Coatings for implantable medical devices and methods for fabricating the same are disclosed. The coatings include a region containing a polycationic peptide, such as, for example, the polycationic peptide known as R7.

SUMMARY OF THE INVENTION

A coating for an implantable medical device, such as a stent, is disclosed. The coating comprises a region including a polycationic peptide and a region free from any polycationic peptides. The polycationic peptide can be poly(L-arginine), poly(D-arginine), poly(D,L-arginine), poly(L-lysine), poly(D-lysine), poly(.delta.-guanidino-.alpha.-aminobutyric acid), and a racemic mixture of poly(L-arginine) or poly(D-arginine). In one embodiment, the region including the polycationic peptide includes a hydrogel containing the polycationic peptide. The hydrogel can be fabricated of substances comprising carboxylated hydrocarbons, polycationic compounds, polyanionic compounds and mixtures thereof. In one embodiment, the region free from the polycationic peptide is positioned on the surface of the device and beneath the region including the polycationic peptide. In an alternative embodiment, the polycationic peptide can be encapsulated in particles in the coating.

A method for fabricating a coating for an implantable medical device, such as a stent, is also disclosed. The method comprises forming a coating on the device, the coating including a polycationic peptide; and treating the coating with a stimulus for enriching a region close to the outer surface of the coating with the polycationic peptide. In one embodiment, the treatment of the coating includes subjecting the device to a humid environment at a selected temperature, for example about 50.degree. C. at a humidity of about 100%. In another embodiment, the treatment can include subjecting the device to an electronic beam or to autoclaving.

A method of modifying a coating for an implantable medical device is disclosed. The method comprises exposing the coating, including a polycationic peptide to ethylene oxide at a selected temperature and conjugating poly(ethylene glycol) to the coating.

A method of fabricating a coating for a medical device is disclosed. The method comprises forming a coating on the device, the coating including a polycationic peptide, and causing some of the bonds of the peptide to be cleaved for increasing the population of the peptide in the coating.

A stent comprising a coating is also disclosed wherein the coating includes a peptide such that the population of the peptide is greater in the outermost region of the coating.

A method of fabricating a coated stent is also disclosed, comprising forming a coating on the stent wherein the coating includes a region containing a peptide and a region free from any peptides.

DETAILED DESCRIPTION OF THE INVENTION

The stent coating according to the embodiments of the present invention may have any one or combination of the following layers or regions in addition to the reservoir layer containing a therapeutic substance: a primer layer, a topcoat layer, and a finishing coat layer. The optional finishing coat layer may also include a drug or a therapeutic substance. The reservoir layer can be applied directly onto the stent surface, or optionally on the primer layer. The optional finishing coat layer can be applied on the topcoat layer and, when present, can be the outermost region of the stent coating. Subsequent to the implantation of the stent, the reservoir layer gradually releases the therapeutic substance.

One example of a drug or therapeutic substance that can be used is a polycationic peptide or a mixture of several polycationic peptides. Representative examples of suitable polycationic peptides include poly(L-arginine), poly(D-arginine), poly(D,L-arginine), poly(L-lysine), poly(D-lysine), poly(.delta.-guanidino-.alpha.-aminobutyric acid), racemic mixtures of poly(L-arginine) and poly(D-arginine), chitosan, and mixtures thereof. L-arginine, also known as R or 2-amino-5-guanidinovaleric acid, is an amino acid having a formula NH.dbd.C(NH.sub.2)--NH--CH.sub.2--CH.sub.2--CH.sub.2--CH(NH.sub.2)--COOH. Polymers and/or oligomers of L-, D-, and/or D, L-arginine that can be used are referred to in the present application as "PArg" and comprise a plurality of repeating monomeric amino acid units connected with peptide bonds. PArg has a general formula H[NH--CHX--CO].sub.p--OH (I) where "p" can be within a range of 5 and 1,000, or, within a range of between 6 and 20. For example, a heptamer (R7) (p=7), or a nonamer (R9) (p=9), can be used.

In formula (I), "X" represents 1-guanidinopropyl radical having the structure --CH.sub.2--CH.sub.2--CH.sub.2--NH--C(NH.sub.2).dbd.NH. The terms "polymers and/or oligomers of D-, L-, and/or D, L-arginine," "poly(L-arginine)," "poly(D-arginine)," "poly(D,L-arginine)," and "PArg" used in the present application are intended to include L-, D-, and/or D,L-arginine in both its polymeric and oligomeric form.

