Aqueous ophthalmic composition

Abstract

To provide an aqueous ophthalmic composition that suppresses a discomfort taste associated with astringency.SOLUTION: An aqueous ophthalmic composition has (A) at least one selected from the group consisting of zinc salt, and glycyrrhizinic acid, azulene sulfonic acid and salt thereof, and (B) at least one selected from the group consisting of chondroitin sulfate and salt thereof, the content of the (B) component being 0.8 w / v% or more relative to the total amount of the aqueous ophthalmic composition.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an aqueous ophthalmic composition.

Background Art

[0002] A preparation applied to the ocular mucosa is either in its undiluted form or diluted by tears, sucked from the lacrimal punctum, transferred from the nasolacrimal duct into the nasal cavity, and then reaches the oral cavity. Therefore, although the user does not directly apply the components contained in the preparation into the oral cavity, an unpleasant taste such as bitterness or astringency may be felt after the application to the ocular mucosa. Such an unpleasant feeling of use is one of the reasons for hesitating to use an ophthalmic composition such as eye drops, and ultimately reduces the compliance of the user. Therefore, it is important to improve the feeling of use by alleviating the unpleasant taste caused by the components contained in the ophthalmic composition (for example, Patent Document 1).

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] The present inventors have conducted various studies on an aqueous ophthalmic composition containing a zinc salt, glycyrrhizic acid, or azulenesulfonic acid, and confirmed that there is a problem that an unpleasant astringency or astringency irritation (hereinafter, these are collectively referred to as "astringency-related taste") is felt after administration.

[0005] An object of the present invention is to provide an aqueous ophthalmic composition that contains a zinc salt and at least one selected from the group consisting of glycyrrhizic acid, azulenesulfonic acid, and salts thereof, and suppresses unpleasant astringency-related taste after administration.

Means for Solving the Problems

[0006] The inventors have surprisingly found that by incorporating at least one selected from the group consisting of chondroitin sulfate and its salts in a specific amount or more into an aqueous ophthalmic composition containing a zinc salt and glycyrrhizic acid, azulenesulfonic acid and their salts, the unpleasant astringency-related taste after administration in the aqueous ophthalmic composition is suppressed. The present invention is based on this finding and provides the following inventions.

[0007] [1] (A) At least one selected from the group consisting of a zinc salt and glycyrrhizic acid, azulenesulfonic acid and their salts, and (B) at least one selected from the group consisting of chondroitin sulfate and its salts, wherein the content of the component (B) is 0.8 w / v% or more based on the total amount of the aqueous ophthalmic composition. [2] The aqueous ophthalmic composition according to [1], wherein the content of the component (A) is 0.0001 w / v% to 5 w / v% based on the total amount of the aqueous ophthalmic composition. [3] The aqueous ophthalmic composition according to [1] or [2], wherein the content of the component (B) is 1 w / v% to 5 w / v% based on the total amount of the aqueous ophthalmic composition. [4] The aqueous ophthalmic composition according to any one of [1] to [3], further containing (C) neostigmine methylsulfate. [5] The aqueous ophthalmic composition according to any one of [1] to [4], further containing (D) a terpenoid. [6] A method for suppressing the unpleasant astringency-related taste after administration in an aqueous ophthalmic composition, which comprises incorporating (A) at least one selected from the group consisting of a zinc salt and glycyrrhizic acid, azulenesulfonic acid and their salts, and (B) at least one selected from the group consisting of chondroitin sulfate and its salts in an amount of 0.8 w / v% or more based on the total amount of the aqueous ophthalmic composition into the aqueous ophthalmic composition. [Advantages of the Invention]

[0008] According to the present invention, there can be provided an aqueous ophthalmic composition containing a zinc salt and at least one selected from the group consisting of glycyrrhizic acid, azulenesulfonic acid and salts thereof, while suppressing an unpleasant astringency-related taste after administration.

Mode for Carrying Out the Invention

[0009] Hereinafter, the embodiments for carrying out the present invention will be described in detail. However, the present invention is not limited to the following embodiments.

[0010] In this specification, unless otherwise specified, the unit “%” of the content means “w / v%” and is synonymous with “g / 100 mL”.

[0011] 〔1. Aqueous Ophthalmic Composition〕 The aqueous ophthalmic composition according to this embodiment contains (A) a zinc salt and at least one selected from the group consisting of glycyrrhizic acid, azulenesulfonic acid and salts thereof (simply referred to as “component (A)”). In the following, at least one selected from the group consisting of glycyrrhizic acid and salts thereof will be referred to as “component (A1)”, the zinc salt will be referred to as “component (A2)”, and at least one selected from the group consisting of azulenesulfonic acid and salts thereof will be referred to as “component (A3)”.

[0012] 〔Component (A)〕 The zinc salt, glycyrrhizic acid, azulenesulfonic acid and salts thereof as component (A) are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Glycyrrhizic acid and azulenesulfonic acid may be in the free form or may be pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable salts.

[0013] Examples of zinc salts include compounds that can become zinc ions in an aqueous ophthalmic composition, such as salts with inorganic acids, salts with organic acids, and chlorides. Examples of salts with inorganic acids include sulfates. Examples of salts with organic acids include lactates. Examples of chlorides include zinc chloride. Preferred zinc salts include zinc sulfate, zinc lactate, and zinc chloride, with zinc sulfate being more preferred. The zinc salt may also be a hydrate (e.g., zinc sulfate heptahydrate).

[0014] Examples of salts of glycyrrhizic acid include alkali metal salts, alkaline earth metal salts, and ammonium salts. Examples of alkali metal salts include sodium salts and potassium salts. Examples of alkaline earth metal salts include magnesium salts and calcium salts.

[0015] Preferred glycyrrhizic acid and its salts include glycyrrhizic acid, alkali metal salts of glycyrrhizic acid, and ammonium salts of glycyrrhizic acid. More preferred are dipotassium glycyrrhizate and ammonium glycyrrhizate, with dipotassium glycyrrhizate being even more preferred.

[0016] Examples of salts of azulenesulfonic acid include alkali metal salts. Examples of alkali metal salts include sodium salts and potassium salts.

[0017] Preferred azulenesulfonic acid and its salts include azulenesulfonic acid and alkali metal salts of azulenesulfonic acid. More preferred are azulenesulfonic acid and sodium azulenesulfonate, with sodium azulenesulfonate being even more preferred.

[0018] Commercially available zinc salts, glycyrrhizic acid, azulenesulfonic acid, and their salts can also be used. The zinc salts, glycyrrhizic acid, azulenesulfonic acid, and their salts may be used alone or in combination of two or more.

[0019] In the eye drops according to this embodiment, the content of component (A) is preferably 0.0001 to 5 w / v%, more preferably 0.0004 to 2 w / v%, still more preferably 0.001 to 1 w / v%, and even more preferably 0.004 to 0.25 w / v%, based on the total amount of the aqueous ophthalmic composition.

[0020] When a zinc salt is used as component (A), the content of the zinc salt is preferably, for example, 0.005 to 2 w / v%, more preferably 0.01 to 1.5 w / v%, still more preferably 0.03 to 1 w / v%, even more preferably 0.05 to 0.75 w / v%, still even more preferably 0.125 to 0.5 w / v%, and particularly preferably 0.15 to 0.25 w / v%, based on the total amount of the aqueous ophthalmic composition.

[0021] When glycyrrhizic acid and its salts are used as component (A), the content of glycyrrhizic acid and its salts is preferably, for example, 0.005 to 2 w / v%, more preferably 0.05 to 1 w / v%, still more preferably 0.125 to 0.5 w / v%, and even more preferably 0.2 to 0.25 w / v%, based on the total amount of the aqueous ophthalmic composition.

[0022] When azulenesulfonic acid and its salts are used as component (A), the content of azulenesulfonic acid and its salts is preferably, for example, 0.0004 to 0.5 w / v%, more preferably 0.001 to 0.1 w / v%, still more preferably 0.004 to 0.05 w / v%, and even more preferably 0.01 to 0.02 w / v%, based on the total amount of the aqueous ophthalmic composition.

[0023] [Component (B)] The aqueous ophthalmic composition according to the present embodiment contains, in addition to the component (A), at least one selected from the group consisting of (B) chondroitin sulfate and its salts (simply referred to as "(B) component").

[0024] (B) chondroitin sulfate and its salts, as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, are not particularly limited. The molecular weight of chondroitin sulfate and its salts is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, but usually, those having a weight average molecular weight of about 10,000 to 100,000, preferably about 50,000 to 500,000, and more preferably about 10,000 to 40,000 can be used.

[0025] Examples of the salts of chondroitin sulfate include alkali metal salts and alkaline earth metal salts. Examples of the alkali metal salts include sodium salts and potassium salts. Examples of the alkaline earth metal salts include magnesium salts and calcium salts.

[0026] As chondroitin sulfate and its salts, chondroitin sulfate and alkali metal salts of chondroitin sulfate are preferred, chondroitin sulfate and sodium chondroitin sulfate are more preferred, and sodium chondroitin sulfate is even more preferred.

[0027] Commercially available chondroitin sulfate and its salts can also be used. Chondroitin sulfate and its salts may be used alone or in combination of two or more.

