Title:  Lubricious, drug-accommodating coating

United States Patent:  6,218,016

Assignee:  Medtronic AVE, Inc. (Santa Rose, CA)

Filed:  September 27, 1999

A coating is provided for a substrate comprising a polyisocyanate; an amine donor and/or hydroxyl donor; an isocyanatosilane adduct having terminal isocyanate groups and at least one hydrolyzable alkoxy group bonded to silicon; and optionally a polymer selected from the group consisting of polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, and polyacrylic acid. The coating can accommodate a drug so that when the coating is applied to a medical device, the medical device becomes drug-releasing when in contact with aqueous body fluid. A coated article as well as a method for preparing the coating is also provided.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

According to the present invention, a lubricious coating is formed by the reaction, on a substrate to be coated, of a mixture comprising a polyisocyanate; an amine donor and/or a hydroxyl donor; an isocyanatosilane adduct having terminal isocyanate groups and at least one hydrolyzable alkoxy group bonded to silicon; and a polymer selected from the group consisting of polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, and polyacrylic acid; in a solvent. The resulting coating is drug-accommodating and, when the optional hydrophilic polymer is incorporated into the mixture, becomes highly lubricious.

It is believed that the isocyanate functional groups of the polyisocyanate and isocyanatosilane react with the amine donor to form a polyurea network or with the hydroxyl donor to form a polyurethane network. Furthermore, the silane groups of the isocyanatosilane are believed to form covalent bonds with the substrate to which the coating is applied when cured in the presence of moisture to form a strongly adherent coating.

The coating mixture is prepared in solution by weighing the appropriate quantities of polyisocyanate; amine donor and/or hydroxyl donor; isocyanatosilane adduct; and a polymer selected from the group consisting of polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, and polyacrylic acid; and adding them into an appropriate mixing vessel. Additional solvents may be added to adjust the viscosity of the mixture. The choice of ingredients in the coating mixture also affects the physical properties of the overall coating. Solids contents in a range of from about 0.2 to about 2.5% are preferred. This solution is mixed well and then applied to an appropriate substrate such as catheter tubes, medical tubing introducers, polymer coated medical wires, stents, dilatation balloons, implants, prostheses, and penile inserts, by conventional coating application methods. Such methods include, but are not limited to, dipping, spraying, wiping, painting, solvent swelling, and the like.

The materials of construction of a suitable substrate include, but are not limited to, polymers, metal, glass, ceramics, composites, and multilayer laminates of the aforementioned materials.

The coatings of the present invention are drug-accommodating. As used herein, the term "drug accommodating" refers to the ability of the polymeric network of the coating to associate with a pharmaceutically active agent. The association of the polymeric network of the coating and a pharmaceutically active agent may be accomplished by any mode of molecular recognition or inclusion including, but not limited to, ionic interactions, hydrogen bonding and other dipole-dipole interactions, covalent attachment, interpenetration by solvent swelling, metal ion-ligand interactions, hydrophilic interactions, hydrophobic interactions including .pi.-.pi. stacking interactions, or any combination thereof.

The terms "pharmaceutically active agent", "biologically active compound", "active agent" and "drug" are used herein interchangeably and include pharmacologically active substances that produce a local or systemic effect in an animal. The terms thus means any substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease or in the enhancement of desirable physical or mental development and conditions in an animal. The term "animal" used herein is taken to include humans, sheep, horses, cattle, pigs, dogs, cats, rats, mice; birds; reptiles; fish; insects; arachnids; protists (e.g. protozoa); and prokaryotic bacteria.

The active agents that can be delivered according to the present invention include inorganic and organic drugs without limitation and include drugs that act on the peripheral nerves, adrenergic receptors, cholinergic receptors, nervous system, skeletal muscles, cardiovascular system, smooth muscles, blood circulatory system, synaptic sites, neuro-effector junctional sites, endocrine system, hormone systems, immunological system, reproductive system, skeletal system, autocoid systems, alimentary and excretory systems, histamine systems, and the like. The active drug that can be delivered for acting on these recipients includes, but is not limited to, anticonvulsants, analgesics, antiparkinsons, antiinflammatories, calcium antagonists, anesthetics, antimicrobials, antimalarials, antiparasitics, antihypertensives, antihistamines, antipyretics, alpha-adrenergic agonists, alpha-blockers, biocides, bactericides, bronchial dilators, beta-adrenergic blocking drugs, contraceptives, cardiovascular drugs, calcium channel inhibitors, depressants, diagnostics, diuretics, electrolytes, enzymes, hypnotics, hormones, hypoglycemics, hyperglycemics, muscle contractants, muscle relaxants, neoplastics, glycoproteins, nucleoproteins, lipoproteins, ophthalmics, psychic energizers, sedatives, steroids sympathomimetics, parasympathomimetics, tranquilizers, urinary tract drugs, vaccines, vaginal drugs, vitamins, collagen, hyaluronic acid, nonsteroidal anti-inflammatory drugs, angiotensin converting enzymes, polynucleotides, polypeptides, polysaccharides, and the like.

