Ophthalmic composition

Abstract

The ophthalmic composition according to the present invention contains: (A) 0.01-0.5 w / w% of a copolymer having structural units represented by formulae (1a)-(1c), the molar ratio of the structural units being a: b: c = 100: 10-400: 2-50, and the weight-average molecular weight being 5,000-2,000,000; (B) from 0.001 w / w% to 0.02 w / w% (inclusive) of benzalkonium chloride; and / or (C) from 0.001 w / w% to 0.05 w / w% (inclusive) of chlorhexidine gluconate. According to the present invention, it is possible to provide an ophthalmic composition that protects corneal cells while exhibiting sufficient storage efficacy.

Description

Technical Field

[0001] This invention relates to ophthalmic compositions. Background Technology

[0002] In recent years, with the increase in the number of contact lens wearers and the widespread use of digital devices, the number of patients complaining of dry eye syndrome, such as eye discomfort and dryness, is increasing. In addition to dry eye symptoms, there has also been a recent surge in complaints about hay fever, with a dramatic increase in hay fever cases over the past decade. To cope with these symptoms, the number of people using eye drops is also increasing year by year.

[0003] Eye drops are typically used repeatedly within several weeks after opening, so preservatives are used to prevent contamination by bacteria in the container. While preservatives help maintain the efficacy of eye drops, prolonged use without following the prescribed usage and dosage may cause ocular superficial keratosis, a condition caused by the death of some cells on the corneal surface.

[0004] In addition, many hay fever sufferers use eye drops beyond the recommended number of times in a short period of time to wash away pollen. In this case, preservatives may cause side effects such as corneal damage and blepharitis. Therefore, in recent years, preservative-free disposable eye drops have been developed, aiming to provide eye drops that are gentler on the eyes.

[0005] Currently, commercially available eye drops often use benzalkonium chloride and chlorhexidine gluconate as preservatives. Benzalkonium chloride, in particular, has a broad antibacterial spectrum and is therefore used in many eye drops. However, even with prolonged use, high frequency and concentration of these preservatives can potentially induce corneal epithelial disorders.

[0006] Normally, if tear production is maintained at a normal level, the concentration of preservatives decreases due to tear turnover, thus not affecting the ocular surface. However, when tear production is reduced due to dry eye symptoms, preservatives can remain on the ocular surface for extended periods, potentially causing damage even at low concentrations. Furthermore, in patients with corneal obstruction or requiring frequent eye drops, corneal damage and infection may occur. Therefore, to ensure safe use by all patients, eye drops that provide adequate preservation efficacy and protect corneal cells from the effects of preservatives are necessary.

[0007] In recent years, the development of additives to protect cells from the effects of cytotoxic substances has been progressing. For example, Non-Patent Literature 1 reports a method for protecting cells from the preservative benzalkonium chloride by incorporating D-mannitol into eye drops.

[0008] Furthermore, Patent Document 1 discloses an eye drop containing a phosphocholine polymer and polyhexamethylene biguanide. Using the eye drop described in Patent Document 1 provides sufficient preservation efficacy, rapidly spreading to the surface of the eye or contact lens to exert moisturizing and lubricating effects.

[0009] Existing technical documents

[0010] Patent documents

[0011] Patent Document 1: Japanese Patent Application Publication No. 2021-20856

[0012] Non-patent literature

[0013] Non-patent literature 1: Journal of Oleo Science, Noriaki Nagai, 2015, vol.64, no.7 Summary of the Invention

[0014] The problem that the invention aims to solve

[0015] Non-Patent Literature 1 describes a method for protecting cells from the preservatives in eye drops, but it does not explicitly describe polymers containing phosphocholine groups. Furthermore, even when a sufficient amount of the specific terpolymer described in Patent Literature 1, which significantly improves lubricity, is used, adequate preservation efficacy is sometimes not achieved depending on the type of preservative.

[0016] In view of the above-mentioned issues, the object of the present invention is to provide an ophthalmic composition that exerts sufficient preservation efficacy and protects corneal cells.

