Copolymer and ophthalmic composition using same

Abstract

Provided is a copolymer which can remain on the surface of a cornea or a contact lens for a long period of time and which can maintain water retention and lubricity for a long period of time. The present invention is a copolymer containing structural units derived from a monomer (a) represented by formula (1a) or a salt thereof and a monomer (b) represented by formula (1b) or (2b), the molar ratio na: nb being 10: 90-70: 309, and the Mw of the copolymer being 10,000-2,000,000. [Formula 1] # imgabs0 # (R1 is H or CH3, X is O or NR2, R2 is H or C1-4 alkyl, and n is 1-4). ) (Formula 2) # imgabs1 # (wherein R3 is H or CH3, Y is O or NR4, R4 is H or C1-4 alkyl, m is 1-6, a hydroxyl group is optionally present in a carbon chain, A is a phosphorylcholine group or a hydroxyl group, and A is optionally H only when m = 1 or when a hydroxyl group is present in a carbon chain. ) [chemical formula 3] # imgabs2 # (R5 is H or CH3, and R6 is C1-4 alkyl or an alkylene group forming a cyclic structure with R5. )

Description

Technical Field

[0001] The present invention relates to a copolymer and an ophthalmic composition using the copolymer. Background Art

[0002] In recent years, due to the decrease in the number of blinks caused by long-term use of digital devices and the increase in the number of contact lens wearers, the number of potential dry eye patients in Japan is said to have reached 8 million. Dry eye is known to be induced by a decrease in the amount of tear fluid secreted by the lacrimal gland, abnormal evaporation of water caused by abnormalities in lipids or mucins in the tear fluid, etc., which causes a decrease in the function of the cornea or conjunctiva, inflammation, and infectious diseases.

[0003] To prevent / treat dry eye that causes these eye diseases, there is known an eye drop having a water retention property that prevents insufficient moistening. For example, in Patent Document 1, it is considered that an eye drop having hyaluronic acid or its salt and a cellulose-based polymer or a vinyl-based polymer can improve the symptoms of dry eye.

[0004] On the other hand, it is said that the number of contact lens users in Japan has reached 15 million, and the wearing time has become longer due to its convenience. There are also reports that the average daily wearing time of contact lens wearers in the young generation is about 14 hours, but long-term wearing easily causes discomfort such as a feeling of dryness and a foreign body sensation. Therefore, there is still a market demand for contact lenses with a continuously good wearing feeling.

[0005] It is considered that the discomfort during contact lens wearing is due to dryness or friction on the surface of the contact lens. As methods for solving these, for example, methods for imparting water retention and lubricity to contact lenses described in Patent Document 2 and Patent Document 3 are known. Patent Document 2 discloses a method of incorporating a hydrophilic polymer such as hyaluronic acid into a contact lens packaging solution. In addition, Patent Document 3 discloses a contact lens lubricating solution using a polyvinyl-based polymer compound or a cellulose-based polymer compound, etc.

[0006] Prior Art Documents

[0007] Patent Documents

[0008] Patent Document 1: Japanese Unexamined Patent Application Publication No. 2014 - 167034

[0009] Patent Document 2: International Publication No. 2013 / 031020

[0010] Patent Document 3: Japanese Unexamined Patent Application Publication No. 2005 - 187345 Summary of the Invention

[0011] Problems to be Solved by the Invention

[0012] However, although the above-mentioned cellulose-based polymers or vinyl-based polymers described in Patent Document 1 can alleviate the symptoms of dry eye by improving water retention, their retention on the cornea is insufficient, and there is a problem with the persistence of the effect. In addition, with the methods described in Patent Document 2 and Patent Document 3, the current situation is that the retention on contact lenses is insufficient and it will flow off over time. Therefore, a compound that can remain on the corneal surface and the contact lens surface for a long time and maintain water retention and lubricity is needed. Here, according to the inventors' opinion, a compound that interacts with mucin present on the surface of corneal epithelial cells or secreted in tears can remain on the corneal surface and the contact lens surface for a long time.

[0013] The present invention has been completed in view of the above problems, and an object thereof is to provide a copolymer that interacts with mucin and can continuously maintain water retention and lubricity for a long time, and an ophthalmic composition using the copolymer.

[0014] Solution to the problem

[0015] The inventors conducted in-depth research and found that a novel copolymer composed of a monomer having a guanidine group and a specific hydrophilic monomer can achieve the above object, thus completing the present invention.

[0016] That is, the present invention consists of the following [1] to [7].

[0017] [1] A copolymer comprising: a structural unit derived from a monomer (a) represented by the following formula (1a) or a salt thereof; and a structural unit derived from a monomer (b) represented by any one of the following formula (1b) and formula (2b), the molar ratio n a : n b is 10:90 to 70:30 (n a is the molar ratio of the structural unit derived from the monomer (a) or a salt thereof in the copolymer, and n b is the molar ratio of the structural unit derived from the monomer (b) in the copolymer.).

[0018] The weight-average molecular weight of the copolymer is 10,000 to 2,000,000.

[0019] [Chemical formula 1]

[0020]

[0021] (In formula (1a), R 1 is a hydrogen atom or a methyl group, X is O or NR 2 , wherein R 2 is H or an alkyl group having 1 to 4 carbon atoms, and n = 1 to 4.).

[0022] [Chemical formula 2]

[0023]

[0024] (In formula (1b), R 3 is a hydrogen atom or a methyl group, Y is O or NR 4 , wherein R 4 is H or an alkyl group having 1 to 4 carbon atoms, m is 1 to 6, and optionally has one or more hydroxyl groups in the carbon chain, A is a phosphorylcholine group or a hydroxyl group, and A is optionally a hydrogen atom only when m = 1 or when the carbon chain has a hydroxyl group.)

[0025] [Chemical formula 3]

[0026]

[0027] (In formula (2b), R 5 is a hydrogen atom or a methyl group, R 6 is an alkyl group having 1 to 4 carbon atoms or an alkylene group having 1 to 4 carbon atoms that forms a cyclic structure by bonding to the terminal of R 5 .)

[0028] [2] The copolymer according to [1], wherein the monomer (b) contains at least one monomer selected from the group consisting of the monomer represented by the following formula (3b), N-vinylpyrrolidone, 2-hydroxyethyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, 2-hydroxybutyl (meth)acrylate, hydroxyethyl (meth)acrylamide, glycerol mono(meth)acrylate, N,N-dimethyl(meth)acrylamide, N-vinylacetamide, and N-vinyl-N-methylacetamide.

