Coating

Abstract

To provide a coating for a medical device.SOLUTION: To provide a lubricious or blood compatible coating for medical devices. The coating formulation comprises a base coat comprising a copolymer of a first tetrahydrofurfuryl acrylate monomer and a second monomer comprising at least one functional group capable of further derivatization, and a top coat polymer comprising more than two reactive sites per molecule.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (Related Applications) This application claims priority to U.S. Provisional Patent Application No. 62 / 879,287, filed July 26, 2019, the entire contents of which are incorporated herein by reference.

[0002] (Technical field) Described herein are coatings for medical devices and methods for applying those coatings. [Background technology]

[0003] Catheters and microcatheters are tubular devices used to perform diagnostic and therapeutic intravascular interventions. One purpose of a catheter is to maintain long-term vascular access, for example, to allow blood sampling or delivery of medications into the bloodstream. Catheters are often made of thermoplastic polymers with high friction. This high friction makes vascular navigation difficult. Furthermore, prolonged blood contact can lead to thrombosis, protein adsorption, and platelet activation. Providing a coated catheter or microcatheter with a lubricious coating as described herein would be useful and beneficial. Summary of the Invention [Means for solving the problem]

[0004] The coatings described herein can be applied to medical devices and the like that can be subjected to human tissue. In some embodiments, the coating can be applied to a medical device and used within a blood vessel or other lumen. In some embodiments, the vessel can be a blood vessel. In some embodiments, the medical device can be a catheter or microcatheter. In some embodiments, the medical device can be a central venous catheter or a dialysis catheter.

[0005] The coating can be synthetic, durable, and lubricious. In some embodiments, the coating can be ultraviolet (UV) cured. The lubricious coating can reduce and / or minimize friction between a medical device, such as a catheter or microcatheter, and the vessel wall, thereby enhancing the trackability of the medical device throughout the vasculature. The lubricious coating can also reduce or minimize thrombosis, protein adsorption, and platelet activation caused by contact between the medical device and the vessel. The catheter surface can be modified with a lubricious coating to reduce friction and enhance the catheter's maneuverability through tortuous or distal vessels.

[0006] In some embodiments, the coatings described herein can include two layers: a base coat and a top coat. The base coat acts as a tie layer between the thermoplastic polymer surface of the catheter and the top coat. The base coat is designed to adhere to the catheter and provide bonding sites for the top coat to adhere. The top coat is designed to adhere to the base coat and provide lubricity to reduce friction as the catheter moves within a blood vessel, improving the hemocompatibility of the catheter in the vascular environment. The top coat can be a synthetic or naturally derived small molecule, protein, glycosaminoglycan, or polymer.

[0007] In some embodiments, the coating can include: a basecoat comprising a copolymer of a first tetrahydrofurfuryl acrylate monomer and a second monomer comprising a functional group amenable to further derivatization and multiple reactive moieties, and a topcoat comprising more than two reactive moieties per molecule.

[0008] Also described is a method for coating a thermoplastic surface, such as the surface of a catheter or microcatheter, that can include applying a basecoat to the thermoplastic surface, the basecoat including a copolymer of a first tetrahydrofurfuryl acrylate monomer and a second monomer, and applying a topcoat to the basecoat, the topcoat including a topcoat polymer that includes more than two reactive sites per molecule.

[0009] Also described are methods of administering a catheter to a subject in need thereof, wherein the catheter is as described herein. The method includes inserting the catheter into the subject and removing the catheter in a time that is about 10% to about 200% longer than the removal time of a catheter without the coating described herein.

[0010] Also described is a method of providing vascular access to a subject in need thereof, comprising inserting into the subject a catheter described herein.

[0011] Also described are methods of withdrawing bodily fluids from a subject in need thereof, comprising inserting a catheter described herein into the subject and withdrawing bodily fluids (e.g., blood) from the subject. The methods can include repeatedly or continuously withdrawing bodily fluids without repeatedly inserting the catheter.

[0012] Also described are methods of administering an agent (e.g., a therapeutic or diagnostic agent) to a subject in need thereof, comprising inserting a catheter described herein into the subject and administering the agent to the subject via the catheter. The methods can include repeatedly or continuously administering the agent without repeated insertion of the catheter.

[0013] The methods described herein can insert a catheter into a subject and remove the catheter in about 10% to about 200% longer (e.g., about 10%, about 20%, about 30%, about 40%, about 50%, about 75%, about 100%, about 125%, about 150%, about 175%, or about 200%) than the time it takes to insert a catheter into a subject and remove a catheter without the coating described herein. DETAILED DESCRIPTION OF THE INVENTION

[0014] (Detailed Description of the Invention) Described herein are coatings for medical devices. In some embodiments, the coatings can enhance the lubricity of the medical device. In some embodiments, the coatings can enhance the hemocompatibility of the medical device. These medical devices can include catheters and microcatheters formed at least in part from thermoplastic polymers / materials. Thermoplastic polymers include, but are not limited to, poly(amide), poly(ethylene terephthalate), poly(urethane), poly(ether sulfone), poly(carbonate), poly(vinyl chloride), copolymers and derivatives thereof.

[0015] These thermoplastic polymers have high frictional forces, which make vascular navigation difficult. Therefore, the coatings described herein can increase the lubricity of the thermoplastic polymer surface. Furthermore, these thermoplastic polymers may lack or have poor hemocompatibility. Therefore, the coatings described herein can increase the hemocompatibility of the thermoplastic polymer surface. In some embodiments, the coating can include a base coat and a top coat. The base coat serves as a bonding layer between the thermoplastic polymer of the catheter and the top coat. The base coat is designed to adhere to the catheter and provide bonding sites for the top coat. The top coat is designed to adhere to the base coat and provide lubricity to reduce frictional forces as the catheter moves within a blood vessel or to improve hemocompatibility when placed within a blood vessel.

