Methods and compositions for reducing or eliminating post-surgical adhesion formation

• US 6,136,333 A
• Filed: 07/11/1997
• Issued: 10/24/2000
• 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, Hotovely, Anna
• Primary Examiner(s): Webman, Edward J.
• Application Number:
  US08/890,802
• Time in Patent Office: 1,201 Days
• Field of Search: 424/486, 424/497, 424/423, 424/443-444, 424/426, 424/78.17
• 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 preferably comprising chain extended, coupled or crosslinked polyester/poly(oxyalkylene) ABA triblocks or AB diblocks having favorable EO/LA ratios 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 prepolymerized polymeric composition comprising chain extended, coupled or crosslinked poly(ester)/poly(oxyalkylene) ABA triblocks or AB diblocks, where A is a polyester unit and B is a polyoxyalkylene polymer unit, said polymeric composition having an EO/LA ratio falling within the range of about 0.1 to about 100.

2. The method according to claim 1 wherein said polyester unit is derived from the polymerization of monomers selected from the group consisting of lactic acid, lactide, glycolic acid, glycolide, β

-propiolactone, ε

-caprolactone, δ

-glutarolactone, δ

-valerolactone, β

-butyrolactone, pivalolactone, α

,α

-diethylpropiolactone, ethylene carbonate, trimethylene carbonate, γ

-butyrolactone, p-dioxanone, 1,4-dioxepan-2-one, 3-methyl-1,4-dioxane-2,5-dione, 3,3,-dimethyl-1-4-dioxane-2,5-dione, cyclic esters of α

-hydroxybutyric acid, α

-hydroxyvaleric acid, α

-hydroxyisovaleric acid, α

-hydroxycaproic acid, α

-hydroxy-α

-ethylbutyric acid, α

-hydroxyisocaproic acid, α

-hydroxy-α

-methyl valeric acid, α

-hydroxyheptanoic acid, α

-hydroxystearic acid, α

-hydroxylignoceric acid, salicylic acid and mixtures, thereof.

3. The method according to claim 1 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 or mixtures thereof.

4. The method according to claim 1 wherein said poly(oxyalkylene) polymer is comprised of poly(ethylene oxide).

5. 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.

6. 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 or mixtures and said poly(oxyalkylene) polymer is comprised of a poly(ethylene oxide) homopolymer or poly(ethylene oxide)-co-poly(propylene oxide) block copolymers.

7. The method according to claim 3 wherein said A block is between about 1 and 400 carboxylic acid units in size and said B block is varies in size from about 100 Da to about 200,000 Da.

8. The method according to claim 5 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).

9. The method according to claim 5 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 about 1,500 and 10,000 Da.

10. The method according to claim 1 wherein said composition is in the form of a preformed structure such as a film, rod, tube, bead, foam or ring or a dispersion, suspension, gel, liquid, spray or viscous solution.

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

12. The method according to claim 1 wherein said composition is chain extended or coupled with a diisocyanate of the general formula:

##STR16## where 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, p-phenylene or a poly(ethylene oxide) containing or poly(ethylene oxide) rich chain.

