Medical coatings and medical devices

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

[Technical Field]

[0001] [Cross-reference of related applications] This application claims priority under Japanese Patent Application No. 2021-161734, filed on 30 September 2021, which is incorporated herein by reference in its entirety. This disclosure relates to medical coatings and medical devices, and more specifically, to technologies for imparting biocompatibility to medical devices used in contact with biological components or tissues. [Background technology]

[0002] Various materials such as synthetic polymers, ceramics, glass, and metals are used as materials for medical devices. On the other hand, when medical devices come into contact with biological components or tissues, the body may recognize the medical device as a foreign object, which could impair the function of the medical device or affect the body. For example, in applications where medical devices come into contact with blood, the body's defense mechanisms may be activated when the medical device is recognized as a foreign object, potentially leading to the formation of blood clots. Therefore, there has been interest in conferring biocompatibility to medical devices 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. [Prior art documents] [Patent Documents]

[0004] [Patent Document 1] Japanese Patent Application Publication No. 04-152952 [Overview of the project] [Problems that the invention aims to solve]

[0005] Platelets and fibrinogen are considered to be the main components in blood involved in thrombus formation. Therefore, the inventors considered it important to prevent these components from recognizing medical devices inserted into the body as foreign objects. In other words, if the substrate surface can be sufficiently imparted with properties that suppress the adsorption of platelets and fibrinogen (hereinafter also referred to as "anti-adsorption properties"), it can be said that medical devices can be given excellent antithrombotic properties and their biocompatibility can be improved.

[0006] This disclosure has been made in view of these circumstances, and its purpose is to provide a medical coating agent that has high anti-adsorption properties for platelets and fibrinogen and excellent anti-thrombotic properties. [Means for solving the problem]

[0007] The following means are provided according to this disclosure.

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

[0009] [2] The medical coating agent according to [1] above, wherein the polymer contains 10% by mass or more of the structural unit (A) relative to the total structural units of the polymer. [3] The polymer is a medical coating agent according to [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 state, measured by differential scanning calorimeter at a heating rate of 5°C / min, is 25°C or more. [4] The polymer is a (meth)acrylic polymer, and is a medical coating agent according to any of [1] to [3] above. [5] A medical device in which any of the medical coating agents described in [1] to [4] above is coated onto a base material. [Effects of the Invention]

[0010] The polymer contained in the medical coating agent of this disclosure exhibits high anti-adsorption properties for platelets and fibrinogen, and has excellent antithrombotic properties. Therefore, by coating a medical device substrate with the medical coating agent of this disclosure, a medical device with excellent antithrombotic properties can be provided. [Modes for carrying out the invention]

[0011] The following provides a detailed explanation of this disclosure. In this specification, "(meth)acrylic" means acrylic and / or methacrylic, and "(meth)acrylate" means acrylate and / or methacrylate.

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

[0013] When water is added to a polymer (P), the water interacting with the polymer (i.e., hydration water) can take on three forms depending on the strength of its interaction with the polymer: "free water," "antifreeze water," and "intermediate water." Of these, "free water" refers to water with a weak interaction with the polymer and a freezing point of 0°C, while "antifreeze water" refers to water with a strong interaction with the polymer and no detectable freezing point. "Intermediate water" refers to water whose interaction with the polymer is intermediate between free water and antifreeze water (i.e., it interacts with the polymer relatively gently) and has a freezing point below 0°C. It is believed that the acquisition of biocompatibility by polymers is related to the fact that hydrated polymers contain a large amount of intermediate water (see, for example, paragraphs 0003 and 0004 of Japanese Patent Application Publication No. 2016-35000).

[0014] More specifically, in vivo, when cells recognize foreign substances within the living body, the body's defense function is activated and a rejection reaction occurs. Therefore, when a medical device comes into contact with a biological component or tissue during treatment, surgery, or the like, if the living body recognizes the medical device as a foreign substance, the body's defense function may act and impede treatment or the like. For example, when a medical device comes into contact with blood, it is conceivable that a blood clot may form, inhibiting the function of the medical device or affecting the living body. On the other hand, a polymer having intermediate water on its surface is considered to be difficult to be recognized as a foreign substance by the living body and can exhibit excellent antithrombotic properties.

[0015] Here, as components in blood involved in blood clot formation, platelets and fibrinogen are known. Platelets are blood cells that are activated by foreign substances and aggregate on the foreign substances to form blood clots (platelet thrombi), contributing to primary hemostasis in the process of hemostasis. Fibrinogen, which is factor I of coagulation, is a protein that is converted into fibrin in the final stage of blood coagulation to form a coagulation thrombus, contributing to secondary hemostasis in the process of hemostasis. That is, both platelets and fibrinogen are major components that form blood clots, and it is considered important for biocompatibility (more specifically, antithrombotic properties) that these components are difficult to adsorb onto the polymer.