[0016] In some embodiments, the base coat includes a polymer that is a copolymer of a first tetrahydrofurfuryl acrylate monomer and at least one other monomer having a functional group capable of further chemical reaction, such as a hydroxyl, amine, or carboxylic acid group. In some embodiments, the at least one other monomer containing a hydroxy group can be hydroxyethyl methacrylate, hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxypropyl methacrylate, hydroxybutyl acrylate, hydroxybutyl methacrylate, combinations thereof, and derivatives thereof. In some embodiments, the at least one other monomer containing an amino group can be N-(3-aminopropyl)methacrylamide, 2-aminoethyl methacrylate, 2-aminoethyl methacrylamide, combinations thereof, and derivatives thereof. In some embodiments, the at least one other monomer containing a carboxylic acid can be acrylic acid, methacrylic acid, β-carboxyethyl acrylate, combinations thereof, and derivatives thereof.

[0017] To prepare the basecoat copolymer, two or more monomers and an optional initiator can be dissolved in a solvent. The solvent can be any solvent that dissolves the two or more monomers and the optional initiator. The solvent can include benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide, dioxane, 2-methyltetrahydrofuran, anisole, benzonitrile, chlorinated aromatic solvents, diisopropyl ether, diglyme, butanol, and combinations thereof.

[0018] An initiator can be used to initiate polymerization of the monomers in solution. Polymerization can be initiated by reduction-oxidation, radiation, heat, or any other method known in the art. Radiation crosslinking of the monomers in solution can be achieved with ultraviolet or visible light using an appropriate initiator, or with ionizing radiation (e.g., electron beam or gamma rays) without an initiator. Polymerization can be achieved by conventional heating of the solution using a heat source such as a heated well, or by applying infrared radiation to the monomers in solution.

[0019] In some embodiments, the initiator is azobisisobutyronitrile (AIBN) or a water-soluble AIBN derivative (e.g., 2,2'-azobis(2-methylpropionamidine) dihydrochloride or 4,4'-azobis(4-cyanopentanoic acid)). Other initiators include N,N,N',N'-tetramethylethylenediamine, ammonium persulfate, benzoyl peroxide, and combinations thereof (including azobisisobutyronitrile).

[0020] In some embodiments, the initiator concentration can be from about 0.25% w / w to about 2% w / w of the mass of the monomers in the solution.

[0021] In some embodiments, the polymerization reaction can be carried out at elevated temperatures, such as in the range of about 65°C to about 85°C.

[0022] In some embodiments, after polymerization is complete, the copolymer can be recovered by precipitating it in a non-solvent and drying under vacuum.

[0023] In some embodiments, the resulting copolymers can have a molecular weight between about 15,000 g / mole and about 150,000 g / mole, or between 25,000 g / mole and 100,000 g / mole, as determined by gel permeation chromatography using polystyrene standards.

[0024] After polymerization, reactive groups such as acrylate and / or methacrylate can be added to the copolymer via the hydroxy, amine, and / or carboxylic acid groups of the second or more monomers. In some embodiments, the derivatizing compound is a heterobifunctional compound. One moiety reacts with the hydroxy, amine, and / or carboxylic acid groups of the copolymer, and the other moiety is an acrylate or methacrylate group. Suitable derivatizing compounds include 2-isocyanatoethyl acrylate, 2-isocyanatoethyl methacrylate, acrylic acid N-hydroxysuccinimide ester, methacrylic acid N-hydroxysuccinimide ester, heterobifunctional polyethylene glycols having acrylate and isocyanate acid groups, combinations thereof, and derivatives thereof.

[0025] To prepare the derivatized copolymer, the copolymer, derivatizing compound, and optionally, any catalyst can be dissolved in a solvent. In some embodiments, any solvent that dissolves the components can be used. Solvents can include dimethylformamide, dimethyl sulfoxide, toluene, acetone, acetonitrile, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, and combinations thereof.

[0026] When derivatizing with nucleophilic groups on the basecoat copolymer, the molar equivalent of the derivatizing agent can range from about 5% to about 80% or from about 10% to about 50% of the available nucleophilic groups. This degree of derivatization corresponds to a range of 4 to 50 reactive groups per molecule. Additionally, in some embodiments, a Lewis base can be added as a catalyst. Lewis bases can include triethylamine and pyridine. The Lewis base can be provided at a concentration of about 1% to about 10% relative to the moles of derivatizing compound added.

[0027] The reaction can proceed at elevated temperatures, such as about 45° C., to form the base coat. After derivatization is complete, the completed modified copolymer can be recovered by precipitation in a non-solvent and drying under vacuum.

[0028] The topcoat can be formed over the basecoat (e.g., the basecoat can form a layer between the surface of the medical device and the topcoat). The topcoat polymer can include a hemocompatible small molecule, a protein, a polysaccharide, a glycosaminoglycan, or a polymer derivatized with a polymerizable group. The topcoat polymer can be any naturally occurring or synthetic polymer, derivatives thereof, and combinations thereof. In some embodiments, the topcoat polymer is at least partially soluble in water.

[0029] The structure of the topcoat polymer can be linear or branched, such as a graft structure, a star structure, a comb structure, a brush structure, a dendrimer structure, or the like.

[0030] The topcoat may comprise albumin, heparin, phosphorylcholine, poly(alkoxyalkyl(meth)acrylate), zwitterionic polymer, nitric oxide releasing polymer, very hydrophilic polymer, or very hydrophobic polymer.