The present invention is particularly suitable for delivering polypeptide drugs which are water soluble. Exemplary drugs include, but are not limited to, insulin; growth factors, such as epidermal growth factor (EGF), insulin-like growth factor (IGF), transforming growth factor (TGF), nerve growth factor (NGF), platelet-derived growth factor (PDGF), bone morphogenic protein (BMP), fibroblast growth factor and the like; somatostatin; somatotropin; somatropin; somatrem; calcitonin; parathyroid hormone; colony stimulating factors (CSF); clotting factors; tumor necrosis factors; interferons; interleukins; gastrointestinal peptides, such as vasoactive intestinal peptide (VIP), cholecytokinin (CCK), gastrin, secretin, and the like; erythropoietins; growth hormone and GRF; vasopressins; octreotide; pancreatic enzymes; dismutases such as superoxide dismutase; thyrotropin releasing hormone (TRH); thyroid stimulating hormone; luteinizing hormone; LHRH; GHRH; tissue plasminogen activators; macrophage activator; chorionic gonadotropin; heparin; atrial natriuretic peptide; hemoglobin; retroviral vectors; relaxin; cyclosporin; oxytocin; and peptide or polypeptide vaccines. Other particularly suitable drugs include polysaccharide including, but not limited to, hyaluronic acid.

Preferred drugs include anti-thrombogenics, such as heparin and heparin complexes, enoxaprin, aspirin and hirudin; anti-proliferatives, such as monoclonal antibodies capable of blocking smooth muscle cell proliferation, heparin, angiopeptin and enoxaprin; and antioxidants, such as nitric oxide.

Preferred heparin complexes include, but are not limited to, heparin-tridodecylmethylammonium chloride, heparin-benzalkonium chloride, heparin-steralkonium chloride, heparin-poly-N-vinyl-pyrrolidone, heparin-lecithin, heparin-didodecyldimethylammonium bromide, heparin-pyridinium chloride, and heparin-synthetic glycolipid complex.

A preferred embodiment of the present invention involves contacting a medical device having a lubricious, drug-accommodating, coating of the invention with an aqueous solution containing a pharmaceutically active agent dissolved or dispersed therein. A hydrophilic polymer coating, or other cellular polymeric coating, when exposed to a solution of an active agent, such as an aqueous solution of heparin, will swell to contain the solution. Upon drying and/or vacuum removal of the solvent, what is left behind is a coated substrate surface which contains the active agent (e.g., heparin) in an inwardly decreasing concentration gradient of an interpenetrating polymeric network. The resulting coating becomes drug releasing when exposed to, and consequently re-hydrated or at least partially dissolved with, aqueous biological fluids.

Another preferred embodiment of the present invention is directed to contacting a medical device having a drug-accommodating coating of the invention with a pharmaceutically active agent capable of forming a covalent bond with one or more functional groups within the polymeric network, such that the pharmaceutically-active agent becomes bound to the coating. In a most preferred embodiment, the nucleophilic nitrogen atoms of the polyurea network are allowed to react with an organic or inorganic compound to form a covalent bond. The resulting coating-active agent bond preferably cleaves to release the active agent when used on a medical device in an environment which can cleave the bond. For example, for covalent bonds subject to cleavage by hydrolysis, the coating becomes drug-releasing in an aqueous environment. For enzymatically-cleavable bonds, the coating becomes drug-releasing in the presence of a suitable enzyme.

An especially preferred active agent for association or bonding to the drug-accommodating coating of the present invention is nitric oxide (NO). Physical association or bonding of an N₂ O₂ or N₂ O₂- functional group to the polymeric network may be achieved by covalent attachment of a nucleophilic moiety of the polymeric coating with N₂ O₂. The nucleophilic residue to which the N₂ O₂ or N₂ O₂ group is attached may form part of the polymer itself, i.e., part of the polymer backbone, or attached as pendant groups on the polymer backbone. The manner in which the N₂ O₂ or N₂ O₂- functional group is associated, part of, or incorporated with or contained within, i.e., "bound," to the polymer is inconsequential to the present invention and all means of association, incorporation and bonding are contemplated herein.