[0016] In this regard, the polymer (P) contained in the medical coating agent of the present disclosure is likely to retain intermediate water during hydration, and can sufficiently suppress the adsorption of platelets and fibrinogen onto the surface of the substrate coated with the polymer (P). Thereby, it is considered that excellent antithrombotic properties can be exhibited.

[0017] In this specification, in the DSC curve obtained by heating a polymer containing water under the condition of a heating rate of 5°C / min, the water-containing state of the polymer when the peak top of the endotherm due to ice melting appears at 0°C is defined as the "saturated water-containing state". However, in this specification, the phrase "when the peak top of the endotherm due to ice melting appears at 0°C" means that as long as the polymer contains sufficient water and can be regarded as being in a saturated water-containing state, an error in which the peak top of the endotherm appears near 0°C (for example, 0°C ± 0.2°C) is allowed.

[0018] Hereinafter, each component contained in the medical coating agent of the present disclosure will be described.

[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] ​​​​​​​​​ CH2=CR , ,

[0023] , , 3 , 3 ,

[0025] ,

[0024] , , , 4 , , 4 , , 6 -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 a group represented by "-(R 5 O) m -R 6 -」(however, R 5 is an alkylene group having 1 to 3 carbon atoms, 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, and any hydrogen atom possessed by the alkylene group may be substituted with an alkoxy group having 1 to 10 carbon atoms, and R 4 is an alkoxy group having 1 to 10 carbon atoms) The compound represented by can be preferably used. <​​​​​​​​​​​​​Specific examples of compounds represented by the above 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 include (((1,3-diethoxypropane-2-yl)oxy)carbonyl)amino)ethyl (meth)acrylate, 2-((((1-methoxy-3-ethoxypropane-2-yl)oxy)carbonyl)amino)ethyl (meth)acrylate, 6-oxo-2,5,10-trioxa-7-azadodecane-12-yl (meth)acrylate, and 7-oxo-3,6,11-trioxa-8-azatodecane-13-yl (meth)acrylate.

[0026] From the viewpoint of introducing a sufficient amount of side chain structures having urethane bonds into the polymer while sufficiently lowering the glass transition temperature (Tg2) of the saturated polymer (P), the polymer (P) preferably contains 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, structural units derived from at least one compound selected from the group consisting of (methoxycarbonyl)aminoalkyl (meth)acrylate and compounds represented by the above general formula (I) (hereinafter also referred to as "monomer (m-1)"), out of the total structural units derived from the monomers constituting the polymer (P). Note that the polymer (P) may have only one type of structural unit derived from monomer (m-1), or it may have two or more types.

[0027] The polymer (P) may consist only of structural units derived from monomer (m-1), but may also have structural units derived from monomers other than monomer (m-1) (hereinafter also referred to as "other monomers") to the extent that it does not impair the effects of the present disclosure, for purposes such as adjusting the glass transition temperature of the polymer.

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

[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, monohydroxyethyl (meth)acrylate succinate, ω-carboxy-caprolactone mono(meth)acrylate, β-carboxyethyl (meth)acrylate, and 4-carboxystyrene. Examples of unsaturated anhydrides include maleic anhydride, itaconic anhydride, and citraconic anhydride.

[0030] Examples of alkyl (meth)acrylates 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, and dicyclopentanyl (meth)acrylate. Specific examples of aromatic esters of (meth)acrylic acid include phenyl (meth)acrylate, benzyl (meth)acrylate, phenoxymethyl (meth)acrylate, 2-phenoxyethyl (meth)acrylate, and 3-phenoxypropyl (meth)acrylate.

[0032] Specific examples of (meth)acrylate alkoxyalkyl esters 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 (meth)acrylate hydroxyalkyl esters 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. Examples of polyalkylene glycol mono(meth)acrylates include polyethylene glycol mono(meth)acrylate, polypropylene glycol mono(meth)acrylate, and polyethylene glycol-polypropylene glycol mono(meth)acrylate.

[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 amino group-containing vinyl compounds 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 vinyl compounds containing amide groups include (meth)acrylamide, N,N-dimethyl(meth)acrylamide, N,N-dimethylaminopropyl(meth)acrylamide, and N-methylol(meth)acrylamide.

[0037] Examples of nitrile group-containing vinyl compounds 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] Aromatic vinyl compounds include styrene, α-methylstyrene, β-methylstyrene, vinylxylene, methylstyrene, ethylstyrene, butylstyrene, methoxystyrene, hydroxystyrene, isopropenylphenol, vinylbenzoic acid, and vinylnaphthalene.

