BIODEGRADABLE POLYMER

Abstract

The invention provides a class of polymeric materials being ABA tri-block or AB di-block, comprised of biodegradable segments and poly(propylene oxide) (PPO) segment and uses thereof.

Claims

1. A polymer selected from a ABA tri-block and a AB di-block, wherein A is a biodegradable segment and B comprises a poly(propylene oxide) (PPO) segment.

2. The polymer according to claim 1 being chain extended, coupled and/or cross-linked.

3. The polymer according to claim 1 or 2 having an average molecular weight of from 1,000 to 5 million Daltons.

4. The polymer according to claim 3, wherein the molecular weight is between 1,000 and 100,000 Da, between 1,000 and 90,000 Da, between 1,000 and 80,000 Da, between 1,000 and 70,000 Da, between 1,000 and 60,000 Da, between 1,000 and 50,000 Da, between 1,000 and 40,000 Da, between 1,000 and 30,000 Da, between 1,000 and 20,000 Da, between 1,000 and 10,000 Da, between 1,000 and 9,000 Da, between 1,000 and 8,000 Da, between 1,000 and 7,000 Da, between 1,000 and 6,000 Da, between 1,000 and 5,000 Da, between 1,000 and 4,000 Da, between 1,000 and 200,000 Da, between 1,000 and 300,000 Da, between 1,000 and 400,000 Da, between 1,000 and 500,000 Da, between 1,000 and 600,000 Da, between 1,000 and 700,000 Da, between 1,000 and 800,000 Da, between 1,000 and 900,000 Da, between 1,000 and 1,000,000 Da, between 1,000 and 2,000,000 Da, between 1,000 and 3,000,000 Da, between 1,000 and 4,000,000 Da, between 1,000 and 1,500,000 Da, between 1,000 and 2,500,000 Da, between 1,000 and 3,500,000 Da, or between 1,000 and 4,500,000 Da.

5. The polymer according to any one of claims 1 to 4, wherein each of A is selected amongst polyester segments.

6. The polymer according to any one of claims 1 to 5, wherein the biodegradable segments are different.

7. The polymer according to any one of claims 1 to 5, wherein the biodegradable segments are different.

8. The polymer according to claim 5, wherein the polyester is derived from a compound selected from an aliphatic hydroxycarboxylic acid or ester, lactone, dimeric ester, carbonate, anhydride, orthoester and dioxanone.

9. The polymer according to claim 8, wherein the compound is selected from lactic acid, lactide, glycolic acid, glycolide, aliphatic α-hydroxycarboxylic acid, 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 any combination thereof.

10. The polymer according to claim 8, wherein the compound is selected from caprolactone, lactide, glycolide and any combination thereof.

11. The polymer according to claim 10, wherein said compound is a caprolactone.

12. The polymer according to claim 1, wherein A is selected from 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 any combination thereof.

13. The polymer according to claim 1, wherein A comprises a poly(hydroxy-carboxylic acid).

14. The polymer according to claim 13, wherein said poly(hydroxy-carboxylic acid) is selected from poly(glycolic acid), poly(L-lactic acid) and poly(D,L-lactic acid), polycaprolactone, and any combination thereof.

15. The polymer according to any one of the preceding claims, wherein B comprises poly(propylene oxide) and each of A comprises poly(caprolactone).

16. The polymer according to claim 15, being chain extended with a diisocyanate.

17. The polymer according to claim 1, being of the general Formula (I):
{-[—(O—(CH.sub.2).sub.j—CHR.sub.1—CO).sub.b—(O—CHCH.sub.3—CH.sub.2—).sub.m—O—(CO—CHR.sub.1—(CH.sub.2).sub.j—O—).sub.a—CO—NH—R′—NH—CO]—}.sub.x   (Formula I) wherein each of a and b, independently of the other, is an integer between 1 and 2,000, m is an integer between 2 and 1,000, each j, independently of the other, is an integer between 0 and 20, R′ is selected from C.sub.2-C.sub.20alkylene, C.sub.5-C.sub.20cycloalkyl, C.sub.5-C.sub.20cycloalkyl-containing group, aryl, aryl-containing group, polymeric segment, oligomeric segment, and each R.sub.1, independently of the other, is H or C.sub.1-C.sub.12 alkyl, and wherein x is an integer between 1 and 1,000.

18. The polymer according to claim 17, wherein x is between 1 and 900, between 1 and 800, between 1 and 700, between 1 and 600, between 1 and 500, between 1 and 400, between 1 and 300, between 1 and 200, between 1 and 100, between 10 and 900, between 20 and 900, between 30 and 900, between 40 and 900, between 50 and 900, between 60 and 900, between 70 and 900, between 80 and 900, between 90 and 900, between 100 and 900, between 200 and 900, between 300 and 900, between 400 and 900, or between 500 and 900.

19. The polymer according to claim 17, wherein a is between 1 and 1,400, between 1 and 1,000, between 1 and 500, between 1 and 200, between 1 and 100, between 1 and 90, between 1 and 80, between 1 and 70, between 1 and 60, between 1 and 50, between 1 and 40, between 1 and 30, between 1 and 20, or between 1 and 10.

20. The polymer according to claim 17, wherein b is between 1 and 1,400, between 1 and 1,000, between 1 and 500, between 1 and 200, between 1 and 100, between 1 and 90, between 1 and 80, between 1 and 70, between 1 and 60, between 1 and 50, between 1 and 40, between 1 and 30, between 1 and 20, or between 1 and 10.

21. The polymer according to claim 17, wherein m is between 2 and 900, between 2 and 500, between 2 and 200, between 2 and 100, between 2 and 90, between 2 and 80, between 2 and 70, between 2 and 60, between 2 and 50, between 2 and 40, between 2 and 30, between 2 and 20, or between 2 and 10.

22. The polymer according to claim 17, wherein j is 0 or 1.

23. The polymer according to claim 17, wherein j is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

24. The polymer according to claim 17, wherein R′ is an aryl or an aryl-containing group.

25. The polymer according to claim 24, wherein said aryl selected from naphthyl and phenyl wherein said aryl-containing group comprises naphthyl or phenyl.

