Antithrombotic coating material, medical device, research instrument, method for producing medical device and research instrument, and adsorption suppression method

Abstract

This antithrombotic coating material contains an addition polymer having a partial structure represented by formula (1), and at least one of an oxiranyl group and an oxetanyl group. In formula (1), R1 is an alkanediyl group. n1 is 0 or 1. n2 is an integer of 0 to 3. R2 is an alkyl group when n2 is 0, and is a hydrogen atom or an alkyl group when n2 is 1 to 3. In formula (1), the sum of the number of carbon atoms in (n2) units of R1 and the number of carbon atoms in R2 is 1 to 12.

Description

Antithrombotic coating material, medical device, research instrument, method for manufacturing medical device and research instrument, and method for inhibiting adsorption

[0001] [Cross-reference of related applications] This application claims priority under Japanese Patent Application No. 2024-197531, filed on 12 November 2024, which is incorporated herein by reference in its entirety. This disclosure relates to antithrombotic coatings, medical devices, research instruments, methods for manufacturing medical devices and research instruments, and methods for inhibiting adsorption.

[0002] Various materials such as synthetic polymers, ceramics, glass, and metals are used as materials for medical devices and instruments for life science research (hereinafter collectively referred to as "medical devices, etc."). On the other hand, it is known that when biological components such as blood come into contact with the surface of various materials of medical devices, etc., the medical devices, etc. may be recognized as foreign bodies, leading to activation of the coagulation system, complement system, platelet system, etc. in biological tissue, and potentially causing the formation of blood clots. For this reason, medical devices, etc. used in contact with biological components are given biocompatibility (also called bioaffinity) on their surface in order to suppress foreign body reactions with biological components caused by the medical devices, etc. being recognized as foreign bodies.

[0003] Various techniques have been proposed to impart biocompatibility to the surface of medical devices, etc., by coating the surface of such devices using biocompatible synthetic polymers (see, for example, Patent Documents 1 and 2). Patent Document 1 discloses that biocompatibility is imparted to the substrate surface of a medical device by using a copolymer having structural units derived from 2-methacryloyloxyethyl phosphorylcholine as a component of the coating material. Patent Document 2 also discloses the use of a synthetic polymer having structural units derived from 2-methoxyethyl acrylate as a biocompatible medical material.

[0004] International Publication No. 2001 / 05855 JP-A-4-152952

[0005] Polymers exhibiting biocompatibility generally have poor adhesion to other material surfaces, and tend to have particularly poor adhesion to inorganic material surfaces such as glass. Furthermore, polymers with hydrophilic side chains, such as those described in Patent Documents 1 and 2, have problems in that relatively high-temperature heat treatments and ultrasonic treatments are limited in order to maintain the shape of the coating (coating layer) or suppress its decomposition and keep the coating in close contact with the substrate during the coating process to impart biocompatibility to the substrate surface, the subsequent sterilization process, and product use. Coating materials used for surface coating of medical devices and the like are required to exhibit good antithrombotic properties while also having excellent adhesion to the substrate surface.

[0006] This disclosure has been made in view of the above-mentioned problems, and one of its objectives is to provide an antithrombotic coating material that can form a film with excellent adhesion to a substrate while exhibiting good antithrombotic properties.

[0007] The present disclosure provides the following antithrombotic coating materials, medical devices, research instruments, methods for manufacturing medical devices and research instruments, and methods for inhibiting adsorption: [1] An antithrombotic coating material comprising an addition polymer having a substructure represented by the following formula (1) and at least one of an oxyranyl group and an oxetanyl group. (In formula (1), R １ is an alkanediyl group. n1 is 0 or 1. n2 is an integer from 0 to 3. R ２ When n2 is 0, it is an alkyl group, and when n2 is 1 to 3, it is a hydrogen atom or an alkyl group. However, the (n2) R in formula (1) １ The number of carbon atoms and R ２The sum of the carbon numbers of the carbon atoms is 1 to 12. (* represents a bond.) [2] The antithrombotic coating material according to [1], wherein the addition polymer comprises a structural unit having a substructure represented by formula (1) and a structural unit having at least one of an oxyranyl group and an oxetanyl group. [3] The antithrombotic coating material according to [1] or [2], wherein the addition polymer has an alicyclic epoxy group. [4] The antithrombotic coating material according to any one of [1] to [3], further comprising a crosslinking agent. [5] The antithrombotic coating material according to [4], wherein the crosslinking agent has two or more of at least one selected from the group consisting of an oxyranyl group, an oxetanyl group, a cyclic carbonate group, a hydroxyl group, a protected hydroxyl group, a carboxyl group, a protected carboxyl group, a mercapto group, a protected mercapto group, an amino group, a protected amino group, an isocyanate group, a protected isocyanate group, and a polymerizable carbon-carbon unsaturated bond group in one molecule. [6] The antithrombotic coating material according to [4] or [5], wherein the crosslinking agent does not have an aromatic ring. [7] A medical device in which the surface of a substrate is coated with the antithrombotic coating material according to any one of [1] to [6]. [8] A research instrument in which the surface of a substrate is coated with the antithrombotic coating material according to any one of [1] to [6]. [9] A method for manufacturing medical devices and research instruments, comprising the step of coating the surface of a substrate with an antithrombotic coating material described in any of [1] to [6].

[10] The method for manufacturing medical devices and research instruments according to [9], further comprising the step of sterilizing the substrate at a temperature of 80°C or higher after coating the surface of the substrate with the antithrombotic coating material.

[11] An adsorption inhibition method for inhibiting the adsorption of platelets to the surface of a substrate, comprising the step of forming a film on the surface of the substrate with an antithrombotic coating material described in any of [1] to [6].

[0008] According to this disclosure, an antithrombotic coating material can be obtained that can form a film with excellent adhesion to a substrate while exhibiting good antithrombotic properties.

[0009] Figure 1 shows an unstained phase-contrast microscope image of normal human dermal fibroblasts one week after the start of culture.

[0010] The following describes in detail matters related to the embodiments. In this specification, numerical ranges indicated using "~" include the numbers indicated before and after "~" as the lower and upper limits, respectively. Unless otherwise specified, each component may be used alone or in combination of two or more types.

[0011] Herein, in this specification, "hydrocarbon group" means a group that includes linear hydrocarbon groups, alicyclic hydrocarbon groups, and aromatic hydrocarbon groups. "Linear hydrocarbon group" means a linear hydrocarbon group or a branched hydrocarbon group that does not contain a cyclic structure and consists only of a linear structure. However, linear hydrocarbon groups may be saturated or unsaturated. "Alicyclic hydrocarbon group" means a hydrocarbon group that contains only the structure of an alicyclic hydrocarbon as its ring structure and does not contain an aromatic ring structure. However, an alicyclic hydrocarbon group does not have to consist only of the structure of an alicyclic hydrocarbon, and may also include a group that has a linear structure as part of it. "Aromatic hydrocarbon group" means a hydrocarbon group that contains an aromatic ring structure as its ring structure. However, an aromatic hydrocarbon group does not have to consist only of an aromatic ring structure, and may include a linear structure or an alicyclic hydrocarbon structure as part of it. "Aromatic ring" means an aromatic hydrocarbon ring and an aromatic heterocycle.