[0028] In the aqueous ophthalmic composition according to this embodiment, the content of component (B) is 0.8 w / v% or more based on the total amount of the aqueous ophthalmic composition. The lower limit of the content of component (B) is not particularly limited as long as it is 0.8 w / v% or more, and is appropriately set according to the type of component (B), the types and contents of other compounding components, the use and dosage form of the aqueous ophthalmic composition, and the like. From the viewpoint of more significantly exhibiting the effects of the present invention, the lower limit of the content of component (B) is preferably, for example, 0.9 w / v% or more, more preferably 1 w / v% or more, still more preferably 2 w / v% or more, and particularly preferably 2.5 w / v% or more. The upper limit of the content of component (B) is not particularly limited and is appropriately set according to the type of component (B), the types and contents of other compounding components, the use and dosage form of the aqueous ophthalmic composition, and the like. From the viewpoints of more significantly exhibiting the effects of the present invention and the feeling of use, the upper limit of the content of component (B) is preferably, for example, 5 w / v% or less, more preferably 4 w / v% or less, still more preferably 3.5 w / v% or less, and still more preferably 3 w / v% or less. Further, the content of component (B) in the aqueous ophthalmic composition according to this embodiment may be, for example, 0.8 to 5 w / v%, 0.8 to 4 w / v%, 0.8 to 3 w / v%, 0.9 to 5 w / v%, 0.9 to 4 w / v%, 0.9 to 3 w / v%, 1 to 5 w / v%, 1 to 4 w / v%, or 1 to 3 w / v% based on the total amount of the aqueous ophthalmic composition. As another aspect, the content of component (B) in the aqueous ophthalmic composition according to this embodiment may be, for example, 2 to 4 w / v%, 2.5 to 3.5 w / v%, or 3 w / v% based on the total amount of the aqueous ophthalmic composition.

[0029] In the aqueous ophthalmic composition according to this embodiment, the content ratio of component (B) to component (A) is not particularly limited and is appropriately set according to the types of component (A) and component (B), the types and contents of other compounding components, the use and dosage form of the aqueous ophthalmic composition, and the like. From the viewpoint of further enhancing the effects according to the present invention, as the content ratio of component (B) to component (A), for example, with respect to 1 part by mass of the total content of component (A) contained in the aqueous ophthalmic composition according to this embodiment, the total content of component (B) is preferably 0.1 to 5000 parts by mass, more preferably 0.5 to 1000 parts by mass, still more preferably 1 to 500 parts by mass, and even more preferably 4 to 300 parts by mass. Further, 5 to 300 parts by mass and 10 to 300 parts by mass are also exemplified as preferable ranges.

[0030] When a zinc salt is used as component (A), as the content ratio of component (B) to component (A), with respect to 1 part by mass of the total content of component (A) contained in the aqueous ophthalmic composition according to this embodiment, the total content of component (B) is preferably 0.1 to 500 parts by mass, more preferably 0.5 to 100 parts by mass, still more preferably 1 to 60 parts by mass, and even more preferably 4 to 25 parts by mass. Further, 5 to 25 parts by mass and 10 to 20 parts by mass are also exemplified as preferable ranges.

[0031] When glycyrrhizic acid and its salts are used as component (A), as the content ratio of component (B) to component (A), with respect to 1 part by mass of the total content of component (A) contained in the aqueous ophthalmic composition according to this embodiment, the total content of component (B) is preferably 0.1 to 500 parts by mass, more preferably 0.5 to 100 parts by mass, still more preferably 1 to 60 parts by mass, and even more preferably 4 to 25 parts by mass. Further, 5 to 40 parts by mass and 10 to 25 parts by mass are also exemplified as preferable ranges.

[0032] When using azulene sulfonic acid and its salts as component (A), the content ratio of component (B) to component (A) is preferably such that the total content of component (B) is 1 to 5000 parts by mass, more preferably 5 to 1000 parts by mass, still more preferably 10 to 750 parts by mass, still more preferably 25 to 500 parts by mass, and particularly preferably 50 to 300 parts by mass, with respect to 1 part by mass of the total content of component (A) contained in the aqueous ophthalmic composition according to this embodiment. Also, 100 to 300 parts by mass and 150 to 300 parts by mass are exemplified as preferable ranges.

[0033] [Component (C)] The aqueous ophthalmic composition according to this embodiment may further contain neostigmine methylsulfate (simply referred to as "component (C)"). By containing component (C) in the aqueous ophthalmic composition, the effects according to the present invention are more significantly exhibited.

[0034] Neostigmine methylsulfate as component (C) is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

[0035] Neostigmine methylsulfate is a known compound also called (3-dimethylcarbamoyloxy phenyl) trimethylammonium methylsulfate.

[0036] The content of component (C) in the aqueous ophthalmic composition according to this embodiment is not particularly limited and is appropriately set according to the types and contents of other compounding components, the use and dosage form of the aqueous ophthalmic composition, etc. From the viewpoint of more significantly exhibiting the effects according to the present invention, the content of component (C) is preferably, for example, 0.00005 to 0.1 w / v%, more preferably 0.0001 to 0.05 w / v%, still more preferably 0.0005 to 0.01 w / v%, and still more preferably 0.001 to 0.005 w / v%, based on the total amount of the aqueous ophthalmic composition.

[0037] In the aqueous ophthalmic composition according to the present embodiment, the content ratio of the component (C) to the component (A) is not particularly limited, and is appropriately set according to the types of the component (A) and the component (C), the types and contents of other compounding components, the use and dosage form of the aqueous ophthalmic composition, and the like. From the viewpoint of further enhancing the effects of the present invention, as the content ratio of the component (C) to the component (A), for example, with respect to 1 part by mass of the total content of the component (A) contained in the aqueous ophthalmic composition according to the present embodiment, the total content of the component (C) is preferably 0.0001 to 50 parts by mass, more preferably 0.0005 to 10 parts by mass, still more preferably 0.001 to 5 parts by mass, and even more preferably 0.004 to 1.25 parts by mass.

[0038] In the aqueous ophthalmic composition according to the present embodiment, the content ratio of the component (C) to the component (B) is not particularly limited, and is appropriately set according to the types of the component (B) and the component (C), the types and contents of other compounding components, the use and dosage form of the aqueous ophthalmic composition, and the like. From the viewpoint of further enhancing the effects of the present invention, as the content ratio of the component (C) to the component (B), for example, with respect to 1 part by mass of the total content of the component (B) contained in the aqueous ophthalmic composition according to the present embodiment, the total content of the component (C) is preferably 0.00005 to 0.05 parts by mass, more preferably 0.0001 to 0.01 parts by mass, still more preferably 0.0003 to 0.005 parts by mass. Also, 0.0005 to 0.003 parts by mass and 0.001 to 0.002 parts by mass are also exemplified as preferred ranges.

[0039] [(D) component] The aqueous ophthalmic composition according to the present embodiment may further contain (D) terpenoid (simply referred to as "(D) component" also). By the aqueous ophthalmic composition containing the component (D), the effects of the present invention are more significantly exhibited.

[0040] The terpenoid which is the component (D) is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

[0041] Examples of terpenoids include cyclic terpenes and acyclic terpenes.

[0042] Cyclic terpenes are terpenoids having at least one ring structure in the molecule. Examples of cyclic terpenes include menthol, camphor, borneol (also referred to as "borneol"), menthone, cineole, carvone, anethole, eugenol, limonene, pinene, and their derivatives.

[0043] Acyclic terpenes are terpenoids having no ring structure in the molecule. Examples of acyclic terpenes include geraniol, citronellol, linalool, linalyl acetate, and their derivatives.

[0044] In the present invention, essential oils containing the above compounds may be used as terpenoids. Examples of such essential oils include eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, perilla oil, star anise oil, cinnamon oil, rose oil, and the like.

[0045] Terpenoids may be in the form of d-form, l-form, or dl-form. Examples include dl-menthol, d-menthol, l-menthol, dl-camphor, d-camphor, l-camphor, dl-borneol, d-borneol, l-borneol, dl-menthone, d-menthone, and l-menthone. However, some terpenoids such as geraniol and cineole may not have optical isomers.

[0046] Preferred terpenoids include menthol, camphor, borneol, menthone, geraniol, eucalyptus oil, and bergamot oil. More preferred are menthol, camphor, and borneol. Even more preferred are l-menthol, d-camphor, dl-camphor, and d-borneol. Even more preferably, it is l-menthol.

[0047] Terpenoids may be commercially available ones. The terpenoids may be used alone or in combination of two or more.

[0048] The content of component (D) in the aqueous ophthalmic composition according to this embodiment is not particularly limited and is appropriately set according to the type of component (D), the types and contents of other compounding components, the use and formulation form of the aqueous ophthalmic composition, etc. From the viewpoint of more significantly exhibiting the effects of the present invention, the content of component (D) is, for example, preferably 0.00001 to 1 w / v% based on the total amount of the aqueous ophthalmic composition, more preferably 0.00005 to 0.5 w / v%, still more preferably 0.0001 to 0.1 w / v%, still more preferably 0.0005 to 0.05 w / v%, and particularly preferably 0.001 to 0.05 w / v%.