[0031] Albumin is a protein found in blood that commonly adsorbs to surfaces of foreign objects, such as catheters and microcatheters. Because albumin does not have a receptor for platelet binding, its use as a coating material may inhibit platelet interaction with the surface. Albumin contains nucleophilic amino acids, such as lysine and serine, which allows for the derivatization and coating processes described herein.

[0032] Heparin is a polysaccharide that inactivates thrombin and inhibits blood coagulation. The use of heparin for surface treatment can reduce platelet adhesion and protein adsorption on medical devices. Because heparin contains carboxyl and hydroxyl groups in its structure, it can be subjected to the derivatization and coating processes described herein.

[0033] In addition to naturally derived compounds, synthetic copolymers can be synthesized to create topcoats for enhanced hemocompatibility.

[0034] In some embodiments, the first component of the copolymer is a compound for enhancing the hemocompatibility of a surface of a medical device (eg, a catheter or microcatheter).

[0035] The second component may include polymerizable acrylates or methacrylates, as well as amines, carboxylic acids, or hydroxy groups. Amine-containing monomers include 3-aminopropyl methacrylamide, 2-aminoethyl methacrylate, N-(3-methylpyridine)acrylamide, 2-(N,N-dimethylamino)ethyl methacrylate, 2-(N,N-dimethylamino)ethyl acrylate, 2-(tert-butylamino)ethyl methacrylate, methacryloyl lysine, N-(2-(4-aminophenyl)ethyl)acrylamide, N-(4-aminobenzyl)acrylamide, or N-(2-(4-imidazolyl)ethyl)acrylamide, derivatives thereof, or combinations thereof. Carboxylic acid-containing monomers include acrylic acid, methacrylic acid, derivatives thereof, or combinations thereof. Hydroxy group-containing monomers include 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, 4-hydroxybutyl acrylate, derivatives thereof, or combinations thereof.

[0036] To prepare the polymer, two or more monomers and an initiator are dissolved in a solvent. Generally, any solvent that dissolves the two or more monomers and the initiator can be used. In some embodiments, the solvent includes methanol / water, ethanol / water, isopropanol / water, dioxane / water, tetrahydrofuran / water, dimethylformamide / water, dimethyl sulfoxide or water, and combinations thereof. For carboxylic acid and hydroxyl-containing monomers, a wider range of solvents can be utilized, such as toluene, xylene, dimethyl sulfoxide, dioxane, tetrahydrofuran, methanol, ethanol, or dimethylformamide.

[0037] A polymerization initiator can be used to initiate polymerization of the monomers in solution. Polymerization can be initiated by reduction-oxidation, radiation, heat, or other methods known in the art. Radiation-induced polymerization of the monomer solution can be achieved with ultraviolet or visible light using an appropriate initiator, or with ionizing radiation (e.g., electron beam or gamma radiation) without an initiator. Polymerization can be achieved by the application of heat, either by conventionally heating the solution using a heat source such as a heating well or by applying infrared light to the monomer solution. In some embodiments, the polymerization initiator is azobisisobutyronitrile (AIBN) or a water-soluble AIBN derivative (e.g., 2,2'-azobis(2-methylpropionamidine) dihydrochloride), or 4,4'-azobis(4-cyanopentanoic acid). Other initiators useful herein include N,N,N',N'-tetramethylethylenediamine, ammonium persulfate, benzoyl peroxide, or combinations thereof (including azobisisobutyronitrile). In some embodiments, the initiator concentration can range from 0.25% to 2% w / w based on the weight of the monomers in the solution. In some embodiments, the polymerization reaction can be carried out at elevated temperatures, preferably in the range of 65 to 85°C. After polymerization is complete, the polymer can be recovered by precipitation in a non-solvent and dried under vacuum. In some embodiments, the molecular weight of the copolymer can range from 500 amu to 100,000 amu, e.g., from 1,000 amu to 40,000 amu.

[0038] One option for the first component to enhance hemocompatibility is to use an alkoxyalkyl(meth)acrylate. The alkoxyalkyl(meth)acrylate can reduce protein adsorption, platelet adhesion, and conformational changes of adsorbed proteins. In some embodiments, the alkoxyalkyl(meth)acrylate is 2-methoxyethyl acrylate. In some embodiments, the alkoxyalkyl(meth)acrylate monomer can be represented by formula (I): [ka] where R 1 is a hydrogen atom or a methyl group. R 2 is an alkylene group having 1 to 4 carbon atoms, and R 3 is an alkylene group having 1 to 4 carbon atoms.

[0039] In some embodiments, the first monomer is methoxyethyl acrylate, where R 1 is a hydrogen atom, and R 2 is an ethyl group, and R 3 is a methyl group.

[0040] In some embodiments, the first component is a zwitterionic monomer, i.e., a monomer containing equal numbers of positive and negative charges to create an overall neutral charge. These compounds are hemocompatible due to their structural similarity to the polar head groups of phospholipids that make up cell membranes. Furthermore, due to their charge, zwitterionic compounds can tightly bind water and suppress conformational changes in proteins.

[0041] In some embodiments, the zwitterionic monomer is 2-methacryloyloxyethyl phosphorylcholine. [ka]

[0042] In some embodiments, the zwitterionic monomer is a monomer synthesized from a betaine (i.e., a carboxylbetaine, a phosphobetaine, or a sulfobetaine). An example of such a monomer is [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide. [ka]

[0043] A third option for the first component is a monomer that releases nitric oxide. Nitric oxide inhibits platelets. The endothelial cell lining of arteries continuously releases nitric oxide. Polymers that release nitric oxide at similar levels may have hemocompatibility similar to that of the endothelial cell lining. Molecules containing (meth)acrylates and nitric oxide-releasing chemicals such as diazeniumdiolates or S-nitrosothiols can be synthesized and then polymerized into copolymers.