Poly(ethylene-co-vinyl alcohol) (EVAL) is one example of a polymer that can be used for any of the coating layers. EVAL is a product of hydrolysis of ethylene-vinyl acetate copolymers and has the general formula --[CH.sub.2--CH.sub.2].sub.m--[CH.sub.2--CH(OH)].sub.n--. EVAL may also include a terpolymer having up to about 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. of Milwaukee, Wis., can be used.

Other examples of polymers that can be used include polyacrylates, such as poly(butyl methacrylate) (PBMA), poly(ethyl methacrylate) (PEMA), and poly(ethyl methacrylate-co-butyl methacrylate) [P(EMA-BMA)]; fluorinated polymers and/or copolymers, such as poly(vinylidene fluoride) (PVDF) and poly(vinylidene fluoride-co-hexafluoro propene) (PVDF-HFP); and blends of polyacrylates and fluorinated polymers and/or copolymers. One example of the blend of a polyacrylate and a fluorinated polymer that can be used can contain between about 10 and about 95% (mass) of the fluorinated polymer.

Representative examples of other suitable polymers include 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.

A. A Solution or Suspension Method for Incorporating PArg into Stent Coatings

The coating can be formed on the stent by dissolving the polymer in a solvent, or a mixture of solvents, and applying the resulting polymer solution on the stent by spraying or immersing the stent in the solution. To incorporate PArg into the reservoir layer and/or the optional finishing coat layer, PArg in a form of a solution can be combined with the polymer solution.

Representative examples of some solvents suitable for making the polymer solution include N,N-dimethylacetamide (DMAC), N,N-dimethylformamide (DMF), tethrahydrofurane (THF), cyclohexanone, xylene, toluene, acetone, i-propanol, methyl ethyl ketone, propylene glycol monomethyl ether, methyl butyl ketone, ethyl acetate, n-butyl acetate, and dioxane. Some solvent mixtures can be used as well. Representative examples of the mixtures include:

(1) DMAC and methanol (e.g., 50:50 by mass mixture);

(2) water, i-propanol, and DMAC (e.g., 10:3:87 by mass mixture);

(3) i-propanol, and DMAC (e.g., 80:20, 50:50, or 20:80 by mass mixtures);

(4) acetone and cyclohexanone (e.g., 80:20, 50:50, or 20:80 by mass mixtures);

(5) acetone and xylene (e.g. 50:50 by mass mixture); and

(6) acetone, FLUX REMOVER AMS, and xylene (e.g., 10:50:40 by mass mixture).

FLUX REMOVER AMS is the trade name of a solvent 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 of methanol, with trace amounts of nitromethane. Those having ordinary skill in the art will select the solvent or a mixture of solvents suitable for a particular polymer being dissolved.

Instead of introducing PArg in a solution, PArg can be introduced as a colloid system, such as a suspension in an appropriate solvent phase. The suspension can be mixed with a polymer solution. One example of the solvent phase can be a mixture of water, i-propanol and DMAC, containing between about 3 and 6 mass % of water, between about 18 and 19% of i-propanol, and the balance, DMAC solvent.

After the stent coating has been formed, the stent can then be additionally treated to enrich the surface with PArg. Various techniques of treatment can be used depending on the kind of PArg and whether a finishing coat layer is used.

In one embodiment, the coated stent can be exposed to the environment of a humidifying chamber. This treatment is particularly useful for R7 or R9. The length of such treatment can be, for example, about 24 hours, at a temperature of about 50.degree. C. and relative humidity of about 100%. Any commercially available chamber can be used. As a result of the exposure of the stent to high humidity levels at elevated temperatures, the outermost surface of the coating is enriched with the peptide (e.g., R7 or R9).

If the finishing coat layer is not used, the stent can be treated after the reservoir layer containing the peptide (e.g., R7 or R9) has been applied, but prior to applying the topcoat layer. Consequently, as a result of the treatment, the surface of the drug-polymer layer gets enriched with the R7 or R9, followed by fabrication of the topcoat layer.

In another embodiment of the invention, the coated stent can be treated with high energy electronic beams. This method of treatment can be most effectively employed when the PArg is higher than nonamer, or in other words, in formula (I), p should be greater than about 20. For example, the PArg can have a weight-average molecular weight of about 5,000, corresponding to a "p" value of about 29. Under the influence of the electronic beam, the peptide bonds of PArg undergo cleavage, causing de-polymerization of PArg. Consequently, the population of the peptide (e.g., R7 or R9) in the stent coating increases. The length of the electronic beam treatment can be about 1 second. The standard equipment used for sterilization of the stents can be used, with the electronic beam having energy of about 2.5 MRad (25 kilograys).

Alternatively, instead of treatment with the electronic beam, the stent can be treated by autoclaving. High pressure and temperature in the autoclave will also cause de-polymerization of PArg leading to the enrichment of the stent coating with the sub-population of R7 or R9. The conditions of autoclaving will be selected by those having ordinary skill in the art.

