Adhesion inhibitor for biological substances

Abstract

The purpose of the present invention is to provide a coating film having a good balance between desired performances.　The present invention provides: a composition for forming a coating film, the composition comprising (1) a polymer of a monomer mixture and (2) a polycarbodiimide containing a structure represented by formula (E), in which the monomer mixture contains monomers respectively represented by formulae (A) to (D) (wherein Ta, Tb, Tc, Td, Ua1, Ua2, Ub1, Ub2, Ub3, Qa, Qb, Qc, Ra, Rb, Rc, Rd, An-, m and n are as described in the description and claims) and the ratio of the total amount of an anionic monomer represented by formula (A) and a cationic monomer represented by formula (B) to the total amount of all of monomers contained in the monomer mixture is 40 mol% or more; a coating film that is a cured article produced from the composition; a method for producing the coating film; a cured article; and a method for producing the cured article.

Description

Material that inhibits adhesion of biological substances

[0001] The present invention relates to a coating film-forming composition, a coating film that is a cured product thereof and a method for producing the same, and a cured product and a method for producing the same.

[0002] To prevent the adhesion of biological substances such as cells, proteins, and sugars, various coating materials capable of preventing the adhesion of biological substances have been proposed and can be applied to medical or research equipment and instruments. In addition, with the progress in research, development, and commercialization of antibody drugs in recent years, there has been an increasing demand for coating materials capable of preventing the adhesion of biological substances that can be applied to their storage containers (product containers).

[0003] The present inventors have previously reported that a coating agent containing a copolymer containing specific anionic groups and cationic groups can be firmly adhered to any type of substrate, and that after adhesion, it forms a coating film that is highly resistant to aqueous solvents and exhibits excellent ability to inhibit the adhesion of biological materials (see, for example, Patent Documents 1 and 2).

[0004] International Publication No. 2014 / 196650 International Publication No. 2021 / 167037

[0005] The present inventors have reported that a coating agent containing a copolymer containing specific anionic groups and cationic groups can form an ion complex to form a coating film with excellent biological material adhesion inhibitory properties, and that the coating film also has excellent adhesion to the substrate. However, for example, in the case of coating films for storage containers for antibody pharmaceuticals, further improvements are required in terms of not only the biological material adhesion inhibitory properties but also antibody aggregation inhibition and elution of coating film components into the pharmaceutical. The present inventors have discovered that by controlling the ion complex ratio and further curing an ion complex material containing a specific bifunctional monomer that can serve as a crosslinking component with a specific crosslinking agent, a coating film with a balanced desired performance can be obtained that has not only the conventional high biological material adhesion inhibitory properties but also high antibody aggregation inhibitory properties and improved elution inhibition, thereby completing the present invention.

[0006] The present invention is as follows: [1] (1) A compound represented by the following formula (A): (In the formula, T ａ , U ａ１ and U ａ２ each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ａ represents a single bond, an ester bond or an amide bond; R ａ represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; and m represents an integer of 1 to 10), an anionic monomer represented by the following formula (B): (In the formula, T ｂ , U ｂ１ , U ｂ２ and U ｂ３ each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ｂ represents a single bond, an ester bond or an amide bond; R ｂ represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; An － represents an anion selected from the group consisting of a halide ion, an inorganic acid ion, a hydroxide ion, and an isothiocyanate ion), a cationic monomer represented by the following formula (C): [In the formula, T ｃ represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ｃ represents a single bond, an ether bond or an ester bond; R ｃ represents a linear or branched alkyl group having 1 to 18 carbon atoms, a cyclic hydrocarbon group having 3 to 10 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 14 carbon atoms, or an aryloxyalkyl group having 7 to 14 carbon atoms (wherein the aryl moiety may be substituted with a linear or branched alkyl group having 1 to 5 carbon atoms which may be substituted with a halogen atom), and a hydrophobic monomer represented by the following formula (D): (In the formula, T ｄ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms; R ｄrepresents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; and n represents an integer of 1 to 10), wherein the total ratio of the anionic monomer represented by formula (A) and the cationic monomer represented by formula (B) to the total monomers contained in the monomer mixture is 40 mol % or more, and (2) a polymer of a monomer mixture containing a bifunctional monomer represented by the following formula (E): A coating film-forming composition comprising a polycarbodiimide having a structure represented by the formula:

[0007] [2] The composition for forming a coating film according to [1], wherein the ratio of the bifunctional monomer represented by formula (D) to the total monomers contained in the monomer mixture is less than 30 mol %. [3] The composition for forming a coating film according to [1] or [2], wherein the polycarbodiimide contains a hydrophilic group. [4] The hydrophilic group is represented by the following formula (F): (In the formula, R １ represents a linear or branched alkyl group having 1 to 5 carbon atoms; R ２ represents a hydrogen atom or a methyl group, and R ２ When there are multiple R ２ may be the same or different, and o represents an integer of 1 to 30.

[0008] [5] A coating film which is a cured product of a coating film of the coating film-forming composition according to any one of [1] to [4]. [6] The coating film according to [5], which has the ability to inhibit adhesion of biological substances. [7] A method for producing a coating film, comprising the steps of applying the coating film-forming composition according to any one of [1] to [4] to a substrate to form a coating film, and drying the coating film to form a cured product. [8] A method for producing a coating film according to [7], which further comprises the step of washing the cured product obtained after the drying step with a hydroalcoholic solvent.

[0009] [9] The following formula (A): (In the formula, T ａ , U ａ１ and Uａ２ each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ａ represents a single bond, an ester bond or an amide bond; R ａ represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; and m represents an integer of 1 to 10), an anionic monomer represented by the following formula (B): (In the formula, T ｂ , U ｂ１ , U ｂ２ and U ｂ３ each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ｂ represents a single bond, an ester bond or an amide bond; R ｂ represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; An － represents an anion selected from the group consisting of a halide ion, an inorganic acid ion, a hydroxide ion, and an isothiocyanate ion), a cationic monomer represented by the following formula (C): [In the formula, T ｃ represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ｃ represents a single bond, an ether bond or an ester bond; R ｃ represents a linear or branched alkyl group having 1 to 18 carbon atoms, a cyclic hydrocarbon group having 3 to 10 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 14 carbon atoms, or an aryloxyalkyl group having 7 to 14 carbon atoms (wherein the aryl moiety may be substituted with a linear or branched alkyl group having 1 to 5 carbon atoms which may be substituted with a halogen atom), and a hydrophobic monomer represented by the following formula (D): (In the formula, T ｄ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms; R ｄrepresents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; and n represents an integer of 1 to 10), wherein the total ratio of the anionic monomer represented by formula (A) and the cationic monomer represented by formula (B) to the total monomers contained in the monomer mixture is 40 mol % or more.

[10] A cured product of a polymer of the monomer mixture according to [9], which contains a pyrophosphate structure.

[0010]

[11] (i) The following formula (A): (In the formula, T ａ , U ａ１ and U ａ２ each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ａ represents a single bond, an ester bond or an amide bond; R ａ represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; and m represents an integer of 1 to 10), an anionic monomer represented by the following formula (B): (In the formula, T ｂ , U ｂ１ , U ｂ２ and U ｂ３ each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ｂ represents a single bond, an ester bond or an amide bond; R ｂ represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; An － represents an anion selected from the group consisting of a halide ion, an inorganic acid ion, a hydroxide ion, and an isothiocyanate ion), a cationic monomer represented by the following formula (C): [In the formula, T ｃ represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ｃ represents a single bond, an ether bond or an ester bond; R ｃrepresents a linear or branched alkyl group having 1 to 18 carbon atoms, a cyclic hydrocarbon group having 3 to 10 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 14 carbon atoms, or an aryloxyalkyl group having 7 to 14 carbon atoms (wherein the aryl moiety may be substituted with a linear or branched alkyl group having 1 to 5 carbon atoms which may be substituted with a halogen atom), and a hydrophobic monomer represented by the following formula (D): (In the formula, T ｄ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms; R ｄ represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; and n represents an integer of 1 to 10), wherein the total ratio of the anionic monomer represented by formula (A) and the cationic monomer represented by formula (B) to the total monomers contained in the monomer mixture is 40 mol % or more to obtain a copolymer; and (ii) polymerizing the copolymer by polymerizing a monomer mixture containing a difunctional monomer represented by formula (E): and a polycarbodiimide having a structure represented by the formula (I) to obtain a cured product.

[0011]

[12] The coating film according to [5], which has the ability to inhibit antibody aggregation.

[13] A storage container for an antibody drug, which has the coating film according to

[12] on at least a part of its surface.

[0012]

[14] (1) The following formula (A): (In the formula, T ａ , U ａ１ and U ａ２ each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ａ represents a single bond, an ester bond or an amide bond; R ａ represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; and m represents an integer of 1 to 10), an anionic monomer represented by the following formula (B): (In the formula, T ｂ , Uｂ１ , U ｂ２ and U ｂ３ each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ｂ represents a single bond, an ester bond or an amide bond; R ｂ represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; An － represents an anion selected from the group consisting of a halide ion, an inorganic acid ion, a hydroxide ion, and an isothiocyanate ion), and a cationic monomer represented by the following formula (C): [In the formula, T ｃ represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ｃ represents a single bond, an ether bond or an ester bond; R ｃ represents a linear or branched alkyl group having 1 to 18 carbon atoms, a cyclic hydrocarbon group having 3 to 10 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 14 carbon atoms, or an aryloxyalkyl group having 7 to 14 carbon atoms (wherein the aryl moiety may be substituted with a linear or branched alkyl group having 1 to 5 carbon atoms which may be substituted with a halogen atom)), wherein the total proportion of the anionic monomer represented by formula (A) and the canionic monomer represented by formula (B) to the total monomers contained in the monomer mixture is 40 mol % or more; and (2) a polymer of a monomer mixture containing a hydrophobic monomer represented by the following formula (E):

[15] A coating film which is a cured product of a coating film of the composition for forming a coating film according to

[14] .

[16] The coating film according to

[15] , which has antibody aggregation-inhibiting ability.

[17] A storage container for an antibody pharmaceutical, which has the coating film according to

[15] or

[16] on at least a part of its surface.

[0013]

[18] The following formula (A): (In the formula, T ａ , U ａ１and U ａ２ each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ａ represents a single bond, an ester bond or an amide bond; R ａ represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; and m represents an integer of 1 to 10), an anionic monomer represented by the following formula (B): (In the formula, T ｂ , U ｂ１ , U ｂ２ and U ｂ３ each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ｂ represents a single bond, an ester bond or an amide bond; R ｂ represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; An － represents an anion selected from the group consisting of a halide ion, an inorganic acid ion, a hydroxide ion, and an isothiocyanate ion), a cationic monomer represented by the following formula (C): [In the formula, T ｃ represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ｃ represents a single bond, an ether bond or an ester bond; R ｃ represents a linear or branched alkyl group having 1 to 18 carbon atoms, a cyclic hydrocarbon group having 3 to 10 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 14 carbon atoms, or an aryloxyalkyl group having 7 to 14 carbon atoms (wherein the aryl moiety may be substituted with a linear or branched alkyl group having 1 to 5 carbon atoms which may be substituted with a halogen atom), and a hydrophobic monomer represented by the following formula (D): (In the formula, T ｄ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms; R ｄ

[19] A coating film-forming composition having antibody aggregation-inhibiting ability, comprising a monomer mixture containing a bifunctional monomer represented by the following formula (A): (In the formula, T ａ , U ａ１ and U ａ２ each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ａ represents a single bond, an ester bond or an amide bond; R ａ represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; and m represents an integer of 1 to 10), an anionic monomer represented by the following formula (B): (In the formula, T ｂ , U ｂ１ , U ｂ２ and U ｂ３ each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ｂ represents a single bond, an ester bond or an amide bond; R ｂ represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; An － represents an anion selected from the group consisting of a halide ion, an inorganic acid ion, a hydroxide ion, and an isothiocyanate ion), a cationic monomer represented by the following formula (C): [In the formula, T ｃ represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ｃ represents a single bond, an ether bond or an ester bond; R ｃrepresents a linear or branched alkyl group having 1 to 18 carbon atoms, a cyclic hydrocarbon group having 3 to 10 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 14 carbon atoms, or an aryloxyalkyl group having 7 to 14 carbon atoms (wherein the aryl moiety may be substituted with a linear or branched alkyl group having 1 to 5 carbon atoms which may be substituted with a halogen atom), and a hydrophobic monomer represented by the following formula (D): (In the formula, T ｄ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms; R ｄ

[20] A coating film having an antibody aggregation-inhibiting ability, comprising a polymer of a monomer mixture containing a bifunctional monomer represented by the formula (A): wherein R represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; and n represents an integer of 1 to 10, wherein the total ratio of the anionic monomer represented by formula (A) and the canionic monomer represented by formula (B) to the total monomers contained in the monomer mixture is 40 mol % or more.

