JP2018145184A - Ophthalmic composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel ophthalmic composition.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 chlorpheniramine and a salt thereof, and (C) at least one selected from the group consisting of pranoprofen and a salt thereof. In such a composition, the ratio of the component (B) to the component (A) 100 pts.mass may be 1-8 pts.mass, and the ratio of the component (C) may be 5-25 pts.mass.SELECTED DRAWING: None

Description

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

Various components are contained in ophthalmic compositions such as eye drops depending on the purpose.
On the other hand, tranilast is known to be effective in treating diseases caused by allergies, and examples of use in ophthalmic compositions have been reported. In such an ophthalmic composition containing tranilast, techniques for combining tranilast and other components are being developed for the purpose of improving efficacy and searching for new functions.
For example, JP-A-2014-234368 (Patent Document 1) discloses that eye drops containing tranilast and specific components (anti-inflammatory agents, water-soluble vitamins, cooling agents) enhance corneal epithelial barrier function. It is described that it is effective.

JP 2014-234368 A (Claims, Examples)

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

As described above, a technique itself for incorporating tranilast into eye drops is known. On the other hand, various components other than tranilast are known as components to be contained in eye drops, and chlorpheniramine maleate and pranoprofen are one of such components.
However, with respect to these components, only examples that can be used alone or in combination with other specific components are reported, and there is no report about an example in which these components are specifically combined.

  Under these circumstances, the present inventors have been studying prescriptions for tranilast, chlorpheniramine maleate, and pranoprofen. When these are used alone or in combination, Even when it is done, it has been found that there are problems that are not known in the past. For example, in the study, it has been confirmed that these alone do not have sufficient storage efficacy, or that the photostability of pranoprofen is not sufficient, and that light stability does not improve even when combined with chlorpheniramine maleate. It was done.

  In response to these findings, the present inventors have made further studies, and even though they are known as tranilast, chlorpheniramine maleate, and pranoprofen alone or as a combination of two kinds, they are specific as combinations. Surprisingly, it has been found that a sufficient composition can be obtained in terms of storage efficacy and photostability as described above by selecting three specific types that have no specific report. The present invention has been completed.

That is, the present invention provides the following inventions, for example.
[1]
(A) one or more selected from the group consisting of tranilast and salts thereof,
(B) one or more selected from the group consisting of chlorpheniramine and its salt, and (C) one or more selected from the group consisting of pranoprofen and its salt,
The ophthalmic composition whose ratio of a component (B) with respect to 100 mass parts of components (A) is 1-8 mass parts, and the ratio of a component (C) is 5-25 mass parts.
[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 chlorpheniramine and a salt thereof, and (C) one or more selected from the group consisting of pranoprofen and a salt thereof,
The component (A) is 0.3 to 0.7 w / v%, the component (B) is 0.007 to 0.04 w / v%, and the component (C) is 0.03 to 0.15 w / v%. An ophthalmic composition containing.
[3]
The ophthalmic composition according to [1] or [2], wherein the ratio of the component (A), the component (B), and the component (C) satisfies any of the following.
(A) component / (B) component / (C) component (mass ratio) = 100/5 to 7/8 to 12
(A) component / (B) component / (C) component (mass ratio) = 100 / 5-7 / 18-22
(A) component / (B) component / (C) component (mass ratio) = 100 / 1-3 / 8-12
(A) component / (B) component / (C) component (mass ratio) = 100 / 1-3 / 18-22
[4]
The ophthalmic composition according to any one of [1] to [3], wherein the ratio of the components (A) to (C) satisfies any of the following:
Ratio in which component (A) is 0.4 to 0.6 w / v%, component (B) is 0.02 to 0.04 w / v%, and component (C) is 0.04 to 0.06 w / v% Ratio in which component (A) is 0.4 to 0.6 w / v%, component (B) is 0.02 to 0.04 w / v%, and component (C) is 0.08 to 0.12 w / v% Ratio in which component (A) is 0.4 to 0.6 w / v%, component (B) is 0.013 to 0.017 w / v%, and component (C) is 0.04 to 0.06 w / v% Ratio in which component (A) is 0.4 to 0.6 w / v%, component (B) is 0.013 to 0.017 w / v%, and component (C) is 0.08 to 0.12 w / v% Ratio in which component (A) is 0.4 to 0.6 w / v%, component (B) is 0.008 to 0.012 w / v%, and component (C) is 0.04 to 0.06 w / v% Component (A) is 0.4 to 0.6 w / %, Component (B) is 0.008~0.012w / v%, the proportion component (C) is 0.08~0.12w / v% [5]
The ophthalmic composition according to any one of [1] to [4], comprising at least one selected from polyvinylpyrrolidone, monoethanolamine and trometamol.
[6]
The ophthalmic composition according to any one of [1] to [5], comprising at least one selected from monoethanolamine and trometamol.
[7]
The ophthalmic composition according to any one of [1] to [6], wherein the sodium ion concentration is 250 mM or less, or the ratio of sodium ions is 25 mol or less with respect to 1 mol of component (A).
[8]
The ophthalmic composition according to any one of [1] to [7], wherein the sodium ion concentration is 20 mM or less, or the ratio of sodium ions is 20 mol or less with respect to 1 mol of component (A).
[9]
The ophthalmic composition according to any one of [1] to [8], which is used for alleviation, improvement, suppression, and / or treatment of allergic symptoms.
[10]
The ophthalmologic according to any one of [1] to [9], which is used for the alleviation, improvement, suppression, and / or treatment of at least one symptom selected from itching, hyperemia, tearing eyes, foreign body sensation, and eyes and eyes. Composition.
[11]
In the ophthalmic composition, the ophthalmic composition containing 1 or 2 components selected from the components (A), (B) and (C) described in [1] contains the remaining 1 or 2 components. A method for improving, improving, imparting and / or expressing at least one selected from (1) storage efficacy, (2) photostability, and (3) resistance to oxygen stress.
[12]
(1) Storage efficacy, (2) Light stability and (3) in an ophthalmic composition comprising 1 or 2 components selected from (A) component, (B) component and (C) component according to [1] ) An agent for improving, improving, imparting and / or developing at least one selected from resistance to oxygen stress and comprising the remaining one or two components.

In the present invention, a novel ophthalmic composition can be provided.
Such an ophthalmic composition contains specific components (A), (B), and (C). For example, compared with the case where these components are used alone or in combination of two types, the specific function ( For example, the effect of improving or improving storage efficacy, stability, etc. can also be exhibited.
For example, in another aspect of the present invention, an ophthalmic composition having resistance to oxygen stress (low oxidative stress) (or not impairing resistance to low oxygen stress) can be obtained. It has been pointed out that oxygen stress is associated with cell damage and various diseases / symptoms (dry eye, cataract, etc.), and it is useful to be able to provide an ophthalmic composition that has or does not impair hypoxic stress resistance.

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

  In the ophthalmic composition of another aspect of the present invention, precipitation can be suppressed. In particular, such a precipitation suppressing effect is often excellent at a low temperature (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 is stable in dissolution not only when it is stored at a low temperature such as a refrigerator, but also in an environment where it is exposed to a lower temperature (such as storage in a cold region or when temperature changes are severe). Can be realized.

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

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

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

[1. Ophthalmic composition)
The ophthalmic composition of the present invention is selected from the group consisting of (A) tranilast and / or a salt thereof, (B) chlorpheniramine and / or a salt thereof, and (C) pranoprofen and / or a salt thereof 1 Contains at least seeds.

(A) Tranilast and / or salt thereof (component (A))
The salt of tranilast may be any salt that is pharmaceutically or physiologically acceptable, such as an organic acid salt [eg, monocarboxylate (acetate, trifluoroacetate, butyrate, palmitate, stearin Acid salt), polyvalent carboxylate (fumarate, maleate, succinate, malonate, etc.), oxycarboxylate (lactate, tartrate, citrate, etc.), organic sulfonate (Methanesulfonate, toluenesulfonate, tosylate, etc.)], inorganic acid salts (for example, hydrochloride, sulfate, nitrate, hydrobromide, phosphate), salts with organic bases (for example, , Salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline), salts with inorganic bases [eg ammonium salts; Metal (sodium, potassium etc.), alkaline earth metal (calcium, magnesium etc.), salts], etc. with a metal such as aluminum and the like.

  In addition, the sodium salt of tranilast is contained in the sodium ion mentioned later. Therefore, when (A) component contains a sodium salt, you may use a sodium salt so that a sodium ion concentration may become the below-mentioned range in the whole composition.

  Preferred tranilasts and / or salts thereof include tranilast and non-sodium salts of tranilast. More preferable tranilast and / or a salt thereof include tranilast and a nonmetallic salt of tranilast, and tranilast is particularly preferable.

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

  The content of the 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 with respect to the total amount of the composition. / V%, more preferably 0.07-2 w / v%, even more preferably 0.1-1 w / v%, particularly preferably 0.2-1 w / v%, most preferably 0.25-0. It may be about 8 w / v%. Among these, 0.3 to 0.7 w / v% (for example, 0.4 to 0.6 w / v%) is preferable, and 0.45 to 0.55 w / v% (such as 0.5 w / v%) is particularly preferable. preferable.

(B) Chlorpheniramine and / or a salt thereof (component (B))
The salt of chlorpheniramine may be a pharmaceutically or physiologically acceptable salt, such as an organic acid salt (eg, maleate, fumarate), an inorganic acid salt (eg, hydrochloride, And the 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 (B) component contains a sodium salt, you may use a sodium salt so that a sodium ion concentration may become the below-mentioned range in the whole composition.

