NOVEL HEPARIN ENTITIES AND METHODS OF USE

• US 20110064781A1
• Filed: 09/17/2009
• Published: 03/17/2011
• Est. Priority Date: 09/17/2009
• Status: Active Grant

• Current Assignee: W. L. Gore & Associates (W.L. Gore & Associates)
• Original Assignee: W. L. Gore & Associates (W.L. Gore & Associates)
• Inventors: LI, MEI, DRUMHELLER, PAUL D., MARDIROSIAN, NORA, CLEEK, ROBERT L.
• Granted Patent: US 8,591,932 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61L 2300/236 Glycosaminoglycans, e.g. heparin, hyaluronic acid, chondroitin
• CPC Class Codes: A61L 2300/42 Anti-thrombotic agents, anticoagulants, anti-platelet agents
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 29/16 Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• CPC Class Codes: A61L 31/022 Metals or alloys
• CPC Class Codes: A61L 31/048 obtained by reactions only involving carbon-to-carbon unsaturated bonds A61L31/041 takes precedence
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61L 33/0011 Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
• CPC Class Codes: A61L 33/08 Polysaccharides
• CPC Class Codes: A61L 33/128 Other specific proteins or polypeptides not covered by A61L33/122 - A61L33/126
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C08L 27/12 containing fluorine atoms

Abstract

The present invention relates to immobilized biologically active entities that retain a significant biological activity following manipulation. The invention also comprises a medical substrate comprising a heparin entity bound onto a substrate via at least one heparin molecule, wherein said bound heparin entity is heparinase-1 sensitive.

Claims

1. A medical substrate comprising:

a heparin entity bound onto a substrate via at least one heparin molecule, wherein said bound heparin entity is heparinase sensitive.

2. The medical substrate of claim 1, wherein said substrate is selected from the group consisting of polyethylene, polyurethane, silicone, polyamide-containing polymers, polypropylene, polytetrafluoroethylene, expanded-polytetrafluoroethylene and biocompatible metals.

3. The medical substrate of claim 2, wherein said substrate is expanded-polytetrafluoroethylene.

4. The medical substrate of claim 2, wherein said biocompatible metal is Nitinol.

5. The medical substrate of claim 1, wherein said substrate is a component of a medical device.

6. The medical substrate of claim 5, wherein said medical device is selected from the group consisting of grafts, vascular grafts, stents, stent-grafts, bifurcated grafts, bifurcated stents, bifurcated stent-grafts, patches, plugs, drug delivery devices, catheters, cardiac leads, balloons and indwelling filers.

7. The medical substrate of claim 6, wherein said stents can be used in cardiac, peripheral or neurological applications.

8. The medical substrate of claim 6, wherein said stent-grafts can be used in cardiac, peripheral or neurological applications.

9. The medical substrate of claim 1, wherein said heparin entity comprises at least one heparin molecule and at least one core molecule.

10. The medical substrate of claim 9, wherein said core molecule is either cyclic, linear, branched, dendritic, Y, T, or star shaped.

11. The medical substrate of claim 9, wherein said core molecule is selected from the group consisting of proteins, hydrocarbons, aminoglycosides, polysaccharides and polymers.

12. The medical substrate of claim 11, wherein said protein is selected from the group consisting of albumin, colistin and polylysine.

13. The medical substrate of claim 11, wherein said polysaccharide is selected from the group consisting of cyclodextrin, cellulose, and chitosan.

14. The medical substrate of claim 11, wherein said polymer is selected from the group consisting of polyethylene glycol (PEG) and co-polymers tetrafluoroethylene.

15. The medical substrate of claim 1, wherein said heparin is derived from bovine or porcine sources.

16. The medical substrate of claim 1, wherein after heparinase treatment heparin or fragments thereof will not be detected on said substrate.

17. The medical substrate of claim 1, wherein after heparinase treatment heparin or fragments thereof will be detected at a significantly lower level than before heparinase treatment on said substrate.

18. The medical substrate of claim 16, wherein heparin or fragments thereof are detected by a label that binds to heparin or fragments thereof.

19. The medical substrate of claim 18, wherein said label that binds to heparin or fragments thereof is selected from the group consisting of dyes, polyclonal antibodies, and proteins

20. The medical substrate of claim 19, wherein said dye is toluidine blue

21. The medical substrate of claim 1, wherein after heparinase treatment an insignificant amount of toluidine blue will bind to residual heparin or fragments thereof but will not be visually detected on said substrate.

22. The medical substrate of claim 1, wherein after heparinase treatment an insignificant amount of toluidine blue will bind to residual heparin or fragments thereof, and wherein detector readings will be about background levels or be insignificantly different from background when compared to a substrate without heparin entities.

23. The heparin entity of claim 1, wherein said heparin entity is bound onto a substrate via at least one heparin molecule and wherein said bound heparin molecule is attached to said substrate via end point attachment.

24. The heparin entity of claim 1, wherein said heparin entity is bound onto a substrate via at least one heparin molecule and wherein said bound heparin molecule is attached to said substrate via loop attachment.

25. The heparin entity of claim 1, wherein said heparin entity is bound onto a substrate via at least one heparin molecule and wherein said bound heparin molecule is attached to said substrate via end point aldehyde.

26. The heparin entity of claim 1, wherein said heparin entity is bound onto a substrate via at least one heparin molecule and wherein said bound heparin molecule is attached to said substrate via aldehydes along the length of said heparin.

27. A heparin entity comprising:

at least one heparin molecule and at least one core molecule such that when said heparin entity is bound onto a substrate via a least one heparin molecule, said heparin entity is heparinase sensitive.