[0044] A fourth option for the first component is to use a highly hydrophilic polymer / copolymer. Hydrophilic surfaces have been shown to reduce protein adsorption by minimizing surface free energy. Hydrophilic monomers include acrylamide, vinyl alcohol, n-vinylpyrrolidone, hydroxyethyl methacrylate, or poly(ethylene glycol).

[0045] Reactive groups such as acrylate and / or methacrylate can be attached to the polymer by a derivatizing compound through any convenient reactive site, such as, but not limited to, hydroxyl, amine, or carboxylic acid. In some embodiments, the derivatizing compound can be a heterobifunctional compound. One site can react with a hydroxy, amine, and / or carboxylic acid group on the copolymer. The other site can be an acrylate or methacrylate group.

[0046] In some embodiments, the derivatized compound can include acryloyl chloride, methacryloyl chloride, 2-isocyanatoethyl acrylate, 2-isocyanatoethyl methacrylate, acrylic acid N-hydroxysuccinimide ester, methacrylic acid N-hydroxysuccinimide ester, heterobifunctional poly(ethylene glycol)s bearing acrylate and isocyanato groups, combinations thereof, and derivatives thereof.

[0047] To prepare the derivatized polymer, the polymer, derivatization compound, and optional catalyst are dissolved in a solvent. In some embodiments, any solvent that dissolves the topcoat polymer, derivatization agent, and optional catalyst can be used. Solvents can include aromatic and chlorinated solvents, including benzene, toluene, xylene, dichloromethane, chloroform, and combinations thereof.

[0048] When the derivatizing agent reacts with reactive sites on the topcoat polymer, the desired derivatization corresponds to less than two groups per molecule. Furthermore, in some embodiments, the derivatization can include the addition of a Lewis base as a catalyst. In some embodiments, the Lewis base can be triethylamine and pyridine at a concentration of about 1% to about 10% of the moles of the derivatizing compound added.

[0049] In some embodiments, the derivatization reaction proceeds at room temperature.

[0050] After derivatization is complete, the activated polymer can be recovered by precipitation into a non-solvent and drying under vacuum.

[0051] The base coat can be applied to a medical device surface, such as a thermoplastic material. The catheter is first cleaned by wiping with a solvent to remove any visible contamination from the surface. In some embodiments, the catheter is wiped with a solvent. In some embodiments, any solvent can be used that does not dissolve or degrade the thermoplastic material of the catheter. Solvents can include glycol ethers, methyl ethyl ketone, chlorinated solvents, tetrahydrofuran, hexane, ethyl acetate, and acetone.

[0052] Following solvent cleaning, in some embodiments, the catheter shaft can be plasma treated to further clean its surface. In some embodiments, the catheter is not plasma treated. Plasmas derived from various gases can be used. In some embodiments, the plasma gas can be argon and oxygen. In some embodiments, both argon and oxygen plasmas can be used.

[0053] The basecoat solution may include a solvent, a basecoat copolymer, an optional initiator, and an optional surfactant. Generally, any solvent or mixture of solvents can be utilized, provided that the components can be dissolved in the solvent or mixture of solvents. Solvents may include water, alcohols, glycol ethers, aromatic solvents, polar aprotic solvents, and combinations thereof. In some embodiments, the solvent may include methanol, ethanol, isopropyl alcohol, 2-ethoxyethanol, propylene glycol monomethyl ether acetate, benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide, and combinations thereof.

[0054] The basecoat copolymer can be dissolved in the solvent at a concentration ranging from about 0.2% w / w to about 35% w / w, about 0.2% w / w to about 40% w / w, about 0.2% w / w to about 50% w / w, about 0.5% w / w to about 35% w / w, 0.5% w / w to about 40% w / w, about 0.5% w / w to about 50% w / w, about 1% w / w to about 35% w / w, about 1% w / w to about 40% w / w, or about 1% w / w to about 50% w / w, depending on the desired viscosity of the basecoat solution. In some embodiments, the basecoat copolymer concentration is about 15% w / w.

[0055] In some embodiments, when an initiator is included, it includes Norrish Type I initiators, Norrish Type II initiators, and combinations thereof. Norrish Type I or free radical photoinitiators can include benzoin derivatives, methylolbenzoin and 4-benzoyl-1,3-dioxolane derivatives, benzil ketals, α,α-dialkoxyacetophenones, α-hydroxyalkylphenones, α-aminoalkylphenones, acylphosphine oxides, bisacylphosphine oxides, acylphosphine sulfides, halogenated acetophenone derivatives, or combinations thereof.In some embodiments, the Norrish Type I photoinitiator is selected from the group consisting of Irgacure 2959 (2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone), Irgacure 651 (benzil dimethyl ketal or 2,2-dimethoxy-1,2-diphenylethanone; Ciba-Geigy), Irgacure 184 (containing 1-hydroxycyclohexyl-phenyl ketone as the active ingredient; Ciba-Geigy), Darocur 1173 (containing 2-hydroxy-2-methyl-1-phenylpropan-1-one), and the like. Ciba-Geigy Co., Ltd.), Irgacure 907 (2-methyl-1-[4-(methylthio)phenyl]-2-morpholinopropan-1-one; Ciba-Geigy Co., Ltd.), Irgacure 369 (2-benzyl-2-dimethylamino-1-(4-morpholinophenyl)-butan-1-one as the active ingredient; Ciba-Geigy Co., Ltd.), Esacure KIP150 (poly{2-hydroxy-2-methyl-1-[4-(1-methylvinyl)phenyl]propan-1-one}, Fratelli Lamberti Lamberti), Esacure KIP100F (a blend of poly{2-hydroxy-2-methyl-1-[4-(1-methylvinyl)phenyl]propan-1-one and 2-hydroxy-2-methyl-1-phenyl-propan-1-one, Fratelli Lamberti), Esacure KTO46 (a blend of poly{2-hydroxy-2-methyl-1-[4-(1-methylvinyl)phenyl]propan-1-one}, 2,4,6-trimethylbenzoyldiphenylphosphine oxide, and methylbenzophenone derivatives, Fratelli Lamberti) acylphosphine oxides such as Lucirin TPO (2,4,6-trimethylbenzoyldiphenylphosphine oxide, BASF), Irgacure 819 (bis(2,4,6-trimethylbenzoyl)-phenylphosphine oxide, Ciba-Geigy), Irgacure 1700 (a 25:75% blend of bis(2,6-dimethoxybenzoyl)2,4,4-trimethyl-pentylphosphine oxide and 2-hydroxy-2-methyl-1-phenyl-propan-1-one, Ciba-Geigy), or combinations thereof.

