Copolymer, and eye composition in which same is used

Abstract

Provided is a copolymer that can interact with a SiHyCL and mucin. This copolymer includes constituent units of a monomer (a) of formula (1a) or a salt thereof, a monomer (b) of formula (1b) or (2b), and a monomer (c) of formula (1c), the molar ratios thereof being na = 10-70, nb = 25-85, and nc = 5-50, and Mw of the polymer being 10,000-2,000,000. (R1 is H or CH3, X is O or NR2, R2 is H or a C1-4 alkyl group, and n = 1-4). (R3 is H or CH3, Y is O or NR4, R4 is H or a C1-4 alkyl group, and m is 1-6; there may be one or more hydroxyl groups in the carbon chain; A is a phosphorylcholine group or a hydroxyl group, and may be H if m = 1 or if there is a hydroxyl group in the carbon chain). (R5 is H or CH3, and R6 is an alkylene group forming a cyclic structure together with R5 or a C1-4 alkyl group). (R7 is H or CH3, Z is O or NR9, R 9 is H or a C1-4 alkyl group, and R8 is a C1-10 alkyl group).

Description

Copolymer and ophthalmic composition using same

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

[0002] Mucin contained in tears forms a layer called a mucin layer on the surface of the cornea, which helps retain tears and prevents dry eyes. If an abnormality occurs in the tear film, including this mucin layer, tears cannot be stably maintained, leading to eye diseases such as dry eye. The number of dry eye patients in Japan is increasing, and one of the causes is said to be the increase in contact lens wearers.

[0003] Silicone hydrogel contact lenses (hereinafter referred to as SiHyCL) have high oxygen permeability and can reduce the adverse effects of oxygen deficiency on the eyes. SiHyCL therefore accounts for approximately 70% of the global contact lens market. While SiHyCL has high oxygen permeability, its high hydrophobicity generally leads to poor wettability, resulting in discomfort when wearing the lenses, such as dryness and a gritty feeling on the eyes. Furthermore, poor wettability can easily cause friction with the upper eyelid, potentially leading to eye disorders such as corneal damage and dry eye. Therefore, to ensure comfortable and safe use of SiHyCL, it is necessary to maintain the SiHyCL surface hydrophilic.

[0004] As a method for hydrophilizing the surface of such SiHyCL, methods of treating the surface of contact lenses have been developed. For example, Patent Document 1 discloses a method of graft polymerizing a hydrophilic monomer onto a plasma-treated contact lens surface. Also, Patent Document 2 discloses a method of coating a hydrophilic polymer onto the surface of a contact lens.

[0005] JP 2003-215509 A JP 2018-022174 A

[0006] However, the plasma treatment and hydrophilic polymer surface treatment of contact lenses described in Patent Documents 1 and 2 require the use of dedicated equipment, which makes their introduction difficult and costly.

[0007] Therefore, there is a need to develop a method that can easily impart hydrophilicity to existing SiHyCL at low cost.

[0008] Mucin, as mentioned above, is a high molecular weight protein that gives tears viscosity and is an important factor in stabilizing tears. Mucin's presence on the cornea stabilizes the tears on the corneal surface, maintaining wettability. However, when wearing SiHyCL, the tear film is disrupted by the SiHyCL, making it prone to instability.

[0009] Therefore, there is a need for a compound that can remain on the corneal surface and SiHyCL surface for a long time and maintain water retention and lubricity. Here, according to the findings of the present inventors, a compound that interacts with both the SiHyCL surface and mucin can retain mucin on the SiHyCL surface, thereby maintaining the SiHyCL surface hydrophilic.

[0010] In view of the above problems, an object of the present invention is to provide a copolymer capable of interacting with both SiHyCL and mucin, and an ophthalmic composition using the copolymer.

[0011] As a result of extensive research, the present inventors have found that a novel copolymer comprising a monomer having a guanidino group, a specific hydrophilic monomer, and a specific hydrophobic monomer can achieve the above object, and have thus completed the present invention. That is, the present invention comprises the following [1] to [6]. [1] A copolymer comprising a structural unit derived from a monomer (a) represented by the following formula (1a) or a salt thereof, a structural unit derived from a monomer (b) represented by either the following formula (1b) or (2b), and a structural unit derived from a monomer (c) represented by the following formula (1c), wherein the molar ratio of each structural unit is n ａ :n ｂ :n ｃ When this is the case, n ａ = 10 to 70, n ｂ = 25 to 85, n ｃ = 5 to 50 (n ａ is the molar ratio of the constituent units derived from the monomer (a) or its salt in the copolymer, and n ｂ is the molar ratio of the constituent units derived from the monomer (b) in the copolymer, and nｃ is the molar ratio of the structural units derived from the monomer (c) in the copolymer, and has a weight average molecular weight of 10,000 to 2,000,000.

[0012]

[0013] (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.

