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

Abstract

Provided is an antithrombotic coating material containing a polyorganosiloxane having at least one of an oxiranyl group and an oxetanyl group, thereby forming a coating film having excellent adhesion to a substrate while exhibiting good antithrombotic properties.

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. 2024-197530, 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] Biocompatible polymers generally have low adhesion to the surface of other materials and tend to be particularly inferior in adhesion to the surface of inorganic materials such as glass and metal. In addition, polymers having hydrophilic side chains such as those in Patent Document 1 and Patent Document 2 maintain the shape of the film (coating layer) or suppress decomposition during the coating process for imparting biocompatibility to the substrate surface, the subsequent sterilization process, and during product use, so that the film remains adhered to the substrate. There was a problem that relatively high-temperature heat treatment and ultrasonic treatment were restricted. As a coating material used for surface coating of medical devices and the like, it is required to have excellent adhesion to the substrate surface while showing good antithrombotic properties.

[0006] The present disclosure has been made in view of the above problems, and an object is to provide an antithrombotic coating material capable of forming a film having excellent adhesion to a substrate while showing good antithrombotic properties.

[0007] According to the present disclosure, the following antithrombotic coating materials, medical devices, research instruments, methods for manufacturing medical devices and research instruments, and adsorption suppression methods are provided. [1] An antithrombotic coating material containing a polyorganosiloxane having at least one of an oxiranyl group and an oxetanyl group. [2] The antithrombotic coating material according to [1], wherein the polyorganosiloxane has at least one selected from the group consisting of a partial structure represented by the following formula (1-1) and a partial structure represented by the following formula (1-2). (In Formula (1-1) and Formula (1-2), X １ and X ２ are, independently of each other, -O-, -S-, -O-CO- or -NR ３ -. R ３ is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. R １ and R ２ are monovalent organic groups independently of each other. "*" represents a bond.) [3] The antithrombotic coating material according to [2], wherein R １ in the above formula (1-1) and R ２ in the above formula (1-2) are represented by the following formula (2). (In Formula (2), R ４is an alkanediyl group. n1 is 0 or 1. n2 is an integer from 0 to 3. R ５ 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 (2) ４ The number of carbon atoms and R ５ The total number of carbon atoms is 1 to 12. (* represents a bond.) [4] The antithrombotic coating material according to any one of [1] to [3], wherein the polyorganosiloxane has an epoxycyclohexyl group. [5] The antithrombotic coating material according to any one of [1] to [4], wherein the polyorganosiloxane has at least one of a cage structure, an incomplete cage structure, and a cyclic structure. [6] The antithrombotic coating material according to any one of [1] to [5], further containing a crosslinking agent. [7] The antithrombotic coating material according to [6], wherein the crosslinking agent has two or more in one molecule 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. [8] The antithrombotic coating material according to [6] or [7], wherein the crosslinking agent does not have an aromatic ring. [9] The antithrombotic coating material according to any one of [1] to [8], further comprising a polymer having a main skeleton different from that of the polyorganosiloxane.

[10] The antithrombotic coating material according to [9], wherein the polymer having a main skeleton different from that of the polyorganosiloxane is at least one selected from the group consisting of polyamic acid, polyamic acid ester, polyimide, and addition polymer.

[11] The antithrombotic coating material according to any one of [1] to

[10] , wherein the polyorganosiloxane is a reaction product of a polymer containing a structural unit represented by the following formula (S1) and at least one selected from the group consisting of carboxylic acids, thiol compounds, amine compounds and alcohol compounds having a substructure represented by the following formula (2). (In formula (S1), R ７(This is a monovalent group having an oxetanyl group or an oxyranyl group.) (In formula (2), R ４ is an alkanediyl group. n1 is 0 or 1. n2 is an integer from 0 to 3. R ５ 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 (2) ４ The number of carbon atoms and R ５ The total number of carbon atoms is 1 to 12. (* represents a bond.)

[12] A medical device in which the surface of a substrate is coated with an antithrombotic coating material according to any one of [1] to

[11] .

[13] A research instrument in which the surface of a substrate is coated with an antithrombotic coating material according to any one of [1] to

[11] .

[14] A method for manufacturing a medical device and a research instrument, comprising the step of coating the surface of a substrate with an antithrombotic coating material according to any one of [1] to

[11] .

[15] A method for manufacturing a medical device and a research instrument according to

[14] , 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.

[16] 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 according to any one of [1] to

[11] .

[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 a polyorganosiloxane having at least one of an oxiranil group and an oxetanil group (hereinafter also referred to as "specific polyorganosiloxane").

[0014] <Specific Polyorganosiloxanes> In specific polyorganosiloxanes, the position of introduction of the epoxy group is not particularly limited. In order to further improve the biocompatibility of the specific polyorganosiloxane, it is preferable that the specific polyorganosiloxane has an epoxy group in its side chain, and more specifically, it is preferable that it has a side chain containing an epoxy group. Examples of side chains containing an epoxy group include a side chain having a glycidyl group and a side chain having an epoxycyclohexyl group. In specific polyorganosiloxanes, a specific example of a side chain containing an epoxy group is a monovalent group containing an epoxy group, and it is preferable that the monovalent group containing an epoxy group is bonded to an atom (preferably a silicon atom) that constitutes the main chain of the polyorganosiloxane. In order to obtain an antithrombotic coating material with excellent storage stability, it is preferable that the specific polyorganosiloxane has an epoxycyclohexyl group.

[0015] From the viewpoint of obtaining a coating with excellent adhesion to the substrate (especially adhesion at high temperatures), the amount of epoxy groups in the specific polyorganosiloxane 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 contained in the specific polyorganosiloxane. Furthermore, from the viewpoint of ensuring the biocompatibility of the specific polyorganosiloxane and obtaining a coating material that exhibits good antithrombotic properties, the amount of epoxy groups in the specific polyorganosiloxane is preferably 95 mol% or less, and more preferably 90 mol% or less, relative to the total amount of structural units contained in the specific polyorganosiloxane.

