JP2023016966A - ophthalmic composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: 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

COPYRIGHT: (C)2023,JPO&INPIT

Description

The present invention relates to ophthalmic compositions (or ophthalmic agents).

Tranilast (N-(3,4-dimethoxycinnamoyl)anthranilic acid) is poorly soluble in water, and even alkali metal salts such as sodium and potassium salts are extremely insoluble in water. Aqueous compositions tend to deposit crystals during storage.
Under these circumstances, techniques are being developed to improve precipitation in compositions containing tranilast.

For example, Patent Document 1 (Japanese Patent Application Laid-Open No. 2006-306765) describes a tranilast aqueous eye drop containing tranilast as an active ingredient, optionally together with metal ions, in an aqueous solution. Tranilast aqueous eye drops are disclosed characterized by a concentration ratio of total metal ions/tranilast≦0.4.

Japanese Patent Application Laid-Open No. 2006-306765 (Claims, Examples)

An object of the present invention is to provide novel ophthalmic compositions containing tranilast.

Another object of the present invention is to provide an ophthalmic composition capable of suppressing precipitation even when containing tranilast.

Another object of the present invention is to provide an ophthalmic composition that has high dissolution stability even if it contains an active ingredient other than tranilast.

In the technique of Patent Document 1, in the conventional technique of adding polyvinylpyrrolidone (PVP) to tranilast, tranilast crystals are likely to precipitate when stored in a cold place, and tranilast reassociates with metal ions such as sodium. With the discovery of this, it seems to be a technique for precipitating tranilast crystals without using a dissolution aid by reducing the concentration ratio of metal ions to tranilast (Patent Document 1, paragraph [0005 ] to [0013], Examples, etc.).

In addition, metals (ions) such as sodium (ions) include pH adjusters (e.g., sodium hydroxide, etc.), tonicity agents (e.g., sodium chloride, etc.), buffering agents (e.g., borax, sodium phosphate, sodium citrate, etc.), and other various components in the form of sodium salts, which are commonly contained in ophthalmic compositions. It is the metal ions contained in the composition that can be said to be unavoidable.

However, according to the studies of the present inventors, even when the metal ion concentration is reduced as in Patent Document 1, depending on other conditions (for example, when other additives are added), In particular, as shown in the examples, Patent Document 1 assumes a system that can be said to be an ideal solution with a small number of components, and in reality, the concentration of metal ions is reduced. alone could result in precipitation.

On the other hand, ophthalmic compositions sometimes require the addition of a plurality of active ingredients, and it has been found that Patent Document 1 is insufficient as a technique capable of meeting such requirements.

Under such circumstances, the present inventors have refocused attention on polyvinylpyrrolidone, which has been denied as a prior art in Patent Document 1, based on a completely different idea, and surprisingly, by combining polyvinylpyrrolidone or trometamol with a specific component, In particular, precipitation in compositions containing tranilast may be suppressed, and even when polyvinylpyrrolidone or the like, which is different from the ideal system as in Patent Document 1, is present in the system, the amount of sodium is reduced. In addition, it is extremely surprising that such a specific component is not just a mere excipient or carrier, but also acts and functions as an active ingredient. The present inventors have found that the composition can be effectively imparted with a medicinal effect other than that derived from tranilast, and after further studies, the present invention has been completed.

That is, the composition (ophthalmic composition) of the present invention provides, for example, the following inventions.
[1]
(A) one or more selected from the group consisting of tranilast and salts thereof;
(B) one or more selected from the group consisting of polyvinylpyrrolidone and trometamol, and (C) one or more selected from the group consisting of (C1) antihistamines, (C2) anti-inflammatory agents, and (C3) amino acids contains the ingredients of
An ophthalmic composition having a sodium ion concentration of 250 mM or less.
[2]
(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) one or more selected from the group consisting of (C1) antihistamines, (C2) anti-inflammatory agents, and (C3) amino acids contains the ingredients of
An ophthalmic composition in which the proportion of sodium ions is 25 mol or less per 1 mol of component (A).
[3]
(C1) the antihistamine contains one or more selected from the group consisting of chlorpheniramine and salts thereof,
(C2) the anti-inflammatory agent contains one or more selected from the group consisting of pranoprofen and salts thereof;
(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 component (C) contains at least one selected from the group consisting of chlorpheniramine and salts thereof.
[5]
(A) The ophthalmic composition according to any one of [1] to [4], containing 0.01 to 10 w/v% of component.
[6]
(B) The ophthalmic composition according to any one of [1] to [5], containing 0.005 to 20 w/v% of component.
[7]
(C) The ophthalmic composition according to any one of [1] to [6], containing 0.001 to 20 w/v% of component.
[8]
The ophthalmic composition according to any one of [1] to [7], wherein the ratio of component (C) to 1 part by mass of component (B) is 0.005 to 30 parts by mass.
[9]
The ophthalmic composition according to any one of [1] to [8], which has a sodium ion concentration of 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 contains one or more selected from the group consisting of chlorpheniramine and salts thereof,
(C2) the anti-inflammatory agent contains one or more selected from the group consisting of pranoprofen and salts thereof;
(C3) amino acids include one or more selected from the group consisting of taurine and salts thereof,
(A) the proportion of the component is 0.1 to 1 w / v%,
(B) the proportion of the component is 0.05 to 5 w / v%,
The proportion of component (C) is 0.01 to 10 w/v%,
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 contains one or more selected from the group consisting of chlorpheniramine and salts thereof,
(C2) the anti-inflammatory agent contains one or more selected from the group consisting of pranoprofen and salts thereof;
(C3) amino acids include one or more selected from the group consisting of taurine and salts thereof,
(A) the proportion of the component is 0.1 to 1 w / v%,
(B) the proportion of the component is 0.05 to 5 w / v%,
The proportion of component (C) is 0.01 to 10 w/v%,
The ratio of sodium ions is 30 mol or less (for example, 10 mol or less) per 1 mol 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]
Component (C) contains at least one selected from the group consisting of chlorpheniramine and salts thereof and at least one selected from the group consisting of pranoprofen and salts thereof [1] to [12] The ophthalmic composition according to any one of
[14]
The ophthalmic composition according to any one of [1] to [13], wherein component (C) contains 0.01 to 0.05 w/v% of chlorpheniramine maleate.
[15]
(B) The ophthalmic composition according to any one of [1] to [14], wherein the component contains trometamol.
[16]
The ophthalmic composition according to any one of [1] to [15], which has a sodium ion concentration of 40 mM or less.
[17]
The ophthalmic composition according to any one of [1] to [16], which has a sodium ion concentration of 20 mM or less.
[18]
The ophthalmic composition according to any one of [1] to [17], which has a sodium ion concentration of 10 mM or less (eg, 0 to 10 mM).
[19]
Furthermore, an ophthalmic composition containing (D) a cooling agent, 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%. The ophthalmic composition according to any one of [1] to [18].
[20]
(B) The ophthalmic composition according to [19], wherein the proportion of component is 2 w/v% or less.
[21]
The ophthalmic composition according to [19] or [20], wherein component (D) contains menthol and the proportion of component (B) is 1.5 w/v% or less.
[22]
(C) The ophthalmic composition according to any one of [15] to [21], wherein the component contains one or more selected from the group consisting of chlorpheniramine and salts thereof.
[23]
(A) A method for suppressing precipitation in an ophthalmic composition containing one or more selected from the group consisting of tranilast and salts thereof (method for improving or improving the dissolution stability), comprising:
(B) one or more selected from the group consisting of polyvinylpyrrolidone and trometamol, and (C) one or more selected from the group consisting of (C1) antihistamines, (C2) anti-inflammatory agents, and (C3) amino acids and the sodium ion concentration of the ophthalmic composition is 250 mM or less, or the ratio of sodium ions is 25 mol or less per 1 mol of component (A).
[24]
The method according to [23], wherein precipitation is suppressed at 5°C or less.