26. The polymer according to claim 17, wherein R′ is selected from 4,4′-diphenylmethane, 3,3′-dimethylphenyl, 3,3′-dimethyl-diphenylmethane, 4,6′-xylylene and p-phenylene.

27. The polymer according to claim 17, wherein R′ is a C.sub.2-C.sub.12alkylene or a C.sub.5-C.sub.12cycloalkyl.

28. The polymer according to claim 17, wherein R′ is selected from 4,4′-dicyclohexylmethane, isophorone, lysine, cyclohexyl, 3,5,5-trimethylcyclohexyl and 2,2,4-trimethylhexamethylene.

29. The polymer according to claim 17, wherein R′ is a polymeric segment or an oligomeric segment.

30. The polymer according to claim 29, wherein the polymeric segment or oligomeric segment is selected from polypropylene oxide, polypropylene oxide-containing chain, polypropylene oxide-rich chain, polytetramethylene oxide, polytetramethylene oxide-containing chain, polytetramethylene oxide-rich chain, polyethylene oxide, polyethylene oxide-containing chain, polyethylene oxide-rich, copolymers of polyethylene oxide and polypropylene oxide, polydimethylsiloxane, polydimethylsiloxane-containing chain, polydimethylsiloxane-rich, polycaprolactone, polycaprolactone-containing chain and polycaprolactone rich chain, olipeptide, oligopeptide-containing chain, oligopeptide-rich chain, oligosaccharide, oligosaccharide-containing chain, oligosaccharide rich chain, oligomer or polymers and copolymers of addition polymers, and combinations thereof.

31. The polymer according to claim 17, wherein j=0.

32. The polymer according to claim 17, wherein R.sub.1 is —CH.sub.3.

33. The polymer according to claim 17, wherein R.sub.1 is —H.

34. The polymer according to claim 17, wherein R′ is isophorone or lysine.

35. The polymer according to claim 17, wherein j=0 and R.sub.1 is —H.

36. The polymer according to claim 17, wherein j=0 and R.sub.1 is —CH.sub.3.

37. The polymer according to claim 17, wherein R′ is a hexamethylene group, j=4 and R.sub.1 is —H.

38. The polymer according to claim 1, wherein the polymer is of the general Formula (II):
{—(O—(CH.sub.2).sub.j—CHR.sub.1—CO).sub.r(—O—CHCH.sub.3—CH.sub.2—).sub.m—O—(CO—CHR.sub.1—(CH.sub.2).sub.j—O—).sub.k—CO—NH—R′—NH—CO—R′″—CO—NH—R′—NH—CO—}.sub.z   (Formula II) wherein each r and k, independently of the other, is an integer between 1 and 2,000, m is an integer between 2 and 1,000, each j, independently of the other, is an integer between 0 and 20, each R′, independently of the other, is selected from C.sub.2-C.sub.20alkylene, C.sub.5-C.sub.20cycloalkyl, C.sub.5-C.sub.20cycloalkyl-containing group, aryl, aryl-containing group, polymeric segment, oligomeric segment, and R′″ is selected from polymeric segment and oligomeric segment, each R.sub.1, independently of the other, is H or C.sub.1-C.sub.12alkyl, z is an integer between 1 and 1,000.

39. The polymer according to claim 38, wherein z is between 1 and 900, between 1 and 800, between 1 and 700, between 1 and 600, between 1 and 500, between 1 and 400, between 1 and 300, between 1 and 200, between 1 and 100, between 10 and 900, between 20 and 900, between 30 and 900, between 40 and 900, between 50 and 900, between 60 and 900, between 70 and 900, between 80 and 900, between 90 and 900, between 100 and 900, between 200 and 900, between 300 and 900, between 400 and 900, or between 500 and 900.

40. The polymer according to claim 38, wherein r is between 1 and 1,400, between 1 and 1,000, between 1 and 500, between 1 and 200, between 1 and 100, between 1 and 90, between 1 and 80, between 1 and 70, between 1 and 60, between 1 and 50, between 1 and 40, between 1 and 30, between 1 and 20, or between 1 and 10.

41. The polymer according to claim 38, wherein k is between 1 and 1,400, between 1 and 1,000, between 1 and 500, between 1 and 200, between 1 and 100, between 1 and 90, between 1 and 80, between 1 and 70, between 1 and 60, between 1 and 50, between 1 and 40, between 1 and 30, between 1 and 20, or between 1 and 10.

42. The polymer according to claim 38, wherein m is between 2 and 900, between 2 and 500, between 2 and 200, between 2 and 100, between 2 and 90, between 2 and 80, between 2 and 70, between 2 and 60, between 2 and 50, between 2 and 40, between 2 and 30, between 2 and 20, or between 2 and 10.

43. The polymer according to claim 38, wherein j is 0.

44. The polymer according to claim 38, wherein j is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

45. The polymer according to claim 38, wherein R′ is an aryl or an aryl-containing group.

46. The polymer according to claim 45, wherein said aryl is selected from naphthyl and phenyl; and wherein said aryl-containing group comprises naphthyl or phenyl.

47. The polymer according to claim 38, wherein R′ is selected from 4,4′-diphenylmethane, 3,3′-dimethylphenyl, 3,3′-dimethyl-diphenylmethane, 4,6′-xylylene and p-phenylene.

48. The polymer according to claim 38, wherein R′ is a C.sub.2-C.sub.12 alkylene or a C.sub.5-C.sub.12 cycloalkyl.

49. The polymer according to claim 38, wherein R′ is selected from 4,4′-dicyclohexylmethane, cyclohexyl, 3,5,5-trimethylcyclohexyl and 2,2,4-trimethylhexamethylene.

