Intravascular delivery of methylprednisolone

• US 20020082677A1
• Filed: 02/13/2001
• Published: 06/27/2002
• Est. Priority Date: 12/22/2000
• Status: Active Grant

• Current Assignee: Avantec Vascular Corporation
• Original Assignee: Avantec Vascular Corporation
• Inventors: Yan, John, Sirhan, Motasim
• Granted Patent: US 7,018,405 B2
• Time in Patent Office: Days
• US Class Current: 623/1.15
• CPC Class Codes: A61F 2/90 characterised by a net-like or mesh-like structure
• CPC Class Codes: A61F 2210/0076 multilayered, e.g. laminated structures
• CPC Class Codes: A61F 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: A61L 2300/41 Anti-inflammatory agents, e.g. NSAIDs
• 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 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence

Abstract

The present invention provides improved devices and methods for minimizing and/or inhibiting restenosis and hyperplasia after intravascular intervention. In particular, the present invention provides luminal prostheses which allow for programmed and controlled methylprednisolone delivery with increased efficacy to selected locations within a patient'"'"'s vasculature to inhibit restenosis. An intraluminal delivery prosthesis may comprise an expansible structure and means on or within the structure for releasing methylprednisolone into the body lumen to inhibit smooth muscle cell proliferation.

Claims

1. A vascular prosthesis comprising:

an expansible structure which is implantable within a body lumen; and

means on or within the structure for releasing methylprednisolone into the body lumen to inhibit smooth muscle cell proliferation.

2. A prosthesis as in claim 1, wherein methylprednisolone is released at a rate between 5 μ

g/day to 200 μ

g/day.

3. A prosthesis as in claim 1, wherein methylprednisolone is released at a rate between 10 μ

g/day to 60 μ

g/day.

4. A prosthesis as in claim 1, wherein methylprednisolone is released at an initial phase wherein a rate of methylprednisolone release is between 0 μ

g/day to 50 μ

g/day and a subsequent phase wherein a rate of methylprednisolone release is between 5 μ

g/day to 200 μ

g/day.

5. A prosthesis as in claim 1, wherein methylprednisolone is released at an initial phase wherein a rate of methylprednisolone release is between 5 μ

g/day to 30 μ

g/day and a subsequent phase wherein a rate of methylprednisolone release is between 10 μ

g/day to 100 μ

g/day.

6. A prosthesis as in claim 1, wherein methylprednisolone is released at an initial phase wherein a rate of methylprednisolone release is between 40 μ

g/day to 300 μ

g/day and a subsequent phase wherein a rate of methylprednisolone release is between 1 μ

g/day to 100 μ

g/day.

7. A prosthesis as in claim 1, wherein methylprednisolone is released at an initial phase wherein a rate of methylprednisolone release is between 40 μ

g/day to 200 μ

g/day and a subsequent phase wherein a rate of methylprednisolone release is between 10 μ

g/day to 40 μ

g/day.

8. A prosthesis as in claim 1, wherein methylprednisolone is released at a constant rate between 5 μ

g/day to 200 μ

g/day.

9. A prosthesis as in claim 1, wherein a total amount of methylprednisolone release is in a range from 100 μ

g to 10 mg.

10. A prosthesis as in claim 1, wherein a total amount of methylprednisolone release is in a range from 300 μ

g to 2 mg.

11. A prosthesis as in claim 1, wherein a total amount of methylprednisolone release is in a range from 500 μ

g to 1.5 mg.

12. A prosthesis as in claim 1, wherein a mammalian tissue concentration of methylprednisolone at an initial phase is within a range from 0 μ

g/mg of tissue to 100 μ

g/mg of tissue.

13. A prosthesis as in claim 1, wherein a mammalian tissue concentration of methylprednisolone at an initial phase is within a range from 0 μ

g/mg of tissue to 10 μ

g/mg of tissue.

14. A prosthesis as in claim 1, wherein a mammalian tissue concentration of methylprednisolone at a subsequent phase is within a range from 1 picogram/mg of tissue to 100 μ

g/mg of tissue.

15. A prosthesis as in claim 1, wherein a mammalian tissue concentration of methylprednisolone at a subsequent phase is within a range from 1 nanogram/mg of tissue to 10 μ

g/mg of tissue.

16. A prosthesis as in claim 1, wherein the expansible structure is a stent or graft.

17. A prosthesis as in claim 1, wherein the means for releasing methylprednisolone comprises a matrix formed over at least a portion of the structure.

18. A prosthesis as in claim 17, wherein the matrix is composed of a material which undergoes degradation.

19. A prosthesis as in claim 17, wherein the matrix is composed of a nondegradable material.

20. A prosthesis as in claim 19, wherein methylprednisolone is released by diffusion through the nondegradable matrix.

21. A prosthesis as in claim 17, wherein the matrix comprises multiple layers, wherein at least one layer contains methylprednisolone and another layer contains methylprednisolone, at least one substance other than methylprednisolone, or no substance.

22. A prosthesis as in claim 21, wherein the at least one substance other than methylprednisolone is an immunosuppressive substance selected from the group consisting of rapamycin, mycophenolic acid, riboflavin, tiazofurin, mizoribine, FK 506, zafirin, and methotrexate.

23. A prosthesis as in claim 21, wherein the at least one substance other than methylprednisolone is an agent selected from the group consisting of anti-platelet agent, anti-thrombotic agent, and IIb/IIIa agent.

24. A prosthesis as in claim 1, wherein the means for releasing methylprednisolone comprises a rate limiting barrier formed over at least a portion of the structure.