[0016] The specific polyorganosiloxane may further contain hydroxyl groups. By further containing hydroxyl groups in the specific polyorganosiloxane, polymers with enhanced solubility in low-boiling solvents suitable for medical applications, such as ethanol and methanol, can be obtained. Furthermore, by further containing hydroxyl groups in the specific polyorganosiloxane, it is possible to improve the applicability and adhesion of the coating material to the substrate, and to obtain a coating film with a higher intermediate water content, which is thought to contribute to the expression of biocompatibility.

[0017] When a specific polyorganosiloxane has hydroxyl groups, the amount of hydroxyl groups in the specific polyorganosiloxane is preferably 10 mol% or more, more preferably 15 mol% or more, and even more preferably 20 mol% or more, relative to the total amount of structural units contained in the specific polyorganosiloxane. Furthermore, the amount of hydroxyl groups in the specific polyorganosiloxane is preferably 95 mol% or less, and more preferably 90 mol% or less, relative to the total amount of structural units contained in the specific polyorganosiloxane.

[0018] In terms of being able to obtain polyorganosiloxanes having epoxy groups and hydroxyl groups in their side chains through simple operations, it is preferable that a specific polyorganosiloxane has at least one selected from the group consisting of the substructure represented by the following formula (1-1) and the substructure represented by the following formula (1-2) in its side chains. (In equations (1-1) and (1-2), X １and X ２ These are independent of each other: -O-, -S-, -O-CO-, or -NR ３ - is R ３ R is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. １ and R ２ These are monovalent organic groups, independent of each other. (* represents a bond.)

[0019] In the above equations (1-1) and (1-2), R １ or R ２ The monovalent organic group represented by this is a monovalent hydrocarbon group having 1 to 13 carbon atoms, and -O-, -S-, -O-CO-, -NR between the carbon-carbon bonds in the hydrocarbon group. ４ -, -CO-NR ４ -, -NR ４ -CO-O- or -NR ４ -CO-NR ５ - A monovalent group having 2 to 13 carbon atoms (hereinafter referred to as "monovalent group W") １ (Also known as) a monovalent hydrocarbon group or monovalent group W having 1 to 13 carbon atoms １ Examples include groups in which one or more hydrogen atoms are substituted. Here, R ４ and R ５ These are, independently of each other, a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. Examples of substituents include halogen atoms, nitro groups, carboxyl groups, and hydroxyl groups.

[0020] Examples of monovalent hydrocarbon groups having 1 to 13 carbon atoms include monovalent linear hydrocarbon groups having 1 to 13 carbon atoms, monovalent alicyclic hydrocarbon groups having 3 to 13 carbon atoms, and monovalent aromatic hydrocarbon groups having 6 to 13 carbon atoms.

[0021] The monovalent linear hydrocarbon group having 1 to 13 carbon atoms may be saturated or unsaturated, and may be linear or branched. Examples of monovalent linear hydrocarbon groups having 1 to 13 carbon atoms include alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, and t-butyl groups; alkenyl groups such as ethenyl, propenyl, and butenyl groups; and alkynyl groups such as ethynyl, propynyl, and butynyl groups. Of these, R １ or R ２When the monovalent linear hydrocarbon group has 1 to 13 carbon atoms, the monovalent linear hydrocarbon group is preferably an alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 4 carbon atoms, and even more preferably a linear alkyl group having 1 to 4 carbon atoms.

[0022] Examples of monovalent alicyclic hydrocarbon groups having 3 to 13 carbon atoms include monovalent monocyclic alicyclic saturated hydrocarbon groups such as cyclopentyl group, cyclohexyl group, methylcyclopentyl group, ethylcyclopentyl group, methylcyclohexyl group, and ethylcyclohexyl group; monovalent monocyclic alicyclic unsaturated hydrocarbon groups such as cyclopentenyl group, cyclohexenyl group, methylcyclopentenyl group, and methylcyclohexenyl group; monovalent polycyclic alicyclic saturated hydrocarbon groups such as norbornyl group and adamantyl group; and monovalent polycyclic alicyclic unsaturated hydrocarbon groups such as norbornenyl group.

[0023] Examples of monovalent aromatic hydrocarbon groups having 6 to 13 carbon atoms include aryl groups such as phenyl, tolyl, xyl, mesityl, naphthyl, and methylnaphthyl groups; and aralkyl groups such as benzyl and phenethyl groups.

[0024] In order to obtain a polyorganosiloxane with excellent biocompatibility while ensuring water non-water solubility, the R in formula (1-1) above １ and R in formula (1-2) above ２ Preferably, R in formula (1-1) above is an alkyl group having 1 to 13 carbon atoms, a monovalent group having 2 to 13 carbon atoms in which part of the methylene group in the alkyl group is replaced with -O-, or a monovalent group having 2 to 13 carbon atoms in which part of the methylene group in the alkyl group is replaced with -O- and the terminal end is a hydroxyl group. Specifically, R in formula (1-1) above is preferable. １ and R in formula (1-2) above ２ It is preferable that it is represented by the following formula (2). (In formula (2), R ４ is an alkanediyl group. n1 is 0 or 1. n2 is an integer from 0 to 3. R ５ 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 (2) ４The number of carbon atoms and R ５ The total number of carbon atoms is between 1 and 12. (* indicates a bond.)

[0025] In the above equation (2), R ４ The alkanediyl group represented by may be linear or branched. In terms of obtaining polymers with superior antithrombotic properties, R ４ The alkanediyl group represented by is preferably linear. ５ The alkyl group represented by is preferably linear.

[0026] (n2) R in equation (2) ４ The number of carbon atoms and R ５ The total number of carbon atoms, including the number of carbon atoms, is preferably 1 to 10, more preferably 2 to 8, and even more preferably 2 to 6, from the viewpoint of ensuring sufficient biocompatibility and solubility in alcohol-based solvents of the specific polyorganosiloxane. Specifically, R ４ The group is preferably an alkanediyl group having 1 to 3 carbon atoms, and more preferably a methylene group or an ethylene group. ５ The alkyl group is preferably a C1-C3 alkyl group, more preferably a methyl group or an ethyl group, and even more preferably a methyl group.