50. The polymer according to claim 38, wherein R′ is a polymeric segment or an oligomeric segment.

51. The polymer according to claim 50, wherein the polymeric segment or oligomeric segment is selected from polypropylene oxide, polypropylene oxide-containing chain, polypropylene oxide-rich chain, polytetramethylene oxide, polytetramethylene oxide-containing chain, polytetramethylene oxide-rich chain, polyethylene oxide, polyethylene oxide-containing chain, polyethylene oxide-rich, copolymers of polyethylene oxide and polypropylene oxide, polydimethylsiloxane, polydimethylsiloxane-containing chain, polydimethylsiloxane-rich, polycaprolactone, polycaprolactone-containing chain and polycaprolactone rich chain, olipeptide, oligopeptide-containing chain, oligopeptide-rich chain, oligosaccharide, oligosaccharide-containing chain, oligosaccharide rich chain, oligomer or polymers and copolymers of addition polymers, and combinations thereof.

52. The polymer according to claim 38, wherein R′″ is a polymeric segment or an oligomeric segment.

53. The polymer according to claim 52, wherein the polymeric segment or oligomeric segment is selected from polypropylene oxide, polypropylene oxide-containing chain, polypropylene oxide-rich chain, polytetramethylene oxide, polytetramethylene oxide-containing chain, polytetramethylene oxide-rich chain, polyethylene oxide, polyethylene oxide-containing chain, polyethylene oxide-rich, copolymers of polyethylene oxide and polypropylene oxide, polydimethylsiloxane, polydimethylsiloxane-containing chain, polydimethylsiloxane-rich, polycaprolactone, polycaprolactone-containing chain and polycaprolactone rich chain, olipeptide, oligopeptide-containing chain, oligopeptide-rich chain, oligosaccharide, oligosaccharide-containing chain, oligosaccharide rich chain, oligomer or polymers and copolymers of addition polymers, and combinations thereof.

54. The polymer according to claim 1, wherein the polymer is of the general Formula (III):
-{-T-CO—NH—R′—NH—CO—}.sub.x   (Formula III) wherein T is {—(O—(CH.sub.2).sub.j—CHR.sub.1—CO).sub.r—(O—CHCH.sub.3—CH.sub.2—).sub.m—O—(CO—CHR.sub.1—(CH.sub.2).sub.j—O—).sub.k}.sub.p, R′ is selected from C.sub.2-C.sub.20alkylene, C.sub.5-C.sub.20cycloalkyl, C.sub.5-C.sub.20cycloalkyl-containing group, aryl, aryl-containing group, polymeric segment, oligomeric segment, p is an integer between 1 and 100, each r and k, independently of the other, is an integer between 1 and 500, m is an integer between 2 and 100, each j, independently of the other, is an integer between 0 and 10, R.sub.1 is H or C.sub.1-C.sub.12alkyl, and x is an integer between 1 and 300.

55. The polymer according to claim 1, wherein the polymer is of the general Formula (IV):
HOOC-T-COOH   (Formula IV) wherein T is {—(O—(CH.sub.2).sub.j—CHR.sub.1—CO).sub.r—(O—CHCH.sub.3—CH.sub.2—).sub.m—O—(CO—CHR.sub.1—(CH.sub.2).sub.j—O—).sub.k}.sub.p, p is an integer between 1 and 100, each r and k, independently of the other, is an integer between 1 and 500, m is an integer between 2 and 100, each of j, independently of the other, is an integer between 0 and 10, and R.sub.1 is H or C.sub.1-C.sub.12 alkyl.

56. The polymer according to claim 1, wherein the polymer is of the general Formula (V):
-{-T-CO—NH—R′—CO—NH—R′—NH—CO—R′″—CO—NH—R′—NH—CO—}.sub.z   (Formula V) wherein T is {—(O—(CH.sub.2).sub.j—CHR.sub.1—CO).sub.r—(O—CHCH.sub.3—CH.sub.2—).sub.m—O—(CO—CHR.sub.1—(CH.sub.2).sub.j—O—).sub.k}.sub.p, each R′, independently of the other, is selected from C.sub.2-C.sub.12alkylene, C.sub.5-C.sub.12cycloalkyl, cycloalkyl-containing group, aryl, aryl-containing group, polymeric segment, oligomeric segment, R′” is selected from polymeric segment and oligomeric segment, x is an integer between 1 and 300, p is an integer between 1 and 100, each r and k, independently of the other, is an integer between 1 and 500, m is an integer between 2 and 100, each of j, independently of the other, is an integer between 0 and 10, and R.sub.1 is H or C.sub.1-C.sub.12alkyl.

57. The polymer according to any one of the preceding claims, wherein the ABA tri-block or AB di-block polymer is chain extended or coupled with a difunctional compound, or cross-linked.

58. The polymer according to claim 57, wherein said difunctional compound is selected from diisocyanates.

59. The polymer according to claim 55, wherein said diisocyanate is hexamethylene diisocyanate (HDI).

60. The polymer according to claim 57, wherein chain extension or coupling is by an extender of Formula (VI):
L′-OC—R″—CO-L   (Formula VI) wherein R″ is selected from C.sub.0-C.sub.12alkylene, optionally substituted by one or more group selected from hydroxyl group, carboxylic acid group, amine group; C.sub.2-C.sub.10 alkene; C.sub.5-C.sub.12 cycloalkyl, optionally substituted by one or more group selected from hydroxyl group, carboxylic acid group, amine group, aryl, aryl-containing group; and L and L′, independently of the other, is selected from hydroxyl, halide and an ester group.

61. The polymer according to any one of the preceding claims, having a PO/CL ratio between about 0.05 and about 100.

62. The polymer according to claim 61, having a PO/CL ratio between about 0.1 and about 30, or between 0.1 to 20, or between 0.1 to 10, or between 0.1 to 5, or between 0.1 to 4, or between 0.1 to 3, or between 0.1 to 2, or between 0.1 to 1, or between about 0.2 and about 10.

