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POLYACRYLATES COATINGS FOR
IMPLANTABLE MEDICAL DEVICES
This is a continuation-in-part of U.S. patent application Ser. No. 09/894,293, filed on Jun. 27, 2001, now abandoned.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention is directed to coatings for implantable medical devices, such as drug eluting vascular stents.
2. Description of Related Art
Percutaneous transluminal coronary angioplasty (PTCA) 15 is a procedure for treating heart disease. A catheter assembly having a balloon portion is introduced percutaneously into the cardiovascular system of a patient via the brachial or femoral artery. The catheter assembly is advanced through the coronary vasculature until the balloon portion is posi- 20 tioned across the occlusive lesion. Once in position across the lesion, the balloon is inflated to a predetermined size to radially compress against the atherosclerotic plaque of the lesion to remodel the lumen wall. The balloon is then deflated to a smaller profile to allow the catheter to be 25 withdrawn from the patient's vasculature.
A problem associated with the above procedure includes formation of intimal flaps or torn arterial linings which can collapse and occlude the conduit after the balloon is deflated. Moreover, thrombosis and restenosis of the artery may 30 develop over several months after the procedure, which may require another angioplasty procedure or a surgical by-pass operation. To reduce the partial or total occlusion of the artery by the collapse of arterial lining and to reduce procedure, which may require another angioplasty proce- 35 dure or a surgical by-pass operation. To reduce the partial or total occlusion of the artery by the collapse of arterial lining and to reduce the chance of the development of thrombosis and restenosis, a stent is implanted in the lumen to maintain the vascular patency. 40
Stents are used not only as a mechanical intervention but also as a vehicle for providing biological therapy. As a mechanical intervention, stents act as scaffoldings, functioning to physically hold open and, if desired, to expand the wall of the passageway. Typically, stents are capable of 45 being compressed, so that they can be inserted through small vessels via catheters, and then expanded to a larger diameter once they are at the desired location. Examples in patent literature disclosing stents which have been applied in PTCA procedures include stents illustrated in U.S. Pat. No. 4,733, 50 665 issued to Palmaz, U.S. Pat. No. 4,800,882 issued to Gianturco, and U.S. Pat. No. 4,886,062 issued to Wiktor.
Biological therapy can be achieved by medicating the stents. Medicated stents provide for the local administration of a therapeutic substance at the diseased site. In order to 55 provide an efficacious concentration to the treated site, systemic administration of such medication often produces adverse or toxic side effects for the patient. Local delivery is a preferred method of treatment in that smaller total levels of medication are administered in comparison to systemic 60 dosages, but are concentrated at a specific site. Local delivery thus produces fewer side effects and achieves more favorable results. One proposed method for medicating stents involves the use of a polymeric carrier coated onto the surface of a stent. A solution which includes a solvent, a 65 polymer dissolved in the solvent, and a therapeutic substance dispersed in the blend is applied to the stent. The
solvent is allowed to evaporate, leaving on the stent surface a coating of the polymer and the therapeutic substance impregnated in the polymer. The embodiments of the invention provide coatings for implantable devices, such as stents, and methods of coating the same.
A coating for an implantable medical device is provided, the coating comprises a thermoplastic polyacrylate material free from acetate species and a therapeutically active agent incorporated therein. The polyacrylate material can include homopolymers, copolymers or terpolymers of alkylacrylates or alkylmethacrylates, and blends thereof. The polyacrylate material can be poly(n-butyl methacrylate). The polyacrylate material can include non-acrylate polymers such as fluorinated polymers or poly(ethylene-co-vinyl alcohol).
According to another embodiment of this invention, a coating for an implantable medical device is provided, the coating comprises a first layer having an active agent incorporated therein and a second layer disposed over the first layer, wherein the second layer comprises a thermoplastic polyacrylate material for modifying the rate of release of the agent.
According to yet another embodiment of the invention, a method of coating an implantable medical device is provided, the method comprises depositing a first layer on the device, the first layer including an active agent for the sustained release of the agent, and depositing a second layer over the first layer, the second layer comprising a thermoplastic polyacrylate material for modifying the rate of release of the agent.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1 and 2 are graphs illustrating a profile of a rate of release of a drug from stents coated according to a method of the present invention.
A coating for an implantable medical device, such as a stent, according to one embodiment of the present invention, can include a drug-polymer layer, an optional topcoat layer, and an optional primer layer. The drug-polymer layer can be applied directly onto the stent surface to serve as a reservoir for a therapeutically active agent or drug which is incorporated into the drug-polymer layer. The topcoat layer, which can be essentially free from any therapeutic substances or drugs, serves as a rate limiting membrane which further controls the rate of release of the drug. The optional primer layer can be applied between the stent and the drug-polymer layer to improve the adhesion of the drug-polymer layer to the stent.