[0014]

[0015] (In formula (1b), R ３ is a hydrogen atom or a methyl group, and Y is O or NR ４ , where R ４ is H or an alkyl group having 1 to 4 carbon atoms, m is 1 to 6 and may have one or more hydroxyl groups in the carbon chain, A is a phosphorylcholine group or a hydroxyl group, and may be a hydrogen atom only when m=1 or when there is a hydroxyl group in the carbon chain.

[0016]

[0017] (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 a group having an R ５ is an alkylene group having 1 to 4 carbon atoms that is bonded to the group to form a cyclic structure.

[0018]

[0019] (In formula (1c), R ７ is a hydrogen atom or a methyl group, and Z is O or NR ９ , R ９ is H or an alkyl group having 1 to 4 carbon atoms, R ８is an alkyl group having 1 to 10 carbon atoms, and may have a linear or branched structure.) [2] The copolymer according to [1], wherein the monomer (b) contains at least one monomer selected from the group consisting of a monomer represented by the following formula (3b), N-vinylpyrrolidone, hydroxyethyl(meth)acrylate, hydroxypropyl(meth)acrylate, hydroxybutyl(meth)acrylate, hydroxyethyl(meth)acrylamide, glycerol mono(meth)acrylate, N,N-dimethyl(meth)acrylamide, N-vinylacetamide, and N-vinyl-N-methylacetamide:

[0020]

[0021] (In formula (3b), R １０ is a hydrogen atom or a methyl group, and W is O or NR １１ , where R １１ is H or an alkyl group having 1 to 4 carbon atoms.) [3] The copolymer according to [1] or [2], wherein the monomer (b) contains at least one of a monomer represented by formula (3b) and N-vinylpyrrolidone. [4] The copolymer according to any one of [1] to [3], wherein the monomer (b) contains 2-(methacryloyloxy)ethyl 2-(trimethylammonio)ethyl phosphate. [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:

[0022]

[0023] (In formula (2a), R １ is a hydrogen atom or a methyl group.)

[0024] [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].

[0025] The copolymer of the present invention interacts with both mucin and SiHyCL, thereby retaining mucin on the contact lens surface, thereby reducing the dryness and grittiness of the eyes when wearing contact lenses and allowing them to be worn comfortably for long periods of time. Therefore, the copolymer of the present invention is useful as an ophthalmic composition and is suitable as a contact lens treatment solution.

[0026] The present invention will be described in more detail below.

[0027] As used herein, "(meth)acrylic" means acrylic or methacrylic (methacrylic), "(meth)acryloyl" means acryloyl or methacryloyl (methacryloyl), "(meth)acrylate" means acrylate or methacrylate (methacrylate), and "(meth)acrylamide" means acrylamide or methacrylamide (methacrylamide).

[0028] The ophthalmic composition of the present invention can be used in the form of a product including a composition applied directly to the eye and a composition used to treat devices worn on the eye, such as contact lenses. Specific examples include eye drops, eyewashes, and contact lens treatment solutions. Specific product forms of the contact lens treatment solution of the present invention include contact lens packing solutions (contact lens shipping solutions), contact lens storage solutions, contact lens cleaning solutions, contact lens cleaning and storage solutions, contact lens disinfectants, and contact lens wear aids.

[0029] In this specification, the term "contact lens packing solution" refers to an aqueous solution that is sealed in a packaging container such as a blister package together with a contact lens when the contact lens is distributed. Since contact lenses are generally used in a state in which they are swollen with an aqueous solution, the lenses are shipped in a packaging container in a state in which they are swollen with an aqueous solution (contact lens packing solution) so that they can be used immediately.

[0030] [Copolymer (P)] The copolymer (P) of the present invention is obtained by copolymerizing a monomer (a) represented by the following formula (1a) or a salt thereof, a monomer (b) represented by either of the following formulas (1b) and (2b), and a monomer (c) represented by the following formula (1c). Therefore, the copolymer (P) contains a structural unit derived from the monomer (a) or a salt thereof, a structural unit derived from the monomer (b), and a structural unit derived from the monomer (c). The copolymer (P) has a molar ratio of each structural unit of n ａ :n ｂ :n ｃ When this is the case, n ａ = 10 to 70, n ｂ = 25 to 85, n ｃ = 5 to 50, and the weight average molecular weight is 10,000 to 2,000,000.

[0031]

[0032] (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.

[0033]

[0034] (In formula (1b), R ３ is a hydrogen atom or a methyl group, and Y is O or NR ４ , where R ４ is H or an alkyl group having 1 to 4 carbon atoms, m is 1 to 6 and may have one or more hydroxyl groups in the carbon chain, A is a phosphorylcholine group or a hydroxyl group, and may be a hydrogen atom only when m=1 or when there is a hydroxyl group in the carbon chain.

[0035]

[0036] (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 a group having an R ５ is an alkylene group having 1 to 4 carbon atoms that is bonded to the group to form a cyclic structure.