[0056] In some embodiments, a mixture of Type I photoinitiators can be used.

[0057] Norrish Type II photoinitiators can also be used in basecoat formulations. These initiators include benzophenone, xanthone, derivatives of benzophenone (e.g., chlorobenzophenone), blends of benzophenone and benzophenone derivatives (e.g., Photocure 81, a 50 / 50 blend of 4-methyl-benzophenone and benzophenone), Michler's ketone, ethyl Michler's ketone, thioxanthone, and other xanthone derivatives such as Quantacure ITX (isopropylthioxanthone), aromatic ketones such as benzil, anthraquinone (e.g., 2-ethylanthraquinone), and coumarin, or chemical derivatives or combinations of these photoinitiators.

[0058] In some embodiments, the basecoat formulation may include a combination of Norrish Type I and Norrish Type II initiators.

[0059] The initiator concentration in the solvent can range from about 0.1% to about 6% w / w, hi some embodiments, the initiator concentration in the solvent can be about 0.6% w / w.

[0060] The basecoat solution may also optionally include a surfactant. In some embodiments, an optional surfactant may be used. Surfactants may include sodium lauryl sulfate, Tween 20, Span 80, Triton X-100, Pluronic F68, Pluronic L-81, combinations thereof, and derivatives thereof. The optional surfactant may be dissolved in the selected solvent at a concentration ranging from about 0.1% w / w to about 15% w / w. In some embodiments, the surfactant concentration is about 0.8% w / w.

[0061] In some embodiments, to apply the base coat to a catheter, the length of the catheter desired to be coated is inserted into the base coat solution. The immersion time, i.e., the amount of time the catheter is left in the base coat solution, is about 0.2 to about 10 minutes, about 0.5 to about 10 minutes, about 2 to about 8 minutes, about 3 to about 6 minutes, or about 0.5 to about 8 minutes. In some embodiments, the immersion time can be about 5 minutes.

[0062] In other embodiments, the base coat can be applied by spraying, brushing, spin coating, or the like, or combinations thereof with or without dip coating.

[0063] In some embodiments, only a portion of the catheter is coated, and thus, a portion of the catheter can be masked to prevent the base coat from being applied to the masked area.

[0064] After applying a base coat by dip coating or other method, the catheter is exposed to ultraviolet light having a wavelength ranging from about 10 nm to about 400 nm, about 100 nm to about 400 nm, about 200 nm to about 400 nm, about 200 nm to about 300 nm, or about 300 nm to about 400 nm. Combinations of wavelengths within this range can also provide a suitable base coat. In one embodiment, the ultraviolet light can be applied at a first wavelength between about 200 nm to about 300 nm and a second wavelength between about 300 nm to about 400 nm. In one embodiment, the wavelengths can include 254 nm and 365 nm.

[0065] The curing time, i.e., the amount of time the catheter is exposed to UV light, ranges from about 0.5 to about 10 minutes, about 1 to about 10 minutes, about 1 to about 8 minutes, about 0.5 to about 6 minutes, about 1 to about 6 minutes, about 1 to about 3 minutes, or about 0.5 to about 30 minutes. In one embodiment, the curing time is about 2 minutes.

[0066] In some embodiments, the basecoat application process is completed after the cure time is complete.

[0067] A topcoat can be applied over the completed basecoat. The topcoat solution can include a solvent, a topcoat polymer, an optional initiator, and an optional surfactant. In some embodiments, any solvent or mixture of solvents can be utilized, provided that the components can be dissolved in the solvent or solvent mixture. Suitable solvents can include water, alcohols, glycol ethers, aromatics, polar aprotic solvents, and combinations thereof. In some embodiments, the solvent can include methanol, ethanol, isopropyl alcohol, 2-ethoxyethanol, propylene glycol monomethyl ether acetate, benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide, and combinations thereof.

[0068] The topcoat polymer may be dissolved in a solvent selected depending on the desired viscosity of the topcoat solution at a concentration ranging from about 5% w / w to about 75% w / w, about 5% w / w to about 80% w / w, about 5% w / w to about 90% w / w, about 10% w / w to about 80% w / w, about 10% w / w to about 75% w / w, about 5% w / w to about 50% w / w, about 5% w / w to about 40% w / w, about 5% w / w to about 40% w / w, about 20% w / w to about 40% w / w, or about 20% w / w to about 30% w / w. In one embodiment, the topcoat polymer concentration is about 25% w / w.