[0027] 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 ５ It is preferable that it be an alkyl group.

[0028] Specific examples of the group represented by formula (2) 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.

[0029] In terms of high storage stability of monomers and ease of ensuring polymer productivity, it is preferable that the specific polyorganosiloxane has a substructure represented by the above formula (1-1), and furthermore, in order to obtain a polymer with excellent biocompatibility, it is preferable that it has a substructure represented by the above formula (1-1) and that the R in the above formula (1-1) １ It is more preferable that the group is represented by the above formula (2).

[0030] The method for synthesizing a specific polyorganosiloxane is not particularly limited. For example, a specific polyorganosiloxane can be obtained by hydrolysis and condensation of a hydrolyzable silane compound having an epoxy group (ms-1), or a mixture of a silane compound (ms-1) and other silane compounds. Furthermore, if the specific polyorganosiloxane has at least one selected from the group consisting of the substructure represented by formula (1-1) and the substructure represented by formula (1-2) in its side chain, the following method (hereinafter also referred to as Method A) can be used to synthesize the polyorganosiloxane.

[0031] [Method A] A silane compound (ms-1), or a mixture of a silane compound (ms-1) and other silane compounds, is hydrolyzed and condensed to synthesize an epoxy group-containing polyorganosiloxane. Then, the obtained epoxy group-containing polyorganosiloxane is mixed with R in formula (1-1) above. １ Or R in formula (1-2) above ２ A method for reacting a carboxylic acid, thiol compound, amine compound, and alcohol compound (hereinafter also referred to as "specific compound") with a carboxylic acid, thiol compound, amine compound, and alcohol compound having a specific compound.

[0032] Method A is simple, and moreover, in the above formula (1-1) R in a specific polyorganosiloxane １ Or R in formula (1-2) above ２ This method is preferable because it allows for a high rate of introduction of the compound. Furthermore, according to Method A, polyorganosiloxanes having epoxy groups and hydroxyl groups in their side chains can be obtained by a simple method. In the following, -X in formula (1-1) above will be used. １ -R １ and -X in the above formula (1-2) ２ -R ２ It is also referred to as a "specific base," encompassing all of these.

[0033] Specific examples of silane compounds (MS-1) include, for example, 3-glycidoxypropyltrimethoxysilane, 3-glycidoxypropyltriethoxysilane, 3-glycidoxypropylmethyldimethoxysilane, 3-glycidoxypropylmethyldiethoxysilane, 2-glycidoxyethyltrimethoxysilane, 2-glycidoxyethylmethyldimethoxysilane, 2-glycidoxyethyldimethylmethoxysilane, 2-glycidoxyethyldimethylethoxysilane, and 4-glyc Examples include doxybutyltrimethoxysilane, 4-glycidoxybutylmethyldimethoxysilane, 4-glycidoxybutylmethyldiethoxysilane, 4-glycidoxybutyldimethylmethoxysilane, 4-glycidoxybutyldimethylethoxysilane, 2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane, 2-(3,4-epoxycyclohexyl)ethyltriethoxysilane, and 3-(3,4-epoxycyclohexyl)propyltrimethoxysilane.

[0034] Other silane compounds are not particularly limited as long as they are hydrolyzable silane compounds. Specific examples include alkoxysilanes such as tetramethoxysilane, tetraethoxysilane, methyltrimethoxysilane, methyltriethoxysilane, phenyltrimethoxysilane, phenyltriethoxysilane, dimethyldimethoxysilane, and dimethyldiethoxysilane; and nitrogen- and sulfur-containing alkoxysilanes such as 3-mercaptopropyltrimethoxysilane, 3-mercaptopropyltriethoxysilane, mercaptomethyltrimethoxysilane, 3-ureidopropyltrimethoxysilane, 3-aminopropyltrimethoxysilane, 3-aminopropyltriethoxysilane, N-(3-cyclohexylamino)propyltrimethoxysilane, and N-2-(aminoethyl)-3-aminopropyltrimethoxysilane. Examples include alkoxysilanes containing unsaturated hydrocarbons such as 3-(meth)acryloyloxypropyltrimethoxysilane, 3-(meth)acryloyloxypropyltriethoxysilane, 6-(meth)acryloyloxyhexyltrimethoxysilane, 3-(meth)acryloxypropylmethyldimethoxysilane, 3-(meth)acryloxypropylmethyldiethoxysilane, vinyltrimethoxysilane, vinyltriethoxysilane, and p-styryltrimethoxysilane; and alkoxysilanes containing acid anhydride groups such as trimethoxysilylpropyl succinic anhydride and triethoxysilylpropyl succinic anhydride.

[0035] The hydrolysis and condensation reaction of silane compounds can be carried out by reacting one or more of the above-mentioned silane compounds with water, preferably in the presence of a suitable catalyst and an organic solvent. The amount of water used in the reaction is preferably 1 to 30 moles per mole of the total amount of silane compounds. Examples of catalysts include acids, alkali metal compounds, organic bases, titanium compounds, and zirconium compounds. The amount of catalyst used varies depending on the type of catalyst, reaction conditions such as temperature, and can be set appropriately. The amount of catalyst used is preferably 0.01 to 3 moles relative to the total amount of silane compounds. Examples of organic solvents include hydrocarbons, ketones, esters, ethers, and alcohols. Of these, it is preferable to use an organic solvent that is insoluble or poorly soluble in water. The amount of organic solvent used is preferably 10 to 10,000 parts by mass per 100 parts by mass of the total amount of silane compounds used in the reaction.

