WO1982002716A1 - Modified synthetic hydrogels - Google Patents
Modified synthetic hydrogels Download PDFInfo
- Publication number
- WO1982002716A1 WO1982002716A1 PCT/US1982/000157 US8200157W WO8202716A1 WO 1982002716 A1 WO1982002716 A1 WO 1982002716A1 US 8200157 W US8200157 W US 8200157W WO 8202716 A1 WO8202716 A1 WO 8202716A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- weight percent
- collagen
- hydrogel
- oxygen
- carbon atoms
- Prior art date
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- 239000001405 butyl (E)-3-phenylprop-2-enoate Substances 0.000 description 1
- OHHIVLJVBNCSHV-KTKRTIGZSA-N butyl cinnamate Chemical compound CCCCOC(=O)\C=C/C1=CC=CC=C1 OHHIVLJVBNCSHV-KTKRTIGZSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 229940018560 citraconate Drugs 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- JJCFRYNCJDLXIK-UHFFFAOYSA-N cyproheptadine Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2C=CC2=CC=CC=C21 JJCFRYNCJDLXIK-UHFFFAOYSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- VVYDVQWJZWRVPE-UHFFFAOYSA-L dimethyltin(2+);diiodide Chemical compound C[Sn](C)(I)I VVYDVQWJZWRVPE-UHFFFAOYSA-L 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 229940124274 edetate disodium Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- FFYWKOUKJFCBAM-UHFFFAOYSA-N ethenyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OC=C FFYWKOUKJFCBAM-UHFFFAOYSA-N 0.000 description 1
- SUPCQIBBMFXVTL-UHFFFAOYSA-N ethyl 2-methylprop-2-enoate Chemical compound CCOC(=O)C(C)=C SUPCQIBBMFXVTL-UHFFFAOYSA-N 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000010528 free radical solution polymerization reaction Methods 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 229940015043 glyoxal Drugs 0.000 description 1
- 238000010559 graft polymerization reaction Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- JDSHMPZPIAZGSV-UHFFFAOYSA-N melamine Chemical compound NC1=NC(N)=NC(N)=N1 JDSHMPZPIAZGSV-UHFFFAOYSA-N 0.000 description 1
- FQPSGWSUVKBHSU-UHFFFAOYSA-N methacrylamide Chemical compound CC(=C)C(N)=O FQPSGWSUVKBHSU-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- LVHBHZANLOWSRM-UHFFFAOYSA-N methylenebutanedioic acid Natural products OC(=O)CC(=C)C(O)=O LVHBHZANLOWSRM-UHFFFAOYSA-N 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 150000002763 monocarboxylic acids Chemical class 0.000 description 1
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 1
- WFKDPJRCBCBQNT-UHFFFAOYSA-N n,2-dimethylprop-2-enamide Chemical compound CNC(=O)C(C)=C WFKDPJRCBCBQNT-UHFFFAOYSA-N 0.000 description 1
- QRWZCJXEAOZAAW-UHFFFAOYSA-N n,n,2-trimethylprop-2-enamide Chemical compound CN(C)C(=O)C(C)=C QRWZCJXEAOZAAW-UHFFFAOYSA-N 0.000 description 1
- OVHHHVAVHBHXAK-UHFFFAOYSA-N n,n-diethylprop-2-enamide Chemical compound CCN(CC)C(=O)C=C OVHHHVAVHBHXAK-UHFFFAOYSA-N 0.000 description 1
- PBSASXNAZJHOBR-UHFFFAOYSA-N n-(2-methylpropyl)prop-2-enamide Chemical compound CC(C)CNC(=O)C=C PBSASXNAZJHOBR-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- JBLADNFGVOKFSU-UHFFFAOYSA-N n-cyclohexyl-2-methylprop-2-enamide Chemical compound CC(=C)C(=O)NC1CCCCC1 JBLADNFGVOKFSU-UHFFFAOYSA-N 0.000 description 1
- ZIWDVJPPVMGJGR-UHFFFAOYSA-N n-ethyl-2-methylprop-2-enamide Chemical compound CCNC(=O)C(C)=C ZIWDVJPPVMGJGR-UHFFFAOYSA-N 0.000 description 1
- SWPMNMYLORDLJE-UHFFFAOYSA-N n-ethylprop-2-enamide Chemical compound CCNC(=O)C=C SWPMNMYLORDLJE-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- YPHQUSNPXDGUHL-UHFFFAOYSA-N n-methylprop-2-enamide Chemical compound CNC(=O)C=C YPHQUSNPXDGUHL-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229920000867 polyelectrolyte Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
- STAUITHDCHQEOL-UHFFFAOYSA-L potassium;sodium;dioxido-oxo-sulfanylidene-$l^{6}-sulfane Chemical compound [Na+].[K+].[O-]S([O-])(=O)=S STAUITHDCHQEOL-UHFFFAOYSA-L 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- FBCQUCJYYPMKRO-UHFFFAOYSA-N prop-2-enyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCC=C FBCQUCJYYPMKRO-UHFFFAOYSA-N 0.000 description 1
- QTECDUFMBMSHKR-UHFFFAOYSA-N prop-2-enyl prop-2-enoate Chemical compound C=CCOC(=O)C=C QTECDUFMBMSHKR-UHFFFAOYSA-N 0.000 description 1
- BWJUFXUULUEGMA-UHFFFAOYSA-N propan-2-yl propan-2-yloxycarbonyloxy carbonate Chemical compound CC(C)OC(=O)OOC(=O)OC(C)C BWJUFXUULUEGMA-UHFFFAOYSA-N 0.000 description 1
- NHARPDSAXCBDDR-UHFFFAOYSA-N propyl 2-methylprop-2-enoate Chemical compound CCCOC(=O)C(C)=C NHARPDSAXCBDDR-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000012966 redox initiator Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229920002379 silicone rubber Polymers 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- APEJMQOBVMLION-VOTSOKGWSA-N trans-cinnamamide Chemical compound NC(=O)\C=C\C1=CC=CC=C1 APEJMQOBVMLION-VOTSOKGWSA-N 0.000 description 1
- ZFDIRQKJPRINOQ-UHFFFAOYSA-N transbutenic acid ethyl ester Natural products CCOC(=O)C=CC ZFDIRQKJPRINOQ-UHFFFAOYSA-N 0.000 description 1
- JLGLQAWTXXGVEM-UHFFFAOYSA-N triethylene glycol monomethyl ether Chemical compound COCCOCCOCCO JLGLQAWTXXGVEM-UHFFFAOYSA-N 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 229960000834 vinyl ether Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- KAKZBPTYRLMSJV-UHFFFAOYSA-N vinyl-ethylene Natural products C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B1/00—Optical elements characterised by the material of which they are made; Optical coatings for optical elements
- G02B1/04—Optical elements characterised by the material of which they are made; Optical coatings for optical elements made of organic materials, e.g. plastics
- G02B1/041—Lenses
- G02B1/043—Contact lenses
-
- 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
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0028—Polypeptides; Proteins; Degradation products thereof
- A61L26/0033—Collagen
-
- 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
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
- A61L26/008—Hydrogels or hydrocolloids
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F289/00—Macromolecular compounds obtained by polymerising monomers on to macromolecular compounds not provided for in groups C08F251/00 - C08F287/00
-
- G—PHYSICS
- G02—OPTICS
- G02C—SPECTACLES; SUNGLASSES OR GOGGLES INSOFAR AS THEY HAVE THE SAME FEATURES AS SPECTACLES; CONTACT LENSES
- G02C7/00—Optical parts
- G02C7/02—Lenses; Lens systems ; Methods of designing lenses
- G02C7/04—Contact lenses for the eyes
Definitions
- This invention relates to the preparation of high water content synthetic hydrogels modified with minor amounts of natural polymers and to processes for producing the same.
- the invention relates to shaped articles fabricated from such hydrogels which are useful for medical and cosmetic purposes, e.g., soft contact lenses, therapeutic eye bandages, etc.
- Hydrogels i.e., gels which contain water
- They can be formed of various natural substances such as gelatin and the poiysaccharides as well as various synthetic polymers such as crosslinked acryiamide polymers, polyelectrolyte complexes, and polymers of hydroxy-alkyl acryiic esters.
- synthetic hydrogels of acrylic polymers or of unsaturated amide polymers, with living tissue have made them particularly useful in alloplastic and prosthetic applications.
- properties such as transparency, good optics, shape stability, inertness to chemicals and bacteria, etc., have made such hydrogels of acrylic polymers the material of choice in the production of daily wear soft contact lenses.
- Synthetic hydrogels can be prepared having a wide variation in certain properties such as water uptake, mechanical properties, gas permeability,optical characteristics, etc.
- certain properties are desired which are actually in conflict with each other.
- extended-wear soft contact lenses i.e., lenses which can be worn for days without removal from the eye as opposed to conventional or daily wear contact lenses which are removed from the eye on a daily basis
- desirabiy should be characterized by high water uptake to achieve good diffusion properties and simultaneously, by good mechanical strength.
- U.S. Patent No. 3,926,869 discloses the hardening of gelatin for use in photographic emulsion layers by incorporating into the gelatin an acrylic acid-acrylamide copolymer. The layers produced are said to be highly water-swellable.
- U.S. Patent No. 4,060,081 discloses a multilayer membrane useful as a synthetic skin, having a first layer which is a cross-linked composite of collagen and a mucopolysaccharide, to which is adhered a flexible film of polyacrylate or polymethacryiate ester or their copolymers which is flexible and which protects the cross-linked collagen layer from moisture.
- the collagen-mucopolysaccharide layer is typically produced by dispersing small amounts of collagen, for example, 0.396 by weight, in a dilute acetic acid solution and agitating the solution as the polysaccharide is slowly added dropwise into the collagen dispersion.
- U.S. Patent No. 4,161,948 discloses synthetic membranes for closing wounds, wherein it is disclosed that it is preferable that the ⁇ -amino acid polymers employed be cross-linked with a diol, such as polyoxyethyiene glycol, in order to have properties resembling those of natural human collagen.
- novel shape retaining hydrogels of high water content of upwards to about 95 weight percent water, based on the weight of the hydrogel, possessing good mechanical properties can be prepared by the practice of the invention described herein.
- Such hydrogels have been observed to possess additional desirable characteristics which make them highly useful in the cosmetic and medical areas.
- These novel hydrogels exhibit high transparency, good diffusion, good oxygen permeability, high optics, inertness to bacteria, chemicals, biocompatibility with living tissue, and other desirable properties.
- the present invention also provides a novel process which comprises reacting an aqueous mixture comprising an ethylenically unsaturated compound and collagen both defined hereinafter under polymerization and/or crosslinking conditions for a period of time sufficient to produce the afore-said novel shape-retaining hydrogels.