63. The polymer according to claim 61, being a tri-block polymer having a PO/CL ratio between 0.05 and 8.

64. The polymer according to claim 60, wherein the PO/CL ratio is between 0.1 and 5, between 0.1 and 4, between 0.1 and 3, between 0.1 and 2, between 0.1 and 1, between 0.1 and 0.9, between 0.1 and 0.8, between 0.1 and 0.7, between 0.1 and 0.6, between 0.1 and 0.5, between 0.1 and 0.4, between 0.1 and 0.3, between 0.1 and 0.2, between 0.2 and 5, between 0.3 and 5, between 0.4 and 5, between 0.5 and 5, between 0.6 and 5, between 0.7 and 5, between 0.8 and 5, between 0.9 and 5, between 1 and 5, between 2 and 5, between 3 and 5, or between 4 and 5.

65. The polymer according to any one of the preceding claims, wherein the polymer is a tri-block polymer having a molecular weight between 1,000 and 200,000 Da.

66. The polymer according to claim 65, wherein the tri-block polymer has a molecular weight of between 2,000 and 200,000, between 2,000 and 190,000, between 2,000 and 180,000, between 2,000 and 170,000, between 2,000 and 160,000, between 2,000 and 150,000, between 2,000 and 140,000, between 2,000 and 130,000, between 2,000 and 1200,000, between 2,000 and 110,000, between 2,000 and 100,000, between 2,000 and 90,000, between 2,000 and 85,000, between 2,000 and 80,000, between 2,000 and 75,000, between 2,000 and 70,000, between 2,000 and 65,000, between 2,000 and 60,000, between 2,000 and 55,000, between 2,000 and 50,000, between 2,000 and 45,000, between 2,000 and 40,000, between 2,000 and 35,000, between 2,000 and 30,000, between 2,000 and 25,000, between 2,000 and 20,000, between 2,000 and 15,000, between 2,000 and 10,000, between 2,000 and 5,000, between 2,000 and 4,000, between 2,000 and 3,000, between 7,000 and 200,000, between 4,000 and 80,000, between 1,000 and 200,000, between 1,000 and 100,000, between 1,000 and 90,000, between 1,000 and 80,000, between 1,000 and 70,000, between 1,000 and 60,000, between 1,000 and 50,000, between 1,000 and 40,000, between 1,000 and 30,000, between 1,000 and 20,000, or between 1,000 and 10,000 Da.

67. The polymer according to claim 65, wherein the tri-block polymer has a molecular weight of 165,320, 86,660, 82,660, 62,280, 60,440, 47,330, 43,330, 40,760, 39,464, 32,640, 30,220, 23,732, 23,665, 22,760, 21,380, 19,732, 17,820, 15,866, 14,920, 14,856, 11,866, 11,690, 9,752, 8,928, 7,933, 5,964, 5,876 or 3,938 Da.

68. The polymer according to claim 17, wherein the tri-block is a polymer of Formula (I), wherein x is between 2 and 300.

69. The polymer according to claim 17, being a tri-block polymer having between 10 and 2,000 caprolactone units.

70. The polymer according to claim 38, wherein the tri-block is a polymer of Formula (II), wherein z is between 2 and 300.

71. The polymer according to claim 38, being a tri-block polymer having between 10 and 2,000 caprolactone units.

72. The polymer according to claim 69 or 71, wherein the number of caprolactone units is between 10 and 2,000, between 10 and 1,000, between 10 and 900, between 10 and 800, between 10 and 700, between 10 and 600, between 10 and 500, between 10 and 400, between 10 and 300, between 10 and 200, between 10 and 100, between 10 and 350, between 10 and 170, between 10 and 113, between 10 and 85, between 10 and 68, between 10 and 37, between 10 and 17, between 26 and 520, between 26 and 260, between 26 and 173, between 26 and 130, between 26 and 104, between 26 and 52, between 35 and 690, between 35 and 345, between 35 and 230, between 35 and 173, between 35 and 138, between 35 and 69, between 69 and 1380, between 69 and 690, between 69 and 460, between 69 and 345, between 69 and 276, or between 69 and 138.

73. The polymer according to claim 72, wherein the number of caprolactone units is selected from 1380, 690, 520, 460, 345, 340, 276, 260, 230, 173, 170, 138, 130, 113, 104, 85, 69, 68, 52, 35, 34, 26 and 17.

74. The polymer according to claim 69 or 71, wherein the number of PPO units in a tri-block polymer is 34, 52, 69 or 138.

75. The polymer according to any one of the preceding claims, being any one tri-block polymer of the polymers numbered 1 to 28 in Table 1: TABLE-US-00003 Polymer PO/CL Total # of CL Mw Mw tri- # PPCA ratio units 2*PCL*114 block 1 2000 0.1 340 38,760 40,760 2  (34) 0.2 170 19,380 21,380 3 0.3 113 12,920 14,920 4 0.4 85 9,690 11,690 5 0.5 68 7,752 9,752 6 1.0 34 3,876 5,876 7 2.0 17 1,938 3,938 8 3000 0.1 520 59,280 62,280 9  (52) 0.2 260 29,640 32,640 10 0.3 173 19,760 22,760 11 0.4 130 14,820 17,820 12 0.5 104 11,856 14,856 13 1.0 52 5,928 8,928 14 2.0 26 2,964 5,964 15 4000 0.1 690 78,660 82,660 16  (69) 0.2 345 39,330 43,330 17 0.3 230 26,220 30,220 18 0.4 173 19,665 23,665 19 0.5 138 15,732 19,732 20 1.0 69 7,866 11,866 21 2.0 35 3,933 7,933 22 8000 0.1 1380 157,320 165,320 23  (138) 0.2 690 78,660 86,660 24 0.3 460 52,440 60,440 25 0.4 345 39,330 47,330 26 0.5 276 31,464 39,464 27 1.0 138 15,732 23,732 28 2.0 69 7,866 15,866

76. The polymer according to claim 75, being a polymer selected from polymer no. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and 28.

77. The polymer according to claim 75, being polymer no. 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23, or 24, or 25, or 26, or 27, or 28.

78. A device composed of a polymer according to any one of claims 1 to 77.

79. The device according to claim 78, being a medical device.

80. The device according to claim 78 or 79, being in the form of a film, fiber, filament, mesh, membrane, rod, a coating, textile fabric, a non-woven structure or gel.