[0049] The content ratio of component (D) to component (A) in the aqueous ophthalmic composition according to this embodiment is not particularly limited and is appropriately set according to the types of components (A) and (D), the types and contents of other compounding components, the use and formulation form of the aqueous ophthalmic composition, etc. From the viewpoint of further enhancing the effects of the present invention, the content ratio of component (D) to component (A) is, for example, preferably 0.00001 to 5 parts by mass with respect to 1 part by mass of the total content of component (A) contained in the aqueous ophthalmic composition according to this embodiment, more preferably 0.00005 to 2 parts by mass, still more preferably 0.0001 to 1 part by mass, and still more preferably 0.0005 to 0.5 part by mass.

[0050] In the aqueous ophthalmic composition according to this embodiment, the content ratio of the component (D) to the component (B) is not particularly limited and is appropriately set according to the types of the component (B) and the component (D), the types and contents of other compounding components, the use and dosage form of the aqueous ophthalmic composition, and the like. From the viewpoint of further enhancing the effects according to the present invention, the content ratio of the component (D) to the component (B) is, for example, 0.00005 to 0.5 parts by mass, preferably 0.0001 to 0.1 parts by mass, more preferably 0.0003 to 0.05 parts by mass, and even more preferably 0.0003 to 0.03 parts by mass, based on 1 part by mass of the total content of the component (B) contained in the aqueous ophthalmic composition according to this embodiment.

[0051] 〔Surfactant〕 The aqueous ophthalmic composition according to this embodiment may further contain a surfactant. By further containing a surfactant in the aqueous ophthalmic composition, the effects according to the present invention are more remarkably exhibited. The surfactant is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

[0052] Examples of the surfactant include nonionic surfactants and ionic (anionic, amphoteric, cationic) surfactants.

[0053] Examples of nonionic surfactants include POE sorbitan fatty acid esters such as POE(20)sorbitan monolaurate (polysorbate 20), POE(20)sorbitan monopalmitate (polysorbate 40), POE(20)sorbitan monostearate (polysorbate 60), POE(20)sorbitan tristearate (polysorbate 65), and POE(20)sorbitan monooleate (polysorbate 80); POE·POP glycols such as poloxamer 407, poloxamer 235, poloxamer 188, poloxamer 403, poloxamer 237, and poloxamer 124; POE hydrogenated castor oils such as POE hydrogenated castor oil 40, POE hydrogenated castor oil 50, POE hydrogenated castor oil 60, and POE hydrogenated castor oil 80; POE castor oils such as POE castor oil 3, POE castor oil 4, POE castor oil 6, POE castor oil 7, POE castor oil 10, POE castor oil 13.5, POE castor oil 17, POE castor oil 20, POE castor oil 25, POE castor oil 30, POE castor oil 35, and POE castor oil 50; polyethylene glycol monostearates such as polyethylene glycol (2E.O.) monostearate, polyethylene glycol (4E.O.) monostearate, polyethylene glycol (9E.O.) monostearate, polyethylene glycol (10E.O.) monostearate, polyethylene glycol (23E.O.) monostearate, polyethylene glycol (25E.O.) monostearate, polyethylene glycol (32E.O.) monostearate, polyethylene glycol (40E.O., polyoxyl 40 stearate), polyethylene glycol (45E.O.) monostearate, polyethylene glycol (55E.O.) monostearate, polyethylene glycol (75E.O.) monostearate, and polyethylene glycol (140E.O.) monostearate; POE alkyl ethers such as POE(9)lauryl ether; POE-POP alkyl ethers such as POE(20)POP(4)cetyl ether; and POE alkyl phenyl ethers such as POE(10)nonyl phenyl ether. In the compounds exemplified above, POE is polyoxyethylene, POP is polyoxypropylene, and the numbers in parentheses indicate the number of added moles.

[0054] Examples of the anionic surfactant include polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl ether sulfates, alkylbenzene sulfonates, alkyl sulfates, and N-acyl taurates.

[0055] Examples of the amphoteric surfactant include lauryldimethylaminoacetic acid betaine and alkyldiaminoethyl glycine hydrochloride.

[0056] Examples of the cationic surfactant include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine gluconate, polyidronium hydrochloride, and cetylpyridinium chloride.

[0057] As the surfactant, a nonionic surfactant is preferred. Preferred nonionic surfactants include POE sorbitan fatty acid esters; POE·POP glycols; POE hydrogenated castor oil; POE castor oil; and polyethylene glycol monostearate. Polysorbate 80, poloxamer 407, POE hydrogenated castor oil 40, POE hydrogenated castor oil 60, POE castor oil 3, POE castor oil 10, POE castor oil 35, and polyoxyl 40 stearate are more preferred. Polysorbate 80, POE hydrogenated castor oil 40, POE hydrogenated castor oil 60, and polyoxyl 40 stearate are even more preferred. Polysorbate 80 and POE hydrogenated castor oil 60 are particularly preferred.

[0058] Commercially available surfactants may be used. The surfactant may be used alone or in combination of two or more.

[0059] The content of the surfactant in the aqueous ophthalmic composition according to this embodiment is not particularly limited and is appropriately set according to the type of the surfactant, the types and contents of other compounding components, the use and dosage form of the aqueous ophthalmic composition, and the like. From the viewpoint of more significantly exhibiting the effects according to the present invention, the content of the surfactant is, for example, preferably 0.00001 to 5 w / v%, more preferably 0.00005 to 1 w / v%, still more preferably 0.0001 to 0.5 w / v%, and even more preferably 0.001 to 0.3 w / v% based on the total amount of the aqueous ophthalmic composition.

[0060] When the surfactant is a nonionic surfactant, the content of the surfactant is, for example, preferably 0.001 to 5 w / v%, more preferably 0.005 to 1 w / v%, and still more preferably 0.01 to 0.5 w / v% based on the total amount of the aqueous ophthalmic composition.

[0061] When the surfactant is a cationic surfactant, the content of the surfactant is, for example, preferably 0.00001 to 1 w / v%, more preferably 0.00005 to 0.1 w / v%, still more preferably 0.0001 to 0.05 w / v%, and even more preferably 0.001 to 0.01 w / v% based on the total amount of the aqueous ophthalmic composition.

[0062] In the aqueous ophthalmic composition according to this embodiment, the content ratio of the surfactant with respect to the component (A) is not particularly limited, and is appropriately set according to the type of the component (A) and the surfactant, the types and contents of other compounding components, the use and dosage form of the aqueous ophthalmic composition, etc. From the viewpoint of further enhancing the effects of the present invention, as the content ratio of the surfactant with respect to the component (A), for example, with respect to 1 part by mass of the total content of the component (A) contained in the aqueous ophthalmic composition according to this embodiment, the total content of the surfactant is preferably 0.00001 to 1000 parts by mass, more preferably 0.00005 to 500 parts by mass, still more preferably 0.0001 to 100 parts by mass, and even more preferably 0.0004 to 75 parts by mass.

[0063] In the aqueous ophthalmic composition according to this embodiment, the content ratio of the surfactant with respect to the component (B) is not particularly limited, and is appropriately set according to the type of the component (B) and the surfactant, the types and contents of other compounding components, the use and dosage form of the aqueous ophthalmic composition, etc. From the viewpoint of further enhancing the effects of the present invention, as the content ratio of the surfactant with respect to the component (B), for example, with respect to 1 part by mass of the total content of the component (B) contained in the aqueous ophthalmic composition according to this embodiment, the total content of the surfactant is preferably 0.00001 to 5 parts by mass, more preferably 0.0005 to 3 parts by mass, still more preferably 0.0001 to 3 parts by mass, even more preferably 0.001 to 1 part by mass, particularly preferably 0.005 to 0.5 parts by mass, and particularly more preferably 0.01 to 0.5 parts by mass.

[0064] 〔Buffer〕 The aqueous ophthalmic composition according to this embodiment preferably further contains a buffer. By the aqueous ophthalmic composition further containing a buffer, the effects of the present invention are more significantly exhibited. The buffer is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

[0065] Examples of the buffer include inorganic buffers which are buffers derived from inorganic acids, and organic buffers which are buffers derived from organic acids or organic bases.

[0066] Examples of the inorganic buffer include, for example, boric acid buffer, phosphate buffer, carbonate buffer and the like. Examples of the boric acid buffer include boric acid or its salts (alkali metal borate, alkaline earth metal borate, etc.). Examples of the phosphate buffer include phosphoric acid or its salts (alkali metal phosphate, alkaline earth metal phosphate, etc.). Examples of the carbonate buffer include carbonic acid or its salts (alkali metal carbonate, alkaline earth metal carbonate, etc.). Further, hydrates of borate, phosphate or carbonate may be used as the boric acid buffer, phosphate buffer or carbonate buffer. More specific examples include, as the boric acid buffer, boric acid or its salts (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); as the phosphate buffer, phosphoric acid or its salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, etc.); as the carbonate buffer, carbonic acid or its salts (sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.).