- the present invention further provides a novel process for the preparation of novel hydrophilic plastic soft contact lenses, particularly those which can be worn on the eye for extended periods of time, e.g., upwards to several weeks if so desired, and to the novel contact lenses per se.
- novel hydrogels can be formed by various techniques known in the polymerization art.
- a liquid mixture desirably an aqueous dispersion or solution, comprising at least one ethylenicaily unsaturated compound, collagen, and optionally, a modifier.
- the ethylenicaily unsaturated compound is characterized by a polymerizable carbon-to-carbon double bond, i.e and is composed of (i) carbon, hydrogen, oxygen and nitrogen in the form of and optionally oxygen in the form of carbonyl as exemplified by N,N-dimethylacrylamide and N-(1,1-dimethyl-3-oxobutyl)acrylamide, (ii) carbon, hydrogen, and oxygen in the form of carbonyloxy and hydroxyl (-OH), and optionally oxygen in the form of etheric oxygen (-O-), e.g., 2-hydroxyethyl methacrylate and diethyleneglycol monomethacrylate, (iii) carbon, hydrogen, carbonyloxy oxygen and etheric oxygen, e.g., methoxytriethylene glycol methacrylate, (iv) carbon, hydrogen, carbonyloxy oxygen, and oxygen in the form of vicinal-epoxy, i.e., e.g., glycid
- the ethylenically unsaturated compound(s) which can be employed in the preparation of the novel hydrogels are at least partially miscible or otherwise compatible with water or with an aqueous solution of water-natural polymer or of water-(C 1 - C 4 )alkanol as illustrated by the unsubstituted, N-substituted and N,N-disubstituted 2-alkenamides
- each N substituent is hydrogen or a monovalent hydrocarbon radical such as aliphatic, cycioaliphatic, or aryl
- each N substituent is hydrogen or a monovalent saturated aliphatic hydrocarbon which preferably is a (C 1 -C 6 )alkyl and preferably still a (C 1 -C 4 )alkyl, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, and n-hexyl
- dialkylaminoalkyi 2- alkenoates wherein the alkyl substituents, individually, desirably contain from 1-4 carbon atoms and wherein the 2-alkenoate group contains from 2-6 carbon atoms, e.g., diethylaminoethyl methacrylate and dipropylaminoethyl methacrylate.
- ethylenically unsaturated amides which are particularly suitable in the preparation of the novel hydrogels can be represented by the following formula:
- R 1 , R 2 , R 3 , and R 4 individually, can be hydrogen or lower alkyl, e.g., methyl, ethyl, propyl, butyl and the like, preferably R 1 and R 2 are hydrpgen or methyl, and R 3 and R 4 are methyl or ethyl, preferably still R 1 is hydrogen, R 2 is methyl, and R 3 and R 4 are methyl or ethyl.
- Illustrative ethylenically unsaturated amides include acrylamide, methacrylamide, crotonamide, N-methylacrylamide,N,N- dimethylacryiamide, N-ethylacrylamide, N,N-diethylacrylamide, N- methyl-N-propyiacrylamide, N-isobutylacrylamide, N- methylmethacrylamide, N,N-dimethylmethacrylamide, N- ethylmethacrylamide, N-methyi-N-butyimethacrylamide, N-cyclohexylmethacrylamide, N,N-dimethyicrotonamide, and N,N-diethyicrotonamide.
- illustrative amide compounds include diacetoneacrylamide, cinnamide, and the like.
- collagen is a major protein of connective tissue such as skin, cornea, etc., and can be solubilized, separated and purified by the treatment with proteolytic enzymes (other than collagenase), e.g., proctase, pepsin, trypsin and pronase.
- proteolytic enzymes other than collagenase
- Enzyme solubilized collagen is telopeptides-poor, relatively inexpensive, and useful as a biomedical material.
- the collagen can be redispersed as a clear aqueous gel, e.g., up to 30 weight percent but generally less due to the high viscosity, the balance being water or aqueous solution of water and a miscible inert, organic liquid, e.g., lower aikanol.
- a useful discussion of collagen appears In the article by K. Stenzel et al entitled “Collagen as a Biomaterial", Annual Review of Biophysics and BioEngineering 3: 231-53 (1974) and to the extent necessary to further describe the solubilized or chemically modified collagens which are contemplated in the practice of the invention(s) said article is hereby incorporated by reference into this disclosure as if it were set out in full text.
- Solubilized collagen is defatted to the extent necessary whenever transparent collagen is required for the contemplated end. use application, e.g., in the preparation of extended wear contact lenses.
- Solubilized collagen contains many NH 2 and COOH groups in its structure, and chemical modificatins of the molecule can be readily made, e.g., all or some of the amino groups may be acylated by reactin with a mixture of acetic anhydride and acetic acid, or other anhydride such as succinic anhydride. All or some of the carboxyl groups contained in the molecule may be esterifled by the standard reaction with acidified alcohol, preferably a water soluble aliphatic alcohol,such as methanol, ethanol, etc.
- crosslinking the solubilized collagen as well as crosslinking the ethylenicaily unsaturated monomer(s) with/without additional ethylenicaily unsaturated modifiers described hereinafter can be accomplished by various means.
- Crosslinking the solubilized collagen is described in the literature and can be accomplished by treating with various chemicals such as aldehyde, e.g., formaldehyde, acrolein, giutaraidehyde glyoxal, or with acids, e.g., chromic acid, or by irradiation, e.g., gamma-irradiation, ultraviolet light, etc.
- the crosslinking of the solubilized collagen is effected under a nitrogen atmosphere in the shape-forming mold such as a lens mold using radiation dosages known in the art; see for example U.S. Pat. No. 4,223,984 issued September 23, 1980.
- Crosslinking the ethylenically unsaturated compound(s) with or without ethylenically unsaturated modifiers contained in the reaction mixture is most suitably effected through the use of crosslinking agents including, for instance, ethylene glycol diacrylate, ethylene glycol dimethacrylate, 1,2-butylene dimethacrylate, 1,3-butyiene dimethacrylate, 1,4-butylene dimethacrylate, propylene glycol diacrylate, propylene glycol dimethacrylate, diethylene glycol dimethacrylate, dipropyiene glycol dimethacrylate, diethylene glycol diacrylate, diethylene glycol crotonate, allyl maieate, triallyl melamine, N,N'-methylenebisacrylamide, glycerine trimethacrylate, divinyl ether, diallyl itaconate, ethylene glycol diester of itaconic acid, polyallyi glucose, e.g., triallyl glucose, polyallyl suc
- cross-linking agents usually, but not necessarily, have at least two ethylenicaily unsaturated double bonds.
- Crosslinking of the ethylenic compound(s) can also be effected by means of irradiation. Though not wishing to be held to any theory of reaction mechanism or theory, it appears that various reactions take place, desirably simultaneously, during the preparation of the novel hydrogels from the liquid medium comprising the reactants.
- Crosslinking of the solubilized collagen occurs as well as vinyl polymerization of the ethylenically unsaturated monomer(s) including the polyethylenically unsaturated crosslinker, if present in the liquid medium, and graft polymerization of the said monomer(s) and the said collagen.
- novel hydrogels are characterized, from an inspection of their IR spectrum, as graft polymer/collagen products (ethylenically unsaturated monomer grafted to the collagen). Also, in view of the basic triple-helical structure of collagen and the polymerization between the ethylenic monomer(s) as well as between the monomer(s) and collagen, there is probably formed a network of interpenetrating polymer/collagen hydrogels.
- the preparation of the novel hydrogels is preferably effected in an aqueous medium or a medium comprising water and alcohol which is miscible and compatible with water, e .g., methanol, ethanol, isopropanol, etc., and in which the reactants form a clear solution or gel, desirably under an inert gas such as nitrogen, argon, etc.
- an aqueous solution or gel of the collagen will generally contain less than 30 weight percent collagen in view of the highly viscous nature of the resulting aqueous medium comprising the collagen (and other reactant).
- an aqueous solution comprising upwards to about 15 weight percent collagen is suitable.
- a solution or dispersion or gel which contains from about 0.5 to about 12 weight percent, based on the total weight of the liquid reaction mixture, is most desirable; from about 1 to about 10 weight percent collagen is preferred.
- the reaction conditions will vary depending, to a significant degree, on the reactants of choice, catalyst, crosslinker, etc.
- conventional types of polymerization known in the art can be employed, such as polymerization by high energy radiation, e.g., gamma or ultraviolet; solution polymerization in which the mixture comprises collagen, ethylenic monomer(s), a chemical crosslinking agent for collagen and monomer, and a redox initiation system for the monomer(s) such as sodium thiosulfate-potassium persulfate; etc.
- Each specific type of polymerization generally requires a specific set of conditions.
- the polymerization desirably is carried out at low temperature (under 30°C and preferably below about 15°C) and under an inert atmosphere in order to minimize degradation of the natural polymer component (collagen) due to high energy radiation.
- the resulting product is usually leached and equilibrated in an aqueous medium to remove traces of unreacted residual monomer(s), catalyst residues, etc.
- the novel process is generally conducted with an amunt of solubilized collagen that is less than 50 weight percent, generally not exceeding about 35 weight percent, of the total charge of reactants, i.e., collagen, ethylenic monomer, crosslinker and mofidier, if present.
- the amount of ethylenicaily unsaturated monomer is at least about 50 and upward to 99.5 weight percent, and generally at least about 68 to about 90 weight percent.
- the use of collagen as low as one weight percent and lower, e.g., as low as 0.5 weight percent gives novel hydrogels of enhanced water uptake. Oftentimes the novel hydrogels exhibit enhanced mechanical properties as compared with the hydrogel prepared from a corresponding reaction mixture which lacks the collagen component therein.
- solubilized collagen is a biodegradable material which characteristic limits its use as a material for extended wear hydrophilic plastic soft contact lenses; yet the novel hydrogels obtained by the practice of the novel process are non-biodegradable under the test conditions employed in the working Examples.
- a modifier(s) i.e., compound(s) which possesses a polymerizable ethylenic carbon-to-carbon bond
- a modifier(s) can be incorporated into the reaction medium and caused to polymerize through its ethylenic bond and with the polymerizable ethylenic bond of the other reactant(s).
- novel hydrogels whose properties can be further altered and varied over a wide spectrum.
- the modifier if employed, may comprise from about 1 to about 30, and desirably from about 3 to about 20 weight percent, based on the total weight of the reactants.
- modifiers include, by way of illustrations, the alkyl 2-alkenoates, e.g., methyl methacrylate, ethyl methacrylate, propyl methacrylate, butyl methacrylate, ethyl crotonate, butyl cinnamate, and the like; the 2-aikenoic acids, e.g., methacrylic acid, acrylic. acid, and the like.
