US4883864A
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Modified collagen compound and method of preparation
Assignee: 3M Co
•
Filing: 1988-10-28
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Granted: 1989-11-28
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Expires: 2008-10-28
Abstract
Abstract Chemically-modified collagen is prepared by reacting native collagen with a di or tri-carboxylic acid halide, di or tri-sulfonyl halide, di or tri-anhydride, or di or tri-reactive active ester coupling agent. The reaction is done in a controlled manner so that the degree of cross-linking is limited. Any remaining lysine epsilon amino groups present in the coupled collagen product may be converted to ureido, β-malicamino carboxyamido or sulfonamido groups by isocyanate, epoxy succinic acid, acid halide, anhydride, sulfonyl halide or active ester aminemodifying agents. The resultant soluble product when dissolved in a physiological buffer provides a viscoelastic solution having therapeutic application in a variety of surgical procedures, particularly in ophthalmic surgery. This viscoelastic solution "melts," i.e., exhibits a dramatic loss of viscosity, when subjected to temperatures of between 32° and 48° C. The resultant insoluble product is suspended in physiological buffer and useful in tissue augmentation. The suspension containing the insoluble product exhibits a dramatic loss in viscosity at temperatures between about 40° and 70° C.
Inventors
- 👤 Matthew T. Scholz
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 12:20
CPC Classifications
C; C07; C07K; C07K14/00; C07K14/435; C07K14/78; A; A61; A61L; A61L27/00; A61L27/14; A61L27/22; A61L27/24; C08; C08H; C08H1/00; C08H1/06; A61F; A61F2310/00; A61F2310/00005; A61F2310/00365; Y; Y10; Y10S; Y10S128/00; Y10S128/08
Claims Analysis
Total Claims: 25
Claim 1
Independent Claim
96 words
A chemically-modified collagen compound comprising at least two native collagen molecules coupled at least one lysine epsilon amino group present on each of said collagen molecules by a coupling group, said coupling group comprising at least two moieties selected from the group consisting of carbonyl and sulfonyl groups, wherein non-coupled lysine epsilon amino groups are linked to amine modifying groups selected from groups of the formula ##STR8## wherein R is a substituted or unsubstituted C 1-8 aliphatic, C 5-8 alicyclic, or C 6-10 aromatic group having 0-5 heteoatoms, and the formula ##STR9## and its metal salts.
Claim 2
Dependent Claim
96 words
A chemically-modified collagen compound comprising at least two native collagen molecules coupled at least one lysine epsilon amino group present on each of said collagen molecules by a coupling group, said coupling group comprising at least two moieties selected from the group consisting of carbonyl and sulfonyl groups, wherein non-coupled lysine epsilon amino groups are linked to amine modifying groups selected from groups of the formula ##STR8## wherein R is a substituted or unsubstituted C 1-8 aliphatic, C 5-8 alicyclic, or C 6-10 aromatic group having 0-5 heteoatoms, and the formula ##STR9## and its metal salts.
Claim 3
Dependent Claim
23 words
The compound of claim 1 wherein at least 60% of the non-coupled lysine epsilon amino groups are linked to the amine modifying groups.
Claim 4
Dependent Claim
37 words
The compound of claim 1 wherein the amine modifying groups are groups of the formula ##STR10## wherein R is a substituted or unsubstituted C 1-8 aliphatic, C 5-8 alicyclic, or C 6-10 aromatic group having 0-5 heteroatoms.
Claim 5
Dependent Claim
25 words
The compound of claim 3 wherein R is C 1-8 alkyl, C 5-8 cycloalkyl, C 6-10 aryl, C 6-10 substituted aryl, or C 6-10 aralkyl.
Claim 6
Dependent Claim
9 words
The compound of claim 4 wherein R is butyl.
Claim 7
Dependent Claim
20 words
The compound of claim 1 wherein the amine modifying groups are groups of the formula ##STR11## or its metal salts.
Claim 8
Dependent Claim
17 words
A collagen fraction comprised of collagen molecules, about 10-80% of which comprises the compound of claim 6.
Claim 9
Dependent Claim
22 words
A viscoelastic collagen solution comprising about 0.5-5.0% by weight of the collagen fraction of claim 7 dissolved in a physiological buffer solution.
