Medical coating agent and medical device

Abstract

This medical coating agent contains a polymer including a structural unit (A) derived from an ethylenically unsaturated monomer having a urethane bond. In a DSC curve obtained by including water into the polymer and increasing the temperature using a differential scanning calorimeter (DSC) at a rate of 5°C / min, the glass transition temperature of the polymer in a water saturated state is -25°C or lower, when the water saturated state is defined as the water-containing state of the polymer in which the peak top of an endothermic process caused by melting of ice appears at 0°C.

Description

Medical coatings and medical devices

[0001] [Cross-reference to related applications] This application claims priority to Japanese Patent Application No. 2021-161734, filed on September 30, 2021, the entire contents of which are incorporated herein by reference. The present disclosure relates to medical coating agents and medical devices, and more particularly to a technology for imparting biocompatibility to medical devices that are used in contact with biological components or biological tissues.

[0002] Various materials, such as synthetic polymers, ceramics, glass, and metals, are used for medical devices. However, when a medical device comes into contact with biological components or tissues, the body may recognize the medical device as a foreign body, which may impair the function of the medical device or affect the body. For example, in applications where a medical device is used in contact with blood, the medical device may be recognized as a foreign body, activating the body's defense mechanism and leading to the formation of a blood clot. Therefore, attention has been focused on imparting biocompatibility to medical devices by using biocompatible synthetic polymers (see, for example, Patent Document 1).

[0003] Patent Document 1 discloses the use of a polymer having structural units derived from 2-methoxyethyl acrylate as a biocompatible medical material.

[0004] Japanese Patent Application Publication No. 04-152952

[0005] Platelets and fibrinogen are thought to be the main components in blood involved in thrombus formation. Therefore, the present inventors considered it important to prevent these components from recognizing a medical device inserted into the body as a foreign body. In other words, if the surface of a substrate can be sufficiently endowed with properties that inhibit the adsorption of platelets and fibrinogen (hereinafter also referred to as "anti-adsorption"), it can be said that excellent antithrombogenicity can be imparted to the medical device, thereby improving its biocompatibility.

[0006] The present disclosure has been made in view of the above circumstances, and its object is to provide a medical coating agent that has high anti-adsorption properties for platelets and fibrinogen and excellent antithrombogenic properties.

[0007] The present disclosure provides the following means.

[0008] [1] A medical coating agent comprising a polymer including a structural unit (A) derived from an ethylenically unsaturated monomer having a urethane bond, wherein the polymer is soaked in water and heated at a rate of 5°C / min using a differential scanning calorimeter (DSC). When the water-saturated state of the polymer is determined as the state at which the peak top of the endothermic heat due to ice melting appears at 0°C in a DSC curve, the glass transition temperature of the polymer in the saturated water-saturated state is -25°C or lower.

[0009] [2] The medical coating agent of [1] above, wherein the polymer contains the structural unit (A) in an amount of 10 mass% or more based on all structural units of the polymer. [3] The medical coating agent of [1] or [2] above, wherein the difference between the glass transition temperature in a dry state and the glass transition temperature in a saturated water-containing state, as measured with a differential scanning calorimeter at a heating rate of 5°C / min, is 25°C or more. [4] The medical coating agent of any of [1] to [3] above, wherein the polymer is a (meth)acrylic polymer. [5] A medical device having a substrate coated with the medical coating agent of any of [1] to [4] above.

[0010] The polymer contained in the medical coating agent of the present disclosure has high anti-adsorption properties for platelets and fibrinogen and excellent antithrombogenic properties. Therefore, by coating the substrate of a medical device with the medical coating agent of the present disclosure, a medical device with excellent antithrombogenic properties can be provided.

[0011] The present disclosure will be described in detail below. In this specification, "(meth)acrylic" means acrylic and / or methacrylic, and "(meth)acrylate" means acrylate and / or methacrylate.

[0012] <Medical Coating Agent> The medical coating agent of the present disclosure contains a polymer (hereinafter also referred to as "polymer (P)") that includes a structural unit (A) derived from an ethylenically unsaturated monomer having a urethane bond (-NH-COO-), and that has a glass transition temperature of -25°C or lower in a saturated water-containing state.

[0013] When water is added to the polymer (P), the water interacting with the polymer (P) (i.e., hydrated water) can take three forms: "free water," "non-freezing water," and "intermediate water," depending on the strength of the interaction with the polymer. Of these, "free water" refers to water that has a weak interaction with the polymer and a freezing point of 0°C, and "non-freezing water" refers to water that has a strong interaction with the polymer and no detectable freezing point. "Intermediate water" refers to water that has an interaction with the polymer that is intermediate between free water and non-freezing water (i.e., that interacts relatively slowly with the polymer) and has a freezing point below 0°C. It is believed that the biocompatibility of a polymer is related to the fact that the hydrated polymer contains a large amount of intermediate water (see, for example, paragraphs 0003 and 0004 of JP 2016-35000 A).

[0014] More specifically, in the body, cells recognize foreign substances, activating the body's defense mechanisms and causing a rejection reaction. Therefore, when a medical device comes into contact with biological components or tissues during treatment, surgery, etc., if the body recognizes the medical device as a foreign body, the body's defense mechanisms may be activated, potentially interfering with treatment. For example, if a medical device comes into contact with blood, a blood clot may form, inhibiting the function of the medical device and affecting the body. On the other hand, polymers with intermediate water on their surfaces are less likely to be recognized as foreign substances by the body and are therefore thought to exhibit excellent antithrombotic properties.

[0015] Here, platelets and fibrinogen are known to be components in blood that are involved in the formation of thrombi. Platelets are blood cells that are activated by foreign substances and form thrombi (platelet thrombi) by aggregating on the foreign substances, contributing to primary hemostasis in the process of hemostasis. Fibrinogen, which is coagulation factor I, is a protein that is converted to fibrin in the final stage of blood coagulation to form coagulated thrombi, contributing to secondary hemostasis in the process of hemostasis. In other words, both platelets and fibrinogen are major components that form thrombi, and it is thought that the resistance of these components to adsorption on polymers is important for biocompatibility (more specifically, antithrombogenicity).

[0016] In this regard, the polymer (P) contained in the medical coating agent of the present disclosure easily retains intermediate water during hydration, and can sufficiently suppress the adsorption of platelets and fibrinogen to the surface of a substrate coated with the polymer (P), which is thought to enable the coating agent to exhibit excellent antithrombotic properties.

[0017] In this specification, the water content state of a polymer when the endothermic peak top due to ice melting appears at 0°C in a DSC curve obtained by heating a water-containing polymer at a temperature rising rate of 5°C / min is defined as a "saturated water content state." However, in this specification, "when the endothermic peak top due to ice melting appears at 0°C" means that the polymer contains enough water and can be considered to be in a saturated water content state, and an error in the endothermic peak top appearing near 0°C (for example, 0°C ± 0.2°C) is acceptable.

[0018] Each component contained in the medical coating agent of the present disclosure will be described below.

[0019] <Polymer (P)> The polymer (P) contains a structural unit derived from an ethylenically unsaturated monomer having a urethane bond (hereinafter also referred to as "monomer (M)").