[0069] Optional initiators can include Norrish Type I initiators, Norrish Type II initiators, and combinations thereof. Norrish Type I or free radical photoinitiators can include benzoin derivatives, methylolbenzoin and 4-benzoyl-1,3-dioxolane derivatives, benzil ketals, α,α-dialkoxyacetophenones, α-hydroxyalkylphenones, α-aminoalkylphenones, acylphosphine oxides, bisacylphosphine oxides, acylphosphine sulfides, halogenated acetophenone derivatives, and the like.Norrish Type I photopolymerization initiators include Irgacure 2959 (2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone), Irgacure 651 (benzil dimethyl ketal or 2,2-dimethoxy-1,2-diphenylethanone, manufactured by Ciba-Geigy), Irgacure 184 (1-hydroxy-cyclohexyl-phenyl ketone as the active ingredient, manufactured by Ciba-Geigy), and Darocure 1173 (2-hydroxy-2-methyl-1-phenylpropan-1-one as the active ingredient). , manufactured by Ciba-Geigy), Irgacure 907 (2-methyl-1-[4-(methylthio)phenyl]-2-morpholinopropan-1-one, manufactured by Ciba-Geigy), Irgacure 369 (2-benzyl-2-dimethylamino-1-(4-morpholinophenyl)-butan-1-one as the active ingredient, manufactured by Ciba-Geigy), Escacur KIP150 (poly{2-hydroxy-2-methyl-1-[4-(1-methylvinyl)phenyl]propan-1-one}, manufactured by Fratelli Lamberti), Escacur KIP10 0F (a blend of poly{2-hydroxy-2-methyl-1-[4-(1-methylvinyl)phenyl]propan-1-one} and 2-hydroxy-2-methyl-1-phenyl-propan-1-one, manufactured by Fratelli Lamberti), Esacure KTO46 (a blend of poly{2-hydroxy-2-methyl-1-[4-(1-methylvinyl)phenyl]propan-1-one}, 2,4,6-trimethylbenzoyldiphenylphosphine oxide, and a methylbenzophenone derivative, manufactured by Fratelli Lamberti), Examples include acylphosphine oxides such as Lucirin TPO (2,4,6-trimethylbenzoyldiphenylphosphine oxide, BASF), Irgacure 819 (bis(2,4,6-trimethylbenzoyl)phenylphosphine oxide, Ciba-Geigy), and Irgacure 1700 (a 25:75% mixture of bis(2,6-dimethoxybenzoyl)2,4,4-trimethylpentylphosphine oxide and 2-hydroxy-2-methyl-1-phenyl-propan-1-one, Ciba-Geigy). Mixtures of Type I photoinitiators can also be used.

[0070] Norrish Type II photoinitiators that can be used include aromatic ketones such as benzophenone, xanthone, derivatives of benzophenone (e.g., chlorobenzophenone), blends of benzophenone and benzophenone derivatives (e.g., Photocure 81, a 50 / 50 blend of 4-methylbenzophenone and benzophenone), Michler's ketone, ethyl Michler's ketone, thioxanthone, other xanthone derivatives such as Quantacure ITX (isopropyl thioxanthone), benzil, anthraquinones (e.g., 2-ethylanthraquinone), coumarin, or other aromatic ketones, or chemical derivatives or combinations thereof.

[0071] In some embodiments, the topcoat formulation may include a combination of Norrish Type I and Norrish Type II initiators.

[0072] The initiator concentration in the solvent can range from about 0.1% to about 6% w / w, hi some embodiments, the initiator concentration in the solvent can be about 0.3% w / w or about 0.5% w / w.

[0073] The topcoat solution may also include a surfactant. In some embodiments, any surfactant can be used. In some embodiments, the surfactant can include sodium lauryl sulfate, Tween 20, Span 80, Triton X-100, Pluronic F68, Pluronic L-81, combinations thereof, and derivatives thereof. The optional surfactant can be dissolved in the selected solvent at a concentration ranging from about 0.1% w / w to about 5% w / w. In some embodiments, the surfactant concentration is about 0.6% w / w.

[0074] In some embodiments, to apply a topcoat to a basecoated catheter, the length of the catheter desired to be coated is inserted into the basecoat solution. The immersion time, i.e., the amount of time the catheter is left in the basecoat solution, is about 0.2 to about 20 minutes, about 0.5 to about 20 minutes, about 2 to about 15 minutes, about 3 to about 15 minutes, or about 8 to about 12 minutes. In some embodiments, the immersion time can be about 10 minutes.

[0075] In other embodiments, the topcoat can be applied by spraying, brushing, spin coating, or the like, or combinations thereof with or without dip coating.

[0076] In some embodiments, only a portion of the catheter is coated with the topcoat, where a portion of the catheter can be masked so that the topcoat is not applied to the masked area.

[0077] After applying the topcoat by dip coating or other methods, the catheter is exposed to ultraviolet light having a wavelength ranging from about 10 nm to about 400 nm, about 100 nm to about 400 nm, about 200 nm to about 400 nm, about 200 nm to about 300 nm, or about 300 nm to about 400 nm. Combinations of wavelengths within this range may also provide a suitable basecoat. In one embodiment, the ultraviolet light may be applied at a first wavelength between about 200 nm and about 300 nm and a second wavelength between about 300 nm and about 400 nm. In one embodiment, the wavelengths include 254 nm and 365 nm.

[0078] The cure time of the topcoat, i.e., the amount of time the catheter is exposed to UV light, ranges from about 0.5 to about 4 minutes, about 1 to about 4 minutes, about 1 to about 3 minutes, about 0.5 to about 3 minutes, about 1 to about 5 minutes, about 0.5 to about 3 minutes, or about 0.5 to about 50 minutes. In one embodiment, the cure time is about 2 minutes.

[0079] The coatings described herein can reduce the maximum dynamic frictional force [gf] when compared to an uncoated device. In some embodiments, the coating can reduce the maximum dynamic frictional force by about 50%. In other embodiments, the coating can reduce the maximum dynamic frictional force by about 75%.

