Methods for reducing or eliminating post-surgical adhesion formation

• US 5,711,958 A
• Filed: 07/11/1996
• Issued: 01/27/1998
• Est. Priority Date: 07/11/1996
• Status: Expired due to Term

• Current Assignee: Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. (Hebrew University of Jerusalem)
• Original Assignee: Life Medical Sciences, Inc. (Pathfinder Cell Therapy, Inc.)
• Inventors: Cohn, Daniel, Pines, Eli
• Primary Examiner(s): KRASS, FREDERICK F
• Application Number:
  US08/678,762
• Time in Patent Office: 565 Days
• Field of Search: 424/423, 424/424, 424/425, 424/78.06, 128/898, 128/514, 128/772.1, 128/772.7
• US Class Current: 424/423
• CPC Class Codes: A61K 31/765 Polymers containing oxygen
• CPC Class Codes: A61K 31/77 of oxiranes
• CPC Class Codes: A61K 31/785 Polymers containing nitrogen
• CPC Class Codes: A61L 31/06 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L31/041 takes precedence
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C08G 63/08 Lactones or lactides
• CPC Class Codes: C08G 63/664 derived from hydroxy carboxylic acids
• CPC Class Codes: C08G 69/44 Polyester-amides
• CPC Class Codes: C08L 67/025 containing polyether sequences
• CPC Class Codes: C08L 67/04 Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence
• CPC Class Codes: C08L 77/12 Polyester-amides

Abstract

The present invention relates to a method for reducing adhesions associated with post-operative surgery. The present method comprises administering or affixing a polymeric composition comprising chain-extended poly(hydroxy-carboxylic acid)/poly(oxyalkylene) ABA triblocks to a site in the body which has been subjected to trauma, e.g. by surgery, excision or inflammatory disease. In the present invention, the polymeric material provides a barrier to prevent or reduce the extent of adhesions forming.

Claims

1. A method for reducing or preventing adhesions in a patient comprising exposing tissue which has been subjected to tissue damage and is at risk for the formation of adhesions to a polymeric composition comprising polymers which are chain-extended, substantially non-water soluble poly(hydroxy-carboxylic acid)/poly(oxyalkylene) ABA triblocks, where A is an aliphatic polyester and B is a polyoxyalkylene polymer unit, said polymeric composition comprising no more than about 1.0% by weight crosslinking and having an EO/LA ratio ranging from about 0.5 to 5.0.

2. The method according to claim 1 wherein said polyester comprises poly(aliphatic α

-hydroxy carboxylic acid).

3. The method according to claim 2 wherein said polyester is obtained from polymerization of an aliphatic hydroxycarboxylic acid or ester selected from the group consisting of L-lactic acid, D,L-lactic acid, glycolic acid, L-lactide, D,L-lactide, glycolide and mixtures thereof.

4. The method according to claim 1 wherein said poly(oxyalkylene) polymer is comprised of a poly(ethylene oxide) homopolymer or poly(ethylene oxide)-co-poly(propylene oxide) block copolymer.

5. The method according to claim 1 wherein said polyester comprises units of an aliphatic hydroxycarboxylic acid or the corresponding cyclic dimeric ester selected from the group consisting of L-lactic acid, D,L-lactic acid, glycolic acid, L-lactide, D,L-lactide, glycolide and mixtures and said poly(oxyalkylene)polymer is comprised of a poly(ethylene oxide) homopolymer or poly(ethylene oxide)-co-poly(propylene oxide) block copolymer.

6. The method according to claim 5 wherein said A block is between about 4 and 50 carboxylic acid units in length and said B block varies in molecular weight from about 200 Da to about 200,000 Da.

7. The method according to claim 6 wherein said A block comprises carboxylic acid units derived from L-lactide or D,L-lactide and said B block is comprised of poly(ethylene oxide).

8. The method according to claim 7 wherein said A block is approximately 6 to 30 carboxylic acid units in length and said B block is comprised of poly(ethylene oxide) having a molecular weight of between 1,500 and 10,000 Da.

9. The method according to claim 1 wherein said composition is in the form of a preformed structure which is selected from the group consisting of film, rod, tube, bead, a foam, ring, a dispersion, suspension, gel, liquid, spray and viscous solution.

10. The method according to claim 1 wherein said composition further includes a bioactive agent.

42. The method according to claim 1 wherein said polymeric composition comprises no more than about 0.05% crosslinking.

11. A method for reducing or preventing adhesions in a patient comprising exposing tissue which has been subjected to tissue damage and is at risk for the formation of adhesions to a polymeric composition comprising polymers of the chemical structure:

##STR5## where m, a and b are positive integers, R is an ethylene group and/or propylene group with the proviso that R is not exclusively a propylene group when m is more than 1, R'"'"' is a C₂ to C₈ alkylene group, a cycloalkyl or cycloalkyl-containing group, an aryl or aryl-containing group, 4,4'"'"'-diphenylmethane, toluene, naphthalene, 4,4'"'"'-dicyclohexylmethane, cyclohexyl, 3,3'"'"'-dimethylphenyl, 3,3'"'"'-dimethyl-diphenylmethane, 4,6'"'"'-xylylene, 3,5,5-trimethylcyclohexyl, 2,2,4-trimethylhexamethylene or p-phenylene and R₁ is H or CH₃, said polymeric composition comprising no more than about 1.0% by weight crosslinking and having an EO/LA ratio ranging from about 0.5 to 5.0.