[0020] The polymer (P) is preferably a (meth)acrylic polymer, in terms of being able to easily increase the reaction rate of the monomers and being easy to produce industrially. Specifically, the proportion of structural units derived from (meth)acrylic monomers among all structural units derived from the monomers constituting the polymer (P) is preferably more than 50% by mass, more preferably 60% by mass or more, even more preferably 70% by mass or more, still more preferably 80% by mass or more, and even more preferably 90% by mass or more.

[0021] The monomer (M) is preferably a compound capable of introducing a structure having a urethane bond into the side chain of a polymer, and is preferably a (meth)acrylic monomer having a urethane bond. When the monomer (M) is a (meth)acrylic monomer, it is preferable because the reaction rate of the monomer can be easily increased. As the monomer (M), one type may be used alone, or two or more types may be used.

[0022] As the monomer (M), (methoxycarbonyl)aminoalkyl(meth)acrylate and a monomer represented by the following general formula (I): CH ２ =CR １ -COO-R ２ -NH-COO-R ３ -R ４ ...(I) (In general formula (I), R １ is a hydrogen atom or a methyl group, and R ２ is an alkylene group having 1 to 5 carbon atoms or "-(R ５ O) ｍ -R ６ -" (wherein R ５ is an alkylene group having 1 to 3 carbon atoms, and R ６ is an alkylene group having 1 to 3 carbon atoms, and m is an integer of 1 to 3, and R ３ is an alkylene group having 1 to 3 carbon atoms, any hydrogen atom of which may be substituted with an alkoxy group having 1 to 10 carbon atoms; R ４ is an alkoxy group having 1 to 10 carbon atoms) can be preferably used.

[0023] Furthermore, from the viewpoint of sufficiently increasing the anti-adsorption properties of platelets and fibrinogen, R ３ In the general formula (I), any hydrogen atom of the alkylene group is more preferably substituted with an alkoxy group having 1 to 4 carbon atoms, and even more preferably with an alkoxy group having 1 to 2 carbon atoms. ４ is more preferably an alkoxy group having 1 to 4 carbon atoms, and even more preferably an alkoxy group having 1 or 2 carbon atoms.

[0024] Specific examples of the (methoxycarbonyl)aminoalkyl (meth)acrylate include (methoxycarbonyl)aminomethyl (meth)acrylate, 2-((methoxycarbonyl)amino)ethyl (meth)acrylate, and 3-((methoxycarbonyl)amino)propyl (meth)acrylate. Of these, 2-((methoxycarbonyl)amino)ethyl acrylate is preferred because it can sufficiently lower the glass transition temperature (Tg2) of the polymer (P) in a saturated water-containing state.

[0025] Specific examples of the compound represented by the general formula (I) include 2-(((2-methoxyethoxy)carbonyl)amino)ethyl (meth)acrylate, 2-(((2-ethoxyethoxy)carbonyl)amino)ethyl (meth)acrylate, 2-(((2-propoxyethoxy)carbonyl)amino)ethyl (meth)acrylate, 2-((((1,3-dimethoxypropan-2-yl)oxy)carbonyl)amino)ethyl (meth)acrylate, 2-( Examples of such acrylates include (((1,3-diethoxypropan-2-yl)oxy)carbonyl)amino)ethyl (meth)acrylate, 2-((((1-methoxy-3-ethoxypropan-2-yl)oxy)carbonyl)amino)ethyl (meth)acrylate, 6-oxo-2,5,10-trioxa-7-azadodecan-12-yl (meth)acrylate, and 7-oxo-3,6,11-trioxa-8-azatridecan-13-yl (meth)acrylate.

[0026] From the viewpoint of sufficiently lowering the glass transition temperature (Tg2) of polymer (P) in a saturated water-containing state while introducing a sufficient amount of side chain structures having urethane bonds into the polymer, polymer (P) preferably contains structural units derived from at least one compound selected from the group consisting of (methoxycarbonyl)aminoalkyl(meth)acrylates and compounds represented by the general formula (I) above (hereinafter also referred to as "monomer (m-1)") in an amount of 10% by mass or more, more preferably 20% by mass or more, even more preferably 30% by mass or more, even more preferably 50% by mass or more, and particularly preferably 60% by mass or more, of all structural units derived from the monomers constituting polymer (P). Note that polymer (P) may contain only one type of structural unit derived from monomer (m-1), or may contain two or more types.

[0027] The polymer (P) may be composed only of structural units derived from the monomer (m-1). However, for the purpose of adjusting the glass transition temperature of the polymer or the like, the polymer (P) may further have structural units derived from monomers other than the monomer (m-1) (hereinafter also referred to as "other monomers") within a range that does not impair the effects of the present disclosure.

[0028] Examples of other monomers include monomers that do not have a urethane bond and are copolymerizable with monomer (m-1). Examples of such monomers include unsaturated carboxylic acids, unsaturated acid anhydrides, (meth)acrylic acid alkyl esters, aliphatic cyclic (meth)acrylic acid esters, aromatic (meth)acrylic acid esters, (meth)acrylic acid alkoxyalkyl esters, (meth)acrylic acid hydroxyalkyl esters, polyalkylene glycol mono(meth)acrylates, vinyl compounds having a heterocyclic structure, amino group-containing vinyl compounds, amide group-containing vinyl compounds, nitrile group-containing vinyl compounds, aromatic vinyl compounds, and maleimide compounds.

[0029] Specific examples of these include unsaturated carboxylic acids such as (meth)acrylic acid, itaconic acid, crotonic acid, maleic acid, fumaric acid, citraconic acid, cinnamic acid, succinic acid monohydroxyethyl (meth)acrylate, ω-carboxy-caprolactone mono(meth)acrylate, β-carboxyethyl (meth)acrylate, 4-carboxystyrene, etc., and unsaturated acid anhydrides such as maleic anhydride, itaconic anhydride, citraconic anhydride, etc.

[0030] Examples of the (meth)acrylic acid alkyl ester include methyl (meth)acrylate, ethyl (meth)acrylate, isopropyl (meth)acrylate, n-propyl (meth)acrylate, n-butyl (meth)acrylate, isobutyl (meth)acrylate, tert-butyl (meth)acrylate, hexyl (meth)acrylate, and 2-ethylhexyl (meth)acrylate.

[0031] Specific examples of aliphatic cyclic esters of (meth)acrylic acid include cyclohexyl (meth)acrylate, methylcyclohexyl (meth)acrylate, tert-butylcyclohexyl (meth)acrylate, cyclododecyl (meth)acrylate, isobornyl (meth)acrylate, adamantyl (meth)acrylate, dicyclopentenyl (meth)acrylate, dicyclopentanyl (meth)acrylate, etc. Specific examples of aromatic esters of (meth)acrylic acid include phenyl (meth)acrylate, benzyl (meth)acrylate, phenoxymethyl (meth)acrylate, 2-phenoxyethyl (meth)acrylate, 3-phenoxypropyl (meth)acrylate, etc.

[0032] Specific examples of the (meth)acrylic acid alkoxyalkyl ester include 2-methoxyethyl (meth)acrylate, 2-ethoxyethyl (meth)acrylate, n-propoxyethyl (meth)acrylate, n-butoxyethyl (meth)acrylate, 3-methoxypropyl (meth)acrylate, 3-ethoxypropyl (meth)acrylate, n-propoxypropyl (meth)acrylate, n-butoxypropyl (meth)acrylate, methoxybutyl (meth)acrylate, ethoxybutyl (meth)acrylate, n-propoxybutyl (meth)acrylate, and n-butoxybutyl (meth)acrylate.