The present invention can provide a novel ophthalmic composition containing tranilast. Such ophthalmic compositions can usually suppress precipitation even when containing tranilast. In particular, such a precipitation suppressing effect is often excellent at low temperatures (for example, 10° C. or lower, preferably 5° C. or lower), and precipitation can be suppressed even at 0° C. or lower. Therefore, the ophthalmic composition of the present invention has dissolution stability not only when stored at a low temperature such as a refrigerator, but also when exposed to a lower temperature (storage in a cold region, when temperature changes drastically, etc.). can be realized.

In another aspect 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) to be combined with tranilast is often an active ingredient that functions as an anti-inflammatory agent and the like, and the combination with tranilast does not impair the efficacy of each other. Furthermore, even if an active ingredient other than the component (C) is added, the respective medicinal effects can be effectively exhibited without impairing the effect of suppressing precipitation.

Moreover, such efficacy can be exhibited 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, in Patent Document 1, it is not actually assumed to add other active ingredients, but in the present invention, by combining polyvinylpyrrolidone and component (C), unexpectedly, Dissolution stability can be ensured even when the concentration of sodium ions is low.

Thus, in another aspect of the present invention, excellent dissolution stability can be achieved while exhibiting the efficacy of tranilast and the efficacy derived from components other than tranilast.

In another aspect of the present invention, it is also possible to efficiently obtain an ophthalmic composition with excellent usability (or without impairing good usability).

Thus, the composition of the present invention is highly practical.

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

[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, anti-inflammatory agent and/or amino acids.

(A) tranilast and/or its salt (component (A))
The salt of tranilast may be any pharmaceutically or physiologically acceptable salt, and examples thereof include organic acid salts [e.g., monocarboxylates (acetate, trifluoroacetate, butyrate, acid salts, etc.), polyvalent carboxylates (fumarate, maleate, succinate, malonate, etc.), oxycarboxylates (lactate, tartrate, citrate, etc.), organic sulfonates (methanesulfonate, toluenesulfonate, tosylate, etc.)], inorganic acid salts (e.g., hydrochlorides, sulfates, nitrates, hydrobromides, phosphates), salts with organic bases (e.g., , methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, salts with organic amines such as picoline), salts with inorganic bases [e.g., ammonium salts; alkali metals (sodium, potassium, etc.), alkaline earth metal salts (calcium, magnesium, etc.), salts with metals such as aluminum] and the like.

Note that the sodium salt of tranilast is included in sodium ions, which will be described later. Therefore, when the 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.

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-metallic salts of tranilast, with tranilast being particularly preferred.

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

The content of component (A) in the composition is, for example, 0.001 w/v% or more, preferably 0.01 to 10 w/v%, more preferably 0.05 to 5 w%, relative to the total amount of the composition. /v%, more preferably 0.07-2 w/v%, still more preferably 0.1-1 w/v%, particularly preferably 0.3-1 w/v%, most preferably 0.45-0. It may be about 6 w/v %. Among them, 0.5 w/v% is particularly preferable.

(B) polyvinylpyrrolidone and/or trometamol (component (B))
Polyvinylpyrrolidone (PVP) is a polymer containing vinylpyrrolidone (N-vinyl-2-pyrrolidone) as a polymer component.

The molecular weight of such polyvinylpyrrolidone is not particularly limited. , Especially preferably about 5000 or more (e.g., 6000 to 300000), 200000 or less (e.g., 2500 to 100000, preferably 5000 to 80000, more preferably 10000 to 50000, particularly preferably 15000 to 40000, most preferably Preferably, it may be about 20000 to 30000).

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

Two or more different types of polyvinylpyrrolidone may be combined.

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

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

In particular, when the component (B) contains polyvinylpyrrolidone, the content of the component (B) in the composition is not too large, for example, less than 3 w/v% (eg, 2.0%) relative to the total amount of the composition. 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), still more preferably may be 1.5 w/v% or less (eg, 1.2 w/v% or less), and more preferably 1 w/v% or less.
By setting the content as described above, even in a composition containing polyvinylpyrrolidone (especially a composition further containing a cooling agent described later), excellent feeling of use (e.g., less stickiness, stains, foreign body sensation, etc.) usability) can be efficiently realized.

Moreover, particularly when the component (B) contains trometamol, the content of the component (B) in the composition is, for example, 0.01 to 10 w/v%, preferably 0.01 to 10 w/v%, based on the total amount of the composition. 02-8 w/v%, more preferably 0.03-7 w/v%, still more preferably 0.05-6 w/v% (eg, 0.08-5 w/v%), still more preferably 0.1 It may be about 4 w/v %.

The ratio of component (B) is, for example, 0.001 to 30 parts by mass, preferably 0.005 to 20 parts by mass, more preferably 0.01 to 15 parts by mass, per 1 part by mass of component (A). Particularly preferably 0.02 to 10 parts by weight, more particularly preferably 0.05 to 8 parts by weight, 0.1 to 15 parts by weight (for example, 0.2 to 12 parts by weight, preferably 0.1 to 15 parts by weight). 3 to 10 parts by mass, more preferably 0.5 to 8 parts by mass, and most preferably 2 to 6 parts by mass).

(C) antihistamines, anti-inflammatory agents and/or amino acids (component (C))
(C1) Antihistamines Antihistamines (hereinafter sometimes referred to as (C1) antihistamines, (C1) component, etc.) are not particularly limited as long as they are substances having antihistamine action, and examples include chlorpheniramine, epinastine, and ketotifen. , olopatadine, levocabastine, iproheptin and salts thereof.

The salt may be any pharmaceutically or physiologically acceptable salt, such as organic acid salts (e.g., maleate, fumarate, etc.), inorganic acid salts (e.g., hydrochloride, sulfate, etc.). , salts exemplified in the section of component (A) such as metal salts.

In addition, a sodium salt is contained in the below-mentioned sodium ion. Therefore, when the 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.

Specific salts include, for example, chlorpheniramine maleate and iproheptine hydrochloride.

Preferred antihistamines are chlorpheniramine and its salts (such as non-metallic salts), especially chlorpheniramine maleate.

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

In such a case, the ratio of one or more selected from the group consisting of chlorpheniramine and salts thereof (especially chlorpheniramine maleate) to the total antihistamine is, 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, or 90% by mass or more (e.g., 95% by mass or more), It may be substantially 100% by mass.

You may use an antihistamine individually or in combination of 2 or more types.
In addition, in the present specification, the antihistamines may generally not contain diphenhydramine and salts thereof. In other words, the antihistamine may be an antihistamine free of diphenhydramine and salts thereof. In such a case, the composition of the present invention may contain no diphenhydramine and its salts as an antihistamine (that is, it may contain an antihistamine free of diphenhydramine and its salts), and optionally contains diphenhydramine and its salts. may contain

(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. profen, indomethacin, allantoin, berberine, azulene sulfonic acid, diclofenac, bromfenac, glycyrrhizic acid, zinc, silver, tranexamic acid, lysozyme and salts thereof.

Examples of the salt include salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases, which are exemplified in the section of component (A) above. Lactate, hydrochloride, chloride salt, sodium salt, potassium salt and the like.

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

Preferred anti-inflammatory agents include pranoprofen, salts of pranoprofen, allantoin, berberine sulfate, sodium azulene sulfonate, dipotassium glycyrrhizinate, zinc sulfate, among others, including pranoprofen and/or its salts. Salts (such as non-metallic salts) are preferred, and pranoprofen is most preferred.

