Medical coating agent and medical device

Abstract

This medical coating agent comprises a polymer including a structural unit (A) derived from an ethylenic unsaturated monomer having a urea bond. The polymer contained in the medical coating agent satisfies Condition (i) in a case where a polymer water-holding state when the peak top of heat absorption due to the melting of ice appears at 0°C is defined as a water saturation state in a DSC curve obtained by letting the polymer absorb water and then heating the polymer at a rate of 5°C / min using a differential scanning calorimeter. Condition (i): The intermediate water amount in the water saturation state is not less than 3.0 mass% with respect to the entire amount of the polymer in the water saturation state.

Description

Medical coatings and medical devices

[0001] [Cross-Reference to Related Applications] This application claims priority to Japanese Patent Application No. 2022-028196, filed February 25, 2022, 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] Fibrinogen, a type of blood coagulation factor, is thought to be one of the main components in blood involved in thrombus formation. Therefore, the present inventors considered that in order to suppress thrombus formation associated with the insertion of a medical device, it is important to prevent fibrinogen from recognizing the inserted medical device as a foreign body. In other words, if the property of inhibiting fibrinogen adsorption (hereinafter also referred to as "anti-adsorption") can be sufficiently imparted to the surface of a medical device, 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 to 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 urea bond, wherein the polymer satisfies the following condition (i), when the water content of the polymer is defined as a saturated water content 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 heating it at a rate of 5°C / min using a differential scanning calorimeter (DSC): Condition (i): The amount of intermediate water contained in the polymer in the saturated water content state is 3.0% by mass or more based on the total amount of the polymer in the saturated water content state.

[0009] [2] The medical coating agent of [1] above, wherein the polymer further satisfies the following condition (ii): Condition (ii): the amount of water of hydration contained in the polymer in a saturated water-containing state is 8.0 mass% or more based on the total amount of the polymer in a saturated water-containing state. [3] The medical coating agent of [1] or [2] above, wherein the polymer further satisfies the following condition (iii): Condition (iii): the ratio of the amount of intermediate water to the amount of nonfreezing water contained in the polymer in a saturated water-containing state is 0.50 or more.

[0010] [4] A medical coating agent comprising a polymer including a structural unit (A) derived from an ethylenically unsaturated monomer having a urea bond, wherein the polymer satisfies the following condition (ii), when the saturated water content of the polymer is determined as the water content of the polymer 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 heating it at a rate of 5°C / min using a differential scanning calorimeter (DSC): Condition (ii): The amount of water of hydration contained in the polymer in the saturated water content state is 8.0 mass% or more based on the total amount of the polymer in the saturated water content state.

[0011] [5] A medical coating agent comprising a polymer including a structural unit (A) derived from an ethylenically unsaturated monomer having a urea bond, wherein the polymer satisfies the following condition (iii), when the saturated water content of the polymer is determined by absorbing water into the polymer and raising the temperature at a rate of 5°C / min using a differential scanning calorimeter (DSC), and the DSC curve is obtained by measuring the temperature at which the peak top of the endothermic heat due to ice melting appears at 0°C: Condition (iii): The ratio of the amount of intermediate water to the amount of nonfreezing water contained in the saturated water content polymer is 0.50 or more.

[0012] [6] The medical coating agent according to any one of [1] to [5] 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. [7] The medical coating agent according to any one of [1] to [6] above, wherein the polymer is a (meth)acrylic polymer. [8] A medical device comprising a substrate coated with the medical coating agent according to any one of [1] to [7] above.

[0013] The polymer contained in the medical coating agent of the present disclosure has high anti-adsorption properties for 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.

[0014] FIG. 1 shows an example of a DSC curve of a polymer containing intermediate water during hydration in a saturated water-containing state.

[0015] The present disclosure will be described in detail below. In this specification, "(meth)acrylic" means acrylic and / or methacrylic, "(meth)acrylate" means acrylate and / or methacrylate, and "(meth)acrylo" means acrylo and / or methacrylo.

[0016] <Medical Coating Agent> A first medical coating agent according to the present disclosure contains a polymer (hereinafter also referred to as "polymer (P)") containing a structural unit (A) derived from an ethylenically unsaturated monomer having a urea bond (-NH-CO-NH-). The polymer (P) contained in the first medical coating agent satisfies the following condition (i), where the water content of the polymer (P) is defined as the water content at which the peak top of the endothermic heat due to ice melting appears at 0°C in a differential scanning calorimeter (DSC) curve obtained by absorbing water into the polymer (P) and heating it at a rate of 5°C / min. Condition (i): The intermediate water content contained in the saturated water-containing polymer (P) is 3.0% by mass or more relative to the total amount of the saturated water-containing polymer (P).

[0017] The second medical coating agent of the present disclosure contains a polymer (P) including a structural unit (A) derived from an ethylenically unsaturated monomer having a urea bond. The polymer (P) contained in the second medical coating agent satisfies the following condition (ii), where the "saturated water-containing state" of the polymer (P) is defined as the state in which the endothermic heat due to ice melting reaches a peak of 0°C in a DSC curve obtained by absorbing water into the polymer (P) and heating it at a rate of 5°C / min using a DSC. Condition (ii): The amount of water of hydration contained in the saturated water-containing polymer (P) is 8.0% by mass or more based on the total amount of the saturated water-containing polymer (P).

