Storage container for antibody drug solution

Abstract

To provide a coating film-forming composition capable of suppressing formation of aggregates of antibody drugs as well as adsorption to a container surface in a simple and versatile technique using a coating process, and a storage container for an antibody drug solution that can be produced thereby.SOLUTION: A storage container for an antibody drug solution includes a coating film with hydrophilicity on at least a part of the surface, where the coating film preferably contains a polymer of a monomer having a hydrophilic functional group. The hydrophilic functional group is preferably selected from phosphoric acid, phosphonic acid, and an ester structure thereof; a betaine structure; an amide structure; an alkylene glycol residue; an amino group; and a sulfinyl group.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a treatment method and a container for suppressing the formation of aggregates of antibody pharmaceuticals and their adsorption to storage containers.

Background Art

[0002] When storing antibody pharmaceuticals, association and aggregation between antibodies occur, which may become impurities and cause problems such as side effects. To solve these problems, the introduction of aggregation inhibitors has been proposed, but there are issues regarding long-term stability and safety concerns due to the contamination of the inhibitors. Patent Document 1 describes a prefilled syringe that can suppress protein aggregation after long-term storage even when filled with a protein solution preparation having a low concentration of a nonionic surfactant. Patent Document 2 discloses an ion complex material having the ability to suppress the adhesion of biological substances and a biological substance adhesion-suppressing coating material using the same.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0004] An object of the present invention is to provide a composition for forming a coating film that can suppress not only the formation of aggregates of antibody pharmaceuticals but also their adsorption to the container surface by a simple and general technique by coating treatment, and a storage container for an antibody pharmaceutical solution that can be manufactured thereby.

Means for Solving the Problems

[0005] The present invention includes the following. [1] A storage container for an antibody pharmaceutical solution, comprising a hydrophilic coating film on at least a part of the surface.

[0006] [2] The storage container for an antibody pharmaceutical solution according to [1], wherein the coating film contains a polymer of a monomer having a hydrophilic functional group.

[0007] [3] The storage container for an antibody pharmaceutical solution according to [2], wherein the hydrophilic functional group is selected from phosphoric acid, phosphonic acid and their ester structures; betaine structures; amide structures; alkylene glycol residues; amino groups; and sulfinyl groups.

[0008] [4] The storage container for an antibody pharmaceutical solution according to [1], wherein the coating film is a copolymer containing a repeating unit containing a group represented by the following formula (a), a repeating unit containing a group represented by the following formula (b), and a repeating unit containing a group represented by the following formula (c):

Chemical formula

[0009] [5] The storage container for the antibody pharmaceutical solution according to any one of [1] to [4], wherein aggregation of the above antibody pharmaceutical is suppressed.

[0010] [6] The storage container for the antibody pharmaceutical solution according to any one of [1] to [5], wherein the above antibody pharmaceutical contains at least one of an antibody and its antigen-binding fragment.

[0011] [7] The storage container for the antibody pharmaceutical solution according to any one of [1] to [6], wherein the above antibody pharmaceutical contains at least one selected from the group consisting of a chimeric antibody, a human antibody, a humanized antibody, and domain antibodies thereof.

[0012] [8] The storage container for the antibody pharmaceutical solution according to any one of [1] to [7], wherein the above antibody pharmaceutical contains at least one selected from the group consisting of ofatumumab, cetuximab, tocilizumab, bevacizumab, canakinumab, golimumab, ustekinumab, eculizumab, omalizumab, trastuzumab, pertuzumab, adalimumab, denosumab, mogamulizumab, rituximab, ranibizumab, infliximab, aflibercept, abatacept, etanercept, gemtuzumab ozogamicin, panitumumab, basiliximab, certolizumab pegol, and palivizumab.

[0013] [9] A polymer of a monomer having a hydrophilic functional group, and a solvent A composition for forming a coating film for manufacturing a storage container for an antibody pharmaceutical solution, comprising the same.

[0014]

[10] (i) A copolymer comprising a repeating unit containing a group represented by the following formula (a), a repeating unit containing a group represented by the following formula (b), and a repeating unit containing a group represented by the following formula (c): [Chemical formula] [In the formula, U a1 , U a2 , 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; R c represents a linear or branched alkyl group having 4 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 halogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms which may be substituted); An - represents an anion selected from the group consisting of halide ions, inorganic acid ions, hydroxide ions, and isothiocyanate ions] and (ii) a solvent A composition for forming a coating film for manufacturing a storage container for an antibody pharmaceutical solution, comprising

[0015]

[11] A method for suppressing aggregation of an antibody pharmaceutical in an antibody pharmaceutical solution, comprising the step of storing the antibody pharmaceutical solution in a container having a coating film comprising a polymer of a monomer having a hydrophilic functional group on at least a part of its surface.

[0016]

[12] A method for suppressing aggregation of an antibody pharmaceutical in an antibody pharmaceutical solution, comprising a copolymer comprising a repeating unit containing a group represented by the following formula (a), a repeating unit containing a group represented by the following formula (b), and a repeating unit containing a group represented by the following formula (c): [Chemical formula] [In the formula, U a1 , U a2 , U b1 , Ub2 and U b3 each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms; R c represents a linear or branched alkyl group having 4 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 halogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms which may be substituted); An - represents an anion selected from the group consisting of halide ions, inorganic acid ions, hydroxide ions, and isothiocyanate ions]. A method for suppressing aggregation of an antibody pharmaceutical in an antibody pharmaceutical solution, which includes a step of storing an antibody pharmaceutical solution in a container having a coating film provided on at least a part of the surface thereof and containing the above.

Brief Description of the Drawings

[0017]

Figure 1

Figure 2

Figure 3

Figure 4

Modes for Carrying Out the Invention

[0018] ≪Explanation of Terms≫ The terms used in the present invention have the following definitions unless otherwise specified.

[0019] In the present invention, the "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0020] In the present invention, the "alkyl group" means a monovalent group of a linear or branched saturated aliphatic hydrocarbon. Examples of the "linear or branched alkyl group having 1 to 5 carbon atoms" include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group, n-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group or 1-ethylpropyl group. Examples of the "linear or branched alkyl group having 1 to 18 carbon atoms" include, in addition to the examples of the "linear or branched alkyl group having 1 to 5 carbon atoms", hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group or octadecyl group, or isomers thereof.

[0021] In the present invention, the "linear or branched alkyl group having 1 to 5 carbon atoms which may be substituted with a halogen atom" means the linear or branched alkyl group having 1 to 5 carbon atoms, or the linear or branched alkyl group having 1 to 5 carbon atoms substituted with one or more of the above halogen atoms. Examples of the "linear or branched alkyl group having 1 to 5 carbon atoms" are as described above. On the other hand, the "linear or branched alkyl group having 1 to 5 carbon atoms substituted with one or more halogen atoms" means that any one or more hydrogen atoms of the linear or branched alkyl group having 1 to 5 carbon atoms are replaced with a halogen atom. Examples include fluoromethyl group, difluoromethyl group, trifluoromethyl group, chloromethyl group, dichloromethyl group, trichloromethyl group, bromomethyl group, iodomethyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group, perfluoroethyl group, perfluorobutyl group, or perfluoropentyl group, etc.

[0022] In the present invention, the "ester bond" means -C(=O)-O- or -O-C(=O)-, the "amide bond" means -NHC(=O)- or -C(=O)NH-, and the ether bond means -O-.