81. The device according to claim 79, being in a form selected from a medical textile, a medical device, an implant, a prostheses, a wound healing device, a coating, a suture, a mesh and a staple.

82. The device according to claim 78, wherein the polymer is in the form of a coating on at least a surface of said device.

83. A fiber comprised of a polymer according to any one of claims 1 to 77.

84. The fiber according to claim 83, being in the form of a filament.

85. A suture comprised of a polymer according to any one of claims 1 to 77.

86. The suture according to claim 85, consisting said polymer.

87. The suture according to claim 85, being composed of a polymer selected from polymers of Formulae I or II or III or IV or V or a polymer of Table 1.

88. The suture according to any one of claims 85 to 87, for use in a surgical procedure of a human or non-human subject.

89. The suture according to claim 88, for use in surgery.

90. The suture according to any one of claims 85 to 89 being in a form selected from a monofilament suture and a multifilament suture.

91. The suture according to claim 90, being a monofilament suture made of a single strand of the polymer.

92. The suture according to claim 90, being a multifilament suture made of a plurality of filaments, each filament being composed of a polymer of the same or different composition.

93. The suture according to any one of claims 85 to 92, coated with at least one coating material selected amongst active and non-active materials.

94. The suture according to claim 93, wherein the active material is selected from bioactive agents.

95. The suture according to claim 94, wherein the active agent is selected from anticoagulants; fibrinolytics; steroidal and non-steroidal anti-inflammatory agents; calcium channel blockers; antioxidants; antibiotics; prokinetic agents to promote bowel motility; agents to prevent collagen crosslinking; and agents which prevent mast cell degranulation.

96. The suture according to claim 93, wherein the non-active material is selected from dyes, polymeric materials, thickening agents, agents affecting hydrophilicity, agents affecting knotability, agents affecting the surface mechanical properties, agents performing as mechanical cushioning to prevent tissue damage and agents affecting lubricity.

97. A biodegradable polymer according to any one of claims 1 to 77, for use in fabricating a device or an object.

98. A biodegradable polymer according to any one of claims 1 to 77, for use as a wound closure device.

99. The biodegradable polymer according to claim 98, wherein said device is selected from a suture, a coating, a mesh and a staple.

100. A coating comprised of a polymer according to any one of claims 1 to 77.

101. A medical device, an implant or prosthesis coated with a coating comprised of a polymer according to any one of claims 1 to 77.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0278] In order to better understand the subject matter that is disclosed herein and to exemplify how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:

[0279] FIGS. 1A-C: surgical sutures degrade too fast and offer maximum support only over a 6-8 week period (Polydioxanone) and, therefore, do not provide sufficient support during the wound healing process, in the majority of patients. FIG. 1A provides data regarding commercial sutures: comparison of loss of tensile strength by time and total resorption times. FIG. 1B exemplifies clinical assessment of PDS sutures versus MAXON sutures, showing in premature degradability. FIG. 1C exemplifies clinical assessment of PDS sutures versus MAXON sutures, showing unsatisfactory knotability.

[0280] FIG. 2 presents data for a PPCA copolymer comprising PPO 2,000 segments, the length of the lateral PCL blocks decreasing, as the PO/CL ratio increases from 0.1 to 2.0. Due to the similar hydrophobicity of both components, changing the PO/CL affects only slightly the contact angle, which decreases from around 80 degrees for PO/CL=0.1, to around 70 degrees, for a PO/CL ratio of 2.0.

[0281] FIG. 3 presents DSC thermograms of four PPCA copolymers, clearly demonstrating the ability to fine tune the crystallinity of the polymers.

[0282] FIG. 4 presents mechanical data for both PPCA copolymers and the clinically used PDS suture, as determined by conducting the Knot-Pull test.

[0283] FIG. 5 shows also the decline of the mechanical properties of PDS and PPCA 0.1 and 0.2.

[0284] FIG. 6 presents the results of the Knot-Pull test performed on PDS and PPCA 0.1 sutures.

[0285] FIGS. 7A-B present also a comparison between the Young's modulus of PDS, 1450 MPa, and the PPCA 0.1 suture.

[0286] FIG. 8 shows sutures according to the invention, in this case, a PPCA 2,000/0.1 suture.

DETAILED DESCRIPTION OF EMBODIMENTS

[0287] Synthesis of Polymers According to the Present Invention

[0288] In general, the synthesis of the present polymers proceeds by first synthesizing an ABA triblock or AB diblock. In this general reaction, a pre-prepared poly(propylene oxide) B block (which can be purchased or synthesized from an initiating diol and an excess of an appropriate epoxide depending upon the length of the block desired) is preferably reacted with a hydroxyacid or its cyclic lactone to produce the low molecular weight ABA triblock or AB diblock. Essentially, the poly(propylene oxide) block which is generally end-capped with hydroxyl groups or, in the case of an AB diblock is capped at one end with a hydroxyl group and at the other end with a non-reactive group, reacts with the hydroxyacid or its cyclic lactone to produce an ABA triblock or AB diblock comprising polypropylene and the biodegradable component which is end-capped with a hydroxyl group or other group(s).

[0289] Once the ABA triblock or AB diblock is formed, the hydroxyl groups at the end(s) of the molecule are reacted with difunctional chain extenders or couplers, for example, diisocyanates. This reaction produces a chain extended or coupled polymer which is readily used to prepare diverse biomedical products, such as fibers, coatings, meshes, non-wovens and films, and various related structures, gels, dispersions, suspensions, and viscous solutions of the present invention. In the case of certain polymers, these are of sufficiently low molecular weight so that they are in liquid form without the need to add a solvent.

[0290] Generally, during the first stage of the reaction in which the low molecular weight ABA triblock or AB diblock is formed, the overall molecular weight and the length of the different segments will be determined by the molecular weight of the poly(propylene oxide) block chosen to initiate the reaction, by the number of moles of hydroxyacid, its cyclic lactone or related compounds, which is reacted with the poly(propylene oxide) block and the catalyst and various experimental parameters such as the heat and the reaction time. Thereafter, the ABA triblock or AB diblock is chain extended, coupled and/or crosslinked to produce polymers containing ABA triblocks or AB diblocks.