[0039] Examples of maleimide compounds include maleimides and N-substituted maleimide compounds. Examples of N-substituted maleimide compounds include N-alkyl-substituted maleimides such as N-methylmaleimide, N-ethylmaleimide, Nn-propylmaleimide, N-isopropylmaleimide, Nn-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 can copolymerize 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. Note that these other monomers may be used individually or in combination of two or more.

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

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

[0043] When the polymer (P) has structural units derived from at least one monomer selected from the group consisting of alkyl (meth)acrylate esters having an alkyl group having 1 to 12 carbon atoms and alkoxyalkyl (meth)acrylate esters having an alkoxyalkyl group having 3 to 12 carbon atoms (hereinafter also referred to as "monomer (N)"), 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, relative to the total structural units derived from the monomers constituting the polymer (P). Regarding the upper limit of the proportion of structural units derived from monomer (N), from the viewpoint of suppressing performance degradation due to the small amount of introduced structural unit (A), it 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, relative to the total structural units derived from the monomers constituting the polymer (P).

[0044] The polymer (P) preferably contains 10% by mass or more of structural units (A) relative to the total structural units of the polymer (P). When the proportion of structural units (A) in the polymer (P) is within the above range, it is preferable that the medical coating agent of this disclosure can be sufficiently imparted to a substrate to which it is coated to suppress the adsorption of platelets and fibrinogen, and a medical device with excellent antithrombotic properties can be obtained. From this viewpoint, the proportion of structural units (A) in the polymer (P) is more preferably 20% by mass or more, even more preferably 30% by mass or more, even more preferably 50% by mass or more, and even more preferably 60% by mass or more, relative to the total structural units of the polymer (P).

[0045] When polymer (P) is a copolymer of monomer (M) and another monomer that does not have urethane bonds, polymer (P) may be a random copolymer, a block copolymer, or a graft copolymer. From the viewpoint of uniformly introducing a structure having urethane bonds throughout the polymer to enhance the antithrombotic effect, 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. When Mw is 2,000 or higher, sufficient mechanical strength of the coating layer formed using the medical coating agent can be ensured. Furthermore, when Mw is 2,000,000 or lower, excessive viscosity of the medical coating agent can be suppressed, ensuring coatability and handling. More preferably, the Mw of the polymer (P) is 5,000 or higher, even more preferably 10,000 or higher, even more preferably 30,000 or higher, and even more preferably 50,000 or higher. The upper limit of the Mw of the polymer (P) is more preferably 1,500,000 or lower, and even more preferably 1,000,000 or lower. 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 polymer (P) is not particularly limited. Polymer (P) can be obtained by polymerizing monomers using known radical polymerization methods such as solution polymerization, suspension polymerization, emulsion polymerization, and bulk polymerization. In the case of solution polymerization, for example, the desired polymer can be obtained by charging an organic solvent and monomers into a reactor, adding a polymerization initiator (e.g., an azo compound), and heating to 40-250°C to polymerize. When isolating and / or purifying the polymer obtained by the polymerization reaction, known methods can be used for these processes.

[0048] The glass transition temperature (Tg1) of the polymer (P) in a dry state is not particularly limited, but is preferably 20°C or lower, and 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, but is preferably -70°C or higher. In this specification, the glass transition temperature of the polymer (P) is the value measured by differential scanning calorimeter (DSC) at a heating rate of 5°C / min. Details of the measurement method are as 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) of -25°C or lower in a saturated water state. If the glass transition temperature (Tg2) of the polymer (P) in a saturated water state is higher than -25°C, there is a concern that sufficient anti-adsorption properties for platelets and fibrinogen cannot be imparted to the substrate surface, and the desired anti-thrombotic properties cannot be imparted. From the viewpoint of sufficiently increasing the anti-adsorption properties for platelets and fibrinogen, the glass transition temperature (Tg2) of the polymer (P) in a saturated water 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 state is not particularly limited, and is, for example, -100°C or higher.

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

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

[0052] <Other ingredients> The medical coating agents of this disclosure may further contain components other than the polymer (P) (hereinafter also referred to as "other components") depending on the purpose of use. If the medical coating agent of this 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] If the medical coating agent of this disclosure contains a solvent, the solvent is preferably one that can dissolve the polymer (P). The solvent contained in the medical coating agent of this 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 this disclosure include solvents, as well as various drugs such as antibacterial agents, anti-inflammatory agents, and antioxidants. One or more of these other components may be used. The content of each other component can be appropriately selected, within a range that does not impair the effects of this disclosure.

[0055] In the medical coating agent of this 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, based on 100 parts by mass of the total amount of solids contained in the medical coating agent (i.e., components other than the solvent in the medical coating agent). Setting the content of polymer (P) within the above range is advantageous because it exhibits excellent antithrombotic properties and can impart stable biocompatibility to the substrate.