[0037]

[0038] (In formula (1c), R ７ is a hydrogen atom or a methyl group, and Z is O or NR ９ , R ９ is H or an alkyl group having 1 to 4 carbon atoms, R ８ is an alkyl group having 1 to 10 carbon atoms, which may have a linear or branched structure.

[0039] [Monomer (a)] The copolymer (P) of the present invention can be obtained by polymerization of a monomer (a) having a guanidino group represented by formula (1a) (hereinafter also referred to as "GE monomer (a)") or its salt. Examples of the salt include hydrochloride, carbonate, bicarbonate, phosphate, and sulfate. Hydrochloride, carbonate, or bicarbonate is preferred, and hydrochloride is more preferred. By including the GE monomer (a) or its salt as a constituent monomer in the copolymer (P), the copolymer (P) can be more easily interacted with mucin, thereby enhancing retention on the corneal surface and contact lens surface. Furthermore, copolymerization of a hydrophobic monomer (a) can be more easily interacted with SiHyCL. The GE monomer (a) is not limited to one type, and one or more types can be used.

[0040] Preferably, the GE monomer (a) is a monomer of formula (1a) where n=2.

[0041] A preferred example of the GE monomer (a) where n=2 is a monomer represented by formula (2a) where X is O.

[0042]

[0043] In the formula (2a), R １ is a hydrogen atom or a methyl group.

[0044] More preferred examples of the monomer represented by formula (2a) include R １ is a methyl group, 2-guanidinoethyl methacrylate.

[0045] Further, other preferred examples of the GE monomer (a) where n=2 include R １ is a methyl group and X is NR ３ , R ３ is H, and 2-guanidinoethyl methacrylamide.

[0046] The monomer represented by formula (1a) can be produced by a known method, for example, by a method of reacting an amino group-containing polymerizable monomer 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 Document 1) and Zhao, Qingqing; et al. Chemical Communications (2020), 56(36), 4954-4957 (hereinafter, Reference Document 2).

[0047] [Monomer (b)] The copolymer (P) of the present invention can be obtained by polymerization of a monomer (b) represented by either formula (1b) or (2b). By copolymerizing such a hydrophilic monomer (b), the drying resistance of an ophthalmic composition containing the copolymer (P) on the cornea or contact lens surface can be improved.

[0048] Preferred examples of the monomer (b) include hydroxyalkyl(meth)acrylates in which Y is O and A is a hydroxyl group, hydroxyalkyl(meth)acrylamides in which Y is NH and A is a hydroxyl group, and monomers in which Y is N and R ４ Another preferred example of the monomer (b) is a monomer represented by formula (3b) in which R in formula (2b) is a methyl group, m=1, and A is a hydrogen atom, N,N-dimethyl(meth)acrylamide in which Y is O, m=3, and A has a hydroxyl group at the 2-position, and glycerol mono(meth)acrylate in which m=2, and A is a phosphorylcholine group. ６ is a methyl group, N-vinylacetamide or N-methyl-N-vinylacetamide, R ５ is a methyl group and R ６and N-vinylpyrrolidone, which has a cyclic structure with an ethylene group. More preferred are monomers represented by the following formula (3b): N-vinylpyrrolidone, hydroxyethyl(meth)acrylate, hydroxypropyl(meth)acrylate, hydroxybutyl(meth)acrylate, hydroxyethyl(meth)acrylamide, glycerol mono(meth)acrylate, N,N-dimethyl(meth)acrylamide, N-vinylacetamide, N-vinyl-N-methylacetamide, and N-vinylpyrrolidone. Even more preferred are monomers represented by formula (3b) or N-vinylpyrrolidone, and even more preferred are monomers represented by (3b). Use of monomers represented by formula (3b) or N-vinylpyrrolidone, particularly monomers represented by formula (3b), can further enhance the drying resistance of ophthalmic compositions containing copolymer (P) on the cornea or contact lens surface. The monomer (b) is not limited to one type, and one or more types can be used.

[0049]

[0050] In the formula (3b), R １０ is a hydrogen atom or a methyl group, and W is O or NR １１ , where R １１ is H or an alkyl group having 1 to 4 carbon atoms.

[0051] Examples of the monomer represented by formula (3b) include 2-((meth)acryloyloxy)ethyl-2-(trimethylammonio)ethyl phosphate and 2-((meth)acrylamido)ethyl-2-(trimethylammonio)ethyl phosphate, and more preferably 2-(methacryloyloxy)ethyl 2-(trimethylammonio)ethyl phosphate (also known as 2-methacryloyloxyethyl phosphorylcholine).

[0052] The monomer represented by formula (3b) can be produced by a known method, for example, by reacting a hydroxyl group-containing polymerizable monomer with 2-bromoethylphosphoryl dichloride in the presence of a tertiary base, and then reacting the compound obtained with a tertiary amine. Alternatively, a method may be used in which a cyclic compound is obtained by reacting a hydroxyl group-containing polymerizable monomer with a cyclic phosphorus compound, and then the cyclic compound is subjected to a ring-opening reaction with a tertiary amine.