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

In such a case, the ratio of one or more selected from the group consisting of pranoprofen and salts thereof (especially pranoprofen) to the total anti-inflammatory agent is, 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, or 90% by mass or more (e.g., 95% by mass or more), It may be substantially 100% by mass.

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

In addition, the anti-inflammatory agent (eg, pranoprofen and its salts) may be in the form of hydrates.

You may use an anti-inflammatory agent individually or in combination of 2 or more types.

(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 analogues, and amino groups and A compound having a carboxyl group or a sulfone group or a derivative thereof is included.

Specifically, amino acids or salts thereof, mucopolysaccharides or salts thereof are exemplified. Among amino acids, amino acids or salts thereof include, for example, monoaminomonocarboxylic acids such as glycine, alanine, aminobutyric acid, aminovaleric acid, and aminocaproic acid; monoaminodicarboxylic acids such as aspartic acid and glutamic acid, or salts thereof; diaminomonocarboxylic acids such as arginine and lysine, or salts thereof; derivatives such as aminoethylsulfonic acid (taurine) or salts thereof;

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

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 and salt of

Chondroitin sulfate is obtained by ester-bonding sulfuric acid to all or part of the hydroxyl groups of the repeated sugar chains of D-glucuronic acid and N-acetylglucosamine. The bonding positions and numbers of sulfuric acid are diverse, and chondroitin sulfate also includes derivatives (for example, N-acetylglucosamine in which all or part of it is substituted with iduronic acid).
Such chondroitin sulfate may have any structure. Examples thereof include chondroitin 4-sulfate (chondroitin sulfate A), chondroitin 6-sulfate (chondroitin sulfate C), chondroitin sulfate E obtained by sulfating N-acetylglucosamine at positions 4 and 6, and the like. Chondroitin sulfate may also be extracted from animals.

Amino acid salts or mucopolysaccharide salts include pharmaceutically, pharmacologically or physiologically acceptable salts. Such salts include salts with organic acids [e.g., monocarboxylic acid salts (acetate, trifluoroacetate, butyric acid salt, palmitate, stearate, etc.), polycarboxylic acid salts (fumarate , maleate, etc.), oxycarboxylates (lactate, tartrate, citrate, succinate, malonate, etc.), organic sulfonates (methanesulfonate, toluenesulfonate, tosylate etc.) etc.], salts with inorganic acids (e.g., hydrochlorides, sulfates, nitrates, hydrobromides, phosphates, etc.), salts with organic bases (e.g., methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, salts with organic amines such as picoline), salts with inorganic bases [e.g., ammonium salts; alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), Salts with metals such as aluminum], etc. can be exemplified, and are appropriately selected depending on the compound.

Specific salts include salts of aspartic acid (such as sodium aspartate, potassium aspartate, magnesium aspartate, magnesium-potassium aspartate mixture), salts of glutamic acid (such as sodium glutamate, magnesium glutamate), sodium chondroitin sulfate, and hyaluronic acid. acid sodium salt, and the like.

In addition, a sodium salt is contained in the below-mentioned sodium ion. Therefore, when the 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.

Amino acids may be D-, L-, or DL-forms.

Preferred amino acids include aminoethylsulfonic acid (taurine) or salts thereof, sodium chondroitin sulfate, aspartates (eg, potassium L-aspartate, magnesium potassium L-aspartate), epsilon aminocaproic acid or salts thereof, hyaluronic acid. Among these, aminoethylsulfonic acid (taurine) and/or salts thereof are preferred, and aminoethylsulfonic acid (taurine) is most preferred.

Therefore, amino acids may include at least one or more selected from the group consisting of aminoethylsulfonic acid and salts thereof (especially aminoethylsulfonic acid).

In such a case, the ratio of one or more selected from the group consisting of aminoethylsulfonic acid and salts thereof (especially aminoethylsulfonic acid) to the total amino acids is, 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, or 90% by mass or more (for example, 95% by mass or more). , may be substantially 100% by mass.

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

Component (C) and its proportion In the composition of the present invention, component (C) contains at least one component selected from the group consisting of components (C1), (C2) and (C3). or a combination of these. For example, the (C1) component and the (C2) component may be combined, the (C1) component and the (C3) component may be combined, and the (C1) component, the (C2) component and the (C3) component may be combined. May be combined.

In particular, in the present invention, the antihistamine is a component (C1) containing one or more selected from the group consisting of chlorpheniramine and salts thereof (especially chlorpheniramine maleate) and other components (C) (e.g. , (C2) component containing one or more selected from the group consisting of pranoprofen and salts thereof (especially pranoprofen)).

By combining a plurality of (C) components in this way, it may be more advantageous in terms of the effect of suppressing precipitation and the like.

The content of component (C) in the composition is, for example, 0.0001 w/v% or more, preferably 0.001 to 20 w/v%, more preferably 0.003 to 10 w%, relative to the total amount of the composition. /v%, 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%. .

When the composition contains component (C1), the content of component (C1) in the composition is, for example, 0.0001 w/v% or more, preferably 0.001 to 10 w/v, relative to the total amount of the composition. v%, more preferably 0.003 to 5 w/v%, still 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% (eg, 0.02-0.1 w/v%), most preferably 0.025-0.05 w/v% (eg, 0.03 w/v%), Generally, it may be about 0.01 to 0.05 w/v%.

When the composition contains the component (C2), the content of the component (C2) in the composition is, for example, 0.0001 w/v% or more, preferably 0.001 to 10 w/v, relative to the total amount of the composition. v%, more preferably 0.003 to 5 w/v%, still more preferably 0.005 to 1 w/v%, still more preferably 0.01 to 0.5 w/v%, particularly preferably 0.015 to 0 0.3 w/v % (eg 0.02-0.1 w/v %), most preferably 0.025-0.07 w/v % (eg 0.05 w/v %).

When the composition contains the (C3) component, the content of the (C3) component in the composition is, for example, 0.001 w/v% or more, preferably 0.01 to 20 w/v, relative to the total amount of the composition. v%, more preferably 0.03 to 15 w/v%, still more preferably 0.05 to 10 w/v%, even more preferably 0.1 to 8 w/v%, particularly preferably 0.15 to 7 w/v %, usually 0.1 to 15 w/v% (eg, 0.2 to 10 w/v%, preferably 0.3 to 8 w/v%, more preferably 0.5 to 7 w/v% %).

When the composition contains component (C1) and component (C2), the ratio of these is the former/latter (mass ratio) = 1/0.01 to 1/100 (e.g., 1/0.05 to 1/ 50), preferably 1/0.1 to 1/20 (for example, 1/0.3 to 1/10), more preferably 1/0.5 to 1/8, particularly preferably 1/1 to 1/ 5 (eg, 1/1.2 to 1/3), most preferably 1/1.3 to 1/2 (eg, 1/1.4 to 1/1.8).

The ratio of component (C) is, 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, per 1 part by mass of component (A). Especially preferably 0.01 to 15 parts by weight, more preferably 0.02 to 10 parts by weight, and most preferably 0.03 to 5 parts by weight.

In particular, when the component (C) contains the component (C1), the ratio of the component (C1) is, for example, 0.001 to 5 parts by mass, preferably 0.003 to 1 part by mass, per 1 part by mass of the component (A). 1 part by mass, more preferably 0.005 to 0.5 parts by mass, particularly preferably 0.01 to 0.3 parts by mass, even more preferably 0.02 to 0.2 parts by mass, most preferably 0.03 It may be up to 0.1 parts by weight (eg, 0.06 parts by weight).

