
• Figure 2 is a schematic diagram of a process for making a collagen film article from collagen gel.
• Figure 3 is a schematic diagram of a process for making a tubular film article such as a condom.
• the collagen raw material for the present invention should have a high collagen content (preferably at least about 30-45%), should be relatively free of ligamentous tissue which is resistant to swelling, and should yield a homogeneous and easily processable collagen gel. In addition, it should be readily available on a large scale and economically recoverable and processable.
• a suitable source of collagen for the present invention is animal tendon. Preferred, is tendon from higher animals such as cattle, sheep, pigs, etc. and especially preferred are bovine digital flexor tendons. Achilles and other tendons would also be suitable, but they are not commer ⁇ cially available. Hide collagen from limed tannery split is also suitable but the economics of limed split proces ⁇ sing are unattractive.
• bovine digital flexor tendons 1, are cleaned, frozen and then ground in an ordinary commercial grinder such as "Butcher Boy",1/ 2, to suitable size pieces (usually 3/16 - 3/8 in.). Ground tendon is dispersed in water (to which
• Rhozyme-41 has been added) and comminuted in a microcutter, 4, (such as a "Stephan” machine, manufactured in West Germany by A. Stephan ⁇ Sohne, GmbH).
• Model TCA-32 manufactured by Lasar Mfg. Co., Inc., Los Angeles, California. the microcutter is sufficient. More than one pass at this stage, adversely affects strength.
• the blade spacing of the microcutter also affects strength of the fiftal product. Generally, the closer the blade spacing, the higher the strength.
• the preferred minimum spacing is 1 mm. Closer spacing (i.e. less than 1 mm) results in reduced throughput and increases the risk of overheating, while wider spacing (e.g. 1.5 mm and over) results in reduced strength. Microcutting may be postponed until after acidification, but if conducted before, a more homogeneous gel results.
• Rhozyme-41 is a proteolytic enzyme derived from Aspergillus oryzae which is advantageously used to break down elastin, which surrounds collagen fibrils and binds them together, as well as other non-collagenous components, the presence of which weakens strength of the final product.
• the enzyme effectively eliminates such undesirable com ⁇ ponents while leaving collagen fibrils substantially intact for maximum strength results.
• Rhozyme-41 (manufac ⁇ tured by Corning Glass Biochemicals, a division of Corning Glass, Inc., Corning, New York), is particularly preferred as it does not require use of either an activator such as cysteine, or an inactivator such as peroxide, and it results in fabricated collagen film articles with tensile strength superior to that of naturally occurring collagen films and superior to that of collagen film articles or films produced using other enzymes, such as pancreatin, ficin, etc.
• Rhozy e 41 is used in an amount ranging between about 0.1 and 0.5% on the basis of dry collagen solids in the slurry. Enzyme treatment, (digestion), 5 may last from about 3 to about 24 hours at room temperature " with 15-18 hrs. being most preferred.
• Blending by e.g. passing the enzyme- containing slurry once through the microcutter, 4, dis ⁇ perses the enzyme uniformly and facilitates enzyme action. Enzyme deactivation, the end of the enzyme treatment, is not necessary when using Rhozyme 41, but may be accomp ⁇ lished,, if desired, by addition of hydrogen peroxide in an amount at least sufficient to deactivate the enzyme, followed by stirring. Slightly higher peroxide amounts are acceptable but unnecessary. 16.5% H 2 0 2 on a dry collagen solid basis is preferred. After addition of peroxide and stirring, the suspension is allowed to stand, preferably for approximately 45 minutes.
• the enzyme-treated slurry is ready for acid swelling, 6.
• Choice of the acid affects the degree of swelling and the strength of the ultimate product. Most preferred are. lactic and maleic acids, but other organic acids such as succinic acid, oxalic acid, malic acid and tartaric acid may be used with satisfactory results.
• Inorganic acids such as HC1 and H.po. impart less swelling and reduced viscosity and produce lower strength causing the film to split during drying. Other properties, such as odor and toxicity may affect choice of the acid depending on the end use of the collagen film or article. Cost is also a factor to be considered.
• a sufficient quantity of acid is added to the slurry to lower the pH to about 3 for maximum tensile strength.
• Lowering the pH to about 2 increases cost because more acid is used, causes the film to adhere to substrates and presents a problem during film forming.
• a pH higher than about 3 fails to accomplish sufficient swelling. Accordingly, a pH of about 3 is preferred.
• the preferred amount is 82% by weight on a dry collagen solids basis.
• Strength of the final product is further enhanced if a small amount of aldehyde is added to the slurry during acid addition to effect partial cross-linking of the collagen.
• Formaldehyde is preferred over glutaraldehyde and glyoxal.
• a preferred amount is 0.36% formaldehyde based on dry collagen solids. After acid swelling, bundles of collagen fibers are still present in the gel. At this point, one pass through a microcutter with a blade clearance of 1 mm is useful to disrupt the remaining fiber bundles, and thus to blend and homogenize the gel.