[0291] A synthesis of the present polymers involves the use of the cyclic ester or lactone of ε-caprolactone, lactic acid and glycolic acid. The use of ε-caprolactone, lactide or glycolide as the reactant will enhance the production of ABA triblocks or AB diblocks which have relatively narrow molecular weight distributions and low polydispersity.

[0292] Once the triblock or diblock is obtained, the hydroxyl end-capped triblock or diblock is reacted with a diisocyanate, preferably hexamethylene diisocyanate and is chain extended, coupled or crosslinked.

[0293] The synthesis of the ABA triblock or AB diblock preferably proceeds by way of a ring-opening mechanism, whereby the ring opening of ε-caprolactone, lactide or glycolide is initiated by the hydroxyl end groups of the poly(propylene oxide) (PPO) chain under the influence of a tin catalyst (typically, stannous octoate). An ABA type triblock or AB type diblock is generated at this point, the molecular weight of which is a function of both the molecular weight of the central PPO chain and the length of the lateral polyester block(s). Typically, the molecular weight of the triblock spans between about 2,000 to about 60,000 (but may be as low as 1,000 or less and as high as 250,000 or more). In the case of the diblock, the molecular weight may range as low as several hundred to upwards of 50,000 or more. After synthesis of the ABA triblock or ABA diblock, the final polymer is preferably obtained by chain extending the hydroxyl terminated triblocks with difunctional reactants such as isocyanates, most preferably hexamethylene diisocyanate.

[0294] The chemical and physical properties of the different polymers will vary as a function of different parameters, the molecular weight of the PPO, the composition, morphology and molecular weight of the polyester segments present along the backbone being of particular importance, as well as the chain extender, coupler or crosslinker.

[0295] The method has several advantageous characteristics including:

[0296] A rapid, nearly quantitative reaction which is complete in from 1 to 3 hours;

[0297] The reaction takes place under moderate reaction conditions (140° C.) thus minimizing side reactions; and

[0298] The resulting tri-block or di-block contains a narrow polydispersity (typically, DP=1.4-1.6 or better.

[0299] The structures to be engineered, such as fibers, coating, meshes and films, among numerous others, for use in the present invention are prepared by first producing the polymer according to the present invention and then manufacturing the product, via different manufacturing processes, among many others, by dissolving the polymer in a suitable solvent, such as chloroform, methylene chloride, dioxane, tetrahydrofuran or a related organic solvent. Films, for example, are preferably prepared by placing the solution containing polymer in a mold or a related receptacle and then allowing the solvent to evaporate. The resulting film is homogeneous and of uniform thickness and density. The film may be used as prepared or cut into segments for application to a desired site in a patient. In addition to the above-described solvent cast method, a continuous solvent cast process, as well as thermal cast method or other methods routinely used in the industry and well known in the art, such as extrusion, among many others, may be used to make the different devices, such as fibers, films and other structures according to the present invention. In order to prepare other three dimensional structures of polymer, such as cylinders and related shapes, these may be cast or molded using various techniques, starting with solid polymer. Methods to produce these structures using these techniques are well known in the art.

[0300] Currently, there are over 50 million laparotomies conducted each year world-wide. In general, closure of the muscle layer of the abdomen is performed using absorbable sutures which should provide enough mechanical support for the tissue, until natural healing occurs and scar stability is achieved. Reports in the medical literature describe the normal healing time of this fascia layer as requiring 8 weeks of support, to recover 80% of its pre-surgery burst strength.

[0301] As these tests were made in healthy subjects, literature today is showing that the fascia of immuno-suppressed patients which are the majority of patients requires significantly more time to heal. For example, a delay in fascia wound-healing of around 35% in liver transplant patients has been reported.

[0302] Surgical sutures today degrade too fast and offer maximum support only over a 6-8 week period (Polydioxanone) and, therefore, they do not provide sufficient support during the wound healing process, in the majority of patients (see FIGS. 1A-C).

[0303] An additional drawback of the sutures currently used in the clinic, e.g. Maxon and PDS, for this indication, is their poor knotability, most probably derived from their somewhat rigid polymeric backbone.

[0304] One aspect of the present invention was, therefore, to develop a synthetic, biodegradable suture displaying a tunable rate of degradation that provides extended support to the closure of the abdominal wall, as required following all laparatomies, minimizing the hazardous incidence of post-surgery hernias. An additional objective of this invention was to generate sutures able to generate stronger, smaller knots that better resist unravelling and that preferably generate a secure knot with less knots.

[0305] The synthesis of these block copolymers was conducted following a two-stage method, and can be exemplified for a copolymer comprising poly(propylene oxide) (PPO) and poly(caprolactone) (PCL) segments, where the poly(caprolactone) chains generate the hard blocks and poly(propylene oxide) forms the soft segments along the copolymeric chain. This copolymer is denominated PPCA. First, a PCL-PPO-PCL triblock is synthesized by the ring opening polymerization of cyclic ε-caprolactone, initiated by the hydroxyl terminal groups of the PPO chain. The second stage of the reaction involves the chain extension of the OH-terminated PCL-PPO-PCL triblock, using a bifunctional coupling agent, typically hexamethylene diisocyanate (HDI), whereby urethane groups are generated along the polymeric backbone. These polymers are called PPCA. When chain extenders having a functionality higher than two are used, the polymers obtained are crosslinked.

[0306] An important feature of the copolymers developed is their multiblock nature. The chain extension of tailor-made tri-blocks allowed to combine the required morphology, mainly derived from the length of both components in the tri-block, and enhanced mechanical properties, largely due to the high molecular weight copolymers obtained after the chain extension step. Each of the two components of these copolymers has, therefore, specific chemical, physical and biological roles to perform, and this modular approach affords vast versatility to these polymeric systems.

