JP2024010178A - Ophthalmic composition - Google Patents

Abstract

To provide an ophthalmic composition.SOLUTION: An ophthalmic composition has (A) at least one selected from the group consisting of epinastine and a salt thereof, (B) at least one selected from the group consisting of pranoprofen and a salt thereof, and (C) at least one selected from the group consisting of alcohol, water-soluble polymer, sugar, polyoxyethylene polyoxypropylene glycol, and polyethylene glycol fatty acid ester.SELECTED DRAWING: None

Description

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

Epinastine hydrochloride is known as an antihistamine, and attempts are being made to use epinastine hydrochloride for ophthalmological use.

For example, Patent Document 1 (Patent No. 6134853) contains only epinastine or its salt at a concentration of more than 0.075% (w/v) as an active ingredient, and has substantially a preservative and antiseptic effect. Ingredient-free eye drops are disclosed.

Patent No. 6134853 (Claims, Examples)

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

As mentioned above, epinastine or its salt is used as a single active ingredient, and ophthalmic preparations in combination with other active ingredients have not yet been developed.

Under these circumstances, the present inventor has made extensive studies to solve the above problems, and has discovered that a novel ophthalmological composition can be obtained by combining epinastine or a salt thereof with a specific active ingredient. They discovered that such ophthalmic compositions can cause precipitation and clouding, and that specific components can effectively suppress such precipitation, and after further studies, they completed the present invention.

That is, the present invention relates to the following inventions, etc.
[1]
(A) one or more selected from the group consisting of epinastine and its salts;
(B) one or more selected from the group consisting of pranoprofen and salts thereof, and (C) selected from the group consisting of alcohol, water-soluble polymer, sugar, polyoxyethylene polyoxypropylene glycol, and polyethylene glycol fatty acid ester An ophthalmic composition containing one or more of:
[2]
Component (C) contains one or more selected from the group consisting of alkanol, alkane polyol, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, oligosaccharide, polysaccharide, polyoxyethylene polyoxypropylene glycol, and polyoxyl stearate. , [1] The ophthalmic composition described in [1].
[3]
The ophthalmic composition according to [1] or [2], wherein component (C) contains at least polyvinylpyrrolidone.
[4]
The ophthalmic composition according to any one of [1] to [3], containing 0.005 to 0.5 w/v% of component (A).
[5]
The ophthalmic composition according to any one of [1] to [4], containing 0.005 to 0.5 w/v% of component (B).
[6]
The ophthalmic composition according to any one of [1] to [5], wherein the proportion of component (B) is 0.01 to 100 parts by mass per 1 part by mass of component (A).
[7]
The ophthalmic composition according to any one of [1] to [6], containing 0.001 to 20 w/v% of component (C).
[8]
The ratio of component (C) is 0.005 parts by mass or more (for example, 0.25 parts by mass or more) to 1 part by mass of component (A), and 0.005 parts by mass to 1 part by mass of component (B). The ophthalmic composition according to any one of [1] to [7] above (for example, 0.25 parts by mass or more).
[9]
The ophthalmic composition according to any one of [1] to [8], which has a pH of 4 to 9.
[10]
(C) component contains one or more selected from the group consisting of alkanol, alkane polyol, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, oligosaccharide, polysaccharide, polyoxyethylene polyoxypropylene glycol, and polyoxyl stearate,
(A) The proportion of the component is 0.01 to 0.1 w/v%,
(B) The proportion of the component is 0.01 to 0.1 w/v%,
(C) The proportion of the component is 0.01 to 10 w/v%,
The ratio of component (B) is 0.1 to 10 parts by mass per 1 part by mass of component (A),
The ophthalmic composition according to any one of [1] to [9], which has a pH of 5 to 8.
[11]
The ophthalmological composition according to any one of [1] to [10], which is free from precipitation.
[12]
The ophthalmic composition according to any one of [1] to [11], which contains water in a proportion of 90% by mass or more based on the total amount of the composition and is free of precipitation.
[13]
Suppressing precipitation in an ophthalmic composition containing (A) one or more selected from the group consisting of epinastine and its salts, and (B) one or more selected from the group consisting of pranoprofen and its salts A method in which an ophthalmic composition contains (C) one or more selected from the group consisting of alcohol, water-soluble polymer, sugar, polyoxyethylene polyoxypropylene glycol, and polyethylene glycol fatty acid ester.