[0017] Methods for solving problems

[0018] The inventors conducted in-depth research and found that as long as an ophthalmic composition contains a specific amount of a copolymer (hereinafter sometimes referred to as "copolymer (P)") having structural units shown in formulas (1a) to (1c), a molar ratio of each structural unit of a:b:c=100:10 to 400:2 to 50, a weight-average molecular weight of 5,000 to 2,000,000, and a specific preservative, it can exert sufficient preservation efficacy and protect corneal cells, thus completing the present invention.

[0019] That is, the present invention is as follows.

[0020] [1] An ophthalmic composition comprising (A) a copolymer of 0.01 w / w% or more and 0.5 w / w% or less, having structural units of formulas (1a) to (1c), wherein the molar ratio of each structural unit 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) benzalkonium chloride of 0.001 w / w% or more and 0.02 w / w% or less; and / or (C) chlorhexidine gluconate of 0.001 w / w% or more and 0.05 w / w% or less;

[0021] [Chemistry 1]

[0022]

[0023] [Chemistry 2]

[0024]

[0025] [Chemistry 3]

[0026]

[0027] In equations (1a) to (1c), a, b, and c represent the molar ratios of the structural units. 1 R 2 and R 5 Each can be used independently to represent a hydrogen atom or a methyl group. R 3 and R 4 Each can independently represent a hydrogen atom, a methyl group, or an ethyl group. R 6 This refers to a monovalent hydrocarbon group containing 12 to 24 carbon atoms.

[0028] [2] The ophthalmic composition according to [1] above contains less than 0.5 w / w% of hydroxypropyl methylcellulose.

[0029] Invention Effects

[0030] The ophthalmic composition of the present invention can protect corneal cells while exerting sufficient preservative efficacy. That is, according to the present invention, an ophthalmic composition can provide excellent protection for corneal cells. Detailed Implementation

[0031] The ophthalmic composition of the present invention comprises: a copolymer of 0.01 w / w% or more and 0.5 w / w% or less as component (A), having structural units shown in formulas (1a) to (1c), wherein the molar ratio of each structural unit is a:b:c=100:10 to 400:2 to 50 and the weight-average molecular weight is 5,000 to 2,000,000; benzalkonium chloride of 0.001 w / w% or more and 0.02 w / w% or less as component (B); and / or chlorhexidine gluconate of 0.001 w / w% or more and 0.05 w / w% or less as component (C).

[0032] [Chemistry 4]

[0033]

[0034] [Chemistry 5]

[0035]

[0036] [Chemistry 6]

[0037]

[0038] 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 of each structural unit is a:b:c=100:10~400:2~50.

[0039] <(1) PC structural unit>

[0040] The copolymer (P) used in the ophthalmic composition of the present invention has a structural unit (hereinafter referred to as "PC structural unit") as shown in formula (1a). The PC structural unit is a structural unit derived from the PC monomer shown in formula (2) described later. The copolymer (P) contains structural units derived from the PC monomer, thereby protecting corneal cells.

[0041] [Chemistry 7]

[0042]

[0043] In equation (1a) above, R 1 denoted as a hydrogen atom or a methyl group. 'a' represents the proportion of the structural units shown in formula (1a) above in the copolymer (P), and represents the molar ratio to the structural units shown in formulas (1b) and (1c).

[0044] The PC structural unit in the copolymer (P) is introduced to impart hydrophilicity to the copolymer (P) and enhance the protective effect on corneal cells.

[0045] The PC structural unit in the copolymer (P) is obtained from the monomer containing a phosphocholine-like group (hereinafter referred to as PC monomer) as shown in the following formula (2) used in the polymerization of the copolymer (P).

[0046] [Chemistry 8]

[0047]

[0048] In formula (2), X is (meth)acryloyloxy. It should be noted that (meth)acryloyl refers to both methacryloyl and acryloyl groups.

