Copolymer, medical coating agent and medical device

Abstract

To provide a copolymer in which a coating film to be obtained has excellent adhesiveness to a substrate, and also has excellent protein attachment inhibiting function, a medical coating agent, and a medical device.SOLUTION: A copolymer includes a structural unit derived from (meth)acrylic acid ester (A) having a specific structure, and a constitutional unit derived from (meth)acrylic acid ester (B) having an alkoxy group, where the (A) includes a constitutional unit derived from a monomer (a) having a dihydroxybenzene structure and / or a monomer (a') having an alkyl group or an alkoxysilyl group, and a constitutional unit derived from a monomer (b) expressed by the following formula (3). (R7 denotes OR, halogen atom, COR, COOR, CN or the like.)SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a copolymer, a medical coating agent, and a medical device. [Background technology]

[0002] In recent years, in the fields of medical instruments, biochemical analysis, and protein separation and purification, various polymer materials (polystyrene, polypropylene, polyethylene, polyurethane, polyvinyl chloride, nylon), glass, stainless steel, and other metals have been used for various parts and containers, such as various reaction vessels, centrifuge tubes, tubing, syringes, pipettes, filters, and separation columns. However, protein adhesion occurs on all materials, and this protein adhesion can cause reduced detection sensitivity, reduced reproducibility, and poor purification.

[0003] Furthermore, catheters, cannulas, stents, membranes for plasma separation, artificial organs such as heart-lung machines, and the like come into contact with circulating blood and metabolic substances in the body, and therefore require biocompatibility to suppress protein adhesion and the formation of thrombi and other conditions caused by protein adhesion.

[0004] Patent Document 1 describes that polymethoxyethyl acrylate (PMEA) has biocompatibility, such as antithrombogenicity and low protein adhesion. However, PMEA has a problem in that it is in a rubbery state at room temperature, resulting in poor dimensional stability and poor practicality.

[0005] Patent Document 2 describes that a block copolymer having specific A and B blocks can achieve both substrate adhesion and antithrombogenicity. However, the block copolymer in Patent Document 2 is synthesized by living radical polymerization, which requires a long polymerization time and has poor productivity.

[0006] Patent Document 3 describes that copolymerization of polymethyl methacrylate (PMMA) macromonomer with methoxyethyl acrylate (MEA) allows for the synthesis of a copolymer that maintains low protein adsorption and moldability with good productivity. However, when the copolymer of Patent Document 3 is used as a coating agent, there is room for further improvement in substrate adhesion.

[0007] Patent Document 4 describes that the use of a monomer having a catechol skeleton contained in the adhesive protein Mefps5 of the mussel improves the adhesion of acrylamide gel to various substrates. However, the use of a monomer having a catechol skeleton has the problem of increasing the amount of protein adsorbed. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Japanese Patent Application Laid-Open No. 2004-161954 [Patent Document 2] International Publication No. 2016 / 143787 [Patent Document 3] International Publication No. 2020 / 066685 [Patent Document 4] International Publication No. 2016 / 190400 Summary of the Invention [Problem to be solved by the invention]

[0009] An object of the present invention is to provide a copolymer, a medical coating agent, and a medical device, which produce a coating film containing the copolymer that has excellent adhesion to a substrate and also has excellent protein adhesion inhibitory properties. [Means for solving the problem]

[0010] As a result of extensive investigations aimed at solving the above-mentioned problems, the present inventors have found that the above-mentioned problems can be solved by a copolymer obtained by polymerizing a macromonomer (A) obtained by polymerizing a specific monomer (a) or a specific monomer (a') and a monomer (b), and a specific monomer (B). That is, the present invention is summarized as follows [1] to

[12] .

[0011] [1] A structural unit derived from a macromonomer (A), A copolymer containing a structural unit derived from a monomer (B) represented by the following formula (4): A copolymer, wherein the macromonomer (A) comprises a constituent unit derived from a monomer (a) represented by the following formula (1) and / or a monomer (a') represented by the following formula (2), and a constituent unit derived from a monomer (b) represented by the following formula (3):

[0012] [ka]

[0013] (In formula (1), X represents NH or O, Y represents a direct bond or a substituted or unsubstituted alkylene group having 1 to 10 carbon atoms, Z represents a direct bond, a carbonyl group, or an ester group, R1 represents a hydrogen atom or a methyl group, and Ar represents an aromatic ring group having at least two hydroxyl groups.)

[0014] [ka]

[0015] (In formula (2), R2 represents a hydrogen atom or a methyl group, X' represents a direct bond, an ester bond, or an amide bond, and Y represents a direct bond or a substituted or unsubstituted alkylene group having 1 to 10 carbon atoms. R3 to R5 each independently represent a hydrogen atom, or an alkyl group or alkoxy group having 4 or less carbon atoms.)

[0016] [ka]

[0017] (In formula (3), R6 represents a hydrogen atom or a methyl group. R7 represents OR 33 , halogen atoms, COR 34 , COOR 35 ,CN,CONR 36 R 37 or R 38 and R 33 ~R 37 each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alicyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alkaryl group, or a substituted or unsubstituted organosilyl group; R 38 represents a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

[0018] [ka]

[0019] (In formula (4), R8 represents a hydrogen atom or a methyl group, R9 represents an alkylene group or an oxyethylene group having 1 to 4 carbon atoms, and R 10 represents a hydrocarbon group having 1 to 6 carbon atoms.

[0020] [2] The copolymer according to [1], which contains a block copolymer and / or a graft copolymer.

[0021] [3] The copolymer according to [2], which comprises a graft copolymer containing a structural unit derived from the macromonomer (A) in a side chain of the monomer (B).

[0022] [4] The copolymer according to any one of [1] to [3], wherein the content of structural units derived from the monomer (a) and / or the monomer (a') is 0.5% by mass or more and 25% by mass or less, relative to 100% by mass of the total mass of structural units derived from the macromonomer (A).

[0023] [5] The copolymer according to any one of [1] to [4], containing 75% by mass or more and 99.5% by mass or less of structural units derived from methyl methacrylate, relative to 100% by mass of the total mass of structural units derived from the macromonomer (A).

[0024] [6] The copolymer according to any one of [1] to [5], wherein the macromonomer (A) comprises a macromonomer (A-1) represented by the following formula (5):

[0025] [ka]

[0026] (In formula (5), R 11 represents a hydrogen atom or a methyl group. 13 , R 14 represents a hydrogen atom, an unsubstituted or substituted alkyl group, an unsubstituted or substituted alicyclic group, an unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group, or an unsubstituted or substituted non-aromatic heterocyclic group. W is a terminal group. X represents NH or O, Y represents a direct bond or a substituted or unsubstituted alkylene group having 1 to 10 carbon atoms, and Z represents a direct bond, a carbonyl group, or an ester group. R 12 represents a hydrogen atom or a methyl group. Ar represents an aromatic ring group having at least two hydroxyl groups. m and n each independently represent an integer of 2 to 10,000. When a plurality of Ar, X, Y, Z, and R 11 , R 12 , R 14 may be the same or different.)

[0027] [7] The copolymer according to any one of [1] to [6], wherein the monomer (B) contains an acrylate ester.

[0028] [8] The copolymer according to [7], wherein the monomer (B) contains 2-methoxyethyl acrylate.

[0029] [9] A resin composition comprising the copolymer according to any one of [1] to [8].

[0030]

[10] A coating agent comprising the copolymer according to any one of [1] to [8].

[0031]

[11] A medical coating agent comprising the copolymer according to any one of [1] to [8].

[0032]

[12] A medical device comprising a coating film made of the medical coating agent according to

[11] on at least one surface of a substrate. [Effects of the Invention]

[0033] According to the present invention, it is possible to provide a copolymer, a medical coating agent, and a medical device in which the resulting coating film containing the copolymer has excellent adhesion to a substrate and also has excellent protein adhesion inhibitory function. DETAILED DESCRIPTION OF THE INVENTION

[0034] The present invention will be described in detail below, but the following description is an example of an embodiment of the present invention, and the present invention is not limited to the following description as long as it does not deviate from the gist of the present invention. The present invention can be implemented by modifying it as desired within the scope of the gist of the present invention.

[0035] The following definitions of terms apply throughout the specification and claims. "(Meth)acrylic" is a general term for acrylic and meta-acrylic. "(Co)polymer" is a general term for polymers and copolymers. The symbol "to" indicating a range of values ​​means that the values ​​before and after it are included as the lower and upper limits. The term "substituted or unsubstituted" or "substituted or unsubstituted" means that "it may or may not have a substituent."

[0036] [Copolymer] The copolymer of the present invention is a copolymer containing structural units derived from a macromonomer (A) and structural units derived from a monomer (B) represented by the following formula (4), wherein the macromonomer (A) contains structural units derived from a monomer (a) represented by the following formula (1) and / or a monomer (a') represented by the following formula (2), and structural units derived from a monomer (b) represented by the following formula (3). That is, the copolymer of the present invention is a copolymer containing a structural unit derived from a macromonomer (A) obtained by polymerizing a monomer (a) represented by the following formula (1) and / or a monomer (a') represented by the following formula (2) with a monomer (b) represented by the following formula (3), and a structural unit derived from a monomer (B) represented by the following formula (4):

[0037] [ka]

[0038] (In formula (1), X represents NH or O, Y represents a direct bond or a substituted or unsubstituted alkylene group having 1 to 10 carbon atoms, Z represents a direct bond, a carbonyl group, or an ester group, R1 represents a hydrogen atom or a methyl group, and Ar represents an aromatic ring group having at least two hydroxyl groups.)

