Ophthalmic components

Abstract

To provide a novel ophthalmic composition. [Solution] The ophthalmic composition is composed of (A) one or more selected from the group consisting of tranilast and its salts, (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. In such a composition, the ratio of component (B) to 100 parts by mass of component (A) may be 1 to 8 parts by mass, and the ratio of component (C) may be 5 to 25 parts by mass.

Description

Technical Field

[0001] The present invention relates to an ophthalmic composition (or an ophthalmic preparation).

Background Art

[0002] Ophthalmic compositions such as eye drops contain various components depending on their purposes. On the other hand, tranilast is known to be effective for treating allergy-induced diseases and the like, and cases of its use in ophthalmic compositions have also been reported. In ophthalmic compositions containing such tranilast, techniques for combining tranilast with other components are currently being developed for purposes such as improving efficacy and exploring new functions. For example, Japanese Unexamined Patent Application Publication No. 2014-234368 (Patent Document 1) describes that an eye drop containing tranilast and specific components (an anti-inflammatory agent, a water-soluble vitamin, and a cooling agent) is effective for enhancing the corneal epithelial barrier function.

Prior Art Literature

Patent Literature

[0003]

Patent Document 1

Summary of the Invention

Problem to be Solved by the Invention

[0004] An object of the present invention is to provide a novel ophthalmic composition.

Means for Solving the Problem

[0005] As described above, the technique of including tranilast in eye drops is already known per se. On the other hand, various components other than tranilast are known as components to be included in eye drops, and chlorpheniramine maleate and pranoprofen are among such components. However, while there have been reports of these ingredients being used individually or in combination with certain other ingredients, there are no reports of specific combinations of these ingredients.

[0006] In this context, the inventors of the present invention were investigating formulations for tranilast, chlorpheniramine maleate, and pranoprofen, and discovered that there were previously unknown problems when these were used individually or in combination. For example, during the investigation, it was confirmed that these substances did not have sufficient preservative efficacy when used alone, that pranoprofen's photostability was insufficient, and that its photostability did not improve even when combined with chlorpheniramine maleate.

[0007] Based on these findings, the inventors conducted further investigations and discovered that by selecting three specific substances—tranilast, chlorpheniramine maleate, and pranoprofen—which are known individually or in combinations of two, but for which no specific combinations have been reported, it was possible to obtain a composition with sufficient preservative efficacy and photostability as described above, thus completing the present invention.

[0008] In other words, the present invention provides, for example, the following inventions. [1] (A) One or more selected from the group consisting of tranilast and its salts, (B) One or more selected from the group consisting of chlorpheniramine and its salts, (C) Contains one or more selected from the group consisting of pranoprofen and its salts, An ophthalmic composition in which 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 per 100 parts by mass of component (A). [2] (A) One or more selected from the group consisting of tranilast and its salts, (B) One or more selected from the group consisting of chlorpheniramine and its salts, (C) A composition containing one or more selected from the group consisting of pranoprofen and its salts, An ophthalmic composition containing component (A) at a ratio of 0.3-0.7 w / v%, component (B) at a ratio of 0.007-0.04 w / v%, and component (C) at a ratio of 0.03-0.15 w / v%. [3] The ophthalmic composition according to [1] or [2], wherein the ratio of component (A), component (B), and component (C) satisfies any of the following conditions. (A) component / (B) component / (C) component (mass ratio) = 100 / 5~7 / 8~12 (A) component / (B) component / (C) component (mass ratio) = 100 / 5~7 / 18~22 (A) component / (B) component / (C) component (mass ratio) = 100 / 1~3 / 8~12 (A) component / (B) component / (C) component (mass ratio) = 100 / 1~3 / 18~22 [4] An ophthalmic composition according to any of [1] to [3], wherein the proportion of components (A) to (C) satisfies any of the following conditions. The proportion of components where component (A) is 0.4-0.6 w / v%, component (B) is 0.02-0.04 w / v%, and component (C) is 0.04-0.06 w / v%. The proportion of components (A) at 0.4-0.6 w / v%, (B) at 0.02-0.04 w / v%, and (C) at 0.08-0.12 w / v%. The proportion of components where 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 components (A) at 0.4-0.6 w / v%, (B) at 0.013-0.017 w / v%, and (C) at 0.08-0.12 w / v%. The proportion of components where component (A) is 0.4-0.6 w / v%, component (B) is 0.008-0.012 w / v%, and component (C) is 0.04-0.06 w / v%. The proportion of components where 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%. [5] The ophthalmic composition according to any one of [1] to [4], comprising at least one selected from 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 proportion of sodium ions is 25 mol or less per 1 mol of 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 proportion of sodium ions is 20 mol or less per 1 mol of 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 alleviating, improving, suppressing and / or treating at least one symptom selected from eye itching, hyperemia, watery eyes, foreign body sensation and eye discharge.

[11] A method for enhancing, improving, imparting and / or expressing at least one selected from (1) preservative efficacy, (2) photostability and (3) oxygen stress resistance in an ophthalmic composition, comprising adding the remaining one or two components to an ophthalmic composition comprising one or two components selected from component (A), component (B) and component (C) according to [1].[

[12] An agent for enhancing, improving, imparting and / or expressing at least one selected from (1) preservative efficacy, (2) photostability and (3) oxygen stress resistance in an ophthalmic composition comprising one or two components selected from component (A), component (B) and component (C) according to [1], wherein the agent comprises the remaining one or two components. Advantageous Effects of Invention

[0009] According to the present invention, a novel ophthalmic composition can be provided. Such an ophthalmic composition contains specific components (A), (B) and (C), and can achieve effects such as increasing or improving specific functions (e.g., preservative efficacy, stability, etc.) compared to, for example, cases where these components are used alone or in a combination of two components. For example, in another aspect of the present invention, an ophthalmic composition having resistance to oxygen stress (hypoxic stress) (or not impairing hypoxic stress resistance) can also be obtained. It has been pointed out that oxygen stress is associated with cytotoxicity and various diseases and conditions (dry eye, cataract, etc.), and it is useful to be able to provide an ophthalmic composition that has or does not impair hypoxic stress resistance.

[0010] In another aspect of the ophthalmic composition of the present invention, even when specific components are contained in combination, the respective functions and medicinal effects can be effectively exerted, and in some cases higher functions can be achieved.

[0011] In the ophthalmic composition according to another aspect of the present invention, precipitation can be suppressed. In particular, such precipitation inhibition effect is often excellent at low temperatures (e.g., 10°C or lower, preferably 5°C or lower), and precipitation can be suppressed even at 0°C or lower. Therefore, the ophthalmic composition of the present invention can achieve dissolution stability not only when stored at a low temperature such as in a refrigerator, but also under environments exposed to lower temperatures (e.g., storage in cold regions, cases with drastic temperature changes, etc.).

[0012] As described above, the composition of the present invention is extremely highly practical. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] [Figure 1] Figure 1 is a graph showing the results of Test Example 8. MODES FOR CARRYING OUT THE INVENTION

[0014] In this specification, the unit of content "w / v%" is synonymous with "g / 100mL". Furthermore, unless otherwise specified, the abbreviation "POE" means polyoxyethylene, and the abbreviation "POP" means polyoxypropylene.

[0015] [1. Ophthalmic composition] The ophthalmic composition of the present invention contains at least one 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.

[0016] (A) Tranilast and / or salts thereof (Component (A)) The salts of tranilast can be any salt that is pharmaceutically or physiologically acceptable, such as organic acid salts [e.g., monocarboxylic acid salts (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polycarboxylic acid salts (fumarate, maleate, succinate, malonate, etc.), oxycarboxylic acid salts (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, etc.), and salts with inorganic bases [e.g., ammonium salts; salts with metals such as alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), and aluminum].

[0017] Furthermore, the sodium salt of tranilast is included in the sodium ions described below. Therefore, if 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.

[0018] Preferred tranilast and / or its salts include tranilast and non-sodium salts of tranilast. More preferred tranilast and / or its salts include tranilast and non-metallic salts of tranilast, with tranilast being particularly preferred.

[0019] Tranilast and / or its salts may be used alone or in combination of two or more.

[0020] 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% relative to the total amount of the composition. Among these, 0.3 to 0.7 w / v% (for example, 0.4 to 0.6 w / v%) is preferred, and 0.45 to 0.55 w / v% (such as 0.5 w / v%) is particularly preferred.

[0021] (B) Chlorpheniramine and / or its salt (Component (B)) The salt of chlorpheniramine can be any salt that is pharmaceutically or physiologically acceptable, such as organic salts (e.g., maleates, fumarates, etc.), inorganic salts (e.g., hydrochlorides, sulfates, etc.), and metal salts, as exemplified in section (A).

[0022] Note that sodium salts are included in the sodium ions described later. Therefore, if component (B) contains sodium salts, sodium salts may be used so that the sodium ion concentration in the entire composition falls within the range described later.

[0023] Preferred chlorpheniramine and / or salts thereof include chlorpheniramine and its nonmetallic salts (such as non-sodium salts), with chlorpheniramine maleate being particularly preferred.

[0024] Chlorpheniramine and / or its salts may be used alone or in combination of two or more.

[0025] 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 around 0.028~0.045 w / v%, with a preference for 0.007~0.04 w / v% (e.g., 0.008~0.035 w / v%, particularly 0.01~0.03 w / v%), and specifically, 0.008~0.012 w / v% (particularly 0.01 w / v%), 0.013~0.017 w / v% (particularly 0.015 w / v%), 0.02~0.04 w / v% (particularly 0.03 w / v%), etc.

