JP7624274B2 - Ophthalmic Composition - Google Patents

Description

The present invention relates to an ophthalmic composition (or ophthalmic agent).

Ophthalmic compositions such as eye drops contain various components depending on their intended purpose.
On the other hand, tranilast is known to be effective in treating diseases caused by allergies, and examples of its use in ophthalmic compositions have been reported. In addition, in such ophthalmic compositions containing tranilast, techniques for combining tranilast with other ingredients are being developed for the purpose of improving efficacy and exploring new functions.
For example, JP 2014-234368 A (Patent Document 1) describes that an eye drop containing tranilast and specific ingredients (anti-inflammatory agent, water-soluble vitamin, and cooling agent) is effective in enhancing the corneal epithelial barrier function.

JP 2014-234368 A (Claims, Examples)

The object of the present invention is to provide a novel ophthalmic composition.

As described above, the technology of incorporating tranilast into eye drops is known. Meanwhile, various other ingredients besides tranilast are known to be incorporated into eye drops, including chlorpheniramine maleate and pranoprofen.
However, there have been only reports of examples in which these components can be used alone or in combination with other specific components, and there have been no reports of examples in which these components are specifically combined.

In the midst of this, the present inventors have been investigating formulations for tranilast, chlorpheniramine maleate, and pranoprofen, and have found that previously unknown problems exist when these are used alone or in combination. For example, during the investigation, it was found that these alone do not have sufficient preservative effectiveness, that the photostability of pranoprofen is insufficient, and that the photostability does not improve when combined with chlorpheniramine maleate.

Based on this finding, the inventors conducted further investigations and unexpectedly discovered that by selecting three specific ingredients - tranilast, chlorpheniramine maleate, and pranoprofen - which are known individually or in combination with two other ingredients but have not been specifically reported as combinations, a composition having sufficient preservative effectiveness and photostability as described above can be obtained, leading to the completion of the present invention.

That is, the present invention provides, for example, the following inventions.
[1]
(A) one or more selected from the group consisting of tranilast and salts thereof,
(B) one or more selected from the group consisting of chlorpheniramine and its salts, and (C) one or more selected from the group consisting of pranoprofen and its salts,
An ophthalmic composition comprising 1 to 8 parts by mass of component (B) and 5 to 25 parts by mass of component (C) relative to 100 parts by mass of component (A).
[2]
(A) one or more selected from the group consisting of tranilast and salts thereof,
A composition comprising: (B) one or more selected from the group consisting of chlorpheniramine and its salts; and (C) one or more selected from the group consisting of pranoprofen and its salts,
An ophthalmic composition comprising 0.3 to 0.7 w/v % of component (A), 0.007 to 0.04 w/v % of component (B), and 0.03 to 0.15 w/v % of component (C).
[3]
The ophthalmic composition according to [1] or [2], wherein the ratio of the components (A), (B), and (C) satisfies any one of the following:
(A) component/(B) component/(C) component (mass ratio) = 100/5 to 7/8 to 12
(A) component / (B) component / (C) component (mass ratio) = 100/5 ~ 7/18 ~ 22
(A) component/(B) component/(C) component (mass ratio) = 100/1 to 3/8 to 12
(A) component / (B) component / (C) component (mass ratio) = 100/1 to 3/18 to 22
[4]
The ophthalmic composition according to any one of [1] to [3], wherein the proportions of the components (A) to (C) satisfy any one of the following:
The proportion of component (A) being 0.4-0.6 w/v%, component (B) being 0.02-0.04 w/v%, and component (C) being 0.04-0.06 w/v% The proportion of component (A) being 0.4-0.6 w/v%, component (B) being 0.02-0.04 w/v%, and component (C) being 0.08-0.12 w/v% The proportion of component (A) being 0.4-0.6 w/v%, component (B) being 0.013-0.017 w/v%, and component (C) being 0.04-0.06 w/v% The proportion of component (A) being 0.4-0.6 w/v%, component (B) being 0.013-0.017 w/v%, and component (C) being 0.08-0.12 w/v% The proportion of component (A) is 0.4 to 0.6 w/v%, the proportion of component (B) is 0.008 to 0.012 w/v%, and the proportion of component (C) is 0.04 to 0.06 w/v%. The proportion of component (A) is 0.4 to 0.6 w/v%, the proportion of component (B) is 0.008 to 0.012 w/v%, and the proportion of component (C) is 0.08 to 0.12 w/v% [5]
The ophthalmic composition according to any one of [1] to [4], comprising at least one selected from the group consisting of polyvinylpyrrolidone, monoethanolamine, and trometamol.
[6]
The ophthalmic composition according to any one of [1] to [5], comprising at least one selected from monoethanolamine and trometamol.
[7]
The ophthalmic composition according to any one of [1] to [6], wherein the sodium ion concentration is 250 mM or less, or the ratio of sodium ions is 25 mol or less per 1 mol of the component (A).
[8]
The ophthalmic composition according to any one of [1] to [7], wherein the sodium ion concentration is 20 mM or less, or the ratio of sodium ions is 20 mol or less per 1 mol of the component (A).
[9]
The ophthalmic composition according to any one of [1] to [8], which is for alleviating, improving, suppressing, and/or treating allergic symptoms.
[10]
The ophthalmic composition according to any one of [1] to [9], which is for relieving, improving, suppressing, and/or treating at least one symptom selected from itchy eyes, bloodshot eyes, watery eyes, foreign body sensation, and eye discharge.
[11]
A method for enhancing, improving, imparting and/or expressing at least one of (1) preservative effectiveness, (2) photostability and (3) oxygen stress resistance in an ophthalmic composition comprising one or two components selected from the components (A), (B) and (C) described in [1], by adding the remaining one or two components to the ophthalmic composition.
[12]
An agent for enhancing, improving, imparting and/or expressing at least one selected from (1) preservative effectiveness, (2) photostability and (3) oxygen stress resistance in an ophthalmic composition comprising one or two components selected from the components (A), (B) and (C) described in [1], the agent comprising the remaining one or two components.

The present invention can provide a novel ophthalmic composition.
Such an ophthalmic composition contains specific components (A), (B), and (C), and can have effects such as enhancing or improving specific functions (e.g., preservative effectiveness, stability, etc.) compared to when these components are used alone or in combination of two types.
For example, in another embodiment of the present invention, an ophthalmic composition having resistance to oxygen stress (low oxidative stress) (or not impairing resistance to hypoxic stress) can be obtained. Oxygen stress has been shown to be related to cell damage and various diseases and symptoms (dry eye, cataract, etc.), and it is useful to be able to provide an ophthalmic composition having or not impairing resistance to hypoxic stress.

In other aspects of the ophthalmic composition of the present invention, even if specific components are combined, each component can effectively exert its function and efficacy, and in some cases can have even higher functionality.

In another embodiment of the ophthalmic composition of the present invention, precipitation can be suppressed. In particular, such a precipitation suppression effect is often excellent at low temperatures (e.g., 10°C or less, preferably 5°C or less), and precipitation can be suppressed even at 0°C or less. Therefore, the ophthalmic composition of the present invention can achieve dissolution stability not only when stored at low temperatures such as those in a refrigerator, but also in environments exposed to lower temperatures (e.g., storage in cold regions or when there are drastic temperature changes).

As such, the composition of the present invention is highly practical.

FIG. 1 is a graph showing the results of Test Example 8.

In this specification, the unit of content "w/v%" is synonymous with "g/100 mL." In addition, in this specification, unless otherwise specified, the abbreviation "POE" means polyoxyethylene, and the abbreviation "POP" means polyoxypropylene.

1. Ophthalmic Compositions
The ophthalmic composition of the present invention contains at least one or more members selected from the group consisting of (A) tranilast and/or a salt thereof, (B) chlorpheniramine and/or a salt thereof, and (C) pranoprofen and/or a salt thereof.

(A) Tranilast and/or a salt thereof (Component (A))
The salt of tranilast may be any pharma- ceutically or physiologically acceptable salt, and examples thereof include organic acid salts (e.g., monocarboxylates (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polycarboxylates (fumarate, maleate, succinate, malonate, etc.), oxycarboxylates (lactate, tartrate, citrate, etc.), organic sulfonates (methanesulfonate, toluenesulfonate, tosylate, etc.)), inorganic acid salts (e.g., hydrochloride, sulfate, nitrate, hydrobromide, phosphate), salts with organic bases (e.g., salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline), salts with inorganic bases (e.g., ammonium salts; salts with alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), aluminum, etc.), and the like.

The sodium salt of tranilast is included in the sodium ion described below. Therefore, when component (A) contains a sodium salt, the sodium salt may be used so that the sodium ion concentration in the entire composition falls within the range described below.

Preferred tranilast and/or salts thereof include tranilast and non-sodium salts of tranilast. More preferred tranilast and/or salts thereof include tranilast and non-metal salts of tranilast, with tranilast being particularly preferred.

Tranilast and/or its salts may be used alone or in combination of two or more.

The content of component (A) in the composition may be, for example, 0.001 w/v% or more, preferably 0.01 to 10 w/v%, more preferably 0.05 to 5 w/v%, even more preferably 0.07 to 2 w/v%, even more preferably 0.1 to 1 w/v%, particularly preferably 0.2 to 1 w/v%, and most preferably about 0.25 to 0.8 w/v%, based on the total amount of the composition. Of these, 0.3 to 0.7 w/v% (e.g., 0.4 to 0.6 w/v%) is preferred, and 0.45 to 0.55 w/v% (e.g., 0.5 w/v%) is particularly preferred.

(B) Chlorpheniramine and/or its salt (component (B))
The salt of chlorpheniramine may be any pharma- ceutically or physiologically acceptable salt, and examples thereof include the salts exemplified in the section on component (A), such as organic acid salts (e.g., maleate, fumarate, etc.), inorganic acid salts (e.g., hydrochloride, sulfate, etc.), and metal salts.

Sodium salts are included in the sodium ions described below. Therefore, when component (B) contains a sodium salt, the sodium salt may be used so that the sodium ion concentration in the entire composition falls within the range described below.

Preferred chlorpheniramine and/or its salts include chlorpheniramine and its non-metallic salts (such as non-sodium salts), with chlorpheniramine maleate being particularly preferred.

Chlorpheniramine and/or its salts may be used alone or in combination of two or more.

The content of component (B) in the composition is, for example, 0.0001 w/v% or more, preferably 0.001 to 10 w/v%, more preferably 0.003 to 5 w/v%, even more preferably 0.005 to 1 w/v%, even more preferably 0.01 to 0.5 w/v%, particularly preferably 0.015 to 0.3 w/v% (e.g., 0.02 to 0.1 w/v%), and most preferably 0.025 to 0.05 w/v% (e.g., For example, it may be about 0.028 to 0.045 w/v%, and preferably 0.007 to 0.04 w/v% (e.g., 0.008 to 0.035 w/v%, particularly 0.01 to 0.03 w/v%). Specifically, it may be 0.008 to 0.012 w/v% (particularly 0.01 w/v%), 0.013 to 0.017 w/v% (particularly 0.015 w/v%), 0.02 to 0.04 w/v% (particularly 0.03 w/v%), etc.

(C) Pranoprofen and/or its salt (component (C))
The salt of pranoprofen may be any pharma- ceutically or physiologically acceptable salt, and examples thereof include the salts exemplified in the section on component (A) above, such as salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases, and examples thereof include sulfate salts, lactate salts, hydrochloride salts, chloride salts, sodium salts, and potassium salts.
Preferred pranoprofen and/or salts thereof are pranoprofen and non-metal salts thereof (such as non-sodium salts), with pranoprofen being particularly preferred.

Pranoprofen and/or its salts may be used alone or in combination of two or more.

The content of component (C) in the composition is, for example, 0.0001 w/v% or more, preferably 0.001 to 10 w/v%, more preferably 0.002 to 5 w/v%, even more preferably 0.003 to 1 w/v%, even more preferably 0.005 to 0.5 w/v%, particularly preferably 0.01 to 0.3 w/v% (e.g., 0.015 to 0.25 w/v%), and most preferably 0.001 to 0.3 w/v% (e.g., 0.015 to 0.25 w/v%), based on the total amount of the composition. Preferably, it may be about 0.02 to 0.2 w/v% (e.g., 0.025 to 0.18 w/v%), and of these, 0.03 to 0.15 w/v% (e.g., 0.04 to 0.12 w/v%, particularly 0.05 to 0.1 w/v%) is preferred, and specifically, it may be 0.04 to 0.06 w/v% (particularly 0.05 w/v%), 0.08 to 0.12 w/v% (particularly 0.1 w/v%), etc.