[0036] The above hydrolysis-condensation reaction is preferably carried out by heating, for example, in an oil bath. In this case, the heating temperature is preferably 130°C or lower, and the heating time is preferably 0.5 to 12 hours. After the reaction is complete, the organic solvent layer separated from the reaction solution is dried with a desiccant as needed, and then the solvent is removed to obtain the desired polyorganosiloxane. Note that the method for synthesizing polyorganosiloxane is not limited to the above hydrolysis-condensation reaction, but may also be carried out by, for example, reacting a hydrolyzable silane compound in the presence of oxalic acid and alcohol.

[0037] In Method A, the epoxy group-containing polyorganosiloxane obtained by the above reaction is then reacted with a specific compound. This causes the epoxy group in the epoxy group-containing polyorganosiloxane to react with the carboxyl group, thiol group, amino group, or alcoholic hydroxyl group in the specific compound, yielding a specific polyorganosiloxane having at least one of the substructures represented by formula (1-1) and formula (1-2) as a side chain. Furthermore, by adjusting the amount of epoxy group and carboxylic acid in the epoxy group-containing polyorganosiloxane, a polyorganosiloxane having epoxy groups as a side chain (i.e., a specific polyorganosiloxane) can be obtained.

[0038] The epoxy group-containing polyorganosiloxane used in Method A preferably has at least one of a cage structure, an incomplete cage structure, and a cyclic structure. One preferred embodiment of the epoxy group-containing polyorganosiloxane has one or both of a cage structure and an incomplete cage structure. Another preferred embodiment of the epoxy group-containing polyorganosiloxane has a cyclic structure. When the epoxy group-containing polyorganosiloxane has both a cage structure and an incomplete cage structure, it typically has a structure in which the cage structure and the incomplete cage structure are mixed. When the epoxy group-containing polyorganosiloxane has one or both of a cage structure and an incomplete cage structure, it is preferable that the epoxy group-containing polyorganosiloxane is a polyorganosiloxane containing a structural unit represented by the following formula (S1). (In formula (S1), R ７ (This is a monovalent group having an oxetanyl group or an oxyranyl group.)

[0039] In the above formula (S1), R ７Examples of monovalent groups represented by include groups having a glycidyl group or an epoxycyclohexyl group. Specifically, examples include glycidyloxymethyl group, 2-glycidyloxyethyl group, 3-glycidyloxypropyl group, 4-glycidyloxybutyl group, 2-(3,4-epoxycyclohexyl)ethyl group, 3-(3,4-epoxycyclohexyl)propyl group, 4-(3,4-epoxycyclohexyl)butyl group, and the like.

[0040] When the epoxy group-containing polyorganosiloxane has a cyclic structure, a cyclic polysiloxane having an oxetanyl group or an oxyranyl group can be used as the epoxy group-containing polyorganosiloxane, and specifically, a compound represented by the following formula (S2) can be used. (In formula (S2), Y １ ~Y ６ These are, independently of each other, a hydrogen atom or a monovalent organic group. However, Y １ ~Y ６ At least one of them is a monovalent group having an oxetanyl group or an oxyranyl group. n is an integer from 1 to 18. If n is 2 or greater, multiple Y １ They are the same or different, multiple Y ２ They are either the same or different.

[0041] In the above formula (S2), Y １ ~Y ６ Specific examples of a monovalent group having an epoxy group include a group having a glycidyl group or an epoxycyclohexyl group. Specific examples of these include R in formula (S1) above. ７ Examples of monovalent groups represented by include groups similar to those exemplified above. １ ~Y ６ However, a specific example of a monovalent organic group that does not have an oxetanyl group or an oxyranyl group is R in formula (1-1) above. １ Or R in formula (1-2) ２ Examples of monovalent organic groups represented by the formula include groups similar to those exemplified above. n is preferably 1 to 15, and more preferably 1 to 10.

[0042] Specific examples of cyclic polysiloxanes having epoxy groups include, for example, the compounds represented by formulas (A1) to (A5) below. Commercially available cyclic polysiloxanes having epoxy groups can also be used. Examples of commercially available products include CS-697, CS-783 (both manufactured by Sigma-Aldrich), KR-470, X-40-2670, and X-40-2678 (all manufactured by Shin-Etsu Silicone Co., Ltd.). (In equations (A1) to (A5), m is an integer between 0 and 17.)

[0043] Examples of specific compounds include compounds having the group exemplified in the description of the group represented by formula (2) above, and at least one selected from the group consisting of a carboxyl group, a thiol group, an amino group, and an alcoholic hydroxyl group. Preferably, specific compounds include compounds having one carboxyl group, thiol group, amino group, or alcoholic hydroxyl group in one molecule (monocarboxylic acid, monothiol, monoamine, monoalcohol), or compounds having one carboxyl group and one alcoholic hydroxyl group in one molecule (hydroxyl group-containing monocarboxylic acid). When a hydroxyl group-containing monocarboxylic acid is used, the carboxyl group preferentially reacts with the epoxy group, thereby obtaining a polyorganosiloxane in which a hydroxyl group derived from the hydroxyl group-containing monocarboxylic acid is introduced into the side chain. Specific examples of specific compounds include compounds represented by the following formula.

[0044] Of the specified compounds, carboxylic acids are preferred from the viewpoint of the reactivity between the epoxy group-containing polyorganosiloxane and the specified compound, and the storage stability of the antithrombotic coating material, and monocarboxylic acids having the group represented by formula (2) above are more preferred. Among these, in particular from the viewpoint of storage stability and productivity of the antithrombotic coating material, R in formula (2) above is preferred. ２ A monocarboxylic acid having a monovalent group in which is an alkyl group is even more preferred. Also, X in formula (1-1) above is preferred. １ and X in the above formula (1-2) ２ -O-CO- is preferred.

[0045] From the viewpoint of obtaining a polymer with excellent biocompatibility, the amount of specific groups in one molecule of specific polyorganosiloxane is preferably 5 mol% or more, more preferably 10 mol% or more, and even more preferably 15 mol% or more, relative to the silicon atoms contained in the specific polyorganosiloxane. Furthermore, from the viewpoint of introducing a sufficient amount of epoxy groups to ensure adhesion of the coating, the amount of specific groups in the specific polyorganosiloxane is preferably 95 mol% or less, and more preferably 90 mol% or less, relative to the silicon atoms contained in the specific polyorganosiloxane.