[0026] (C) Pranoprofen and / or salts thereof ((C) component) The salt of pranoprofen can be any pharmaceutically or physiologically acceptable salt, such as the salts exemplified in section (A) above, including salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases. Examples include sulfates, lactates, hydrochlorides, chlorides, sodium salts, and potassium salts. Preferred pranoprofen and / or salts thereof are pranoprofen and its nonmetallic salts (such as non-sodium salts), with pranoprofen being particularly preferred.

[0027] Pranoprofen and / or its salts may be used alone or in combination of two or more.

[0028] 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% (for example, 0.015 to 0.25 w / v%), and most preferably, relative to the total amount of the composition. It may be as low as 0.02-0.2 w / v% (for example, 0.025-0.18 w / v%), with 0.03-0.15 w / v% (for example, 0.04-0.12 w / v%, particularly 0.05-0.1 w / v%) being preferred. Specifically, it may be 0.04-0.06 w / v% (particularly 0.05 w / v%), 0.08-0.12 w / v% (particularly 0.1 w / v%), etc.

[0029] (A) ~ (C) Percentage between components The proportion of component (B) may be, 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), and particularly preferably 1 to 8 parts by mass (e.g., 1.2 to 7.5 parts by mass) per 100 parts by mass of component (A), with 1.5 to 7 parts by mass (e.g., 2 to 6 parts by mass) being the most preferred. 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.

[0030] The proportion of component (C) 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) per 100 parts by mass of component (A), with 8 to 22 parts by mass (e.g., 10 to 20 parts by mass) being preferred, and more 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.

[0031] The proportion of component (B) 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) per 100 parts by mass of component (C), with 15 to 65 parts by mass (e.g., 20 to 60 parts by mass) being the most preferred, and specifically 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.

[0032] The ratio of the total amount of component (B) and component (C) 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) per 100 parts by mass of component (A), with 10 to 35 parts by mass (e.g., 16 to 30 parts by mass) being the most preferred, and more 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.

[0033] The ratio of component (A), component (B), and component (C) may be, for example, (A) / (B) / (C) (mass ratio) = 100 / 0.1~100 / 0.5~200 (for example, 100 / 0.2~50 / 1~100), preferably 100 / 0.3~30 / 2~80, more preferably 100 / 0.5~20 / 3~50, and particularly preferably 100 / 0.8~10 / 4~30, with 100 / 1~8 / 5~25 (for example, 100 / 2~6 / 10~20) being preferred, specifically 100 / 5~7 / 8~12 (for example, 100 / 5.5~6.5 / 9~11, particularly 100 It may also be 100 / 6 / 10), 100 / 5~7 / 18~22 (for example, 100 / 5.5~6.5 / 19~21, especially 100 / 6 / 20), 100 / 2~4 / 8~12 (for example, 100 / 2.5~3.5 / 9~11, especially 100 / 3 / 10), 100 / 2~4 / 18~22 (for example, 100 / 2.5~3.5 / 19~21, especially 100 / 3 / 20), 100 / 1~3 / 8~12 (for example, 100 / 1.5~2.5 / 9~11, especially 100 / 2 / 10), 100 / 1~3 / 18~22 (for example, 100 / 1.5~2.5 / 19~21, especially 100 / 2 / 20), etc.

[0034] [Other ingredients] The composition of the present invention may contain other components in addition to components (A) to (C). In the present invention, the effects of the present invention can often be guaranteed even if other components are included. Furthermore, in some cases, the effects of the present invention can be realized more effectively by including other components.

[0035] (D) Solubilizer (Component (D)) Component (A) is usually poorly soluble in water. Therefore, the composition of the present invention may contain a component (component (D)) to promote or assist in the dissolution of component (A). Such component (D) can also be called a solubilizer or dissolving aid.

[0036] (D) The components are not particularly limited, but examples include polyvinylpyrrolidone (PVP), hydroxyalkylamines (or aminoalkanols or alkanolamines, such as monoethanolamine, diethanolamine, triethanolamine, trometamol, etc.), alcohols (such as polyols like propylene glycol), and caffeine.

[0037] Polyvinylpyrrolidone (PVP) is a polymer whose polymerization component is vinylpyrrolidone (N-vinyl-2-pyrrolidone).

[0038] The molecular weight of such polyvinylpyrrolidone is not particularly limited, but may be, for example, 1000 or more (e.g., 1500 to 3000000), preferably 2000 or more (e.g., 2500 to 2000000), more preferably 3000 or more (e.g., 4000 to 1000000), particularly preferably 5000 or more (e.g., 6000 to 300000), or even 200000 or less (e.g., 2500 to 100000, preferably 5000 to 80000, more preferably 10000 to 50000, particularly preferably 15000 to 40000, most preferably 20000 to 30000).

[0039] Representative polyvinylpyrrolidones include polyvinylpyrrolidone K25, K30, and K90.

[0040] (D) Component may be used alone or in combination of two or more types.

[0041] Of these, polyvinylpyrrolidone and hydroxyalkylamines (e.g., monoethanolamine, trometamol) are preferred, and polyvinylpyrrolidone and monoethanolamine are particularly preferred.

[0042] 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).

[0043] 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%, relative to the total amount of the composition, or 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%).

[0044] In particular, if the composition contains polyvinylpyrrolidone, the polyvinylpyrrolidone content in the composition may be, for example, 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 especially preferably about 0.7 to 4 w / v% (e.g., 1 to 3 w / v%) relative to the total amount of the composition.

[0045] 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 preferably 0.05 to 8 parts by mass, per 1 part by mass of component (A), or it may be around 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).

[0046] When combining polyvinylpyrrolidone with hydroxyalkylamines (for example, at least one selected from monoethanolamine and trometamol), the ratio of hydroxyalkylamines to 100 parts by mass of polyvinylpyrrolidone can be selected from a range of about 0.01 to 1000 parts by mass, for example, 0.1 to 500 parts by mass (for example, 0.2 to 300 parts by mass), preferably 0.3 to 250 parts by mass (for example, 0.4 to 220 parts by mass), more preferably 0.5 to 200 parts by mass (for example, 1 to 180 parts by mass), particularly preferably 2 to 150 parts by mass (for example, 2.5 to 120 parts by mass), or even about 3 to 100 parts by mass.

[0047] (E) Amino acids The composition of the present invention may contain amino acids (sometimes referred to as component (E), etc.). Examples of amino acids include amino acids or their salts, and amino acid analogs, as well as compounds or derivatives thereof that have an amino group and a carboxyl group or a sulfone group in their molecule.

[0048] Specifically, examples include amino acids or their salts, and mucopolysaccharides or their salts. Among amino acids, examples of amino acids or their salts include monoaminomonocarboxylic acids such as glycine, alanine, aminobutyric acid, aminovaleric acid, and aminocaproic acid; monoaminodicarboxylic acids such as aspartic acid and glutamic acid or their salts; diaminomonocarboxylic acids such as arginine and lysine or their salts; and derivatives such as aminoethylsulfonic acid (taurine) or their salts.

[0049] Furthermore, among amino acids, examples of mucopolysaccharides or their derivatives or salts include acidic mucopolysaccharides such as chondroitin sulfate, hyaluronic acid, alginic acid, and their derivatives or salts.

[0050] Specific examples of 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.

[0051] Chondroitin sulfate is formed by esterifying sulfuric acid to all or part of the hydroxyl groups of the repeating sugar chains of D-glucuronic acid and N-acetylglucosamine. The position and number of sulfuric acid bonds vary, and derivatives of chondroitin sulfate also exist (for example, in which all or part of N-acetylglucosamine is replaced with iduronic acid). Such chondroitin sulfates 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 4th and 6th positions of N-acetylglucosamine are sulfated. Furthermore, chondroitin sulfates may be extracted from animals.

[0052] The salts of amino acids or mucopolysaccharides include salts that are pharmaceutically, pharmacologically, or physiologically acceptable. Examples of such salts include salts with organic acids [e.g., monocarboxylates (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polycarboxylic acids (fumarate, maleate, etc.), oxycarboxylates (lactate, tartrate, citrate, succinate, malonate, etc.), organic sulfonates (methanesulfonate, toluenesulfonate, tosylate, etc.)], salts with inorganic acids (e.g., hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), salts with organic bases (e.g., salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.), and salts with inorganic bases [e.g., ammonium salts; salts with metals such as alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), and aluminum, etc.], etc.], and are appropriately selected depending on the compound.

[0053] Specific examples of salts include salts of aspartic acid (sodium aspartate, potassium aspartate, magnesium aspartate, magnesium-potassium aspartate mixture, etc.), salts of glutamic acid (sodium glutamate, magnesium glutamate, etc.), sodium chondroitin sulfate, and sodium hyaluronate.

[0054] Note that sodium salts are included in the sodium ions described later. Therefore, if 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 later.

[0055] The amino acids may be in D, L, or DL ​​form.

[0056] Preferred amino acids include aminoethylsulfonic acid (taurine) or its salts, chondroitin sulfate sodium, aspartates (e.g., L-potassium aspartate, L-magnesium potassium aspartate), epsilonaminocaproic acid or its salts, hyaluronic acid or its salts (such as sodium hyaluronate), and among these, aminoethylsulfonic acid (taurine) and / or its salts and chondroitin sulfate sodium are preferred, with aminoethylsulfonic acid (taurine) being the most preferred.

[0057] Therefore, the amino acids may contain at least one selected from the group consisting of aminoethylsulfonic acid and its salts (in particular, aminoethylsulfonic acid). Using these amino acids (such as taurine) is expected to promote the healing of damaged corneal epithelial cells.