The ratio of the (B) component to the (A) components is, for example, 0.1 to 500 parts by mass (e.g., 0.3 to 100 parts by mass), preferably 0.4 to 50 parts by mass (e.g., 0.5 to 30 parts by mass), more preferably 0.7 to 20 parts by mass (e.g., 0.8 to 10 parts by mass), particularly preferably 1 to 8 parts by mass (e.g., 1.2 to 7.5 parts by mass), and particularly preferably 1.5 to 7 parts by mass (e.g., 2 to 6 parts by mass). Specifically, it may be 1 to 3 parts by mass (e.g., 1.5 to 2.5 parts by mass, particularly 2 parts by mass), 2 to 4 parts by mass (e.g., 2.5 to 3.5 parts by mass, particularly 3 parts by mass), 5 to 7 parts by mass (e.g., 5.5 to 6.5 parts by mass, particularly 6 parts by mass), etc., relative to 100 parts by mass of the (A) component.

The proportion of the (C) component, relative to 100 parts by mass of the (A) component, may be, for example, 0.1 to 500 parts by mass (e.g., 0.5 to 100 parts by mass), preferably 1 to 50 parts by mass (e.g., 2 to 40 parts by mass), more preferably 3 to 35 parts by mass (e.g., 4 to 30 parts by mass), and particularly preferably 5 to 25 parts by mass (e.g., 6 to 23 parts by mass), and among these, 8 to 22 parts by mass (e.g., 10 to 20 parts by mass) is preferred, and specifically, 8 to 12 parts by mass (e.g., 9 to 11 parts by mass, particularly 10 parts by mass), 18 to 22 parts by mass (e.g., 19 to 21 parts by mass, particularly 20 parts by mass), etc.

The proportion of the (B) component, relative to 100 parts by mass of the (C) component, may be, for example, 0.1 to 300 parts by mass (e.g., 0.5 to 150 parts by mass), preferably 1 to 100 parts by mass, more preferably 2 to 90 parts by mass (e.g., 3 to 80 parts by mass), and particularly preferably 5 to 75 parts by mass (e.g., 10 to 70 parts by mass), and among these, 15 to 65 parts by mass (e.g., 20 to 60 parts by mass) is preferred, and specifically, it may be 15 to 25 parts by mass (e.g., 18 to 22 parts by mass, particularly 20 parts by mass), 25 to 35 parts by mass (e.g., 28 to 32 parts by mass, particularly 30 parts by mass), 55 to 65 parts by mass (e.g., 58 to 62 parts by mass, particularly 60 parts by mass), etc.

The total amount of the (B) and (C) components may be, for example, 0.1 to 300 parts by mass (e.g., 0.5 to 100 parts by mass), preferably 1 to 80 parts by mass, more preferably 2 to 60 parts by mass (e.g., 3 to 50 parts by mass), and particularly preferably 5 to 45 parts by mass (e.g., 8 to 40 parts by mass) relative to 100 parts by mass of the (A) component. Of these, 10 to 35 parts by mass (e.g., 16 to 30 parts by mass) is preferred, and specifically, 12 to 20 parts by mass (e.g., 14 to 18 parts by mass, particularly 16 parts by mass), 22 to 30 parts by mass (e.g., 24 to 28 parts by mass, particularly 26 parts by mass), 26 to 34 parts by mass (e.g., 28 to 32 parts by mass, particularly 30 parts by mass), etc.

The ratio of the (A) component, the (B) component, and the (C) component may be, for example, (A) component/(B) component/(C) component (mass ratio) = 100/0.1 to 100/0.5 to 200 (e.g., 100/0.2 to 50/1 to 100), preferably 100/0.3 to 30/2 to 80, more preferably 100/0.5 to 20/3 to 50, and particularly preferably 100/0.8 to 10/4 to 30, of which 100/1 to 8/5 to 25 (e.g., 100/2 to 6/10 to 20) is preferred, and specifically, 100/5 to 7/8 to 12 (e.g., 100/5.5 to 6.5/9 to 11, particularly 100 /6/10), 100/5-7/18-22 (e.g., 100/5.5-6.5/19-21, particularly 100/6/20), 100/2-4/8-12 (e.g., 100/2.5-3.5/9-11, particularly 100/3/10), 100/2-4/18-22 (e.g., 100/2.5-3.5/19-21, particularly 100/3/20), 100/1-3/8-12 (e.g., 100/1.5-2.5/9-11, particularly 100/2/10), 100/1-3/18-22 (e.g., 100/1.5-2.5/19-21, particularly 100/2/20), etc. may also be used.

[Other ingredients]
The composition of the present invention may further contain other components in addition to the components (A) to (C). In the present invention, even if other components are contained, the effects of the present invention can often be ensured. In addition, by containing other components, the effects of the present invention may be realized more effectively in some cases.

(D) Solubilizing agent (component (D))
Component (A) is usually poorly soluble in water. Therefore, the composition of the present invention may contain a component (component (D)) for promoting or assisting the dissolution of component (A). Such component (D) can also be called a dissolution aid or solubilizer.

Component (D) is not particularly limited, but examples thereof include polyvinylpyrrolidone (PVP), hydroxyalkylamines (or aminoalkanols or alkanolamines, such as monoethanolamine, diethanolamine, triethanolamine, trometamol, etc.), alcohols (e.g. polyols such as propylene glycol), caffeine, etc.

Polyvinylpyrrolidone (PVP) is a polymer whose polymerization component is vinylpyrrolidone (N-vinyl-2-pyrrolidone).

The molecular weight of such polyvinylpyrrolidone is not particularly limited, but may be, for example, about 1000 or more (e.g., 1500 to 3,000,000), preferably 2000 or more (e.g., 2500 to 2,000,000), more preferably 3000 or more (e.g., 4,000 to 1,000,000), particularly preferably 5,000 or more (e.g., 6,000 to 300,000), or about 200,000 or less (e.g., 2,500 to 100,000, preferably 5,000 to 80,000, more preferably 10,000 to 50,000, particularly preferably 15,000 to 40,000, and most preferably 20,000 to 30,000).

Representative polyvinylpyrrolidones include polyvinylpyrrolidone K25, K30, K90, etc.

Component (D) may be used alone or in combination of two or more types.

Of these, polyvinylpyrrolidone, hydroxyalkylamines (e.g., monoethanolamine, trometamol), etc. are preferred, with polyvinylpyrrolidone and monoethanolamine being particularly preferred.

Therefore, component (D) (or the composition of the present invention) may contain at least one selected from polyvinylpyrrolidone and hydroxyalkylamines (e.g., monoethanolamine and/or trometamol).

The content of component (D) in the composition may be, for example, 0.001 w/v% or more, preferably 0.005 to 20 w/v%, more preferably 0.01 to 10 w/v%, even more preferably 0.03 to 5 w/v%, and even more preferably about 0.05 to 5 w/v%, or may be 0.1 to 10 w/v% (for example, 0.2 to 7 w/v%, preferably 0.3 to 5 w/v%, even more preferably 0.5 to 4.5 w/v%, and particularly preferably 1.0 to 3 w/v%), based on the total amount of the composition.

In particular, when the composition contains polyvinylpyrrolidone, the content of polyvinylpyrrolidone in the composition may be, for example, about 0.001 w/v% or more (e.g., 0.005 to 20 w/v%), preferably 0.01 to 10 w/v% (e.g., 0.05 to 5 w/v%), more preferably 0.07 to 10 w/v% (e.g., 0.1 to 5 w/v%), more preferably 0.3 to 7 w/v% (e.g., 0.5 to 5 w/v%), and particularly preferably about 0.7 to 4 w/v% (e.g., 1 to 3 w/v%), based on the total amount of the composition.

The proportion of component (D) may be, for example, 0.001 to 30 parts by mass, preferably 0.005 to 20 parts by mass, more preferably 0.01 to 15 parts by mass, particularly preferably 0.02 to 10 parts by mass, and even more particularly preferably 0.05 to 8 parts by mass, or may be about 0.1 to 15 parts by mass (for example, 0.2 to 12 parts by mass, preferably 0.3 to 10 parts by mass, more preferably 0.5 to 8 parts by mass, and most preferably 2 to 6 parts by mass) per part by mass of component (A).

When polyvinylpyrrolidone is combined with hydroxyalkylamines (e.g., at least one selected from monoethanolamine and trometamol), the ratio of hydroxyalkylamines to 100 parts by mass of polyvinylpyrrolidone can be selected from the range of about 0.01 to 1000 parts by mass, and may be, for example, about 0.1 to 500 parts by mass (e.g., 0.2 to 300 parts by mass), preferably about 0.3 to 250 parts by mass (e.g., 0.4 to 220 parts by mass), more preferably about 0.5 to 200 parts by mass (e.g., 1 to 180 parts by mass), particularly preferably about 2 to 150 parts by mass (e.g., 2.5 to 120 parts by mass), or may be about 3 to 100 parts by mass.

(E) Amino Acids The composition of the present invention may contain amino acids (sometimes referred to as component (E)).
The amino acid includes, for example, an amino acid or a salt thereof, and an amino acid analogue, and also includes a compound having an amino group and a carboxyl group or a sulfone group in the molecule, or a derivative thereof.

Specific examples include amino acids or their salts, and mucopolysaccharides or their salts. Among amino acids, examples of amino acids or their salts include monoamino monocarboxylic acids such as glycine, alanine, aminobutyric acid, aminovaleric acid, and aminocaproic acid; monoamino dicarboxylic acids such as aspartic acid and glutamic acid, and their salts; diamino monocarboxylic acids such as arginine and lysine, and their salts; and derivatives of aminoethylsulfonic acid (taurine), and their salts.

Among amino acids, mucopolysaccharides or their derivatives or salts thereof include, for example, acidic mucopolysaccharides such as chondroitin sulfate, hyaluronic acid, alginic acid, and the like, or their salts.

Specific amino acids and mucopolysaccharides include glycine, alanine, gamma-aminobutyric acid, gamma-aminovaleric acid, epsilon aminocaproic acid, aspartic acid, glutamic acid, arginine, aminoethylsulfonic acid, chondroitin sulfate, hyaluronic acid, alginic acid, or salts thereof.

Chondroitin sulfate is a sugar chain in which D-glucuronic acid and N-acetylglucosamine are repeated and sulfate is ester-bonded to all or some of the hydroxyl groups. The bond positions and number of sulfates vary, and chondroitin sulfate also has derivatives (e.g., chondroitin sulfate in which all or some of the N-acetylglucosamine is replaced with iduronic acid).
Such chondroitin sulfate may have any structure. Examples include chondroitin 4-sulfate (chondroitin sulfate A), chondroitin 6-sulfate (chondroitin sulfate C), and chondroitin sulfate E in which the 4- and 6-positions of N-acetylglucosamine are sulfated. Chondroitin sulfate may also be extracted from animals.

The salts of amino acids or salts of mucopolysaccharides include medicamentously, pharmacologically or physiologically acceptable salts. Examples of such salts include salts with organic acids [e.g., monocarboxylates (acetates, trifluoroacetates, butyrates, palmitates, stearates, etc.), polycarboxylates (fumarates, maleates, etc.), oxycarboxylates (lactates, tartrates, citrates, succinates, malonates, etc.), organic sulfonates (methanesulfonates, toluenesulfonates, tosylates, etc.)], salts with inorganic acids (e.g., hydrochlorides, sulfates, nitrates, hydrobromides, phosphates, etc.), salts with organic bases (e.g., salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.), salts with inorganic bases [e.g., ammonium salts; salts with alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), aluminum, etc.], and the salts are appropriately selected depending on the compound.

Specific salts include salts of aspartic acid (such as sodium aspartate, potassium aspartate, magnesium aspartate, and a mixture of magnesium and potassium aspartate), salts of glutamic acid (such as monosodium glutamate and magnesium glutamate), sodium chondroitin sulfate, and sodium hyaluronate.

Note that sodium salts are included in the sodium ions described below. Therefore, when component (E) contains a sodium salt, the sodium salt may be used so that the sodium ion concentration in the entire composition falls within the range described below.