28. The heparin entity of claim 27, wherein said substrate is selected from the group consisting of polyethylene, polyurethane, silicone, polyamide-containing polymers, polypropylene, polytetrafluoroethylene, expanded-polytetrafluoroethylene and biocompatible metals.

29. The heparin entity of claim 27, wherein said substrate is expanded-polytetrafluoroethylene.

30. The heparin entity of claim 28, wherein said biocompatible metal is Nitinol.

31. The heparin entity of claim 27, wherein said substrate is a component of a medical device.

32. The heparin entity of claim 31, wherein said medical device is selected from the group consisting of grafts, vascular grafts, stents, stent-grafts, bifurcated grafts, bifurcated stents, bifurcated stent-grafts, patches, plugs, drug delivery devices, catheters, cardiac leads, balloons and indwelling filters.

33. The heparin entity of claim 32, wherein said stents can be used in cardiac, peripheral or neurological applications.

34. The heparin entity of claim 32, wherein said stent-grafts can be used in cardiac, peripheral or neurological applications.

35. The heparin entity of claim 27, wherein said core molecule is either cyclic, linear, branched, dendritic, T, Y or star shaped.

36. The heparin entity of claim 27, wherein said core molecule is selected from the group consisting of proteins, polypeptides, hydrocarbons, polysaccharides, aminoglycosides, and polymers.

37. The heparin entity of claim 36, wherein said protein is selected from the group consisting of albumin, colistin and polylysine.

38. The heparin entity of claim 36, wherein said polysaccharide is selected from the group consisting of cyclodextrin, cellulose, and chitosan.

39. The heparin entity of claim 36, wherein said polymer is selected from the group consisting of polyethylene glycol (PEG) and co-polymers of tetrafluoroethylene.

40. The heparin entity of claim 27, wherein said heparin is derived from bovine or porcine sources.

41. The heparin entity of claim 27, wherein after heparinase treatment heparin or fragments thereof will not be detected on said substrate.

44. The medical substrate of claim 27, wherein after heparinase treatment heparin or fragments thereof will be detect at a significantly lower level than before heparinase treatment.

45. The heparin entity of claim 41, wherein heparin or fragments thereof is detected by a label that binds to heparin or fragments thereof.

46. The heparin entity of claim 45, wherein said label that binds to heparin or fragments thereof is selected from the group consisting of dyes, antibodies, and proteins.

47. The heparin entity of claim 46, wherein said dye is toluidine blue.

48. The heparin entity of claim 27, wherein after heparinase treatment an insignificant amount of toluidine blue will bind to residual heparin or fragments thereof but will not be visually detected on said substrate.

49. The heparin entity of claim 27, wherein after heparinase treatment an insignificant amount of toluidine blue will bind to residual heparin or fragments thereof, and wherein detector readings will be about background levels or be insignificantly different from background levels when compared to a substrate without heparin entities.

50. The heparin entity of claim 27, wherein said heparin entity is bound onto a substrate via at least one heparin molecule and wherein said bound heparin molecule is attached to said substrate via end point attachment.

51. The heparin entity of claim 27, wherein said heparin entity is bound onto a substrate via at least one heparin molecule and wherein said bound heparin molecule is attached to said substrate via loop attachment.

52. The heparin entity of claim 27, wherein said heparin entity is bound onto a substrate via at least one heparin molecule and wherein said bound heparin molecule is attached to said substrate via end point aldehyde.

53. The heparin entity of claim 27, wherein said heparin entity is bound onto a substrate via at least one heparin molecule and wherein said bound heparin molecule is attached to said substrate via aldehydes along the length said heparin.

54. An ATIII binding entity comprising;

a core molecule,

a polysaccharide chain attached to the core molecule, and

a free terminal aldehyde moiety on the polysaccharide chain.

55. The ATIII binding entity of claim 54, wherein said polysaccharide chain is heparin.

56. The ATIII binding entity of claim 54, wherein said core molecule is selected from the group consisting of a protein, a hydrocarbon, an aminoglycoside, a polysaccharide and a polymer.

57. The ATIII binding entity of claim 56, wherein said protein is selected from the group consisting of albumin, colistin, and polylysine.

58. The ATIII binding entity of claim 56, wherein said polysaccharide is selected from the group consisting of cyclodextrin, cellulose, and chitosan.

59. The ATIII binding entity of claim 56, wherein said polymer is selected from the group consisting of polyethylene glycol (PEG) and co-polymers of tetrafluoroethylene.

60. The ATIII binding entity of claim 55, wherein said heparin is derived from bovine or porcine sources.

61. The ATIII binding entity of claim 55, wherein said heparin is bound onto the core molecule via end point attachment.

62. The ATIII binding entity of claim 55, wherein said heparin is bound onto a substrate via end point attachment.

63. The ATIII binding entity of claim 62, wherein said substrate is selected from the group consisting of polyethylene, polyurethane, silicone, polyamide-containing polymers, and polypropylene, polytetrafluoroethylene, expanded-polytetrafluoroethylene and biocompatible metals.

64. The ATIII binding entity of claim 63, wherein said substrate is expanded-polytetrafluoroethylene.

65. The ATIII binding entity of claim 63, wherein said biocompatible metal is Nitinol.

66. The ATIII binding entity of claim 62, wherein said substrate is a component of a medical device.

67. The heparin entity of claim 66, wherein said medical device is selected from the group consisting of grafts, vascular grafts, stents, stent-grafts, bifurcated grafts, bifurcated stents, bifurcated stent-grafts, patches, plugs, drug delivery devices, catheters and cardiac leads.

68. The heparin entity of claim 67, wherein said stents can be used in cardiac, peripheral or neurological applications.