The present invention can provide a novel ophthalmic composition. Such an ophthalmic composition contains pranoprofen and/or a salt thereof in addition to epinastine or a salt thereof, and is an ophthalmic composition of an unprecedented combination type.

In another aspect of the present invention, it is possible to provide an ophthalmic composition that can suppress precipitation (cloudiness). According to the study of the present inventor, precipitation may occur in preparations containing a combination of epinastine and/or its salt and pranoprofen and/or its salt. According to the ophthalmic composition of the present invention containing a specific component selected from among the components, such precipitation can be efficiently suppressed.

In other embodiments of the present invention, the precipitation suppressing effect can be effectively exhibited even when other components (pH adjuster, buffer, etc.) are included, or when a high proportion of water is included.

In other embodiments of the present invention, specific components can be effectively exerted without impairing their functions. For example, among component (C), water-soluble polymers (polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, etc.) are also used as thickening agents and dispersants, but component (A) and (B) ) component (and other components), it can still effectively function as a thickener, dispersant, etc.

As described above, the composition of the present invention has extremely high practicality.

In this specification, the unit of content "w/v%" has the same meaning as "g/100mL". Further, in this specification, unless otherwise specified, the abbreviation "POE" means polyoxyethylene, and "POP" means polyoxypropylene.

[1. Ophthalmic composition]
The ophthalmic composition of the present invention contains at least (A) epinastine and/or a salt thereof, and (B) pranoprofen or a salt thereof.

(A) Epinastine and/or its salt ((A) component)
Salts of epinastine are not particularly limited as long as they are pharmaceutically or physiologically acceptable salts, and examples include organic acid salts [e.g., monocarboxylic acid salts (acetate, trifluoroacetate, butyrate, palmitate salt, stearate, etc.), polycarboxylate (fumarate, maleate, succinate, malonate, etc.), oxycarboxylate (lactate, tartrate, citrate, etc.), organic sulfonates (methanesulfonate, toluenesulfonate, tosylate, etc.)], inorganic acid salts (for example, hydrochloride, sulfate, nitrate, hydrobromide, phosphate), and the like.

Preferred epinastine and/or salts thereof include epinastine hydrochloride (monohydrochloride).

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

The content of component (A) in the composition is, for example, 0.0001 w/v% or more (for example, 0.0003 to 5 w/v%), preferably 0.0005 w/v, based on the total amount of the composition. % or more (for example, 0.001 to 1 w/v%), more preferably 0.003 w/v% or more (for example, 0.005 to 0.5 w/v%), even more preferably 0.005 w/v% or more (for example, 0.007 to 0.2 w/v%), even more preferably 0.008 w/v% or more (for example, 0.01 to 0.1 w/v%), particularly preferably 0.02 w/v% or more (e.g. 0.03-0.1 w/v%), most preferably 0.03 w/v% or more (e.g. 0.04-0.08 w/v%, 0.045-0.06 w/v%) etc.). Among these, 0.05 w/v%, 0.1 w/v%, etc. are preferable, and 0.05 w/v% is particularly preferable.

(B) Pranoprofen and/or its salt ((B) component)
The composition of the present invention contains pranoprofen and/or a salt thereof in addition to epinastine and/or a salt thereof. According to the composition of the present invention, even if it contains a plurality of active ingredients as described above, each of the functions (medicinal efficacy) can be efficiently exerted.

The salt of pranoprofen may be any pharmaceutically or physiologically acceptable salt, including salts with acids (for example, salts with inorganic acids, salts with organic acids, etc.) salts with bases {e.g., salts with organic bases (e.g., salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.), Salts with inorganic bases [for example, ammonium salts; salts with metals such as alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), aluminum], etc.], and examples include sulfates. , lactate, hydrochloride, chloride salt, sodium salt, potassium salt, etc.
Preferred pranoprofen and/or salts thereof are pranoprofen and metal salts thereof, with pranoprofen being particularly preferred.