[0012] The "main chain" of a polymer refers to the "trunk" portion of the polymer, which consists of the longest chain of atoms. This "trunk" portion may contain a ring structure. For example, "having a specific structure in the main chain" means that the specific structure constitutes a part of the main chain. A "side chain" refers to a portion of a polymer that branches off from the "trunk" portion. A "structural unit" is typically a repeating unit composed of a single monomer. In this specification, a structural unit may be obtained by reacting a repeating unit having a reactive group with a compound having a functional group that can react with the reactive group. "(meth)acrylo" is a term that encompasses "acrylo" and "methacrylo". "(meth)acryloxy" is a term that encompasses "acryloxy" and "methacryloxy". In this specification, oxyranyl groups and oxetanyl groups are collectively referred to as "epoxy groups".

[0013] ≪Antithrombotic Coating Material≫ The antithrombotic coating material of this disclosure (hereinafter also simply referred to as "this coating material") is used to impart biocompatibility to the substrate surface of medical devices and research instruments (particularly life science research instruments). In this specification, biocompatibility means that the adsorption of biological substances (e.g., platelets and proteins) is suppressed. By imparting biocompatibility to the substrate surface, it is considered possible to suppress the formation of thrombi when the substrate surface comes into contact with blood, etc. This coating material contains an addition polymer having at least one of an oxiranil group and an oxetanil group and a substructure represented by the following formula (1). Hereinafter, the substructure represented by the following formula (1) will also be referred to as the "specific substructure," and the addition polymer having at least one of an oxiranil group and an oxetanil group and the substructure represented by the following formula (1) will also be referred to as the "specific polymer." (In formula (1), R １ is an alkanediyl group. n1 is 0 or 1. n2 is an integer from 0 to 3. R ２ When n2 is 0, it is an alkyl group, and when n2 is 1 to 3, it is a hydrogen atom or an alkyl group. However, the (n2) R in formula (1) １ The number of carbon atoms and R ２The total number of carbon atoms is 1 to 12. “*” represents a bond.)

[0014] <Specific polymer> The specific polymer is an addition polymer and contains a structural unit derived from a monomer having a polymerizable carbon-carbon unsaturated bond. Examples of the monomer constituting the specific polymer include (meth)acrylic monomers, styrene monomers, maleimide monomers, vinyl ether monomers, vinyl acetate, and the like. In the polymer, it is preferable that the specific polymer contains a structural unit derived from a (meth)acrylic monomer in terms of being able to increase the content of intermediate water considered to contribute to the expression of biocompatibility and being excellent in biocompatibility, and in terms of being easy to introduce a specific partial structure into the polymer.

[0015] In the specific polymer, the proportion of the structural unit derived from the (meth)acrylic monomer is preferably 50% by mass or more, more preferably 65% by mass or more, still more preferably 80% by mass or more, and particularly preferably 90% by mass or more based on the total amount of the structural units constituting the specific polymer.

[0016] - Specific partial structure The specific partial structure is considered useful for increasing the content of intermediate water in the polymer. In the above formula (1), the alkane diyl group represented by R １ may be linear or branched. The alkane diyl group represented by R １ is preferably linear in terms of obtaining a polymer with high biocompatibility and more excellent antithrombotic properties. Also for the same reason, the alkyl group represented by R ２ is preferably linear.

[0017] The total number of carbon atoms of the (n2) R １ in the above formula (1) and the number of carbon atoms of R ２ is preferably 1 to 10, more preferably 2 to 8, and still more preferably 2 to 6 from the viewpoint of sufficiently ensuring the biocompatibility of the specific polymer and the solubility in an alcohol-based solvent. Specifically, R １ is preferably an alkane diyl group having 1 to 3 carbon atoms, and more preferably a methylene group or an ethylene group. R ２ is preferably an alkyl group having 1 to 3 carbon atoms, more preferably a methyl group or an ethyl group, and still more preferably a methyl group.

[0018] In formula (1) above, considering the availability of monomers that provide a specific substructure and the biocompatibility to be imparted to the polymer, it is preferable that n1 is 0 and n2 is 1 to 3, or that n1 is 1 and n2 is 0. When n1 and n2 are n1 is 0 and n2 is 1 to 3, or n1 is 1 and n2 is 0, R ２ It is preferable that it be an alkyl group.

[0019] Specific examples of the group represented by formula (1) above include alkyl groups such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, and tert-butyl group; alkoxyalkyl groups such as methoxymethyl group, methoxyethyl group, methoxypropyl group, methoxybutyl group, ethoxymethyl group, ethoxyethyl group, ethoxypropyl group, and methoxyethoxymethyl group; dialoxyalkyl groups such as methoxyethoxymethyl group and ethoxyethoxymethyl group; trialkoxyalkyl groups such as methoxyethoxyethoxymethyl group, methoxyethoxyethoxyethyl group, and ethoxyethoxyethoxymethyl group; hydroalkyl groups such as 2-hydroxyethyl group and 3-hydroxypropyl group; and hydroxyalkoxyalkyl groups such as 2-hydroxyethyloxymethyl group. Of these, alkoxyalkyl groups, dialoxyalkyl groups, or trialkoxyalkyl groups are preferred because they are water-insoluble, allow for a high intermediate water content in the polymer, and make it easier to obtain a polymer with excellent biocompatibility. Alkoxyalkyl groups or dialoxyalkyl groups are more preferred, alkoxyalkyl groups are even more preferred, and methoxyethyl groups are particularly preferred.

[0020] The substructure represented by formula (1) above may be directly bonded to the atoms constituting the main chain of the polymer, or it may be bonded via a divalent linking group. Examples of divalent linking groups include: * １ -CO-O-, * １ -O-CO-, -O-, * １ -NH-CO-, * １ Examples include -CO-NH-, divalent aromatic ring groups (e.g., phenylene group), etc. １" represents a bond that binds to an atom constituting the main chain of the polymer. The partial structure represented by the above formula (1) is preferably bonded to an atom constituting the main chain of the polymer via a divalent linking group, * １ It is more preferable that it is bonded to an atom constituting the main chain of the polymer via -CO-O- or -O-.

[0021] The specific polymer may have the specific partial structure in the side chain of the polymer or at the polymer terminal. Also, the specific polymer may have the specific partial structure in both the side chain and the terminal of the polymer. From the viewpoint of forming a coating excellent in biocompatibility, it is preferable that the specific polymer has the specific partial structure at least in the side chain, and it is more preferable that it contains a structural unit having the specific partial structure.

[0022] From the viewpoint of obtaining a coating excellent in biocompatibility, the amount of the specific partial structure in the specific polymer is preferably 5 mol% or more, more preferably 10 mol% or more, and still more preferably 15 mol% or more with respect to the total amount of the structural units constituting the specific polymer. Also, from the viewpoint of maintaining a good balance between the biocompatibility of the coating formed by this coating material and the adhesion to the substrate, the amount of the specific partial structure in the specific polymer is preferably 95 mol% or less, more preferably 90 mol% or less, and still more preferably 85 mol% or less with respect to the total amount of the structural units constituting the specific polymer.

[0023] - Epoxy group The specific polymer may have an epoxy group in the side chain of the polymer or at the polymer terminal. Also, the specific polymer may have an epoxy group in both the side chain and the terminal of the polymer. From the viewpoint of forming a coating excellent in adhesion to the substrate, it is preferable that the specific polymer has at least a side chain containing an epoxy group. Examples of the side chain containing an epoxy group include a side chain having a glycidyl group and a side chain having an alicyclic epoxy group. In addition, when the specific polymer has a side chain containing an epoxy group, specifically, it means that a monovalent group containing an epoxy group is bonded to an atom (preferably a carbon atom) that is an atom constituting the main chain of the addition polymer and is located between both ends of the polymer.

[0024] An "alicyclic epoxy group" is a group formed when two adjacent carbon atoms in an alicyclic ring are bonded to the same oxygen atom. The alicyclic ring may be monocyclic or polycyclic. Specific examples of alicyclic epoxy groups include epoxycyclohexyl groups and epoxytricyclohexyl groups. [5.2.1.0] ２，６ Examples include decyl groups.

