Ophthalmic composition

Abstract

An ophthalmic composition according to the present invention comprises: (A) 0.01-0.5 w / w% of a copolymer which has structural units represented by formula (1a) to formula (1c), in which the molar ratio a:b:c between the structural units is 100 : 10-400 : 2-50, and which has a weight-average molecular weight of 5,000-2,000,000; (B) 0.001-0.02 w / w% of benzalkonium chloride; and / or (C) 0.001-0.05 w / w% of chlorhexidine gluconate.　The present invention makes it possible to provide an ophthalmic composition that exhibits sufficient preservative efficacy and protects corneal cells.

Description

Ophthalmic composition

[0001] The present invention relates to ophthalmic compositions.

[0002] In recent years, the rise in contact lens wearers and the widespread use of digital devices have led to an increase in the number of dry eye patients complaining of eye discomfort and dryness. In addition to dry eye symptoms, many people have also recently complained of hay fever, a condition that has seen a sharp increase over the past decade. The use of eye drops to address and treat these symptoms has been increasing year by year. Eye drops typically contain preservatives to prevent bacterial contamination within the container, as they are used repeatedly over several weeks after opening. While preservatives contribute to the preservative efficacy of eye drops, prolonged use without following the recommended dosage and administration can lead to superficial corneal keratopathy, which occurs when some cells on the surface of the cornea die. Furthermore, many hay fever patients exceed the prescribed number of instillations in a short period of time in an attempt to wash away pollen. In such cases, the preservatives may cause side effects such as corneal damage and blepharitis. For these reasons, disposable, preservative-free eye drops have been developed in recent years, and there is a demand for eye drops that are gentler on the eyes.

[0003] Currently available eye drops contain preservatives such as benzalkonium chloride and chlorhexidine gluconate. Benzalkonium chloride, in particular, has a broad antibacterial spectrum and is therefore widely used. However, eye drops containing these preservatives may induce corneal epithelial damage if used frequently or at high concentrations, even if not administered for a long period of time. Normally, if tear production is maintained at a normal level, the preservative concentration decreases with tear turnover, preventing any adverse effects on the ocular surface. However, when tear production is reduced due to dry eye symptoms, the preservative remains on the ocular surface for a long time, potentially affecting the ocular surface even at low concentrations. Furthermore, in patients with corneal damage or requiring frequent instillation, corneal damage or infection may occur. Therefore, there is a need for eye drops that provide sufficient preservative efficacy and protect corneal cells from preservatives, ensuring safe use for all patients.

[0004] In recent years, development of additives that protect cells from cytotoxic substances has progressed. For example, Non-Patent Document 1 reports a method of protecting cells from the preservative benzalkonium chloride by incorporating D-mannitol into an eye drop. Furthermore, Patent Document 1 discloses an eye drop containing a phosphorylcholine group-containing polymer and polyhexamethylene biguanide. The use of the eye drop described in Patent Document 1 provides sufficient preservative efficacy, quickly spreads on the surface of the eye or contact lens, and exerts moisturizing and lubricating effects.

[0005] Japanese Patent Application Laid-Open No. 2021-20856

[0006] Journal of Oleo Science, Noriaki Nagai, 2015, vol. 64, no. 7

[0007] Although Non-Patent Document 1 describes a method for protecting cells from preservatives in eye drops, it does not specify a phosphorylcholine group-containing polymer. Furthermore, when a sufficient amount of the specific terpolymer that significantly contributes to improving lubricity as described in Patent Document 1 is blended, sufficient preservative effect may not be obtained depending on the type of preservative.

[0008] In view of the above problems, an object of the present invention is to provide an ophthalmic composition that exhibits sufficient preservative effect and protects corneal cells.

