Coatings and methods of forming coatings for implantable medical devices, such as stents, are described. The coatings are used for the sustained release of a therapeutic agent or drug.

Description of the Invention

SUMMARY

In accordance with one embodiment, a stent having a coating is provided. The coating comprises a first region including a thermoplastic polyacrylate material and a therapeutic substance and a second region free from any therapeutic substances disposed on the surface of the stent and beneath the first region. The thermoplastic polyacrylate material can comprise oligomers, pre-polymers, homopolymers, copolymers, or terpolymers of alkylacrylates or alkylmethacrylates. In one embodiment, the polyacrylate material is poly(n-butyl methacrylate). The second region can include a non-acrylate polymer, such as an ethylene vinyl alcohol copolymer. In one embodiment, the coating can include a third region disposed over the first region, the third region including a thermoplastic polyacrylate material and optionally a therapeutic substance. The first region can have a variable thickness along at least a segment of the length of the stent such that the concentration of the substance varies along the length of the stent.

In accordance with another embodiment of the invention, a stent is provided comprising a coating, wherein the coating includes a first, second, and third layers disposed over one another wherein at least two of the layers include a thermoplastic polyacrylate material and wherein at least one of the layers includes a therapeutic substance. In one embodiment, the first layer is disposed on the outer surface of the stent, the second and third layers include the thermoplastic polyacrylate material, and the therapeutic substance is contained in the second layer and optionally the third layer but not the first layer. In accordance with another embodiment, the first layer and the third layer include the therapeutic substance but not the second layer and the second layer and the third layer include the thermoplastic polyacrylate material. In accordance with yet another embodiment, the first, second and third layers include the thermoplastic polyacrylate material and at least one of the layers is free from any therapeutic substances.

A stent comprising a coating having a variable thickness along at least a portion of the length of the stent is also provided so as to provide a concentration gradient of an active agent or agents along from a thin region of the coating to a thicker region of the coating.

In accordance with yet another embodiment, a method of coating a stent is provided, the method comprises forming a coating on the stent, the coating including a first region having a thermoplastic polyacrylate material and a therapeutic substance and a second region free from any therapeutic substances disposed on the surface of the stent beneath the first region.

In accordance with yet another embodiment of the invention, a method of coating a stent is provided comprising forming at least three layers of coating on a stent, wherein at least two of the layers include a thermoplastic polyacrylate material and wherein at least one of the layers includes a therapeutic substance.

In accordance with yet another embodiment of the invention, a method of coating a stent is provided comprising depositing a coating on the stent wherein the coating has a variable thickness along at least a segment of the length of the stent.

In accordance with yet another embodiment of the invention, a method of coating a stent, is provided comprising, depositing a first layer on the stent, the first layer including a first therapeutic substance; masking a region of the first layer; depositing a second layer on the first layer not covered by the masking layer, the second layer including a second therapeutic substance.

DETAILED DESCRIPTION

A stent coating having an engineered drug release rate can be fabricated by depositing on the stent any combination of the following layers, but for a reservoir layer which must be present in the coating: a primer layer; a reservoir layer of or containing an active agent or a drug; a topcoat layer free from any agents or drugs for serving as a rate reducing membrane; and a finishing coat layer. The finishing coat layer, which if used would be the outermost layer in the coating configuration for contacting the vessel tissues, can include an active agent or can be modified to have therapeutic materials, such as heparin, attached or conjugated to the surface thereof. Alternatively, the finishing coat layer can be made from a very bio-friendly material such a poly ethylene glycol (PEG). The purpose of the finishing coat layer is to reduce or prevent any adverse effects, such as more than acceptable degrees of inflammation or thrombi accumulation, which may be caused by the presence of the coated stent. The finishing coat layer can also serve as a rate limiting membrane for reducing the rate of release of the agent from the reservoir layer.

To deposit any of the coating layers, techniques known to those having ordinary skill in the art can be used. For example, a polymer can be dissolved in a solvent, or a mixture of solvents, and the resulting composition can be sprayed on the stent or the stent can be immersed in the composition. In one embodiment, thermoplastic polyacrylate materials can be used for any of the aforementioned layers or combination of layers. "Thermoplastic polyacrylate materials" are broadly defined as materials which include thermoplastic polyacrylates. "Polyacrylates" are defined to include oligomers, pre-polymers, homopolymers, copolymers, terpolymers, etc. of alkylacrylates or alkylmethacrylates, and blends thereof. Thermoplastic polyacrylate materials can also include blends of thermoplastic polyacrylates with non-acrylic materials.

Representative alkyl groups in alkylacrylates or alkylmethacrylates include C.sub.1-C.sub.12 straight-chained or branched alkyls. Examples of alkylacrylates or alkylmethacrylates that can be used include poly(n-butyl methacrylate) (PBMA), poly(ethyl methacrylate) (PEMA), and poly(ethyl methacrylate-co-butyl methacrylate) [P(EMA-BMA)].