[21] A storage container for an antibody pharmaceutical, comprising the coating film according to

[19] on at least a part of its surface.

[0014] The coating film of the present invention can be formed by forming a coating film-forming composition containing a polymer of a monomer mixture containing an anionic monomer represented by formula (A), a cationic monomer represented by formula (B), a hydrophobic monomer represented by formula (C), and a bifunctional monomer represented by formula (D), wherein the anionic monomer represented by formula (A) and the cationic monomer represented by formula (B) are present in a specific ratio, and a specific crosslinking agent, and then drying the resulting composition. That is, the coating film of the present invention is cured by crosslinking with the bifunctional monomer and post-crosslinking with the specific crosslinking agent while controlling the ion complex ratio, thereby achieving not only the conventional ability to inhibit adhesion of biological materials, but also further improvements in terms of antibody aggregation inhibition and elution of coating film components into pharmaceuticals, resulting in a coating film with a well-balanced desired performance.

[0015] <Explanation of Terms> Unless otherwise specified, the terms used in the present invention have the following definitions.

[0016] In the present invention, the term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0017] In the present invention, the term "alkyl group" refers to a linear or branched, saturated aliphatic hydrocarbon monovalent group. Examples of "linear or branched alkyl groups having 1 to 5 carbon atoms" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and 1-ethylpropyl. Examples of "linear or branched alkyl groups having 1 to 6 carbon atoms" include the examples of "linear or branched alkyl groups having 1 to 5 carbon atoms" as well as hexyl and isomers thereof. Similarly, examples of the "straight-chain or branched alkyl group having 1 to 18 carbon atoms" include, in addition to the examples of the "straight-chain or branched alkyl group having 1 to 5 carbon atoms", a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a hexadecyl group, a heptadecyl group, an octadecyl group, or an isomer thereof.

[0018] In the present invention, "a linear or branched alkyl group having 1 to 5 carbon atoms which may be substituted with a halogen atom" means the above linear or branched alkyl group having 1 to 5 carbon atoms, or the above linear or branched alkyl group having 1 to 5 carbon atoms which is substituted with one or more halogen atoms. Examples of the "linear or branched alkyl group having 1 to 5 carbon atoms" are as described above. On the other hand, "a linear or branched alkyl group having 1 to 5 carbon atoms which is substituted with one or more halogen atoms" means the above linear or branched alkyl group having 1 to 5 carbon atoms in which one or more arbitrary hydrogen atoms have been replaced with a halogen atom, and examples thereof include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, a trichloromethyl group, a bromomethyl group, an iodomethyl group, a 2,2,2-trifluoroethyl group, a 2,2,2-trichloroethyl group, a perfluoroethyl group, a perfluorobutyl group, and a perfluoropentyl group.

[0019] In the present invention, an "ester bond" means -C(=O)-O- or -O-C(=O)-, an "amide bond" means -NHC(=O)- or -C(=O)NH-, and an ether bond means -O-.

[0020] In the present invention, the term "a linear or branched alkylene group having 1 to 10 carbon atoms and optionally substituted with a halogen atom" refers to a linear or branched alkylene group having 1 to 10 carbon atoms, or a linear or branched alkylene group having 1 to 10 carbon atoms and substituted with one or more halogen atoms. Here, the term "alkylene group" refers to a divalent organic group corresponding to the alkyl group described above. Examples of the "linear or branched alkylene group having 1 to 10 carbon atoms" include methylene, ethylene, propylene, trimethylene, tetramethylene, 1-methylpropylene, 2-methylpropylene, dimethylethylene, ethylethylene, pentamethylene, 1-methyl-tetramethylene, 2-methyl-tetramethylene, 1,1-dimethyl-trimethylene, 1,2-dimethyl-trimethylene, 2,2-dimethyl-trimethylene, 1-ethyl-trimethylene, hexamethylene, octamethylene, and decamethylene. Of these, ethylene, propylene, octamethylene, and decamethylene are preferred, and linear or branched alkylene groups having 1 to 5 carbon atoms, such as ethylene, propylene, trimethylene, and tetramethylene, are more preferred, with ethylene or propylene being particularly preferred. The term "straight-chain or branched alkylene group having 1 to 10 carbon atoms substituted with one or more halogen atoms" means the above-mentioned alkylene group in which any one or more hydrogen atoms have been replaced with halogen atoms, and particularly preferred is an ethylene group or a propylene group in which some or all of the hydrogen atoms have been replaced with halogen atoms.

[0021] In the present invention, the term "C cyclic hydrocarbon group" refers to a monocyclic or polycyclic, saturated or partially unsaturated, aliphatic hydrocarbon monovalent group having 3 to 10 carbon atoms. Among these, a monovalent, monocyclic or bicyclic, saturated aliphatic hydrocarbon group having 3 to 10 carbon atoms is preferred, and examples thereof include cycloalkyl groups having 3 to 10 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, or a cyclohexyl group, and bicycloalkyl groups having 4 to 10 carbon atoms, such as a bicyclo[3.2.1]octyl group, a bornyl group, or an isobornyl group.

[0022] In the present invention, the term "C 6-10 aryl group" refers to a monovalent group of a monocyclic or polycyclic aromatic hydrocarbon having 6 to 10 carbon atoms, and examples thereof include a phenyl group, a naphthyl group, an anthryl group, etc. The "C 6-10 aryl group" may be substituted with one or more of the above-mentioned "linear or branched alkyl groups having 1 to 5 carbon atoms which may be substituted with a halogen atom(s)".

[0023] In the present invention, the "aralkyl group having 7 to 14 carbon atoms" refers to a group -R-R' (wherein R represents the above-mentioned "alkylene group having 1 to 5 carbon atoms" and R' represents the above-mentioned "aryl group having 6 to 10 carbon atoms"), and examples thereof include a benzyl group, a phenethyl group, and an α-methylbenzyl group. The aryl portion of the "aralkyl group having 7 to 14 carbon atoms" may be substituted with one or more of the above-mentioned "linear or branched alkyl groups having 1 to 5 carbon atoms which may be substituted with one or more halogen atoms".

[0024] In the present invention, the "aryloxyalkyl group having 7 to 14 carbon atoms" means a group -R-O-R' (wherein R represents the above-mentioned "alkylene group having 1 to 5 carbon atoms" and R' represents the above-mentioned "aryl group having 6 to 10 carbon atoms"), and examples thereof include a phenoxymethyl group, a phenoxyethyl group, and a phenoxypropyl group. The aryl portion of the "aryloxyalkyl group having 7 to 14 carbon atoms" may be substituted with one or more of the above-mentioned "linear or branched alkyl groups having 1 to 5 carbon atoms which may be substituted with one or more halogen atoms".

[0025] In the present invention, the term "halide ion" refers to a fluoride ion, a chloride ion, a bromide ion, or an iodide ion. In the present invention, the term "inorganic acid ion" refers to a carbonate ion, a sulfate ion, a phosphate ion, a hydrogen phosphate ion, a dihydrogen phosphate ion, a nitrate ion, a perchlorate ion, or a borate ion. － Preferred are halide ions, sulfate ions, phosphate ions, hydroxide ions and isothiocyanate ions, and particularly preferred are halide ions.

[0026] In the present invention, the term "(meth)acrylate compound" refers to both acrylate compounds and methacrylate compounds. For example, "(meth)acrylic acid" refers to acrylic acid and methacrylic acid.

[0027] In the present invention, the term "anionic monomer" refers to a monomer having an anionic group, including those having a group that can dissociate in water to become anionic. Similarly, in the present invention, the term "cationic monomer" refers to a monomer having a cationic group, including those having a group that can dissociate in water to become cationic.

[0028] <Description of the Present Invention> <Composition for Forming a Coating Film> A first embodiment of the composition for forming a coating film of the present invention includes: (1) a polymer of a monomer mixture containing an anionic monomer represented by formula (A), a cationic monomer represented by formula (B), a hydrophobic monomer represented by formula (C), and a bifunctional monomer represented by formula (D), wherein the total ratio of the anionic monomer represented by formula (A) and the cationic monomer represented by formula (B) to the total monomers contained in the monomer mixture is 40 mol % or more; and (2) a polycarbodiimide having a structure represented by formula (E).

[0029] (Polymer) The monomer mixture according to the present invention comprises a monomer represented by formula (A): (In the formula, T ａ , U ａ１ and U ａ２ each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ａ represents a single bond, an ester bond or an amide bond; R ａ represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; and m represents an integer of 1 to 10. The anionic monomer may contain two or more types of anionic monomers represented by formula (A).

[0030] In one embodiment of the anionic monomer represented by formula (A), T ａis preferably a hydrogen atom, a methyl group or an ethyl group, more preferably a hydrogen atom or a methyl group. ａ１ and U ａ２ is preferably a hydrogen atom, a methyl group, or an ethyl group, and more preferably a hydrogen atom. ａ R is preferably a single bond or an ester bond, more preferably an ester bond. ａ is preferably a methylene group, an ethylene group, or a propylene group which may be substituted with a chlorine atom, and more preferably an ethylene group or a propylene group. m is preferably an integer of 2 to 8, and more preferably an integer of 3 to 6.

[0031] Specific examples of the monomer of formula (A) include acid phosphooxyethyl (meth)acrylate, 3-chloro-2-acid phosphooxypropyl (meth)acrylate, acid phosphooxypropyl (meth)acrylate, acid phosphooxymethyl (meth)acrylate, acid phosphooxypolyoxyethylene glycol mono(meth)acrylate, and acid phosphooxypolyoxypropylene glycol mono(meth)acrylate, and among these, acid phosphooxyethyl methacrylate (=2-(methacryloyloxy)ethyl phosphate), acid phosphooxypolyoxyethylene glycol monomethacrylate, and acid phosphooxypolyoxypropylene glycol monomethacrylate are preferably used.

[0032] The structural formulas of acid phosphooxyethyl methacrylate (=2-(methacryloyloxy)ethyl phosphate), acid phosphooxypolyoxyethylene glycol monomethacrylate, and acid phosphooxypolyoxypropylene glycol monomethacrylate are represented by the following formulas (A-1) to (A-3), respectively.

[0033]

[0034] The monomer mixture according to the present invention comprises a monomer having the formula (B): (In the formula, T ｂ , U ｂ１ , U ｂ２ and U ｂ３each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ｂ represents a single bond, an ester bond or an amide bond; R ｂ represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; An － represents an anion selected from the group consisting of a halide ion, an inorganic acid ion, a hydroxide ion, and an isothiocyanate ion). The cationic monomer may contain two or more cationic monomers represented by formula (B).

[0035] In one embodiment of the cationic monomer represented by formula (B), T ｂ is preferably a hydrogen atom, a methyl group or an ethyl group, more preferably a hydrogen atom or a methyl group. ｂ１ , U ｂ２ and U ｂ３ are each independently preferably a hydrogen atom, a methyl group, an ethyl group or a t-butyl group, and more preferably a methyl group or an ethyl group. ｂ R is preferably a single bond or an ester bond, more preferably an ester bond. ｂ An is preferably a methylene group, an ethylene group, or a propylene group which may be substituted with a chlorine atom, and more preferably an ethylene group or a propylene group. － As the cation, a halide ion is preferred, and a chloride ion is more preferred.

[0036] Specific examples of the monomer of formula (B) include dimethylaminoethyl (meth)acrylate, diethylaminoethyl (meth)acrylate, dimethylaminopropyl (meth)acrylate, 2-(t-butylamino)ethyl (meth)acrylate, and methacryloylcholine chloride. Among these, dimethylaminoethyl (meth)acrylate, methacryloylcholine chloride, and 2-(t-butylamino)ethyl (meth)acrylate are preferably used.