[0039] [ka]

[0040] (In formula (2), R2 represents a hydrogen atom or a methyl group, X' represents a direct bond, an ester bond, or an amide bond, and Y represents a direct bond or a substituted or unsubstituted alkylene group having 1 to 10 carbon atoms. R3 to R5 each independently represent a hydrogen atom, or an alkyl group or alkoxy group having 4 or less carbon atoms.)

[0041] [ka]

[0042] (In formula (3), R6 represents a hydrogen atom or a methyl group. R7 represents OR 33 , halogen atoms, COR 34 , COOR 35 ,CN,CONR 36 R 37 or R 38 and R 33 ~R 37 each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alicyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alkaryl group, or a substituted or unsubstituted organosilyl group; R 38 represents a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

[0043] [ka]

[0044] (In formula (4), R8 represents a hydrogen atom or a methyl group, R9 represents an alkylene group or an oxyethylene group having 1 to 4 carbon atoms, and R 10 represents a hydrocarbon group having 1 to 6 carbon atoms.

[0045] From the viewpoint of achieving both substrate adhesion and low protein adsorption, the copolymer of the present invention preferably contains a block copolymer and / or a graft copolymer. In particular, it is preferred that the copolymer contains at least one selected from a block copolymer having a constitutional unit derived from macromonomer (A) and a constitutional unit derived from monomer (B), and a graft copolymer having a constitutional unit derived from macromonomer (A) in the side chain of monomer (B). In particular, from the viewpoint of substrate adhesion, it is preferred that the copolymer contains a graft copolymer having a constitutional unit derived from macromonomer (A) in the side chain of monomer (B). Furthermore, the copolymer of the present invention may contain a polymer consisting only of structural units derived from macromonomer (A), an unreacted macromonomer (A), and a polymer consisting only of structural units derived from monomer (B).

[0046] [Macromonomer (A)] The copolymer of the present invention must contain a structural unit derived from a macromonomer (A) obtained by polymerizing a monomer (a) represented by the formula (1) and / or a monomer (a') represented by the formula (2) with a monomer (b) represented by the formula (3).

[0047] <Monomer (a)> The monomer (a) has a structure represented by the above formula (1). In formula (1), R1 represents a hydrogen atom or a methyl group, and X represents NH or O. Y represents a direct bond or a substituted or unsubstituted alkylene group having 1 to 10 carbon atoms. In the case of a substituted alkylene group having 1 to 10 carbon atoms, it is preferable that some of the hydrogen atoms are substituted with hydroxyl groups. Furthermore, among direct bonds and alkylene groups having 1 to 10 carbon atoms, direct bonds or alkylene groups having 1 to 5 carbon atoms are preferred. Ar represents an aromatic ring group having at least two hydroxyl groups, and preferably an aromatic ring group having two or three hydroxyl groups.

[0048] Examples of such monomer (a) when X is NH include N-[2-(3,4-dihydroxyphenyl)methyl](meth)acrylamide, N-[2-(3,4-dihydroxyphenyl)ethyl](meth)acrylamide (hereinafter sometimes referred to as "dopamine(meth)acrylamide" or simply abbreviated as DOPA), N-[2-(3,4-dihydroxyphenyl)propyl](meth)acrylamide, N-[2-(3,4-dihydroxyphenyl)butyl](meth)acrylamide, N- Examples include [2-(3,4-dihydroxyphenyl)pentyl](meth)acrylamide, N-[2-(3,4-dihydroxyphenyl)hexyl](meth)acrylamide, N-[2-(3,4-dihydroxyphenyl)heptyl](meth)acrylamide, N-[2-(3,4-dihydroxyphenyl)octyl](meth)acrylamide, N-[2-(3,4-dihydroxyphenyl)nonyl](meth)acrylamide, and N-[2-(3,4-dihydroxyphenyl)decyl](meth)acrylamide.

[0049] Furthermore, when X is O, examples thereof include 2-[(2-methyl-1-oxo-2-propenyl)oxy]ethyl 3,4,5-trihydroxybenzoate, 2-ethyl 3,4-dihydroxybenzoate, (3,4-dihydroxyphenyl)2-(meth)acryloyloxymethyl 3,4-dihydroxybenzoate, 2-(meth)acryloyloxymethyl 3,4,5-trihydroxybenzoate [2-hydroxy(3-(meth)acryloyloxy)propyl], and 2-hydroxy(3-(meth)acryloyloxy)propyl] 3,4-dihydroxybenzoate.

[0050] Among these, it is preferable to use N-[2-(3,4-dihydroxyphenyl)ethyl](meth)acrylamide and 2-[(2-methyl-1-oxo-2-propenyl)oxy]ethyl 3,4,5-trihydroxybenzoate as monomer (a) because they exhibit particularly high adhesion to the substrate. The monomer (a) may be used alone or in combination of two or more.

[0051] <Monomer (a')> The monomer (a') has a structure represented by the above formula (2). In formula (2), R2 represents a hydrogen atom or a methyl group, and X' represents a direct bond, an ester bond, or an amide bond. Y represents a direct bond or a substituted or unsubstituted alkylene group having 1 to 10 carbon atoms, preferably a direct bond or an alkylene group having 1 to 4 carbon atoms, and particularly preferably a methylene group or an ethylene group. The carbon atoms R3 to R5 each independently represent a hydrogen atom or an alkyl or alkoxy group having 4 or less carbon atoms.

[0052] Examples of the monomer (a') include silane coupling agent-containing monomers such as 3-(meth)acryloxypropyltrimethoxysilane, 3-(meth)acryloxypropylmethyldiethoxysilane, 3-(meth)acryloxypropyltriethoxysilane, vinyltrimethoxysilane, and vinyltriethoxysilane.

[0053] Among these, 3-(meth)acryloxypropyltrimethoxysilane and 3-(meth)acryloxypropyltriethoxysilane are preferred as the monomer (a') from the viewpoints of low cost and functionality. The monomer (a') may be used alone or in combination of two or more.

[0054] <Monomer (b)> The production of the macromonomer (A) requires the monomer (b) represented by the above formula (3).

[0055] The monomer (b) is preferably a (meth)acrylic acid ester, since this provides good adhesion to the substrate. R7 in the formula (3) is preferably COOR. 35 is preferred.

[0056] R in formula (3) 33 ~R 37Examples of the unsubstituted alkyl group include branched or linear alkyl groups having 1 to 22 carbon atoms. Specific examples of branched or linear alkyl groups having 1 to 22 carbon atoms include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl (amyl), i-pentyl, hexyl, heptyl, 2-ethylhexyl, octyl, i-octyl, nonyl, i-nonyl, decyl, i-decyl, undecyl, dodecyl (lauryl), tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl (stearyl), i-octadecyl, nonadecyl, icosyl, and docosyl groups. R 33 ~R 37 The unsubstituted alicyclic group may be monocyclic or polycyclic, and examples thereof include alicyclic groups having 3 to 20 carbon atoms. Specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a bicyclo[2.2.1]heptyl group, a cyclooctyl group, and an adamantyl group. R 33 ~R 37 and R 38 Examples of the unsubstituted aryl group include aryl groups having a carbon number of 6 to 18. Specific examples of the aryl group having a carbon number of 6 to 18 include a phenyl group and a naphthyl group. R 33 ~R 37 and R 38 Examples of the unsubstituted heteroaryl group include heteroaryl groups having 4 to 18 carbon atoms. Specific examples of the heteroaryl group having 4 to 18 carbon atoms include a pyridyl group and a carbazolyl group. R 33 ~R 37Examples of the unsubstituted non-aromatic heterocyclic group include heterocyclic groups having 4 to 18 carbon atoms. Specific examples of the heterocyclic group having 4 to 18 carbon atoms include oxygen atom-containing heterocyclic groups such as a tetrahydrofuryl group, a tetrahydropyranyl group, a γ-butyrolactonyl group, and an ε-caprolactonyl group, and nitrogen atom-containing heterocyclic groups such as a pyrrolidinyl group, a pyrrolidone group, and a morpholino group. R 33 ~R 37 Examples of the unsubstituted aralkyl group include a benzyl group and a phenylethyl group. R 33 ~R 37 Examples of the unsubstituted alkaryl group include a tolyl group and a xylyl group.

[0057] R 33 ~R 37 Examples of the unsubstituted organosilyl group include -SiR 17 R 18 R 19 (where R 17 ~R 19 each independently represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted alicyclic group, and a substituted or unsubstituted aryl group. R 17 ~R 19 Examples of the substituted or unsubstituted alkyl group in include the same as those described above, such as a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-amyl group, an n-hexyl group, an n-octyl group, an n-dodecyl group, a stearyl group, a lauryl group, an isopropyl group, an isobutyl group, an s-butyl group, a 2-methylisopropyl group, and a benzyl group. R 17 ~R 19 The substituted or unsubstituted alicyclic group in the formula (I) includes the same as those described above, such as a cyclohexyl group. R 17 ~R 19 The substituted or unsubstituted aryl group in the formula (I) includes the same as those described above, such as phenyl group, p-methylphenyl, etc. R 17 ~R19 may be the same or different.

