Intravascular delivery of mycophenolic acid

• US 6,471,980 B2
• Filed: 02/13/2001
• Issued: 10/29/2002
• Est. Priority Date: 12/22/2000
• Status: Expired due to Fees

• Current Assignee: Avantec Vascular Corporation
• Original Assignee: Avantec Vascular Corporation
• Inventors: Yan, John, Sirhan, Motasim
• Primary Examiner(s): AZPURU, CARLOS A
• Application Number:
  US09/782,927
• Publication Number:
  US 20020114823A1
• Time in Patent Office: 623 Days
• Field of Search: 424/423, 424/424, 424/425, 424/426
• US Class Current: 424/423
• CPC Class Codes: A61F 2/90 characterised by a net-like or mesh-like structure
• CPC Class Codes: A61F 2/91 made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
• CPC Class Codes: A61F 2/915 with bands having a meander structure, adjacent bands being connected to each other
• CPC Class Codes: A61F 2/95 Instruments specially adapted for placement or removal of stents or stent-grafts
• CPC Class Codes: A61F 2002/91533 characterised by the phase between adjacent bands
• 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 2300/416 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 mycophenolic acid 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 mycophenolic acid at a rate selected 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 mycophenolic acid at a rate selected to inhibit smooth muscle cell proliferation.

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

g/day to 200 μ

g/day.

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

g/day to 60 μ

g/day.

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

g/day to 50 μ

g/day and a subsequent phase wherein the rate of mycophenolic acid release is between 5 μ

g/day to 200 μ

g/day.

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

g/day to 30 μ

g/day and a subsequent phase wherein the rate of mycophenolic acid release is between 10 μ

g/day to 100 μ

g/day.

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

g/day to 300 μ

g/day and a subsequent phase wherein the rate of mycophenolic acid release is between 1 μ

g/day to 100 μ

g/day.

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

g/day to 200 μ

g/day and a subsequent phase wherein the rate of mycophenolic acid release is between 10 μ

g/day to 40 μ

g/day.

8. A prosthesis as in claim 1, wherein mycophenolic acid 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 mycophenolic acid release is in a range from 100 μ

g to 10 mg.

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

g to 2 mg.

11. A prosthesis as in claim 1, wherein a total amount of mycophenolic acid 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 mycophenolic acid 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 mycophenolic acid 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 mycophenolic acid 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 mycophenolic acid 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 mycophenolic acid 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 mycophenolic acid 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 mycophenolic acid and another layer contains mycophenolic acid, at least one substance other than mycophenolic acid, or no substance.

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

23. A prosthesis as in claim 21, wherein the at least one substance other than mycophenolic acid 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 mycophenolic acid comprises a rate limiting barrier formed over at least a portion of the structure.

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

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

27. A prosthesis as in claim 1, wherein mycophenolic acid is on or within the expansible structure in a pattern that provides the desired release rate.

28. A prosthesis as in claim 1, wherein mycophenolic acid is disposed within a matrix or rate limiting membrane in a pattern that provides the desired release rate.

29. A vascular prosthesis comprising:

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

a rate limiting barrier on the structure for releasing mycophenolic acid at a rate selected to inhibit smooth muscle cell proliferation;

wherein the barrier comprises multiple layers, each layer comprising PARYLAST™

or parylene and having a thickness in a range from 50 nm to 10 microns.

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

g/day to 200 μ

g/day.

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

33. A vascular prosthesis comprising:

an expansible structure;

a source of mycophenolic acid on or within the structure, wherein the mycophenolic acid 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 mycophenolic acid 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, mizoribine, riboflavin, tiazofurin, methylprednisolone, 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.