According to one embodiment of the present invention, polymers of esters having the general formula (I)
—[CH2—C(X") (COOR")t— (I)
or blends thereof, can be used for making the stent coatings.
In formula (I), X, X', and X" is each, independently, a hydrogen atom (acrylates) or an alkyl group, such as a methyl group CH3 (methacrylates); R, R' and R" is each, independently, a C1 to C12 straight chained or branched aliphatic radical; "m" is an integer larger than 1, and "n" and "p" is each 0 or an integer. If both n=0 and p=0, the polymer of formula (I) is a homopolymer (i.e., PBMA). If n^lO and
p=0, or n=0 and p*0, the polymer of formula (I) is a copolymer, and if n*0 and p*0, the polymer of formula (I) is a terpolymer.
Polymers of formula (I) can be used for making either the drug-polymer layer, the topcoat membrane, the optional 5 primer layer, or any combination thereof. For the purposes of the present invention, such polymers, or blends thereof, are defined as "polyacrylates" or as "polyacrylate materials."
One example of a polyacrylate suitable for fabricating 10 either the drug-polymer layer or the topcoat membrane is poly(n-butyl methacrylate) (PBMA), described by formula (I) where X=CH3, n=0, p=0, and "R" is a n-butyl radical C H9 (—CH2—CH2—CH2—CH3). PBMA has good biocompatibility, is soluble in many common solvents, has 15 good mechanical and physical properties, and adheres well to the underlying stent surface or the primer layer. PBMA is available commercially from Aldrich Chemical Co. of Milwaukee, Wis., and from Esschem, Inc. of Lynwood, Pa.
The rate of release of the drug through the polymer, such 2Q as the topcoat membrane, is related to the rate of diffusion of the drug through the matrix. The slower the rate of diffusion, the greater the polymer's ability to prolong the
PBMA is one of such polyacrylates having the Tg of about 20° C. Examples of other suitable polyacrylates having low Tg include poly(n-hexyl methacrylate) (T =-5° C.) and poly(methyl acrylate) (T ==9° C).
For a copolymer of these polyacrylates, the Tg (on the Kelvin scale) is generally the mass-fraction weighted average of the constituent components of the copolymer. Consequently, a copolymer or terpolymer of formula (I) with predetermined higher or lower value of Tg can be used as a drug-polymer layer and/or a topcoat membrane, thus providing a desirable lower or higher rate of release of the drug, respectively. For example, a random poly(methyl methacrylate-co-n-butyl methacrylate) [P(MMA-BMA)], having about 30 molar percent of methyl-methacrylate-derived units and about 70 molar percent of n-butyl-methacrylatederived units, has a theoretical Tg of about 45.50° C. Therefore, a topcoat membrane made of P(MMA-BMA) will provide faster drug release than pure PMMA but slower than pure PBMA. Similarly, blends of individual polyacrylates, e.g., PBMA and PMMA can be used.
Some examples of polyacrylates that are suitable for fabrication of the coating, e.g., the drug-polymer layer and/or the topcoat membrane, are summarized in Table 1.
rate of release and the residence time of the drug at the implantation site. The rate of diffusion is in turn related to the water adsorption rate, the degree of crystallinity, if any, 45 and the glass transition temperature (Jg) of the polymer.
As a general rule, the more water the polymer absorbs at body temperature, the faster the drug diffuses out of the polymer, and the greater the degree of crystallinity in the polymer's structure, the slower a drug will diffuse out of the polymer. Since all of the R, R and R" groups in these polyacrylates are aliphatic, water adsorption tends to be low. One common technique for producing these polymers is by free radical polymerization yielding amorphous polymers with no crystallinity. Hence, it is the glass transition temperature that is one of the important discriminating charac- 55 teristic for these polymers.
Consequently, the present invention allows manipulating the rate of release of the drug into the blood stream by varying Tg of the polymer or the blend of polymers forming the drug-polymer layer and/or the membrane. Typically, it is 60 desirable to decrease the rate of release. In order to do so, the polyacrylates having higher values of T can be used. Examples of such polyacrylates include poly(methyl methacrylate) (T =105° C.) and poly(tert-butyl methacrylate) (T ==107° C> 65
However, if it is desirable to increase the rate of release, the polyacrylates having low values of Tg can be used.
Only homo- and copolymers are listed in Table 1 (that is, the polymers of formula (I) where p=0), but it should be understood that terpolymers corresponding to formula (I) (when n*0 and p*0) can be used as well.
To fabricate the coating, one of the polyacrylates, or a blend thereof can be applied on the stent using commonly used techniques known to those having ordinary skill in the art. For example, the polyacrylate can be applied to the stent by dissolving the polymer in a solvent, or a mixture of solvents, and applying the resulting solution on the stent by spraying or immersing the stent in the solution.
