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.

BACKGROUND OF THE INVENTION
 1. Field of the Invention
 This invention relates generally to a lubricious, drug-accommodating,
 coating which may be applied to a substrate in one step. More
 particularly, the invention relates to a drug-coating complex which is
 drug-releasing in physiological media. The invention also relates to a
 method for the production of a lubricious coating and the use thereof as a
 drug eluting or drug releasing coating.
 2. Related Art
 It has long been known that hydrophilic coatings with low friction
 (coefficient of friction of 0.3 or less) are useful for a variety of
 medical devices such as catheters, catheter introducers and the like. When
 low friction surfaces are used, the devices, upon introduction into the
 body, slide easily within arteries, veins and other body orifices and
 passageways. There have been a wide variety of methods used to provide the
 surfaces desired. In some cases the material of the catheter or medical
 device is formed of a material having good anti-friction properties such
 as poly(tetrafluoroethylene) or other plastics which tend to avoid
 abrasion with the body. However, in many cases the selection of materials
 does not provide the anti-slip properties desired in conjunction with
 other desirable properties for the particular medical device.
 Prior art hydrophilic coatings typically rely on a two step, two coating
 process, usually involving a primer coat of isocyanate or
 isocyanate/polymer blend which is dried, followed by a second coat
 containing at least one hydrophilic polymer such as polyvinyl pyrrolidone
 or polyethylene oxide. The two coatings, one superimposed on the other,
 are then baked to effect a cure. This forms an interpolymer complex or a
 network including the hydrophilic polymer. Several disadvantages to this
 process exist.
 First, the exact ratio of primer material to the hydrophilic polymer is
 difficult to control, as it depends on whatever amounts of primer and
 hydrophilic polymer happen to be deposited by the wet film during the
 respective coating steps. Second, the primer may begin to redissolve in
 the second coating solution, causing some loss of primer and further
 resulting in difficulty in controlling the primer/hydrophilic polymer
 ratio. Third, the hydrophilic polymer is not covalently bonded to the
 substrate and may bond to other materials in the area leading the coating
 to lose its desired properties. Fourth, additional facilities and time are
 needed for coating with a two step process, as compared to a one step
 process.
 Prior patents have suggested applying solutions of polyvinylpyrrolidone
 with isocyanate and/or polyurethane in multi-step operations. These
 coatings often lack good durability. For example, U.S. Pat. No. 4,585,666
 issued to Lambert discloses medical devices having hydrophilic coatings
 formed from an isocyanate layer overcoated with a polyvinylpyrrolidone
 layer. However, the multistep procedure makes it difficult to tailor the
 properties and values of the final coatings.
 U.S. Pat. No. 4,625,012, Rizk et al., describes a one step method for
 preparing moisture curable polyurethane polymers having pendant
 alkoxysilane groups and isocyanate terminals on a substrate. The method
 includes reacting an isocyanatosilane adduct and an isocyanate different
 from the isocyanatosilane with a polyol. The isocyanatosilane adduct and
 the isocyanate have at least two isocyanato groups each. Furthermore, the
 isocyanatosilane is produced by reacting an isocyanate having at least
 three isocyanato groups with an organofunctional alkoxysilane. The coating
 formed, however, is not lubricious.
 In U.S. Pat. No. 4,373,009, Winn, a coating process for preparing a
 lubricious coating is disclosed. A coupling agent is first applied to the
 substrate. A coating is then applied on top of the coupling agent. The
 coupling agent bonds the coating to the substrate. Although the coupling
 agent and coating may be applied to the substrate from the same solution,
 the preferred method is to apply them separately.
 U.S. Pat. No. 5,645,931, Fan et al., describes a one step coating process
 for preparing a thromboresistant lubricious coating. The coating is
 comprised of a substantially homogeneous composite of polyethylene oxide
 and polyisocyanate in an inert solvent. However, the one step coating
 process is only suitable for polymeric substrates.
 U.S. Pat. No. 5,662,960, Hostettler et al., describes a process for
 producing slippery, tenaciously adhering hydrogel coatings containing a
 polyurethane-polyurea (PU/PUR) hydrogel commingled with a poly(N-vinyl
 pyrolidone) hydrogel. The coating may be applied on plastic, rubber, or
 metallic substrates. However, the process is performed in several steps.
 Initially, plastic substrates are activated by oxidative chemical
 treatments and plasma treatments with oxygen or nitrogen containing plasma
 gases. Metallic substrates are treated with aminosilane primers. Then, a
 base coat of PU/PUR hydrogel is applied to the substrate followed by the
 application of a coat of a second hydrogel.