[0029] [Chemical formula 4]

[0030]

[0031] (In formula (3b), R 7 is a hydrogen atom or a methyl group, Z is O or NR 8 , wherein R 8 is H or an alkyl group having 1 to 4 carbon atoms.)

[0032] [3] The copolymer according to [1] or [2], wherein the monomer (b) contains at least one of the monomer represented by formula (3b) and N-vinylpyrrolidone.

[0033] [4] The copolymer according to any one of [1] to [3], wherein the monomer (b) contains 2-(methacryloyloxy)ethyl 2-(trimethylammonio)ethyl phosphate.

[0034] [5] The copolymer according to any one of [1] to [4], wherein the monomer (a) or a salt thereof contains a monomer represented by the following formula (2a) or a salt thereof.

[0035] [Chemical Formula 5]

[0036]

[0037] (In formula (2a), R 1 is a hydrogen atom or a methyl group.)

[0038] [6] An ophthalmic composition containing 0.001 w / v% or more and 5.0 w / v% or less of the copolymer (P) according to any one of [1] to [5].

[0039] [7] The ophthalmic composition according to [6], further containing 0.001 w / v% or more and 10.0 w / v% or less of a polysaccharide or a glycoprotein.

[0040] Advantages of the Invention

[0041] The copolymer of the present invention can impart water retention and lubricity to the corneal surface or the surface of a contact lens, and can remain on the corneal surface or the surface of a contact lens for a long time to continuously exhibit these effects. Therefore, the copolymer of the present invention is useful as an ophthalmic composition and is suitable as an eye drop or a treatment solution for contact lenses. Brief Description of the Drawings

[0042] Figure 1 is a graph showing the 1 1H NMR measurement results of the copolymer (P1) in the examples. Detailed Description of the Invention

[0043] Hereinafter, the present invention will be described in more detail.

[0044] In this specification, when a preferred numerical range (such as a concentration range or a weight average molecular weight range, etc.) is described in stages, each lower limit value and upper limit value can be combined independently. For example, in the description of "preferably 10 to 100, more preferably 20 to 90", the "preferred lower limit value: 10" can be combined with the "more preferred upper limit value: 90" to be "10 or more and 90 or less". That is, it can be set to "10 to 90".

[0045] In the present invention, "(meth)acryloyl group" means acryloyl group or methacryloyl group, "(meth)acrylamide group" means acrylamide group or methacrylamide group, "(meth)acrylate" means acrylate or methacrylate, and "(meth)acrylamide" means acrylamide or methacrylamide.

[0046] As the product forms of the ophthalmic composition of the present invention, including the composition directly applied to the eye and the composition used for treating devices worn on the eye such as contact lenses, the following product forms can be described. Specifically, examples include eye drops, eye washes, contact lens treatment solutions, etc. Further, as specific product forms of the contact lens treatment solution of the present invention, examples include contact lens packaging solutions (contact lens factory solutions), contact lens preservation solutions, contact lens cleaning solutions, contact lens cleaning and preservation solutions, contact lens disinfectants, contact lens lubricating solutions, etc.

[0047] In this specification, the contact lens packaging solution refers to an aqueous solution encapsulated in a packaging container such as a blister package together with the contact lens during the distribution of the contact lens. Since contact lenses are generally used in a state swollen by the aqueous solution, the lenses are encapsulated in the packaging container in a state swollen by the aqueous solution (contact lens packaging solution) at the time of factory shipment so that they can be used immediately.

[0048] [Copolymer (P)]

[0049] The copolymer (P) of the present invention is obtained by polymerizing the monomer (a) represented by the following formula (1a) or its salt and the monomer (b) represented by any one of the following formula (1b) and formula (2b). Therefore, the copolymer (P) contains a structural unit derived from the monomer (a) or its salt and a structural unit derived from the monomer (b). In the copolymer (P), the molar ratio n a :n b is 10:90 to 70:30, and the weight average molecular weight of the copolymer (P) is 10,000 to 2,000,000.

[0050] [Chemical Formula 6]

[0051]

[0052] In the formula (1a), R 1 is a hydrogen atom or a methyl group, X is O or NR 2 , where R 2 is H or an alkyl group having 1 to 4 carbon atoms, and n = 1 to 4.

[0053] [Chemical Formula 7]

[0054]

[0055] In the formula (1b), R 3 is a hydrogen atom or a methyl group, Y is O or NR 4 , where R 4R is H or an alkyl group having 1 to 4 carbon atoms, m is 1 to 6, the carbon chain optionally has one or more hydroxyl groups, A is a phosphorylcholine group or a hydroxyl group, and A is optionally a hydrogen atom only when m = 1 or when the carbon chain has a hydroxyl group.

[0056] [Chemical Formula 8]

[0057]

[0058] In the formula (2b), R 5 is a hydrogen atom or a methyl group, R 6 is an alkyl group having 1 to 4 carbon atoms or an alkylene group having 1 to 4 carbon atoms that is terminally bonded to R 5 to form a cyclic structure.

[0059] [Monomer (a)]

[0060] The copolymer (P) of the present invention is obtained by using a monomer (a) having a guanidine group represented by the formula (1a) (hereinafter, also referred to as "GE monomer (a)") or a salt thereof in the polymerization. Examples of the type of salt include: hydrochloride, carbonate, bicarbonate, phosphate, sulfate, etc. Hydrochloride, carbonate or bicarbonate is preferred, and hydrochloride is more preferred. Since the copolymer (P) has GE monomer (a) or a salt thereof as a constituent monomer, the copolymer (P) easily interacts with mucin, and its retention on the corneal surface and the contact lens surface can be improved. It should be noted that GE monomer (a) is not limited to one kind, and one kind or two or more kinds can be used.

[0061] GE monomer (a) is preferably a monomer with n = 2 in the formula (1).

[0062] As a preferred example of GE monomer (a) with n = 2, a monomer represented by the formula (2a) in which X is O can be cited.

[0063] [Chemical Formula 9]

[0064]

[0065] In the formula (2a), R 1 is a hydrogen atom or a methyl group.

[0066] As a more preferred example of the monomer represented by the formula (2a), 2-guanidinoethyl methacrylate in which R 1 is a methyl group can be cited.

