Immobilized biologically active entities having a high degree of biological activity

• US 8,945,599 B2
• Filed: 02/05/2013
• Issued: 02/03/2015
• 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: Cleek, Robert L., Daly, Michael D., Pietrzak, Krzysztof R.
• Primary Examiner(s): Barham, Bethany
• Assistant Examiner(s): FRAZIER, BARBARA S
• Application Number:
  US13/759,842
• Publication Number:
  US 20130150284A1
• Time in Patent Office: 728 Days
• US Class Current: 424/423
• CPC Class Codes: A61K 31/727 Heparin; Heparan
• CPC Class Codes: A61K 38/1709 from mammals
• 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 2300/416 Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2300/42 Anti-thrombotic agents, anticoagulants, anti-platelet agents
• CPC Class Codes: A61L 2300/45 Mixtures of two or more drugs, e.g. synergistic mixtures
• CPC Class Codes: A61L 27/20 Polysaccharides
• 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: A61L 31/042 Polysaccharides
• 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 33/0029 using an intermediate layer of polymer
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C08L 5/02 Dextran; Derivatives thereof
• CPC Class Codes: C08L 5/10 Heparin; Derivatives thereof

Abstract

The present invention relates to immobilized biologically active entities having heparin cofactor II binding activity.

Claims

1. A medical device comprising:

a polymeric substrate material,

a plurality of biologically active entities having heparin cofactor II binding activity covalently attached to at least a portion of said polymeric substrate material; and

a biologically compatible composition combined with said plurality of biologically active entities,

wherein said biologically active entities have a heparin cofactor II binding activity of at least 5 picomoles heparin cofactor II per square centimeter (pmol/cm²).

2. The medical device of claim 1 wherein said biologically compatible composition is covalently combined with said plurality of biologically active entities.

3. The medical device of claim 1 wherein said biologically compatible composition is non-covalently combined with said plurality of biologically active entities.

4. The medical device of claim 1 wherein said biologically compatible composition is covalently combined with said polymeric substrate material.

5. The medical device of claim 1 wherein said biologically compatible composition is non-covalently combined with said polymeric substrate material.

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

7. The medical device of claim 1 wherein said plurality of biologically active entities comprises dermatan disulfate.

8. The medical device of claim 1 wherein said plurality of biologically active entities comprises end-point attached dermatan disulfate.

9. The medical device of claim 1 wherein said medical device is capable of releasing at least a portion of said biologically compatible composition, and wherein upon exposure to a 0.15M phosphate buffer solution having a temperature of about thirty-seven degrees centigrade and a substantially neutral pH, at least a portion of said biologically compatible composition is released from said medical device.

10. The medical device of claim 1 wherein said biologically compatible composition comprises an organic compound.

11. The medical device of claim 10 wherein said organic compound is a polysaccharide.

12. The medical device of claim 11 wherein said polysaccharide is a glycosaminoglycan.

13. The medical device of claim 11 wherein said polysaccharide is dextran.

14. The medical device of claim 11 wherein said polysaccharide is dextran sulfate.

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

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

17. The medical device of claim 16 wherein said antiproliferative agent is dexamethasone.

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

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

20. The medical device of claim 19 wherein said inorganic compound comprises a phosphate.

21. The medical device of claim 1 wherein said medical device is capable of being sterilized and said plurality of biologically active entities have a heparin cofactor II binding activity of at least 5 picomoles heparin cofactor II per square centimeter (pmol/cm²) substrate material when measured following said sterilization of said polymeric substrate material.

22. The medical device of claim 1 wherein said medical device is capable of being compacted and expanded and said plurality of biologically active entities have a heparin cofactor II binding activity of at least 5 picomoles heparin cofactor II per square centimeter (pmol/cm²) substrate material when measured following said compaction and expansion of said polymeric substrate material.

23. The medical device of claim 1 wherein said biologically compatible composition comprises the co-immobilization of heparin and dermatan disulfate.

24. A medical device comprising:

a polymeric substrate material,

a first plurality of biologically active entities having heparin cofactor II binding activity and a second plurality of biologically active entities having anti-thrombin Ill binding activity covalently attached to at least a portion of said polymeric substrate material; and

a biologically compatible composition combined with said first plurality of biologically active entities and said second plurality of biologically active entities,

wherein said biologically active entities have a heparin cofactor II binding activity of at least 5 picomoles heparin cofactor II per square centimeter (pmol/cm²) and at least 5 picomoles anti-thrombin Ill per square centimeter.

25. The medical device of claim 24 wherein said biologically compatible composition is covalently combined with said said first plurality of biologically active entities and said second plurality of biologically active entities.

26. The medical device of claim 24 wherein said biologically compatible composition is non-covalently combined with said said first plurality of biologically active entities and said second plurality of biologically active entities.

27. The medical device of claim 24 wherein said biologically compatible composition is covalently combined with said polymeric substrate material.

28. The medical device of claim 24 wherein said biologically compatible composition is non-covalently combined with said polymeric substrate material.

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

30. The medical device of claim 24 wherein said first plurality of biologically active entities comprises dermatan disulfate.

31. The medical device of claim 24 wherein said first plurality of biologically active entities comprises end-point attached dermatan disulfate.

32. The medical device of claim 24 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.

33. The medical device of claim 24 wherein said biologically compatible composition comprises an organic compound.

34. The medical device of claim 33 wherein said organic compound is a polysaccharide.

35. The medical device of claim 34 wherein said polysaccharide is a glycosaminoglycan.

36. The medical device of claim 34 wherein said polysaccharide is dextran.

37. The medical device of claim 34 wherein said polysaccharide is dextran sulfate.

38. The medical device of claim 24 wherein said biologically compatible composition is polyethylene glycol.

39. The medical device of claim 24 wherein said biologically compatible composition is an antiproliferative agent.

40. The medical device of claim 39 wherein said antiproliferative agent is dexamethasone.

41. The medical device of claim 24 wherein said biologically compatible composition comprises a synthetic non-polar molecule.

42. The medical device of claim 24 wherein said biologically compatible composition comprises an inorganic compound.

43. The medical device of claim 42 wherein said inorganic compound comprises a phosphate.

44. The medical device of claim 24 wherein said first plurality of biologically active entities have a heparin cofactor II binding activity of at least 5 picomoles heparin cofactor II per square centimeter (pmol/cm²) substrate material following sterilization of said polymeric substrate material.

45. The medical device of claim 24 wherein said first plurality of biologically active entities have a heparin cofactor II binding activity of at least 5 picomoles heparin cofactor II per square centimeter (pmol/cm²) substrate material following compaction and expansion of said polymeric substrate material.

46. The medical device of claim 24 wherein said biologically compatible composition comprises the co-immobilization of heparin and dermatan disulfate.