[0058] R 33 ~R 38 When each of the above substituents has a substituent, the substituent may be, for example, an alkyl group (where R 33 ~R 37 is an alkyl group having a substituent), an aryl group, -COOR 21 , cyano group, -OR 22 , -NR 23 R 24 , -CONR 25 R 26 , a halogen atom, an allyl group, an epoxy group, a siloxy group, and a group exhibiting hydrophilicity or ionicity. where R 21 ~R 26 each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alicyclic group, or a substituted or unsubstituted aryl group. Examples of the alkyl group and aryl group in the substituent include the same as the unsubstituted alkyl group and unsubstituted aryl group described above.

[0059] Since the polymerization reaction easily proceeds, -COOR in the above substituents 21 R 21 is preferably a hydrogen atom or an unsubstituted alkyl group. 21 is preferably a carboxy group or an alkoxycarbonyl group. Examples of the alkoxycarbonyl group include a methoxycarbonyl group. In addition, since polymerization becomes easy, -OR in the substituent 22 R 22 is preferably a hydrogen atom or an unsubstituted alkyl group. 22 is preferably a hydroxy group or an alkoxy group. Examples of the alkoxy group include alkoxy groups having 1 to 12 carbon atoms, and a specific example is a methoxy group. -NR in the above substituents 23 R 24 Examples of the amino group include an amino group, a monomethylamino group, and a dimethylamino group. -CONR in the above substituents 25 R 26 Examples of the alkyl group include a carbamoyl group (-CONH2), an N-methylcarbamoyl group (-CONHCH3), and an N,N-dimethylcarbamoyl group (dimethylamide group: -CON(CH3)2). Examples of the halogen atom in the substituent include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the hydrophilic or ionic group in the substituent include cationic substituents such as alkali salts of a carboxy group or alkali salts of a sulfo group, poly(alkylene oxide) groups such as polyethylene oxide groups and polypropylene oxide groups, and quaternary ammonium bases.

[0060] Specific examples of the monomer (b) include the following polymerizable monomers. Methyl (meth)acrylate, ethyl (meth)acrylate, n-propyl (meth)acrylate, isopropyl (meth)acrylate, n-butyl (meth)acrylate, isobutyl (meth)acrylate, t-butyl (meth)acrylate, isoamyl (meth)acrylate, hexyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, octyl (meth)acrylate, isooctyl (meth)acrylate, nonyl (meth)acrylate, isononyl (meth)acrylate, decyl (meth)acrylate, isodecyl (meth)acrylate, lauryl (meth)acrylate, hexadecyl (meth)acrylate, (meth) Hydrocarbon group-containing (meth)acrylic acid esters such as stearyl acrylate, isostearyl (meth)acrylate, phenyl (meth)acrylate, benzyl (meth)acrylate, cyclohexyl (meth)acrylate, tetrahydrofurfuryl (meth)acrylate, isobornyl (meth)acrylate, 3,5,5-trimethylcyclohexyl (meth)acrylate, dicyclopentanyl (meth)acrylate, dicyclopentenyl (meth)acrylate, dicyclopentenyloxyethyl (meth)acrylate, terpene acrylate and derivatives thereof, hydrogenated rosin acrylate and derivatives thereof, and docosyl (meth)acrylate; hydroxyl group-containing (meth)acrylic acid esters such as 2-hydroxyethyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, 2-hydroxybutyl (meth)acrylate, 3-hydroxybutyl (meth)acrylate, 4-hydroxybutyl (meth)acrylate, and glycerol (meth)acrylate; (Meth)acrylic acid, 2-(meth)acryloyloxyethyl hexahydrophthalic acid, 2-(meth)acryloyloxypropyl hexahydrophthalic acid, 2-(meth)acryloyloxyethyl phthalic acid, 2-(meth)acryloyloxypropyl phthalic acid, 2-(meth)acryloyloxyethyl maleic acid, 2-(meth)acryloyloxypropyl maleic acid, 2-(meth)acryloyloxyethyl succinic acid, 2-(meth)acrylic acid carboxyl group-containing vinyl monomers such as methyl hydroxypropyl succinate, crotonic acid, fumaric acid, maleic acid, itaconic acid, citraconic acid, monomethyl maleate, monoethyl maleate, monooctyl maleate, monomethyl itaconate, monoethyl itaconate, monobutyl itaconate, monooctyl itaconate, monomethyl fumarate, monoethyl fumarate, monobutyl fumarate, monooctyl fumarate, and monoethyl citraconic acid; Epoxy group-containing vinyl monomers such as glycidyl (meth)acrylate, α-ethyl glycidyl acrylate, and 3,4-epoxybutyl (meth)acrylate; Amino group-containing (meth)acrylic acid ester vinyl monomers such as dimethylaminoethyl (meth)acrylate and diethylaminoethyl (meth)acrylate; vinyl monomers containing an amide group, such as (meth)acrylamide, dimethyl(meth)acrylamide, diethyl(meth)acrylamide, Nt-butyl(meth)acrylamide, N-methylol(meth)acrylamide, N-isopropylacrylamide, hydroxyethylacrylamide, N-methoxymethyl(meth)acrylamide, N-butoxymethyl(meth)acrylamide, and diacetone acrylamide; vinyl monomers such as styrene, α-methylstyrene, vinyltoluene, (meth)acrylonitrile, vinyl chloride, vinyl acetate, and vinyl propionate; Divinylbenzene, ethylene glycol di(meth)acrylate, 1,3-butylene glycol di(meth)acrylate, 1,4-butanediol di(meth)acrylate, 1,6-hexanediol di(meth)acrylate, diethylene glycol di(meth)acrylate, triethylene glycol di(meth)acrylate, tetraethylene glycol di(meth)acrylate, polyethylene glycol di(meth)acrylate, tripropylene glycol di(meth)acrylate, neopentyl glycol polyfunctional vinyl monomers such as diol di(meth)acrylate, 1,9-nonanediol di(meth)acrylate, 1,10-decanediol di(meth)acrylate, trimethylolpropane tri(meth)acrylate, pentaerythritol tetra(meth)acrylate, dipentaerythritol hexa(meth)acrylate, allyl (meth)acrylate, triallyl cyanurate, diallyl maleate, polypropylene glycol diallyl ether, and N,N'-methylenebis(meth)acrylamide; Heterocyclic monomers such as (meth)acryloylmorpholine, vinylpyrrolidone, vinylpyridine, and vinylcarbazole; Polyethylene glycol (meth)acrylate, polypropylene glycol (meth)acrylate, methoxyethyl (meth)acrylate, ethoxyethyl (meth)acrylate, n-butoxyethyl (meth)acrylate, isobutoxyethyl (meth)acrylate, t-butoxyethyl (meth)acrylate, ethoxyethoxyethyl (meth)acrylate, phenoxyethyl (meth)acrylate, nonylphenoxyethyl (meth)acrylate, 3-methoxybutyl (meth)acrylate, acetoxyethyl (meth)acrylate, "Placcel FM" (trade name of caprolactone addition monomer manufactured by Daicel Chemical Industries, Ltd.), "Blemmer PME-100" (trade name of methoxypolyethylene glycol methacrylate (ethylene glycol chain length: 2) manufactured by NOF Corporation), "Blemmer PME-200" (trade name of methoxypolyethylene glycol methacrylate manufactured by NOF Corporation) glycol ester monomers such as acrylate (having 4 ethylene glycol chains), trade name), "BLEMMER PME-400" (manufactured by NOF Corporation, methoxypolyethylene glycol methacrylate (having 9 ethylene glycol chains), trade name), "BLEMMER 50POEP-800B" (manufactured by NOF Corporation, octoxypolyethylene glycol-polypropylene glycol-methacrylate (having 8 ethylene glycol chains and 6 propylene glycol chains), trade name), "BLEMMER 20ANEP-600" (manufactured by NOF Corporation, nonylphenoxy (ethylene glycol-polypropylene glycol) monoacrylate, trade name), "BLEMMER AME-100" (manufactured by NOF Corporation, trade name), "BLEMMER AME-200" (manufactured by NOF Corporation, trade name), and "BLEMMER 50AOEP-800B" (manufactured by NOF Corporation, trade name); halogenated olefins such as vinyl chloride, vinylidene chloride, vinyl fluoride, vinylidene fluoride, and chlorotrifluoroethylene; 2-Isocyanatoethyl (meth)acrylate, 2,2,2-trifluoroethyl (meth)acrylate, 2,2,3,3,3-pentafluorophenyl (meth)acrylate, 2-(perfluorobutyl)ethyl (meth)acrylate, 3-(perfluorobutyl)-2-hydroxypropyl (meth)acrylate, 2-(perfluorohexyl)ethyl (meth)acrylate, 3-perfluorohexyl-2-hydroxypropyl (meth)acrylate, 3-(perfluoro-3-methylbutyl)-2-hydroxypropyl (meth)acrylate, 2,2,3,3-tetrafluoroethylene Fluorine-containing monomers (excluding halogenated olefins), such as trifluoropropyl (meth)acrylate, 1H,1H,5H-octafluoropentyl (meth)acrylate, 1H,1H,5H-octafluoropentyl (meth)methacrylate, 1H,1H,2H,2H-tridecafluorooctyl (meth)acrylate, 1H-1-(trifluoromethyl)trifluoroethyl (meth)acrylate, 1H,1H,3H-hexafluorobutyl (meth)acrylate, and 1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl (meth)acrylate; Monomers with an acetal structure such as 1-butoxyethyl (meth)acrylate, 1-(2-ethylhexyloxy)ethyl (meth)acrylate, 1-(cyclohexyloxy)ethyl methacrylate, and 2-tetrahydropyranyl (meth)acrylate, 4-methacryloyloxybenzophenone, and 2-isocyanatoethyl (meth)acrylate:

[0061] These polymerizable monomers as the monomer (b) may be used singly or in combination of two or more kinds.