[0056] When the medical coating agent of this disclosure is in solution, the solid content concentration in the medical coating agent (here, the ratio of the mass of components other than the solvent in the medical coating agent to the volume of the solvent used in the preparation of the medical coating agent) is not particularly limited, but is preferably 0.001 to 30 (w / v)%. By setting the solid content concentration to 0.001 (w / v)% or higher, a coating layer with sufficient thickness and mechanical strength can be formed on the substrate. If the solid content concentration is 30 (w / v)% or lower, good coatability can be ensured, and it is easy to form a coating layer of uniform thickness. The solid content 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 devices The medical device of this disclosure is formed by coating a substrate with the medical coating agent of this disclosure described above. Part or all of the surface of the medical device of this disclosure is covered with polymer (P) contained in the medical coating agent of this disclosure. As a result, it has high anti-adsorption properties for platelets and fibrinogen and excellent antithrombotic properties.

[0058] The substrate of a medical device to which the medical coating agent of this disclosure is applied is not particularly limited. Examples of materials constituting the substrate include various materials such as resins, rubber, metals, glass, and ceramics. Among these, examples of resins include polycarbonate, polyethylene terephthalate, polyvinyl chloride, polyethylene, polypropylene, polymethylpentene, polyurethane, poly(meth)acrylate, polystyrene, polyacetal, polysulfone, polyethersulfone, fluororesins (polyvinylidene fluoride, tetrafluoroethylene, etc.), acrylonitrile-butadiene-styrene (ABS) resin, polyamide, and ethylene-vinyl acetate resin. Examples of rubber include silicone rubber and urethane rubber. Examples of metals include various metallic 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 a substrate surface with the medical coating agent of this disclosure is not particularly limited. For example, if the medical coating agent is in a solution state, a medical device can be obtained in which at least a portion of the substrate surface is coated with polymer (P) by applying the medical coating agent to the substrate surface and removing the solvent by means of heating or other means.

[0060] The coating method can be appropriately set according to the shape of the substrate and the intended use. Examples of coating methods include bar coaters, applicators, doctor blades, dip coaters, roll coaters, spin coaters, flow coaters, knife coaters, comma coaters, reverse coaters, die coaters, lip coaters, gravure coaters, microgravure coaters, and injet coatings. The amount of medical coating agent applied can be appropriately selected according to the application and materials of the medical device, so that the thickness of the coating layer formed by the medical coating agent is within the desired range.

[0061] The medical devices whose substrate surfaces are coated with the medical coating agent of this disclosure are not particularly limited and can be applied to a variety of medical devices. Specifically, examples include stents, catheters, blood bags, transfusion devices, surgical instruments, dental instruments, blood circulation devices, blood purification devices, plasma separators, artificial blood vessels, and artificial organs (e.g., cardiopulmonary bypass machines, artificial kidneys, etc.). Furthermore, the purpose and use of applying the medical coating agent of this disclosure to medical devices are not particularly limited. For example, the medical coating agent of this disclosure may be used as an antibacterial and antifouling coating agent. Considering that the medical coating agent of this disclosure can impart excellent antithrombotic properties to the substrate surface, it is particularly suitable for use as a coating material for substrates of medical devices that come into direct contact with blood. [Examples]

[0062] The present disclosure will be described in detail below based on the 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 stirring bar was added to a 300 mL three-necked flask, and 50 mL of tetrahydrofuran (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added 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 the starting alcohol. A thermometer, a 50 mL dropping funnel, and a three-way stopcock were then attached. Subsequently, 10.58 g of 2-acryloyloxyethyl isocyanate (manufactured by Showa Denko Corporation, trade name: Karenz AOI, hereinafter also referred to as "AOI") was added to the dropping funnel. Next, nitrogen was flowed through a three-way stopcock at a rate of 100 mL / min for 10 minutes. After the 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 a dropping funnel while maintaining the internal temperature below 10°C. Once the dropwise addition was complete, the temperature was raised to room temperature (25°C), and stirring was continued overnight. Subsequently, 10 mL of saturated sodium bicarbonate solution was added dropwise to the flask to terminate the reaction. 200 mL of the solution was transferred to a separatory funnel to separate the organic layer from the aqueous layer. 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 solution was added to the recovered organic layer and shaken to wash it. This shaking and washing procedure was repeated twice. 30 mg of anhydrous sodium sulfate (Fujifilm Wako Pure Chemical Industries, Ltd.) was added to the washed organic layer and stirred for 1 hour to dehydrate it. The mixture was filtered using pleated filter paper to remove the sodium sulfate, and paramethoxyphenol was added to a theoretical yield of 250 ppm. Next, the solvent was removed using a rotary evaporator while the sample was immersed in a 40°C water bath. After removing the solvent, the sample was left to stand under reduced pressure for 1 hour using a vacuum pump to remove any remaining solvent. The recovered sample was purified by silica gel column chromatography using a solvent mixture of hexane and 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] Except for adding 3.46 g of ethanol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) as the raw material alcohol, the same procedure as in Synthesis Example 1 was carried out 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] Except for adding 6.28 g of 2-methoxyethanol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) as the starting alcohol, the same procedure as in Synthesis Example 1 was carried out 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] Except for adding 9.91 g of 1,3-dimethoxy-2-propanol (manufactured by Combi-Blocks) as the starting alcohol, the same procedure as in Synthesis Example 1 was carried out 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] Except for adding 9.91 g of 1,3-diethoxy-2-propanol (manufactured by Tokyo Chemical Industry Co., Ltd.) as the starting alcohol, the same procedure as in Synthesis Example 1 was carried out 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] Except for adding 4.96 g of 2-propanol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) as the starting alcohol, the same procedure as in Synthesis Example 1 was carried out to obtain 2-((isopropoxycarbonyl)amino)ethyl acrylate (hereinafter also referred to as "IPOCNA").