[0053] [Monomer (c)] The copolymer (P) of the present invention can be obtained by using a monomer (c) represented by formula (1c) in polymerization. By copolymerizing the hydrophobic monomer (c), it is possible to facilitate the interaction of the copolymer (P) with SiHyCL. The hydrophobic monomer (c) is not limited to one type, and one or more types can be used.

[0054] Preferred examples of the monomer (c) include those represented by the formula (1c) in which Z is O, R ８ is an alkyl group having 4 carbon atoms, Z is NH, R ８ is a linear alkyl group having 8 carbon atoms, and Z is O, R ８ and octyl(meth)acrylate, in which the alkyl group has 8 carbon atoms. More preferred is butyl(meth)acrylate. The monomer (c) is not limited to one type, and one or more types can be used.

[0055] [Ratio of GE Monomer (a), Monomer (b), and Monomer (c)] The molar ratio of each structural unit in the copolymer [P] is n ａ :n ｂ :n ｃ When this is the case, n ａ = 10 to 70, n ｂ = 25 to 85, n ｃ = 5 to 50, preferably n ａ = 15 to 60, n ｂ = 30 to 80, n ｃ = 5 to 40, and more preferably n ａ = 20 to 50, n ｂ = 40 to 70, n ｃ = 10 to 40. Here, n ａis the molar ratio of the constituent units derived from the monomer (a) or its salt in the copolymer, and n ｂ is the molar ratio of the constituent units derived from the monomer (b) in the copolymer, and n ｃ is the molar ratio of the constituent units derived from the monomer (c) in the copolymer. In addition, multiple types of GE monomers (a) can be used in combination at any ratio. In that case, n ａ indicates the total number of moles of all GE monomers. At the same time, multiple monomers (b) and (c) can be used in combination in any ratio. In that case, n ｂ , n ｃ indicates the total number of moles of all monomers (b) and (c), respectively.

[0056] n ａ By increasing n, the interaction of the copolymer (P) with mucin can be strengthened. ｂ By increasing n, the solubility of the copolymer (P) in water can be increased, and the ophthalmic composition can be easily prepared. ｃ By increasing the value of , the interaction of the copolymer (P) with SiHyCL can be strengthened.

[0057] [Other Monomers] The copolymer (P) of the present invention may contain a monomer (d) other than the GE monomer (a), the monomer (b) and the monomer (c) within a range that does not impair the effects of the present invention.

[0058] The monomer (d) can be arbitrarily selected from the monomers (d) copolymerizable with the GE monomers (a), (b) and (c).

[0059] Examples of such monomer (d) include styrene sulfonic acid, (meth)acryloyloxyphosphonic acid, 2-hydroxy-3-(meth)acryloyloxypropyltrimethylammonium chloride, polyethylene glycol (meth)acrylate, aminoethyl (meth)acrylate, N,N-dimethylaminoethyl (meth)acrylate, N-acryloylmorpholine, cyclohexyl (meth)acrylate, dodecyl (meth)acrylate, stearyl (meth)acrylate, styrene, α-methylstyrene, vinyltoluene, indene, vinylnaphthalene, vinylaniline, ethylene, propylene, butadiene, isobutylene, alkenes such as octene, acrylonitrile, methacrylonitrile, polypropylene glycol (meth)acrylate, and glycidyl (meth)acrylate, and one or more of these may be used. The proportion of monomer (d) in all monomers used in preparing the copolymer of the present invention is preferably 30 mol% or less, and more preferably 15 mol% or less. The lower limit of the ratio of the monomer (d) is not particularly limited, but can be set to 0 mol % or more, because the effects of the present invention are preferably exhibited.

[0060] [Weight-Average Molecular Weight of Copolymer (P)] 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 even more preferably 200,000 to 400,000. By increasing the weight-average molecular weight of the copolymer (P) to more than 10,000, it is possible to increase the retention time of the copolymer (P) on the corneal surface or contact lens surface, and also to enhance the lubricity and water-retaining properties imparted to the cornea or contact lens by an ophthalmic composition containing the copolymer (P). As a result, the dryness resistance of the ophthalmic composition containing the copolymer (P) on the cornea or contact lens surface can be improved. By decreasing the weight-average molecular weight of the copolymer (P) to less than 2,000,000, it is possible to facilitate its handling.

[0061] The weight average molecular weight of the copolymer (P) can be determined in terms of pullulan by GPC (gel permeation chromatography) measurement.

[0062] [Polymerization form of copolymer (P)] The copolymer (P) is usually a random copolymer, but may also be an alternating copolymer or a block copolymer in which each monomer is regularly arranged, or may have a graft structure in part.

[0063] [Method for Producing Copolymer (P)] The copolymer (P) can be produced by copolymerizing a GE monomer (a) having a guanidino group represented by the following formula (1a), a monomer (b) represented by either of the following formulas (1b) and (2b), and a monomer (c) represented by the following formula (1c).