[0033] Specific examples of the hydroxyalkyl (meth)acrylate include 2-hydroxyethyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, 3-hydroxypropyl (meth)acrylate, 2-hydroxybutyl (meth)acrylate, 3-hydroxybutyl (meth)acrylate, and 4-hydroxybutyl (meth)acrylate, etc. Examples of the polyalkylene glycol mono(meth)acrylate include polyethylene glycol mono(meth)acrylate, polypropylene glycol mono(meth)acrylate, and polyethylene glycol-polypropylene glycol mono(meth)acrylate, etc.

[0034] Examples of vinyl compounds having a heterocyclic structure include glycidyl (meth)acrylate, (3,4-epoxycyclohexyl)methyl (meth)acrylate, and tetrahydrofurfuryl (meth)acrylate.

[0035] Examples of the amino group-containing vinyl compound include dimethylaminomethyl (meth)acrylate, diethylaminomethyl (meth)acrylate, 2-dimethylaminoethyl (meth)acrylate, 2-diethylaminoethyl (meth)acrylate, 2-(di-n-propylamino)ethyl (meth)acrylate, 2-dimethylaminopropyl (meth)acrylate, 2-diethylaminopropyl (meth)acrylate, 2-(di-n-propylamino)propyl (meth)acrylate, 3-dimethylaminopropyl (meth)acrylate, 3-diethylaminopropyl (meth)acrylate, and 3-(di-n-propylamino)propyl (meth)acrylate.

[0036] Examples of the amide group-containing vinyl compound include (meth)acrylamide, N,N-dimethyl(meth)acrylamide, N,N-dimethylaminopropyl(meth)acrylamide, and N-methylol(meth)acrylamide.

[0037] Examples of the nitrile group-containing vinyl compound include cyanomethyl (meth)acrylate, 1-cyanoethyl (meth)acrylate, 2-cyanoethyl (meth)acrylate, 1-cyanopropyl (meth)acrylate, 2-cyanopropyl (meth)acrylate, 3-cyanopropyl (meth)acrylate, 4-cyanobutyl (meth)acrylate, 6-cyanohexyl (meth)acrylate, 2-ethyl-6-cyanohexyl (meth)acrylate, 8-cyanooctyl (meth)acrylate, (meth)acrylonitrile, α-ethylacrylonitrile, α-isopropylacrylonitrile, α-chloroacrylonitrile, and α-fluoroacrylonitrile.

[0038] Examples of aromatic vinyl compounds include styrene, α-methylstyrene, β-methylstyrene, vinylxylene, methylstyrene, ethylstyrene, butylstyrene, methoxystyrene, hydroxystyrene, isopropenylphenol, vinylbenzoic acid, and vinylnaphthalene.

[0039] Examples of the maleimide compound include maleimide and N-substituted maleimide compounds. Examples of the N-substituted maleimide compound include N-alkyl-substituted maleimides such as N-methylmaleimide, N-ethylmaleimide, N-n-propylmaleimide, N-isopropylmaleimide, N-n-butylmaleimide, N-isobutylmaleimide, and N-tert-butylmaleimide; N-cycloalkyl-substituted maleimides such as N-cyclopentylmaleimide and N-cyclohexylmaleimide; N-aralkyl-substituted maleimides such as N-benzylmaleimide; and N-aryl-substituted maleimides such as N-phenylmaleimide, N-(4-hydroxyphenyl)maleimide, N-(4-acetylphenyl)maleimide, and N-(4-methoxyphenyl)maleimide.

[0040] In addition to the above, other monomers that have a urethane bond and are copolymerizable with monomer (m-1) can also be used. Examples of such monomers include 2-((ethoxycarbonyl)amino)ethyl(meth)acrylate and 2-((isopropoxycarbonyl)amino)ethyl acrylate. One type of other monomer may be used alone, or two or more types may be used in combination.

[0041] From the viewpoint of obtaining a water-insoluble and highly biocompatible polymer, the other monomer is preferably at least one selected from the group consisting of (meth)acrylic acid alkyl esters, aliphatic cyclic esters of (meth)acrylic acid, aromatic esters of (meth)acrylic acid, (meth)acrylic acid alkoxyalkyl esters, amino group-containing vinyl compounds, and amide group-containing vinyl compounds, and more preferably at least one selected from the group consisting of (meth)acrylic acid alkyl esters and (meth)acrylic acid alkoxyalkyl esters.

[0042] Among these other monomers, at least one selected from the group consisting of alkyl (meth)acrylates having an alkyl group containing 1 to 12 carbon atoms and alkoxyalkyl (meth)acrylates having an alkoxyalkyl group containing 3 to 12 carbon atoms is preferred, alkoxyalkyl (meth)acrylates having an alkoxyalkyl group containing 3 to 12 carbon atoms are more preferred, alkoxyalkyl (meth)acrylates having an alkoxyalkyl group containing 3 to 4 carbon atoms are even more preferred, and 2-methoxyethyl (meth)acrylate is particularly preferred. By obtaining polymer (P) using one or more of these compounds, a coating agent highly effective in suppressing the adsorption of platelets and fibrinogen can be obtained.

[0043] When polymer (P) has structural units derived from at least one monomer (hereinafter also referred to as "monomer (N)") selected from the group consisting of (meth)acrylic acid alkyl esters having an alkyl group containing 1 to 12 carbon atoms and (meth)acrylic acid alkoxyalkyl esters having an alkoxyalkyl group containing 3 to 12 carbon atoms, the proportion of structural units derived from monomer (N) is preferably 5% by mass or more, more preferably 10% by mass or more, and even more preferably 20% by mass or more, based on all structural units derived from the monomers constituting polymer (P). From the viewpoint of suppressing performance degradation due to a small amount of structural unit (A) introduced, the upper limit of the proportion of structural units derived from monomer (N) is preferably 90% by mass or less, more preferably 80% by mass or less, even more preferably 70% by mass or less, even more preferably 50% by mass or less, and even more preferably 40% by mass or less, based on all structural units derived from the monomers constituting polymer (P).

[0044] The polymer (P) preferably contains the structural unit (A) in an amount of 10% by mass or more, based on the total structural units contained in the polymer (P). When the proportion of the structural unit (A) in the polymer (P) is within the above range, the medical coating agent of the present disclosure can be applied to a substrate to sufficiently inhibit the adsorption of platelets and fibrinogen, which is advantageous in that it can produce a medical device with excellent antithrombotic properties. From this perspective, the proportion of the structural unit (A) in the polymer (P) is preferably 20% by mass or more, more preferably 30% by mass or more, even more preferably 50% by mass or more, and even more preferably 60% by mass or more, based on the total structural units contained in the polymer (P).

[0045] When the polymer (P) is a copolymer of the monomer (M) and another monomer not having a urethane bond, the polymer (P) may be any of a random copolymer, a block copolymer, a graft copolymer, etc. From the viewpoint of uniformly introducing a structure having a urethane bond into the entire polymer to enhance the effect of improving antithrombotic properties, the polymer (P) is preferably a random copolymer.