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

The content of component (B) in the composition is, for example, 0.0001 w/v% or more (for example, 0.0003 to 5 w/v%), preferably 0.0005 w/v, based on the total amount of the composition. % or more (for example, 0.001 to 1 w/v%), more preferably 0.003 w/v% or more (for example, 0.005 to 0.5 w/v%), even more preferably 0.005 w/v% or more (for example, 0.007 to 0.2 w/v%), even more preferably 0.008 w/v% or more (for example, 0.01 to 0.1 w/v%), particularly preferably 0.02 w/v% or more (e.g. 0.03-0.1 w/v%), most preferably 0.03 w/v% or more (e.g. 0.04-0.08 w/v%, 0.045-0.06 w/v%) etc.). Among these, 0.05 w/v%, 0.1 w/v%, etc. are preferable, and 0.05 w/v% is particularly preferable.

The proportion of component (B) is, for example, 0.001 to 1000 parts by mass, preferably 0.005 to 200 parts by mass, more preferably 0.01 to 100 parts by mass, per 1 part by mass of component (A). Particularly preferably about 0.05 to 20 parts by mass, most preferably about 0.1 to 10 parts by mass (for example, 0.2 to 5 parts by mass, 0.3 to 3 parts by mass, 0.5 to 2 parts by mass, etc.) The amount may be particularly preferably 1 part by mass.

(C) Specific component ((C) component)
The composition of the present invention may contain a specific component (C). By combining component (A), component (B), and component (C), precipitation in the composition can be efficiently suppressed.

Component (C) includes alcohol, water-soluble polymer, sugar, polyoxyethylene polyoxypropylene glycol, polyethylene glycol fatty acid ester, and the like.
Examples of the alcohol include monools [e.g., alkanols (e.g., lower alkanols such as ethanol)], polyols (polyhydric alcohols) {e.g., diols [e.g., alkanediols (e.g., ethylene glycol, butanediol, etc.)], polyalkanediols (e.g., diethylene glycol, etc.), polyols having three or more hydroxyl groups (e.g., triols (e.g., alkanetriols such as glycerin), tetraols (e.g., alkanetetraols such as erythritol), pentaols (e.g., alkanetriols such as erythritol), For example, alkanolamines (alkanolamines [hydroxyl and amino groups in the alkane skeleton), hexaols (tri-hexaols such as mannitol, sorbitol, etc.) Examples include mono- or poly(hydroxyalkyl)amines (e.g., diethanolamine, triethanolamine, triisopropanolamine, etc.), hydroxyalkylaminoalkanes (e.g., trometamol, etc.), etc.).
Note that the alcohol may be water-soluble (water-miscible).

Examples of water-soluble polymers include water-soluble synthetic polymers {e.g., hydroxy group-containing polymers (e.g., polyvinyl alcohol), acid group-containing polymers (e.g., acrylic acid polymers (e.g., polyacrylic acid or its salts, carboxyvinyl oxyalkylene group-containing polymers [e.g., polyethylene glycol (e.g., macrogol such as Macrogol 200, 400, 1500, 4000, 6000, etc.)], lactam-based polymers [e.g., polyvinylpyrrolidone (e.g., polyvinylpyrrolidone K25, K30, K90), etc.], water-soluble cellulose derivatives (for example, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, etc.).

Sugar (saccharides) may be a concept that includes all sugars, derivatives thereof, and salts thereof. Examples of sugars (saccharides) include monosaccharides (e.g., glucose), oligosaccharides {e.g., disaccharides (e.g., maltose, trehalose, sucrose), trisaccharides (e.g., maltotriose), fructooligosaccharides, galactooligosaccharides, Malto-oligosaccharides, isomalto-oligosaccharides, cyclic oligosaccharides [e.g., cyclodextrin (e.g., α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin), etc.], amino sugars (e.g., glucosamine, galactosamine, etc.), polysaccharides (Polysaccharides) [e.g., glucose-derived polysaccharides (e.g., dextran, dextrin, starch, etc.), mucopolysaccharides (e.g., heparin analogs, heparin, heparin sulfate, heparan sulfate, heparinoids, hyaluronic acid, hyaluronate (sodium alginic acid, chondroitin, chondroitin sulfate, chitosan, chitin, derivatives thereof, etc.).
Sugars (such as polysaccharides) may be water-soluble (water-miscible).

Examples of the polyoxyethylene polyoxypropylene glycol include poloxamer 407, poloxamer 235, poloxamer 188, poloxamer 403, poloxamer 237, and poloxamer 124.