[0067] In addition, as other preferred examples of GE monomer (a) with n = 2, 2-guanidinoethyl methacrylamide in which R 1 is a methyl group and X is NR 3 , R 3 is H, etc. can be cited.

[0068] The monomer represented by the formula (1a) can be produced by a known method. For example, it can be produced by the method of reacting a polymerizable monomer containing an amino group with 1-amidinopyrazole hydrochloride in the presence of a base as described in Barner-Kowollik, Christopher; et al Polymer Chemistry (2020), 11(26), 4213-4220 (hereinafter, Reference 1) and Zhao, Qingqing; et al Chemical Communications (2020), 56(36), 4954-4957 (hereinafter, Reference 2).

[0069] [Monomer (b)]

[0070] The copolymer (P) of the present invention is obtained by using the monomer (b) represented by any one of the formulas (1b) and (2b) in the polymerization. By copolymerizing these hydrophilic monomers (b), the dry resistance of the ophthalmic composition containing the copolymer (P) on the corneal surface or the contact lens surface can be improved.

[0071] Preferred examples of the monomer (b) include: hydroxyalkyl (meth)acrylate in which Y in the formula (1b) is O and A is a hydroxyl group; hydroxyalkyl (meth)acrylamide in which Y is NH and A is a hydroxyl group; N,N-dimethyl (meth)acrylamide in which Y is N, R4 is a methyl group, m = 1, and A is a hydrogen atom; glycerol mono(meth)acrylate in which Y is O, m = 3, and a hydroxyl group is present at the 2-position and A is a hydroxyl group; the monomer represented by the formula (3b) in which m = 2 and A is a phosphorylcholine group. Other preferred examples of the monomer (b) include: N-vinylacetamide or N-methyl-N-vinylacetamide in which R6 in the formula (2b) is a methyl group; N-vinylpyrrolidone having a cyclic structure in which R6 is an ethylene group. More preferably, the monomer represented by the following formula (3b), N-vinylpyrrolidone, 2-hydroxyethyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, 2-hydroxybutyl (meth)acrylate, hydroxyethyl (meth)acrylamide, glycerol mono(meth)acrylate, N,N-dimethyl (meth)acrylamide, N-vinylacetamide, N-vinyl-N-methylacetamide, N-vinylpyrrolidone are mentioned. Further preferably, the monomer represented by the formula (3b) or N-vinylpyrrolidone is mentioned, and even more preferably, the monomer represented by (3b) is cited. If the monomer represented by the formula (3b) or N-vinylpyrrolidone, particularly the monomer represented by the formula (3b), is used, the dry resistance of the ophthalmic composition containing the copolymer (P) on the corneal surface or the contact lens surface can be further improved. It should be noted that these monomers (b) are not limited to one kind, and one kind or two or more kinds can be used.

[0072] [Chemical Formula 10]

[0073]

[0074] In the formula (3b), R 7 is a hydrogen atom or a methyl group, and Z is O or NR 8 , where R 8 is H or an alkyl group having 1 to 4 carbon atoms.

[0075] Examples of the monomer represented by the formula (3b) include 2-((meth)acryloyloxy)ethyl-2-(trimethylammonio)ethyl phosphate and 2-((meth)acrylamide)ethyl-2-(trimethylammonio)ethyl phosphate, and more preferably 2-(methacryloyloxy)ethyl 2-(trimethylammonio)ethyl phosphate (alias: 2-methacryloyloxyethyl phosphorylcholine).

[0076] The monomer represented by the formula (3b) can be produced by a known method. For example, a method of reacting a hydroxyl group-containing polymerizable monomer with 2-bromoethylphosphoryl dichloride in the presence of a tertiary base and reacting the resulting compound with a tertiary amine can be mentioned. In addition, a method of obtaining a cyclic compound by reacting a hydroxyl group-containing polymerizable monomer with a cyclic phosphorus compound and then performing a ring-opening reaction with a tertiary amine can also be used.

[0077] [Ratio of GE monomer (a) to monomer (b)]

[0078] The molar ratio n a : n b of the structural unit derived from the GE monomer (a) or its salt to the structural unit derived from the monomer (b) in the copolymer (P) is 10:90 to 70:30, preferably 20:80 to 60:40, and more preferably 30:70 to 50:50. Here, n a is the molar fraction of the structural unit derived from the GE monomer (a) or its salt in the copolymer (P), and n b is the molar fraction of the structural unit derived from the monomer (b) in the copolymer (P). In addition, a plurality of GE monomers (a) can be used in any ratio. In this case, n a refers to the total number of moles of all the GE monomers. Similarly, a plurality of monomers (b) can be used in any ratio. In this case, n b refers to the total number of moles of all the monomers (b).

[0079] By increasing n a or decreasing n b, can enhance the interaction of the copolymer (P) with the ocular surface or the contact lens surface, enabling it to remain on the corneal surface or the contact lens surface for a longer time. In addition, it can also improve the lubricity imparted to the cornea or the contact lens by the ophthalmic composition containing the copolymer (P). Furthermore, by increasing n b , the solubility of the copolymer (P) in water can be increased, making it easier to formulate the ophthalmic composition.

[0080] [Other monomers]

[0081] Within the scope that does not impair the effects of the present invention, the copolymer (P) of the present invention may also contain a monomer (c) other than the GE monomer (a) and the monomer (b).

[0082] The monomer (c) can be arbitrarily selected from monomers (c) that can copolymerize with the GE monomer (a) and the monomer (b).

[0083] Examples of such a monomer (c) include: styrenesulfonic acid, (meth)acryloyloxyphosphonic acid, 2-hydroxy-3-(meth)acryloyloxypropyltrimethylammonium chloride, polyethylene glycol (meth)acrylate, (meth)acrylic acid aminoethyl ester, (meth)acrylic acid N,N-dimethylaminoethyl ester, N-acryloylmorpholine, (meth)acrylic acid ethyl ester, (meth)acrylic acid propyl ester, (meth)acrylic acid butyl ester, (meth)acrylic acid cyclohexyl ester, (meth)acrylic acid 2-ethylhexyl ester, (meth)acrylic acid n-octyl ester, (meth)acrylic acid isononyl ester, (meth)acrylic acid dodecyl ester, (meth)acrylic acid stearyl ester, styrene, α-methylstyrene, vinyltoluene, indene, vinylnaphthalene, vinylaniline, ethylene, propylene, butadiene, isobutene, octene and other olefins, acrylonitrile, methacrylonitrile, polypropylene glycol (meth)acrylate, glycidyl (meth)acrylate, etc. One or more of them can be used. The ratio of the monomer (c) in all the monomers used in formulating the copolymer of the present invention is preferably set to 30 mol% or less, more preferably set to 15 mol% or less. The lower limit value of the ratio of the monomer (c) is not particularly limited and can be set to 0 mol% or more. This is because the effects of the present invention are preferably manifested.