[0064]

[0065] In the 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.

[0066]

[0067] In the formula (1b), R ３ is a hydrogen atom or a methyl group, and Y is O or NR ４ , where R ４ is H or an alkyl group having 1 to 4 carbon atoms, m is 1 to 6 and may have one or more hydroxyl groups in the carbon chain, A is a phosphorylcholine group or a hydroxyl group, and may be a hydrogen atom only when m=1 or when a hydroxyl group is present in the carbon chain.

[0068]

[0069] 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 a group having an R ５ is an alkylene group having 1 to 4 carbon atoms that is bonded to the above to form a cyclic structure.

[0070]

[0071] In the formula (1c), R ７ is a hydrogen atom or a methyl group, and Z is O or NR ９ , R ９ is H or an alkyl group having 1 to 4 carbon atoms, R ８ is an alkyl group having 1 to 10 carbon atoms, which may have a straight chain structure or a branched structure.

[0072] The polymerization reaction can be carried out by a known method such as radical polymerization, e.g., bulk polymerization, suspension polymerization, emulsion polymerization, or solution polymerization, in the presence of a radical polymerization initiator in an atmosphere substituted with an inert gas such as nitrogen, carbon dioxide, argon, or helium. From the viewpoint of purification, solution polymerization is preferred. The copolymer can be purified by a common purification method such as reprecipitation, dialysis, or ultrafiltration.

[0073] Examples of the radical polymerization initiator include an azo-based radical polymerization initiator, an organic peroxide, and a persulfate.

[0074] Examples of the azo 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-azobisisobutylamide dihydrate, 2,2-azobis(2,4-dimethylvaleronitrile), and 2,2-azobisisobutyronitrile (AIBN).

[0075] Examples of organic peroxides include t-butyl peroxyneodecanoate (Perbutyl (registered trademark) ND), benzoyl peroxide, diisopropyl peroxydicarbonate, t-butylperoxy-2-ethylhexanoate, t-butyl peroxypivalate, t-butyl peroxydiisobutyrate, lauroyl peroxide, and succinic acid peroxide (succinyl peroxide).

[0076] Examples of persulfate include ammonium persulfate, potassium persulfate, and sodium persulfate.

[0077] As the radical polymerization initiator, it is preferable to use an azo radical polymerization initiator, and it is more preferable to use 2,2'-azobis(2-methylpropionamidine) dihydrochloride (V-50).

[0078] These radical polymerization initiators can be used alone or in combination of two or more. The amount of the polymerization initiator used is usually 0.001 to 10 parts by mass, preferably 0.01 to 5.0 parts by mass, per 100 parts by mass of the monomer composition of copolymer (P).

[0079] The polymerization reaction can be carried out in the presence of a solvent, and any solvent that dissolves the monomer composition but does not react with it can be used. Examples of the solvent include water, alcoholic solvents such as 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, alcohol, or a mixture thereof is used, and more preferably water.

[0080] [Ophthalmic composition] In the ophthalmic composition of the present invention, the concentration of copolymer (P) is 0.001 w / v% or more, preferably 0.01 w / v% or more, more preferably 0.1 w / v% or more. In addition, the concentration of copolymer (P) is 5.0 w / v% or less, preferably 2.0 w / v% or less, more preferably 0.7 w / v% or less. By making the concentration of copolymer (P) 0.001 w / v% or more, sufficient lubricity and water retention properties can be obtained, and from the viewpoint of the manufacturability of the ophthalmic composition, it is desirable to make the concentration of copolymer (P) 5.0 w / v% or less.

[0081] In the present invention, "w / v %" refers to the mass of a component in 100 mL of solution, expressed in grams (g). For example, "the composition of the present invention contains 1.0 w / v % of copolymer (P)" means that 100 mL of solution contains 1.0 g of copolymer (P).

[0082] The solvent used in the ophthalmic composition of the present invention may be water, alcohols such as ethanol, n-propanol, isopropanol, glycerol, or propylene glycol, or a mixture thereof. Preferred is water or a mixture of water and an alcohol, and more preferred is water.

[0083] The water used in the ophthalmic composition of the present invention may be water typically used in the production of pharmaceuticals or medical devices, such as ion-exchanged water, purified water, sterilized purified water, distilled water, and water for injection.

[0084] The ophthalmic composition of the present invention may contain a buffer. By containing a buffer, the pH and osmotic pressure of the ophthalmic composition of the present invention can be adjusted, and the feeling during use can also be further improved.

[0085] In the present invention, from the viewpoint of obtaining the above-mentioned effects more fully, it is desirable to use one or more buffers selected from a phosphate buffer and a borate buffer. In this specification, the phosphate buffer is a buffer containing 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 containing boric acid, borax, hydrochloric acid, sodium hydroxide, potassium hydroxide, etc.