Examples of polyethylene glycol fatty acid esters include polyoxyl stearate [or polyoxyethylene monostearate or polyethylene glycol stearate, such as polyethylene glycol monostearate (2E.O.), polyethylene glycol monostearate (4E.O.), and 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.), polyethylene glycol monostearate (40E.O., polyoxyl stearate 40), polyethylene glycol monostearate (45E.O.), polyethylene glycol monostearate (55E.O.) ), polyethylene glycol monostearate (75E.O.), polyethylene glycol monostearate (140E.O.), etc.].

Among these components (C), alkanols (e.g., ethanol), alkane polyols (e.g., glycerin), polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, oligosaccharides (cyclodextrin, etc.), polysaccharides (glucose-derived polysaccharides, etc.) ), polyoxyethylene polyoxypropylene glycol, polyoxyl stearate, etc. are preferred, and polyvinylpyrrolidone is particularly preferred.

Therefore, component (C) may contain at least these components.

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

When combining components (C), components of the same system (same classification) may be combined, or components of different systems (different classifications) may be combined.

When containing component (C), the content of component (C) in the composition is, for example, 0.001 w/v% or more (for example, 0.001 to 20 w/v%) based on the total amount of the composition. ), preferably 0.005 w/v% or more (for example, 0.007 to 15 w/v%), more preferably 0.01 w/v% or more (for example, 0.03 to 10 w/v%), particularly preferably It may be 0.05 w/v% or more (for example, 0.1 to 5 w/v%).

When component (C) contains alcohol, the content of alcohol in the composition is, for example, 0.01 w/v% or more (for example, 0.01 to 15 w/v%) based on the total amount of the composition. , preferably 0.05 w/v% or more (for example, 0.05 to 12.5 w/v%), more preferably 0.075 w/v% or more (for example, 0.075 to 10 w/v%), particularly preferably may be 0.1 w/v% or more (for example, 0.1 to 8.0 w/v%).

When component (C) contains a water-soluble polymer, the content of the water-soluble polymer in the composition is, for example, 0.01 w/v% or more (for example, 0.01 w/v% or more) based on the total amount of the composition. ~10 w/v%), preferably 0.05 w/v% or more (for example, 0.05 to 7.5 w/v%), more preferably 0.075 w/v% or more (for example, 0.075 to 5. 0 w/v %), particularly preferably 0.1 w/v % or more (for example, 0.1 to 3.0 w/v %).

When component (C) contains sugar, the content of sugar in the composition is, for example, 0.01 w/v% or more (for example, 0.01 to 3.0 w/v) based on the total amount of the composition. %), preferably 0.05 w/v% or more (for example, 0.05 to 2.0 w/v%), more preferably 0.75 w/v% or more (for example, 0.75 to 1.5 w/v%) ), particularly preferably 0.1 w/v% or more (for example, 0.1 to 1.0 w/v%).

When component (C) contains polyoxyethylene polyoxypropylene glycol, the content of polyoxyethylene polyoxypropylene glycol in the composition is, for example, 0.01 w/v% or more based on the total amount of the composition. (for example, 0.03 to 20 w/v%), preferably 0.05 w/v% or more (for example, 0.05 to 15 w/v%), more preferably 0.075 w/v% or more (for example, 0.07 w/v% or more). 075 to 12 w/v%), particularly preferably 0.1 w/v% or more (for example, 0.2 to 10 w/v%), and 0.5 w/v% or more (for example, 0.7 w/v%). v% or more, 0.8 w/v% or more, 0.9 w/v% or more, 1 w/v% or more, 5 w/v% or more, 1 to 10 w/v%, etc.).

When component (C) contains a polyethylene glycol fatty acid ester, the content of the polyethylene glycol fatty acid ester in the composition is, for example, 0.01 w/v % or more (for example, 0.03 w/v % or more) based on the total amount of the composition. 20 w/v%), preferably 0.05 w/v% or more (for example, 0.05 to 15 w/v%), more preferably 0.075 w/v% or more (for example, 0.075 to 12 w/v%) ), particularly preferably 0.1 w/v% or more (for example, 0.2 to 10 w/v%), 0.5 w/v% or more (for example, 0.7 w/v% or more, 0. 8 w/v% or more, 0.9 w/v% or more, 1 w/v% or more, 5 w/v% or more, 1 to 10 w/v%, etc.).