The amino acids may be D-, L-, or DL-.

Preferred amino acids include aminoethylsulfonic acid (taurine) or its salts, sodium chondroitin sulfate, aspartates (e.g., potassium L-aspartate, magnesium potassium L-aspartate), epsilon aminocaproic acid or its salts, hyaluronic acid or its salts (sodium hyaluronate, etc.), and among these, aminoethylsulfonic acid (taurine) and/or its salts and sodium chondroitin sulfate are preferred, and aminoethylsulfonic acid (taurine) is most preferred.

Therefore, the amino acids may contain at least one or more types selected from the group consisting of aminoethylsulfonic acid and salts thereof (particularly aminoethylsulfonic acid).
The use of such amino acids (such as taurine) is expected to promote the healing of damaged corneal epithelial cells.

In such a case, the ratio of one or more selected from the group consisting of aminoethylsulfonic acid and its salts (particularly aminoethylsulfonic acid) to the total amount of amino acids may be, for example, 10% by mass or more, preferably 30% by mass or more, and more preferably 50% by mass or more.

Amino acids may be used alone or in combination of two or more.

When the composition contains component (E), the content of component (E) in the composition may be, for example, 0.001 w/v% or more, preferably 0.01 to 20 w/v%, more preferably 0.03 to 15 w/v%, even more preferably 0.05 to 10 w/v%, even more preferably 0.1 to 8 w/v%, and particularly preferably about 0.15 to 7 w/v%, and may usually be 0.1 to 15 w/v% [for example, 0.2 to 10 w/v%, preferably 0.3 to 8 w/v%, even more preferably 0.5 to 7 w/v%, and particularly preferably 0.6 to 6 w/v% (for example, 0.7 to 5 w/v%)] based on the total amount of the composition.

(F) Cooling agent ((F) component)
The composition of the present invention may contain a cooling agent (hereinafter, sometimes referred to as (F) cooling agent, (F) component, etc.).
The combination of components (A), (B) and (C) may reduce or impair the feeling of use, but the cooling agent can improve or enhance such feeling of use. For example, While it may be advantageous to increase the pH of the composition from the viewpoint of dissolving the component (A) (tranilast), the higher the pH of the composition, the stronger the discomfort and the worse the feeling of use. However, the use of a freshening agent can alleviate such discomfort and efficiently improve the feeling of use.

The cooling agent is not particularly limited, but examples thereof include terpenoids such as menthol, anethole, eugenol, camphor, geraniol, cineol, borneol, limonene, and lycopersicon gracilis. These may be in the d-, l-, or dl-form. Other examples include essential oils such as peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, bergamot oil, eucalyptus oil, and rose oil.

Of these, terpenoids are preferred, and among these, menthol, camphor, geraniol, cineol, borneol, and ryuuno are preferred, with menthol, camphor, and borneol being more preferred, and menthol and borneol being even more preferred.
Moreover, from the viewpoint of more significantly exhibiting the effects of the present invention, eucalyptus oil is also preferred.

The cooling agent may be used alone or in combination of two or more kinds. In particular, the cooling agent preferably contains one or more kinds selected from the group consisting of menthol, borneol, and eucalyptus oil, and when two or more kinds are combined, it is preferable to combine at least these (for example, combining menthol, borneol, and eucalyptus oil).

The proportion of component (F) relative to the total amount of the composition may be, for example, 0.00001 w/v% or more, 0.00005 w/v% or more, 0.0001 w/v% or more, 0.0003 w/v% or more, 0.0005 w/v% or more, 0.0007 w/v% or more, 0.0008 w/v% or more, 0.0009 w/v% or more, or 0.001 w/v% or more.

The proportion of component (F) may be 5 w/v% or less, 3 w/v% or less, 2 w/v% or less, 1.5 w/v% or less, 1.2 w/v% or less, 1 w/v% or less, 0.9 w/v% or less, 0.8 w/v% or less, 0.7 w/v% or less, or 0.6 w/v% or less, based on the total amount of the composition.

In particular, when the composition of the present invention contains menthol, the proportion of menthol may be, for example, about 0.00001 w/v% or more (e.g., 0.00005 to 2 w/v%), preferably about 0.0001 to 0.2 w/v% (e.g., 0.0003 to 0.1 w/v%), and more preferably about 0.0005 to 0.05 w/v% (e.g., 0.001 to 0.02 w/v%) relative to the total amount of the composition.
The proportion of menthol may be about 0.0001 part by mass or more (e.g., 0.0003 to 0.5 part by mass), preferably about 0.0005 to 0.1 part by mass (e.g., 0.0007 to 0.08 part by mass), and more preferably about 0.001 to 0.05 part by mass (e.g., 0.002 to 0.04 part by mass) per part by mass of component (A).
The proportion of menthol may be about 0.0001 part by mass or more (e.g., 0.0005 to 2 parts by mass), preferably about 0.001 to 1 part by mass (e.g., 0.003 to 0.7 parts by mass), and more preferably about 0.005 to 0.5 parts by mass (e.g., 0.01 to 0.4 parts by mass) per part by mass of component (C).

In particular, when the composition of the present invention contains borneol, the proportion of borneol may be, for example, about 0.00001 w/v % or more (e.g., 0.00005 to 3 w/v %), preferably about 0.0001 to 2 w/v % (e.g., 0.0003 to 1 w/v %), and more preferably about 0.0005 to 0.8 w/v % (e.g., 0.001 to 0.5 w/v %) relative to the total amount of the composition.
The proportion of borneol may be about 0.0001 part by mass or more (e.g., 0.0003 to 3 parts by mass), preferably about 0.0005 to 2 parts by mass (e.g., 0.0007 to 1.5 parts by mass), and more preferably about 0.001 to 1.2 parts by mass (e.g., 0.002 to 1 part by mass) per part by mass of component (A).
The proportion of borneol may be about 0.0001 part by mass or more (e.g., 0.0005 to 30 parts by mass), preferably about 0.001 to 20 parts by mass (e.g., 0.003 to 15 parts by mass), and more preferably about 0.005 to 12 parts by mass (e.g., 0.01 to 10 parts by mass) per part by mass of component (C).

In particular, when the composition of the present invention contains eucalyptus oil, the proportion of eucalyptus oil may be, for example, about 0.00001 w/v% or more (e.g., 0.00005 to 1 w/v%), preferably about 0.0001 to 0.1 w/v% (e.g., 0.0003 to 0.05 w/v%), and more preferably about 0.0005 to 0.02 w/v% (e.g., 0.001 to 0.01 w/v%) relative to the total amount of the composition.
The proportion of eucalyptus oil may be at least 0.0001 parts by mass (e.g., 0.0003 to 0.3 parts by mass), preferably 0.0005 to 0.05 parts by mass (e.g., 0.0007 to 0.04 parts by mass), and more preferably 0.001 to 0.03 parts by mass (e.g., 0.002 to 0.02 parts by mass) per part by mass of component (A).
The proportion of eucalyptus oil may be about 0.0001 parts by mass or more (e.g., 0.0005 to 1 part by mass), preferably 0.001 to 0.5 parts by mass (e.g., 0.003 to 0.3 parts by mass), and more preferably 0.005 to 0.3 parts by mass (e.g., 0.01 to 0.2 parts by mass) per part by mass of component (C).

(G) Fat-soluble antioxidant (ingredient (G))
The composition of the present invention may contain a fat-soluble antioxidant (hereinafter, may be referred to as (G) fat-soluble antioxidant, (G) component, etc.).

Examples of fat-soluble antioxidants include butyl-containing phenols such as dibutylhydroxytoluene (BHT) and butylhydroxyanisole (BHA); nordihydroguaiaretic acid (NDGA); ascorbic acid esters such as ascorbyl palmitate, ascorbyl stearate, aminopropyl ascorbyl phosphate, tocopherol ascorbyl phosphate, ascorbyl triphosphate, and ascorbyl phosphate palmitate; gallic acid esters such as ethyl gallate, propyl gallate, octyl gallate, and dodecyl gallate; propyl gallate; 3-butyl-4-hydroxyquinolin-2-one; carotenoids such as lutein and astaxanthin; polyphenols such as anthocyanins, catechin, tannin, and curcumin; and CoQ10.

Of these, dibutylhydroxytoluene is preferred. On the other hand, the composition of the present invention may not contain BHT.

The fat-soluble antioxidants may be used alone or in combination of two or more.

The content of component (G) in the composition may be, for example, about 0.0001 to 0.1 w/v%, preferably 0.0005 to 0.01 w/v%, more preferably 0.0007 to 0.009 w/v%, even more preferably 0.001 to 0.008 w/v%, even more preferably 0.003 to 0.007 w/v%, and most preferably about 0.0045 to 0.006 w/v%, based on the total amount of the composition.

(H) Antiallergic Agent (Component (H))
The composition of the present invention may contain an antiallergic agent (hereinafter, sometimes referred to as (H) antiallergic agent, (H) component, etc.).

Examples of antiallergic agents (antiallergic agents other than tranilast and/or its salts) include cromoglicate, ibudilast, azalast, tazanolast, suplatast, pemirolast, levocabastine, olopatadine, ketotifen, amlexanox, oxatomide, and salts thereof.

Examples of salts include the salts exemplified in the sections on components (A) to (C) above, such as alkali metal or alkaline earth metal salts (sodium cromoglycate, potassium cromoglycate, magnesium cromoglycate, calcium cromoglycate, etc.), inorganic acid salts (such as olopatadine hydrochloride), and organic acid salts [such as tosylate salts and fumarate salts (ketotifen fumarate, etc.)].

Of these, cromoglycic acid and its salts are preferred, with sodium cromoglycate being more preferred.

Antiallergic agents may be used alone or in combination of two or more.

The content of component (H) in the composition may be, for example, about 0.1 to 10 w/v%, preferably 0.2 to 8 w/v%, more preferably 0.3 to 5 w/v%, even more preferably 0.5 to 3 w/v%, particularly preferably 0.7 to 2 w/v%, even more particularly preferably 0.8 to 1.5 w/v%, and most preferably about 0.9 to 1.2 w/v%, based on the total amount of the composition.

(I) Antihistamine The composition of the present invention may contain an antihistamine (hereinafter sometimes referred to as (I) antihistamine, (I) component, etc.).
The antihistamine (antihistamine other than chlorpheniramine and/or its salts) is not particularly limited as long as it is a substance having an antihistamine effect, and examples thereof include diphenhydramine, epinastine, ketotifen, olopatadine, levocabastine, iproheptine, and salts thereof.

The salt may be any pharma- ceutically or physiologically acceptable salt, and examples thereof include organic acid salts (e.g., maleate, fumarate, etc.), inorganic acid salts (e.g., hydrochloride, sulfate, etc.), metal salts, etc., as exemplified in the section on component (A).

Specific examples of salts include diphenhydramine hydrochloride and iproheptine hydrochloride.

Antihistamines may be used alone or in combination of two or more.

When the composition contains component (I), the content of component (I) in the composition may be, for example, 0.0001 w/v% or more, preferably 0.001 to 10 w/v%, more preferably 0.003 to 5 w/v%, even more preferably 0.005 to 1 w/v%, even more preferably 0.01 to 0.5 w/v%, particularly preferably 0.015 to 0.3 w/v% (e.g., 0.02 to 0.1 w/v%), and most preferably about 0.025 to 0.05 w/v% (e.g., 0.03 w/v%), and usually about 0.01 to 0.05 w/v%, based on the total amount of the composition.

(J) Anti-inflammatory Agent The composition of the present invention may contain an anti-inflammatory agent (hereinafter sometimes referred to as (J) anti-inflammatory agent, (J) component, etc.).
The anti-inflammatory agent (anti-inflammatory agent other than pranoprofen and/or a salt thereof) is not particularly limited as long as it is a substance having an anti-inflammatory effect, and examples thereof include indomethacin, allantoin, berberine, azulene sulfonic acid, diclofenac, bromfenac, glycyrrhizic acid, zinc, silver, tranexamic acid, lysozyme, and salts thereof.

Examples of salts include salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, and the like exemplified in the section on component (A) above, such as sulfates, lactates, hydrochlorides, chloride salts, sodium salts, and potassium salts.