[0046] The weight-average molecular weight (Mw) of the polymer (P) is preferably in the range of 2,000 to 2,000,000. An Mw of 2,000 or more ensures sufficient mechanical strength of the coating layer formed using the medical coating agent. Furthermore, an Mw of 2,000,000 or less can prevent the viscosity of the medical coating agent from becoming too high, ensuring coatability and handleability. The Mw of the polymer (P) is more preferably 5,000 or more, even more preferably 10,000 or more, even more preferably 30,000 or more, and even more preferably 50,000 or more. The upper limit of the Mw of the polymer (P) is more preferably 1,500,000 or less, even more preferably 1,000,000 or less. In this specification, the Mw of the polymer is a standard polystyrene-equivalent value obtained using gel permeation chromatography (GPC).

[0047] The polymerization method for producing the polymer (P) is not particularly limited. The polymer (P) can be obtained by polymerizing the monomers using a known radical polymerization method such as solution polymerization, suspension polymerization, emulsion polymerization, or bulk polymerization. In the case of solution polymerization, for example, an organic solvent and monomers are charged into a reactor, a polymerization initiator (e.g., an azo compound) is added, and the mixture is heated to 40 to 250°C to polymerize, thereby obtaining the target polymer. When the polymer obtained by the polymerization reaction is subjected to isolation and / or purification treatment, known methods can be used for these treatments.

[0048] The glass transition temperature (Tg1) of the polymer (P) in a dry state is not particularly limited, but is, for example, 20°C or lower, preferably 10°C or lower. The lower limit of the glass transition temperature (Tg1) of the polymer (P) in a dry state is also not particularly limited, and is, for example, -70°C or higher. In this specification, the glass transition temperature of the polymer (P) is a value measured using a differential scanning calorimeter (DSC) at a heating rate of 5°C / min. Details of the measurement method follow the method described in the examples below (the same applies to the glass transition temperature (Tg2) of the polymer in a saturated water-containing state).

[0049] The polymer (P) has a glass transition temperature (Tg2) in a saturated water-containing state of -25°C or lower. If the glass transition temperature (Tg2) of the polymer (P) in a saturated water-containing state is higher than -25°C, there is a concern that the anti-adsorption properties of platelets and fibrinogen cannot be sufficiently imparted to the substrate surface, and the desired antithrombogenic properties cannot be imparted. From the viewpoint of sufficiently enhancing the anti-adsorption properties of platelets and fibrinogen, the glass transition temperature (Tg2) of the polymer (P) in a saturated water-containing state is preferably -30°C or lower, more preferably -40°C or lower, and even more preferably -50°C or lower. The lower limit of the glass transition temperature (Tg2) of the polymer (P) in a saturated water-containing state is not particularly limited, and is, for example, -100°C or higher.

[0050] The glass transition temperature (Tg2) of the polymer (P) in a saturated water-containing state can be adjusted to a value within a desired temperature range by adjusting the type and amount of the monomers constituting the polymer (P). For example, if the glass transition temperature of a homopolymer composed of the monomer (M) used in the production of the polymer (P) in a saturated water-containing state is higher than the desired temperature, the glass transition temperature (Tg2) of the polymer (P) in a saturated water-containing state can be adjusted by using, as a copolymerization component, a monomer whose glass transition temperature in a saturated water-containing state when converted into a homopolymer is lower than that of the monomer (M).

[0051] Furthermore, from the viewpoint of sufficiently enhancing the anti-adsorption properties of platelets and fibrinogen, the difference ΔTg (=Tg1-Tg2) between the glass transition temperature (Tg1) in a dry state and the glass transition temperature (Tg2) in a saturated water-containing state of the polymer (P) is preferably 25° C. or higher. The difference ΔTg is preferably 30° C. or higher, and more preferably 35° C. or higher.

[0052] <Other Components> The medical coating agent of the present disclosure may further contain components other than the polymer (P) (hereinafter also referred to as "other components") depending on the purpose of use, etc. When the medical coating agent of the present disclosure is a liquid, one embodiment of the medical coating agent is a polymer composition in which the polymer (P) is dissolved or dispersed in a solvent as necessary.

[0053] When the medical coating agent of the present disclosure contains a solvent, a solvent capable of dissolving the polymer (P) is preferably used as the solvent. The solvent contained in the medical coating agent of the present disclosure is preferably an organic solvent. Specific examples include alcohols such as methanol, ethanol, n-propanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; ethers such as ethylene glycol monomethyl ether, propylene glycol monomethyl ether, tetrahydrofuran, and dioxane; esters such as ethylene glycol monomethyl ether acetate and ethyl acetate; amide solvents such as N,N-dimethylformamide (DMF) and N,N-dimethylacetamide; hydrocarbons such as n-hexane, cyclohexane, toluene, and xylene; and dimethyl sulfoxide. The solvent may be used alone or in combination of two or more.

[0054] Other components that may be incorporated into the medical coating agent of the present disclosure include, in addition to solvents, various drugs such as antibacterial agents, anti-inflammatory agents, and antioxidants. One or more of these other components may be used. The content of the other components may be appropriately selected depending on each component, as long as the effects of the present disclosure are not impaired.

[0055] In the medical coating agent of the present disclosure, the content of polymer (P) is preferably 50 parts by mass or more, more preferably 70 parts by mass or more, even more preferably 80 parts by mass or more, even more preferably 90 parts by mass or more, and even more preferably 95 parts by mass or more, relative to 100 parts by mass of the total solid content contained in the medical coating agent (i.e., components other than the solvent in the medical coating agent). By setting the content of polymer (P) within the above range, it is advantageous in that excellent antithrombogenicity is exhibited and stable biocompatibility can be imparted to the substrate.

[0056] When the medical coating agent of the present disclosure is in a solution state, the solids concentration in the medical coating agent (here, the ratio by mass of components other than the solvent in the medical coating agent to the volume of the solvent used in preparing the medical coating agent) is not particularly limited, but is preferably 0.001 to 30 (w / v)%. By setting the solids concentration to 0.001 (w / v)% or more, a coating layer with sufficient thickness and mechanical strength can be formed on the substrate. When the solids concentration is 30 (w / v)% or less, good coatability can be ensured and a coating layer with a uniform thickness can be easily formed. The solids concentration in the polymer composition is more preferably 0.01 to 25 (w / v)%, and even more preferably 0.05 to 20 (w / v)%.

[0057] <Medical Device> The medical device of the present disclosure is formed by coating a substrate with the medical coating agent of the present disclosure. The medical device of the present disclosure has a surface partially or entirely coated with the polymer (P) contained in the medical coating agent of the present disclosure. As a result, the medical device has high anti-adsorption properties for platelets and fibrinogen and excellent antithrombogenic properties.

[0058] The substrate of the medical device to which the medical coating agent of the present disclosure is applied is not particularly limited. Examples of materials constituting the substrate include various materials such as resin, rubber, metal, glass, and ceramic. Examples of resins include various resin materials such as polycarbonate, polyethylene terephthalate, polyvinyl chloride, polyethylene, polypropylene, polymethylpentene, polyurethane, poly(meth)acrylate, polystyrene, polyacetal, polysulfone, polyethersulfone, fluorine-based resins (such as polyvinylidene fluoride and polyethylene tetrafluoride), acrylonitrile-butadiene-styrene (ABS) resin, polyamide, and ethylene-vinyl acetate resin. Examples of rubbers include silicone rubber and urethane rubber. Examples of metals include various metal materials such as stainless steel, titanium, and aluminum. The material constituting the substrate of the medical device may be a mixture of two or more materials.