[0046] In the synthesis of specific polyorganosiloxanes by Method A, the amount of the compound having the group represented by the above formula (2) among the specific compounds used is preferably 2 mol% or more, more preferably 5 mol% or more, and even more preferably 15 mol% or more, based on the total amount of specific compounds used in the reaction with the epoxy group-containing polyorganosiloxane, in order to obtain a polymer with excellent biocompatibility.

[0047] The reaction between the epoxy group-containing polyorganosiloxane and the specific compound can preferably be carried out in the presence of a catalyst and an organic solvent. The catalyst used can be appropriately determined depending on the type of specific compound. For example, when a carboxylic acid is used as the specific compound, an organic base or a compound known as a curing accelerator that promotes the reaction of the epoxy compound (e.g., tertiary organic amines, quaternary organic amines, quaternary ammonium salts, etc.) can be used as the catalyst. The amount of catalyst used is preferably 100 parts by mass or less, more preferably 0.1 to 20 parts by mass, per 100 parts by mass of the epoxy group-containing polyorganosiloxane.

[0048] Examples of organic solvents used in the above reaction include hydrocarbons, ethers, esters, ketones, amides, and alcohols. The organic solvent is preferably used in a proportion such that the solid content concentration (the ratio of the total mass of components other than the solvent in the reaction solution to the total weight of the solution) is 0.1% by mass or more, and more preferably 5% by mass or more. In the above reaction, the reaction temperature is preferably 0 to 200°C, and more preferably 50 to 150°C. The reaction time is preferably 0.1 to 50 hours, and more preferably 0.5 to 20 hours. After the reaction is complete, it is preferable to wash the organic solvent layer separated from the reaction solution with water. After washing with water, the organic solvent layer is dried with a suitable drying agent as needed, and then the solvent is removed to obtain the target product, a specific polyorganosiloxane.

[0049] The specific polyorganosiloxane is preferably a reaction product of a polymer containing the structural unit represented by formula (S1) and a specific compound, or a reaction product of a cyclic polysiloxane having an oxetanyl group or an oxiranyl group and a specific compound. By reacting a polymer containing the structural unit represented by formula (S1) with a specific compound, a polyorganosiloxane having one or both of a cage-type structure and an incomplete cage-type structure can be obtained. Furthermore, by reacting a cyclic polysiloxane having an oxetanyl group or an oxiranyl group with a specific compound, a polyorganosiloxane having a cyclic structure can be obtained. It should be noted that whether a polyorganosiloxane has one or both of a cage-type structure and an incomplete cage-type structure can be determined, for example, by NMR measurement.

[0050] The specified polyorganosiloxane preferably has a solution viscosity of 1 to 500 mPa·s when it is prepared as a 10% by mass solution, and more preferably has a solution viscosity of 3 to 200 mPa·s. The weight-average molecular weight (Mw) of the specified polyorganosiloxane in terms of polystyrene, as measured by GPC, is preferably 500 to 200,000. Specifically, if the specified polyorganosiloxane has one or both of a cage structure and an incomplete cage structure, the Mw of the specified polyorganosiloxane is preferably 1,000 to 200,000, more preferably 2,000 to 50,000, and even more preferably 3,000 to 20,000. When the specific polyorganosiloxane has a cyclic structure, the Mw of the specific polyorganosiloxane is preferably 500 to 2,000, more preferably 600 to 1,500, and even more preferably 800 to 1,500.

[0051] <Other Components> This coating material may contain only a specific polyorganosiloxane, or it may further contain a component different from the specific polyorganosiloxane (other components) together with the specific polyorganosiloxane. 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 a main skeleton different from that of the polyorganosiloxane (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.

[0052] (Other Polymers) Other polymers are not particularly limited, as long as they have a main skeleton different from polyorganosiloxanes. Examples of other polymers include polyamic acid, polyimide, polyamic acid ester, polyamide, polyurea, polyurethane, polyester, cellulose derivative, polyacetal, addition polymer, polyether, etc. Examples of addition polymers include (meth)acrylic polymers, styrene polymers, maleimide polymers, (meth)acrylic-styrene copolymers, (meth)acrylic-maleimide copolymers, (meth)acrylic-styrene-maleimide copolymers, and styrene-maleimide copolymers. Known monomers can be used as appropriate as the monomers constituting the other polymers.

[0053] 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 the epoxy groups of specific polyorganosiloxanes 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, and addition polymers is preferred, with polyamic acid or poly(meth)acrylic acid being more preferred.

[0054] When other polymers are included in this coating material, the content of the other polymers is preferably 1 part by mass or more, more preferably 2 parts by mass or more, and even more preferably 5 parts by mass or more, per 100 parts by mass of the specified polyorganosiloxane. Furthermore, the content of the other polymers is preferably 30 parts by mass or less, and more preferably 25 parts by mass or less, per 100 parts by mass of the specified polyorganosiloxane.

[0055] (Crosslinking agent) This coating material may further contain a crosslinking agent. By containing a crosslinking agent together with a specific polyorganosiloxane, this coating material can form a film with superior adhesion to the substrate.

[0056] The crosslinking agent preferably has two or more crosslinkable groups in one molecule that can react with the reactive groups of a specific polyorganosiloxane 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 oxiranyl 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.

[0057] 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.

[0058] 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.

[0059] Examples of compounds having a cyclic carbonate group include the compounds represented by the following formulas (d1-1) and (d1-2).

[0060] 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).

[0061] 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.

[0062] 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.

[0063] Examples of compounds having an amino group or a protected amino group include compounds represented by the following formulas (d4-1) to (d4-5).

[0064] 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).

[0065] 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.