[0069] [Synthesis example 7: 6-oxo-2,5,10-trioxa-7-azadodecane-12-ylmethacrylate] Except for adding 14.94 g of 2-(2-methacryloyloxyethyloxy)ethyl isocyanate (manufactured by Showa Denko, trade name: Karenz MOI-EG, hereinafter also referred to as "MOI-EG") instead of AOI, and 6.28 g of 2-methoxyethanol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) as the starting alcohol, the same procedure as in Synthesis Example 1 was carried out to obtain 6-oxo-2,5,10-trioxa-7-azadodecane-12-ylmethacrylate (hereinafter also referred to as "MEOCNMA-EG").

[0070] 2. Production and Analysis of Polymers Each polymer was prepared according to the following production examples 1-9 and comparative production examples 1-3. For each obtained polymer, the weight-average molecular weight (Mw), glass transition temperature in the dry state (Tg1), glass transition temperature in the saturated water state (Tg2), and saturated water content were measured by the following methods.

[0071] <Measurement of weight-average molecular weight (Mw) of polymers> The weight-average molecular weight (Mw) of the polymer was measured by gel permeation chromatography (GPC) analysis under the following conditions. (Measurement conditions for GPC analysis) • Device: Tosoh Corporation, model number HLC-8320GPC • Detector: RI detector • Column: Tosoh TSKgel SuperMultiporeHZ-M x 3 Column temperature: 40°C • Eluent: Tetrahydrofuran (containing 0.03% sulfur as an internal standard) ·Flow rate: 350μL / min Calibration curve: Standard polystyrene

[0072] <Measurement of the glass transition temperature (Tg1) of polymers in a dry state> Each obtained polymer was dried overnight under reduced pressure conditions of 60°C and 1000 Pa. Each dried polymer was weighed into an aluminum pan. Then, using a differential scanning calorimeter (measuring instrument: NETZSCH DSC214Polyma, measurement atmosphere: air atmosphere), the samples were cooled from 100°C to -80°C at a heating rate of 5°C / min, held at -80°C for 5 minutes, and then heated to 100°C. The glass transition temperature (Tg1) of the polymer in the dry state was determined by this method.

[0073] <Measurement of glass transition temperature (Tg2) of polymers in a saturated water state> Each polymer was immersed in a large excess of pure water (10 g of pure water per 30 mg of polymer) and left to stand at room temperature (25°C) for 3 days to allow it to absorb water. The absorbed polymers were removed from the pure water using tweezers, and any remaining water was removed from each polymer using weighing paper. Then, 0.003 to 0.005 g of each absorbed polymer was weighed into an aluminum pan. The weighed value at this time was denoted as "X (unit: g)". Subsequently, the glass transition temperature (Tg2) of the polymer in a saturated water state was determined by using a differential scanning calorimeter, similar to the measurement of the glass transition temperature (Tg1) of the polymer in a dry state, cooling from 40°C to -100°C at a heating rate of 5°C / min, holding at -100°C for 5 minutes, and then heating back up to 40°C. Furthermore, in the DSC curve obtained by DSC measurement under the condition of a heating rate of 5°C / min, the water content state of the polymer when the peak of endothermic heating due to ice melting appeared 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 of endothermic heating due to ice melting appeared at 0°C.