[0062] As the polymerizable monomer, in terms of copolymerizability, a (meth)acrylic acid ester is preferred, a hydrocarbon group-containing (meth)acrylic acid ester is more preferred, methyl (meth)acrylate is particularly preferred, and methyl methacrylate is most preferred.

[0063] As the monomer (b) used in producing the macromonomer (A), it is particularly preferable to use a monomer mixture with one or more methacrylic acid esters such as methyl methacrylate and isobornyl methacrylate, from the viewpoint of maintaining the elastic modulus of the coating film.

[0064] <Other Monomers> As the raw material monomers for macromonomer (A), in addition to monomer (a) and / or monomer (a') and monomer (b), one or more other polymerizable monomers such as unsaturated carboxylic acids such as (meth)acrylic acid and / or derivatives thereof can be used depending on the purpose. The unsaturated carboxylic acid and / or its derivatives include, for example, maleic acid and maleic anhydride.

[0065] <Mass Proportion of Structural Units Derived from Monomer (a) and / or Monomer (a') and Structural Units Derived from Monomer (b) in Macromonomer (A)> In order to obtain better adhesion to the substrate, the mass ratio of the structural units derived from monomer (a) and / or monomer (a') to all structural units of macromonomer (A) is preferably 0.5 to 25 mass%, more preferably 1 to 20 mass%, even more preferably 1.5 to 18 mass%, and most preferably 2 to 16 mass%. When the mass ratio of the structural units derived from monomer (a) and / or monomer (a') to all structural units of macromonomer (A) is at least the lower limit, better adhesion to the substrate can be obtained, and when it is at most the upper limit, lower protein adsorption can be maintained. Furthermore, the mass ratio of the structural units derived from monomer (b) to all structural units of macromonomer (A) is preferably 75 to 99.5 mass%, more preferably 80 to 99 mass%, even more preferably 82 to 98.5 mass%, and most preferably 84 to 98 mass%. When the mass ratio of the structural units derived from monomer (b) to all structural units of macromonomer (A) is at least the lower limit, synthesis of the macromonomer is easy, and when it is at most the upper limit, the functions of the structural units derived from monomer (a) and / or monomer (a') can be exhibited.

[0066] Therefore, since substrate adhesion is improved, the content of monomer (a) and / or monomer (a') in the monomer mixture used as the raw material for producing macromonomer (A) is preferably 0.5 to 25 mass%, more preferably 1 to 20 mass%, even more preferably 1.5 to 18 mass%, particularly preferably 2 to 16 mass%, and most preferably 3 to 14 mass%. Furthermore, from the viewpoints of ease of synthesis and handleability of the coating film, the content of monomer (b) is preferably 75 to 99.5 mass%, more preferably 80 to 99 mass%, even more preferably 82 to 98.5 mass%, and most preferably 86 to 97 mass%.

[0067] When a monomer other than the monomer (a) and / or the monomer (a') and the monomer (b), such as an unsaturated carboxylic acid, is used as a raw material monomer for producing the macromonomer (A), the content of the other monomer in the raw material monomer mixture for producing the macromonomer (A) is preferably 10% by mass or less, more preferably 5% by mass or less, from the viewpoint of copolymerizability with the monomer (B).

[0068] As one embodiment of the macromonomer (A) used in the present invention, it is preferable to include a macromonomer (A-1) represented by the following formula (5), since this provides a good balance between substrate adhesion and protein adsorption inhibition performance.

[0069] [ka]

[0070] (In formula (5), R 11 represents a hydrogen atom or a methyl group. 13 , R 14 represents a hydrogen atom, an unsubstituted or substituted alkyl group, an unsubstituted or substituted alicyclic group, an unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group, or an unsubstituted or substituted non-aromatic heterocyclic group. W is a terminal group. X represents NH or O, Y represents a direct bond or a substituted or unsubstituted alkylene group having 1 to 10 carbon atoms, and Z represents a direct bond, a carbonyl group, or an ester group. R12 represents a hydrogen atom or a methyl group. Ar represents an aromatic ring group having at least two hydroxyl groups. m and n each independently represent an integer of 2 to 10,000. When a plurality of Ar, X, Y, Z, and R 11 , R 12 , R 14 may be the same or different.)

[0071] Z in formula (5) is a terminal group of the macromonomer (A-1), and examples of Z include a hydrogen atom, a group derived from a radical polymerization initiator, a radical polymerizable group, and the like, similar to terminal groups of copolymers obtained by known radical polymerization.

[0072] R 13、14 Examples of the unsubstituted or substituted alkyl group, unsubstituted or substituted alicyclic group, unsubstituted or substituted aryl group, unsubstituted or substituted heteroaryl group, or unsubstituted or substituted non-aromatic heterocyclic group include R 33 ~R 37 Examples of the unsubstituted or substituted alkyl group, the unsubstituted or substituted alicyclic group, the unsubstituted or substituted aryl group, the unsubstituted or substituted heteroaryl group, and the unsubstituted or substituted non-aromatic heterocyclic group include those exemplified above.

[0073] R in equation (5) 13、 R 14 From the viewpoint of maintaining hydrophobicity, each of the groups is preferably an alkyl group, an alicyclic group, an aryl group, a heteroaryl group, or a non-aromatic heterocyclic group, more preferably an alkyl group or an alicyclic group, and particularly preferably an alkyl group.

[0074] The content of the macromonomer (A-1) in the macromonomer (A) is preferably 5% by mass or more, particularly preferably 10 to 100% by mass.

[0075] Although the notation of formula (5) may at first glance resemble that of a block copolymer, formula (5) merely indicates a constituent unit of the copolymer, and the macromonomer (A-1) represented by formula (5) is preferably a random copolymer.

[0076] <Molecular weight of macromonomer (A)> The number average molecular weight (Mn) of the macromonomer (A) is preferably 500 or more and 1,00,000 or less. When the Mn of the macromonomer (A) is 500 or more, the solution viscosity of the copolymer of the present invention obtained by copolymerizing the macromonomer (A) and the monomer (B) tends to be low, and the appearance of the coating film formed tends to be good. When the Mn of the macromonomer (A) is 1,000,000 or less, the adhesion between the substrate and the coating film formed using the copolymer of the present invention obtained by copolymerizing the macromonomer (A) and the monomer (B) tends to be good. The lower limit of Mn of the macromonomer (A) is more preferably at least 1,000, and even more preferably at least 5,000. The upper limit of Mn of the macromonomer (A) is more preferably at most 80,000, and even more preferably at most 50,000.

[0077] The molecular weight distribution (weight average molecular weight (Mw) / number average molecular weight (Mn)) of the macromonomer (A) is preferably 1.1 or more and 10 or less. When the Mw / Mn of the macromonomer (A) is 1.1 or more and 10.0 or less, the copolymer of the present invention having an unsaturated bond introduced at the terminal by copolymerization with the monomer (B) tends to be obtained. The lower limit of Mw / Mn of the macromonomer (A) is more preferably 1.2 or more, and even more preferably 1.5 or more, and the upper limit of Mw / Mn of the macromonomer (A) is more preferably 9.0 or less, and even more preferably 6.0 or less.

[0078] The Mw and Mn of the macromonomer (A) are measured by the method described in the Examples section below.

[0079] <Method for producing macromonomer (A)> Examples of methods for producing the macromonomer (A) include a method using a cobalt chain transfer agent (U.S. Pat. No. 4,680,352), a method using an α-substituted unsaturated compound such as α-bromomethylstyrene as a chain transfer agent (WO 1988 / 04304), a method of chemically bonding a polymerizable group (JP-A No. 60-133007 and U.S. Pat. No. 5,147,952), and a method using thermal decomposition (JP-A No. 11-240854). Among these, the method for producing the macromonomer (A) is preferably a method using a cobalt chain transfer agent, since it requires fewer production steps and uses a catalyst with a high chain transfer constant. Examples of methods for producing the macromonomer (A) using a cobalt chain transfer agent include aqueous dispersion polymerization methods such as bulk polymerization, solution polymerization, suspension polymerization, and emulsion polymerization. Among these, the solution polymerization method is preferred from the viewpoint of the introduction of various monomers into the macromonomer (A).