[0066] (In formula (d2-5), Ac is an acetyl group.)

[0067] 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.

[0068] 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.

[0069] 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 specified polyorganosiloxane 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 specified polyorganosiloxane. Furthermore, the crosslinking agent content is preferably 25 parts by mass or less, more preferably 20 parts by mass or less, and even more preferably 15 parts by mass or less, per 100 parts by mass of the specified polyorganosiloxane. 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.

[0070] (Solvent) The coating material may be provided as a liquid composition in which a specific polyorganosiloxane is dissolved or dispersed in a solvent. As the solvent, any solvent capable of dissolving or dispersing the specific polyorganosiloxane can be used as appropriate. Specific examples of solvents include water, organic solvents, and mixed solvents thereof. The solvent is preferably an organic solvent.

[0071] 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 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 polyorganosiloxanes.

[0072] 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.

[0073] ≪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.

[0074] Furthermore, since the main component of this coating material, a specific polyorganosiloxane, is water-insoluble, it is less likely to leach into biological components such as blood when in contact with them. Therefore, medical devices and research instruments of this disclosure having a coating formed with this coating material exhibit less 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.

[0075] 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).

[0076] 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.

[0077] <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).

[0078] 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.

[0079] 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.

[0080] 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 main component of the coating material, a specific polyorganosiloxane, 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.

[0081] 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.

[0082] ≪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.

[0083] 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.

[0084] 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

[0085] 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.

[0086] (Silane compounds) S-1, S-2

[0087] (Cyclic polysiloxane)

[0088] (Carboxylic acid) C-1 to C-3

[0089] (Acrylic monomers) A-1 to A-3

[0090] (Crosslinking agent) AD-1

[0091] 1. Synthesis of Polyorganosiloxane [Synthesis Example 1-1] 100.0 g of 2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane (compound (S-1)), 500 g of methyl isobutyl ketone, and 10.0 g of triethylamine were charged into a 1,000 mL three-necked flask and mixed at room temperature. Then, 100 g of deionized water was added dropwise from a dropping funnel over 30 minutes, and the reaction was carried out at 80°C for 6 hours while mixing under reflux. After the reaction was complete, the organic layer was removed and washed with 0.2% by mass aqueous solution of ammonium nitrate until the water after washing was neutral, and then the solvent and water were removed under reduced pressure. An appropriate amount of methyl isobutyl ketone was added to obtain a 50% by mass solution of polymer (ESSQ-1), which is a polyorganosiloxane having epoxy groups. In a 500 mL three-necked flask, compound (C-1) was added at a concentration of 15 mol% relative to the amount of epoxy groups in the polymer (ESSQ-1), along with 1.00 g of tetrabutylammonium bromide, 20.0 g of a solution containing the polymer (ESSQ-1), and 290.0 g of cyclopentanone. The mixture was stirred at 100°C for 8 hours. After cooling to room temperature, the reaction mixture was added dropwise to distilled water for reprecipitation and purification. The precipitate was dried in a vacuum dryer. The resulting dry material was dissolved in ethanol to a solid content concentration of 10% by mass to obtain an ethanol solution of polyorganosiloxane (referred to as polymer (PS-1)). １ H-NMR measurement, ２９ Structural analysis of the polymer (PS-1) using Si-NMR, gel permeation chromatography (GPC), and quadrupole time-of-flight mass spectrometry (QTOF-MS) confirmed that it is a polyorganosiloxane primarily composed of a mixture of cage-like and incomplete cage-like structures. The weight-average molecular weight of polymer (PS-1) was 3,000.

[0092] [Synthesis Examples 1-2 to 1-7] 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 (PS-2) to (PS-7), respectively. Structural verification of polymers (PS-2) to (PS-7) was performed in the same manner as in Synthesis Example 1-1, and it was confirmed that they are polyorganosiloxanes mainly consisting of a structure in which cage-like structures and incomplete cage-like structures are mixed.

[0093]

[0094] [Synthesis Example 1-8] In a 500 mL three-necked flask, 40 g of cyclic siloxane (ESSQ-2), compound (C-1) at 25 mol% relative to the amount of epoxy groups in cyclic siloxane (ESSQ-2), 1.00 g of tetrabutylammonium bromide, and 290.0 g of cyclopentanone were added and the mixture was stirred at 100°C for 8 hours. After cooling to room temperature, the reaction mixture was added dropwise to distilled water for reprecipitation and purification, and the precipitate was dried in a vacuum dryer. The obtained dry product was dissolved in ethanol to a solid content concentration of 10% by mass to obtain an ethanol solution of polyorganosiloxane (referred to as polymer (PS-8)). The weight-average molecular weight of polymer (PS-8) was 1,000.

[0095] 2. Synthesis of Polyamic Acids [Synthesis Example 2-1] 100 moles of 2,3,5-tricarboxycyclopentylacetic acid dianhydride as a tetracarboxylic dianhydride and 100 moles of 3,5-diaminobenzoic acid as a diamine compound were dissolved in N-methyl-2-pyrrolidone (NMP), and the reaction was carried out at 60°C for 6 hours to obtain a solution containing 20% ​​by mass of polyamic acid (referred to as polymer (PI-1)).

[0096] 3. Synthesis of Addition Polymers [Synthesis Example 3-1] 10 g of 2-methoxyethyl acrylate, 50 g of cyclopentanone, and 0.27 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 the polymer (PA-1). The Mw of the obtained polymer (PA-1) was 30,000.

[0097] [Synthesis Examples 3-2, 3-3] The same procedure as in Synthesis Example 3-1 was performed, except that the types and amounts of compounds used in the synthesis were changed as shown in Table 2, to obtain polymer (PA-2) and polymer (PA-3), respectively.

[0098]

[0099] 4. Preparation and Evaluation of Antithrombotic Coating Material [Example 1] (1) Preparation of Antithrombotic Coating Material 100 parts by mass of polymer (PS-1) and 6 parts by mass of additive (AD-1) were diluted with ethanol to prepare a coating material (CA-1) so that the total solid content concentration of the polymer and additive was 5.0% by mass.