[0009] As a result of intensive studies, the present inventors have found that an ophthalmic composition containing a copolymer (hereinafter, sometimes referred to as "copolymer (P)") having structural units represented by formulas (1a) to (1c), in which the molar ratio of the structural units is a:b:c=100:10 to 400:2 to 50, and having a weight-average molecular weight of 5,000 to 2,000,000, and a specific preservative in specific amounts, can exert sufficient preservative effect and protect corneal cells, which led to the completion of the present invention.

[0010] That is, the present invention is as follows: [1] An ophthalmic composition comprising: (A) 0.01 w / w % or more and 0.5 w / w % or less of a copolymer having structural units represented by formulas (1a) to (1c), wherein the molar ratio of the structural units is a:b:c=100:10 to 400:2 to 50 and the weight-average molecular weight is 5,000 to 2,000,000; (B) 0.001 w / w % or more and 0.02 w / w % or less of benzalkonium chloride and / or (C) 0.001 w / w % or more and 0.05 w / w % or less of chlorhexidine gluconate. [In formulas (1a) to (1c), a, b, and c represent the molar ratio of each structural unit. R １ , R ２ and R ５ R each independently represents a hydrogen atom or a methyl group. ３ and R ４ R each independently represents a hydrogen atom, a methyl group, or an ethyl group. ６ represents a monovalent hydrocarbon group having 12 to 24 carbon atoms.] [2] The ophthalmic composition according to the above [1], which contains 0.5 w / w % or less of hydroxypropyl methylcellulose.

[0011] The ophthalmic composition of the present invention can protect corneal cells while exhibiting sufficient preservative effect. That is, the present invention can provide an ophthalmic composition that is excellent in protecting corneal cells.

[0012] The ophthalmic composition of the present invention contains, as component (A), 0.01 w / w % or more and 0.5 w / w % or less of a copolymer having structural units represented by formulas (1a) to (1c), wherein the molar ratio of the structural units is a:b:c=100:10 to 400:2 to 50 and the weight-average molecular weight is 5,000 to 2,000,000, and 0.001 w / w % or more and 0.02 w / w % or less of benzalkonium chloride as component (B) and / or 0.001 w / w % or more and 0.05 w / w % or less of chlorhexidine gluconate as component (C).

[0013]

[0014] The copolymer (P) used in the ophthalmic composition of the present invention has the following three structural units (1) to (3), and the molar ratio a:b:c of the structural units is 100:10 to 400:2 to 50. <(1) PC structural unit> The copolymer (P) used in the ophthalmic composition of the present invention has a structural unit represented by the following formula (1a) (hereinafter abbreviated as "PC structural unit"). The PC structural unit is a structural unit derived from a PC monomer represented by formula (2) described below. The copolymer (P) contains a structural unit derived from a PC monomer, thereby protecting corneal cells.

[0015] In the above formula (1a), R １ represents a hydrogen atom or a methyl group. a represents the proportion of the number of structural units represented by the above formula (1a) in copolymer (P) and represents the molar ratio to the structural units represented by formulas (1b) and (1c). The PC structural units in copolymer (P) are introduced to impart hydrophilicity to copolymer (P) and enhance the protective effect on corneal cells. The PC structural units in copolymer (P) are obtained from a phosphorylcholine-like group-containing monomer (hereinafter abbreviated as PC monomer) represented by the following formula (2) which is used during polymerization of copolymer (P).

[0016] In formula (2), X is a (meth)acryloyloxy group. Note that (meth)acryloyl refers to both methacryloyl and acryloyl. As the PC monomer, for example, 2-((meth)acryloyloxy)ethyl-2'-(trimethylammonio)ethyl phosphate is preferred from the viewpoint of availability, and 2-(methacryloyloxy)ethyl-2'-(trimethylammonio)ethyl phosphate (hereinafter referred to as MPC) represented by the following formula (3) is more preferred.

[0017]

[0018] <(2) Amide Structural Unit> The copolymer (P) used in the ophthalmic composition of the present invention has a structural unit represented by the following formula (1b) (hereinafter abbreviated as "amide structural unit").