  Preferred chlorpheniramine and / or a salt thereof include chlorpheniramine and a non-metal salt thereof (such as a non-sodium salt), and chlorpheniramine maleate is particularly preferable.

  Chlorpheniramine and / or a salt thereof may be used alone or in combination of two or more.

  The content of the component (B) in the composition is, for example, 0.0001 w / v% or more, preferably 0.001 to 10 w / v%, more preferably 0.003 to 5 w with respect to the total amount of the composition. / V%, more preferably 0.005 to 1 w / v%, even more preferably 0.01 to 0.5 w / v%, particularly preferably 0.015 to 0.3 w / v% (for example, 0.02 ~ 0.1 w / v%), most preferably 0.025 to 0.05 w / v% (for example, 0.028 to 0.045 w / v%), and 0.007 to 0. 04 w / v% (for example, 0.008 to 0.035 w / v%, particularly 0.01 to 0.03 w / v%) is preferable, and specifically, 0.008 to 0.012 w / v% (particularly 0.01 w / v%), 0.013 to 0.017 w / v% (particularly 0.015 w / v) %), 0.02~0.04w / v% (particularly 0.03 w / v%), or the like.

(C) Planoprofen and / or a salt thereof (component (C))
The salt of pranoprofen may be any salt that is pharmaceutically or physiologically acceptable, such as a salt with an inorganic acid, a salt with an organic acid, a salt with an inorganic base, a salt with an organic base, etc. Examples thereof include salts exemplified in the section of component A), and examples thereof include sulfates, lactates, hydrochlorides, chloride salts, sodium salts, potassium salts and the like.
The preferred pranoprofen and / or salt thereof is pranoprofen and non-metal salts thereof (such as non-sodium salt), and pranoprofen is particularly preferred.

  Planoprofen and / or a salt thereof may be used alone or in combination of two or more.

  Content of (C) component in a composition is 0.0001 w / v% or more with respect to the whole quantity of a composition, Preferably it is 0.001-10 w / v%, More preferably, it is 0.002-5 w / V%, more preferably 0.003 to 1 w / v%, even more preferably 0.005 to 0.5 w / v%, particularly preferably 0.01 to 0.3 w / v% (for example, 0.015 ˜0.25 w / v%), most preferably 0.02 to 0.2 w / v% (for example, 0.025 to 0.18 w / v%). 15 w / v% (for example, 0.04 to 0.12 w / v%, particularly 0.05 to 0.1 w / v%) is preferable, specifically, 0.04 to 0.06 w / v% (particularly 0.05 w / v%), 0.08 to 0.12 w / v% (particularly 0.1 w / v%), etc. .

(A)-(C) Ratio between components The ratio of (B) component is 0.1-500 mass parts (for example, 0.3-100 mass parts) with respect to 100 mass parts of (A) component, for example. Preferably, it is 0.4-50 mass parts (for example, 0.5-30 mass parts), More preferably, it is 0.7-20 mass parts (for example, 0.8-10 mass parts), Most preferably, it is 1-8. A mass part (for example, 1.2-7.5 mass parts) may be sufficient, and 1.5-7 mass parts (for example, 2-6 mass parts) are preferable especially, 1-3 mass is specifically ,. Parts (for example, 1.5 to 2.5 parts by mass, particularly 2 parts by mass), 2 to 4 parts by mass (for example, 2.5 to 3.5 parts by mass, particularly 3 parts by mass), 5 to 7 parts by mass ( For example, it may be 5.5 to 6.5 parts by mass, particularly 6 parts by mass).

  The ratio of (C) component is 0.1-500 mass parts (for example, 0.5-100 mass parts) with respect to 100 mass parts of (A) component, Preferably it is 1-50 mass parts (for example, 2 to 40 parts by mass), more preferably 3 to 35 parts by mass (for example, 4 to 30 parts by mass), and particularly preferably 5 to 25 parts by mass (for example, 6 to 23 parts by mass). To 22 parts by mass (for example, 10 to 20 parts by mass), specifically, 8 to 12 parts by mass (for example, 9 to 11 parts by mass, particularly 10 parts by mass), and 18 to 22 parts by mass (for example, 19 parts by mass). To 21 parts by mass, particularly 20 parts by mass).

  The ratio of (B) component is 0.1-300 mass parts (for example, 0.5-150 mass parts) with respect to 100 mass parts of (C) component, Preferably it is 1-100 mass parts, More preferably, it is. May be 2 to 90 parts by mass (for example, 3 to 80 parts by mass), particularly preferably 5 to 75 parts by mass (for example, 10 to 70 parts by mass), and 15 to 65 parts by mass (for example, 20 to 20 parts by mass). 60 parts by mass), specifically 15-25 parts by mass (for example, 18-22 parts by mass, especially 20 parts by mass), 25-35 parts by mass (for example, 28-32 parts by mass, especially 30 parts by mass) ) 55-65 parts by mass (for example, 58-62 parts by mass, particularly 60 parts by mass).

  The ratio of the total amount of component (B) and component (C) is, for example, 0.1 to 300 parts by mass (for example, 0.5 to 100 parts by mass), preferably 1 with respect to 100 parts by mass of component (A). -80 parts by mass, more preferably 2-60 parts by mass (for example, 3-50 parts by mass), particularly preferably 5-45 parts by mass (for example, 8-40 parts by mass). A mass part (for example, 16-30 mass parts) is preferable, and specifically, 12-20 mass parts (for example, 14-18 mass parts, especially 16 mass parts), 22-30 mass parts (for example, 24-28 mass parts). Part by mass, especially 26 parts by mass), 26-34 parts by mass (for example, 28-32 parts by mass, in particular 30 parts by mass), and the like.

  The ratio of the component (A), the component (B), and the component (C) is, for example, (A) component / (B) component / (C) component (mass ratio) = 100 / 0.1 to 100/0. 5 to 200 (for example, 100 / 0.2 to 50/1 to 100), preferably 100 / 0.3 to 30/2 to 80, more preferably 100 / 0.5 to 20/3 to 50, particularly preferably May be 100 / 0.8 to 10/4 to 30 and preferably 100/1 to 8/5 to 25 (for example, 100/2 to 6/10 to 20). / 5 to 7/8 to 12 (for example, 100 / 5.5 to 6.5 / 9 to 11, particularly 100/6/10), 100/5 to 7/18 to 22 (for example, 100 / 5.5) -6.5 / 19-21, in particular 100/6/20), 100 / 2-4 / 8-12 (e.g. 100 / 2.5-3) 5/9 to 11, especially 100/3/10), 100/2 to 4/18 to 22 (for example, 100 / 2.5 to 3.5 / 19 to 21, especially 100/3/20), 100 / 1 to 3/8 to 12 (for example, 100 / 1.5 to 2.5 / 9 to 11, particularly 100/2/10), 100/1 to 3/18 to 22 (for example, 100 / 1.5 to 2.5 / 19 to 21, particularly 100/2/20).

[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, the effects of the present invention can often be secured even if other components are contained. Moreover, the effect of this invention may be implement | achieved more effectively by containing another component.

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

  The component (D) is not particularly limited. For example, polyvinylpyrrolidone (PVP), hydroxyalkylamines (or aminoalkanols or alkanolamines such as monoethanolamine, diethanolamine, triethanolamine, trometamol, etc.), Examples include alcohols (for example, polyols such as propylene glycol), caffeine and the like.

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

  The molecular weight of such polyvinylpyrrolidone is not particularly limited, but is, for example, 1000 or more (for example, 1500 to 3000000), preferably 2000 or more (for example, 2500 to 2000000), more preferably 3000 or more (for example, 4000 to 1000000). In particular, it may be about 5,000 or more (for example, 6,000 to 300,000), 200,000 or less (for example, 2500 to 100,000, preferably 5,000 to 80,000, more preferably 10,000 to 50,000, particularly preferably 15,000 to 40,000, Preferably, it may be about 20000-30000).

  Typical polyvinyl pyrrolidone includes polyvinyl pyrrolidone K25, K30, K90 and the like.

  (D) A component may be individual or may be combined 2 or more types.

  Of these, polyvinylpyrrolidone, hydroxyalkylamines (for example, monoethanolamine, trometamol) and the like are preferable, and polyvinylpyrrolidone and monoethanolamine are particularly preferable.

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

  Content of (D) component in a composition is 0.001 w / v% or more with respect to the whole quantity of a composition, Preferably it is 0.005-20 w / v%, More preferably, it is 0.01-10 w / 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 to 5 w / v%, more preferably 0.5 to 4.5 w / v%, particularly preferably 1.0 to 3 w / v%).

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

  (D) The ratio of a component is 0.001-30 mass parts with respect to 1 mass part of (A) component, for example, Preferably it is 0.005-20 mass parts, More preferably, it is 0.01-15 mass parts, Particularly preferably, it may be 0.02 to 10 parts by mass, more particularly preferably 0.05 to 8 parts by mass, and 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).

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

(E) Amino acids The composition of the present invention may contain amino acids (sometimes referred to as (E) component).
Examples of amino acids include amino acids or salts thereof, and amino acid analogs, and include compounds having amino groups and carboxyl groups or sulfone groups in the molecule, or derivatives thereof.

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

  Among amino acids, examples of the mucopolysaccharide or a derivative thereof or a salt thereof include, for example, a derivative such as chondroitin sulfate, hyaluronic acid, or alginic acid or a salt thereof as an acidic mucopolysaccharide.

  Specific 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 the like And the like.