[0084] [Weight-average molecular weight of the copolymer (P)]

[0085] The weight-average molecular weight of the copolymer (P) used in the present invention is 10,000 to 2,000,000, preferably 100,000 to 1,000,000, more preferably 150,000 to 600,000, and still more preferably 200,000 to 400,000. By making the weight-average molecular weight of the copolymer (P) greater than 10,000, it can be retained on the corneal surface or the contact lens surface for a longer time. In addition, the effects of lubricity and water retention imparted to the cornea or contact lens by the ophthalmic composition containing the copolymer (P) can be improved. As a result, the dry resistance of the ophthalmic composition containing the copolymer (P) on the corneal surface or the contact lens surface can be improved. By making the weight-average molecular weight of the copolymer (P) less than 2,000,000, its handling becomes easy.

[0086] It should be noted that the weight-average molecular weight of the copolymer (P) is determined by GPC (gel permeation chromatography) and calculated in terms of pullulan conversion.

[0087] [Polymerization form of copolymer (P)]

[0088] The copolymer (P) is usually a random copolymer, but it can also be an alternating copolymer or a block copolymer in which each monomer is regularly arranged, and it can also have a graft structure in part.

[0089] [Manufacturing method of copolymer (P)]

[0090] The copolymer (P) can be produced by copolymerizing the guanidine group-containing GE monomer (a) represented by the following formula (1a) with the monomer (b) represented by any one of the following formulas (1b) and (2b).

[0091] [Chemical formula 11]

[0092]

[0093] In the formula (1a), R 1 is a hydrogen atom or a methyl group, X is O or NR 2 , where R 2 is H or an alkyl group having 1 to 4 carbon atoms, and n = 1 to 4.

[0094] [Chemical formula 12]

[0095]

[0096] In the formula (1b), R 3 is a hydrogen atom or a methyl group, Y is O or NR 4 , where R 4R is H or an alkyl group having 1 to 4 carbon atoms, m is 1 to 6, and the carbon chain optionally has one or more hydroxyl groups. A is a phosphorylcholine group or a hydroxyl group, and A is optionally a hydrogen atom only when m = 1 or when the carbon chain has a hydroxyl group.

[0097] [Chemical Formula 13]

[0098]

[0099] In the formula (2b), R 5 is a hydrogen atom or a methyl group, and R 6 is an alkyl group having 1 to 4 carbon atoms or an alkylene group having 1 to 4 carbon atoms that is terminally bonded to R 5 to form a cyclic structure.

[0100] The above polymerization reaction can be carried out by radical polymerization, such as bulk polymerization, suspension polymerization, emulsion polymerization, solution polymerization, etc., in the presence of a radical polymerization initiator, in an atmosphere replaced with an inert gas such as nitrogen, carbon dioxide, argon, helium, etc. From the viewpoints of purification, etc., solution polymerization is preferably cited. The purification of the copolymer can be carried out by general purification methods such as reprecipitation method, dialysis method, ultrafiltration method, etc.

[0101] Examples of the radical polymerization initiator include azo-based radical polymerization initiators, organic peroxides, persulfates, etc.

[0102] Examples of the azo-based radical polymerization initiator include 2,2'-azobis(2-methylpropionamidine) dihydrochloride (V-50), 2,2-azobis(2-diaminopropyl) dihydrochloride, 2,2-azobis(2-(5-methyl-2-imidazolin-2-yl)propane) dihydrochloride, 4,4-azobis(4-cyanovaleric acid), 2,2-azobisisobutyramide dihydrate, 2,2-azobis(2,4-dimethylvaleronitrile), 2,2-azobisisobutyronitrile (AIBN), etc.

[0103] Examples of the organic peroxide include tert-butyl peroxyneodecanoate (PERBUTYL (registered trademark) ND), benzoyl peroxide, diisopropyl peroxydicarbonate, tert-butyl peroxy-2-ethylhexanoate, tert-butyl peroxypivalate, tert-butyl diisobutyrate, lauroyl peroxide, succinic peroxide (peroxysuccinyl), etc.

[0104] Examples of the persulfate include ammonium persulfate, potassium persulfate, sodium persulfate, etc.

[0105] As the radical polymerization initiator, an azo-based radical polymerization initiator is preferably used, and 2,2'-azobis(2-methylpropionamidine) dihydrochloride (V-50) is more preferably used.

[0106] These radical polymerization initiators can be used alone or in combination of two or more. Based on 100 parts by mass of the monomer composition of the copolymer (P), the amount of the polymerization initiator is usually 0.001 to 10 parts by mass, preferably 0.01 to 5.0 parts by mass.

[0107] The polymerization reaction can be carried out in the presence of a solvent. As the solvent, a solvent that can dissolve the monomer composition and does not react can be used. Examples of such solvents include: alcohol solvents such as water, methanol, ethanol, n-propanol, and isopropanol; ketone solvents such as acetone, methyl ethyl ketone, and diethyl ketone; ester solvents such as ethyl acetate; linear or cyclic ether solvents such as ethyl cellosolve, tetrahydrofuran, and N-methylpyrrolidone; and nitrogen-containing solvents such as acetonitrile and nitromethane. Preferably, water or alcohol or a mixed solvent thereof is mentioned, and more preferably water.

[0108] [Ophthalmic composition of the present invention]

[0109] In the ophthalmic composition of the present invention, the concentration of the copolymer (P) is 0.001 w / v% or more, preferably 0.01 w / v% or more, and more preferably 0.1 w / v% or more. In addition, the concentration of the copolymer (P) is 5.0 w / v% or less, preferably 2.0 w / v% or less, and more preferably 0.7 w / v% or less. By setting the concentration of the copolymer (P) to 0.001 w / v% or more, sufficient lubricity and water retention can be obtained. In addition, from the viewpoint of the manufacturability of the ophthalmic composition, it is preferable to set the concentration of the copolymer (P) to 5.0 w / v% or less.