[0080] Examples of solvents used when obtaining macromonomer (A) by solution polymerization include hydrocarbons such as toluene, ethers such as diethyl ether and tetrahydrofuran, glycol ethers such as methyl cellosolve, halogenated hydrocarbons such as dichloromethane and chloroform, ketones such as acetone, alcohols such as methanol, nitriles such as acetonitrile, vinyl esters such as ethyl acetate, carbonates such as ethylene carbonate, and supercritical carbon dioxide. These may be used alone or in combination of two or more.

[0081] For the production of the copolymer of the present invention, the macromonomer (A) produced in this manner may be recovered and purified and used as a powder, or a suspension of the macromonomer (A) synthesized by suspension polymerization may be used as is.

[0082] In producing the copolymer of the present invention, one type of macromonomer (A) may be used alone, or two or more types may be used in combination.

[0083] [Monomer (B)] The copolymer of the present invention is required to contain a structural unit derived from the monomer (B) represented by the above formula (4). When the copolymer of the present invention contains a structural unit derived from the monomer (B) represented by the following formula (4), adhesion of proteins to the copolymer is particularly suppressed.

[0084] In the formula (4), R8 represents a hydrogen atom or a methyl group, R9 represents an alkylene group or an oxyethylene group having 1 to 4 carbon atoms, and R 10 represents a hydrocarbon group having 1 to 6 carbon atoms. R 10 Examples of the hydrocarbon group having 1 to 6 carbon atoms include a linear alkyl group, a branched alkyl group, and an alkenyl group having 1 to 6 carbon atoms.

[0085] Specific examples of the monomer (B) include methoxymethyl acrylate, methoxyethyl acrylate, methoxypropyl acrylate, methoxybutyl acrylate, ethoxymethyl acrylate, ethoxyethyl acrylate, ethoxypropyl acrylate, ethoxybutyl acrylate, propoxymethyl acrylate, propoxyethyl acrylate, propoxypropyl acrylate, propoxybutyl acrylate, butoxymethyl acrylate, butoxyethyl acrylate, butoxypropyl acrylate, butoxybutyl acrylate, methoxymethyl methacrylate, methoxyethyl methacrylate, methoxypropyl acrylate, methoxybutyl methacrylate, and ethoxymethyl methacrylate. methacrylate, ethoxyethyl methacrylate, ethoxypropyl methacrylate, ethoxybutyl methacrylate, propoxymethyl methacrylate, propoxyethyl methacrylate, propoxypropyl methacrylate, propoxybutyl methacrylate, butoxymethyl methacrylate, butoxyethyl methacrylate, butoxypropyl methacrylate, butoxybutyl methacrylate, "BLEMMER PME-100" (methoxypolyethylene glycol methacrylate (having two ethylene glycol chains), product name, manufactured by NOF Corporation), and "BLEMMER PME-200" (methoxypolyethylene glycol methacrylate (having four ethylene glycol chains), product name, manufactured by NOF Corporation).

[0086] Among these, from the viewpoint of inhibiting protein adhesion, methoxyalkyl (meth)acrylates such as methoxymethyl acrylate, methoxyethyl acrylate, methoxypropyl acrylate, methoxybutyl acrylate, methoxymethyl methacrylate, methoxyethyl methacrylate, methoxypropyl methacrylate, and methoxybutyl methacrylate are preferred, methoxyethyl acrylate and methoxyethyl methacrylate are more preferred, and acrylic acid esters such as 2-methoxyethyl acrylate are particularly preferred.

[0087] The monomer (B) may be used alone or in combination of two or more.

[0088] [Copolymer] <Method of producing copolymer> The method for producing the copolymer of the present invention is not particularly limited, and various methods can be used, such as solution polymerization, suspension polymerization, emulsion polymerization, bulk polymerization, etc. Solution polymerization is preferred in terms of copolymer productivity and coating film performance of a coating film formed using the obtained copolymer. An example of a method for producing the copolymer of the present invention by solution polymerization will be shown below, but the method for producing the copolymer of the present invention is not limited to the following method.

[0089] In solution polymerization, the macromonomer (A) and the monomer (B) produced by the above-mentioned method are used as raw material monomers in a predetermined ratio, and these are dissolved in a solvent to prepare a monomer composition, to which a radical polymerization initiator is added to carry out polymerization. The polymerization can be carried out by a known method using a known radical polymerization initiator. For example, the raw material monomers of the macromonomer (A) and the monomer (B) produced by the above-mentioned method are reacted in the presence of a radical initiator in an inert atmosphere at a reaction temperature of 60 to 120°C for 2 to 14 hours. During the polymerization, a chain transfer agent may be used as needed.

[0090] As the solvent used in the solution polymerization, for example, a general organic solvent such as toluene, xylene, methyl cellosolve, propylene glycol monomethyl ether acetate, methyl isobutyl ketone, ethyl acetate, n-butyl acetate, or ethyl 3-ethoxypropionate can be used.

[0091] As the radical polymerization initiator, known ones can be used, and examples thereof include azo compounds such as 2,2-azobisisobutyronitrile, 2,2-azobis(2,4-dimethylvaleronitrile), and 2,2-azobis(2-methylbutyronitrile); and organic peroxides such as benzoyl peroxide, cumene hydroperoxide, lauryl peroxide, di-t-butyl peroxide, t-butylperoxy-2-ethylhexanoate, and 1,1,3,3-tetramethylbutylperoxy-2-ethylhexanoate.

[0092] As the chain transfer agent, known agents can be used, and examples thereof include mercaptans such as n-dodecyl mercaptan, thioglycolic acid esters such as octyl thioglycolate, α-methylstyrene dimer, and terpinolene.

[0093] <Molecular weight of copolymer> The weight average molecular weight (Mw) of the copolymer of the present invention is preferably 10,000 or more and 500,000 or less. When the Mw of the copolymer is 10,000 or more, the adhesion of the formed coating film to the substrate is good. When the Mw of the copolymer is 500,000 or less, the coatability of the copolymer is good. The lower limit of the Mw of the copolymer is more preferably 15,000 or more, and even more preferably 20,000 or more. Furthermore, the upper limit of the Mw of the copolymer is more preferably 400,000 or less, and even more preferably 300,000 or less.

[0094] The molecular weight distribution (Mw / Mn) of the copolymer of the present invention is preferably from 1.5 to 15, more preferably from 1.8 to 10. When Mw / Mn is within the above range, the coating film performance is good.

[0095] Here, the Mw and Mn of the copolymer are measured by the method described in the Examples section below.

[0096] <Content of each constituent unit> The copolymer of the present invention preferably contains 20 to 80 mass% of structural units derived from macromonomer (A) and 20 to 80 mass% of structural units derived from monomer (B), and preferably contains 0.1 to 25 mass% of structural units derived from monomer (a) and / or monomer (a').

[0097] The macromonomer (A) is intended to impart to the copolymer of the present invention the functions of substrate adhesion and maintaining elastic modulus, and if the proportion of structural units derived from macromonomer (A) contained in the copolymer of the present invention is at least the above-mentioned lower limit, the elastic modulus can be maintained, and if it is at most the above-mentioned upper limit, the functions of the copolymerization components are not impaired. The mass proportion of structural units derived from macromonomer (A) in the copolymer of the present invention is more preferably 10 to 80 mass%, and even more preferably 25 to 75 mass%.

[0098] Monomer (B) is used to impart the function of inhibiting protein adhesion to the copolymer of the present invention, and when the proportion of structural units derived from monomer (B) contained in the copolymer of the present invention is equal to or greater than the above-mentioned lower limit, the copolymer has excellent low protein adhesion properties, while when it is equal to or less than the above-mentioned upper limit, the function of the structural units derived from macromonomer (A) is not impaired. The mass proportion of structural units derived from monomer (B) in the copolymer of the present invention is more preferably 20 to 90 mass%, and even more preferably 25 to 75 mass%.

[0099] The constituent units derived from monomer (a) and / or monomer (a') are intended to impart substrate adhesion properties to the copolymer of the present invention, and when the proportion of constituent units derived from monomer (a) and / or monomer (a') contained in the copolymer of the present invention is equal to or greater than the above-mentioned lower limit, the substrate adhesion is good, while when it is equal to or less than the above-mentioned upper limit, the substrate adhesion to the coating film is maintained while good low protein adhesion properties can be achieved. The mass proportion of constituent units derived from monomer (a) and / or monomer (a') in the copolymer of the present invention is more preferably 0.5 to 20 mass%. The copolymer of the present invention may be a polymer consisting only of structural units derived from the monomer (B), or may contain at least one monomer selected from the group consisting of unreacted monomer (B), monomer (a), monomer (a'), and monomer (b) remaining in the production of the macromonomer (A).

[0100] The copolymer of the present invention may have structural units derived from other monomers other than the structural units derived from macromonomer (A) and the structural units derived from monomer (B). In order to more effectively obtain the effects of the copolymer of the present invention, which is composed of structural units derived from macromonomer (A) and structural units derived from monomer (B), the mass proportion of structural units derived from other monomers other than the structural units derived from macromonomer (A) and the structural units derived from monomer (B) relative to all structural units of the copolymer of the present invention is preferably 20 mass% or less, and more preferably 10 mass% or less.