In particular, when component (C) contains component (C2), the proportion of component (C2) is, for example, 0.001 to 5 parts by mass, preferably 0.01 to 5 parts by mass, per 1 part by mass of component (A). It may be 1 part by mass, more preferably 0.05 to 0.5 parts by mass (eg, 0.1 part by mass).

In particular, when the component (C) contains the component (C3), the ratio of the component (C3) is, for example, 0.001 to 20 parts by mass, preferably 0.01 to 1 part by mass, per 1 part by mass of the component (A). It may be 10 parts by mass, more preferably 0.2 to 5 parts by mass (eg, 2 parts by mass).

The ratio of component (C) is, for example, 0.001 to 50 parts by mass, preferably 0.002 to 40 parts by mass, more preferably 0.005 to 30 parts by mass, per 1 part by mass of component (B), Particularly preferably 0.007 to 25 parts by weight, more particularly preferably 0.008 to 20 parts by weight, most preferably 0.01 to 15 parts by weight.

In particular, when component (C) contains component (C1), the proportion of component (C1) is, for example, 0.001 to 2 parts by mass, preferably 0.002 to 1 part by mass of component (B). 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, most preferably 0.008 to 1 part by mass, most preferably 0.01 It may be up to 0.5 parts by mass.

The proportion of component (C) is, for example, 0.0005 to 50 parts by mass, preferably 0.001 to 30 parts by mass, more preferably 0 part by mass, relative to 1 part by mass of the total amount of components (A) and (B). 0.003 to 25 parts by weight, particularly preferably 0.005 to 20 parts by weight, more particularly preferably 0.007 to 15 parts by weight, most preferably 0.01 to 10 parts by weight.

In particular, when the component (C) contains the component (C1), the ratio of the component (C1) is, for example, 0.0005 to 1 part by mass with respect to 1 part by mass of the total amount of the components (A) and (B). , preferably 0.001 to 0.5 parts by mass, more preferably 0.003 to 0.3 parts by mass, particularly preferably 0.005 to 0.2 parts by mass, more particularly preferably 0.007 to 0.15 parts by weight, most preferably 0.008 to 0.1 parts by weight.

[Other ingredients]
The composition of the present invention may further contain other components in addition to components (A) to (C). In the present invention, since specific components are 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 included.

(D) Cooling agent (component (D))
The composition of the present invention may contain a cooling agent (hereinafter sometimes referred to as (D) cooling agent, (D) component, etc.).

Cooling agents include, but are not limited to, menthol, anethole, eugenol, camphor, geraniol, cineol, borneol, limonene, terpenoids such as ryuno. These may be d-, l- or dl-isomers. In addition, essential oils such as peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, bergamot oil, eucalyptus oil and rose oil are also included.

Among them, terpenoids are preferred, menthol, camphor, geraniol, cineole, borneol and ryuno are preferred, menthol, camphor and borneol are more preferred, and menthol is even more preferred.
In addition, eucalyptus oil is also preferable from the viewpoint of exhibiting the effects of the present invention more remarkably.

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) achieves excellent usability in combination with the component (B) (especially in combination with the component (B) containing polyvinylpyrrolidone at a predetermined ratio). easy and suitable.

The ratio of component (D) to the total amount of the composition is, 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.

The ratio of component (D) to the total amount of the composition is 1 w/v% or less, 0.1 w/v% or less, 0.09 w/v% or less, 0.09 w/v% or less. 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, 0.02 w/v% v% or less may be sufficient.

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

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

Of these, dibutylhydroxytoluene is preferred. On the other hand, the compositions of the present invention may be free of BHT.

You may use a fat-soluble antioxidant individually or in combination of 2 or more types.

The content of component (E) in the composition is, for example, 0.0001 to 0.1 w/v%, preferably 0.0005 to 0.01 w/v%, more preferably 0.0007 to 0.009 w/v%, more preferably 0.001 to 0.008 w/v%, even more preferably 0.003 to 0.007 w/v%, most preferably 0.0045 to 0.006w /v%.

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

Antiallergic agents (antiallergic agents other than tranilast and/or salts thereof) include, for example, cromoglycic acid, ibudilast, acitazanolast, tazanolast, suplatast, pemirolast, levocabastine, olopatadine, ketotifen, amlexanox, oxatomide and salts thereof. is mentioned.

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

Among these, cromoglycate and its salts are preferred, and sodium cromoglycate is more preferred.

You may use an anti-allergic agent individually or in combination of 2 or more types.

The content of component (F) in the composition is, relative to the total amount of the composition, for example, 0.1 to 10 w/v%, preferably 0.2 to 8 w/v%, more preferably 0.3 to 5 w/v %, even more preferably 0.5 to 3 w/v %, particularly preferably 0.7 to 2 w/v %, even more preferably 0.8 to 1.5 w/v %, most preferably 0.5 w/v %. It may be about 9 to 1.2 w/v%.

The composition of the present invention may contain various components (for example, components not belonging to the categories of components (A) to (F)). Examples of such components (additives) include surfactants, preservatives, buffers, pH adjusters, tonicity agents, thickeners or thickening agents, stabilizers, oils, sugars, high Examples include molecular compounds, polyhydric alcohols, inorganic salts, non-fat-soluble antioxidants (or water-soluble antioxidants), and the like.

An additive can be used individually or in combination of 2 or more types. Moreover, each additive can be used individually or in combination of 2 or more types.

Specific examples of additives are shown below.

Surfactant The composition of the present invention may contain a surfactant. Surfactants include, for example, non-on-surfactants.

Examples of nonionic surfactants include POE (20) sorbitan monolaurate (polysorbate 20), POE (20) sorbitan monopalmitate (polysorbate 40), POE (20) sorbitan monostearate (polysorbate 60), and POE tristearate. (20) Polysorbates (POE sorbitan fatty acid esters) such as sorbitan (polysorbate 65), POE monooleate (20) sorbitan (polysorbate 80); Poloxamer 407, Poloxamer 235, Poloxamer 188, Poloxamer 403, Poloxamer 237, Poloxamer 124 POE/POP glycols such as; POE hydrogenated castor oils such as POE hydrogenated castor oil 40, POE hydrogenated castor oil 50, POE hydrogenated castor oil 60, POE hydrogenated castor oil 80; POE castor oil 3, POE castor oil 4, POE castor Oil 6, POE castor oil 7, POE castor oil 10, POE castor oil 13.5, POE castor oil 17, POE castor oil 20, POE castor oil 25, POE castor oil 30, POE castor oil 35, POE castor oil 50, etc. of POE castor oil; polyethylene glycol monostearate (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 Stearate 40), Polyethylene Glycol Monostearate (45 E.O.), Polyethylene Glycol Monostearate (55 E.O.), Polyethylene Glycol Monostearate (75 E.O.), 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; POE (10) nonylphenyl ether. and POE alkylphenyl ethers such as In the compounds exemplified above, POE is polyoxyethylene, POP is polyoxypropylene, and numbers in parentheses indicate the number of added moles.

Among them, POE sorbitan fatty acid esters; POE/POP glycols; POE hydrogenated castor oil; Castor oil 3, POE castor oil 10, POE castor oil 35 and polyoxyl stearate 40 are more preferred, polysorbate 80 and POE hydrogenated castor oil 60 are more preferred, and polysorbate 80 is particularly preferred.

You may use surfactant individually or in combination of 2 or more types.

When an ionic surfactant is added to the composition of the present invention, the proportion of the ionic surfactant is, for example, 0.001 w/v% or more, preferably 0.005 w/v% or more, relative to the total amount of the composition. , more preferably 0.01 w/v% or more, particularly preferably 0.05 w/v% or more.