[0110] It should be noted that in the present invention, "w / v%" is a unit representing the mass of a certain component in 100 mL of a solution in grams (g). For example, "the composition of the present invention contains 1.0 w / v% of the copolymer (P)" means that 100 mL of the solution contains 1.0 g of the copolymer (P).

[0111] As the solvent used in the ophthalmic composition of the present invention, water, ethanol, n-propanol, isopropanol, glycerin, propylene glycol, or other alcohols or a mixed solvent thereof can be used. Preferably, water or a mixed solvent of water and alcohol is used, and more preferably water.

[0112] As the water used in the ophthalmic composition of the present invention, water usually used in the manufacture of drugs or medical devices can be used. Specifically, ion-exchanged water, purified water, sterilized purified water, distilled water, and water for injection can be used.

[0113] The ophthalmic composition of the present invention may contain a buffering agent. By containing a buffering agent, the ophthalmic composition of the present invention can adjust the pH and osmotic pressure, and can further improve the usability.

[0114] In the present invention, from the viewpoint of more fully obtaining the above effects, it is preferable to use one or more selected from phosphate buffers and borate buffers as the buffer. In this specification, the phosphate buffer is a buffer composed of disodium hydrogen phosphate, sodium dihydrogen phosphate, anhydrous sodium dihydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, sodium hydroxide, potassium hydroxide, etc., and the borate buffer is a buffer composed of boric acid, borax, hydrochloric acid, sodium hydroxide, potassium hydroxide, etc.

[0115] The concentration of the buffer in the ophthalmic composition of the present invention is preferably 0.0001 w / v% or more and 15 w / v% or less, more preferably 0.001 w / v% or more and 10 w / v% or less, and still more preferably 0.01 w / v% or more and 5.0 w / v% or less.

[0116] Especially when using one or more selected from phosphate buffers and borate buffers as the buffer, expressed as the total of the components of the phosphate buffer and the borate buffer, the concentration is preferably 0.001 w / v% or more and 10 w / v% or less, more preferably 0.01 w / v% or more and 5.0 w / v% or less, and still more preferably 0.1 w / v% or more and 5.0 w / v% or less.

[0117] The ophthalmic composition of the present invention may also be formulated with a congestion-removing component, an anti-inflammatory / astringent component, vitamins, a cooling agent, an isotonic agent, a pH adjuster, an antioxidant, a stabilizer, a preservative, a mucin secretion promoter, a thickener, etc., which can generally be used in ophthalmic preparations, as needed.

[0118] Examples of the congestion-removing component include: adrenaline or its salt, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline or its salt, phenylephrine, methylephedrine hydrochloride.

[0119] Examples of the anti-inflammatory / astringent component include: ε-aminocaproic acid, allantoin, berberine or its salt, sodium azulene sulfonate, glycyrrhizic acid or its salt, zinc lactate, zinc sulfate, lysozyme chloride.

[0120] Examples of the vitamins include: sodium flavin adenine dinucleotide, cyanocobalamin, retinyl acetate, retinyl palmitate, pyridoxine hydrochloride, panthenol, sodium pantothenate, calcium pantothenate.

[0121] Examples of the cooling agent include: menthol, camphor.

[0122] Examples of the isotonic agent include: sodium chloride, potassium chloride, magnesium chloride, calcium chloride, aspartic acid or its salt, aminoethylsulfonic acid.

[0123] Examples of the pH adjuster include: citric acid, sulfuric acid, acetic acid, tris(hydroxymethyl)aminomethane, monoethanolamine, sodium bicarbonate, sodium citrate.

[0124] Examples of antioxidants include tocopheryl acetate, butylated hydroxytoluene, and sodium bisulfite.

[0125] Examples of stabilizers include sodium ethylenediaminetetraacetate, glycine, and taurine.

[0126] Examples of preservatives include benzalkonium chloride, chlorhexidine gluconate, potassium sorbate, methyl paraben, ethyl paraben, propyl paraben, isopropyl paraben, butyl paraben, isobutyl paraben, polyhexamethylene biguanide hydrochloride, sulfamethoxazole or its salts, sulfafurazole, sulfamethazine sodium.

[0127] Examples of mucin secretion promoters include diclofenac sodium and rebamipide.

[0128] Examples of thickeners include poly(meth)acrylic acid, (meth)acrylic acid-acrylic (meth)acrylate copolymer, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and polyethylene glycol.

[0129] The ophthalmic composition of the present invention may contain a polysaccharide or glycoprotein in an amount of 0.001 w / v% or more and 10.0 w / v% or less. Examples of such compounds include, as polysaccharides, hyaluronic acid or its salts, chondroitin sulfate or its salts, alginic acid or its salts, chitosan, pullulan, agar, starch, xanthan gum, and gellan gum. Examples of glycoproteins include proteoglycans. Hyaluronic acid or its salts, chondroitin sulfate or its salts, and proteoglycans are preferred, and hyaluronic acid or proteoglycans are more preferred.

[0130] From the viewpoint of irritation to the eye, the pH of the ophthalmic composition of the present invention is preferably 3.0 or more and 8.0 or less, more preferably 3.8 or more and 7.8 or less, and further preferably 4.0 or more and 7.6 or less.

[0131] From the viewpoint of irritation to the eye, the osmotic pressure of the ophthalmic composition of the present invention is 200 mOsm or more and 400 mOsm or less, more preferably 225 mOsm or more and 375 mOsm or less, and further preferably 230 mOsm or more and 340 mOsm or less. The osmotic pressure ratio is preferably 0.7 or more and 1.4 or less, more preferably 0.7 or more and 1.3 or less, and further preferably 0.8 or more and 1.2 or less.

[0132] It should be noted that the osmotic pressure of the treatment liquid for contact lenses in this specification refers to the value measured according to the General Test Method 2.47 Osmotic Pressure Measurement Method (Osmolality Measurement Method) in the 18th Revised Japanese Pharmacopoeia, and the osmotic pressure ratio refers to the value obtained by dividing the measured osmotic pressure value by the osmotic pressure value (286 mOsm) of 0.9 mass% physiological saline.

[0133] Example

[0134] Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples. It should be noted that various measurements in the examples (and comparative examples) were carried out according to the methods shown below.