Claim 10
Dependent Claim
67 words
A viscoelastic collagen solution comprising about 0.5 to 5.0 percent by weight of the collagen compound of claim 6 dissolved in a physiological buffer solution, wherein the coupling group is present in said chemically-modified collagen compound to such an extent that a 2 percent by weight solution of said collagen compound in said physiological buffer has a melt temperature of between about 32° C. and 48° C.
Claim 11
Dependent Claim
17 words
A collagen fraction comprised of collagen molecules, about 10-80% of which comprise the compound of claim 1.
Claim 12
Dependent Claim
23 words
A chemically modified collagen composition comprising about 0.5-5.0% by weight of the collagen fraction of claim 10 suspended in a physiological buffer solution.
Claim 13
Dependent Claim
26 words
A chemically modified collagen composition comprising about 0.5 to 5.0 percent by weight of the collagen compound of claim 1 suspended in a physiological buffer solution.
Claim 14
Dependent Claim
50 words
The chemically modified collagen composition of claim 12 wherein the coupling group is present in said chemically-modified collagen compound to such an extent that a 2 percent by weight suspension of said collagen compound in said physiological buffer has a melt temperature of between about 40° C. and 70° C.
Claim 15
Dependent Claim
35 words
The chemically modified collagen composition of claim 12 wherein said coupling group is --CO(CH 2 ) 2 --CO-- or--CO(CH 2 ) 3 --CO--, and said modifying group is --CONH(CH 2 ) 3 CH 3 .
Claim 16
Dependent Claim
29 words
The chemically modified collagen composition of claim 12 wherein said coupling group is --CO(CH 2 ) 3 --CO-- or--CO(CH 2 ) 2 --CO--, and said modifying group is --CHCOOH--CHOH--COOH.
Claim 17
Independent Claim
245 words
A method of making a chemically-modified collagen compound comprising the steps of (a) adding to an aqueous solution of at least about 0.05 percent by weight native collagen, a coupling agent in an amount equal to about 1 to 600 moles of coupling agent per mole of native collagen, said coupling agent selected from the group consisting of di- and tri-carboxylic acid halides, di- and tri-sulfonyl halides, di- and tri-anhydrides, di- and tri-reactive active esters, and compounds having at least two moieties selected from the group consisting of carboxylic acid halide, sulfonyl halide, anhydride and active ester; (b) reacting said native collagen and said coupling agent at a pH of above about 8 and at a temperature of between about 0 and 35° C., for a time period sufficient to either react or hydrolyze substantially all of said coupling agent; (c) adding to said reaction mixture a mono-reactive amine-modifying agent, said amine-modifying agent being selected from agents of the formula O═C═N--R wherein R is a substituted or unsubstituted C 1-8 aliphatic, C 5-8 alicyclic, or C 6-10 aromatic group having 0-5 heteroatoms, and epoxy succinic acid in an amount equal to at least about 100 moles of amine-modifying agent per mole of native collagen; and (d) conducting the amine-modification reaction at a pH of greater than about 8 and at a temperature of between about 0 and 35° C., for a time period sufficient to either react or hydrolyze substantially all of said amine-modifying agent
Claim 18
Independent Claim
245 words
A method of making a chemically-modified collagen compound comprising the steps of (a) adding to an aqueous solution of at least about 0.05 percent by weight native collagen, a coupling agent in an amount equal to about 1 to 600 moles of coupling agent per mole of native collagen, said coupling agent selected from the group consisting of di- and tri-carboxylic acid halides, di- and tri-sulfonyl halides, di- and tri-anhydrides, di- and tri-reactive active esters, and compounds having at least two moieties selected from the group consisting of carboxylic acid halide, sulfonyl halide, anhydride and active ester; (b) reacting said native collagen and said coupling agent at a pH of above about 8 and at a temperature of between about 0 and 35° C., for a time period sufficient to either react or hydrolyze substantially all of said coupling agent; (c) adding to said reaction mixture a mono-reactive amine-modifying agent, said amine-modifying agent being selected from agents of the formula O═C═N--R wherein R is a substituted or unsubstituted C 1-8 aliphatic, C 5-8 alicyclic, or C 6-10 aromatic group having 0-5 heteroatoms, and epoxy succinic acid in an amount equal to at least about 100 moles of amine-modifying agent per mole of native collagen; and (d) conducting the amine-modification reaction at a pH of greater than about 8 and at a temperature of between about 0 and 35° C., for a time period sufficient to either react or hydrolyze substantially all of said amine-modifying agent
Claim 19
Dependent Claim
49 words
The method of claim 16 wherein said coupling agent is selected from the group consisting of terephthaloyl chloride; bicyclo-(2,2,)-oct-7 -ene-2,3,5,6-tetracarboxylic-2,3,5,6-dianhydride; 1,2,4,5-benzenetetracarboxylic dianhydride; p-fluorosulfonylbenzenesulfonyl chloride; and wherein the pH of the reaction mixture is initially maintained at about 3 to about 5.5 before raising the pH to above about 8.