[0018] A third medical coating agent according to the present disclosure contains a polymer (P) including a structural unit (A) derived from an ethylenically unsaturated monomer having a urea bond. The polymer (P) contained in the third medical coating agent satisfies the following condition (iii), where the "saturated water-containing state" of the polymer (P) is defined as the state in which the endothermic heat due to ice melting reaches a peak of 0°C in a DSC curve obtained by adding water to the polymer (P) and heating the curve at a rate of 5°C / min using a DSC. Condition (iii): The ratio of the amount of intermediate water to the amount of nonfreezing water contained in the saturated water-containing polymer (P) is 0.50 or more.

[0019] 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. "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 hydrated polymer containing a large amount of intermediate water (see, for example, paragraphs 0003 and 0004 of JP 2016-35000 A).

[0020] 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, when a medical device comes into contact with blood, the body's defense mechanisms may be activated, resulting in the formation of blood clots, which may impair the function of the medical device or affect 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 be able to exhibit excellent antithrombotic properties.

[0021] 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, a 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. Fibrinogen is one of the main components in blood that is involved in the formation of thrombi, and it is believed that the resistance of fibrinogen to adsorption onto polymers is important for imparting biocompatibility (more specifically, antithrombogenicity) to medical devices.

[0022] In this regard, the polymer (P) contained in the first to third medical coating agents of the present disclosure easily retains intermediate water during hydration, and can sufficiently suppress adsorption of fibrinogen to the polymer (P), thereby enabling the first to third medical coating agents of the present disclosure to impart excellent antithrombotic properties to medical devices.

[0023] Hereinafter, each component contained in the first to third medical coating agents of the present disclosure will be described.

[0024] <First medical coating agent> <Polymer (P)> The polymer (P) contained in the first medical coating agent contains a structural unit derived from an ethylenically unsaturated monomer having a urea bond (hereinafter also referred to as "monomer (M)").

[0025] The polymer (P) is preferably a (meth)acrylic polymer, in terms of being able to easily increase the reaction rate of the monomer and being easy to produce industrially. Specifically, in the polymer (P), 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 mass%, more preferably 60 mass% or more, even more preferably 70 mass% or more, still more preferably 80 mass% or more, and even more preferably 90 mass% or more.

[0026] The monomer (M) is preferably a compound capable of introducing a structure having a urea bond into the side chain of a polymer, and is preferably a (meth)acrylic monomer having a urea 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.

[0027] The monomer (M) is a monomer represented by the following general formula (I): CH ２ =CR １ -COO-R ２ -NH-CO-NH-(R ３ O)n-R４ ...(I) (In general formula (I), R １ is a hydrogen atom or a methyl group, and R ２ is an alkylene group having 2 to 5 carbon atoms, and R ３ is an alkylene group having 1 to 3 carbon atoms, and R ４ is an alkyl group having 1 to 12 carbon atoms, and n is an integer of 0 to 2, provided that "-(R ３ The total number of carbon atoms in "R ３ the number of carbon atoms multiplied by n) and R ４ and the total number of carbon atoms of the aryl group is 4 or more.

[0028] Furthermore, from the viewpoint of sufficiently increasing the anti-adsorption property of fibrinogen and ensuring excellent biocompatibility, n in general formula (I) is preferably 1 or 2, and more preferably 1. From the same viewpoint, R ４ is more preferably an alkyl group having 1 to 5 carbon atoms, and even more preferably an alkyl group having 1 or 2 carbon atoms.

[0029] Specific examples of the compound represented by the general formula (I) include 2-(3-(2-ethoxyethyl)ureido)ethyl(meth)acrylate, 2-(3-(3-methoxypropyl)ureido)ethyl(meth)acrylate, 2-(3-(3-ethoxypropyl)ureido)ethyl(meth)acrylate, 2-(3-(4-methoxybutyl)ureido)ethyl(meth)acrylate, 3-(3-(2-ethoxyethyl)ureido) propyl (meth)acrylate, 3-(3-(3-methoxypropyl)ureido)propyl (meth)acrylate, 4-(3-(2-ethoxyethyl)ureido)butyl (meth)acrylate, 2-(3-(n-butyl)ureido)ethyl (meth)acrylate, 2-(3-(n-octyl)ureido)ethyl (meth)acrylate, 2-(3-(n-dodecyl)ureido)ethyl (meth)acrylate, and the like.

[0030] Among the above, the monomer (M) is a monomer represented by the general formula (I) in which n is 1 and R ４is an alkyl group having 1 to 5 carbon atoms, and in general formula (I), n is 1 and R ４ is an alkyl group having 1 or 2 carbon atoms. Of these, at least one selected from the group consisting of 2-(3-(2-ethoxyethyl)ureido)ethyl(meth)acrylate, 2-(3-(3-methoxypropyl)ureido)ethyl(meth)acrylate, 3-(3-(2-ethoxyethyl)ureido)propyl(meth)acrylate, and 3-(3-(3-methoxypropyl)ureido)propyl(meth)acrylate is particularly preferred.

[0031] The polymer (P) may be composed solely of structural units derived from the monomer (M). Alternatively, the polymer (P) may further contain structural units derived from a monomer other than the monomer (M) (hereinafter also referred to as "other monomers"), for the purpose of adjusting the glass transition temperature of the polymer, within a range that does not impair the effects of the present disclosure.

[0032] Examples of other monomers include monomers that do not have a urea bond and are copolymerizable with the monomer (M). Examples of such monomers include unsaturated carboxylic acids, unsaturated acid anhydrides, (meth)acrylic acid alkyl esters, (meth)acrylic acid aliphatic cyclic esters, (meth)acrylic acid aromatic 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] Examples of the alkoxyalkyl (meth)acrylate 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.

[0037] 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. 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.