In addition, chondroitin sulfate is a product in which sulfuric acid is ester-bonded to all or part of the hydroxyl groups of sugar chains in which D-glucuronic acid and N-acetylglucosamine repeat. The binding position and number of sulfuric acid are various, and there are derivatives of chondroitin sulfate (for example, those in which all or part of N-acetylglucosamine is substituted with iduronic acid).
Such chondroitin sulfate may have any structure. Examples thereof include chondroitin sulfate sulfate (chondroitin sulfate A), chondroitin hexasulfate (chondroitin sulfate C), chondroitin sulfate E in which the 4th and 6th positions of N-acetylglucosamine are sulfated. In addition, chondroitin sulfate may be extracted from animals.

  Amino acid salts or mucopolysaccharide salts include pharmaceutically, pharmacologically or physiologically acceptable salts. Examples of such salts include salts with organic acids [for example, monocarboxylates (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylate (fumarate , Maleate, etc.), oxycarboxylate (lactate, tartrate, citrate, succinate, malonate, etc.), organic sulfonate (methanesulfonate, toluenesulfonate, tosylate) Etc.), salts with inorganic acids (eg, hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), salts with organic bases (eg, methylamine, triethylamine, triethanolamine, Salts with organic amines such as morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.), salts with inorganic bases [eg ammonium salts; alkali metals (sodium, potassium, etc.), alkaline earths Metal (calcium, magnesium etc.), salts with metals such as aluminum, etc.] or the like can be illustrated, it is appropriately selected depending on the compound.

  Specific salts include aspartic acid salts (sodium aspartate, potassium aspartate, magnesium aspartate, magnesium aspartate and potassium mixtures, etc.), glutamate salts (sodium glutamate, magnesium glutamate, etc.), sodium chondroitin sulfate, hyaluron Examples include sodium acid.

  In addition, a sodium salt is contained in the below-mentioned sodium ion. Therefore, when (E) component contains a sodium salt, you may use a sodium salt so that a sodium ion concentration may become the below-mentioned range in the whole composition.

  Amino acids may be any of D-form, L-form, and DL-form.

  Preferred amino acids include aminoethylsulfonic acid (taurine) or a salt thereof, chondroitin sulfate sodium, aspartate (eg, potassium L-aspartate, magnesium potassium potassium L-aspartate), epsilon aminocaproic acid or a salt thereof, hyaluron Acids or salts thereof (such as sodium hyaluronate) are included, and among these, aminoethylsulfonic acid (taurine) and / or a salt thereof and sodium chondroitin sulfate are preferable, and aminoethylsulfonic acid (taurine) is most preferable.

Therefore, the amino acids may contain at least one or more selected from the group consisting of aminoethylsulfonic acid and a salt thereof (particularly aminoethylsulfonic acid).
By using such amino acids (such as taurine), an effect of promoting the healing of damaged corneal epithelial cells can be expected.

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

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

  When the composition contains the component (E), the content of the component (E) in the composition is, for example, 0.001 w / v% or more, preferably 0.01 to 20 w / w, based on the total amount of the composition. v%, more preferably 0.03 to 15 w / v%, further 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% [e.g. 0.2 to 10 w / v%, preferably 0.3 to 8 w / v%, more preferably 0.5 to 7 w / v %, Particularly 0.6 to 6 w / v% (for example, 0.7 to 5 w / v%)].

(F) Cooling agent (component (F))
The composition of the present invention may contain a refreshing agent (hereinafter sometimes referred to as (F) refreshing agent, (F) component, etc.).
Combining the (A) component, the (B) component, and the (C) component may reduce or impair the feeling of use, but such a feeling of use can be improved or improved by a cooling agent. For example, while it may be advantageous to increase the pH of the composition from the viewpoint of dissolution of the component (A) (tranilast), the higher the pH of the composition, the more unpleasant and the feeling of use will be impaired. However, the use of a refreshing agent can relieve such discomfort and improve the feeling of use efficiently.

  Although it does not specifically limit as a refreshing agent, For example, terpenoids, such as menthol, anethole, eugenol, camphor, geraniol, cineol, borneol, limonene, and agate, are mentioned. These may be any of d-form, l-form or dl-form. Moreover, essential oils such as mint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, bergamot oil, eucalyptus oil, rose oil and the like can also be mentioned.

Among these, terpenoids are preferable, and among these, menthol, camphor, geraniol, cineol, borneol, and agate are preferable, menthol, camphor, and borneol are more preferable, and menthol and borneol are more preferable.
Moreover, eucalyptus oil is also preferable from the standpoint of achieving the effects of the present invention more remarkably.

  The cooling agents may be used alone or in combination of two or more. In particular, the refreshing agent preferably includes at least one selected from the group consisting of menthol, borneol and eucalyptus oil, and also combines at least two when combining two or more (for example, menthol, borneol and eucalyptus oil are combined) Is preferred.

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

  Moreover, the ratio of (F) component is 5 w / v% or less, 3 w / v% or less, 2 w / v% or less, 1.5 w / v% or less, 1.2 w / v% with respect to the whole quantity of a composition. Hereinafter, it may be 1 w / v% or less, 0.9 w / v% or less, 0.8 w / v% or less, 0.7 w / v% or less, or 0.6 w / v% or less.

In particular, when the composition of the present invention contains menthol, the ratio of menthol is, for example, 0.00001 w / v% or more (for example, 0.00005 to 2 w / v%), preferably, based on the total amount of the composition. 0.0001 to 0.2 w / v% (for example, 0.0003 to 0.1 w / v%), more preferably 0.0005 to 0.05 w / v% (for example, 0.001 to 0.02 w / v) %) Degree.
The proportion of menthol is 0.0001 parts by mass or more (for example, 0.0003 to 0.5 parts by mass), preferably 0.0005 to 0.1 parts by mass (for example, for 1 part by mass of component (A)). 0.0007 to 0.08 parts by mass), more preferably about 0.001 to 0.05 parts by mass (for example, 0.002 to 0.04 parts by mass).
The proportion of menthol is 0.0001 parts by mass or more (for example, 0.0005 to 2 parts by mass), preferably 0.001 to 1 parts by mass (for example, 0.003 to 3 parts by mass, relative to 1 part by mass of component (C)). 0.7 parts by mass), more preferably about 0.005 to 0.5 parts by mass (for example, 0.01 to 0.4 parts by mass).

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

In particular, when the composition of the present invention contains eucalyptus oil, the ratio of eucalyptus oil is, for example, 0.00001 w / v% or more (for example, 0.00005 to 1 w / v%) with respect to the total amount of the composition, Preferably it is 0.0001-0.1 w / v% (for example, 0.0003-0.05 w / v%), More preferably, it is 0.0005-0.02 w / v% (for example, 0.001-0.01 w) / V%).
The ratio of eucalyptus oil is 0.0001 parts by mass or more (for example, 0.0003 to 0.3 parts by mass), preferably 0.0005 to 0.05 parts by mass (for example, for 1 part by mass of component (A)). 0.0007 to 0.04 parts by mass), more preferably about 0.001 to 0.03 parts by mass (for example, 0.002 to 0.02 parts by mass).
The ratio of eucalyptus oil is 0.0001 parts by mass or more (for example, 0.0005 to 1 part by mass), preferably 0.001 to 0.5 parts by mass (for example, 0 to 1 part by mass of component (C)). 0.003 to 0.3 parts by mass), more preferably about 0.005 to 0.3 parts by mass (for example, 0.01 to 0.2 parts by mass).

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

  Examples of the fat-soluble antioxidant include butyl group-containing phenols such as dibutylhydroxytoluene (BHT) and butylhydroxyanisole (BHA); nordihydroguaiaretic acid (NDGA); ascorbyl palmitate, ascorbate stearate, Ascorbic acid esters such as aminopropyl ascorbate phosphate, tocopherol ascorbate phosphate, ascorbyl triphosphate, ascorbyl phosphate palmitate; ethyl gallate, propyl gallate, octyl gallate, gallic acid such as dodecyl gallate Esters; propyl gallate; 3-butyl-4-hydroxyquinolin-2-one; carotenoids such as lutein and astaxanthin; polyphenols such as anthocyanins, catechins, tannins, curcumin Lumpur like; etc. CoQ10 and the like.

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

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

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

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

  Examples of antiallergic agents (antiallergic agents other than tranilast and / or salts thereof) include cromoglycic acid, ibudilast, acitazanolast, tazanolast, suplatast, pemirolast, levocabastine, olopatadine, ketotifen, amlexanox, oxatomide and the salts thereof Is mentioned.

  Examples of the salt include salts exemplified in the section of the above-mentioned components (A) to (C), for example, alkali metal or alkaline earth metal salts (sodium cromoglycate, potassium cromoglycate, magnesium cromoglycate, Chromoglycate, etc.), inorganic acid salts (eg, olopatadine hydrochloride, etc.), organic acid salts [eg, tosylate, fumarate (eg, ketotifen fumarate, etc.), etc.].

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

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

  The content of the component (H) in the composition is, for example, 0.1 to 10 w / v%, preferably 0.2 to 8 w / v%, more preferably 0.3 to the total amount of the composition. 5 w / v%, even more preferably 0.5 to 3 w / v%, particularly preferably 0.7 to 2 w / v%, still more preferably 0.8 to 1.5 w / v%, most preferably 0. It may be about 9 to 1.2 w / v%.

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

  The salt may be a pharmaceutically or physiologically acceptable salt, for example, an organic acid salt (eg, maleate, fumarate, etc.), an inorganic acid salt (eg, hydrochloride, sulfate, etc.) And salts exemplified in the section of component (A) such as metal salts.

  Specific examples of the salt include diphenhydramine hydrochloride and iproheptin hydrochloride.