[0100] (2) Evaluation of solubility in alcohol-based solvents The ethanol solution of the polymer (PS-1) obtained in Synthesis Example 1-1 was concentrated in an evaporator, and the residue was dried in a vacuum dryer. 1 g of the dried polymer (PS-1) was added to a 200 mL sample bottle, and then 99 g of ethanol was added and thoroughly mixed. After 30 minutes, dissolution was confirmed by visual inspection. If no ethanol-insoluble matter was visible, it was judged as "good (○)", and if ethanol-insoluble matter was visible or the mixture was in a suspended state, it was judged as "poor (×)". Solubility evaluation was also performed in the same manner using methanol instead of ethanol. As a result, in this example, the solubility in both ethanol and methanol was evaluated as good (○).

[0101] (3) Evaluation of substrate adhesion (3-1) Evaluation of substrate adhesion to ultrasonic treatment 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 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, aggregates, or unevenness due to film thickness non-uniformity were observed after ultrasonic cleaning; acceptable (△) if no peeling was observed but aggregates or unevenness were seen; and poor (×) if peeling was observed. Furthermore, substrate adhesion was evaluated in the same way as for the glass substrate, except that polycarbonate (PC) substrates and titanium substrates were used instead of glass substrates. As a result, in this example, substrate adhesion was evaluated as good (○) for all of the glass, PC, and titanium substrates.

[0102] (3-2) Evaluation of substrate adhesion to steam injection 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, steam at a water vapor temperature of 110°C was injected onto the film-forming surface of the substrate for 5 minutes. Then, the substrate was dried by heating in a 100°C oven with nitrogen purging for 10 minutes. 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 steam injection. Compared to the film state before steam injection, if no peeling, agglutination, or unevenness due to film thickness non-uniformity was observed after steam injection, the substrate adhesion was evaluated as good (○). If no peeling was observed but agglutination or unevenness was observed, it was evaluated as acceptable (△). If peeling was observed, it was evaluated as poor (×). Furthermore, the substrate adhesion was evaluated in the same way as for the glass substrate, except that a titanium substrate was used instead of a glass substrate. As a result, in this example, the substrate adhesion was evaluated as good (○) for both the glass substrate and the titanium substrate.

[0103] (3-3) 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 (○).

[0104] (3-4) Evaluation of substrate adhesion to dry heat sterilization 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 further heated in a 180°C oven for 30 minutes to perform dry heat sterilization treatment. After that, the film surface of the substrate was observed with an optical microscope to evaluate the adhesion of the film to the substrate to dry heat sterilization treatment. Compared to the film state before dry heat sterilization treatment, 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 dry heat sterilization treatment was evaluated as good (○). Furthermore, the adhesion to the substrate was evaluated in the same manner as in the case of 180°C, except that the dry heat sterilization temperature was changed from 180°C to 200°C. As a result, in this example, the adhesion to the substrate was evaluated as good (○) under both dry heat sterilization temperature conditions of 180°C and 200°C.

[0105] (4) 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 experiments and collected in the United States, was used in the experiment within 5 days of collection. The human whole blood, which had been kept 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 ２ PRP 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). ２Platelets were adhered by loading and incubating at 37°C for 1 hour. Subsequently, the platelet suspension was removed, and after washing twice with PBS, it was immersed in a 1% glutaraldehyde (diluted 1 / 25 with PBS(-) from 25% glutaraldehyde, polyscience, Inc. 01909) solution and incubated at 37°C for 2 hours to immobilize the adsorbed platelets on the substrate. After immobilization, washing was performed by immersing once each 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 containing silica gel for more than 1 day. After drying, the number of adsorbed platelets was counted by observing the substrate surface with a scanning electron microscope (Scanning Electron Microscope; SEM, KEYENCE, 3D real surface view microscope VE-9800). The above series of operations was performed 3 times, and when the average value of the three adhesion numbers of platelets was less than 0.7×10 ５ cells / cm ２ it was evaluated as "good (○)"; when it was 0.7×10 ５ cells / cm ２ or more and less than 1.5×10 ５ cells / cm ２ it was evaluated as "fair (△)"; when it was 1.5×10 ５ cells / cm ２ or more, it was evaluated as "poor (×)". As a result, in this example, the antithrombogenicity was evaluated as good (○). In addition, as a negative control, the average number of adhered platelets to a glass substrate and a PC substrate not coated with the coating material (CA-1) was counted in the same manner. The glass substrate had 6.0×10 ５ cells / cm ２ and the PC substrate had 9.4×10 ５ cells / cm ２ .

[0106] [Examples 2-9] Antithrombotic coating materials were produced in the same manner as in Example 1, except that the types and amounts of polymers and additives were changed as shown in Table 3. The obtained antithrombotic coating materials and polymers were evaluated in the same manner as in Example 1. The evaluation results are shown in Table 3.

[0107] [Comparative Examples 1-4] Antithrombotic coating materials were manufactured in the same manner as in Example 1, except that the types and amounts of polymers and additives were changed as shown in Table 3, and the solvent was changed to methanol. In Comparative Examples 1-4, the solvent used to prepare the antithrombotic coating materials was changed to methanol because the solubility of PA-1 to PA-3 in ethanol was insufficient. The obtained antithrombotic coating materials and polymers were evaluated in the same manner as in Example 1. The evaluation results are shown in Table 3. Note that the antithrombotic coating material of Comparative Example 1, which contains polymer (PA-1), corresponds to a commercially available product. Therefore, in order to evaluate the antithrombotic properties of the antithrombotic coating materials of Examples 1-8 using the evaluation results of the antithrombotic coating material of Comparative Example 1 as an indicator, the glass substrate was changed to a PC substrate when evaluating the antithrombotic properties of the antithrombotic coating material of Comparative Example 1. For Comparative Examples 1 to 4, since the evaluation results for substrate adhesion in (3) above included poor (×), the antithrombotic properties were evaluated only for Comparative Example 1, and not for Comparative Examples 2 to 4. Therefore, in Table 3, "-" is indicated in the column for the antithrombotic properties evaluation results for Comparative Examples 2 to 4.

