Immobilized biologically active entities having a high degree of biological activity following sterilization

• US 20070264301A1
• Filed: 05/12/2006
• Published: 11/15/2007
• Est. Priority Date: 05/12/2006
• Status: Active Grant

• Current Assignee: W. L. Gore & Associates (W.L. Gore & Associates)
• Original Assignee: W. L. Gore & Associates (W.L. Gore & Associates)
• Inventors: Daly, Michael, Cleek, Robert, Pietrzak, Krzysztof
• Granted Patent: US 8,496,953 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61L 2/206 Ethylene oxide
• CPC Class Codes: A61L 33/0011 Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate

Abstract

The present invention is directed to immobilized biologically active entities that retain significant biological activity following sterilization of the immobilized biologically active entities.

Claims

1. A sterilized medical device comprising:

a substrate material;

a polymeric covering material attached to at least a portion of a surface of said substrate material, a plurality of biologically active entities having anti-thrombin III binding activity covalently attached to at least a portion of said polymeric covering material; and

a biologically compatible organic composition non-covalently combined with said polymeric covering material and said biologically active entities,

wherein said biologically active entities have an anti-thrombin III binding activity of at least 5 picomoles anti-thrombin III per square centimeter (pmol/cm²) substrate material following sterilization of said biologically active entities.

2. The sterilized medical device of claim 1 wherein said plurality of biologically active entities comprises a glycosaminoglycan.

3. The sterilized medical device of claim 1 wherein said plurality of biologically active entities comprises end-point attached heparin.

4. The sterilized medical device of claim 1 wherein at least a portion of said biologically compatible organic composition is released from said sterilized medical device in a 0.15M phosphate buffer solution having a temperature of about thirty-seven degrees centigrade and a substantially neutral pH.

5. The sterilized medical device of claim 1 wherein said biologically compatible organic composition is a polysaccharide.

6. The sterilized medical device of claim 5 wherein said polysaccharide comprises a glycosaminoglycan.

7. The sterilized medical device of claim 6 wherein said glycosaminoglycan is heparin.

8. The sterilized medical device of claim 5 wherein said polysaccharide is dextran.

9. The sterilized medical device of claim 5 wherein said polysaccharide is dextran sulfate.

10. The sterilized medical device of claim 1 wherein said biologically compatible organic composition is polyethylene glycol.

11. The sterilized medical device of claim 1 wherein said biologically compatible organic composition is an antiproliferative agent.

12. The sterilized medical device of claim 11 wherein said antiproliferative agent is dexamethasone.

13. The sterilized medical device of claim 1 wherein said biologically compatible organic composition comprises a synthetic non-polar molecule.

14. The sterilized medical device of claim 1 wherein said sterilization includes ethylene oxide.

15. The sterilized medical device of claim 1 wherein said plurality of biologically active entities have an anti-thrombin III binding activity of at least 6 picomoles anti-thrombin III per square centimeter (pmol/cm²) substrate material following sterilization of said biologically active entities.

16. The sterilized medical device of claim 15 wherein said plurality of biologically active entites comprises a glycosaminoglycan.

17. The sterilized medical device of claim 15 wherein said plurality of biologically active entities comprises end-point attached heparin.

18. The sterilized medical device of claim 15 wherein at least a portion of said biologically compatible organic composition is released from said sterilized medical device in a 0.15M phosphate buffer solution having a temperature of about thirty-seven degrees centigrade and a substantially neutral pH.

19. The sterilized medical device of claim 1 wherein said plurality of biologically active entities have an anti-thrombin III binding activity of at least 7 picomoles anti-thrombin III per square centimeter (pmol/cm²) substrate material following sterilization of said biologically active entities.

20. The sterilized medical device of claim 19 wherein said plurality of biologically active entities comprises a glycosaminoglycan.

21. The sterilized medical device of claim 19 wherein said plurality of biologically active entities comprises end-point attached heparin.

22. The sterilized medical device of claim 19 wherein at least a portion of said biologically compatible organic composition is released from said sterilized medical device in a 0.15M phosphate buffer solution having a temperature of about thirty-seven degrees centigrade and a substantially neutral pH.

23. The sterilized medical device of claim 1 wherein said plurality of biologically active entities have an anti-thrombin III binding activity of at least 8 picomoles anti-thrombin III per square centimeter (pmol/cm²) substrate material following sterilization of said biologically active entities.

24. The sterilized medical device of claim 23 wherein said plurality of biologically active entities comprises a glycosaminoglycan.

25. The sterilized medical device of claim 23 wherein said plurality of biologically active entities comprises end-point attached heparin.