[0135] Synthesis of copolymer

[0136] <Measurement of weight-average molecular weight>

[0137] The obtained copolymer was dissolved in ion-exchanged water to a concentration of 0.1 wt%, and the weight-average molecular weight was measured by gel permeation chromatography (GPC).

[0138] Column: Shodex (GSM-700)

[0139] Mobile phase: 0.1 mol / L aqueous sodium sulfate solution

[0140] Standard substance: Pullulan (PSS-pulkitr1h) (manufactured by Polymer Standards)

[0141] Detection instrument: Differential refractive index RI-8020 (manufactured by Tosoh Corporation)

[0142] Calculation method of weight-average molecular weight: Molecular weight calculation program (GPC program for SC-8020)

[0143] Flow rate: 1.0 mL per minute

[0144] Injection volume: 100 μL

[0145] Column oven: 40 °C

[0146] Measurement time: 30 minutes

[0147] <Example 1-1>

[0148] Weigh 3.3 g of 2-guanidinoethyl methacrylate hydrochloride as monomer (a) and 4.7 g of 2-(methacryloyloxy)ethyl 2-(trimethylammonio)ethyl phosphate (hereinafter also referred to as MPC) as monomer (b) into a four-necked flask, add 31.0 g of ion-exchanged water and heat to 70 °C for dissolution. Then, add 0.06 g of 2,2'-azobis(2-methylpropionamidine) dihydrochloride diluted with 1 g of ion-exchanged water and carry out a polymerization reaction at 70 °C for 2 hours. After the reaction is completed, dialysis purification is carried out to obtain a copolymer of 2-guanidinoethyl methacrylate hydrochloride / 2-methacryloyloxyethyl phosphorylcholine (P1). The polymerization conditions and weight-average molecular weight are shown in Table 1. The synthesis of 2-guanidinoethyl methacrylate hydrochloride is carried out by the method described in the above reference 1.

[0149] For the copolymer (P1), 1 the 1H NMR measurement results are as Figure 1 shown below.

[0150] 1 1H NMR measurement results

[0151] C(=O)-O- CH2―CH2 -O-, P-O- CH2 -CH2-, C(=O)-O- CH2 -CH2-NH-: 4.2 to 3.8 ppm, CH2 -N + (CH3)3, C(=O)-O-CH2- CH2 -NH-: 3.6 to 3.3 ppm, N + (CH3)3: 3.1 ppm, C(CH3)- CH2 -: 2.0 to 1.6 ppm, C( CH3 )-CH2-: 1.2 to 0.6 ppm

[0152] <Examples 1-2 to 1-6>

[0153] As shown in Table 1, set the feeding composition and concentration of the monomers and carry out the synthesis in the same operation steps as in Example 1-1 to obtain copolymers P2 to P6. The measurement results of the weight-average molecular weight are shown in Table 1. The synthesis of 2-guanidinoethyl methacrylamide is carried out by the method described in the above reference 2.

[0154] For the copolymers (P2 to P6), 1 the 1H NMR measurement results are as follows.

[0155] 1 1H NMR measurement results

[0156] (P2)C(=O)-O-CH2―CH2 —O—, P—O— CH2 —CH2—, C(=O)—O— CH2 —CH2—NH—: 4.2 to 3.8 ppm, CH2 —N + (CH3)3, C(=O)—O—CH2— CH2 —NH—: 3.6 to 3.3 ppm, N + (CH3)3: 3.1 ppm, C(CH3)— CH2 —: 2.0 to 1.6 ppm, C( CH3 )—CH2—: 1.2 to 0.6 ppm

[0157] (P3)C(=O)—O— CH2 —CH2—NH—: 4.2 to 3.8 ppm, CH2— CH —N—: 3.7 ppm, C(=O)—O—CH2— CH2 —NH—: 3.6 to 3.3 ppm, (C=O)N—CH2—: 3.2 ppm, N(C=O)—CH2—: 2.3 ppm, CH2 —CH—N—: 2.0 ppm, C(CH3)- CH2 -: 2.0 to 1.6 ppm, CH2— CH2 —CH2—: 1.7 ppm, C( CH3 )—CH2—: 1.2 to 0.6 ppm

[0158] (P4)C(=O)—O— CH2―CH2 —O—, P—O— CH2 —CH2—: 4.2 to 3.8 ppm, CH2 —N + (CH3)3: 3.6 to 3.3 ppm, C(=O)—NH— CH2―CH2 —NH-: 3.4 to 3.2 ppm, N + (CH3)3: 3.1 ppm, C(CH3)- CH2 -: 2.0 to 1.6 ppm, C( CH3 )—CH2—: 1.2 to 0.6 ppm

[0159] (P5)C(=O)—O— CH2―CH2 —O—, P—O— CH2 —CH2—: 4.2 to 3.8 ppm, CH2— CH -N-: 3.7 ppm, CH2 —N + (CH3)3, C(=O)—O—CH2— CH2―NH―: 3.6 - 3.3 ppm, (C=O)N―CH2―: 3.2 ppm, N + (CH3)3: 3.1 ppm, N(C=O)―CH2―: 2.3 ppm, CH2 ―CH―N―: 2.0 ppm, C(CH3)― CH2 ―: 2.0 - 1.6 ppm, CH2― CH2 ―CH2―: 1.7 ppm, C( CH3 )―CH2―: 1.2 - 0.6 ppm

[0160] (P6)C(=O)―O― CH2―CH2 ―O―, P―O― CH2 ―CH2―, C(=O)―O― CH2 ―CH2―NH―: 4.2 - 3.8 ppm, CH2 ―N + (CH3)3, C(=O)―O―CH2― CH2 ―NH―: 3.6 - 3.3 ppm, N + (CH3)3: 3.1 ppm, C(CH3)― CH2 ―: 2.0 - 1.6 ppm, C( CH3 )―CH2―: 1.2 - 0.6 ppm

[0161] Table 1

[0162]

[0163] <Comparative Example 1 - 1>

[0164] Weighed 4.0 g of 2 - guanidinoethyl methacrylate hydrochloride into a four - necked flask, added 31.0 g of ion - exchanged water and heated to 70 °C for dissolution. Then, added 0.06 g of 2,2’ - azobis(2 - methylpropionamidine) dihydrochloride diluted with 1.0 g of ion - exchanged water, and carried out a polymerization reaction at 70 °C for 2 hours. After the reaction was completed, dialysis purification was carried out to obtain a homopolymer Q1 of 2 - guanidinoethyl methacrylate hydrochloride (weight - average molecular weight: 570,000).