[0058] In such cases, the proportion of one or more aminoethylsulfonic acid and its salts (particularly aminoethylsulfonic acid) selected from the group consisting of aminoethylsulfonic acid and its salts 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.

[0059] Amino acids may be used individually or in combination of two or more types.

[0060] If 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 around 0.15 to 7 w / v%, with respect to the total amount of the composition, 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 0.6 to 6 w / v% (for example, 0.7 to 5 w / v%)].

[0061] (F) Cooling agent ((F) ingredient) The composition of the present invention may contain a cooling agent (hereinafter referred to as (F) cooling agent, (F) component, etc.). Combining components (A), (B), and (C) may reduce or impair the user experience, but a cooling agent can improve or enhance this experience. For example, while increasing the pH of the composition may be advantageous in terms of dissolving component (A) (tranilast), a higher pH can lead to increased discomfort and impaired user experience. However, the use of a cooling agent can alleviate this discomfort and efficiently improve the user experience.

[0062] The cooling agent is not particularly limited, but examples include terpenoids such as menthol, anethole, eugenol, camphor, geraniol, cineole, borneol, limonene, and bonito flakes. These may be in d, l, or dl form. Essential oils such as peppermint oil, cool mint oil, spearmint oil, fennel oil, cinnamon oil, bergamot oil, eucalyptus oil, and rose oil can also be used.

[0063] Among these, terpenoids are preferred, and among these, menthol, camphor, geraniol, cineole, borneol, and liquor are preferred, menthol, camphor, and borneol are more preferred, and menthol and borneol are even more preferred. Furthermore, eucalyptus oil is also preferred from the viewpoint of achieving the effects of the present invention more significantly.

[0064] The cooling agent may be used alone or in combination of two or more. In particular, it is preferable that the cooling agent includes one or more selected from the group consisting of menthol, borneol, and eucalyptus oil, and when two or more are used in combination, it is preferable to use at least these (for example, a combination of menthol, borneol, and eucalyptus oil).

[0065] The proportion of component (F) 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, relative to the total amount of the composition.

[0066] Furthermore, 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, relative to the total amount of the composition.

[0067] In particular, if the composition of the present invention contains menthol, the proportion of menthol may be, for example, 0.00001 w / v% or more (e.g., 0.00005 to 2 w / v%), preferably 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 0.0001 parts by mass or more (for example, 0.0003 to 0.5 parts by mass), preferably 0.0005 to 0.1 parts by mass (for example, 0.0007 to 0.08 parts by mass), and more preferably about 0.001 to 0.05 parts by mass (for example, 0.002 to 0.04 parts by mass) per 1 part by mass of component (A). The proportion of menthol may be 0.0001 parts by mass or more (for example, 0.0005 to 2 parts by mass), preferably 0.001 to 1 part by mass (for example, 0.003 to 0.7 parts by mass), and more preferably about 0.005 to 0.5 parts by mass (for example, 0.01 to 0.4 parts by mass) per 1 part by mass of component (C).

[0068] In particular, when the composition of the present invention contains borneol, the proportion of borneol may be, for example, 0.00001 w / v% or more (e.g., 0.00005 to 3 w / v%), preferably 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 0.0001 parts by mass or more (for example, 0.0003 to 3 parts by mass), preferably 0.0005 to 2 parts by mass (for example, 0.0007 to 1.5 parts by mass), and more preferably about 0.001 to 1.2 parts by mass (for example, 0.002 to 1 part by mass) per 1 part by mass of component (A). The proportion of borneol may be 0.0001 parts by mass or more (for example, 0.0005 to 30 parts by mass), preferably 0.001 to 20 parts by mass (for example, 0.003 to 15 parts by mass), and more preferably 0.005 to 12 parts by mass (for example, 0.01 to 10 parts by mass), per 1 part by mass of component (C).

[0069] In particular, if the composition of the present invention contains eucalyptus oil, the proportion of eucalyptus oil may be, for example, 0.00001 w / v% or more (e.g., 0.00005 to 1 w / v%), preferably 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 0.0001 parts by mass or more (for example, 0.0003 to 0.3 parts by mass), preferably 0.0005 to 0.05 parts by mass (for example, 0.0007 to 0.04 parts by mass), and more preferably about 0.001 to 0.03 parts by mass (for example, 0.002 to 0.02 parts by mass) per 1 part by mass of component (A). The proportion of eucalyptus oil may be 0.0001 parts by mass or more (for example, 0.0005 to 1 part by mass), preferably 0.001 to 0.5 parts by mass (for example, 0.003 to 0.3 parts by mass), and more preferably about 0.005 to 0.3 parts by mass (for example, 0.01 to 0.2 parts by mass) per 1 part by mass of component (C).

[0070] (G) Lipid-soluble antioxidant ((G) component) The composition of the present invention may contain a lipid-soluble antioxidant (hereinafter referred to as (G) lipid-soluble antioxidant, (G) component, etc.).

[0071] Examples of lipid-soluble antioxidants include butyl group-containing phenols such as dibutylhydroxytoluene (BHT) and butylhydroxyanisole (BHA); nordihydroguaiaretic acid (NDGA); ascorbic acid esters such as ascorbic acid palmitate, ascorbic acid stearate, aminopropyl ascorbic acid phosphate, tocopherol ascorbic acid phosphate, ascorbic acid triphosphate, and ascorbic acid phosphate palmitate; gallic acid esters such as ethyl gallate, propyl gallate, octyl gallate, and dodecyl gallate; propyl gallate; 3-butyl-4-hydroxyquinoline-2one; carotenoids such as lutein and astaxanthin; polyphenols such as anthocyanins, catechins, tannins, and curcumin; and CoQ10.

[0072] Of these, dibutylhydroxytoluene is preferred. On the other hand, the composition of the present invention may not contain BHT.

[0073] Lipid-soluble antioxidants may be used alone or in combination of two or more types.

[0074] The content of component (G) in the composition may be, for example, 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%, relative to the total amount of the composition.

[0075] (H) Antiallergic agent ((H) component) The composition of the present invention may contain an anti-allergic agent (hereinafter referred to as (H) anti-allergic agent, (H) component, etc.).

[0076] Examples of antiallergic agents (other than tranilast and / or its salts) include cromoglycic acid, ibudilast, acitazanollast, tazanollast, suplatast, pemirolast, levocabastine, olopatadine, ketotifen, anlexanox, oxatomide, and their salts.

[0077] Examples of salts include those exemplified in sections (A) to (C) above, such as alkali metal or alkaline earth metal salts (e.g., sodium cromoglycate, potassium cromoglycate, magnesium cromoglycate, calcium cromoglycate), inorganic salts (e.g., olopatadine hydrochloride), and organic salts [e.g., tosylates, fumarates (e.g., ketotifen fumarate)].

[0078] Of these, cromoglycic acid and its salts are preferred, and sodium cromoglycate is more preferred.

[0079] Antiallergic agents may be used alone or in combination of two or more types.

[0080] The content of component (H) in the composition may be, for example, 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 preferably 0.8 to 1.5 w / v%, and most preferably 0.9 to 1.2 w / v%, relative to the total amount of the composition.

[0081] (I) Antihistamines The composition of the present invention may contain an antihistamine (hereinafter referred to as (I) antihistamine, (I) component, etc.). Antihistamines (antihistamines other than chlorpheniramine and / or its salts) are not particularly limited as long as they are substances that have antihistamine activity, and examples include diphenhydramine, epinastine, ketotifen, olopatadine, levocabastine, iproheptine and their salts.

[0082] The salt can be any pharmaceutically or physiologically acceptable salt, such as organic salts (e.g., maleates, fumarates, etc.), inorganic salts (e.g., hydrochlorides, sulfates, etc.), and metal salts, as exemplified in section (A).

[0083] Specific examples of salts include diphenhydramine hydrochloride and iproheptin hydrochloride.

[0084] Antihistamines may be used alone or in combination of two or more types.

[0085] If 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%), most preferably 0.025 to 0.05 w / v% (e.g., 0.03 w / v%), and usually around 0.01 to 0.05 w / v%.

[0086] (J) Anti-inflammatory agents The composition of the present invention may contain an anti-inflammatory agent (hereinafter referred to as (J) anti-inflammatory agent, (J) component, etc.). Anti-inflammatory agents (anti-inflammatory agents other than pranoprofen and / or its salts) are not particularly limited as long as they are substances that have anti-inflammatory effects, and examples include indomethacin, allantoin, berberine, azulene sulfonic acid, diclofenac, bromfenac, glycyrrhizic acid, zinc, silver, tranexamic acid, lysozyme and their salts.

[0087] Examples of salts include those exemplified in section (A) above, such as salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases. Examples include sulfates, lactates, hydrochlorides, chlorides, sodium salts, and potassium salts.

[0088] Specific examples of salts include berberine sulfate, berberine chloride, dipotassium glycyrrhizinate, sodium azulene sulfonate, diclofenac sodium, bromfenac sodium, zinc sulfate, zinc lactate, silver nitrate, and lysozyme chloride.

[0089] Anti-inflammatory agents may be used alone or in combination of two or more. Furthermore, the ophthalmic composition of the present invention may not substantially contain glycyrrhizic acid and its salts.

[0090] If the composition contains component (J), the content of component (J) 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 0.07 w / v% (e.g., 0.05 w / v%) relative to the total amount of the composition.

[0091] The composition of the present invention may contain various components (for example, components not belonging to the categories of components (A) to (J) above). Examples of such components (additives) include surfactants, preservatives, buffering agents, pH adjusters, isotonic agents, thickeners or viscosity modifiers, stabilizers, oils, sugars, polymer compounds, polyhydric alcohols, inorganic salts, non-lipid soluble antioxidants (or water-soluble antioxidants).