Examples of suitable non-acrylic materials that can be blended with thermoplastic polyacrylates include fluorinated polymers and/or copolymers, such as poly(vinylidene fluoride) (PVDF) and poly(vinylidene fluoride-co-hexafluoro propene) (PVDF-HFP). One example of a commercially available fluorinated polymer that can be used is a PVDF resin distributed by ATOFINA Chemicals, Inc. of Philadelphia, Pa. under the trade name KYNAR. A suitable blend of a thermoplastic polyacrylate and a fluorinated polymer can contain between about 10 and about 95% mass of the fluorinated polymer. In another embodiment, the non-acrylic polymer can be poly(ethylene-co-vinyl alcohol) (also known as EVAL or EVOH). Poly(ethylene-co-vinyl alcohol) is available from Adrich Co., Milwaukee Wis. or EVAL Company of America, Lisle, Ill. These non-acrylic polymers, however, need not be used with the thermoplastic polyacrylate and can be used alone or in combination with other polymers to form any of the coating layers.

Representative examples of other polymers that can be used for any of the coating layer included poly(hydroxyvalerate), poly(L-lactic acid), polycaprolactone, poly(lactide-co-glycolide), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolic acid-co-trimethylene carbonate), polyphosphoester, polyphosphoester urethane, 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, vinyl halide polymers and copolymers (such as polyvinyl chloride), polyvinyl ethers (such as polyvinyl methyl ether), polyvinylidene chloride, 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, cellophane, cellulose nitrate, cellulose propionate, cellulose ethers, and carboxymethyl cellulose.

Representative examples of some solvents suitable for making the composition include N,N-dimethylacetamide (DMAC), N,N-dimethylformamide (DMF), tethrahydrofurane (THF), cyclohexanone, xylene, toluene, and acetone. Solvent mixtures can also be used as well. One representative examples of a suitable mixture is FLUX REMOVER AMS, a trade name of a solvent mixture manufactured by Tech Spray, Inc. of Amarillo, Tex. comprising about 93.7% of a mixture of 3,3-dichloro-1,1,1,2,2-pentafluoropropane and 1,3-dichloro-1,1,2,2,3-pentafluoropropane, and the balance methanol, with trace amounts of nitromethane.

In on embodiment, the agent or drug can be dissolved in the composition or dispersed in the composition in fine particles for manufacturing the reservoir layer and the finishing coating layer. The agent can include any substance capable of exerting a therapeutic or prophylactic effect in the practice of the present invention. The drug may include small molecule drugs, peptides, proteins, and oligonucleotides. One example of an agent that can be used by being incorporated into the reservoir layer or the finishing coating layer is estradiol. By way of example, the mass ratio between estradiol and the polymer can be between about 5:1 and 0.2:1 for the finishing coat layer and between about 1:2 and 1:0.6 for the reservoir layer. Examples of other drugs include those that fall under the genus of antiproliferative, antineoplastic, anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, antiallergic and antioxidant substances. Specific examples include actinomycin D, paclitaxel, docetaxel, methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride, mitomycin, sodium heparin, low molecular weight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein IIbilia platelet membrane receptor antagonist antibody, recombinant hirudin, angiopeptin, angiotensin converting enzyme inhibitors such as captopril, cilazapril or lisinopril, calcium channel blockers (such as nifedipine), colchicine, fibroblast growth factor (FGF) antagonists, fish oil (.omega.-3-fatty acid), histamine antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol lowering drug), monoclonal antibodies (such as those specific for Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors, suramin, serotonin blockers, steroids, thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), and nitric oxide. An example of an antiallergic agent is permirolast potassium. Other therapeutic substances or agents which may be appropriate include alpha-interferon, genetically engineered epithelial cells, rapamycin and structural derivatives or functional analogs thereof, such as 40-O-(2-hydroxy)ethyl-rapamycin (known by the trade name of EVEROLIMUS available from Novartis), 40-O-(3-hydroxy)propyl-rapamycin and 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin; tacrolimus and dexamethasone.

The drug can be also included in micro-depot areas of a stent. Different drugs can be used with the same stent. For example, paclitaxel can be loaded in the micro-depot areas, everolimus in the drug-reservoir layer, and dexamethasone in the finishing coat layer.

In accordance with another embodiment, the drug, such as estradiol, can be incorporated into a polymeric reservoir layer or the optional finishing coat layer in the form of particles of micron to sub-micron size. For example, the particles can have a diameter between about 0.5 and 4.0 .mu.m. The drug can be encapsulated into the particles, followed by suspending the particles in the polymer solution. The suspension can be then applied to the stent. By way of example, the mass ratio between micro- or nanoparticles and the polymer in the suspension can be within a range of between about 1:5 and 1:10.

The particles can be defined by spherical outer shells made of an encapsulating polymer which include an inside space filled with the drug. When the stent is in contact with body fluids, the polymer forming the outer shell of the particles can hydrolyze and degrade thus releasing the drug. The particles can be made by emulsion method according to techniques known to those having ordinary skill in the art. Examples of suitable encapsulating polymers include poly(glycolic acid) (PGA), poly(D-lactic acid)(PDLA), poly(L-lactic acid)(PLLA), poly(butylene terephtalate-co-ethylene glycol)(PBT-PEG), and mixtures thereof.