[0023] In the present invention, the "linear or branched alkylene group having 1 to 10 carbon atoms which may be substituted with a halogen atom" means 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 substituted with one or more halogen atoms. Here, the "alkylene group" means a divalent organic group corresponding to the above alkyl group. Examples of the "linear or branched alkylene group having 1 to 10 carbon atoms" include a methylene group, an ethylene group, a propylene group, a trimethylene group, a tetramethylene group, a 1-methylpropylene group, a 2-methylpropylene group, a dimethylethylene group, an ethylethylene group, a pentamethylene group, a 1-methyl-tetramethylene group, a 2-methyl-tetramethylene group, a 1,1-dimethyl-trimethylene group, a 1,2-dimethyl-trimethylene group, a 2,2-dimethyl-trimethylene group, a 1-ethyl-trimethylene group, a hexamethylene group, an octamethylene group, a decamethylene group, etc. Among these, an ethylene group, a propylene group, an octamethylene group, and a decamethylene group are preferred. For example, a linear or branched alkylene group having 1 to 5 carbon atoms such as an ethylene group, a propylene group, a trimethylene group, a tetramethylene group, etc. is more preferred, and particularly an ethylene group or a propylene group is preferred. The "linear or branched alkylene group having 1 to 10 carbon atoms substituted with one or more halogen atoms" means that one or more arbitrary hydrogen atoms of the above alkylene group are replaced with a halogen atom. In particular, those in which some or all of the hydrogen atoms of an ethylene group or a propylene group are replaced with a halogen atom are preferred.

[0024] In the present invention, the "cyclic hydrocarbon group having 3 to 10 carbon atoms" means a monovalent group of a saturated or partially unsaturated aliphatic hydrocarbon having 3 to 10 carbon atoms, which is monocyclic or polycyclic. Among these, a monovalent group of a saturated aliphatic hydrocarbon having 3 to 10 carbon atoms, which is monocyclic or bicyclic, is preferred. Examples include cycloalkyl groups having 3 to 10 carbon atoms such as a cyclopropyl group, a cyclobutyl group, or a cyclohexyl group, or bicycloalkyl groups having 4 to 10 carbon atoms such as a bicyclo[3.2.1]octyl group, a bornyl group, an isobornyl group, etc.

[0025] In the present invention, the "aryl group having 6 to 10 carbon atoms" means a monocyclic or polycyclic monovalent group of aromatic hydrocarbons having 6 to 10 carbon atoms, and examples thereof include a phenyl group, a naphthyl group, and an anthryl group. The "aryl group having 6 to 10 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 a halogen atom".

[0026] In the present invention, the "aralkyl group having 7 to 14 carbon atoms" means 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, or an α-methylbenzyl group. The aryl moiety 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 a halogen atom".

[0027] 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, or a phenoxypropyl group. The aryl moiety 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 a halogen atom".

[0028] In the present invention, the "halide ion" means a fluoride ion, a chloride ion, a bromide ion, or an iodide ion.

[0029] In the present invention, the "inorganic acid ion" means 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.

[0030] The above An -Preferred are halide ions, sulfate ions, phosphate ions, hydroxide ions and isothiocyanate ions, and particularly preferred are halide ions.

[0031] In the present invention, the (meth)acrylate compound means both acrylate compounds and methacrylate compounds. For example, (meth)acrylic acid means acrylic acid and methacrylic acid.

[0032] <Storage container for antibody pharmaceutical solution> (Coating film having hydrophilicity) The storage container for the antibody pharmaceutical solution of the present invention is provided with a coating film having hydrophilicity on at least a part of the surface of the container in contact with the antibody pharmaceutical solution. Aggregation of antibody pharmaceuticals (antibodies = immunoglobulins (proteins)) is known to occur with small aggregates as nuclei due to denaturation of the protein. In the storage container for the antibody pharmaceutical solution of the present invention, since the surface of the container in contact with the antibody pharmaceutical solution is hydrophilic, even when a hydrophilic antibody pharmaceutical contacts the container surface, no structural changes such as denaturation occur, and it is considered that the dissolved state of the antibody can be maintained.

[0033] The fact that the coating film is hydrophilic means, for example, in the static contact angle measurement using a contact angle meter (for example, a fully automatic contact angle meter (Kyowa Interface Science Co., Ltd., DM-701)), the contact angle of a bubble in water (room temperature, for example, 25 ± 5 ° C) is 140 ° or more, preferably 150 ° or more. The above-mentioned coating film having hydrophilicity may be provided on at least a part of the surface of the container in contact with the antibody pharmaceutical solution described later, but it is preferable that the coating film is formed over the entire surface in contact with the antibody pharmaceutical solution.

[0034] (Polymer of monomer having hydrophilic functional group) Preferably, the coating film having hydrophilicity contains a polymer of a monomer having a hydrophilic functional group.

[0035] The polymer of the monomer having a hydrophilic functional group according to the present invention may be a polymer of an ethylenically unsaturated monomer having a hydrophilic functional group or structure, or a polysaccharide or its derivative. Examples of the ethylenically unsaturated monomer include one or more ethylenically unsaturated monomers selected from the group consisting of (meth)acrylic acid and its esters; vinyl acetate; vinyl pyrrolidone; ethylene; and vinyl alcohol. Examples of the polysaccharide or its derivative include cellulose-based polymers such as hydroxyalkyl cellulose (for example, hydroxyethyl cellulose or hydroxypropyl cellulose), starch, dextran, and curdlan.

[0036] The hydrophilic functional group (that is, a hydrophilic functional group or structure) is preferably selected from phosphoric acid, phosphonic acid and their ester structures; betaine structure; amide structure; alkylene glycol residue; amino group; and sulfinyl group.

[0037] 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, for example, a phosphorylcholine group:

Chemical formula

[0038] The amide structure is represented by the following formula:

Chemical formula

[0039] The alkylene glycol residue means an alkyleneoxy group (-Alk-O-) remaining after the hydroxyl group at one or both terminals of an alkylene glycol (HO-Alk-OH; where Alk is a linear or branched alkylene group having 1 to 10 carbon atoms) undergoes a condensation reaction with another compound, and also includes a poly(alkyleneoxy) group in which alkyleneoxy units are repeated. Examples of the ethylenically unsaturated monomer having such a structure include 2-hydroxyethyl (meth)acrylate, methoxypolyethylene glycol (meth)acrylate, and the like. Further, monomers or polymers having such a structure are disclosed, for example, in JP-A-2008-533489 and the like.

[0040] The amino group is represented by the formula: -NH2, -NHR 19 or -NR 20 R 21 [where R 19 , R 20 and R 21 are, independently of one another, organic groups (for example, a linear or branched alkyl group having 1 to 5 carbon atoms, etc.)]. The amino group in the present invention includes a quaternized or chlorinated amino group. Examples of the ethylenically unsaturated monomer having such a structure include dimethylaminoethyl (meth)acrylate, 2-(t-butylamino)ethyl (meth)acrylate, methacryloylcholine chloride, and the like.

[0041] The sulfinyl group is represented by the following formula:

Chemical formula

[0042] The polymer contained in the coating film provided on at least a part of the surface of the storage container for the antibody pharmaceutical solution of the present invention may be a copolymer containing a repeating unit containing a group represented by the following formula (a), a repeating unit containing a group represented by the following formula (b), and a repeating unit containing a group represented by the following formula (c): [Chemical formula] [In the formula, U a1 、U a2 、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; R c is a linear or branched alkyl group having 4 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 halogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms which may be substituted); An - represents an anion selected from the group consisting of halide ions, inorganic acid ions, hydroxide ions, and isothiocyanate ions.