[0019] In the above formula (1b), R ２ represents a hydrogen atom or a methyl group, and R３ and R ４ each independently represents a hydrogen atom, a methyl group, or an ethyl group. ３ and R ４ are each independently preferably a methyl group or an ethyl group, more preferably a methyl group. b represents the proportion of the number of structural units represented by the above formula (1b) in the copolymer (P) and represents the molar ratio to the structural units represented by formulas (1a) and (1c). The amide structural units in the copolymer (P) are introduced to increase the molecular weight of the copolymer (P) and enhance its adhesiveness to corneal cells. The proportion of the amide structural units in the copolymer (P), where b is the PC structural unit a of 100, is b / a = 10 / 100 or more and 400 / 100 or less, preferably 30 / 100 or more and 250 / 100 or less. If b is too large, the sterile filtration required for producing the ophthalmic composition may be difficult, and if it is too small, the protective effect on corneal cells cannot be expected.

[0020] The amide structural units in the copolymer (P) are obtained from the monomer represented by the following formula (1b'), i.e., (meth)acrylamide or a (meth)acrylamide derivative, used in the polymerization of the copolymer (P). In other words, the amide structural units are structural units derived from the monomer represented by formula (1b').

[0021] R in formula (1b') ２ , R ３ , R ４ are R in formula (1b), respectively. ２ , R ３ , R ４ Examples of (meth)acrylamide or (meth)acrylamide derivatives represented by the above formula (1b') include N,N-dimethyl(meth)acrylamide and N,N-diethyl(meth)acrylamide, and preferably N,N-dimethylacrylamide.

[0022] <(3) Hydrophobic Structural Unit> The copolymer (P) used in the ophthalmic composition of the present invention has a structural unit represented by the following formula (1c) (hereinafter abbreviated as "hydrophobic structural unit").

[0023] In the above formula (1c), R ５ represents a hydrogen atom or a methyl group, and R ６ represents a monovalent hydrocarbon group having 12 to 24 carbon atoms, such as a lauryl group, a stearyl group, or a behenyl group. ６ is preferably a monovalent hydrocarbon group having 12 to 20 carbon atoms, more preferably 14 to 20 carbon atoms, and even more preferably 17 to 19 carbon atoms. c represents the proportion of the number of structural units represented by the above formula (1c) in copolymer (P), and represents the molar ratio to the structural units represented by formulas (1a) and (1b). The hydrophobic structural units in copolymer (P) are introduced to enhance adhesiveness to corneal cells.

[0024] The ratio of hydrophobic structural units in copolymer (P), where a of the PC structural unit is 100, is c / a = 2 / 100 or more and 50 / 100 or less, preferably 5 / 100 or more and 25 / 100 or less. If c is too large, the hydrophilicity of copolymer (P) decreases, which reduces its solubility in water, making it difficult to produce an ophthalmic composition. If c is too small, the adhesiveness to corneal cells decreases, and the protective effect of corneal cells cannot be expected.

[0025] The hydrophobic structural unit in copolymer (P) is obtained from a hydrophobic monomer represented by the following formula (1c') used during polymerization of copolymer (P). In other words, the hydrophobic structural unit is a structural unit derived from a monomer represented by formula (1c').

[0026] R in formula (1c') ５ and R ６ are R in formula (1c), respectively. ５ and R ６ Examples of the hydrophobic monomer represented by formula (1c') include linear alkyl (meth)acrylates such as lauryl (meth)acrylate, stearyl (meth)acrylate, and behenyl (meth)acrylate, and preferably stearyl methacrylate.

[0027] The weight-average molecular weight of copolymer (P) is 5,000 to 2,000,000. If the weight-average molecular weight is less than 5,000, the corneal cell protective effect may not be expected, while if it exceeds 2,000,000, the sterile filtration required for producing an ophthalmic composition may become difficult. From the viewpoint of improving the corneal cell protective effect, the weight-average molecular weight of copolymer (P) is preferably 10,000 to 1,000,000, and more preferably 50,000 to 500,000. The weight-average molecular weight refers to a value calculated as polyethylene glycol (PEG) as measured by gel permeation chromatography (GPC).