Specific salts include berberine sulfate, berberine chloride, dipotassium glycyrrhizinate, sodium azulene sulfonate, diclofenac sodium, bromfenac sodium, zinc sulfate, zinc lactate, silver nitrate, and lysozyme chloride.

The anti-inflammatory agents may be used alone or in combination of two or more kinds.
The ophthalmic composition of the present invention may be substantially free of glycyrrhizinic acid and salts thereof.

When the composition contains component (J), the content of component (J) in the composition may be, for example, about 0.0001 w/v% or more, preferably 0.001 to 10 w/v%, more preferably 0.003 to 5 w/v%, even more preferably 0.005 to 1 w/v%, even more preferably 0.01 to 0.5 w/v%, particularly preferably 0.015 to 0.3 w/v% (e.g., 0.02 to 0.1 w/v%), and most preferably about 0.025 to 0.07 w/v% (e.g., 0.05 w/v%), relative to the total amount of the composition.

The composition of the present invention may contain various components (e.g., components that do not belong to the categories of the above-mentioned components (A) to (J)). Examples of such components (additives) include surfactants, preservatives, buffers, pH adjusters, isotonicity agents, thickeners or viscosifiers, stabilizers, oils, sugars, polymeric compounds, polyhydric alcohols, inorganic salts, and non-fat-soluble antioxidants (or water-soluble antioxidants).

The additives can be used alone or in combination of two or more. In addition, each additive can be used alone or in combination of two or more.

Specific examples of additives are given below.

Surfactant The composition of the present invention may contain a surfactant. Examples of the surfactant include a nonionic surfactant.

Nonionic surfactants include polysorbates (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); poloxamer 407, poloxamer 235, poloxamer 188, poloxamer 235 ... POE-POP glycols such as POE-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; poly(monostearate) Ethylene glycol (2 E.O.), polyethylene glycol monostearate (4 E.O.), polyethylene glycol monostearate (9 E.O.), polyethylene glycol monostearate (10 E.O.), polyethylene glycol monostearate (23 E.O.), polyethylene glycol monostearate (25 E.O.), polyethylene glycol monostearate (32 E.O.), polyethylene glycol monostearate (40 E.O., polyoxyl 40 stearate), poly Examples of such polyethylene glycol monostearate include ethylene glycol (45 E.O.), polyethylene glycol monostearate (55 E.O.), polyethylene glycol monostearate (75 E.O.), and polyethylene glycol monostearate (140 E.O.); 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) nonylphenyl ether. In the above-listed compounds, POE stands for polyoxyethylene, POP stands for polyoxypropylene, and the numbers in parentheses stand for the number of moles added.

Among these, POE sorbitan fatty acid esters; POE-POP glycols; POE hydrogenated castor oil; POE castor oil; and polyethylene glycol monostearate are preferred, with 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 stearate 40 being more preferred, with polysorbate 80 and POE hydrogenated castor oil 60 being even more preferred, and polysorbate 80 being particularly preferred.

The surfactants may be used alone or in combination of two or more kinds.
The composition of the present invention may be substantially free of POE hydrogenated castor oil or POE castor oil.

When a nonionic surfactant is incorporated into the composition of the present invention, the proportion of the nonionic surfactant may be, for example, 0.001 w/v% or more, preferably 0.005 w/v% or more, more preferably 0.01 w/v% or more, and particularly preferably 0.05 w/v% or more, based on the total amount of the composition.

The proportion of the nonionic surfactant may be, for example, 5 w/v% or less, preferably 1 w/v% or less, relative to the total amount of the composition.

Preservatives The compositions of the present invention may contain a preservative.
Examples of preservatives include polydonium chloride, alkyl polyaminoethyl glycines (e.g., alkyl diaminoethyl glycine hydrochloride, etc.), sodium benzoate, ethanol, quaternary ammonium salts (e.g., benzalkonium chloride, benzethonium chloride, etc.), chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxybenzoic acid esters (e.g., methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc.), oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (e.g., polyhexanide hydrochloride, etc.), and Gloquil (manufactured by Rhodia).

Among these, alkyl polyaminoethyl glycines (e.g., alkyl diaminoethyl glycine hydrochloride), sodium benzoate, ethanol, quaternary ammonium salts, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, paraoxybenzoic acid esters, and biguanide compounds are preferred, with quaternary ammonium salts, chlorhexidine gluconate, chlorobutanol, and biguanide compounds being more preferred, and benzalkonium chloride and polyhexanide hydrochloride being even more preferred.

On the other hand, the composition of the present invention may not contain sorbic acid or its salts (such as potassium sorbate).

When a preservative is incorporated into the composition of the present invention, an example of the amount of the preservative incorporated is 0.000001 w/v% or more, preferably 0.00001 w/v% or more, preferably 0.00005 w/v% or more, preferably 0.001 w/v% or more, preferably 0.005 w/v% or more, based on the total amount of the composition. Also, an example of the amount of the preservative incorporated is 1 w/v% or less, preferably 0.1 w/v% or less, preferably 0.05 w/v% or less, preferably 0.03 w/v% or less, preferably 0.025 w/v% or less, based on the total amount of the composition.

Buffering Agents The compositions of the present invention may comprise a buffering agent.
Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer and the like.

The components of borate buffers include boric acid and borate salts (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.). The borate salts may be hydrated.

Phosphate buffer components include phosphoric acid and phosphate salts (such as disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, and calcium dihydrogen phosphate). Phosphates may be hydrates.

The components of the carbonate buffer include carbonic acid and carbonates (potassium carbonate, sodium carbonate, calcium carbonate, potassium bicarbonate, sodium bicarbonate, magnesium carbonate, etc.). The carbonates may be hydrated.

Components of citrate buffer include citric acid and citrate salts (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.). Citrate salts may be in the form of hydrates.

Components of acetate buffers include acetic acid and acetate salts (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.). Acetate salts may be hydrates.

Among these, boric acid buffers and phosphate buffers are preferred, with boric acid buffers being more preferred. As boric acid buffers, a combination of boric acid and its salts is preferred, a combination of boric acid and an alkali metal salt and/or an alkaline earth metal salt of boric acid is more preferred, a combination of boric acid and an alkali metal salt of boric acid is even more preferred, and a combination of boric acid and borax is even more preferred.

When a buffering agent is blended into the composition of the present invention, the blending amount of the buffering agent varies depending on the type of buffering agent and the types and amounts of other blended ingredients, and cannot be uniformly specified. However, examples of the amount of the buffering agent relative to the total amount of the composition include a total amount of 0.001 w/v% or more, preferably 0.01 w/v% or more, preferably 0.05 w/v% or more, and preferably 0.1 w/v% or more. Also, examples of the total amount of the buffering agent relative to the total amount of the composition include a total amount of 10 w/v% or less, preferably 5 w/v% or less, preferably 3 w/v% or less, preferably 2.5 w/v% or less, and preferably 2 w/v% or less.

In particular, when a boric acid buffer is used, the proportion of the buffer in the composition may be about 0.1 to 10 w/v%, preferably 0.2 to 5 w/v%, more preferably 0.5 to 4 w/v%, and even more preferably 1 to 3 w/v%, based on the total composition.

pH Adjusting Agents Examples of pH adjusting agents include hydrochloric acid, sulfuric acid, polyphosphoric acid, organic acids (propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, tartaric acid, malic acid, succinic acid, etc.), sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, and diisopropanolamine.
The pH adjusters may be used alone or in combination of two or more kinds.

Isotonicity Agents Examples of isotonicity agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, potassium acetate, sodium acetate, magnesium sulfate, glycerin, and propylene glycol.
The isotonicity agents may be used alone or in combination of two or more kinds.

Thickener or Viscosifier The ophthalmic composition of the present invention can contain a thickener or a viscosity enhancer to the extent that the effect of the present invention is not impaired.

Examples of thickening agents or viscosifying agents include guar gum, hydroxypropyl guar gum, cellulose-based polymer compounds (e.g., methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, etc.), gum arabic, karaya gum, xanthan gum, agar, alginic acid, α-cyclodextrin, dextrin, dextran, mucopolysaccharides (e.g., heparinoids, heparin, heparin sulfate, heparan sulfate, heparinoid, hyaluronic acid, hyaluronate (sodium salt, etc.), etc.), starch, chitin and derivatives thereof, chitosan and derivatives thereof, carrageenan, sorbitol ... Examples of the polyacrylic acid include tallow, polyvinyl polymer compounds (polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, etc.), alkali metal salts of polyacrylic acid (sodium salts, potassium salts, etc.), amine salts of polyacrylic acid (monoethanolamine salts, diethanolamine salts, triethanolamine salts, etc.), casein, gelatin, collagen, pectin, elastin, ceramide, liquid paraffin, glycerin, polyethylene glycol, macrogol, polyethyleneimine alginate (sodium salts, etc.), alginate esters (propylene glycol esters, etc.), powdered tragacanth, and triisopropanolamine.
The thickening or viscosifying agents may be used alone or in combination of two or more.

Stabilizers Stabilizers include, for example, trometamol, sodium formaldehyde sulfoxylate (Rongalit), monoethanolamine, aluminum monostearate, and glyceryl monostearate.
The stabilizers may be used alone or in combination of two or more kinds.

Oils Examples of oils include animal oils such as squalane and refined lanolin, mineral oils such as liquid paraffin and white petrolatum, and vegetable oils such as castor oil and sesame oil.
The oils may be used alone or in combination of two or more.
The ophthalmic composition of the present invention may be substantially free of petrolatum (such as white petrolatum).
In addition, the ophthalmic composition of the present invention may be substantially free of castor oil, sesame oil, and the like.
For example, the ophthalmic composition of the present invention may be (1) a composition excluding a composition containing a combination of polyoxyethylene castor oil and sesame oil, or (2) a composition excluding a composition containing a combination of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and sesame oil.

Sugars Examples of sugars include monosaccharides and disaccharides, specifically, glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, sorbitol, mannitol, and the like.
The sugars may be used alone or in combination of two or more kinds.

Polyhydric Alcohols Examples of polyhydric alcohols include polyethylene glycol, glycerin, propylene glycol, xylitol, diethylene glycol, mannitol, sorbitol, and polyvinyl alcohol.
The polyhydric alcohols may be used alone or in combination of two or more kinds.

Inorganic salts Examples of inorganic salts include potassium chloride, sodium chloride, calcium chloride, magnesium chloride, sodium bicarbonate, sodium carbonate (including dry sodium carbonate), potassium bicarbonate, potassium carbonate, magnesium sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium hydrogen sulfite, sodium sulfite, potassium acetate, sodium acetate, and sodium thiosulfate.
Among these, potassium chloride, sodium chloride, calcium chloride, sodium hydrogen carbonate, sodium carbonate (including dry sodium carbonate), magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate are preferred, potassium chloride, sodium chloride, calcium chloride, sodium hydrogen phosphate, and sodium dihydrogen phosphate are more preferred, and potassium chloride and sodium chloride are even more preferred.
The inorganic salts may be used alone or in combination of two or more kinds.

Water-soluble antioxidants Examples of water-soluble antioxidants include ascorbic acid, ascorbic acid derivatives (such as disodium ascorbic acid 2-sulfate, sodium ascorbate, magnesium ascorbyl 2-phosphate, and sodium ascorbyl 2-phosphate), sodium hydrogen sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, edetic acid, or a salt thereof (such as disodium edetate and tetrasodium edetate).
The water-soluble antioxidants may be used alone or in combination of two or more kinds.

The composition of the present invention may further contain ingredients that have pharmacological or physiological activity.

The pharmacologically active or physiologically active ingredients can be used alone or in combination of two or more.

Examples of such pharmacologically active ingredients and physiologically active ingredients include the active ingredients in various medicines listed in the 2012 edition of the General Pharmaceutical Manufacturing and Sales Approval Standards (supervised by the Japan Society of Regulatory Science). Examples include decongestants, eye muscle regulating agents, astringents, vitamins, amino acids, antibacterial or disinfectant agents, local anesthetic ingredients, analgesics, and sulfa drugs. Specific examples of these drugs are given below.

Decongestants (vasoconstrictors)
Decongestants include, for example, α-adrenergic agonists, specifically imidazoline decongestants such as oxymetazoline, tetrahydrozoline, naphazoline, or salts thereof such as hydrochlorides and nitrates, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine hydrogen tartrate, etc. These may be in any of the d-, l- or dl-forms.