[0101] [Coating agent] The copolymer of the present invention can be used as a coating agent, and is particularly preferably used as a medical coating agent because of its excellent compatibility with living bodies.

[0102] The coating agent of the present invention contains the copolymer of the present invention, and is used by mixing, dispersing, or dissolving the copolymer of the present invention in a solvent as needed. The coating agent of the present invention may contain only one type of copolymer of the present invention, or may contain two or more types of copolymers of the present invention. The solvent used in the coating agent is water, an organic solvent, or a mixture thereof. The type of solvent used and the concentration of the copolymer of the present invention vary depending on the composition and molecular weight of the copolymer of the present invention, the type of substrate to be coated, its surface properties, etc., and can be appropriately selected. Usually, the concentration of the copolymer of the present invention in the coating agent of the present invention is about 0.1 to 95% by mass.

[0103] The coating agent of the present invention may contain other components, such as those exemplified below, in addition to the copolymer of the present invention and the solvent. The content of the other components is not particularly limited as long as it is within a range that does not impair the effects of the present invention. Typically, the content of the other components is preferably 0 to 20% by mass, and more preferably 0.1 to 5% by mass, relative to the total mass (100% by mass) of the coating agent of the present invention.

[0104] Other components may be added to the coating agent as needed. Examples of other components include release agents, antioxidants, heat stabilizers, impact modifiers, flexibility imparting agents, weather resistance modifiers, colorants, inorganic pigments, organic pigments, carbon black, ferrite, conductivity imparting agents, ultraviolet absorbers, infrared absorbers, lubricants, inorganic fillers, reinforcing agents, plasticizers, antiplasticizers, neutralizing agents, crosslinking agents, flame retardants, preservatives, insect repellents, fragrances, radical scavengers, sound absorbing materials, and core-shell rubber.

[0105] [Medical devices] The coating agent of the present invention is preferably applied to at least one surface of a substrate described below to form a coating film, and used as a medical device.

[0106] [Base material] The substrate of the medical device to be coated is not particularly limited, and a wide variety of materials can be used, including, for example, polyvinyl chloride, polycarbonate, polyethylene terephthalate, polyethylene, polypropylene, polymethylpentene, thermoplastic polyurethane, thermosetting polyurethane, polyamide, polyether, block amide, nylon, silicone rubber such as crosslinked polydimethylsiloxane, polymethyl methacrylate, polyvinylidene fluoride, tetrafluoroethylene, polysulfone, polyethersulfone, polyacetal, polystyrene, ABS, and other resins and mixtures of these resins; metals such as stainless steel, titanium, and aluminum, and their alloys; glass; and ceramics.

[0107] [Shape of substrate] The shape of the substrate may be any shape or form such as a plate, sheet, straw, pipe, fiber, sphere, nonwoven fabric, porous material, or the like. The coating agent of the present invention can form a uniform coating film with good adhesion on these substrates.

[0108] [Coating film manufacturing method] There are no particular limitations on the manufacturing method for coating the coating agent of the present invention onto a substrate such as the medical device to obtain a coating film. Specific examples of coating methods include an immersion method in which a substrate is immersed in a coating agent for a long period of time; a method in which the substrate is sprayed with a spray; a method in which the substrate is applied with a brush or with flocking; and a method in which the substrate is brought into contact with a solution in which the coating agent is dissolved. Among these methods, the method of bringing the substrate into contact with a solution of the coating agent is preferred because it is easy to control the coating film that is formed. The coating may be performed once or multiple times. When multiple coatings are performed, different coating methods or coating agents containing different copolymers may be used.

[0109] [Coating film shape] The thickness of the coating film formed by the coating agent of the present invention varies depending on the application of the object to be coated, such as a medical device, the film formation method, etc., but is usually about 0.1 to 200 μm. If the thickness is 0.1 μm or more, the performance of the coating film can be maintained, and if it is 200 μm or less, excellent productivity can be achieved. After the coating film is formed, the medical device may be used as is, or may be used after priming with physiological saline or the like.

[0110] [Medical device use] The medical device of the present invention is particularly suitable for use in direct contact with blood, biopharmaceuticals, living organisms, and protein preparations, etc., since it has a coating film made of the copolymer of the present invention, which has excellent biocompatibility such as protein adhesion inhibitory properties, formed with good adhesion to the substrate.

[0111] Specific examples of the medical devices of the present invention include catheters (catheters, balloons of balloon catheters, guide wires, etc.), artificial blood vessels, vascular bypass tubes, artificial valves, blood filters, plasma separation devices, artificial organs (artificial lungs, artificial kidneys, artificial hearts, etc.), blood transfusion equipment, extracorporeal blood circulation circuits, blood bags, anti-adhesion membranes, wound dressings, scalpels, tweezers, contact lenses, cannulas, catheters, syringes, syringe needles, intravenous lines, intravenous needles, intravenous bags, blood bags, gauze, stents, endoscopes, and other medical instruments; biochemical instruments such as pipette tips, petri dishes, cells, microplates, storage bags, plates, reagent storage containers, and tubes; cell therapy devices such as mixers, bioreactors, and jar fermenters; and cell therapy devices such as cell therapy devices. Examples of suitable products include culture dishes, cell culture cells, cell culture microplates, cell culture bags, cell culture plates, cell culture tubes, cell culture flasks, biopharmaceutical dishes, biopharmaceutical cells, biopharmaceutical microplates, biopharmaceutical plates, biopharmaceutical tubes, biopharmaceutical bags, biopharmaceutical containers, biopharmaceutical syringes, biopharmaceutical flasks, antibody pharmaceutical dishes, antibody pharmaceutical cells, antibody pharmaceutical microplates, antibody pharmaceutical plates, antibody pharmaceutical tubes, antibody pharmaceutical bags, antibody pharmaceutical containers, antibody pharmaceutical syringes, antibody pharmaceutical flasks, blood bags (whole blood, plasma, platelets, red blood cells), blood product vials, and blood product bags. [Example]

[0112] The present invention will be described in more detail below with reference to examples and comparative examples, but the present invention is not limited to these examples. In the following examples and comparative examples, "parts" means "parts by mass."

[0113] [Measurement and evaluation methods] The evaluations in the examples and comparative examples were carried out by the following methods.

[0114] <Weight average molecular weight (Mw) / Number average molecular weight (Mn)> Measurement was carried out using gel permeation chromatography (GPC) (HLC-8220, manufactured by Tosoh Corporation). 10 mg of the obtained macromonomer or copolymer was dissolved in 20 mL of dimethylformamide, and the solution was filtered through a 0.45 μm filter to prepare a sample for GPC measurement. A polymer measurement guard column (manufactured by Tosoh Corporation, trade name: TSKguardcolumn α) and two polymer measurement columns (manufactured by Tosoh Corporation, trade name: TSKgel α-M) were used, connected in series. A calibration curve was prepared using polystyrenes with known molecular weights (F288 / F1 / 28 / F80 / F40 / F20 / F2 / A1000 (manufactured by Tosoh Corporation, trade name: TSKgel standard polystyrene) as standard polymers, and Mw and Mn were determined.

[0115] <Protein adhesion test> The fibrinogen (Fib) concentration and the sensor area (4.8 cm) were measured using a quartz crystal microbalance (QCM) device (AFFNIX Q8, ULVAC, Inc.). 2 ) adsorption amount (ng / cm 2 ) and correlation was calculated. The sensor chip was cleaned using an electrodeless excimer 172 nm irradiation device (model number: MDIRH-M-1-330, manufactured by MDCOM Co., Ltd.) The device was set so that the sensor chip surface was within the treatment range, and treatment was carried out 20 times at 5 mm / sec in automatic transport mode, cleaning the sensor chip surface and making it hydrophilic. The copolymer to be tested was dissolved in methyl cellosolve as a solvent to prepare a copolymer solution with a copolymer concentration of 0.1 to 0.5 mass %. The copolymer solution was spin-coated onto an excimer-treated sensor chip so that the amount of copolymer applied per unit area was 20.7 ng to 62 ng, and the chip was dried at 80°C for 15 minutes to immobilize the copolymer on the sensor chip. Fibrinogen (derived from human plasma) was dissolved in phosphate buffer (99.0435% by mass of water, 0.9% by mass of sodium chloride, 0.0421% by mass of disodium hydrogen phosphate, 0.0144% by mass of potassium dihydrogen phosphate, pH 7.1 to 7.3) to a predetermined concentration to prepare a test solution. The fibrinogen concentration in the test solution was 1000 (unit: ppm by mass). The surface of the sensor chip was immersed in the phosphate buffer solution for 12 hours or more to stabilize it, and then the sensor was placed in the quartz crystal microbalance device again in the specified amount of phosphate buffer solution, and measurement of the oscillation frequency was initiated. After the oscillation frequency was stabilized for about 30 minutes to 1 hour, the test solution was added dropwise every 15 minutes. The amount of each drop was 0.5 to 1.0 μL. The amount of fibrinogen adsorbed to the sensor was calculated from the measurement data of the transmission frequency. Analysis software (AQUA, manufactured by ULVAC, Inc.) was used to analyze the measurement data. From the graph showing the correlation between the fibrinogen concentration in the system into which the test liquid was dropped and the amount of adsorption to the sensor, the sensor area (4.8 mm) at a fibrinogen concentration of 34 ppm (by mass) was calculated. 2 Fibrinogen adhesion amount per 1000μg (unit: ng / cm 2 ) was sought.