[0092] Additives can be used individually or in combination of two or more. Furthermore, each additive can be used individually or in combination of two or more.

[0093] Specific examples of additives are given below.

[0094] surfactants The composition of the present invention may contain a surfactant. Examples of surfactants include non-ionic surfactants.

[0095] 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 POE·POP glycols such as -403, poloxamer 237, poloxamer 124; POE hydrogenated castor oils such as POE hydrogenated castor oil 40, POE hydrogenated castor oil 50, POE hydrogenated castor oil 60, 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, POE castor oil 50; polymonostearate 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 include polyethylene glycol monostearate such as 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 alkylphenyl ethers such as POE(10) nonylphenyl ether.In the compounds exemplified above, POE stands for polyoxyethylene, POP stands for polyoxypropylene, and the numbers in parentheses indicate the number of moles added.

[0096] 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, polysorbate 80 and POE hydrogenated castor oil 60 being even more preferred, and polysorbate 80 being particularly preferred.

[0097] Surfactants may be used alone or in combination of two or more types. Furthermore, the composition of the present invention may not substantially contain POE hydrogenated castor oil or POE castor oil.

[0098] 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, relative to the total amount of the composition.

[0099] Furthermore, the proportion of 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.

[0100] Preservatives The composition of the present invention may contain a preservative. Examples of preservatives include polydronium chloride, alkyl polyaminoethylglycines (e.g., alkyldiaminoethylglycine hydrochloride), sodium benzoate, ethanol, quaternary ammonium salts (e.g., benzalkonium chloride, benzethonium chloride), chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, parahydroxybenzoic acid esters (e.g., methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate), oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (e.g., polyhexanide hydrochloride), and Glokill (manufactured by Rhodia).

[0101] Among these, alkyl polyaminoethylglycines (e.g., alkyldiaminoethylglycine hydrochloride), sodium benzoate, ethanol, quaternary ammonium salts, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, parahydroxybenzoic acid esters, and biguanide compounds are preferred, quaternary ammonium salts, chlorhexidine gluconate, chlorobutanol, and biguanide compounds are more preferred, and benzalkonium chloride and polyhexanide hydrochloride are even more preferred.

[0102] On the other hand, the composition of the present invention does not necessarily have to contain sorbic acid and its salts (such as potassium sorbate).

[0103] When a preservative is added to the composition of the present invention, examples of the amount to be added include a total amount of preservative of 0.000001 w / v% or more, more specifically 0.00001 w / v% or more, more specifically 0.00005 w / v% or more, more specifically 0.001 w / v% or more, and more specifically 0.005 w / v% or more, relative to the total amount of the composition. Alternatively, a total amount of preservative of 1 w / v% or less, more specifically 0.1 w / v% or less, more specifically 0.05 w / v% or less, more specifically 0.03 w / v% or less, and more specifically 0.025 w / v% or less, relative to the total amount of the composition.

[0104] cushioning agent The composition of the present invention may contain a buffering agent. Examples of buffering agents include boric acid buffers, phosphate buffers, carbonate buffers, citrate buffers, and acetate buffers.

[0105] The components of boric acid buffers include boric acid and borates (such as sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, and borax). The borates may also be in hydrate form.

[0106] Components of phosphate buffers include phosphoric acid and phosphates (such as disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, and calcium dihydrogen phosphate). The phosphates may also be in hydrate form.

[0107] The components of a carbonate buffer include carbonic acid and carbonates (potassium carbonate, sodium carbonate, calcium carbonate, potassium bicarbonate, sodium bicarbonate, magnesium carbonate, etc.). The carbonate may also be in hydrate form.

[0108] The components of citrate buffers include citric acid and citrate salts (such as sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, and disodium citrate). The citrate salts may also be in hydrate form.

[0109] Components of acetic acid buffers include acetic acid and acetates (such as ammonium acetate, potassium acetate, calcium acetate, and sodium acetate). The acetates may also be in hydrate form.

[0110] Among these, boric acid buffers and phosphate buffers are preferred, with boric acid buffers being more preferred. As for 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 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.

[0111] When a buffering agent is incorporated into the composition of the present invention, the amount of buffering agent to be incorporated will vary depending on the type of buffering agent, the type and amount of other components, etc., and cannot be uniformly specified. However, for example, the total amount of buffering agent relative to the total amount of the composition may be 0.001 w / v% or more, more specifically 0.01 w / v% or more, more specifically 0.05 w / v% or more, or more specifically 0.1 w / v% or more. Alternatively, the total amount of buffering agent relative to the total amount of the composition may be 10 w / v% or less, more specifically 5 w / v% or less, more specifically 3 w / v% or less, more specifically 2.5 w / v% or less, or more specifically 2 w / v% or less.

[0112] In particular, when using a boric acid buffer, the proportion of the buffer in the composition may be 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%, relative to the total composition.

[0113] pH adjuster Examples of pH adjusting agents include hydrochloric acid, sulfuric acid, polyphosphate, 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. pH adjusters may be used alone or in combination of two or more types.

[0114] Isotonic agent Examples of isotonic agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, potassium acetate, sodium acetate, magnesium sulfate, glycerin, and propylene glycol. Isotonic agents may be used alone or in combination of two or more types.

[0115] Thickening agent or viscosity-enhancing agent The ophthalmic composition of the present invention may contain a thickening agent or viscosity-enhancing agent, to the extent that it does not impair the effects of the present invention.

[0116] Examples of thickeners or viscosity-enhancing agents include guar gum, hydroxypropyl guar gum, cellulosic polymers (e.g., methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, etc.), acacia gum, karaya gum, xanthan gum, agar, alginic acid, α-cyclodextrin, dextrin, dextran, mucopolysaccharides (e.g., heparinoids, heparin, heparin sulfate, heparan sulfate, heparinoids, hyaluronic acid, hyaluronic acid salts (sodium salts, etc.), etc.), starch, chitin and its derivatives, chitosan and its derivatives, carrageenan, sorbitan Examples include tol, polyvinyl polymer compounds (polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, etc.), alkali metal salts of polyacrylic acid (sodium salt and potassium salt, etc.), amine salts of polyacrylic acid (monoethanolamine salt, diethanolamine salt, triethanolamine salt, etc.), casein, gelatin, collagen, pectin, elastin, ceramide, liquid paraffin, glycerin, polyethylene glycol, macrogol, polyethyleneimine alginate (sodium salt, etc.), alginate esters (propylene glycol ester, etc.), tragacanth powder, and triisopropanolamine. Thickening agents or viscosity-reducing agents may be used alone or in combination of two or more types.

[0117] Stabilizer Examples of stabilizers include trometamol, sodium formaldehyde sulfoxylate (longalit), monoethanolamine, aluminum monostearate, and glyceryl monostearate. Stabilizers may be used alone or in combination of two or more types.

[0118] oil 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. Oils may be used alone or in combination of two or more types. Furthermore, the ophthalmic composition of the present invention may not substantially contain petrolatum (such as white petrolatum). Furthermore, the ophthalmic composition of the present invention does not necessarily have to contain castor oil, sesame oil, etc. For example, the ophthalmic composition of the present invention may be (1) a composition that excludes a composition containing a combination of polyoxyethylene castor oil and sesame oil, or (2) a composition that excludes a composition containing a combination of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and sesame oil.

[0119] Sugars Examples of sugars include monosaccharides and disaccharides, specifically glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, sorbitol, and mannitol. Sugars may be used individually or in combination of two or more types.

[0120] polyhydric alcohols Examples of polyhydric alcohols include polyethylene glycol, glycerin, propylene glycol, xylitol, diethylene glycol, mannitol, sorbitol, and polyvinyl alcohol. Polyhydric alcohols may be used alone or in combination of two or more types.

[0121] Inorganic salts Examples of inorganic salts include potassium chloride, sodium chloride, calcium chloride, magnesium chloride, sodium bicarbonate, sodium carbonate (including anhydrous 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 bisulfite, sodium sulfite, potassium acetate, sodium acetate, and sodium thiosulfate. Among these, potassium chloride, sodium chloride, calcium chloride, sodium bicarbonate, sodium carbonate (including anhydrous 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. Inorganic salts may be used individually or in combination of two or more types.

[0122] Water-soluble antioxidants Examples of water-soluble antioxidants include ascorbic acid, ascorbic acid derivatives (such as disodium ascorbic acid-2-sulfate, sodium ascorbate, magnesium ascorbic acid-2-phosphate, and sodium ascorbic acid-2-phosphate), sodium bisulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, EDTA or its salts (such as disodium EDTA and tetrasodium EDTA). Water-soluble antioxidants may be used alone or in combination of two or more types.

[0123] The composition of the present invention may further contain components having pharmacological or physiological activity.

[0124] Pharmacologically active ingredients or physiologically active ingredients can be used alone or in combination of two or more.

[0125] Examples of such pharmacologically and physiologically active ingredients include the active ingredients in various pharmaceuticals listed in the 2012 edition of the Standards for Approval of Manufacturing and Marketing of Over-the-Counter Drugs (supervised by the Japan Regulatory Science Society). Examples include decongestants, ocular muscle regulators, astringents, vitamins, amino acids, antibacterial or antiseptic agents, local anesthetic components, analgesics, and sulfonamides. Specific examples of these drugs are given below.

[0126] Decongestive agents (vasoconstrictors) Examples of decongestants include α-adrenergic agonists, specifically imidazoline-based decongestants such as oxymetazoline, tetrahydrozoline, naphazoline, or their hydrochloride salts, nitrates, etc., as well as epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, methyl ephedrine hydrochloride, and epinephrine bitartrate. These may be in d-isomer, l-isomer, or dl-isomer.

