Ophthalmic composition

Abstract

To provide an ophthalmic composition that prevents the occurrence of precipitation and the like.SOLUTION: An ophthalmic composition contains (A) at least one selected from the group consisting of tranilast and a salt thereof, (B) at least one selected from the group consisting of polyvinyl pyrrolidone and trometamol, and (C) at least one component selected from the group consisting of (C1) anti-histamine agent, (C2) anti-inflammatory agent, and (C3) amino acid, wherein a sodium ion concentration is set to be 250 mM or less, or the ratio of sodium ions is set to be 25 mol or less relative to (A) component 1 mol.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an ophthalmic composition (or ophthalmic agent). [Background technology]

[0002] Tranilast (N-(3,4-dimethoxycinnamoyl)anthranilic acid) is poorly soluble in water, and even its alkali metal salts such as the sodium salt and potassium salt are extremely poorly soluble in water, and aqueous compositions containing tranilast or its salts are prone to crystallization during storage. Under these circumstances, techniques are being developed to improve precipitation in compositions containing tranilast.

[0003] For example, Patent Document 1 (JP Patent Publication No. 2006-306765) discloses an aqueous tranilast ophthalmic solution containing tranilast as an active ingredient in an aqueous solution together with appropriate metal ions, characterized in that the molar concentration ratio of the total metal ions to tranilast in the aqueous solution is total metal ions / tranilast ≦0.4. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] JP 2006-306765 A (Claims, Examples) Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a novel ophthalmic composition containing tranilast.

[0006] Another object of the present invention is to provide an ophthalmic composition which can suppress precipitation even when it contains tranilast.

[0007] Another object of the present invention is to provide an ophthalmic composition which has high dissolution stability even when it contains an active ingredient other than tranilast. [Means for solving the problem]

[0008] The technology of Patent Document 1 is based on the discovery that the conventional technology of adding polyvinylpyrrolidone (PVP) to tranilast is prone to precipitating crystals of tranilast when stored in a cold place, and that tranilast reassociates with metal ions such as sodium. This technology appears to be a technology that allows for the precipitating of tranilast crystals without the use of a solubilizing agent by reducing the concentration ratio of metal ions to tranilast (paragraphs

[0005] to

[0013] and examples of Patent Document 1, etc.).

[0009] Metals (ions) such as sodium (ion) are commonly contained in ophthalmic compositions as pH adjusters (e.g., sodium hydroxide, etc.), isotonicity agents (e.g., sodium chloride, etc.), buffers (e.g., borax, sodium phosphate, sodium citrate, etc.), and various other components in the form of sodium salts. As such, metal ions are generally contained in the composition to an extent that they can be said to be unavoidable, unless it is intended to actively reduce them, as in Patent Document 1.

[0010] However, according to the investigations of the present inventors, even when the concentration of metal ions is reduced as in Patent Document 1, precipitation may occur depending on other conditions (for example, when other additives are added). In particular, as shown in the examples of Patent Document 1, the system assumed is an ideal solution with a small number of components, and in reality, precipitation may occur simply by reducing the concentration of metal ions.

[0011] On the other hand, there are cases where an ophthalmic composition requires the addition of multiple active ingredients, and it has been found that Patent Document 1 is insufficient as a technique capable of meeting such requirements.

[0012] In this situation, the inventors, based on a completely different idea of ​​focusing again on polyvinylpyrrolidone, which is rejected as prior art in Patent Document 1, have discovered that by combining polyvinylpyrrolidone or trometamol with a specific component, it is possible to unexpectedly suppress precipitation in a composition containing tranilast, and that even when polyvinylpyrrolidone or the like, which is different from the ideal system as in Patent Document 1, is present in the system, precipitation may be more likely to occur if the amount of sodium is large. Furthermore, it is quite surprising that such specific components are not simply excipients or carriers, but are often components that act and function as active ingredients, and can effectively impart medicinal effects other than those derived from tranilast to the composition. After further investigation, they have completed the present invention.

[0013] That is, the composition (ophthalmic composition) of the present invention provides, for example, the following inventions. [1] (A) one or more members selected from the group consisting of tranilast and salts thereof, (B) one or more selected from the group consisting of polyvinylpyrrolidone and trometamol, and (C) containing one or more components selected from the group consisting of (C1) antihistamines, (C2) anti-inflammatory agents, and (C3) amino acids; An ophthalmic composition having a sodium ion concentration of 250 mM or less. [2] (A) one or more members selected from the group consisting of tranilast and salts thereof, (B) one or more selected from the group consisting of polyvinylpyrrolidone and trometamol, and (C) containing one or more components selected from the group consisting of (C1) antihistamines, (C2) anti-inflammatory agents, and (C3) amino acids; An ophthalmic composition having a ratio of sodium ions of 25 moles or less per mole of component (A). [3] (C1) The antihistamine comprises one or more selected from the group consisting of chlorpheniramine and its salts, (C2) The anti-inflammatory agent comprises one or more selected from the group consisting of pranoprofen and its salts, (C3) The ophthalmic composition according to [1] or [2], wherein the amino acids include one or more selected from the group consisting of taurine and salts thereof. [4] The ophthalmic composition according to any one of [1] to [3], wherein the component (C) comprises at least one or more members selected from the group consisting of chlorpheniramine and salts thereof. [5] The ophthalmic composition according to any one of [1] to [4], comprising 0.01 to 10 w / v % of component (A). [6] The ophthalmic composition according to any one of [1] to [5], comprising 0.005 to 20 w / v % of component (B). [7] The ophthalmic composition according to any one of [1] to [6], comprising 0.001 to 20 w / v % of component (C). [8] The ophthalmic composition according to any one of [1] to [7], wherein the ratio of the component (C) to 1 part by mass of the component (B) is 0.005 to 30 parts by mass. [9] The ophthalmic composition according to any one of [1] to [8], wherein the sodium ion concentration is 200 mM or less.

[10] The ophthalmic composition according to any one of [1] to [9], which has a pH of 5 to 9.

[11] (C1) The antihistamine comprises one or more selected from the group consisting of chlorpheniramine and its salts, (C2) The anti-inflammatory agent comprises one or more selected from the group consisting of pranoprofen and its salts, (C3) the amino acids include one or more selected from the group consisting of taurine and salts thereof; The proportion of component (A) is 0.1 to 1 w / v%, The proportion of component (B) is 0.05 to 5 w / v%, The proportion of the component (C) is 0.01 to 10 w / v%, The sodium ion concentration is 150 mM or less, The ophthalmic composition according to any one of [1] to

[10] , which has a pH of 5.5 to 8.5.

[12] (C1) The antihistamine comprises one or more selected from the group consisting of chlorpheniramine and its salts, (C2) The anti-inflammatory agent comprises one or more selected from the group consisting of pranoprofen and its salts, (C3) the amino acids include one or more selected from the group consisting of taurine and salts thereof; The proportion of component (A) is 0.1 to 1 w / v%, The proportion of component (B) is 0.05 to 5 w / v%, The proportion of the component (C) is 0.01 to 10 w / v%, The ratio of sodium ions is 30 moles or less (for example, 10 moles or less) per mole of component (A), The ophthalmic composition according to any one of [1] to

[11] , which has a pH of 5.5 to 8.5.

[13] The ophthalmic composition according to any one of [1] to

[12] , wherein component (C) comprises one or more selected from the group consisting of chlorpheniramine and salts thereof, and one or more selected from the group consisting of pranoprofen and salts thereof.

[14] The ophthalmic composition according to any one of [1] to

[13] , wherein the component (C) contains 0.01 to 0.05 w / v % chlorpheniramine maleate.

[15] The ophthalmic composition according to any one of [1] to

[14] , wherein component (B) includes trometamol.

[16] The ophthalmic composition according to any one of [1] to

[15] , wherein the sodium ion concentration is 40 mM or less.

[17] The ophthalmic composition according to any one of [1] to

[16] , wherein the sodium ion concentration is 20 mM or less.

[18] The ophthalmic composition according to any one of [1] to

[17] , wherein the sodium ion concentration is 10 mM or less (for example, 0 to 10 mM).

[19] The ophthalmic composition according to any one of [1] to

[18] , further comprising a cooling agent (D), wherein the component (B) contains polyvinylpyrrolidone, the component (D) contains a terpenoid, and the proportion of the component (B) is less than 3 w / v %.

[20] The ophthalmic composition according to

[19] , wherein the proportion of component (B) is 2 w / v % or less. [twenty one] The ophthalmic composition according to

[19] or

[20] , wherein the (D) component contains menthol and the proportion of the (B) component is 1.5 w / v % or less. [twenty two] The ophthalmic composition according to any one of

[15] to

[21] , wherein the component (C) comprises one or more members selected from the group consisting of chlorpheniramine and salts thereof. [twenty three] (A) A method for inhibiting precipitation in an ophthalmic composition containing one or more selected from the group consisting of tranilast and salts thereof (a method for improving or enhancing dissolution stability), comprising the steps of: (B) one or more selected from the group consisting of polyvinylpyrrolidone and trometamol, and (C) A method comprising comprising comprising containing one or more components selected from the group consisting of (C1) antihistamines, (C2) anti-inflammatory agents, and (C3) amino acids, and adjusting the sodium ion concentration of the ophthalmic composition to 250 mM or less, or adjusting the ratio of sodium ions to 25 mol or less per mol of component (A). [twenty four] A method described in

[23] that suppresses precipitation at temperatures below 5°C. Effect of the Invention

[0014] The present invention can provide a novel ophthalmic composition containing tranilast. Such an ophthalmic composition can usually suppress precipitation even if it contains tranilast. In particular, such a precipitation suppression effect is often excellent at low temperatures (for example, 10°C or less, preferably 5°C or less), and precipitation can be suppressed even at 0°C or less. Therefore, the ophthalmic composition of the present invention can achieve dissolution stability not only when stored at low temperatures such as a refrigerator, but also in environments exposed to lower temperatures (storage in cold regions, when the temperature changes drastically, etc.).