[0067] Examples of the organic buffer include citric acid buffer, acetic acid buffer, lactic acid buffer, succinic acid buffer, Tris buffer, AMPD buffer, etc. Examples of the citric acid buffer include citric acid or its salts (such as alkali metal salts of citric acid, alkaline earth metal salts of citric acid, etc.). Examples of the acetic acid buffer include acetic acid or its salts (such as alkali metal salts of acetic acid, alkaline earth metal salts of acetic acid, etc.). Examples of the lactic acid buffer include lactic acid or its salts (such as alkali metal salts of lactic acid, alkaline earth metal salts of lactic acid, etc.). Examples of the succinic acid buffer include succinic acid or its salts (such as alkali metal salts of succinic acid, etc.). Further, as the citric acid buffer, acetic acid buffer, lactic acid buffer or succinic acid buffer, hydrates of citrate, acetate, lactate or succinate may be used. More specific examples include, as the citric acid buffer, citric acid or its salts (such as sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.); as the acetic acid buffer, acetic acid or its salts (such as ammonium acetate, sodium acetate, potassium acetate, calcium acetate, etc.); as the lactic acid buffer, lactic acid or its salts (such as sodium lactate, potassium lactate, calcium lactate, etc.); as the succinic acid buffer, succinic acid or its salts (such as sodium succinate, disodium succinate, etc.). Examples of the Tris buffer include, for example, tromethol or its salts (such as tromethol hydrochloride, etc.). Examples of the AMPD buffer include, for example, 2-amino-2-methyl-1,3-propanediol or its salts.

[0068] Preferred buffers include boric acid buffer (such as a combination of boric acid and borax, etc.), phosphate buffer (such as a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate, etc.), and Tris buffer (such as tromethol). More preferred is the boric acid buffer. Even more preferred are boric acid and its salts. Even more preferably, it is a combination of boric acid and borax.

[0069] Commercially available buffers may be used. The buffer may be used alone or in combination of two or more.

[0070] The content of the buffering agent in the aqueous ophthalmic composition according to the present embodiment is not particularly limited and is appropriately set according to the type of the buffering agent, the types and contents of other compounding components, the use and dosage form of the aqueous ophthalmic composition, and the like. From the viewpoint of more significantly exerting the effects of the present invention, the content of the buffering agent is preferably, for example, 0.01 to 10 w / v% based on the total amount of the aqueous ophthalmic composition, more preferably 0.05 to 5 w / v%, and still more preferably 0.1 to 3 w / v%.

[0071] The content ratio of the buffering agent to the component (A) in the aqueous ophthalmic composition according to the present embodiment is not particularly limited and is appropriately set according to the types of the component (A) and the buffering agent, the types and contents of other compounding components, the use and dosage form of the aqueous ophthalmic composition, and the like. From the viewpoint of further enhancing the effects of the present invention, the content ratio of the buffering agent to the component (A) is preferably, for example, 0.05 to 5000 parts by mass of the total content of the buffering agent with respect to 1 part by mass of the total content of the component (A) contained in the aqueous ophthalmic composition according to the present embodiment, more preferably 0.1 to 1000 parts by mass, and still more preferably 0.4 to 750 parts by mass.

[0072] The content ratio of the buffering agent to the component (B) in the aqueous ophthalmic composition according to the present embodiment is not particularly limited and is appropriately set according to the types of the component (B) and the buffering agent, the types and contents of other compounding components, the use and dosage form of the aqueous ophthalmic composition, and the like. From the viewpoint of further enhancing the effects of the present invention, the content ratio of the buffering agent to the component (B) is preferably, for example, 0.01 to 10 parts by mass of the total content of the buffering agent with respect to 1 part by mass of the total content of the component (B) contained in the aqueous ophthalmic composition according to the present embodiment, more preferably 0.1 to 5 parts by mass, still more preferably 0.5 to 3 parts by mass, and even more preferably 0.5 to 1 part by mass.

[0073] [Thickening agent] The aqueous ophthalmic composition according to this embodiment preferably further contains a thickener. By further containing a thickener in the aqueous ophthalmic composition, the effects according to the present invention are more remarkably exhibited. The thickener is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

[0074] Examples of the thickener include cellulose-based polymer compounds (e.g., methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, etc.), polyvinyl-based polymer compounds (polyvinylpyrrolidone, polyvinyl alcohol, etc.), carboxyvinyl polymer, guar gum, hydroxypropyl guar gum, gum arabic, karaya gum, xanthan gum, agar, alginic acid and its salts (sodium salt, etc.), mucopolysaccharides other than component (B) (e.g., heparin-like substances, heparin, heparin sulfate, heparan sulfate, heparinoid, hyaluronic acid and its salts (sodium salt, etc.)), starch, chitin and its derivatives, chitosan and its derivatives, carrageenan, etc.

[0075] As the thickener, mucopolysaccharides other than component (B) are preferred, hyaluronic acid and its salts are more preferred, and sodium hyaluronate is even more preferred.

[0076] Commercially available thickeners may be used. The thickener may be used alone or in combination of two or more.

[0077] The content of the thickener in the aqueous ophthalmic composition according to this embodiment is not particularly limited and is appropriately set according to the type of the thickener, the types and contents of other compounding components, the use and dosage form of the aqueous ophthalmic composition, etc. From the viewpoint of more significantly exhibiting the effects of the present invention, the content of the thickener is, for example, preferably 0.0001 to 5 w / v% based on the total amount of the aqueous ophthalmic composition, more preferably 0.001 to 1 w / v%, still more preferably 0.01 to 0.5 w / v%, even more preferably 0.05 to 0.3 w / v%, and particularly preferably 0.1 to 0.15 w / v%.

[0078] The content ratio of the thickener to the component (A) in the aqueous ophthalmic composition according to this embodiment is not particularly limited and is appropriately set according to the types of the component (A) and the thickener, the types and contents of other compounding components, the use and dosage form of the aqueous ophthalmic composition, etc. From the viewpoint of further enhancing the effects of the present invention, the content ratio of the thickener to the component (A) is, for example, preferably 0.01 to 1000 parts by mass, more preferably 0.05 to 500 parts by mass, and still more preferably 0.1 to 100 parts by mass with respect to 1 part by mass of the total content of the component (A) contained in the aqueous ophthalmic composition according to this embodiment.

[0079] The content ratio of the thickener to the component (B) in the aqueous ophthalmic composition according to this embodiment is not particularly limited and is appropriately set according to the types of the component (B) and the thickener, the types and contents of other compounding components, the use and dosage form of the aqueous ophthalmic composition, etc. From the viewpoint of further enhancing the effects of the present invention, the content ratio of the thickener to the component (B) is, for example, preferably 0.0001 to 5 parts by mass, more preferably 0.001 to 1 part by mass, still more preferably 0.01 to 0.5 part by mass, even more preferably 0.05 to 0.3 part by mass, and particularly preferably 0.1 to 0.12 part by mass with respect to 1 part by mass of the total content of the component (B) contained in the aqueous ophthalmic composition according to this embodiment.

[0080] The pH of the aqueous ophthalmic composition according to this embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable range. The pH of the aqueous ophthalmic composition according to this embodiment may be, for example, 4.0 to 9.5, preferably 4.0 to 9.0, more preferably 4.5 to 9.0, still more preferably 4.5 to 8.5, still more preferably 5.0 to 8.5, particularly preferably 5.5 to 8.0, and particularly more preferably 5.5 to 7.0.

[0081] The aqueous ophthalmic composition according to this embodiment can be adjusted to an osmotic pressure ratio within a range acceptable to the living body, if necessary. Although appropriate osmotic pressure ratios vary depending on the application site, dosage form, etc., from the viewpoint of more significantly exhibiting the effects of the present invention, for example, it is preferably 0.05 to 6, more preferably 0.4 to 5, still more preferably 0.6 to 3, and still more preferably 0.8 to 2. Adjustment of the osmotic pressure can be performed by using inorganic salts, polyhydric alcohols, etc. by a method known in the art. The osmotic pressure ratio is defined as the ratio of the osmotic pressure of the sample to 286 mOsm (the osmotic pressure of a 0.9 w / v% aqueous sodium chloride solution) based on the 17th revised Japanese Pharmacopoeia, and the osmotic pressure is measured with reference to the osmotic pressure measurement method (freezing point depression method) described in the Japanese Pharmacopoeia. For the standard solution for measuring the osmotic pressure ratio (0.9 w / v% aqueous sodium chloride solution), sodium chloride (Japanese Pharmacopoeia standard reagent) is dried at 500 to 650 °C for 40 to 50 minutes, then allowed to cool in a desiccator (silica gel), 0.900 g of it is accurately weighed, dissolved in purified water and made up to exactly 100 mL, or a commercially available standard solution for measuring the osmotic pressure ratio (0.9 w / v% aqueous sodium chloride solution) can be used.

[0082] The viscosity of the aqueous ophthalmic composition according to the present embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable range. As the viscosity of the aqueous ophthalmic composition according to the present embodiment, for example, the viscosity at 20°C measured with a rotational viscometer (TV-20 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor; 1°34’×R24) is preferably 0.1 to 10,000 mPa·s, more preferably 1 to 3,000 mPa·s, still more preferably 1 to 1,000 mPa·s, even more preferably 1 to 100 mPa·s, particularly preferably 1 to 50 mPa·s, particularly more preferably 1 to 10 mPa·s, particularly still more preferably 1.3 to 5 mPa·s, and most preferably 1.5 to 3 mPa·s.