[0086] 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 even more preferably 0.01 w / v% or more and 5.0 w / v% or less.

[0087] In particular, when one or more buffers selected from a phosphate buffer and a borate buffer are used as the buffer, the concentration thereof, in terms of the total of the components of the phosphate buffer and the borate buffer, 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 even more preferably 0.1 w / v% or more and 5.0 w / v% or less.

[0088] The ophthalmic composition of the present invention may further contain, as necessary, a decongestant component, an anti-inflammatory / astringent component, vitamins, a refreshing agent, an isotonicity agent, a pH adjuster, an antioxidant, a stabilizer, a preservative, a mucin secretion promoter, a thickener, and the like that can generally be used in ophthalmic preparations.

[0089] Decongestant ingredients include, for example, epinephrine or a salt thereof, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline or a salt thereof, phenylephrine, and methylephedrine hydrochloride.

[0090] Examples of anti-inflammatory and astringent ingredients include epsilon-aminocaproic acid, allantoin, berberine or a salt thereof, sodium azulene sulfonate, glycyrrhizic acid or a salt thereof, zinc lactate, zinc sulfate, and lysozyme chloride.

[0091] Examples of vitamins include flavin adenine dinucleotide sodium, cyanocobalamin, retinol acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, sodium pantothenate, and calcium pantothenate.

[0092] Examples of the cooling agent include menthol and camphor.

[0093] Examples of the isotonic agent include sodium chloride, potassium chloride, magnesium chloride, calcium chloride, aspartic acid or a salt thereof, and aminoethylsulfonic acid.

[0094] Examples of pH adjusters include citric acid, sulfuric acid, acetic acid, trishydroxymethylaminomethane, monoethanolamine, sodium hydrogen carbonate, and sodium citrate.

[0095] Examples of antioxidants include tocopherol acetate, dibutylhydroxytoluene, and sodium hydrogen sulfite.

[0096] Stabilizers include, for example, sodium edetate, glycine, and taurine.

[0097] Examples of preservatives include benzalkonium chloride, chlorhexidine gluconate, potassium sorbate, methylparaben, ethylparaben, propylparaben, isopropylparaben, butylparaben, isobutylparaben, polyhexanide hydrochloride, sulfamexazole or a salt thereof, sulfisoxazole, and sulfisomidine sodium.

[0098] Examples of mucin secretion promoters include diquafosol sodium and rebamipide.

[0099] Examples of thickeners include poly(meth)acrylic acid, (meth)acrylic acid-acrylic(meth)acrylate copolymer, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and polyethylene glycol.

[0100] 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 even more preferably 4.0 or more and 7.6 or less, from the viewpoint of eye irritation.

[0101] From the viewpoint of eye irritation, the osmotic pressure of the ophthalmic composition of the present invention is preferably 200 mOsm or more and 400 mOsm or less, more preferably 225 mOsm or more and 375 mOsm or less, and even more 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 even more preferably 0.8 or more and 1.2 or less.

[0102] In this specification, the osmotic pressure of the contact lens treatment solution refers to a value measured in accordance with the 18th Edition of the Japanese Pharmacopoeia, General Test Method 2.47, Osmolality Measurement Method (Osmolality Measurement Method), and the osmotic pressure ratio refers to the value obtained by dividing the obtained osmotic pressure value by the osmotic pressure value (286 mOsm) of 0.9% by mass physiological saline solution.

[0103] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these. Various measurements in the examples (and comparative examples) were carried out according to the methods shown below.

[0104] Synthesis of Copolymer <Measurement of Weight-Average Molecular Weight> 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). Column: Shodex (GSM-700) Mobile phase: 0.1 mol / L aqueous sodium sulfate Standard substance: Pullulan (PSS-pulkitr1h) (Polymer Standards) Measuring instrument: Differential refractive index RI-8020 (Tosoh Corporation) Calculation method for weight-average molecular weight: Molecular weight calculation program (GPC program for SC-8020) Flow rate: 1.0 mL per minute Injection volume: 100 μL Column oven: 40°C Measurement time: 30 minutes

[0105] Example 1-1 2.9 g of 2-guanidinoethyl methacrylate hydrochloride as GE monomer (a), 4.1 g of 2-(methacryloyloxy)ethyl 2-(trimethylammonio)ethyl phosphate (hereinafter also referred to as MPC) as monomer (b), and 1.0 g of butyl methacrylate (hereinafter also referred to as BMA) as hydrophobic monomer (c) were weighed into a four-neck flask, and 31.0 g of ion-exchanged water was added and heated to 70°C for dissolution. Then, 0.06 g of 2,2'-azobis(2-methylpropionamidine) dihydrochloride diluted in 1 g of ion-exchanged water was added, and the mixture was polymerized at 70°C for 2 hours. After completion of the reaction, the mixture was dialyzed and purified to obtain a 2-guanidinoethyl methacrylate hydrochloride-2-methacryloyloxyethyl phosphorylcholine-butyl methacrylate copolymer (P1). The polymerization conditions and weight-average molecular weight are shown in Table 1. 2-Guanidinoethyl methacrylate hydrochloride was synthesized by the method described in Reference 1 above.