[0080] The coatings described herein can reduce the average dynamic friction force [gf] over 100 cycles at 60 mm displacement when compared to an uncoated device. In some embodiments, the coating can reduce the maximum dynamic friction force by about 50%. In other embodiments, the coating can reduce the maximum dynamic friction force by about 75%.

[0081] The coatings described herein can provide increased lubricity compared to uncoated devices. In some embodiments, the coatings can increase lubricity by about 50%. In other embodiments, the coatings can increase lubricity by about 75%.

[0082] Example 1: Preparation of basecoat polymer Add 80.0 g of tetrahydrofurfuryl acrylate, 18.5 g of 4-hydroxybutyl acrylate, and 250 mL of toluene to a 1 L round-bottom flask. Purge and degas the solution with argon gas for 30 minutes. Next, add 1.0 g of AIBN initiator, and purge the mixture with argon for an additional 10 minutes. The flask is immersed in an 80 °C oil bath and refluxed with a reflux condenser equipped with an argon inlet. The mixture is heated under argon for 16 hours. The reaction is cooled and precipitated with 1.2 L of cold MTBE. The precipitated product is collected and dried in vacuo. Typical yields are 85-95%.

[0083] The dried polymer was dissolved in dry DMF (200 mL, approximately 0.5 g / mL) and treated with 0.84 mL of triethylamine and 3.0 mL of isocyanatoethyl acrylate. The mixture was heated to 45 °C for 5 h. The polymer was precipitated with 1.2 L of cold MTBE, washed with 2 x 200 mL of MTBE, and dried under high vacuum.

[0084] Example 2: Preparation of a liquid basecoat solution In a suitable container, 6.75 g of the polymer from Example 1 is dissolved in 45.0 mL of propylene glycol monomethyl ether acetate. Next, 0.34 g of Pluronic L-81 surfactant, 135 mg of benzophenone, and 135 mg of 1-hydroxycyclohexyl phenyl ketone are added. Shake for 30 minutes to completely dissolve the polymer, resulting in a clear, homogeneous solution.

[0085] [Example 3: Coating of microcatheter with base coat liquid] A 12-inch (0.027-inch outer diameter) microcatheter length, the outer surface of which is made of Grilamid L25, is prepared for coating by first inserting a tight-fitting stainless steel mandrel into the hollow lumen and wiping the outer surface with acetone. The microcatheter length is then plasma treated with argon plasma (365 sccm, 300 watts, 500 mtorr) followed by oxygen plasma (120 sccm, 150 watts, 400 mtorr). The liquid basecoat formulation prepared in Example 2 is transferred into a sealed-bottom glass tube (12 inches long, 0.22-inch inner diameter). The microcatheter length is then placed in the coating solution within the glass tube and allowed to dwell for 5 minutes. The microcatheter length is then removed and immediately exposed to ultraviolet light (254 nmλ, 1.3 J / cm). 2 Cure for 2 minutes using UV light to polymerize the base coat onto the Grilamid substrate.

[0086] Example 4: Preparation of macromer for top coat Dissolve 50 g (382 mmol) of methoxyethyl acrylate (MEA) and 13.8 g (96 mmol) of 4-hydroxybutyl acrylate (HBtAc) in 250 mL of 1,4-dioxane in a 1 L RB flask. Add 0.75 g of AIBN and stir to dissolve. Attach a water-cooled condenser. Immerse the flask in a preheated oil bath at 75 °C and stir the mixture for 16 h. Cool the reaction mixture and pour it into 1.2 L of MTBE. Collect the precipitate, wash twice with 200 mL of MTBE, separate, and dry in vacuo.

[0087] The resulting MEA-co-HBtAc copolymer was dissolved in anhydrous DMF (200 mL), and triethylamine (0.24 mL, 1.7 mmol) followed by 2-isocyanatoethyl acrylate (1.05 mL, 8.5 mmol) was added. The reaction was stirred for 16 hours. The product was precipitated from 1.2 L of MTBE, washed twice with 200 mL of MTBE, separated, and dried in vacuo.

[0088] Example 5: Preparation of topcoat solution In a container, 9.0 g of the MEA-co-HBtAc topcoat macromer prepared in Example 4 was dissolved in 45.0 mL of Dowanol with shaking. Next, 0.23 g of Pluronic L-81 surfactant, 90 mg of benzophenone, and 90 mg of 1-hydroxycyclohexyl phenyl ketone were added. After shaking for 1 minute, complete dissolution resulted in a clear, homogeneous solution.

[0089] Example 6: Coating of microcatheter with topcoat solution The topcoat solution prepared in Example 5 was transferred to a glass tube with a stopper at the bottom, and the microcatheter region coated with the base coat of Example 3 was placed in the glass tube and allowed to dwell in the topcoat solution for 10 minutes. Thereafter, the microcatheter region was removed and immediately exposed to ultraviolet light (254 nm λ, ultraviolet dose 1.3 J / cm ). 2 ) for 2 minutes to polymerize the top coat onto the base coat.

[0090] It can be seen that the coating of Example 6 has improved blood compatibility compared to the uncoated sample.

[0091] While the specification and accompanying drawings describe preferred embodiments, it will be understood that many variations and modifications will be suggested to those skilled in the relevant art. Accordingly, the scope of the present invention is not limited to the specific embodiments and examples described herein, but should be considered to encompass alternative embodiments and equivalents.

[0092] Unless otherwise indicated, all numerical values ​​expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and the like used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should, at the very least, be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0093] As used in the context of describing the present invention (particularly in the context of the claims below), the terms "a," "an," "the," and similar reference words shall be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method for individually referencing each separate value falling within the range. Unless otherwise indicated herein, each separate value is incorporated herein as if it were individually referenced herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "etc.") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention as otherwise claimed. No language in the specification should be construed as indicating a non-claimed element essential to the practice of the invention.