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

  When the composition contains the component (I), the content of the component (I) in the composition is, for example, 0.0001 w / v% or more, preferably 0.001 to 10 w / w with respect 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% (for example, 0.02 to 0.1 w / v%), most preferably about 0.025 to 0.05 w / v% (for example, 0.03 w / v%), Usually, it may be about 0.01 to 0.05 w / v%.

(J) Anti-inflammatory Agent The composition of the present invention may contain an anti-inflammatory agent (hereinafter sometimes referred to as (J) anti-inflammatory agent, (J) component, etc.).
The anti-inflammatory agent (anti-inflammatory agent other than pranoprofen and / or a salt thereof) is not particularly limited as long as it is a substance having an anti-inflammatory action. For example, indomethacin, allantoin, berberine, azulenesulfonic acid, diclofenac, Examples include 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, salts with organic bases, the salts exemplified in the above section (A), such as sulfates, Examples thereof include lactate, hydrochloride, chloride salt, sodium salt and potassium salt.

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

Anti-inflammatory agents may be used alone or in combination of two or more.
In addition, the ophthalmic composition of this invention does not need to contain substantially glycyrrhizic acid and its salt.

  When the composition contains the component (J), the content of the component (J) in the composition is, for example, 0.0001 w / v% or more, preferably 0.001 to 10 w / w with respect 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 It may be about 3 w / v% (for example, 0.02 to 0.1 w / v%), most preferably about 0.025 to 0.07 w / v% (for example, 0.05 w / v%).

  The composition of the present invention may contain various components (for example, components not belonging to the category of the components (A) to (J)). Examples of such components (additives) include surfactants, preservatives, buffers, pH adjusters, isotonic agents, thickeners or thickeners, 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 the additive are exemplified below.

Surfactant The composition of the present invention may contain a surfactant. Examples of the surfactant include a non-on surfactant.

  Nonionic surfactants include monolauric acid POE (20) sorbitan (polysorbate 20), monopalmitic acid POE (20) sorbitan (polysorbate 40), monostearic acid POE (20) sorbitan (polysorbate 60), and tristearic acid POE. (20) Polysorbates (POE sorbitan fatty acid esters) such as sorbitan (polysorbate 65) and monooleic acid POE (20) sorbitan (polysorbate 80); Poloxamer 407, Poloxamer 235, Poloxamer 188, Poloxamer 403, Poloxamer 237, Poloxamer 124 POE hardened castor oil such as POE hardened castor oil 40, POE hardened castor oil 50, POE hardened castor oil 60, POE hardened castor oil 80, etc. 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 such as POE castor oil 35, POE castor oil 50; polyethylene glycol monostearate (2E.O.), polyethylene glycol monostearate (4E.O.), polyethylene glycol monostearate (9E.O. .), Polyethylene glycol monostearate (10E.O.), polyethylene glycol monostearate (23E.O.), polyethylene glycol monostearate (25E.O.), polyethylene glycol monostearate (32E.O.) , Monostearic acid polyethylene Glycol (40E.O., polyoxyl 40 stearate), polyethylene glycol monostearate (45E.O.), polyethylene glycol monostearate (55E.O.), polyethylene glycol monostearate (75E.O.), Polyethylene glycol monostearate such as polyethylene glycol monostearate (140EO); POE alkyl ethers such as POE (9) lauryl ether; POE-POP alkyl ethers such as POE (20) POP (4) cetyl ether POE alkyl phenyl ethers such as POE (10) nonyl phenyl ether. In the compounds exemplified above, POE is polyoxyethylene, POP is polyoxypropylene, and the numbers in parentheses indicate the number of moles added.

  Among them, POE sorbitan fatty acid esters; POE / POP glycols; POE hydrogenated castor oil; POE castor oil; polyethylene glycol monostearate is preferable, polysorbate 80, poloxamer 407, POE hydrogenated castor oil 40, POE hydrogenated castor oil 60, POE Castor oil 3, POE castor oil 10, POE castor oil 35, and polyoxyl 40 stearate are more preferable, polysorbate 80, POE hydrogenated castor oil 60 are more preferable, and polysorbate 80 is particularly preferable.

You may use surfactant individually or in combination of 2 or more types.
In addition, the composition of this invention does not need to contain POE hydrogenated castor oil or POE castor oil substantially.

  When a nonionic surfactant is added to the composition of the present invention, the ratio of the nonionic surfactant is, for example, 0.001 w / v% or more, preferably 0.005 w / v, based on the total amount of the composition. % Or more, more preferably 0.01 w / v% or more, particularly preferably 0.05 w / v% or more.

  Moreover, the ratio of a nonionic surfactant may be 5 w / v% or less with respect to the whole quantity of a composition, for example, Preferably it may be 1 w / v% or less.

Preservative The composition of the present invention may contain a preservative.
Examples of preservatives include polydronium chloride, alkyl polyaminoethyl glycines (eg, alkyldiaminoethyl glycine hydrochloride), sodium benzoate, ethanol, quaternary ammonium salts (eg, benzalkonium chloride, benzethonium chloride, etc.), Chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxybenzoate (eg, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate), oxyquinoline sulfate , Phenethyl alcohol, benzyl alcohol, biguanide compounds (for example, polyhexanide hydrochloride, etc.), glowkill (manufactured by Rhodia) and the like.

  Among them, alkylpolyaminoethylglycines (for example, alkyldiaminoethylglycine hydrochloride), sodium benzoate, ethanol, quaternary ammonium salt, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, paraoxybenzoate, biguanide compound Are preferred, quaternary ammonium salts, chlorhexidine gluconate, chlorobutanol, and biguanide compounds are more preferred, and benzalkonium chloride and polyhexanide hydrochloride are more preferred.

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

  When the preservative is blended in the composition of the present invention, as an example of the blending amount, the total amount of the preservative is 0.000001 w / v% or more, particularly 0.00001 w / v% or more, based on the total amount of the composition. In particular, 0.00005 w / v% or more, especially 0.001 w / v% or more, especially 0.005 w / v% or more. The total amount of the preservative 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, 0.025 w / v% or less is mentioned.

Buffering Agent The composition of the present invention may contain a buffering agent.
Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, and acetate buffer.

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

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

  Examples of the component of the carbonate buffer include carbonic acid and carbonate (such as potassium carbonate, sodium carbonate, calcium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, magnesium carbonate). The carbonate may be a hydrate.

  Examples of the citrate buffer component include citric acid and citrate (such as sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, and disodium citrate). The citrate may be a hydrate.

  Examples of the component of the acetate buffer include acetic acid and acetate (such as ammonium acetate, potassium acetate, calcium acetate, and sodium acetate). The acetate salt may be a hydrate.

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

  When blending a buffering agent in the composition of the present invention, the blending amount of the buffering agent varies depending on the type of buffering agent, the type and amount of other blending components, and cannot be uniformly defined. The total amount of the buffering agent is 0.001 w / v% or more, particularly 0.01 w / v% or more, especially 0.05 w / v% or more, especially 0.1 w / v% or more with respect to the total amount of the composition. It is done. Further, the total amount of the buffering agent with respect to the total amount of the composition 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%. The following are mentioned.

  In particular, when a borate buffer is used, the ratio of the buffer in the composition is 0.1 to 10 w / v%, preferably 0.2 to 5 w / v%, more preferably based on the whole composition. May be about 0.5 to 4 w / v%, more preferably about 1 to 3 w / v%.

pH regulators Examples of pH regulators 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, water Examples include potassium oxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, and diisopropanolamine.
You may use a pH adjuster individually or in combination of 2 or more types.

Isotonic agents isotonic agents, such as sodium chloride, potassium chloride, calcium chloride, magnesium chloride, potassium acetate, sodium acetate, magnesium sulfate, glycerin, and propylene glycol.
You may use an isotonizing agent individually or in combination of 2 or more types.

Thickener or thickener The ophthalmic composition of the present invention can contain a thickener or thickener as long as the effects of the present invention are not impaired.

Examples of thickeners or thickeners include guar gum, hydroxypropyl guar gum, cellulosic polymer compounds (for example, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, etc.), gum arabic, karaya gum, xanthan gum, agar , Alginic acid, α-cyclodextrin, dextrin, dextran, mucopolysaccharide (eg, heparin analog, heparin, heparin sulfate, heparan sulfate, heparinoid, hyaluronic acid, hyaluronate (sodium salt, etc.)), starch, chitin and Its derivatives, chitosan and its derivatives, carrageenan, sorbitol, polyvinyl polymer compounds (polyvinylpyrrolidone, polyvinyl alcohol, carbo Sivinyl polymer, etc.), polyacrylic acid alkali metal salts (sodium salt, potassium salt, etc.), polyacrylic acid amine salts (monoethanolamine salt, diethanolamine salt, triethanolamine salt, etc.), casein, gelatin, collagen Pectin, elastin, ceramide, liquid paraffin, glycerin, polyethylene glycol, macrogol, polyethyleneimine alginate (such as sodium salt), alginate (such as propylene glycol ester), tragacanth powder, and triisopropanolamine.
You may use a thickener or a thickener individually or in combination of 2 or more types.

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

Examples of the oil component 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.
In addition, the ophthalmic composition of this invention does not need to contain petrolatum (white petrolatum etc.) substantially.
Moreover, the ophthalmic composition of this invention does not need to contain castor oil, sesame oil, etc. substantially.
For example, the ophthalmic composition of the present invention may be a composition excluding (1) a composition containing a combination of polyoxyethylene castor oil and sesame oil, and (2) polyoxyethylene castor oil, polyoxyethylene cured It may be a composition excluding a composition containing a combination of castor oil and sesame oil.

Examples of the sugar saccharide 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.