25. A prosthesis as in claim 24, wherein methylprednisolone is released by diffusion through the rate limiting barrier.

26. A prosthesis as in claim 1, wherein the means for releasing methylprednisolone comprises a reservoir on or within the structure containing methylprednisolone and a cover over the reservoir.

27. A prosthesis as in claim 1, wherein methylprednisolone is on or within the expansible structure.

28. A prosthesis as in claim 1, wherein methylprednisolone is disposed within a matrix or rate limiting membrane.

30. A prosthesis as in claim 29, wherein methylprednisolone is released at a rate between 5 μ

g/day to 200 μ

g/day.

31. A prosthesis as in claim 29, wherein methylprednisolone is released at a rate between 10 μ

g/day to 60 μ

g/day.

32. A prosthesis as in claim 29, wherein at least one layer contains methylprednisolone and another layer contains methylprednisolone, at least one substance other than methylprednisolone, or no substance.

29. A vascular prosthesis comprising:

an expansible structure implantable within a body lumen; and

a rate limiting barrier on the structure for releasing methylprednisolone into the body lumen to inhibit smooth muscle cell proliferation;

wherein the barrier comprises multiple layers, each layer comprising parylast or paralene and having a thickness in a range from 50 nm to 10 microns.

33. A vascular prosthesis comprising:

an expansible structure;

a source of methylprednisolone on or within the structure, wherein the methylprednisolone is released from the source when the expansible structure is implanted in a blood vessel; and

a source of at least one other substance in addition to methylprednisolone on or within the structure, wherein the at least one additional substance is released from the source when the expansible structure is implanted in a blood vessel.

34. A prosthesis as in claim 33, wherein the at least one additional substance is an immunosuppressive substance selected from the group consisting of rapamycin, mycophenolic acid, riboflavin, tiazofurin, mizoribine, FK 506, zafurin, and methotrexate.

35. A prosthesis as in claim 33, wherein the at least one additional substance comprises at least one agent selected from the group consisting of anti-platelet agent, anti-thrombotic agent, and IIb/IIIa agent.

36. A prosthesis as in claim 33, wherein each source comprises a matrix, rate limiting membrane, or reservoir.

38. A method as in claim 37, wherein methylprednisolone is released at a rate between 5 μ

g/day to 200 μ

g/day.

39. A method as in claim 37, wherein methylprednisolone is released at a rate between 10 μ

g/day to 60 μ

g/day.

40. A method as in claim 37, wherein methylprednisolone is released within a time period of 1 day to 45 days in a vascular environment.

41. A method as in claim 37, wherein methylprednisolone is released within a time period of 7 days to 21 days in a vascular environment.

42. A method as in claim 37, further comprising releasing at least one other substance in addition to methylprednisolone simultaneously with methylprednisolone release.

43. A method as in claim 37, further comprising releasing at least one other substance in addition to methylprednisolone sequentially with methylprednisolone release.

44. A method as in claim 42 or 43, wherein the at least one additional substance is an immunosuppressive substance selected from the group consisting of rapamycin, mycophenolic acid, riboflavin, tiazofurin, mizoribine, FK 506, zafurin, and methotrexate.

45. A method as in claim 37, wherein the releasing comprises delaying substantial release of methylprednisolone for at least one hour following implantation of the prosthesis.

46. A method as in claim 45, wherein delaying release comprises slowing release from a reservoir with a material that at least partially degrades in a vascular environment over said one hour.

47. A method as in claim 45, wherein delaying release comprises slowing release with a matrix that at least partially degrades in a vascular environment over said one hour.

48. A method as in claim 45, wherein delaying release comprises slowing release with a nondegradable matrix that allows diffusion of methylprednisolone through the nondegradable matrix after said one hour.

49. A method as in claim 45, wherein delaying release comprises slowing release with a rate limiting barrier that allows diffusion of methylprednisolone through the barrier after said one hour.

50. A method as in any one of claims 47-49, wherein the prosthesis is coated with the matrix or barrier by spraying, dipping, deposition, or painting.

51. A method as in claim 37, wherein the prosthesis incorporates methylprednisolone by coating, spraying, dipping, deposition, chemical bonding, or painting methylprednisolone on the prosthesis.

37. A method for inhibiting restenosis in a blood vessel following recanalization of the blood vessel, said method comprising:

implanting a vascular prosthesis in the blood vessel; and

releasing methylprednisolone into the blood vessel so as to inhibit smooth muscle cell proliferation.

52. A method for inhibiting restenosis in a blood vessel following recanalization of the blood vessel, said method comprising:

implanting a vascular prosthesis in the blood vessel; and

releasing methylprednisolone and at least one other substance in addition to methylprednisolone from the prosthesis when implanted in the blood vessel.

53. A method as in claim 52, wherein the at least one additional substance is an immunosuppressive substance selected from the group consisting of rapamycin, mycophenolic acid, riboflavin, tiazofurin, mizoribine, FK 506, zafurin, and methotrexate.

54. A method as in claim 53, wherein the immunosuppressive substance is mycophenolic acid.

55. A method as in claim 53, wherein the immunosuppressive substance is mizoribine.

56. A method as in claim 52, wherein methylprednisolone is released within a time period of 2 days to 3 months.

57. A method as in claim 52, wherein the at least one additional substance comprises at least one agent selected from the group consisting of anti-platelet agent, antithrombotic agent, and IIb/IIIa agent.

58. A method as in claim 52, wherein methylprednisolone and the at least one additional substance are released simultaneously.

59. A method as in claim 52, wherein methylprednisolone and the at least one additional substance are released sequentially.