Immobilized Biologically Active Entities Having High Biological Activity Following Mechanical Manipulation

• US 20070264308A1
• Filed: 05/10/2007
• 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 8,986,713 B2
• Time in Patent Office: Days
• US Class Current: 424/426
• CPC Class Codes: A61L 2300/222 Steroids, e.g. corticosteroids
• CPC Class Codes: A61L 2300/236 Glycosaminoglycans, e.g. heparin, hyaluronic acid, chondroitin
• CPC Class Codes: A61L 2300/252 Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
• CPC Class Codes: A61L 2300/416 Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: C08L 79/02 Polyamines
• CPC Class Codes: Y10T 428/31544 Addition polymer is perhalogenated

Abstract

The present invention relates to immobilized biologically active entities that retain significant biological activity following mechanical manipulation of a substrate material to which the entities are immobilized.

Claims

1. A 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 composition covalently combined with said polymeric covering material,

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 compaction and expansion of said substrate material.

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

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

4. The medical device of claim 1 wherein at least a portion of said biologically compatible composition is released from said 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 medical device of claim 1 wherein said biologically compatible composition comprises an organic compound.

6. The medical device of claim 5 wherein said organic compound is a polysaccharide.

7. The medical device of claim 6 wherein said polysaccharide is a glycosaminoglycan.

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

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

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

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

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

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

14. The medical device of claim 1 wherein said biologically compatible composition comprises an inorganic compound.

15. The medical device of claim 14 wherein said inorganic compound comprises a phosphate.

16. The medical device of claim 1 wherein said device is sterilized.

17. The 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 compaction and expansion of said substrate material.

18. The medical device of claim 17 wherein said plurality of biologically active entities comprises a glycosaminoglycan.

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

20. The medical device of claim 17 wherein at least a portion of said biologically compatible organic composition is released from said medical device in a 0.15M phosphate buffer solution having a temperature of about thirty-seven degrees centigrade and a substantially neutral pH.

21. The 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 compaction and expansion of said substrate material.

22. The medical device of claim 21 wherein said plurality of biologically active entities comprises a glycosaminoglycan.

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

24. The medical device of claim 21 wherein at least a portion of said biologically compatible organic composition is released from said medical device in a 0.15M phosphate buffer solution having a temperature of about thirty-seven degrees centigrade and a substantially neutral pH.

25. The 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 compaction and expansion of said substrate material.

26. The medical device of claim 25 wherein said plurality of biologically active entities comprises a glycosaminoglycan.

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

28. The medical device of claim 25 wherein at least a portion of said biologically compatible organic composition is released from said medical device in a 0.15M phosphate buffer solution having a temperature of about thirty-seven degrees centigrade and a substantially neutral pH.

29. The 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 compaction and expansion of said substrate material.

30. The medical device of claim 29 wherein said plurality of biologically active entities comprises a glycosaminoglycan.

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

32. The medical device of claim 29 wherein at least a portion of said biologically compatible organic composition is released from said medical device in a 0.15M phosphate buffer solution having a temperature of about thirty-seven degrees centigrade and a substantially neutral pH.

33. The 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 compaction and expansion of said substrate material.

34. The medical device of claim 33 wherein said plurality of biologically active entities comprises a glycosaminoglycan.

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

36. The medical device of claim 33 wherein at least a portion of said biologically compatible organic composition is released from said medical device in a 0.15M phosphate buffer solution having a temperature of about thirty-seven degrees centigrade and a substantially neutral pH.

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

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

39. The medical device of claim 38 wherein said polymeric substrate material is fluoropolymeric in composition.

40. The medical device of claim 39 wherein said fluoropolymeric material is polytetrafluoroethylene.

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

42. The medical device of claim 41 wherein said metallic composition is a nic like and titanium metal alloy.

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

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

45. A 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 composition 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 compaction and expansion of said substrate material.

46. The medical device of claim 45 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.

47. The medical device of claim 45 wherein said biologically compatible composition comprises an organic compound.

48. The medical device of claim 47 wherein said organic compound comprises a polysaccharide.

49. The medical device of claim 48 wherein said polysaccharide comprises a glycosaminoglycan.

50. The medical device of claim 49 wherein said glycosaminoglycans is an anticoagulation agent.

51. The medical device of claim 50 wherein said anticoagulation agent is heparin.

52. The medical device of claim 48 wherein said polysaccharide is dextran.

53. The medical device of claim 48 wherein said polysaccharide is dextran sulfate.

54. The medical device of claim 45 wherein said biologically compatible composition is polyethylene glycol.

55. The medical device of claim 45 wherein said biologically compatible composition is an antiproliferative agent.

56. The medical device of claim 55 wherein said antiproliferative agent is dexamethasone.

57. The medical device of claim 45 wherein said biologically compatible composition comprises a synthetic non-polar molecule.