[0025] It is preferable that the specific polymer contains structural units having epoxy groups, as this allows for the simple and sufficient introduction of epoxy groups into the addition polymer, thereby enabling the formation of a coating with excellent adhesion to the substrate. From the viewpoint of obtaining a coating with excellent adhesion to the substrate (especially at high temperatures), the amount of epoxy groups in the specific polymer is preferably 5 mol% or more, more preferably 10 mol% or more, and even more preferably 15 mol% or more, relative to the total amount of structural units constituting the specific polymer. Furthermore, from the viewpoint of ensuring the biocompatibility of the specific polymer, the amount of epoxy groups in the specific polymer is preferably 95 mol% or less, more preferably 90 mol% or less, and even more preferably 85 mol% or less, relative to the total amount of structural units constituting the specific polymer.

[0026] It is preferable that the specific polymer has an alicyclic epoxy group because it offers high storage stability for the monomer and facilitates the production of the polymer. Furthermore, it is even more preferable that the specific polymer contains a structural unit having an alicyclic epoxy group because it allows for the introduction of a sufficient amount of alicyclic epoxy group into the addition polymer, resulting in a coating with excellent adhesion to the substrate. From the viewpoint of balancing storage stability and reactivity in polymerization reactions, the alicyclic epoxy group in the specific polymer is preferably an epoxycyclohexyl group.

[0027] In order to ensure good biocompatibility while improving adhesion to the substrate, it is preferable that the specific polymer contains a structural unit having a specific substructure (referred to as the first structural unit) and a structural unit having an epoxy group (referred to as the second structural unit). An addition polymer containing the first structural unit and the second structural unit can be synthesized using a known polymerization method, by creating a monomer composition containing a monomer that gives the first structural unit and a monomer that gives the second structural unit. Therefore, it is also useful in that a polymer with high adhesion to the substrate can be obtained through simple operations while ensuring biocompatibility.

[0028] - First Structural Unit As the monomer that gives the first structural unit, a monomer having a specific substructure and a radical polymerizable group (referred to as the first monomer) can be preferably used due to its ease of synthesis and high degree of freedom in monomer selection. Examples of radical polymerizable groups that the first monomer may have include a (meth)acryloyl group, a vinylphenyl group, a vinyl ether group, a maleimide group, a vinyl group, etc. Of these, the (meth)acryloyl group is preferred as the radical polymerizable group that the first monomer may have due to its high reactivity in polymerization reactions and the ability to form a coating with superior biocompatibility. In this case, a preferred specific example of the first structural unit is the structural unit represented by the following formula (1A). (In formula (1A), R ３ R is a hydrogen atom or a methyl group. １ , R ２ n1 and n2 are, respectively, R in formula (1) above. １ , R ２ (This is synonymous with n1 and n2.)

[0029] Specific examples of the first monomer include alkyl (meth)acrylates such as methyl (meth)acrylate, ethyl (meth)acrylate, n-propyl (meth)acrylate, isopropyl (meth)acrylate, n-butyl (meth)acrylate, isobutyl (meth)acrylate, sec-butyl (meth)acrylate, and tert-butyl (meth)acrylate; alkoxyalkyl (meth)acrylates such as methoxymethyl (meth)acrylate, methoxyethyl (meth)acrylate, methoxypropyl (meth)acrylate, methoxybutyl (meth)acrylate, ethoxymethyl (meth)acrylate, ethoxyethyl (meth)acrylate, and ethoxypropyl (meth)acrylate; and dialkoxyalkyl (meth)acrylates such as methoxyethoxymethyl (meth)acrylate, methoxyethoxyethyl (meth)acrylate, and ethoxyethoxymethyl (meth)acrylate. Examples include trialkoxyalkyl esters of (meth)acrylic acid such as methoxyethoxyethoxymethyl (meth)acrylate, ethoxyethoxyethoxymethyl (meth)acrylate, and methoxyethoxyethoxyethyl (meth)acrylate; and hydroxyl group-containing (meth)acrylic acid esters such as 2-hydroxyethyl (meth)acrylate, 3-hydroxypropyl (meth)acrylate, and 2-hydroxyethyloxymethyl (meth)acrylate.

[0030] The first monomer is preferably at least one selected from the group consisting of alkyl (meth)acrylates, alkoxyalkyl (meth)acrylates, and trialkoxyalkyl (meth)acrylates, in order to obtain a polymer with excellent biocompatibility while ensuring water non-soluble properties. Among these, methoxyethyl (meth)acrylate can yield a polymer with excellent biocompatibility, and poly(methoxyethyl (meth)acrylate) has already been used as a material for bio-related applications and is particularly preferable from the viewpoint of safety.

[0031] - Second Structural Unit As the monomer that gives the second structural unit, a monomer having an epoxy group and a radical polymerizable group (referred to as the second monomer) can be preferably used due to its ease of synthesis and high degree of freedom in monomer selection. The radical polymerizable group of the second monomer is also preferably a (meth)acryloyl group, similar to the first monomer. In this case, a preferred specific example of the second structural unit is the structural unit represented by the following formula (1B). (In formula (1B), R ４ R is a hydrogen atom or a methyl group. ５ X is a single bond, a divalent hydrocarbon group, or a divalent group containing -O- between the carbon-carbon bonds of a divalent hydrocarbon group. １ (These are oxetanyl groups, oxyranyl groups, or epoxycyclohexyl groups.)

[0032] In the above formula (1B), R ５ Examples of divalent hydrocarbon groups represented by include chain hydrocarbon groups, alicyclic hydrocarbon groups, and aromatic hydrocarbon groups. Of these, R ５ The divalent hydrocarbon group represented is preferably a chain-like hydrocarbon group, and more preferably an alkanediyl group. ５ The number of carbon atoms in the divalent hydrocarbon group represented by is preferably 1 to 10, more preferably 1 to 5, and even more preferably 1 to 3, from the viewpoint of further enhancing the effect of improving adhesion with the substrate. １ An epoxycyclohexyl group is preferred.

[0033] Specific examples of the second monomer include, for example, glycidyl (meth)acrylate, 3,4-epoxycyclohexyl (meth)acrylate, 3,4-epoxycyclohexylmethyl (meth)acrylate, 2-(3,4-epoxycyclohexyl)ethyl (meth)acrylate, and 3,4-epoxytricyclo[5.2.1.0 ２，６ ] Decyl (meth)acrylate, 2-hydroxyethyl methacrylate [3,4-epoxytricyclo(5.2.1.0 ２，６Examples include decane-9-yl, (3-methyloxetan-3-yl)methyl (meth)acrylate, (3-ethyloxetan-3-yl)methyl (meth)acrylate, (oxetan-3-yl)methyl (meth)acrylate, 3-(meth)acryloyloxymethyl-3-ethyloxetane, o-vinylbenzylglycidyl ether, m-vinylbenzylglycidyl ether, p-vinylbenzylglycidyl ether, etc.

[0034] Among these, (meth)acrylates having alicyclic epoxy groups are particularly preferred because they can form a coating with excellent adhesion to the substrate (especially at high temperatures) while ensuring the storage stability of the monomer and the biocompatibility of the polymer.