[0038] Examples of vinyl compounds having a heterocyclic structure include glycidyl (meth)acrylate, (3,4-epoxycyclohexyl)methyl (meth)acrylate, and tetrahydrofurfuryl (meth)acrylate.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] Examples of aromatic vinyl compounds include styrene, α-methylstyrene, β-methylstyrene, vinylxylene, methylstyrene, ethylstyrene, butylstyrene, methoxystyrene, hydroxystyrene, isopropenylphenol, vinylbenzoic acid, and vinylnaphthalene.

[0043] 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. As the other monomer, one type may be used alone, or two or more types may be used in combination.

[0044] 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.

[0045] 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 or 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 medical coating agent highly effective in suppressing fibrinogen adsorption can be obtained.

[0046] The polymer (P) preferably contains the structural unit (A) in an amount of 10% by mass or more relative to the total structural units of the polymer (P). When the proportion of the structural unit (A) in the polymer (P) is within the above range, the effect of inhibiting fibrinogen adsorption can be sufficiently imparted to the substrate coated with the first medical coating agent, which is advantageous in that a medical device with excellent antithrombotic properties can be obtained. 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, even more preferably 60% by mass or more, and even more preferably 80% by mass or more relative to the total structural units of the polymer (P).

[0047] When the polymer (P) is a copolymer of the monomer (M) and another monomer, the polymer (P) may be any of a random copolymer, a block copolymer, a graft copolymer, etc. Among the above, the random copolymer is preferred from the viewpoint of uniformly introducing a structure having a urea bond into the entire polymer to enhance the effect of improving antithrombotic properties.

[0048] 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, these treatments can be carried out by using known methods. When the polymer is isolated and / or purified by a reprecipitation method, a water-insoluble polymer may be recovered at a high purity by using an aqueous solvent.

[0049] In the hydrated polymer (P), the water (hydration water) interacting with the polymer (P) can be classified into free water, non-freezing water, and intermediate water. The presence of intermediate water in the hydrated polymer (P), and the amounts of hydration water, intermediate water, non-freezing water, and free water contained in the hydrated polymer (P) can be calculated by performing differential scanning calorimetry on the hydrated polymer (P) as a sample.

[0050] Figure 1 shows an example of a DSC curve of a polymer containing intermediate water during hydration in a saturated water-containing state. Note that water that melts near 0°C during the temperature rise process is defined as "free water," and water that has a crystallization temperature different from that of free water, forms crystals at a lower temperature than free water, and melts below 0°C during the temperature rise process is defined as "intermediate water." Figure 1 shows the DSC curve of a polymer that is sufficiently saturated with water, when the temperature is lowered and raised using a differential scanning calorimeter (DSC) in the temperature range from -100°C to 40°C at a temperature rise and fall rate of 5°C / min.

[0051] During the temperature drop process from 40°C to -100°C, a crystallization peak due to supercooling of free water is first observed, and then, at a lower temperature, a low-temperature crystallization peak due to intermediate water (exothermic peak P1 in Figure 1) is observed. During the subsequent temperature rise process from -100°C to 40°C, a low-temperature crystallization peak due to intermediate water (more specifically, intermediate water that could not be frozen during the temperature drop process) (exothermic peak P2 in Figure 1) is observed. The low-temperature crystallization peak during the temperature drop process is due to low-temperature crystal formation of intermediate water that is close to free water, and the low-temperature crystallization peak during the temperature rise process is due to intermediate water that could not be frozen during the temperature drop process, and both are classified as intermediate water.

[0052] Furthermore, an endothermic peak with a peak top at 0°C is observed due to the melting of ice formed by crystallization of free water and intermediate water (see P3 in Figure 1). The part of the endothermic peak P3 at a temperature lower than 0°C is the melting peak due to the melting of ice formed by crystallization of intermediate water, and the part at a temperature higher than 0°C is the melting peak due to the melting of ice formed by crystallization of free water.

[0053] The relationship between the amount of hydration water, free water, nonfreezing water, and intermediate water (unit: g) contained in a hydrated polymer is expressed by the following mathematical formula (1): Amount of hydration water = Amount of free water + Amount of nonfreezing water + Amount of intermediate water (1) The amounts of free water and intermediate water contained in a hydrated polymer can be calculated from the amount of latent heat transferred due to phase transition (i.e., the amount of enthalpy change). The amount of hydration water of a polymer can be calculated by subtracting the mass of the polymer before hydration (i.e., the polymer in a dry state) from the total amount of hydrated polymer. The amount of nonfreezing water can be calculated by subtracting the amount of free water and intermediate water from the amount of hydration water according to the above mathematical formula (1). Details of the methods for measuring and calculating the amounts of hydration water, free water, nonfreezing water, and intermediate water in a hydrated polymer follow the methods described in the Examples below.

[0054] In this specification, the water content state of a polymer when the peak top of the endothermic heat due to ice melting appears at 0°C in a DSC curve obtained by heating a polymer in a water-containing state at a rate of 5°C / min is defined as a "saturated water-containing state." This is because, in a polymer that forms intermediate water during hydration, when the polymer contains sufficient water, i.e., when the polymer is in a saturated water-containing state, the peak top of the endothermic heat due to ice melting appears at 0°C (see P3 in Figure 1). However, in this specification, "when the peak top of the endothermic heat due to ice melting appears at 0°C" means that a slight error (e.g., 0°C ± 0.2°C) in the endothermic peak top appearing near 0°C is acceptable, as long as the polymer contains sufficient water and can be considered to be in a saturated water-containing state.