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

Preservatives The compositions of the present invention may contain preservatives.
Examples of antiseptics include polydronium chloride, alkylpolyaminoethylglycines (e.g., alkyldiaminoethylglycine hydrochloride, etc.), sodium benzoate, ethanol, quaternary ammonium salts (e.g., benzalkonium chloride, benzethonium chloride, etc.), Chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, parahydroxybenzoic acid ester (e.g., methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, etc.), oxyquinoline sulfate , phenethyl alcohol, benzyl alcohol, biguanide compounds (eg, polyhexanide hydrochloride, etc.), and Grokyl (manufactured by Rhodia).

Among others, alkylpolyaminoethylglycines (e.g., alkyldiaminoethylglycine hydrochloride), sodium benzoate, ethanol, quaternary ammonium salts, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, paraoxybenzoic acid esters, biguanide compounds are preferred, quaternary ammonium salts, chlorhexidine gluconate, chlorobutanol and biguanide compounds are more preferred, and benzalkonium chloride and polyhexanide hydrochloride are even more preferred.

On the other hand, the composition of the present invention may be free of sorbic acid and its salts (such as potassium sorbate).

When a preservative is added to the composition of the present invention, the amount of the preservative is, for example, 0.000001 w/v% or more, especially 0.00001 w/v% or more, based on the total amount of the composition. , 0.00005 w/v% or more, 0.001 w/v% or more, 0.005 w/v% or more. In addition, the total amount of preservatives relative to the total amount of the composition is 1 w/v% or less, especially 0.1 w/v% or less, especially 0.05 w/v% or less, especially 0.03 w/v% or less, especially 0.025 w/v% or less.

Buffering Agents The compositions of the present invention may contain a buffering agent.
Buffers include, for example, borate buffers, phosphate buffers, carbonate buffers, citrate buffers, acetate buffers and the like.

Components of the borate buffer include boric acid, borates (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.) and the like. A borate may be a hydrate.

Phosphate buffer components include phosphoric acid, phosphates (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.). The phosphate may be a hydrate.

Carbonic acid, carbonate (potassium carbonate, sodium carbonate, calcium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, magnesium carbonate, etc.) and the like can be mentioned as components of the carbonate buffer. The carbonate may be a hydrate.

Components of citric acid buffers include citric acid, citrates (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.) and the like. The citrate may be a hydrate.

Components of acetate buffers include acetic acid, acetates (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.) and the like. The acetate may be a hydrate.

Among them, borate buffers and phosphate buffers are preferred, and borate buffers are more preferred. The boric acid buffer is preferably a combination of boric acid and a salt thereof, more preferably a combination of boric acid and an alkali metal salt of boric acid and/or an alkaline earth metal salt, and boric acid and an alkali metal of boric acid. A combination with a salt is more preferred, and a combination of boric acid and borax is even more preferred.

When a buffering agent is added to the composition of the present invention, the blending amount of the buffering agent varies depending on the type of buffering agent, the types and amounts of other ingredients, etc., and cannot be uniformly defined. With respect to the total amount of the composition, the total amount of the buffering agent is 0.001 w/v% or more, especially 0.01 w/v% or more, especially 0.05 w/v% or more, especially 0.1 w/v% or more. be done. Further, the total amount of the buffering agent is 10 w/v% or less, especially 5 w/v% or less, especially 3 w/v% or less, especially 2.5 w/v% or less, especially 2 w/v% or less, based on the total amount of the composition. These include:

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

pH adjusters pH adjusters include, for example, 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, water Potassium oxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diisopropanolamine and the like.
You may use a pH adjuster individually or in combination of 2 or more types.

Tonicity agents Tonicity agents include, for example, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, potassium acetate, sodium acetate, magnesium sulfate, glycerin, and propylene glycol.
A tonicity agent may be used alone or in combination of two or more.

Thickening Agent or Thickening Agent The ophthalmic composition of the present invention may contain a thickening agent or a thickening agent within a range that does not impair the effects of the present invention.

Thickeners or thickening 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, and agar. , alginic acid, α-cyclodextrin, dextrin, dextran, mucopolysaccharides (e.g., heparinoids, heparin, heparin sulfate, heparan sulfate, heparinoids, hyaluronic acid, hyaluronic acid salts (sodium salts, etc.), starch, chitin and Its derivatives, chitosan and its derivatives, carrageenan, sorbitol, polyvinyl-based polymer compounds (polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, etc.), alkali metal salts of polyacrylic acid (sodium salt, potassium salt, etc.), polyacrylic acid amine salts (monoethanolamine salts, diethanolamine salts, triethanolamine salts, etc.), casein, gelatin, collagen, pectin, elastin, ceramide, liquid paraffin, glycerin, polyethylene glycol, macrogol, polyethyleneimine alginate (sodium salt, etc.) ), alginate (propylene glycol ester, etc.), tragacanth powder, and triisopropanolamine.
You may use a thickener or a thickening agent individually or in combination of 2 or more types.

Stabilizers Stabilizers include, for example, trometamol, sodium formaldehyde sulfoxylate (Rongalite), monoethanolamine, aluminum monostearate, and glyceryl monostearate.
You may use a stabilizer individually or in combination of 2 or more types.

Oils and 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.
You may use an oil component individually or in combination of 2 or more types.

Sugars include monosaccharides and disaccharides, specifically glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, sorbitol, mannitol and the like.
You may use saccharides individually or in combination of 2 or more types.

Polyhydric alcohols Polyhydric alcohols include polyethylene glycol, glycerin, propylene glycol, xylitol, diethylene glycol, mannitol, sorbitol, polyvinyl alcohol and the like.
You may use a polyhydric alcohol individually or in combination of 2 or more types.

Inorganic salts Examples of inorganic salts include potassium chloride, sodium chloride, calcium chloride, magnesium chloride, sodium hydrogen carbonate, sodium carbonate (including dry sodium carbonate), potassium hydrogen carbonate, 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, sodium thiosulfate and the like.
Among them, 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, and 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.
You may use inorganic salts individually or in combination of 2 or more types.

Water-soluble antioxidants Water- soluble antioxidants include, for example, ascorbic acid, ascorbic acid derivatives (disodium ascorbate-2-sulfate, sodium ascorbate, magnesium ascorbate-2-phosphate, ascorbate-2- sodium phosphate, etc.), sodium bisulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, edetic acid or salts thereof (disodium edetate, tetrasodium edetate, etc.), and the like.
You may use a water-soluble antioxidant individually or in combination of 2 or more types.

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

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

Examples of such pharmacologically active ingredients and physiologically active ingredients include active ingredients in various drugs described in the 2012 version of the Standards for Approval of Manufacturing and Marketing of OTC Drugs (supervised by the Japanese Society of Regulatory Science). Examples thereof include decongestants, ocular muscle regulating agents, astringents, vitamins, amino acids, antibacterial agents or bactericidal agents, local anesthetic ingredients, analgesics, sulfa agents and the like. Specific examples of these agents are given below.

decongestant (vasoconstrictor)
Examples of decongestants include α-adrenergic agonists, specifically imidazoline decongestants such as oxymetazoline, tetrahydrozoline, naphazoline, or salts such as hydrochlorides and nitrates thereof, epinephrine, epinephrine hydrochloride, and hydrochloric acid. Examples include ephedrine, phenylephrine hydrochloride, methylephedrine hydrochloride, and epinephrine hydrogen tartrate. These may be d-, l- or dl-isomers.

In detail about the imidazoline vasoconstrictor, the salt of the imidazoline vasoconstrictor may be a pharmaceutically or physiologically acceptable salt, for example, organic acid salts such as maleate and fumarate; Inorganic acid salts such as salts and sulfates; and salts such as metal salts. Among the salts, inorganic acid salts are preferred, hydrochlorides or nitrates are more preferred, and hydrochlorides (tetrahydrozoline hydrochloride, etc.) are particularly preferred.

