Medical implants containing fk506 (tacrolimus) methods of making and methods of use thereof

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.

1 .- 33 . (canceled) 
     
     
         34 . An intravascular implant comprising:
 FK506 chemically covalently bound or non-covalently bound or physically immobilized to a substrate, and, optionally, at least one other active agent,   wherein the implant comprises the substrate which is coated with FK506 and the substrate has at least one closed or perforated layer or surface which consists of a metal or a metal alloy and is homogenous or formed from various strands.   
     
     
         35 . The implant as claimed in  claim 34 , wherein the implant is suitable for the treatment or prophylaxis of coronary or peripheral vascular constrictions or occlusions. 
     
     
         36 . The implant as claimed in  claim 34 , wherein the implant is suitable for the treatment or prophylaxis of restenosis. 
     
     
         37 . The implant as claimed in  claim 34 , wherein the implant has at least one closed or perforated layer or surface which consists of a polymer and is homogenous or formed from various strands. 
     
     
         38 . The implant as claimed in  claim 34 , wherein at least one polymer layer covers completely or partly a closed or perforated layer or surface which consists of a metal or a metal allow and is homogenous or formed from various strands. 
     
     
         39 . The implant as claimed in  claim 34 , wherein the implant is a stent, a sent graft, a graft, a graft connector, a guide wire, a catheter or a catheter pump, preferably a stent, a stent graft, a graft or a graft connector, in particular a stent or a stent graft. 
     
     
         40 . The implant as claimed in  claim 34 , wherein the substrate has a ceramic coating of aluminum oxide or iridium oxide, to which FK506 is bound or physically immobilized in. 
     
     
         41 . The implant as claimed in  claim 34 , wherein the substrate has a polymeric coating, in particular of methacrylate polymers, polyurethane, PTFE, hydrogel or hydrogel/polyurethane blend to which FK506 is bound or in which FK506 is physically immobilized in. 
     
     
         42 . The implant as claimed in  claim 34 , wherein the metal of the implant has recesses which have been introduced by means of a laser and which are filled with FK506. 
     
     
         43 . The implant as claimed in  claim 34 , wherein the FK506 is present in the form of loaded nanoparticles or liposomes. 
     
     
         44 . The implant as claimed in  claim 34 , wherein the FK506 is configured to be released upon contact with vascular tissue. 
     
     
         45 . The implant as claimed in  claim 34 , wherein the implant comprises at least one other active agent selected from the following active agents or derivatives thereof:
 (Group 1:) molsidomine, linsidomine, sodium nitroprusside, nitroglycerin, general NO donors; stimulators of soluble guanylate cyclase (sGC), BAY 41-2272 (5-(cyclopropyl-2-[1-(2-fluorobenzyl)-1H-pyrozolo[3,4-n]pyridine-3-yl]pyrimidin-4-ylamine); hydralazine, verapamil, siltiazem, nifedipine, nimodipine, Ca 2+  channel blockers; captopril, enalapril, lisinopril, quinapril, inhibitors of angiotensin converting enzymes; losartan, candesartan, irbesartan, valsartan, antagonists of the angiotensin II receptor;   (Group 2:) dexamethasone, bethamethasone, prednisone, or other corticosteroids; 17-beta-estradiol; cyclosporine; mycophenolic acid; VEGF, VEGF receptor activators; tranilast; meloxicam, celbrex, vioxx; COX-2 antagonists; indomethancin, diclofenac, ibuprofen, naproxen or other COX-1 inhibitors; inhibitors of plasminogen activator 1 (plasminogen activator inhibitors-1), serpins; thrombin inhibitors, hirudin, hirulog, agratroban, PPACK; interleukin-10;   (Group 3:) sirlimus, rapamycin, SDZ RAD (40-O-(2-hydroxyethyl)rapamycin, rapamycin derivatives; PDGF antagonists, paclitaxel, 7-hexanoyl-taxol; cisplatin; vinblastine; mitoxantrone; combretastatin A4; toactinomycin D; Rheopro/abciximab or probucol.   
     
     
         46 . An implant produced by a process in which:
 a) a substrate having at least one closed or perforated layer or surface which consists of a metal or a metal alloy and is homogeneous or formed from various strands, which substrate is coated with a ceramic coating is employed,   
       or
 b) a substrate having at least one closed or perforated layer or surface which consists of a polymer and is homogenous or formed from various strands is employed, 
 
       or
 c) a substrate which is coated with a coating which is polymerized to form a methacrylate polymer, polyurethane, PTFE, hydrogel or hydrogel/polyurethane blend is employed 
 
       or
 d) a substrate having at least one closed or perforated layer or surface which consists of a metal or a metal alloy and is homogenous or formed from various strands, and into which recesses have been introduced by means of a laser, which are filled with FK506, and then the substrate is coated with a biodegradable coating which is polymerized on the surface is employed; and wherein 
 e) the substrate according to a), b), c) or d) is brought into contact with an FK506 solution in aqueous or organic solvent by sprinkling, spraying or immersing, optionally under vacuum, 
 f) optionally, removing all or a portion of the organic solvent contacted contacted with the FK506 in step (e), 
 g) optionally, repeating step (f) 1 to 5 times; and 
 h) optionally, rinsing the substrate with water or isotonic saline; and 
 i) optionally, drying the rinsed substrate of step (h). 
 
     
     
         47 . The implant as claimed in  claim 46 , wherein the FK506 is dissolved in an alcohol in step (e). 
     
     
         48 . The implant as claimed in  claim 46 , wherein the FK506 is immersed in an aqueous or organic solvent and steps (f) and (g) are not performed and steps (h) and (i) are performed. 
     
     
         49 . The implant as claimed in  claim 46 , wherein in step (e) the concentration of FK506 in the solution is in a range of 0.5-5 g/l. 
     
     
         50 . The implant as claimed in  claim 46 , wherein the implant is a stent, a sent graft, a graft, a graft connector, a guide wire, a catheter or a catheter pump, preferably a stent, a stent graft, a graft or a graft connector, in particular a stent or a stent graft. 
     
     
         51 . The implant as claimed in  claim 46 , wherein the substrate has a ceramic coating of aluminum oxide or iridium oxide, to which FK506 is bound or physically immobilized in. 
     
     
         52 . The implant as claimed in  claim 46 , wherein the substrate has a polymeric coating, in particular of methacrylate polymers, polyurethane, PTFE, hydrogel or hydrogel/polyurethane blend to which FK506 is bound or in which FK506 is physically immobilized in. 
     
     
         53 . The implant as claimed in  claim 46 , wherein the metal of the implant has recesses which have been introduced by means of a laser and which are filled with FK506. 
     
     
         54 . The implant as claimed in  claim 46 , wherein the FK506 is configured to be released upon contact with vascular tissue.