[0083] The aqueous ophthalmic composition according to the present embodiment may contain, in an appropriate amount, components selected from various pharmacologically active components and physiologically active components in addition to the above components as long as the effects of the present invention are not impaired. The component is not particularly limited, and for example, the active ingredients in ophthalmic drugs described in the General Pharmaceutical Manufacturing and Sales Approval Standards 2012 Edition (supervised by the Regulatory Science Society of Japan) can be exemplified. Specific examples of the components used in ophthalmic drugs include the following components. Anti-allergic agents: For example, sodium cromoglycate, tranilast, pemirolast potassium, etc. Anti-histamine agents: For example, diphenhydramine hydrochloride, iproheptine, chlorpheniramine maleate, levocabastine hydrochloride, ketotifen fumarate, pemirolast potassium, olopatadine hydrochloride, etc. From the viewpoint of enhancing the effects of the present invention, the aqueous ophthalmic composition according to the present embodiment preferably does not contain diphenhydramine or a salt thereof. Anti-inflammatory agents other than component (A): For example, methyl salicylate, glycol salicylate, allantoin, tranexamic acid, lysozyme, lysozyme chloride, indomethacin, pranoprofen, ibuprofen, ibuprofen picolol, ketoprofen, felbinac, bendazac, piroxicam, bufexamac, butyl flufenamate, epsilon-aminocaproic acid, berberine chloride, berberine sulfate, etc. When the aqueous ophthalmic composition according to the present embodiment contains epsilon-aminocaproic acid, from the viewpoint of further enhancing the effects of the present invention, the content of epsilon-aminocaproic acid is preferably less than 3 w / v% based on the total amount of the aqueous ophthalmic composition. Further, from the viewpoint of further enhancing the effects of the present invention, the aqueous ophthalmic composition according to the present embodiment preferably does not contain epsilon-aminocaproic acid. Steroid agents: For example, fluticasone propionate, fluticasone furancarboxylate, mometasone furancarboxylate, beclomethasone propionate, flunisolide, etc. Decongestants: For example, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, naphazoline hydrochloride, naphazoline nitrate, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, etc. From the viewpoint of enhancing the effects of the present invention, the aqueous ophthalmic composition according to the present embodiment preferably does not contain phenylephrine hydrochloride. Ocular muscle regulating agents other than component (C): For example, cholinesterase inhibitors having an active center similar to acetylcholine, specifically, tropicamide, helenine, atropine sulfate, etc. Vitamins: For example, retinol acetate, retinol palmitate, tocopherol acetate, flavin adenine dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride, panthenol, calcium pantothenate, ascorbic acid, sodium ascorbate, etc. Amino acids: For example, glutamic acid, aspartic acid, arginine, aminoethylsulfonic acid (taurine) and their salts, etc. Inorganic salts: For example, metal chlorides such as calcium chloride, magnesium chloride, sodium chloride, potassium chloride, etc.; ammonium chloride; metal sulfates such as calcium sulfate, magnesium sulfate, sodium sulfate, potassium sulfate, ammonium sulfate, etc. Others: For example, sulfamethoxazole, sulfisoxazole, sulfisomidine and their salts, etc.

[0084] In the aqueous ophthalmic composition according to this embodiment, within the range that does not impair the effects of the present invention, various additives may be appropriately selected according to the use and dosage form and contained in an appropriate amount by combining one or more of them according to a conventional method. As such additives, for example, various additives described in the Pharmaceutical Additives Dictionary 2007 (edited by the Japan Pharmaceutical Additives Association) can be exemplified. The following additives are listed as typical components. Carriers: For example, aqueous solvents such as water, hydrous ethanol, etc. Chelating agents: For example, ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (EDTA), N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), etc. Bases: For example, octyldodecanol, titanium oxide, potassium bromide, plastic base, etc. pH adjusters: For example, hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, diisopropanolamine, etc. Stabilizers: For example, sodium formaldehyde sulfoxylate (rongalite), sodium bisulfite, sodium pyrosulfite, aluminum monostearate, glycerin monostearate, cyclodextrin, monoethanolamine, dibutylhydroxytoluene, etc. Antiseptic, bactericide or antibacterial agent: For example, sodium benzoate, ethanol, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexanide hydrochloride (polyhexamethylene biguanide), etc.), glochil (trade name, manufactured by Rhodia), etc. From the viewpoint of further enhancing the effects of the present invention, the aqueous ophthalmic composition according to the present embodiment preferably does not contain a paraoxybenzoic acid ester (paraben). Isotonic agent: For example, sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol, etc. Sugars: For example, glucose, cyclodextrin, etc. Sugar alcohols: For example, xylitol, sorbitol, mannitol, glycerin, etc. These may be in the form of d-form, l-form or dl-form. Oils: For example, vegetable oils such as sesame oil, castor oil, soybean oil, olive oil, animal oils such as squalane, and mineral oils such as liquid paraffin, petrolatum, etc.

[0085] When the aqueous ophthalmic composition according to the present embodiment contains water, from the viewpoint of more significantly exhibiting the effects of the present invention, for example, based on the total amount of the aqueous ophthalmic composition, the water content is preferably 80 w / v% or more and less than 100 w / v%, more preferably 85 w / v% or more and 99.5 w / v% or less, and still more preferably 90 w / v% or more and 99.2 w / v% or less.

[0086] The water used in the aqueous ophthalmic composition according to this embodiment may be pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such water include distilled water, tap water, purified water, sterilized purified water, water for injection, and distilled water for injection. These definitions are based on the seventeenth revised Japanese Pharmacopoeia.

[0087] The aqueous ophthalmic composition according to this embodiment can be prepared, for example, by adding and mixing the component (A), the component (B), and other optional components as needed to a desired content. Specifically, for example, the above components can be dissolved or suspended in purified water, adjusted to a predetermined pH and osmotic pressure, and sterilized by filtration sterilization or the like.

[0088] The aqueous ophthalmic composition according to this embodiment can take various dosage forms according to the purpose, and examples include solutions, gels, semi-solid agents (such as ointments), etc. Among these, solutions are preferred, and aqueous solutions are more preferred.

[0089] The aqueous ophthalmic composition according to this embodiment can be used, for example, as eye drops (also referred to as eye drops or eye medications. Eye drops include artificial tears and eye drops that can be instilled during contact lens wear.), eye washes (also referred to as eye washes or eye medications. Eye washes include eye washes that can be used during contact lens wear.), contact lens compositions [contact lens soaking solutions, contact lens care compositions (contact lens disinfectants, contact lens preservatives, contact lens cleaners, contact lens cleaning and preservative solutions), etc.]. Note that "contact lens" includes hard contact lenses, soft contact lenses (including both ionic and non-ionic, and including both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).

[0090] Since the aqueous ophthalmic composition according to the present embodiment can exhibit the effects of the present invention more remarkably, it is preferably an eye drop (including an eye drop that can be instilled during contact lens wear). When the aqueous ophthalmic composition according to the present embodiment is an eye drop, its usage and dosage are not particularly limited as long as they are effective and have few side effects. For example, in the case of adults (15 years old or older) and children 7 years old or older, a method of instilling 1 to 2 drops once a day 2 to 4 times, or 4 times, or a method of instilling 1 to 2 drops, 1 to 3 drops, or 2 to 3 drops once a day 5 to 6 times can be exemplified.

[0091] The aqueous ophthalmic composition according to the present embodiment is provided in any container. The container for containing the aqueous ophthalmic composition according to the present embodiment is not particularly limited. For example, it may be made of glass or plastic. Preferably, it is made of plastic. Examples of plastics include polyethylene terephthalate, polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, polyimide, copolymers of the monomers constituting these, and mixtures of two or more of these. Preferably, they are polypropylene, polyethylene, and polyethylene terephthalate, and more preferably, polyethylene terephthalate. Further, the container for containing the aqueous ophthalmic composition according to the present embodiment may be a transparent container through which the inside of the container can be visually recognized, or an opaque container in which it is difficult to visually recognize the inside of the container. Preferably, it is a transparent container. Here, the "transparent container" includes both a colorless transparent container and a colored transparent container.

[0092] A nozzle may be attached to the container that houses the aqueous ophthalmic composition according to this embodiment. The material of the nozzle is not particularly limited, and for example, it may be made of glass or plastic. Preferably, it is made of plastic. Examples of plastics include polybutylene terephthalate, polyethylene, polypropylene, polyethylene naphthalate, copolymers of the monomers that constitute these, and mixtures of two or more of these. From the viewpoint of further enhancing the effects of the present invention, polypropylene, polyethylene, polyethylene terephthalate, and polyethylene naphthalate are preferable as the material of the nozzle, and polyethylene is more preferable.

[0093] The container that houses the aqueous ophthalmic composition according to this embodiment may be a multi-dose type that accommodates multiple usage amounts, or a unit-dose type that accommodates a single usage amount. However, since the effects of the present invention can be more significantly exhibited, a multi-dose type is preferable.