- the reactants i.e., collagen, ethylenic compound, and the crosslinker and modifier, if employed, are miscible or soluble or partially soluble in water (at least to the extent necessary to prepare the novel hydrogels described herein) or soluble in a compatible water-organic liquid medium such as water-lower alkanol mixture.
- the reaction medium can include, and desirably does include, a crosslinking agent(s).
- crosslinking of the solubilized collagen and the ethylenic reactant can be accomplished by irradiation; also, either the collagen or the ethylenic reactant(s) can be crosslinked by irradiation and the other by chemical crosslinking agents; or both the collagen and ethylenic reactants can be crosslinked by chemidal agents.
- the amount of crosslinking agent employed in the novel process will depend, to a significant degree, on the tyupe of polymerization, the reactants of choice, the concentration of the reactants, the degree of water-uptake desired in the novel hydrogel, and other factors.
- hydrogels of combined collagen/amide products can be obtained using a reaction medium which contains up to about 5 weight percent crosslinking agent, based on the total weight of reactants. More or less than 5 weight percent chemical crosslinker is within the scope of the invention. For the preparation of hydrogels of high water content, an amount not exceeding about 2 weight percent crosslinking agent is generally preferred.
- Weight percent based on total weight of combined components (excluding water).
- a minimum of 1 to 3 weight percent modifier can alter the properties of the ultimate novel hydrogel.
- the hydrogels obtained by the practice of the invention can possess a water content as high as 95 weight percent, based on the weight of the hydrogel.
- shape-retaining novel hydrogels which are characterized by biocompatibility with living tissue, non-biodegradability under our test conditions, high oxygen permeability, transparency, water and various common chemicals, good optical geometry, and good mechanical properties.
- the novel hydrogels in the shape of contact lenses and which have a water content of at least about 55 weight percent, desirably at least about 65 weight percent, and preferably at least about 75 weight percent, are especially suitable as extended wear contact lenses.
- the upper limit with respect to the water content can be, as indicated previously, as high as 95 weight percent, generally upwards to about 90 weight percent.
- the following Examples are illustrative and are not to be construed as limiting the inventions). Certain materials employed in these Examples as well as methods of evaluation of certain characteristics of the resulting hydrogel product are described below. Water content of the hydrogel is expressed as follows:
- Weight Percent H 2 O Hydrated Weight - Dried Weight ⁇ 100%
- Mechanical strength is expressed as a "tear strength" which is a method employed in evaluation of soft contact lenses.
- the hydrogel test sample (about 10 mm in length and abut 5 mm in width) is split initially at its width. The split end is fastened to an instrument equipped with a transducer and a recorder. The sample is kept in water during this test. The pulling force needed to tear the sample along its whole length (at the split) is recorded (in grams) and normalized for 1 mm thickness. All comparisons are based on Hydron ® soft contact lens material having a water content of about 38 weight percent.
- the Hydron ® material is prepared from a polymerizable mixture comprising about 99 weight percent hydroxyethyl methacrylate, about 0.3 to about 0.5 weight percent of ethylene glycol dimethacrylate, and diisopropyi peroxydicarbonate catalyst. Hydron ® is a registered trademark of National Patent Development Corporation.
- Oxygen permeability method used is the standard procedure used to measure the oxygen permeability of hydrogels (Y. Yasuda and W. Stone, J. of Polymer Sci., 4, 1314-1316 (1966) ). A similar procedure can be used to measure the permeability of films (ASTM - Volume 27, D1344).
- Oxygen permeability of a hydrogel is primarily a function of the water content of the hydrogel. It can be either measured experimentally or interpolated from a graph constructed from values of oxygen permeability measured on hydrogel membranes of varying water content. The correlation of oxygen permeability values with hydrogels of 38, 58, 70 and 85 weight percent water content is shown in the Table I below: TABLE I
- a soft contact lens material must be biologically stable, i.e., non-biodegradable. To determine the degree of resistance a material may exhibit to various strains of
- Pseudomonas aeruginosa the following experiment is performed on each formulation of hydrogel material. Discs of the material measuring 14 mm in diameter and 0.5 mm in center thickness are immersed in 10 ml aliquots of nutrient media which have been inoculated with approximately 10 viable cells per ml. Tubes are incubated at 37°C and samples are inspected macroscopically each day for changes that may have appeared in edge and surface quality, clarity and mechanical strength. The experiment is concluded for each sample as soon as any change is observed. If no change is observed after 12 days the sample is considered non-biodegradable.
- Boil 'N Soak ® is a registered trademark of Burton, Parsons & Co., Inc. It is a sterilized buffered isotonic aqueous solution containing boric acid, sodium borate, sodium chloride (0.7 weight percent) and preserved with thimerosal (0.001 weight percent) and edetate disodium. In the working Examples the lenses are equiiibtrated or leached for about 48 hours.
- Atellocollagen telopeptide-poor collagen used in the Examples is prepared from split calf hide (obtained from Ocean Leather Co.) by grinding the hide into fibers, washing with sodium bicarbonate solution and water respectively, centrifuging to remove liquids, and disolving in water of pH 3. The collagen solution is then treated with pepsin for 5-10 days. Pepsin is known to digest the protease labile non-helical end regions of the tropocollagen. These structures are termed "telopeptides" and when digested with proteolytic enzymes, the collagen is considered “teiopeptide-poor". Stenzel et al have coined the term "atelocollagen" to describe such solubilized collagen (K.
- EXAMPLE 1 In one vessel collagen (3.5 grams) is soaked in 39.5 cc of distilled water and hereafter its pH is adjusted with 0.1 M HCl to pH 3. The mixture is homogenized thoroughly until a clear gel results. In a second vessel there is dissolved 0.07 gram of N-methylolacrylamide in 6.93 grams of N,N , -dimethylacryIamide. Both solutions are mixed together, transferred into disposable plastic syringes, degassed under vacuum, and centrifuged at 4,000 rpm for 60 minutes at 15°C to remove air bubbles. The resulting solution comprising N,N-dimethylacrylamide and collagen is injected from the syringe into plastic contact lens molds under a nitrogen atmosphere.
- the molds are then transferred to nitrogen filled plastic bags and placed in a plastic vessel of ice contained therein.
- the polymerization is effected by exposure to Co 60 radiation for a period of 1.5 hours, the total dosage being 1.5 Mrads.
- the lenses are removed from the molds and equilibrated in Boil 'N Soak ® solution for 72 hours.
- the lenses are transparent, biologically stable, and mechanically comparable to commercial Hydron ® lenses. Its water content is 82 percent by weight.
- EXAMPLE 2 Collagen (3.5 grams) and chondroitin sulfate (0.35 gram), in their fibrous form, are mixed together in a small, high-speed blender. The mixture is then transferred to a 25 cc round-bottom flask and heated to 60°C under vacuum (0.1 - 0.5 mm Hg) for a period of four hours to enhance the condensation reaction between the carboxyl groups of collagen and the hydroxyl groups of chondroitin sulfate. The resulting reaction product mixture is transferred to a small beaker and 39.5 cc of distilled water is added thereto. This mixture is agitated until a h omogeneous mass is formed. It is allowed to swell overnight.
- EXAMPLE 3 Atelocollagen (3.5 grams) is allowed to swell overnight in 43 cc of distilled water, then acidified with 0.1 M HCl, and thereafter homogenized into a clear gel. In a separate container, there is dissolved 0.04 gram of N,N-methylenebisacryiamide in 3.47 grams of N,N-dimethyIacrylamide. Both solutions are then mixed together. The resulting gel is transferred into plastic disposable syringes, degassed under vacuum, centrifuged at 4,000 rpm at 15°C to remove air bubbles, and placed under nitrogen atmosphere. The resulting gel is injected into circular molds made of glass slides provided with silicon rubber spacers.
- the slides are transferred into nitrogen filled plastic bags, heat-sealed, and placed into a plastic container with ice cubes.
- Polymerization is effected by exposure to Co 60 radiation for a period of 3 hours, the total dosage being 1.0 Mrads.
- the resulting hydrogel discs are leached for 72 hours in Boil 'N Soak solution.
- Boil 'N Soak solution There is obtained a hydrogel product which is characterized by excellent light transmission, 86 percent by weight water content, and non-biodegradability. Its mech-anical strength is comparable to Hydron ® lenses.
- the hydrogel product is dried and analyzed by infrared (IR) absorption.
- EXAMPLE 4 Atelocollagen (3.5 grams) is allowed to hydrate overnight in 39.5 cc of 1 M glucose (which contains 0.25 gram of sodium thiosulfate and 8 grams of ethylene glycol), is acidified with 0.25 M citric acid to pH 3 and then homogenized to a clear gel. Thereafter, its pH is raised to 7 with 2 M sodium hydroxide. Precipitation of the atelocoiiagen does not occur due to the presence of the glucose. In separate vessel, 0.07 gram of N,N'-methyienebisacryiamide is dissolved in 6.93 grams of N,N-dimethylacryIamide.
- the ateloco llagen gel and amide solution are mixed together, homogenized, and maintained at about -5°C.
- a solution of crosslinking agents and initiator is prepared by dissolving 0.125 gram of 1-ethyI-3-(3-dimethyiamino-n-propyl)carbodiimide hydrochloride, 0.079 gram of N-hydroxysuccinamide, and 0.25 gram of potassium persulfate.
- the solution of crosslinking agents and the ateiocoilagen/amide solution are added together, under agitation, and maintained below 0°C.
- the resulting solution is transferred into cold plastic disposable syringes and centrifuged for 20 minutes at 0°C and 15,000 rpm to remove air bubbles, and thereafter is injected into molds of desired shape and allowed to react overnight at room temperature, e.g., about 20°C or slightly above room temperature.
- the resulting products are then leached for 48 hours in Boil 'N Soak solution.
- membranes which are transparent, flexible and non-biodegradable. The water content of these membranes is about Z0 percent by weight.
- novel shaped products are exceptional candidates for use as extended wear soft contact lenses. Their properties of high oxygen permeability and high water uptake are attained without sacrifice in tear strength (actually improved compared to poiymacon) and nonbiodegradability (far superior to collagen).
- the syringe containing the degassed lens solution is placed in a centrifuge and centrifuged for one hour at 6000 rpm at 10°C. f.
- the syringe is transferred into a glove box filled with nitrogen.
- An amount of the lens solution is injected from the syringe into several bottom mold portions (female mold portions) of the plastic lens mold system.
- the mold systems are closed by inserting a top mold portion (male mold portion) into each bottom mold portion.
- the closed molds are placed in plastic bags filled with nitrogen and the bags are sealed. The bags are then transferred into an insulated box and covered with ice. h.
- the simultaneous reactions e.g., polymerization involving the amide monomers, collagen-amide polymer graft reaction, and crosslinking reaction of collagen, is promoted by gamma radiation of 1.0 Mrad total dose.