[0043] [Formation of coating film] The antibody pharmaceutical solution storage container of the present invention can be manufactured by applying a composition capable of forming a known hydrophilic coating film (composition for forming a coating film) to at least a part of the inner surface of the container described below, preferably to the surface in contact with the solution on the inner surface of the container, more preferably to the entire inner surface of the container, by a known method. The description of the hydrophilic coating film is as described above.

[0044] In one embodiment of the present invention, the coating film is a copolymer containing (i) a repeating unit containing a group represented by the following formula (a), a repeating unit containing a group represented by the following formula (b), and a repeating unit containing a group represented by the following formula (c): [Chemical formula] [In the formula, U a1 , U a2 , 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; R c is a linear or branched alkyl group having 4 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 halogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms which may be substituted); An - represents an anion selected from the group consisting of halide ions, inorganic acid ions, hydroxide ions, and isothiocyanate ions], and (ii) a method including a step of applying a composition for forming a coating film containing a solvent to a substrate.

[0045] The copolymer related to the coating film of the present invention is not particularly limited as long as it is a copolymer containing a repeating unit containing a group represented by the above formula (a), a repeating unit containing a group represented by the above formula (b), and a repeating unit containing a group represented by the above formula (c). In the present invention, the repeating unit containing a group represented by the above formula (c) is different from the repeating unit containing a group represented by the above formula (a) and the repeating unit containing a group represented by the above formula (b). The polymer is preferably obtained by radical polymerization of a monomer containing a group represented by the above formula (a), a monomer containing a group represented by the above formula (b), and a monomer containing a group represented by the above formula (c), but those obtained by polycondensation or polyaddition reaction can also be used. Examples of the copolymer include vinyl polymerization polymers reacted with olefins, polyamides, polyesters, polycarbonates, polyurethanes, etc. Among these, vinyl polymerization polymers reacted with olefins or (meth)acrylic polymers obtained by polymerizing (meth)acrylate compounds are particularly preferred.

[0046] The proportion of the repeating unit containing a group represented by the formula (a) in the copolymer related to the coating film of the present invention is 3 mol% to 80 mol%, preferably 3.5 mol% to 50 mol%, and more preferably 4 mol% to 30 mol%. The copolymer according to the present invention may contain two or more repeating units containing a group represented by the formula (a). The proportion of the repeating unit containing a group represented by the formula (b) in the copolymer related to the coating film of the present invention is 3 mol% to 80 mol%, preferably 5 mol% to 70 mol%, and more preferably 8 mol% to 65 mol%. The copolymer according to the present invention may contain two or more repeating units containing a group represented by the formula (b). The proportion of the repeating unit containing the group represented by the formula (c) in the copolymer according to the present invention may be the remainder obtained by subtracting the above formulas (a) and (b) from the entire copolymer, or may be the remainder obtained by subtracting the total proportion of the above formulas (a) and (b) and the fourth component described below. For example, it is 1 mol% to 90 mol%, preferably 3 mol% to 88 mol%. More preferably, it is 5 mol% to 87 mol%. Most preferably, it is 50 mol% to 86 mol%. The copolymer according to the present invention may contain repeating units containing two or more groups represented by the formula (c).

[0047] The combination of the proportions of the repeating units containing the groups represented by the above formulas (a), (b), and (c) in the copolymer according to the present invention is preferably Formula (a): 3 mol% to 80 mol%, Formula (b): 3 mol% to 80 mol%, Formula (c): 1 mol% to 90 mol%, more preferably Formula (a): 3.5 mol% to 50 mol%, Formula (b): 5 mol% to 70 mol%, Formula (c): 3 mol% to 88 mol%, even more preferably Formula (a): 4 mol% to 30 mol%, Formula (b): 8 mol% to 65 mol%, Formula (c): 5 mol% to 87 mol%, most preferably Formula (a): 4 mol% to 30 mol%, Formula (b): 8 mol% to 65 mol%, Formula (c): 50 mol% to 86 mol%, is

[0048] As the copolymer contained in the composition for forming a coating film according to the present invention, a copolymer containing repeating units of the following formulas (a1), (b1), and (c1) is particularly preferably used.

Chemical formula

[0049] The above copolymer has the following formulas (A), (B) and (C):

Chemical formula

[0050] In another embodiment of the present invention, the copolymer may further contain units derived from an optional fourth component. For example, it may contain a crosslinked structure derived from a (meth)acrylate compound having two or more functional groups as the fourth component. Examples of such a fourth component include bis(methacryloyloxymethyl) phosphate, bis[(2-methacryloyloxy)ethyl] phosphate, bis[3-(methacryloyloxy)propyl] phosphate, phosphinylidene tris(oxy-2,1-ethanediyl) triacrylate, and the like.

[0051] Furthermore, as the fourth component, the following formula (D):

Chemical formula

[0052] Specific examples of the compounds of the above formula (D) include poly(ethylene glycol) di(meth)acrylate, poly(trimethylene glycol) di(meth)acrylate, poly(propylene glycol) di(meth)acrylate, and the like.

[0053] For example, the structural formulas of di(ethylene glycol) dimethacrylate, poly(ethylene glycol) dimethacrylate, and poly(propylene glycol) dimethacrylate are represented by the following formulas (D-1) to (D-3), respectively.

[0054]

Chemical formula

[0055] For example, the proportion of the units derived from the fourth component in the copolymer is 0 mol% to 50 mol%, preferably 5 mol% to 45 mol%, and most preferably 10 mol% to 40 mol%.

[0056] Examples of the solvent contained in the composition for forming the coating film described above 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-hexanol, 2-hexanol, 3-hexanol, 2,3-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. A single solvent or a mixed solvent of a combination thereof may be used. From the viewpoint of dissolving the copolymer, it is preferably selected from water, PBS, ethanol, propanol, and a mixed solvent thereof, and more preferably selected from water, ethanol, and a mixed solvent thereof.

[0057] As the concentration of the solid content in the composition for forming a coating film according to the present invention, 0.01 to 50% by mass is desirable in order to uniformly form a coating film. Further, as the concentration of the copolymer in the composition for forming a coating film, it is preferably 0.01 to 4% by mass, more preferably 0.01 to 3% by mass, particularly preferably 0.01 to 2% by mass, and even more preferably 0.01 to 1% by mass. When the concentration of the copolymer is 0.01% by mass or less, the concentration of the copolymer in the resulting composition for forming a coating film is too low to form a coating film with a sufficient film thickness. When it is 4% by mass or more, the storage stability of the composition for forming a coating film deteriorates, and precipitation or gelation of the dissolved matter may occur.

[0058] In order to form the coating film of the present invention, the above-described composition for forming a coating film is applied to at least a part of the surface of the container. The coating method is not particularly limited, and ordinary coating methods such as spin coating, dip coating, and solvent casting method are used.

[0059] The method for obtaining a container provided with the coating film according to the present invention may include a drying step of the coating film in addition to the above-described coating step. The drying step of the coating film is preferably performed in the range of temperature -200°C to 200°C under the atmosphere or under vacuum. By the drying step, the solvent in the above-described composition for forming a coating film is removed, and the formulas (a) and (b) of the copolymer according to the present invention form an ionic bond and completely adhere to the container.

