Claims for Patent: 8,187,320

Summary for Patent: 8,187,320

Title:	Medical implants containing FK506 (tacrolimus)
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.
Inventor(s):	Wnendt; Stephan (Aachen, DE), Von Oepen; Randolf (Tuebingen, DE), Kuttler; Bernd (Reutlingen, DE), Lang; Gerhard (Sulz, DE), Lorenz; Guenter (Tuebingen, DE), Grandt; Axel (Strassberg, DE)
Assignee:	Abbott Laboratories Vascular Enterprises Limited (Dublin, IE) Astellas Pharma Inc. (Tokyo, JP)
Application Number:	10/641,787
Patent Claims:	1. A method of treating and/or preventing restenosis in a blood vessel, the method comprising: providing an implant including an elongate member having one or more recesses formed in a surface thereof so as to provide one or more reservoirs and having an effective amount of FK506 (tacrolimus) for treating and/or preventing restenosis, the effective amount including a multi-stage release portion of FK506 (tacrolimus) disposed in the one or more internal reservoirs, the multi-stage release portion in communication with an exterior of the implant; inserting the implant into a vessel; expanding the implant into contact with a wall of the vessel; eluting FK506 from the plurality of internal lumen reservoirs into the wall of the vessel in the vicinity of the implant in an amount sufficient for treating and/or preventing restenosis in the blood vessel, the effective amount of FK506 eluted by the implant for treating and/or preventing restenosis producing a blood concentration of FK506 that ranges from about: about 7 ng/ml to about 17 ng/ml of blood at one hour after implantation of the implant; about 6 ng/ml to about 11 ng/ml of blood at eight hours after implantation of the implant; and/or about 2 ng/ml to about 4 ng/ml of blood twenty-four hours after implantation of the implant. 2. The method as in claim 1, wherein the implant comprises: an effective amount FK506 for treating and/or preventing restenosis in a blood vessel in a subject, the FK506 being in chemically covalently bound or noncovalently bound or physically immobilized form, the FK506 being disposed in the one or more internal lumen reservoirs. 3. The method of claim 2, wherein the at least one closed or perforated layer or surface comprises a metal or metal alloy. 4. The method of claim 3, wherein the metal or metal alloy has a lattice-like structure. 5. The method of claim 3, further comprising a layer or surface coating of polymer disposed on the metal or metal alloy. 6. The method of claim 5, wherein the polymer is selected from the group consisting of: Dacron, polytetrafluoroethylene, polyurethane, methacrylate polymers, a hydrogel or hydrogel/polyurethane blend. 7. The method of claim 2, wherein the at least one closed or perforated layer or surface comprises a polymer. 8. The method of claim 2, 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. 9. The method of claim 2, wherein the FK506 is loaded in nanoparticles or liposomes. 10. The method of claim 2, wherein the FK506 is applied by spraying, brush-loading or dipping. 11. The method of claim 2, wherein the FK506 is released after implantation of the implant. 12. The method of claim 11, further comprising a delayed release of the FK506. 13. The method of claim 12, wherein the delayed release of the FK506 from the implant occurs over a period ranging from 24 hr to more than 96 hr after implantation. 14. The method of claim 11, wherein release of the FK506 occurs in multiple stages. 15. The method of claim 2, further comprising at least one other pharmaceutically active agent. 16. The method of claim 15, 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), BAY 41-2272 (5-cyclopropyl-2-[1-fluorobenzyl)-1H-pyrazolo [3, 4-n] pyridine-3-yl] pyrimidin-4-ylamine); hydralazine, verapamil, diltiazem, nifedipine, nimodipine or other Ca.sup.t' 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; dexamethasone, betamethasone, prednisone or other corticosteroids; 17-beta-esradiol; 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, hirudin, hirulog, agratroban, PPACK; interleukin-10; sirolimus, rapamycin derivatives; PDGF antagonists; paclitaxel or 7-hexanoyl-taxol; cisplatin; vinblastine; mitoxantrone; combretastatin A4; topotecan; methotrexate; flavopiridol; actinomycin D; Rheopro/abciximab or probucol. 17. The method as in claim 1, wherein the implant comprises: at least one closed or perforated layer or surface comprising a metal or metal alloy; and an effective amount FK506 for treating and/or preventing restenosis in a blood vessel in a subject, the FK506 being in chemically covalently bound or noncovalently bound or physically immobilized form, wherein the metal or metal alloy further comprises a ceramic coating to which the FK506 is bound, wherein the effective amount of FK506 (tacrolimus) covalently bound or noncovalently bound or physically immobilized on the implant ranges from about 10 .mu.g/cm of the implant to about 200 .mu.g/cm of the implant. 