Medical implants containing FK506 (tacrolimus), methods of making and methods of use thereof

• US 20040117008A1
• Filed: 08/15/2003
• Published: 06/17/2004
• Est. Priority Date: 02/16/2001
• Status: Active Grant

• Current Assignee: Abbott Laboratories Limited (Abbott Laboratories Incorporated), Astellas Pharma Incorporated
• Original Assignee: Abbott Laboratories Limited (Abbott Laboratories Incorporated), Fujisawa Pharmaceutical Co., Ltd. (Astellas Pharma Incorporated)
• Inventors: Lang, Gerhard, Von Oepen, Randolf, Wnendt, Stephan, Grandt, Axel, Lorenz, Guenter, Kuttler, Bernd
• Granted Patent: US 8,187,320 B2
• Time in Patent Office: Days
• US Class Current: 623/1.46
• 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 2300/606 Coatings
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence

Abstract

Implants and methods of making same are provided for treatment or prophylaxis of coronary or peripheral vascular constrictions or vascular occlusions, and particularly, stenoses or restenoses, that comprise FK506 in chemically covalently bound, non-covalently bound or physically immobilized form.

Claims

1. An endovascular implant comprising a hollow tubular body having open ends, a lateral sidewall, a contracted delivery configuration and a deployed configuration wherein the tubular body supports a vessel wall,

the improvement comprising that a coating disposed on the hollow tubular body, the secondary coating comprising an amount of tacrolimus.

2. The endovascular implant of claim 1 wherein the coating is biodegradable.

3. The endovascular implant of claim 1 wherein the coating is non-biodegradable.

4. The endovascular implant of claim 1 wherein the tacrolimus is uniformly distributed in the coating.

5. The endovascular implant of claim 2 wherein the coating comprises polylactic acid.

6. The endovascular implant of claim 5 wherein a concentration of tacrolimus in the coating yields a dose of about 10-20 ng of tacrolimus per ml of tissue volume.

7. A method of treating a blood vessel comprising:

inserting an implant into a vessel;

expanding the implant into contact with a wall of the vessel;

eluting tacrolimus from the implant into wall of the vessel in the vicinity of the implant.

8. An implant for the prophylaxis of restenosis, the implant comprising FK506 in chemically covalently bound or noncovalently bound or physically immobilized form, and, optionally, at least one other active agent.

9. The implant of claim 8 wherein the implant has at least one closed or perforated layer or surface.

11. The implant of claim 9 wherein the at least one closed or perforated layer or surface comprises a metal or metal alloy.

12. The implant of claim 9 wherein the at least one closed or perforated layer or surface comprises a polymer.

13. The implant of claim 11 further comprising a layer or surface coating of polymer disposed on the metal or metal alloy.

14. The implant of claim 13 wherein the polymer is selected from the group consisting of:

Dacron, polytetrafluoroethylene, polyurethane, methacrylate polymers, a hydrogel or hydrogel/polyurethane blend.

15. The implant of claim 8 wherein the implant is selected from the group consisting of:

a stent, a stent graft, a graft, a graft connector, a guide wire, a catheter or a catheter pump.

16. The implant of claim 8 wherein the implant is coated with FK506.

17. The implant of claim 11 wherein the metal or metal alloy further comprises a ceramic coating to which FK506 is bound.

18. The implant of claim 17 wherein further comprising a polymeric layer that completely or partly covers the ceramic coating.

19. The implant of claim 18 wherein the polymeric coating is selected from the group consisting of:

methacrylate polymers, polyurethane, PTFE, a hydrogel or hydrogel/polyurethane blend.

20. The implant of claim 11 wherein the metal or metal alloy further comprises recesses that are filled with FK506.

21. The implant of claim 11 wherein the metal or metal alloy further comprises internal lumens that communicate with an exterior surface of the implant by one or more passageways.

22. The implant of claim 20 further comprising a biodegradable polymeric material disposed to seal the recesses.

23. The implant of claim 8 wherein the FK506 is loaded in nanoparticles or liposomes.

24. The implant of claim 8 wherein the FK506 is applied by spraying, brush-loading or dipping.

25. The implant of claim 12 wherein the FK506 has been dissolved in a polymerization material before the formation of at least one closed or perforated layer or surface comprising a polymer.

26. The implant of claim 8 wherein the FK506 is released after implantation of the implant.

27. The implant of claim 26 wherein delayed release of the FK506 occurs.

28. The implant of claim 27 wherein the FK506 is released from the implant over a period ranging from 24 hr to more than 96 hr after implantation.

29. The implant of claim 26 wherein release of the FK506 occurs in multiple stages.

30. The implant of claim 8 further comprising at least one other pharmaceutically active agent.

31. The implant of claim 30 wherein the pharmaceutically active agent is selected from the group consisting of:

molsidomine, linsidomine, sodium nitroprusside, nitroglycerin or general NO donors;

stimulators of soluble guanylate cyclase (sGC), for example BAY 41-2272 (5-(cyclopropyl-2-[1-fluorobenzyl)-1H-pyrazolo[3,4-n]pyridin-3-yl]pyrimidin-4-ylamine);

hydralazine, verapamil, diltiazem, nifedipine, nimodipine or other Ca²⁺ channel blockers;

captopril, enalapril, lisinopril, quinapril or other inhibitors of angiotensin converting enzymes (angiotensin converting enzyme inhibitors);

losartan, candesartan, irbesartan, valsartan or other antagonists of the angiotensin II receptor.

32. The implant of claim 30 wherein the pharmaceutically active agent is selected from the group consisting of:

dexamethasone, betamethasone, prednisone or other corticosteriods;

17-beta-estradiol;

cyclosporin;

mycophenolic acid;

VEGF, VEGF receptor activators;

tranilast;

meloxicam, celebrex, vioxx or other COX-2 antagonists;

indomethacin, diclofenac, ibuprofen, naproxen or other COX-1 inhibitors;

inhibitors of plasminogen activator 1 (plasminogen activator inhibitors-1) or serpins;

thrombin inhibitors, for example hirudin, hirulog, agratroban, PPACK;

interleukin-10.

33. The implant of claim 30 wherein the pharmaceutically active agent is selected from the group consisting of:

sirolimus, rapamycin, SDZ RAD (40-O-(2-hydroxyethyl) rapamycin or other rapamycin derivatives;

PDGF antagonists;

paclitaxel or 7-hexanoyl-taxol;

cisplatin;

vinblastine;

mitoxantrone;

combretastatin A4;

topotecan;

methotrexate;

flavopiridol;

actinomycin D;

Rheopro/abciximab or probucol.

10. The implant of 9 wherein the metal or metal alloy has a lattice-like structure.