[0055] When quantifying the water of hydration of a hydrated polymer, a dry polymer is immersed in a large excess of water (specifically, more than 100 times the mass of the polymer) and allowed to stand at room temperature (25°C) for several days (e.g., 3 days), after which the polymer is removed from the water. Under conditions where a dry polymer is immersed in more than 100 times the mass of the polymer in water and allowed to stand at room temperature (25°C) for 3 days (these are referred to as immersion conditions), if the hydrated polymer can be removed from the water using tweezers or the like, the polymer is water-insoluble. On the other hand, if the polymer dissolves in water under the above immersion conditions and cannot be removed from the water using tweezers or the like, the polymer is water-soluble. The polymer (P) contained in the first medical coating agent is water-insoluble.

[0056] The polymer (P) contained in the first medical coating agent is a polymer that satisfies the above-mentioned condition (i). That is, the amount of intermediate water contained in the polymer (P) in a saturated water-containing state is 3.0% by mass or more relative to the total amount of the polymer (P) in a saturated water-containing state. Having an intermediate water amount of 3.0% by mass or more can impart high anti-adsorption properties to fibrinogen to the substrate surface when a coating layer is formed on the surface of a substrate using the first medical coating agent. From this perspective, the amount of intermediate water contained in the polymer (P) in a saturated water-containing state is preferably 3.5% by mass or more relative to the total amount of the polymer (P) in a saturated water-containing state, more preferably 5.0% by mass or more, even more preferably 5.5% by mass or more, even more preferably 7.5% by mass or more, and even more preferably 10.0% by mass or more. The upper limit of the amount of intermediate water contained in the polymer (P) in a saturated water-containing state is not particularly limited, but is, for example, 40.0% by mass or less relative to the total amount of the polymer (P) in a saturated water-containing state. It should be noted that a water-soluble polymer dissolves in water and does not reach a saturated water content state, and therefore does not satisfy the condition (i).

[0057] From the viewpoint of sufficiently suppressing adsorption of fibrinogen to the polymer (P) and imparting excellent antithrombogenicity to the substrate surface, the polymer (P) contained in the first medical coating agent preferably satisfies one or both of the following conditions (ii) and (iii) in addition to condition (i), and more preferably satisfies both conditions (ii) and (iii): Condition (ii): The amount of hydration water contained in the polymer (P) in a saturated water-containing state is 8.0 mass% or more based on the total amount of the polymer (P) in a saturated water-containing state; and Condition (iii): The ratio of the amount of intermediate water to the amount of nonfreezing water contained in the polymer (P) in a saturated water-containing state is 0.50 or more.

[0058] Regarding condition (ii), the amount of hydration water contained in the polymer (P) in a saturated water-containing state (hereinafter also referred to as "saturated water content") is represented by the total amount of free water, non-frozen water, and intermediate water. A saturated water content of 8.0% by mass or more relative to the total amount of the polymer (P) in a saturated water-containing state is preferable because a sufficient amount of intermediate water is present on the surface of the polymer (P), thereby imparting high anti-adsorption properties to the substrate surface against fibrinogen. From this perspective, the saturated water content of the polymer (P) is more preferably 10.0% by mass or more, even more preferably 15.0% by mass or more, still more preferably 17.0% by mass or more, and even more preferably 20.0% by mass or more relative to the total amount of the polymer (P) in a saturated water-containing state. The upper limit of the saturated water content of the polymer (P) relative to the total amount of the polymer (P) in a saturated water-containing state is not particularly limited, and is, for example, 60.0% by mass or less.

[0059] Regarding condition (iii), when the ratio of the amount of intermediate water to the amount of nonfreezing water contained in the polymer (P) in a saturated hydrated state is within the above range, the polymer (P) contains a relatively large amount of intermediate water relative to the amount of nonfreezing water, which is advantageous in that it can sufficiently impart anti-adsorption properties to a substrate surface-treated with the first medical coating agent. For the hydration water retained by the polymer (P) in a saturated hydrated state, the ratio of the amount of intermediate water to the amount of nonfreezing water is more preferably 0.70 or more, even more preferably 0.85 or more, and even more preferably 0.90 or more. The upper limit of the ratio of the amount of intermediate water to the amount of nonfreezing water is not particularly limited, and is, for example, 2.0 or less. Water-soluble polymers do not reach a saturated hydrated state and therefore do not satisfy conditions (ii) and (iii).

[0060] The preferred numerical range of the intermediate water content, saturated water content and ratio of the intermediate water content to the amount of non-freezing water in the polymer (P) of saturated water content state can be set by appropriately combining the respective preferred numerical ranges described above.Specifically, the hydration water properties in the polymer (P) of saturated water content state are that the intermediate water content is 3.5% by mass or more relative to the total amount of the polymer (P) of saturated water content state, the saturated water content is 10.0% by mass or more relative to the total amount of the polymer (P) of saturated water content state, and the ratio of the intermediate water content to the amount of non-freezing water is preferably 0.70 or more, more preferably that the intermediate water content is 5.0% by mass or more relative to the total amount of the polymer (P) of saturated water content state, the saturated water content is 15.0% by mass or more relative to the total amount of the polymer (P) of saturated water content state, and the ratio of the intermediate water content to the amount of non-freezing water is 0.85 or more.

[0061] The glass transition temperature (Tg1) of the polymer (P) in a dry state is, for example, 80°C or lower, preferably 65°C or lower. The lower limit of the glass transition temperature (Tg1) of the polymer (P) in a dry state is, for example, -50°C or higher. The glass transition temperature (Tg1) of the polymer (P) in a dry state is not particularly limited, but is preferably -35°C or higher, more preferably -30°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).