- the irradiation is effected by using Co 60 as the source of radiation, generally, at low temperature, 5-10oC, in nitrogen atmosphere to minimize any denaturation of collagen and minimize bond scission which can occur during a high energy radiation.
- composition Wt. % Wt. grams
- Composition Wt. % Wt. grams Atelocollagen 5.00 1 .250 N-isopropylacrylamide 4.97 1 .243 N,N-dimethylacryiamide 4.97 1 .243 N,N'-methylenebisacryiamide 0.06 0. 15 Distilled Water 85.00 21 .250
- Atelocollagen (1.25 g) is dispersed in 21.25 g of distilled water.
- Atelocollagen is solubilized in step (a) by adding 1.0 M HCl until pH 3 is reached.
- N-isopropyiacrylamide (1.243) and 0.015 g of N,N'- methylenebisacrylamide are dissolved in 1.243 g of N,N- dimethyiacrylamide. This monomeric amide solution is added to the atelocollagen solution (step b) and the resulting solution agitated until homogeneous.
- d. Continue with step (d) of Example 5.
- composition Wt. % Wt. grams Atellocollagen 5.00 1 .250
- EXAMPLE 9 Composition: Wt. % Wt. grams Atelocollagen 9.0 2.7 Distilled Water 91 .0 27.3 100.00% 0.0 g Procedure: a. Atelocollagen (2.7 g) is dispersed in 27.3 g of distilled water and solubilized by bringing the pH to pH 3 with 1.0 M HCl. b. Continue with step (d) of Example 5. Properties of the Equilibrated Lenses:
- EXAMPLE 11 Composition: Wt. % Atelocollagen 7.0 Poly(N,N-dimethyiacryiamide) 7.0 Distilled Water 86.00
- the poly(N,N-dimethyiacryiamide) exmployed in this Example is obtained via the polymerization of an aqueous solution of 50 weight percent N,N-dimethyiacryiamide. Polymerization is initiated using 0.5 wt. %(NH 4 S 2 O 8 plus 0.5 wt. % NaHSO 3 redox system at 20°C. An exothermic temperature of about 60°C is reached. The resulting poly(N,N-dimethylacryiamide) product is precipitated from acetone and vacuum dried at 80°C. Its molecular weight is of the order of 500,000. Procedure: a.
- Figure 1 is the infrared (IR) spectrum of the crosslinked ateiocollagen/N,N-dimethylacrylamide product of Example 10. Its IR spectrum exhibits a sharp peak at 1260 cm and new absorption peaks at 800 cm -1 and 1020 cm -1 , not found in collagen or N,N-dimethylacrylamide, indicating formation of new bonds attributable apparently to coilagen-N,N-dimethylacrylamide grafts.
- Figure 2 is the infrared spectrum of the ateiocollagen/poly(N,N-dimethyiacrylamide) "product" of Example 11. Its IR spectrum and the IR spectrum of atelocollagen are very similar.
- Figure 3 is the infrared spectrum of the poly(N,N-dimethylacrylamide) and is included in this discussion for purposes of comparison with the IR spectra of Figures 1 and 2.
- Figure 4 is the infrared spectrum of atelocoiiagen after gamma-irradiation (Example 9 above).
- the IR spectrum of gammairradiated atelocoiiagen (Example 9, Figure 4) and the IR spectrum of ateiocollagen/poly(N,N-dimethylacryiamide) "product" (Example 11, Figure 2) are very similar.
- the IR spectrum of the "product" of Example 11 confirms that the poly(dimethylacryiamide) component was extracted during the equilibration or leaching step.
Abstract
Hydrogels are prepared by subjecting to polymerization conditions an aqueous mixture comprising a major amount of an organic compound which is characterized by a polymerizable ethylenic group (> C = C <) as illustrated by N, N-dimethylacrylamide, 2-hydroxyethyl methacrylate, dimethylaminoethyl methacrylate or methoxytriethylene glycol methacrylate, and a minor amount of solubilized collagen. The reactants employed are at least partially soluble in the aqueous reaction medium. The hydrogels thus prepared are novel shaped articles having utility in the medical and cosmetic fields. Contact lenses of such hydrogels exhibit high water content, high oxygen permeabilty and good mechanical strength characteristics.
Description
MODIFIED SYNTHETIC HYDROGELS BACKGROUND OF THE INVENTION
This invention relates to the preparation of high water content synthetic hydrogels modified with minor amounts of natural polymers and to processes for producing the same. In one aspect, the invention relates to shaped articles fabricated from such hydrogels which are useful for medical and cosmetic purposes, e.g., soft contact lenses, therapeutic eye bandages, etc.
Hydrogels, i.e., gels which contain water, are well knwn in the art. They can be formed of various natural substances such as gelatin and the poiysaccharides as well as various synthetic polymers such as crosslinked acryiamide polymers, polyelectrolyte complexes, and polymers of hydroxy-alkyl acryiic esters. The outstanding biocompatibility characteristic of synthetic hydrogels of acrylic polymers or of unsaturated amide polymers, with living tissue, have made them particularly useful in alloplastic and prosthetic applications. Moreover, properties such as transparency, good optics, shape stability, inertness to chemicals and bacteria, etc., have made such hydrogels of acrylic polymers the material of choice in the production of daily wear soft contact lenses.
Synthetic hydrogels can be prepared having a wide variation in certain properties such as water uptake, mechanical properties, gas permeability,optical characteristics, etc. In various applications involving hydrogels certain properties are desired which are actually in conflict with each other. For example, extended-wear soft contact lenses, i.e., lenses which can be worn for days without removal from the eye as opposed to conventional or daily wear contact lenses which are removed from the eye on a daily basis,desirabiy should be characterized by high water uptake to achieve good diffusion properties and simultaneously, by good mechanical strength. However, it is recognized in the art that to attain hydrogels of very high water content, e.g., upwards of 90 weight percent, and more, other properties are usually sacrificed, e.g., such hydrogeis exhibit relatively low mechanical properties.
U.S. Patent No. 3,926,869 discloses the hardening of gelatin for use in photographic emulsion layers by incorporating into the gelatin an acrylic acid-acrylamide copolymer. The layers produced are said to be highly water-swellable. U.S. Patent No. 4,060,081 discloses a multilayer membrane useful as a synthetic skin, having a first layer which is a cross-linked composite of collagen and a mucopolysaccharide, to which is adhered a flexible film of polyacrylate or polymethacryiate ester or their copolymers which is flexible and which protects the cross-linked collagen layer from moisture. The collagen-mucopolysaccharide layer is typically produced by dispersing small amounts of collagen, for example, 0.396 by weight, in a dilute acetic acid solution and agitating the solution as the polysaccharide is slowly added dropwise into the collagen dispersion. The collagen and mucopolysaccharide coprecipitate into a tangled mass of collagen fibrils coated with mucopoiy-saccharide.
U.S. Patent No. 4,161,948 discloses synthetic membranes for closing wounds, wherein it is disclosed that it is preferable that the α-amino acid polymers employed be cross-linked with a diol, such as polyoxyethyiene glycol, in order to have properties resembling those of natural human collagen. SUMMARY OF THE INVENTION
It has now been unexpectedly discovered that novel shape retaining hydrogels of high water content of upwards to about 95 weight percent water, based on the weight of the hydrogel, possessing good mechanical properties can be prepared by the practice of the invention described herein. Such hydrogels have been observed to possess additional desirable characteristics which make them highly useful in the cosmetic and medical areas. These novel hydrogels exhibit high transparency, good diffusion, good oxygen permeability, high optics, inertness to bacteria, chemicals, biocompatibility with living tissue, and other desirable properties.
The present invention also provides a novel process which comprises reacting an aqueous mixture comprising an ethylenically
unsaturated compound and collagen both defined hereinafter under polymerization and/or crosslinking conditions for a period of time sufficient to produce the afore-said novel shape-retaining hydrogels.
The present invention further provides a novel process for the preparation of novel hydrophilic plastic soft contact lenses, particularly those which can be worn on the eye for extended periods of time, e.g., upwards to several weeks if so desired, and to the novel contact lenses per se.
These and other objectives can be achieved by practicing the teachings herein disclosed and suggested to the art. DESCRIPTION OF THE INVENTION
It was unexpectedly found that in the practice of various embodiments of the invention there could be produced novel hydrogels of high water content oftentimes having mechanical strength characteristics, e.g., tear strength, which were superior to relatively low water-containing hydrogels of sparingly crossiinked 2-hydroxyethyl methacrylate polymers, e.g., Hydron® polymers. These characteristics together with properties described previously make the novel shape retaining hydrogels highly useful in the form of extended wear hydrophilic plastic soft contact lenses.
The novel hydrogels can be formed by various techniques known in the polymerization art. In general, there is formed a liquid mixture, desirably an aqueous dispersion or solution, comprising at least one ethylenicaily unsaturated compound, collagen, and optionally, a modifier.
The ethylenicaily unsaturated compound is characterized by a polymerizable carbon-to-carbon double bond, i.e
and is composed of (i) carbon, hydrogen, oxygen and nitrogen in the form of and optionally oxygen in the form of carbonyl
as exemplified by N,N-dimethylacrylamide and N-(1,1-dimethyl-3-oxobutyl)acrylamide, (ii) carbon, hydrogen, and
oxygen in the form of carbonyloxy and hydroxyl (-OH), and
optionally oxygen in the form of etheric oxygen (-O-), e.g., 2-hydroxyethyl methacrylate and diethyleneglycol monomethacrylate, (iii) carbon, hydrogen, carbonyloxy oxygen and etheric oxygen, e.g., methoxytriethylene glycol methacrylate, (iv) carbon, hydrogen, carbonyloxy oxygen, and oxygen in the form of vicinal-epoxy, i.e., e.g., glycidyl methacrylate, or (v)
carbon, hydrogen, carbonyloxy oxygen, and amino nitrogen, (-N^ ), e.g., dimethylaminoethyl methacrylate.