 Exposure to a medical device which is implanted or inserted into the body
 of a patient can cause the body tissue to exhibit adverse physiological
 reactions. For instance, the insertion or implantation of certain
 catheters or stents can lead to the formation of emboli or clots in blood
 vessels. Similarly, the implantation of urinary catheters can cause
 infections, particularly in the urinary tract. Other adverse reactions to
 medical devices include inflammation and cell proliferation which can lead
 to hyperplasia, occlusion of blood vessels, platelet aggregation,
 rejection of artificial organs, and calcification.
 To counter the adverse reactions which often accompany a medical implant or
 insert, pharmaceutically-active agents have been applied to or embedded
 within medical devices by covering the surface with a coating containing
 the active agent. Accordingly, medical device coatings are known which
 release a pharmaceutically-active agent via dissolution of the active or
 by cleavage of the active from the coating. Other drug-releasing coatings
 operate by hydrolyzing or otherwise cleaving a coating-active agent bond.
 One approach to the incorporation of a pharmaceutically active agent into a
 polymeric network is to absorb the active agent into the coating from a
 solution. Hydrophilic polymers in contact with an aqueous solution of an
 active agent, such as by soaking the polymer in a solution of the active
 agent, will swell to contain the solution and absorb the active agent
 dissolved therein. Upon drying, the polymeric network includes the
 associated active agent. The use of such a polymeric network as a coating
 for a medical device allows for the association and immobilization of a
 water soluble active agent with and/or within the medical device. The
 active agent can then be released from the coating upon contact with
 aqueous body fluids.
 Another approach to the association of a pharmaceutically-active agent with
 a polymeric coating is by chemical attachment, e.g., covalent attachment,
 of the active agent to the coating. For example, coating compositions are
 known which include a nitric oxide-releasing functional group bound to a
 polymer. U.S. Pat. Nos. 5,676,963 and 5,525,357 disclose such polymeric
 coating compositions.
 Nitric oxide (NO), has been implicated in a variety of bioregulatory
 processes, including normal physiological control of blood pressure,
 macrophage-induced cytostasis and cytoxicity, and neurotransmission. NO
 inhibits the aggregation of platelets. NO also reduces smooth muscle
 proliferation, which is known to reduce restenosis. Consequently, NO can
 be used to prevent and/or treat complications such as restenosis and
 thrombus formation when delivered to treatment sites inside an individual
 that have come in contact with synthetic medical devices.
 Nitric oxide appears to play a primary role in the development of an
 erection and the controllable and predictable release of NO to the penis
 by a catheter or other delivery means coated with or made of a
 NO-releasing polymer is described in U.S. Pat. No. 5,910,316.
 Because nitric oxide, in its pure form, is a highly reactive gas having
 limited solubility in aqueous media, it is difficult to introduce in a
 reliable and controllable form. NO is too reactive to be used without some
 means of stabilizing the molecule until it reaches the treatment site.
 Thus, NO is generally delivered to treatment sites in an individual by
 means of polymers and small molecules which release NO.
 The present invention combines the benefits of a lubricious coating with
 the therapeutic and prophylactic benefits associated with a drug-releasing
 coating by providing a one step coating which can be made lubricious
 and/or drug-accommodating and which may be applied in a single step,
 alleviates the need for a primer or coupling agent, and can be applied on
 various substrates, including, but not limited to, polymers and metals.
 SUMMARY OF THE INVENTION
 One aspect of the present invention is directed to a coated substrate
 comprising (a) a substrate; and (b) a polyurea and/or polyurethane network
 capable of accommodating a pharmaceutically-active agent, said polyurea
 and/or polyurethane network formed from the reaction, on at least a
 portion of the surface of said substrate to be coated, of a mixture
 comprising a polyisocyanate; an amine donor and/or a hydroxyl donor; an
 isocyanatosilane adduct having at least one terminal isocyanate group 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.
 It is a further aspect of the present invention to provide an article
 comprising a substrate on which a coating is formed comprising a polyurea
 and/or polyurethane network capable of accommodating a
 pharmaceutically-active agent, formed from 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
 optionally, a polymer selected from the group consisting of polyethylene
 oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, and
 polyacrylic acid; in a solvent.