[0049] From the viewpoint of availability, 2-((meth)acryloyloxy)ethyl-2'-(trimethylammonium)ethyl phosphate is preferred as a PC monomer, and 2-(methacryloyloxy)ethyl-2'-(trimethylammonium)ethyl phosphate (hereinafter referred to as MPC) as shown in formula (3) below is even more preferred.

[0050] [Chemistry 9]

[0051]

[0052] <(2) Amide structural unit>

[0053] The copolymer (P) used in the ophthalmic composition of the present invention has the structural unit shown in the following formula (1b) (hereinafter referred to as "amide structural unit").

[0054] [Chemistry 10]

[0055]

[0056] In equation (1b) above, R 2 R represents a hydrogen atom or a methyl group. 3 and R 4 Each can independently represent a hydrogen atom, a methyl group, or an ethyl group. Wherein, R... 3 and R 4 Each is preferably methyl or ethyl, more preferably methyl. b represents the proportion of the number of structural units shown in formula (1b) in the copolymer (P), and represents the molar ratio with the structural units shown in formulas (1a) and (1c).

[0057] The amide structural units in the copolymer (P) are introduced to increase the molecular weight of the copolymer (P) and improve its adhesion to corneal cells.

[0058] Regarding the proportion of amide structural units in the copolymer (P), and regarding b when a of the PC structural unit is set to 100, 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, sterile filtration required for manufacturing ophthalmic compositions may become difficult; if b is too small, the protective effect on corneal cells cannot be expected.

[0059] The amide structural units in the copolymer (P) are obtained from the monomer shown in formula (1b') used in the polymerization of the copolymer (P), namely (meth)acrylamide or (meth)acrylamide derivatives. In other words, the amide structural units are structural units derived from the monomer shown in formula (1b').

[0060] [Chemistry 11]

[0061]

[0062] R in equation (1b') 2 R 3 R 4 Respectively with R in equation (1b) 2 R 3 R 4 same.

[0063] Examples of (meth)acrylamide or (meth)acrylamide derivatives represented by formula (1b') above include N,N-dimethyl (meth)acrylamide or N,N-diethyl (meth)acrylamide, with N,N-dimethylacrylamide being preferred.

[0064] <(3) Hydrophobic structural unit>

[0065] The copolymer (P) used in the ophthalmic composition of the present invention has structural units shown in the following formula (1c) (hereinafter referred to as "hydrophobic structural units").

[0066] [Chemistry 12]

[0067]

[0068] In equation (1c) above, R 5 R represents a hydrogen atom or a methyl group. 6 R represents a monovalent hydrocarbon group with 12 to 24 carbon atoms, such as lauryl, stearyl, and benzyl. 6 Preferably, it is a monovalent hydrocarbon group with 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 shown in formula (1c) above in the copolymer (P), and represents the molar ratio with the structural units shown in formulas (1a) and (1b).

[0069] The hydrophobic structural units in the copolymer (P) are introduced to improve adhesion to corneal cells.

[0070] Regarding the proportion of hydrophobic structural units in the copolymer (P), and regarding c when a of the PC structural unit is set to 100, c / a = 2 / 100 or more and 50 / 100 or less, preferably 5 / 100 or more and 25 / 100 or less. When c is too large, the hydrophilicity of the copolymer (P) decreases, thereby reducing its water solubility and making the manufacture of the ophthalmic composition difficult. When c is too small, the adhesion to corneal cells decreases, and the protective effect on corneal cells is not observed.

[0071] The hydrophobic structural units in the copolymer (P) are obtained from the hydrophobic monomer shown in formula (1c') used in the polymerization of the copolymer (P). In other words, the hydrophobic structural units are structural units derived from the monomer shown in formula (1c').

[0072] [Chemistry 13]

[0073]

[0074] R in equation (1c') 5 and R 6 respectively with R in equation (1c) 5 and R 6 same.