13. The method according to claim 12 wherein said poly(oxyalkylene) comprises poly(ethylene oxide).

14. The method according to claim 1 wherein said composition comprises ABA triblocks.

15. The method according to claim 1 wherein said composition is crosslinked.

16. The method according to claim 2 wherein said composition is crosslinked.

26. The method according to claim 1 wherein said EO/LA ratio ranges from about 0.5 to about 30.

27. The method according to claim 1 wherein said EO/LA ratio ranges from about 0.5 to about 10.0.

28. The method according to claim 1 wherein said EO/LA ratio ranges from about 1.0 to about 5.0.

29. The method according to claim 1 wherein said EO/LA ratio ranges from about 1.5 to about 4.5.

30. The method according to claim 1 wherein said EO/LA ratio ranges from about 2.5 to about 3.5.

31. The method according to claim 1 wherein said EO/LA ratio is aobut 3.0.

32. The method according to claim 2 wherein said EO/LA ratio ranges from about 0.5 to about 30.

33. The method according to claim 2 wherein said EO/LA ratio ranges from about 0.5 to about 10.0.

34. The method according to claim 2 wherein said EO/LA ratio ranges from about 1.0 to about 5.0.

35. The method according to claim 2 wherein said EO/LA ratio ranges from about 1.5 to about 4.5.

36. The method according to claim 2 wherein said EO/LA ratio ranges from about 2.5 to about 3.5.

37. The method according to claim 2 wherein said EO/LA ratio is about 3.0.

38. The method according to claim 3 wherein said EO/LA ratio ranges from about 0.5 to about 30.

39. The method according to claim 3 wherein said EO/LA ratio ranges from about 0.5 to about 10.0.

40. The method according to claim 3 wherein said EO/LA ratio ranges from about 1.0 to about 5.0.

41. The method according to claim 3 wherein said EO/LA ratio ranges from about 1.5 to about 4.5.

42. The method according to claim 3 wherein said EO/LA ratio ranges from about 2.5 to about 3.5.

43. The method according to claim 4 wherein said EO/LA ratio ranges from about 0.5 to about 30.

44. The method according to claim 4 wherein said EO/LA ratio ranges from about 0.5 to about 10.0.

45. The method according to claim 4 wherein said EO/LA ratio ranges from about 1.0 to about 5.0.

46. The method according to claim 4 wherein said EO/LA ratio ranges from about 1.5 to about 4.5.

47. The method according to claim 4 wherein said EO/LA ratio ranges from about 2.5 to about 3.5.

48. The method according to claim 4 wherein said EO/LA ratio is about 3.0.

49. The method according to claim 6 wherein said EO/LA ratio ranges from about 0.5 to about 30.

50. The method according to claim 6 wherein said EO/LA ratio ranges from about 0.5 to about 10.0.

51. The method according to claim 6 wherein said EO/LA ratio ranges from about 1.0 to about 5.0.

52. The method according to claim 6 wherein said EO/LA ratio ranges from about 1.5 to about 4.5.

53. The method according to claim 6 wherein said EO/LA ratio ranges from about 2.5 to about 3.5.

54. The method according to claim 6 wherein said EO/LA ratio is aobut 3.0.

55. The method according to claim 7 wherein said EO/LA ratio ranges from about 0.5 to about 30.

56. The method according to claim 7 wherein said EO/LA ratio ranges from about 0.5 to about 10.0.

57. The method according to claim 7 wherein said EO/LA ratio ranges from about 1.0 to about 5.0.

58. The method according to claim 7 wherein said EO/LA ratio ranges from about 1.5 to about 4.5.

59. The method according to claim 7 wherein said EO/LA ratio ranges from about 2.5 to about 3.5.

60. The method according to claim 7 wherein said EO/LA ratio is aobut 3.0.

61. The method according to claim 9 wherein said EO/LA ratio ranges from about 0.5 to about 10.0.

62. The method according to claim 9 wherein said EO/LA ratio ranges from about 1.0 to about 5.0.

63. The method according to claim 9 wherein said EO/LA ratio ranges from about 1.5 to about 4.5.

64. The method according to claim 9 wherein said EO/LA ratio ranges from about 2.5 to about 3.5.

65. The method according to claim 9 wherein said EO/LA ratio is about 3.0.

66. The method according to claim 12 wherein said EO/LA ratio ranges from about 0.5 to about 10.0.

67. The method according to claim 12 wherein said EO/LA ratio ranges from about 1.0 to about 5.0.

68. The method according to claim 12 wherein said EO/LA ratio ranges from about 1.5 to about 4.5.

69. The method according to claim 12 wherein said EO/LA ratio ranges from about 2.5 to about 3.5.

70. The method according to claim 12 wherein said EO/LA ratio is about 3.0.

71. The method according to claim 13 wherein said EO/LA ratio ranges from about 0.5 to about 10.0.

72. The method according to claim 13 wherein said EO/LA ratio ranges from about 1.0 to about 5.0.

73. The method according to claim 13 wherein said EO/LA ratio ranges from about 1.5 to about 4.5.

74. The method according to claim 13 wherein said EO/LA ratio ranges from about 2.5 to about 3.5.

75. The method according to claim 13 wherein said EO/LA ratio is about 3.0.

76. The method according to claim 14 wherein said EO/LA ratio ranges from about 0.5 to about 30.

77. The method according to claim 14 wherein said EO/LA ratio ranges from about 0.5 to about 10.0.

78. The method according to claim 14 wherein said EO/LA ratio ranges from about 1.0 to about 5.0.

79. The method according to claim 14 wherein said EO/LA ratio ranges from about 1.5 to about 4.5.

80. The method according to claim 14 wherein said EO/LA ratio ranges from about 2.5 to about 3.5.

17. 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:

##STR17## 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 R'"'"' contains an absence of poly(ethylene oxide), 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, p-phenylene, or a poly(ethylene oxide) containing or poly(ethylene oxide) rich chain and R₁ is H or CH₃.

18. The method according to claim 17 wherein R₁ is CH₃.

19. The method according to claim 17 wherein m is 4 to about 5,000, R₁ is CH₃ and R is an ethylene group.

20. The method according to claim 17 wherein m is about 30 to about 230, R₁ is CH₃ and R is an ethylene group.

21. The method according to claim 17 wherein R'"'"' is a C₆ alkylene group.

22. The method according to claim 17 wherein said composition is in the form of a preformed structure such as a film, rod, tube, bead, foam, ring or a viscous liquid, dispersion, suspension, viscous solution, spray or gel.

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

24. The method according to claim 17 wherein said polymeric composition includes a bioactive agent.

25. The method according to claim 17 wherein said poly(oxyalkylene) is poly(ethylene oxide).

81. The method according to claim 17 wherein said EO/LA ratio ranges from about 0.5 to about 10.0.

82. The method according to claim 17 wherein said EO/LA ratio ranges from about 1.0 to about 5.0.

83. The method according to claim 17 wherein said EO/LA ratio ranges from about 1.5 to about 4.5.

84. The method according to claim 17 wherein said EO/LA ratio ranges from about 2.5 to about 3.5.

85. The method according to claim 22 wherein said EO/LA ratio ranges from about 0.5 to about 10.0.

86. The method according to claim 22 wherein said EO/LA ratio ranges from about 1.0 to about 5.0.

87. The method according to claim 22 wherein said EO/LA ratio ranges from about 1.5 to about 4.5.

88. The method according to claim 22 wherein said EO/LA ratio ranges from about 2.5 to about 3.5.

89. The method according to claim 22 wherein said EO/LA ratio is about 3.0.