[0037] The structural formulas of dimethylaminoethyl acrylate (= 2-(dimethylamino)ethyl acrylate), diethylaminoethyl methacrylate (= 2-(diethylamino)ethyl methacrylate), dimethylaminoethyl methacrylate (= 2-(dimethylamino)ethyl methacrylate), methacryloylcholine chloride, and 2-(t-butylamino)ethyl methacrylate (= 2-(t-butylamino)ethyl methacrylate) are represented by the following formulas (B-1) to (B-5), respectively.

[0038]

[0039] The monomer mixture according to the present invention comprises a monomer having the formula (C): [In the formula, T ｃ represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ｃ represents a single bond, an ether bond or an ester bond; R ｃ represents a linear or branched alkyl group having 1 to 18 carbon atoms, a cyclic hydrocarbon group having 3 to 10 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 14 carbon atoms, or an aryloxyalkyl group having 7 to 14 carbon atoms (wherein the aryl moiety may be substituted with a linear or branched alkyl group having 1 to 5 carbon atoms which may be substituted with a halogen atom). The polymerizable monomer may contain two or more hydrophobic monomers represented by formula (C).

[0040] In one embodiment of the hydrophobic monomer represented by formula (C), T ｃ is preferably a hydrogen atom, a methyl group, or an ethyl group, and more preferably a hydrogen atom or a methyl group. ｃ R is preferably a single bond or an ester bond, more preferably an ester bond. ｃ As the alkyl group, a linear or branched alkyl group having 1 to 18 carbon atoms or a cyclic hydrocarbon group having 3 to 10 carbon atoms is preferable, and a linear or branched alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 10 carbon atoms is more preferable.

[0041] Specific examples of the monomer of formula (C) include linear or branched alkyl esters of (meth)acrylic acid such as butyl(meth)acrylate, 2-ethylhexyl(meth)acrylate, lauryl(meth)acrylate, and stearyl(meth)acrylate; cyclic alkyl esters of (meth)acrylic acid such as cyclohexyl(meth)acrylate and isobornyl(meth)acrylate; aralkyl esters of (meth)acrylic acid such as benzyl(meth)acrylate and phenethyl(meth)acrylate; styrene-based monomers such as styrene, methylstyrene, and chloromethylstyrene; vinyl ether-based monomers such as methyl vinyl ether and butyl vinyl ether; and vinyl ester-based monomers such as vinyl acetate and vinyl propionate. Of these, butyl(meth)acrylate or cyclohexyl(meth)acrylate is preferably used.

[0042] The structural formulas of butyl methacrylate (=butyl methacrylate) and cyclohexyl methacrylate (=cyclohexyl methacrylate) are represented by the following formulas (C-1) and (C-2), respectively.

[0043]

[0044] The monomer mixture according to the present invention comprises a monomer having the formula (D): (In the formula, T ｄ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms; R ｄ represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; and n represents an integer of 1 to 10. The copolymer may contain two or more bifunctional monomers represented by formula (D).

[0045] In one embodiment of the bifunctional monomer represented by formula (D), T ｄ R is preferably a hydrogen atom, a methyl group, or an ethyl group, and more preferably a hydrogen atom or a methyl group. ｄ is preferably a methylene group, an ethylene group, or a propylene group which may be substituted with a chlorine atom, and more preferably an ethylene group or a propylene group.

[0046] Specific examples of the bifunctional monomer of formula (D) include poly(ethylene glycol) di(meth)acrylate, poly(trimethylene glycol) di(meth)acrylate, and poly(propylene glycol) di(meth)acrylate.

[0047] For example, the structural formulas of ethylene glycol dimethacrylate, poly(ethylene glycol) dimethacrylate, and poly(propylene glycol) dimethacrylate are represented by the following formulas (D-1) to (D-3), respectively.

[0048]

[0049] In the monomer mixture according to the present invention, the total ratio of the anionic monomer represented by formula (A) and the cationic monomer represented by formula (B) to the total monomers is 40 mol% or more, preferably 40 mol% to 70 mol%, more preferably 40 mol% to 60 mol%, and particularly preferably 40 mol% to 55 mol%. The molar ratio of the anionic monomer represented by formula (A) to the cationic monomer represented by formula (B) is not particularly limited, but is preferably in the range of 1:2 to 2:1, more preferably 1:1.5 to 1.5:1, and particularly preferably 1:1.2 to 1.2:1.

[0050] In the monomer mixture according to the present invention, the ratio of the bifunctional monomer represented by formula (D) to the total monomers is preferably less than 30 mol%, more preferably 5 mol% or more and less than 30 mol%, more preferably 10 mol% or more and less than 30 mol%, and particularly preferably 15 mol% or more and less than 30 mol%. In particular, when post-crosslinking with a crosslinking agent can be expected in the coating film of the present invention, the ratio of the bifunctional monomer in the monomer mixture can also be reduced.

[0051] In the monomer mixture according to the present invention, the ratio of the hydrophobic monomer represented by formula (C) to the total monomers may be the entire remainder after subtracting the ratios of the monomers of formulas (A), (B), and (D) from the total monomers, or may be the remainder after subtracting the total ratio of the monomers of formulas (A), (B), and (D) and any monomer component described below. The ratio is, for example, 1 mol% to 55 mol%, preferably 3 mol% to 50 mol%, and more preferably 5 mol% to 50 mol%.

[0052] The monomer mixture according to the present invention may further contain, as an optional monomer component, a repeating unit derived from an ethylenically unsaturated monomer or a polysaccharide or a derivative thereof. Examples of the ethylenically unsaturated monomer include one or more ethylenically unsaturated monomers selected from the group consisting of (meth)acrylic acid esters, vinyl acetate, vinylpyrrolidone, ethylene, vinyl alcohol, and hydrophilic functional derivatives thereof. Examples of polysaccharides or derivatives thereof include cellulose-based polymers such as hydroxyalkyl cellulose (e.g., hydroxyethyl cellulose or hydroxypropyl cellulose), starch, dextran, and curdlan.

[0053] The hydrophilic functional derivative refers to an ethylenically unsaturated monomer having a hydrophilic functional group or structure. Examples of the hydrophilic functional group or structure include a betaine structure, an amide structure, an alkylene glycol residue, an amino group, and a sulfinyl group.

[0054] The betaine structure means a monovalent or divalent group of a compound having an amphoteric center of a quaternary ammonium type cation structure and an acidic anion structure, and is, for example, a phosphorylcholine group: Examples of ethylenically unsaturated monomers having such a structure include 2-methacryloyloxyethyl phosphorylcholine (MPC).

[0055] The amide structure has the following formula: [where R １６ , R １７ and R １８are each independently a hydrogen atom or an organic group (for example, an optionally substituted linear or branched alkyl group having 1 to 5 carbon atoms, specifically, a methyl group, an isopropyl group, a hydroxymethyl group, a hydroxyethyl group, etc.). Examples of ethylenically unsaturated monomers having such a structure include (meth)acrylamide, N-isopropylacrylamide, and N-(hydroxymethyl)(meth)acrylamide. Furthermore, monomers having such a structure are disclosed, for example, in JP 2010-169604 A.

[0056] The alkylene glycol residue refers to an alkyleneoxy group (-Alk-O-) remaining after one or both terminal hydroxyl groups of alkylene glycol (HO-Alk-OH; where Alk is an alkylene group having 1 to 10 carbon atoms) undergo a condensation reaction with another compound, and also encompasses poly(alkyleneoxy) groups in which alkyleneoxy units are repeated. Examples of ethylenically unsaturated monomers having such a structure include 2-hydroxyethyl (meth)acrylate and methoxypolyethylene glycol (meth)acrylate. Furthermore, monomers having such a structure are disclosed, for example, in JP 2008-533489 A.

[0057] An amino group has the formula: -NH ２ , -NHR １９ or -NR ２０ R ２１ [where R １９ , R ２０ and R ２１ are each independently an organic group (for example, a linear or branched alkyl group having 1 to 5 carbon atoms). The amino group in the present invention includes quaternized or salified amino groups. Examples of ethylenically unsaturated monomers having such a structure include dimethylaminoethyl (meth)acrylate, 2-(t-butylamino)ethyl (meth)acrylate, and methacryloylcholine chloride.

[0058] The sulfinyl group has the following formula: [where R２２ is an organic group (for example, an organic group having 1 to 10 carbon atoms, preferably an alkyl group having 1 to 10 carbon atoms and one or more hydroxy groups). Examples of a method for introducing a sulfinyl group include the methods disclosed in JP-A-2014-48278 and the like.

[0059] The weight molecular weight of the polymer contained in the coating film-forming composition of the present invention may be several thousand to several million, preferably 5,000 to 5,000,000, and more preferably 10,000 to 2,000,000. The polymer may be a random copolymer, a block copolymer, or a graft copolymer, but a random copolymer is preferred.

[0060] The polymer contained in the coating film-forming composition of the present invention is obtained by polymerizing a monomer mixture containing the monomers represented by the above formulas (A) to (D) (and optionally any optional monomer components). The polymerization can be carried out by a method known per se (for example, the method described in JP 2014-162865 A and WO 2020 / 040247 A). For example, the polymer can be synthesized by a method such as radical polymerization, anionic polymerization, or cationic polymerization, which are common methods for synthesizing acrylic polymers or methacrylic polymers. Various methods are possible for the polymerization, such as solution polymerization, suspension polymerization, emulsion polymerization, and bulk polymerization.

[0061] The polymer can be prepared, for example, by a production method including a step of reacting (polymerizing) the monomers represented by the above formulas (A) to (D) in a solvent.

[0062] The reaction conditions are as follows: a reaction vessel containing various raw materials (monomers, solvent, initiator, etc.) is heated to 50°C to 200°C in an oil bath or the like, and the mixture is stirred for 1 to 48 hours, more preferably at 80°C to 150°C, for 5 to 30 hours, thereby progressing the polymerization reaction and obtaining the copolymer according to the present invention. The reaction atmosphere is preferably a nitrogen atmosphere.

[0063] The solvent used in the polymerization reaction may be water, a phosphate buffer solution, an alcohol such as ethanol, or a mixed solvent of these, but preferably contains water or ethanol. It is more preferable that the solvent contains 10% by mass or more and 100% by mass or less of water or ethanol. It is even more preferable that the solvent contains 50% by mass or more and 100% by mass or less of water or ethanol. It is even more preferable that the solvent contains 80% by mass or more and 100% by mass or less of water or ethanol. It is even more preferable that the solvent contains 90% by mass or more and 100% by mass or less of water or ethanol. Preferably, the total of water and ethanol is 100% by mass.

[0064] As a reaction procedure, all raw materials may be placed in a reaction solvent at room temperature and then heated to the above temperature to polymerize, or all or part of the raw material mixture may be added dropwise to a preheated solvent. For example, since the anionic monomer represented by formula (A) is a monomer that easily associates, it may be added dropwise to the reaction solvent in small amounts so that it can be quickly dispersed when added dropwise to the reaction system. In this case, the reaction solvent may be heated (e.g., to 40°C to 100°C) to increase the solubility of the monomer and polymer.

[0065] In order to efficiently promote the polymerization reaction, it is desirable to use a polymerization initiator, particularly a radical polymerization initiator. Examples of the radical polymerization initiator include azo polymerization initiators such as dimethyl 1,1'-azobis(1-cyclohexanecarboxylate) (VE-073, manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd.), 2,2'-azobis(2,4-dimethylvaleronitrile) (V-65, manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd.), 2,2'-azobis(isobutyronitrile) (AIBN, manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd.), 2,2'-azobis[N-(2-carboxyethyl)-2-methylpropionamidine]n-hydrate (VA-057, manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd.), and 2,2'-(N-butyl-2-methylpropionamide) (VAm-110, manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd.).

[0066] The amount of the polymerization initiator added is 0.05% by mass to 10% by mass based on the total weight of the monomers used in the polymerization.