[0015] In another embodiment of the present invention, an ophthalmic composition having high dissolution stability can be provided even if it contains an active ingredient other than tranilast. That is, in the present invention, the component (C) combined with tranilast is often an active ingredient that functions as an anti-inflammatory agent, etc., and even when combined with tranilast, the efficacy of each is not impaired. Furthermore, even when an active ingredient other than the component (C) is added, the precipitation inhibitory effect is not impaired, and each of the active ingredients can effectively exert its efficacy.

[0016] Moreover, such efficacy can be exerted even when the sodium ion concentration is extremely low (for example, 40 mM or less, preferably 20 mM or less, substantially in the absence of sodium ions). As described above, Patent Document 1 does not actually assume the addition of other active ingredients, but in the present invention, by combining polyvinylpyrrolidone with component (C), it is unexpectedly possible to ensure dissolution stability even when the sodium ion concentration is low.

[0017] Thus, in another embodiment of the present invention, excellent dissolution stability can be achieved while exerting the medicinal effects of tranilast and the medicinal effects of ingredients other than tranilast.

[0018] In another embodiment of the present invention, an ophthalmic composition having an excellent usability (or not impairing a good usability) can be efficiently obtained.

[0019] Thus, the composition of the present invention is highly practical. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] In this specification, the unit of content "w / v%" is synonymous with "g / 100 mL." In addition, in this specification, unless otherwise specified, the abbreviation "POE" means polyoxyethylene, and the abbreviation "POP" means polyoxypropylene.

[0021] [1. Ophthalmic composition] The ophthalmic composition of the present invention contains at least (A) tranilast and / or a salt thereof, (B) polyvinylpyrrolidone and / or trometamol, and (C) an antihistamine, an anti-inflammatory agent, and / or amino acids.

[0022] (A) Tranilast and / or its salt (ingredient (A)) The salt of tranilast may be any pharma- ceutically or physiologically acceptable salt, and examples thereof include organic acid salts (e.g., monocarboxylates (acetates, trifluoroacetates, butyrates, palmitates, stearates, etc.), polycarboxylates (fumarates, maleates, succinates, malonates, etc.), oxycarboxylates (lactates, tartrates, citrates, etc.), organic sulfonates (methanesulfonates, toluenesulfonates, tosylates, etc.), inorganic acid salts (e.g., hydrochlorides, sulfates, nitrates, hydrobromides, phosphates), salts with organic bases (e.g., salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.), salts with inorganic bases (e.g., ammonium salts; salts with alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), aluminum, etc.), and the like.

[0023] The sodium salt of tranilast is included in the sodium ion described below. Therefore, when component (A) contains a sodium salt, it is necessary to use the sodium salt so that the sodium ion concentration in the entire composition falls within the range described below.

[0024] Preferred tranilast and / or salts thereof include tranilast and non-sodium salts of tranilast. More preferred tranilast and / or salts thereof include tranilast and non-metal salts of tranilast, with tranilast being particularly preferred.

[0025] Tranilast and / or a salt thereof may be used alone or in combination of two or more kinds.

[0026] The content of the 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 0.3 to 1 w / v%, and most preferably about 0.45 to 0.6 w / v%, relative to the total amount of the composition. Of these, 0.5 w / v% is particularly preferred.

[0027] (B) Polyvinylpyrrolidone and / or trometamol (component (B)) Polyvinylpyrrolidone (PVP) is a polymer whose polymerization component is vinylpyrrolidone (N-vinyl-2-pyrrolidone).

[0028] The molecular weight of such polyvinylpyrrolidone is not particularly limited, and may be, for example, about 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 about 200000 or less (e.g., 2500 to 100000, preferably 5000 to 80000, more preferably 10000 to 50000, particularly preferably 15000 to 40000, and most preferably 20000 to 30000).

[0029] Representative polyvinylpyrrolidones include polyvinylpyrrolidone K25, K30, K90, and the like.

[0030] Two or more different types of polyvinylpyrrolidone may be combined.

[0031] Component (B) may contain polyvinylpyrrolidone or trometamol (tris(hydroxymethyl)aminomethane), or these may be used in combination.

[0032] The content of component (B) in the composition may be, for example, 0.001 w / v% or more, preferably 0.005 to 20 w / v%, more preferably 0.01 to 10 w / v%, even more preferably 0.03 to 5 w / v%, and even more preferably about 0.05 to 5 w / v%, or may be 0.1 to 10 w / v% (e.g., 0.2 to 7 w / v%, preferably 0.3 to 5 w / v%, even more preferably 0.5 to 4.5 w / v%, and most preferably 1.0 to 3.0 w / v%), or may be less than 3 w / v%, relative to the total amount of the composition.

[0033] In particular, when component (B) contains polyvinylpyrrolidone, the content of component (B) in the composition may be an amount that is not too high, for example, less than 3 w / v% (e.g., 2.7 w / v% or less), preferably 2.5 w / v% or less (e.g., 2.2 w / v% or less), more preferably 2 w / v% or less (e.g., 1.7 w / v% or less), even more preferably 1.5 w / v% or less (e.g., 1.2 w / v% or less), and even more preferably 1 w / v% or less, relative to the total amount of the composition. By setting the content as described above, it is possible to efficiently achieve an excellent feeling when used (e.g., a feeling when used with less stickiness, stains, a foreign body sensation, etc.) even in a composition containing polyvinylpyrrolidone (particularly a composition further containing a cooling agent described below).

[0034] Furthermore, particularly when component (B) contains trometamol, the content of component (B) in the composition may be, for example, about 0.01 to 10 w / v%, preferably 0.02 to 8 w / v%, more preferably 0.03 to 7 w / v%, even more preferably 0.05 to 6 w / v% (e.g., 0.08 to 5 w / v%), and even more preferably 0.1 to 4 w / v%, relative to the total amount of the composition.

[0035] The proportion of the (B) component, per 1 part by mass of the (A) component, may, for example, be 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 more particularly preferably 0.05 to 8 parts by mass, or may be about 0.1 to 15 parts by mass (for example, 0.2 to 12 parts by mass, preferably 0.3 to 10 parts by mass, more preferably 0.5 to 8 parts by mass, and most preferably 2 to 6 parts by mass).

[0036] (C) Antihistamines, anti-inflammatory agents and / or amino acids (ingredient (C)) (C1) Antihistamines The antihistamine (hereinafter, sometimes referred to as (C1) antihistamine, (C1) component, etc.) is not particularly limited as long as it is a substance having an antihistamine effect, and examples thereof include chlorpheniramine, epinastine, ketotifen, olopatadine, levocabastine, iproheptine, and salts thereof.

[0037] The salt may be any pharma- ceutically or physiologically acceptable salt, and examples thereof include the salts exemplified in the section on component (A), such as organic acid salts (e.g., maleate, fumarate, etc.), inorganic acid salts (e.g., hydrochloride, sulfate, etc.), and metal salts.

[0038] Note that sodium salts are included in the sodium ions described below. Therefore, when component (C1) contains a sodium salt, it is necessary to use the sodium salt so that the sodium ion concentration in the entire composition falls within the range described below.

[0039] Specific examples of the salt include chlorpheniramine maleate and iproheptine hydrochloride.

[0040] Preferred antihistamines are chlorpheniramine and its salts (such as non-metallic salts), with chlorpheniramine maleate being particularly preferred.

[0041] Therefore, the antihistamine may contain at least one or more selected from the group consisting of chlorpheniramine and salts thereof (particularly, chlorpheniramine maleate).

[0042] In such a case, the proportion of one or more selected from the group consisting of chlorpheniramine and salts thereof (particularly, chlorpheniramine maleate) relative to the entire antihistamine may be, for example, 10% by mass or more, preferably 30% by mass or more, more preferably 50% by mass or more, particularly preferably 70% by mass or more, most preferably 80% by mass or more, 90% by mass or more (e.g., 95% by mass or more), or may be substantially 100% by mass.

[0043] The antihistamines may be used alone or in combination of two or more. In the present specification, the antihistamine may not generally contain diphenhydramine and its salts. In other words, the antihistamine may not contain diphenhydramine and its salts. In such a case, the composition of the present invention may not contain diphenhydramine and its salts as the antihistamine (i.e., it may contain an antihistamine that does not contain diphenhydramine and its salts), and may contain diphenhydramine and its salts as an optional component.

[0044] (C2) Anti-inflammatory agent The anti-inflammatory agent (hereinafter sometimes referred to as (C2) anti-inflammatory agent, (C2) component, etc.) is not particularly limited as long as it is a substance having an anti-inflammatory effect, and examples thereof include pranoprofen, indomethacin, allantoin, berberine, azulene sulfonic acid, diclofenac, bromfenac, glycyrrhizic acid, zinc, silver, tranexamic acid, lysozyme, and salts thereof.

[0045] Examples of the salt include salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, and the like, as exemplified in the section on component (A), such as sulfate salts, lactate salts, hydrochloride salts, chloride salts, sodium salts, and potassium salts.

[0046] Specific salts include berberine sulfate, berberine chloride, dipotassium glycyrrhizinate, sodium azulene sulfonate, diclofenac sodium, bromfenac sodium, zinc sulfate, zinc lactate, silver nitrate, and lysozyme chloride.

[0047] Preferred anti-inflammatory agents include pranoprofen, salts of pranoprofen, allantoin, berberine sulfate, sodium azulene sulfonate, dipotassium glycyrrhizinate, zinc sulfate, etc., of which pranoprofen and / or its salts (such as non-metallic salts) are preferred, with pranoprofen being most preferred.

[0048] Therefore, the anti-inflammatory agent may particularly include at least one or more selected from the group consisting of pranoprofen and salts thereof (particularly, pranoprofen).

[0049] In such a case, the proportion of one or more selected from the group consisting of pranoprofen and salts thereof (particularly, pranoprofen) relative to the entire anti-inflammatory agent may be, for example, 10% by mass or more, preferably 30% by mass or more, more preferably 50% by mass or more, particularly preferably 70% by mass or more, most preferably 80% by mass or more, 90% by mass or more (e.g., 95% by mass or more), or substantially 100% by mass.