The ethylenically unsaturated compound(s) which can be employed in the preparation of the novel hydrogels are at least partially miscible or otherwise compatible with water or with an aqueous solution of water-natural polymer or of water-(C1- C4)alkanol as illustrated by the unsubstituted, N-substituted and N,N-disubstituted 2-alkenamides wherein each N substituent is hydrogen or a monovalent hydrocarbon radical such as aliphatic, cycioaliphatic, or aryl, desirably each N substituent is hydrogen or a monovalent saturated aliphatic hydrocarbon which preferably is a (C1-C6)alkyl and preferably still a (C1-C4)alkyl, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, and n-hexyl, and wherein the 2-alkenoyl group of the 2-aikenamide molecule contains from 2-6 carbon atoms; theethylenically unsaturated lactams, e.g., N-vinylpyrrolidone, N-vinyicaprolactam, and methyI-2-vinyIpyrrolidone; the vicinalepoxyalkyl 2-aIkenoates wherein the vicinal-epoxyalkyi group desirably contains from 2 to 4 carbon atoms and wherein the 2-alkenoate group contains from 2-6 carbon atoms, e.g., glycidyl acrylate, glycidyl methacrylate, 2,3-epoxybutyl methacryiate, and glycidyl crotonate; the esters of aliphatic polyhydroxy alcohols and ethylenically unsaturated monocarboxylic acids such as the hydroxy(alkoxy) alkyl 2-alkenoates wherein n is an integer having a value of zero and upwards to 4, wherein the alkyl and alkoxy substituents have from 2-4 carbon atoms, and wherein the 2-
alkenoate group contains from 2-6 carbon atoms, e.g., 2-hydroxyethyl methacrylate, 2-hydroxyethyi acrylate, 2-hydroxypropyi acrylate,2- hydroxypropyl methacrylate, 2-hydroxyethoxyethyl methacrylate, 2- hydroxyethoxyethyl acrylate, 2-hydroxypropoxyethyl methacrylate, and 2-hydroxyethyl crotonate; the alkoxy(alkoxy)n alkyl 2-alkenoates wherein n alkyl, alkoxy, and the 2-alkenoate group have the values assigned above, with the proviso that the terminal alkoxy substituent of the molecule contains from 1 to 4 carbon atoms, e.g., 2- methoxyethyl acrylate, methoxyethyl methacrylate, methoxydiethylene glycol methacrylate, methoxydiethylene glycol . acrylate, methoxytriethylene glycol methacrylate, and methoxytriethylene glycol crotonate; the dialkylaminoalkyi 2- alkenoates wherein the alkyl substituents, individually, desirably contain from 1-4 carbon atoms and wherein the 2-alkenoate group contains from 2-6 carbon atoms, e.g., diethylaminoethyl methacrylate and dipropylaminoethyl methacrylate.
The ethylenically unsaturated amides which are particularly suitable in the preparation of the novel hydrogels can be represented by the following formula:
wherein R1, R2, R3, and R4, individually, can be hydrogen or lower alkyl, e.g., methyl, ethyl, propyl, butyl and the like, preferably R 1 and R2 are hydrpgen or methyl, and R 3 and R4 are methyl or ethyl, preferably still R1 is hydrogen, R2 is methyl, and R3 and R4 are methyl or ethyl. Illustrative ethylenically unsaturated amides include acrylamide, methacrylamide, crotonamide, N-methylacrylamide,N,N- dimethylacryiamide, N-ethylacrylamide, N,N-diethylacrylamide, N- methyl-N-propyiacrylamide, N-isobutylacrylamide, N- methylmethacrylamide, N,N-dimethylmethacrylamide, N-
ethylmethacrylamide, N-methyi-N-butyimethacrylamide, N-cyclohexylmethacrylamide, N,N-dimethyicrotonamide, and N,N-diethyicrotonamide. Other illustrative amide compounds include diacetoneacrylamide, cinnamide, and the like. As stated in U.S. Pat. No. 4,223,984, issued September 23, 1980, collagen is a major protein of connective tissue such as skin, cornea, etc., and can be solubilized, separated and purified by the treatment with proteolytic enzymes (other than collagenase), e.g., proctase, pepsin, trypsin and pronase. Enzyme solubilized collagen is telopeptides-poor, relatively inexpensive, and useful as a biomedical material. The collagen can be redispersed as a clear aqueous gel, e.g., up to 30 weight percent but generally less due to the high viscosity, the balance being water or aqueous solution of water and a miscible inert, organic liquid, e.g., lower aikanol. A useful discussion of collagen appears In the article by K. Stenzel et al entitled "Collagen as a Biomaterial", Annual Review of Biophysics and BioEngineering 3: 231-53 (1974) and to the extent necessary to further describe the solubilized or chemically modified collagens which are contemplated in the practice of the invention(s) said article is hereby incorporated by reference into this disclosure as if it were set out in full text.
Solubilized collagen is defatted to the extent necessary whenever transparent collagen is required for the contemplated end. use application, e.g., in the preparation of extended wear contact lenses. Solubilized collagen contains many NH2 and COOH groups in its structure, and chemical modificatins of the molecule can be readily made, e.g., all or some of the amino groups may be acylated by reactin with a mixture of acetic anhydride and acetic acid, or other anhydride such as succinic anhydride. All or some of the carboxyl groups contained in the molecule may be esterifled by the standard reaction with acidified alcohol, preferably a water soluble aliphatic alcohol,such as methanol, ethanol, etc. In the above reactions the isoelectric point of collagen can be controlled, either negative or positive, or completely neutralized.
Crosslinking the solubilized collagen as well as crosslinking the ethylenicaily unsaturated monomer(s) with/without additional ethylenicaily unsaturated modifiers described hereinafter can be accomplished by various means. Crosslinking the solubilized collagen is described in the literature and can be accomplished by treating with various chemicals such as aldehyde, e.g., formaldehyde, acrolein, giutaraidehyde glyoxal, or with acids, e.g., chromic acid, or by irradiation, e.g., gamma-irradiation, ultraviolet light, etc. In the practice of highly desirable embodiments of the invention, the crosslinking of the solubilized collagen is effected under a nitrogen atmosphere in the shape-forming mold such as a lens mold using radiation dosages known in the art; see for example U.S. Pat. No. 4,223,984 issued September 23, 1980.
Crosslinking the ethylenically unsaturated compound(s) with or without ethylenically unsaturated modifiers contained in the reaction mixture is most suitably effected through the use of crosslinking agents including, for instance, ethylene glycol diacrylate, ethylene glycol dimethacrylate, 1,2-butylene dimethacrylate, 1,3-butyiene dimethacrylate, 1,4-butylene dimethacrylate, propylene glycol diacrylate, propylene glycol dimethacrylate, diethylene glycol dimethacrylate, dipropyiene glycol dimethacrylate, diethylene glycol diacrylate, diethylene glycol crotonate, allyl maieate, triallyl melamine, N,N'-methylenebisacrylamide, glycerine trimethacrylate, divinyl ether, diallyl itaconate, ethylene glycol diester of itaconic acid, polyallyi glucose, e.g., triallyl glucose, polyallyl sucrose, e.g., pentaallyl sucrose, sucrose diacrylate, glucose dimethacrylate, pentaerythritol tetraacrylate, sorbitol dimethacrylate diallyl aconitate, divinyl citraconate, diallyl fumarate, glycidyl acrylate, glycidyl methacrylate, allyl methacrylate, allyl acrylate, vinyl methacrylate. The cross-linking agents usually, but not necessarily, have at least two ethylenicaily unsaturated double bonds. Crosslinking of the ethylenic compound(s) can also be effected by means of irradiation.
Though not wishing to be held to any theory of reaction mechanism or theory, it appears that various reactions take place, desirably simultaneously, during the preparation of the novel hydrogels from the liquid medium comprising the reactants. Crosslinking of the solubilized collagen occurs as well as vinyl polymerization of the ethylenically unsaturated monomer(s) including the polyethylenically unsaturated crosslinker, if present in the liquid medium, and graft polymerization of the said monomer(s) and the said collagen. The novel hydrogels are characterized, from an inspection of their IR spectrum, as graft polymer/collagen products (ethylenically unsaturated monomer grafted to the collagen). Also, in view of the basic triple-helical structure of collagen and the polymerization between the ethylenic monomer(s) as well as between the monomer(s) and collagen, there is probably formed a network of interpenetrating polymer/collagen hydrogels.
The preparation of the novel hydrogels is preferably effected in an aqueous medium or a medium comprising water and alcohol which is miscible and compatible with water, e .g., methanol, ethanol, isopropanol, etc., and in which the reactants form a clear solution or gel, desirably under an inert gas such as nitrogen, argon, etc. In the practice of the process invention it is desirable to form an aqueous solution or gel of the collagen. Such solutions or gels will generally contain less than 30 weight percent collagen in view of the highly viscous nature of the resulting aqueous medium comprising the collagen (and other reactant). Thus an aqueous solution comprising upwards to about 15 weight percent collagen is suitable. A solution or dispersion or gel which contains from about 0.5 to about 12 weight percent, based on the total weight of the liquid reaction mixture, is most desirable; from about 1 to about 10 weight percent collagen is preferred.
The reaction conditions will vary depending, to a significant degree, on the reactants of choice, catalyst, crosslinker, etc. In general, conventional types of polymerization known in the art can be employed, such as polymerization by high energy radiation, e.g.,
gamma or ultraviolet; solution polymerization in which the mixture comprises collagen, ethylenic monomer(s), a chemical crosslinking agent for collagen and monomer, and a redox initiation system for the monomer(s) such as sodium thiosulfate-potassium persulfate; etc. Each specific type of polymerization generally requires a specific set of conditions. For example, when gamma-radiation is used, the polymerization desirably is carried out at low temperature (under 30°C and preferably below about 15°C) and under an inert atmosphere in order to minimize degradation of the natural polymer component (collagen) due to high energy radiation. The resulting product is usually leached and equilibrated in an aqueous medium to remove traces of unreacted residual monomer(s), catalyst residues, etc.
The novel process is generally conducted with an amunt of solubilized collagen that is less than 50 weight percent, generally not exceeding about 35 weight percent, of the total charge of reactants, i.e., collagen, ethylenic monomer, crosslinker and mofidier, if present. The amount of ethylenicaily unsaturated monomer is at least about 50 and upward to 99.5 weight percent, and generally at least about 68 to about 90 weight percent. The use of collagen as low as one weight percent and lower, e.g., as low as 0.5 weight percent gives novel hydrogels of enhanced water uptake. Oftentimes the novel hydrogels exhibit enhanced mechanical properties as compared with the hydrogel prepared from a corresponding reaction mixture which lacks the collagen component therein. It is of interest to note that solubilized collagen is a biodegradable material which characteristic limits its use as a material for extended wear hydrophilic plastic soft contact lenses; yet the novel hydrogels obtained by the practice of the novel process are non-biodegradable under the test conditions employed in the working Examples.