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

[0075] [Manufacturing Example 1: Manufacturing of Polymer A] In a two-necked test tube, 3 g of MOCNA as the monomer, 0.272 g of 2,2'-azobis(2,4-dimethylvaleronitrile) (manufactured by Fujifilm Wako Pure Chemical Industries, hereafter also referred to as "V-65 initiator") as a radical initiator, and 12 g of acetonitrile as a solvent were added. Then, a stirring bar was 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 through the three-way stopcock, and argon was blown into the solution at 100 mL / min for 30 minutes to deoxygenate it. After that, the three-way stopcock was closed and the test tube was sealed. The test tube was placed in a heat block set to 60°C and polymerization was started. The temperature of the heat block was adjusted as needed to maintain an internal temperature of 60°C. After 3 hours, the test tube was cooled in an ice bath to stop polymerization. The reaction solution was reprecipitation and purified twice using a solvent of hexane and acetone mixed in a mass ratio of 3:7 as the reprecipitation and purification solvent. Subsequently, the recovered polymer was reprecipitated and purified using pure water as a solvent to obtain polymer A. GPC analysis of polymer A revealed that its weight-average molecular weight was 71,300. The glass transition temperature of polymer A in the dry state was 7°C, the glass transition temperature in the saturated water state was -30°C, the difference ΔTg between the glass transition temperature in the saturated water state and the glass transition temperature in the dry state was 37°C, and the saturated water content was 12.0% by mass.

[0076] [Manufacturing Example 2: Manufacturing 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 a radical initiator, 27 g of ethyl acetate was used as the solvent, and a solvent of hexane and acetone mixed in a mass ratio of 4:6 was used as the solvent for reprecipitation purification. GPC measurement of polymer B showed that the weight-average molecular weight was 100,800. Furthermore, the glass transition temperature of polymer B in the dry state was -10°C, the glass transition temperature in the saturated water state was -60°C, the difference ΔTg between the glass transition temperature in the saturated water state and the glass transition temperature in the dry state was 50°C, and the saturated water content was 31.5% by mass.

[0077] [Manufacturing Example 3: Manufacturing of Polymer C] Polymer C was obtained by following 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 as the solvent, and a solvent prepared by mixing hexane and acetone in a 5:5 mass ratio as the reprecipitation purification solvent, and stopping after 5 hours. GPC measurement of polymer C revealed that the weight-average molecular weight was 710,300. Furthermore, the glass transition temperature of polymer C in the dry state was -11°C, the glass transition temperature in the saturated water state was -60°C, the difference ΔTg between the glass transition temperature in the saturated water state and the glass transition temperature in the dry state was 49°C, and the saturated water content was 30.0 mass%.

[0078] [Manufacturing Example 4: Manufacturing 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 of hexane and acetone mixed in a 5:5 mass ratio as a reprecipitation purification solvent. GPC measurement of polymer D showed that the weight-average molecular weight was 132,300. Furthermore, the glass transition temperature of polymer D in the dry state was -22°C, the glass transition temperature in the saturated water state was -62°C, the difference ΔTg between the glass transition temperature in the saturated water state and the glass transition temperature in the dry state was 40°C, and the saturated water content was 22.4 mass%.

[0079] [Manufacturing Example 5: Manufacturing of Polymer E] Polymer E was obtained by the same procedure 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 was used as a radical initiator, 12 g of ethyl acetate was used as a solvent, and a solvent of hexane and acetone mixed in a 5:5 mass ratio was used as a solvent for reprecipitation purification. GPC measurement of polymer E revealed that the weight-average molecular weight was 114,000. Furthermore, the glass transition temperature of polymer E in the dry state was -30°C, the glass transition temperature in the saturated water state was -61°C, the difference ΔTg between the glass transition temperature in the saturated water state and the glass transition temperature in the dry state was 31°C, and the saturated water content was 14.5% by mass.

[0080] [Manufacturing Example 6: Manufacturing of Polymer F] Polymer F was obtained by the same procedure 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 of hexane and acetone mixed in a mass ratio of 6:4 as a reprecipitation purification solvent. GPC measurement of polymer F revealed that the weight-average molecular weight was 125,200. Furthermore, the glass transition temperature of polymer F in the dry state was -23°C, the glass transition temperature in the saturated water state was -42°C, the difference ΔTg between the glass transition temperature in the saturated water state and the glass transition temperature in the dry state was 19°C, and the saturated water content was 7.7 mass%.

[0081] [Manufacturing Example 7: Manufacturing 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 was used as the radical initiator, 12 g of ethyl acetate was used as the solvent, and a solvent of hexane and acetone mixed in a mass ratio of 6:4 was used as the solvent for reprecipitation purification. GPC measurement of polymer G revealed that the weight-average molecular weight was 96,300. Furthermore, the glass transition temperature of polymer G in the dry state was -10°C, the glass transition temperature in the saturated water state was -58°C, the difference ΔTg between the glass transition temperature in the saturated water state and the glass transition temperature in the dry state was 48°C, and the saturated water content was 23.4% by mass.