[0067] After the reaction is complete, the resulting polymer may be isolated and purified by a known method, for example, by adding a poor solvent to the reaction solution, or the reaction solution may be used as it is as a copolymer-containing solution for preparing the coating film-forming composition of the present invention.

[0068] (Polycarbodiimide) The polycarbodiimide of the present invention is represented by the following formula (E): It includes a structure represented by:

[0069] The reaction between the polymer and polycarbodiimide according to the present invention is believed to proceed according to the following reaction formula: As shown in this reaction formula, the carbodiimide promotes dehydration condensation between phosphate groups, forming a pyrophosphate structure between the polymers, which is thought to promote the crosslinking reaction (hardening) of the polymer.

[0070]

[0071] The polycarbodiimide of the present invention may be a polycarbodiimide compound derived from an aliphatic diisocyanate compound having at least one primary isocyanate group, and the polycarbodiimide compound may have a structure in which all terminals are blocked with an organic compound having a functional group reactive with an isocyanate group.

[0072] For example, the aliphatic diisocyanate compound having at least one primary isocyanate group may be at least one selected from the group consisting of chain aliphatic isocyanate compounds such as ethylene diisocyanate, tetramethylene diisocyanate, hexamethylene diisocyanate, and 2,2,4-trimethylhexamethylene diisocyanate; cyclic aliphatic diisocyanate compounds such as isophorone diisocyanate, 1,3-bis(isocyanatomethyl)cyclohexane, and norbornane diisocyanate; and aliphatic diisocyanate compounds having an aromatic ring such as xylylene diisocyanate.

[0073] The polycarbodiimide of the present invention may be, for example, an isocyanate-terminated polycarbodiimide having at least two carbodiimide groups represented by formula (E) in the molecule, which is obtained by a condensation reaction accompanied by decarbonation of an aliphatic diisocyanate compound having at least one primary isocyanate group, or may be a polycarbodiimide having a structure in which the terminals are blocked with an organic compound having a functional group reactive with an isocyanate group.

[0074] The functional group of the organic compound may be at least one selected from a hydroxy group, an amino group, an isocyanate group, an epoxy group, and a carboxy group.

[0075] Examples of the organic compound include organic compounds having a hydroxy group such as polyethylene glycol monomethyl ether, polyethylene glycol monoethyl ether, polypropylene glycol monomethyl ether, polypropylene glycol monoethyl ether, triethylene glycol monomethyl ether, triethylene glycol monoethyl ether, tetraethylene glycol monomethyl ether, tetraethylene glycol monoethyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, ethyl alcohol, propyl alcohol, butyl alcohol, pentyl alcohol, hexyl alcohol, octyl alcohol, and dodecyl alcohol; methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, octylamine, dodecylamine, diethylamine, dipropylamine, dibutylamine, and cyclohexylamine. , adamantanamine, allylamine, polyoxyethylene laurylamine, polyoxymethylenestearylamine, aniline, diphenylamine, 3-aminopropyltrimethoxysilane, 3-aminopropyltriethoxysilane, N-phenyl-3-aminopropyltrimethoxysilane, 2,2-difluoroamine, fluorobenzylamine, trifluoroethylamine, [[4-(trifluoromethyl)cyclohexyl]methyl]amine, and organic compounds having an amino group such as butyl isocyanate, pentyl isocyanate, hexyl isocyanate, octyl isocyanate, dodecyl isocyanate, cyclohexyl isocyanate, 1-adamantyl isocyanate, 3-isocyanatopropyltriethoxysilane, 2-isocyanatoethyl acrylate, benzyl isocyanate, 2-phenylethyl isocyanate, and organic compounds having an isocyanate group such as derivatives thereof;Examples of organic compounds having an epoxy group include 1,2-epoxyheptane, 1,2-epoxyhexane, 1,2-epoxydecane, 1,2-epoxy-5-hexene, ethyl glycidyl ether, 2-ethylhexyl glycidyl ether, glycidyl lauryl ether, allyl glycidyl ether, diethoxy(3-glycidyloxypropyl)methylsilane, 3-[2-(perfluorohexyl)ethoxy]-1,2-epoxypropane, and derivatives thereof; and organic compounds having a carboxy group, such as acetic acid, ethanoic acid, propionic acid, butanoic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, cyclohexanecarboxylic acid, adamantaneacetic acid, phenylacetic acid, benzoic acid, undecenoic acid, and derivatives thereof.

[0076] The organic compound may further have a hydrophilic group in addition to the functional group.

[0077] The polycarbodiimide preferably contains a hydrophilic group.

[0078] The hydrophilic group is represented by the following formula (F): (In the formula, R １ represents a linear or branched alkyl group having 1 to 5 carbon atoms; R ２ represents a hydrogen atom or a methyl group, and R ２ When there are multiple R ２ may be the same or different, and o represents an integer of 1 to 30.

[0079] Examples of organic compounds having a hydrophilic group, particularly the hydrophilic group represented by the above formula (F), in addition to a functional group reactive with an isocyanate group include polyethylene glycol monomethyl ether (MPEG), tetraethylene glycol monomethyl ether (MTEG), etc. These may be used alone or in combination of two or more. By capping the terminals of an isocyanate-terminated polycarbodiimide with such an organic compound, a polycarbodiimide having the hydrophilic group represented by the above formula (F) introduced therein can be obtained.

[0080] As the polycarbodiimide, the polycarbodiimide compound described in WO 2018 / 194102 can be used. Other details of the polycarbodiimide compound of the present invention are in accordance with the contents described in WO 2018 / 194102.

[0081] The polycarbodiimide may be a commercially available product, and examples of the commercially available product names include "Carbodilite V-02," "Carbodilite V-02-L2," "Carbodilite SV-02," "Carbodilite V-04," "Carbodilite V-10," "Carbodilite E-02," and "Carbodilite E-05" (all of which are product names manufactured by Nisshinbo Chemical Inc.).

[0082] (Coating Film-Forming Composition) The coating film-forming composition of the present invention is obtained by mixing the above-mentioned polymer and polycarbodiimide. The ratio of polycarbodiimide to polymer is, for example, in the range of 1 to 30 parts by weight, preferably 1 to 20 parts by weight, more preferably 3 to 20 parts by weight, and particularly preferably 5 to 20 parts by weight, per 100 parts by weight of the polymer. Note that when the polymer according to the present invention contains a bifunctional monomer, the ratio of polycarbodiimide to polymer in the coating film-forming composition can be reduced.

[0083] The coating film-forming composition of the present invention contains a solvent in addition to the polymer and polycarbodiimide described above. The solvent may be derived from the reaction solution of the copolymer or may be added separately.

[0084] Examples of the solvent contained in the coating film-forming composition of the present invention include water, phosphate buffered saline (PBS), and alcohol. Examples of the alcohol include alcohols having 2 to 6 carbon atoms, such as ethanol, propanol, isopropanol, 1-butanol, 2-butanol, isobutanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 1-heptanol, 2-heptanol, 2,2-dimethyl-1-propanol (neopentyl alcohol), 2-methyl-1-propanol, 2-methyl-1-butanol, 2-methyl-2-butanol (t-amyl alcohol), 3-methyl-1-butanol, 3-methyl-3-pentanol, cyclopentanol, 1-hexanol, 2-hexanol, 3-hexanol, and 2,3- Examples of suitable solvents include dimethyl-2-butanol, 3,3-dimethyl-1-butanol, 3,3-dimethyl-2-butanol, 2-ethyl-1-butanol, 2-methyl-1-pentanol, 2-methyl-2-pentanol, 2-methyl-3-pentanol, 3-methyl-1-pentanol, 3-methyl-2-pentanol, 3-methyl-3-pentanol, 4-methyl-1-pentanol, 4-methyl-2-pentanol, 4-methyl-3-pentanol, and cyclohexanol. These solvents may be used alone or in combination, but from the viewpoint of dissolving the copolymer, they are preferably selected from water, PBS, ethanol, and propanol.

[0085] The concentration of solids in the coating film-forming composition according to the present invention is preferably 0.01 to 50% by mass in order to form a uniform coating film.

[0086] Furthermore, in addition to the above-mentioned polymer, polycarbodiimide, and solvent, the coating film-forming composition of the present invention may contain other substances as needed within the range that does not impair the performance of the resulting coating film. Examples of other substances include preservatives, surfactants, primers that improve adhesion to the substrate, antifungal agents, and sugars.

[0087] In order to adjust the ion balance of the copolymer in the coating film-forming composition according to the present invention, the preparation of the coating film of the present invention may further include a step of preliminarily adjusting the pH of the coating film-forming composition. The pH adjustment may be carried out, for example, by adding a pH adjuster to a composition containing the copolymer and a solvent to adjust the pH of the composition to 3.0 to 13.5, preferably 3.5 to 8.5, more preferably 3.5 to 5.5, or preferably 8.5 to 13.5, more preferably 10.0 to 13.5. The type and amount of the pH adjuster to be used are appropriately selected depending on the concentration of the copolymer, the ratio of anions to cations, and other factors.

[0088] Examples of pH adjusters include organic amines such as ammonia, triethylamine, diethanolamine, pyridine, N-methyl-D-glucamine, and tris(hydroxymethyl)aminomethane; alkali metal hydroxides such as potassium hydroxide and sodium hydroxide; alkali metal halides such as potassium chloride and sodium chloride; inorganic acids or alkali metal salts thereof such as sulfuric acid, phosphoric acid, hydrochloric acid, and carbonic acid; quaternary ammonium cations such as choline, and mixtures thereof (e.g., buffer solutions such as phosphate-buffered saline). Among these, ammonia, triethylamine, diethanolamine, sodium hydroxide, choline, N-methyl-D-glucamine, and tris(hydroxymethyl)aminomethane are preferred, with ammonia, triethylamine, diethanolamine, sodium hydroxide, and choline being particularly preferred.

[0089] A second embodiment of the coating film-forming composition of the present invention comprises a polymer of a monomer mixture containing an anionic monomer represented by formula (A), a cationic monomer represented by formula (B), and a hydrophobic monomer represented by formula (C), wherein the total ratio of the anionic monomer represented by formula (A) and the cationic monomer represented by formula (B) to the total monomers contained in the monomer mixture is 40 mol % or more, and a polycarbodiimide having a structure represented by formula (E). The descriptions and preferred embodiments of the monomers represented by formulas (A) to (C) and their polymers, the polycarbodiimide having a structure represented by formula (E), and the coating film-forming composition in the first embodiment apply to the second embodiment, except for those related to the bifunctional monomer represented by formula (D).

[0090] A third embodiment of the coating film-forming composition of the present invention is a monomer mixture containing, among the above-mentioned polymers, an anionic monomer represented by formula (A), a cationic monomer represented by formula (B), a hydrophobic monomer represented by formula (C), and a bifunctional monomer represented by formula (D), wherein the total ratio of the anionic monomer represented by formula (A) and the cationic monomer represented by formula (B) to the total monomers contained in the monomer mixture is 40 mol % or more, and the composition does not contain polycarbodiimide. The descriptions and preferred embodiments of the monomers represented by formulas (A) to (D) and their polymers, and the coating film-forming composition in the first embodiment, apply to the third embodiment, except for those related to polycarbodiimide.

[0091] <Coating Film / Cured Product> The first and second embodiments of the coating film of the present invention are cured products of the coating film of the coating film-forming composition described in the first and second embodiments, respectively. The cured product can be formed by applying the coating film-forming composition of the present invention to at least a part of the surface of a substrate and drying it. The application method is not particularly limited, and conventional application methods such as spin coating, dip coating, spray coating, and solvent casting can be used.

[0092] Specific application methods include, for example, immersing a substrate (as described below) in the coating film-forming composition, adding the coating film-forming composition to a container and leaving it to stand for a predetermined period of time, or applying the coating film-forming composition to the surface of a container or substrate. In the case of a container, such as a cell culture container, the coating film-forming composition can be added to the container and left to stand for a predetermined period of time. The addition can be carried out, for example, by adding the coating film-forming composition in an amount 0.5 to 1 times the total volume of the container using a syringe or the like. The time and temperature for leaving the composition to stand are appropriately selected depending on the material of the substrate and the components of the coating film-forming composition. For example, the composition can be left to stand for 1 minute to 24 hours, preferably 5 minutes to 3 hours, at 10 to 80°C. This allows a coating film to be formed on at least a portion of, and preferably over the entire surface of, the container.