[0060] The coating film can be formed, for example, by drying at room temperature (10°C to 35°C, for example, 25°C). However, in order to form the coating film more rapidly, it may be dried at, for example, 40°C to 50°C. Further, a drying step at an extremely low temperature to a low temperature (-200°C to around -30°C) by a freeze-drying method may be used. Freeze-drying is also called vacuum freeze-drying, and it is a method of cooling the material to be dried with a refrigerant and removing the solvent by sublimation in a vacuum state. General refrigerants used in freeze-drying include a mixed medium of dry ice and methanol (-78°C), liquid nitrogen (-196°C), and the like.

[0061] When the drying temperature is -200°C or lower, a non-general refrigerant must be used, lacking versatility, and it takes a long time for drying due to solvent sublimation, resulting in poor efficiency. When the drying temperature is 200°C or higher, the ionic bond reaction on the surface of the coating film progresses too much, causing the surface to lose hydrophilicity and the ability to suppress the adhesion of biological substances not to be exerted. A more preferable drying temperature is 10°C to 180°C, and a more preferable drying temperature is 25°C to 150°C.

[0062] After drying, in order to remove impurities, unreacted monomers, etc. remaining on the coating film, and further to adjust the ionic balance of the copolymer in the film, a step of washing with at least one solvent selected from aqueous solutions containing water and electrolytes may be carried out. Washing is preferably by running water washing or ultrasonic washing, etc. The above aqueous solution containing water and electrolytes may be, for example, heated in the range of 40°C to 95°C. The aqueous solution containing electrolytes is preferably PBS, physiological saline (containing only sodium chloride), Dulbecco's phosphate buffered saline, Tris buffered saline, HEPES buffered saline, and Veronal buffered saline, and PBS is particularly preferred. After fixation, the coating film remains firmly fixed to the substrate without eluting even when washed with water, PBS, alcohol, etc. The formed coating film can be easily removed by subsequent water washing or the like even when biological substances adhere to it.

[0063] If necessary, treatments such as γ-rays, ethylene oxide, autoclave, etc. may be carried out for sterilization.

[0064] The film thickness of the coating film of the present invention is preferably 10 to 1000 Å, more preferably 10 to 500 Å, and most preferably 20 to 400 Å.

[0065] (Container) As the shape of the storage container for the antibody pharmaceutical solution of the present invention, there is no particular limitation as long as it can store the antibody pharmaceutical solution (liquid at room temperature), such as a bottle shape, a tube shape, etc. It is preferable to have a lid or the like that can be sealed at the upper part of the container so that it can be stored in a sealed manner.

[0066] Examples of the material of the storage container for the antibody pharmaceutical solution of the present invention include glass, metal-containing compounds or metalloid-containing compounds, or resins. From the viewpoint of versatility, glass or resin moldings are preferably used. Metal-containing compounds or metalloid-containing compounds include, for example, ceramics which are sintered bodies with a metal oxide as the basic component and hardened by heat treatment at high temperature, semiconductors such as silicon, metal oxides or metalloid oxides (silicon oxide, alumina, etc.), metal carbides or metalloid carbides, metal nitrides or metalloid nitrides (silicon nitride, etc.), and inorganic solid materials such as moldings of inorganic compounds such as metal borides or metalloid borides, and metals such as aluminum, nickel titanium, and stainless steels (SUS304, SUS316, SUS316L, etc.). The resin may be either a natural resin or its derivative, or a synthetic resin. Examples of natural resins or their derivatives include cellulose, cellulose triacetate (CTA), nitrocellulose (NC), cellulose immobilized with dextran sulfate, etc. Examples of synthetic resins include polyacrylonitrile (PAN), polyimide (PI), polyester-based 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), cycloolefin polymer (COP), polyvinyl chloride (PVC), polytetrafluoroethylene (PTFE), ultra-high molecular weight polyethylene (UHPE), polydimethylsiloxane (PDMS), acrylonitrile-butadiene-styrene resin (ABS), or Teflon (registered trademark) is preferably used.

[0067] When the container of the present invention is used, it becomes possible to store the antibody pharmaceutical while suppressing the aggregation of the antibody pharmaceutical. Suppressing the aggregation of the above antibody pharmaceutical means that, as shown in the examples, after a certain period of time has elapsed, it can be confirmed by visual observation whether there is turbidity in the antibody pharmaceutical solution.

[0068] (Antibody drug) An antibody drug is a drug that utilizes an antibody, and an antibody is a protein composed of immunoglobulins. Preferably, the above antibody drug contains at least one of an antibody and its antigen-binding fragment. Preferably, the above antibody drug contains at least one selected from the group consisting of chimeric antibodies, human antibodies, humanized antibodies, and domain antibodies thereof.

[0069] Specific examples of the above antibody drugs include ofatumumab (trade name "Arzerra (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 "Prolia (registered trademark)", trade name "Lumbar (registered trademark)"), mogamulizumab (trade name "Poteligeo (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 pegol (trade name "Cimzia (registered trademark)"), and palivizumab (trade name "Synagis (registered trademark)").

[0070] Among these, it is preferably included an antibody obtained from a clone derived from a single antibody-producing cell, or a monoclonal antibody which is an antibody molecule, more preferably a monoclonal antibody consisting of an anti-human CD20 human antibody, and still more preferably included rituximab or abatacept. Note that the antibody pharmaceutical may contain one kind of antibody, or may contain two or more kinds of antibodies. That is, the antibody pharmaceutical of the present invention may contain both an antibody and an antigen-binding fragment, may contain two or more kinds of antibodies, or may contain two or more kinds of antigen-binding fragments.

[0071] The above antibody pharmaceutical is often stored in a solution state dissolved in a solvent. As the solvent of the antibody pharmaceutical solution, aqueous buffer solutions such as water, phosphate buffered saline (PBS), acetate buffer solution, and citrate buffer solution are used.

[0072] The pH of the antibody pharmaceutical solution is not particularly limited, but can be, for example, 3.0 or more and 8.0 or less.

[0073] Here, the concentration of the antibody pharmaceutical in the antibody pharmaceutical solution is preferably 0.005 mg / mL or more, more preferably 0.01 mg / mL or more, still more preferably 0.05 mg / mL or more, preferably 500 mg / mL or less, more preferably 300 mg / mL or less, and still more preferably 200 mg / mL or less. If the concentration of the antibody in the antibody pharmaceutical solution is 0.005 mg / mL or more, when the antibody pharmaceutical is administered to a human body or the like, the intended effect of the antibody pharmaceutical can be sufficiently obtained. If it is 500 mg / mL or less, when the antibody pharmaceutical is stored for a long time, aggregation of the antibody in the antibody pharmaceutical solution can be sufficiently suppressed.

[0074] <Composition for forming a coating film for manufacturing a storage container of an antibody pharmaceutical solution> The composition for forming a coating film for manufacturing a storage container of an antibody pharmaceutical solution of the present invention comprises: (i) a polymer of a monomer having the above hydrophilic functional group, preferably a copolymer containing a repeating unit containing a group represented by the following formula (a), a repeating unit containing a group represented by the following formula (b), and a repeating unit containing a group represented by the following formula (c): [Chemical formula] [In the formula, U a1 、U a2 、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; R c represents a linear or branched alkyl group having 4 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 halogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms which may be substituted); An - represents an anion selected from the group consisting of halide ions, inorganic acid ions, hydroxide ions, and isothiocyanate ions] and (ii) a solvent is included.

[0075] The composition for forming a coating film according to the present invention may be prepared by diluting a desired polymer to a predetermined concentration with a desired solvent. Specific embodiments of the (co)polymer and the solvent are as described in <Formation of the Coating Film> above.