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

[0083] [Manufacturing Example 9: Manufacturing 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 of hexane and acetone mixed in a mass ratio of 9:1 was used for reprecipitation and purification. GPC measurement of Polymer I showed that the weight-average molecular weight was 135,100. Furthermore, the glass transition temperature of Polymer I in the dry state was -18°C, the glass transition temperature in the saturated water state was -50°C, the difference ΔTg between the glass transition temperature in the saturated water state and the glass transition temperature in the dry state was 32°C, and the saturated water content was 31.9% by mass.

[0084] [Comparative manufacturing 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 was used as the radical initiator, 27 g of ethyl acetate was used as the solvent, and a solvent of hexane and acetone mixed in a mass ratio of 6:4 was used as the solvent for reprecipitation and purification. GPC measurement of polymer J revealed that the weight-average molecular weight was 100,400. Furthermore, the glass transition temperature of polymer J in the dry state was 2°C, the glass transition temperature in the saturated water state was -20°C, the difference ΔTg between the glass transition temperature in the saturated water state and the glass transition temperature in the dry state was 22°C, and the saturated water content was 5.7 mass%.

[0085] [Comparative manufacturing 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 a radical initiator, 27 g of ethyl acetate was used as the solvent, and a solvent of hexane and acetone mixed in a mass ratio of 7:3 was used for reprecipitation and purification. GPC measurement of polymer K revealed that the weight-average molecular weight was 93,200. Furthermore, the glass transition temperature of polymer K in the dry state was 18°C, the glass transition temperature in the saturated water state was -8°C, the difference ΔTg between the glass transition temperature in the saturated water state and the glass transition temperature in the dry state was 26°C, and the saturated water content was 4.5% by mass.

[0086] [Comparative manufacturing example 3: Manufacturing 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 a radical initiator, 27 g of ethyl acetate as the solvent, and a solvent of hexane and acetone mixed in a mass ratio of 6:4 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 the dry state was -37°C, the glass transition temperature in the saturated water state was -60°C, the difference ΔTg between the glass transition temperature in the saturated water state and the glass transition temperature in the dry state was 23°C, and the saturated water content was 8.4% by mass.

[0087] 3. Manufacturing and evaluation of medical coating agents [Examples 1-9 and Comparative Examples 1-3] Polymer solutions were prepared as medical coating agents using each polymer produced according to Production Examples 1-9 and Comparative Production Examples 1-3, and fibrinogen adsorption tests (MicroBCA assay) and platelet adsorption tests were performed. Details of each evaluation method are as follows.

[0088] <Fibrinogen adsorption test (MicroBCA assay)> 0.2(w / v)% solutions of each polymer (Example 1: acetone solution, Comparative Examples 1 and 2: ethyl acetate solution, Examples 2-9 and Comparative Example 3: methanol solution) were prepared and used as medical coating agents. 15 μL of each medical coating agent was dropped into each well of a 96-well plate (Corning General Assay Plate, polypropylene 96-well perfect plate, flat bottom, non-sterile), and allowed to stand and dry for 3 days to obtain coating substrate 1 for evaluation. Then, 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 substrates were then incubated at 37°C for 10 minutes. After incubation, the internal solution was removed, and each well was washed with 200 μL of PBS(-), and this was repeated 7 times. After drying, 50 μL of extract (a solution prepared by mixing 5% SDS aqueous solution and 0.1N sodium hydroxide aqueous solution in a 1:1 volume ratio) was added to each well. The cells were then incubated at 37°C for 2 hours. 50 μL of PBS(-) was added to each well after incubation, followed by 100 μL of Working Reagent prepared according to the instructions for the Micro BCA Protein Assay Kit (Thermo Scientific). The mixture was then heated at 60°C for 1 hour. After heating, the absorbance at 540 nm was measured using a plate reader (Fujifilm Wako Pure Chemical Industries, Vmax KINETIC MICROPLATE READER). Based on the fibrinogen concentration of the obtained extract, the amount of fibrinogen adsorbed per unit area (μg / cm²) on the evaluation coating substrate 1 was determined. 2 The FIB adsorption amount (hereinafter also referred to as "FIB adsorption amount") was calculated. A smaller value indicates superior antithrombotic properties. The concentration chart was prepared using bovine serum albumin included with the Micro BCA Protein Assay Kit (Thermo Scientific), following the instructions.