[0116] <Substrate adhesion evaluation> A methyl cellosolve solution containing 2% copolymer by mass was prepared and applied to a glass substrate using a bar coater. After coating, the substrate was air-dried for 30 minutes and then dried in a dryer at 80°C for 15 minutes to form a dry coating film with a thickness of approximately 0.5 μm. The dried coating film was scored in a grid pattern with a cutter, immersed in a phosphate buffer solution for 24 hours, and then washed with pure water for 5 seconds. If the coating film did not peel off from the glass substrate, it was evaluated as having good substrate adhesion (◯), if only a portion of the film peeled off, it was evaluated as having slightly poor substrate adhesion (△), and if the film peeled off completely, it was evaluated as having poor substrate adhesion (×).

[0117] [Production Example 1: Synthesis of Dispersant (1)] A 1,200 L reaction vessel equipped with a stirrer, a condenser, and a thermometer was charged with 61.6 parts of a 17% by mass aqueous potassium hydroxide solution, 19.1 parts of Acryester M (MMA, trade name, manufactured by Mitsubishi Chemical Corporation), and 19.3 parts of deionized water. The liquid in the reaction vessel was then stirred at room temperature, and after an exothermic peak was confirmed, the mixture was further stirred for 4 hours. Thereafter, the reaction liquid in the reaction vessel was cooled to room temperature to obtain an aqueous potassium methacrylate solution. Next, 900 parts of deionized water, 60 parts of Acryester SEM-Na (2-sulfoethyl sodium methacrylate, product name, manufactured by Mitsubishi Chemical Corporation), 10 parts of the potassium methacrylate aqueous solution, and 12 parts of Acryester M (Mitsubishi Chemical Corporation, product name, MMA) were placed in a 1,050 L reaction vessel equipped with a stirrer, a condenser, and a thermometer, and the contents were stirred. The atmosphere inside the polymerization reactor was replaced with nitrogen, and the temperature was raised to 50°C. 0.08 parts of V-50 (2,2'-azobis(2-methylpropionamidine) dihydrochloride, product name, manufactured by Wako Pure Chemical Industries, Ltd.) was added as a polymerization initiator, and the temperature was further raised to 60°C. After the temperature was raised, Acryester M (Mitsubishi Chemical Corporation, product name, MMA) was continuously added dropwise at a rate of 0.24 parts / min for 75 minutes using a dropping pump. The reaction solution was kept at 60°C for 6 hours and then cooled to room temperature to obtain a dispersant (1) in the form of a transparent aqueous solution with a solid content of 10 mass%.

[0118] [Production Example 2: Synthesis of Co complex (1)] In a synthesis apparatus equipped with a stirrer, 2.00 g (8.03 mmol) of cobalt (II) acetate tetrahydrate (Wako Pure Chemical Industries, Ltd., Wako Special Grade), 3.86 g (16.1 mmol) of diphenylglyoxime (Tokyo Chemical Industry Co., Ltd., EP Grade), and 100 mL of diethyl ether that had been deoxygenated in advance by nitrogen bubbling were placed under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. Next, 20 mL of boron trifluoride diethyl ether complex (manufactured by Tokyo Chemical Industry Co., Ltd., EP grade) was added, and the mixture was further stirred for 6 hours. The obtained mixture was filtered, and the filtered solid was washed with diethyl ether and dried at 20°C under 100 kPa or less for 12 hours to obtain 5.02 g (7.93 mmol, yield 99% by mass) of Co complex (1) as a brown solid.

[0119] [Production Example 3: Synthesis of Macromonomer (MM-1)] A monomer composition containing 95 parts of methyl methacrylate (MMA) (manufactured by Mitsubishi Chemical Corporation) as monomer (b), 5 parts of N-[2-[3,4-dihydroxyphenyl]ethyl]acrylamide (DOPA) (manufactured by Osaka Organic Chemicals) as monomer (a), 0.0005 parts of the Co complex (1) produced in Production Example 2, and 150 parts of methyl cellosolve (Wako Pure Chemical Industries, Ltd.) as a solvent was added to a flask, and the inside was purged with nitrogen by nitrogen bubbling. Next, the monomer composition was heated and the internal temperature was maintained at 80°C. 0.4 parts of 2,2'-azobisisobutyronitrile (AIBN) (manufactured by Wako Pure Chemical Industries, Ltd., Wako Special Grade) was added as a radical polymerization initiator to the monomer composition, and the mixture was maintained for 5 hours to complete the polymerization. The resulting polymerization solution was added dropwise to diisopropyl ether, and the precipitate was collected. The collected copolymer was dried at 70°C for 24 hours to obtain a macromonomer (MM-1). The obtained macromonomer (MM-1) had a mass ratio of MMA structural units / DOPA structural units of 95 / 5, a weight-average molecular weight (Mw) of 38,900, a number-average molecular weight (Mn) of 18,400, and a molecular weight distribution (Mw / Mn) of 2.1.

[0120] [Production Example 4: Synthesis of Macromonomer (MM-2)] A monomer composition containing 94 parts of MMA as monomer (b), 6 parts of 3-trimethoxysilylpropyl methacrylate (hereinafter abbreviated as "SiO") (Tokyo Chemical Industry Co., Ltd.) as monomer (a), 0.0005 parts of the Co complex (1) produced in Production Example 2, and 150 parts of methyl cellosolve (Wako Pure Chemical Industries, Ltd.) as a solvent was added to a flask, and the inside was purged with nitrogen by nitrogen bubbling. Next, the monomer composition was heated and the internal temperature was maintained at 80°C. 0.4 parts of 2,2'-azobisisobutyronitrile (AIBN) (Wako Pure Chemical Industries, Ltd., Wako Special Grade) was added as a radical polymerization initiator to the monomer composition, and the mixture was maintained for 5 hours to complete the polymerization. The resulting polymerization solution was added dropwise to diisopropyl ether, and the precipitate was collected. The collected copolymer was dried at 70°C for 24 hours to obtain a macromonomer (MM-2). The obtained macromonomer (MM-2) had a mass ratio of MMA structural units / SiO structural units of 94 / 6, a weight average molecular weight (Mw) of 26,100, a number average molecular weight (Mn) of 12,800, and a molecular weight distribution (Mw / Mn) of 2.03.

[0121] [Production Example 5: Synthesis of Macromonomer (MM-3)] A polymerization apparatus equipped with a stirrer, a condenser, and a thermometer was charged with 145 parts of deionized water, 0.1 parts of sodium sulfate (NaSO), and 0.26 parts of the dispersant (1) (solids content 10% by mass) produced in Production Example 1, and the mixture was stirred to form a uniform aqueous solution. Next, 95 parts of methyl methacrylate (MMA), 5 parts of methyl acrylate (MA) (Mitsubishi Chemical Corporation, trade name: Methyl Acrylate), 0.0016 parts of the Co complex (1) produced in Production Example 2, and 0.1 parts of Perocta O (NOF Corporation, trade name: 1,1,3,3-tetramethylbutylperoxy 2-ethylhexanoate) were added as a polymerization initiator to form an aqueous dispersion. The atmosphere inside the polymerization apparatus was then thoroughly purged with nitrogen, and the aqueous dispersion was heated to 80°C and maintained there for 4 hours, then heated to 92°C and maintained there for 2 hours. The reaction mixture was then cooled to 40°C to obtain an aqueous suspension of the macromonomer. This aqueous suspension was filtered through a filter cloth, and the filtered product was washed with deionized water and dried at 40° C. for 16 hours to obtain a macromonomer (MM-3). The obtained macromonomer (MM-3) had a mass ratio of MMA structural units / MA structural units of 95 / 5, a weight average molecular weight (Mw) of 34,500, a number average molecular weight (Mn) of 15,000, and a molecular weight distribution (Mw / Mn) of 2.3.

[0122] Table 1 shows the monomer compositions of the macromonomers (MM-1) to (MM-3).

[0123] [Table 1]

[0124] [Example 1: Synthesis of copolymer (X1)] A monomer composition containing 50 parts of the macromonomer (MM-1) produced in Production Example 3, 50 parts of 2-methoxyethyl acrylate (hereinafter abbreviated as "MEA") (manufactured by Osaka Organic Chemicals) as the monomer (B), and 230 parts of methyl cellosolve (manufactured by Wako Pure Chemical Industries, Ltd.) as the solvent was added to a flask, and the inside was purged with nitrogen by nitrogen bubbling. Next, the monomer composition was heated and the internal temperature was maintained at 80°C. 0.2 parts of 2,2'-azobisisobutyronitrile (AIBN) (manufactured by Wako Pure Chemical Industries, Ltd., Wako Special Grade) was added as a radical polymerization initiator to the monomer composition, and the mixture was maintained for 5 hours to complete the polymerization. The resulting polymerization solution was added dropwise to diisopropyl ether, and the precipitate was collected. The collected copolymer was dried at 70°C for 24 hours to obtain the copolymer (X1) of the present invention. The resulting copolymer (X1) had an Mw of 87,900 and an Mn of 30,000.