• Both the acid and the formaldehyde are preferably added to the slurry at the point of its introduction into the microcutter 6.
• the resulting gel is further homogenized and dearated by mixing, 7, in e.g., a Ross planetary raixer-1/ under vacuum.
• the gel is ready for film and article formation.
• the gel prefer ⁇ ably contains about 0.95 to 1.3% total solids, most preferably, about 1.2% solids.
• Preferred gel viscosity is about 1300 to about 3000 cps, most preferably 1200 cps, for dipping, and higher for extrusion.
• Rhozyme-41 0.10bg 0.136g formaldehyde 0.83m1 1.04m1 lactic acid 54m1 68m1 total solids of gel 1.15% 1.47% pH 2.7 2.7 viscosity 1320 cps 2660cps
• Film thickness may be increased, if desired, without increasing the number of gel coats (the increase in thickness is proportional to starch content).
• Viscosity of the gel is substantially unaffected even after addition of relatively large amounts of starch (up to about at least 100% by weight based on collagen solids in the gel). Accordingly, film formation is not inhibited.
• the gel becomes translucent (instead of transparent) and acquires a skin-like feel and appearance. This is particularly desirable when manufacturing condoms.
• the unit cost of corn starch is about 10% that of collagen solids. Moreover, less expensive equipment such as molds or substrates for film formation may be used because of the improved flexibility, elasticity and releasability of the film.
• the process for making gel that will result in translucent film is the same as that for making gel that will result in clear film through the Rhozyme digestion step. After digestion, a starch suspension to which the required amounts of formaldehyde and lactic acid have been added is mixed into the enzyme digested collagen dispersion. The resulting mixture contains about 20-100% of starch by weight based on the collagen solids content of the slurry and most preferably about 60% of starch.
• a thin layer of film is formed by applying, 21, at least one coat of gel on a substrate surface.
• the substrate may be a mold such as a mandrel which may be dipped in the collagen gel. Film thickness is controlled by the viscosity and solids content of the gel, and the number of such dippings or coats.
• the thus formed film is subsequently dried in air, 22 at about 65-95oC and preferably at about 85oC.
• a four coat film is dried after the deposition of each of the first two coats 31, at which time a retaining elastic band 32, is placed on the film at the upper part of the mandrel 33 (See Fig. 3). Over the first two coats (and the elastic band) each of two additional coats is deposited and dried. After drying of the fourth coat and the remaining process steps (described below) are completed, the film including the band may simply be rolled off the mandrel.
• a tubular article such as a condom is formed from clear gel, the following method is used.
• a mandrel is used as a mold.
• the mandrel is preferably made from an acrylic polymer (such as plexi- tapered cylindrical shape (as shown in Fig. 3).
• the mandrel is dipped in the gel and air dried repeatedly as many times as desired. Each dipping causes deposition of a thin coat of gel on the mandrel or on the previously deposited coat.
• Four coats of clear gel of the most preferred composition described above are sufficient to produce a film 30-35 microns thick, which is the preferred thickness for a condom of this type.
• the mandrel is preferably rotated in opposite directions during each of successive dippings.
• the rotation of the mandrel is preferably adjusted so as to produce a film of about 20% more strength in the longitudinal (as compared to the transverse) direction, i.e. in the direc ⁇ tion parallel to the mandrel axis.
• the preferred mandrel rate of rotation ranges between about 0.4 and 0.8 times most preferably 0.63 times the rate at which the mandrel is withdrawn from the gel.
• the finally dried film is neutralized 23, by soaking the film gel in an alkaline bath such as a 0.14-1.3N ammonium hydroxide bath (preferably 0.71% NH 4 OH) for 30 sec. - 5 min. , preferably 1.5 min. Hydroxides of alkali metals such as sodium or potassium may also be used but NH.OH is preferred for its ease of removal from the film. Thereafter, the neutralized film is rinsed with water, 24.
• an alkaline bath such as a 0.14-1.3N ammonium hydroxide bath (preferably 0.71% NH 4 OH) for 30 sec. - 5 min. , preferably 1.5 min.
• Hydroxides of alkali metals such as sodium or potassium may also be used but NH.OH is preferred for its ease of removal from the film.
• the neutralized film is rinsed with water, 24.
• the rinsed film is tanned for about 30 sec. - 5 min., preferably for 30 sec, in a tanning solution, 25, containing 0.05-1.0% (at a pH 6.9-4.5) and preferably 0.1% (at a pH of 6.8) glutaraldehyde mainly to enhance film and stability, and to facilitate separation of the film from the mandrel.
• the duration of the tanning step should be kept to a minimum as overtanning will make the film brittle.
• glutaraldehyde it is possible to use formaldehyde or glyoxal.
• tanning agents such as reducing sugars, chromium salts or vegetable tannins may also be used, but they produce lower tensile strengths, and may be unsuitable for some applications of the present invention.
