Method for preparing a biocompatible crosslinked matrix and matrix provided thereby

• US 20050027070A1
• Filed: 08/13/2004
• Published: 02/03/2005
• Est. Priority Date: 12/18/1995
• Status: Abandoned Application

• Current Assignee: Frank A. Delustro, Richard A. Berg, Woonza M. Rhee
• Original Assignee: Frank A. Delustro, Richard A. Berg, Woonza M. Rhee
• Inventors: Rhee, Woonza M., Berg, Richard A., DeLustro, Frank A.
• Application Number:
  US10/918,502
• Publication Number:
  US 20050027070A1
• Time in Patent Office: Days
• US Class Current: 525/54.100
• CPC Class Codes: A61L 2300/232 Monosaccharides, disaccharides, polysaccharides, lipopolysaccharides
• CPC Class Codes: A61L 2300/252 Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
• CPC Class Codes: A61L 2300/606 Coatings
• CPC Class Codes: A61L 24/043 Mixtures of macromolecular materials
• CPC Class Codes: A61L 24/08 Polysaccharides A61L24/043 takes precedence
• CPC Class Codes: A61L 27/26 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 31/041 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: C08B 37/0075 Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
• CPC Class Codes: C08G 65/329 with organic compounds
• CPC Class Codes: C08H 1/00 Macromolecular products derived from proteins food proteins A23; glue, gelatine C09H
• CPC Class Codes: C08H 1/06 derived from horn, hoofs, hair, skin or leather
• CPC Class Codes: C08L 5/16 Cyclodextrin; Derivatives thereof
• CPC Class Codes: C08L 71/00 Compositions of polyethers obtained by reactions forming an ether link in the main chain of polyacetals C08L59/00; of epoxy resins C08L63/00; of polythioether-ethers C08L81/02; of polyether-sulfones C08L81/06; Compositions of derivatives of such polymers
• CPC Class Codes: C08L 71/02 Polyalkylene oxides
• CPC Class Codes: Y10S 623/90 Stent for heart valve
• CPC Class Codes: Y10S 623/901 Method of manufacturing prosthetic device

Abstract

Provided are crosslinked polymer compositions that include a first synthetic polymer containing multiple nucleophilic groups covalently bound to a second synthetic polymer containing multiple electrophilic groups. The first synthetic polymer is preferably a synthetic polypeptide or a polyethylene glycol that has been modified to contain multiple nucleophilic groups, such as primary amino (—NH₂) or thiol (—SH) groups. The second synthetic polymer may be a hydrophilic or hydrophobic synthetic polymer, which contains or has been derivatized to contain, two or more electrophilic groups, such as succinimidyl groups. The compositions may further include other components, such as naturally occurring polysaccharides or proteins (such as glycosaminoglycans or collagen) and/or biologically active agents. Also disclosed are methods for using the crosslinked polymer compositions to effect adhesion between a first surface and a second surface; to effect tissue augmentation; to prevent the formation of surgical adhesions; and to coat a surface of a synthetic implant.

Claims

1. A method for preparing a biocompatible crosslinked matrix, comprising admixing, under crosslinking conditions, (a) a first crosslinkable component having m nucleophilic groups, wherein m≧

2, with (b) a second crosslinkable component having n electrophilic groups capable of reaction with the m nucleophilic groups to form covalent bonds, wherein n≧

2 and m+n≧

5, wherein each of the first and second crosslinkable components is biocompatible and synthetic, and crosslinking of the components results in the biocompatible crosslinked matrix.

2. The method of claim 1, wherein the m nucleophilic groups in the first crosslinkable component are identical.

3. The method of claim 1, wherein at least two of the m nucleophilic groups in the first crosslinkable component are different.

4. The method of claim 1, wherein the n electrophilic groups in the second crosslinkable component are identical.

5. The method of claim 2, wherein the n electrophilic groups in the second crosslinkable component are identical.

6. The method of claim 3, wherein the n electrophilic groups in the second crosslinkable component are identical.

7. The method of claim 1, wherein at least two of the n electrophilic groups in the second crosslinkable component are different.