In accordance with one embodiment of the invention, the reservoir layer can have a variable thickness along at least a segment of the length of the stent. Referring to FIGS. 1A, 1B, and 1C (see Original Patent), there is illustrated a portion of the length of a stent substrate 10. An optional primer layer 12 can be deposited on an outer surface 14 of the substrate 10. The primer layer 12 should be free from any therapeutic substances so as to serve as an adhesive tie layer between the surface 14 of the stent, which is typically made from a metallic material such as stainless steel, and a reservoir layer 16. A first layer 16a for the reservoir layer 16 can deposited on the primer layer 12 followed by masking a portion of the first layer 16a. The masking can be accomplished by any variety of methods known to one having ordinary skill in the art, such as by a plastic tape. By way of example, at least 50% of the length of the first layer 16a can be covered, followed by the deposition of a second layer 16b. The steps of masking and deposition can be repeated to form any suitable number of sub-layers. FIGS. 1B and 1C (see Original Patent) illustrate additionally masking and deposition steps for forming third and forth layers 16c and 16d. Each sub layer 16a-16d can include the same drug, a different drug, or a different combination of drugs. In one embodiment, the more water soluble drugs can be incorporated in the more deeper areas of reservoir layer 16 (e.g., layers 16a or 16b) and the less water soluble drugs can be in the shallower regions (e.g., 16c or 16d).

When the last desired sub-layer of the reservoir layer 16 has been formed, the masking material is removed and discarded, and a topcoat layer 18 or a finishing coat layer 20 can be deposited on reservoir layer 16. If a topcoat layer is used, the finishing coat layer can be applied over the topcoat layer. FIG. 2 (see Original Patent) illustrates a cross sectional view of a segment of the end product of the coating configuration. As illustrated in FIG. 2, the reservoir layer 16 has a variable thickness along the longitudinal length of at least a segment of the stent, which provides for a concentration gradient for the drug in the reservoir layer 16. The thicker portions of the reservoir layer 16 will have a higher quantity of a drug or combination of drugs that the thinner portions. The thickness of the reservoir layer 16 increases from one region of the stent in a step-wise configuration towards a second region of the substrate 10. The addition of the topcoat layer 18 or a finishing coating layer 20, however, produces a planar topography for the finished product.

In accordance with one embodiment of the invention, a stent coating that develops cracks immediately upon expansion of the stent can be fabricated. This coating can be used if a high rate of release of the drug is desired. The cracks which typically develop across the entire coating may help to achieve such high rate of release by providing a channel through which the drug would easily and quickly diffuse from the drug-polymer layer through the topcoat membrane.

The coatings and methods of the present invention have been described in conjunction with a stent. The stent can be a balloon-expandable or self-expandable stent, or can include micro-depot areas to contain drugs. The use of the coating, however, is not limited to stents and the coating can also be used with a variety of other medical devices. Examples of the implantable medical device that can be used in conjunction with the embodiments of this invention include stent-grafts, grafts (e.g., aortic grafts), artificial heart valves, cerebrospinal fluid shunts, pacemaker electrodes, axius coronary shunts and endocardial leads (e.g., FINELINE and ENDOTAK, available from Guidant Corporation).

The underlying structure of the device can be of virtually any design. The device can be made of a metallic material or an alloy such as, but not limited to, cobalt-chromium alloys (e.g., ELGILOY), stainless steel (316L), "MP35N," "MP20N," ELASTINITE (Nitinol), tantalum, tantalum-based alloys, nickel-titanium alloy, platinum, platinum-based alloys such as, e.g., platinum-iridium alloy, iridium, gold, magnesium, titanium, titanium-based alloys, zirconium-based alloys, or combinations thereof. Devices made from bioabsorbable or biostable polymers can also be used with the embodiments of the present invention. "MP35N" and "MP20N" are trade names for alloys of cobalt, nickel, chromium and molybdenum available from Standard Press Steel Co. of Jenkintown, Pa. "MP35N" consists of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum. "MP20N" consists of 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum.
 

Claim 1 of 18 Claims

1. A stent having a coating, the coating comprising a first region including a thermoplastic polyacrylate material and a therapeutic substance and a second region free from any therapeutic substances disposed on the surface of the stent and beneath the first region, wherein the second region comprises a polymer selected from the group consisting of a fluorinated polymers, poly(ethylene-co-vinyl alcohol), polydioxanone, poly(glycolic acid-co-trimethylene carbonate), polyphosphoester, polyphosphoester urethane, polycyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), co-poly(ether-esters), polyalkylene oxalates, polyurethanes, silicones, polyisobutylene, ethylene-alphaolefin copolymers, vinyl halide polymers and copolymers, polyvinyl ethers, polyvinylidene chloride, polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics, ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, polyamides, alkyd resins, polyoxymethylenes, polyimides, polyethers, epoxy resins, polyurethanes, rayon, rayon-triacetate, fibrin, fibrinogen, cellulose, collagen, hyaluronic acid, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellophane, cellulose nitrate, cellulose propionate, cellulose ethers, and carboxymethyl cellulose.

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