To elaborate on the imidazoline vasoconstrictor, the salt of the imidazoline vasoconstrictor may be any pharma- ceutically or physiologically acceptable salt, and examples of such salts include organic acid salts such as maleate and fumarate; inorganic acid salts such as hydrochloride and sulfate; and metal salts. Among the salts, inorganic acid salts are preferred, with hydrochloride or nitrate being more preferred, and hydrochloride (e.g., tetrahydrozoline hydrochloride) being particularly preferred.

Among decongestants (vasoconstrictors), imidazoline vasoconstrictors are preferred, tetrahydrozoline, naphazoline, or salts thereof are more preferred, and tetrahydrozoline or salts thereof are even more preferred.

Ocular muscle regulating agents Examples of ocular muscle regulating agents include cholinesterase inhibitors having an active center similar to that of acetylcholine, specifically neostigmine methylsulfate, tropicamide, helenien, and atropine sulfate.

Vitamins Examples of vitamins include flavin adenine dinucleotide or a salt thereof (e.g., sodium flavin adenine dinucleotide), cobalamin or a salt thereof (e.g., cyanocobalamin, methylcobalamin), retinol, a salt thereof or a derivative thereof (e.g., retinol acetate, retinol palmitate), pyridoxine or a salt thereof (e.g., pyridoxine hydrochloride), panthenol, pantothenic acid or a salt thereof (e.g., sodium pantothenate, potassium pantothenate, calcium pantothenate, magnesium pantothenate), tocopherol, a salt thereof or a derivative thereof (e.g., tocopherol acetate, tocopherol succinate, tocopherol nicotinate), pyridoxal or a salt thereof (e.g., pyridoxal phosphate), ascorbic acid or a salt thereof (e.g., sodium ascorbate, calcium ascorbate), and the like.

Among these, flavin adenine dinucleotide or a salt thereof (particularly sodium flavin adenine dinucleotide), cobalamin or a salt thereof (particularly cyanocobalamin), retinol, a salt thereof or a derivative thereof (particularly retinol acetate and retinol palmitate), pyridoxine or a salt thereof (particularly pyridoxine hydrochloride), panthenol, pantothenic acid or a salt thereof (particularly sodium pantothenate and calcium pantothenate), tocopherol, a salt thereof or a derivative thereof (particularly tocopherol acetate) are preferred, with pyridoxine hydrochloride and tocopherol acetate being more preferred.
The composition of the present invention may not contain pyridoxine or a salt thereof.

Antibacterial or Bactericidal Agents Examples of antibacterial or bactericidal agents include sulfa drugs such as sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxazole monoethanolamine, sulfisomazole sodium, and sulfisomidine sodium, alkylpolyaminoethylglycine, chloramphenicol, ofloxacin, norfloxacin, levofloxacin, and lomefloxacin hydrochloride.

Local anesthetic components Examples of local anesthetic components include procaine hydrochloride and lidocaine hydrochloride.

Analgesic Agents Analgesic agents include, for example, procaine hydrochloride.

Sulfa drugs Examples of sulfa drugs include sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, and sulfisomidine sodium.

Base or Carrier The composition of the present invention may comprise a base or carrier.
A composition containing such a base or carrier can be prepared, for example, by mixing each of the above-mentioned components with a pharma- ceutically acceptable base or carrier, according to a conventional method described in, for example, the 17th edition of the Japanese Pharmacopoeia.

Examples of bases or carriers include water, polar solvents (particularly water-soluble solvents) such as ethanol, and oil-based bases. The bases or carriers can be used alone or in combination of two or more.

In particular, the composition of the present invention may be an aqueous composition (e.g., a composition containing water or a mixture of water and a water-soluble solvent).

The properties of the composition of the present invention are not particularly limited, and may be any of liquid, fluid, gel, or semi-solid. Also includes those that are liquid, fluid, gel, or semi-solid when prepared at the time of use. Semi-solid refers to a property that has plasticity that can be deformed by applying force, such as an ointment.

As described above, the composition may be an aqueous composition (mainly containing an aqueous or hydrophilic base or carrier), an oil-based composition (mainly containing an oil-based or hydrophobic base or carrier), or in particular an aqueous composition.

In the case of an aqueous composition, the water content is preferably 50% by mass or more, more preferably 75% by mass or more, and even more preferably 90% by mass or more, based on the total amount of the composition (or preparation). The base or carrier may consist of only water.

In the case of an oil-based composition, the water content is preferably less than 50% by mass, more preferably 30% by mass or less, and even more preferably 20% by mass or less, based on the total amount of the composition (or preparation).

Sodium ion amount The composition of the present invention may have a sodium ion (or sodium) amount in a specific range. By combining such a sodium ion amount with the specific component, it may be possible to obtain more advantageous effects in terms of precipitation suppression effect, dissolution stability, and the like.

For example, the sodium ion concentration of the composition of the present invention may be 300 mM or less, 250 mM or less (e.g., 240 mM or less), more preferably 230 mM or less, particularly preferably 200 mM or less, and most preferably 150 mM or less.

The sodium ion concentration of the composition of the present invention may be relatively low, for example, 100 mM or less (e.g., 90 mM or less), preferably 80 mM or less (e.g., 70 mM or less), more preferably 60 mM or less (e.g., 50 mM or less), and most preferably 40 mM or less (e.g., 30 mM or less), or may be even lower (e.g., 35 mM or less, 30 mM or less, 25 mM or less, 20 mM or less, 15 mM or less, preferably 10 mM or less, 5 mM or less, substantially 0 mM or the detection limit).

The amount of sodium ions can also be specified as a ratio to the (A) component. For example, in the composition of the present invention, the ratio of sodium ions can be selected from a range of about 30 moles or less per mole of the (A) component, and may be 25 moles or less, preferably 20 moles or less, more preferably 15 moles or less, particularly preferably 12 moles or less, and most preferably 10 moles or less (e.g., 9.5 moles or less), or may be a relatively low ratio [e.g., 9 moles or less (e.g., 8 moles or less), preferably 7 moles or less (e.g., 6 moles or less), more preferably 5 moles or less, particularly preferably 4 moles or less, and most preferably 3 moles or less], or may be an even lower ratio (e.g., 3.5 moles or less, 3 moles or less, 2.5 moles or less, 2 moles or less, 1.5 moles or less, preferably 1 mole or less, more preferably 0.5 moles or less, particularly preferably 0.1 moles or less, substantially 0 moles or detection limit).

In addition, the sodium ion may be any ion that can be a free ion in the composition, and may form a salt.For example, even if tranilast forms a salt with sodium in the composition and the sodium ion is not in a free state, the sodium (ion) derived from such a salt is also included in the sodium ion.
The amount or concentration of sodium (ion) may be obtained by measuring the amount or concentration in the composition (direct measurement), or by calculating the amount or concentration in the composition from the amount or concentration of sodium (ion) in the components (raw materials) that constitute the composition (indirect measurement). The amount or concentration of sodium (ion) in the composition or raw materials may be measured by a conventional method or device (e.g., ion chromatography, etc.).

As mentioned above, sodium ions include sodium derived from each component, and therefore, when each component contains sodium as a salt, it is necessary to adjust the sodium ion concentration to the above-mentioned level. From this perspective, when reducing the amount of sodium in the composition of the present invention, it is desirable to contain small amounts or no sodium chloride, borax, sodium edetate, etc., which are commonly used in eye drops and other applications.

From this perspective, it may be preferable to use components that do not contain sodium (for example, in the case of a salt, a salt that is not a sodium salt (non-sodium salt)) as each of the components constituting the composition of the present invention (for example, components (A) to (C) and other components, etc.).

pH
The pH of the composition of the present invention is preferably 3 or more (e.g., 4 or more), more preferably 5 or more (e.g., 5.5 or more), and even more preferably 6 or more. The pH is preferably 10 or less, more preferably 9 or less, and even more preferably 8.5 or less.

The pH of the composition of the present invention may be, for example, 4 to 10, preferably 5 to 9, and more preferably 5.5 to 8.5 (e.g., 6.0 to 8.3), or 6.5 to 8.5 (e.g., 7 to 8, 7.2 to 7.7, etc.).
In the present invention, the effects of the present invention can be efficiently achieved even at the above pH.

The osmotic pressure ratio of the composition of the present invention is, for example, preferably 0.4 or more, more preferably 0.5 or more, and even more preferably 0.6 or more. Also, it is preferably 5 or less, more preferably 3 or less, and even more preferably 2 or less.

The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to the osmotic pressure of 286 mOsm (0.9 w/v% sodium chloride aqueous solution) based on the Japanese Pharmacopoeia, 17th Edition. The osmotic pressure is measured according to the osmotic pressure measurement method (freezing point depression method) described in the Japanese Pharmacopoeia, 17th Edition.

Dosage form The dosage form (form, shape, structure) of the composition of the present invention is not particularly limited, and examples thereof include eye drops (also called eye drops or eye drops. Eye drops include eye drops that can be applied while wearing contact lenses), eye washes, eye ointments (water-soluble eye ointments, oil-soluble eye ointments), contact lens wetting solutions, intraocular injections (e.g., intravitreal injections), contact lens solutions (cleaning solutions, storage solutions, disinfectants, multipurpose solutions, package solutions), preservatives for excised eye tissues such as corneas for transplantation, irrigation solutions for surgery, etc. Eye drops, eye washes, and eye ointments also include those used when wearing contact lenses.

The term "contact lenses" includes hard contact lenses and soft contact lenses (including both ionic and non-ionic, and both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).

Preferred dosage forms of the composition of the present invention include eye drops, eye washes, eye ointments (water-soluble eye ointments, oil-soluble eye ointments), contact lens wearing solutions, contact lens solutions (cleaning solutions, storage solutions, disinfectants, multipurpose solutions, packaging solutions), etc., more preferred are eye drops, eye washes, contact lens wearing solutions, contact lens solutions (cleaning solutions, storage solutions, disinfectants, multipurpose solutions), etc., even more preferred are eye drops and eye washes, and particularly preferred are eye drops.

Such compositions of the present invention may exclude ophthalmic compositions (particularly eye drops, eye washes, or eye ointments) that are used or applied when wearing (putting on) or during the wearing of contact lenses (hard contact lenses, soft contact lenses, especially silicone hydrogel contact lenses).

The composition of the present invention may be a single-use unit dose or a multi-dose that can be used repeatedly, and may be stored and used in a multi-dose form.

Container The composition of the present invention may be contained (filled, injected, sealed) in a container.
The container may be any packaging material having a part (surface) that comes into contact with the composition (formulation), and may be composed of, for example, a container body that contains the composition (e.g., a liquid composition), a part that includes the container's extraction port (nozzle, inner plug), a suction tube, a cap, etc.

The material constituting the container can be selected from a wide range of materials, and examples include plastics [e.g., olefin resins, styrene resins, acrylic resins, polyester resins, polycarbonate resins, fluororesins, chlorine resins (such as polyvinyl chloride), polyamide resins, polyacetal resins, polyphenylene ether resins (such as modified polyphenylene ether), polyarylates, polysulfones, polyimide resins, cellulose resins (such as cellulose acetate), hydrocarbon resins which may be substituted with halogen atoms, etc.] and metals (such as aluminum), at least a part or all of the part which comes into contact with the composition.

The container may be made of a single material or two or more materials.

Examples of olefin-based resins include ethylene-based resins [e.g., polyethylene (including high-density polyethylene, low-density polyethylene, very low-density polyethylene, linear low-density polyethylene, ultra-high molecular weight polyethylene, etc.), ethylene-propylene copolymers, etc.], propylene-based resins [e.g., polypropylene (PP) (including isotactic polypropylene, syndiotactic polypropylene, atactic polypropylene, etc.), propylene-ethylene copolymers, etc.], and methylpentene-based resins (e.g., polymethylpentene, etc.).

Examples of styrene-based resins include polystyrene and acrylonitrile-containing styrene-based resins (e.g., acrylonitrile-styrene copolymer (AS resin), acrylonitrile-butadiene-styrene copolymer (ABS resin), etc.).

Examples of acrylic resins include resins whose polymerization components include acrylic acid esters such as methyl acrylate, and methacrylic acid esters such as methyl methacrylate, cyclohexyl methacrylate, and t-butylcyclohexyl methacrylate.