[0165] <Comparative Example 1 - 2>

[0166] Dissolved 12.8 g of MPC in 26.2 g of ion - exchanged water, added it to a four - necked flask and purged with nitrogen for 30 minutes. Then, added 0.1 g of 2,2’ - azobis(2 - methylpropionamidine) dihydrochloride diluted with 1.0 g of ion - exchanged water, and carried out a polymerization reaction at 70 °C for 6 hours. After the reaction was completed, dialysis purification was carried out to obtain a homopolymer Q2 of MPC (weight - average molecular weight: 330,000).

[0167] <Comparative Examples 1-3>

[0168] The N-vinylpyrrolidone homopolymer (PVP K30) (weight-average molecular weight: 50,000) (manufactured by FUJIFILM Wako Pure Chemical Corporation) was used as the comparative polymer Q3.

[0169] 2. Evaluation of the copolymer

[0170] The copolymers of the present invention and copolymers other than the present invention were evaluated according to the following method. The following lenses were used as test contact lenses. The solution compositions and evaluation results are shown in Tables 2 to 4.

[0171] Lens A: Commercially available etafilcon A

[0172] Lens B: Commercially available hioxyfilcon A

[0173] <Preparation of physiological saline>

[0174] With reference to the literature (ISO 18369-3: 2006, Ophthalmic Optics - Contact Lenses Part 3: Measurement Methods.), physiological saline was prepared.

[0175] 8.3 g of sodium chloride, 5.993 g of disodium hydrogen phosphate dodecahydrate, and 0.528 g of sodium dihydrogen phosphate dihydrate were weighed, dissolved in water to make 1000 mL, and filtered to prepare physiological saline.

[0176] <Preparation of contact lens treatment solution>

[0177] Using the above-prepared ISO physiological saline and the copolymer, they were formulated according to Tables 2 and 3, thereby preparing the contact lens treatment solutions of Examples 2-1 to 2-10 and Comparative Examples 2-1 to 2-4.

[0178] <Evaluation of hydrophilicity>

[0179] In the examples and comparative examples, the hydrophilicity evaluation of the contact lenses was carried out according to the following procedure.

[0180] ○ Evaluation assuming the situation at the start of contact lens wearing

[0181] (1) One test contact lens taken out from the blister package was immersed in physiological saline and shaken for 6 hours.

[0182] (2) The test contact lens was taken out and sealed in a glass vial containing 5 mL of the above contact lens treatment solution.

[0183] (3) Sterilize under the conditions of 121 °C for 20 minutes.

[0184] (4) Take out the test contact lens and measure the time (BUT) until the water film on the lens surface breaks with a stopwatch, and evaluate the difference from the measured value of the test contact lens treated in the same way with ISO physiological saline according to the following criteria.

[0185] ○ Evaluation assuming the situation at the end of contact lens wearing

[0186] (1) Immerse one test contact lens taken out from the blister pack in physiological saline and shake for 6 hours.

[0187] (2) Take out the test contact lens and encapsulate it in a glass vial containing 5 mL of the above-mentioned treatment solution for contact lenses.

[0188] (3) Sterilize under the conditions of 121 °C for 20 minutes.

[0189] (4) Immerse one test contact lens taken out from the glass vial in physiological saline and shake for 6 hours.

[0190] (5) Take out the test contact lens and measure the time (BUT) until the water film on the lens surface breaks with a stopwatch, and evaluate the difference from the measured value of the test contact lens treated in the same way with ISO physiological saline according to the following criteria.

[0191] It should be noted that the BUT of lens A treated in the same way with ISO physiological saline is 8.4 seconds, and the BUT of lens B is 8.6 seconds.

[0192] Scoring criteria

[0193] Extended by more than 10 seconds: Score "3"

[0194] Extended by more than 5 seconds and less than 10 seconds: Score "2"

[0195] Extended by more than 1 second and less than 5 seconds: Score "1"

[0196] Extended by less than 1 second: Score "0"

[0197] <Lubricity evaluation>

[0198] In the examples and comparative examples, the lubricity evaluation of the contact lenses was carried out according to the following operating steps.

[0199] ○ Evaluation assuming the situation at the start of contact lens wearing

[0200] (1) Immerse one test contact lens taken out from the blister pack in physiological saline and shake for 6 hours.

[0201] (2) Take out the test contact lens and encapsulate it in a small glass bottle containing 5 mL of the above-mentioned contact lens treatment solution.

[0202] (3) Perform sterilization treatment under the conditions of 121 °C for 20 minutes.

[0203] (4) Take out the test contact lens and evaluate the degree of lubricity when rubbing with the index finger and thumb according to the following criteria.

[0204] ○ Evaluation considering the situation at the end of contact lens wearing

[0205] (1) Immerse one test contact lens taken out from the blister package in physiological saline and shake for 6 hours.

[0206] (2) Take out the test contact lens and encapsulate it in a small glass bottle containing 5 mL of the above-mentioned contact lens treatment solution.

[0207] (3) Perform sterilization treatment under the conditions of 121 °C for 20 minutes.

[0208] (4) Immerse one test contact lens taken out from the small glass bottle in physiological saline and shake for 6 hours.

[0209] (5) Take out the test contact lens and evaluate the degree of lubricity when rubbing with the index finger and thumb according to the following criteria.

[0210] Scoring criteria

[0211] Set the score of Polymacon as 2 points and the score of omafilcon A as 8 points, and score within the range of 1 - 10 points. Compare with the scores of the test contact lenses treated with ISO physiological saline and evaluate according to the following criteria. Note that the score of lens A treated with ISO physiological saline is 3 points and the score of lens B is 5 points.

[0212] Improved by more than 5 points: Score "3"

[0213] Improved by 3 - 4 points: Score "2"

[0214] Improved by 1 - 2 points: Score "1"

[0215] Same or lower: Score "0"

[0216] <Continuous evaluation>

[0217] In the examples and comparative examples, continuous evaluation is performed when the scores of hydrophilicity and lubricity at the start of wearing are both 1 or above. The continuous evaluation is based on the evaluation of hydrophilicity and lubricity and is evaluated according to the following criteria.