When containing component (C), the proportion of component (C) is, for example, 0.005 parts by mass or more (for example, 0.0075 parts by mass or more, 0.01 parts by mass) per 1 part by mass of component (A). parts by mass or more, 0.02 parts by mass or more, 0.03 parts by mass or more), 0.25 parts by mass or more (for example, 0.25 to 200 parts by mass), preferably 0.5 parts by mass or more. (for example, 0.5 to 175 parts by mass), more preferably 0.75 parts by mass or more (for example, 0.75 to 150 parts by mass), particularly preferably 1.0 parts by mass or more (for example, 1.0 to 125 parts by mass) (parts by mass), most preferably about 1.5 parts by mass or more (for example, 1.5 to 100 parts by mass).

When component (C) contains alcohol, the proportion of alcohol is, for example, 1.0 parts by mass or more (for example, 1.0 to 200 parts by mass), preferably 1 part by mass, per 1 part by mass of component (A). .5 parts by mass or more (for example, 1.5 to 150 parts by mass), more preferably 1.75 parts by mass or more (for example, 1.75 to 120 parts by mass), particularly preferably 2.0 parts by mass or more (for example, (2.0 to 100 parts by mass), most preferably about 2.25 parts by mass or more (for example, 2.25 to 80 parts by mass).

When component (C) contains a water-soluble polymer, the proportion of the water-soluble polymer is, for example, 0.25 parts by mass or more (for example, 0.25 to 200 parts by mass) per 1 part by mass of component (A). parts), preferably 0.5 parts by mass or more (for example, 0.5 to 175 parts by mass), more preferably 0.75 parts by mass or more (for example, 0.75 to 150 parts by mass), particularly preferably 1.0 parts by mass) The amount may be about 1.5 parts by mass or more (for example, 1.0 to 125 parts by mass), most preferably about 1.5 parts by mass or more (for example, 1.5 to 100 parts by mass).

When component (C) contains sugar, the proportion of sugar is, for example, 0.5 parts by mass or more (for example, 0.5 to 150 parts by mass), preferably 0.0 to 1 part by mass of component (A). .75 parts by mass or more (for example, 0.75 to 125 parts by mass), more preferably 1.0 parts by mass or more (for example, 1.0 to 100 parts by mass), particularly preferably 1.25 parts by mass or more (for example, (1.25 to 75 parts by mass), most preferably 1.5 parts by mass or more (for example, 1.5 to 50 parts by mass).

When component (C) contains polyoxyethylene polyoxypropylene glycol, the proportion of polyoxyethylene polyoxypropylene glycol is, for example, 0.2 parts by mass or more (for example, 0.6 to 400 parts by mass), preferably 1 part by mass or more (for example, 1 to 300 parts by mass), more preferably 1.5 parts by mass or more (for example, 1.5 to 240 parts by mass), particularly preferably 2 It may be 10 parts by mass or more (for example, 14 parts by mass or more, 16 parts by mass or more, 18 parts by mass or more, 20 parts by mass or more, 100 parts by mass or more, 20 to 200 parts by mass, etc.).

When component (C) contains polyethylene glycol fatty acid ester, the proportion of polyethylene glycol fatty acid ester is, for example, 0.2 parts by mass or more (for example, 0.6 to 400 parts by mass) per 1 part by mass of component (A). parts), preferably 1 part by weight or more (for example, 1 to 300 parts by weight), more preferably 1.5 parts by weight or more (for example, 1.5 to 240 parts by weight), particularly preferably 2 parts by weight or more (for example, 4 to 200 parts by mass), and 10 parts by mass or more (for example, 14 parts by mass or more, 16 parts by mass or more, 18 parts by mass or more, 20 parts by mass or more, 100 parts by mass or more, 20 to 200 parts by mass, etc.) ).