8. The method of claim 2, wherein at least two of the n electrophilic groups in the second crosslinkable component are different.

9. The method of claim 3, wherein at least two of the n electrophilic groups in the second crosslinkable component are different.

10. The method of claim 1, wherein the m nucleophilic groups are bound to the first crosslinkable component through linking groups.

11. The method of claim 1, wherein the n electrophilic groups are bound to the second crosslinkable component through linking groups.

12. The method of claim 1, wherein at least one of the first and second crosslinkable components is comprised of a hydrophilic polymer.

13. The method of claim 1, wherein at least one of the first and second crosslinkable components is comprised of a hydrophobic polymer.

14. The method of claim 1, wherein the m nucleophilic groups are primary amino groups.

15. The method of claim 14, wherein the first crosslinkable component is C₂-C₆ hydrocarbyl substituted with amino groups.

16. The method of claim 14, wherein the first crosslinkable component is a secondary or tertiary amine NR₁R₂R₃ wherein R₁ is hydrogen or an amino-substituted lower alkyl group, and R₂ and R₃ are amino-substituted lower alkyl groups.

17. The method of claim 14, wherein the n electrophilic groups are selected from the group consisting of succinimidyl ester, sulfosuccinimidyl ester, maleimido, epoxy, isocyanato, thioisocyanato, and ethenesulfonyl.

18. The method of claim 17, wherein the n electrophilic groups are selected from the group consisting of succinimidyl ester and sulfosuccinimidyl ester.

19. The method of claim 1, wherein the m nucleophilic groups are sulfhydryl groups.

20. The method of claim 19, wherein the n electrophilic groups are sulfhydryl-reactive groups selected so as to form a thioester, thioether, or disulfide linkage upon reaction with the sulfhydryl groups.

21. The method of claim 1, wherein n=2.

22. The method of claim 1, wherein m=2.

23. The method of claim 1, wherein the crosslinking conditions comprise admixture in an aqueous medium.

24. The method of claim 23, wherein the first and second crosslinkable components each represent-about 0.5 wt. % to about 20 wt. % of the composition formed upon admixture.

25. The method of claim 23, wherein the crosslinking conditions further comprise admixture at a pH in the range of 7 to 8.

26. The method of claim 25, wherein the first and second crosslinkable components are at concentrations of 20 mg/ml to 200 mg/ml of the composition formed upon admixture.

27. The method of claim 1, wherein the first crosslinkable component is in an aqueous solution, the second crosslinkable component is in dry, particulate form, and admixing comprises combining the second crosslinkable component with the aqueous solution of the first crosslinkable component.

28. The method of claim 27, the first and second crosslinkable components each represent about 0.5 wt. % to about 20 wt. % of the composition formed upon admixture.

29. The method of claim 27, wherein the crosslinking conditions further comprise admixture at a pH in the range of 7 to 8.

30. The method of claim 29, wherein the first and second crosslinkable components are at concentrations of 20 mg/ml to 200 mg/ml of the composition formed upon admixture.

31. The method of claim 1, wherein the first crosslinkable component is present in a molar excess relative to the second crosslinkable component.

32. The method of claim 1, wherein the second crosslinkable component is present in a molar excess relative to the first crosslinkable component.

33. A biocompatible crosslinked matrix prepared by the process comprising admixing, under crosslinking conditions, (a) a first crosslinkable component having m nucleophilic groups, wherein m≧

2, with (b) a second crosslinkable component having n electrophilic groups capable of reaction with the m nucleophilic groups to form covalent bonds, wherein n≧

2 and m+n≧

5 wherein each of the first and second crosslinkable components is biocompatible and synthetic, and crosslinking of the components results in the biocompatible crosslinked matrix.