[0093] The coating film is then subjected to a drying process to form a cured product. The drying process is carried out in air or under vacuum at a temperature ranging from -200°C to less than 200°C. The cured product can be formed, for example, by drying at room temperature (10°C to 35°C, e.g., 25°C). However, to more quickly form a cured coating film, drying at, for example, 40°C to 100°C may also be used. A drying process at extremely low to low temperatures (around -200°C to -30°C) using the freeze-drying method may also be used. Freeze-drying, also known as vacuum freeze-drying, is a method in which the material to be dried is typically cooled with a refrigerant and the solvent is removed by sublimation under vacuum. Common refrigerants used in freeze-drying include a mixture of dry ice and methanol (-78°C) and liquid nitrogen (-196°C). This drying process allows the anionic groups of the polymer to undergo a crosslinking reaction via the polycarbodiimide compound, as shown in the reaction formula above, to form a cured product, thereby forming a coating film.

[0094] The coating film of the present application may be obtained by further washing after forming a cured product through the above process. The washing may be performed by a known method, but preferably includes washing with running water or ultrasonic washing. Examples of washing solvents include water, an aqueous solution containing an electrolyte, and alcohol. Here, the aqueous solution containing an electrolyte is preferably PBS, saline (containing only sodium chloride), Dulbecco's phosphate-buffered saline, Tris-buffered saline, HEPES-buffered saline, or Veronal-buffered saline, with PBS being particularly preferred. The alcohol is preferably an alcohol having 2 to 6 carbon atoms, and ethanol is particularly preferred. The washing solvent is preferably a hydroalcoholic solvent, which is a mixture of water or an aqueous solution containing an electrolyte and an alcohol, and more preferably a hydroethanolic solvent, which is a mixture of water and ethanol. The washing solvent is usually used at room temperature (e.g., 10 to 35°C), but may also be heated, for example, to a temperature in the range of 40 to 95°C. After being fixed, the coating film does not dissolve even when washed with water, PBS, alcohol, etc., and remains firmly fixed to the substrate, and there is little change in film thickness before and after washing, i.e., there is an effect that the coating film is little dissolved into the solvent.

[0095] The thickness of the coating film of the present invention is in the range of 1 to 1000 nm, preferably in the range of 5 to 500 nm, 10 to 300 nm, 10 to 200 nm, 10 to 100 nm, or 10 to 50 nm.

[0096] A third embodiment of the coating film of the present invention is a coating film of the coating film-forming composition described in the third embodiment. The coating film can be formed by applying the coating film-forming composition of the present invention to at least a part of the surface of a substrate and drying it. The description of the coating film production method in the first embodiment, particularly the application method of the coating film-forming composition and the drying and washing steps, as well as the description of preferred embodiments, apply to the third embodiment, except for those related to curing.

[0097] (Substrate) The substrate in the present invention may be a flat substrate having a flat surface, or may be a container, device, or the like having an arbitrary structure. Examples of such substrates include instruments for collecting or delivering the above-mentioned biological materials (e.g., blood glucose meters, syringe needles, catheters, etc.), containers for storing the above-mentioned biological materials (e.g., bags, bottles, vials, etc., specifically, blood bags, storage containers for antibody pharmaceuticals, etc.), instruments for separating, isolating, or analyzing the above-mentioned biological materials (e.g., microscope peripherals such as carriers and cover glasses, microfluidic devices including flow cytometers such as cell sorters, cuvettes, cell culture substrates, cell spheroid arrays, cell separation columns, microchannel chips, microwell array chips, assay chips, biochips, magnetic beads, measurement cells for fully automated analyzers, etc.), bioprocessing instruments (e.g., reaction vessels, transfer tubes, transfer pipes, purification instruments, cell culture plates, etc.), prosthetic materials (e.g., implants, bone fixation materials, sutures, adhesion barriers, artificial blood vessels, etc.), as well as drug delivery vehicles such as vesicles, microparticles, nanoparticles, etc., materials for diagnostic devices such as gastroscopes, and materials for medical applications such as microfibers, nanofibers, and magnetic particles. The coating film-forming composition can be applied to the surface of a substrate and then dried to produce a substrate having the ability to inhibit adhesion of biological materials. Here, the "surface" refers to the surface that comes into contact with biological materials.

[0098] The cell culture substrate is a cell culture substrate having the coating film on at least a portion of the substrate surface. It is preferable that the coating film is formed over the entire surface on which cell culture is performed. Particular examples of cell culture substrates include dishes (Petri dishes) commonly used for cell culture, such as Petri dishes, tissue culture dishes, and multi-dishes; flasks such as cell culture flasks and spinner flasks; bags such as plastic bags, Teflon (registered trademark) bags, and culture bags; plates such as microplates, microwell plates, multi-plates, and multi-well plates; chamber slides, tubes, trays, bottles such as roller bottles; culture vessels with internal stirring blades for stirring cell suspensions; large culture tanks; bioreactors; and the like. Preferred examples include dishes, plates, and trays.

[0099] Examples of the substrate material include glass, metal, metal-containing compounds or semimetal-containing compounds, activated carbon, and resin. Examples of metals include typical metals (alkali metals: Li, Na, K, Rb, Cs; alkaline earth metals: Ca, Sr, Ba, Ra), magnesium group elements: Be, Mg, Zn, Cd, Hg, aluminum group elements: Al, Ga, In, rare earth elements: Y, La, Ce, Pr, Nd, Sm, Eu, tin group elements: Ti, Zr, Sn, Hf, Pb, Th, iron group elements: Fe, Co, Ni, earth elements: V, Nb, Ta, chromium group elements: Cr, Mo, W, U, manganese group elements: Mn, Re, noble metals: Cu, Ag, Au, and platinum group elements: Ru, Rh, Pd, Os, Ir, Pt, etc. Examples of metal-containing compounds or metalloid-containing compounds include ceramics, which are sintered bodies whose basic component is a metal oxide and which are hardened by heat treatment at high temperatures; semiconductors such as silicon; inorganic solid materials such as molded bodies of inorganic compounds such as metal oxides or metalloid oxides (silicon oxide, alumina, etc.); metal carbides or metalloid carbides; metal nitrides or metalloid nitrides (silicon nitride, etc.); and metal borides or metalloid borides; aluminum, nickel titanium, and stainless steel (SUS304, SUS316, SUS316L, etc.).

[0100] The resin may be a natural resin or a derivative thereof, or a synthetic resin. Preferred examples of the natural resin or a derivative thereof include cellulose, cellulose triacetate (CTA), nitrocellulose (NC), and cellulose with immobilized dextran sulfate. Preferred examples of the synthetic resin include polyacrylonitrile (PAN), polyester polymer alloy (PEPA), polystyrene (PS), polysulfone (PSF), polyethylene terephthalate (PET), polymethyl methacrylate (PMMA), polyvinyl alcohol (PVA), polyurethane (PU), ethylene vinyl alcohol (EVAL), polyethylene (PE), polyester, polypropylene (PP), polyvinylidene fluoride (PVDF), polyethersulfone (PES), polycarbonate (PC), polyvinyl chloride (PVC), polytetrafluoroethylene (PTFE), ultra-high molecular weight polyethylene (UHPE), cycloolefin polymer (COP), cycloolefin copolymer (COC), polydimethylsiloxane (PDMS), acrylonitrile-butadiene-styrene resin (ABS), and Teflon (registered trademark). In the production of the cell culture substrate of the present invention, when the coating film-forming composition is coated so that it is present on at least a portion of the surface of the substrate, no high-temperature treatment is required, so resins with low heat resistance can also be used.

[0101] The substrate may be made of one material or a combination of two or more materials. Among these materials, glass, silicon, silicon oxide, polystyrene (PS), polypropylene (PP), polyethersulfone (PES), polyethylene terephthalate (PET), polycarbonate (PC), polyvinyl chloride (PVC), Teflon (registered trademark), cycloolefin polymer (COP), cycloolefin copolymer (COC), polydimethylsiloxane (PDMS), or stainless steel (SUS304, SUS316, SUS316L, etc.) is preferred, either alone or in combination, and glass, polystyrene (PS), polypropylene (PP), stainless steel (SUS304, SUS316, SUS316L, etc.), cycloolefin polymer (COP), cycloolefin copolymer (COC), or polydimethylsiloxane (PDMS) is particularly preferred.

[0102] (Biological Substances) The coating film of the present invention is preferably a coating film having the ability to inhibit adhesion of biological substances. Similarly, the coating film-forming composition of the present invention is preferably a coating film-forming composition having the ability to inhibit adhesion of biological substances. In the present invention, examples of biological substances include proteins, sugars, viruses, nucleic acids, and cells, or combinations thereof, or biological tissues and body fluids containing them. Examples of the proteins include fibrinogen, bovine serum albumin (BSA), human albumin, various globulins, β-lipoprotein, various antibodies (IgG, IgA, IgM), peroxidase, various complements, various lectins, fibronectin, lysozyme, von Willebrand factor (vWF), serum γ-globulin, pepsin, ovalbumin, insulin, histone, ribonuclease, collagen, and cytochrome c. Examples of the sugars include glucose, galactose, mannose, fructose, heparin, and hyaluronic acid. Examples of the nucleic acids include deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). The above cells include fibroblasts, bone marrow cells, B lymphocytes, T lymphocytes, neutrophils, erythrocytes, platelets, macrophages, monocytes, bone cells, pericytes, dendritic cells, keratinocytes, adipocytes, mesenchymal cells, epithelial cells, epidermal cells, endothelial cells, vascular endothelial cells, hepatocytes, chondrocytes, cumulus cells, nervous system cells, glial cells, neurons, oligodendrocytes, microglia, astrocytes, cardiac cells, esophageal cells, muscle cells (e.g., smooth muscle cells or skeletal muscle cells), pancreatic beta cells, melanocytes, hematopoietic progenitor cells, mononuclear cells, embryonic stem cells (ES cells), embryonic tumor cells, embryonic germ stem cells, and artificial Examples of such cells include pluripotent stem cells (iPS cells), neural stem cells, hematopoietic stem cells, mesenchymal stem cells, hepatic stem cells, pancreatic stem cells, muscle stem cells, germline stem cells, intestinal stem cells, cancer stem cells, hair follicle stem cells, and various cell lines (e.g., HCT116, Huh7, HEK293 (human embryonic kidney cells), HeLa (human cervical cancer cell line), HepG2 (human liver cancer cell line), UT7 / TPO (human leukemia cell line), CHO (Chinese hamster ovary cell line), MDCK, MDBK, BHK, C-33A, HT-29, AE-1, 3D9, Ns0 / 1, Jurkat, NIH3T3, PC12, S2, Sf9, Sf21, High Five, and Vero).

[0103] The biological material of the present invention may be a substance that can be administered to a living body and act thereon. Examples of such substances include small-molecular-weight pharmaceuticals such as peptides (cyclic peptides) and small-molecular-weight compounds, and biopharmaceuticals such as enzymes, blood coagulation and fibrinolysis factors, serum proteins, hormones, vaccines, interferons, erythropoietins, cytokines, toxins, antibodies, antibody-drug conjugates, and fusion proteins.

[0104] <Storage container for antibody pharmaceuticals> The coating film of the present invention is preferably a coating film having an antibody aggregation-inhibiting ability. Similarly, the coating film-forming composition of the present invention is preferably a coating film-forming composition having an antibody aggregation-inhibiting adhesion-inhibiting ability. Therefore, the present invention particularly relates to a storage container for antibody pharmaceuticals, which has any of the coating films described in the first to third embodiments above on at least a portion of its surface. The shape and material of the storage container are as described above in the section (Substrate).

[0105] An antibody drug is a drug that utilizes an antibody, which is a protein composed of immunoglobulin. The antibody drug preferably contains at least one of an antibody and its antigen-binding fragment. The antibody drug preferably contains at least one selected from the group consisting of a chimeric antibody, a human antibody, a humanized antibody, and domain antibodies thereof.