[0108]

[0109] As shown in Table 3, the antithrombotic coating materials of Examples 1 to 9 containing polyorganosiloxane having an epoxy group showed good antithrombotic properties, excellent solubility of the polymer in alcohol solvents, and excellent adhesion to the substrate against various treatments (ultrasonic treatment, steam injection treatment, autoclave sterilization treatment, and dry heat sterilization treatment). On the other hand, the films formed by the antithrombotic coating materials of Comparative Examples 1 to 4 using polymers (PA-1) to (PA-3) instead of polyorganosiloxane having an epoxy group were easily peeled off from the glass substrate and titanium substrate by a plurality of treatments among ultrasonic treatment, steam injection treatment, autoclave sterilization treatment, and dry heat sterilization treatment, and the adhesion to the substrate was inferior to that of Examples 1 to 9. In addition, the polymers used in the preparation of the antithrombotic coating materials of Comparative Examples 1 to 4 had poor solubility in ethanol.

[0110] 5. Evaluation of cytotoxicity using normal human dermal fibroblasts Coating material (CA-1) was applied to a φ14 mm circular cover glass using a spin coater, heated on a hot plate at 80 °C for 1 minute, and then heated in an oven at 150 °C with nitrogen substitution in the chamber for 20 minutes to form a film with an average film thickness of 100 nm. The glass substrate with a film formed by the coating material (CA-1) was further heated in an oven at 180 °C with nitrogen substitution in the chamber for 30 minutes to perform dry heat sterilization treatment. A dry heat sterilized glass substrate with a film formed by the coating material (CA-1) was set in the wells of a 24-well microplate for adherent cells (IWAKI, 3820-024) previously coated with poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate), 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 a culture medium prepared to be 10% FBS (Biosera, FB-1001 / 500) was added to DMEM / F12 (Thermo Fisher Scientific, 11320033), and preconditioning was performed at 37 °C under 5% CO2 for 1 hour. Seeding density 1×10 4 cells / cm 2Normal 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 5 × 10⁶. 4 cells / cm 2 The 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 a polyorganosiloxane having at least one of an oxiranil group and an oxetanil group.

2. The antithrombotic coating material according to claim 1, wherein the polyorganosiloxane has at least one selected from the group consisting of a substructure represented by the following formula (1-1) and a substructure represented by the following formula (1-2). (In equations (1-1) and (1-2), X １ and X ２ These are independent of each other: -O-, -S-, -O-CO-, or -NR ３ - is R ３ R is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. １ and R ２ These are monovalent organic groups, independent of each other. (* represents a bond.) 3. R in the above formula (1-1) １ and R in the above formula (1-2) ２ are represented by the following formula (2), and the antithrombotic coating material according to claim 2 (In formula (2), R ４ is an alkanediyl group. n1 is 0 or 1. n2 is an integer from 0 to 3. R ５ is an alkyl group when n2 is 0, and is a hydrogen atom or an alkyl group when n2 is 1 to 3. However, the total number of carbon atoms of (n2) R ４ in formula (2) and the number of carbon atoms of R ５ is 1 to 12. "*" represents a bond.) 4. The antithrombotic coating material according to claim 1, wherein the polyorganosiloxane has epoxycyclohexyl groups.

5. The antithrombotic coating material according to claim 1, wherein the polyorganosiloxane has at least one of a cage structure, an incomplete cage structure, and an annular structure.

6. The antithrombotic coating material according to claim 1, further containing a crosslinking agent.

7. The antithrombotic coating material according to claim 6, wherein the crosslinking agent has two or more in one molecule at least one selected from the group consisting of an oxiranyl 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.

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

9. The antithrombotic coating material according to claim 1, further comprising a polymer having a different main skeleton from the polyorganosiloxane.

10. The antithrombotic coating material according to claim 9, wherein the polymer, which has a different main skeleton from the polyorganosiloxane, is at least one selected from the group consisting of polyamic acid, polyamic acid ester, polyimide, and addition polymer.

11. The antithrombotic coating material according to claim 1, wherein the polyorganosiloxane is a reaction product of a polymer containing a structural unit represented by the following formula (S1) and at least one selected from the group consisting of carboxylic acids, thiol compounds, amine compounds, and alcohol compounds having a substructure represented by the following formula (2). (In formula (S1), R ７ (This is a monovalent group having an oxetanyl group or an oxyranyl group.) (In formula (2), R ４ is an alkanediyl group. n1 is 0 or 1. n2 is an integer from 0 to 3. R ５ 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 (2) ４ The number of carbon atoms and R ５ The total number of carbon atoms is between 1 and 12. (* indicates a bond.) 12. The antithrombotic coating material according to claim 1, wherein the polyorganosiloxane is a reaction product of a cyclic polysiloxane having an oxetanyl group or an oxyranyl group and at least one selected from the group consisting of carboxylic acids, thiol compounds, amine compounds and alcohol compounds having a substructure represented by the following formula (2). (In formula (2), R ４ is an alkanediyl group. n1 is 0 or 1. n2 is an integer from 0 to 3. R ５ 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 (2) ４ The number of carbon atoms and R ５ The total number of carbon atoms is between 1 and 12. (* indicates a bond.) 13. 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 12.

14. A research instrument having a substrate surface coated with an antithrombotic coating material according to any one of claims 1 to 12.

15. 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 12.

16. A method for manufacturing medical devices and research instruments according to claim 15, further comprising the step of sterilizing the surface of the substrate with the antithrombotic coating material at a temperature of 80°C or higher.

17. A method for inhibiting platelet adsorption to the surface of a substrate, comprising the step of forming a film on the surface of the substrate using an antithrombotic coating material according to any one of claims 1 to 12.

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