Claim 20
Independent Claim
281 words
A method of making a chemically-modified collagen compound comprising the steps of: (a) adding to an aqueous solution of at least about 0.05 percent by weight native collagen, a coupling agent in an amount equal to about 1 to 600 moles of coupling agent per mole of native collagen and a mono-reactive amine-modifying agent in an amount equal to at least about 50 moles of amine-modifying agent per mole of native collagen; said coupling agent selected from the group consisting of di- and tri-carboxylic acid halides, di- and tri-sulfonyl halides, di- and tri-anhydrides, di- and tri-reactive active esters and compounds having at least two moieties selected from the group consisting of carboxylic acid halide, sulfonyl halide, anhydride and active ester; and wherein said amine-modifying agent is selected from groups of the formula O═C═N--R wherein R is a substituted or unsubstituted C 1-8 aliphatic, C 5-8 alicyclic, or C 6-10 aromatic group having 0-5 heteroatoms, and epoxy succinic acid; (b) allowing the reaction mixture to react at a pH of greater than about 8 and at a temperature of between about 0 and 35° C., for a time period sufficient to either react or hydrolyze substantially all of said coupling agent and said amine-modifying agent; (c) adding to the reaction mixture of step (b) additional mono-reactive amine-modifying agent in an amount equal to at least about 50 moles of modifying agent per mole of native collagen; and (d) allowing the reaction mixture of step (c) to react at a pH of greater than about 8 and at a temperature of between 0 and 35° C., for a period of time sufficient to either react or hydrolyze substantially all of said modifying agent.
Claim 21
Independent Claim
281 words
A method of making a chemically-modified collagen compound comprising the steps of: (a) adding to an aqueous solution of at least about 0.05 percent by weight native collagen, a coupling agent in an amount equal to about 1 to 600 moles of coupling agent per mole of native collagen and a mono-reactive amine-modifying agent in an amount equal to at least about 50 moles of amine-modifying agent per mole of native collagen; said coupling agent selected from the group consisting of di- and tri-carboxylic acid halides, di- and tri-sulfonyl halides, di- and tri-anhydrides, di- and tri-reactive active esters and compounds having at least two moieties selected from the group consisting of carboxylic acid halide, sulfonyl halide, anhydride and active ester; and wherein said amine-modifying agent is selected from groups of the formula O═C═N--R wherein R is a substituted or unsubstituted C 1-8 aliphatic, C 5-8 alicyclic, or C 6-10 aromatic group having 0-5 heteroatoms, and epoxy succinic acid; (b) allowing the reaction mixture to react at a pH of greater than about 8 and at a temperature of between about 0 and 35° C., for a time period sufficient to either react or hydrolyze substantially all of said coupling agent and said amine-modifying agent; (c) adding to the reaction mixture of step (b) additional mono-reactive amine-modifying agent in an amount equal to at least about 50 moles of modifying agent per mole of native collagen; and (d) allowing the reaction mixture of step (c) to react at a pH of greater than about 8 and at a temperature of between 0 and 35° C., for a period of time sufficient to either react or hydrolyze substantially all of said modifying agent.