[0089] <Platelet adsorption test> 0.2(w / v)% solutions of each polymer (Example 1: acetone solution, Comparative Examples 1 and 2: ethyl acetate solution, Examples 2-9 and Comparative Example 3: methanol solution) were prepared and used as medical coating agents. Subsequently, polyethylene terephthalate (PET) sheets (size: 5 cm square, thickness: 125 μm, manufactured by Mitsubishi Chemical Corporation, product name "DIAFOILT-100E") were thoroughly washed with acetone, and then 650 μL of each medical coating agent was applied to the PET sheets by spin coating. The spin coating conditions were 500 rpm, 5s → 1,500 rpm, 10s → 1,500 to 4,000 rpm (slope), 5s → 4,000 rpm, 10s → 4,000 to 0 rpm (slope), 5s. After that, the samples were dried at room temperature (25°C) for 3 days to obtain evaluation coating substrates 2 for each medical coating agent. The obtained evaluation coating substrate 2 was cut into 8 mm squares, and platelet seeding density was applied to the cut evaluation coating substrate 2 at 4 × 10⁻¹⁶. 7 200 μL of plasma solution, adjusted to a density of 1 / cm², was placed on each sample. After incubation at 37°C for 1 hour, the evaluation coating substrate 2 was washed twice with PBS(-). Subsequently, the evaluation coating substrate 2 was immersed in a 1% glutaraldehyde PBS(-) solution and left to stand overnight at 4°C. The evaluation coating substrate 2 was removed and washed first with PBS(-), then with an aqueous solution of PBS(-) and water in a 1:1 volume ratio, and finally with pure water. Before each wash, the evaluation coating substrate 2 was immersed in the target washing solution for 10 minutes. After washing, the evaluation coating substrate 2 was air-dried at room temperature (25°C) for 3 days. Then, the number of platelets adsorbed on the surface of the evaluation coating substrate 2 was measured using a scanning electron microscope (JEOL Ltd., JSM-7900F, vacuum 30 Pa, acceleration voltage 15 kV). For each substrate, 5 fields of view (magnification 1,500x, 4.8 × 10⁶) were measured. -5 The measurement was performed in square centimeters. The number of platelets observed per field of view was measured, and the average of the five fields of view was used as the platelet adsorption count (platelets / field of view). A smaller value indicates superior antithrombotic properties.

[0090] [Comparative Example 4] In the fibrinogen adsorption test and platelet adsorption test, each test was conducted 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] Table 1 shows the properties of the polymers used in Examples 1-9 and Comparative Examples 1-3, the evaluation results of the medical coating agents, and the evaluation results of Comparative Example 4.

[0092] [Table 1]

[0093] 4. Evaluation Results As is clear from the results in Table 1, medical coating agents containing polymers that include structural unit (A) and have a glass transition temperature (Tg2) of -25°C or lower in a saturated water state exhibited low fibrinogen adsorption (FIB adsorption) and platelet adsorption, and thus demonstrated excellent antithrombotic 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 substances by biological components, thus enabling them to exhibit excellent antithrombotic properties.

[0094] In contrast, the medical coating agents of Comparative Examples 1 and 2, which contain polymers J and K having structural unit (A) but a glass transition temperature (Tg2) higher than -25°C in a saturated water state, showed higher fibrinogen adsorption (FIB adsorption) and platelet adsorption numbers than the medical coating agents of Examples 1 to 9, confirming that their antithrombotic properties were insufficient. Furthermore, the medical coating agent of Comparative Example 3, which contains polymer L having MEA units but lacking structural unit (A), also showed higher fibrinogen adsorption (FIB adsorption) and platelet adsorption numbers than the medical coating agents of Examples 1 to 9, confirming that its antithrombotic properties were inferior.

[0095] The present invention is not limited to the embodiments described above, and encompasses various modifications and variations within the scope of equivalents, without departing from the spirit of the invention. Therefore, various combinations and forms, as well as other combinations and forms that include only one, more, or fewer of these elements, should be understood to fall within the scope and conceptual range of the present invention in light of the above teachings.

Claims

1. The polymer contains a structural unit (A) derived from an ethylenically unsaturated monomer having a urethane bond, A medical coating agent wherein, when the polymer is impregnated with water and heated at a rate of 5°C / min using a differential scanning calorimeter (DSC), the DSC curve obtained shows that the saturated water state of the polymer is defined as the state at which the peak of endothermic heating due to ice melting appears at 0°C, and the glass transition temperature of the polymer in the saturated water state is -25°C or lower.

2. The medical coating agent according to claim 1, wherein the polymer contains 10% by mass or more of the structural unit (A) relative to the total structural units of the polymer.

3. The medical coating agent according to claim 1 or 2, wherein the polymer has a glass transition temperature in a dry state measured by differential scanning calorimeter at a heating rate of 5°C / min, and the difference between the glass transition temperature in a saturated water-containing state is 25°C or more.

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

5. A medical device in which a medical coating agent according to claim 1 or 2 is coated on a substrate.

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