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

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, Examples thereof include 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, potassium dihydrogen phosphate are preferable, potassium chloride, Sodium chloride, calcium chloride, sodium hydrogen phosphate, and sodium dihydrogen phosphate are more preferable, and potassium chloride and sodium chloride are still more preferable.
You may use inorganic salt individually or in combination of 2 or more types.

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

  The composition of the present invention can further contain a component having pharmacological activity or physiological activity.

  A pharmacologically active ingredient or a physiologically active ingredient can be used individually or in combination of 2 or more types.

  Examples of such pharmacologically active ingredients and physiologically active ingredients include active ingredients in various pharmaceuticals described in the General Occupational Drug Manufacturing and Sales Approval Standards 2012 edition (supervised by the Japanese Society for Regulatory Science). Examples include decongestants, eye muscle modifiers, astringents, vitamins, amino acids, antibacterial agents or fungicides, local anesthetic ingredients, soothing agents, sulfa drugs, and the like. Specific examples of these drugs are illustrated below.

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

  The imidazoline vasoconstrictor will be described in detail. The salt of the imidazoline vasoconstrictor may be a pharmaceutically or physiologically acceptable salt, for example, an organic acid salt such as maleate or fumarate; hydrochloric acid Inorganic acid salts such as salts and sulfates; and salts such as metal salts. Among the salts, inorganic acid salts are preferable, hydrochlorides or nitrates are more preferable, and hydrochlorides (tetrahydrozoline hydrochloride and the like) are particularly preferable.

  Among the decongestants (vasoconstrictors), imidazoline vasoconstrictors are preferable, tetrahydrozoline, naphazoline, or a salt thereof is more preferable, and tetrahydrozoline, or a salt thereof is more preferable.

The ocular muscles modifier ocular muscles regulators such as, cholinesterase inhibitors having similar activity center and acetylcholine, specifically neostigmine methylsulfate, tropicamide, Herenien, and the like atropine sulfate.

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

Among them, flavin adenine dinucleotide or a salt thereof (especially flavin adenine dinucleotide sodium), cobalamin or a salt thereof (particularly cyanocobalamin), retinol, a salt thereof or a derivative thereof (particularly retinol acetate, retinol palmitate), pyridoxine or a salt thereof Preferred are salts (especially pyridoxine hydrochloride), panthenol, pantothenic acid or salts thereof (especially sodium pantothenate, calcium pantothenate), tocopherols, salts or derivatives thereof (especially tocopherol acetate), and pyridoxine hydrochloride and tocopherol acetate. More preferred.
In addition, the composition of this invention does not need to contain pyridoxine and its salt.

Antibacterial agent or bactericidal agent As the antibacterial agent or bactericidal agent, for example, sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxazole monoethanolamine, Examples include sulfa drugs such as sulfisomezole sodium and sulfisomidine sodium, alkylpolyaminoethylglycine, chloramphenicol, ofloxacin, norfloxacin, levofloxacin, and lomefloxacin hydrochloride.

Local anesthetic component Examples of the local anesthetic component include procaine hydrochloride and lidocaine hydrochloride.

As the soothing agent , for example, procaine hydrochloride and the like can be mentioned.

The sulfa sulfa agents such as sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulphates iso spermidine sodium and the like.

Base or Carrier The composition of the present invention may comprise a base or carrier.
A composition containing such a base or carrier can be prepared, for example, by mixing the above-mentioned components with a pharmaceutically acceptable base or carrier, for example, as described in the 17th revised Japanese Pharmacopoeia Manual. It can be prepared by the method.

  Examples of the base or carrier include water, polar solvents such as ethanol (particularly water-soluble solvents), oily bases, and the like. A base or a support | carrier can be used individually by 1 type or in combination of 2 or more types.

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

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

  Further, as described above, the composition may be an aqueous composition (mainly containing an aqueous or hydrophilic base or carrier), or an oily composition (oil or hydrophobic base or carrier). And mainly an aqueous composition.

  The content of water in the case of an aqueous composition is preferably 50% by mass or more, more preferably 75% by mass or more, and still more preferably 90% by mass or more, with respect to the total amount of the composition (or formulation). In addition, the base or carrier may be composed only of water.

  The content of water in the case of an oily composition is preferably less than 50% by mass, more preferably 30% by mass or less, and still more preferably 20% by mass or less, with respect to the total amount of the composition (or formulation).

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

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

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

  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 proportion of sodium ions can be selected from the range of about 30 mol or less, 1 mol of component (A), 25 mol or less, preferably 20 mol or less, more preferably 15 mol. Hereinafter, it may be 12 mol or less, most preferably 10 mol or less (for example, 9.5 mol or less), and a relatively low ratio [for example, 9 mol or less (for example, 8 mol or less), preferably 7 moles or less (for example, 6 moles or less), more preferably 5 moles or less, particularly preferably 4 moles or less, most preferably 3 moles or less], and a lower ratio (for example, 3.5 moles or less, 3 mol or less, 2.5 mol or less, 2 mol or less, 1.5 mol or less, preferably 1 mol or less, more preferably 0.5 mol or less, particularly preferably 0.1 mol or less, substantially It may be a mole or detection limit).

In addition, the sodium ion should just be what can become a free ion in a composition, and may form the salt. For example, in the composition, even when tranilast forms a salt with sodium and the sodium ion is not in a free state, sodium (ion) derived from such a salt is also included in the sodium ion.
Further, 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 component (raw material) constituting the composition. May be obtained by calculating (indirectly measuring) the amount or concentration in the composition. In addition, you may measure the amount or density | concentration of sodium (ion) in a composition or a raw material with a conventional method or apparatus (for example, ion chromatography method etc.).

  Moreover, since sodium derived from each component is contained in the sodium ion as described above, when each component contains sodium as a salt or the like, it is necessary to adjust the sodium ion concentration to be the above. From this point of view, when the amount of sodium in the composition of the present invention is reduced, sodium chloride, borax, sodium edetate, and the like that are widely used in eye drops and the like are included or not included in a small amount. It is desirable.

  From such a viewpoint, in particular, as each component constituting the composition of the present invention (for example, the components (A) to (C), other components, etc.), a component not containing sodium [for example, when it is a salt May be a salt that is not a sodium salt (non-sodium salt)].

pH
The pH of the composition of the present invention is preferably 3 or more (for example, 4 or more), more preferably 5 or more (for example, 5.5 or more), and still more preferably 6 or more. Moreover, 10 or less is preferable, 9 or less is more preferable, and 8.5 or less is further more preferable.

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 (for example, 6.0 to 8.3). It may be 5 to 8.5 (for example, 7 to 8, 7.2 to 7.7, etc.).
In the present invention, the effects of the present invention can be realized efficiently even at the pH as described above.

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

  The osmotic pressure ratio is a 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 revision Japanese Pharmacopoeia.

Dosage Form The dosage form (dosage form, shape, structure) of the composition of the present invention is not particularly limited. For example, eye drops (also referred to as eye drops or eye drops. Eye drops can be instilled while wearing contact lenses). Eye drops, eye wash, eye ointment (water-soluble ointment, oil-soluble eye ointment), contact lens mounting solution, intraocular injection (eg, intravitreal injection), contact lens solution (cleaning solution, storage) Liquids, disinfectants, multipurpose solutions, package solutions), preservatives for isolated eye tissue such as the cornea for transplantation, and perfusate during surgery. Eye drops, eye washes and eye ointments include those used when wearing contact lenses.

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

  The dosage form of the composition of the present invention is preferably eye drops, eye wash, eye ointment (water-soluble eye ointment, oil-soluble eye ointment), contact lens mounting liquid, contact lens liquid (cleaning liquid, preservative liquid, disinfectant liquid) , Multipurpose solutions, package solutions), and more preferably eye drops, eyewashes, contact lens mounting solutions, contact lens solutions (cleaning solutions, storage solutions, disinfecting solutions, multipurpose solutions), etc. More preferred are eye drops and eye wash, and particularly preferred are eye drops.

  Such a composition of the present invention is an ophthalmic composition used or applied when a contact lens (hard contact lens, soft contact lens, especially a silicone hydrogel contact lens) is worn (when worn) or while worn (when worn) ( 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 or a multi-dose that can be used repeatedly, or may be contained and used in the form of a multi-dose.

Container The composition of the present invention may be contained (filled, injected, sealed) in a container.
The container may be a package having a part (surface) that comes into contact with the composition (formulation), for example, a container body part that contains the composition (for example, a liquid composition), a part that includes the extraction port of the container. (Nozzle, inner plug), suction tube, cap and the like.

  The material constituting the container can be selected from a wide range. For example, at least part or all of the contact portion with the composition is plastic [for example, olefin resin, styrene resin, acrylic resin, polyester resin, polycarbonate. Resin, fluororesin, 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 which may be substituted with halogen atoms, etc.], metals (aluminum etc.) and the like.

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

  Examples of olefin resins include ethylene resins [eg, 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, etc. ], Propylene resins [eg, polypropylene (PP) (including isotactic polypropylene, syndiotactic polypropylene, atactic polypropylene, etc.), propylene-ethylene copolymers, etc.], methylpentene resins (eg, polymethylpentene) Etc.).

  Examples of the styrene resin include polystyrene and acrylonitrile-containing styrene resin (for example, acrylonitrile-styrene copolymer (AS resin), acrylonitrile-butadiene-styrene copolymer (ABS resin), and the like).

  Examples of the acrylic resin include resins having a polymerization component such as an acrylate ester such as methyl acrylate, a methacrylate ester such as methyl methacrylate, cyclohexyl methacrylate, and t-butyl cyclohexyl methacrylate.

