Rapid-gelling biocompatible polymer composition and associated methods of preparation and use
First Claim
1. A method for preparing a biocompatible gel, comprising:
- (a) forming a reactive composition by admixing a biocompatible crosslinking component A having m sulfhydryl groups with a biocompatible crosslinking component B having n sulfhydryl-reactive groups, wherein m≧
2, n≧
2 and m+n>
4, and further wherein the sulfhydryl-reactive groups are capable of covalent reaction with the m sulfhydryl groups upon admixture of components A and B under effective crosslinking conditions to form a gel in less than one minute; and
(b) allowing the components of the reactive composition to crosslink and thereby form a gel.
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Abstract
A method is provided for the rapid formation of a biocompatible gel, and may be carried out in situ, i.e., at a selected site within a patient'"'"'s body. The method involves admixing a biocompatible crosslinking component A having m sulfhydryl groups wherein m≧2 and a biocompatible crosslinking component B having n sulfhydryl-reactive groups wherein n≧2 and m+n>4, wherein the sulfhydryl-reactive groups are capable of covalent reaction with the sulfhydryl groups upon admixture of the components under effective crosslinking conditions to form a gel in less than one minute. Suitable reaction conditions for carrying out the crosslinking reaction will depend on the particular components and the type of reaction involved; that is, the “effective crosslinking conditions” may involve reaction in bulk or in a solvent, addition of a base, and/or irradiation of the admixture in the presence of a free radical initiator. Exemplary uses include tissue augmentation, biologically active agent delivery, bioadhesion, and prevention of adhesions following surgery or injury. Reactive gel-forming compositions and systems are also provided.
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Citations
47 Claims
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1. A method for preparing a biocompatible gel, comprising:
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(a) forming a reactive composition by admixing a biocompatible crosslinking component A having m sulfhydryl groups with a biocompatible crosslinking component B having n sulfhydryl-reactive groups, wherein m≧
2, n≧
2 and m+n>
4, and further wherein the sulfhydryl-reactive groups are capable of covalent reaction with the m sulfhydryl groups upon admixture of components A and B under effective crosslinking conditions to form a gel in less than one minute; and
(b) allowing the components of the reactive composition to crosslink and thereby form a gel. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47)
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19. The method of claim 18, wherein at least one of R1 and R2 is a hydrophilic polymer.
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20. The method of claim 19, wherein the polymer is a synthetic hydrophilic polymer.
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21. The method of claim 20, wherein the synthetic hydrophilic polymer is a linear, branched, dendrimeric, hyperbranched, or star polymer.
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22. The method of claim 20, wherein the synthetic hydrophilic polymer is selected from the group consisting of polyalkylene oxides;
- poly(oxyalkylene)-substituted diols;
poly(oxyalkylene)-substituted polyols;
poly(oxyalkylene)-substituted saccharides;
acrylate-based polymers;
poly(maleic acid);
poly(acrylamide)s;
poly(olefinic alcohols);
poly(N-vinyl lactams); and
copolymers thereof.
- poly(oxyalkylene)-substituted diols;
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23. The method of claim 22, wherein the synthetic hydrophilic polymer is selected from the group consisting of:
- polyethylene glycol;
ethylene oxide copolymers;
mono-, di- and tri-polyoxyethylated glycerol;
poly(oxyethylene)-substituted polyglycerol;
mono- and di-polyoxyethylated propylene glycol;
mono- and di-polyoxyethylated trimethylene glycol;
polyoxyethylated sorbitol;
polyoxyethylated glucose;
polyacrylic acid, polymethacrylic acid, poly(hydroxyethylmethacrylate), poly(hydroxyethylacrylate), poly(methylalkylsulfoxide methacrylate)s, poly(methylalkylsulfoxide acrylate)s, and copolymers thereof with additional acrylate species;
polymaleic acid;
poly(acrylamide);
poly(methacrylamide);
poly(dimethylacrylamide);
poly(N-isopropyl-acrylamide);
poly(vinyl alcohol);
poly(vinyl pyrrolidone);
poly(N-vinyl caprolactam); and
copolymers thereof.
- polyethylene glycol;
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24. The method of claim 22, wherein the synthetic hydrophilic polymer is a polyalkylene oxide.
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28. The method of claim 19, wherein both R1 and R2 are hydrophilic polymers.
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29. The method of claim 19, wherein one of R1 and R2 is a hydrophilic polymer and the other is C2 to C14 hydrocarbyl containing zero to 2 heteroatoms selected from N, O and S.
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30. The method of claim 18, wherein Q1 and/or Q2 contains at least one biodegradable linkage.
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31. The method of claim 30, wherein the biodegradable linkage is a hydrolyzable linkage.
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32. The method of claim 30, wherein the biodegradable linkage is an enzymatically cleavable linkage.
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33. The method of claim 2, wherein the sulfhydryl-reactive groups are selected so as to form a thioester, disulfide, or thioether linkage upon reaction with the sulfhydryl groups.
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34. The method of claim 33, wherein the linkage formed is a thioester linkage.
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35. The method of claim 34, wherein the sulfhydryl-reactive groups are selected from the group consisting of esters, anhydrides, acid chlorides, ketenes, and isocyanates.
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36. The method of claim 35, wherein the sulfhydryl-reactive groups are esters.
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37. The method of claim 36, wherein the sulfhydryl-reactive groups are selected from the group consisting of succinimidyl ester and sulfosuccinimidyl ester.
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38. The method of claim 33, wherein the linkage formed is a disulfide linkage.
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39. The method of claim 38, wherein the sulfhydryl-reactive groups have the structure —
- S—
S—
Ar where Ar is a substituted or unsubstituted nitrogen-containing heteroaromatic moiety or a non-heterocyclic aromatic group substituted with an electron-withdrawing moiety.
- S—
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40. The method of claim 33, wherein the linkage formed is a thioether linkage.
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41. The method of claim 40, wherein the sulfhydryl-reactive groups are selected from the group consisting of haloalkyl, haloaryl, epoxy, imino, aziridino, alkynyl, and Michael-type groups containing a carbon-carbon double bond substituted with an electron-withdrawing moiety.
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42. The method of claim 41, wherein the sulfhydryl-reactive groups are Michael-type groups containing a carbon-carbon double bond substituted with an electron-withdrawing moiety selected from nitro, halo, carbonyl, and sulfonyl.
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43. The method of claim 42, wherein the sulfhydryl-reactive groups are selected from the group consisting of maleimido, ethyleneimino, acrylate, methacrylate, ethenesulfonyl, and α
- ,β
-unsaturated aldehydes and ketones.
- ,β
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44. The method of claim 42, wherein the sulfhydryl-reactive groups are selected from the group consisting of maleimido, acrylate and methacrylate.
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45. The method of claim 1, wherein the sulfhydryl-reactive groups are selected so as to form said gel in less than 30 seconds.
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46. The method of claim 45, wherein the sulfhydryl-reactive groups are selected so as to form said gel in less than 15 seconds.
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47. The method of claim 1, wherein a fibrous tensile strength enhancer is incorporated into the admixture in step (a).
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- 25. The method of 24, wherein the polyalkylene oxide is selected from the group consisting of polyethylene glycol and copolymers of ethylene oxide.
Specification