[0028] The copolymer (P) represented by formula (1) has the structural units derived from formulas (1a) to (1c), but the arrangement of the structural units in the copolymer (P) is not particularly limited and may be random or block.

[0029] The copolymer (P) of component (A) can be produced, for example, as follows. It can be produced by radical polymerization of a monomer composition containing various monomers for forming the structural units of formulas (1a) to (1c), i.e., the above-mentioned PC monomer, the monomer represented by formula (1b'), and the monomer represented by formula (1c'), in the presence of a radical polymerization initiator and in an inert gas-substituted or inert gas atmosphere such as nitrogen, carbon dioxide, argon, or helium. The polymerization method can be known, such as bulk polymerization, suspension polymerization, emulsion polymerization, or solution polymerization. The copolymer (P) can be purified by known methods such as reprecipitation, dialysis, and ultrafiltration. Examples of the radical polymerization initiator include azo-based radical polymerization initiators, organic peroxides, and persulfates.

[0030] Examples of azo radical polymerization initiators include 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). Examples of organic peroxides include benzoyl peroxide, diisopropyl peroxydicarbonate, t-butylperoxy-2-ethylhexanoate, lauroyl peroxide, t-butylperoxyneodecanate, and succinic acid peroxide. Examples of persulfates include ammonium persulfate, potassium persulfate, and sodium persulfate. 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 w / w % or more and 10 w / w % or less, preferably 0.01 w / w % or more and 5.0 w / w % or less, based on 100 w / w % of the monomer composition.

[0031] The production of the copolymer (P) can be carried out in the presence of a solvent. The solvent may be any solvent that dissolves the monomer composition and does not react with it, such as alcohol solvents, ketone solvents, ester solvents, linear or cyclic ether solvents, and nitrogen-containing solvents. Examples of alcohol solvents include water, methanol, ethanol, n-propanol, and isopropanol. Examples of ketone solvents include acetone, methyl ethyl ketone, and diethyl ketone. Examples of ester solvents include ethyl acetate. Examples of linear or cyclic ether solvents include ethyl cellosolve, tetrahydrofuran, and N-methylpyrrolidone. Examples of nitrogen-containing solvents include acetonitrile and nitromethane. Water, alcohol, or a mixture thereof is preferred.

[0032] The amount of component (A) in the ophthalmic composition of the present invention is 0.01 w / w% or more and 0.5 w / w% or less. If this amount is less than 0.01 w / w%, the corneal cell protective effect may not be fully exerted, and if this amount is more than 0.5 w / w%, the sterile filtration required for producing the ophthalmic composition may become difficult. From the viewpoint of exhibiting a more sufficient cell protective effect, the amount of component (A) is preferably 0.02 w / w% or more and 0.4 w / w% or less, more preferably 0.03 w / w% or more and 0.3 w / w% or less, and even more preferably 0.05 w / w% or more and 0.2 w / w% or less.

[0033] The ophthalmic composition of the present invention contains at least one of (B) benzalkonium chloride and (C) chlorhexidine gluconate as a preservative. That is, the ophthalmic composition of the present invention may contain only (B) benzalkonium chloride (component (B)), only (C) chlorhexidine gluconate (component (C)), or both (B) and (C) as a preservative.

[0034] When the ophthalmic composition of the present invention contains component (B), the amount of benzalkonium chloride (component (B)) in the ophthalmic composition is 0.001 w / w% or more and 0.02 w / w% or less. If this amount is less than 0.001 w / w%, the preservative effect may not be sufficient, and if it is more than 0.02 w / w%, corneal epithelial damage may occur. From the viewpoint of exhibiting a more sufficient cell protective effect, the amount of component (B) is preferably 0.005 w / w% or more and 0.015 w / w% or less.