Examples of polyester resins include aromatic polyester resins [e.g., resins having alkylene terephthalate units (alkylene terephthalate resins: e.g., polyethylene terephthalate (PET), polytrimethylene terephthalate, polybutylene terephthalate (PBT)), etc.), resins having alkylene naphthalate units (e.g., polyethylene naphthalate (PEN), polybutylene naphthalate, etc.)].

Fluorine resins include fluorine-substituted polyethylene (polytetrafluoroethylene, polychlorotrifluoroethylene, etc.), polyvinylidene fluoride, polyvinyl fluoride, perfluoroalkoxy fluorine resins, tetrafluoroethylene-hexafluoropropylene copolymer, ethylene-tetrafluoroethylene copolymer, ethylene-chlorotrifluoroethylene copolymer, etc.

Polyacetal resins include those that are composed only of oxymethylene units, as well as those that contain some oxyethylene units.

Examples of modified polyphenylene ethers include polystyrene-modified polyphenylene ethers.

Examples of polyarylates include amorphous polyarylates.

Examples of polyimide resins include aromatic polyimides, such as those obtained by polymerizing pyromellitic dianhydride and 4,4'-diaminodiphenyl ether.

Examples of cellulose acetate include cellulose diacetate and cellulose triacetate.

As materials for the container, plastics such as olefin-based resins, styrene-based resins, and polyester-based resins (i.e., plastic containers) are preferred, with ethylene-based resins, propylene-based resins, alkylene terephthalate-based resins, and polystyrene being more preferred, with polypropylene, polyethylene terephthalate, and polystyrene being even more preferred, and polyethylene terephthalate being even more preferred.

The container material may be a polymer blend with a polymer other than the above polymer. When the container material for storing the ophthalmic composition of the present invention is a blend polymer with the above polymer, the mixing ratio of the above polymer to the polymer other than the above polymer is not particularly limited as long as the effects of the present invention are achieved, but the total weight of the polymers relative to the total amount of the entire constituent materials is preferably 30 w/w% or more, more preferably 50 w/w% or more, even more preferably 65 w/w% or more, and particularly preferably 80 w/w% or more.

At least a portion of the surface of the container that comes into contact with the composition of the present invention may be made of the above material. For example, a layer or film made of the above material may be formed on the inner surface of the container, or the container itself may be molded from the above material. From the viewpoint of achieving a significant effect of the present invention, it is preferable that the container itself is molded from the above material.

In addition, the parts constituting the container (container body, part including the container's extraction port (nozzle, inner plug), suction tube, cap, etc.) may be made of the above materials, or the entire container may be made of the above materials. In particular, from the viewpoint of significantly achieving the effects of the present invention, it is preferable that the container body is made of the above materials, and it is more preferable that the entire container body is made of the above materials (a state in which some layers constituting the container body are not made of the above materials).

Target disease (use)
The target disease (use) of the composition of the present invention is not particularly limited, so long as it is for ophthalmic use. For example, the composition is useful for alleviating, improving, suppressing, or treating allergic symptoms, eye itching, bloodshot eyes, foreign body sensation (gritty feeling, etc.), corneal damage, corneal injury, watery eyes (epiphora), palpebral conjunctival follicles, ocular discharge (eye discharge), etc., as well as for enhancing, normalizing, and protecting the cornea barrier function.

Watery eyes are a symptom that occurs when the tear drainage pathway from the lacrimal puncta to the lacrimal canaliculus, lacrimal sac, and nasolacrimal duct becomes blocked by eye discharge or when excessive tears are produced due to irritation.

In this specification, "alleviation" includes alleviation of symptoms and inhibition of progression of symptoms, and "improvement," "inhibition," and "treatment" include alleviation of symptoms, inhibition of progression of symptoms, cure, or complete recovery.

In particular, the composition of the present invention is suitable for alleviating, improving, suppressing, or treating allergic symptoms (eye allergy symptoms).

Allergens causing allergic symptoms are not particularly limited, but may be pollen (e.g., cedar pollen, cypress pollen), house dust, etc.

In another aspect, the composition of the present invention is suitable for alleviating, improving, suppressing, or treating symptoms such as itchy eyes, bloodshot eyes, watery eyes, foreign body sensation, and eye discharge. These symptoms may or may not be caused by allergies.

Method of Use The method of use (mode of use) of the composition of the present invention can be appropriately selected depending on its properties, etc.

For example, when the composition of the present invention is a preparation to be applied to the eyes, such as eye drops, eye washes, or eye ointments, the method of administration varies depending on the symptoms to be treated, but can be, for example, one or more times, two or more times, three or more times, four or more times, five or more times, or six or more times per day. It can also be nine or less times, eight or less times, seven or less times, six or less times, five or less times, or four or less times per day. Administration four times per day is particularly preferred.

When the composition of the present invention is an eye drop, for example, 1 to 3 drops may be instilled at one time, or 1 to 2 drops or 2 to 3 drops may be instilled. Preferably, 1 to 2 drops may be instilled. It is also possible to instill 1 drop. The amount of one drop instilled may preferably be 30 to 50 μL.

When the composition of the present invention is an eyewash, for example, 1 to 30 mL, preferably 1 to 20 mL, and more preferably 4 to 6 mL, may be used for each eyewash.

When the composition of the present invention is an eye ointment, for example, 0.001 to 5 g may be applied to the eye each time.

When the composition of the present invention is a contact lens wearing solution, when putting on or taking off a contact lens, for example, 1 to 3 drops, preferably 1 to 2 drops, may be dropped onto one and/or both sides of the contact lens each time to wet the lens before wearing, and it is preferable to wet both sides of the contact lens before wearing.

[2. Preservative Effectiveness]
The ophthalmic composition according to this embodiment has an effect of being able to increase or improve (or be able to impart or express) the preservation effectiveness (storage stability) of the ophthalmic composition.
Therefore, as one embodiment of the present invention, there is provided a method for enhancing or improving (a method for imparting or expressing) preservative effectiveness (storage stability) in an ophthalmic composition, comprising incorporating the remaining one or two components selected from component (A), component (B), and component (C) into an ophthalmic composition containing component (A) (e.g., incorporating component (B) and component (C) into an ophthalmic composition containing component (A)).
In addition, as one embodiment of the present invention, there is provided an agent (preservative) for enhancing or improving (imparting or expressing) preservative effectiveness in an ophthalmic composition containing one or two components selected from component (A), component (B), and component (C), and the agent contains the remaining one or two components.
In these methods and agents, the microorganisms, bacteria, molds, etc. that exhibit a preservative effect are not particularly limited, and examples thereof include Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Candida, Aspergillus, etc.

3. Stability
The ophthalmic composition according to this embodiment has the effect of improving or improving (imparting or expressing) the stability (e.g., thermal stability and/or light stability, particularly at least light stability) of the ophthalmic composition.
Therefore, as one embodiment of the present invention, there is provided a method for enhancing or improving (imparting or expressing) stability in an ophthalmic composition, comprising incorporating the remaining one or two components selected from component (A), component (B), and component (C) into an ophthalmic composition containing component (A) (e.g., incorporating component (B) and component (C) into an ophthalmic composition containing component (A)).
In addition, as one embodiment of the present invention, there is provided an agent (light stabilizer, heat stabilizer, heat and light stabilizer) for enhancing or improving (imparting or expressing) stability in an ophthalmic composition comprising one or two components selected from component (A), component (B), and component (C), and comprising the remaining one or two components.

[4. Oxygen stress resistance]
The ophthalmic composition according to this embodiment has an effect of improving or improving (conferring or expressing) oxygen (hypoxia) stress resistance in the ophthalmic composition.
Therefore, as one embodiment of the present invention, there is provided a method for enhancing or improving (imparting or expressing) oxygen (hypoxic) stress resistance in an ophthalmic composition, comprising incorporating one or two components selected from component (A), component (B), and component (C) into an ophthalmic composition containing component (A) and the remaining one or two components (e.g., incorporating component (B) and component (C) into an ophthalmic composition containing component (A)).
Furthermore, as one embodiment of the present invention, there is provided an agent (oxygen stress resistance improving agent) for enhancing or improving (imparting or expressing) oxygen (hypoxia) stress resistance in an ophthalmic composition comprising one or two components selected from component (A), component (B), and component (C), and comprising the remaining one or two components.

[5. Suppression of precipitation and cloudiness]
The ophthalmic composition according to this embodiment has an effect of being able to suppress precipitation (cloudiness) in the ophthalmic composition (or being able to enhance or improve the dissolution stability).
Therefore, as one embodiment of the present invention, there is provided a method for suppressing precipitation (cloudiness) in an ophthalmic composition (a method for improving or enhancing dissolution stability), which comprises incorporating the remaining one or two components selected from component (A), component (B), and component (C) into an ophthalmic composition containing component (A) (e.g., incorporating component (B) and component (C) into an ophthalmic composition containing component (A)).
In this method, the sodium ion concentration of the ophthalmic composition may be adjusted to the above-mentioned concentration (for example, 250 mM or less) or a solubilizing agent (for example, polyvinylpyrrolidone) may be contained.
In one embodiment of the present invention, there is provided an agent for suppressing precipitation (cloudiness) in an ophthalmic composition (or an agent for enhancing or improving dissolution stability) that contains one or two components selected from component (A), component (B), and component (C), and that contains the remaining one or two components. This agent may further contain a solubilizing agent (such as polyvinylpyrrolidone).
In these methods and agents, the temperature at which the precipitation suppression effect (improvement or improvement of dissolution stability) is exerted is not particularly limited, but may be particularly effective at a relatively low temperature. Therefore, the method and agent may be a method and agent that suppresses precipitation (improves or improves dissolution stability) at a low temperature (e.g., 10° C. or lower, preferably 5° C. or lower, 0° C. or lower, etc.).

In each of the above embodiments, the types and contents of the components (A) to (C), the types and contents of other components, the formulation form and uses of the ophthalmic composition, etc. are as described in [1. Ophthalmic composition].

The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these examples, and many modifications can be made by those with ordinary skill in the art within the technical concept of the present invention.

In the following test examples and formulation examples, the amount and concentration of sodium (ions) were calculated based on the amount of sodium (ions) in the raw materials. The table below shows ingredients that contain sodium (ions) and examples of how to calculate the amount or concentration of that sodium.

Sodium ion concentration (mM) =
Amount blended (w/v%)/molecular weight x number of sodium (per molecular weight) x 10,000

For polysaccharides, calculations were made based on the molecular weight of the sugar moiety to which sodium is bound. For example, sodium chondroitin sulfate is a polymer whose repeating structural units are disaccharides of N-acetyl-D-galactosamine and D-glucuronic acid, and the Na concentration was calculated based on a molecular weight of 503.3 per disaccharide unit.

Test Example 1 (Preservative Efficacy)
Aqueous ophthalmic compositions (eye drops) having the compositions shown in Table 2 below were prepared by a conventional method, and their preservative effectiveness was evaluated as follows.

Staphylococcus aureus (ATCC6538)) was inoculated on the surface of a soybean casein digest slant medium and cultured at 33° C. for 24 hours. The cultured bacteria was aseptically collected with a platinum loop and suspended in an appropriate amount of sterile physiological saline to prepare a bacterial suspension containing about 1×10 ⁷ CFU/mL of live bacteria. The viable bacteria count of the suspension was measured by separate culture. Next, 10 mL of each of the filter-sterilized aqueous ophthalmic compositions was filled into a 15 mL CORNING conical tube (PET). The aqueous ophthalmic composition was inoculated with a Staphylococcus aureus suspension so that the viable bacteria count (final concentration) was about 10 ⁵ CFU/mL, and the mixture was thoroughly stirred to prepare a sample.
The samples were stored for 5 days in the dark at 23° C. After 5 days, the samples containing bacteria were prepared to a concentration appropriate for counting, and inoculated onto soybean casein digest agar medium (SCD agar medium). After overnight incubation at 33° C., the number of colonies observed was counted to determine the viable bacterial count.
From the obtained viable cell count, the following value (Log Reduction Value LRV) was calculated and used as an index of preservative effectiveness.
Log reduction value=log (viable cell count in suspension/100)−log (viable cell count after 5 days)

In the aqueous ophthalmic compositions in Table 2 below, the units for each component are (w/v%) (same below).