If desired, a modifier(s), i.e., compound(s) which possesses a polymerizable ethylenic carbon-to-carbon bond, can be incorporated into the reaction medium and caused to polymerize through its ethylenic bond and with the polymerizable ethylenic bond of the
other reactant(s). By the practice of this embodiment there can be prepared novel hydrogels whose properties can be further altered and varied over a wide spectrum. There can be included in the reaction medium upwards to about 35 weight percent of modifier, based on the total weight of reactants. In general, the modifier, if employed, may comprise from about 1 to about 30, and desirably from about 3 to about 20 weight percent, based on the total weight of the reactants. It is apparent that the use of a modifier can appreciably alter the ultimate properties of the hydrogel to yield "tailor-made" products. Examples of modifiers include, by way of illustrations, the alkyl 2-alkenoates, e.g., methyl methacrylate, ethyl methacrylate, propyl methacrylate, butyl methacrylate, ethyl crotonate, butyl cinnamate, and the like; the 2-aikenoic acids, e.g., methacrylic acid, acrylic. acid, and the like. The reactants, i.e., collagen, ethylenic compound, and the crosslinker and modifier, if employed, are miscible or soluble or partially soluble in water (at least to the extent necessary to prepare the novel hydrogels described herein) or soluble in a compatible water-organic liquid medium such as water-lower alkanol mixture. As indicated previously, the reaction medium can include, and desirably does include, a crosslinking agent(s). As indicated previously, crosslinking of the solubilized collagen and the ethylenic reactant can be accomplished by irradiation; also, either the collagen or the ethylenic reactant(s) can be crosslinked by irradiation and the other by chemical crosslinking agents; or both the collagen and ethylenic reactants can be crosslinked by chemidal agents. The amount of crosslinking agent employed in the novel process will depend, to a significant degree, on the tyupe of polymerization, the reactants of choice, the concentration of the reactants, the degree of water-uptake desired in the novel hydrogel, and other factors. For example, particularly suitable hydrogels of combined collagen/amide products can be obtained using a reaction medium which contains up to about 5 weight percent crosslinking agent, based on the total weight of reactants. More or less than 5 weight percent chemical
crosslinker is within the scope of the invention. For the preparation of hydrogels of high water content, an amount not exceeding about 2 weight percent crosslinking agent is generally preferred.
The proportions of the combined components in the novel hydrogels are as follows:
MOST
COMPONENT BROAD(1) PREFERRED( 1 ) PREFERRED(1)
Ethylenic Compound ~50-99.5 ~60-95 ~ 68-90 Collagen < 50-0.5 ~ 5-45 ~10-35
Modifier 0-35 0-30(2) 0-20 (2)
Crosslinking Agent 0-5 0-2 0-1
(1) Weight percent, based on total weight of combined components (excluding water).
(2) A minimum of 1 to 3 weight percent modifier can alter the properties of the ultimate novel hydrogel.
The hydrogels obtained by the practice of the invention can possess a water content as high as 95 weight percent, based on the weight of the hydrogel. In general, shape-retaining novel hydrogels which are characterized by biocompatibility with living tissue, non-biodegradability under our test conditions, high oxygen permeability, transparency, water and various common chemicals, good optical geometry, and good mechanical properties. The novel hydrogels in the shape of contact lenses and which have a water content of at least about 55 weight percent, desirably at least about 65 weight percent, and preferably at least about 75 weight percent, are especially suitable as extended wear contact lenses. The upper limit with respect to the water content can be, as indicated previously, as high as 95 weight percent, generally upwards to about 90 weight percent.
The following Examples are illustrative and are not to be construed as limiting the inventions). Certain materials employed in these Examples as well as methods of evaluation of certain characteristics of the resulting hydrogel product are described below. Water content of the hydrogel is expressed as follows:
Weight Percent H2O = Hydrated Weight - Dried Weight × 100%
Hydrated Weight
Mechanical strength is expressed as a "tear strength" which is a method employed in evaluation of soft contact lenses. The hydrogel test sample (about 10 mm in length and abut 5 mm in width) is split initially at its width. The split end is fastened to an instrument equipped with a transducer and a recorder. The sample is kept in water during this test. The pulling force needed to tear the sample along its whole length (at the split) is recorded (in grams) and normalized for 1 mm thickness. All comparisons are based on Hydron® soft contact lens material having a water content of about 38 weight percent. The Hydron® material is prepared from a polymerizable mixture comprising about 99 weight percent hydroxyethyl methacrylate, about 0.3 to about 0.5 weight percent of ethylene glycol dimethacrylate, and diisopropyi peroxydicarbonate catalyst. Hydron® is a registered trademark of National Patent Development Corporation.
Oxygen permeability method used is the standard procedure used to measure the oxygen permeability of hydrogels (Y. Yasuda and W. Stone, J. of Polymer Sci., 4, 1314-1316 (1966) ). A similar procedure can be used to measure the permeability of films (ASTM - Volume 27, D1344). Oxygen permeability of a hydrogel is primarily a function of the water content of the hydrogel. It can be either measured experimentally or interpolated from a graph constructed from values of oxygen permeability measured on hydrogel membranes of varying water content. The correlation of oxygen permeability values with hydrogels of 38, 58, 70 and 85 weight percent water content is shown in the Table I below:
TABLE I
Weight % Water Oxygen Permeability × 10- 10 (1 )
38 (Hydron®) 10.0 58 (Duragel®) 23.3 70 (Duragel®) (2) 34.8 85 (Permalens®) (3) 42.8 - - - - - - - - - - - - - - - - - - - - - - - - - - -
(1) cm3 .cm cm2 · Hg sec
(at standard pressure, 34ºC) using Delta Scientific Model 2110, Dissolved Oxygen BOD and Temperature Analyzer.
(2) Duragel is a trademark of
(3) Permalens is a registered trademark of Cooper Laboratories, Inc.
Biological Stability: A soft contact lens material must be biologically stable, i.e., non-biodegradable. To determine the degree of resistance a material may exhibit to various strains of
Pseudomonas aeruginosa, the following experiment is performed on each formulation of hydrogel material. Discs of the material measuring 14 mm in diameter and 0.5 mm in center thickness are immersed in 10 ml aliquots of nutrient media which have been inoculated with approximately 10 viable cells per ml. Tubes are incubated at 37°C and samples are inspected macroscopically each day for changes that may have appeared in edge and surface quality, clarity and mechanical strength. The experiment is concluded for each sample as soon as any change is observed. If no change is observed after 12 days the sample is considered non-biodegradable.
Boil 'N Soak® is a registered trademark of Burton, Parsons & Co., Inc. It is a sterilized buffered isotonic aqueous solution containing boric acid, sodium borate, sodium chloride (0.7 weight percent) and preserved with thimerosal (0.001 weight percent) and edetate disodium. In the working Examples the lenses are equiiibtrated or leached for about 48 hours.
Atellocollagen (telopeptide-poor collagen) used in the Examples
is prepared from split calf hide (obtained from Ocean Leather Co.) by grinding the hide into fibers, washing with sodium bicarbonate solution and water respectively, centrifuging to remove liquids, and disolving in water of pH 3. The collagen solution is then treated with pepsin for 5-10 days. Pepsin is known to digest the protease labile non-helical end regions of the tropocollagen. These structures are termed "telopeptides" and when digested with proteolytic enzymes, the collagen is considered "teiopeptide-poor". Stenzel et al have coined the term "atelocollagen" to describe such solubilized collagen (K. Stenzel et al, "Collagen as a Biomaterial," Annual Review of Biophysics and BioEngineering 3: 231-53 (1974) ). The resulting atelocoiiagen solution is then filtered through 0.65 Millipore filter and reprecipitated at elevated pH. The fibrous collagen is centrifuged to remove liquid and extracted impurities therefrom and Is thereafter freeze-dried. The collagen used in Examples 1-2 is acid soluble calf skin collagen obtained from Calbiochem-Behring Corporation.
The plastic lens mold system used in the Examples are described in U.S. Pat. Nos. 4,121,896 and 4,208,364 which patents are hereby incorporated by reference as if their full texts were set out in this specification.
EXAMPLE 1 In one vessel collagen (3.5 grams) is soaked in 39.5 cc of distilled water and hereafter its pH is adjusted with 0.1 M HCl to pH 3. The mixture is homogenized thoroughly until a clear gel results. In a second vessel there is dissolved 0.07 gram of N-methylolacrylamide in 6.93 grams of N,N,-dimethylacryIamide. Both solutions are mixed together, transferred into disposable plastic syringes, degassed under vacuum, and centrifuged at 4,000 rpm for 60 minutes at 15°C to remove air bubbles. The resulting solution comprising N,N-dimethylacrylamide and collagen is injected from the syringe into plastic contact lens molds under a nitrogen atmosphere. The molds are then transferred to nitrogen filled plastic bags and placed in a plastic vessel of ice contained therein. The
polymerization is effected by exposure to Co60 radiation for a period of 1.5 hours, the total dosage being 1.5 Mrads. After polymerization is complete, the lenses are removed from the molds and equilibrated in Boil 'N Soak® solution for 72 hours. The lenses are transparent, biologically stable, and mechanically comparable to commercial Hydron® lenses. Its water content is 82 percent by weight.
EXAMPLE 2 Collagen (3.5 grams) and chondroitin sulfate (0.35 gram), in their fibrous form, are mixed together in a small, high-speed blender. The mixture is then transferred to a 25 cc round-bottom flask and heated to 60°C under vacuum (0.1 - 0.5 mm Hg) for a period of four hours to enhance the condensation reaction between the carboxyl groups of collagen and the hydroxyl groups of chondroitin sulfate. The resulting reaction product mixture is transferred to a small beaker and 39.5 cc of distilled water is added thereto. This mixture is agitated until a h omogeneous mass is formed. It is allowed to swell overnight. Thereafter, the mixture is adjusted to a pH of 3 with 0.1 M HCl and then agitated until homogeneous and clear. In a separate beaker there is dissolved 0.14 gram of N,N'-methyienebisacrylamide in 6.86 grams of N,N-dimethyiacrylamide. Both solutions are added together and thoroughly mixed, then transferred into disposable plastic syringes, degassed under vacuum (0.5 - 0.5 mm Hg), and centrifuged at 4,000 rpm for 60 minutes at 15°C to remove air bubbles. The resulting gel is injected into plastic lens molds and the procedure and conditions of Example 1 followed. There is obtained contact lenses which are optically clear, biologically stable, and mechanically strong. The lenses are further characterized by 80 percent by weight water content.
EXAMPLE 3 Atelocollagen (3.5 grams) is allowed to swell overnight in 43 cc of distilled water, then acidified with 0.1 M HCl, and thereafter homogenized into a clear gel. In a separate container, there is dissolved 0.04 gram of N,N-methylenebisacryiamide in 3.47 grams of
N,N-dimethyIacrylamide. Both solutions are then mixed together. The resulting gel is transferred into plastic disposable syringes, degassed under vacuum, centrifuged at 4,000 rpm at 15°C to remove air bubbles, and placed under nitrogen atmosphere. The resulting gel is injected into circular molds made of glass slides provided with silicon rubber spacers. The slides are transferred into nitrogen filled plastic bags, heat-sealed, and placed into a plastic container with ice cubes. Polymerization is effected by exposure to Co60 radiation for a period of 3 hours, the total dosage being 1.0 Mrads. After polymerization is complete, the resulting hydrogel discs are leached for 72 hours in Boil 'N Soak solution. There is obtained a hydrogel product which is characterized by excellent light transmission, 86 percent by weight water content, and non-biodegradability. Its mech-anical strength is comparable to Hydron® lenses. The hydrogel product is dried and analyzed by infrared (IR) absorption. Its IR spectrum is compared to IR scans of pure collagen and pure, poly(dimethylacryiamide). The IR spectrum of this product shows absorption characteristics for both pure collagen and poly(dimethylacrylamide) plus new absorption bands at 800 cm- 1 and 1020 cm-1 which indicates formation of a graft copolymer.
