Medical devices having nanoporous layers and methods for making the same

Abstract

The present invention relates generally to medical devices with therapy eluting components and methods for making same. More specifically, the invention relates to implantable medical devices having at least one porous layer, and methods for making such devices, and loading such devices with therapeutic agents. A mixture or alloy is placed on the surface of a medical device, then one component of the mixture or alloy is generally removed without generally removing the other components of the mixture or alloy. In some embodiments, a porous layer is adapted for bonding non-metallic coating, including drug eluting polymeric coatings. A porous layer may have a random pore structure or an oriented or directional grain porous structure. One embodiment of the invention relates to medical devices, including vascular stents, having at least one porous layer adapted to resist stenosis or cellular proliferation without requiring elution of therapeutic agents. The invention also includes methods, devices, and specifications for loading of drugs and other therapeutic agents into nanoporous coatings.

1 . A stent for insertion into a body structure, comprising: 
 a tubular member comprising: 
 a first end and a second end,  
 a lumen extending along a longitudinal axis between the first end and the second end,  
 an ablumenal surface,  
 a lumenal surface;  
 a first porous layer, the first porous layer comprising a first surface, a first interstitial structure and a first interstitial space;  
   wherein the porous layer has a tortuosity factor of greater than about 1.1, an average thickness of less than 10 microns and a peak-valley surface roughness of less than about 2 microns.    
   
   
       2 . The stent for insertion into a body structure of  claim 1 , wherein the porous layer has a tortuosity factor of greater than about 1.6.  
   
   
       3 . The stent for insertion into a body structure of  claim 1 , wherein the tubular member further comprises a second porous layer, the second porous layer comprising a second surface, a second interstitial structure and a second interstitial space.  
   
   
       4 . The stent for insertion into a body structure of  claim 1 , wherein the tubular member comprises a second porous layer, the second porous layer comprising a second interstitial structure, a second interstitial space, and a first porous layer interface between the first porous layer and the second porous layer.  
   
   
       5 . The stent for insertion into a body structure of  claim 1 , wherein the tubular member exhibits improved radio-opacity compared a similar tubular member lacking the first porous layer.  
   
   
       6 . The stent for insertion into a body structure of  claim 1 , wherein the average thickness of the first porous layer is less than about 5 microns.  
   
   
       7 . The stent for insertion into a body structure of  claim 1 , wherein the tortuosity factor of the first porous layer is measured in a porous volume comprising at least four pores.  
   
   
       8 . The stent for insertion into a body structure of  claim 1 , wherein the first interstitial space has an angular component.  
   
   
       9 . The stent for insertion into a body structure of  claim 1 , wherein the first porous layer is located on the outer surface of the tubular member.  
   
   
       10 . The stent for insertion into a body structure of  claim 1 , wherein the first porous layer is located on the inner surface of the tubular member.  
   
   
       11 . The stent for insertion into a body structure of  claim 1 , wherein the first porous layer further comprises at least one therapeutic agent within at least a portion of the interstitial space.  
   
   
       12 . The stent for insertion into a body structure of  claim 1 , wherein the first porous layer is a metallic porous layer.  
   
   
       13 . The stent for insertion into a body structure of  claim 1 , wherein the first porous layer is a nanoporous layer.  
   
   
       14 . The stent for insertion into a body structure of  claim 1 , wherein the nanoporous layer has an average pore diameter of less than about 200 nm.  
   
   
       15 . The stent for insertion into a body structure of  claim 14 , wherein the nanoporous layer has an average pore diameter of less than about 5 nm.  
   
   
       16 . The stent for insertion into a body structure of  claim 11 , wherein the therapeutic agents within at least a portion of the first interstitial space are selected from a group comprising: actinomycin-D, batimistat, c-myc antisense, dexamethasone, paclitaxel, taxanes, sirolimus, tacrolimus and everolimus, unfractionated heparin, low-molecular weight heparin, enoxaprin, bivalirudin, tyrosine kinase inhibitors, Gleevec, wortmannin, PDGF inhibitors, AG1295, rho kinase inhibitors, Y27632, calcium channel blockers, amlodipine, nifedipine, and ACE inhibitors, synthetic polysaccharides, ticlopinin, dipyridamole, clopidogrel, fondaparinux, streptokinase, urokinase, r-urokinase, r-prourokinase, rt-PA, APSAC, TNK-rt-PA, reteplase, alteplase, monteplase, lanoplase, pamiteplase, staphylokinase, abciximab, tirofiban, orbofiban, xemilofiban, sibrafiban, roxifiban, ABT-578, CCI-779, biolimus-A9, temsirolimus, anti-CD34 antibodies, mycophenolic acid, Vitamin E, omega-3 fatty acids, tempamine, and docetaxel, an agent for altering cytochrome P450 function, cyclosporine, an azole antifungal agent, itraconazole, ketoconazole, a macrolide antibiotic, clarithromycin, erythromycin, troleandomycin, an non-nucleoside reverse transcriptase inhibitor, delavirdine, a protease inhibitor, indinavir, ritonavir, saquinavir, ritonavir, grapefruit juice extract, mifepristone, nefazodone, an anti-restenosis agent, an anti-thrombogenic agent, an antibiotic, an anti-platelet agent, an anti-clotting agent, an anti-inflammatory agent, an anti-neoplastic agent, a chelating agent, penicillamine, triethylene tetramine dihydrochloride, EDTA, DMSA (succimer), deferoxamine mesylate, a radiocontrast agent, a radio-isotope, a prodrug, antibody fragments, antibodies, live cells, therapeutic drug delivery microspheres or microbeads, gene therapy agents, viral vectors and plasmid DNA vectors.  
   