As is clear from the results in Table 2 above, the combination of tranilast, chlorpheniramine maleate, and pranoprofen showed a higher preservative effect against Staphylococcus aureus than when any of these three ingredients, tranilast or chlorpheniramine maleate, was used alone or when chlorpheniramine maleate was combined with pranoprofen.

Test Example 2 (Preservative Efficacy)
Aqueous ophthalmic compositions (eye drops) having the compositions shown in Table 3 below were prepared by a conventional method, and their preservative effectiveness was evaluated in the same manner as in Test Example 1, except that the storage period was changed from 5 days to 1 week.

As is clear from the results in Table 3 above, the same preservative effectiveness was obtained even if the storage period was extended to one week and the ratio of the three ingredients was changed.

Test Example 3 (Preservative Efficacy)
An aqueous ophthalmic composition (eye drop) having the composition shown in Table 4 below was prepared by a conventional method, and its preservation effectiveness was evaluated in the same manner as in Test Example 2 (storage period: 1 week), except that a heat treatment (thermal aging) was performed before storage.
The heat treatment was carried out by filling 13 mL of the prepared aqueous ophthalmic composition into a 13 mL PET container, packaging it in plastic film, and storing it at 60° C. for 7 days under light-shielded conditions.

As is clear from the results in Table 4 above, the preservative effect was maintained even when heat-treated before storage.

Test Example 4 (Preservative Efficacy)
An aqueous ophthalmic composition (eye drop) having the composition shown in Table 5 below was prepared by a conventional method, and a log reduction value A was obtained in the same manner as in Test Example 2 (storage period: 1 week).
On the other hand, an aqueous ophthalmic composition having the same composition was used, and in Test Example 2 (storage period: 1 week), a log reduction value B was obtained in the same manner as in Test Example 2, except that a heat treatment similar to that in Test Example 3 was performed before storage.
From these results, the difference in logarithmic reduction (A-B) was calculated to evaluate the degree of deterioration in preservative effectiveness due to heat aging.

As is clear from the results in Table 5 above, by combining the three ingredients, it was possible to suppress the decrease in preservative effectiveness due to heat treatment.

Test Example 5 (Preservative Effectiveness)
An aqueous ophthalmic composition (eye drop) having the composition shown in Table 6 below was prepared by a conventional method, and its preservation effectiveness was evaluated in the same manner as in Test Example 2 (storage period: 1 week), except that the composition was exposed to light before storage.
The light exposure was carried out by filling 13 mL of the prepared aqueous ophthalmic composition into a 13 mL PET container, and then continuously irradiating the composition with light of 4,500 lx/hr at room temperature using a photostability tester ("LT-120A-WCD type", manufactured by Nagano Scientific Co., Ltd.) using a white lamp as a light source for 24 hours until the accumulated irradiation amount of the aqueous ophthalmic composition reached 100,000 lx hr.

As is clear from the results in Table 6 above, the preservative effect was maintained even when exposed to light.

Test Example 6 (Preservative Efficacy)
Aqueous ophthalmic compositions (eye drops) having the compositions shown in Table 7 below were prepared by a conventional method, and the preservative effectiveness was evaluated in the same manner as in Test Example 2 (storage period 1 week), except that Escherichia coli (ATCC 8739) was used instead of Staphylococcus aureus.

As is clear from the results in Table 7 above, the combination of tranilast, chlorpheniramine maleate, and pranoprofen demonstrated preservative effectiveness even when the type of bacteria was changed.

Test Example 7-1 (Photostability)
Aqueous ophthalmic compositions (eye drops) having the compositions shown in Table 8 below were prepared by a conventional method, and their photostability was evaluated as follows.
A 13 mL PET container was filled with 13 mL of the prepared aqueous ophthalmic composition. Using a photostability tester ("LT-120A-WCD type", manufactured by Nagano Scientific Co., Ltd.), a white lamp was used as a light source, and light of 4,500 lx/hr was continuously irradiated for 24 hours at room temperature, exposing the aqueous ophthalmic composition to light with an accumulated irradiation amount of 900,000 lx·hr. After the exposure, the turbidity of the aqueous ophthalmic composition was measured using a haze meter ("NDH-300A", manufactured by Nippon Denshoku Co., Ltd.).

As is clear from the results in Table 8 above, it was found that excellent photostability can be achieved by combining the three components. In particular, of the three components, chlorpheniramine maleate itself appears to have high photostability, while pranoprofen appears to have low photostability. However, simply combining these components does not improve the photostability of pranoprofen, but rather reduces it drastically. The finding that combining the three components achieved photostability similar to that of chlorpheniramine maleate was extremely surprising.

Test Example 7-2 (Photostability)
In Test Example 7-1, for compositions 7A and 7D which showed a large difference in turbidity, the amount of chlorpheniramine maleate (residual amount) after exposure to a cumulative irradiation amount of 900,000 lx·hr was measured by HPLC (high performance liquid chromatography).

Then, the decomposition rate (%) of chlorpheniramine maleate [100 - remaining rate (%)] was calculated for each of compositions 7A and 7D from the amount of chlorpheniramine maleate after exposure and the amount of chlorpheniramine maleate before exposure, and the decomposition ratio and decomposition inhibition rate were calculated using the following formula, which were 0.529 and 47.08%, respectively.

Decomposition ratio = Decomposition rate of composition 7A (%) / Decomposition rate of composition 7D (%)
Decomposition inhibition rate (%)=[1−decomposition rate of composition 7A (%)/decomposition rate of composition 7D (%)]×100

These results show that the combination of these three components can effectively inhibit the decomposition of chlorpheniramine maleate caused by light.

Test Example 8 (Hypoxic Stress Resistance)
The compositions shown in Table 9 below were dissolved in a culture medium (DMEM/F12, Gibco) to prepare the compositions. Tranilast was dissolved in dimethyl sulfoxide (Wako Pure Chemical Industries, Ltd.) and then dissolved in the culture medium. For compositions not containing tranilast, the same amount of dimethyl sulfoxide as that used when tranilast was dissolved was added.

The hypoxic stress resistance of the obtained composition was evaluated as follows.
Human immortalized corneal epithelial cells (HCE-T) were seeded at 1.6×10 ⁵ cells/well in a 6-well plate (Corning Incorporated) and cultured for 72 hours under conditions of 37° C., 5% CO ₂ and 90% humidity.
According to the compositions in Table 9, chlorpheniramine maleate alone, a combination of pranoprofen and chlorpheniramine maleate, and a combination of each of the components of pranoprofen, chlorpheniramine maleate, and tranilast were added to the cells, and then the cells were cultured under anaerobic conditions at 37°C for 18 hours using Anaeropack Kenki (Mitsubishi Gas Chemical Company, Inc.). The expression level of hGPX1 mRNA, known as an antioxidant gene, was quantified by quantitative real-time PCR using Quant Studio 7 Real-Time PCR System (Applied Biosystems, Inc.).

The test results are shown in Figure 1.
As is clear from the results in Figure 1, the combination of three types of ingredients, pranoprofen, chlorpheniramine maleate, and tranilast (Test Example 8C), showed a significant increase in hGPX1 expression compared to chlorpheniramine maleate alone (Test Example 8A) and the combination of two types of ingredients, pranoprofen and chlorpheniramine maleate (Test Example 8B) (*p<0.05, t-test). In addition, even when the ratio of the three ingredients was changed, a similar hGPX1 expression effect was observed (Test Example 8D). It was revealed that the formulation with a combination of three ingredients has a particularly remarkable effect on enhancing the expression of antioxidant genes compared to the formulations with one and two combinations.

Test Example 9 (Human Sensory Test)
Aqueous ophthalmic compositions (eye drops) having the compositions shown in Table 10 below were prepared, and sensory tests were carried out as follows.

The subjects were five people with hay fever who were experiencing eye symptoms. From the start of the study, eye drops 9A were instilled into the left eye and 9B into the right eye four times a day. During the instillation period, subjects were asked to complete a questionnaire on specific symptoms throughout the day regarding itching and congestion on the first, second, and fifth nights.
The maximum score for the symptom questionnaire was 100 points, with higher scores indicating stronger symptoms. The values were the average of the five subjects.

The results are shown in the table below.

Test Example 9B produced similar or less itching and redness than Test Example 9A.

Test Example 9A contains sodium cromoglycate, which is a formulation that is known to have an effect of improving itching, etc. Therefore, the fact that the value of Test Example 9B was equal to or smaller than that of Test Example 9A means that the combination of tranilast, chlorpheniramine maleate, and pranoprofen is comparable to or better than that of Test Example 9A in terms of the effect of improving itching and congestion, etc.

Test Example 10 (Precipitation Test)
Aqueous ophthalmic compositions (eye drops) having the compositions shown in Table 12 below were prepared, and precipitation was evaluated as follows.

The prepared composition was filled into a screw vial (Maruemu Co., Ltd., No. 3L) and stored at temperatures of 4°C and -2°C for 2 days each. After confirming precipitation, the screw vial was stirred at maximum stirring speed for 10 seconds using a vortex mixer (As One Co., Ltd., Vortex Jenny 2), and the turbidity of the aqueous ophthalmic composition was measured using a haze meter ("NDH-300A", Nippon Denshoku Co., Ltd.).

The results are shown in Table 12 below.
In the table below, the precipitation improvement rate is a value represented by the following formula.

Precipitation improvement rate (%) =
(Turbidity of Test Example 10A−Turbidity of each Test Example)/Turbidity of Test Example 10A×100

As is clear from the results in Table 12 above, it was found that precipitation occurs when polyvinylpyrrolidone (and further monoethanolamine) is added to tranilast (and further when the sodium ion concentration is set to 0). On the other hand, this precipitation increases when diphenhydramine hydrochloride is added, but can be suppressed by coexisting chlorpheniramine maleate or pranoprofen, and can be suppressed particularly when the three components are combined.
In particular, the above test example also contains ingredients such as chlorpheniramine maleate and pranoprofen, but the inclusion of these ingredients does not impair the stability of the formulation, such as precipitation or turbidity, and rather, precipitation and turbidity can be suppressed by combining the three ingredients.

In addition, although the above formulation uses a combination of polyvinylpyrrolidone and monoethanolamine, similar precipitation improvement effects were observed even when polyvinylpyrrolidone was not used, or when trometamol was used instead of polyvinylpyrrolidone and/or monoethanolamine.

Furthermore, according to the inventors' research, when tranilast was combined with monoethanolamine or the like, precipitation sometimes occurred after drying, but in the formulation of the above test example, no precipitation occurred after drying even when these were combined.

Test Example 11 (Precipitation Test)
Aqueous ophthalmic compositions (eye drops) having the compositions shown in Table 13 below were prepared, and precipitation was evaluated as follows.

The prepared composition was filled into a screw vial (No. 3 L, manufactured by Maruemu Co., Ltd.) and stored for 2 days at 4° C. After confirming precipitation, the screw vial was stirred for 10 seconds at maximum stirring speed using a vortex mixer (Vortex Jenny 2, manufactured by AS ONE Co., Ltd.), and 1.5 mL of the composition after stirring was filled into a 1.5 mL sample tube (Neutral micro test tube with cap type, manufactured by Eppendorf Co., Ltd.).
The sample tube was centrifuged at 1000 rpm for 10 minutes, the height (mm) of the accumulated precipitate was measured, and the precipitation improvement rate, represented by the following formula, was calculated.

Precipitation improvement rate (%) = (Y-X)/Y x 100
[In the formula, X is the height of the precipitate in each test example, Y is the height of the precipitate in each test example (blank) in which chlorpheniramine maleate and pranoprofen were not added and the concentrations of each component were the same. The height of the precipitate is shown.]

As is clear from the results in Table 13 above, it was found that precipitation could be effectively suppressed even at other sodium ion concentrations (85 mM, 115 mM), especially when the three components were combined.

Test Example 12 (Precipitation Test)
Aqueous ophthalmic compositions (eye drops) having the compositions shown in Table 14 below were prepared, and precipitation was evaluated in the same manner as in Test Example 11.

As is clear from the results in Table 14 above, it was found that precipitation could be effectively suppressed even if the sodium ion concentration was further increased to 135 mM.

Test Example 13 (Clinical Trial)
Aqueous ophthalmic compositions (eye drops) having the compositions shown in Table 15 below were prepared and subjected to clinical trials as follows.