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

Ocular Muscle Modulating Agents Ocular muscle modulating agents include, for example, cholinesterase inhibitors having an active center similar to that of acetylcholine, specifically neostigmine methyl sulfate, tropicamide, helenien, and atropine sulfate.

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

Among them, flavin adenine dinucleotide or its salt (especially flavin adenine dinucleotide sodium), cobalamin or its salt (especially cyanocobalamin), retinol, its salt or its derivative (especially retinol acetate, retinol palmitate), pyridoxine or its Salts (especially pyridoxine hydrochloride), panthenol, pantothenic acid or salts thereof (especially sodium pantothenate, calcium pantothenate), tocopherol, salts thereof or derivatives thereof (especially tocopherol acetate) are preferred, and pyridoxine hydrochloride and tocopherol acetate are preferred. more preferred.
In addition, the composition of the present invention may not contain pyridoxine and its salts.

Antimicrobials or Bactericides Antimicrobials or fungicides include, for example, sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxazole monoethanolamine, sulfa drugs such as sulfisomezole sodium, sulfisomidine sodium, alkylpolyaminoethylglycine, chloramphenicol, ofloxacin, norfloxacin, levofloxacin, and lomefloxacin hydrochloride;

Local Anesthetic Ingredients Examples of local anesthetic ingredients include procaine hydrochloride and lidocaine hydrochloride.

Analgesic agents Analgesics include, for example, procaine hydrochloride and the like.

Sulfa drugs Sulfa drugs include, for example, sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulfisomidine sodium and the like.

Base or Carrier The compositions of the present invention may contain a base or carrier.
A composition containing such a base or carrier can be prepared, for example, by mixing each of the above components with a pharmaceutically acceptable base or carrier, and then using the conventional formula described in the Japanese Pharmacopoeia Commentary, 17th Edition. can be prepared by the method of

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

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

Properties The properties of the composition of the present invention are not particularly limited, and may be liquid, fluid, gel or semi-solid. It also includes those that have become liquid, fluid, gel, or semi-solid by preparation at the time of use. A semi-solid state refers to a property having plasticity that can be deformed by applying force, such as an ointment.

In addition, as described above, the composition may be an aqueous composition (mainly including an aqueous or hydrophilic base or carrier) or an oily composition (an oily or hydrophobic base or carrier). (mainly including those of), and in particular, it may be an aqueous composition.

The water content of the aqueous composition is preferably 50% by mass or more, more preferably 75% by mass or more, and even more preferably 90% by mass or more, relative to the total amount of the composition (or formulation). Moreover, it may be 95% by mass or more, or 98% by mass or more. Also, the base or carrier may consist of water only.

In the case of an oily composition, the water content is preferably less than 50% by mass, more preferably 30% by mass or less, and even more preferably 20% by mass or less, relative to the total amount of the composition (or formulation).

Sodium Ion Content The composition of the present invention may have a sodium ion (or sodium) content within a specific range. Combining such an amount of sodium ions with the above-mentioned specific component may be more advantageous in terms of the effect of suppressing precipitation and dissolution stability.

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

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

The amount of sodium ions can also be defined as a ratio to the component (A). For example, in the composition of the present invention, the ratio of sodium ions can be selected from the range of about 30 mol or less, preferably 25 mol or less, preferably 20 mol or less, more preferably 15 mol, per 1 mol of component (A). below, particularly preferably 12 mol or less, most preferably 10 mol or less (e.g., 9.5 mol or less), and a relatively low proportion [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], and a lower proportion (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).

In addition, the sodium ion may 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 salt is also included in the sodium ion.
In addition, the amount or concentration of sodium (ion) may be obtained by measuring (directly measuring) the amount or concentration in the composition, and the amount or concentration of sodium (ion) in the components (raw materials) constituting the composition may be obtained by calculating (indirectly measuring) the amount or concentration in the composition from The amount or concentration of sodium (ion) in the composition or raw material may be measured by a conventional method or apparatus (eg, ion chromatography method, etc.).

In addition, since sodium ions contain sodium derived from each component as described above, when each component contains sodium as a salt or the like, it is necessary to adjust the sodium ion concentration to the above-described sodium ion concentration. From this point of view, the composition of the present invention desirably contains little or no sodium chloride, borax, sodium edetate and the like, which are commonly used for eye drops and the like.

From such a point of view, in particular, each component constituting the composition of the present invention (e.g., (A) to (C) components, other components) contains no sodium [e.g., when it is a salt , salts that are not sodium salts (non-sodium salts)] may be suitably used.

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

The pH of the composition of the present invention may be, for example, 4 to 10, preferably 5 to 9, more preferably 5.5 to 8.5 (eg, 6.0 to 8.3);7. It may be greater than 5 [eg, 7.6-9 (eg, 7.7-8.5), 7.8 or higher (eg, 7.8-8.3)].
In the present invention, the effects of the present invention (precipitation suppression effect, etc.) can be efficiently realized even at the above pH.

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

The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to the osmotic pressure of 286 mOsm (0.9 w/v % sodium chloride aqueous solution) based on the 17th revision of the Japanese Pharmacopoeia. The osmotic pressure is measured according to the osmotic pressure measurement method (freezing point depression method) described in the Japanese Pharmacopoeia 17th Edition. The standard solution for osmotic pressure ratio measurement (0.9 w/v% sodium chloride aqueous solution) was obtained by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650 ° C. for 40 to 50 minutes and then placing it in a desiccator (silica gel). Allow to cool, accurately weigh 0.900 g, dissolve in purified water to make exactly 100 mL, or use a commercially available standard solution for osmotic pressure ratio measurement (0.9 w/v % sodium chloride aqueous solution).

Dosage form The dosage form (dosage form, shape, structure) of the composition of the present invention is not particularly limited. eye drops), 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 solution, antiseptic solution, multi-purpose solution, package solution), preservatives for excised ocular tissue such as cornea for transplantation, perfusate during surgery, and the like. Eye drops, eye washes and eye ointments also include those used when wearing contact lenses.

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

The dosage forms of the composition of the present invention are preferably eye drops, eye washes, eye ointments (water-soluble eye ointment, oil-soluble eye ointment), contact lens wetting solution, contact lens solution (cleaning solution, preservative solution, antiseptic solution). , multi-purpose solutions, package solutions), and more preferably eye drops, eye washes, contact lens-wearing solutions, contact lens solutions (cleaning solutions, storage solutions, disinfectants, multi-purpose solutions), etc., and further Eye drops and eye washes are more preferred, and eye drops are particularly preferred.

Such a composition of the present invention is an ophthalmic composition ( In particular, eye drops, eye washes, or eye ointments) may be excluded.

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

Container The composition of the present invention may be contained (filled, injected, enclosed) in a container.
The container may be a packaging body having a portion (surface) that contacts the composition (formulation). (nozzle, inner plug), a suction tube, a cap, and the like.

The material constituting the container can be selected from a wide range. resin, fluorine resin, chlorine resin (polyvinyl chloride, etc.), polyamide resin, polyacetal resin, polyphenylene ether resin (modified polyphenylene ether, etc.), polyarylate, polysulfone, polyimide resin, cellulose resin (cellulose acetate) etc.), hydrocarbon resins optionally substituted with halogen atoms, etc.), metals (aluminum, etc.), and the like.

The container may be composed of one material or two or more materials.

Olefin-based resins include ethylene-based resins [for example, polyethylene (including high-density polyethylene, low-density polyethylene, ultra-low-density polyethylene, linear low-density polyethylene, ultra-high molecular weight polyethylene, etc.), ethylene-propylene copolymer, and the like. ], propylene-based resin [e.g., polypropylene (PP) (including isotactic polypropylene, syndiotactic polypropylene, atactic polypropylene, etc.), propylene-ethylene copolymer, etc.], methylpentene-based resin (e.g., polymethylpentene etc.).