   
       17 . The stent for insertion into a body structure of  claim 11 , wherein the first porous layer further comprises at least one metabolic agent within at least a portion of the interstitial space for altering the metabolization of the at least one therapeutic agent.  
   
   
       18 . The stent for insertion into a body structure of  claim 17 , wherein the at least one metabolic agent is a cytochrome P450 inhibitor.  
   
   
       19 . The stent for insertion into a body structure of  claim 18 , wherein the at least one metabolic agent is ritonavir.  
   
   
       20 . The stent for insertion into a body structure of  claim 1 , further comprising a polymeric coating bonded to at least a portion of the outer surface of the porous layer.  
   
   
       21 . The stent for insertion into a body structure of  claim 1 , wherein the polymeric coating is a drug eluting coating.  
   
   
       22 . The stent for insertion into a body structure of  claim 1 , wherein the polymeric coating is an elution rate-controlling coating.  
   
   
       23 . The stent for insertion into a body structure of  claim 20 , wherein the polymeric coating comprises a material selected from a group consisting of: polyurethanes, silicones, polyesters, polyolefins, polyisobutylene, ethylene-alphaolefin copolymers, acrylic polymers and copolymers, vinyl halide polymers and copolymers such as polyvinyl chloride, polyvinyl ethers such as polyvinyl methyl ether, polyvinylidene halides such as polyvinylidene fluoride and polyvinylidene chloride, polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics such as polystyrene, polyvinyl esters such as polyvinyl acetate; copolymers of vinyl monomers, copolymers of vinyl monomers and olefins such as ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, ethylene-vinyl acetate copolymers, polyamides such as Nylon 66 and polycaprolactone, alkyd resins, polycarbonates, polyoxymethylenes, polyimides, polyethers, epoxy resins, polyurethanes, rayon-triacetate, cellulose, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellophane, cellulose nitrate, cellulose propionate, cellulose ethers, carboxymethyl cellulose, collagens, chitins, polylactic acid, polyglycolic acid, and polylactic acid-polyethylene oxide copolymers. Other coating materials may include lactone-based copolyesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester) copolymers, and blends of such polymers, poly (ethylene)vinylacetate, poly(hydroxy)ethylmethylmethacrylate, polyvinal pyrrolidone; polytetrafluoroethylene, cellulose esters, elastomeric polymers such as silicones (e.g. polysiloxanes and substituted polysiloxanes), polyurethanes, thermoplastic elastomers, ethylene vinyl acetate copolymers, polyolefin elastomers, and EPDM rubbers, EVAL, poly(hydroxyvalerate), poly(L-lactic acid), polycaprolactone,. poly(lactide-co-glycolide), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoesters, polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolic acid-co-trimethylene carbonate), polyphosphoesters, polyphosphoester urethanes, poly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), co-poly(ether-esters) (e.g. PEO/PLA), polyalkylene oxalates, polyphosphazenes, biomolecules (such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid), polyurethanes, silicones, polyesters, polyolefins, polyisobutylene and ethylene-alphaolefin copolymers, acrylic polymers and copolymers, vinyl halide polymers and copolymers (such as polyvinyl chloride), polyvinylidene halides (such as polyvinylidene fluoride and polyvinylidene chloride), polyvinyl ethers (such as polyvinyl methyl-ether), polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics (such as polystyrene), polyvinyl esters (such as polyvinyl acetate), copolymers of vinyl monomers with each other and olefins (such as ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetate copolymers), polyamides (such as NYLON 66 and polycaprolactam), alkyd resins, polycarbonates, polyoxymethylenes, polyimides, polyethers, epoxy resins, polyurethanes, rayon, rayon-triacetate, cellulose, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellulose nitrate, cellulose propionate, cellulose ethers, carboxymethyl cellulose, CELLOPHANE, PEG, PEG-acrylate or methacrylate, silk-elastin protein block-copolymer, and mixtures thereof.  
   
   
       24 . A device for insertion into a body, comprising a biocompatible device with a porous surface having a tortuosity factor of greater than about 1.1, an average thickness of less than 10 microns and a peak-valley surface roughness of less than about 2 microns.  
   
   
       25 . The device for insertion into a body as in  claim 24 , wherein the porous surface has a tortuosity factor of greater than about 1.6.  
   
   
       26 . The device for insertion into a body as in  claim 24 , further comprising at least one therapeutic agent at least partially contained with the porous surface.  
   
   
       27 . The device for insertion into a body as in  claim 24 , further comprising a means for controlling elution of the therapeutic agent from the porous surface.