[0106] Specific examples of the antibody drugs include ofatumumab (trade name "Arzera (registered trademark)"), cetuximab (trade name "Erbitux (registered trademark)"), tocilizumab (trade name "Actemra (registered trademark)"), bevacizumab (trade name "Avastin (registered trademark)"), canakinumab (trade name "Ilaris (registered trademark)"), golimumab (trade name "Simponi (registered trademark)"), ustekinumab (trade name "Stelara (registered trademark)"), eculizumab (trade name "Soliris (registered trademark)"), omalizumab (trade name "Xolair (registered trademark)"), trastuzumab (trade name "Herceptin (registered trademark)"), pertuzumab (trade name "Perjeta (registered trademark)"), adalimumab (trade name "Humira (registered trademark)"), Denosumab (trade name "Pralia (registered trademark)", "Ranmark (registered trademark)"), mogamulizumab (trade name "Potelizio (registered trademark)"), rituximab (trade name "Rituxan (registered trademark)"), ranibizumab (trade name "Lucentis (registered trademark)"), infliximab (trade name "Remicade (registered trademark)"), aflibercept (trade name "Eylea (registered trademark)"), abatacept (trade name "Orencia (registered trademark)"), etanercept (trade name "Enbrel (registered trademark)"), gemtuzumab ozogamicin (trade name "Mylotarg (registered trademark)"), panitumumab (trade name "Vectibix (registered trademark)"), basiliximab (trade name "Simulect (registered trademark)"), certolizumab Examples include pegol (trade name Cimzia (registered trademark)), palivizumab (trade name Synagis (registered trademark)), casirivimab / imdevimab (trade name Lonapriv (registered trademark)), and sotrolvimab (trade name Zevudi).

[0107] Among these, it is preferable that the antibody be an antibody obtained from a clone derived from a single antibody-producing cell, or that the antibody molecule be a monoclonal antibody, and it is preferable that the antibody be a monoclonal antibody consisting of an anti-human CD20 human antibody, and it is preferable that the antibody be rituximab or abatacept. The antibody pharmaceutical may contain one type of antibody or two or more types of antibodies. That is, the antibody pharmaceutical of the present invention may contain both an antibody and an antigen-binding fragment, or may contain two or more types of antibodies, or may contain two or more types of antigen-binding fragments.

[0108] Having the ability to inhibit protein adhesion means that, in IgG antibody HRP measurement performed by the method described in the Examples, the relative average absorbance (%) ((average absorbance in the Examples / (average absorbance without coating film)) compared to the case without a coating film is 50% or less, preferably 30% or less, and more preferably 20% or less.

[0109] The present invention will be described in more detail below based on synthesis examples, preparation examples, examples, test examples, etc., but the present invention is not limited to these.

[0110] Synthesis Example 1 5.03 g of acid phosphooxy polypropylene glycol monomethacrylate (average number of moles of propylene oxide added: 5; molecular weight per phosphate group calculated by titration: 618) (product name: PPM-5P, manufactured by Toho Chemical Industry Co., Ltd.), 2.10 g of an approximately 80% aqueous solution of methcroylcholine chloride (manufactured by Tokyo Chemical Industry Co., Ltd.), 2.02 g of butyl methacrylate (manufactured by Tokyo Chemical Industry Co., Ltd.), 2.06 g of ethylene glycol dimethacrylate (manufactured by Tokyo Chemical Industry Co., Ltd.), 48.6 g of ethanol (manufactured by Kanto Chemical Co., Inc.), and 0.107 g of dimethyl-1,1′-azobis(1-cyclohexanecarboxylate) (product name: VE-073, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were added and stirred uniformly to prepare a mixed solution. Meanwhile, 48.6 g of ethanol (Kanto Chemical Co., Ltd.) was added to a four-neck flask equipped with a condenser, the flask was replaced with nitrogen, and the temperature was raised to the reflux temperature while stirring. While maintaining this state, the above mixture was added dropwise over 1.5 hours, and after the addition, the mixture was heated and stirred while maintaining the above environment for 24 hours. After the reaction was completed, the mixture was cooled to obtain a copolymer-containing solution with a solid content of approximately 9.9% by mass. The obtained copolymer-containing liquid was reprecipitated in hexane, a poor solvent, and the precipitate was collected by filtration and dried under reduced pressure to obtain a solid copolymer.

[0111] Synthesis Example 2 5.01 g of acid phosphooxy polypropylene glycol monomethacrylate (average number of moles of propylene oxide added: 5; molecular weight per phosphate group calculated by titration: 618) (product name: PPM-5P, manufactured by Toho Chemical Industry Co., Ltd.), 2.10 g of an approximately 80% aqueous solution of methcroylcholine chloride (manufactured by Tokyo Chemical Industry Co., Ltd.), 2.31 g of butyl methacrylate (manufactured by Tokyo Chemical Industry Co., Ltd.), 1.62 g of ethylene glycol dimethacrylate (manufactured by Tokyo Chemical Industry Co., Ltd.), 47.9 g of ethanol (manufactured by Kanto Chemical Co., Inc.), and 0.054 g of dimethyl-1,1′-azobis(1-cyclohexanecarboxylate) (product name: VE-073, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were added and stirred uniformly to prepare a mixed solution. Meanwhile, 47.9 g of ethanol (Kanto Chemical Co., Ltd.) was added to a four-neck flask equipped with a condenser, the flask was purged with nitrogen, and the temperature was raised to the reflux temperature while stirring. While maintaining this state, the above mixture was added dropwise over 1.5 hours, and after the addition, the mixture was heated and stirred while maintaining the above environment for 24 hours. After the reaction was completed, the mixture was cooled to obtain a copolymer-containing solution with a solid content of approximately 10.1% by mass. The obtained copolymer-containing liquid was reprecipitated in hexane, a poor solvent, and the precipitate was collected by filtration and dried under reduced pressure to obtain a solid copolymer.

[0112] Synthesis Example 3 5.51 g of acid phosphooxy polypropylene glycol monomethacrylate (average number of moles of propylene oxide added: 5; molecular weight per phosphate group calculated by titration: 618) (product name: PPM-5P, manufactured by Toho Chemical Industry Co., Ltd.), 2.30 g of an approximately 80% aqueous solution of methcroylcholine chloride (manufactured by Tokyo Chemical Industry Co., Ltd.), 1.27 g of butyl methacrylate (manufactured by Tokyo Chemical Industry Co., Ltd.), 1.78 g of ethylene glycol dimethacrylate (manufactured by Tokyo Chemical Industry Co., Ltd.), 47.2 g of ethanol (manufactured by Kanto Chemical Co., Inc.), and 0.106 g of dimethyl-1,1′-azobis(1-cyclohexanecarboxylate) (product name: VE-073, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were added and stirred uniformly to prepare a mixed solution. Meanwhile, 47.2 g of ethanol (Kanto Chemical Co., Ltd.) was added to a four-neck flask equipped with a condenser, the flask was replaced with nitrogen, and the temperature was raised to the reflux temperature while stirring. While maintaining this state, the above mixture was added dropwise over 1.5 hours, and after the addition, the mixture was heated and stirred while maintaining the above environment for 24 hours. After the reaction was completed, the mixture was cooled to obtain a copolymer-containing solution with a solid content of approximately 9.9% by mass. The obtained copolymer-containing liquid was reprecipitated in hexane, a poor solvent, and the precipitate was collected by filtration and dried under reduced pressure to obtain a solid copolymer.

[0113] Synthesis Example 4 5.31 g of acid phosphooxy polypropylene glycol monomethacrylate (average number of moles of propylene oxide added: 5; molecular weight per phosphate group calculated by titration: 618) (product name: PPM-5P, manufactured by Toho Chemical Industry Co., Ltd.), 2.24 g of an approximately 80% aqueous solution of methcroylcholine chloride (manufactured by Tokyo Chemical Industry Co., Ltd.), 1.63 g of butyl methacrylate (manufactured by Tokyo Chemical Industry Co., Ltd.), 1.89 g of ethylene glycol dimethacrylate (manufactured by Tokyo Chemical Industry Co., Ltd.), 48.2 g of ethanol (manufactured by Kanto Chemical Co., Inc.), and 0.106 g of dimethyl-1,1′-azobis(1-cyclohexanecarboxylate) (product name: VE-073, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were added and stirred uniformly to prepare a mixed solution. Meanwhile, 48.2 g of ethanol (Kanto Chemical Co., Ltd.) was added to a four-neck flask equipped with a condenser, the flask was replaced with nitrogen, and the temperature was raised to the reflux temperature while stirring. While maintaining this state, the above mixture was added dropwise over 1.5 hours, and after the addition, the mixture was heated and stirred while maintaining the above environment for 24 hours. After the reaction was completed, the mixture was cooled to obtain a copolymer-containing solution with a solid content of approximately 10.2 mass%. The obtained copolymer-containing liquid was reprecipitated in hexane, a poor solvent, and the precipitate was collected by filtration and dried under reduced pressure to obtain a solid copolymer.

[0114] Synthesis Example 5 5.34 g of acid phosphooxy polypropylene glycol monomethacrylate (average number of moles of propylene oxide added: 5; molecular weight per phosphate group calculated by titration: 618) (product name: PPM-5P, manufactured by Toho Chemical Industry Co., Ltd.), 2.24 g of an approximately 80% aqueous solution of methcroylcholine chloride (manufactured by Tokyo Chemical Industry Co., Ltd.), 1.90 g of butyl methacrylate (manufactured by Tokyo Chemical Industry Co., Ltd.), 1.51 g of ethylene glycol dimethacrylate (manufactured by Tokyo Chemical Industry Co., Ltd.), 47.7 g of ethanol (manufactured by Kanto Chemical Co., Inc.), and 0.106 g of dimethyl-1,1′-azobis(1-cyclohexanecarboxylate) (product name: VE-073, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were added and stirred uniformly to prepare a mixed solution. Meanwhile, 47.7 g of ethanol (Kanto Chemical Co., Inc.) was added to a four-neck flask equipped with a condenser, the atmosphere in the flask was replaced with nitrogen, and the temperature was raised to the reflux temperature while stirring. While maintaining this state, the above mixture was added dropwise over 1.5 hours, and after the addition, the mixture was heated and stirred while maintaining the above environment for 24 hours. After the reaction was completed, the mixture was cooled to obtain a copolymer-containing solution with a solids content of approximately 10.3% by mass.

[0115] Synthesis Example 6 The copolymer-containing liquid obtained in Synthesis Example 5 was reprecipitated in hexane, a poor solvent, and the precipitate was recovered by filtration and dried under reduced pressure to obtain a solid copolymer.

[0116] Synthesis Example 7 The copolymer-containing liquid obtained in Synthesis Example 5 was reprecipitated in methyl isobutyl ketone, a poor solvent, and the precipitate was recovered by filtration and dried under reduced pressure to obtain a solid copolymer.

[0117] Comparative Synthesis Example 1 5.00 g of acid phosphooxy polypropylene glycol monomethacrylate (average number of moles of propylene oxide added: 5; molecular weight per phosphate group calculated by titration: 618) (product name: PPM-5P, manufactured by Toho Chemical Industry Co., Ltd.), 2.12 g of an approximately 80% aqueous solution of methcroylcholine chloride (manufactured by Tokyo Chemical Industry Co., Ltd.), 1.73 g of butyl methacrylate (manufactured by Tokyo Chemical Industry Co., Ltd.), 2.41 g of ethylene glycol dimethacrylate (manufactured by Tokyo Chemical Industry Co., Ltd.), 48.9 g of ethanol (manufactured by Kanto Chemical Co., Inc.), and 0.056 g of dimethyl-1,1′-azobis(1-cyclohexanecarboxylate) (product name: VE-073, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were added and stirred uniformly to prepare a mixed solution. Meanwhile, 48.9 g of ethanol (Kanto Chemical Co., Ltd.) was added to a four-neck flask equipped with a condenser, the flask was purged with nitrogen, and the temperature was raised to the reflux temperature while stirring. While maintaining this state, the above mixture was added dropwise over 1.5 hours, and after the addition, the mixture was heated and stirred while maintaining the above environment for 24 hours. After the reaction was completed, the mixture was cooled to obtain a copolymer-containing solution with a solid content of approximately 10.2 mass%. The obtained copolymer-containing liquid was reprecipitated in hexane, a poor solvent, and the precipitate was collected by filtration and dried under reduced pressure to obtain a solid copolymer.