The NO-releasing N₂ O₂ or N₂ O₂- functional group is preferably a nitric oxide/nucleophile adduct, e.g., the reaction product of nitric oxide and a nucleophile. The nucleophilic residue is preferably that of a primary amine, a secondary amine, a polyamine or derivatives thereof. Most preferably, the nucleophilic adduct is a urea derivative, such as the polyurea network formed by the reaction of the amine donor with the polyisocyanate and/or isocyanatosilane of the coating composition.

The nitric oxide-releasing N₂ O₂ or N₂ O₂- functional groups that are bound to the polymer generally are capable of releasing nitric oxide in an aqueous environment such as body fluid, i.e., they do not require activation through redox or electron transfer. While the polymer-bound NO-releasing coating compositions of the present invention are capable of releasing NO in an aqueous solution, such a composition preferably releases NO under physiological conditions.

After applying the coating solution to a substrate, the solvent is preferably allowed to evaporate from the coated substrate, such as by exposure to ambient conditions for at least 5 minutes.

The coating is subsequently cured. The cure time, temperature, and humidity vary with the choice of solvent, polyisocyanate; polyol and polyamine; isocyanatosilane adduct; and the composition of the substrate. The curing rate may be increased by the addition of small amounts water to the coating mixture prior to applying the coating to the substrate.

Cure temperatures may range from about 75^oF. to about 350^oF. Cure times may range from about 2 minutes to about 72 hours, depending upon the solvent, cure temperature and the reactivity of the polyisocyanate, amine donor, and isocyanatosilane adduct. Preferred cure conditions are about 150^oF. to about 220^oF. for about 20 minutes to about 8 hours. In all cases the cure conditions should be non-deleterious to the underlying substrate.

After the coating is cured, it is preferable to rinse or soak the coating in water to remove any uncomplexed polymers. Generally, a brief rinse of 10-15 seconds is sufficient, however, a longer rinse or soak is acceptable since the coating is cured and forms a stable gel when in contact with water. After rinsing, the coating may be dried either at ambient conditions, or at elevated temperatures or combinations thereof at reduced pressure.

After the coating is formed, the coating can imbibe water from an aqueous solution prior to introduction to the body and can become lubricious. Alternatively, the coating can imbibe water solely from body fluids, even if not exposed to water prior to introduction into the body. Because the coating is a cross-linked system, it adheres well to the substrate even when hydrated. The coating retains its lubricating properties even after subsequent drying and rehydration. If the coating is to be used in a body-related application, such as in catheters, introducer tubes and the like, the materials selected should be compatible with the body and non-toxic to the body. Biocompatible materials include, but are not limited to, polyethylene, polypropylene, polyurethane, naturally occurring polymers, stainless steel and other alloys.

The coating may be applied to various substrates, including, but not limited to, metals, ceramics, polymers, and glass.

The coating may be applied to metal substrates such as the stainless steel used for guide wires, stents, catheters and other devices.

Organic substrates which may be coated with the coatings of this invention include, but are not limited to, polyether block amide, polyethylene terephthalate, polyetherurethane, polyesterurethane, other polyurethanes, natural rubber, rubber latex, synthetic rubbers, polyester-polyether copolymers, polycarbonates, and other organic materials. Some of these materials are available under various trademarks such as Pebax.TM. available from Atochem, Inc. of Glen Rock, N.J.; Mylar.TM. available from E. I. duPont deNemours and Co. of Wilmington, Del.; Texin.TM. 985A from Bayer Corporation of Pittsburgh, Pa.; Pellethane.TM. available from Dow Chemical of Midland, Mich.; and Lexan.TM. available from General Electric Company of Pittsfield, Mass.

The polyisocyanate is preferably an aromatic polyisocyanate. More preferably, the polyisocyanate is an aromatic polyisocyanate based on toluene diisocyanate and is dissolved in propylene glycol monomethyl acetate and xylene. Preferably, the amount of polyisocyanate ranges from about 0.2 to about 10 percent by weight based upon 100% total weight of coating mixture. Particularly preferred polyisocyanates include m-xylylene diisocyanate, m-tetramethylxylylene diisocyanate known as meta-TMXDI available from Cytec Industries, Inc., Stamford, Conn., and the aromatic polyisocyanate known as Desmodur CB 60N available from Bayer Corporation, Pittsburgh, Pa.