[0076] As the concentration of the solid content in the composition for forming a coating film according to the present invention, 0.01 to 50% by mass is desirable in order to uniformly form a coating film. Further, as the concentration of the copolymer in the composition for forming a coating film, it is preferably 0.01 to 4% by mass, more preferably 0.01 to 3% by mass, particularly preferably 0.01 to 2% by mass, and even more preferably 0.01 to 1% by mass. When the concentration of the copolymer is 0.01% by mass or less, the concentration of the copolymer in the resulting composition for forming a coating film is too low to form a coating film with a sufficient film thickness. When it is 4% by mass or more, the storage stability of the composition for forming a coating film deteriorates, and precipitation of dissolved substances or gelation may occur.

[0077] Furthermore, in addition to the above polymer and solvent, the composition for forming a coating film of the present invention can also add other substances as necessary within a range that does not impair the performance of the resulting coating film. Examples of other substances include preservatives, surfactants, primers that enhance adhesion to the substrate, fungicides, and saccharides.

[0078] In order to adjust the ion balance of the polymer in the composition for forming a coating film according to the present invention, when obtaining the coating film of the present invention, it may further include a step of preliminarily adjusting the pH in the composition for forming a coating film. The pH adjustment can be carried out, for example, by adding a pH adjuster to the composition containing the above polymer and solvent, and setting 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 that can be used are appropriately selected according to the concentration of the above polymer, the abundance ratio of its anions and cations, and the like.

[0079] Examples of the pH adjuster include organic amines such as ammonia, 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 such as sulfuric acid, phosphoric acid, hydrochloric acid, and carbonic acid or their alkali metal salts; quaternary ammonium cations such as choline, or mixtures thereof (e.g., buffer solutions such as phosphate buffered saline). Among these, ammonia, diethanolamine, sodium hydroxide, choline, N-methyl-D-glucamine, and tris(hydroxymethyl)aminomethane are preferred, and particularly ammonia, diethanolamine, sodium hydroxide, and choline are preferred.

[0080] Therefore, the present invention relates to a composition for forming a coating film, comprising (i) a polymer of a monomer having the above hydrophilic functional group, preferably a copolymer comprising a repeating unit containing a group represented by the above formula (a), a repeating unit containing a group represented by the above formula (b), and a repeating unit containing a group represented by the above formula (c), (ii) a solvent, and optionally (iii) a pH adjuster. Specific examples of the polymer, solvent, and pH adjuster are as described above. For the coating film, copolymer, and composition for forming a coating film of the present invention, the coating film, copolymer, and composition for forming a coating film described in International Publication No. 2016 / 093293 can be used.

[0081] <Method for Suppressing Aggregation of Antibody Medicinal Product in Antibody Medicinal Product Solution> The method for suppressing aggregation of the antibody medicinal product in the antibody medicinal product solution of the present invention is (i) A polymer of a monomer having the above hydrophilic functional group, preferably a copolymer comprising a repeating unit containing a group represented by the following formula (a), a repeating unit containing a group represented by the following formula (b), and a repeating unit containing a group represented by the following formula (c): [Chemical formula] [In the formula, Ua1 , U a2 , 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; R c represents a linear or branched alkyl group having 4 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 halogen atom or may be substituted with a linear or branched alkyl group having 1 to 5 carbon atoms); An - represents an anion selected from the group consisting of halide ions, inorganic acid ions, hydroxide ions, and isothiocyanate ions]. A method for suppressing aggregation of an antibody pharmaceutical in an antibody pharmaceutical solution, which includes a step of storing an antibody pharmaceutical solution in a container having a coating film on at least a part of the surface.

[0082] By this method, when storing an antibody pharmaceutical solution in a container, aggregation is suppressed and the solution state can be maintained. The antibody pharmaceutical solution is usually stored at normal temperature (15°C or higher and less than 35°C, preferably 20°C or higher and less than 30°C), but may be within the range of 10°C or higher and less than 50°C, and may be stored frozen (about -30°C or higher and about -18°C), refrigerated (about 3 to 10°C), or at a high temperature (about 35°C or higher and about 50°C).

Example

[0083] Hereinafter, the present invention will be described in more detail based on synthesis examples, examples, test examples, etc., but the present invention is not limited thereto.

[0084] <Synthesis Example 1> 260 g of acid phosphoxyethyl methacrylate (product name: Hosmer M, manufactured by Unichemical Co., Ltd., non-volatile content at 100 °C for 1 hour: 91.8%, a mixture of acid phosphoxyethyl methacrylate (44.2% by mass), bis[2-(methacryloyloxy)ethyl] phosphate (28.6% by mass), and other substances (27.2% by mass)) was put into 390 g of ethanol, and while cooling to 35 °C or lower, 310 g of choline (48 - 50% aqueous solution: manufactured by Tokyo Chemical Industry Co., Ltd.) was added and stirred until uniform. To this mixed solution, 220 g of 80% aqueous solution of methacryloylcholine chloride (manufactured by Tokyo Chemical Industry Co., Ltd.) and 300 g of butyl methacrylate (manufactured by Tokyo Chemical Industry Co., Ltd.) were added, and additionally 260 g of ethanol was added and stirred. Further, an aqueous solution prepared by dissolving 22 g of 2,2’-azobis(N-(2-carboxyethyl)-2-methylpropionamidine) n-hydrate (product name: VA-057, manufactured by Fujifilm Wako Pure Chemical Corporation) in 230 g of pure water was added to the above solution while maintaining the temperature at 35 °C or lower, and after sufficient stirring to make it uniform, the mixed solution containing all of the above was introduced into a three-necked flask via a dropping pump. On the other hand, separately, 650 g of pure water and 980 g of ethanol were added to a three-necked flask equipped with a condenser, and nitrogen was flowed while heating with stirring to the reflux temperature. While maintaining this state, the above mixed solution was dropped into the boiling liquid of pure water and ethanol over 1.5 hours using a dropping pump via a Teflon tube. After dropping, heating and stirring were carried out while maintaining the above environment for 2 hours. After 2 hours, by cooling, 3610 g of a copolymer-containing varnish with a solid content of about 24.20% by mass was obtained. The weight average molecular weight of the obtained liquid in gel filtration chromatography (GFC) was about 23,225.

[0085] <Synthesis Example 2> 5.03 g of acid phosphoxypolypropylene glycol monomethacrylate (average number of moles of propylene oxide added: 5) (product name: PPM-5P, manufactured by Toho Chemical Industry Co., Ltd., absolute mass % (purity): 97.3 mass %), about 80% aqueous solution of methacryloylcholine chloride (manufactured by Tokyo Chemical Industry Co., Ltd.) 2.10 g, butyl methacrylate (manufactured by Tokyo Chemical Industry Co., Ltd.) 2.02 g, and ethylene glycol dimethacrylate (manufactured by Tokyo Chemical Industry Co., Ltd.) 2.06 g were put into 48.6 g of ethanol (manufactured by Junsei Chemical Co., Ltd.), and 107.1 mg of dimethyl-1,1'-azobis(1-cyclohexanecarboxylate) (product name: VE-073, manufactured by Fujifilm Wako Pure Chemical Corporation) was added and stirred uniformly to prepare a mixed solution. On the other hand, 48.6 g of ethanol (manufactured by Junsei Chemical Co., Ltd.) was added to a four-necked flask equipped with a condenser, the inside of the flask was purged with nitrogen, and the temperature was raised to the reflux temperature while stirring. While maintaining this state, the above mixed solution was dropped into the boiling ethanol solution with a dropping pump over 1.5 hours, and after dropping, it was heated and stirred for 24 hours while maintaining the above environment. After completion of the reaction, it was cooled to obtain a copolymer-containing solution with a solid content of about 9.7 mass %. The obtained copolymer-containing liquid was reprecipitated with hexane, which is a poor solvent, and the precipitate was collected by filtration and dried under reduced pressure. The weight average molecular weight of the obtained powder in GFC was about 220,000.