[0118] Comparative Synthesis Example 2 4.20 g of acid phosphooxy polypropylene glycol monomethacrylate (average number of moles of propylene oxide added: 5; molecular weight per phosphate group calculated by titration: 618) (product name: PPM-5P, manufactured by Toho Chemical Industry Co., Ltd.), 1.78 g of an approximately 80% aqueous solution of methcroylcholine chloride (manufactured by Tokyo Chemical Industry Co., Ltd.), 2.89 g of butyl methacrylate (manufactured by Tokyo Chemical Industry Co., Ltd.), 2.24 g of ethylene glycol dimethacrylate (manufactured by Tokyo Chemical Industry Co., Ltd.), 48.9 g of ethanol (manufactured by Kanto Chemical Co., Inc.), and 0.108 g of dimethyl-1,1′-azobis(1-cyclohexanecarboxylate) (product name: VE-073, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were added and stirred uniformly to prepare a mixed solution. Meanwhile, 48.9 g of ethanol (Kanto Chemical Co., Ltd.) was added to a four-neck flask equipped with a condenser, the flask was replaced with nitrogen, and the temperature was raised to the reflux temperature while stirring. While maintaining this state, the above mixture was added dropwise over 1.5 hours, and after the addition, the mixture was heated and stirred while maintaining the above environment for 24 hours. After the reaction was completed, the mixture was cooled to obtain a copolymer-containing solution with a solid content of approximately 10.0 mass%. The obtained copolymer-containing liquid was reprecipitated in hexane, a poor solvent, and the precipitate was collected by filtration and dried under reduced pressure to obtain a solid copolymer.

[0119] Comparative Synthesis Example 3 3.99 g of acid phosphooxy polypropylene glycol monomethacrylate (average number of moles of propylene oxide added: 5; molecular weight per phosphate group calculated by titration: 618) (product name: PPM-5P, manufactured by Toho Chemical Industry Co., Ltd.), 1.67 g of an approximately 80% aqueous solution of methacryloylcholine chloride (manufactured by Tokyo Chemical Industry Co., Ltd.), 2.78 g of butyl methacrylate (manufactured by Tokyo Chemical Industry Co., Ltd.), 32.5 g of ethanol (manufactured by Kanto Chemical Co., Ltd.), and 0.021 g of dimethyl-1,1'-azobis(1-cyclohexanecarboxylate) (product name: VE-073, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were added and stirred uniformly to prepare a mixed solution. The atmosphere in the flask was replaced with nitrogen, and the temperature was raised to the reflux temperature while stirring. The mixture was heated and stirred while maintaining the above environment for 24 hours, yielding a copolymer-containing solution with a solids content of approximately 23.5% by mass.

[0120] Preparation Example 1: 4.65 g of ethanol, 6.29 g of pure water, and 3.00 g of 1N aqueous ammonia were added to 0.30 g of the copolymer obtained in Synthesis Example 2 above, and the mixture was thoroughly stirred. 0.77 g of a solution prepared by diluting Carbodilite V-02 (manufactured by Nisshinbo Chemical Inc., solids content: approximately 40% by mass) 10 times with pure water was added thereto, and the mixture was thoroughly stirred to prepare a composition for forming a coating film. The pH was 10.1.

[0121] Preparation Example 2: 7.74 g of ethanol, 11.38 g of pure water, and 5.57 g of 1N aqueous ammonia were added to 0.50 g of the copolymer obtained in Synthesis Example 3 above, and the mixture was thoroughly stirred. 1.25 g of a solution prepared by diluting Carbodilite V-02 (manufactured by Nisshinbo Chemical Inc., solids content: approximately 40% by mass) 10 times with pure water was added thereto, and the mixture was thoroughly stirred to prepare a composition for forming a coating film. The pH was 10.0.

[0122] Preparation Example 3: 4.86 g of ethanol, 6.18 g of pure water, and 3.01 g of 1N aqueous ammonia were added to 0.30 g of the copolymer obtained in Synthesis Example 3 above, and the mixture was thoroughly stirred. 1.50 g of a solution prepared by diluting Carbodilite V-02 (manufactured by Nisshinbo Chemical Inc., solids content: approximately 40% by mass) 10 times with pure water was added thereto, and the mixture was thoroughly stirred to prepare a composition for forming a coating film. The pH was 10.0.

[0123] Preparation Example 4 To 0.30 g of the copolymer obtained in Synthesis Example 4 above, 4.75 g of ethanol, 6.24 g of pure water, and 3.01 g of 1N aqueous ammonia were added and thoroughly stirred. 1.12 g of a solution prepared by diluting Carbodilite V-02 (manufactured by Nisshinbo Chemical Inc., solids content: approximately 40% by mass) 10 times with pure water was added thereto and thoroughly stirred, thereby preparing a composition for forming a coating film. The pH was 10.0.

[0124] Preparation Example 5: 3.31 g of ethanol, 6.10 g of pure water, and 1.13 g of 1N aqueous ammonia were added to 0.10 g of the copolymer obtained in Synthesis Example 4 above, and the mixture was thoroughly stirred. 0.25 g of a solution prepared by diluting Carbodilite V-02-L2 (manufactured by Nisshinbo Chemical Inc., solids content: approximately 40% by mass) 10 times with pure water was added thereto, and the mixture was thoroughly stirred to prepare a composition for forming a coating film. The pH was 10.0.

[0125] Preparation Example 6 To 0.30 g of the copolymer obtained in Synthesis Example 6, 4.76 g of ethanol, 6.31 g of pure water, and 3.01 g of 1N aqueous ammonia were added and thoroughly stirred. 1.13 g of a solution prepared by diluting Carbodilite V-02 (manufactured by Nisshinbo Chemical Inc., solids content: approximately 40% by mass) 10 times with pure water was added and thoroughly stirred to prepare a composition for forming a coating film. The pH was 10.0.

[0126] Preparation Example 7 To 0.10 g of the copolymer obtained in Synthesis Example 6, 3.32 g of ethanol, 6.25 g of pure water, and 1.13 g of 1N aqueous ammonia were added and thoroughly stirred. 0.38 g of a solution prepared by diluting Carbodilite V-02 (manufactured by Nisshinbo Chemical Inc., solids content: approximately 40% by mass) 10 times with pure water was added and thoroughly stirred to prepare a composition for forming a coating film. The pH was 10.0.

[0127] Preparation Example 8 To 0.10 g of the copolymer obtained in Synthesis Example 6, 3.08 g of ethanol, 5.97 g of pure water, and 1.16 g of 1N aqueous ammonia were added and thoroughly stirred. 0.13 g of a solution prepared by diluting Carbodilite V-02-L2 (manufactured by Nisshinbo Chemical Inc., solids content: approximately 40% by mass) 10 times with pure water was added and thoroughly stirred to prepare a composition for forming a coating film. The pH was 10.0.

[0128] Preparation Example 9 To 5.00 g of the copolymer-containing liquid obtained in Synthesis Example 5, 3.68 g of ethanol, 12.12 g of pure water, and 5.16 g of 1N aqueous ammonia were added and thoroughly stirred. 1.94 g of a solution prepared by diluting Carbodilite V-02 (manufactured by Nisshinbo Chemical Inc., solids content: approximately 40% by mass) 10 times with pure water was added and thoroughly stirred to prepare a composition for forming a coating film. The pH was 10.0.

[0129] Preparation Example 10: 7.91 g of ethanol, 11.74 g of pure water, and 5.01 g of 1N aqueous ammonia were added to 0.50 g of the copolymer obtained in Synthesis Example 7 above, and the mixture was thoroughly stirred. 1.88 g of a solution prepared by diluting Carbodilite V-02 (manufactured by Nisshinbo Chemical Inc., solids content: approximately 40% by mass) 10 times with pure water was added thereto, and the mixture was thoroughly stirred to prepare a composition for forming a coating film. The pH was 10.0.

[0130] Preparation Example 11: 13.91 g of ethanol, 21.44 g of pure water, and 9.01 g of 1N aqueous ammonia were added to 0.90 g of the copolymer obtained in Synthesis Example 7 above, and the mixture was thoroughly stirred. 2.25 g of a solution prepared by diluting Carbodilite V-02 (manufactured by Nisshinbo Chemical Inc., solids content: approximately 40% by mass) 10 times with pure water was added thereto, and the mixture was thoroughly stirred to prepare a composition for forming a coating film. The pH was 10.0.

[0131] Preparation Example 12 To 0.50 g of the copolymer obtained in Synthesis Example 7, 7.55 g of ethanol, 12.08 g of pure water, and 5.00 g of 1N aqueous ammonia were added and thoroughly stirred. 0.63 g of a solution prepared by diluting Carbodilite V-02 (manufactured by Nisshinbo Chemical Inc., solids content: approximately 40% by mass) 10 times with pure water was added and thoroughly stirred to prepare a composition for forming a coating film. The pH was 10.0.

[0132] Preparation Example 13 To 5.00 g of the copolymer-containing liquid obtained in Synthesis Example 5, 3.11 g of ethanol, 11.55 g of pure water, and 5.14 g of 1N aqueous ammonia were added and thoroughly stirred. 1.24 g of a solution prepared by diluting Carbodilite V-02 (manufactured by Nisshinbo Chemical Inc., solids content: approximately 40% by mass) 10 times with pure water was added and thoroughly stirred to prepare a composition for forming a coating film. The pH was 10.0.

[0133] Preparation Example 14 To 5.00 g of the copolymer-containing liquid obtained in Synthesis Example 5, 2.93 g of ethanol, 11.76 g of pure water, and 5.08 g of 1N aqueous ammonia were added and thoroughly stirred. 0.62 g of a solution prepared by diluting Carbodilite V-02 (manufactured by Nisshinbo Chemical Inc., solids content: approximately 40% by mass) 10 times with pure water was added and thoroughly stirred to prepare a composition for forming a coating film. The pH was 10.0.

[0134] Comparative Preparation Example 1: 27.45 g of ethanol and 10.58 g of pure water were added to 0.80 g of the copolymer obtained in Comparative Synthesis Example 1 and thoroughly stirred to prepare a composition for forming a coating film. The pH was 2.9.

[0135] Comparative Preparation Example 2 To 0.80 g of the copolymer-containing liquid obtained in Comparative Synthesis Example 1, 12.36 g of ethanol, 15.77 g of pure water, and 9.00 g of 1N aqueous ammonia were added and thoroughly stirred. 2.00 g of a solution prepared by diluting Carbodilite V-02 (manufactured by Nisshinbo Chemical Inc., solids content: approximately 40% by mass) 10 times with pure water was added and thoroughly stirred to prepare a composition for forming a coating film. The pH was 10.1.

[0136] Comparative Preparation Example 3: 8.58 g of ethanol and 3.68 g of pure water were added to 0.25 g of the copolymer obtained in Comparative Synthesis Example 2 and thoroughly stirred to prepare a composition for forming a coating film. The pH was 2.9.

[0137] Comparative Preparation Example 4: 27.51 g of ethanol and 11.76 g of pure water were added to 0.80 g of the copolymer obtained in Synthesis Example 1 and thoroughly stirred to prepare a composition for forming a coating film. The pH was 2.8.

[0138] Comparative Preparation Example 5: 8.59 g of ethanol and 3.70 g of pure water were added to 0.25 g of the copolymer obtained in Synthesis Example 2 above, and the mixture was thoroughly stirred to prepare a composition for forming a coating film. The pH was 2.9.

[0139] Comparative Preparation Example 6: 8.60 g of ethanol and 3.69 g of pure water were added to 0.26 g of the copolymer obtained in Synthesis Example 3 and thoroughly stirred to prepare a composition for forming a coating film. The pH was 2.8.

[0140] Comparative Preparation Example 7 To 3.02 g of the copolymer-containing liquid obtained in Comparative Synthesis Example 3, 8.87 g of ethanol, 14.47 g of pure water, and 7.04 g of 1N aqueous ammonia were added and thoroughly stirred. 2.66 g of a solution prepared by diluting Carbodilite V-02 (manufactured by Nisshinbo Chemical Inc., solids content: approximately 40% by mass) 10 times with pure water was added and thoroughly stirred to prepare a composition for forming a coating film. The pH was 10.0.