[0035] The method for synthesizing the specific polymer is not particularly limited. The specific polymer can be produced, for example, using the monomers described above, in a suitable solvent, in the presence of a polymerization initiator, etc., according to known methods such as radical polymerization. Examples of polymerization initiators include azo compounds such as 2,2'-azobis(isobutyronitrile), 2,2'-azobis(2,4-dimethylvaleronitrile), and 2,2'-azobis(isobutyric acid)dimethyl. The amount of polymerization initiator used is preferably 0.01 to 30 parts by mass per 100 parts by mass of the total amount of monomers used in the reaction. Examples of polymerization solvents include alcohols, ethers, ketones, esters, hydrocarbons, etc. The amount of polymerization solvent used is preferably such that the total amount of monomers used in the reaction is 0.1 to 60% by mass of the total amount of reaction solution.

[0036] When synthesizing a specific polymer, the amount of each monomer used can be appropriately set so that the content ratio of the specific substructure and epoxy group falls within the above preferred range. For example, the amount of the first monomer used is preferably 5 mol% or more, more preferably 10 mol% or more, and even more preferably 15 mol% or more, relative to the total amount of structural units constituting the specific polymer. Furthermore, the amount of the first monomer used is preferably 95 mol% or less, more preferably 90 mol% or less, and even more preferably 85 mol% or less, relative to the total amount of structural units constituting the specific polymer.

[0037] Furthermore, the amount of the second monomer used is preferably 5 mol% or more, more preferably 10 mol% or more, and even more preferably 15 mol% or more, relative to the total amount of structural units constituting the specific polymer. The amount of the second monomer used is preferably 95 mol% or less, more preferably 90 mol% or less, and even more preferably 85 mol% or less, relative to the total amount of structural units constituting the specific polymer. In the specific polymer, the amount of monomer used (i.e., the amount added) and the content ratio of structural units derived from each monomer in the polymer are basically equivalent.

[0038] In the synthesis of a specific polymer, a monomer different from both the first monomer and the second monomer (hereinafter also referred to as "other monomers") may be used in combination. The other monomers are not particularly limited, as long as they do not impair the effects of the present invention and are copolymerizable with the first monomer and the second monomer. Specific examples of other monomers include, for example, unsaturated carboxylic acids, unsaturated carboxylic acid anhydrides, (meth)acrylic acid esters having an alicyclic structure, (meth)acrylic acid esters having an aromatic ring structure, (meth)acrylic acid esters having a cyclic ether structure with 5 or more ring members, (meth)acrylamide compounds, sulfide group-containing (meth)acrylic acid esters, sulfinyl group-containing (meth)acrylic acid esters, sulfonyl group-containing (meth)acrylic acid esters, phosphorylcholine group-containing (meth)acrylic acid esters, urea group-containing (meth)acrylic acid esters, and the like.

[0039] Further specific examples of other monomers include unsaturated carboxylic acids such as (meth)acrylic acid, α-ethylacrylic acid, maleic acid, fumaric acid, itaconic acid, and vinylbenzoic acid. Examples of unsaturated carboxylic acid anhydrides include maleic anhydride and itaconic anhydride.

[0040] Examples of (meth)acrylic acid esters having an alicyclic structure include cyclohexyl (meth)acrylate, 2-methylcyclohexyl (meth)acrylate, 4-butylcyclohexyl (meth)acrylate, 4-hydroxymethylcyclohexyl (meth)acrylate, tricyclo[5.2.1.02,6]decane-8-yl (meth)acrylate, tricyclo[5.2.1.02,5]decane-8-yloxyethyl (meth)acrylate, and isobolonyl (meth)acrylate. Examples of (meth)acrylic acid esters having an aromatic ring structure include phenyl (meth)acrylate, benzyl (meth)acrylate, naphthylmethyl (meth)acrylate, naphthylethyl (meth)acrylate, and phenoxyethyl (meth)acrylate.

[0041] Examples of (meth)acrylic acid esters having a cyclic ether structure with five or more ring members include tetrahydrofuran-3-ylmethyl acrylate and tetrahydrofurfuryl (meth)acrylate. Examples of (meth)acrylamide compounds include (meth)acrylamide, N-methyl(meth)acrylamide, N,N-dimethyl(meth)acrylamide, (meth)acryloylmorpholine, and N-(2-hydroxyethyl)(meth)acrylamide.

[0042] Examples of sulfide group-containing (meth)acrylic acid esters include 2-(methylthio)ethyl (meth)acrylate, 2-(ethylthio)ethyl (meth)acrylate, and 3-(methylthio)propyl (meth)acrylate. Examples of sulfinyl group-containing (meth)acrylic acid esters include 2-(methylsulfinyl)ethyl (meth)acrylate and 2-(ethylsulfide)ethyl (meth)acrylate. Examples of sulfonyl group-containing (meth)acrylic acid esters include 2-(methylsulfonyl)ethyl (meth)acrylate, 2-(ethylsulfonyl)ethyl (meth)acrylate, and 3-(methylsulfonyl)propyl (meth)acrylate.

[0043] Examples of phosphorylcholine group-containing (meth)acrylic acid esters include 2-(meth)acryloyloxyethyl phosphorylcholine and 3-(meth)acryloyloxypropyl phosphorylcholine. Examples of urea group-containing (meth)acrylic acid esters include 2-(3-(2-ethoxyethyl)ureido)ethyl (meth)acrylate and 2-(3-(3-methoxypropyl)ureido)ethyl (meth)acrylate.

[0044] As other monomers, monomers having substructures capable of exhibiting good biocompatibility can be preferably used from the above list. Specifically, as other monomers, at least one selected from the group consisting of unsaturated carboxylic acids, unsaturated carboxylic acid anhydrides, (meth)acrylic acid esters having a cyclic ether structure with 5 or more ring members, (meth)acrylamide compounds, sulfide group-containing (meth)acrylic acid esters, sulfinyl group-containing (meth)acrylic acid esters, sulfonyl group-containing (meth)acrylic acid esters, phosphorylcholine group-containing (meth)acrylic acid esters, and urea group-containing (meth)acrylic acid esters can be preferably used.

[0045] When synthesizing the specific polymer, the amount of other monomers used can be appropriately set within a range that does not impair the effects of the present invention. Specifically, the amount of other monomers used is preferably 30 mol% or less, more preferably 20 mol% or less, and even more preferably 10 mol% or less, relative to the total amount of structural units constituting the specific polymer.

[0046] In polymerization to obtain a specific polymer, the reaction temperature is usually 30°C to 180°C. The reaction time varies depending on the type of polymerization initiator and monomer and the reaction temperature, but is usually 0.5 to 10 hours. The polymer obtained by the polymerization reaction may be used in the preparation of an antithrombotic coating material while still dissolved in the reaction solution, or it may be isolated from the reaction solution and then used in the preparation of an antithrombotic coating material. Polymer isolation can be performed by known isolation methods such as pouring the reaction solution into a large amount of poor solvent and drying the resulting precipitate under reduced pressure; or distilling the reaction solution under reduced pressure using an evaporator.

[0047] The weight-average molecular weight (Mw) of the specific polymer, calculated as polystyrene equivalent by gel permeation chromatography (GPC), is preferably 2,000 or more. An Mw of 2,000 or more is preferable because it allows for the acquisition of a coating with sufficiently high heat resistance and chemical resistance. The Mw of the specific polymer is more preferably 5,000 or more, even more preferably 6,000 or more, and particularly preferably 7,000 or more. Furthermore, from the viewpoint of improving film-forming properties, the Mw of the specific polymer is preferably 100,000 or less, more preferably 80,000 or less, and even more preferably 50,000 or less.

[0048] For a specific polymer, the molecular weight distribution (Mw / Mn), expressed as the ratio of the weight-average molecular weight (Mw) to the number-average molecular weight (Mn) in polystyrene terms calculated by GPC, is preferably 4.0 or less, and more preferably 3.0 or less.