34. The matrix of claim 33, wherein the m nucleophilic groups in the first crosslinkable component are identical.

35. The matrix of claim 33, wherein at least two of the m nucleophilic groups in the first crosslinkable component are different.

36. The matrix of claim 33, wherein the n electrophilic groups in the second crosslinkable component are identical.

37. The matrix of claim 34, wherein the n electrophilic groups in the second crosslinkable component are identical.

38. The matrix of claim 35, wherein the n electrophilic groups in the second crosslinkable component are identical.

39. The matrix of claim 33, wherein at least two of the n electrophilic groups in the second crosslinkable component are different.

40. The matrix of claim 34, wherein at least two of the n electrophilic groups in the second crosslinkable component are different.

41. The matrix of claim 35, wherein at least two of the n electrophilic groups in the second crosslinkable component are different.

42. The matrix of claim 33, wherein the m nucleophilic groups are bound to the first crosslinkable component through linking groups.

43. The matrix of claim 33, wherein the n electrophilic groups are bound to the second crosslinkable component through linking groups.

44. The matrix of claim 33, wherein at least one of the first and second crosslinkable components is comprised of a hydrophilic polymer.

45. The matrix of claim 33, wherein at least one of the first and second crosslinkable components is comprised of a hydrophobic polymer.

46. The matrix of claim 33, wherein the m nucleophilic groups are primary amino groups.

47. The matrix of claim 46, wherein the first crosslinkable component is C₂-C₆ hydrocarbyl substituted with amino groups.

48. The matrix of claim 46, wherein the first crosslinkable component is a secondary or tertiary amine NR₁R₂R₃ wherein R₁ is hydrogen or an amino-substituted lower alkyl group, and R₂ and R₃ are amino-substituted lower alkyl groups.

49. The matrix of claim 46, wherein the n electrophilic groups are selected from the group consisting of succinimidyl ester, sulfosuccinimidyl ester, maleimido, epoxy, isocyanato, thioisocyanato, and ethenesulfonyl.

50. The matrix of claim 49, wherein the n electrophilic groups are selected from the group consisting of succinimidyl ester and sulfosuccinimidyl ester.

51. The matrix of claim 33, wherein them nucleophilic groups are sulfbydryl groups.

52. The matrix of claim 51, wherein the n electrophilic groups are sulfhydryl-reactive groups selected so as to form a thioester, thioether, or disulfide linkage upon reaction with the sulfhydryl groups.

53. The matrix of claim 33, wherein n=2.

54. The matrix of claim 33, wherein m=2.

55. The matrix of claim 33, wherein the crosslinking conditions comprise admixture in an aqueous medium.

56. The matrix of claim 55, wherein the first and second crosslinkable components each represent about 0.5 wt. % to about 20 wt. % of the composition formed upon admixture.

57. The matrix of claim 55, wherein the crosslinking conditions further comprise admixture at a pH in the range of 7 to 8.

58. The matrix of claim 57, wherein the first and second crosslinkable components are at concentrations of 20 mg/ml to 200 mg/ml of the composition formed upon admixture.

59. The matrix of claim 33, wherein the first crosslinkable component is in an aqueous solution, the second crosslinkable component is in dry, particulate form, and admixing comprises combining the second crosslinkable component with the aqueous solution of the first crosslinkable component.

60. The matrix of claim 59, the first and second crosslinkable components each represent about 0.5 wt. % to about 20 wt. % of the composition formed upon admixture.

61. The matrix of claim 59, wherein the crosslinking conditions further comprise admixture at a pH in the range of 7 to 8.

62. The matrix of claim 61, wherein the first and second crosslinkable components are at concentrations of 20 mg/ml to 200 mg/ml of the composition formed upon admixture.

63. The matrix of claim 33, wherein the first crosslinkable component is present in a molar excess relative to the second crosslinkable component.

64. The matrix of claim 33, wherein the second crosslinkable component is present in a molar excess relative to the first crosslinkable component.