Examples of suitable amine donors which may be incorporated in the mixture in addition to or in lieu of a hydroxyl donor include, but are not limited to, C₁ -C₁₀ cycloalkyl, alkyl and alkenyl monoamines such as methylamine, ethylamine, diethylamide, ethylmethylamine, triethylamine, n-propylamine, allylamine, isopropylamine, n-butylamine, n-butylmethylamine, n-amylamine, n-hexylamine, 2-ethylhexylamine, cyclohexylamine, ethylenediamine, polyethyleneamine, 1,4-butanediamine, 1,6-hexanediamine, N-methylcyclohexylamine and alkylene amines such as ethyleneimine. Preferred amine donors include triethylene glycolamine which has the formula H₂ NCH₂ CH₂ OCH₂ CH₂ OCH₂ CH₂ NH₂ and an approximate molecular weight of about 148 available as Jeffamine.TM. XTJ-504 from Huntsman Corp., Salt Lake City, Utah; polyetherdiamines such as Jeffamine.TM. XTJ-500 and XTJ-501 which have a predominantly polyethylene oxide backbone and an approximate molecular weight of 600 and 900, respectively, available from Huntsman Corp., Salt Lake City, Utah; polyethertriamines such as Jeffamine.TM. T-403 which is a polypropylene oxide-based triamine and has an approximate molecular weight of 440 available from Huntsman Corp., Salt Lake City, Utah; and amine terminated polypropyleneglycols such as Jeffamine.TM. D-400 and Jeffamine.TM. D-2000 which have approximate molecular weights of 400 and 2000, respectively. Other amine donors include urethane modified melamine polyols containing amine and hydroxyl groups available as Cylink HPC.TM. from Lytec Industries, West Patterson, N.J.

The hydroxyl donor is preferably a polyol. Polyols useful in this invention may be any of a large number of polyols reactive with the polyisocyanate and isocyanatosilane to form a polyurethane network. Examples of suitable polyols include, but are not limited to, polyester polyols, polyether polyols, modified polyether polyols, polyester ether polyols, castor oil polyols, and polyacrylate polyols, including Desmophen.TM. A450, A365, and A160 available from Bayer Corporation, Pittsburgh, Pa. Preferred polyols include castor oil derivatives (triglyceride of 12-hydroxyoleic acid) such as DB oil, Polycin.TM. 12, Polycin.TM. 55, and Polycin.TM. 99F available from CasChem, Inc. of Bayonne, N.J. More preferably, the polyol is polyester based, such as Desmophen.TM. 1800. Suitable diols include, but are not limited to, poly(ethylene adipates), poly(ethyleneglycol adipates), polycaprolactone diols, and polycaprolactone-polyadipate copolymer diols, poly(ethyleneterephthalate) polyols, polycarbonate diols, polytetramethylene ether glycol, ethyleneoxide adducts of polypropylene triols. Suitable products include Desmophen.TM. 651A-65, 1300-75 and 800 available from Bayer Corporation of Pittsburgh, Pa., Niax.TM. E-59 and others available from Union Carbide of Danbury, Conn., Desmophen.TM. 550DU, 1600U, 1920D, and 1150 available from Bayer Corporation. Many other polyols are available and may be used as known to those skilled in the art.

Coating solutions containing amine donors are typically easier to process, quicker to cure, and form more rigid, lower viscosity coatings than coating solutions containing hydroxyl donor and no amine donor. Coating solutions containing amine donors, however, typically have a shorter pot life and form less flexible coatings than coating solutions containing hydroxyl donors.

Hydroxyl donors in the coating solution cause the formation of polyurethane. In contrast, amine donors in the coating solution cause formation of a polyurea network. A polyurea network may provide better biocompatibility and stability than a polyurethane network since chain cleavage does not occur. Further, polyurea networks typically have better network properties, such as fatigue resistance, than polyurethane networks.

The amount of hydroxyl and amine donor in the coating mixture may be varied to obtain desirable surface properties for the coating. For example, the amine donor may be varied to obtain a desired lubricity. Preferably, the amount of hydroxyl donor ranges from about 0.2 to about 10 percent by weight and the amount of amine donor ranges from about 0.2 to about 10 percent by weight based upon 100% total weight of coating mixture.