[0050] The salt of pranoprofen may be any pharma- ceutically or physiologically acceptable salt, and examples thereof include salts with inorganic bases such as alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, etc.), ammonium salts, and metal salts (aluminum salt, etc.); and salts with organic bases such as organic amine salts (methylamine salt, triethylamine salt, diethylamine salt, triethanolamine salt, morpholine salt, piperazine salt, pyrrolidine salt, tripyridine salt, picoline salt, etc.).

[0051] The anti-inflammatory agent (eg, pranoprofen and its salts) may be in the form of a hydrate.

[0052] The anti-inflammatory agents may be used alone or in combination of two or more kinds.

[0053] (C3) Amino acids Amino acids (hereinafter sometimes referred to as (C3) amino acids, (C3) components, etc.) include, for example, amino acids or salts thereof, and amino acid analogs, and also include compounds having an amino group and a carboxyl group or a sulfone group in the molecule, or derivatives thereof.

[0054] Specific 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, and their salts, diaminomonocarboxylic acids such as arginine and lysine, and derivatives of aminoethylsulfonic acid (taurine), and their salts.

[0055] Among the amino acids, examples of mucopolysaccharides or derivatives or salts thereof include acidic mucopolysaccharides such as derivatives of chondroitin sulfate, hyaluronic acid, alginic acid, etc., or salts thereof.

[0056] Specific examples of amino acids and mucopolysaccharides include glycine, alanine, γ-aminobutyric acid, γ-aminovaleric acid, epsilon aminocaproic acid, aspartic acid, glutamic acid, arginine, aminoethylsulfonic acid, chondroitin sulfate, hyaluronic acid, alginic acid, or salts thereof.

[0057] Chondroitin sulfate is a sugar chain in which D-glucuronic acid and N-acetylglucosamine are repeated, and sulfate is ester-linked to all or some of the hydroxyl groups. The positions and number of sulfate bonds vary, and chondroitin sulfate also has derivatives (e.g., those in which all or some of the N-acetylglucosamine is replaced with iduronic acid). Such chondroitin sulfate may have any structure. Examples include chondroitin 4-sulfate (chondroitin sulfate A), chondroitin 6-sulfate (chondroitin sulfate C), and chondroitin sulfate E in which the 4- and 6-positions of N-acetylglucosamine are sulfated. Chondroitin sulfate may also be extracted from animals.

[0058] The salt of an amino acid or the salt of a mucopolysaccharide includes a medicamentously, pharmacologically or physiologically acceptable salt. Examples of such salts include salts with organic acids [e.g., monocarboxylates (acetates, trifluoroacetates, butyrates, palmitates, stearates, etc.), polycarboxylates (fumarates, maleates, etc.), oxycarboxylates (lactates, tartrates, citrates, succinates, malonates, etc.), organic sulfonates (methanesulfonates, toluenesulfonates, tosylates, etc.)], salts with inorganic acids (e.g., hydrochlorides, sulfates, nitrates, hydrobromides, phosphates, etc.), salts with organic bases (e.g., salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.), salts with inorganic bases [e.g., ammonium salts; salts with metals such as alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), and aluminum], and the like, and the salts are appropriately selected depending on the compound.

[0059] Specific 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.

[0060] Note that sodium salts are included in the sodium ions described below. Therefore, when component (C3) contains a sodium salt, it is necessary to use the sodium salt so that the sodium ion concentration in the entire composition falls within the range described below.

[0061] The amino acids may be of D-, L- or DL-form.

[0062] Preferred amino acids include aminoethylsulfonic acid (taurine) or a salt thereof, sodium chondroitin sulfate, aspartates (e.g., potassium L-aspartate, magnesium potassium L-aspartate), epsilon-aminocaproic acid or a salt thereof, sodium hyaluronate, and the like. Among these, aminoethylsulfonic acid (taurine) and / or a salt thereof are preferred, and aminoethylsulfonic acid (taurine) is most preferred.

[0063] Therefore, the amino acids may contain at least one or more types selected from the group consisting of aminoethylsulfonic acid and salts thereof (particularly aminoethylsulfonic acid).

[0064] In such a case, the proportion of one or more types selected from the group consisting of aminoethylsulfonic acid and salts thereof (particularly, aminoethylsulfonic acid) relative to the total amount of amino acids may be, for example, 10% by mass or more, preferably 30% by mass or more, more preferably 50% by mass or more, particularly preferably 70% by mass or more, most preferably 80% by mass or more, 90% by mass or more (e.g., 95% by mass or more), or substantially 100% by mass.

[0065] The amino acids may be used alone or in combination of two or more kinds.

[0066] (C) Ingredients and their proportions In the composition of the present invention, the component (C) may contain one or more components selected from the group consisting of the components (C1), (C2), and (C3), and may be a combination of these. For example, the components (C1) and (C2) may be combined, the components (C1) and (C3) may be combined, or the components (C1), (C2), and (C3) may be combined.

[0067] In particular, in the present invention, the antihistamine may be a combination of a (C1) component containing one or more selected from the group consisting of chlorpheniramine and salts thereof (particularly, chlorpheniramine maleate) and another (C) component (for example, a (C2) component containing one or more selected from the group consisting of pranoprofen and salts thereof (particularly, pranoprofen)).

[0068] Combining a plurality of components (C) in this manner may be more advantageous in terms of, for example, the effect of inhibiting precipitation.

[0069] The content of component (C) in the composition may be, for example, 0.0001 w / v% or more, preferably 0.001 to 20 w / v%, more preferably 0.003 to 10 w / v%, even more preferably 0.005 to 8 w / v%, even more preferably about 0.01 to 7 w / v%, and usually about 0.01 to 10 w / v%, relative to the total amount of the composition.

[0070] When the composition contains component (C1), the content of component (C1) 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%, still more preferably 0.01 to 0.5 w / v%, particularly preferably 0.015 to 0.3 w / v% (e.g., 0.02 to 0.1 w / v%), and most preferably about 0.025 to 0.05 w / v% (e.g., 0.03 w / v%), and typically about 0.01 to 0.05 w / v%, relative to the total amount of the composition.

[0071] When the composition contains component (C2), the content of component (C2) in the composition may be, for example, about 0.0001 w / v% or more, preferably 0.001 to 10 w / v%, more preferably 0.003 to 5 w / v%, even more preferably 0.005 to 1 w / v%, still 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.

[0072] When the composition contains the (C3) component, the content of the (C3) component in the composition may be, for example, 0.001 w / v% or more, preferably 0.01 to 20 w / v%, more preferably 0.03 to 15 w / v%, even more preferably 0.05 to 10 w / v%, even more preferably 0.1 to 8 w / v%, and particularly preferably about 0.15 to 7 w / v%, and may usually be 0.1 to 15 w / v% (e.g., 0.2 to 10 w / v%, preferably 0.3 to 8 w / v%, and even more preferably 0.5 to 7 w / v%) relative to the total amount of the composition.

[0073] When the composition contains the (C1) component and the (C2) component, the ratio thereof (mass ratio) of the former / the latter may be about 1 / 0.01 to 1 / 100 (e.g., 1 / 0.05 to 1 / 50), preferably about 1 / 0.1 to 1 / 20 (e.g., 1 / 0.3 to 1 / 10), more preferably about 1 / 0.5 to 1 / 8, particularly preferably about 1 / 1 to 1 / 5 (e.g., 1 / 1.2 to 1 / 3), and most preferably about 1 / 1.3 to 1 / 2 (e.g., 1 / 1.4 to 1 / 1.8).

[0074] The proportion of the (C) component may be, for example, 0.001 to 30 parts by mass, preferably 0.003 to 25 parts by mass, more preferably 0.005 to 20 parts by mass, particularly preferably 0.01 to 15 parts by mass, even more particularly preferably 0.02 to 10 parts by mass, and most preferably 0.03 to 5 parts by mass, per part by mass of the (A) component.

[0075] In particular, when the (C) component includes the (C1) component, the proportion of the (C1) component may be, for example, 0.001 to 5 parts by mass, preferably 0.003 to 1 part by mass, further preferably 0.005 to 0.5 parts by mass, particularly preferably 0.01 to 0.3 parts by mass, further particularly preferably 0.02 to 0.2 parts by mass, and most preferably 0.03 to 0.1 parts by mass (for example, 0.06 parts by mass) per part by mass of the (A) component.

[0076] In particular, when the (C) component includes the (C2) component, the proportion of the (C2) component may be, for example, 0.001 to 5 parts by mass, preferably 0.01 to 1 part by mass, and more preferably 0.05 to 0.5 parts by mass (e.g., 0.1 part by mass) per 1 part by mass of the (A) component.

[0077] In particular, when the (C) component includes the (C3) component, the proportion of the (C3) component may be, for example, 0.001 to 20 parts by mass, preferably 0.01 to 10 parts by mass, and more preferably 0.2 to 5 parts by mass (e.g., 2 parts by mass) per part by mass of the (A) component.

[0078] The proportion of the (C) component may be, for example, 0.001 to 50 parts by mass, preferably 0.002 to 40 parts by mass, further preferably 0.005 to 30 parts by mass, particularly preferably 0.007 to 25 parts by mass, further particularly preferably 0.008 to 20 parts by mass, and most preferably 0.01 to 15 parts by mass, per 1 part by mass of the (B) component.

[0079] In particular, when the (C) component includes the (C1) component, the proportion of the (C1) component may be, for example, 0.001 to 2 parts by mass, preferably 0.002 to 1.8 parts by mass, more preferably 0.005 to 1.5 parts by mass, particularly preferably 0.007 to 1.2 parts by mass, even more particularly preferably 0.008 to 1 part by mass, and most preferably 0.01 to 0.5 parts by mass, per 1 part by mass of the (B) component.

[0080] The proportion of the (C) component may be, for example, 0.0005 to 50 parts by mass, preferably 0.001 to 30 parts by mass, further preferably 0.003 to 25 parts by mass, particularly preferably 0.005 to 20 parts by mass, further particularly preferably 0.007 to 15 parts by mass, and most preferably 0.01 to 10 parts by mass, per 1 part by mass of the total amount of the (A) component and the (B) component.