26. The sterilized medical device of claim 23 wherein at least a portion of said biologically compatible organic composition is released from said sterilized medical device in a 0.15M phosphate buffer solution having a temperature of about thirty-seven degrees centigrade and a substantially neutral pH.

27. The sterilized medical device of claim 1 wherein said plurality of biologically active entities have an anti-thrombin III binding activity of at least 9 picomoles anti-thrombin III per square centimeter (pmol/cm²) substrate material following sterilization of said biologically active entities.

28. The sterilized medical device of claim 27 wherein said plurality of biologically active entities comprises a glycosaminoglycan.

29. The sterilized medical device of claim 27 wherein said plurality of biologically active entities comprises end-point attached heparin.

30. The sterilized medical device of claim 27 wherein at least a portion of said biologically compatible organic composition is released from said sterilized medical device in a 0.15M phosphate buffer solution having a temperature of about thirty-seven degrees centigrade and a substantially neutral pH.

31. The sterilized medical device of claim 1 wherein said plurality of biologically active entities have an anti-thrombin III binding activity of at least 10 picomoles anti-thrombin III per square centimeter (pmol/Cm²) substrate material following sterilization of said biologically active entities.

32. The sterilized medical device of claim 31 wherein said plurality of biologically active entities comprises a glycosaminoglycan.

33. The sterilized medical device of claim 31 wherein said plurality of biologically active entities comprises end-point attached heparin.

34. The sterilized medical device of claim 31 wherein at least a portion of said biologically compatible organic composition is released from said sterilized medical device in a 0.15M phosphate buffer solution having a temperature of about thirty-seven degrees centigrade and a substantially neutral pH.

35. The sterilized medical device of claim 1 wherein said polymeric covering material comprises multiple layers, wherein chemical components of at least one layer are cross-linked.

36. The sterilized medical device of claim 1 wherein said substrate material is polymeric in composition.

37. The sterilized medical device of claim 36 wherein said polymeric substrate material is fluoropolymeric in composition.

38. The sterilized medical device of claim 37 wherein said fluoropolymeric material is polytetrafluoroethylene.

39. The sterilized medical device of claim 1 wherein said substrate material is metallic in composition.

40. The sterilized medical device of claim 39 wherein said metallic composition is a nickel and titanium metal alloy.

41. The sterilized medical device of claim 39 wherein said metallic composition is stainless steel.

42. The sterilized medical device of claim 1 wherein said polymeric covering material comprises at least one layer of polyethylene imine.

43. A sterilized medical device comprising:

a substrate material;

a polymeric covering material attached to at least a portion of a surface of said substrate material;

a first plurality of heparin molecules having anti-thrombin III binding activity end point attached to at least a portion of said polymeric covering material; and

a biologically compatible organic composition non-covalently combined with said polymeric covering material and said first plurality of heparin molecules, wherein said first plurality of heparin molecules have an anti-thrombin III binding activity of at least 10 picomoles anti-thrombin III per square centimeter (pmol/cm²) substrate material following sterilization of said first plurality of heparin molecules.

44. The sterilized medical device of claim 43 wherein at least a portion of said biologically compatible organic composition is released from said sterilized medical device in a 0.15M phosphate buffer solution having a temperature of about thirty-seven degrees centigrade and a substantially neutral pH.

45. The sterilized medical device of claim 43 wherein said biologically compatible organic composition is a polysaccharide.

46. The sterilized medical device of claim 45 wherein said polysaccharide comprises a glycosaminoglycan.

47. The sterilized medical device of claim 45 wherein said polysaccharide is an anticoagulation agent.

48. The sterilized medical device of claim 47 wherein said anticoagulation agent is heparin.

49. The sterilized medical device of claim 45 wherein said polysaccharide is dextran.

50. The sterilized medical device of claim 45 wherein said polysaccharide is dextran sulfate.

51. The sterilized medical device of claim 43 wherein said biologically compatible organic composition is polyethylene glycol.

52. The sterilized medical device of claim 43 wherein said biologically compatible organic composition is an antiproliferative agent.

53. The sterilized medical device of claim 43 wherein said antiproliferative agent is dexamethasone.

54. The sterilized medical device of claim 43 wherein said biologically compatible organic composition comprises a synthetic non-polar molecule.

55. The sterilized medical device of claim 43 wherein said sterilization includes ethylene oxide.

56. The sterilized medical device of claim 43 wherein said polymeric covering material comprises at least one layer of polyethylene imine.

57. The sterilized medical device of claim 43 wherein said polymeric covering material comprises multiple layers, wherein chemical components of at least one layer are cross-linked.