[0049] The content of the specific polymer in this coating material is preferably 50% by mass or more, more preferably 70% by mass or more, even more preferably 80% by mass or more, and particularly preferably 90% by mass or more, based on the total amount of solids contained in the coating material. By setting the content of the specific polymer in this coating material within the above range, sufficient biocompatibility can be imparted to the substrate. In this specification, "solids" refers to components other than solvents that are optionally blended into the antithrombotic coating material. That is, "solids contained in this coating material" refers to components that are the specific polymer plus components other than solvents. Therefore, even if an additive component is liquid, it is considered to be included in the solids.

[0050] <Other Components> This coating material may contain only the specific polymer, or it may further contain components different from the specific polymer (other components) together with the specific polymer. The other components are not particularly limited as long as they do not impair the effects of the present invention. Examples of other components include polymers with monomer compositions different from the specific polymer (hereinafter also referred to as "other polymers"), crosslinking agents, antioxidants, thermal polymerization initiators, photopolymerization initiators, metal chelating compounds, curing accelerators, surfactants, fillers, dispersants, colorants, softeners, plasticizers, adhesion aids, ultraviolet absorbers, solvents, etc. The content of other components in this coating material can be appropriately selected according to each compound as long as it does not impair the effects of the present invention.

[0051] (Other Polymers) The main skeleton of other polymers is not particularly limited. Examples of main skeletons of other polymers include polyamic acid, polyimide, polyamic acid ester, polyamide, polyurea, polyorganosiloxane, polyurethane, polyester, cellulose derivative, polyacetal, polyether, addition polymer, etc. Known monomers can be used as appropriate as the monomers constituting the other polymers.

[0052] Other polymers that can be used include polymers having carboxyl groups. These polymers, by functioning as polymer crosslinking agents in the coating material, are thought to react with epoxy groups of specific polymers upon heating during film formation to form a crosslinked structure. The formation of this crosslinked structure allows for the creation of a coating with excellent adhesion to the substrate (especially at high temperatures). Among these, at least one polymer selected from the group consisting of polyamic acid, polyamic acid esters, polyimides, polyorganosiloxanes, and addition polymers is preferred, with polyamic acid or poly(meth)acrylic acid being more preferred.

[0053] The content of other polymers in this coating material is preferably 20 parts by mass or less, and more preferably 15 parts by mass or less, per 100 parts by mass of the specific polymer.

[0054] (Crosslinking agent) This coating material may further contain a crosslinking agent. By containing a crosslinking agent together with a specific polymer, this coating material can form a film with superior adhesion to the substrate.

[0055] The crosslinking agent preferably has two or more crosslinkable groups in one molecule that can react with the reactive groups (specifically epoxy groups) of a particular polymer to form a covalent bond. Preferably, the crosslinking agent is a compound having two or more crosslinkable groups in one molecule selected from the group consisting of oxyranyl groups, oxetanyl groups, cyclic carbonate groups, hydroxyl groups, protected hydroxyl groups, carboxyl groups, protected carboxyl groups, mercapto groups, protected mercapto groups, amino groups, protected amino groups, isocyanate groups, protected isocyanate groups, and polymerizable carbon-carbon unsaturated bond groups.

[0056] The number of crosslinkable groups in one molecule of the crosslinking agent is preferably 2 to 10, and more preferably 2 to 6, from the viewpoint of sufficiently improving the adhesion of the film formed by this coating material to the substrate. In addition, either a low molecular weight crosslinking agent or a high molecular weight crosslinking agent may be used as the crosslinking agent. The molecular weight of the low molecular weight crosslinking agent is preferably 100 to 1,000, more preferably 100 to 800, and even more preferably 100 to 600. A low molecular weight crosslinking agent is preferably used as the crosslinking agent to be included in this coating material because it is easier to adjust the degree of crosslinking.

[0057] Specific examples of crosslinking agents include compounds having an oxyranil group or an oxetanil group, such as ethylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, propylene glycol diglycidyl ether, tripropylene glycol diglycidyl ether, triglycidyl isocyanurate, glycerol polyglycidyl ether, pentaerythritol tetraglycidyl ether, 1,4-cyclohexanedimethanol diglycidyl ether, N,N',N',N'-tetraglycidyl glycol uryl, 1,6-hexanediol diglycidyl ether, trimethylolpropane triglycidyl ether, and 1,3-bis(oxy Examples include silane-2-ylmethoxy)-2,2-bis[(oxiran-2-ylmethoxy)methyl]propane, 2,2-dibromoneopentyl glycol diglycidyl ether, N,N,N',N'-tetraglycidyl-m-xylylenediamine, 1,3-bis(N,N-diglycidylaminomethyl)cyclohexane, N,N,N',N'-tetraglycidyl-4,4'-diaminodiphenylmethane, N,N-diglycidyl-benzylamine, N,N-diglycidyl-aminomethylcyclohexane, N,N-diglycidyl-cyclohexylamine, and epoxidation products of 2,2'-diallylbisphenol A diallyl ether with hydrogen peroxide.

[0058] Examples of compounds having a cyclic carbonate group include the compounds represented by the following formulas (d1-1) and (d1-2).

[0059] Compounds having a hydroxyl group or a protected hydroxyl group can preferably include compounds having a methylol group, a protected methylol group, a hydroxyalkylamide group, or a protected hydroxyalkylamide group. Specific examples of these include, for example, the compounds represented by the following formulas (d2-1) to (d2-6) and (d3-1) to (d3-8).

[0060] Examples of compounds having a carboxyl group or a protected carboxyl group include maleic acid, itaconic acid, trimellitic acid, 1,2,3,4-cyclopentanetetracarboxylic acid, 1,2,4,5-benzenetetracarboxylic acid, 1,2,3,4-butanetetracarboxylic acid, cis-1,2,3,4-tetrahydrophthalic acid, 2-carboxylat-2-hydroxy-1,3-propanedicarboxylic acid, ethylene glycol bistrimate, propylene glycol bistrimate, and 4,4'-oxydiphthalic acid. In addition, polymers having a carboxyl group (such as polyamic acid, polyamic acid esters, polyimides, or poly(meth)acrylic acid) may be used as crosslinking agents.

[0061] Examples of compounds having a mercapto group or a protected mercapto group include 1,2-ethanedithiol, 1,3-propanedithiol, 1,3,4-thiadiazole-2,5-dithiol, 1,10-decanedithiol, pentaerythritol tetrakis(3-mercaptobutyrate), and 1,3,5-tris(2-(3-sulfanylbutanoyloxy)ethyl)-1,3,5-triazinan-2,4,6-trione.

[0062] Examples of compounds having an amino group or a protected amino group include compounds represented by the following formulas (d4-1) to (d4-5).

[0063] Examples of compounds having an isocyanate group include tolylene diisocyanate, xylylene diisocyanate, chlorphenyl diisocyanate, hexamethylene diisocyanate, tetramethylene diisocyanate, isophorone diisocyanate, and diphenylmethane diisocyanate. Examples of compounds having a protected isocyanate group include compounds in which the isocyanate group in the compound having an isocyanate group is protected with 3,6-dimethylpyrazole, methyl ethyl ketoxime, diethyl malonate, or ε-caprolactam, and compounds represented by the following formula (d5-1).

[0064] Compounds having polymerizable carbon-carbon bonded groups include compounds having (meth)acryloyl groups, maleimide groups, alkenyl groups, vinylphenyl groups, vinyl ether groups, or 3-methylenetetrahydrofuran-2(3H)-on-5-yl groups. Specific examples of these include ethylene glycol di(meth)acrylate, 1,6-hexanediol di(meth)acrylate, pentaerythritol tri(meth)acrylate, and compounds represented by formulas (d6-1) to (d6-9) below.