 It is a further aspect of the present invention to provide a drug-releasing
 coating comprising an active agent associated with and releaseable from a
 polymeric network formed from the reaction, on a substrate to be coated,
 of a mixture comprising a polyisocyanate; an amine donor; and an
 isocyanatosilane adduct having terminal isocyanate groups and at least one
 hydrolyzable alkoxy group bonded to silicon; and optionally, a hydroxyl
 donor and/or a polymer selected from the group consisting of polyethylene
 oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, and
 polyacrylic acid; in a solvent.
 According to yet another aspect of the present invention, a method is
 provided of preparing a lubricious coating on a substrate to be coated
 comprising: forming a mixture of a polyisocyanate, an amine donor and/or a
 hydroxyl donor; a polymer selected from the group consisting of
 polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene
 glycol, and polyacrylic acid; and an isocyanatosilane adduct having
 terminal isocyanate groups and at least one hydrolyzable alkoxy group
 bonded to silicon, in a solvent; applying the mixture to the substrate;
 and curing the mixture on the substrate to form the coating.
 A further aspect of the present invention is to provide a method of
 preparing a drug-releasing coating on a substrate to be coated,
 comprising: forming a mixture of a polyisocyanate, an amine donor, an
 isocyanatosilane adduct having terminal isocyanate groups and at least one
 hydrolyzable alkoxy group bonded to silicon, and optionally a hydroxyl
 donor and/or a polymer selected from the group consisting of polyethylene
 oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, and
 polyacrylic acid, in a solvent; applying the mixture to the substrate;
 contacting the coated substrate with a pharmaceutically-active agent; and
 curing the mixture on the substrate to form the coating.
 It is a further aspect of the present invention to provide a drug-releasing
 coated article or medical device produced by or produceable by the coating
 method of the present invention.
 These and other features and objects of the invention are more fully
 appreciated from the following detailed description of a preferred
 embodiment of the invention.
 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 N.sub.2 O.sub.2 or N.sub.2
 O.sub.2.sup.- functional group to the polymeric network may be achieved by
 covalent attachment of a nucleophilic moiety of the polymeric coating with
 N.sub.2 O.sub.2. The nucleophilic residue to which the N.sub.2 O.sub.2 or
 N.sub.2 O.sub.2 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 N.sub.2 O.sub.2 or N.sub.2
 O.sub.2.sup.- 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 N.sub.2 O.sub.2 or N.sub.2 O.sub.2.sup.- 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 N.sub.2 O.sub.2 or N.sub.2 O.sub.2.sup.-
 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.degree. F. to about 350.degree.
 F. 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.degree. F. to about 220.degree. F. 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, C.sub.1 -C.sub.10 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 H.sub.2 NCH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2
 OCH.sub.2 CH.sub.2 NH.sub.2 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 N.sub.2 O.sub.2.
 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.

The following non-limiting example is meant to be an illustrative
 embodiment of the present invention.
 EXAMPLE 1
 A coating solution was prepared by combining the following ingredients and
 mixing them thoroughly:
 (a) 0.32 g. of an aromatic polyisocyanate adduct based on toluene
 diisocyanate and dissolved in propylene glycol monomethyl acetate and
 xylene having an NCO content of about 10.5% and a molecular weight of
 about 400 available as Desmodur.TM. CB 60 from Bayer Corporation;
 (b) 0.67 g. of a solvent-free, saturated polyester resin (polyol) available
 as Desmophen.TM. 1800 from Bayer Corporation;
 (c) 0.91 g. of polyethylene oxide available as Polyox.TM. having a
 molecular weight of about 300,000 from Union Carbide Corp.,
 (d) 76.97 g. acetonitrile;
 (e) 21.82 g. THF; and
 (f) 2.02 g. 3-isocyanyopropyltriethoxysilane available as UCTI7840-KG from
 United Chemical Technologies, Bristol, Pa.
 Five 18" inch wires were coated with the solution by dipping for 11
 seconds. The solvent was evaporated at ambient conditions for
 approximately 20 minutes. The wires were then placed in an oven at
 40.degree. C. for 10 hours to cure the coating.
 Upon removal from the oven, the wires were rinsed in water and dried.
 The coating was tested by ASTM D 1894-87 Standard Test Methods for Static
 and Kinetic Coefficients of Friction of Plastic Film and Sheeting.
 Having now fully described this invention, it will be understood to those
 of ordinary skill in the art that the same can be performed within a wide
 and equivalent range of conditions, formulations, and other parameters
 without affecting the scope of the invention or any embodiment thereof.
 All patents and publications cited herein are fully incorporated by
 reference herein in their entirety.