[0086] <Synthesis Example 3> 5.01 g of acid phosphoxypolypropylene glycol monomethacrylate (average number of moles of propylene oxide added: 5) (product name: PPM-5P, manufactured by Toho Chemical Industry Co., Ltd., absolute mass % (purity): 97.3 mass %), about 80% aqueous solution of methacryloylcholine chloride (manufactured by Tokyo Chemical Industry Co., Ltd.) 2.10 g, butyl methacrylate (manufactured by Tokyo Chemical Industry Co., Ltd.) 2.31 g, and ethylene glycol dimethacrylate (manufactured by Tokyo Chemical Industry Co., Ltd.) 1.62 g were put into 47.9 g of ethanol (manufactured by Junsei Chemical Co., Ltd.), and 54.3 mg of dimethyl-1,1′-azobis(1-cyclohexanecarboxylate) (product name: VE-073, manufactured by Fujifilm Wako Pure Chemical Corporation) was added and stirred uniformly to prepare a mixed solution. On the other hand, 47.9 g of ethanol (manufactured by Junsei Chemical Co., Ltd.) was added to a four-necked flask equipped with a condenser, the inside of the flask was purged with nitrogen, and the temperature was raised to the reflux temperature while stirring. While maintaining this state, the above mixed solution was dropped into the boiling ethanol solution with a dropping pump over 1.5 hours, and after dropping, it was heated and stirred for 24 hours while maintaining the above environment. After completion of the reaction, it was cooled to obtain a copolymer-containing solution with a solid content of about 9.8 mass %. The obtained copolymer-containing liquid was reprecipitated with hexane, which is a poor solvent, and the precipitate was collected by filtration and dried under reduced pressure. The weight average molecular weight of the obtained powder in GFC was about 260,000.

[0087] <Synthesis Example 4> 5.51 g of acid phosphoxypolypropylene glycol monomethacrylate (average number of moles of propylene oxide added: 5) (product name: PPM-5P, manufactured by Toho Chemical Industry Co., Ltd., absolute mass % (purity): 97.3 mass %), approximately 80% aqueous solution of methacryloylcholine chloride (manufactured by Tokyo Chemical Industry Co., Ltd.) 2.30 g, butyl methacrylate (manufactured by Tokyo Chemical Industry Co., Ltd.) 1.27 g, and ethylene glycol dimethacrylate (manufactured by Tokyo Chemical Industry Co., Ltd.) 1.78 g were put into 47.2 g of ethanol (manufactured by Junsei Chemical Co., Ltd.), and 105.7 mg of dimethyl-1,1′-azobis(1-cyclohexanecarboxylate) (product name: VE-073, manufactured by Fujifilm Wako Pure Chemical Corporation) was added and stirred uniformly to prepare a mixed solution. On the other hand, 47.2 g of ethanol (manufactured by Junsei Chemical Co., Ltd.) was added to a four-necked flask equipped with a condenser, the inside of the flask was purged with nitrogen, and the temperature was raised to the reflux temperature while stirring. While maintaining this state, the above mixed solution was dropped into the boiling ethanol solution over 1.5 hours using a dropping pump, and after dropping, heating and stirring were carried out for 24 hours while maintaining the above environment. After completion of the reaction, cooling was performed to obtain a copolymer-containing solution with a solid content of about 9.8 mass %. The obtained copolymer-containing liquid was reprecipitated with hexane, which is a poor solvent, and the precipitate was recovered by filtration and dried under reduced pressure. The weight average molecular weight of the obtained powder in GFC was about 220,000.

[0088] <Synthesis Example 5> 6.01 g of acid phosphoxypolypropylene glycol monomethacrylate (average number of moles of propylene oxide added: 5) (product name: PPM-5P, manufactured by Toho Chemical Industry Co., Ltd., absolute mass % (purity): 97.3 mass %), about 80% aqueous solution of methacryloylcholine chloride (manufactured by Tokyo Chemical Industry Co., Ltd.) 1.69 g, butyl methacrylate (manufactured by Tokyo Chemical Industry Co., Ltd.) 1.16 g, and ethylene glycol dimethacrylate (manufactured by Tokyo Chemical Industry Co., Ltd.) 1.60 g were put into 45.9 g of ethanol (manufactured by Junsei Chemical Co., Ltd.), and 101.1 mg of dimethyl-1,1′-azobis(1-cyclohexanecarboxylate) (product name: VE-073, manufactured by Fuji Film Wako Pure Chemical Corporation) was added and stirred uniformly to prepare a mixed solution. On the other hand, 45.9 g of ethanol (manufactured by Junsei Chemical Co., Ltd.) was added to a four-necked flask equipped with a condenser, the inside of the flask was purged with nitrogen, and the temperature was raised to the reflux temperature while stirring. While maintaining this state, the above mixed solution was dropped into the boiling ethanol solution with a dropping pump over 1.5 hours, and after dropping, it was heated and stirred for 24 hours while maintaining the above environment. After completion of the reaction, it was cooled to obtain a copolymer-containing solution with a solid content of about 10.0 mass %. The obtained copolymer-containing liquid was reprecipitated with hexane, which is a poor solvent, and the precipitate was collected by filtration and dried under reduced pressure. The weight average molecular weight of the obtained copolymer in GFC was about 210,000.

[0089] <Preparation Example 1> To 568 g of the copolymer varnish obtained in Synthesis Example 1 above, 157 g of 1 mol / L hydrochloric acid (1N) (manufactured by Kanto Chemical Co., Ltd.), 1697 g of pure water, and 4456 g of ethanol were added and stirred well to prepare a composition for forming a coating film. The pH was 2.6.

[0090] <Preparation Example 2> To 0.80 g of the copolymer obtained in Synthesis Example 2 above, 27.51 g of ethanol and 11.76 g of pure water were added and stirred well to prepare a composition for forming a coating film. The pH was 2.9.

[0091] <Preparation Example 3> To 0.25 g of the copolymer obtained in Synthesis Example 3 above, 8.59 g of ethanol and 3.70 g of pure water were added and stirred well to prepare a composition for forming a coating film. The pH was 2.8.

[0092] <Preparation Example 4> To 0.26 g of the copolymer obtained in Synthesis Example 4 above, 8.60 g of ethanol and 3.69 g of pure water were added and stirred well to prepare a composition for forming a coating film. The pH was 2.8.

[0093] <Preparation Example 5> To 0.30 g of the copolymer obtained in Synthesis Example 5 above, 10.30 g of ethanol and 4.01 g of pure water were added and stirred well to prepare a composition for forming a coating film. The pH was 2.9.

[0094] <Example 1> 1.5 mL each of the composition for forming a coating film obtained in Preparation Example 1 was placed in polypropylene (PP) microtubes (manufactured by FCR&Bio, #JRDS-0M) and allowed to stand at 25 °C for 0.5 hour. After removing the composition for forming a coating film from the tubes, it was dried at 25 °C for 3 hours. Then, the tubes were thoroughly washed with pure water to obtain PP tubes with a coating film formed thereon. Hereinafter, they are referred to as 'coated tubes', and tubes that have not been treated with the composition for forming a coating film are referred to as 'untreated tubes'.