[0307] Even though a rich arsenal of sutures is available to surgeons, there are no sutures in existence that successfully address to incisions that have a mid-range healing kinetics. Basically, there are several sutures that degrade too fast for this frequently encountered clinical scenario, such as PGA, P(DL)LA, Vicryl and also PDS and Maxon, or there are long lasting sutures, degrading by far too slowly, such as those based on P(L)LA and PCL.

[0308] The paradox in this area has to do, therefore, with the large gap existing between the increasing clinical demand for mid-range biodegradable sutures, on one hand, and the lack of polymers clinically able to provide a solution to this important wound closure need, on the other hand. The lack of suitable sutures able to successfully perform in these cases has resulted, most often, in the use of sutures degrading too fast, resulting in a 10% to 20% occurrence of dangerous post-surgical incisional hernias.

[0309] The polymers disclosed hereby are can be used to manufacture new biodegradable monofilament sutures for a diversity of sites and indications, including providing a solution to this unmet clinical need. More specifically, some of the polymers of the present invention generate sutures able to retain most of their initial strength over a period of three-four months, being significantly absorbed within a period between six and nine months.

[0310] The “multicomponent” approach guiding this project allowed us to vary, quite independently, various parameters of the copolymeric system. Consequently, the properties of the different polymers can be adjusted and balanced by variations of the composition, morphology and molecular weight of their different components.

[0311] The different triblocks are characterized by GPC and NMR, to prove the occurrence of the ring opening polymerization reaction of the lactone (typically caprolactone units), initiated by PPO's OH end groups, and the composition of the resulting triblocks, respectively. This is a key step, since it is the composition of the triblock that will largely determine its morphology and rate of degradation, while the high molecular weight polymers obtained after performing the chain extension (or coupling or crosslinking) reaction, is determined by GPC. DSC and XRD analysis are used to shed light on their morphology.

[0312] Sutures of the different polymers were produced, and characterized at time zero both compositionally as well as morphologically, and their mechanical properties were measured.

[0313] The in vitro rate of degradation of the sutures was studied under pseudo-physiological conditions (saline solution, 37° C., pH 7.0). These studies included gravimetric measurements, GPC and DSC analysis, as well as measuring the mechanical properties of the polymers over time. Work was also devoted to assessing the knotability of the fibers.

[0314] Having generally described the invention, reference is now made to the following examples intended to illustrate preferred embodiments and comparisons but which are not to be construed as limiting to the scope of this invention as more broadly set forth above and in the appended claims.

[0315] Synthesis of Polymers of the Invention

[0316] 1. ABA triblocks were synthesized as follows:

[0317] Polypropylene oxide (PPO, MW=2,000) was dried in vacuum overnight at 80° C. Thereafter, the PPO was cooled down to room temperature, the vacuum was broken by flushing dry N.sub.2 through the system and ε-caprolactone was thereafter added in an appropriate amount (depending upon the length of the A block desired). The mixture of PPO and ε-caprolactone was placed in an oil bath at 140° C. and after 2-3 minutes (which is generally required to homogenize the system), stannous octoate was added (the catalyst/lactide mole ratio was 1/400). The mixture was then flushed with N.sub.2 for a period of about 5 minutes, whereupon the N.sub.2 was removed and the flask containing PPO and E-caprolactone was capped and stirred at 140° C., in an oil bath, for 2 hours. At the end of a 2-hour period, the mixture was removed from the oil bath, was allowed to cool, dissolved in chloroform and precipitated in ether. The precipitate was thereafter collected and dried overnight in vacuum at 50° C. It was then solubilized in chloroform and the chloroform was evaporated to form a film of approximately 250 micrometer thickness.

[0318] 2. The Polymer was synthesized as follows:

[0319] The synthesis of the polymers was completed by chain extending the ABA tri-blocks by reacting their hydroxyl-terminated groups with diisocyanates, typically hexamethylene diisocyanate (HDI). The tri-block obtained above was dried at 80° C. under vacuum for a period of two hours. After the two-hour period, vacuum was broken by flushing N.sub.2 through the system and a minimal amount of dry dioxane was added to dissolve the tri-block. The required amount of catalyst was dissolved in dioxane (about 5 ml) and added to the tri-block. 15 ml of dry dioxane were introduced into a separation funnel and the required amount of HDI was added (the HDI:catalyst molar ratio is 5:1), and the HDI was typically in a 7-12% molar excess respective to the tri-block. The typical Tri-block:HDI:Catalyst molar ratios were, therefore, 1.0:1.07:0.2, respectively. Once the tri-block was fully dissolved, the HDI solution was added dropwise (over a period of 30 minutes) to the tri-block solution. A condenser was then connected to the reaction flask to prevent dioxane loss and the reaction was continued for a period of 2.5 hours. Then, the reaction was removed from the oil bath, allowed to cool and the polymer solution was precipitated with ether. The precipitated polymer was then collected and dried overnight at 50° C. The material was then solubilized in chloroform and the chloroform was evaporated, initially at room temperature overnight, followed by 5 hours under vacuum at 40° C., to form a film of approximately 140 μm thickness.

[0320] Table 2 below reports the Stress at Break and Modulus values of films of three polymers representative of the PPCA copolymers family

TABLE-US-00002 TABLE 2 Stress at Break and Modulus values of three PPCA copolymers. Stress at Break Modulus Tri-block (MPa) (MPa) CL.sub.10-PPG-CL.sub.10 10.7 18.3 CL.sub.15-PPG-CL.sub.15 10.2 65.1 CL.sub.20-PPG-CL.sub.20 16.3 98.0

[0321] Since PPO is an amorphous polymer with a very low glass transition temperature, by controlling the length of the PCL segment and, thus, its degree of crystallinity, especially flexible PPCA polymers are produced. On the other hand, by choosing shorter PPO chains, and longer, and therefore, more crystalline PCL blocks, copolymers of higher stiffness and strength are produced.

[0322] By controlling the natured and balance between the two basic components present in the copolymer and their respective length, the rate of degradation is controlled, over a wide range of time periods. The co-polymeric systems of the present invention can be rendered with a controllable degree of hydrophilicity by chain extending the PPO based tri-blocks with a hydrophilic chain extender, or coupling agent or crosslinker, in the corresponding cases. An example of this type of copolymers can be given by the OCN-HDI-{PEO}.sub.w-HDI-NCO, where w denotes the number of ethylene oxide units present in the PEO chain.