[0062] The polymer (P) preferably has a glass transition temperature (Tg2) in a saturated water-containing state of -35°C or lower. When the polymer (P) has a glass transition temperature (Tg2) in a saturated water-containing state of -35°C or lower, the anti-adsorption properties of fibrinogen can be sufficiently imparted to the substrate surface, and antithrombogenicity can be enhanced. From the viewpoint of sufficiently enhancing the anti-adsorption properties of fibrinogen, the glass transition temperature (Tg2) of the polymer (P) in a saturated water-containing state is preferably -40°C or lower, more preferably -50°C or lower, and even more preferably -55°C or lower. The lower limit of the glass transition temperature (Tg2) of the polymer (P) in a saturated water-containing state is, for example, -100°C or higher.

[0063] 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).

[0064] Furthermore, from the viewpoint of sufficiently enhancing the anti-adsorption properties of 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, more preferably 35° C. or higher, even more preferably 50° C. or higher, still more preferably 55° C. or higher, and even more preferably 60° C. or higher.

[0065] <Other Components> The first medical coating agent 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 first medical coating agent 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.

[0066] When the first medical coating agent contains a solvent, a solvent capable of dissolving the polymer (P) is preferably used as the solvent. The solvent contained in the first medical coating agent 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.

[0067] Other components that may be blended into the first medical coating agent 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.

[0068] In the first medical coating agent, 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., the 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.

[0069] When the first medical coating agent is in a solution state, the solids concentration of 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 preparing the medical coating agent) 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 strength can be formed on the substrate. A solids concentration of 30 (w / v)% or less ensures good coatability and makes it easy to form a coating layer with a uniform thickness. The solids concentration of the medical coating agent is more preferably 0.01 to 25 (w / v)%, and even more preferably 0.05 to 20 (w / v)%.

[0070] <<Second Medical Coating Agent>> Next, the second medical coating agent of the present disclosure will be described. Note that, in the following description, the description of the first medical coating agent will be used to refer to the same components as those of the first medical coating agent, and their description will be omitted. The polymer (P) contained in the second medical coating agent satisfies the above-mentioned condition (ii). That is, the polymer (P) contained in the second medical coating agent has a saturated water content of 8.0% by mass or more of the water of hydration contained in the polymer in a saturated water content state relative to the total amount of the polymer in a saturated water content state. By having the saturated water content of the polymer (P) be 8.0% by mass or more relative to the total amount of the polymer (P) in a saturated water content state, a sufficient amount of intermediate water can be present on the surface of the polymer (P), and high fibrinogen adsorption resistance can be imparted to the substrate surface.

[0071] For details of the type and amount of monomers constituting the polymer (P) contained in the second medical coating agent, the properties of the polymer (P), the preferred range of condition (ii), other components that may be contained in the second medical coating agent, etc., the description of the first medical coating agent can be cited.

[0072] From the viewpoint of sufficiently suppressing the adsorption of fibrinogen to the polymer (P) and imparting excellent antithrombotic properties to the surface of the substrate, it is preferable that the polymer (P) contained in the second medical coating agent satisfies the above-mentioned condition (iii) in addition to the condition (ii). For details of the condition (iii), the explanation of the first medical coating agent can be cited.

[0073] <<Third Medical Coating Agent>> Next, the third medical coating agent of the present disclosure will be described. Note that, in the following description, the description of the first medical coating agent will be used for the same components as those of the first medical coating agent, and the description thereof will be omitted. The polymer (P) contained in the third medical coating agent satisfies the above-mentioned condition (iii). That is, the polymer (P) contained in the third medical coating agent has a ratio of the amount of intermediate water to the amount of nonfreezing water contained in the polymer (P) in a saturated water-containing state of 0.50 or more. When the ratio of the amount of intermediate water to the amount of nonfreezing water contained in the polymer (P) in a saturated water-containing state is within the above range, the polymer (P) contains a relatively large amount of intermediate water relative to the amount of nonfreezing water, thereby imparting high anti-adsorption properties to the substrate surface against fibrinogen.

[0074] For details of the types and amounts of monomers constituting the polymer (P) contained in the third medical coating agent, the properties of the polymer (P), the preferred range of condition (iii), other components that may be contained in the third medical coating agent, etc., the explanation of the first medical coating agent can be cited.

[0075] <Medical Device> The medical device of the present disclosure is formed by coating a substrate with any of the first to third medical coating agents 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 first to third medical coating agents of the present disclosure. This provides high anti-adsorption properties for fibrinogen and excellent antithrombogenic properties.

[0076] The substrate of the medical device to which the first to third medical coating agents of the present disclosure are 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 to which the medical coating agent is applied may be a mixture of two or more materials.

[0077] The method for coating a substrate surface with the first to third medical coating agents 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 substrate surface, and the solvent is removed by heating or other means, thereby obtaining a medical device in which at least a portion of the substrate surface is coated with the polymer (P).

[0078] 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.

[0079] The medical devices whose substrate surfaces are coated with the first to third medical coating agents of the present disclosure are not particularly limited, and can be applied to medical devices for a variety of purposes. Considering that the first to third medical coating agents of the present disclosure can impart excellent antithrombotic properties to the substrate surface, the first to third medical coating agents of the present disclosure are particularly preferably used as materials for coating the substrates of medical devices used in direct contact with blood. 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.).

[0080] 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.