[0081] In particular, when the (C) component includes the (C1) component, the proportion of the (C1) component may be, for example, 0.0005 to 1 part by mass, preferably 0.001 to 0.5 parts by mass, further preferably 0.003 to 0.3 parts by mass, particularly preferably 0.005 to 0.2 parts by mass, further particularly preferably 0.007 to 0.15 parts by mass, and most preferably 0.008 to 0.1 parts by mass, per 1 part by mass of the total amount of the (A) and (B) components.

[0082] [Other ingredients] The composition of the present invention may further contain other components in addition to the components (A) to (C). In the present invention, since a specific component is combined with tranilast (and the sodium ion concentration is set to a specific concentration), dissolution stability can often be ensured even when other components are contained.

[0083] (D) Cooling agent ((D) ingredient) The composition of the present invention may contain a cooling agent (hereinafter, may be referred to as (D) cooling agent, (D) component, etc.).

[0084] The cooling agent is not particularly limited, but examples thereof include terpenoids such as menthol, anethole, eugenol, camphor, geraniol, cineol, borneol, limonene, and ryunou. These may be in the d-, l-, or dl-form. Other examples include essential oils such as peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, bergamot oil, eucalyptus oil, and rose oil.

[0085] Of these, terpenoids are preferred, and among these, menthol, camphor, geraniol, cineol, borneol, and rhubarb are preferred, with menthol, camphor, and borneol being more preferred, and menthol being even more preferred. Moreover, from the viewpoint of more significantly exhibiting the effects of the present invention, eucalyptus oil is also preferred.

[0086] The cooling agents may be used alone or in combination of two or more. In particular, a cooling agent (for example, a terpenoid such as menthol) is suitable in combination with the component (B) (particularly in combination with a component (B) containing a predetermined proportion of polyvinylpyrrolidone) because it easily provides an excellent feeling when used.

[0087] The proportion of component (D) relative to the total amount of the composition may be, for example, 0.0001 w / v% or more, 0.0005 w / v% or more, 0.001 w / v% or more, 0.002 w / v% or more, 0.003 w / v% or more, 0.004 w / v% or more, 0.005 w / v% or more, 0.006 w / v% or more, 0.007 w / v% or more, 0.008 w / v% or more, 0.009 w / v% or more, or 0.01 w / v% or more.

[0088] In addition, the proportion of the (D) component, in terms of the total amount of the (D) component relative to the total amount of the composition, may be 1 w / v% or less, 0.1 w / v% or less, 0.09 w / v% or less, 0.08 w / v% or less, 0.07 w / v% or less, 0.06 w / v% or less, 0.05 w / v% or less, 0.04 w / v% or less, 0.03 w / v% or less, or 0.02 w / v% or less.

[0089] (E) Fat-soluble antioxidant (ingredient (E)) The composition of the present invention may contain a fat-soluble antioxidant (hereinafter, may be referred to as (E) fat-soluble antioxidant, (E) component, etc.).

[0090] Examples of fat-soluble antioxidants include butyl-containing phenols such as dibutylhydroxytoluene (BHT) and butylhydroxyanisole (BHA); nordihydroguaiaretic acid (NDGA); ascorbic acid esters such as ascorbyl palmitate, ascorbyl stearate, aminopropyl ascorbyl phosphate, tocopherol ascorbyl phosphate, ascorbyl triphosphate, and ascorbyl phosphate palmitate; gallic acid esters such as ethyl gallate, propyl gallate, octyl gallate, and dodecyl gallate; propyl gallate; 3-butyl-4-hydroxyquinolin-2-one; carotenoids such as lutein and astaxanthin; polyphenols such as anthocyanins, catechin, tannin, and curcumin; and CoQ10.

[0091] Of these, dibutylhydroxytoluene is preferred. On the other hand, the composition of the present invention may not contain BHT.

[0092] The fat-soluble antioxidants may be used alone or in combination of two or more kinds.

[0093] The content of component (E) in the composition may be, for example, about 0.0001 to 0.1 w / v%, preferably 0.0005 to 0.01 w / v%, more preferably 0.0007 to 0.009 w / v%, even more preferably 0.001 to 0.008 w / v%, even more preferably 0.003 to 0.007 w / v%, and most preferably 0.0045 to 0.006 w / v%, relative to the total amount of the composition.

[0094] Antiallergic agent (ingredient (F)) The composition of the present invention may contain an antiallergic agent (hereinafter, may be referred to as (F) antiallergic agent, (F) component, etc.).

[0095] Examples of antiallergic agents (antiallergic agents other than tranilast and / or a salt thereof) include cromoglicate, ibudilast, ashitazanolast, tazanolast, suplatast, pemirolast, levocabastine, olopatadine, ketotifen, amlexanox, oxatomide, and salts thereof.

[0096] Examples of the salts include the salts exemplified in the sections on components (A) to (C) above, such as alkali metal or alkaline earth metal salts (sodium cromoglycate, potassium cromoglycate, magnesium cromoglycate, calcium cromoglycate, etc.), inorganic acid salts (for example, olopatadine hydrochloride, etc.), and organic acid salts [for example, tosylate salts, fumarate salts (ketotifen fumarate, etc.)].

[0097] Of these, cromoglycic acid and its salts are preferred, with sodium cromoglycate being more preferred.

[0098] The antiallergic agents may be used alone or in combination of two or more kinds.

[0099] The content of component (F) in the composition may be, for example, about 0.1 to 10 w / v%, preferably 0.2 to 8 w / v%, more preferably 0.3 to 5 w / v%, even more preferably 0.5 to 3 w / v%, particularly preferably 0.7 to 2 w / v%, even more particularly preferably 0.8 to 1.5 w / v%, and most preferably 0.9 to 1.2 w / v%, relative to the total amount of the composition.

[0100] The composition of the present invention may contain various components (for example, components not belonging to the categories of the above-mentioned components (A) to (F)). Examples of such components (additives) include surfactants, preservatives, buffers, pH regulators, isotonicity agents, thickeners or viscosifiers, stabilizers, oils, sugars, polymeric compounds, polyhydric alcohols, inorganic salts, and non-fat-soluble antioxidants (or water-soluble antioxidants).

[0101] The additives may be used alone or in combination of two or more thereof. Furthermore, each additive may be used alone or in combination of two or more thereof.

[0102] Specific examples of the additives are given below.

[0103] Surfactants The composition of the present invention may contain a surfactant. Examples of the surfactant include a nonionic surfactant.

[0104] Nonionic surfactants include polysorbates (POE sorbitan fatty acid esters) such as POE(20) sorbitan monolaurate (polysorbate 20), POE(20) sorbitan monopalmitate (polysorbate 40), POE(20) sorbitan monostearate (polysorbate 60), POE(20) sorbitan tristearate (polysorbate 65), and POE(20) sorbitan monooleate (polysorbate 80); poloxamer 407, poloxamer 235, poloxamer 188, poloxamer 235 ... POE·POP glycols such as POE 403, Poloxamer 237, and Poloxamer 124; POE hydrogenated castor oils such as POE hydrogenated castor oil 40, POE hydrogenated castor oil 50, POE hydrogenated castor oil 60, and POE hydrogenated castor oil 80; POE castor oils such as POE castor oil 3, POE castor oil 4, POE castor oil 6, POE castor oil 7, POE castor oil 10, POE castor oil 13.5, POE castor oil 17, POE castor oil 20, POE castor oil 25, POE castor oil 30, POE castor oil 35, and POE castor oil 50; poly(monostearate) Ethylene glycol (2 E.O.), polyethylene glycol monostearate (4 E.O.), polyethylene glycol monostearate (9 E.O.), polyethylene glycol monostearate (10 E.O.), polyethylene glycol monostearate (23 E.O.), polyethylene glycol monostearate (25 E.O.), polyethylene glycol monostearate (32 E.O.), polyethylene glycol monostearate (40 E.O., Polyoxyl 40 stearate), poly Examples of the polyethylene glycol monostearate include ethylene glycol (45 E.O.), polyethylene glycol monostearate (55 E.O.), polyethylene glycol monostearate (75 E.O.), and polyethylene glycol monostearate (140 E.O.); POE alkyl ethers such as POE (9) lauryl ether; POE-POP alkyl ethers such as POE (20) POP (4) cetyl ether; and POE alkyl phenyl ethers such as POE (10) nonylphenyl ether.In the above compounds, POE stands for polyoxyethylene, POP stands for polyoxypropylene, and the numbers in parentheses stand for the number of moles added.

[0105] 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 40 stearate being more preferred, with polysorbate 80 and POE hydrogenated castor oil 60 being even more preferred, and polysorbate 80 being particularly preferred.

[0106] The surfactants may be used alone or in combination of two or more kinds.

[0107] When an ionic surfactant is incorporated into the composition of the present invention, the proportion of the ionic 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.

[0108] The proportion of the ionic surfactant may be, for example, 5 w / v% or less, preferably 1 w / v% or less, more preferably 0.5 w / v% or less, and particularly 0.3 w / v% or less, relative to the total amount of the composition.

[0109] Preservatives The compositions of the present invention may also contain a preservative. Examples of preservatives include polydonium chloride, alkyl polyaminoethyl glycines (e.g., alkyl diaminoethyl glycine hydrochloride, etc.), sodium benzoate, ethanol, quaternary ammonium salts (e.g., benzalkonium chloride, benzethonium chloride, etc.), chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxybenzoic acid esters (e.g., methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc.), oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (e.g., polyhexanide hydrochloride, etc.), and Glokill (manufactured by Rhodia).

[0110] Among these, alkyl polyaminoethyl glycines (e.g., alkyl diaminoethyl glycine hydrochloride), sodium benzoate, ethanol, quaternary ammonium salts, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, paraoxybenzoic acid esters, and biguanide compounds are preferred, with quaternary ammonium salts, chlorhexidine gluconate, chlorobutanol, and biguanide compounds being more preferred, and benzalkonium chloride and polyhexanide hydrochloride being even more preferred.