[0059] The method for coating the surface of a substrate with the medical coating agent of the present disclosure is not particularly limited. For example, when the medical coating agent is in a solution state, the medical coating agent is applied to the surface of a substrate, and the solvent is removed by heating or other means, thereby obtaining a medical device in which at least a portion of the surface of the substrate is coated with the polymer (P).

[0060] The coating method can be appropriately selected depending on the shape of the substrate, the intended use, etc. Examples of coating methods include various coating methods such as those using a bar coater, applicator, doctor blade, dip coater, roll coater, spin coater, flow coater, knife coater, comma coater, reverse coater, die coater, lip coater, gravure coater, microgravure coater, and ink jet. The amount of coating of the medical coating agent can be appropriately selected depending on the application and material of the medical device, etc., so that the thickness of the coating layer formed by the medical coating agent falls within the desired range.

[0061] The medical device whose substrate surface is coated with the medical coating agent of the present disclosure is not particularly limited, and can be applied to a variety of medical devices. Specific examples include various medical devices such as stents, catheters, blood bags, transfusion instruments, surgical instruments, dental instruments, blood circulation devices, blood purification devices, plasma separation devices, artificial blood vessels, and artificial organs (e.g., heart-lung machines, artificial kidneys, etc.). Furthermore, when applying the medical coating agent of the present disclosure to a medical device, the purpose and use thereof are not particularly limited. For example, the medical coating agent of the present disclosure may be used as an antibacterial and antifouling coating agent. Considering that the medical coating agent of the present disclosure can impart excellent antithrombogenic properties to the substrate surface, the medical coating agent of the present disclosure is particularly preferably used as a material for coating the substrate of a medical device that is used in direct contact with blood.

[0062] The present disclosure will be specifically described below based on examples. However, the present disclosure is not limited to these examples. In the following, "parts" and "%" mean "parts by mass" and "% by mass", respectively, unless otherwise specified.

[0063] 1. Synthesis of Ethylenically Unsaturated Monomers [Synthesis Example 1: Synthesis of 2-((methoxycarbonyl)amino)ethyl acrylate] A stirrer was added to a 300 mL three-neck flask, and 50 mL of tetrahydrofuran (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) as a solvent, 0.09 g of dibutyltin dilaurate (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) as a catalyst, and 2.64 g of methanol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) as a raw material alcohol were added thereto, followed by attachment of a thermometer, a 50 mL dropping funnel, and a three-way cock. Subsequently, 10.58 g of 2-acryloyloxyethyl isocyanate (manufactured by Showa Denko KK, trade name: Karenz AOI, hereinafter also referred to as "AOI") was added to the dropping funnel. Next, nitrogen was flowed through the three-way cock at 100 mL / min for 10 minutes. After nitrogen flow, a nitrogen-filled rubber balloon was attached to the three-way stopcock, and the flask was cooled to below 5°C in an ice bath. Subsequently, AOI was added dropwise from the dropping funnel while maintaining the internal temperature below 10°C. Upon completion of the dropwise addition, the temperature was raised to room temperature (25°C) and stirring was continued overnight. Then, 10 mL of saturated aqueous sodium bicarbonate solution was added dropwise to the flask to terminate the reaction. 200 mL of the internal solution was transferred to a separatory funnel, and the organic and aqueous layers were separated. 30 mL of ethyl acetate (Fujifilm Wako Pure Chemical Industries, Ltd., special grade) was added to the aqueous layer and shaken to extract the aqueous layer. This shaking and aqueous layer extraction procedure was repeated twice. 30 mL of saturated saline was added to the recovered organic layer and shaken to wash it. This shaking and organic layer washing procedure was repeated twice. 30 mg of anhydrous sodium sulfate (Fujifilm Wako Pure Chemical Industries, Ltd.) was added to the washed organic layer, stirred for 1 hour, and dehydrated. The mixture was filtered using fluted filter paper to remove sodium sulfate, and paramethoxyphenol was added to a theoretical yield of 250 ppm. Subsequently, the solvent was removed using a rotary evaporator while immersed in a 40°C water bath. After the solvent was removed, the mixture was left standing under reduced pressure for 1 hour using a vacuum pump, and the remaining solvent was again removed. The collected sample was purified by silica gel column chromatography using a solvent mixture of hexane / ethyl acetate in a 1:1 volume ratio to obtain 2-((methoxycarbonyl)amino)ethyl acrylate (hereinafter also referred to as "MOCNA").

[0064] Synthesis Example 2: Synthesis of 2-((ethoxycarbonyl)amino)ethyl acrylate The same procedure as in Synthesis Example 1 was carried out, except that 3.46 g of ethanol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added as the raw material alcohol, to obtain 2-((ethoxycarbonyl)amino)ethyl acrylate (hereinafter also referred to as "EOCNA").

[0065] Synthesis Example 3: Synthesis of 2-(((2-methoxyethoxy)carbonyl)amino)ethyl acrylate The same operation as in Synthesis Example 1 was carried out, except that 6.28 g of 2-methoxyethanol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added as the raw material alcohol, to obtain 2-(((2-methoxyethoxy)carbonyl)amino)ethyl acrylate (hereinafter, also referred to as "MEOCNA").

[0066] Synthesis Example 4: Synthesis of 2-((((1,3-dimethoxypropan-2-yl)oxy)carbonyl)amino)ethyl acrylate The same operation as in Synthesis Example 1 was carried out, except that 9.91 g of 1,3-dimethoxy-2-propanol (manufactured by Combi-Blocks) was added as the raw material alcohol, to obtain 2-((((1,3-dimethoxypropan-2-yl)oxy)carbonyl)amino)ethyl acrylate (hereinafter, also referred to as "DMPOCNA").

[0067] Synthesis Example 5: Synthesis of 2-((((1,3-diethoxypropan-2-yl)oxy)carbonyl)amino)ethyl acrylate The same operations as in Synthesis Example 1 were carried out, except that 9.91 g of 1,3-diethoxy-2-propanol (manufactured by Tokyo Chemical Industry Co., Ltd.) was added as the raw material alcohol, to obtain 2-((((1,3-diethoxypropan-2-yl)oxy)carbonyl)amino)ethyl acrylate (hereinafter, also referred to as "DEPOCNA").

[0068] Synthesis Example 6: Synthesis of 2-((isopropoxycarbonyl)amino)ethyl acrylate The same operation as in Synthesis Example 1 was carried out, except that 4.96 g of 2-propanol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added as the raw material alcohol, to obtain 2-((isopropoxycarbonyl)amino)ethyl acrylate (hereinafter also referred to as "IPOCNA").

[0069] Synthesis Example 7 6-oxo-2,5,10-trioxa-7-azadodecan-12-yl methacrylate The same operation as in Synthesis Example 1 was carried out, except that 14.94 g of 2-(2-methacryloyloxyethyloxy)ethyl isocyanate (manufactured by Showa Denko K.K., trade name: Karenz MOI-EG, hereinafter also referred to as "MOI-EG") was used instead of AOI, and 6.28 g of 2-methoxyethanol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was used as the raw material alcohol, to obtain 6-oxo-2,5,10-trioxa-7-azadodecan-12-yl methacrylate (hereinafter also referred to as "MEOCNMA-EG").