EXAMPLE 4 Atelocollagen (3.5 grams) is allowed to hydrate overnight in 39.5 cc of 1 M glucose (which contains 0.25 gram of sodium thiosulfate and 8 grams of ethylene glycol), is acidified with 0.25 M citric acid to pH 3 and then homogenized to a clear gel. Thereafter, its pH is raised to 7 with 2 M sodium hydroxide. Precipitation of the atelocoiiagen does not occur due to the presence of the glucose. In separate vessel, 0.07 gram of N,N'-methyienebisacryiamide is dissolved in 6.93 grams of N,N-dimethylacryIamide. The ateloco llagen gel and amide solution are mixed together, homogenized, and maintained at about -5°C. A solution of crosslinking agents and initiator is prepared by dissolving 0.125 gram of 1-ethyI-3-(3-dimethyiamino-n-propyl)carbodiimide hydrochloride, 0.079 gram of N-hydroxysuccinamide, and 0.25 gram of potassium
persulfate. The solution of crosslinking agents and the ateiocoilagen/amide solution are added together, under agitation, and maintained below 0°C. The resulting solution is transferred into cold plastic disposable syringes and centrifuged for 20 minutes at 0°C and 15,000 rpm to remove air bubbles, and thereafter is injected into molds of desired shape and allowed to react overnight at room temperature, e.g., about 20°C or slightly above room temperature. The resulting products are then leached for 48 hours in Boil 'N Soak solution. There are obtained membranes which are transparent, flexible and non-biodegradable. The water content of these membranes is about Z0 percent by weight.
The products obtained from Examples 1 through 3 are compared with commercial Hydron® polymer and irradiated cross-linked collagen with respect to water content, tear strength, biodegradability, and oxygen permeability. The data is set forth in Table I below:
TABLE I
TEAR BIO¬
Wt. % STRENGTH DEGRAD- O2PERMEABILITY
COMPOS1TION H2O g mm-1 ABILITY (3) × 10-10 (4)
HYDRON(1) nonbio¬
POLYMER 38 2.2 degradable 10
COLLAGEN(2) 91 2.5 liquified 54 after 2 days
EXAMPLE 1 82 2.6 nonbio40 degradable
EXAMPLE 2 80 2.5 nonbio40 degradable
EXAMPLE 3 86 2-2 nonbio43 degradabie
(1) Prepared from a mixture containing about 99 wt. % hydroxyethyl methacrylate, about 0.3-0.5 wt. % ethylene glycol dimethacrylate, and diisopropyl peroxydicarbonate as the catalyst therefor.
(2) Gamma-irradiated crosslinked collagen gel.
(3) Visual observation after 12 days.
(4) Values from O2 permeability - % water relationship.
From a consideration of the data presented in TABLE I supra the following observations can be made. Gamma-irradiated
crosslinked collagen gel is extremely biodegradable and degrades to a liquid solution after two days. On the other hand, the chemically modified collagen/N,N-dimethyiacrylamide products of Example 2 and the atelocoilagen/N,N-dimethylacryiamide products of Examples 3 and 4 give hydrogel products which have high oxygen permeability, good tear strength, and high water content. Moreover, these products are non-biodegradable. The characteristics of a typical commercial Hydron(R) polymer (known as "polymacon" in the soft contact lens field) are set forth for purposes of comparison. The novel shaped products are exceptional candidates for use as extended wear soft contact lenses. Their properties of high oxygen permeability and high water uptake are attained without sacrifice in tear strength (actually improved compared to poiymacon) and nonbiodegradability (far superior to collagen). EXAMPLE 5
Composition Wt. % Wt. grams Atelocollagen 5.00 1.500 N-isopropylacrylamide 9.94 2, 982 N ,N'-methylenebisacrylamide 0.06 0.018 Distilled Water 85.00 25.500
30.00 g
Procedure: a. Dissolve 2.982 g of N-isopropyiacrylamide and 0.018 g of N,N'methyienebisacryiamide in 25.5 g of distilled water. b. Add 1.5 g of atelocollagen to (a) and disperse thoroughly. c. Solubilize the atelocollagen in the resulting admixture by acidifying with 1.0 M HCl to pH 3. d. The resulting (lens) solution is filtered through a 10 filter and filled in a 10 ml disposable piastic syringe. The syringe is placed under vacuum, degassed in few stages, the air being replaced with nitrogen. e. The syringe containing the degassed lens solution is placed in a centrifuge and centrifuged for one hour at 6000 rpm at 10°C.
f. In the next step, the syringe is transferred into a glove box filled with nitrogen. An amount of the lens solution is injected from the syringe into several bottom mold portions (female mold portions) of the plastic lens mold system. The mold systems are closed by inserting a top mold portion (male mold portion) into each bottom mold portion. g. The closed molds are placed in plastic bags filled with nitrogen and the bags are sealed. The bags are then transferred into an insulated box and covered with ice. h. The simultaneous reactions, e.g., polymerization involving the amide monomers, collagen-amide polymer graft reaction, and crosslinking reaction of collagen, is promoted by gamma radiation of 1.0 Mrad total dose. The irradiation is effected by using Co60 as the source of radiation, generally, at low temperature, 5-10ºC, in nitrogen atmosphere to minimize any denaturation of collagen and minimize bond scission which can occur during a high energy radiation.
Properties of the Equilibrated Lenses:
Water Content: 86 wt. % Light Transmission at 660 nm: 97%
Tear Strength (Propagation): 3.0 g/mm
Biological Stability: No biodegradability observed.
EXAMPLE 6
Composition: Wt. % Wt. grams
Atelocollagen 5.00 1.500
Diacetoneacrylamide 4.97 1.491
N,N-dimethylacrylamide 4.97 1.491
N,N--methylenebisacryiamide 0.06 0.018 Distilled Water 85.00 25.500
100.00% 30.00 g
Procedure: a. Diacetoneacrylamide (1.491 g) and 0.018 g of N,N'- methylenebisacrylamide are dissolved in a solution of 25.5 g of distilled water containing 1.491 g of N,N-dimethylacrylamide. b. To the aqueous monomeric solution of step (a) there is added and dispersed therein 1.5 g of atelocollagen. c. Atelocollagen in the resulting admixture is solubilized by adding 1.0 M HCl until pH 3 is reached. d. Continue with step (d) of Example 5. Properties of the Equilibrated Lenses:
Water Content: 86.5 wt. %
Light Transmission at 660 nm: 97%
Tear Strength (Propagation): 2.2 g/mm
Biological Stability: No biodegradability observed.
EXAMPLE 7
Composition: Wt. % Wt. grams Atelocollagen 5.00 1 .250 N-isopropylacrylamide 4.97 1 .243 N,N-dimethylacryiamide 4.97 1 .243 N,N'-methylenebisacryiamide 0.06 0. 15 Distilled Water 85.00 21 .250
100.00% 25.00 g
Procedure: a. Atelocollagen (1.25 g) is dispersed in 21.25 g of distilled water. b. Atelocollagen is solubilized in step (a) by adding 1.0 M HCl until pH 3 is reached. c. N-isopropyiacrylamide (1.243) and 0.015 g of N,N'- methylenebisacrylamide are dissolved in 1.243 g of N,N- dimethyiacrylamide. This monomeric amide solution is added to the atelocollagen solution (step b) and the resulting solution agitated until homogeneous.
d. Continue with step (d) of Example 5. Properties of the Equilibrated Lenses:
Water Content: 88 wt. %
Light Transmission at 660 nm: 99% Tear Strength (Propagation): 2.0 g/mm
Biological Stability: No biodegradability observed.
EXAMPLE 8
Composition: Wt. % Wt. grams Atellocollagen 5.00 1 .250
N,N-dimethyiacrylamide 4.95 1.238
Hydroxyethyl Methacrylate 4.95 1 .238
N ,N'-methylenebisacry lamide 0. 10 0.025
Distilled Water 85.00 21.250
100.00% 25.00 g
Procedure: a. Atelocollagen (1.25 g) is dispersed in 21.25 g of distilled water and solubilized by adjusting the pH with 1.0 M HCl to pH 3. b. N,N'-methylenebisacrylamide (0.025 g) is dissolved in a solution of 1.238 g of N,N-dimethylacrylamide and 1.238 g of 2- hydroxyethyl methacrylate. c. The solution of step (b) is added to the atelocoiiagen solution of step (a) and agitated until homogeneous. d. Continue with step (d) of Example 5. Properties of the Equilibrated Lenses:
Water Content: 89 wt. %
Light Transmission at 660 nm: 97%
Tear Strength (Propagation): 0.8 g/mm
Biological Stability: No biodegradability observed.
EXAMPLE 9
Composition: Wt. % Wt. grams Atelocollagen 9.0 2.7 Distilled Water 91 .0 27.3 100.00% 0.0 g Procedure: a. Atelocollagen (2.7 g) is dispersed in 27.3 g of distilled water and solubilized by bringing the pH to pH 3 with 1.0 M HCl. b. Continue with step (d) of Example 5. Properties of the Equilibrated Lenses:
Water Content: 91 Wt. %
Light Transmission at 660 nm: 96%
Tear Strength (Propagation): 3.8 g/mm
Biological Stability: Total liquefaction in 24 hours.
EXAMPLE 10
Composition: Wt. %
Atelocollagen 7.0
N-isopropylacryiamide 7.0
N,N'-methylenebisacryiamide 0. 1
Distilled Water 85.9
100.00%
Procedure: a. Dissolve the N-isopropyiacrylamide and N,N'- methylenebisacrylamide in distilled water. b. Add the atelocollagen to (a) and disperse thoroughly. c. Solubilize the atelocollagen in the resulting admixture by acidifying with 1.0 M HCl to pH 3. d. Continue with step (d) of Example 5. Properties of the Equilibrated Lenses:
Water Content: 86.3 wt. % Light Transmission at 660 nm: 91.4%
Biological Stability: No biodegradability observed.