[0094] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referenced and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When such inclusion or deletion is made, the specification is deemed to include the group as modified, and accordingly conforms to all Markush group descriptions used in the appended claims.

[0095] Certain embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors expect skilled artisans to adopt such variations as appropriate, and the inventors intend the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0096] Additionally, throughout this specification, numerous patents and printed publications are referenced, and each of the above cited patents and printed publications is individually incorporated herein by reference in its entirety.

[0097] Finally, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, and not of limitation, alternative configurations of the invention may be utilized in accordance with the teachings herein. Accordingly, the invention is not limited to that precisely as shown and described.

[0098] (Addendum) (Appendix 1) a base coat comprising a copolymer of a first tetrahydrofurfuryl acrylate monomer and a second monomer comprising at least one functional group capable of further derivatization; and a topcoat polymer containing more than two reactive sites per molecule; A coating formulation comprising:

[0099] (Appendix 2) 2. The coating formulation of claim 1, wherein the copolymer has a molecular weight of between about 15,000 g / mole and about 150,000 g / mole.

[0100] (Appendix 3) 2. The coating formulation of claim 1, wherein the top coat is on top of the base coat.

[0101] (Appendix 4) 2. The coating formulation of claim 1, wherein the top coat is a blood-compatible top coat.

[0102] (Appendix 5) 2. The coating formulation of claim 1, wherein the topcoat polymer is a blood-compatible small molecule, protein, polysaccharide, glycosaminoglycan, or polymer derivatized with at least one (e.g., at least two, or more than two) polymerizable group.

[0103] (Appendix 6) 2. The coating formulation of claim 1, wherein the top coat polymer is albumin, heparin, phosphorylcholine, poly(alkoxyalkyl(meth)acrylate), a zwitterionic polymer, a nitric oxide-releasing polymer, a very hydrophilic polymer, a very hydrophobic polymer, or a combination thereof.

[0104] (Appendix 7) 2. The coating formulation of claim 1, wherein the top coat polymer has a molecular weight of about 500 amu to about 100,000 amu.

[0105] (Appendix 8) A coating formulation according to Appendix 1 that improves lubricity or blood compatibility of a medical device.

[0106] (Appendix 9) The coating formulation of claim 8, wherein the medical device is a catheter or a microcatheter.

[0107] (Appendix 10) 2. The coating formulation of claim 1, wherein the at least one functional group is independently hydroxyl, amine, or carboxylic acid.

[0108] (Appendix 11) 1. A method for coating a surface of a thermoplastic material, comprising: applying a base coat comprising a copolymer of a first tetrahydrofurfuryl acrylate monomer and a second monomer comprising at least one functional group capable of further derivatization to the surface of the thermoplastic; and applying a top coat to the base coat; The method of claim 1, wherein the topcoat comprises a topcoat polymer containing more than two reactive sites per molecule.

[0109] (Appendix 12) 12. The method of claim 11, wherein the thermoplastic surface is cleaned before applying the base coat.

[0110] (Appendix 13) 12. The method of claim 11, wherein the surface of the thermoplastic material is plasma treated before applying the base coat.

[0111] (Appendix 14) 12. The method of claim 11, wherein the base coat is applied by dipping.

[0112] (Appendix 15) 12. The method of claim 11, wherein the base coat is exposed to ultraviolet light.

[0113] (Appendix 16) 16. The method according to claim 15, wherein the ultraviolet light has a wavelength in the range of about 10 nm to about 400 nm.

[0114] (Appendix 17) 17. The method of claim 16, wherein the base coat is cured for about 0.5 to about 10 minutes.

[0115] (Appendix 18) 2. The method of claim 1, wherein the top coat is applied by dipping.

[0116] (Appendix 19) 2. The method of claim 1, wherein the top coat is exposed to ultraviolet light.

[0117] (Appendix 20) 20. The method according to claim 19, wherein the ultraviolet light has a wavelength in the range of about 10 nm to about 400 nm.

[0118] (Appendix 21) 20. The method of claim 19, wherein the top coat is cured for about 0.5 to about 10 minutes.

[0119] (Appendix 22) 10. A method of administering a catheter to a subject in need thereof, comprising inserting the catheter into the subject and removing the catheter from the subject, wherein the catheter is coated with the coating formulation of claim 1.

[0120] (Appendix 23) 10. A method of providing vascular access to a subject in need thereof, comprising inserting into the subject a catheter coated with the coating formulation of claim 1.

[0121] (Appendix 24) 10. A method for withdrawing bodily fluid from a subject in need thereof, comprising inserting a catheter coated with the coating formulation of Appendix 1 into the subject and withdrawing the bodily fluid from the subject.

[0122] (Appendix 25) 25. The method of claim 24, comprising repeatedly or continuously withdrawing the bodily fluid without repeatedly inserting the catheter.

[0123] (Appendix 26) 10. A method of administering a drug (e.g., a therapeutic or diagnostic agent) to a subject in need thereof, comprising inserting into the subject a catheter coated with the coating formulation of Appendix 1, and administering the drug to the subject via the catheter.

[0124] (Appendix 27) 27. The method of claim 26, comprising administering the agent repeatedly or continuously without repeated insertion of the catheter.

[0125] (Appendix 28) 28. The method of any one of Appendix 22 to 27, wherein the catheter is removed from the subject in a time that is about 10% to about 200% longer than the removal time of a catheter that does not include the coating of Appendix 1.

Claims

[Claim 1] a basecoat comprising a copolymer of a first tetrahydrofurfuryl acrylate monomer and a second monomer comprising at least one functional group capable of further derivatization; and a topcoat polymer containing more than two reactive sites per molecule; A coating formulation comprising:

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