[0075] Examples of hydrophobic monomers represented by formula (1c') include lauryl methacrylate, stearyl methacrylate, benzyl methacrylate, and other straight-chain alkyl esters of methacrylate, with stearyl methacrylate being preferred.

[0076] Furthermore, the weight-average molecular weight of the copolymer (P) is 5,000 to 2,000,000. When the weight-average molecular weight is less than 5,000, corneal cell protection may not be expected, and when it exceeds 2,000,000, sterile filtration required for manufacturing ophthalmic compositions may become difficult. Moreover, from the viewpoint of improving corneal cell protection, the weight-average molecular weight of the copolymer (P) is preferably 10,000 to 1,000,000, more preferably 50,000 to 500,000. It should be noted that the above-mentioned weight-average molecular weight refers to the value converted from polyethylene glycol (PEG) as determined by gel permeation chromatography (GPC).

[0077] The copolymer (P) shown in formula (1) has structural units from formulas (1a) to (1c), but the arrangement of the structural units in the copolymer (P) is not particularly limited and can be random or block.

[0078] (A) The copolymer (P) can be manufactured, for example, as follows. It can be manufactured by free radical polymerization of a monomer composition containing various monomers for forming the structural units of formulas (1a) to (1c), namely the aforementioned PC monomer, the monomer shown in formula (1b'), and the monomer shown in formula (1c'), in the presence of a free radical polymerization initiator and under an atmosphere of inert gas replacement such as nitrogen, carbon dioxide, argon, or helium. The polymerization method can be any known method such as bulk polymerization, suspension polymerization, emulsion polymerization, or solution polymerization. The copolymer (P) can be purified by any known method such as reprecipitation, dialysis, or ultrafiltration.

[0079] Examples of free radical polymerization initiators include azo-based free radical polymerization initiators, organic peroxides, and persulfates.

[0080] Examples of azo-based free 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-cyanopentanoic acid), 2,2-azobisisobutylamide dihydrate, 2,2-azobis(2,4-dimethylpentanonitrile), and 2,2-azobisisobutyronitrile (AIBN).

[0081] Examples of organic peroxides include benzoyl peroxide, diisopropyl peroxide dicarbonate, tert-butyl-2-ethylhexanoate peroxide, lauroyl peroxide, tert-butyl peroxyneodecanate, and succinic acid peroxide.

[0082] Examples of persulfates include ammonium persulfate, potassium persulfate, and sodium persulfate.

[0083] These free radical polymerization initiators can be used alone, or two or more can be used in combination. The amount of polymerization initiator used relative to 100 w / w% of the monomer composition is generally 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.

[0084] The copolymer (P) can be manufactured in the presence of a solvent. Any solvent that dissolves the monomer composition without reacting can be used, such as alcohol solvents, ketone solvents, ester solvents, linear or cyclic ether solvents, and nitrogen-containing solvents.

[0085] Examples of alcohol-based solvents include water, methanol, ethanol, n-propanol, and isopropanol.

[0086] Examples of ketone solvents include acetone, methyl ethyl ketone, and diethyl ketone.

[0087] Examples of ester-based solvents include ethyl acetate.

[0088] Examples of linear or cyclic ether solvents include ethyl cellosolve, tetrahydrofuran, and N-methylpyrrolidone.

[0089] Examples of nitrogen-containing solvents include acetonitrile and nitromethane. Water, alcohol, or mixtures thereof are preferred.

[0090] 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 it is less than 0.01 w / w%, the corneal cell protection effect may not be fully realized, and if it is greater than 0.5 w / w%, the sterile filtration required for manufacturing the ophthalmic composition may become difficult. From the viewpoint of exhibiting a more sufficient cell protection 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.

[0091] 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.

[0092] When component (B) is incorporated into the ophthalmic composition of the present invention, the amount of benzalkonium chloride in component (B) of the ophthalmic composition is 0.001 w / w% or more and 0.02 w / w% or less. If it is less than 0.001 w / w%, sufficient preservation efficacy may not be achieved, and if it is greater than 0.02 w / w%, corneal epithelial damage may be caused. From the viewpoint of exhibiting a more sufficient cytoprotective effect, the amount of component (B) is preferably 0.005 w / w% or more and 0.015 w / w% or less.