Preferably, the polymer selected from the group consisting of polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, and polyacrylic acid is polyethylene oxide. More preferably, the polymer is polyethylene oxide having a molecular weight of about 300,000, such as Polyox.TM. available from Union Carbide Corp of South Charleston, W. Va. The polymer preferably has a mean molecular weight of from about 100,000 to about 2,000,000, Preferably, the amount of the polymer ranges from about 0.2 to about 20 percent by weight based upon 100% total weight of coating mixture. Reduction of the concentration of the water soluble polymer in the coating matrix will increase the amine concentration in the polymer, thereby increasing the number of nucleophilic amine sites available for reaction with a pharmaceutically-active agent, e.g., by nitrosylation with N₂ O₂.

The isocyanatosilane adduct has one or more unreacted isocyanate functional groups. An isocyanatosilane having two or more unreacted isocyanate functional groups may be produced by reacting a silane, such as aminosilane or mercaptosilane, with polyisocyanate. The isocyanatosilane has at least one hydrozable alkoxy bonded to silicon. Preferably, the amount of isocyanatosilane ranges from about 0.1 to about 10 percent by weight based upon 100% total weight of coating mixture.

The solvent should not react with the polyisocyanate; amine donor; hydroxy donor; polymer selected from the group consisting of polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, and polyacrylic acid; or isocyanatosilane adduct but is a solvent for all the components of the mixture. The solvent is preferably free of reactive amine, hydroxyl and carboxyl groups. Suitable solvents include, but are not limited to, methylene chloride, tetrahydrofuran (THF), acetonitrile, chloroform, dichloroethane, dichloroethylene, and methylene bromide. Preferably, the solvent is acetonitrile and THF, especially with a ratio of acetonitrile to THF of about 3:1.

Wetting agents may be added to the coating solution to improve wettability to hydrophobic surfaces. Wetting agents include, but are not limited to, fluorinated alkyl esters, such as Fluorad.TM. FC-430 available from 3M Corp., and octylphenol ethylene oxide condensates, such as Triton.TM. X-100 available from Union Carbide. A preferred concentration of wetting agent in the coating solution is from about 0.01 to about 0.2% by weight based upon 100% solids in the coating solution.

Viscosity and flow control agents may be added to the coating mixture to adjust the viscosity and thixotropy of the mixture to a desired level. Preferably, the viscosity is such that the coating may be formed on the substrate at the desired thickness. Viscosities of from about 50 cps to about 500 cps may be used although higher or lower viscosities may be useful in certain instances. Viscosity control agents include, but are not limited to, fumed silica, cellulose acetate butyrate, and ethyl acrylate/2-ethyl hexyl acrylate copolymer. Flow control agents are preferably present in amounts of from about 0.05 to about 5 percent by weight based upon 100% total weight of coating mixture.

Antioxidants may be added to the coating mixture to improve oxidative stability of the cured coatings. Antioxidants include, but are not limited to, tris(3,5-di-t-butyl-4-hydroxybenzyl)isocyanurate, 2,2'-methylenebis(4-methyl-6-t-butylphenol), 1,3,5-trimethyl-2,4,6-tris(3,5-di-t-butyl-4-hydroxybenzyl)benzene, butylhydroxytoluene, octadecyl 3,5-di-t-butyl-4-hydroxyhydrocinnamate, 4,4 methylenebis(2,6-di-butylphenol), p,p'-dioctyl diphenylamine, and 1,1,3-tris-(2-methyl-4-hydroxy-5-t-butylphenyl)butane. Antioxidants are preferably present in amounts from 0.01 to 1 percent by weight based upon 100% total weight of coating mixture.

Conventional pigments may be added to the coating mixture to impart color or radiopacity, or to improve the appearance of the coatings.

Air release agents or defoamers which are optionally included in the coating solution include, but are not limited to, polydimethyl siloxanes, 2,4,7,9-tetramethyl-5-decyn-4,7-diol, 2-ethylhexyl alcohol, and n-beta-aminoethyl-gamma-amino-propyl-trimethoxysilane. Air release agents are preferably added in amounts from 0.005 to 0.5 percent by weight based upon 100% total weight of coating mixture.

Claim 1 of 38 Claims

What is claimed is:

1. A drug-releasing coating, comprising:

at least one drug associated with and releasable from a polyurea network formed from the reaction on a substrate to be coated of a mixture comprising:

(a) a polyisocyanate;

(b) an amine;

(c) an isocyanatosilane adduct having at least one terminal isocyanate group and at least one hydrolyzable alkoxy group bonded to silicon; and optionally

(d) a polymer selected from the group consisting of polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, and polyacrylic acid.

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