[0035] When the ophthalmic composition of the present invention contains component (C), the amount of chlorhexidine gluconate (C) in the ophthalmic composition is 0.001 w / w% or more and 0.05 w / w% or less. If this amount is less than 0.001 w / w%, the preservative effect may not be sufficient, and if it is more than 0.05 w / w%, corneal epithelial damage may occur. From the viewpoint of exhibiting a more sufficient cell protective effect, the amount of component (C) is preferably 0.005 w / w% or more and 0.015 w / w% or less.

[0036] The ophthalmic composition of the present invention preferably contains 0.5 wt% or less of hydroxypropyl methylcellulose. If this is greater than 0.5 wt%, the sterile filtration required for producing the ophthalmic composition may become difficult. From the viewpoint of sterile filtration, the content is preferably 0.3 wt% or less. When hydroxypropyl methylcellulose is incorporated into the ophthalmic composition of the present invention, the amount of hydroxypropyl methylcellulose incorporated in the ophthalmic composition is preferably 0.01 wt% or more, more preferably 0.05 wt% or more. Hydroxypropyl methylcellulose may be any hydroxypropyl methylcellulose used in ordinary pharmaceuticals, and for example, products listed in the Japanese Pharmacopoeia may be used.

[0037] The ophthalmic composition of the present invention may contain other components in addition to the above components (A) to (C). Examples of such other components include polyhydric alcohols, cooling agents, inorganic salts, organic acid salts, acids, bases, antioxidants, and mucin secretion promoters. Examples of polyhydric alcohols include propylene glycol, glycerin, glucose, mannitol, sorbitol, xylitol, and trehalose. Examples of cooling agents include menthol and camphor. Examples of inorganic salts include potassium chloride, sodium chloride, borax, sodium bicarbonate, sodium hydrogen phosphate, and anhydrous sodium dihydrogen phosphate. Examples of organic acid salts include sodium citrate and sodium acetate. Examples of acids include boric acid, phosphoric acid, citric acid, sulfuric acid, acetic acid, and hydrochloric acid. Examples of bases include sodium hydroxide, potassium hydroxide, trometamol, and monoethanolamine. Examples of antioxidants include tocopherol acetate and dibutylhydroxytoluene. Examples of mucin secretion promoters include diquafosol sodium and rebamipide.

[0038] The present invention will be specifically described below with reference to examples, but the present invention is not limited to the scope of the following examples. [Evaluation] The following evaluations were carried out for the examples and comparative examples. (1) Evaluation of cell viability Cell viability was evaluated using rabbit corneal epithelial cells (SIRC cells). SIRC cells were pre-cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10 v / v % FBS (fetal bovine serum), and were treated with trypsin to obtain 1.0 x 10 ５ A cell suspension of 0.1 mL / mL was prepared. The cell suspension was seeded into a 96-well plate at 0.1 mL / well and cultured for 24 hours to allow the cells to adhere. Then, 0.05 mL / well of each of the ophthalmic compositions of Examples 1 to 11 and Comparative Examples 1 to 9 was added every hour for a total of five times, and the cells were cultured for another 24 hours. After the culture, the medium was removed, and a 50 μg / mL neutral red solution was added to allow the neutral red to be incorporated into the viable cells. After 3 hours, the cells were washed with PBS (phosphate-buffered saline), and neutral red was extracted with a 1 v / v% acetic acid / 50 v / v% ethanol aqueous solution, and the absorbance at 540 nm was measured. The absorbance without the addition of the sample solution was taken as 100% cell viability, and the cell viability was calculated with the addition of the ophthalmic compositions of Examples 1 to 11 and Comparative Examples 1 to 9, and the 50% inhibitory concentration (IC ５０ ) was calculated. ５０ When the IC is 15% or more but less than 100%, the cell survival rate is considered high and is given a good grade "A"; ５０ If the IC is 10% or more but less than 15%, the cell viability is considered to be moderate and is graded as "B"; ５０ When the value was greater than 0% and less than 10%, the cell viability was deemed low and was evaluated as unacceptable "C".