[0111] On the other hand, the composition of the present invention may not contain sorbic acid and its salts (such as potassium sorbate).

[0112] When a preservative is added to the composition of the present invention, an example of the amount of the preservative to be added is 0.000001 w / v% or more, preferably 0.00001 w / v% or more, preferably 0.00005 w / v% or more, preferably 0.001 w / v% or more, preferably 0.005 w / v% or more, based on the total amount of the composition. Also, the total amount of the preservative to be added is 1 w / v% or less, preferably 0.1 w / v% or less, preferably 0.05 w / v% or less, preferably 0.03 w / v% or less, preferably 0.025 w / v% or less, based on the total amount of the composition.

[0113] Buffer The compositions of the present invention may also include a buffering agent. Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer and the like.

[0114] Components of the borate buffer include boric acid, borate salts (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.), etc. The borate salts may be hydrates.

[0115] Ingredients of the phosphate buffer include phosphoric acid, phosphate salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.), etc. The phosphate salts may be hydrates.

[0116] Components of the carbonate buffer include carbonic acid, carbonates (potassium carbonate, sodium carbonate, calcium carbonate, potassium bicarbonate, sodium bicarbonate, magnesium carbonate, etc.), etc. The carbonates may be hydrates.

[0117] Components of the citrate buffer include citric acid, citrate salts (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.), etc. The citrate salts may be in the form of a hydrate.

[0118] Components of the acetate buffer include acetic acid, acetate salts (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.), etc. The acetate salts may be hydrates.

[0119] Among them, boric acid buffers and phosphate buffers are preferred, and boric acid buffers are more preferred. As the boric acid buffer, a combination of boric acid and its salts is preferred, a combination of boric acid and an alkali metal salt and / or an alkaline earth metal salt of boric acid is more preferred, a combination of boric acid and an alkali metal salt of boric acid is even more preferred, and a combination of boric acid and borax is even more preferred.

[0120] When a buffer is added to the composition of the present invention, the amount of the buffer varies depending on the type of buffer, the type and amount of other ingredients, etc., and cannot be uniformly specified, but examples of the buffer amount include 0.001 w / v% or more, particularly 0.01 w / v% or more, particularly 0.05 w / v% or more, particularly 0.1 w / v% or more, based on the total amount of the composition. Also, the buffer amount includes 10 w / v% or less, particularly 5 w / v% or less, particularly 3 w / v% or less, particularly 2.5 w / v% or less, particularly 2 w / v% or less, based on the total amount of the composition.

[0121] In particular, when a borate buffer is used, the proportion of the buffer in the composition may be about 0.001 to 10 w / v%, preferably 0.01 to 5 w / v%, more preferably 0.05 to 3 w / v%, even more preferably 0.1 to 2 w / v%, and even more preferably 0.1 to 1 w / v%, based on the total composition.

[0122] pH Adjustment Agent Examples of pH adjusters include hydrochloric acid, sulfuric acid, polyphosphoric acid, organic acids (propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, tartaric acid, malic acid, succinic acid, etc.), sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, and diisopropanolamine. The pH adjusters may be used alone or in combination of two or more kinds.

[0123] 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. The isotonicity agents may be used alone or in combination of two or more kinds.

[0124] Thickeners or Viscosifiers The ophthalmic composition of the present invention may contain a thickening agent or a viscosifying agent to the extent that the effect of the present invention is not impaired.

[0125] Examples of thickening agents or viscosifying agents include guar gum, hydroxypropyl guar gum, cellulose-based polymer compounds (e.g., methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, etc.), gum arabic, karaya gum, xanthan gum, agar, alginic acid, α-cyclodextrin, dextrin, dextran, mucopolysaccharides (e.g., heparinoids, heparin, heparin sulfate, heparan sulfate, heparinoid, hyaluronic acid, hyaluronate (sodium salt, etc.), etc.), starch, chitin and derivatives thereof, chitosan and derivatives thereof, carrageenan, sorbitol ... Examples of suitable alginate salts include tallow, polyvinyl polymer compounds (polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, etc.), alkali metal salts of polyacrylic acid (sodium salt, 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.), powdered tragacanth, and triisopropanolamine. The thickening or viscosifying agents may be used alone or in combination of two or more.

[0126] Stabilizers Stabilizers include, for example, trometamol, sodium formaldehyde sulfoxylate (Rongalit), monoethanolamine, aluminum monostearate, and glyceryl monostearate. The stabilizers may be used alone or in combination of two or more kinds.

[0127] 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. The oils may be used alone or in combination of two or more.

[0128] Sugars Examples of sugars include monosaccharides and disaccharides, specifically glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, sorbitol, and mannitol. The sugars may be used alone or in combination of two or more kinds.

[0129] Polyhydric alcohol Examples of the polyhydric alcohol include polyethylene glycol, glycerin, propylene glycol, xylitol, diethylene glycol, mannitol, sorbitol, and polyvinyl alcohol. The polyhydric alcohols may be used alone or in combination of two or more kinds.

[0130] Inorganic salts Examples of inorganic salts include potassium chloride, sodium chloride, calcium chloride, magnesium chloride, sodium bicarbonate, sodium carbonate (including dry sodium carbonate), potassium bicarbonate, potassium carbonate, magnesium sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium hydrogen sulfite, sodium sulfite, potassium acetate, sodium acetate, and sodium thiosulfate. Among these, potassium chloride, sodium chloride, calcium chloride, sodium hydrogen carbonate, sodium carbonate (including dry sodium carbonate), magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate are preferred, potassium chloride, sodium chloride, calcium chloride, sodium hydrogen phosphate, and sodium dihydrogen phosphate are more preferred, and potassium chloride and sodium chloride are even more preferred. The inorganic salts may be used alone or in combination of two or more kinds.

[0131] Water-soluble antioxidants Examples of water-soluble antioxidants include ascorbic acid, ascorbic acid derivatives (such as disodium ascorbic acid 2-sulfate, sodium ascorbate, magnesium ascorbyl 2-phosphate, and sodium ascorbyl 2-phosphate), sodium hydrogen sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, edetic acid, or a salt thereof (such as disodium edetate and tetrasodium edetate). The water-soluble antioxidants may be used alone or in combination of two or more kinds.

[0132] The composition of the present invention may further contain a component having pharmacological activity or physiological activity.

[0133] The pharmacologically active ingredients or physiologically active ingredients can be used alone or in combination of two or more kinds.

[0134] Examples of such pharmacologically active ingredients and physiologically active ingredients include active ingredients in various medicines listed in the 2012 edition of the General Drug Manufacturing and Sales Approval Standards (supervised by the Japan Society of Regulatory Science). Examples include decongestants, eye muscle regulating agents, astringents, vitamins, amino acids, antibacterial agents or disinfectants, local anesthetic ingredients, analgesics, and sulfa drugs. Specific examples of these drugs are listed below.

[0135] Decongestants (vasoconstrictors) Decongestants include, for example, α-adrenergic agonists, specifically imidazoline decongestants such as oxymetazoline, tetrahydrozoline, naphazoline, or salts thereof such as hydrochlorides and nitrates, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine bitartrate, etc. These may be in any of the d-, l- or dl-forms.

[0136] To explain the imidazoline vasoconstrictor in detail, the salt of the imidazoline vasoconstrictor may be any salt that is pharma- ceutically or physiologically acceptable, and examples of such salts include organic acid salts such as maleate and fumarate, inorganic acid salts such as hydrochloride and sulfate, metal salts, etc. Among the salts, inorganic acid salts are preferred, hydrochloride or nitrate are more preferred, and hydrochloride (e.g., tetrahydrozoline hydrochloride) is particularly preferred.

[0137] Among decongestants (vasoconstrictors), imidazoline vasoconstrictors are preferred, tetrahydrozoline, naphazoline, or a salt thereof is more preferred, and tetrahydrozoline or a salt thereof is even more preferred.

[0138] Eye muscle regulator Examples of eye muscle adjusting agents include cholinesterase inhibitors having an active center similar to that of acetylcholine, specifically neostigmine methylsulfate, tropicamide, helenien, and atropine sulfate.

[0139] Vitamins Examples of vitamins include flavin adenine dinucleotide or a salt thereof (e.g., sodium flavin adenine dinucleotide), cobalamin or a salt thereof (e.g., cyanocobalamin, methylcobalamin), retinol, a salt thereof or a derivative thereof (e.g., retinol acetate, retinol palmitate), pyridoxine or a salt thereof (e.g., pyridoxine hydrochloride), panthenol, pantothenic acid or a salt thereof (e.g., sodium pantothenate, potassium pantothenate, calcium pantothenate, magnesium pantothenate), tocopherol, a salt thereof or a derivative thereof (e.g., tocopherol acetate, tocopherol succinate, tocopherol nicotinate), pyridoxal or a salt thereof (e.g., pyridoxal phosphate), ascorbic acid or a salt thereof (e.g., sodium ascorbate, calcium ascorbate), and the like.

[0140] Among these, flavin adenine dinucleotide or a salt thereof (particularly sodium flavin adenine dinucleotide), cobalamin or a salt thereof (particularly cyanocobalamin), retinol, a salt thereof or a derivative thereof (particularly retinol acetate and retinol palmitate), pyridoxine or a salt thereof (particularly pyridoxine hydrochloride), panthenol, pantothenic acid or a salt thereof (particularly sodium pantothenate and calcium pantothenate), tocopherol, a salt thereof or a derivative thereof (particularly tocopherol acetate) are preferred, with pyridoxine hydrochloride and tocopherol acetate being more preferred. The composition of the present invention may not contain pyridoxine or a salt thereof.

[0141] Antibacterial or disinfectant Examples of antibacterial or bactericidal agents include sulfa drugs such as sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxazole monoethanolamine, sulfisomazole sodium, and sulfisomidine sodium, alkylpolyaminoethylglycine, chloramphenicol, ofloxacin, norfloxacin, levofloxacin, and lomefloxacin hydrochloride.