58. The sterilized medical device of claim 43 wherein said substrate material is polymeric in composition.

59. The sterilized medical device of claim 58 wherein said polymeric substrate material is fluoropolymeric in composition.

60. The sterilized medical device of claim 59 wherein said fluoropolymeric material is polytetrafluoroethylene.

61. The sterilized medical device of claim 43 wherein said substrate material is metallic in composition.

62. The sterilized medical device of claim 61 wherein said metallic composition is a nickel and titanium metal alloy.

63. The sterilized medical device of claim 61 wherein said metallic composition is stainless steel.

64. The sterilized medical device of claim 43 wherein said polymeric covering material comprises at least one layer of polyethylene imine.

65. A sterilized medical device comprising:

a polymeric substrate material;

a polymeric covering material attached to at least a portion of a surface of said substrate material;

a first plurality of heparin molecules having anti-thrombin III binding activity end point attached to at least a portion of said polymeric covering material; and

a composition comprising a second plurality of heparin molecules non-covalently combined with said polymeric covering material,

wherein said first plurality of heparin molecules have an anti-thrombin III binding activity of at least 10 picomoles anti-thrombin III per square centimeter (pmol/cm²) substrate material following sterilization of said first plurality of heparin molecules.

66. The sterilized medical device of claim 65 wherein at least a portion of said second plurality of heparin molecules is released from said sterilized medical device in a 0.15M phosphate buffer solution having a temperature of about thirty-seven degrees centigrade and a substantially neutral pH.

67. The sterilized medical device of claim 65 wherein said polymeric covering material comprises multiple layers, wherein chemical components of at least one layer are cross-linked.

68. The sterilized medical device of claim 65 wherein said substrate material is polymeric in composition.

69. The sterilized medical device of claim 68 wherein said polymeric substrate material is fluoropolymeric in composition.

70. The sterilized medical device of claim 69 wherein said fluoropolymeric material is polytetrafluoroethylene.

71. The sterilized medical device of claim 65 wherein said substrate material is metallic in composition.

72. The sterilized medical device of claim 71 wherein said metallic composition is a nickel and titanium metal alloy.

73. The sterilized medical device of claim 71 wherein said metallic composition is stainless steel.

74. The sterilized medical device of claim 65 wherein further comprising an antiproliferative agent.

75. The sterilized medical device of claim 74 wherein said antiproliferative agent is dexamethasone.

76. The sterilized medical device of claim 65 wherein said sterilization includes ethylene oxide.

77. The sterilized medical device of claim 65 wherein said polymeric covering material comprises at least one layer of polyethylene imine.

78. A sterilized medical device comprising:

a polymeric substrate material;

a polymeric covering material attached to at least a portion of a surface of said substrate material;

a first plurality of heparin molecules having anti-thrombin III binding activity end point attached to at least a portion of said polymeric covering material; and

a composition comprising a second plurality of heparin molecules non-covalently combined with said polymeric covering material,

wherein said first plurality of heparin molecules have an anti-thrombin III binding activity of at least 100 picomoles anti-thrombin III per square centimeter (pmol/cm²) substrate material following sterilization of said first plurality of heparin molecules.

79. The sterilized medical device of claim 78 wherein at least a portion of said second plurality of heparin molecules is released from said sterilized medical device in a 0.15M phosphate buffer solution having a temperature of about thirty-seven degrees centigrade and a substantially neutral pH.

80. The sterilized medical device of claim 78 wherein said polymeric covering material comprises multiple layers, wherein chemical components of at least one layer are cross-linked.

81. The sterilized medical device of claim 78 wherein said substrate material is polymeric in composition.

82. The sterilized medical device of claim 81 wherein said polymeric substrate material is fluoropolymeric in composition.

83. The sterilized medical device of claim 82 wherein said fluoropolymeric material is polytetrafluoroethylene.

84. The sterilized medical device of claim 78 wherein said substrate material is metallic in composition.

85. The sterilized medical device of claim 84 wherein said metallic composition is a nickel and titanium metal alloy.

86. The sterilized medical device of claim 84 wherein said metallic composition is stainless steel.

87. The sterilized medical device of claim 78 wherein further comprising an antiproliferative agent.

88. The sterilized medical device of claim 87 wherein said antiproliferative agent is dexamethasone.

89. The sterilized medical device of claim 78 wherein said sterilization includes ethylene oxide.

90. The sterilized medical device of claim 78 wherein said polymeric covering material comprises at least one layer of polyethylene imine.

91. A sterilized medical device comprising a substrate material with a plurality of chemical entities having anti-thrombin III binding activity present on at least a portion of a surface of said substrate material, wherein at least ninety percent of said anti-thrombin III binding activity is retained following sterilization of said chemical entities.