[0094] [2. Method for improving unpleasant astringency-related taste after administration in an aqueous ophthalmic composition] The aqueous ophthalmic composition according to this embodiment contains a zinc salt, at least one selected from the group consisting of glycyrrhizic acid, azulenesulfonic acid, and their salts, and at least one selected from the group consisting of chondroitin sulfate and its salts at 0.8 w / v% or more based on the total amount of the aqueous ophthalmic composition. By blending these, the unpleasant astringency-related taste after administration in the aqueous ophthalmic composition is improved. Therefore, as one embodiment of the present invention, there is provided a method for improving the unpleasant astringency-related taste after administration in the aqueous ophthalmic composition, which includes blending (A) a zinc salt, at least one selected from the group consisting of glycyrrhizic acid, azulenesulfonic acid, and their salts, and (B) one or more selected from the group consisting of chondroitin sulfate and its salts at 0.8 w / v% or more based on the total amount of the aqueous ophthalmic composition.

[0095] In addition, regarding the type and content of component (A), the type and content of component (B), the type and content of other components, the dosage form and use of the aqueous ophthalmic composition, etc. in this embodiment, they are as described in [1. Aqueous Ophthalmic Composition].

[0096] 〔3. Method for Improving Defoaming Rate in Aqueous Ophthalmic Composition〕 The aqueous ophthalmic composition according to this embodiment contains at least one selected from the group consisting of glycyrrhizic acid and its salts, and at least one selected from the group consisting of chondroitin sulfate and its salts at 0.8 w / v% or more based on the total amount of the aqueous ophthalmic composition. By this, the defoaming rate in the aqueous ophthalmic composition is significantly improved. Therefore, as one embodiment of the present invention, there is provided a method for improving the defoaming rate in the aqueous ophthalmic composition, which includes blending (A1) at least one selected from the group consisting of glycyrrhizic acid and its salts, and (B) one or more selected from the group consisting of chondroitin sulfate and its salts at 0.8 w / v% or more based on the total amount of the aqueous ophthalmic composition.

[0097] In addition, regarding the type and content of component (A1), the type and content of component (B), the type and content of other components, the dosage form and use of the aqueous ophthalmic composition, etc. in this embodiment, they are as described in [1. Aqueous Ophthalmic Composition].

[0098] 〔4. Method for Reducing Foaming Amount in Aqueous Ophthalmic Composition〕 The aqueous ophthalmic composition according to this embodiment contains at least one selected from the group consisting of glycyrrhizic acid and its salts, and at least one selected from the group consisting of chondroitin sulfate and its salts at 0.8 w / v% or more based on the total amount of the aqueous ophthalmic composition, whereby the amount of foaming in the aqueous ophthalmic composition is significantly reduced. Therefore, as one embodiment of the present invention, there is provided a method for reducing the amount of foaming in an aqueous ophthalmic composition, which comprises blending (A1) at least one selected from the group consisting of glycyrrhizic acid and its salts, and (B) one or more selected from the group consisting of chondroitin sulfate and its salts at 0.8 w / v% or more based on the total amount of the aqueous ophthalmic composition.

[0099] Regarding the type and content of the component (A1), the type and content of the component (B), the type and content of other components, the dosage form and use of the aqueous ophthalmic composition, etc. in this embodiment, they are as described in [1. Aqueous Ophthalmic Composition].

[0100] [5. Method for Suppressing the Occurrence of Cloudiness in Aqueous Ophthalmic Composition] The aqueous ophthalmic composition according to this embodiment contains a zinc salt and at least one selected from the group consisting of chondroitin sulfate and its salts at 0.8 w / v% or more based on the total amount of the aqueous ophthalmic composition, whereby the occurrence of cloudiness in the aqueous ophthalmic composition is significantly suppressed. Therefore, as one embodiment of the present invention, there is provided a method for suppressing the occurrence of cloudiness in an aqueous ophthalmic composition, which comprises blending (A2) a zinc salt and (B) one or more selected from the group consisting of chondroitin sulfate and its salts at 0.8 w / v% or more based on the total amount of the aqueous ophthalmic composition.

[0101] Regarding the type and content of the component (A2), the type and content of the component (B), the type and content of other components, the dosage form and use of the aqueous ophthalmic composition, etc. in this embodiment, they are as described in [1. Aqueous Ophthalmic Composition].

[0102] The aqueous ophthalmic composition according to this embodiment contains a zinc salt and at least one selected from the group consisting of chondroitin sulfate and its salts at 0.8 w / v% or more based on the total amount of the aqueous ophthalmic composition, and thus the generation of precipitates in the aqueous ophthalmic composition is significantly suppressed. Therefore, as one embodiment of the present invention, there is provided a method for suppressing the generation of precipitates in an aqueous ophthalmic composition, which includes formulating (A2) a zinc salt and (B) one or more selected from the group consisting of chondroitin sulfate and its salts at 0.8 w / v% or more based on the total amount of the aqueous ophthalmic composition.

[0103] Regarding the type and content of the component (A2), the type and content of the component (B), the type and content of other components, the formulation form and use of the aqueous ophthalmic composition, etc. in this embodiment, they are as described in [1. Aqueous Ophthalmic Composition].

[0104] ​​The aqueous ophthalmic composition according to this embodiment contains at least one selected from the group consisting of azulene sulfonic acid and its salts, and at least one selected from the group consisting of chondroitin sulfate and its salts at 0.8 w / v% or more based on the total amount of the aqueous ophthalmic composition. By this, the stability of azulene sulfonic acid and its salts in the aqueous ophthalmic composition is improved, and discoloration is suppressed. Therefore, as one embodiment of the present invention, there is provided a method for stabilizing at least one selected from the group consisting of azulene sulfonic acid and its salts in the aqueous ophthalmic composition, which includes blending (A3) at least one selected from the group consisting of azulene sulfonic acid and its salts, and (B) one or more selected from the group consisting of chondroitin sulfate and its salts at 0.8 w / v% or more based on the total amount of the aqueous ophthalmic composition. Further, as one embodiment of the present invention, there is provided a method for suppressing discoloration in the aqueous ophthalmic composition, which includes blending (A3) at least one selected from the group consisting of azulene sulfonic acid and its salts, and (B) one or more selected from the group consisting of chondroitin sulfate and its salts at 0.8 w / v% or more based on the total amount of the aqueous ophthalmic composition.

[0105] Regarding the type and content of the (A3) component, the type and content of the (B) component, the type and content of other components, the formulation form and use of the aqueous ophthalmic composition, etc. in this embodiment, they are as described in [1. Aqueous Ophthalmic Composition].

Examples

[0106] Hereinafter, the present invention will be specifically described based on test examples, but the present invention is not limited thereto.

[0107] 〔Test Example 1: Taste Evaluation (1)〕 The aqueous ophthalmic compositions (100 mL) of each of the examples and comparative examples shown in Table 1 were prepared by a conventional method. The unit of each component in Table 1 is w / v%. Next, using a taste recognition device (SA402B; manufactured by Intelligent Sensor Technology Co., Ltd.), the astringency and each index of astringency stimulation of each aqueous ophthalmic composition were measured. The measurement method was in accordance with the instruction manual of SA402B, and the potential difference between the reference solution and each aqueous ophthalmic composition was measured as each index of astringency and astringency stimulation. Using the obtained measurement values, the difference from Comparative Example 1-1 was calculated for each of the astringency and astringency stimulation of each example according to the following formula 1. The results are shown in Table 1. [Formula 1] Difference in index from Comparative Example 1-1 = Measured value of Comparative Example 1-1 - Measured value of Example As the sodium chondroitin sulfate, topical sodium chondroitin sulfate for eye drops and injection (manufactured by Maruha Nichiro Foods Co., Ltd.) was used.

[0108]

Table 1

[0109] In the aqueous ophthalmic compositions of Examples 1-1 and 1-2 in which 1 w / v% or 3 w / v% of sodium chondroitin sulfate was blended with dipotassium glycyrrhizinate, it was confirmed that the indices of astringency and astringency stimulation both decreased compared with the aqueous ophthalmic composition of Comparative Example 1-1 containing only dipotassium glycyrrhizinate.

[0110] 〔Test Example 2: Taste Evaluation (2)〕 The aqueous ophthalmic compositions (100 mL) of each of the examples and comparative examples shown in Table 2 were prepared by a conventional method. The unit of each component in Table 2 is w / v%. Next, measurement was carried out in the same manner as in Test Example 1 except that the indices to be measured were astringency and sourness, and the difference from Comparative Example 2-1 was calculated for each of the astringency and sourness of Example 2-1. The results are shown in Table 2. As the sodium chondroitin sulfate, topical sodium chondroitin sulfate for eye drops and injection (manufactured by Maruha Nichiro Foods Co., Ltd.) was used, and as the zinc sulfate, zinc sulfate heptahydrate was used.

[0111]

Table 2

[0112] In the aqueous ophthalmic composition of Example 2-1 in which 3 w / v% sodium chondroitin sulfate was blended with zinc sulfate, it was confirmed that the indices of astringency and sourness both decreased as compared with the aqueous ophthalmic composition of Comparative Example 2-1 containing only zinc sulfate.