[0127] Regarding imidazoline vasoconstrictors, the salts of imidazoline vasoconstrictors can be any pharmaceutically or physiologically acceptable salts, such as organic salts like maleates and fumarates; inorganic salts like hydrochlorides and sulfates; and metal salts. Among the salts, inorganic salts are preferred, hydrochlorides or nitrates are more preferred, and hydrochlorides (such as tetrahydrozoline hydrochloride) are particularly preferred.

[0128] Among decongestants (vasoconstrictors), imidazoline-based vasoconstrictors are preferred, tetrahydrozoline, naphazoline, or their salts are more preferred, and tetrahydrozoline or its salts are even more preferred.

[0129] Eye muscle regulator Examples of ocular muscle modulators include cholinesterase inhibitors that have an active site similar to acetylcholine, specifically neostigmine methylsulfate, tropicamide, helenien, and atropine sulfate.

[0130] Vitamins Examples of vitamins include flavin adenine dinucleotide or its salts (e.g., flavin adenine dinucleotide sodium), cobalamin or its salts (e.g., cyanocobalamin, methylcobalamin), retinol, its salts or derivatives (e.g., retinol acetate, retinyl palmitate), pyridoxine or its salts (e.g., pyridoxine hydrochloride), panthenol, pantothenic acid or its salts (e.g., sodium pantothenate, potassium pantothenate, calcium pantothenate, magnesium pantothenate), tocopherol, its salts or derivatives (e.g., tocopherol acetate, tocopherol succinate, tocopherol nicotinate), pyridoxal or its salts (e.g., pyridoxal phosphate), ascorbic acid or its salts (e.g., sodium ascorbate, calcium ascorbate), and others.

[0131] Among these, flavin adenine dinucleotide or its salts (especially flavin adenine dinucleotide sodium), cobalamin or its salts (especially cyanocobalamin), retinol, its salts or derivatives (especially retinol acetate, retinyl palmitate), pyridoxine or its salts (especially pyridoxine hydrochloride), panthenol, pantothenic acid or its salts (especially sodium pantothenate, calcium pantothenate), tocopherol, its salts or derivatives (especially tocopherol acetate) are preferred, with pyridoxine hydrochloride and tocopherol acetate being more preferred. The composition of the present invention may not contain pyridoxine or its salts.

[0132] Antibacterial agent or disinfectant Examples of antibacterial or disinfectant agents include sulfonamides such as sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxazole monoethanolamine, sulfisomazole sodium, and sulfisomidine sodium, as well as alkylpolyaminoethylglycine, chloramphenicol, ofloxacin, norfloxacin, levofloxacin, and lomefloxacin hydrochloride.

[0133] Local anesthetic components Examples of local anesthetic components include procaine hydrochloride and lidocaine hydrochloride.

[0134] Pain reliever Examples of pain relievers include procaine hydrochloride.

[0135] Sulfonamides Examples of sulfonamides include sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, and sulfisomidine sodium.

[0136] Base or carrier The composition of the present invention may contain a base or a carrier. Compositions containing such bases or carriers can be prepared, for example, by mixing each of the above components with a pharmaceutically acceptable base or carrier, using the conventional methods described in the 17th edition of the Japanese Pharmacopoeia Commentary.

[0137] Examples of bases or carriers include water, polar solvents such as ethanol (especially water-soluble solvents), and oily bases. The base or carrier can be used individually or in combination of two or more.

[0138] In particular, the composition of the present invention may be an aqueous composition (for example, a composition containing water or a mixed solvent of water and a water-soluble solvent).

[0139] Properties The properties of the composition of the present invention are not particularly limited, and may be any of the following: liquid, fluid, gel, or semi-solid. It may also be a liquid, fluid, gel, or semi-solid when prepared at the time of use. A semi-solid state refers to a state that has plasticity and can be deformed by applying force, such as an ointment.

[0140] Furthermore, the composition may be an aqueous composition (mainly containing an aqueous or hydrophilic base or carrier), an oily composition (mainly containing an oily or hydrophobic base or carrier), or in particular an aqueous composition.

[0141] 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 formulation). Furthermore, the base or carrier may consist solely of water.

[0142] In the case of an oily 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 formulation).

[0143] Sodium ion content The composition of the present invention may have a sodium ion (or sodium) content within a specific range. Combining such a sodium ion content with the aforementioned specific component may provide advantages in terms of precipitation inhibition and solubility.

[0144] For example, the sodium ion concentration of the composition of the present invention may be 300 mM or less, 250 mM or less (for example, 240 mM or less), more preferably 230 mM or less, particularly preferably 200 mM or less, and most preferably 150 mM or less.

[0145] 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), most preferably 40 mM or less (e.g., 30 mM or less), and 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 below the detection limit).

[0146] The amount of sodium ions can also be defined as a percentage of component (A). For example, in the composition of the present invention, the percentage of sodium ions can be selected from a range of about 30 moles or less per mole of component (A), and may be 25 moles or less, preferably 20 moles or less, more preferably 15 moles or less, particularly preferably 12 moles or less, most preferably 10 moles or less (e.g., 9.5 moles or less), or a relatively low percentage [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, most preferably 3 moles or less], or an even lower percentage (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 the detection limit).

[0147] Furthermore, sodium ions only need to be free ions in the composition, and may even form salts. For example, even if tranilast forms a salt with sodium in the composition and sodium ions are not in a free state, sodium (ions) derived from such salts are also included in the sodium ions. Furthermore, the amount or concentration of sodium (ions) may be obtained by directly measuring the amount or concentration in the composition, or by indirectly calculating the amount or concentration in the composition from the amount or concentration of sodium (ions) in the components (raw materials) constituting the composition. The amount or concentration of sodium (ions) in the composition or raw materials may also be measured by conventional methods or apparatus (for example, ion chromatography).

[0148] Furthermore, as mentioned above, sodium ions contain sodium derived from each component. Therefore, if each component contains sodium as a salt or the like, 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 include or omit sodium chloride, borax, sodium edetate, etc., which are commonly used in eye drops and the like, in small amounts.

[0149] From this viewpoint, in particular, sodium-free components (for example, non-sodium salts in the case of a salt) may be suitably used as each component constituting the composition of the present invention (for example, components (A) to (C), other components, etc.).

[0150] pH The pH of the composition of the present invention is preferably 3 or higher (for example, 4 or higher), more preferably 5 or higher (for example, 5.5 or higher), and even more preferably 6 or higher. Furthermore, it is preferably 10 or lower, more preferably 9 or lower, and even more preferably 8.5 or lower.

[0151] The pH of the composition of the present invention may be, for example, 4 to 10, preferably 5 to 9, 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 this invention, the effects of the present invention can be efficiently realized even at the pH levels described above.

[0152] Osmotic pressure The osmotic pressure ratio of the composition of the present invention is preferably 0.4 or higher, more preferably 0.5 or higher, and even more preferably 0.6 or higher. It is also preferably 5 or lower, more preferably 3 or lower, and even more preferably 2 or lower.

[0153] The osmotic pressure ratio is defined as 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 17th edition of the Japanese Pharmacopoeia. The osmotic pressure is measured according to the osmotic pressure measurement method (freezing point depression method) described in the 17th edition of the Japanese Pharmacopoeia.

[0154] Dosage form The dosage form (form, shape, structure) of the composition of the present invention is not particularly limited and includes, for example, eye drops (also called eye solutions or eye drops; eye drops include eye drops that can be instilled while wearing contact lenses), eye washes, eye ointments (water-soluble eye ointments, oil-soluble eye ointments), contact lens insertion solutions, intraocular injections (e.g., intravitreal injections), contact lens solutions (cleaning solutions, storage solutions, disinfecting solutions, multi-purpose solutions, packaged solutions), preservatives for excised eye tissue such as corneas for transplantation, and surgical irrigation solutions. Eye drops, eye washes, and eye ointments also include those used while wearing contact lenses.

[0155] Furthermore, "contact lenses" include hard contact lenses and soft contact lenses (which encompass both ionic and non-ionic types, and both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).

[0156] Preferably, the composition of the present invention can be in the form of eye drops, eye wash, eye ointment (water-soluble eye ointment, oil-soluble eye ointment), contact lens insertion solution, contact lens solution (cleaning solution, storage solution, disinfecting solution, multi-purpose solution, packaging solution), more preferably eye drops, eye wash, contact lens insertion solution, contact lens solution (cleaning solution, storage solution, disinfecting solution, multi-purpose solution), even more preferably eye drops and eye wash, and particularly preferably eye drops.

[0157] Such compositions of the present invention may exclude ophthalmic compositions (especially eye drops, eye washes, or eye ointments) used or applied during the wearing (wearing) of contact lenses (hard contact lenses, soft contact lenses, and especially silicone hydrogel contact lenses).

[0158] The composition of the present invention may be in single-use unit doses or reusable multi-dose forms, and may be contained and used in multi-dose form.

[0159] container The composition of the present invention may be contained in a container (filled, injected, sealed). The container can be any packaging body having a portion (surface) that comes into contact with the composition (formulation), and may consist of, for example, a container body portion that contains the composition (e.g., a liquid composition), a portion of the container including an outlet (nozzle, inner stopper), a suction tube, a cap, etc.

[0160] The materials that make up the container can be selected from a wide range, for example, at least part or all of the part that comes into contact with the composition may be plastic [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), polyarylate, polysulfone, polyimide resins, cellulose resins (such as cellulose acetate), hydrocarbon resins which may be substituted with halogen atoms, etc.], metals (such as aluminum), etc.