[0093] When component (C) is incorporated into the ophthalmic composition of the present invention, the amount of chlorhexidine gluconate in component (C) of the ophthalmic composition is 0.001 w / w% or more and 0.05 w / w% or less. If it is less than 0.001 w / w%, sufficient preservation efficacy may not be achieved, and if it is greater than 0.05 w / w%, corneal epithelial damage may occur. From the viewpoint of exhibiting a more sufficient cytoprotective effect, the amount of component (C) is preferably 0.005 w / w% or more and 0.015 w / w% or less.

[0094] The ophthalmic composition of the present invention preferably contains 0.5 w / w or less of hydroxypropyl methylcellulose. If it is greater than 0.5 w / w, the aseptic filtration required for manufacturing the ophthalmic composition may become difficult. From the viewpoint of aseptic filtration, it is preferably 0.3 w / w or less.

[0095] When hydroxypropyl methylcellulose is incorporated into the ophthalmic composition of the present invention, the amount of hydroxypropyl methylcellulose in the ophthalmic composition is preferably 0.01 w / w% or more, more preferably 0.05 w / w% or more.

[0096] Hydroxypropyl methylcellulose can be any type of hydroxypropyl methylcellulose used in common pharmaceutical products, such as those listed in the Japanese Pharmacopoeia.

[0097] The ophthalmic composition of the present invention may contain other components besides those listed in (A) to (C) above. Examples of other components include polyols, cooling agents, inorganic salts, salts of organic acids, acids, bases, antioxidants, and mucin secretion promoters.

[0098] Examples of polyols include propylene glycol, glycerol, glucose, mannitol, sorbitol, xylitol, and trehalose.

[0099] Examples of cooling agents include menthol and camphor.

[0100] Examples of inorganic salts include potassium chloride, sodium chloride, borax, sodium bicarbonate, sodium hydrogen phosphate, and anhydrous sodium dihydrogen phosphate.

[0101] Examples of salts of organic acids include sodium citrate and sodium acetate.

[0102] Examples of acids include boric acid, phosphoric acid, citric acid, sulfuric acid, acetic acid, and hydrochloric acid.

[0103] Examples of bases include sodium hydroxide, potassium hydroxide, tromethamine, and monoethanolamine.

[0104] Examples of antioxidants include tocopherol acetate and butylated hydroxytoluene.

[0105] Examples of mucin secretion promoters include diquarfosol sodium and rebamipide.

[0106] Example

[0107] The following examples illustrate the present invention in detail, but the present invention is not limited to the scope of the following examples.

[0108] [evaluate]

[0109] The following evaluations were made of the embodiments and comparative examples.

[0110] (1) Evaluation of cell viability

[0111] Rabbit corneal epithelial cells (SIRC cells) were used to evaluate cell viability. Pre-cultured SIRC cells were treated with trypsin in Durbeco Modified Eagle Medium (DMEM) supplemented with 10 v / v% FBS (fetal bovine serum) to prepare 1.0 × 10⁶ cells. 5 Cell suspension at 0.1 mL / well was seeded into each well of a 96-well plate and cultured for 24 hours. After seeding, 0.05 mL / well of the ophthalmic compositions of Examples 1-11 and Comparative Examples 1-9 was added every hour for a total of 5 times, and the plates were cultured for another 24 hours. After culture, the culture medium was removed, and 50 μg / mL of neutral red solution was added to allow neutral red to enter the viable cells. After 3 hours, the cells were washed with PBS (phosphate-buffered saline), and neutral red was extracted with 1 v / v% acetic acid / 50 v / v% ethanol aqueous solution. The absorbance at 540 nm was measured. The absorbance without the sample solution was taken as 100% cell viability. The cell viability with the ophthalmic compositions of Examples 1-11 and Comparative Examples 1-9 was calculated, and the 50% inhibitory concentration (IC50) was calculated. 50 ). In IC 50 A cell viability of 15% or higher but less than 100% is considered high and thus rated as "good" (A). In the IC50 assay... 50 A cell viability of 10% or more but less than 15% is considered moderate and is classified as "B" (British). In IC50... 50 If the percentage is greater than 0% and less than 10%, it is considered as low cell viability and is therefore deemed unsuitable for "C".