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

  Fluorine resins include fluorine-substituted polyethylene (polytetrafluoroethylene, polychlorotrifluoroethylene, etc.), polyvinylidene fluoride, polyvinyl fluoride, perfluoroalkoxy fluororesin, tetrafluoroethylene / hexafluoropropylene copolymer, ethylene / tetra Examples thereof include a fluorinated ethylene copolymer and an ethylene / chlorotrifluoroethylene copolymer.

  Examples of the polyacetal-based resin include those containing only oxymethylene units and those partially containing oxyethylene units.

  Examples of the modified polyphenylene ether include polystyrene-modified polyphenylene ether.

  Examples of polyarylate include amorphous polyarylate.

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

  Examples of cellulose acetate include cellulose diacetate and cellulose triacetate.

  The material of the container is preferably a plastic such as an olefin resin, a styrene resin, or a polyester resin (that is, a plastic container), more preferably an ethylene resin, a propylene resin, an alkylene terephthalate resin, or polystyrene, polypropylene, Polyethylene terephthalate and polystyrene are more preferred, and polyethylene terephthalate is even more preferred.

  The container may be a polymer blend with a polymer other than the polymer as a container material. When the container material of the container containing the ophthalmic composition of the present invention is a polymer blended with the polymer, the mixing ratio of the polymer and a 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. It is especially preferable that it is 80 w / w% or more.

  As for a container, at least one part of the surface which contacts the composition of this invention may be comprised with the said 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 remarkably exhibiting the effects of the present invention, the container itself is preferably molded from the above-mentioned material.

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

Target disease (use)
The target disease (use) of the composition of the present invention is not particularly limited as long as it is ophthalmic, and includes, for example, allergic symptoms, itchy eyes, redness, foreign body sensation (feeling of crumbling), corneal damage, etc. , Corneal damage, lacrimation (tears), follicles of eyelid conjunctiva, eye oil (eye and eyes), etc. are useful for relief, improvement, suppression or treatment, enhancement of corneal barrier function, normalization, corneal protection, etc. .

  In addition, the teardrop is a symptom that occurs when the drainage path of tears from the punctum to the lacrimal canal, lacrimal sac, and nasolacrimal duct becomes obstructed by the eyes or the like, or excessive tears are made by stimulation. .

  In this specification, “relief” includes symptom relief, symptom progression inhibition, and “improvement”, “suppression”, and “treatment” mean symptom relief, symptom progression inhibition, healing or completeness. Include.

  In particular, the composition of the present invention is suitable for alleviation, improvement, suppression, or treatment of allergic symptoms (eye allergic symptoms).

  The allergic allergen is not particularly limited, and may be pollen (cedar pollen, cypress pollen, etc.), house dust (indoor dust), or the like.

  In another aspect, the composition of the present invention is suitable for use in the alleviation, improvement, suppression, or treatment of symptoms such as itchy eyes, redness, tears, foreign body sensation, and eye oil (in the eyes and eyes). These symptoms may be derived from allergic symptoms or may not be derived.

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

  For example, when the composition of the present invention is a preparation to be applied to the eye such as an eye drop, an eye wash, an eye ointment, etc., the usage varies depending on the target symptom, but for example, once or more twice a day. As mentioned 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 per day. It is particularly preferred to administer 4 times a day.

  When the composition of the present invention is an eye drop, for example, 1 to 3 drops may be applied per time, or 1 to 2 drops or 2 to 3 drops may be used. Preferably, 1 to 2 drops may be applied. One drop can also be used. Moreover, the amount of eyedrops may be preferably 30 to 50 μL.

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

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

  When the composition of the present invention is a contact lens mounting solution, at the time of wearing or removing the contact lens, for example, 1 to 3 drops, preferably 1 to 2 drops per side and / or one side of the contact lens. It may be worn after being dripped onto both sides and wetted, and it is preferable to wear after wetting both sides of the contact lens.

[2. (Preservation efficacy)
The ophthalmic composition according to the present embodiment has an effect that the storage efficacy (storage stability) in the ophthalmic composition can be improved or improved (or can be imparted or expressed).
Therefore, as one embodiment of the present invention, the ophthalmic composition containing one or two components selected from the components (A), (B) and (C) contains the remaining one or two components (for example, A method for improving or improving the storage efficacy (storage stability) in the ophthalmic composition, which comprises adding (B) component and (C) component to the ophthalmic composition containing the component (A) A method of expression) is provided.
Moreover, as one embodiment of the present invention, the preservation efficacy in an ophthalmic composition containing one or two components selected from the components (A), (B) and (C) is improved or improved (given or expressed). An agent (preservative) for use, which comprises the remaining one or two components.
In these methods and agents, microorganisms, fungi, molds, etc. that exhibit storage efficacy are not particularly limited, and examples include S. aureus, E. coli, Pseudomonas aeruginosa, Candida, Aspergillus and the like.

[3. Stability〕
The ophthalmic composition according to the present embodiment has an effect that the stability (for example, thermal stability and / or light stability, particularly at least light stability) in the ophthalmic composition can be improved or improved (given or expressed). Play.
Therefore, as one embodiment of the present invention, the ophthalmic composition containing one or two components selected from the components (A), (B) and (C) contains the remaining one or two components (for example, A method for improving or improving (giving or expressing) the stability of the ophthalmic composition, which comprises adding the component (B) and the component (C) to the ophthalmic composition containing the component (A). The
Moreover, as one embodiment of the present invention, the stability in an ophthalmic composition containing one or two components selected from the components (A), (B) and (C) is improved or improved (given or expressed). Agents for light (light stabilizers, heat stabilizers, heat and light stabilizers) comprising the remaining one or two components are provided.

[4. (Oxygen stress tolerance)
The ophthalmic composition which concerns on this embodiment has an effect that the oxygen (hypoxic) stress tolerance in an ophthalmic composition can be improved or improved (given or expressed).
Therefore, as one embodiment of the present invention, the ophthalmic composition containing one or two components selected from the components (A), (B) and (C) contains the remaining one or two components (for example, And (O) the ophthalmic composition containing the component (B) and the component (C) are added) to improve or improve (provide or express) oxygen (hypoxic) stress resistance in the ophthalmic composition. A method is provided.
Further, as one embodiment of the present invention, the oxygen (hypoxia) stress resistance in an ophthalmic composition containing one or two components selected from the components (A), (B) and (C) is improved or improved ( An agent for imparting or expressing) (oxygen stress tolerance improving agent), which comprises the remaining one or two components.

[5. Suppression of precipitation and cloudiness)
The ophthalmic composition which concerns on this embodiment has an effect that precipitation (white turbidity) in an ophthalmic composition can be suppressed (or dissolution stability can be improved or improved).
Therefore, as one embodiment of the present invention, the ophthalmic composition containing one or two components selected from the components (A), (B) and (C) contains the remaining one or two components (for example, A method for suppressing precipitation (white turbidity) in the ophthalmic composition (improvement or improvement in dissolution stability), including the addition of the component (B) and the component (C) to the ophthalmic composition containing the component (A) Is provided).
In this method, the sodium ion concentration of the ophthalmic composition may be set to the above concentration (for example, 250 mM or less), or a solubilizing agent (for example, polyvinylpyrrolidone) may be contained.
Moreover, as one embodiment of the present invention, an agent for suppressing precipitation (white turbidity) in an ophthalmic composition containing one or two components selected from the components (A), (B) and (C) (or An agent for improving or improving the dissolution stability), comprising the remaining one or two components. This agent may further contain a solubilizing agent (such as polyvinylpyrrolidone).
In these methods and agents, the temperature at which the effect of suppressing precipitation (improving or improving dissolution stability) is not particularly limited, but may be an effect at a relatively low temperature. Therefore, the method and the agent may be a method and an agent that suppress precipitation (improve or improve dissolution stability) at a low temperature (for example, 10 ° C. or less, preferably 5 ° C. or less, 0 ° C. or less). .

  In addition, about the formulation form of an ophthalmic composition, a use, etc., such as the kind and content of other components, such as the kind and content of (A)-(C) component in said each embodiment, [1. As described in [Ophthalmic composition].

  EXAMPLES The present invention will be described more specifically with reference to the following examples. However, the present invention is not limited to these examples, and many modifications are within the technical scope of the present invention. This is possible by those with ordinary knowledge.

  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 a calculation example of a component containing sodium (ion) and its sodium amount or concentration.

Sodium ion concentration (mM) =
Blending amount (w / v%) / molecular weight × sodium number (per molecular weight) × 10000

  In addition, about polysaccharide, it computed based on the molecular weight of the saccharide | sugar part which sodium has couple | bonded. For example, sodium chondroitin sulfate is a polymer having N-acetyl-D-galactosamine and D-glucuronic acid disaccharides as repeating structural units, and the Na concentration is calculated with a molecular weight per disaccharide unit of 503.3. Is going.

Test Example 1 (Preservation efficacy)
An aqueous ophthalmic composition (eye drops) having the composition shown in Table 2 below was prepared by a conventional method, and the storage efficacy was evaluated as follows.