[0106] <Examples 1-2 to 1-6> Copolymers P2 to P6 were obtained by synthesizing the same procedures as in Example 1-1, with the monomer charging compositions and concentrations set as shown in Table 1. The results of measuring the weight-average molecular weight are shown in Table 1. 2-Guanidinoethyl methacrylamide was synthesized by the method described in Reference 2 above.

[0107]

[0108] Comparative Example 1-1: 3.3 g of 2-guanidinoethyl methacrylate hydrochloride as GE monomer (a) and 4.7 g of 2-(methacryloyloxy)ethyl 2-(trimethylammonio)ethyl phosphate (hereinafter also referred to as MPC) as monomer (b) were weighed into a four-neck flask, and 31.0 g of ion-exchanged water was added and heated to 70°C for dissolution. Thereafter, 0.06 g of 2,2'-azobis(2-methylpropionamidine) dihydrochloride diluted in 1 g of ion-exchanged water was added, and the mixture was polymerized at 70°C for 2 hours. After completion of the reaction, the mixture was purified by dialysis to obtain 2-guanidinoethyl methacrylate hydrochloride / 2-methacryloyloxyethyl phosphorylcholine copolymer Q1 (weight average molecular weight: 260,000).

[0109] Comparative Example 1-2: 12.8 g of MPC was dissolved in 26.2 g of ion-exchanged water, and the solution was placed in a four-neck flask. Nitrogen was then blown into the solution for 30 minutes. Then, 0.1 g of 2,2'-azobis(2-methylpropionamidine) dihydrochloride diluted in 1.0 g of ion-exchanged water was added, and the solution was polymerized at 70°C for 6 hours. After the reaction was completed, the solution was purified by dialysis to obtain MPC homopolymer Q2 (weight average molecular weight: 330,000).

[0110] Comparative Examples 1-3 An MPC-BMA copolymer (Lipidure-PMB, manufactured by NOF Corporation) was used as comparative polymer Q3 (weight average molecular weight).

[0111] 2. Evaluation of Copolymers The above copolymers of the present invention and copolymers other than those of the present invention were evaluated by the following method. The following test contact lenses were used. The solution compositions and evaluation results are shown in Tables 2 and 3. Lens A: commercially available senofilcon A Lens B: commercially available midafilcon A

[0112] <Preparation of Saline Solution> A saline solution was prepared with reference to the literature (ISO 18369-3:2006, Ophthalmic Optics—Contact Lenses Part 3: Measurement Methods).

[0113] 8.3 g of sodium chloride, 5.993 g of sodium hydrogen phosphate dodecahydrate, and 0.528 g of sodium dihydrogen phosphate dihydrate were weighed out, dissolved in water to make 1000 mL, and filtered to make a physiological saline solution.

[0114] <Preparation of borate buffer> A borate buffer was prepared with reference to the literature (WO2020 / 194110). 9.275 g of boric acid, 1.850 g of sodium tetraborate decahydrate, and 13.99 g of sodium sulfate were weighed out, dissolved in water to make 1000 mL, and filtered to obtain a borate buffer.

[0115] <Preparation of Contact Lens Treatment Solution> Using the borate buffer solution and copolymer prepared above, contact lens treatment solutions of Examples 2-1 to 2-7 and Comparative Examples 2-1 to 2-3 were prepared by blending the ingredients as shown in Table 2.

[0116] <Evaluation of Interaction with SiHyCL> In the Examples and Comparative Examples, the evaluation of the interaction of the polymer with SiHyCL was carried out according to the following procedure. The formulation of the treatment solution and the results are shown in Table 2. (1) One test contact lens removed from the blister pack was immersed in borate buffer and shaken for 6 hours. (2) The test contact lens was removed and sealed in a glass vial containing 5 mL of the contact lens treatment solution. (3) The test contact lens was sterilized at 121°C for 20 minutes. (4) The test contact lens was removed and immersed three times in 20 mL of borate buffer, and then placed in a sample tube containing 3 mL of ion-exchanged water. (5) The sample tube containing the test contact lens was treated in an ultrasonic cleaner for 10 minutes to extract the polymer adsorbed on the test contact lens. (6) The same treatment was carried out on nine similar test contact lenses, and extracts for a total of 10 test contact lenses were prepared for each treatment solution. (7) A blank lens extract was prepared by treating a contact lens without using a polymer and with a borate buffer solution in the same manner. (8) A total phosphorus quantitative test was conducted using the test contact lens extract as the test solution. The following equipment and reagents were used for the test, and the measurement method followed their recommended methods. Measuring equipment: Simple total nitrogen / total phosphorus meter TNP-A type (manufactured by Central Scientific Co., Ltd.) Reagent: Spectroquant (registered trademark) Phosphoric Acid Cell Test (manufactured by Merck) (9) The total phosphorus amount in the blank lens extract was subtracted from the total phosphorus amount in the test contact lens extract, and the amount of polymer adsorption per test contact lens (μg / lens) was calculated from the phosphorus content of each polymer. Scores were evaluated according to the following criteria.