Styrene-based resins include, for example, polystyrene and acrylonitrile-containing styrene-based resins (eg, acrylonitrile-styrene copolymer (AS resin), acrylonitrile-butadiene-styrene copolymer (ABS resin), etc.).

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

Polyester-based resins include, for example, 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.), Examples thereof include resins having alkylene naphthalate units (eg, polyethylene naphthalate (PEN), polybutylene naphthalate, etc.).

Examples of fluororesin include fluorine-substituted polyethylene (polytetrafluoroethylene, polychlorotrifluoroethylene, etc.), polyvinylidene fluoride, polyvinyl fluoride, perfluoroalkoxy fluororesin, ethylene tetrafluoride/propylene hexafluoride copolymer, ethylene/tetrafluoroethylene Fluorinated ethylene copolymers, ethylene/chlorotrifluoroethylene copolymers, and the like.

Examples of polyacetal-based resins include those composed only of oxymethylene units and those partially containing oxyethylene units.

Modified polyphenylene ethers include polystyrene-modified polyphenylene ethers.

Examples of polyarylates include amorphous polyarylates.

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

Cellulose acetate includes cellulose diacetate, cellulose triacetate and the like.

As the container material, plastics such as olefin-based resins, styrene-based resins, and polyester-based resins (that is, plastic containers) are preferable, and ethylene-based resins, propylene-based resins, alkylene terephthalate-based resins, and polystyrene are more preferable, and polypropylene, More preferred are polyethylene terephthalate and polystyrene, and even more preferred is polyethylene terephthalate.

The container material may be a polymer blend with a polymer other than the above polymer. When the material of the container containing the ophthalmic composition of the present invention is a blend polymer with the polymer, the mixing ratio of the polymer and the polymer other than the polymer is not particularly limited as long as the effect of the present invention is achieved. , The total weight of the polymer is preferably 30 w/w% or more, more preferably 50 w/w% or more, and even more preferably 65 w/w% or more, based on the total amount of the constituent materials. , 80 w/w % or more.

At least 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 exhibiting the effects of the present invention remarkably, it is preferable that the container itself is molded from the above material.

In addition, parts constituting the container (container body, parts including the extraction port of the container (nozzle, inner plug), suction tube, cap, etc.) may be made of the above materials, and all parts of the container may be made of the above materials. may be composed of In particular, from the viewpoint of exhibiting the effect of the present invention remarkably, it is preferable that the container main body portion is made of the above material, and that the whole of the container main body portion is made of the above material (part of the container main body). layer is not composed of a material other than the above) is more preferable.

Target disease (use)
The target disease (application) of the composition of the present invention is not particularly limited as long as it is for ophthalmology. It is useful for mitigation, improvement, suppression or treatment of (lacrimation) and the like, enhancement and normalization of corneal barrier function, corneal protection, and the like.

Watery eyes are a symptom that occurs when the drainage tract of tears from the lacrimal punctum to the canaliculus, lacrimal sac, and nasolacrimal duct is blocked by eye mucus, etc., or when excessive tears are produced due to irritation. .

As used herein, "alleviation" includes alleviation of symptoms and suppression of progression of symptoms, and "improvement", "suppression", and "treatment" are alleviation of symptoms, suppression of progression of symptoms, cure or complete recovery. contain.

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

Allergens for allergic symptoms are not particularly limited, but may be pollen (cedar pollen, cypress pollen, etc.), house dust (indoor dust), and the like.

Method of use The method of use (mode of use) of the composition of the present invention can be appropriately selected according to its properties and the like.

For example, when the composition of the present invention is a formulation to be applied to the eye such as eye drops, eye washes, eye ointments, etc., the usage varies depending on the target symptom, but for example, once or more, twice a day. Above, it can be 3 times or more, 4 times or more, 5 times or more, or 6 times or more. Also, it can be 9 times or less, 8 times or less, 7 times or less, 6 times or less, 5 times or less, or 4 times or less. Administration four times a day is particularly preferred.

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 applied per application. Preferably, 1 to 2 drops may be instilled into the eye. It can also be 1 drop. Also, the volume of one eye drop may preferably be 30 to 50 μL.

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

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

When the composition of the present invention is a contact lens wetting solution, when the contact lens is worn or removed, for example, 1 to 3 drops, preferably 1 to 2 drops are added to one side of the contact lens and / or The contact lens may be worn after being dripped onto both surfaces to wet them, preferably after wetting both surfaces of the contact lens.

[2. Suppression of precipitation and cloudiness]
The ophthalmic composition according to the present embodiment has the effect of being able to suppress precipitation (white turbidity) (or improve or improve the dissolution stability) in the ophthalmic composition.
Therefore, as one embodiment of the present invention, (A) an ophthalmic composition containing one or more selected from the group consisting of tranilast and salts thereof, (B) one selected from the group consisting of polyvinylpyrrolidone and trometamol Precipitation (white turbidity ) (method for improving or enhancing dissolution stability) is provided.
In this method, the sodium ion concentration of the ophthalmic composition may be the above concentration (for example, 250 mM or less).
Further, as one embodiment of the present invention, (A) an agent for suppressing precipitation (cloudiness) in an ophthalmic composition containing one or more selected from the group consisting of tranilast and salts thereof (or dissolution stability) (B) one or more selected from the group consisting of polyvinylpyrrolidone and trometamol, and (C) (C1) an antihistamine, (C2) an anti-inflammatory agent, and (C3) Agents containing one or more components selected from the group consisting of amino acids are provided.
In these methods and agents, the temperature at which the effect of inhibiting precipitation (improving or improving dissolution stability) is achieved is the temperature at which the ophthalmic composition is used, for example, room temperature or normal temperature (according to the General Rules of the Japanese Pharmacopoeia 17th Edition, 1 to 30° C. and 15 to 25° C., respectively), relatively low temperatures, etc., and are not particularly limited, but may be particularly effective at relatively low temperatures. Therefore, the method and agent may be methods and agents that suppress precipitation (improve or improve dissolution stability) at low temperatures [e.g., 10°C or lower, preferably 5°C or lower, 0°C or lower, etc.]. .
The types and contents of the components (A) to (C), the types and contents of other components, and the formulation forms and uses of the ophthalmic composition in each of the above embodiments are described in [1. ophthalmic composition].

The present invention will be described in more detail below with reference to Examples, but the present invention is not limited by these Examples, and many modifications can be made in the art within the technical spirit of the present invention. It is possible by a person with ordinary knowledge.

In addition, in the following test examples and formulation examples, the sodium (ion) amount and concentration were calculated based on the sodium (ion) amount in the raw material. The following table shows components containing sodium (ions) and calculation examples of the amount or concentration of sodium.

Sodium ion concentration (mM) =
Compounding amount (w/v%) / molecular weight x number of sodium (per molecular weight) x 10000

Note that the polysaccharide was calculated based on the molecular weight of the sugar moiety to which sodium is bound. For example, sodium chondroitin sulfate is a polymer having a repeating structural unit of disaccharides of N-acetyl-D-galactosamine and D-glucuronic acid, and the Na concentration is calculated based on the molecular weight per disaccharide unit of 503.3. Is going.

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

The prepared composition was filled in a screw vial (No. 3L, manufactured by Maruem Co., Ltd.) and stored at temperatures of 4° C. and −2° C. for 2 days. After confirming the precipitation, the screw vial is stirred for 10 seconds at the maximum stirring speed using a vortex mixer (manufactured by AS ONE, VORTEX Jenny 2), and a turbidity meter (manufactured by Nippon Denshoku Industries Co., Ltd., NDH-300A) is used. The turbidity was measured according to JIS K 7105.