[0142] Local anesthetic ingredients Examples of local anesthetic ingredients include procaine hydrochloride and lidocaine hydrochloride.

[0143] Pain reliever An example of the soothing agent is procaine hydrochloride.

[0144] Sulfa drugs Examples of sulfa drugs include sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, and sulfisomidine sodium.

[0145] Base or Carrier The compositions of the present invention may include a base or carrier. Compositions containing such bases or carriers can be prepared, for example, by mixing each of the above-mentioned components with a pharma- ceutically acceptable base or carrier, for example, by a conventional method described in the 17th Edition of the Japanese Pharmacopoeia.

[0146] Examples of the base or carrier include water, polar solvents (particularly water-soluble solvents) such as ethanol, oily bases, etc. The base or carrier may be used alone or in combination of two or more.

[0147] In particular, the composition of the present invention may be an aqueous composition (eg, a composition containing water or a mixture of water and a water-soluble solvent).

[0148] Properties The properties of the composition of the present invention are not particularly limited, and may be any of liquid, fluid, gel, semi-solid, etc. Also includes those that are liquid, fluid, gel, or semi-solid by preparation at the time of use. Semi-solid refers to a property that has plasticity that can be deformed by applying force, such as an ointment.

[0149] Furthermore, as described above, 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.

[0150] In the case of an aqueous composition, the content of water is preferably 50% by mass or more, more preferably 75% by mass or more, and even more preferably 90% by mass or more, based on the total amount of the composition (or preparation). It may also be 95% by mass or more, or 98% by mass or more. The base or carrier may consist of only water.

[0151] In the case of an oil-based composition, the water content is preferably less than 50% by mass, more preferably 30% by mass or less, and even more preferably 20% by mass or less, based on the total amount of the composition (or preparation).

[0152] Sodium ion content The composition of the present invention may have a sodium ion (or sodium) content within a specific range. By combining such a sodium ion content with the specific component, it may be possible to achieve more advantageous effects such as suppressing precipitation and dissolution stability.

[0153] For example, the sodium ion concentration of the composition of the present invention can be selected from a range of about 300 mM or less, and may be 250 mM or less (e.g., 240 mM or less), more preferably 230 mM or less, particularly preferably 200 mM or less, and most preferably 150 mM or less.

[0154] The sodium ion concentration of the composition of the present invention may be relatively low, for example, 100 mM or less (e.g., 90 mM or less), preferably 80 mM or less (e.g., 70 mM or less), more preferably 60 mM or less (e.g., 50 mM or less), and most preferably 40 mM or less (e.g., 30 mM or less), or may be even lower (e.g., 20 mM or less, preferably 10 mM or less, substantially 0 mM or the detection limit).

[0155] The amount of sodium ions can also be defined as a ratio to the (A) component. For example, in the composition of the present invention, the ratio of sodium ions can be selected from a range of about 30 mol or less relative to 1 mol of the (A) component, and may be 25 mol or less, preferably 20 mol or less, more preferably 15 mol or less, particularly preferably 12 mol or less, most preferably 10 mol or less (e.g., 9.5 mol or less), or may be a relatively low ratio [e.g., 9 mol or less (e.g., 8 mol or less), preferably 7 mol or less (e.g., 6 mol or less), more preferably 5 mol or less, particularly preferably 4 mol or less, most preferably 3 mol or less], or may be an even lower ratio (e.g., 2 mol or less, preferably 1 mol or less, more preferably 0.5 mol or less, particularly preferably 0.1 mol or less, substantially 0 mol or detection limit).

[0156] In addition, the sodium ion may be any ion that can be a free ion in the composition, and may form a salt.For example, even if tranilast forms a salt with sodium in the composition and the sodium ion is not in a free state, the sodium (ion) derived from such a salt is also included in the sodium ion. The amount or concentration of sodium (ion) may be obtained by measuring (directly measuring) the amount or concentration in the composition, or by calculating (indirectly measuring) the amount or concentration in the composition from the amount or concentration of sodium (ion) in the components (raw materials) that constitute the composition. The amount or concentration of sodium (ion) in the composition or raw materials may be measured by a conventional method or device (e.g., ion chromatography, etc.).

[0157] In addition, since sodium ions include sodium derived from each component as described above, when each component contains sodium as a salt, it is necessary to adjust the sodium ion concentration to the above range. From this viewpoint, it is desirable that the composition of the present invention contains small amounts or no sodium chloride, borax, sodium edetate, etc., which are widely used in eye drops and the like.

[0158] From this viewpoint, it may be preferable to use, in particular, a component that does not contain sodium [for example, in the case of a salt, a salt that is not a sodium salt (non-sodium salt)] as each of the components constituting the composition of the present invention (for example, components (A) to (C) and other components).

[0159] pH The pH of the composition of the present invention is preferably 3 or more (e.g., 4 or more), more preferably 5 or more (e.g., 5.5 or more), and even more preferably 6 or more. Also, the pH is preferably 10 or less, more preferably 9 or less, and even more preferably 8.5 or less.

[0160] The pH of the composition of the present invention may be, for example, 4 to 10, preferably 5 to 9, and more preferably 5.5 to 8.5 (e.g., 6.0 to 8.3), or may be greater than 7.5 [e.g., 7.6 to 9 (e.g., 7.7 to 8.5), 7.8 or more (e.g., 7.8 to 8.3)]. In the present invention, even at the above pH, the effects of the present invention (such as the effect of inhibiting precipitation) can be efficiently achieved.

[0161] Osmolarity The osmotic pressure ratio of the composition of the present invention is, for example, preferably 0.4 or more, more preferably 0.5 or more, and even more preferably 0.6 or more, and is preferably 5 or less, more preferably 3 or less, and even more preferably 2 or less.

[0162] The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to the osmotic pressure of 286 mOsm (0.9 w / v% sodium chloride aqueous solution) based on the 17th revised Japanese Pharmacopoeia. The osmotic pressure is measured according to the osmotic pressure measurement method (freezing point depression method) described in the 17th revised Japanese Pharmacopoeia. The standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) is prepared by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650°C for 40-50 minutes, cooling it in a desiccator (silica gel), accurately weighing 0.900 g of it, dissolving it in purified water to make exactly 100 mL, or by using a commercially available standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution).

[0163] Dosage form The dosage form (form, shape, structure) of the composition of the present invention is not particularly limited, and examples thereof include eye drops (also called eye drops or eye drops. Eye drops include eye drops that can be applied while wearing contact lenses), eye washes, eye ointments (water-soluble eye ointments, oil-soluble eye ointments), contact lens wetting solutions, intraocular injections (e.g., intravitreal injections), contact lens solutions (cleaning solutions, storage solutions, disinfectants, multipurpose solutions, package solutions), preservatives for excised eye tissues such as corneas for transplantation, and irrigation solutions for surgery. Eye drops, eye washes, and eye ointments also include those used when wearing contact lenses.

[0164] It should be noted that the term "contact lenses" includes hard contact lenses and soft contact lenses (including both ionic and non-ionic, and both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).

[0165] Preferred dosage forms of the composition of the present invention include eye drops, eye wash, eye ointment (water-soluble eye ointment, oil-soluble eye ointment), contact lens wearing solution, contact lens solution (cleaning solution, storage solution, disinfectant, multi-purpose solution, packaging solution), etc., more preferred are eye drops, eye wash, contact lens wearing solution, contact lens solution (cleaning solution, storage solution, disinfectant, multi-purpose solution), etc., even more preferred are eye drops and eye wash, and particularly preferred are eye drops.

[0166] Such compositions of the present invention may exclude ophthalmic compositions (particularly, eye drops, eye washes, or eye ointments) that are used or applied when wearing (putting on) or while wearing (putting on) contact lenses (hard contact lenses, soft contact lenses, especially silicone hydrogel contact lenses).

[0167] The composition of the present invention may be in the form of a single-use unit dose or a multi-dose that can be used repeatedly, and may be contained and used in a multi-dose form.

[0168] container The composition of the present invention may be contained (filled, injected, sealed) in a container. The container may be any packaging material having a part (surface) that comes into contact with the composition (formulation), and may be composed of, for example, a container body that contains the composition (e.g., a liquid composition), a part that includes the container's extraction port (nozzle, inner plug), a suction tube, a cap, etc.

[0169] The material constituting the container can be selected from a wide range of materials, and examples thereof include those in which at least a part or all of the portion in contact with the composition is made of plastic (e.g., olefin-based resins, styrene-based resins, acrylic-based resins, polyester-based resins, polycarbonate-based resins, fluororesins, chlorine-based resins (polyvinyl chloride, etc.), polyamide-based resins, polyacetal-based resins, polyphenylene ether-based resins (modified polyphenylene ether, etc.), polyarylates, polysulfones, polyimide-based resins, cellulose-based resins (cellulose acetate, etc.), hydrocarbon-based resins which may be substituted with halogen atoms, etc.), metals (aluminum, etc.), etc.

[0170] The container may be made of a single material or two or more materials.

[0171] Examples of olefin-based resins include ethylene-based resins [e.g., polyethylene (including high-density polyethylene, low-density polyethylene, very low-density polyethylene, linear low-density polyethylene, ultra-high molecular weight polyethylene, etc.), ethylene-propylene copolymers, etc.], propylene-based resins [e.g., polypropylene (PP) (including isotactic polypropylene, syndiotactic polypropylene, atactic polypropylene, etc.), propylene-ethylene copolymers, etc.], and methylpentene-based resins (e.g., polymethylpentene, etc.).

[0172] Examples of styrene-based resins include polystyrene and acrylonitrile-containing styrene-based resins (such as acrylonitrile-styrene copolymers (AS resins), acrylonitrile-butadiene-styrene copolymers (ABS resins)).

[0173] Examples of acrylic resins include resins containing, as a polymerization component, acrylic acid esters such as methyl acrylate, and methacrylic acid esters such as methyl methacrylate, cyclohexyl methacrylate, and t-butylcyclohexyl methacrylate.