[0112] (2) Preservation efficacy test

[0113] Preservation efficacy tests were conducted in accordance with the "Eighteenth Amendment to the Japanese Pharmacopoeia Reference Information Preservation Efficacy Test Method". Three bacteria were used: *Escherichia coli* (NBRC 3972), *Pseudomonas aeruginosa* (NBRC 13275), and *Staphylococcus aureus* (NBRC 13276). Two fungi were used: *Candida albicans* (NBRC 1594) and *Aspergillus brasiliensis* (NBRC 9455).

[0114] Redissolve the above Ec, Pa, Sa, Ca, and Ab in BIOBALL (registered trademark) (manufactured by bioMerieux Japan Co., Ltd.), and set each 1 mL as 10. 8 CFU (Colony Forming Unit) was used as the test bacterial solution. This test bacterial solution was added to the ophthalmic compositions of Examples 1-11 and Comparative Examples 1-9 at a rate of 1 v / v%, with each mL containing 10 CFU / v. 6 Adjust the CFU method and store at 25°C.

[0115] For each bacterial strain, samples were taken, cultured, and viable cell counts were determined 14 and 28 days after inoculation. No colonies were observed after 28 days, and the result was classified as "Good" (A). Colonies were observed after 28 days, but the cell count did not increase from the number observed after 14 days, and the result was classified as "Acceptable" (B). The cell count after 28 days was considered "Unacceptable" (C) as it increased from the number observed after 14 days.

[0116] In addition, in the comprehensive evaluation, the situation in which no colonies are produced by any bacterial species after 28 days is judged as good "A", the situation in which colonies are produced after 28 days but the number of bacteria is less than that after 14 days is judged as acceptable "B", and the situation in which at least one bacterial species increases the number of bacteria after 28 days compared to the number of bacteria after 14 days is judged as unacceptable "C".

[0117] The copolymers and homopolymers used in the following examples or comparative examples are described below.

[0118] [Synthesis Example] Synthesis of copolymer P

[0119] 31.8 g of 2-methacryloyloxyethyl phosphocholine (MPC, manufactured by Nippon Oil Co., Ltd.), 3.6 g of stearyl methacrylate (SMA, manufactured by Nippon Oil Co., Ltd.), and 9.6 g of N,N-dimethylacrylamide (DMAA, manufactured by KJ Chemicals Co., Ltd.) were placed in a four-necked flask and dissolved in 55.0 g of ethanol. Nitrogen gas was then introduced for 30 minutes. The mixture was then heated to 48°C, and 0.10 g of polymerization initiator (PERBUTYL ND (PB-ND), manufactured by Nippon Oil Co., Ltd.) was added. Polymerization was carried out for 8 hours. After polymerization, the polymer solution was added dropwise to 3 liters of diethyl ether while stirring. The precipitate was filtered and dried under vacuum at room temperature for 48 hours to obtain a powder. The yield was 40.2 g.

[0120] Copolymer (P): Copolymer of MPC, DMAA and SMA (copolymer composition ratio of MPC, DMAA and SMA [MPC / DMAA / SMA (molar ratio) = 10 / 9 / 1], weight average molecular weight: 100,000)

[0121] It should be noted that the weight-average molecular weight of the copolymer (P) was determined as follows.

[0122] [Determination of weight-average molecular weight]

[0123] The obtained copolymer (P) was dissolved in 5 mg of a methanol / chloroform mixture (80:20) to prepare a sample solution. The concentration of copolymer (P) in the sample solution was 0.5% by mass. The analytical conditions were as follows.