[0039] (2) Preservative Effectiveness Test The preservative effectiveness test was carried out in accordance with the section "Preservative Effectiveness Test Method, Reference Information, Japanese Pharmacopoeia, 18th Edition." Three types of bacteria were used: Escherichia coli (hereinafter abbreviated as E.c.) (NBRC3972), Pseudomonas aeruginosa (hereinafter abbreviated as P.a.) (NBRC13275), and Staphylococcus aureus (hereinafter abbreviated as S.a.) (NBRC13276), and two types of fungi were used: Candida albicans (hereinafter abbreviated as C.a.) (NBRC1594) and Aspergillus brasiliensis (hereinafter abbreviated as A.b.) (NBRC9455). BIOBALL (registered trademark) (bioMérieux Japan Co., Ltd.) containing 10 a.a., 10 a.b., and 10 b.a. were reconstituted and diluted to 10 mL. ８ The test bacterial solution was added to the ophthalmic compositions of Examples 1 to 11 and Comparative Examples 1 to 9 so as to have a concentration of 1 v / v %. The number of inoculated bacteria was 10 per mL. ６ The samples were adjusted to CFU and stored at 25°C. For each bacterial species, samples were taken 14 and 28 days after inoculation, cultured, and the viable cell count was measured. Those in which no colonies were generated after 28 days were rated as "good" (A); those in which colonies were generated after 28 days but the number of bacteria after 28 days did not increase from the number of bacteria after 14 days were rated as "passable" (B); and those in which the number of bacteria after 28 days increased from the number of bacteria after 14 days were rated as "unacceptable" (C). In addition, for the overall evaluation, those in which no colonies were generated for any bacterial species after 28 days were rated as "good" (A); those in which colonies were generated after 28 days but the number of bacteria after 28 days was lower than the number of bacteria after 14 days were rated as "passable" (B); and those in which the number of bacteria after 28 days for at least one bacterial species increased from the number of bacteria after 14 days were rated as "unacceptable" (C).

[0040] The copolymers and homopolymers used in the following examples and comparative examples are as follows. [Synthesis Example] (Synthesis of Copolymer P) 31.8 g of 2-methacryloyloxyethyl phosphorylcholine (MPC, manufactured by NOF Corporation), 3.6 g of stearyl methacrylate (SMA, manufactured by NOF Corporation), and 9.6 g of N,N-dimethylacrylamide (DMAA, manufactured by KJ Chemicals Co., Ltd.) were placed in a four-neck flask and dissolved in 55.0 g of ethanol. Nitrogen gas was then blown in for 30 minutes. The temperature was then raised to 48°C, and 0.10 g of a polymerization initiator (Perbutyl ND (PB-ND), manufactured by NOF Corporation) was added, followed by polymerization for 8 hours. After the polymerization reaction, the polymerization solution was added dropwise to 3 liters of diethyl ether while stirring. The precipitate was filtered and vacuum dried at room temperature for 48 hours to obtain a powder. The yield was 40.2 g. Copolymer (P): a copolymer of MPC, DMAA, and SMA (copolymerization composition ratio of MPC, DMAA, and SMA [MPC / DMAA / SMA (molar ratio) = 10 / 9 / 1], weight average molecular weight: 100,000). The weight average molecular weight of copolymer (P) was measured as follows.