[0218] The scores for imagining the situation at the start of wearing and the scores for imagining the situation at the end of wearing are the same in both evaluations: score "3"

[0219] The score for imagining the situation at the end of wearing decreases by 1 in either evaluation: score "2"

[0220] The scores for imagining the situation at the end of wearing decrease by 1 in both evaluations: score "1"

[0221] The score for imagining the situation at the end of wearing decreases by 2 or more in at least one evaluation: score "0" <Evaluation of interaction with mucin>

[0222] In Examples 3-1 to 3-6 and Comparative Examples 3-1 to 3-3, the evaluation of the interaction with mucin was carried out according to the following procedure. The composition and results of the test solutions are shown in Table 4.

[0223] (1) Dilute mucin and the polymer to 10 ppm with ISO physiological saline respectively, and perform DLS measurement using a particle size analyzer (zetasizer).

[0224] (2) Perform the same measurement on the solution after mixing the polymer and mucin.

[0225] (3) When the particle size distribution divided by scattering intensity of the mixed solution shifts to the high molecular weight side compared with before mixing, it is considered to have an interaction with mucin, and the case where no significant change is found is considered to have no interaction.

[0226] <Drying resistance>

[0227] In Examples 4-1 to 4-6 and Comparative Examples 4-1 to 4-4, the evaluation of drying resistance was carried out according to the following procedure. Test contact lenses B were used. The composition and results of the test solutions are shown in Table 5.

[0228] (1) Immerse one test contact lens taken out from the blister pack in ISO physiological saline and shake for 6 hours.

[0229] (2) For each glass vial containing 4 mL of the solution prepared as shown in Table 4, immerse one test contact lens in the glass vial and let it stand for 3 hours.

[0230] (3) Take out the test contact lens from the glass vial and let it stand under the conditions of temperature 20 - 25 °C, humidity 30 - 35%, and no wind. Measure the time until it dries and deforms, and evaluate according to the following criteria.

[0231] Scoring criteria

[0232] 7 points or more: score "3"

[0233] Above 6 points to less than 7 points: score "2"

[0234] Above 5 points to less than 6 points: score "1"

[0235] Less than 5 points: score "0"

[0236] Table 2

[0237]

[0238] Table 3

[0239]

[0240] * Since the scores for hydrophilicity and lubricity at the start of wearing in Comparative Example 2-1 were 0, continuous evaluation was not performed.

[0241] ** The lens of Comparative Example 2-3 was deformed, so subsequent evaluation was not performed.

[0242] Table 4

[0243]

[0244] Table 5

[0245]

[0246] <Evaluation>

[0247] From the results of Table 2 and Table 3, it can be seen that the contact lens treatment solutions using copolymers P1 to P6 improved the hydrophilicity and lubricity of the contact lenses, and the effects were sustained for a long time. From the results of Table 4, it can be seen that copolymers P1 to P6 interacted with mucin. From the results of Table 5, it can be seen that copolymers P1 to P6 had high dry resistance.

[0248] This application claims priority based on Japanese Application No. 2022-204230 filed on December 21, 2022. The contents described in the specification and claims of that application are incorporated herein by reference.

[0249] Industrial Applicability

[0250] The copolymer and ophthalmic composition of the present invention, when used as a contact lens treatment solution, can improve the wearing feeling of the contact lens and sustain the effect for a long time. Further, when used as an eye drop, it can stay on the corneal surface for a long time through interaction with mucin, making the moisturizing effect last for a long time.

Claims

1. A copolymer comprising: a structural unit derived from monomer a represented by the following formula (1a) or a salt thereof; and a structural unit derived from monomer b represented by any one of the following formulas (1b) and (2b), The molar ratio n of each structural unit a : n b is 10:90 to 70:30, where n a is the molar proportion of the structural unit derived from monomer a or its salt in the copolymer, and n b is the molar proportion of the structural unit derived from monomer b in the copolymer. wherein the copolymer has a weight-average molecular weight of 10,000 to 2,000,000, [Chemical formula 1] In formula (1a), R 1 is a hydrogen atom or a methyl group, and X is O or NR 2 , where R 2 is H or an alkyl group having 1 to 4 carbon atoms, and n = 1 to 4; [Chemical formula 2] In formula (1b), R 3 is a hydrogen atom or a methyl group, Y is O or NR 4 , wherein R 4 is H or an alkyl group having 1 to 4 carbon atoms, m is 1 to 6, and the carbon chain optionally has one or more hydroxyl groups. A is a phosphorylcholine group or a hydroxyl group, and A is optionally a hydrogen atom only when m = 1 or when the carbon chain has a hydroxyl group; [Chemical formula 3] In formula (2b), R 5 is a hydrogen atom or a methyl group, and R 6 is an alkyl group having 1 to 4 carbon atoms or an alkylene group having 1 to 4 carbon atoms that is terminally bonded to R 5 to form a cyclic structure.

2. The copolymer according to claim 1, wherein monomer b comprises at least one monomer selected from the group consisting of the monomer represented by the following formula (3b), N-vinylpyrrolidone, 2-hydroxyethyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, 2-hydroxybutyl (meth)acrylate, 2-hydroxyethyl (meth)acrylamide, glycerol mono(meth)acrylate, N,N-dimethyl(meth)acrylamide, N-vinylacetamide, and N-vinyl-N-methylacetamide, [Chemical formula 4] In formula (3b), R 7 is a hydrogen atom or a methyl group, and Z is O or NR 8 , where R 8 is H or an alkyl group having 1 to 4 carbon atoms.

3. The copolymer according to claim 1 or 2, wherein monomer b comprises at least one of the monomer represented by formula (3b) and N-vinylpyrrolidone.

4. The copolymer according to any one of claims 1 to 3, wherein monomer b comprises 2-(methacryloyloxy)ethyl 2-(trimethylammonio)ethyl phosphate.

5. The copolymer according to any one of claims 1 to 4, wherein monomer a or its salt comprises the monomer represented by the following formula (2a) or a salt thereof, [Chemical formula 5] In formula (2a), R 1 is a hydrogen atom or a methyl group.

6. An ophthalmic composition containing 0.001 w / v% or more and 5.0 w / v% or less of the copolymer P according to any one of claims 1 to 5.

7. The ophthalmic composition according to claim 6, wherein it further contains 0.001 w / v% or more and 10.0 w / v% or less of a polysaccharide or a glycoprotein.

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