12. The method according to claim 11 wherein R₁ is CH₃.

13. The method according to claim 11 wherein m is 4 to about 5,000, R₁ is CH₃ and R is an ethylene group.

14. The method according to claim 11 wherein m is about 30 to about 230, R₁ is CH₃ and R is an ethylene group.

15. The method according to claim 11 wherein R'"'"' is a C₆ alkylene group.

16. The method according to claim 11 wherein said composition is in the form of a preformed structure which a film, rod, tube, bead, foam, ring, viscous liquid, dispersion, suspension, viscous solution, spray and gel.

17. The method according to claim 11 wherein a and b are the same integer.

18. The method according to claim 11 wherein said polymeric composition includes a bioactive agent.

43. The method according to claim 11 wherein said polymeric composition comprises no more than about 0.05% crosslinking.

19. A method for reducing or preventing adhesions in a patient comprising exposing tissue which has been subjected to tissue damage and is at risk for the formation of adhesions to a polymeric composition comprising polymers of the chemical structure:

##STR6## where m, x and y are positive integers, R is an ethylene and/or propylene group with the proviso that R is not exclusively a propylene group when m is greater than 1, R₁ is a hydrogen or methyl group, R" is a C₀ to C₁₂ alkylene group or a hydroxyl or carboxylic acid substituted alkyl group, a cycloalkyl, a hydroxyl-containing cyclo alkyl, or cycloalkyl-containing group, an aryl or aryl-containing group, or a polyoxyalkylene chain comprised of poly(ethylene oxide) or poly(ethylene oxide)-co-poly(propylene oxide), said polymeric composition comprising no more than about 1.0% by weight crosslinking and having an EO/LA ratio ranging from about 0.5 to 5.0.

20. The method according to claim 19 wherein R₁ is CH₃.

21. The method according to claim 19 wherein m is 4 to about 5,000, R₁ is CH₃ and R is an ethylene group.

22. The method according to claim 19 wherein m is about 30 to about 230, R₁ is CH₃ and R is an ethylene group.

23. The method according to claim 21 wherein R" is a C₆ alkylene group.

24. The method according to claim 19 wherein said composition is in the form of a preformed structure which is selected from the group consisting of a film, rod, tube, bead, foam, ring, a viscous liquid, gel, dispersion, suspension, spray and viscous solution.

25. The method according to claim 19 wherein said composition includes a bioactive agent.

44. The method according to claim 19 wherein said polymeric composition comprises no more than about 0.05% crosslinking.

26. A method for reducing or preventing adhesions in a patient comprising exposing tissue which has been subjected to tissue damage and is at risk for the formation of adhesions to a polymeric composition comprising polymers of the chemical structure:

##STR7## where j, k and m are positive integers, R is an ethylene or propylene group with the proviso that R is not exclusively a propylene group when m is greater than 1, R'"'"' is a C₂ to C₁₂ alkylene group, a cycloalkyl or cycloalkyl-containing group, an aryl or aryl-containing group, 4,4'"'"'-diphenylmethane, toluene, naphthalene, 4,4'"'"'-dicyclohexylmethane, cyclohexyl, 3,3'"'"'-dimethylphenyl, 3,3'"'"'-dimethyl-diphenylmethane, 4,6'"'"'-xylylene, 3,5,5-trimethylcyclohexyl, 2,2,4-trimethylhexamethylene or p-phenylene, R'"'"'" is a polyoxyalkylene chain comprising poly(ethylene oxide) or poly(ethylene oxide)-co-poly(propylene oxide) and R₁ is H or CH₃, said polymeric composition comprising no more than about 1.0% by weight crosslinking and having an EO/LA ratio ranging from about 0.5 to 5.0.

27. The method according to claim 26 wherein R₁ is CH₃.

28. The method according to claim 26 wherein m is 4 to about 5,000, R₁ is CH₃ and R is an ethylene group.

29. The method according to claim 26 wherein m is about 30 to about 230, R₁ is CH₃ and R is an ethylene group.

30. The method according to claim 26 wherein R'"'"' is a C₆ alkylene group.

31. The method according to claim 26 wherein said composition is in the form of a preformed structure which is selected from the group consisting of a film, rod, tube, bead, foam ring, a viscous liquid, dispersion, suspension, viscous solution, spray and gel.

32. The method according to claim 26 wherein j and k are the same integer.

33. The method according to claim 26 wherein said polymeric composition includes a bioactive agent.

34. The method according to claim 26 where R'"'"'" has a molecular weight ranging from about 200 Da to about 10,000 Da.

35. The method according to claim 26 wherein R'"'"' is a C₂ to C₈ alkylene group.

45. The method according to claim 26 wherein said polymeric composition comprises no more than about 0.05% crosslinking.

36. A method for reducing or preventing adhesions in a patient comprising exposing tissue which has been subjected to tissue damage and is at risk for the formation of adhesions to a polymeric composition comprising polymers which are chain-extended, substantially non-water soluble poly(hydroxy-carboxylic acid)/polyethylene oxide ABA triblocks, where said A block comprises an aliphatic polyester and said B block comprises poly(ethyleneoxide) or poly(ethyleneoxide)-co-poly(propylene oxide), said polymeric composition comprising no more than about 1.0% by weight crosslinking and having an EO/LA ratio ranging from about 0.5 to 5.0.

37. The method according to claim 36 wherein said poly(hydroxy-carboxylic acid) is derived from lactic acid, glycolic acid, lactide, glycolide or mixtures, thereof.

38. The method according to claim 37 wherein said polymeric composition comprises no more than about 0.05% crosslinking.

39. The method according to claim 37 wherein said poly(hydroxy-carboxylic acid) is derived from lactide.

40. The method according to claim 37, wherein said EO/LA ratio ranges from about 2.0 to 5.0.

41. The method according to claim 39 wherein said EO/LA ratio ranges from about 2.5 to 40.