When containing component (C), the proportion of component (C) is, for example, 0.005 parts by mass or more (for example, 0.0075 parts by mass or more, 0.01 parts by mass) per 1 part by mass of component (B). parts by mass or more, 0.02 parts by mass or more, 0.03 parts by mass or more), 0.25 parts by mass or more (for example, 0.25 to 200 parts by mass), preferably 0.5 parts by mass or more. (for example, 0.5 to 175 parts by mass), more preferably 0.75 parts by mass or more (for example, 0.75 to 150 parts by mass), particularly preferably 1.0 parts by mass or more (for example, 1.0 to 125 parts by mass) (parts by mass), most preferably about 1.5 parts by mass or more (for example, 1.5 to 100 parts by mass).

When component (C) contains alcohol, the proportion of alcohol is, for example, 1.0 parts by mass or more (for example, 1.0 to 200 parts by mass), preferably 1 part by mass, per 1 part by mass of component (B). .5 parts by mass or more (for example, 1.5 to 150 parts by mass), more preferably 1.75 parts by mass or more (for example, 1.75 to 120 parts by mass), particularly preferably 2.0 parts by mass or more (for example, (2.0 to 100 parts by mass), most preferably about 2.25 parts by mass or more (for example, 2.25 to 80 parts by mass).

When component (C) contains a water-soluble polymer, the proportion of the water-soluble polymer is, for example, 0.25 parts by mass or more (for example, 0.25 to 1 part by mass) per 1 part by mass of component (B). 200 parts by mass), preferably 0.5 parts by mass or more (for example, 0.5 to 175 parts by mass), more preferably 0.75 parts by mass or more (for example, 0.75 to 150 parts by mass), particularly preferably 1 The amount may be about .0 parts by weight or more (eg, 1.0 to 125 parts by weight), most preferably about 1.5 parts by weight or more (eg, 1.5 to 100 parts by weight).

When component (C) contains sugar, the proportion of sugar is, for example, 0.5 parts by mass or more (for example, 0.5 to 150 parts by mass), preferably 0.0 to 1 part by mass of component (B). .75 parts by mass or more (for example, 0.75 to 125 parts by mass), more preferably 1.0 parts by mass or more (for example, 1.0 to 100 parts by mass), particularly preferably 1.25 parts by mass or more (for example, (1.25 to 75 parts by mass), most preferably 1.5 parts by mass or more (for example, 1.5 to 50 parts by mass).

When component (C) contains polyoxyethylene polyoxypropylene glycol, the proportion of polyoxyethylene polyoxypropylene glycol is, for example, 0.2 parts by mass or more (for example, 0.6 to 400 parts by mass), preferably 1 part by mass or more (for example, 1 to 300 parts by mass), more preferably 1.5 parts by mass or more (for example, 1.5 to 240 parts by mass), particularly preferably 2 It may be 10 parts by mass or more (for example, 14 parts by mass or more, 16 parts by mass or more, 18 parts by mass or more, 20 parts by mass or more, 100 parts by mass or more, 20 to 200 parts by mass, etc.).

When component (C) contains polyethylene glycol fatty acid ester, the proportion of polyethylene glycol fatty acid ester is, for example, 0.2 parts by mass or more (for example, 0.6 to 400 parts by mass) per 1 part by mass of component (B). parts), preferably 1 part by weight or more (for example, 1 to 300 parts by weight), more preferably 1.5 parts by weight or more (for example, 1.5 to 240 parts by weight), particularly preferably 2 parts by weight or more (for example, 4 to 200 parts by mass), and 10 parts by mass or more (for example, 14 parts by mass or more, 16 parts by mass or more, 18 parts by mass or more, 20 parts by mass or more, 100 parts by mass or more, 20 to 200 parts by mass, etc.) ).

When containing component (C), the proportion of component (C) is, for example, 0.005 parts by mass or more (for example, 0.0075 parts by mass) per 1 part by mass of the total amount of components (A) and (B). parts or more, 0.01 parts by mass or more, 0.02 parts by mass or more, 0.04 parts by mass or more), 0.5 parts by mass or more (for example, 0.5 to 400 parts by mass), Preferably 1.0 parts by mass or more (for example, 1.0 to 350 parts by mass), more preferably 1.5 parts by mass or more (for example, 1.5 to 300 parts by mass), particularly preferably 1.25 parts by mass or more. (for example, 1.25 to 200 parts by mass), most preferably about 2.0 parts by mass or more (for example, 2.0 to 200 parts by mass).