58. The medical device of claim 45 wherein said biologically compatible composition comprises an inorganic compound.

59. The medical device of claim 58 wherein said inorganic compound comprises a phosphate.

60. The medical device of claim 45 wherein said sterilization includes ethylene oxide.

61. The medical device of claim 45 wherein said polymeric covering material comprises at least one layer of polyethylene imine.

62. The medical device of claim 45 wherein said polymeric covering material comprises multiple layers, wherein chemical components of at least one layer are cross-linked.

63. The sterilized medical device of claim 45 wherein said substrate material is polymeric in composition.

64. The medical device of claim 63 wherein said polymeric substrate material is fluoropolymeric in composition.

65. The medical device of claim 64 wherein said fluoropolymeric material is polytetrafluoroethylene.

66. The medical device of claim 45 wherein said substrate material is metallic in composition.

67. The medical device of claim 66 wherein said metallic composition is a nickel and titanium metal alloy.

68. The medical device of claim 66 wherein said metallic composition is stainless steel.

69. 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 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 plurality of polyethylene glycol molecules covalently combined with said polymeric covering material,

wherein said first plurality of heparin molecules have an anti-thrombin III binding activity of at least 50 picomoles anti-thrombin III per square centimeter (pmol/cm²) substrate material following compaction and expansion of said substrate material.

70. The medical device of claim 69 wherein at least a portion of said plurality of phosphate 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.

71. The medical device of claim 69 wherein said polymeric covering material comprises multiple layers, wherein chemical components of at least one layer are cross-linked.

72. The medical device of claim 69 wherein said substrate material is polymeric in composition.

73. The medical device of claim 72 wherein said polymeric substrate material is fluoropolymeric in composition.

74. The medical device of claim 73 wherein said fluoropolymeric material is polytetrafluoroethylene.

75. The medical device of claim 69 wherein said substrate material is metallic in composition.

76. The medical device of claim 75 wherein said metallic composition is a nickel and titanium metal alloy.

77. The medical device of claim 75 wherein said metallic composition is stainless steel.

78. The medical device of claim 69 wherein further comprising an antiproliferative agent.

79. The medical device of claim 78 wherein said antiproliferative agent is dexamethasone.

80. The medical device of claim 69 wherein said sterilization includes ethylene oxide.

81. The s medical device of claim 69 wherein said polymeric covering material comprises at least one layer of polyethylene imine.

82. A 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.

83. The medical device of claim 82 further comprising an anti-inflammatory agent combined therewith.

84. A medical device comprising:

a substrate material;

a plurality of chemical entities having anti-thrombin III binding activity present on at least a portion of said substrate material;

a first biologically compatible composition combined with said substrate material; and

a second biologically compatible composition admixed therewith following compaction and expansion of said substrate material, chemical entities, and first biologically compatible composition.

85. The medical device of claim 84 wherein said chemical entities having anti-thrombin III binding activity are covalently bound to said substrate material.

86. The medical device of claim 84 wherein said first biologically compatible composition is covalently bound to said substrate material.

87. The medical device of claim 84 wherein said first biologically compatible composition is non-covalently bound to said substrate material.

88. The medical device of claim 84 wherein said second biologically compatible composition is dexamethasone.

89. The medical device of claim 84 wherein said second biologically compatible composition is bacitracin.

90. A 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 chemical entities having anti-thrombin III binding activity present on at least a portion of said polymeric covering material;

a first biologically compatible composition combined with said substrate material; and

a second biologically compatible composition admixed therewith following compaction and expansion of said substrate material, chemical entities, and first biologically compatible composition.

91. The medical device of claim 90 wherein said chemical entities having anti-thrombin III binding activity are covalently bound to said polymeric covering material.

92. The medical device of claim 90 wherein said first biologically compatible composition is covalently bound to said polymeric covering material.

93. The medical device of claim 90 wherein said first biologically compatible composition is non-covalently bound to said polymeric covering material.

94. The medical device of claim 90 wherein said second biologically compatible composition is dexamethasone.

95. The medical device of claim 90 wherein said second biologically compatible composition is bacitracin.