[0125] [Example 2: Synthesis of copolymer (X2)] The same procedure as in Example 1 was repeated, except that the macromonomer (MM-2) produced in Production Example 4 was used instead of the macromonomer (MM-1). The resulting copolymer (X2) had an Mw of 76,700 and an Mn of 26,200.

[0126] [Comparative Example 1: Synthesis of Comparative Copolymer (x1)] Comparative copolymer (x1) was produced in the same manner as in Example 1, except that the macromonomer (MM-3) synthesized in Preparation Example 5 was used instead of macromonomer (MM-1). The Mw and Mn of comparative copolymer (x1) were as shown in Table 2.

[0127] [Comparative Example 2: Synthesis of Comparative Copolymer (x2)] A monomer composition containing 47 parts of the macromonomer (MM-3) produced in Production Example 5, 50 parts of 2-methoxyethyl acrylate (MEA) (Osaka Organic Chemicals), 3 parts of N-[2-[3,4-dihydroxyphenyl]ethyl]acrylamide (DOPA) (Osaka Organic Chemicals), and 230 parts of methyl cellosolve (Wako Pure Chemical Industries, Ltd.) as a solvent was charged into a flask, and the inside was purged with nitrogen by nitrogen bubbling. Next, the monomer composition was heated and the internal temperature was maintained at 80°C. 0.2 parts of 2,2'-azobisisobutyronitrile (AIBN) (Wako Pure Chemicals, Wako Special Grade) was added as a radical polymerization initiator to the monomer composition, and the mixture was maintained for 5 hours to complete the polymerization. The resulting polymerization solution was added dropwise to diisopropyl ether, and the precipitate was collected. The collected copolymer was dried at 70° C. for 24 hours to obtain a comparative copolymer (x2). The Mw and Mn of the obtained comparative copolymer (x2) are shown in Table 2.

[0128] [Comparative Example 3: Synthesis of Comparative Polymer (x3)] A monomer composition containing 100 parts of 2-methoxyethyl acrylate (MEA) (Osaka Organic Chemicals) and 400 parts of dioxane (Wako Pure Chemical Industries, Ltd.) as a solvent was charged into a flask, and the inside was replaced with nitrogen by nitrogen bubbling. Next, the monomer composition was heated and the internal temperature was maintained at 75°C, and 0.1 parts of 2,2'-azobisisobutyronitrile (AIBN) (Wako Pure Chemical Industries, Ltd., Wako Special Grade) as a radical polymerization initiator was added to the monomer composition, and the mixture was maintained for 6 hours to complete the polymerization. The resulting polymerization solution was added dropwise to hexane, and the precipitated polymer was collected. The collected polymer was stirred in pure water for 24 hours, and the remaining polymer was collected and dried at 70°C for 24 hours to obtain a comparative polymer (x3). The Mw and Mn of the comparative polymer (x3) obtained were as shown in Table 2.

[0129] [Comparative Example 4: Synthesis of Comparative Copolymer (x4)] A monomer composition containing 50 parts of 2-methoxyethyl acrylate (MEA) (Osaka Organic Chemicals), 47 parts of methyl methacrylate (MMA), 3 parts of 3-trimethoxysilylpropyl methacrylate (SiO) (Tokyo Chemical Industry Co., Ltd.), and 230 parts of butyl acetate (Fujifilm Wako Pure Chemical Industries, Ltd.) as a solvent was charged into a flask, and the inside was purged with nitrogen by nitrogen bubbling. Next, the monomer composition was heated and the internal temperature was maintained at 80°C. 0.1 parts of 2,2'-azobisisobutyronitrile (AIBN) (Wako Pure Chemical Industries, Wako Special Grade) was added as a radical polymerization initiator to the monomer composition, and the mixture was maintained for 6 hours to complete the polymerization. The resulting polymerization solution was added dropwise to hexane, and the precipitated copolymer was collected. The collected copolymer was stirred in pure water for 24 hours, and the remaining copolymer was collected and dried at 70°C for 24 hours to obtain comparative copolymer (x4). The Mw and Mn of the comparative copolymer (x4) obtained were as shown in Table 2.

[0130] The results of the protein adhesion test and the substrate adhesion evaluation for the copolymers (X1) to (X2) of the present invention obtained in Examples 1 and 2 and the comparative (co)polymers (x1) to (x4) obtained in Comparative Examples 1 to 4 are shown in Table 2, along with the monomer composition, Mw, and Mn of each.

[0131] [Table 2]

[0132] From Table 2, it can be seen that the copolymer (X1) of the present invention can form a coating film that is excellent in protein adhesion suppression effect and substrate adhesion. In contrast, Comparative Example 1, which did not use the monomer (a) or the monomer (a'), and Comparative Example 3, which used an MEA homopolymer, exhibited poor substrate adhesion. Comparative Example 3 was also poor in the protein adhesion inhibitory effect. Although monomer (a) was used, Comparative Example 2, in which this was not introduced into the macromonomer, exhibited poor protein adhesion inhibitory effects. Comparative Example 4, which used a copolymer not having a structural unit derived from macromonomer (A), exhibited poor protein adhesion inhibitory effect and poor substrate adhesion. [Industrial Applicability]

[0133] The medical device of the present invention, which has a coating film formed by coating a substrate with a medical coating agent containing the copolymer of the present invention, has excellent adhesion between the substrate and the coating film and also has excellent biocompatibility, and therefore the copolymer, medical coating agent, and medical device of the present invention are useful for various devices used in the medical field.

Claims

1. A structural unit derived from a macromonomer (A), A copolymer containing a structural unit derived from a monomer (B) represented by the following formula (4): A copolymer, wherein the macromonomer (A) contains a structural unit derived from a monomer (a) represented by the following formula (1) and / or a monomer (a') represented by the following formula (2), and a structural unit derived from a monomer (b) represented by the following formula (3): 【Chemical 1】 (In formula (1), X represents NH or O, Y represents a direct bond or a substituted or unsubstituted alkylene group having 1 to 10 carbon atoms, and Z represents a direct bond, a carbonyl group, or an ester group. R １ represents a hydrogen atom or a methyl group; and Ar represents an aromatic ring group having at least two hydroxyl groups. 【Chemistry 2】 (In formula (2), R ２ represents a hydrogen atom or a methyl group, X' represents a direct bond, an ester bond or an amide bond, and Y represents a direct bond or a substituted or unsubstituted alkylene group having 1 to 10 carbon atoms. ３ ~R ５ each independently represents a hydrogen atom or an alkyl or alkoxy group having 4 or less carbon atoms. 【Chemistry 3】 (In formula (3), R ６ represents a hydrogen atom or a methyl group. ７ is OR ３３ , halogen atom, COR ３４ , COOR ３５ , C.N., C.O.R. ３６ R ３７ or R ３８ and R ３３ ~R ３７ each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alicyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted alkaryl group, or a substituted or unsubstituted organosilyl group; R ３８ represents a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. 【Chemistry 4】 (In formula (4), R ８ represents a hydrogen atom or a methyl group, R ９ represents an alkylene group or an oxyethylene group having 1 to 4 carbon atoms, and R １０ represents a hydrocarbon group having 1 to 6 carbon atoms.

2. The copolymer of claim 1 comprising a block copolymer and / or a graft copolymer.

3. The copolymer according to claim 2 , comprising a graft copolymer containing a structural unit derived from the macromonomer (A) in a side chain of the monomer (B).

4. 2. The copolymer according to claim 1, wherein the content of the structural units derived from the monomer (a) and / or the monomer (a') is 0.5% by mass or more and 25% by mass or less, relative to 100% by mass of the total mass of the structural units derived from the macromonomer (A).

5. The copolymer according to claim 1, comprising 75% by mass or more and 99.5% by mass or less of structural units derived from methyl methacrylate, relative to 100% by mass of the total mass of structural units derived from the macromonomer (A).

6. The copolymer according to claim 1, wherein the macromonomer (A) comprises a macromonomer (A-1) represented by the following formula (5): 【Chemistry 5】 (In formula (5), R １１ represents a hydrogen atom or a methyl group. １３ , R １４ represents a hydrogen atom, an unsubstituted or substituted alkyl group, an unsubstituted or substituted alicyclic group, an unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group, or an unsubstituted or substituted non-aromatic heterocyclic group. W is a terminal group. X represents NH or O, Y represents a direct bond or a substituted or unsubstituted alkylene group having 1 to 10 carbon atoms, and Z represents a direct bond, a carbonyl group, or an ester group. R １２ represents a hydrogen atom or a methyl group. Ar represents an aromatic ring group having at least two hydroxyl groups. m and n each independently represent an integer of 2 to 10,000. １１ , R １２ , R １４ may be the same or different.)

7. The copolymer of claim 1 , wherein the monomer (B) comprises an acrylate ester.

8. The copolymer of claim 7, wherein the monomer (B) comprises 2-methoxyethyl acrylate.

9. A resin composition comprising the copolymer according to any one of claims 1 to 8.

10. A coating agent comprising the copolymer according to any one of claims 1 to 8.

11. A medical coating agent comprising the copolymer according to any one of claims 1 to 8.

12. A medical device comprising a substrate and a coating film formed on at least one surface thereof, the coating film comprising the medical coating agent according to claim 11.

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