Claim 22
Independent Claim
323 words
A method of making a chemically-modified collagen compound comprising the steps of: (a) adding to an aqueous solution of at least about 0.05 percent by weight native collagen a mono-reactive amine-modifying agent in an amount equal to at least about 25 moles of amine-modifying agent per mole of native collagen, said amine-modifying agent being selected from groups of the formula O═C═N--R wherein R is a substituted or unsubstituted C 1-8 aliphatic, C 5-8 alicyclic, or C 6-10 aromatic group having 0-5 heteroatoms, and epoxy succinic acid; (b) allowing the reaction mixture of step (a) to react at a pH of greater than about 8 and at a temperature of about 0 to 35° C. for a period of time sufficient to either react or hydrolyze substantially all of said amine-modifying agent; (c) adding to the mixture produced in step (b) a coupling agent in an amount equal to about 1 to 600 moles of coupling agent selected from the group consisting of di- and tri-carboxylic acid halides, di- and tri-sulfonyl halides, di- and tri-anhydrides and di- and tri-reactive active esters, and compounds having at least two moieties selected from the group consisting of carboxylic acid halide, sulfonyl halide, anhydride and active ester; and (d) allowing the reaction mixture of step (c) to react at a pH of greater than about 8 and at a temperature of about 0 to 35° C. for a time period sufficient to either react or hydrolyze substantially all of said coupling agent; (e) adding to the reaction mixture of step (d) additional amine-modifying agent in a concentration of at least about 75 moles of modifying agent per mole of native collagen; and (f) allowing the reaction mixture of step (d) to react at a pH of greater than about 8, and at a temperature of between about 0 and 35° C., for a period of time sufficient to either react or hydrolyze substantially all of said amine-modifying agent.
Claim 23
Independent Claim
323 words
A method of making a chemically-modified collagen compound comprising the steps of: (a) adding to an aqueous solution of at least about 0.05 percent by weight native collagen a mono-reactive amine-modifying agent in an amount equal to at least about 25 moles of amine-modifying agent per mole of native collagen, said amine-modifying agent being selected from groups of the formula O═C═N--R wherein R is a substituted or unsubstituted C 1-8 aliphatic, C 5-8 alicyclic, or C 6-10 aromatic group having 0-5 heteroatoms, and epoxy succinic acid; (b) allowing the reaction mixture of step (a) to react at a pH of greater than about 8 and at a temperature of about 0 to 35° C. for a period of time sufficient to either react or hydrolyze substantially all of said amine-modifying agent; (c) adding to the mixture produced in step (b) a coupling agent in an amount equal to about 1 to 600 moles of coupling agent selected from the group consisting of di- and tri-carboxylic acid halides, di- and tri-sulfonyl halides, di- and tri-anhydrides and di- and tri-reactive active esters, and compounds having at least two moieties selected from the group consisting of carboxylic acid halide, sulfonyl halide, anhydride and active ester; and (d) allowing the reaction mixture of step (c) to react at a pH of greater than about 8 and at a temperature of about 0 to 35° C. for a time period sufficient to either react or hydrolyze substantially all of said coupling agent; (e) adding to the reaction mixture of step (d) additional amine-modifying agent in a concentration of at least about 75 moles of modifying agent per mole of native collagen; and (f) allowing the reaction mixture of step (d) to react at a pH of greater than about 8, and at a temperature of between about 0 and 35° C., for a period of time sufficient to either react or hydrolyze substantially all of said amine-modifying agent.
Claim 24
Dependent Claim
24 words
A method of achieving hemostasis comprising placing an effective amount of the chemically-modified collagen compound of claim 1 in contact with a bleeding wound.
Claim 25
Dependent Claim
25 words
A method of augmenting soft tissue comprising placing an effective amount of the chemically-modified collagen composition of claim 11 in contact with the augmentation site.
References Cited (Backward Citations)
US2127841A
Cited
US3949073A
Cited
US4141973A
Cited
US4141973B1
Cited
US4164559A
Cited
US4264493A
Cited
US4268131A
Cited
US4264155A
Cited
US4260228A
Cited
US4404033A
Cited
US4328803A
Cited
US4328803B1
Cited
US4382081A
Cited
US4424208A
Cited
US4409332A
Cited
US4559304A
Cited
US4540568A
Cited
US4532267A
Cited
WO1985004413A1
Cited
EP0164569A2
Cited
US4553974A
Cited
EP0183136A1
Cited
EP0191994A1
Cited
US4713446A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1992-11-27 | 1993-05-29 | 1993-11-28 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1996-11-27 | 1997-05-29 | 1997-11-28 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2000-11-27 | 2001-05-29 | 2001-11-28 | $7700.00 | Window Closed / Lapsed |