[0174] Examples of polyester-based resins include aromatic polyester-based resins [e.g., resins having alkylene terephthalate units (alkylene terephthalate-based resins: e.g., polyethylene terephthalate (PET), polytrimethylene terephthalate, polybutylene terephthalate (PBT)), etc.), and resins having alkylene naphthalate units (e.g., polyethylene naphthalate (PEN), polybutylene naphthalate, etc.).

[0175] Examples of fluororesin include fluorine-substituted polyethylene (polytetrafluoroethylene, polychlorotrifluoroethylene, etc.), polyvinylidene fluoride, polyvinyl fluoride, perfluoroalkoxy fluororesin, tetrafluoroethylene-hexafluoropropylene copolymer, ethylene-tetrafluoroethylene copolymer, and ethylene-chlorotrifluoroethylene copolymer.

[0176] The polyacetal resin may be one consisting only of oxymethylene units, or one partially containing oxyethylene units.

[0177] The modified polyphenylene ether may, for example, be polystyrene-modified polyphenylene ether.

[0178] The polyarylate may be, for example, amorphous polyarylate.

[0179] The polyimide resin may be an aromatic polyimide, for example, a polymer of pyromellitic dianhydride and 4,4'-diaminodiphenyl ether.

[0180] Examples of the cellulose acetate include cellulose diacetate and cellulose triacetate.

[0181] As the material for the container, plastics such as olefin-based resins, styrene-based resins, and polyester-based resins (i.e., plastic containers) are preferred, with ethylene-based resins, propylene-based resins, alkylene terephthalate-based resins, and polystyrene being more preferred, with polypropylene, polyethylene terephthalate, and polystyrene being even more preferred, and polyethylene terephthalate being even more preferred.

[0182] The container may be made of a material that is a blend of a polymer with a polymer other than the polymer. When the container material for storing the ophthalmic composition of the present invention is a blend of a polymer with the polymer, the mixing ratio of the polymer to the polymer other than the polymer is not particularly limited as long as the effects of the present invention are achieved, but the total weight of the polymers is preferably 30 w / w% or more, more preferably 50 w / w% or more, even more preferably 65 w / w% or more, and particularly preferably 80 w / w% or more, based on the total weight of the entire constituent materials.

[0183] At least a part of the surface of the container that comes into contact with the composition of the present invention may be made of the above material. For example, a layer or film made of the above material may be formed on the inner surface of the container, or the container itself may be molded from the above material. From the viewpoint of significantly achieving the effects of the present invention, it is preferable that the container itself is molded from the above material.

[0184] Furthermore, the parts constituting the container (the container body, the part including the container's extraction port (nozzle, inner plug), suction tube, cap, etc.) may be made of the above materials, or the entire container may be made of the above materials. In particular, from the viewpoint of significantly achieving the effects of the present invention, it is preferable that the container body is made of the above materials, and it is more preferable that the entire container body is made of the above materials (a state in which no part of the layers constituting the container body is made of a material other than those listed above).

[0185] Target disease (use) The target disease (use) of the composition of the present invention is not particularly limited, so long as it is for ophthalmic use. For example, the composition is useful for alleviating, improving, suppressing, or treating allergic symptoms, foreign body sensation (gritty sensation, etc.), corneal damage, corneal injury, watery eyes (epiphora), and the like, as well as for enhancing and normalizing the corneal barrier function and protecting the cornea.

[0186] Watery eyes are a symptom that occurs when the tear drainage pathway from the lacrimal puncta to the lacrimal canaliculus, lacrimal sac, and nasolacrimal duct becomes blocked by eye discharge or when excessive tears are produced due to irritation.

[0187] As used herein, "alleviation" includes alleviation of symptoms and inhibition of progression of symptoms, and "improvement," "inhibition," and "treatment" include alleviation of symptoms, inhibition of progression of symptoms, cure, or complete recovery.

[0188] In particular, the composition of the present invention is suitable for use in alleviating, improving, suppressing, or treating allergic symptoms (eye allergic symptoms).

[0189] Allergens causing allergic symptoms are not particularly limited, but may be pollen (such as cedar pollen and cypress pollen), house dust (indoor dust), and the like.

[0190] How to use The method of use (mode of use) of the composition of the present invention can be appropriately selected depending on its properties, etc.

[0191] For example, when the composition of the present invention is a preparation to be applied to the eyes, such as eye drops, eye washes, or eye ointments, the method of use varies depending on the symptoms to be treated, and may be, for example, once or more, twice or more, three or more, four or more, five or more, or six or more times per day. It may also be 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, or 4 or less times per day. It is particularly preferred to administer the composition four times per day.

[0192] When the composition of the present invention is an eye drop, for example, 1 to 3 drops, 1 to 2 drops, or 2 to 3 drops may be administered each time. Preferably, 1 to 2 drops are administered. One drop may also be administered. The amount of one drop administered may preferably be 30 to 50 μL.

[0193] When the composition of the present invention is an eyewash, for example, 1 to 30 mL, preferably 1 to 20 mL, and more preferably 4 to 6 mL may be used for each eyewash.

[0194] When the composition of the present invention is an eye ointment, for example, 0.001 to 5 g may be applied to the eye each time.

[0195] When the composition of the present invention is a contact lens wetting solution, when putting on or taking off a contact lens, for example, 1 to 3 drops, preferably 1 to 2 drops, may be dropped onto one and / or both sides of the contact lens each time to wet the lens before wearing, and it is preferable to wet both sides of the contact lens before wearing.

[0196] 2. Suppression of precipitation and cloudiness The ophthalmic composition according to this embodiment exhibits an effect of being able to suppress precipitation (cloudiness) in the ophthalmic composition (or being able to enhance or improve the dissolution stability). Therefore, as one embodiment of the present invention, there is provided a method for suppressing precipitation (cloudiness) in an ophthalmic composition (a method for improving or enhancing dissolution stability), comprising adding to an ophthalmic composition containing (A) one or more components selected from the group consisting of tranilast and its salts, (B) one or more components selected from the group consisting of polyvinylpyrrolidone and trometamol, and (C) one or more components selected from the group consisting of (C1) antihistamines, (C2) anti-inflammatory agents, and (C3) amino acids. In this method, the sodium ion concentration of the ophthalmic composition may further be adjusted to the above-mentioned concentration (for example, 250 mM or less). Also, as one embodiment of the present invention, there is provided an agent for suppressing precipitation (cloudiness) in an ophthalmic composition containing (A) one or more selected from the group consisting of tranilast and its salts (or an agent for enhancing or improving dissolution stability), which comprises (B) one or more selected from the group consisting of polyvinylpyrrolidone and trometamol, and (C) one or more components selected from the group consisting of (C1) antihistamines, (C2) anti-inflammatory agents, and (C3) amino acids. In these methods and agents, the temperature at which the precipitation-inhibiting effect (improving or improving dissolution stability) is exhibited may be the temperature at which the ophthalmic composition is used, for example, room temperature or about normal temperature (1 to 30°C and 15 to 25°C, respectively, according to the General Rules of the Japanese Pharmacopoeia, 17th Edition), or a relatively low temperature, and is not particularly limited, but may be an effect at a relatively low temperature. Therefore, the method and agent may be a method and agent that inhibits precipitation (improves or improves dissolution stability) at a low temperature [for example, 10°C or lower, preferably 5°C or lower, 0°C or lower, etc.]. In each of the above embodiments, the types and contents of the components (A) to (C), the types and contents of other components, the formulation form and use of the ophthalmic composition, etc. are as described in [1. Ophthalmic Composition]. EXAMPLES

[0197] The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to these examples, and many modifications can be made by those skilled in the art within the technical spirit of the present invention.

[0198] 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 following table shows ingredients containing sodium (ions) and examples of how to calculate the amount or concentration of sodium.

[0199] [Table 1]

[0200] Sodium ion concentration (mM) = Amount blended (w / v%) / molecular weight x sodium number (per molecular weight) x 10,000

[0201] For polysaccharides, calculations were based on the molecular weight of the sugar moiety to which sodium is bound. For example, sodium chondroitin sulfate is a polymer whose repeating structural unit is a disaccharide of N-acetyl-D-galactosamine and D-glucuronic acid, and the Na concentration was calculated based on a molecular weight of 503.3 per disaccharide unit.

[0202] Test Example 1 (Precipitation test at sodium concentrations of 0 mM and 10 mM) Aqueous ophthalmic compositions (eye drops) having the compositions shown in Table 2 below were prepared, and precipitation was evaluated as follows.

[0203] The prepared composition was filled into a screw vial (Maruemu Co., Ltd., No. 3L) and stored for 2 days at temperatures of 4° C. and −2° C. After confirmation of precipitation, the screw vial was stirred for 10 seconds at maximum stirring speed using a vortex mixer (AS ONE Corporation, Vortex Jenny 2), and the turbidity was measured in accordance with JIS K 7105 using a turbidimeter (Nippon Denshoku Industries Co., Ltd., NDH-300A).

[0204] The results are shown in the following Table 2. In the aqueous ophthalmic compositions in the following table, the unit of each component is (w / v %) (the same applies to the other tables below). In the table below, the precipitation improvement rate is a value represented by the following formula.

[0205] Precipitation improvement rate (%) of test examples 1B, 1C and 1D = (Turbidity of Test Example 1A - Turbidity of each Test Example) / Turbidity of Test Example 1A x 100 Precipitation improvement rate (%) of test example 1F = (Turbidity of Test Example 1E - Turbidity of Test Example 1F) / Turbidity of Test Example 1E x 100

[0206] [Table 2]

[0207] As is clear from the results in Table 2 above, it was found that precipitation occurs when polyvinylpyrrolidone is added to tranilast and the sodium ion concentration is set to a very low concentration of 0 mM or 10 mM. On the other hand, this precipitation increases when diphenhydramine hydrochloride is added, but can be suppressed by coexisting with chlorpheniramine maleate or pranoprofen.

[0208] Test Example 2 (Effect of Chlorpheniramine Maleate on Precipitation) Aqueous ophthalmic compositions (eye drops) having the compositions shown in Table 3 below were prepared, and precipitation was evaluated as follows.