[0065] (In formula (d2-5), Ac is an acetyl group.)

[0066] In order to maintain good storage stability of this coating material while allowing the crosslinking reaction to proceed sufficiently by heating during film formation, thereby forming a film with excellent adhesion to the substrate, the crosslinking agent is preferably a compound having two or more crosslinkable groups selected from the group consisting of carboxyl groups, protected carboxyl groups, amino groups, protected amino groups, and protected isocyanate groups in one molecule, and more preferably a compound having two or more crosslinkable groups selected from the group consisting of carboxyl groups, protected carboxyl groups, amino groups, and protected amino groups in one molecule.

[0067] As a crosslinking agent, compounds without aromatic rings (hereinafter also referred to as "aliphatic crosslinking agents") can be preferably used because they can obtain a coating with high adhesion to the substrate while ensuring the hydrophilicity of the coating. Aliphatic crosslinking agents may be compounds with a chain structure or may have a cyclic structure. Specific examples of aliphatic crosslinking agents include compounds without aromatic rings among the compounds exemplified above.

[0068] If the coating material contains a crosslinking agent, the crosslinking agent content is preferably 0.2 parts by mass or more per 100 parts by mass of the specific polymer contained in the coating material. More preferably, the crosslinking agent content is 0.5 parts by mass or more, and even more preferably 1 part by mass or more, per 100 parts by mass of the specific polymer. Furthermore, the crosslinking agent content is preferably 20 parts by mass or less, more preferably 15 parts by mass or less, and even more preferably 10 parts by mass or less, per 100 parts by mass of the specific polymer. By keeping the crosslinking agent content in the coating material within the above ranges, the adhesion of the coating film formed by the coating material to the substrate can be improved.

[0069] (Solvent) The coating material may be provided as a liquid composition in which a specific polymer is dissolved or dispersed in a solvent. Any solvent capable of dissolving or dispersing the specific polymer can be used as the solvent. Specific examples of solvents include water, organic solvents, and mixed solvents thereof. The solvent is preferably an organic solvent.

[0070] Examples of organic solvents include alcohol-based solvents, ether-based solvents, ketone-based solvents, amide-based solvents, ester-based solvents, and hydrocarbon-based solvents. Of these, alcohol-based solvents such as methanol, ethanol, n-propanol, isopropanol, or a mixture of two or more of these are preferred as organic solvents because they are highly safe, widely used in medical applications, and have relatively low boiling points while still being able to dissolve specific polymers.

[0071] When the coating material contains a solvent, the solid content concentration of the coating material (the ratio of the total mass of components other than the solvent to the total mass of the antithrombotic coating material) can be appropriately selected considering the viscosity of the coating material and the volatility of the solvent. When the coating material contains a solvent, the solid content concentration is, for example, 0.2 to 20% by mass, and more preferably 0.5 to 10% by mass. The temperature when preparing the coating material is, for example, 0 to 60°C.

[0072] ≪Medical Devices and Research Instruments≫ The medical devices and research instruments of this disclosure are provided with a coating (i.e., a coating layer) formed by coating the surface of a substrate with the antithrombotic coating material of this disclosure described above. Medical devices and research instruments in which at least a portion of the substrate is covered with a coating layer formed by this coating material can be provided with biocompatibility to the portion covered by the coating layer. This makes it possible to suppress foreign body reactions even when biological components such as blood come into contact with the medical device or research instrument. In other words, with this coating material, it is possible to obtain medical devices and the like with excellent antithrombotic properties.

[0073] Furthermore, since the specific polymer that is the main component of this coating material is water-insoluble, it is less likely to leach into biological components such as blood when it comes into contact with them. Therefore, medical devices and research instruments of this disclosure having a coating formed with this coating material exhibit little change in antithrombotic properties over time and can demonstrate stable biocompatibility. Moreover, the coating formed with this coating material has a low risk of cytotoxicity and is useful as a coating material for medical devices and research instruments.

[0074] The medical devices and research instruments are not particularly limited and can be preferably applied to various devices used in contact with in vivo tissues, blood, etc. Specific examples of medical devices include, for example, implantable artificial organs (artificial hearts, artificial lungs, artificial kidneys, etc.), implantable therapeutic devices, artificial blood vessels, extracorporeal circulation artificial organs, extracorporeal circulation therapeutic devices (dialysis machines, blood circulation devices, blood purification devices, etc.), catheters (angiography catheters, PTCA catheters, digestive catheters, urological catheters, etc.), guide wires, stents, tubes, blood bags, syringes, needles, indwelling needles, surgical instruments, diagnostic tips, cell culture supports, sutures, wound dressings, artificial joints, contact lenses, etc. Specific examples of research instruments include, for example, various instruments for life science research such as dispensers, pipettes, analytical instruments, flasks, petri dishes, microtubes, plates, and microfluidic devices (lab-on-a-chip).

[0075] The material and shape of the substrate constituting the medical devices and research instruments coated with this coating material are not particularly limited. Examples of substrate materials include glass, resin, metal, rubber, and ceramics. Examples of glass include float glass, soda glass, and quartz glass. Examples of resins include polyethylene terephthalate, polybutylene terephthalate, polysulfone, polyethersulfone, polycarbonate, polyolefin (polypropylene, etc.), polystyrene, polyimide, nylon, polyester, polyacrylonitrile, halogenated polyolefin, polyurethane, polyamide, poly(meth)acrylate, ethylene-vinyl alcohol copolymer, and butadiene-acrylonitrile copolymer. Examples of metals include titanium, stainless steel, aluminum, and nickel-titanium alloy. Furthermore, the substrate material may be a combination of two or more different materials.

[0076] <Method for Manufacturing Medical Devices and Research Instruments> The medical devices and research instruments of this disclosure can be manufactured by a method that includes a step of coating the surface of a substrate with the coating material (coating step).

[0077] The method for coating the surface of the substrate with this coating material is not particularly limited, and known methods can be used as appropriate depending on the type, application, and material of the medical device or research instrument. Coating methods that can be employed include roll coating, spin coating, inkjet coating, bar coating, impregnation coating, gravure coating, and liquid flow through the inside of a tube.

[0078] After applying the coating material to the substrate surface, the coating surface may be heated (baked) to form a coating film. At this time, preheating (pre-baking) may be performed for purposes such as preventing dripping of the applied coating material. The pre-baking temperature is preferably 30 to 150°C, and the pre-baking time is preferably 0.25 to 10 minutes. After that, a firing (post-baking) step may be performed for purposes such as thoroughly removing the solvent in the applied coating material. The firing temperature (post-baking temperature) at this time is preferably 80 to 250°C, more preferably 80 to 180°C. The post-baking time is preferably 5 to 200 minutes. The thickness of the film formed in this way is preferably 0.05 to 10 μm.

[0079] The medical devices and research instruments of this disclosure are preferably manufactured by a method that further includes, in addition to the coating step described above, a step of sterilizing the medical devices or research instruments coated with the coating material at a temperature of 80°C or higher (sterilization step). The specific polymer, which is the main component of the coating material, has high heat resistance, and the coating layer is less likely to peel off the substrate even when sterilized at a temperature of 80°C or higher. Therefore, according to this manufacturing method, medical devices and research instruments that have been given biocompatibility (bioaffinity) on the substrate surface and have been sterilized can be obtained by a simple method. Furthermore, according to this manufacturing method, even when the sterilization temperature is preferably 90°C or higher, more preferably 100°C or higher, medical devices and research instruments with biocompatibility on the substrate surface can be obtained, which is useful.