In accordance with yet another embodiment, the coated stent can be sterilized at a high temperature, for example, above about 100.degree. C. During sterilization, PArg contained in the outermost layer of the stent coating can be exposed to ethylene oxide.

Under conditions of high temperature, the proton at the nitrogen atom of the peptide bond --NH--CO-- of PArg will be activated and will attack the oxyran ring of ethylene oxide causing the ring to open forming an ethylene glycol (--CH.sub.2--CH.sub.2--O--) moiety. As a result poly(ethylene glycol) (PEG) can be chemically bonded to the coating's surface. The path of the reaction can be shown as reaction (II):

##STR00001##

The high temperature treatment in the presence of ethylene glycol thus makes it possible to sterilize the stent and to simultaneously conjugate PEG, a biologically active substance, to the stent coating.

B. Incorporating PArg into Stent Coatings Using Hydrogels

PArg can be incorporated in the stent coating by using hydrogel technology. For example, a hydrogel can be prepared by mixing R7 and poly(glutamic acid) (PGlA). A R7: PGlA ratio can be between about 1:1 and 5:1. Instead of PGlA, other highly carboxylated hydrocarbons can be used in the alternative, for instance, polyalginate, sulfonated dextran, or mixtures thereof. A portion of PGlA or its alternatives can be replaced with other polycationic or polyanionic compounds. Examples of such polycationic or polyanionic compounds include PArg, polylysine, poly(dimethylaminoethyl methacrylate) (PDMAEM), poly(acrylic acid), and polysaccharides.

The hydrogel containing R7 can be mixed with the polymer solution forming the drug-polymer layer or the optional finishing coat layer. The hydrogel can be used to cause endothelialization. Those having ordinary skills in the art may also choose to use the hydrogel in applications not involving stent coatings. Examples of such applications include using the hydrogel in tissue sealants, with biological adhesives designed to accelerate healing, and with biocompatible viscosifiers such as hyaluronic acid or carboxymethyl cellulose.

C. Incorporating PArg into Stent Coatings Using Micro- or Nanoparticles

PArg can be incorporated in the stent coating by being first incorporated into particles of micron to sub-micron size (i.e., micro- or nanoparticles). For example, the particles can have diameter between about 0.5 and 4.0 .mu.m. The particles comprise a sphere-type outer shell made of an encapsulating polymer and an inside space filled with PArg. The particles can be made by an emulsion method according to techniques known to those having ordinary skill in the art. Examples of suitable encapsulating polymers having varying rates of hydrolysis include poly(glycolic acid) (PGA), poly(D-lactic acid) (PDLA), poly(L-lactic acid) (PLLA), poly(butylene terephthalate-co-ethylene glycol), PBT-PEG, and mixtures thereof.

The micro- or nanoparticles containing R7 can be suspended in the polymer solution forming the drug-polymer layer and/or the finishing coat layer and applied onto the stent. The peptide particles-to-polymer ratio can be within a range of between about 1:5 and 1:10. When the stent is in contact with body fluids, the polymer forming the outer shell of the particles will hydrolyze and degrade thus releasing the peptide, such as the R7.

The polycationic peptides can be introduced alone or blended with other active agent(s). Generally speaking, the active agent can include any substance capable of exerting a therapeutic or prophylactic effect in the practice of the present invention. Examples of agents include antiproliferative substances such as actinomycin D, or derivatives and analogs thereof. Synonyms of actinomycin D include dactinomycin, actinomycin IV, actinomycin II, actinomycin X.sub.1, and actinomycin C.sub.1. 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-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein IIb/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 (.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, derivatives and analogs of rapamycin, estradiol, clobetasol, and dexamethasone. Functional derivatives or structural analogs of the aforementioned drugs can also be used, such as any suitable derivative of rapamycin.

PArg can be synthesized as a dendritic (branched to a large degree) polymer which can fully envelop and thus host the active substance, more particularly cationic agents, leading to synergistic effects. Examples of the biologically active substances suitable of being hosted by PArg in the dendritic form include silver cation and sulfonyl amide.

The coatings and methods of the present invention have been described with reference to a stent, such as a balloon expandable or self-expandable stent. The use of the coating is not limited to stents, however, and the coating can also be used with a variety of other medical devices. Examples of implantable medical devices 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 22 Claims

1. A method for fabricating a coating for an implantable medical device, comprising: (a) forming a coating on the device, the coating including a polycationic peptide; and (b) treating the coating with a stimulus that cleaves peptide bonds for enriching a region close to the outer surface of the coating with the polycationic peptide.
 

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