[0081] 1. Synthesis of Ethylenically Unsaturated Monomers [Synthesis Example 1: Synthesis of 2-(3-(2-ethoxyethyl)ureido)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 and 10.58 g of 2-acryloyloxyethyl isocyanate (Karenz AOI, manufactured by Showa Denko K.K.) as an isocyanate compound were added. Then, a thermometer, a 100 mL dropping funnel, and a three-way cock were attached. To the attached dropping funnel, 4.41 g of 2-ethoxyethylamine (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) as a raw material amine and 50 mL of tetrahydrofuran as a solvent were added. Next, nitrogen was flowed at 100 mL / min via the three-way cock for 10 minutes. After the nitrogen flow, a nitrogen-filled rubber balloon was attached to the three-way cock. Next, the amine solution was added dropwise from the dropping funnel. Stirring was then continued overnight at room temperature (25°C). 10 mL of 1 N diluted hydrochloric acid was added dropwise to the flask to terminate the reaction. The internal solution was transferred to a 200 mL 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 operation was repeated twice. 30 mL of saturated saline was added to the recovered organic layer and shaken to wash, and this operation 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 pleated filter paper to remove sodium sulfate, and paramethoxyphenol was added to achieve a theoretical yield of 250 ppm. The solvent was removed using a rotary evaporator while immersed in a 40°C water bath. After removing the solvent, the mixture was left standing under reduced pressure for 1 hour using a vacuum pump, and the remaining solvent was again removed to obtain 2-(3-(2-ethoxyethyl)ureido)ethyl acrylate (hereinafter also referred to as "EEA-UA").

[0082] Synthesis Example 2: Synthesis of 2-(3-(2-ethoxyethyl)ureido)ethyl methacrylate The same procedure as in Synthesis Example 1 was carried out, except that 6.98 g of 2-methacryloyloxyethyl isocyanate (Karends MOI manufactured by Showa Denko K.K., hereinafter also referred to as "MOI") was added as the isocyanate compound, to obtain 2-(3-(2-ethoxyethyl)ureido)ethyl methacrylate (hereinafter also referred to as "EEA-UMA").

[0083] Synthesis Example 3: Synthesis of 2-(3-(3-methoxypropyl)ureido)ethyl methacrylate The same operations as in Synthesis Example 1 were carried out, except that 4.41 g of 3-methoxypropylamine (manufactured by Tokyo Chemical Industry Co., Ltd.) was added as the raw material amine, and 6.98 g of MOI was added as the isocyanate compound, to obtain 2-(3-(3-methoxypropyl)ureido)ethyl methacrylate (hereinafter, also referred to as "MPA-UMA").

[0084] Synthesis Example 4: Synthesis of 2-(3-(2-methoxyethyl)ureido)ethyl acrylate The same operation as in Synthesis Example 1 was carried out, except that 5.63 g of 2-methoxyethylamine (manufactured by Tokyo Chemical Industry Co., Ltd.) was added as the raw material amine, to obtain 2-(3-(2-methoxyethyl)ureido)ethyl acrylate (hereinafter also referred to as "MEA-UA").

[0085] 2. Production and Analysis of Polymers Polymers were produced according to the following Production Examples 1 to 6 and Comparative Production Examples 1 and 2. For each polymer obtained in Production Examples 1 to 6 and Comparative Production Example 2, the amount of hydration water contained in the polymer in a saturated water content state was quantified, and the intermediate water content, unfreezable water content, and saturated water content were calculated, and the glass transition temperatures of the polymer in a dry state and in a saturated water content state were measured. Details of the measurement and calculation methods are as follows:

[0086] <Quantification of Hydration Water> The quantification of hydration water contained in the polymer was carried out using a differential scanning calorimeter (DSC). (Differential Scanning Calorimetry) The obtained polymers were each 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 hydration. The hydrated polymers were removed from the pure water using tweezers, and water adhering to each hydrated polymer was removed using a drug wrapper. 0.003 to 0.005 g of each hydrated polymer was then weighed into an aluminum pan. The weighed value was recorded as "XA (unit: g)." Using a differential scanning calorimeter (measuring instrument: DSC214Polymer manufactured by NETZSCH, measurement atmosphere: air atmosphere), each weighed 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. Based on the observed exothermic transition during low-temperature crystallization of water, the water contained in each polymer in a hydrated state was classified into intermediate water, free water, and non-freezing water according to the following method, and quantified.

[0087] (Classification of Hydrated Water) Water observed at an exothermic peak temperature of -35°C or lower during the temperature-lowering (cooling) process in differential scanning calorimetry, and water observed at an exothermic peak during the temperature-raising (heating) process, were both classified as "intermediate water." Water observed at an exothermic peak temperature above -35°C during the temperature-lowering process was classified as "free water." Water that did not form low-temperature crystals even at -100°C, the lower limit of the temperature range in differential scanning calorimetry, was classified as "non-freezing water."

[0088] (Quantitative Analysis) After differential scanning calorimetry, the aluminum pan was pierced and 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 amounts of hydration water classified above (intermediate water, free water, and unfrozen water) were quantified according to the following mathematical formulas (2) to (4). (amount of intermediate water: g) = (total enthalpy change of intermediate water: J) ÷ (latent heat of fusion of water: 334 J / g) (2) (amount of free water: g) = (total enthalpy change of free water: J) ÷ (latent heat of fusion of water: 334 J / g) (3) (amount of unfreezable water: g) = (amount of hydration water of polymer: g) - (amount of intermediate water: g) - (amount of free water: g) (4) The total enthalpy change of the intermediate water is calculated based on the sum of the peak area of ​​the peak observed at an exothermic peak temperature of -35°C or lower during the temperature drop process and the peak area of ​​the exothermic peak observed during the temperature rise process.