[0070] 2. Production and Analysis of Polymers Polymers were produced according to the following Production Examples 1 to 9 and Comparative Production Examples 1 to 3. Furthermore, for each of the obtained polymers, the weight average molecular weight (Mw), glass transition temperature in a dry state (Tg1), glass transition temperature in a saturated water-containing state (Tg2), and saturated water content were measured by the following methods.

[0071] <Measurement of Weight-Average Molecular Weight (Mw) of Polymer> The weight-average molecular weight (Mw) of the polymer was measured by gel permeation chromatography (GPC) analysis under the following measurement conditions: (Measurement conditions for GPC analysis) Apparatus: Model HLC-8320GPC manufactured by Tosoh Corporation Detector: RI detector Column: TSKgel SuperMultiporeHZ-M x 3 manufactured by Tosoh Corporation Column temperature: 40°C Eluent: tetrahydrofuran (containing 0.03% sulfur as an internal standard) Flow rate: 350 μL / min Calibration curve: standard polystyrene

[0072] <Measurement of Glass Transition Temperature (Tg1) of Polymer in Dry State> Each of the obtained polymers was dried overnight under reduced pressure conditions of 60°C and 1000 Pa. Each dried polymer was weighed into an aluminum pan. Thereafter, using a differential scanning calorimeter (measuring instrument: DSC214Polymer manufactured by NETZSCH, measurement atmosphere: air atmosphere), the polymer was cooled from 100°C to -80°C at a temperature increase / decrease rate of 5°C / min, held at -80°C for 5 minutes, and then heated to 100°C. In this way, the glass transition temperature (Tg1) of the polymer in a dry state was determined.

[0073] <Measurement of Glass Transition Temperature (Tg2) of Polymer in Saturated Water-Containing State> Each polymer was immersed in a large excess of pure water (10 g of pure water per 30 mg of polymer) and allowed to stand at room temperature (25°C) for 3 days to allow it to absorb water. The hydrated polymer was removed from the pure water using tweezers, and water adhering to each hydrated polymer was removed using a medicine wrapping paper. 0.003 to 0.005 g of each hydrated polymer was weighed into an aluminum pan. The weighed value at this time was recorded as "X (unit: g)." Thereafter, using the same differential scanning calorimeter as used to measure the glass transition temperature (Tg1) of the polymer in the dry state, the polymer was cooled from 40°C to -100°C at a heating rate of 5°C / min, held at -100°C for 5 minutes, and then heated to 40°C to determine the glass transition temperature (Tg2) of the polymer in the saturated water-containing state. In addition, in a DSC curve obtained by DSC measurement under the condition of a temperature increase rate of 5°C / min, the water content state of the polymer when the peak top of the endothermic heat due to ice melting appears at 0°C was defined as the "saturated water content state," and the glass transition temperature (Tg2) of the polymer in the saturated water content state was determined from the DSC curve when the peak top of the endothermic heat due to ice melting appears at 0°C.

[0074] <Measurement of saturated water content> After differential scanning calorimetry, holes were made in the aluminum pan, and the pan was vacuum dried for 4 days at 110°C and 1 Pa. The change in mass before and after drying was taken as the amount of hydration water contained in each polymer (referred to as "amount of hydration water of polymer" (unit: g)). The amount of hydration water of the polymer in a saturated water-containing state was defined as "saturated water content," and the ratio (unit: mass%) of the saturated water content to the weighed value (X (unit: g)) was calculated using the following mathematical formula (1): (saturated water content: mass%) = (amount of hydration water of polymer: g) ÷ X × 100 ... (1)

[0075] [Production Example 1: Production of Polymer A] 3 g of MOCNA as a monomer, 0.272 g of 2,2'-azobis(2,4-dimethylvaleronitrile) (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., hereinafter also referred to as "V-65 initiator") as a radical initiator, and 12 g of acetonitrile as a solvent were added to a two-neck test tube. A stirrer was then placed in the test tube, a thermometer was attached to the side tube, and a three-way stopcock was attached to the main tube. A syringe needle was inserted into the three-way stopcock, and argon was blown into the solution at 100 mL / min for 30 minutes to deoxygenate it. The three-way stopcock was then closed, and the test tube was sealed. The test tube was inserted into a heat block set to 60°C, and polymerization was initiated. The temperature of the heat block was adjusted appropriately so that the internal temperature reached 60°C. After 3 hours, the test tube was cooled in an ice bath to terminate the polymerization. The reaction solution was subjected to reprecipitation purification twice using a solvent obtained by mixing hexane and acetone in a mass ratio of 3:7 as the reprecipitation purification solvent. Thereafter, the recovered polymer was subjected to reprecipitation purification using pure water as the solvent, to obtain Polymer A. GPC measurement of Polymer A revealed that the weight average molecular weight was 71,300. Furthermore, the glass transition temperature of Polymer A in a dry state was 7°C, the glass transition temperature in a saturated water-containing state was -30°C, the difference ΔTg between the glass transition temperature in a saturated water-containing state and the glass transition temperature in a dry state was 37°C, and the saturated water content was 12.0% by mass.

[0076] [Production Example 2: Production of Polymer B] Polymer B was obtained by the same procedure as in Production Example 1, except that 3 g of MEOCNA was used as the monomer, 0.358 g of 2,2'-azobis(2-methylbutyronitrile) (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., hereinafter also referred to as "V-59 initiator") was used as the radical initiator, 27 g of ethyl acetate was used as the solvent, and a solvent obtained by mixing hexane and acetone in a 4:6 mass ratio was used as the reprecipitation purification solvent. GPC measurement of Polymer B revealed that it had a weight average molecular weight of 100,800. Furthermore, the glass transition temperature of Polymer B in a dry state was -10°C, the glass transition temperature in a saturated water-containing state was -60°C, the difference ΔTg between the glass transition temperature in a saturated water-containing state and the glass transition temperature in a dry state was 50°C, and the saturated water content was 31.5% by mass.

[0077] [Production Example 3: Production of Polymer C] Polymer C was obtained by the same procedure as in Production Example 1, except that 7.5 g of MEOCNA was used as the monomer, 0.003 g of V-65 initiator as a radical initiator, 11.2 g of ethyl acetate was used as the solvent, and a solvent obtained by mixing hexane and acetone in a 5:5 mass ratio was used as the reprecipitation purification solvent, and the reprecipitation was stopped after 5 hours. GPC measurement of Polymer C showed that the weight average molecular weight was 710,300. Furthermore, the glass transition temperature of Polymer C in a dry state was −11° C., the glass transition temperature in a saturated water-containing state was −60° C., the difference ΔTg between the glass transition temperature in a saturated water-containing state and the glass transition temperature in a dry state was 49° C., and the saturated water content was 30.0 mass%.

[0078] [Production Example 4: Production of Polymer D] Polymer D was obtained by the same procedure as in Production Example 1, except that 1.8 g of MEOCNA and 1.2 g of 2-methoxyethyl acrylate (hereinafter also referred to as "MEA") were used as monomers, 0.174 g of V-65 initiator as a radical initiator, 12 g of ethyl acetate as a solvent, and a solvent obtained by mixing hexane and acetone in a 5:5 mass ratio as a reprecipitation purification solvent were used. GPC measurement of Polymer D revealed that it had a weight average molecular weight of 132,300. Furthermore, the glass transition temperature of Polymer D in a dry state was −22° C., the glass transition temperature in a saturated water-containing state was −62° C., the difference ΔTg between the glass transition temperature in a saturated water-containing state and the glass transition temperature in a dry state was 40° C., and the saturated water content was 22.4 mass%.