[0124] Column: PLgel-mixed-C

[0125] Standard substance: polyethylene glycol

[0126] Detector: Differential refractometer RI-8020 (manufactured by Tosoh Corporation)

[0127] Method for calculating weight-average molecular weight: Molecular weight calculation program (SC-8020 using GPC program)

[0128] Flow rate: 1 mL / min

[0129] Injection volume: 100μL

[0130] Column oven: fixed temperature around 40℃

[0131] [Preparation of Ophthalmic Compositions]

[0132] (Example 1)

[0133] Approximately 50g of purified water was heated to 80°C, and 0.1g of hydroxypropyl methylcellulose (Shin-Etsu Chemical Industry Co., Ltd., "60SH-50 (Hydroxypropyl Methylcellulose)") was added and stirred. After visually confirming uniform dispersion, the mixture was cooled to 47.5°C and stirred further. While maintaining the temperature at 47.5°C, 0.62g of sodium chloride, 0.1g of potassium chloride, 0.4g of boric acid, 0.04g of borax, 0.01g of benzalkonium chloride (Nippon Oil Co., Ltd., "NISSANCATION M2-100R") as component (B), and 0.1g of copolymer (P) as component (A) were added sequentially and stirred. Then, purified water was added in a total volume of 100g. The mixture was then filtered and sterilized to prepare a sterile ophthalmic composition. Table 1 shows the content (w / w%) of each component in the ophthalmic composition.

[0134] (Examples 2-11)

[0135] The ingredients, in the types and amounts shown in Table 1, were prepared following the same steps as in Example 1. It should be noted that ingredients with the same composition and proportions as those in the Examples and Comparative Examples are considered common ingredients and are shown in Table 2.

[0136] (Comparative Examples 1-9)

[0137] The ingredients, in the types and amounts shown in Table 3, were prepared following the same steps as in Example 1.

[0138] [Table 1]

[0139]

[0140] [Table 2]

[0141]

[0142] [Table 3]

[0143]

[0144] Table 4 shows the cell viability results. In Comparative Example 1 (without copolymer (P)) and Comparative Examples 4 and 9 (with low amounts of copolymer (P), cell viability was low; however, in Examples 1-11 (with copolymer (P), cell viability was high. As described above, the ophthalmic composition of the present invention protects corneal cells.

[0145] [Table 4]

[0146]

[0147] Table 5 shows the results of the preservation efficacy test. 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 1-11 met the evaluation criteria against any bacteria or fungi. As described above, the ophthalmic composition of the present invention exhibits sufficient preservation efficacy.

[0148] [Table 5]

[0149]

[0150] Table 6 shows the results of all tests. The results demonstrate that the ophthalmic composition of the present invention exhibits sufficient preservative efficacy and protects corneal cells.

[0151] [Table 6]

[0152]

[0153] Industrial availability

[0154] According to the present invention, an ophthalmic composition that exerts sufficient preservative efficacy and protects corneal cells can be obtained.

Claims

1. An ophthalmic composition comprising: (A) A copolymer with a weight ratio of 0.01 w / w% or more and 0.5 w / w% or less, having structural units as shown in formulas (1a) to (1c) below, wherein 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) Benzalkonium chloride at a concentration of ≥0.001 w / w% and ≤0.02 w / w%; and / or (C) Chlorhexidine gluconate at a concentration of ≥0.001 w / w% and ≤0.05 w / w%. [Chemistry 1] [Chemistry 2] [Chemistry 3] In equations (1a) to (1c), a, b, and c represent the molar ratios of the structural units, and R 1 R 2 and R 5 Each can be used independently to represent a hydrogen atom or a methyl group, R 3 and R 4 Each can independently represent a hydrogen atom, a methyl group, or an ethyl group; R 6 A monovalent hydrocarbon group representing 12 to 24 carbon atoms.

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

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