[0095] <Examples 2 to 5> 1.5 mL each of the compositions for forming a coating film obtained in Preparation Examples 2 to 5 was placed in polypropylene (PP) microtubes (manufactured by Nippon Genetics Co., Ltd., #11510) and allowed to stand at 25 °C for 0.5 hour. After removing the composition for forming a coating film from the tubes, it was dried at 50 °C for 3 hours. Then, the tubes were thoroughly washed with pure water to obtain PP tubes with a coating film formed thereon. Hereinafter, the PP tubes treated with the compositions for forming a coating film obtained in Preparation Examples 2 to 5 are referred to as 'coated tube 2' to 'coated tube 5', respectively.

[0096] <Example 6> 100 μg of the coating film-forming composition obtained in Preparation Example 1 was applied to a polypropylene (PP) microtube (#11510, manufactured by Nippon Genetics Co., Ltd.) using a commercially available spray coating and cleaning device, and the liquid accumulated at the bottom of the tube was removed by suction. Subsequently, the rack on which the tube was set was rotated 180°, and the tube was dried at 30 °C for 3 hours with the tube upside down. Subsequently, 1.7 mL of ultrapure water was added, and the operation of suction removal was repeated 3 times. After washing the tube, the tube was dried at 30 °C for 3 hours with the tube upside down to obtain a PP tube on which a coating film was formed. Hereinafter, it is referred to as "Coating Tube 6".

[0097] <Test Example 1> The rituximab solution (Rituxan intravenous drip injection, manufactured by Chugai Pharmaceutical Co., Ltd., #R1102AC) was purified, adjusted to a concentration of 1.0 mg / mL, and then sterilized by filtration through a 0.22 μm filter in a sterile environment. 0.5 mL of the prepared rituximab solution was filled into the untreated tube and the treated tube obtained in Example 1, respectively, and stored statically at 4 ± 3 °C for 24 hours. Also, it was set on a microtube stirring and shaking machine and shaken at 22 ± 3 °C and 2500 rpm for 24 hours. The presence or absence of turbidity was visually confirmed for the tubes stored under each condition. The appearance photograph is shown in Fig. 1. In the untreated tube, obvious turbidity was confirmed after stirring and shaking, and it was not seen in the coating tube. That is, it was confirmed that aggregation was clearly suppressed.

[0098] <Test Example 1-2> The solvent of Rituxan intravenous drip injection (manufactured by Zenyaku Kogyo Co., Ltd.) was exchanged, and a rituximab solution with a concentration of 1.0 mg / mL was prepared. After that, sterilization by filtration through a 0.22 μm filter was performed in a sterile environment. 0.5 mL of the prepared rituximab solution was filled into Coating Tubes 2 to 5 and the uncoated tubes obtained in Examples 2 to 5, respectively, and set on a microtube stirring and shaking machine and shaken at 22 ± 3 °C and 2500 rpm for 24 hours. After stirring and shaking, the solution in the tube was replaced with a transparent vial, and the presence or absence of turbidity was visually confirmed. The appearance photograph is shown in Fig. 2. In the untreated tube, obvious turbidity was confirmed after agitation and oscillation. On the other hand, in Coating Tubes 2 to 5, the turbidity was suppressed compared to the untreated tube, and it was confirmed that the generation of aggregates was suppressed.

[0099] <Test Example 1-3> After exchanging the solvent of Rituxan intravenous drip (manufactured by Chugai Pharmaceutical Co., Ltd.) and adjusting the rituximab solution to a concentration of 1.0 mg / mL, filtration sterilization treatment was performed with a 0.22 μm filter in a sterile environment. The prepared rituximab solution was filled into Coating Tube 6 obtained in Example 6, the untreated tube, ProteoSAVE SS 1.5 mL microtube (manufactured by Sumitomo Bakelite Co., Ltd., #MS-4215M, hereinafter referred to as Comparative Tube 1), 1.5 mL protein adsorption control sampling tube (manufactured by Sarstedt, #72.41152.006, hereinafter referred to as Comparative Tube 2), and Protein LoBind Tube 1.5 mL (Eppendorf, #0030108116, hereinafter referred to as Comparative Tube 3), 0.5 mL each, and stored statically at 4 ± 3 °C for 24 hours, or set in a microtube stirring oscillator and oscillated at 22 ± 3 °C and 2500 rpm for 24 hours. The tubes after stirring and oscillation at 22 °C for 24 hours were visually checked for the presence or absence of turbidity. The appearance photograph is shown in Figure 3. In the untreated tube and Comparative Tubes 1 to 3, obvious turbidity was confirmed after agitation and oscillation. On the other hand, in Coating Tube 6, the turbidity was suppressed, and it was confirmed that the generation of aggregates was suppressed.

[0100] <Test Example 1-4> After exchanging the solvent of Orenci intravenous drip (manufactured by Bristol-Myers Squibb) and adjusting the alectinib solution to a concentration of 1.0 mg / mL, filtration sterilization treatment was performed with a 0.22 μm filter in a sterile environment. The prepared alectinib solution was filled into Coating Tube 6 obtained in Example 6 and the uncoated tube, 0.5 mL each, set in a microtube stirring oscillator and oscillated at 22 ± 3 °C and 2500 rpm for 24 hours. After agitation and oscillation, the solution in the tube was replaced with a transparent vial, and the presence or absence of turbidity was visually checked. The appearance photograph is shown in Figure 4. In the untreated tube, obvious turbidity was confirmed after agitation and oscillation. In the coated tube 6, the turbidity was suppressed compared to the untreated tube, and it was confirmed that the generation of aggregates was suppressed.

[0101] <Test Example 2> The untreated tube and the coated tube that were shaken at 22°C for 24 hours obtained in Test Example 1 above were analyzed by size exclusion chromatography; SEC (HPLC system e2695, manufactured by Alliance) using a UV / Vis detector 2489 UV / Vis Detector for LC to detect UV at 215 nm and 280 nm. The column used was TSKgel G3000SWXL (manufactured by Tosoh Corporation), and 20 μL of the sample was eluted with PBS solution pH 7.4, a flow rate of 0.5 mL / min, and a column temperature of 30°C. Table 1 shows the percentage (%) of the total peak area under each condition when the average value of the total peak area of the coated tube after standing at 4°C for 24 hours was set to 100%. In the untreated tube after shaking at 22°C for 24 hours, only about 20% of the ratio of the total peak area of the coated tube after shaking at 22°C for 24 hours was confirmed. Despite measuring the same amount and the same concentration, since the ratio of the total peak area of the untreated tube after shaking at 22°C decreased, it was confirmed that the amount dissolved in the solution due to aggregation decreased.

[0102]

Table 1

[0103] <Test Example 2-2> The coated tube 6 and the untreated tube that were shaken at 22°C for 24 hours obtained in Test Examples 1-3 above were subjected to SEC analysis under the same conditions as in Test Example 2. Table A shows the value of the monomer area per 20 μL of the supernatant and the percentage (%) of the monomer area under each condition when the average value of the monomer area of the coated tube 6 after standing at 4°C for 24 hours was set to 100%.