Staphylococcus aureus (ATCC 6538) was inoculated on the surface of soybean casein digest slope medium and cultured at 33 ° C. for 24 hours. The cultured cells were aseptically collected with a platinum loop and suspended in an appropriate amount of sterile physiological saline to prepare a bacterial suspension containing about 1 × 10 ⁷ CFU / mL viable bacteria. The number of viable bacteria in the suspension was measured by separately culturing. Next, 15 mL capacity CORNING conical tube (PET) was filled with 10 mL of each aqueous ophthalmic composition sterilized by filtration. This aqueous ophthalmic composition was inoculated with a suspension of Staphylococcus aureus so that the viable count (final concentration) was about 10 ⁵ CFU / mL, and stirred well to prepare a sample.
Samples were stored for 5 days at 23 ° C., protected from light. Five days later, a sample containing bacteria was prepared to an appropriate concentration for counting, seeded on a soy bean casein digest agar medium (SCD agar medium), cultured at 33 ° C overnight, and the number of colonies observed. Was counted to determine the number of viable bacteria.
The following values (Log Reduction Value LRV, log reduction value) were calculated from the obtained viable cell count and used as an index of preservation efficacy.
Log reduction value = log (viable cell count in suspension / 100)-log (viable cell count after 5 days)

  In the aqueous ophthalmic composition shown in Table 2 below, the unit of each component is (w / v%) (the same applies hereinafter).

  As is clear from the results in Table 2 above, by combining tranilast, chlorpheniramine maleate, and pranoprofen, among these three components, when tranilast or chlorpheniramine maleate is used alone or maleic acid Compared with the combination of chlorpheniramine and pranoprofen, it showed higher preservation efficacy against S. aureus.

Test Example 2 (Preservation efficacy)
An aqueous ophthalmic composition (eye drops) having the composition shown in Table 3 below was prepared by a conventional method and stored in the same manner as in Test Example 1 except that the storage period was changed from 5 days to 1 week in Test Example 1. Efficacy was evaluated.

  As is clear from the results of Table 3 above, the same storage efficacy was obtained even when the storage period was extended to 1 week or the ratio of the three components was changed.

Test Example 3 (Preservation efficacy)
Test Example 2 except that an aqueous ophthalmic composition (eye drops) having the composition shown in Table 4 below was prepared by a conventional method and heat-treated (thermal aging) before storage in Test Example 2 (storage period 1 week). The storage efficacy was evaluated in the same manner as described above.
The heat treatment was performed by filling the prepared aqueous ophthalmic composition in a 13 mL capacity PET container with 13 mL, packaging the plastic film, and storing it at 60 ° C. for 7 days under light shielding conditions.

  As is clear from the results in Table 4 above, the storage efficacy could be maintained even when heat-treated before storage.

Test Example 4 (Preservation efficacy)
An aqueous ophthalmic composition (eye drops) having the composition shown in Table 5 below was prepared by a conventional method, and a logarithmic decrease value A was obtained in the same manner as in Test Example 2 (storage period 1 week).
On the other hand, a logarithmic decrease was performed in the same manner as in Test Example 2, except that the same ophthalmic composition having the same composition was used and the same heat treatment as in Test Example 3 was performed before storage in Test Example 2 (storage period 1 week). A value B was obtained.
From these results, the difference in logarithmic decrease value (A-B) was calculated, and the degree of decrease in storage efficacy due to thermal aging was evaluated.

  As is clear from the results in Table 5 above, the combination of the three components could suppress a decrease in storage efficacy due to heat treatment.

Test Example 5 (Preservation efficacy)
An aqueous ophthalmic composition (eye drops) having the composition shown in Table 6 below was prepared by a conventional method and stored in Test Example 2 (storage period 1 week) in the same manner as Test Example 2 except that it was exposed to light before storage. Efficacy was evaluated.
In addition, after the exposure, the prepared aqueous ophthalmic composition was filled in 13 mL of a 13 mL capacity PET container, and then a white lamp was used using a light stability test apparatus (“LT-120A-WCD type”, manufactured by Nagano Science Co., Ltd.). As a photogen, 4500 lx / hr of light was continuously irradiated at room temperature for a time until the cumulative dose of the aqueous ophthalmic composition reached 100,000 lx · hr.

  As is clear from the results in Table 6 above, the preservation efficacy could be maintained even after exposure.

Test Example 6 (preservation efficacy)
An aqueous ophthalmic composition (eye drops) having the composition shown in Table 7 below was prepared by a conventional method, and Escherichia coli (ATCC 8739) was used instead of Staphylococcus aureus in Test Example 2 (storage period 1 week). Except for the above, the storage efficacy was evaluated in the same manner as in Test Example 2.

  As is clear from the results in Table 7 above, it was found that even when the type of bacteria was changed, storage efficacy was exhibited by combining tranilast, chlorpheniramine maleate, and pranoprofen.

Test Example 7-1 (light stability)
An aqueous ophthalmic composition (eye drops) having the composition shown in Table 8 below was prepared by a conventional method, and photostability was evaluated as follows.
13 mL of the prepared aqueous ophthalmic composition was filled in a 13 mL PET container. Using a light stability tester (“LT-120A-WCD type”, manufactured by Nagano Science Co., Ltd.), a white lamp is used as a photogen, and light is continuously irradiated at 4500 lx / hr at room temperature for a time. The object was exposed to light with an integrated irradiation amount of 900,000 lx · hr. After exposure, the turbidity of the aqueous ophthalmic composition was measured using a haze meter (“NDH-300A”, manufactured by Nippon Denshoku).

  As apparent from the results in Table 8 above, it was found that excellent light stability can be realized by combining the three components. In particular, among the three components, chlorpheniramine maleate itself has high photostability and pranoprofen seems to have low photostability, but simply combining them improves the photostability of planoprofen. The fact that the light stability similar to that of chlorpheniramine maleate was obtained by combining the three components was extremely surprising as opposed to being extremely lowered.

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

  And, from the obtained amount of chlorpheniramine maleate after exposure and the amount of chlorpheniramine maleate before exposure, the degradation rate (%) of chlorpheniramine maleate [100-residual rate (%)] The composition was determined for each of the compositions 7A and 7D, and the decomposition ratio and decomposition suppression rate calculated from the following formulas were calculated to be “0.529” and “47.08%”, respectively.

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

  From this result, it was found that the decomposition of chlorpheniramine maleate by light can be efficiently suppressed by combining the three components.

Test Example 8 (Hydroxygen stress tolerance)
A composition having the composition shown in Table 9 below was prepared by dissolving in a culture medium (DMEM / F12, Gibco). Tranilast was dissolved in dimethyl sulfoxide (Wako Pure Chemical Industries, Ltd.) and then dissolved in the culture medium. Further, the same amount of dimethyl sulfoxide was added to the composition containing no tranilast as in the case of dissolving tranilast.

And the low oxygen stress tolerance of the obtained composition was evaluated as follows.
Human immortalized corneal epithelial cells (HCE-T) were seeded in 6 well plate (Corning) at 1.6 × 10 ⁵ cells / well, and maintained at 37 ° C., 5% CO ₂ and 90% humidity for 72 hours. Cultured.
After adding chlorpheniramine maleate alone or a combination of pranoprofen and chlorpheniramine maleate and a combination of pranoprofen, chlorpheniramine maleate and tranilast to cells according to the composition of Table 9 The cells were cultured at 37 ° C. for 18 hours under anaerobic conditions using Aneropac Kenki (Mitsubishi Gas Chemical Co., Ltd.). Then, the mRNA expression level of hGPX1 known as an antioxidant gene was quantified by a quantitative real-time PCR method using Quant Studio 7 Real-Time PCR System (Applied Biosystems).

The test results are shown in FIG.
As is apparent from the results of FIG. 1, in the combination of pranoprofen, chlorpheniramine maleate and tranilast (Test Example 8C), chlorpheniramine maleate alone (Test Example 8A) and pranoprofen and malein The expression of hGPX1 was significantly higher than the two combinations of chlorpheniramine acid (Test Example 8B) (* p <0.05, by t-test). Moreover, even if the ratio of the three components was changed, the same expression effect of hGPX1 was shown (Test Example 8D). It was clarified that the prescription based on the combination of the three components has a particularly remarkable effect on the enhancement of the expression of antioxidant genes, as compared with the prescription of the combination of one kind and two kinds.

Test Example 9 (human sensory test)
An aqueous ophthalmic composition (eye drops) having the composition shown in Table 10 below was prepared, and a sensory test was performed as follows.

Five subjects with hay fever and eye symptoms were included. From the test start date, the eye drops of 9A for the left eye and 9B for the right eye are instilled at a rate of 4 times a day, and during the instillation period, 1 on the night of the first day, the second day, and the fifth day. Subjective symptoms were surveyed for specific items throughout the day.
The subjective symptom questionnaire was rated as 100 out of 100. The larger the value, the stronger the subjective symptom. The value is an average value of five people.

The results are shown in the table below.

  Test Example 9B was similar to or less than Test Example 9A in itching and hyperemia.

  Test Example 9A contains sodium cromoglycate and is a prescription known to have an improvement effect such as itching from the beginning. Therefore, the value of Test Example 9B shows a value equal to or smaller than that of Test Example 9A. Even if tranilast, chlorpheniramine maleate, and pranoprofen are combined, the effect of improving itchiness and hyperemia It means that there is no fading or better than that.

Test Example 10 (Precipitation test)
An aqueous ophthalmic composition (eye drops) having the composition shown in Table 12 below was prepared, and precipitation was evaluated as follows.

  The prepared composition was filled in a screw vial (manufactured by Maruemu, No. 3L) and stored at 4 ° C. and −2 ° C. for 2 days, respectively. After confirming the precipitation, the screw vial was stirred for 10 seconds at the maximum stirring speed using a vortex mixer (manufactured by ASONE, vortex jenny 2), and aqueous using a haze meter (“NDH-300A”, manufactured by Nippon Denshoku). Turbidity in the ophthalmic composition was measured.