[0079] [Production Example 5: Production of Polymer E] Polymer E was obtained by the same operation as in Production Example 1, except that 0.9 g of MEOCNA and 2.1 g of MEA were used as monomers, 0.174 g of V-65 initiator as a radical initiator, 12 g of ethyl acetate as a solvent, and a solvent obtained by mixing hexane and acetone in a 5:5 mass ratio as a reprecipitation purification solvent were used. GPC measurement of Polymer E revealed that it had a weight average molecular weight of 114,000. Furthermore, the glass transition temperature of Polymer E in a dry state was −30° C., the glass transition temperature in a saturated water-containing state was −61° C., the difference ΔTg between the glass transition temperature in a saturated water-containing state and the glass transition temperature in a dry state was 31° C., and the saturated water content was 14.5% by mass.

[0080] [Production Example 6: Production of Polymer F] Polymer F was obtained by the same operation as in Production Example 1, except that 1.8 g of MEOCNA and 1.2 g of butyl acrylate (hereinafter also referred to as "BA") were used as monomers, 0.174 g of V-65 initiator as a radical initiator, 12 g of ethyl acetate as a solvent, and a solvent obtained by mixing hexane and acetone in a mass ratio of 6:4 as a reprecipitation purification solvent were used. GPC measurement of Polymer F revealed that the weight average molecular weight was 125,200. Furthermore, the glass transition temperature of Polymer F in a dry state was −23° C., the glass transition temperature in a saturated water-containing state was −42° C., the difference ΔTg between the glass transition temperature in a saturated water-containing state and the glass transition temperature in a dry state was 19° C., and the saturated water content was 7.7% by mass.

[0081] Production Example 7 Production of Polymer G Polymer G was obtained by the same procedure as in Production Example 1, except that 3 g of DMPOCNA was used as the monomer, 0.114 g of V-65 initiator as the radical initiator, 12 g of ethyl acetate was used as the solvent, and a solvent obtained by mixing hexane and acetone in a mass ratio of 6:4 was used as the reprecipitation purification solvent. As a result of GPC measurement of Polymer G, the weight average molecular weight was 96,300. Furthermore, the glass transition temperature of Polymer G in a dry state was −10° C., the glass transition temperature in a saturated water-containing state was −58° C., the difference ΔTg between the glass transition temperature in a saturated water-containing state and the glass transition temperature in a dry state was 48° C., and the saturated water content was 23.4% by mass.

[0082] [Production Example 8: Production of Polymer H] Polymer H was obtained by the same operation as in Production Example 1, except that 3 g of DEPOCNA was used as the monomer, 0.104 g of V-65 initiator as the radical initiator, 12 g of ethyl acetate was used as the solvent, and a solvent obtained by mixing hexane and acetone in a mass ratio of 8:2 was used as the reprecipitation purification solvent. As a result of GPC measurement of Polymer H, the weight average molecular weight was 104,800. Furthermore, the glass transition temperature of Polymer H in a dry state was −12° C., the glass transition temperature in a saturated water-containing state was −46° C., the difference ΔTg between the glass transition temperature in a saturated water-containing state and the glass transition temperature in a dry state was 34° C., and the saturated water content was 6.6% by mass.

[0083] Production Example 9: Production of Polymer I Polymer I was obtained by the same procedure as in Production Example 1, except that 4.5 g of MEOCNMA-EG was used as the monomer, 0.029 g of V-65 initiator was used as the radical initiator, 10.5 g of ethyl acetate was used as the solvent, and a solvent obtained by mixing hexane and acetone in a 9:1 mass ratio was used as the reprecipitation purification solvent. GPC measurement of Polymer I revealed that the weight average molecular weight was 135,100. Furthermore, the glass transition temperature of Polymer I in a dry state was −18° C., the glass transition temperature in a saturated water-containing state was −50° C., the difference ΔTg between the glass transition temperature in a saturated water-containing state and the glass transition temperature in a dry state was 32° C., and the saturated water content was 31.9 mass%.

[0084] Comparative Production Example 1: Production of Polymer J Polymer J was obtained by the same procedure as in Production Example 1, except that 3 g of EOCNA was used as the monomer, 0.332 g of V-59 initiator as the radical initiator, 27 g of ethyl acetate was used as the solvent, and a solvent obtained by mixing hexane and acetone in a mass ratio of 6:4 was used as the reprecipitation purification solvent. GPC measurement of Polymer J revealed that it had a weight average molecular weight of 100,400. Furthermore, Polymer J had a glass transition temperature of 2°C in a dry state, a glass transition temperature of -20°C in a saturated water-containing state, a difference ΔTg between the glass transition temperature in a saturated water-containing state and the glass transition temperature in a dry state of 22°C, and a saturated water content of 5.7% by mass.

[0085] Comparative Production Example 2: Production of Polymer K Polymer K was obtained by the same procedure as in Production Example 1, except that 3 g of IPOCNA was used as the monomer, 0.358 g of 2,2'-azobis(2-methylbutyronitrile) (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was used as the radical initiator, 27 g of ethyl acetate was used as the solvent, and a solvent obtained by mixing hexane and acetone in a 7:3 mass ratio was used as the reprecipitation purification solvent. GPC measurement of Polymer K revealed that the weight-average molecular weight was 93,200. Furthermore, the glass transition temperature of Polymer K in a dry state was 18°C, the glass transition temperature in a saturated water-containing state was −8°C, the difference ΔTg between the glass transition temperature in a saturated water-containing state and the glass transition temperature in a dry state was 26°C, and the saturated water content was 4.5% by mass.

[0086] Comparative Production Example 3 Production of Polymer L Polymer L was obtained by the same procedure as in Production Example 1, except that 3 g of MEA was used as the monomer, 0.555 g of V-59 initiator as the radical initiator, 27 g of ethyl acetate was used as the solvent, and a solvent obtained by mixing hexane and acetone in a mass ratio of 6:4 was used as the reprecipitation purification solvent. GPC measurement of Polymer L revealed that the weight average molecular weight was 84,000. Furthermore, the glass transition temperature of Polymer L in a dry state was −37° C., the glass transition temperature in a saturated water-containing state was −60° C., the difference ΔTg between the glass transition temperature in a saturated water-containing state and the glass transition temperature in a dry state was 23° C., and the saturated water content was 8.4% by mass.

[0087] 3. Production and Evaluation of Medical Coating Agents [Examples 1 to 9 and Comparative Examples 1 to 3] Polymer solutions were produced as medical coating agents using the polymers produced in Production Examples 1 to 9 and Comparative Production Examples 1 to 3, and a fibrinogen adsorption test (MicroBCA assay) and a platelet adsorption test were carried out. Details of each evaluation method are as follows.