[0117] Score criteria 3.00 μg / sheet or more: Score "3" 2.00 μg / sheet or more to less than 3.00 μg / sheet: Score "2" 1.00 μg / sheet or more to less than 2.00 μg / sheet: Score "1" 0.00 μg / sheet or more to less than 1.00 μg / sheet: Score "0"

[0118] <Evaluation of Interaction with Mucin> In Examples 3-1 to 3-6 and Comparative Examples 3-1 to 3-3, evaluation of interaction with mucin was carried out according to the following procedure. The component compositions of the test solutions and the results are shown in Table 3.

[0119] Evaluation by DLS (Dynamic Light Scattering) Evaluation was performed using a Zetasizer (Nano ZS, manufactured by Malvern Panalytical) based on changes in particle size. (1) Mucin and polymer were each diluted to 50 ppm with ISO physiological saline, and DLS measurements were performed using a Zetasizer. (2) Similar measurements were performed on a solution prepared by mixing polymer and mucin. (3) When the particle size distribution by scattering intensity of the mixed solution had shifted to the higher molecular weight side compared to before mixing, it was judged that there was an interaction with mucin; when no significant change was observed, it was judged that there was no interaction.

[0120]

[0121]

[0122] <Evaluation> The results in Table 2 show that the contact lens treatment solutions containing copolymers P1 to P6 are adsorbed to SiHyCL, whereas the contact lens treatment solutions containing comparative polymers Q1 to Q3 are less adsorbed to SiHyCL.

[0123] The results in Table 3 show that copolymers P1 to P6 interact with mucin.

[0124] This application claims priority based on Japanese Application No. 2024-056624, filed on March 29, 2024, and the contents of the specification and claims of that application are incorporated herein by reference.

[0125] The copolymer and ophthalmic composition of the present invention, when used as a contact lens treatment solution, can retain mucin on the contact lens and stabilize the tear film on the surface of the contact lens, thereby maintaining hydrophilicity, and are effective in improving wearing comfort and preventing dry eyes.

Claims

1. A polymer comprising a structural unit derived from a monomer (a) represented by the following formula (1a) or a salt thereof, a structural unit derived from a monomer (b) represented by either the following formula (1b) or (2b), and a structural unit derived from a monomer (c) represented by the following formula (1c), wherein the molar ratio of each structural unit is n ａ :n ｂ :n ｃ When this is the case, n ａ = 10 to 70, n ｂ = 25 to 85, n ｃ = 5 to 50 (n ａ is the molar ratio of the constituent units derived from the monomer (a) or its salt in the copolymer, and n ｂ is the molar ratio of the constituent units derived from the monomer (b) in the copolymer, and n ｃ is the molar ratio of the structural units derived from the monomer (c) in the copolymer, and has a weight average molecular weight of 10,000 to 2,000,000. (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. (In formula (1b), R ３ is a hydrogen atom or a methyl group, and Y is O or NR ４ , where R ４ is H or an alkyl group having 1 to 4 carbon atoms, m is 1 to 6 and may have one or more hydroxyl groups in the carbon chain, A is a phosphorylcholine group or a hydroxyl group, and may be a hydrogen atom only when m=1 or when there is a hydroxyl group in the carbon chain. (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 a group having an R ５ is an alkylene group having 1 to 4 carbon atoms that is bonded to the group to form a cyclic structure. (In formula (1c), R ７ is a hydrogen atom or a methyl group, and Z is O or NR ９ , R ９ is H or an alkyl group having 1 to 4 carbon atoms, R ８ is an alkyl group having 1 to 10 carbon atoms, which may have a linear or branched structure.

2. The copolymer according to claim 1, wherein the monomer (b) comprises at least one monomer selected from the group consisting of a monomer represented by the following formula (3b), N-vinylpyrrolidone, hydroxyethyl(meth)acrylate, hydroxypropyl(meth)acrylate, hydroxybutyl(meth)acrylate, hydroxyethyl(meth)acrylamide, glycerol mono(meth)acrylate, N,N-dimethyl(meth)acrylamide, N-vinylacetamide, and N-vinyl-N-methylacetamide: (In formula (3b), R １０ is a hydrogen atom or a methyl group, and W is O or NR １１ , where R １１ is H or an alkyl group having 1 to 4 carbon atoms.

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

4. The copolymer of claim 1, wherein said monomer (b) comprises 2-(methacryloyloxy)ethyl 2-(trimethylammonio)ethyl phosphate.

5. The copolymer according to claim 1, wherein the monomer (a) or a salt thereof comprises a monomer represented by the following formula (2a) or a salt thereof: (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.

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