Representative examples of some suitable solvents include N,N-dimethylacetamide (DMAC), N,N-dimethylformamide (DMF), tethrahydrofurane (THF), cyclohexanone, xylene, toluene, acetone, methyl ethyl ketone, propylene glycol monomethyl ether, methyl butyl ketone, ethyl acetate, n-butylacetate, and dioxane. Examples of suitable mixtures of solvents include mixtures of DMAC and methanol (e.g., a 50:50 by mass mixture), cyclohexanone and acetone (e.g., 80:20, 50:50, 20:80 by mass mixtures), acetone and xylene (e.g. a 50:50 by mass mixture), and acetone, FLUX REMOVER AMS, and xylene (e.g., a 10:50: 40 by mass mixture). FLUX REMOVER AMS is trade name of a solvent manufactured by Tech Spray, Inc. of Amarillo, Tex. comprising about 93.7% of a mixture of 3,3-dichloro5
1,1,1,2,2-pentafluoropropane and 1,3-dichloro-l, 1,2,2,3pentafluoropropane, and the balance methanol, with trace amounts of nitromethane.
In addition, blends of polyacrylates with polymers other than polyacrylates can be used to fabricate the coating. In 5 one embodiment, the blend of polyacrylates with nonacrylate materials is free from acetate species. Poly(ethylene-co-vinyl alcohol) (EVAL) is one example of a suitable non-acrylate polymer. EVAL has the general formula —[CH2—CH2]?—[CH2—CH(OH)] —, where "q" and "r" 1Q is each an integer. EVAL may also include up to 5 molar % of units derived from styrene, propylene and other suitable unsaturated monomers. A brand of copolymer of ethylene and vinyl alcohol distributed commercially under the trade name EVAL by Aldrich Chemical Co., or manufactured by EVAL Company of America of Lisle, 111., can be used. 15
Examples of other polymers with which polyacrylates can be blended include fluorinated polymers, such as poly(vinylidene fluoride) (PVDF) and poly(vinylidene fluoride-cohexafluoro propene) (PVDF-HFP). The blend of a polyacrylate and a fluorinated polymer can contain between about 10 20 and about 95% (mass) of the fluorinated polymer.
The polyacrylates can be used to manufacture the primer layer, drug-polymer layer, topcoat membrane, or all three layers. For example, the polyacrylates can be used to make both the drug-polymer layer and the topcoat membrane, but 25 not the primer layer. Any combination of the three layers can include a polyacrylate, so long as at least one of the layers includes the material. If a polyacrylate is used to make only one of the layers, the other layer or layers can be made of an alternative polymer. 30
Representative examples of suitable alternative polymers include EVAL, poly(hydroxyvalerate), poly(L-lactic acid), polycaprolactone, poly(lactide-co-glycolide), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid), 35 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, col- 40 lagen and hyaluronic acid), polyurethanes, silicones, polyesters, polyolefins, polyisobutylene and ethylenealphaolefin copolymers, acrylic polymers and copolymers other than polyacrylates, vinyl halide polymers and copolymers (such as polyvinyl chloride), polyvinyl ethers (such as 45 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), acrylonitrile-styrene copolymers, ABS resins, and ethylene- 50 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, cello- 55 phane, cellulose nitrate, cellulose propionate, cellulose ethers, and carboxymethyl cellulose.
The coating of the present invention has been described in conjunction with a stent. However, the coating can also be used with a variety of other medical devices. Examples of the implantable medical device, that can be used in con- 60 junction 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 65 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, tantalumbased alloys, nickel-titanium alloy, platinum, platinumbased 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.
The active agent or the drug can include any substance capable of exerting a therapeutic or prophylactic effect for a patient. The drug may include small molecule drugs, peptides, proteins, oligonucleotides, and the like. The active agent could be designed, for example, to inhibit the activity of vascular smooth muscle cells. It can be directed at inhibiting abnormal or inappropriate migration and/or proliferation of smooth muscle cells to inhibit restenosis. Examples of drugs include antiproliferative substances such as actinomycin D, or derivatives and analogs thereof. Synonyms of actinomycin D include dactinomycin, actinomycin IV, actinomycin I1; actinomycin X1; and actinomycin Cr The active agent can also fall under the genus of antineoplastic, anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, antiallergic and antioxidant substances. Examples of such antineoplastics and/or antimitotics include paclitaxel, docetaxel, methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin, hydrochloride, and mitomycin. Examples of such antiplatelets, anticoagulants, antifibrin, and antithrombins include sodium heparin, low molecular weight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran, D-phepro-arg-chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein Ilb/IIIa platelet membrane receptor antagonist antibody, recombinant hirudin, and thrombin. Examples of such cytostatic or antiproliferative agents include 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 (co-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.
Some embodiments of the present invention are illustrated by the following Examples.