[0323] Fibers of the polymers of the present invention were produced by various techniques, such as extrusion and gel spinning

[0324] FIG. 2 presents data for a PPCA copolymer comprising PPO 2000 segments, the length of the lateral PCL blocks decreasing, as the PO/CL ratio increases from 0.1 to 2.0. Due to the similar hydrophobicity of both components, changing the PO/CL affects only slightly the contact angle, which decreases from around 80 degrees for PO/CL=0.1, to around 70 degrees, for a PO/CL ratio of 2.0.

[0325] FIG. 3 presents DSC thermograms of four PPCA copolymers, clearly demonstrating the ability to fine tune the crystallinity of the polymers.

[0326] FIG. 4 presents mechanical data for both PPCA copolymers and the clinically used PDS suture, as determined by conducting the Knot-Pull test. It is apparent from the findings, that PPCA copolymers having low PO/CL ratios, especially 0.1 and 0.2, yield at stresses well have the 320 MPa threshold, with the PPCA 0.4 copolymer being also very close to this lower bound. It is also worth stressing that PDS shows a high Young's modulus of almost 1.5 GPa, while PPCA 0.1 and 0.2 exhibit much lower values, namely 755 MPa and 330 MPa, respectively. As will be shown below, the enhanced flexibility of PPCA backbones renders PPCA sutures with enhanced knotability.

[0327] FIG. 5 shows also the decline of the mechanical properties of PDS and PPCA 0.1 and 0.2. While the PDS suture, currently being used clinically crosses the 320 MPa threshold already after 60 days and loses all its strength after three months, PPCA copolymers displayed a remarkably different behavior. Of special interest are PPCA 0.1 and PPCA 0.2, which remain at the 320 MPa minimal strength requirements for 300 and 180 days, respectively.

[0328] FIG. 6 presents the results of the Knot-Pull test performed on PDS and PPCA 0.1 sutures, highlighting the clearly superior behavior of PPCA 0.1. While PDS sutures lost all their strength prematurely (already after eight weeks), PPCA 0.1 sutures displayed a yield strength of around 350 MPa, also after 16 weeks.

[0329] FIGS. 7A-B present also a comparison between the Young's modulus of PDS, 1450 MPa, and the PPCA 0.1 suture, which exhibited (FIG. 7A) a modulus half as high. This difference in rigidity is seen as being responsible for the enhanced knotability of PPCA 0.1 sutures, when compared to that of PDS sutures, as shown in FIG. 7B.

[0330] While three small, tight knots were sufficient to securely knot PPCA 0.1 sutures, PDS sutures required seven knots. It is also worth stressing not only the bulkiness of knots formed by the PDS suture, but also, and even more importantly, their tendency to unravel as clearly shown in FIG. 7B.

[0331] The sutures were sterilized using a fully validated, low temperature (˜32 degrees centigrades) ETO cycle. The sutures were manufactured following a two stage process, starting by extruding the polymer, going then through a cooling step and then stretching it substantially, to obtain the suture.

[0332] Once the sutures were manufactured, they were sent to an outside source, to connect the needles to the suture, to sterilize them and finally, to pack them. The sutures were sterilized using a fully validated, low temperature (˜32 degrees centigrades) ETO cycle. FIG. 8 shows one of the sutures, in this case, a PPCA 2000/0.1 suture.

[0333] In light of the fact that incorporating PEO segments along the backbone of an aliphatic polyester was widely used to speed up the degradation of said polyester, it was totally unexpected and most surprising that copolymers of the present invention, comprising hydrophobic PPO chains, degrade at a similar rate, when compared with their PEO-containing counterparts. This is exemplified hereby by the comparison between PPCA2000/0.1 and its PEO-containing counterpart. After ˜100 days in vitro degradation at 37 degrees, Knot Pull Test performed on both sutures, showed that the Stress Yield of the PPCA 2,000/0.1 suture decreased by approximately 37% (from around 520 MPa to 330 MPa), while its PEO-containing counterpart decreased by approximately 31% (from 480 MPa to around 330 MPa).

[0334] Samples of this polymer were implanted in rats near the sciatic nerve and degraded over a period of three months.

[0335] The animals study was conducted in a female rat model and PPCA 2,000/0.1 sutures were compared with the commercially available PDS suture, currently in clinical use. After the animals were anaesthetised, a longitudinal cut was performed in the abdomen and the muscle was exposed. The cut was sutured with the control (PDS) or the experimental suture (PPCA 2,000/0.1) and the skin was closed with a commercial Nylon suture. Explantations were conducted at five time points: 2, 5, 8, 12 and 16 weeks (6 rats sutured with PPC2000/0.1 and two rats sutured with PDS, at each time point), and the relevant tissues were analyzed histologically. Additionally, the sutures were inspected visually and their mechanical properties using the Knot-Pull strength and molecular weight were determined.

[0336] It was apparent from the results of the pre-clinical study that PPCA 0.1 sutures performed much better than the clinically used PDS sutures. While the PDS sutures weakened rapidly, not being able to sustain the minimal physiological 320 MPa stress, already after 8 weeks, losing all their strength after 12 weeks. In striking contrast, after 12 weeks, PPCA 0.1 sutures displayed values around 400 MPa, decreasing only slightly after four additional weeks, displaying stress yield values of around 370 MPa, after 16 weeks in vivo

[0337] Also the pathological analysis of tissues surrounding the sutures after 16 weeks implantation, revealed that PPCA 0.1 performed extremely well, eliciting only a minimal inflammatory response.

[0338] It is to be understood that the examples and embodiments described hereinabove are for the purposes of providing a description of the present invention by way of example and are not to be viewed as limiting the present invention in any way. Various modifications or changes that may be made to that described hereinabove by those of ordinary skill in the art are also contemplated by the present invention and are to be included within the spirit and purview of this application and the following claims.