[0161] The container may be made of a single material or two or more materials.

[0162] Examples of olefin resins include ethylene resins [for example, polyethylene (including high-density polyethylene, low-density polyethylene, ultra-low-density polyethylene, linear low-density polyethylene, ultra-high molecular weight polyethylene, etc.), ethylene-propylene copolymers, etc.], propylene resins [for example, polypropylene (PP) (including isotactic polypropylene, syndiotactic polypropylene, atactic polypropylene, etc.), propylene-ethylene copolymers, etc.], and methylpentene resins (for example, polymethylpentene, etc.).

[0163] 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.).

[0164] Examples of acrylic resins include resins that use acrylic acid esters such as methyl acrylate, methacrylate esters such as methyl methacrylate, cyclohexyl methacrylate, and t-butylcyclohexyl methacrylate as polymerization components.

[0165] Examples of polyester resins include aromatic polyester resins [for example, resins having alkylene terephthalate units (alkylene terephthalate resins: for example, polyethylene terephthalate (PET), polytrimethylene terephthalate, polybutylene terephthalate (PBT), etc.), resins having alkylene naphthalate units (for example, polyethylene naphthalate (PEN), polybutylene naphthalate, etc.)].

[0166] Examples of fluororesins include fluorine-substituted polyethylene (polytetrafluoroethylene, polychlorotrifluoroethylene, etc.), polyvinylidene fluoride, polyvinyl fluoride, perfluoroalkoxy fluororesins, tetrafluoroethylene-hexafluoropropylene copolymer, ethylene-tetrafluoroethylene copolymer, and ethylene-chlorotrifluoroethylene copolymer.

[0167] Polyacetal resins include those consisting solely of oxymethylene units, as well as those containing some oxyethylene units.

[0168] Examples of modified polyphenylene ethers include polystyrene-modified polyphenylene ether.

[0169] Examples of polyarylates include amorphous polyarylates.

[0170] Examples of polyimide resins include aromatic polyimides, such as those obtained by polymerizing pyromellitic dianhydride and 4,4'-diaminodiphenyl ether.

[0171] Examples of cellulose acetates include cellulose diacetate and cellulose triacetate.

[0172] The container material is preferably plastic (i.e., plastic container) such as olefin resin, styrene resin, or polyester resin, more preferably ethylene resin, propylene resin, alkylene terephthalate resin, or polystyrene, even more preferably polypropylene, polyethylene terephthalate, or polystyrene, and even more preferably polyethylene terephthalate.

[0173] The container material may also be a polymer blend with polymers other than the aforementioned polymer. When the container material of the container for containing the ophthalmic composition of the present invention is a blend polymer with the aforementioned polymer, the mixing ratio of the aforementioned polymer and polymers other than the aforementioned polymer is not particularly limited as long as the effects of the present invention are achieved, but it is preferable that the total weight of the aforementioned polymer is 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, relative to the total amount of the constituent material.

[0174] The container may have at least a portion of its surface that comes into contact with the composition of the present invention 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 significantly achieving the effects of the present invention, it is preferable that the container itself is molded from the above material.

[0175] Furthermore, the parts constituting the container (the container body, the part including the dispenser opening (nozzle, inner stopper), the suction tube, the cap, etc.) may be made of the above material, and the entire container may be made of the above material. 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 material, and it is more preferable that the entire container body is made of the above material (where only a part of the layers constituting the container body is made of the above material).

[0176] Target diseases (uses) The target diseases (uses) of the composition of the present invention are not particularly limited as long as they are for ophthalmic use, but are useful for alleviating, improving, suppressing, or treating allergic symptoms, itchy eyes, redness, foreign body sensation (such as a gritty feeling), corneal damage, corneal injury, watery eyes (epiphora), palpebral conjunctival follicles, eye discharge, etc., as well as for enhancing, normalizing, and protecting the corneal barrier function.

[0177] Watery eyes are a symptom that occurs when the tear drainage pathway, from the puncta to the lacrimal canaliculi, lacrimal sac, and nasolacrimal duct, becomes blocked by eye discharge or other substances, or when excessive tears are produced due to irritation.

[0178] In this specification, "alleviation" encompasses the reduction of symptoms and the suppression of symptom progression, while "improvement," "suppression," and "treatment" encompass the reduction of symptoms, the suppression of symptom progression, and cure or complete recovery.

[0179] In particular, the compositions of the present invention are suitable for alleviating, improving, suppressing, or treating allergic symptoms (allergic symptoms of the eyes).

[0180] The allergens causing allergic symptoms are not limited to any one other, but may include pollen (such as cedar pollen and cypress pollen) and house dust (indoor dust).

[0181] In another embodiment, the compositions of the present invention are suitable for alleviating, improving, suppressing, or treating symptoms such as itchy eyes, redness, watery eyes, foreign body sensation, and eye discharge. These symptoms may or may not be caused by allergies.

[0182] How to use The method (mode of use) of the composition of the present invention can be appropriately selected according to its properties and other factors.

[0183] For example, if the composition of the present invention is a formulation applied to the eye, such as eye drops, eye wash, or eye ointment, the method of use will vary depending on the target symptoms, but for example, it may be administered once or more, twice or more, three or more, four or more, five or more, or six or more times a day. It may also be administered nine or fewer times a day, eight or fewer times a day, seven or fewer times a day, six or fewer times a day, five or fewer times a day, or four or fewer times a day. Administering it four times a day is particularly preferable.

[0184] When the composition of the present invention is an eye drop, for example, it is sufficient to instill 1 to 3 drops per dose, or 1 to 2 drops, or 2 to 3 drops. Preferably, 1 to 2 drops are sufficient. It can also be 1 drop. Furthermore, the amount of one drop may preferably be 30 to 50 μL.

[0185] If the composition of the present invention is an eye wash, for example, 1 to 30 mL should be used per wash, preferably 1 to 20 mL, and more preferably 4 to 6 mL.

[0186] If the composition of the present invention is an eye ointment, for example, 0.001 to 5 g should be applied to the eye at one time.

[0187] When the composition of the present invention is a contact lens insertion solution, when inserting or removing contact lenses, for example, 1 to 3 drops, preferably 1 to 2 drops, are dropped onto one and / or both sides of the contact lens to wet it before insertion, and it is preferable to wet both sides of the contact lens before insertion.

[0188] [2. Preservative effect] The ophthalmic composition according to this embodiment has the effect of improving or enhancing (or imparting, exhibiting) the preservative efficacy (storage stability) of the ophthalmic composition. Accordingly, as one embodiment of the present invention, a method for improving or enhancing (imparting or expressing) the preservative efficacy (storage stability) of an ophthalmic composition is provided, which includes adding the remaining one or two components to an ophthalmic composition containing one or two components selected from components (A), (B), and (C) (for example, adding components (B) and (C) to an ophthalmic composition containing component (A)). Furthermore, as an embodiment of the present invention, an agent (preservative) for improving or enhancing (imparting or exhibiting) the preservative effect in an ophthalmic composition comprising one or two components selected from component (A), component (B), and component (C), is provided, the agent comprising the remaining one or two components. Furthermore, the microorganisms, fungi, and molds that exhibit preservative effects in these methods and agents are not particularly limited, and examples include Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Candida, and Aspergillus.

[0189] [3. Stability] The ophthalmic composition according to this embodiment has the effect of improving or enhancing (imparting or exhibiting) the stability (e.g., thermal stability and / or photostability, particularly at least photostability) of the ophthalmic composition. Accordingly, as one embodiment of the present invention, a method is provided for improving or enhancing (imparting or expressing) the stability of an ophthalmic composition, which includes adding the remaining one or two components to an ophthalmic composition containing one or two components selected from components (A), (B), and (C) (for example, adding components (B) and (C) to an ophthalmic composition containing component (A)). Furthermore, as an embodiment of the present invention, an agent (light stabilizer, heat stabilizer, heat and light stabilizer) for improving or enhancing (imparting or expressing) the stability of an ophthalmic composition comprising one or two components selected from component (A), component (B), and component (C), is provided, the agent comprising the remaining one or two components.

[0190] [4. Oxygen stress tolerance] The ophthalmic composition according to this embodiment has the effect of improving or enhancing (imparting or expressing) oxygen (hypoxia) stress tolerance in the ophthalmic composition. Accordingly, as one embodiment of the present invention, a method is provided for improving or enhancing (imparting or expressing) oxygen (hypoxia) stress tolerance in an ophthalmic composition, which includes adding the remaining one or two components to an ophthalmic composition containing one or two components selected from component (A), component (B), and component (C) (for example, adding components (B) and (C) to an ophthalmic composition containing component (A)). Furthermore, as an embodiment of the present invention, an agent (oxygen stress tolerance improving agent) for improving or enhancing (imparting or expressing) oxygen (hypoxia) stress tolerance in an ophthalmic composition comprising one or two components selected from component (A), component (B), and component (C), is provided, the agent comprising the remaining one or two components.