[0113] 〔Test Example 3: Taste Evaluation (3)〕 The aqueous ophthalmic compositions (100 mL) of each Example and Comparative Example shown in Table 3 were prepared by a conventional method. The unit of each component in Table 3 is w / v%. Next, measurement was carried out in the same manner as in Test Example 1 except that the indices to be measured were astringency stimulation and bitter off-flavor, and the difference from Comparative Example 3-1 was calculated for each of the astringency stimulation and bitter off-flavor of each Example. The results are shown in Table 3. In addition, as the sodium chondroitin sulfate, topical sodium chondroitin sulfate for eye drops and injection (manufactured by Maruha Nichiro Foods, Inc.) was used.

[0114]

Table 3

[0115] In the aqueous ophthalmic compositions of Examples 3-1 and 3-2 in which 1 w / v% or 3 w / v% sodium chondroitin sulfate was blended with sodium azulene sulfonate, it was confirmed that the indices of astringency stimulation and bitter off-flavor both decreased as compared with the aqueous ophthalmic composition of Comparative Example 3-1 containing only sodium azulene sulfonate.

[0116] 〔Test Example 4: Evaluation of Foaming Property and Defoaming Property (1)〕 The aqueous ophthalmic compositions (100 mL) of each example and comparative example shown in Table 4 were prepared by a conventional method. The unit of each component in Table 4 is w / v%. Next, a polyethylene terephthalate (PET) container (a 50-mL centrifuge tube, No. 430304 manufactured by Corning) was filled with 30 mL of the prepared aqueous ophthalmic composition, and the defoaming rate was evaluated by the following method. Each aqueous ophthalmic composition filled in the container was shaken 1500 times (5 minutes at 300 rpm / min) using a strong shaker SR-2DW (manufactured by TAITEC). Immediately after the shaking was completed, the foam portion and the aqueous solution portion were visually confirmed, and the volume of the foam portion was measured (index of foaming property). Next, they were allowed to stand, and the time until the amount of foam was reduced by half was measured (index of defoaming property). The evaluation of the foaming property was performed by calculating the ratio of the volume of the foam portion in Example 4-1 to that in Comparative Example 4-1 immediately after the shaking was completed, with the volume of the foam portion in Comparative Example 4-1 being set to 100. The results are shown in Table 4. As the sodium chondroitin sulfate, externally regulated sodium chondroitin sulfate for eye drops and injections (manufactured by Maruha Nichiro Foods Co., Ltd.) was used.

[0117]

Table 4

[0118] In the aqueous ophthalmic composition of Example 4-1 containing 3 w / v% of sodium chondroitin sulfate, it was confirmed that it was less likely to foam and significantly defoamed compared to the aqueous ophthalmic composition of Comparative Example 4-1 containing no sodium chondroitin sulfate.

[0119] 〔Test Example 5: Evaluation of Defoaming Property〕 The aqueous ophthalmic compositions (100 mL) of each example and comparative example shown in Table 5 were prepared by a conventional method. The unit of each component in Table 5 is w / v%. Next, a polyethylene terephthalate (PET) container (a 50-mL centrifuge tube, No. 430304 manufactured by Corning) was filled with 30 mL of the prepared aqueous ophthalmic composition, and the defoaming rate was evaluated by the following method. Each aqueous ophthalmic composition filled in a container was shaken 1500 times (at 300 rpm / min for 5 minutes) using a strong shaker SR-2DW (manufactured by TAITEC Co., Ltd.). Immediately after the shaking was completed, the foam portion and the aqueous solution portion were visually confirmed, and the volume of the foam portion was measured. Next, they were allowed to stand, and the time until the amount of foam was reduced by half was measured. As the sodium chondroitin sulfate, sodium chondroitin sulfate for ophthalmic and injection use (manufactured by Maruha Nichiro Foods Co., Ltd.) was used.

[0120]

Table 5

[0121] In the aqueous ophthalmic composition of Example 5-1 containing 1 w / v% of sodium chondroitin sulfate, it was confirmed that defoaming was significantly improved compared to the aqueous ophthalmic composition of Comparative Example 5-1 that did not contain sodium chondroitin sulfate. Furthermore, when 0.1 w / v% of sodium hyaluronate was contained, it was confirmed that defoaming was more significant (Example 5-2).

[0122] 〔Test Example 6: Turbidity Evaluation〕 The aqueous ophthalmic compositions (100 mL) of each Example and Comparative Example shown in Table 6 were prepared by a conventional method. The unit of each component in Table 6 is w / v%. Each prepared aqueous ophthalmic composition was filled into a 20 mL transparent glass screw vial with a volume of 20 mL, and observed visually at a brightness of 5000 lux, and the turbidity was evaluated according to the following evaluation criteria. <Turbidity Evaluation Criteria> The background cannot be confirmed, and it is clearly turbid: +++ The background can be confirmed, but it is clearly turbid: ++ Turbidity can be confirmed against a black background: + Turbidity cannot be confirmed even against a black background: - Further, each aqueous ophthalmic composition was placed in a 96-well plate (Tissue Culture Plate (manufactured by FALCON)) at 200 μL each, and the absorbance at 660 nm was measured using a plate reader (Versa Max (manufactured by Molecular Devices)) and used as an index for turbidity evaluation. Also, the absorbance of purified water at 660 nm was measured as a control. As the sodium chondroitin sulfate, topical sodium chondroitin sulfate for eye drops and injections (manufactured by Maruha Nichiro Foods Co., Ltd.) was used, and as the zinc sulfate, zinc sulfate heptahydrate was used. The results are shown in Table 6.

[0123]

Table 6

[0124] In the aqueous ophthalmic composition of Comparative Example 6-1 containing only zinc sulfate, obvious turbidity was observed. Also, turbidity was observed in the aqueous ophthalmic composition of Comparative Example 6-2 in which 0.5 w / v% of sodium chondroitin sulfate was added to zinc sulfate. On the other hand, in the aqueous ophthalmic composition of Example 6-1 in which 1 w / v% of sodium chondroitin sulfate was added to zinc sulfate, it was confirmed that the turbidity was significantly suppressed. The absorbances at 660 nm of the aqueous ophthalmic composition of Example 6-1 and purified water were 0.047 and 0.046, respectively, and it was confirmed that Example 6-1 had the same clarity as purified water.

[0125] 〔Test Example 7: Evaluation of Precipitate Generation (1)〕 The aqueous ophthalmic compositions (100 mL) of each of the examples and comparative examples shown in Table 7 were prepared by a conventional method. The unit of each component in Table 7 is w / v%. Next, 0.5 mL of each aqueous ophthalmic composition was placed in a 24-well plate (IWAKI MICROPLATE: 3820-024) and allowed to stand overnight at 60 °C in a drying oven for experimental equipment (LabWare Drying Oven, DG82; manufactured by Yamato Scientific Co., Ltd.) to dry. The state of each aqueous ophthalmic composition after drying was visually observed, and the occurrence of precipitates was evaluated according to the following evaluation criteria (N = 2). The results are shown in Table 7. <Evaluation Criteria for Precipitate Generation> There are clearly visible precipitates on the entire bottom surface of the well: +++ There are clearly visible precipitates in part of the well: ++ There are unclear precipitates in part of the well: + There are no precipitates: - Note that as sodium chondroitin sulfate, topical sodium chondroitin sulfate for eye drops and injections (manufactured by Maruha Nichiro Foods Co., Ltd.) was used, and as zinc sulfate, zinc sulfate heptahydrate was used.

[0126]

Table 7

[0127] Precipitate generation was observed in the aqueous ophthalmic composition of Comparative Example 7-1 containing only zinc sulfate. In contrast, it was confirmed that no precipitates occurred in the aqueous ophthalmic compositions of Examples 7-1 and 7-2 in which 1 w / v% or 3 w / v% of sodium chondroitin sulfate was blended with zinc sulfate.

[0128] 〔Test Example 8: Evaluation of Stability〕 The aqueous ophthalmic compositions (100 mL) of each of the examples and comparative examples shown in Table 8 were prepared by a conventional method. The unit of each component in Table 8 is w / v%. Next, 5 mL of each aqueous ophthalmic composition was filled into a glass ampoule (volume: 10 mL), sealed, and then stored in a thermostat at 60 °C for 7 days in the dark. For each aqueous ophthalmic composition before and after storage, 200 μL was placed in a 96-well plate (Tissue Culture Plate (manufactured by FALCON)), and the absorbance at 568 nm was measured using a plate reader (Versa Max (manufactured by Molecular Devices)). Using the measured absorbance, the discoloration rate of each aqueous ophthalmic composition was calculated using the following formula 2 as an index for stability evaluation. The results are shown in Table 8. [Formula 2] Discoloration rate (%) = {(Absorbance before storage - Absorbance after storage) / Absorbance before storage} × 100 As the sodium chondroitin sulfate, topical sodium chondroitin sulfate for eye drops and injection (manufactured by Maruha Nichiro Foods Co., Ltd.) was used.

[0129]

Table 8

[0130] Compared with the aqueous ophthalmic composition of Comparative Example 8-1 containing only sodium azulene sulfonate, in the aqueous ophthalmic composition of Example 8-1 in which 1 w / v% of sodium chondroitin sulfate was blended with sodium azulene sulfonate, the stability of sodium azulene sulfonate was improved and discoloration was significantly suppressed.