The eye drops having the formulation shown in Table 15 did not cause problems such as precipitation, as did the formulations of the other test examples mentioned above.

The efficacy and safety of the test formulation was confirmed when 1-2 drops were instilled into the eyes, 4 times a day for 14 days, in patients with mild or moderate allergic conjunctivitis (including hay fever) who were found to have type I allergy through allergy testing and who had subjective symptoms of itchy eyes.

The score of objective findings (follicles in the palpebral conjunctiva) was set as the evaluation item, and the amount of change was measured. The principal investigator or subinvestigator performed a slit lamp examination and judged the severity according to the following. The score was calculated as follows: +++: 3 points, ++: 2 points, +: 1 point, -: 0 point.
3 (severe): 20 or more 2 (moderate): 10-19 1 (mild): 1-9 0 (none): no findings

The degree of improvement for each symptom was assessed using a five-point scale (marked improvement, moderate improvement, mild improvement, unchanged, and worsening) based on the objective findings scores, as shown in Table 16 below. In addition, descriptive statistics were calculated for the amount of change in the objective findings scores.

As a result of the study, among the subjects who had follicular findings in the palpebral conjunctiva from the start to the end of the study, the percentage of subjects whose findings improved to a moderate or greater degree was 66.0%. In addition, the average change in the follicular score in the palpebral conjunctiva was -0.7.
In contrast, it has been reported that the improvement rates of moderate or better improvement for an aqueous ophthalmic solution containing tranilast at a concentration of 5 mg/mL and an aqueous ophthalmic solution containing sodium cromoglycate at a concentration of 20 mg/L were 25.7% and 12.5%, respectively (Clinical Medicine, Vol. 9, No. 3 (March), 1993, pp. 669-683). Also, it has been reported that the improvement rates of moderate or better improvement for an ophthalmic solution containing levogabastine hydrochloride at a concentration of 0.25 mg/mL were 13% and 15.9% after 2 weeks of administration (New Ophthalmology 12(2): 317-332, 333-350, 1995). Furthermore, it has been reported that the average change in palpebral conjunctival follicular score after two weeks of administration of an aqueous eye drop containing 0.05% epinastine hydrochloride was “approximately -0.2” (New Ophthalmology 31(1) 97-104, 2014).

In addition, the rate of moderate or better improvement among subjects who had mild or severe follicles in the palpebral conjunctiva at the start of treatment was 82.5%, and the rate of subjects who had moderate or severe follicles that improved significantly was 100%.

These findings demonstrate that the above formulation is remarkably effective in improving follicles in the palpebral conjunctiva.

In addition, we also examined the improvement of the subjects' subjective symptoms. The subjective symptom scores (watery eyes, foreign body sensation, eye discharge (eye discharge)) were set as shown in Table 17 below, and the amount of change was measured. The scores for the past three days (excluding the day of the examination) were calculated.

The degree of symptom improvement was assessed on a 5-point scale (marked improvement, moderate improvement, mild improvement, unchanged, worsening) based on the average score of subjective symptoms and in accordance with Table 16 above.

As a result, moderate or greater improvement was observed for each subjective symptom, as shown in Table 18. The improvement in these subjective symptoms was particularly high in subjects who had follicles in the palpebral conjunctiva at the start of treatment.

[Formulation example]
Ophthalmic compositions were prepared according to the formulations shown in the following tables, in which the units of each component are (w/v %).

The present invention provides an ophthalmic composition that is useful as an eye drop, etc.

Claims (15)

(A) one or more selected from the group consisting of tranilast and salts thereof,
An ophthalmic composition comprising: (B) one or more selected from the group consisting of chlorpheniramine and its salts; and (C) one or more selected from the group consisting of pranoprofen and its salts,
The ratio of component (B) is 1 to 8 parts by mass and the ratio of component (C) is 5 to 25 parts by mass relative to 100 parts by mass of component (A);
An ophthalmic composition having a sodium ion concentration of 115 mM or less (excluding the compositions (a) to (c) below).
(a) A composition containing 0.05 w/v% pranoprofen, 0.5 w/v% tranilast, 0.1 w/v% allantoin, 0.025 w/v% berberine chloride, 0.01 w/v% cyanocobalamin, 0.01 w/v% sodium pantothenate, and 0.01 w/v% chlorpheniramine maleate. (b) A composition containing tranilast, pranoprofen, dibutylhydroxytoluene, pyridoxine hydrochloride, berberine sulfate, epsilon aminocaproic acid, dipotassium glycyrrhizinate, chlorpheniramine maleate, aminoethylsulfonic acid, panthenol, and potassium aspartate. (c) A composition containing tranilast, pranoprofen, dibutylhydroxytoluene, pyridoxine hydrochloride, sodium azulene sulfonate, dipotassium glycyrrhizinate, allantoin, zinc sulfate, chlorpheniramine maleate, aminoethylsulfonic acid, sodium flavin adenine dinucleotide, panthenol, and potassium aspartate. (A) one or more selected from the group consisting of tranilast and salts thereof,
An ophthalmic composition comprising: (B) one or more selected from the group consisting of chlorpheniramine and its salts; and (C) one or more selected from the group consisting of pranoprofen and its salts,
The composition contains 0.3 to 0.7 w/v% of component (A), 0.007 to 0.04 w/v% of component (B), and 0.03 to 0.15 w/v% of component (C),
An ophthalmic composition having a sodium ion concentration of 115 mM or less (excluding a composition containing 0.5 w/v% of component (A), 0.03 w/v% of component (B), and 0.05 w/v% of component (C)). 3. The ophthalmic composition according to claim 1, wherein the ratio of the components (A), (B) and (C) satisfies any one of the following:
(A) component/(B) component/(C) component (mass ratio) = 100/5 to 7/8 to 12
(A) component / (B) component / (C) component (mass ratio) = 100/5 ~ 7/18 ~ 22
(A) component / (B) component / (C) component (mass ratio) = 100/1 to 3/8 to 12
(A) component / (B) component / (C) component (mass ratio) = 100/1 to 3/18 to 22 (A) one or more selected from the group consisting of tranilast and salts thereof,
An ophthalmic composition comprising: (B) one or more selected from the group consisting of chlorpheniramine and its salts; and (C) one or more selected from the group consisting of pranoprofen and its salts,
The ratio of components (A) to (C) satisfies any one of the following:
An ophthalmic composition having a sodium ion concentration of 115 mM or less.
The proportion of component (A) is 0.4 to 0.6 w/v%, the proportion of component (B) is 0.02 to 0.04 w/v%, and the proportion of component (C) is 0.04 to 0.06 w/v% (excluding the proportions of component (A) 0.5 w/v%, component (B) 0.03 w/v%, and component (C) 0.05 w/v%)
The proportion of component (A) is 0.4-0.6 w/v%, component (B) is 0.013-0.017 w/v%, and component (C) is 0.04-0.06 w/v%. The proportion of component (A) is 0.4-0.6 w/v%, component (B) is 0.013-0.017 w/v%, and component (C) is 0.08-0.12 w/v%. The proportion of component (A) is 0.4-0.6 w/v%, component (B) is 0.008-0.012 w/v%, and component (C) is 0.08-0.12 w/v%. The ophthalmic composition according to any one of claims 1 to 4, which contains at least one selected from polyvinylpyrrolidone, monoethanolamine, and trometamol. The ophthalmic composition according to any one of claims 1 to 5, which contains at least one selected from monoethanolamine and trometamol. The ophthalmic composition according to any one of claims 1 to 6, wherein the sodium ion concentration is 85 mM or less, or the ratio of sodium ions is 5.7 moles or less per mole of component (A). The ophthalmic composition according to any one of claims 1 to 7, wherein the sodium ion concentration is 20 mM or less. The ophthalmic composition according to any one of claims 1 to 8, having a pH of 5.5 to 8.5. The ophthalmic composition according to any one of claims 1 to 9, which is used for alleviating, improving, suppressing, and/or treating allergic symptoms. The ophthalmic composition according to any one of claims 1 to 10, which is used for alleviating, improving, suppressing, and/or treating at least one symptom selected from itchy eyes, bloodshot eyes, watery eyes, foreign body sensation, and eye discharge. (A) one or more selected from the group consisting of tranilast and salts thereof,
The present invention relates to a method for improving, improving, imparting and/or expressing at least one property selected from (1) preservative effectiveness, (2) photostability and (3) oxygen stress resistance in an ophthalmic composition, comprising adding one or two remaining properties not selected from the group consisting of (A), (B) and (C) to an ophthalmic composition comprising one or two properties selected from the group consisting of (B) chlorpheniramine and salts thereof, and (C) pranoprofen and salts thereof,
A method for preparing an ophthalmic composition, comprising the steps of: (a) providing an ophthalmic composition having a sodium ion concentration of 115 mM or less; and (b) satisfying the following (a) or (b):
(a) The ratio of component (B) is 1 to 8 parts by mass and the ratio of component (C) is 5 to 25 parts by mass relative to 100 parts by mass of component (A). (b) The ratio of component (A) is 0.3 to 0.7 w/v%, the ratio of component (B) is 0.007 to 0.04 w/v%, and the ratio of component (C) is 0.03 to 0.15 w/v% (excluding the cases where the ratio of component (A) is 0.5 w/v%, the ratio of component (B) is 0.03 w/v%, and the ratio of component (C) is 0.05 w/v%). (A) one or more selected from the group consisting of tranilast and salts thereof,
An agent for enhancing, improving, imparting and/or expressing at least one selected from (1) preservative effectiveness, (2) photostability and (3) oxygen stress resistance in an ophthalmic composition comprising one or two components selected from the group consisting of (B) one or more components selected from the group consisting of chlorpheniramine and salts thereof, and (C) one or more components selected from the group consisting of pranoprofen and salts thereof, the agent comprising the remaining one or two components not selected from among components (A), (B) and (C), wherein the ophthalmic composition has a sodium ion concentration of 115 mM or less and satisfies the following (a) or (b).
(a) The ratio of component (B) is 1 to 8 parts by mass and the ratio of component (C) is 5 to 25 parts by mass relative to 100 parts by mass of component (A). (b) The ratio of component (A) is 0.3 to 0.7 w/v%, the ratio of component (B) is 0.007 to 0.04 w/v%, and the ratio of component (C) is 0.03 to 0.15 w/v% (excluding the cases where the ratio of component (A) is 0.5 w/v%, the ratio of component (B) is 0.03 w/v%, and the ratio of component (C) is 0.05 w/v%). The method according to claim 12 , except when the ophthalmic composition is any one of the following compositions (a) to (c):
(a) A composition containing 0.05 w/v% pranoprofen, 0.5 w/v% tranilast, 0.1 w/v% allantoin, 0.025 w/v% berberine chloride, 0.01 w/v% cyanocobalamin, 0.01 w/v% sodium pantothenate, and 0.01 w/v% chlorpheniramine maleate. (b) A composition containing tranilast, pranoprofen, dibutylhydroxytoluene, pyridoxine hydrochloride, berberine sulfate, epsilon aminocaproic acid, dipotassium glycyrrhizinate, chlorpheniramine maleate, aminoethylsulfonic acid, panthenol, and potassium aspartate. (C) A composition containing tranilast, pranoprofen, dibutylhydroxytoluene, pyridoxine hydrochloride, sodium azulene sulfonate, dipotassium glycyrrhizinate, allantoin, zinc sulfate, chlorpheniramine maleate, aminoethylsulfonic acid, sodium flavin adenine dinucleotide, panthenol, and potassium aspartate. The method according to claim 12 or 14 , wherein the proportions of components (A) to (C) in the ophthalmic composition satisfy any one of the following:
Percentage of component (A) 0.4-0.6 w/v%, component (B) 0.02-0.04 w/v%, and component (C) 0.04-0.06 w/v% Percentage of component (A) 0.4-0.6 w/v%, component (B) 0.013-0.017 w/v%, and component (C) 0.04-0.06 w/v% Percentage of component (A) 0.4-0.6 w/v%, component (B) 0.013-0.017 w/v%, and component (C) 0.08-0.12 w/v% Percentage of component (A) 0.4-0.6 w/v%, component (B) 0.013-0.017 w/v%, and component (C) 0.08-0.12 w/v% Percentage of component (A) 0.4-0.6 w/v%, component (B) 0.008-0.012 w/v%, and component (C) 0.08-0.12 w/v%