[0191] [5. Suppression of precipitation and turbidity] The ophthalmic composition according to this embodiment has the effect of suppressing precipitation (clouding) in the ophthalmic composition (or improving or enhancing the solubility stability). Accordingly, as one embodiment of the present invention, a method for suppressing precipitation (clouding) in an ophthalmic composition (a method for improving or enhancing solubility stability) is provided, which includes adding the remaining one or two components to an ophthalmic composition containing one or two components selected from components (A), (B), and (C) (for example, adding components (B) and (C) to an ophthalmic composition containing component (A)). In this method, the sodium ion concentration of the ophthalmic composition may be set to the aforementioned concentration (for example, 250 mM or less), or a solubilizer (for example, polyvinylpyrrolidone) may be included. Furthermore, as an embodiment of the present invention, an agent for suppressing precipitation (opacification) in an ophthalmic composition comprising one or two components selected from component (A), component (B), and component (C) (or an agent for improving or enhancing solubility) is provided, comprising the remaining one or two components. This agent may further contain a solubilizer (such as polyvinylpyrrolidone). In addition, the temperature at which these methods and agents exhibit a precipitation suppression effect (improvement or enhancement of dissolution stability) is not particularly limited, but the effect may be particularly pronounced at relatively low temperatures. Therefore, the above methods and agents may be methods and agents that suppress precipitation (improvement or enhancement of dissolution stability) at low temperatures (for example, 10°C or below, preferably 5°C or below, 0°C or below, etc.).

[0192] The types and amounts of components (A) to (C) in each of the above embodiments, the types and amounts of other components, the formulation form and use of the ophthalmic composition, etc., are as described in [1. Ophthalmic Composition]. [Examples]

[0193] The present invention will be described in more detail below with reference to examples, but the present invention is not limited in any way by these examples, and many modifications are possible within the technical concept of the present invention by those with ordinary skill in the art.

[0194] 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 examples of components containing sodium (ions) and the calculation of their sodium amount or concentration.

[0195] [Table 1]

[0196] Sodium ion concentration (mM) = Amount of ingredients (w / v%) / Molecular weight × Number of sodium molecules (per molecular weight) × 10000

[0197] For polysaccharides, the calculation was based on the molecular weight of the sugar portion to which sodium is bound. For example, sodium chondroitin sulfate is a polymer with repeating disaccharide units of N-acetyl-D-galactosamine and D-glucuronic acid, and the Na concentration was calculated using a molecular weight of 503.3 per disaccharide unit.

[0198] Test Example 1 (Preservative Efficacy) Aqueous ophthalmic compositions (eye drops) with the compositions shown in Table 2 below were prepared by conventional methods, and their preservative efficacy was evaluated as follows.

[0199] Staphylococcus aureus (ATCC6538) was inoculated onto the surface of soybean casein digest slant agar and incubated at 33°C for 24 hours. The cultured cells were aseptically collected using a platinum loop and suspended in an appropriate amount of sterile physiological saline, resulting in approximately 1 × 10⁶ cells. 7 A bacterial suspension containing viable bacteria at CFU / mL was prepared. The number of viable bacteria in the suspension was measured separately by culturing. Next, 10 mL each of filtered and sterilized aqueous ophthalmic compositions was filled into 15 mL capacity Corning conical tubes (PET). In these aqueous ophthalmic compositions, the number of viable bacteria (final concentration) was approximately 10. 5 A suspension of Staphylococcus aureus was inoculated to a concentration of CFU / mL and thoroughly mixed to prepare the sample. The samples were stored at 23°C under light protection for 5 days. After 5 days, the bacterial-containing samples were prepared to an appropriate concentration for counting, inoculated onto soybean casein digest agar (SCD agar), and incubated overnight at 33°C. The number of viable bacteria was determined by counting the number of colonies observed. From the calculated number of viable bacteria, the following value (Log Reduction Value LRV) was calculated and used as an indicator of preservation effectiveness. Logarithmic decrease value = log(number of viable bacteria in suspension / 100) - log(number of viable bacteria after 5 days)

[0200] In the aqueous ophthalmic compositions listed in Table 2 below, the units for each component are (w / v%) (the same applies hereafter).

[0201] [Table 2]

[0202] As is clear from the results in Table 2 above, the combination of tranilast, chlorpheniramine maleate, and pranoprofen showed higher preservative efficacy against Staphylococcus aureus compared to the use of tranilast or chlorpheniramine maleate alone, or the combination of chlorpheniramine maleate and pranoprofen.

[0203] Test Example 2 (Preservative Efficacy) Aqueous ophthalmic compositions (eye drops) with the compositions shown in Table 3 below were prepared by conventional methods, and their preservative efficacy was evaluated in the same manner as in Test Example 1, except that the storage period was changed from 5 days to 1 week.

[0204] [Table 3]

[0205] As is clear from the results in Table 3 above, similar preservative efficacy was obtained even when the storage period was extended to one week, and even when the proportions of the three components were changed.

[0206] Test Example 3 (Preservative Efficacy) Aqueous ophthalmic compositions (eye drops) with the compositions shown in Table 4 below were prepared by conventional methods, and their preservative efficacy was evaluated in the same manner as in Test Example 2 (storage period of 1 week), except that they were heat-treated (heat aging) before storage. The heat treatment was performed by filling 13 mL of the prepared aqueous ophthalmic composition into 13 mL PET containers, packaging them in plastic film, and storing them at 60°C for 7 days under light-shielding conditions.

[0207] [Table 4]

[0208] As is clear from the results in Table 4 above, the preservative effect could be maintained even when heat treatment was performed before storage.

[0209] Test Example 4 (Preservative Efficacy) Aqueous ophthalmic compositions (eye drops) with the compositions shown in Table 5 below were prepared by conventional methods, and a logarithmic decrease value A was obtained in the same manner as in Test Example 2 (storage period of 1 week). On the other hand, using an aqueous ophthalmic composition of the same composition, in Test Example 2 (storage period of 1 week), the logarithmic decrease value B was obtained in the same manner as in Test Example 2, except that the same heat treatment as in Test Example 3 was performed before storage. Based on these results, the difference in logarithmic decrease values ​​(AB) was calculated to evaluate the degree of deterioration in preservation effectiveness due to thermal aging.

[0210] [Table 5]

[0211] As is clear from the results in Table 5 above, combining the three components made it possible to suppress the decrease in preservative effectiveness due to heat treatment.

[0212] Test Example 5 (Preservative Efficacy) Aqueous ophthalmic compositions (eye drops) with the compositions shown in Table 6 below were prepared by conventional methods, and their preservative efficacy was evaluated in the same manner as in Test Example 2 (storage period of 1 week), except that they were exposed to light before storage. For the light exposure test, the prepared aqueous ophthalmic composition was filled into a 13 mL PET container (13 mL capacity) and then continuously irradiated with 4500 lx / hr of light using a white lamp as the light source at room temperature using a photostability tester ("LT-120A-WCD" model, manufactured by Nagano Scientific Co., Ltd.) until the cumulative irradiation dose to the aqueous ophthalmic composition reached 100,000 lx·hr.

[0213] [Table 6]

[0214] As is clear from the results in Table 6 above, the preservative effect was maintained even after exposure to light.

[0215] Test Example 6 (Preservative Efficacy) An aqueous ophthalmic composition (eye drop) having the composition shown in Table 7 below was prepared by a conventional method. In Test Example 2 (storage period: 1 week), the preservation efficacy was evaluated in the same manner as in Test Example 2, except that *Escherichia coli* (ATCC 8739) was used instead of *Staphylococcus aureus*.

[0216]

Table 7

[0217] As is clear from the results of Table 7 above, it was found that even when the type of bacterium was changed, the combination of tranilast, chlorpheniramine maleate and pranoprofen exhibited preservation efficacy.

[0218] Test Example 7-1 (Photostability) An aqueous ophthalmic composition (eye drop) having the composition shown in Table 8 below was prepared by a conventional method, and photostability was evaluated as follows. 13 mL of the prepared aqueous ophthalmic composition was filled into a 13 mL-capacity PET container. Using a photostability test apparatus ("LT-120A-WCD model", manufactured by Nagano Science Co., Ltd.), with a white lamp as the light source, 4500 lx / hr of light was continuously irradiated at room temperature, and the aqueous ophthalmic composition was exposed to light with an integrated irradiation dose of 900,000 lx·hr. After exposure, the turbidity of the aqueous ophthalmic composition was measured using a haze meter ("NDH-300A", manufactured by Nippon Denshoku Industries Co., Ltd.).

[0219]

Table 8

[0220] 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, among the three components, chlorpheniramine maleate itself has high photostability, while pranoprofen appears to have low photostability. However, simply combining these three components did not improve the photostability of pranoprofen, but rather drastically reduced it. The finding that combining the three components resulted in photostability similar to that of chlorpheniramine maleate was extremely surprising.

[0221] Test Example 7-2 (Photostability) In Test Example 7-1, for compositions 7A and 7D, which showed a significant difference in turbidity, the amount of chlorpheniramine maleate (remaining amount) after exposure to a cumulative irradiation dose of 900,000 lx·hr was measured by HPLC (high-performance liquid chromatography).

[0222] Then, using the amount of chlorpheniramine maleate obtained after exposure and the amount of chlorpheniramine maleate before exposure, the degradation rate (%) [100 - remaining rate (%)] of chlorpheniramine maleate was determined for each of compositions 7A and 7D, and the degradation ratio and degradation inhibition rate calculated using the following formula were found to be "0.529" and "47.08%", respectively.

[0223] 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

[0224] These results show that combining the three components can efficiently suppress the degradation of chlorpheniramine maleate by light.

[0225] Test Example 8 (Hypoxic Stress Tolerance) Compositions with the compositions shown in Table 9 below were prepared by dissolving them in culture medium (DMEM / F12, Gibco). Tranilast was dissolved in dimethyl sulfoxide (Wako Pure Chemical Industries, Ltd.) before being dissolved in the culture medium. For compositions without tranilast, the same amount of dimethyl sulfoxide used for tranilast dissolution was added.