[0131] 〔Test Example 9: Evaluation of foaming and defoaming properties (2)〕 The aqueous ophthalmic compositions (100 mL) of each of the examples and comparative examples shown in Table 9 were prepared by a conventional method. The unit of each component in Table 9 is w / v%. Next, 30 mL of the prepared aqueous ophthalmic composition was filled into a polyethylene terephthalate (PET) container (a 50 mL centrifuge tube, No. 430304 manufactured by Corning), and the defoaming rate was evaluated by the following method. Each aqueous ophthalmic composition filled in a container was shaken 1500 times (for 5 minutes at 300 rpm / min) using a strong shaker SR-2DW (manufactured by TAITEC). Immediately after the shaking was completed, the foam portion and the aqueous solution portion were visually confirmed, and the volume of the foam portion was measured (index of foaming property). Next, they were allowed to stand, and the time until the amount of foam was reduced by half was measured and taken as the foam half-life (index of defoaming property). Using the measured foam half-life, the foam half-life shortening rate (%) was calculated by the following formula 3. The results are shown in Table 9. [Formula 3] Foam half-life shortening rate (%) = { (Foam half-life of the comparative example as the target - Foam half-life of the example) / Foam half-life of the comparative example as the target} × 100 The comparative examples as the target are Comparative Example 9-1 for Examples 9-1 and 9-2, and Comparative Example 9-2 for Examples 9-3 and 9-4. Also, the evaluation of the foaming property was performed by calculating the ratio of the volume of the foam portion in the corresponding example when the volume of the foam portion in the comparative example as the target immediately after the shaking was completed was set to 100. The results are shown in Table 9. As the sodium chondroitin sulfate, topical sodium chondroitin sulfate (manufactured by Seikagaku Corporation, weight average molecular weight of about 20,000) was used.

[0132]

Table 9

[0133] In the aqueous ophthalmic composition of the example containing sodium chondroitin sulfate, it was confirmed that it was less likely to foam and significantly defoamed compared to the aqueous ophthalmic composition of the comparative example not containing sodium chondroitin sulfate.

[0134] 〔Test Example 10: Evaluation of foaming property and defoaming property (3)〕 The aqueous ophthalmic compositions (100 mL) of each example and comparative example shown in Table 10 were prepared by a conventional method. The unit of each component in Table 10 is w / v%. Next, 30 mL of the aqueous ophthalmic composition prepared was filled in a polyethylene terephthalate (PET) container (a centrifuge tube with a capacity of 50 mL, No. 430304 manufactured by Corning), and the defoaming rate was evaluated by the following method. Each aqueous ophthalmic composition filled in a container was shaken 1500 times (5 minutes at 300 rpm / min) using a strong shaker SR-2DW (manufactured by TAITEC). Immediately after the shaking was completed, the foam portion and the aqueous solution portion were visually confirmed, and the volume of the foam portion was measured (as an index of foaming property). Next, they were allowed to stand, and the time until the amount of foam was reduced by half was measured and taken as the foam half-life (as an index of defoaming property). As the sodium chondroitin sulfate, externally regulated sodium chondroitin sulfate (manufactured by Seikagaku Corporation, weight average molecular weight of about 20,000) was used.

[0135]

Table 10

[0136] The foam half-life of Example 10-1 containing sodium chondroitin sulfate was 5 minutes, which was significantly shorter compared to the foam half-life of Comparative Example 10-1 not containing sodium chondroitin sulfate. Also, the volume of the foam portion immediately after shaking in Example 10-1 was significantly suppressed compared to the volume of the foam portion immediately after shaking in Comparative Example 10-1.

[0137] 〔Test Example 11: Evaluation of Precipitate Generation (2)〕 The aqueous ophthalmic compositions (100 mL) of each example and comparative example shown in Table 11 were prepared by a conventional method. The unit of each component in Table 11 is w / v%. Next, 0.5 mL of each aqueous ophthalmic composition was placed in a 24-well plate (IWAKI MICROPLATE: 3820-024) and allowed to stand overnight at 60°C in a dryer for experimental instruments (LabWare Drying Oven, DG82; manufactured by Yamato Scientific Co., Ltd.) to dry. The state of each dried aqueous ophthalmic composition was visually observed, and the generation of precipitates was evaluated according to the following evaluation criteria (N = 2). The results are shown in Table 11. <Evaluation Criteria for Precipitate Generation> There are clearly visible precipitates on the entire bottom surface of the well: +++ There are clearly visible precipitates in a part of the well: ++ There are unclear precipitates in part of the well :+ There are unclear and fine precipitates in part of the well :± There are no precipitates :- In addition, as the sodium chondroitin sulfate, externally regulated sodium chondroitin sulfate (manufactured by Seikagaku Corporation, weight average molecular weight of about 20,000) was used.

[0138]

Table 11

[0139] In the aqueous ophthalmic compositions of Comparative Examples 11-1 and 11-2 containing only zinc sulfate hydrate, the generation of precipitates was observed. On the other hand, in the aqueous ophthalmic compositions of Examples 11-1, 11-2, 11-4, and 11-5 in which 1 w / v% or 3 w / v% of sodium chondroitin sulfate was blended with zinc sulfate hydrate, and in the aqueous ophthalmic composition of Example 11-3 in which 3 w / v% of sodium chondroitin sulfate and neostigmine methylsulfate were blended with zinc sulfate hydrate, it was confirmed that no precipitates occurred.

[0140] 〔Formulation Examples〕 The following Table 12 and 13 show formulation examples. The units of each component in Table 12 and 13 are all w / v% except as specified in the table. Formulation Examples 1 to 13 are all eye drops. Each formulation example is filled into a polyethylene terephthalate container in 10 mL portions, and those with a polyethylene nozzle attached are designated as Formulation Examples 1' to 13'. Each formulation example is filled into a polyethylene terephthalate container in 10 mL portions, and those with a polybutylene terephthalate nozzle attached are designated as Formulation Examples 1'' to 13''. In addition, the eye drops of Formulation Examples 1 to 13 can be used as eye drops that can be instilled when wearing hard contact lenses, eye drops that can be instilled when wearing soft contact lenses, or eye drops that can be instilled when not wearing contact lenses.

[0141]

Table 12

[0142]

Table 13

Claims

1. An aqueous ophthalmic composition comprising (A) at least one selected from the group consisting of azulene sulfonic acid and a salt thereof, and (B) at least one selected from the group consisting of chondroitin sulfate and a salt thereof, the content of component (B) being 0.8 w / v% or more based on the total amount of the aqueous ophthalmic composition (provided that (i) sodium chondroitin sulfate, hydroxypropylmethylcellulose, phenylephrine hydrochloride, neostigmine methylsulfate, epsilon-aminocaproic acid, allantoin, sodium azulene sulfonate, zinc sulfate, sodium cromoglycate, sodium flavin adenine dinucleotide, cyanocobalamin, hydroxyethylcellulose, boric acid, chlorhexidine gluconate, (ii) eye drops containing sodium edetate, polysorbate 80, propylene glycol, l-menthol, dl-camphor and borneol, (iii) ophthalmic compositions containing sodium cromoglycate, and chlorpheniramine maleate, d-chlorpheniramine maleate, diphenhydramine, diphenhydramine hydrochloride, clemastine fumarate, mequitazine, ketotifen fumarate or levocabastine hydrochloride, and (iv) eye drops containing berberine, berberine sulfate, berberine chloride, Phellodendron Bark or Coptis Rhizome.

2. 2. The aqueous ophthalmic composition according to claim 1, wherein the content of the component (A) is 0.0001 w / v % to 5 w / v % based on the total amount of the aqueous ophthalmic composition.

3. 3. The aqueous ophthalmic composition according to claim 1, wherein the content of component (B) is 1 w / v % to 5 w / v % based on the total amount of the aqueous ophthalmic composition.

4. The aqueous ophthalmic composition of any one of claims 1 to 3, further comprising (C) neostigmine methylsulfate.

5. The aqueous ophthalmic composition according to any one of claims 1 to 4, further comprising (D) a terpenoid.

6. 1. An aqueous ophthalmic composition comprising: (A) at least one selected from the group consisting of azulene sulfonic acid and a salt thereof; and (B) at least one selected from the group consisting of chondroitin sulfate and a salt thereof in an amount of 0.8 w / v % or more based on the total amount of the aqueous ophthalmic composition, wherein the aqueous ophthalmic composition is further formulated with at least one selected from the group consisting of chondroitin sulfate and a salt thereof, and wherein the aqueous ophthalmic composition is further formulated with at least one selected from the group consisting of chondroitin sulfate and a salt thereof in an amount of 0.8 w / v % or more based on the total amount of the aqueous ophthalmic composition ... 80, propylene glycol, l-menthol, dl-camphor and borneol, (ii) eye drops containing sodium cromoglycate, and methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate or butyl parahydroxybenzoate, (iii) ophthalmic compositions containing sodium cromoglycate, and chlorpheniramine maleate, d-chlorpheniramine maleate, diphenhydramine, diphenhydramine hydrochloride, clemastine fumarate, mequitazine, ketotifen fumarate or levocabastine hydrochloride, and (iv) eye drops containing berberine, berberine sulfate, berberine chloride, Phellodendron Bark or Coptis Rhizome.

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