[0104]

Table 2

[0105] In the untreated tube after shaking at 22°C for 24 hours, the monomer peak area ratio was 0.1% or less of that of the coated tube 6 after standing at 4°C for 24 hours, and in the coated tube 6 after shaking at 22°C for 24 hours, it was 97.8%. Despite measuring the same amount and the same concentration, since the monomer ratio in the untreated tube after shaking at 22°C decreased significantly, it was confirmed that the amount dissolved in the solution due to aggregation decreased.

[0106] <Test Example 3> Table 2 shows the results of particle measurement of the untreated tube and the coated tube shaken at 22°C for 24 hours obtained in Test Example 1 above using a flow imaging device (FlowCam 8100, manufactured by Fluid Imaging Technologies). Since the particle concentration of the untreated tube was too high to measure, it was measured after diluting 100 times. After shaking the untreated tube at 22°C for 24 hours, the particle concentration was several tens of thousands to several hundreds of thousands of times higher than that after standing at 4°C for 24 hours. In the coated tube, the particle concentration increased by several tens to several hundreds of times. That is, after shaking at 22°C for 24 hours, the untreated tube showed a particle concentration several hundred times higher than that of the coated tube. From these results, it was shown that the coated tube suppresses the increase in particle concentration due to stirring compared to the untreated tube.

[0107]

Table 3

[0108] <Test Example 3-2> The particle measurement of the coated tubes 6 oscillated at 22°C / 24 hours obtained in Test Examples 1-3 above, the untreated tubes, Comparative Tubes 1-3, and the coated tubes 6 oscillated at 22°C / 24 hours and the untreated tubes obtained in Test Example 1-4 was carried out under the same conditions as in Test Example 3 using a flow imaging device. The results using the rituximab solution are shown in Table B, and the results using the apatacept solution are shown in Table C. Note that since the particle concentration of the untreated tube tested using the rituximab solution was too high to be measured, it was diluted 100-fold and measured.

[0109]

Table 4

[0110]

Table 5

[0111] In the test using the rituximab solution, the particle concentration of the coated tube 6 was approximately 40 times lower than that of the untreated tube, and the effect of suppressing aggregate generation was confirmed. On the other hand, in Comparative Tubes 1-3, it was higher than the particle concentration of the untreated tube, and no effect of suppressing aggregate generation was observed. In the test using the apatacept solution, the particle concentration of the coated tube 6 was approximately 1000 times lower than that of the untreated tube, and the effect of suppressing aggregate generation was confirmed.

[0112] <Test Example 4> Regarding the coated tube 6 oscillated at 22°C / 24 hours and the untreated tube obtained in Test Examples 1-3 above, aggregates with a size of 5 μm or less were measured using a resonant mass measurement system Archimedes (manufactured by Malvern Panalytical). The results are shown in Table D. Note that since the particle concentration of the untreated tube was above the measurement limit of the device, it was diluted 100-fold and measured.

[0113]

Table 6

[0114] The particle concentration in the coating tube 6 was about 20 times lower than that in the untreated tube, and the effect of suppressing the generation of submicron-sized aggregates was confirmed.

Industrial Applicability

[0115] According to the present invention, a storage container for an antibody pharmaceutical solution capable of suppressing aggregation of an antibody pharmaceutical and a method for suppressing aggregation of an antibody pharmaceutical during storage can be provided.

Claims

1. A storage container for an antibody pharmaceutical solution, which has a hydrophilic coating film on at least a portion of its surface, wherein the coating film contains a polymer of a monomer having a hydrophilic functional group selected from phosphoric acid, phosphonic acid and their ester structures; a betaine structure; an amide structure; an alkylene glycol residue; an amino group; and a sulfinyl group, and the contact angle of air bubbles in water (25±5°C) is 150° or more.

2. The coating film is a copolymer including a repeating unit including a group represented by the following formula (a), a repeating unit including a group represented by the following formula (b), and a repeating unit including a group represented by the following formula (c): 【Chemistry 1】 [In the formula, U ａ１ , U ａ２ , 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; R ｃ represents a linear or branched alkyl group having 4 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 portion may be substituted with a linear or branched alkyl group having 1 to 5 carbon atoms which may be substituted with a halogen atom); A － The storage container for an antibody pharmaceutical solution according to claim 1 , wherein the coating film contains an anion selected from the group consisting of halide ions, inorganic acid ions, hydroxide ions and isothiocyanate ions.

3. The storage container for an antibody drug solution according to claim 1 or 2, in which aggregation of the antibody drug is suppressed.

4. The storage container for an antibody drug solution according to any one of claims 1 to 3, wherein the antibody drug comprises at least one of an antibody and an antigen-binding fragment thereof.

5. The storage container for an antibody pharmaceutical solution according to any one of claims 1 to 4, wherein the antibody pharmaceutical comprises at least one selected from the group consisting of a chimeric antibody, a human antibody, a humanized antibody, and a domain antibody thereof.

6. The antibody pharmaceutical solution storage container according to any one of claims 1 to 5, wherein the antibody pharmaceutical comprises at least one selected from the group consisting of ofatumumab, cetuximab, tocilizumab, bevacizumab, canakinumab, golimumab, ustekinumab, eculizumab, omalizumab, trastuzumab, pertuzumab, adalimumab, denosumab, mogamulizumab, rituximab, ranibizumab, infliximab, aflibercept, abatacept, etanercept, gemtuzumab ozogamicin, panitumumab, basiliximab, certolizumab pegol and palivizumab.

7. A polymer of a monomer having a hydrophilic functional group selected from phosphoric acid, phosphonic acid and their ester structures; a betaine structure; an amide structure; an alkylene glycol residue; an amino group; and a sulfinyl group, and a solvent. A composition for forming a coating film for producing a storage container for an antibody pharmaceutical solution, comprising:

8. (i) A copolymer comprising a repeating unit containing a group represented by the following formula (a), a repeating unit containing a group represented by the following formula (b), and a repeating unit containing a group represented by the following formula (c): 【Chemistry 2】 [In the formula, U ａ１ , U ａ２ , 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; R ｃ represents a linear or branched alkyl group having 4 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 portion may be substituted with a linear or branched alkyl group having 1 to 5 carbon atoms which may be substituted with a halogen atom); A － represents an anion selected from the group consisting of a halide ion, an inorganic acid ion, a hydroxide ion, and an isothiocyanate ion; and (ii) Solvent A coating film-forming composition for producing a storage container for an antibody pharmaceutical solution, comprising:

9. A method for suppressing aggregation of an antibody drug in an antibody drug solution, comprising the step of storing the antibody drug solution in a container having, on at least a portion of its surface, a coating film comprising a polymer of a monomer having a hydrophilic functional group selected from phosphoric acid, phosphonic acid and their ester structures; a betaine structure; an amide structure; an alkylene glycol residue; an amino group; and a sulfinyl group.

10. The method according to claim 9, wherein the coating film has a contact angle of an air bubble in water (25±5° C.) of 150° or more.

11. A method for suppressing aggregation of an antibody drug in an antibody drug solution, comprising: A copolymer comprising a repeating unit containing a group represented by the following formula (a), a repeating unit containing a group represented by the following formula (b), and a repeating unit containing a group represented by the following formula (c): 【Chemistry 3】 [In the formula, U ａ１ , U ａ２ , 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; R ｃ represents a linear or branched alkyl group having 4 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 portion may be substituted with a linear or branched alkyl group having 1 to 5 carbon atoms which may be substituted with a halogen atom); A － represents an anion selected from the group consisting of halide ions, inorganic acid ions, hydroxide ions, and isothiocyanate ions],

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