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

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

As is clear from the results in Table 12 above, it was found that precipitation was also caused when polyvinylpyrrolidone (and monoethanolamine) was added to tranilast (and when the sodium ion concentration was 0). On the other hand, this precipitation increases when diphenhydramine hydrochloride is added, whereas it can be suppressed by coexisting chlorpheniramine maleate and pranoprofen, and particularly when three components are combined. all right.
In particular, in the above-mentioned test examples, components such as chlorpheniramine maleate and pranoprofen are included, but even if such components are included, the stability of the formulation such as precipitation and turbidity is not impaired, Rather, precipitation and turbidity could be suppressed by combining the three components.

  In the above formulation, polyvinylpyrrolidone and monoethanolamine are used in combination. However, when polyvinylpyrrolidone is not used, the same precipitation improving effect is observed even when trometamol is used instead of polyvinylpyrrolidone and / or monoethanolamine. It was.

  Furthermore, according to the study by the present inventors, when tranilast and monoethanolamine were combined, precipitation sometimes occurred after drying. In the prescription of the above test example, precipitation after drying even when these were combined. Did not occur.

Test Example 11 (Precipitation test)
An aqueous ophthalmic composition (eye drops) having the composition shown in Table 13 below was prepared, and precipitation was evaluated as follows.

The prepared composition was filled in a screw vial (manufactured by Maruem, No. 3L) and stored at 4 ° C. for 2 days. After confirming the precipitation, the screw vial was stirred for 10 seconds at a maximum stirring speed using a vortex mixer (manufactured by ASONE, vortex jenny 2), and 1.5 mL of the stirred composition was 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 the accumulated precipitate was measured, and the precipitation improvement rate represented by the following formula was calculated.

Deposition improvement rate (%) = (Y−X) / Y × 100
[In the formula, X is the height of the precipitate in each test example, Y is the test example (blank) in which each component concentration is the same without adding chlorpheniramine maleate and pranoprofen in each test example. The height of the precipitate is shown. ]

  As is apparent from the results in Table 13 above, it was found that precipitation can be efficiently suppressed even when other three ion concentrations (85 mM, 115 mM) are combined, particularly when the three components are combined.

Test Example 12 (Precipitation test)
An aqueous ophthalmic composition (eye drops) having the composition shown in Table 14 below was prepared, and precipitation was evaluated in the same manner as in Test Example 11.

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

Test Example 13 (clinical test)
Aqueous ophthalmic compositions (eye drops) having the compositions shown in Table 15 below were prepared, and clinical trials were conducted as follows.

  In addition, the eye drop of the prescription shown in Table 15 did not cause problems such as precipitation as in the prescriptions of the other test examples.

  For patients with mild or moderate allergic conjunctivitis (including hay fever) who are clearly associated with type I allergy by allergy testing and who have subjective symptoms of itchy eyes, The efficacy and safety of instilling 1 to 2 drops once, 4 times a day for 14 days were confirmed.

Scores of objective findings (follicles of the eyelid conjunctiva) were set as evaluation items, and the amount of change was measured. The investigator or study investigator performed slit lamp microscopy and determined the severity according to the following: In the determination, ++++: 3 points, ++: 2 points, +: 1 point, −: 0 points were calculated.
3 (altitude): 20 or more 2 (moderate): 10 to 19 1 (mild): 1 to 9 0 (none): not considered

  The degree of improvement by symptom was determined from the objective findings score according to the following Table 16 in 5 stages (significant improvement, moderate improvement, mild improvement, unchanged, worsening). In addition, descriptive statistics were calculated for the amount of change in the objective finding score.

As a result of the test, the percentage of subjects whose findings improved more than moderate improvement among the subjects who showed follicles of the eyelid conjunctiva from the start to the end of the test was 66.0%. The average amount of change in the score of the follicle of the eyelid conjunctiva was -0.7.
On the other hand, the improvement rate over the moderate improvement for the aqueous ophthalmic solution containing tranilast at a concentration of 5 mg / mL and the aqueous ophthalmic solution containing sodium cromoglycate at a concentration of 20 mg / L was “25.7%”, respectively. There is a report that it was “12.5%” (Clinical Medicine Vol. 9 No. 3 (March) 1993, 669-683). In addition, there is a report that the improvement rate over the moderate improvement for the ophthalmic solution containing levogavastin hydrochloride at a concentration of 0.25 mg / mL was “13%” or “15.9%” after 2 weeks of administration (newly Ophthalmology 12 (2): 317-332, 333-350, 1995). Furthermore, there is a report that the average amount of change in the score of the follicle of the eyelid conjunctiva for an aqueous ophthalmic solution containing 0.05% epinastine hydrochloride was “about −0.2” for 2 weeks after administration (New Ophthalmology 31 ( 1) 97-104, 2014).

  In addition, the improvement rate of moderate improvement or higher in subjects whose follicles of the eyelid conjunctiva were mild or higher at the start of administration was 82.5%, and the rate of significant improvement in subjects who were moderate or high was 100%.

  From these results, it was found that the effect of improving the follicles of the eyelid conjunctiva by the above-described formulation was remarkably excellent.

  Furthermore, the improvement of the subjective symptoms of the subjects was also examined. Subjective symptom (smooth eyes, foreign body sensation, eye grease (eyes and eyes)) scores were set as shown in Table 17 below, and the amount of change was measured. The score for the past 3 days (not including the date of examination) at the time of the examination was calculated.

  From the average value of the subjective symptom score, the degree of improvement by symptom was determined in 5 stages (significant improvement, moderate improvement, mild improvement, unchanged, worsening) according to Table 16.

  As a result, it was as shown in Table 18 that each subjective symptom improved more than moderate improvement. The subjects who had follicles of the eyelid conjunctiva at the start of administration were particularly effective in improving these subjective symptoms.

[Formulation example]
An ophthalmic composition was prepared according to the formulation described in the table below. In the table below, the unit of each component is (w / v%).

  In the present invention, an ophthalmic composition useful as an eye drop or the like can be provided.

Claims (12)

(A) one or more selected from the group consisting of tranilast and salts thereof,
(B) one or more selected from the group consisting of chlorpheniramine and its salt, and (C) one or more selected from the group consisting of pranoprofen and its salt,
The ophthalmic composition whose ratio of a component (B) with respect to 100 mass parts of components (A) is 1-8 mass parts, and the ratio of a component (C) is 5-25 mass parts. (A) one or more selected from the group consisting of tranilast and salts thereof,
(B) one or more selected from the group consisting of chlorpheniramine and a salt thereof, and (C) one or more selected from the group consisting of pranoprofen and a salt thereof,
The component (A) is 0.3 to 0.7 w / v%, the component (B) is 0.007 to 0.04 w / v%, and the component (C) is 0.03 to 0.15 w / v%. An ophthalmic composition containing. The ophthalmic composition according to claim 1 or 2, wherein a ratio of the component (A), the component (B), and the component (C) satisfies any of the following.
(A) component / (B) component / (C) component (mass ratio) = 100/5 to 7/8 to 12
(A) component / (B) component / (C) component (mass ratio) = 100 / 5-7 / 18-22
(A) component / (B) component / (C) component (mass ratio) = 100 / 1-3 / 8-12
(A) component / (B) component / (C) component (mass ratio) = 100 / 1-3 / 18-22 The ophthalmic composition according to any one of claims 1 to 3, wherein the ratio of the components (A) to (C) satisfies any of the following.
Ratio in which component (A) is 0.4 to 0.6 w / v%, component (B) is 0.02 to 0.04 w / v%, and component (C) is 0.04 to 0.06 w / v% Ratio in which component (A) is 0.4 to 0.6 w / v%, component (B) is 0.02 to 0.04 w / v%, and component (C) is 0.08 to 0.12 w / v% Ratio in which component (A) is 0.4 to 0.6 w / v%, component (B) is 0.013 to 0.017 w / v%, and component (C) is 0.04 to 0.06 w / v% Ratio in which component (A) is 0.4 to 0.6 w / v%, component (B) is 0.013 to 0.017 w / v%, and component (C) is 0.08 to 0.12 w / v% Ratio in which component (A) is 0.4 to 0.6 w / v%, component (B) is 0.008 to 0.012 w / v%, and component (C) is 0.04 to 0.06 w / v% Component (A) is 0.4 to 0.6 w / %, Component (B) is 0.008~0.012w / v%, the proportion component (C) is 0.08~0.12w / v%   The ophthalmic composition according to any one of claims 1 to 4, comprising at least one selected from polyvinylpyrrolidone, monoethanolamine and trometamol.   The ophthalmic composition according to claim 1, comprising at least one selected from monoethanolamine and trometamol.   The ophthalmic composition according to any one of claims 1 to 6, wherein the sodium ion concentration is 250 mM or less, or the ratio of sodium ions is 25 mol or less with respect to 1 mol of the component (A).   The ophthalmic composition according to any one of claims 1 to 7, wherein the sodium ion concentration is 20 mM or less, or the ratio of sodium ions is 20 mol or less with respect to 1 mol of component (A).   The ophthalmic composition according to any one of claims 1 to 8, which is used for alleviating, improving, suppressing and / or treating allergic symptoms.   The ophthalmic composition according to any one of claims 1 to 9, which is used for alleviating, ameliorating, suppressing and / or treating at least one kind of symptom selected from itching, hyperemia, tearing eyes, foreign body sensation, and eyes and eyes. .   The ophthalmic composition containing 1 or 2 components selected from the components (A), (B) and (C) according to claim 1 contains the remaining 1 or 2 components, A method for improving, improving, imparting and / or expressing at least one selected from (1) storage efficacy, (2) photostability, and (3) resistance to oxygen stress.   In an ophthalmic composition comprising one or two components selected from the components (A), (B) and (C) according to claim 1, (1) storage efficacy, (2) light stability and (3 ) An agent for improving, improving, imparting and / or developing at least one selected from resistance to oxygen stress and comprising the remaining one or two components.