18. The method of claim 17, the implant furthercomprising a polymeric layer that completely or partly covers the ceramic coating. 19. The method of claim 18, wherein the polymericcoating is selected from the group consisting of: methacrylate polymers, polyurethane, PTFE, a hydrogel or hydrogel/polyurethane blend. 20. The method of claim 1, further comprising one or more openings formed in an outer surface of the implant and a biodegradable polymeric material disposed to at least partially seal the one or more openings formed in the outer surface of the implant. 21. The method as in claim 1, wherein the implant comprises: at least one closed or perforated layer or surface comprising a polymer; and an effective amount FK506 for treating and/or preventing restenosis in a blood vessel in a subject, the FK506 being in chemically covalently bound or noncovalently bound or physically immobilized form, wherein the FK506 has been dissolved in a polymerization material before the formation of the at least one closed or perforated layer or surface, wherein the effective amount of FK506 (tacrolimus) covalently bound or noncovalently bound or physically immobilized on the implant ranges from about 10 .mu.g/cm of the implant to about 200 .mu.g/cm of the implant. 22. The method of claim 1, wherein the implant is characterized by at least one of the following: the FK506 is released after implantation of the implant; the release of FK506 is delayed after implantation of the implant; the FK506 is released from the implant over a period ranging from 24 hr to more than 96 hr after implantation; or release of the FK506 occurs in multiple stages. 23. The method of claim 1, wherein the implant is characterized by at least one of the following: the implant having at least one closed or perforated layer or surface having one or more internal lumen reservoirs therein, wherein the FK506 is combined with a polymer and disposed in the one or more internal lumen reservoirs. 24. The method of claim 1, wherein the effective amount of FK506 (tacrolimus) disposed on the implant for treating and/or preventing restenosis ranges from about 10 .mu.g/cm of the implant to about 200 .mu.g/cm of the implant. 25. The method of claim 1, wherein the effective amount of FK506 eluted by the implant produces at least a 53% reduction in neointima formation and a detectable decrease in formation of inflammation foci following insertion of the implant into the vessel. 26. A method of treating and/or preventing restenosis in a blood vessel, the method comprising: providing an implant including an elongate member having one or more internal reservoirs, the internal reservoir formed from a tubular wire and having an effective amount of FK506 (tacrolimus) for treating and/or preventing restenosis, the effective amount including a multi-stage release, a long-term release portion of FK506 (tacrolimus) being disposed in the one or more internal reservoirs in communication with an outer surface of the implant via one or more openings formed in the tubular wire and a rapid release portion of FK506 (tacrolimus) being disposed in an overcoat layer formed over the elongate member of the implant, wherein, the effective amount of FK506 (tacrolimus) in the rapid release portion and the long-term release portion ranges from about 10 .mu.g/cm of the implant to about 200 .mu.g/cm of the implant; inserting the implant into a vessel; expanding the implant into contact with a wall of the vessel; eluting FK506 from the one or more internal lumen reservoirs and/or the overcoat layer into the wall of the vessel in the vicinity of the implant in an amount sufficient for treating and/or preventing restenosis in the blood vessel, elution of the rapid release portion of the FK506 (tacrolimus) occurring over a first period of time of about 0 to about 2 days after implantation and elution of the long-term release portion of the FK506 (tacrolimus) occurring over a second period of time of about 2 days to about 21 days after implantation, and the multi-stage release including producing a blood concentration of FK506 that ranges from about: 7 ng/ml to about 17 ng/ml of blood at one hour after implantation of the implant; and about 6 ng/ml to about 11 ng/ml of blood at eight hours after implantation of the implant. 27. The method of claim 26, 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. 28. The method of claim 26, the overcoat layer including at least one material capable of inhibiting release from the continued release portion during the first period of time. 29. The method of claim 26, the implant being a stent having a plurality of struts and the one or more internal reservoirs being laser-cut into the at least a subset of the plurality of struts.

Details for Patent 8,187,320

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Janssen Biotech, Inc.	REOPRO	abciximab	Injection	103575	12/22/1994		2021-02-16