[0089] Finally, the ratios of the intermediate water content (unit: g) and the unfrozen water content (unit: g) to the weighed value (XA (unit: g)) were calculated according to the following mathematical formulas (5) and (6). A 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 absorb water. A DSC curve was obtained at a heating rate of 5°C / min. The water content of the polymer when the endothermic peak top due to ice melting appeared at 0°C was defined as the "saturated water content" and the amount of hydration water of the polymer in the saturated water content state was defined as the "saturated water content." The ratio (unit: mass%) of the saturated water content to the weighed value (XA (unit: g)) was calculated according to the following mathematical formula (7). (Intermediate water content: mass %) = (intermediate water content: g) ÷ XA × 100 ... (5) (Antifreeze water amount: mass %) = (antifreeze water amount: g) ÷ XA × 100 ... (6) (saturated water content: mass %) = (hydration water amount of polymer: g) ÷

[0090] <Measurement of Glass Transition Temperature> (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 of the dried polymers 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.

[0091] (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 "XA (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. As in the case of quantifying water of hydration, the water content of the polymer when the top of the endothermic peak due to ice melting appears at 0°C in the DSC curve obtained by DSC measurement at a temperature rise rate of 5°C / min was defined as the "saturated water content state."

[0092] [Production Example 1: Production of Polymer A] 3 g of EEA-UA as a monomer, 0.129 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 dimethylformamide 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 ethyl acetate as an organic reprecipitation purification solvent. The recovered polymer was then subjected to reprecipitation purification using pure water as an aqueous reprecipitation purification solvent, yielding Polymer A. The saturated water content of Polymer A in a saturated water-containing state was 34.5% by mass, the intermediate water content was 19.1% by mass, and the non-freezing water content was 14.2% by mass. The glass transition temperature (Tg1) of Polymer A in a dry state was 23°C, and the glass transition temperature (Tg2) in a saturated water-containing state was -64°C. Table 1 below shows the saturated water content, intermediate water content, non-freezing water content, glass transition temperature (Tg1) in a dry state, and glass transition temperature (Tg2) in a saturated water-containing state, as well as the ratio of the intermediate water content to the non-freezing water content and the difference ΔTg between Tg2 and Tg1 (the same applies to the following Production Examples and Comparative Production Examples).

[0093] [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 EEA-UMA was used as the monomer, 0.044 g of V-65 initiator as the radical initiator, and 7 g of dimethylformamide as the solvent were used. Polymer B in a saturated water-containing state had a saturated water content of 29.8% by mass, an intermediate water content of 12.1% by mass, and an unfreezable water content of 17.3% by mass. Furthermore, the glass transition temperature (Tg1) of Polymer B in a dry state was 52°C, and the glass transition temperature (Tg2) in a saturated water-containing state was -61°C.

[0094] [Production Example 3: Production of Polymer C] Polymer C was obtained by the same procedure as in Production Example 1, except that 3 g of MPA-UMA was used as the monomer, 0.044 g of V-65 initiator as the radical initiator, and 7 g of dimethylformamide as the solvent were used. Polymer C in a saturated water-containing state had a saturated water content of 38.7% by mass, an intermediate water content of 18.2% by mass, and an unfreezable water content of 19.5% by mass. Furthermore, the glass transition temperature (Tg1) of Polymer C in a dry state was 54°C, and the glass transition temperature (Tg2) in a saturated water-containing state was -56°C.

[0095] [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 EEA-UA and 1.2 g of 2-methoxyethyl acrylate (hereinafter also referred to as "MEA") were used as monomers, and 0.169 g of V-65 initiator was used as the radical initiator. Polymer D in a saturated water-containing state had a saturated water content of 29.2 mass%, an intermediate water content of 10.9 mass%, and an unfreezable water content of 12.1 mass%. Furthermore, the glass transition temperature (Tg1) of Polymer D in a dry state was -2°C, and the glass transition temperature (Tg2) in a saturated water-containing state was -62°C.

[0096] [Production Example 5: Production of Polymer E] Polymer E was obtained by the same procedure as in Production Example 1, except that 0.9 g of EEA-UA and 2.1 g of MEA were used as monomers, and 0.199 g of V-65 initiator was used as the radical initiator. The saturated water content of Polymer E in a saturated water-containing state was 17.7% by mass, the intermediate water content was 7.5% by mass, and the non-freezing water content was 8.2% by mass. Furthermore, the glass transition temperature (Tg1) of Polymer E in a dry state was −22° C., and the glass transition temperature (Tg2) in a saturated water-containing state was −60° C.

[0097] [Production Example 6: Production of Polymer F] Polymer F was obtained by the same procedure as in Production Example 1, except that 0.3 g of EEA-UA and 2.7 g of MEA were used as monomers, and 0.219 g of V-65 initiator was used as the radical initiator. Polymer F in a saturated water-containing state had a saturated water content of 10.2 mass%, an intermediate water content of 4.5 mass%, and an unfreezable water content of 5.2 mass%. Furthermore, the glass transition temperature (Tg1) of Polymer F in a dry state was −30° C., and the glass transition temperature (Tg2) in a saturated water-containing state was −63° C.

[0098] Comparative Production Example 1: Production of Polymer G An attempt was made to obtain Polymer G consisting of MEA-UA by performing the same operation as in Production Example 1, except that 3 g of MEA-UA was used as the monomer. However, reprecipitation purification of the polymer using pure water as a reprecipitation purification solvent could not be performed, and it was found that Polymer G was water-soluble. For this reason, it was not possible to quantify the amount of water of hydration for Polymer G. Furthermore, measurement of the glass transition temperature for Polymer G was discontinued.