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

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

As is clear from the results in Table 2 above, it was found that precipitation occurred even when polyvinylpyrrolidone was added to tranilast and the sodium ion concentration was set to a very low concentration of 0 mM or 10 mM. On the other hand, it was found that this precipitation increased when diphenhydramine hydrochloride was added, but could be suppressed by the coexistence of chlorpheniramine maleate and pranoprofen.

Test Example 2 (Effect of chlorpheniramine maleate on precipitation)
Aqueous ophthalmic compositions (eye drops) having compositions shown in Table 3 below were prepared, and precipitation was evaluated as follows.

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

Precipitation improvement rate (%) = (Y - X) / Y x 100
[In the formula, X is the height of the precipitate in each test example, Y is the test in which each component concentration was the same without adding component (C) (chlorpheniramine maleate in this example) in each test example. Figure 2 shows the height of the deposits in the example (blank). ]

The results are shown in Table 3 below.

As is clear from the results in Table 3 above, precipitation occurs even in the presence of Na ions, and this precipitation increases further with diphenhydramine hydrochloride, but by adding the antihistamine chlorpheniramine maleate, the precipitation is reduced. It turned out that it can be suppressed.

Test Example 3 (effect of temperature on precipitation)
In Test Example 2, 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.

The results are shown in Table 4 below.

As is clear from the results in Table 4 above, it was found that addition of chlorpheniramine maleate can suppress precipitation even at 4°C.

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

The results are shown in Table 5 below.

As is clear from the results of the above test examples, it was found that precipitation can be suppressed even when pranoprofen, an anti-inflammatory agent, and taurine, an amino acid, are used.

Moreover, from the results of Test Examples 4A to 4D, such a precipitation suppressing effect can be obtained over a wide range of sodium ion concentrations, and from the results of Test Example 4A, even at a lower sodium ion concentration (45 mM). I found out.

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

The prepared composition was filled in a screw vial (No. 3L, manufactured by Maruem Co., Ltd.) and allowed to stand at each temperature of room temperature and 4° C. for 1 hour. After confirming the precipitation, the screw vial is stirred for 10 seconds at the maximum stirring speed using a vortex mixer (manufactured by AS ONE, VORTEX Jenny 2), and a turbidity meter (manufactured by Nippon Denshoku Industries Co., Ltd., NDH-300A) is used. The turbidity was measured according to JIS K 7105.

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

Precipitation improvement rate (%) of Test Example B2
= (turbidity of Test Example B1 - turbidity of Test Example B2) / turbidity of Test Example B1 x 100

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

Such results for trometamol were confirmed even when the sodium ion concentration, the concentration of trometamol, pH, temperature, etc. were changed.
For example, in the above Test Examples B1 and B2, the sodium ion concentration was changed to 40 mM (tranilast 1 mol) by changing the sodium chloride concentration from 0.12 (w/v%) to 0.235 (w/v%). The turbidity at room temperature was measured in the same manner, except that it was 2.6 mol per), and the precipitation improvement rate when chlorpheniramine maleate was added at a concentration of 0.03 (w / v%) was calculated. As a result, it was 75.4%.
Moreover, even when sodium chloride was not contained and the sodium ion concentration was set to 0 mM, a favorable improvement in precipitation was observed.

Test Example 6 (effect on precipitation when component (C) is used in combination)
In Test Examples 2 and 3, as shown in Table 7 below, precipitation improvement rate was obtained in the same manner as in Test Examples 2 and 3, except that pranoprofen was used in addition to chlorpheniramine maleate at each temperature. was calculated.

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

As is clear from the results in the above table, it was found that the combination of component (C), particularly the combination of chlorpheniramine maleate and pranoprofen, provides a much higher effect of suppressing precipitation.

Test Example 7 (human sensory test)
Aqueous ophthalmic compositions (eye drops) having compositions shown in Table 8 below were prepared, and sensory tests were conducted as follows.

Subjects were 5 subjects who had hay fever and developed eye symptoms. From the start of the test, 6A eye drops were applied to the left eye and 6B eye drops were applied to the right eye four times a day. That is, a questionnaire was conducted on eye pain 3 days after the start of the test, on itching and dryness 4 days after the start of the test, and on hyperemia 5 days after the start of the test.
The subjective symptom questionnaire was given on a 100-point scale, and the higher the score, the stronger the subjective symptoms. Moreover, the value is an average value of 5 persons.

Results are shown in the table below.

As is clear from the above results, Test Example 6B showed smaller values of itching, hyperemia, and dryness than Test Example 6A. In addition, eye pain values were the same or slightly lower.

Test Example 6A contains tranilast, and is a formulation known to have an effect of improving itching, hyperemia, and the like. Therefore, the fact that the value of Test Example 6B was equal to or smaller than that of Test Example 6A indicates that the combination of tranilast and chlorpheniramine maleate is effective in improving itching and hyperemia. It means comparable or better. More surprisingly, it showed an excellent effect on dry feeling.

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

A combination of different compositions (V and P, W and Q, X and R) was applied to the left and right eyes, respectively, with or without L-menthol. ” were evaluated (scored) according to the following criteria.
1 point: Not at all 2 points: Slightly 3 points: Somewhat 4 points: Fairly 5 points: Very strong

Regarding the average value of the evaluation (the value obtained by dividing the total score by the number of people who evaluated), among the compositions P to R containing a cooling agent (menthol) and the compositions V to X not containing a cooling agent, PVP was Table 10 below shows the respective relative values when the average value of the evaluation of the compositions (P, V) containing 3 w/v% is set to 100, together with the composition of the aqueous ophthalmic composition.

As is apparent from the above table, in compositions containing a cooling agent (such as a terpenoid) such as menthol and polyvinylpyrrolidone, as the amount of polyvinylpyrrolidone decreases, the "stickiness", "foreign body sensation" and "eye irritation" increase. It was found that the tendency of "heavy" is reduced. In particular, "stickiness" was significantly improved by reducing polyvinylpyrrolidone. On the other hand, it was found that the tendency of "foreign body sensation" and "heavy eyes" did not change or increased, even if the amount of polyvinylpyrrolidone was reduced in the composition containing no cooling agent. Also, the degree of reduction in "stickiness" was not so remarkable as compared with compositions containing cooling agents.

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

Regarding the average evaluation value (value obtained by dividing the total score by the number of people evaluated), the average value of compositions V to X that do not contain a cooling agent at each PVP concentration is set to 100, and the cooling agent is added. Table 11 below shows the evaluation of the blended compositions P to R as relative values.

"Blemishes" are generally felt more strongly in compositions containing cooling agents. However, as is clear from the above table, in the composition shown in Table 10, in which tranilast and chlorpheniramine maleate were blended, the relative value of the "stain" evaluation of the composition containing the cooling agent was lower than that of the composition not containing the cooling agent. It was less than the same level as the thing. Furthermore, when the amount of polyvinylpyrrolidone contained was less than 3 w/v%, the composition containing the cooling agent had a smaller tendency to "blemish" than the composition containing no cooling agent.

From these Test Examples 8 and 9, it was found that the composition containing tranilast and chlorpheniramine maleate containing less than 3 w/v% polyvinylpyrrolidone and containing a cooling agent (menthol) was "sticky". , ``foreign body sensation'', ``heavy eyes'', and ``blemish''.

[Formulation example]
Ophthalmic compositions were prepared according to the formulations shown in the table below. In addition, in the following table, the unit of each component is (w/v%).

The present invention can provide ophthalmic compositions useful as eye drops and the like.

Claims (1)

The inventions described herein.