[0209] The prepared composition was filled into a screw vial (Maruemu, No. 3L) and stored for 2 days at -2° C. After confirming the precipitation, the screw vial was stirred for 10 seconds at the maximum stirring speed using a vortex mixer (As One, Vortex Jenny 2), and 1.5 mL of the composition after stirring was filled into a 1.5 mL sample tube (Eppendorf, Neutral micro test tube with cap type). The sample tube was centrifuged at 1000 rpm for 10 minutes, the height (mm) of the accumulated precipitate was measured, and the precipitation improvement rate, which is represented by the following formula, was calculated.

[0210] 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 a test example (blank) in which component (C) (in this example, chlorpheniramine maleate) was not added and the concentrations of each component were the same.]

[0211] The results are shown in Table 3 below.

[0212] [Table 3]

[0213] As is clear from the results in Table 3 above, precipitation occurs even in the presence of Na ions, and this precipitation is further increased by diphenhydramine hydrochloride, but it was found that precipitation can be suppressed by adding chlorpheniramine maleate, an antihistamine.

[0214] Test Example 3 (Effect of Temperature on Precipitation) The precipitation improvement rate was calculated in the same manner as in Test Example 2, except that the storage temperature of the prepared composition was changed from -2°C to 4°C.

[0215] The results are shown in Table 4 below.

[0216] [Table 4]

[0217] As is clear from the results in Table 4 above, it was found that precipitation could be suppressed even at 4°C by adding chlorpheniramine maleate.

[0218] Test Example 4 (Effects of other components (C) and sodium ion concentration on precipitation) In Test Example 2, an aqueous ophthalmic composition (eye drops) having the composition shown in Table 5 below was used, and the precipitation improvement rate was calculated in the same manner as in Test Example 2, except that the storage temperature and sodium ion concentration were appropriately selected.

[0219] The results are shown in Table 5 below.

[0220] [Table 5]

[0221] As is clear from the results of the above test examples, it was found that precipitation could be suppressed even when the anti-inflammatory drug pranoprofen and the amino acid taurine were used.

[0222] Moreover, the results of Test Examples 4A to 4D demonstrated that such a precipitation suppression effect was obtained over a wide range of sodium ion concentrations, and furthermore, the results of Test Example 4A demonstrated that such an effect was obtained even at a lower sodium ion concentration (45 mM).

[0223] Test Example 5 (Effect of trometamol on precipitation) Aqueous ophthalmic compositions (eye drops) having the compositions shown in Table 6 below were prepared, and precipitation was evaluated as follows.

[0224] The prepared composition was filled into a screw vial (Maruemu Co., Ltd., No. 3L) and allowed to stand for 1 hour at room temperature and at 4° C. After confirmation of precipitation, the screw vial was stirred for 10 seconds at maximum stirring speed using a vortex mixer (AS ONE Corporation, Vortex Jenny 2), and the turbidity was measured in accordance with JIS K 7105 using a turbidimeter (Nippon Denshoku Industries Co., Ltd., NDH-300A).

[0225] The results are shown in Table 6 below. In the table below, the precipitation improvement rate is a value represented by the following formula.

[0226] Precipitation improvement rate (%) of test example B2 = (Turbidity of Test Example B1 - Turbidity of Test Example B2) / Turbidity of Test Example B1 x 100

[0227] [Table 6]

[0228] As is clear from the results in Table 6 above, it was found that precipitation could be suppressed even when trometamol was used as component B.

[0229] Furthermore, these trometamol results were also confirmed when the sodium ion concentration, trometamol concentration, pH, temperature, etc. were changed. For example, in the above test examples B1 and B2, the sodium chloride concentration was changed from 0.12 (w / v%) to 0.235 (w / v%), respectively, so that the sodium ion concentration was 40 mM (2.6 mol per mol of tranilast). In the same manner, the turbidity was measured at room temperature, and the precipitation improvement rate was calculated to be 75.4% when chlorpheniramine maleate was added at a concentration of 0.03 (w / v%). Furthermore, when sodium chloride was not contained and the sodium ion concentration was set to 0 mM, a favorable improvement in precipitation was also observed.

[0230] Test Example 6 (Effect of Combined Use of Component (C) on Precipitation) In Test Examples 2 and 3, the precipitation improvement rate was calculated in the same manner as in Test Examples 2 and 3, except that pranoprofen was used in addition to chlorpheniramine maleate at each temperature, as shown in Table 7 below.

[0231] The results are shown in Table 7. For comparison, the precipitation improvement rate in parentheses shows the precipitation improvement rate when chlorpheniramine maleate was used alone [Test Example 5A corresponds to Test Example 3B, Test Example 5B corresponds to Test Examples 2C and 3C, and Test Example 5C corresponds to Test Examples 2D and 3D, respectively].

[0232] [Table 7]

[0233] As is clear from the results in the above table, it was found that by combining components (C), in particular by combining chlorpheniramine maleate with pranoprofen, an even higher precipitation inhibition effect was obtained.

[0234] Test Example 7 (Human Sensory Test) Aqueous ophthalmic compositions (eye drops) having the compositions shown in Table 8 below were prepared, and sensory tests were carried out as follows.

[0235] [Table 8]

[0236] The subjects were five people with hay fever who were experiencing eye symptoms. From the first day of the study, they instilled eye drops 6A in the left eye and 6B in the right eye four times a day, and during the instillation period, they completed a questionnaire on subjective symptoms about specific items throughout the day each night. That is, they completed a questionnaire about eye pain three days after the start of the study, about itching and dryness four days after the start of the study, and about congestion five days after the start of the study. The maximum score for the symptom questionnaire was 100, with higher scores indicating stronger symptoms. The values ​​were the average of the five subjects.

[0237] The results are shown in the table below. [Table 9]

[0238] As is clear from the above results, Test Example 6B had lower values ​​for itching, congestion, and dryness compared to Test Example 6A, and the value for eye pain was the same or slightly lower.

[0239] In addition, Test Example 6A contains tranilast, and is a formulation that is known to have an effect of improving itching, congestion, etc. Therefore, the value of Test Example 6B is equal to or smaller than that of Test Example 6A, which means that the combination of tranilast and chlorpheniramine maleate is comparable to or better than that of Test Example 6A in terms of the effect of improving itching and congestion.More surprisingly, it showed an excellent effect on dryness.

[0240] Test Example 8 (Human Sensory Test 1) Aqueous ophthalmic compositions (eye drops) having the compositions shown in Table 10 below were prepared, and sensory tests were carried out as follows.

[0241] Eye drops were administered to the left and right eyes using combinations of compositions with or without L-menthol (V and P, W and Q, X and R), and the three items of "stickiness," "foreign body sensation," and "heavy eyes" were evaluated (scored) using the following criteria. 1 point: Not at all 2 points: A little 3 points: Yes 4 points: Quite a bit 5 points: Very strong

[0242] Regarding the average evaluation scores (total score divided by the number of evaluators), the relative scores for compositions P to R containing a cooling agent (menthol) and compositions V to X containing no cooling agent, with the average evaluation score for compositions (P, V) containing 3 w / v% PVP, taken as 100, are shown in Table 10 below, along with the composition of the aqueous ophthalmic composition.

[0243] [Table 10]

[0244] As is clear from the above table, in a composition containing a cooling agent such as menthol (e.g., terpenoid) and polyvinylpyrrolidone, the tendency for "stickiness," "foreign body sensation," and "heavy eyes" decreased as the amount of polyvinylpyrrolidone decreased. In particular, the tendency for "stickiness" was greatly improved by reducing the amount of polyvinylpyrrolidone. On the other hand, in a composition not containing a cooling agent, it was found that the tendency for "foreign body sensation" and "heavy eyes" remained unchanged or even increased even if the amount of polyvinylpyrrolidone was reduced. In addition, the degree of reduction in "stickiness" was not as remarkable as that of a composition containing a cooling agent.

[0245] Test Example 9 (Human Sensory Test 2) In the same manner as in Test Example 8, the aqueous ophthalmic compositions (eye drops) P to X in Table 10 above were subjected to a sensory test regarding "staining."

[0246] The average evaluation scores (total score divided by the number of people who evaluated) for compositions P to R containing a cooling agent at each PVP concentration are shown in Table 11 below as relative values, with the average score for compositions V to X not containing a cooling agent set at 100.

[0247] [Table 11]

[0248] Generally, the composition containing a freshener is more likely to show "stains". However, as is clear from the above table, in the composition containing tranilast and chlorpheniramine maleate as shown in Table 10, the relative value of the "stains" evaluation of the composition containing a freshener was equal to or lower than that of the composition not containing a freshener. Furthermore, when the amount of polyvinylpyrrolidone was less than 3 w / v%, the composition containing a freshener had a smaller tendency to show "stains" than the composition not containing a freshener.

[0249] From these Test Examples 8 and 9, it was found that, for compositions containing tranilast and chlorpheniramine maleate, compositions containing less than 3 w / v % polyvinylpyrrolidone and a cooling agent (menthol) were significantly superior in terms of the sensory symptoms of "stickiness," "foreign body sensation," "heavy eyes," and "stains."

[0250] [Formulation example] Ophthalmic compositions were prepared according to the formulations shown in the following tables, in which the units of each component are (w / v%).

[0251] [Table 12]

[0252] [Table 13]

[0253] [Table 14]

[0254] [Table 15]

[0255] [Table 16]

[0256] [Table 17]

[0257] [Table 18]

[0258] [Table 19]

[0259] [Table 20] [Industrial Applicability]

[0260] The present invention can provide an ophthalmic composition useful as an eye drop or the like.

Claims

[Claim 1] (A) one or more selected from the group consisting of tranilast and salts thereof, (B) one or more selected from the group consisting of polyvinylpyrrolidone and trometamol, and (C) containing one or more components selected from the group consisting of (C1) an antihistamine, (C2) an anti-inflammatory agent, and (C3) an amino acid; An ophthalmic composition having a sodium ion concentration of 250 mM or less.

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