• the excess tanning solution is removed by rinsing in water and the thus prepared film is removed from the mandrel or other substrate.
• a condom is made from translucent (starch- containing gel)
• the procedure is generally the same as above, except that, if a mandrel is used, a less expensive tapered glass mandrel may be substituted for the acrylic one.
• tanning is unnecessary.
• the dried film is neutralized as in the transparent film case, and afterwards it is washed and removed from the mandrel.
• Four coats of gel are also preferred. If the gel contains 60% starch, as is preferred, a final film thickness of 55 +- 5 microns will result.
• Example 1 serve to further illustrate the present invention but not to limit its scope.
• Bovine digital flexor tendon was ground through a plate with 3/16" diameter holes.
• the coarsely ground tendon contained 42.4% solids.
• a 0.308 Kg portion of the ground tendon was dispersed into 11.05 Kg water at 15oC, to which had been added 0.131 g Rhozyme-41.
• the total dispersion was passed once through a Stephan Microcutter with a 1mm blade clearance.
• the comminuted mass was allowed to stand at room temperature to allow the enzyme to work.
• 70 ml of lactic acid containing 1 ml 37% formaldehyde were stirred into the enzyme treated slurry.
• the acidified mass was passed once through the Microcutter to enhance swelling and to homogenize the resultant gel.
• the homogenized gel was transferred to a Ross planetary mixer and stirred under vacuum for 20 minutes to remove entrained air.
• the gel had a solids content of 1.35% and a viscosity of 1192 cps.
• Example 3 7.20 Kg H-0 containing 0.131 g Rhozyme-41.
• the disper ⁇ sion was comminuted and digested as in Example 1. Then 3.64 Kg. H-0 containing 26.1 g starch, 1 ml formaldehyde and 65 ml lactic acid was stirred into the digested slurry, and the acidified slurry was passed once through the Microcutter then deaerated. The resulting gel had a solids content of 1.51% and viscosity of 1278 cps.
• a film made as in Example 1 had a wet thickness of 47 microns and a wet breaking strength of 2.41 kg.
• Example 3 Example 3
• Example 4 A gel was made exactly as in Example 2 except that 130.5 g of starch were used. The resulting gel had a solids content of 2.69%, and viscosity of 1212 cps. Film made as in Example 1 had a wet thickness of 65 microns and breaking strength of 2.23 Kg. Example 4
• Example 3 355 g of tendon containing 36.738 solids were used to make a gel as in Example 3. The gel had a solids content of 2.07%, and viscosity of 1390 cps. Films were made as in Example 3 except that the dried films were not treated with ammonium hydroxide and • glutaraldehyde. Instead the dried films were washed with water for 30 minutes, and then removed from the mandrels. The wet film was 47 microns thick and had a breaking strength of 1.70 Kg.
• Example 5 355 g of tendon containing 36.738 solids were used to make a gel as in Example 3. The gel had a solids content of 2.07%, and viscosity of 1390 cps. Films were made as in Example 3 except that the dried films were not treated with ammonium hydroxide and • glutaraldehyde. Instead the dried films were washed with water for 30 minutes, and then removed from the mandrels. The wet film was 47 microns thick
• Example 4 A gel as in Example 4, except that after addition of the lactic acid, starch, formaldehyde mixture the acidified slurry was allowed to age 24 hours at 4oC before microcutting and deaeration.
• the gel contained 2.02% 0 solids and had a viscosity of 1194 cps.
• Films made from this gel as in Example 4 had wet thickness of 52 iprons and breaking strength of 2.26 Kg.
• Example 6 A gel was made as in Example 5. It contained 5 1.98% solids and its viscosity was 970 cps. Films were made as in Example 3, except that the glutaraldehyde treatment was omitted. The wet film was 52 microns thick and had a breaking strength of 2.31 Kg.

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• Heart & Thoracic Surgery (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Animal Behavior & Ethology (AREA)
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• 1984
  • 1984-10-26 WO PCT/US1984/001744 patent/WO1985001949A1/en not_active Application Discontinuation
  • 1984-10-26 JP JP59504117A patent/JPS61501153A/ja active Granted
  • 1984-10-26 EP EP19840904240 patent/EP0162077A4/en not_active Withdrawn
  • 1984-10-26 AU AU36156/84A patent/AU579122B2/en not_active Ceased
  • 1984-10-29 ZA ZA848412A patent/ZA848412B/xx unknown
  • 1984-10-29 CA CA000466495A patent/CA1239103A/en not_active Expired
  • 1984-10-30 IT IT8468083A patent/IT1196752B/it active
  • 1984-10-30 NZ NZ210035A patent/NZ210035A/xx unknown
  • 1984-10-31 ES ES537299A patent/ES8605825A1/es not_active Expired
  • 1984-11-13 IN IN860/MAS/84A patent/IN163124B/en unknown
• 1985
  • 1985-05-17 FI FI851993A patent/FI82703C/fi not_active IP Right Cessation

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