[0041] [Measurement of weight-average molecular weight] 5 mg of the obtained copolymer (P) was dissolved in a methanol / chloroform mixed solution (80:20) to prepare a sample solution. The concentration of copolymer (P) in the sample solution was 0.5% by mass. The analysis conditions were as follows: Column: PLgel-mixed-C Standard substance: polyethylene glycol Detector: differential refractometer RI-8020 (manufactured by Tosoh Corporation) Calculation method for weight-average molecular weight: molecular weight calculation program (GPC program for SC-8020) Flow rate: 1 mL / min Injection volume: 100 μL Column oven: constant temperature around 40°C

[0042] [Preparation of Ophthalmic Composition] (Example 1) Approximately 50 g of purified water was heated to 80°C, and 0.1 g of hydroxypropyl methylcellulose [60SH-50 (hypromellose) manufactured by Shin-Etsu Chemical Co., Ltd.] was added thereto and stirred. After visually confirming uniform dispersion, the mixture was cooled to 47.5°C and further stirred. While maintaining the temperature at 47.5°C, 0.62 g of sodium chloride, 0.1 g of potassium chloride, 0.4 g of boric acid, 0.04 g of borax, and benzalkonium chloride [Nissan Cation M manufactured by NOF Corporation] as component (B) were added. ２ 0.01 g of hydroxybenzoate (-100R) and 0.1 g of copolymer (P) as component (A) were added sequentially and stirred. Purified water was then added to the mixture so that the total amount became 100 g. The mixture was then sterilized by filtration to obtain a sterile ophthalmic composition. Table 1 shows the content (w / w%) of each component in the ophthalmic composition.

[0043] (Examples 2 to 11) The types and amounts of components shown in Table 1 were used, and the preparations were carried out in the same manner as in Example 1. Note that components and blending amounts common to the examples and comparative examples are shown in Table 2 as common components.

[0044] Comparative Examples 1 to 9 The types and amounts of components shown in Table 3 were used, and the same procedures as in Example 1 were used to produce the compositions.

[0045]

[0046]

[0047]

[0048] The results of the cell viability are shown in Table 4. The cell viability was low in Comparative Example 1, which did not contain copolymer (P), and in Comparative Examples 4 and 9, which contained a small amount of copolymer (P), but was high in Examples 1 to 11, which contained copolymer (P). From the above, the ophthalmic composition of the present invention protects corneal cells.

[0049]

[0050] The results of the preservative effectiveness test are shown in Table 5. Comparative Example 3, which did not contain benzalkonium chloride, and Comparative Examples 6, 8, and 9, which contained small amounts of benzalkonium chloride or chlorhexidine gluconate, did not meet the evaluation criteria. On the other hand, Examples 1 to 11 met the evaluation criteria for all bacteria and fungi. From the above, the ophthalmic composition of the present invention exhibits sufficient preservative effectiveness.

[0051]

[0052] The results of all test items are shown in Table 6. From the above results, it is clear that the ophthalmic composition of the present invention exerts sufficient preservative effect and protects corneal cells.

[0053] According to the present invention, an ophthalmic composition that exhibits sufficient preservative effect and protects corneal cells can be obtained.

Claims

1. An ophthalmic composition comprising: (A) 0.01 w / w% or more and 0.5 w / w% or less of a copolymer having structural units represented by the following formulas (1a) to (1c), in which the molar ratio of each structural unit is a:b:c=100:10-400:2-50 and the weight average molecular weight is 5,000-2,000,000; (B) 0.001 w / w% or more and 0.02 w / w% or less of benzalkonium chloride; and / or (C) 0.001 w / w% or more and 0.05 w / w% or less of chlorhexidine gluconate. [In the formulas (1a) to (1c), a, b, and c represent the molar ratios of each structural unit. R １ , R ２ and R ５ R each independently represents a hydrogen atom or a methyl group. ３ and R ４ R each independently represents a hydrogen atom, a methyl group, or an ethyl group. ６ represents a monovalent hydrocarbon group having 12 to 24 carbon atoms.

2. The ophthalmic composition according to claim 1, containing 0.5 w / w% or less of hydroxypropyl methylcellulose.

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