[0099] Comparative Production Example 2: Production of Polymer H Polymer H 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 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 6:4 mass ratio was used as the organic reprecipitation purification solvent. Polymer H in a saturated water-containing state had a saturated water content of 8.4 mass%, an intermediate water content of 3.4 mass%, and an unfrozen water content of 3.7 mass%. Furthermore, the glass transition temperature (Tg1) of Polymer H in a dry state was −37° C., and the glass transition temperature (Tg2) in a saturated water-containing state was −60° C.

[0100] 3. Production and Evaluation of Medical Coating Agents [Examples 1 to 6 and Comparative Example 2] Polymer solutions were produced as medical coating agents using the polymers produced in Production Examples 1 to 6 and Comparative Production Example 2, and a fibrinogen adsorption test (MicroBCA assay) was performed. Details of each evaluation method are as follows.

[0101] <Fibrinogen Adsorption Test (MicroBCA Assay)> A 0.2 (w / v)% solution of each polymer (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 a coating substrate for evaluation. 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 each well was washed with 200 μL of PBS(-). This process was repeated seven times. After drying, 50 μL of extraction solution (a 1:1 volumetric mixture of 5% SDS aqueous solution and 0.1 N sodium hydroxide aqueous solution) 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 obtained extract, the amount of fibrinogen adsorption per unit area on the coating substrate for evaluation (hereinafter also referred to as "FIB adsorption amount") was calculated. This value (unit: μg / cm ２ The smaller the value of the β-amyloid index (β), the better the antithrombotic activity. 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 manufacturer's instructions.

[0102] Comparative Example 1: A fibrinogen adsorption test was conducted on a medical coating agent containing polymer G. However, as mentioned above, polymer G is water-soluble, and even if the substrate surface of a medical device is coated with polymer G, when the medical device is inserted into blood, polymer G in the coating layer on the substrate surface will leach into the blood. For this reason, the fibrinogen adsorption test was discontinued in Comparative Example 1.

[0103] Comparative Example 3 In the fibrinogen adsorption test, the test was carried out in the same manner as in Examples 1 to 6 and Comparative Example 2, except that the 96-well plate was not coated with a medical coating agent.

[0104] The properties of the polymers used in Examples 1 to 6 and Comparative Examples 1 and 2, and the evaluation results of the medical coating agents, as well as the evaluation results of Comparative Example 3, are shown in Table 1. In Table 1, "-" indicates that measurement was not possible or was not performed.

[0105]

[0106] 4. Evaluation Results As is clear from the results in Table 1, the medical coating agents of Examples 1 to 6 had low fibrinogen adsorption (FIB adsorption) and excellent antithrombotic properties. This is thought to be because Polymers A to F contained in the medical coating agents of Examples 1 to 6 have a large amount of intermediate water on the polymer surface, making them less likely to be recognized as foreign matter by biological components, and thereby enabling them to exhibit excellent antithrombotic properties.

[0107] In contrast, the medical coating agent of Comparative Example 1, which contains polymer G consisting of MEA-UA units, is difficult to use as a medical coating agent because polymer G is water-soluble and the coating layer easily peels off in vivo. Furthermore, the medical coating agent of Comparative Example 2, which uses polymer H consisting of MEA units, exhibited a higher FIB adsorption amount than the medical coating agents of Examples 1 to 6, and was confirmed to have inferior antithrombotic properties.

[0108] 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 urea bond, The polymer satisfies the following condition (i): 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 adding water to the polymer and raising the temperature at a rate of 5°C / min using a differential scanning calorimeter (DSC): Condition (i): the amount of intermediate water contained in the polymer in a saturated water-containing state is 3.0% by mass or more based on the total amount of the polymer in a saturated water-containing state. A medical coating agent that meets the above requirements.

2. The polymer satisfies the following condition (ii): Condition (ii): the amount of water of hydration contained in the polymer in a saturated water-containing state is 8.0% by mass or more based on the total amount of the polymer in a saturated water-containing state. The medical coating agent according to claim 1 , further satisfying the following:

3. The polymer satisfies the following condition (iii): Condition (iii): the ratio of the amount of intermediate water to the amount of nonfreezing water contained in the polymer in a saturated water-containing state is 0.50 or more; The medical coating agent according to claim 1 , further satisfying the following:

4. The polymer contains a structural unit (A) derived from an ethylenically unsaturated monomer having a urea bond, The polymer satisfies the following condition (ii): when the water content of the polymer is saturated when a peak top of the endothermic heat due to ice melting appears at 0°C in a DSC curve obtained by adding water to the polymer and heating the polymer at a rate of 5°C / min using a differential scanning calorimeter (DSC): Condition (ii): the amount of water of hydration contained in the polymer in a saturated water-containing state is 8.0% by mass or more based on the total amount of the polymer in a saturated water-containing state. A medical coating agent that meets the above requirements.

5. The polymer contains a structural unit (A) derived from an ethylenically unsaturated monomer having a urea bond, The polymer satisfies the following condition (iii): when the water content of the polymer is saturated when a peak top of the endothermic heat due to ice melting appears at 0°C in a DSC curve obtained by adding water to the polymer and raising the temperature at a rate of 5°C / min using a differential scanning calorimeter (DSC): Condition (iii): the ratio of the amount of intermediate water to the amount of nonfreezing water contained in the polymer in a saturated water-containing state is 0.50 or more; A medical coating agent that meets the above requirements.

6. 6. 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.

7. The medical coating agent according to any one of claims 1 to 5, wherein the polymer is a (meth)acrylic polymer.

8. A medical device comprising a substrate coated with the medical coating agent according to any one of claims 1 to 5.