[0141] Test Example 1: Evaluation of Coating Film Elution The coating film-forming compositions obtained in Preparation Examples 1 to 14 and Comparative Preparation Examples 1 to 7 were each spin-coated onto an HMDS-treated silicon wafer at 1,500 rpm / 60 seconds and dried under the drying conditions shown in Table 1. Subsequently, the wafer was washed with pure water or a mixed solution of pure water and ethanol and then dried at 50°C for 1 hour to obtain a coating film on the HMDS-treated silicon wafer. The film thickness was measured using a spectroscopic ellipsometer, and this film thickness was defined as the initial film thickness. As an elution test for the coating film, the wafer was immersed in PBS for 24 hours, then washed with pure water and dried at 50°C for 1 hour, and the film thickness was measured using a spectroscopic ellipsometer. The initial film thickness and the film thickness after immersion in PBS were compared, and the remaining film ratio after immersion in PBS, with the initial film thickness defined as 100%, was used as an index of elution. The results are shown in Table 1.

[0142] Test Example 2: Evaluation of Protein Adsorption (Preparation of Coated Plates) Each of the coating film-forming compositions obtained in Preparation Examples 1 to 14 and Comparative Preparation Examples 1 to 7 was added to a 96-well plate (Corning, #3363, volume 0.32 mL, made of polypropylene) at 150 μL / well, 5 wells at a time. After standing at room temperature for 1 hour, the liquid was drained and the plate was dried in an oven under the drying conditions shown in Table 1. Thereafter, each well was washed three times with 200 μL of pure water or a mixed solution of pure water and ethanol, and then dried in an oven at 50° C. for 1 hour to prepare a coated plate. As a negative control, wells of an uncoated 96-well plate (Corning, #3363, volume 0.32 mL, made of polypropylene) were used.

[0143] (Preparation of IgG-HRP Dilution) Goat anti-mouse IgG antibody-HRP conjugate (manufactured by Southern Biotechnology Associates) was diluted with PBS to a concentration of 1 mg / g to prepare an IgG-HRP dilution.

[0144] (Protein Adsorption Evaluation) 100 μL / well of the IgG-HRP diluted solution was added to each well of the plate prepared above, as well as to the negative control, and the plate was left to stand at room temperature for 30 minutes. The IgG-HRP diluted solution was then drained, and each well was washed three times with 200 μL of PBS. 100 μL / well of TMB solution (SureBlue, manufactured by Sera Care) was added, and after one minute, 100 μL / well of TMB STOP solution (manufactured by Sera Care) was added. Absorbance at 450 nm and 650 nm was measured using a microplate reader (Infinite M200PRO, manufactured by TECAN). The absorbance at 650 nm was subtracted from the absorbance at 450 nm to calculate the average absorbance of five wells for each coating film-forming composition. The results are shown in Table 1.

[0145] Test Example 3: Evaluation of antibody aggregation (Preparation of coated tubes) 1.5 mL of each of the coating film-forming compositions obtained in Preparation Examples 1 to 14 and Comparative Preparation Examples 1 to 7 was placed in a polypropylene (PP) microtube (Nippon Genetics Co., Ltd., #11510) and allowed to stand at 25°C for 0.5 hours. After removing the coating film-forming composition from the tube, it was dried under the drying conditions shown in Table 1. Thereafter, the tube was thoroughly washed with pure water or a mixed solution of pure water and ethanol to obtain a coated tube on which a coating film had been formed. As a negative control, an uncoated polypropylene (PP) microtube (Nippon Genetics Co., Ltd., #11510) was used.

[0146] (Antibody Aggregation Evaluation) Rituximab solution was purified, adjusted to a concentration of 1.0 mg / mL, and then sterilized by filtration using a 0.22 μm filter in a sterile environment. The prepared rituximab solution was filled into the coated tube obtained above in 0.5 mL portions, placed in a microtube agitator / shaker, and shaken at 22±3°C and 2500 rpm for 24 hours. After agitation and shaking, the solution was transferred from the tube to a transparent vial, and the appearance of opacity was visually evaluated according to the following evaluation criteria to confirm the inhibitory effect on aggregate formation. The results are shown in Table 1.

[0147] [Evaluation criteria] ○: Colorless and transparent with no turbidity △: Slightly turbid ×: White turbidity

[0148]

[0149] As shown in Comparative Example 1, without a coating film, the solution after antibody aggregation evaluation was cloudy, confirming the formation of aggregates. Furthermore, in Comparative Examples 2 to 7, the absorbance in the protein adsorption evaluation was significantly reduced compared to Comparative Example 1 without a coating film, confirming the suppression of protein adsorption. However, in the antibody aggregation evaluation of Comparative Examples 2 to 4, which used coating agents that did not contain the polymer of the present invention, the solution appeared cloudy, indicating that no antibody aggregation inhibitory effect was observed. Furthermore, in Comparative Examples 5 to 7, which used coating agents that contained the polymer of the present invention but did not contain the crosslinking agent polycarbodiimide, the antibody aggregation inhibitory effect was observed, but the residual film rate was low and the coating film tended to dissolve compared to the coating agents of the present invention containing the same polymer (see, for example, Example 1 and Comparative Example 6, and Example 2 or 3 and Comparative Example 7). In contrast, in Examples 1 to 20, the residual film rate was high, suppressing the dissolution of the coating film, and the coating film exhibited excellent protein adsorption inhibitory and antibody aggregation inhibitory abilities, demonstrating a well-balanced desired performance.

[0150] According to the present invention, there are provided a coating film-forming composition having the ability to inhibit adhesion of biological materials and the ability to inhibit aggregation of antibody pharmaceuticals, a coating film that is a cured product thereof, a method for producing the same, and a cured product and a method for producing the same. Furthermore, the coating film of the present invention is excellent in practical use because it inhibits elution of coating film components into pharmaceuticals.

Claims

1. (1) The following formula (A): 【Chemistry 42】 (In the formula, T ａ , U ａ１ and U ａ２ each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ａ represents a single bond, an ester bond or an amide bond; R ａ represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; m represents an integer of 1 to 10. an anionic monomer represented by the following formula (B): 【Chemistry 43】 (In the formula, T ｂ , U ｂ１ , U ｂ２ and U ｂ３ each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ｂ represents a single bond, an ester bond or an amide bond; R ｂ represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; An － represents an anion selected from the group consisting of a halide ion, an inorganic acid ion, a hydroxide ion, and an isothiocyanate ion. a cationic monomer represented by the following formula (C): 【Chemical Formula 44】 [In the formula, T ｃ represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ｃ represents a single bond, an ether bond, or an ester bond; R ｃ represents a linear or branched alkyl group having 1 to 18 carbon atoms, a cyclic hydrocarbon group having 3 to 10 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 14 carbon atoms, or an aryloxyalkyl group having 7 to 14 carbon atoms (wherein the aryl moiety is optionally substituted with a linear or branched alkyl group having 1 to 5 carbon atoms which may be substituted with a halogen atom) and a hydrophobic monomer represented by the following formula (D): 【Chemistry 45】 (In the formula, T ｄ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms; R ｄ represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; n represents an integer of 1 to 10. a monomer mixture containing a bifunctional monomer represented by the formula (A), wherein the total ratio of the anionic monomer represented by the formula (A) and the cationic monomer represented by the formula (B) to the total monomers contained in the monomer mixture is 40 mol % or more; and (2) The following formula (E): 【Chemistry 46】 Polycarbodiimide containing a structure represented by A coating film-forming composition comprising:

2. 2. The composition for forming a coating film according to claim 1, wherein the proportion of the bifunctional monomer represented by formula (D) relative to the total monomers contained in the monomer mixture is less than 30 mol%.

3. The composition for forming a coating film according to claim 1 , wherein the polycarbodiimide contains a hydrophilic group.

4. The hydrophilic group is represented by the following formula (F): 【Chemistry 47】 (In the formula, R 1 represents a linear or branched alkyl group having 1 to 5 carbon atoms; R 2 represents a hydrogen atom or a methyl group, and when a plurality of R 2 s are present, the R 2 s may be the same or different, and o represents an integer of 1 to 30. The composition for forming a coating film according to claim 3 , represented by the formula:

5. A coating film which is a cured product of a coating film of the composition for forming a coating film according to any one of claims 1 to 4.

6. The coating film according to claim 5 , which has the ability to inhibit adhesion of biological substances.

7. 5. A method for producing a coating film, comprising: applying the composition for forming a coating film according to claim 1 to a substrate to form a coating film; and drying the coating film to form a cured product.

8. The method for producing a coating film according to claim 7, further comprising a step of washing the cured product obtained after the drying step with a hydroalcoholic solvent.

9. The following formula (A): 【Chemistry 48】 (In the formula, T ａ , U ａ１ and U ａ２ each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ａ represents a single bond, an ester bond or an amide bond; R ａ represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; m represents an integer of 1 to 10. an anionic monomer represented by the following formula (B): 【Chemistry 49】 (In the formula, T ｂ , U ｂ１ , U ｂ２ and U ｂ３ each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ｂ represents a single bond, an ester bond or an amide bond; R ｂ represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; An － represents an anion selected from the group consisting of a halide ion, an inorganic acid ion, a hydroxide ion, and an isothiocyanate ion. a cationic monomer represented by the following formula (C): 【Chemistry 50】 [In the formula, T ｃ represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ｃ represents a single bond, an ether bond, or an ester bond; R ｃ represents a linear or branched alkyl group having 1 to 18 carbon atoms, a cyclic hydrocarbon group having 3 to 10 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 14 carbon atoms, or an aryloxyalkyl group having 7 to 14 carbon atoms (wherein the aryl moiety is optionally substituted with a linear or branched alkyl group having 1 to 5 carbon atoms which may be substituted with a halogen atom) and a hydrophobic monomer represented by the following formula (D): 【Chemistry 51】 (In the formula, T ｄ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms; R ｄ represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; n represents an integer of 1 to 10. wherein the total ratio of the anionic monomer represented by formula (A) and the cationic monomer represented by formula (B) to the total monomers contained in the monomer mixture is 40 mol % or more.

10. The cured product according to claim 9, comprising a pyrophosphate structure.

11. (i) The following formula (A): 【Chemistry 52】 (In the formula, T ａ , U ａ１ and U ａ２ each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ａ represents a single bond, an ester bond or an amide bond; R ａ represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; m represents an integer of 1 to 10. an anionic monomer represented by the following formula (B): 【Chemistry 53】 (In the formula, T ｂ , U ｂ１ , U ｂ２ and U ｂ３ each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ｂ represents a single bond, an ester bond or an amide bond; R ｂ represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; An － represents an anion selected from the group consisting of a halide ion, an inorganic acid ion, a hydroxide ion, and an isothiocyanate ion. a cationic monomer represented by the following formula (C): 【Chemical 54】 [In the formula, T ｃ represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; Q ｃ represents a single bond, an ether bond, or an ester bond; R ｃ represents a linear or branched alkyl group having 1 to 18 carbon atoms, a cyclic hydrocarbon group having 3 to 10 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 14 carbon atoms, or an aryloxyalkyl group having 7 to 14 carbon atoms (wherein the aryl moiety is optionally substituted with a linear or branched alkyl group having 1 to 5 carbon atoms which may be substituted with a halogen atom) and a hydrophobic monomer represented by the following formula (D): 【Chemistry 55】 (In the formula, T ｄ represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms; R ｄ represents a linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom; n represents an integer of 1 to 10. a step of polymerizing a monomer mixture containing a bifunctional monomer represented by the formula (A) and the cationic monomer represented by the formula (B) in a total proportion of 40 mol % or more relative to the total monomers contained in the monomer mixture to obtain a copolymer; and (ii) The copolymer is reacted with a compound represented by the following formula (E): 【Chemical 56】 and a polycarbodiimide having a structure represented by the formula (I) to obtain a cured product. A method for producing a cured product, comprising:

12. The coating film according to claim 5 , which has an ability to inhibit antibody aggregation.

13. A storage container for an antibody pharmaceutical, comprising the coating film according to claim 12 on at least a portion of its surface.

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