EXAMPLE 11 Composition: Wt. % Atelocollagen 7.0 Poly(N,N-dimethyiacryiamide) 7.0 Distilled Water 86.00
100.00% The poly(N,N-dimethyiacryiamide) exmployed in this Example is obtained via the polymerization of an aqueous solution of 50 weight percent N,N-dimethyiacryiamide. Polymerization is initiated using 0.5 wt. %(NH4 S2O8 plus 0.5 wt. % NaHSO3 redox system at 20°C. An exothermic temperature of about 60°C is reached. The resulting poly(N,N-dimethylacryiamide) product is precipitated from acetone and vacuum dried at 80°C. Its molecular weight is of the order of 500,000. Procedure: a. To an aqueous monomeric solution of the poly(N,N- dimethylacrylamide) there is added and dispersed therein the atelocollagen. b. Atelocollagen in the resulting admixture is solubilized by adding 1.0 M HCl until pH 3 is reached. c. Continue with step (d) of Example 5. Properties of the Equilibrated Lenses:
Water Content: 90.1 wt. % Light Transmission at 660 nm: 87.6% Biological Stability: Liquefied after 24 hours.
Figure 1 is the infrared (IR) spectrum of the crosslinked ateiocollagen/N,N-dimethylacrylamide product of Example 10. Its IR spectrum exhibits a sharp peak at 1260 cm and new absorption peaks at 800 cm-1 and 1020 cm-1 , not found in collagen or N,N-dimethylacrylamide, indicating formation of new bonds attributable apparently to coilagen-N,N-dimethylacrylamide grafts.
Figure 2 is the infrared spectrum of the ateiocollagen/poly(N,N-dimethyiacrylamide) "product" of Example 11. Its IR spectrum and the IR spectrum of atelocollagen are very similar. Figure 3 is the infrared spectrum of the poly(N,N-dimethylacrylamide) and is included in this discussion for purposes of comparison with the IR spectra of Figures 1 and 2.
Figure 4 is the infrared spectrum of atelocoiiagen after gamma-irradiation (Example 9 above). The IR spectrum of gammairradiated atelocoiiagen (Example 9, Figure 4) and the IR spectrum of ateiocollagen/poly(N,N-dimethylacryiamide) "product" (Example 11, Figure 2) are very similar. The IR spectrum of the "product" of Example 11 confirms that the poly(dimethylacryiamide) component was extracted during the equilibration or leaching step.
Claims
1. A polymerized hydrophilic water-swellable composition consisting essentially of:
(a) solubilized collagen; and
(b) an ethylenicaily unsaturated compound which is characterized by a polymerizable carbon-to-carbon double bond and is composed of atoms of the group consisting of
(i) carbon, hydrogen, oxygen and nitrogen in the form of amido and optionally oxygen in the form of carbonyl,
(ii) carbon, hydrogen, and oxygen in the form of carbonyloxy and hydroxyl, and optionally oxygen in the form of etheric oxygen, (iii) carbon, hydrogen, carbonyloxy oxygen and etheric oxygen, (iv) carbon, hydrogen, carbonyloxy oxygen, and oxygen in the form of vicinal-epoxy, and (v) carbon, hydrogen, carbonyloxy oxygen, and amino nitrogen;
(c) said polymerized composition containing from 0.5 to less than 50 weight percent of solubilized collagen, from 99.5 to about 50 weight percent of the polymerized ethylenically unsaturated compound, from 0 to 35 weight percent modifier, and from 0 to 5 weight percent crosslinking agent, based on the total weight of the afore-mentioned components.
2. The polymerized hydrophilic composition of claim 1 wherein the weight percent range of the combined components are as follows:
COMPONENT WEIGHT PERCENT
Ethylenically Unsaturated ~ 60-95 Compound
Solubilized Collagen ~5-45
Modifier 0-30
Crosslinking Agent 0-2
3. The polymerized hydrophilic composition of claim 1 wherein said ethylenically unsaturated compound is of the group consisting of the following:
(a) the unsubstituted, N-substituted and N,N-disubstituted 2- alkenamides each N substituent is. hydrogen or a (C1-C6)alkyl, and wherein the 2-alkenoyl group of the 2-alkenamide molecule contains from 2-6 carbon atoms;
(b) the vicinal-epoxyaikyl 2-alkenoates wherein the vicinalepoxyalkyl group contains from 2 to 4 carbn atoms and wherein the 2- alkenoate group contains from 2-6 carbon atoms;
(c) the hydroxy(alkoxy) alkyl 2-alkenoates wherein the alkyl and alkoxy groups contain from 2 to 4 carbon atoms, wherein n is an integer of from zero to 4, and wherein the 2-alkenoate groups contains from 2 to 6 carbon atoms;
(d) the alkoxy(alkoxy) alkyl 2-alkenoates wherein the alkyl and alkoxy groups contain from 2 to 4 carbon atoms, with the proviso that the terminal alkoxy group contains from 1 to 4 carbn atoms, wherein n is an integer of from zero to 4, and wherein the 2-alkenoate group contains from 2 to 6 carbon atoms;
(e) the dialkylaminoalkyl 2-alkenoates wherein the alkyl groups contain from 1 to 4 arbon atoms and wherein the 2-alkenoate group contains from 2 to 6 carbon atoms; and
(f) N-vinylpyrrolidone.
4. Shape-retaining hydrogel characterized by biocompatibility with living tissue, substantial non-biodegradabϊlity, high oxygen permeability, and high water content, comprised of a polymerized hydrophilic composition defined in claim 3.
5. The shape-retaining hydrogel of claim 4 wherein said hydrogel has a water content of from about 55 to about 95 weight percent.
6. The shape retaining hydrogel of claim 5 wherein the combined components are as follows:
COMPONENT WEIGHT PERCENT
Ethylenically Unsaturated Compound ~ 68-90
Collagen ~ 10-35
Modifier 0-20
Crosslinking Agent 0-1 and wherein said hydrogel has a water content of from about 65 to about 90 weight percent.
7. The shape-retaining hydrogel of claim 4 in the form of a contact lens.
8. The shape-retaining hydrogel of claim 5 in the form of a contact lens.
9. The shape-retaining hydrogel of claim 6 in the form of a contact lens.
10. The shape-retaining hydrogel of claim 4 in the forrή of a contact lens wherein said ethylenicaily unsaturated compounds are the unsubstituted, N-substituted and N,N-disubstituted 2-alkenamides wherein each N substituent is hydrogen or a (C1-C6)alkyl, and wherein the 2-alkenoyl group of the 2-alkenamide molecule contains from 2-6 carbon atoms.
11. The shape-retaining hydrogel of claim 4 in the form of a contact lens wherein said ethylenicaily unsaturated compounds are the hydroxy(alkoxy)nalkyl 2-alkenoates wherein the alkyl and alkoxy groups contain from 2 to 4 carbon atoms, wherein n is an integer of from zero to 4, and wherein the 2-alkenoate group contains from 2 to 6 carbon atoms.
12. The contact lens of claim 10 wherein said ethylenically unsaturated compound is N,N-dimethylacrylamide.
13. A process for preparing shape-retaining hydrogels which comprises preparing an aqueous solution of reactants comprising
(a) solubilized collagen; and
(b) an ethylenically unsaturated compound defined in claim 1;
(c) said solution containing less than 30 weight percent of said collagen;
(d) said solution containing at least about 50 to about 99.5 weight percent of said ethylenically unsaturated compound based on the total weight of the reactants;
(e) effecting the polymerization reaction of said aqueous solution of reactants in a mold using crosslinking means of the group consisting of irradiation, polyethylenically unsaturated cross-linkingcompounds, and mixtures thereof;
(f) for a period of time sufficient to produce shaperetaining hydrogel products; and
(g) recovering said hydrogel product.
14. The process of claim 13 wherein said aqueous solution of reactants comprises a polyethylenically unsaturated cross-linking compound, and from about 0.5 to about 12 weight percent of said solubilized collagen.
15. The process of claim 13 wherein said shape-retaining hydrogel products are in the form of contact lenses and are characterized by biocompatibility with living tissue, substantial non- biodegradability, high oxygen permeability, and high water content.
16. The process of claim 15 wherein said solution contains at least about 68 to about 90 weight percent of N,N-dimethylacrylamide, based on the total weight of the reactants.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE8282900881T DE3274454D1 (en) | 1981-02-09 | 1982-02-08 | Contact lenses made from modified synthetic hydrogels |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/232,749 US4452925A (en) | 1981-02-09 | 1981-02-09 | Biologically stabilized compositions comprising collagen as the minor component with ethylenically unsaturated compounds used as contact lenses |
US232749810209 | 1981-02-09 |
Publications (1)
Publication Number | Publication Date |
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WO1982002716A1 true WO1982002716A1 (en) | 1982-08-19 |
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PCT/US1982/000157 WO1982002716A1 (en) | 1981-02-09 | 1982-02-08 | Modified synthetic hydrogels |
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US (1) | US4452925A (en) |
EP (1) | EP0070897B1 (en) |
JP (1) | JPS58500287A (en) |
AU (1) | AU548496B2 (en) |
DE (1) | DE3274454D1 (en) |
WO (1) | WO1982002716A1 (en) |
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- 1982-02-08 WO PCT/US1982/000157 patent/WO1982002716A1/en active IP Right Grant
- 1982-02-08 EP EP82900881A patent/EP0070897B1/en not_active Expired
- 1982-02-08 JP JP57501004A patent/JPS58500287A/en active Granted
- 1982-02-08 AU AU82723/82A patent/AU548496B2/en not_active Ceased
- 1982-02-08 DE DE8282900881T patent/DE3274454D1/en not_active Expired
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US4035330A (en) * | 1975-12-22 | 1977-07-12 | Itek Corporation | Hydrophilic copolymer of N,N-di(C1 -C2 alkyl)acrylamide cross-linked with a glycidyl ester |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996003147A1 (en) * | 1994-07-26 | 1996-02-08 | Fidia Advanced Biopolymers, S.R.L. | Synthesis of chemical gels from polyelectrolyte polysaccharides by gamma-irradiation |
EP2666462A4 (en) * | 2011-01-19 | 2016-03-09 | Sewon Cellontech Co Ltd | Radiation cross-linked collagen gel, and preparation method and usage method thereof |
CN110041475A (en) * | 2019-04-11 | 2019-07-23 | 中国科学技术大学 | A kind of amphipathic nature block polymer, its shell crosslinking micella and preparation method and application |
Also Published As
Publication number | Publication date |
---|---|
EP0070897B1 (en) | 1986-11-26 |
AU8272382A (en) | 1982-08-26 |
US4452925A (en) | 1984-06-05 |
EP0070897A1 (en) | 1983-02-09 |
EP0070897A4 (en) | 1983-06-17 |
JPH0433801B2 (en) | 1992-06-04 |
AU548496B2 (en) | 1985-12-12 |
DE3274454D1 (en) | 1987-01-15 |
JPS58500287A (en) | 1983-02-24 |
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