[0080] The sterilization method used here is not particularly limited and can be carried out by known heating methods commonly used for medical devices and research instruments. Specifically, examples include moist heat sterilization, autoclaving, and dry heat sterilization.

[0081] ≪Method for inhibiting platelet adsorption≫ According to this disclosure, a method for inhibiting platelet adsorption is provided, which includes the step of forming a film on the surface of a substrate using the antithrombotic coating material of this disclosure described above. Details of the antithrombotic coating material, substrate, and application method are as described above.

[0082] The present invention will be described in detail below with reference to examples, but the present invention is not limited to the following examples. In the following examples, "parts" and "%" refer to mass unless otherwise specified.

[0083] In the following example, the weight-average molecular weight (Mw) and number-average molecular weight (Mn) of the polymer were measured by the following method. <Mw, Mn of polymer> The weight-average molecular weight (Mw) and number-average molecular weight (Mn) were measured by gel permeation chromatography (GPC) under the following conditions. Apparatus: Showa Denko K.K.'s "GPC-101" GPC column: Shimadzu GLC Co., Ltd.'s "GPC-KF-801", "GPC-KF-802", "GPC-KF-803", and "GPC-KF-804" bound mobile phase: Tetrahydrofuran (THF) Column temperature: 40°C Flow rate: 1.0 mL / min Sample concentration: 1.0% by mass Sample injection volume: 100 μL Detector: Differential refractometer Standard material: Monodisperse polystyrene

[0084] The abbreviations for the compounds used in the following examples are shown below. For convenience, the compound represented by formula (X) may be simply referred to as "compound (X)" below.

[0085] (Acrylic monomers) A-1 to A-3

[0086] (Crosslinking agent) AD-1

[0087] 1. Synthesis of Polymers [Synthesis Example 1-1] 1.66 g of 2-methoxyethyl acrylate, 2.32 g of (3,4-epoxycyclohexyl)methyl acrylate, 15.94 g of cyclopentanone, and 0.080 g of 2,2'-azobis(isobutyrate)dimethyl were mixed in a reaction solution, and the mixture was stirred for 30 minutes while passing dry nitrogen gas through it to purge the reaction system with nitrogen. Then, polymerization was carried out by stirring under a nitrogen stream in an oil bath set at 60°C for 6 hours, and then stirring at 100°C for 1 hour. Next, the reaction solution was added dropwise to distilled water for reprecipitation and purification, and the precipitate was dried in a vacuum dryer. Then, the solid content was adjusted with methanol to 10% by mass to obtain a methanol solution of polymer (PA-1). The Mw of the obtained polymer (PA-1) was 25,000.

[0088] [Synthesis Examples 1-2 to 1-5] The same procedure as in Synthesis Example 1-1 was performed, except that the types and amounts of compounds used in the synthesis were changed as shown in Table 1, to obtain polymers (PA-2) to (PA-5), respectively.

[0089]

[0090] 2. Preparation and evaluation of antithrombotic coating material [Example 1] (1) Preparation of antithrombotic coating material 100 parts by mass of polymer (PA-1) and 2 parts by mass of additive (AD-1) were diluted with methanol to prepare a coating material (CA-1) so that the total solid content concentration of the polymer and additive was 5.0% by mass.

[0091] (2) Evaluation of substrate adhesion (2-1) Evaluation of substrate adhesion to ultrasonic treatment A coating material (CA-1) was applied to a glass substrate using a spin coater, heated on an 80°C hot plate for 1 minute, and then heated in a 150°C oven with nitrogen purging for 20 minutes to form a film with an average thickness of 100 nm. The film-forming surface of the substrate was observed with an optical microscope and it was confirmed that the film was formed uniformly. Subsequently, the substrate with the film formed was ultrasonically cleaned in ultrapure water for 30 minutes using an ultrasonic cleaner. The water temperature after cleaning was 40°C. The substrate was removed from the ultrasonic cleaner and then dried by heating in a 100°C oven with nitrogen purging for 10 minutes. The film-forming surface of the dried substrate was observed again with an optical microscope to evaluate the adhesion of the film to the substrate to ultrasonic treatment. Compared to the film condition before ultrasonic cleaning, substrate adhesion was evaluated as good (○) if no peeling, agglutination, or unevenness due to film thickness non-uniformity was observed after ultrasonic cleaning; acceptable (△) if no peeling was observed but agglutination or unevenness was observed; and poor (×) if peeling was observed. Furthermore, substrate adhesion was evaluated in the same way as for the glass substrate, except that a polycarbonate (PC) substrate was used instead of a glass substrate. As a result, in this example, substrate adhesion was evaluated as good (○) for both the glass substrate and the PC substrate.

[0092] (2-2) Evaluation of substrate adhesion to autoclave sterilization A coating material (CA-1) was applied to a glass substrate using a spin coater, heated on an 80°C hot plate for 1 minute, and then heated in a 150°C oven with nitrogen purging for 20 minutes to form a film with an average thickness of 100 nm. The film-forming surface of the substrate was observed with an optical microscope and it was confirmed that the film was formed uniformly. Subsequently, the substrate with the film formed was placed in a sterilization bag and autoclaved at 115°C for 20 minutes using an autoclave apparatus. After that, the substrate was dried at room temperature. The film-forming surface of the substrate after drying was observed again with an optical microscope to evaluate the adhesion of the film to the substrate to autoclave sterilization. Compared to the film state before autoclave sterilization, if no peeling of the film was observed after treatment, the substrate adhesion was evaluated as good (○), and if peeling of the film was observed, it was evaluated as poor (×). As a result, in this example, the substrate adhesion to autoclave sterilization was evaluated as good (○).

[0093] (3) Evaluation of antithrombotic properties: The coating material (CA-1) was applied to a glass substrate using a spin coater, heated on an 80°C hot plate for 1 minute, and then heated in a 150°C oven with nitrogen purging for 20 minutes to form a coating with an average thickness of 100 nm. Human whole blood, purchased for experimental purposes and collected in the United States, was used in the experiment within 5 days of collection. The human whole blood, which had been refrigerated, was allowed to return to room temperature by being left at room temperature for about 30 minutes. After that, it was mixed by inversion three times and centrifuged at 400 rcf for 5 minutes using a tabletop centrifuge (2420, KUBOTA). Approximately 500 μL of the supernatant (pale yellow semi-transparent liquid) was collected and used as platelet-rich plasma (PRP). After collection, the sample was centrifuged at 2,500 rcf for 10 minutes, and approximately 2 mL of the supernatant (pale yellow clear liquid) was collected and designated as Platelet Poor Plasma (PPP). Using a hemocytometer, the platelets in the PRP diluted 800-fold with PBS(-) were counted to calculate the platelet concentration in the PRP, and the seeding concentration was found to be 3.0 × 10⁶. ７ cells / cm ２PRP was diluted with PPP to prepare a platelet suspension. 150 μL (approximately 100 μL / cm³) of the prepared platelet suspension was added to each substrate (sample). ２ Platelets were placed on the substrate and incubated at 37°C for 1 hour to allow them to adhere. After that, the platelet suspension was removed, washed twice with PBS, and then immersed in a 1% glutaraldehyde solution (25% glutaraldehyde, polyscience, Inc. 01909 diluted to 1 / 25 with PBS(-)) and incubated at 37°C for 2 hours to immobilize the adhered platelets onto the substrate. After immobilization, the substrate was washed once each by immersion in PBS(-) (10 minutes), PBS(-):water = 1:1 (8 minutes), and water (8 minutes, 10 minutes). After washing, it was air-dried for 3 hours, and then dried in a container with silica gel for more than 1 day. After drying, the number of adhered platelets was counted by observing the substrate surface with a scanning electron microscope (SEM, KEYENCE, 3D Real Surface View Microscope VE-9800). The above series of operations was performed three times, and the average of the platelet adhesion count over the three measurements was 1.0 × 10⁻⁶. ５ cells / cm ２ If it is less than 1.0, it is marked as "Good (○)", 1.0 x 10 ５ cells / cm ２ If the above conditions were met, it was evaluated as "Poor (×)". As a result, in this example, the antithrombotic activity was evaluated as good (○). As a negative control, the average number of platelets adhering to glass substrates and PC substrates that were not coated with the coating material (CA-1) was counted in the same manner, and the glass substrate was 6.0 × 10 ５ cells / cm ２ The PC substrate is 9.4 x 10 ５ cells / cm ２ That was the case.