[0088] <Fibrinogen Adsorption Amount Test (MicroBCA Assay)> A 0.2 (w / v)% solution of each polymer (Example 1: acetone solution; Comparative Examples 1 and 2: ethyl acetate solutions; Examples 2 to 9 and Comparative Example 3: methanol solution) was prepared and used as a medical coating agent. 15 μL of each medical coating agent was dropped into each well of a 96-well plate (Corning Incorporated, General Assay Plate, Polypropylene 96-well Perfect Plate, Flat Bottom, Non-sterile) and allowed to dry for 3 days to obtain evaluation coated substrate 1. Subsequently, 50 μL of a solution prepared by dissolving fibrinogen in PBS(-) (Fujifilm Wako Pure Chemical Industries, Ltd.) to a concentration of 1 mg / mL was added to each well. The plates were then incubated at 37°C for 10 minutes. After incubation, the internal solution was removed, and 200 μL of PBS(-) was added to each well for washing. This process was repeated 7 times. After drying, 50 μL of extract solution (a solution prepared by mixing 5% SDS aqueous solution and 0.1 N sodium hydroxide aqueous solution at a volume ratio of 1:1) was added to each well. The plates were then cultured at 37°C for 2 hours. After the culture, 50 μL of PBS(-) was added to each well, followed by 100 μL of Working Reagent prepared according to the instructions for the Micro BCA Protein Assay Kit (manufactured by Thermo Scientific). The plates were then heated at 60°C for 1 hour. After heating, the absorbance at 540 nm was measured using a plate reader (Vmax KINETIC MICROPLATE READER, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.). Based on the fibrinogen concentration of the resulting extract, the fibrinogen adsorption amount per unit area on the evaluation coating substrate 1 (μg / cm) was calculated. ２ ) (hereinafter also referred to as "FIB adsorption amount") was calculated. The smaller this value, the better the antithrombotic properties can be judged. The benchmark lines for calculating the concentration were prepared using bovine serum albumin included in the Micro BCA Protein Assay Kit (manufactured by Thermo Scientific) according to the instructions.

[0089] <Platelet Adsorption Test> A 0.2 (w / v)% solution of each polymer (Example 1: acetone solution; Comparative Examples 1 and 2: ethyl acetate solutions; Examples 2 to 9 and Comparative Example 3: methanol solutions) was prepared and used as a medical coating agent. Subsequently, a polyethylene terephthalate (PET) sheet (size: 5 cm square, thickness: 125 μm, manufactured by Mitsubishi Chemical Corporation, product name "DIAFOILT-100E") was thoroughly washed with acetone, and then 650 μL of each medical coating agent was applied to the PET sheet by spin coating. The spin coating conditions were as follows: 500 rpm, 5 s → 1,500 rpm, 10 s → 1,500 to 4,000 rpm (slope), 5 s → 4,000 rpm, 10 s → 4,000 to 0 rpm (slope), 5 s. Thereafter, the substrate was dried at room temperature (25°C) for 3 days to obtain a coated substrate for evaluation 2 for each medical coating agent. The obtained coated substrate for evaluation 2 was cut into 8 mm squares, and platelets were seeded onto the cut coated substrate for evaluation 2 at a density of 4 x 10 ７ 200 μL of plasma solution adjusted to platelets / cm 2 was placed on each plate. After incubation at 37°C for 1 hour, the evaluation coated substrate 2 was washed twice with PBS(-). The evaluation coated substrate 2 was then immersed in a 1% glutaraldehyde solution in PBS(-) and allowed to stand overnight at 4°C. The evaluation coated substrate 2 was removed and washed first with PBS(-), then with an aqueous solution prepared by mixing PBS(-) and water at a volume ratio of 1:1, and finally with pure water. Before each wash, the evaluation coated substrate 2 was immersed in the corresponding cleaning solution for 10 minutes. After washing, the evaluation coated substrate 2 was air-dried at room temperature (25°C) for 3 days, and the number of platelets adsorbed on the surface of the evaluation coated substrate 2 was measured using a scanning electron microscope (JEOL Ltd., JSM-7900F, vacuum degree 30 Pa, accelerating voltage 15 kV). Measurements were performed on five fields of view (magnification 1,500x, 4.8 x 10 －５ The number of platelets observed per visual field was counted, and the average of the five visual fields was taken as the number of platelets adsorbed (number / visual field). The smaller this value, the better the antithrombotic properties can be judged to be.

[0090] Comparative Example 4 In the fibrinogen adsorption test and platelet adsorption test, each test was carried out in the same manner as in Examples 1 to 9 and Comparative Examples 1 to 3, except that the 96-well plate or PET sheet was not coated with a medical coating agent.

[0091] The properties of the polymers used in Examples 1 to 9 and Comparative Examples 1 to 3, the evaluation results of the medical coating agents, and the evaluation results of Comparative Example 4 are shown in Table 1.

[0092]

[0093] 4. Evaluation Results As is clear from the results in Table 1, medical coating agents containing polymers that contain the structural unit (A) and have a glass transition temperature (Tg2) of -25°C or lower in a saturated water-containing state had low fibrinogen adsorption (FIB adsorption) and low platelet adsorption, and exhibited excellent antithrombogenic properties. This is thought to be because polymers A to I used in Examples 1 to 9 had a high saturated water content of 6% or more, and therefore had a large amount of intermediate water on the polymer surface, making them less likely to be recognized as foreign matter by biological components, thereby enabling them to exhibit excellent antithrombogenic properties.

[0094] In contrast, the medical coating agents of Comparative Examples 1 and 2, which contained polymers J and K having the structural unit (A) but a glass transition temperature (Tg2) in a saturated water-containing state higher than -25°C, had both a higher fibrinogen adsorption amount (FIB adsorption amount) and a higher platelet adsorption number than the medical coating agents of Examples 1 to 9, demonstrating insufficient antithrombotic properties. Furthermore, the medical coating agent of Comparative Example 3, which contained polymer L having MEA units but no structural unit (A), also had both a higher fibrinogen adsorption amount (FIB adsorption amount) and a higher platelet adsorption number than the medical coating agents of Examples 1 to 9, demonstrating inferior antithrombotic properties.

[0095] The present invention is not limited to the above-described embodiments, and encompasses various modifications and equivalent modifications within the scope of the spirit of the present invention. Therefore, in light of the above teachings, various combinations and forms, as well as other combinations and forms including only one element, more than one element, or less than one element, are to be understood as falling within the scope and spirit of the present invention.

Claims

1. The polymer contains a structural unit (A) derived from an ethylenically unsaturated monomer having a urethane bond, The medical coating agent has a glass transition temperature of -25°C or lower when the polymer is saturated with water, when the water content of the polymer is saturated when the peak top of the endothermic heat due to ice melting appears at 0°C in a DSC curve obtained by absorbing water into the polymer and raising the temperature at a rate of 5°C / min using a differential scanning calorimeter (DSC).

2. The medical coating agent according to claim 1 , wherein the polymer contains the structural unit (A) in an amount of 10 mass % or more based on all structural units contained in the polymer.

3. 3. The medical coating agent according to claim 1, wherein the difference between the glass transition temperature of the polymer in a dry state and the glass transition temperature of the polymer in a saturated hydrated state is 25°C or more, as measured using a differential scanning calorimeter at a heating rate of 5°C / min.

4. The medical coating agent according to claim 1 or 2, wherein the polymer is a (meth)acrylic polymer.

5. A medical device comprising a substrate coated with the medical coating agent according to claim 1 or 2.