[0226] [Table 9]

[0227] The hypoxic stress tolerance of the obtained compositions was then evaluated as follows. Human immortalized corneal epithelial cells (HCE-T) were placed in a 6-well plate (Corning) in a 1.6 × 10⁶ arrangement. 5 Cells were seeded in wells and cultured for 72 hours under conditions of 37°C, 5% CO2, and 90% humidity. According to the compositions shown in Table 9, cells were treated with chlorpheniramine maleate alone, a combination of pranoprofen and chlorpheniramine maleate, or a combination of pranoprofen, chlorpheniramine maleate, and tranilast. The cells were then cultured under anaerobic conditions at 37°C for 18 hours using Aneropack Kenki (Mitsubishi Gas Chemical Company). The mRNA expression level of hGPX1, a known antioxidant gene, was then quantified using quantitative real-time PCR with the Quant Studio 7 Real-Time PCR System (Applied Biosystems).

[0228] The test results are shown in Figure 1. As is clear from the results in Figure 1, the combination of three components: 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 components: pranoprofen and chlorpheniramine maleate (Test Example 8B) (*p<0.05, by t-test). Furthermore, even when the ratio of the three components was changed, the same hGPX1 expression effect was exhibited (Test Example 8D). It has been clarified that the formulation comprising a combination of the three components has a particularly remarkable effect on enhancing the expression of antioxidant genes, compared with formulations comprising one component and a combination of two components.

[0229] Test Example 9 (Human Sensory Test) An aqueous ophthalmic composition (eye drops) having the composition shown in Table 10 below was prepared, and a sensory test was conducted as follows.

[0230]

Table 10

[0231] Five subjects with hay fever who had developed ocular symptoms were enrolled in the study. From the start day of the test, the eye drop of 9A was instilled into the left eye and the eye drop of 9B was instilled into the right eye four times a day. During the instillation period, a subjective symptom questionnaire on specific items throughout the day was conducted on the evening of day 1, day 2 and day 5 regarding itching and hyperemia. The subjective symptom questionnaire was scored on a 100-point scale, with a higher score indicating more severe subjective symptoms. In addition, the values are the average values of the five subjects.

[0232] The results are shown in the table below.

Table 11

[0233] Test Example 9B showed the same or lower levels of itching and hyperemia compared to Test Example 9A.

[0234] Furthermore, Test Example 9A contains sodium cromoglycate, a formulation that is known to have an effect in improving itching and other symptoms. Therefore, the fact that the value of Test Example 9B was equivalent to or lower than that of Test Example 9A means that the combination of tranilast, chlorpheniramine maleate, and pranoprofen is comparable to or even superior in terms of improving itching and redness.

[0235] Test Example 10 (Precipitation Test) Aqueous ophthalmic compositions (eye drops) with the compositions shown in Table 12 below were prepared, and precipitation was evaluated as follows.

[0236] The prepared compositions were filled into screw vials (Maruemu Co., Ltd., No. 3L) and stored for 2 days at 4°C and -2°C, respectively. After confirming precipitation, the screw vials were stirred for 10 seconds at maximum stirring speed using a vortex mixer (AS ONE Corporation, Vortex Genie 2), and the turbidity of the aqueous ophthalmic composition was measured using a haze meter ("NDH-300A," Nippon Denshoku Co., Ltd.).

[0237] The results are shown in Table 12 below. In the table below, the precipitation improvement rate is the value expressed by the following formula.

[0238] Precipitation improvement rate (%)= (Turbidity of test example 10A - Turbidity of each test example) / Turbidity of test example 10A × 100

[0239] [Table 12]

[0240] As is clear from the results in Table 12 above, precipitation occurred even when polyvinylpyrrolidone (and even monoethanolamine) was added to tranilast (and even when the sodium ion concentration was set to 0). On the other hand, this precipitation increased when diphenhydramine hydrochloride was added, but it could be suppressed by the presence of chlorpheniramine maleate or pranoprofen, and it was found that it could be suppressed particularly when all three components were combined. In particular, the above test examples included ingredients such as chlorpheniramine maleate and pranoprofen, but even with the inclusion of these ingredients, the stability of the formulation, such as precipitation or turbidity, was not compromised. In fact, combining the three ingredients was able to suppress precipitation and turbidity.

[0241] Furthermore, although the above formulation uses polyvinylpyrrolidone and monoethanolamine in combination, a similar precipitation improvement effect was observed when polyvinylpyrrolidone was not used, or when trometamol was used instead of polyvinylpyrrolidone and / or monoethanolamine.

[0242] Furthermore, our investigations revealed that when tranilast was combined with monoethanolamine, etc., precipitation sometimes occurred after drying. However, in the formulation of the above test example, no precipitation occurred after drying even when these were combined.

[0243] Test Example 11 (Precipitation Test) Aqueous ophthalmic compositions (eye drops) with the compositions shown in Table 13 below were prepared, and precipitation was evaluated as follows.

[0244] The prepared composition was packed into a screw vial (Maruemu Co., Ltd., No. 3L) and stored at 4°C for 2 days. After confirming precipitation, the screw vial was stirred for 10 seconds at maximum stirring speed using a vortex mixer (AS ONE Corporation, Vortex Genie 2), and 1.5 mL of the stirred composition was packed into a 1.5 mL sample tube (Eppendorf, Neutral micro test tube with cap type). The sample tubes were centrifuged at 1000 rpm for 10 minutes, the height (mm) of the accumulated precipitate was measured, and the precipitation improvement rate, expressed by the following formula, was calculated.

[0245] Precipitation improvement rate (%)=(YX) / Y×100 [In the formula, X represents the height of the precipitate in each test example, and Y represents the height of the precipitate in the blank test example, where the concentrations of each component were kept the same without the addition of chlorpheniramine maleate and pranoprofen.]

[0246] [Table 13]

[0247] As is clear from the results in Table 13 above, it was found that precipitation can be efficiently suppressed at other sodium ion concentrations (85 mM, 115 mM) as well, especially when the three components are combined.

[0248] Test Example 12 (Precipitation Test) Aqueous ophthalmic compositions (eye drops) with the compositions shown in Table 14 below were prepared, and precipitation was evaluated in the same manner as in Test Example 11.

[0249] [Table 14]

[0250] As is clear from the results in Table 14 above, it was found that precipitation can be effectively suppressed even when the sodium ion concentration is further increased to 135 mM.

[0251] Example 13 (Clinical Trial) Aqueous ophthalmic compositions (eye drops) with the compositions shown in Table 15 below were prepared, and clinical trials were conducted as follows.

[0252] [Table 15]

[0253] Furthermore, the eye drops with the formulations shown in Table 15 did not cause any problems such as precipitation, similar to the formulations in the other test examples mentioned above.

[0254] In patients with mild to moderate allergic conjunctivitis (including hay fever) who had a clear indication of type I allergy through allergy testing and who experienced subjective symptoms of ocular itching, the efficacy and safety of the test formulation were confirmed when 1-2 drops were instilled four times a day for 14 days.

[0255] Objective findings (follicular palpebral follicles) were scored as an evaluation item, and the change in these scores was measured. The principal investigator or co-investigator performed slit-lamp microscopy and determined the severity according to the following criteria. In the determination, points were calculated as follows: +++: 3 points, ++: 2 points, +: 1 point, -: 0 points. 3 (Advanced): 20 or more 2 (moderate): 10-19 pieces 1 (Mild): 1-9 items 0 (none): No findings.

[0256] Based on the objective findings scores, the degree of improvement for each symptom was determined on a five-point scale (marked improvement, moderate improvement, slight improvement, no change, worsening) according to Table 16 below. Descriptive statistics were also calculated for the change in objective findings scores.

[0257] [Table 16]

[0258] The study results showed that among subjects who exhibited palpebral conjunctival follicle findings from the start to the end of the study, 66.0% showed improvement of moderate or greater. The mean change in the palpebral conjunctival follicle score was -0.7. In contrast, there are reports that the improvement rates for moderate or greater improvement with aqueous eye drops containing tranilast at a concentration of 5 mg / mL and aqueous eye drops 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). There are also reports that the improvement rates for moderate or greater improvement with eye drops 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, one report indicates that the mean change in the score of palpebral conjunctival follicles after 2 weeks of administration of aqueous eye drops containing 0.05% epinastine hydrochloride was "approximately -0.2" (Atarashii Ganka 31(1)97~104, 2014).

[0259] Furthermore, among subjects with mild or severe palpebral conjunctival follicles at the start of administration, the improvement rate of moderate or greater improvement was 82.5%, and the percentage of subjects with moderate or severe follicles that showed marked improvement was 100%.

[0260] These findings indicate that the above prescription is remarkably effective in improving palpebral conjunctival follicles.

[0261] Furthermore, we also examined the improvement in the subjects' subjective symptoms. Subjective symptom scores (watery eyes, foreign body sensation, eye discharge) were set as shown in Table 17 below, and the amount of change was measured. Scores were calculated for the three days prior to the examination (excluding the day of the examination).

[0262] [Table 17]

[0263] Based on the average score of subjective symptoms, the degree of improvement for each symptom was determined on a five-point scale (marked improvement, moderate improvement, slight improvement, no change, worsening) according to Table 16 above.

[0264] As a result, Table 18 shows that moderate or greater improvement was observed for each subjective symptom. Furthermore, the improvement in these subjective symptoms was particularly high in subjects who had findings of palpebral conjunctival follicle at the start of administration.

[0265] [Table 18]

[0266] [Examples of formulations] The ophthalmic composition was prepared according to the formulations listed in the table below. In the table below, the units for each component are (w / v%).

[0267] [Table 19]

[0268] [Table 20] [Industrial applicability]

[0269] The present invention provides ophthalmic compositions that are useful as eye drops and the like.

Claims

[Claim 1] The invention described herein.

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