[0094] [Examples 2 and 3] Antithrombotic coating materials were produced by performing the same procedure as in Example 1, except that the types and amounts of polymers and additives were changed as shown in Table 2. The obtained antithrombotic coating materials and polymers were evaluated in the same manner as in Example 1. The evaluation results are shown in Table 2.

[0095] [Comparative Examples 1-3] Antithrombotic coating materials were manufactured using the same procedure as in Example 1, except that the types and amounts of polymers and additives were changed as shown in Table 2. The obtained antithrombotic coating materials and polymers were evaluated in the same manner as in Example 1. The evaluation results are shown in Table 2. Note that the antithrombotic coating material of Comparative Example 1, which contains polymer (PA-4), corresponds to a commercially available product. Considering this, in order to use the antithrombotic coating material of Comparative Example 1 as a reference sample for antithrombotic evaluation, the glass substrate was changed to a PC substrate when evaluating the antithrombotic properties of the antithrombotic coating material of Comparative Example 1. For the antithrombotic coating materials of Comparative Examples 2 and 3, the evaluation results for substrate adhesion (substrate adhesion to ultrasonic treatment, substrate adhesion to autoclave sterilization treatment) in (2) above included poor (×), so the antithrombotic properties were not evaluated. Therefore, "-" is indicated in Table 2.

[0096]

[0097] As shown in Table 2, the antithrombotic coating materials of Examples 1 to 3, which contained an addition polymer having an epoxy group and a substructure represented by formula (1) above, exhibited good antithrombotic properties while also showing excellent adhesion of the polymer to the substrate during ultrasonic treatment and to autoclave sterilization. In contrast, the antithrombotic coating materials of Comparative Examples 1 to 3, which used polymers (PA-4) and (PA-5) having the substructure represented by formula (1) above but lacking epoxy groups, instead of the addition polymer having an epoxy group and a substructure represented by formula (1) above, showed inferior adhesion to the glass substrate compared to Examples 1 to 3.

[0098] 3. Evaluation of cytotoxicity using normal human dermal fibroblasts A coating material (CA-1) was applied to a φ14 mm circular cover glass using a spin coater, heated on an 80°C hot plate for 1 minute, and then heated in a 150°C oven with nitrogen purging for 20 minutes to form a film with an average thickness of 100 nm. The glass substrate coated with the coating material (CA-1) was further heated in a 180°C oven with nitrogen purging for 30 minutes to perform dry heat sterilization. The dry heat sterilized glass substrate coated with the coating material (CA-1) was placed in the wells of a 24-well microplate for adherent cells (IWAKI, 3820-024) that had been previously coated with poly(2-methacryloyloxyethyl phosphorylcholine-co-methacrylate n-butyl), and UV sterilization was performed for 1 hour. After washing the wells with 1 mL of PBS prepared from PBS Tablets (Thermo Fisher Scientific, 18912014), 1 mL of culture medium prepared to be 10% FBS (Biosera, FB-1001 / 500) in DMEM / F12 (Thermo Fisher Scientific, 11320033) was added, and preconditioning was performed at 37°C under 5% CO2 for 1 hour. Seeding density 1 × 10⁶ 4 cells / cm 2 Normal human dermal fibroblasts (LONZA, CC-2511) prepared in the following manner were seeded at 1 mL / well and cultured in an incubator at 37°C and 5% CO2. After one week, a 24-well microplate for adherent cells was removed from the incubator and replaced with medium containing 10% Cell Counting Kit-8 (Dojin Chemical Research Institute) relative to the volume of medium in each well. The cells were then cultured in an incubator at 37°C and 5% CO2 for 2 hours. After completion, the cells were transferred to a 96-well plate, and the number of cells adhering to the glass substrate was counted by measuring the absorbance (λ = 450 nm) with a microplate reader. The average number of cells across the three glass substrates was 4 × 10⁶. 4 cells / cm 2The study confirmed that normal human dermal fibroblasts were adhering to and proliferating on the substrate. Figure 1 shows images of normal human dermal fibroblasts observed under an unstained phase-contrast microscope one week after the start of culture (unstained phase-contrast microscope images). Figure 1 shows images of two wells (N=2). The notation "CA-1" in Figure 1 represents the name of the coating material used. Microscopic observation confirmed that normal human dermal fibroblasts were adhering to and proliferating on the substrate coated with the coating material (CA-1). This indicated that the film formed by the coating material (CA-1) poses a low risk of cytotoxicity.

Claims

1. An antithrombotic coating material containing an addition polymer having a substructure represented by the following formula (1) and at least one of an oxyranyl group and an oxetanyl group. (In formula (1), R １ is an alkanediyl group. n1 is 0 or 1. n2 is an integer from 0 to 3. R ２ When n2 is 0, it is an alkyl group, and when n2 is 1 to 3, it is a hydrogen atom or an alkyl group. However, the (n2) R in formula (1) １ The number of carbon atoms and R ２ The total number of carbon atoms is between 1 and 12. (* indicates a bond.) 2. The antithrombotic coating material according to claim 1, wherein the addition polymer comprises a structural unit having a substructure represented by formula (1) and a structural unit having at least one of an oxyranyl group and an oxetanyl group.

3. The antithrombotic coating material according to claim 1, wherein the addition polymer has an alicyclic epoxy group.

4. The antithrombotic coating material according to claim 1, further comprising a crosslinking agent.

5. The antithrombotic coating material according to claim 4, wherein the crosslinking agent has two or more in one molecule at least one selected from the group consisting of an oxiranil group, an oxetanil group, a cyclic carbonate group, a hydroxyl group, a protected hydroxyl group, a carboxyl group, a protected carboxyl group, a mercapto group, a protected mercapto group, an amino group, a protected amino group, an isocyanate group, a protected isocyanate group, and a polymerizable carbon-carbon unsaturated bond group.

6. The antithrombotic coating material according to claim 5, wherein the crosslinking agent does not have an aromatic ring.

7. A medical device in which the surface of a substrate is coated with an antithrombotic coating material according to any one of claims 1 to 6.

8. A research instrument in which the surface of a substrate is coated with an antithrombotic coating material according to any one of claims 1 to 6.

9. A method for manufacturing medical devices and research instruments, comprising the step of coating the surface of a substrate with an antithrombotic coating material described in any one of claims 1 to 6.

10. A method for manufacturing a medical device and research instrument according to claim 9, further comprising the step of sterilizing the surface of the substrate with the antithrombotic coating material at a temperature of 80°C or higher.

11. An adsorption inhibition method for inhibiting the adsorption of platelets onto the surface of a substrate, comprising the step of forming a film on the surface of the substrate with an antithrombotic coating material according to any one of claims 1 to 6.

Images