When component (C) contains alcohol, the proportion of alcohol is, for example, 2.0 parts by mass or more (for example, 2.0 to 400 parts by mass) per 1 part by mass of the total amount of components (A) and (B). parts by weight), preferably 3.0 parts by weight or more (for example, 3.0 to 300 parts by weight), more preferably 3.5 parts by weight or more (for example, 3.5 to 240 parts by weight), particularly preferably 4. The amount may be about 0 parts by weight or more (eg, 4.0 to 200 parts by weight), most preferably about 4.5 parts by weight or more (eg, 4.5 to 160 parts by weight).

When component (C) contains a water-soluble polymer, the proportion of the water-soluble polymer is, for example, 0.5 parts by mass or more (for example, 0 .5 to 400 parts by weight), preferably 1.0 parts by weight or more (for example, 1.0 to 350 parts by weight), more preferably 1.5 parts by weight or more (for example, 1.5 to 300 parts by weight), especially The amount may preferably be about 2.0 parts by mass or more (for example, 2.0 to 250 parts by mass), and most preferably about 3.0 parts by mass or more (for example, 3.0 to 200 parts by mass).

When component (C) contains sugar, the proportion of sugar is, for example, 1.0 parts by mass or more (for example, 1.0 to 300 parts by mass) per 1 part by mass of the total amount of components (A) and (B). (parts by weight), preferably 1.5 parts by weight or more (for example, 1.5 to 250 parts by weight), more preferably 2.0 parts by weight or more (for example, 2.0 to 200 parts by weight), particularly preferably 2.0 parts by weight or more (for example, 2.0 to 200 parts by weight). The amount may be about 5 parts by weight or more (eg, 2.5 to 150 parts by weight), most preferably about 3.0 parts by weight or more (eg, 3.0 to 100 parts by weight).

When component (C) contains polyoxyethylene polyoxypropylene glycol, the proportion of polyoxyethylene polyoxypropylene glycol is, for example, 0. 1 part by mass or more (for example, 0.3 to 200 parts by mass), preferably 0.5 part by mass or more (for example, 0.5 to 150 parts by mass), more preferably 0.75 part by mass or more (for example, 0.5 to 150 parts by mass). 75 to 120 parts by weight), particularly preferably 1 part by weight or more (for example, 2 to 100 parts by weight), and 5 parts by weight or more (for example, 7 parts by weight or more, 8 parts by weight or more, 9 parts by weight or more). , 10 parts by mass or more, 50 parts by mass or more, 10 to 100 parts by mass, etc.).

When component (C) contains a polyethylene glycol fatty acid ester, the proportion of the polyethylene glycol fatty acid ester is, for example, 0.1 part by mass or more (e.g. , 0.3 to 200 parts by mass), preferably 0.5 parts by mass or more (for example, 0.5 to 150 parts by mass), more preferably 0.75 parts by mass or more (for example, 0.75 to 120 parts by mass) , particularly preferably 1 part by mass or more (for example, 2 to 100 parts by mass), 5 parts by mass or more (for example, 7 parts by mass or more, 8 parts by mass or more, 9 parts by mass or more, 10 parts by mass or more, The amount may be about 50 parts by mass or more, 10 to 100 parts by mass, etc.).

By setting the ratio as above, precipitation can be efficiently suppressed.

[Other ingredients]
The composition of the present invention may further contain other components. In the present invention, even if other components are contained, the effects of the present invention can often be ensured. Furthermore, by containing other components, the effects of the present invention may be achieved even more effectively.

Note that other components may correspond to the above component (C).

Amino Acids The compositions of the present invention may contain amino acids.
The amino acid includes, for example, an amino acid or a salt thereof, and an amino acid analog, and includes a compound having an amino group and a carboxyl group or a sulfone group in the molecule, or a derivative thereof.

Specifically, amino acids or salts thereof, mucopolysaccharides or salts thereof are exemplified. Among amino acids, examples of amino acids or salts thereof include monoaminomonocarboxylic acids such as glycine, alanine, aminobutyric acid, aminovaleric acid, and aminocaproic acid; monoaminodicarboxylic acids such as aspartic acid and glutamic acid, or salts thereof; Examples 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 mucopolysaccharides, derivatives thereof, or salts thereof include acidic mucopolysaccharides such as chondroitin sulfate, hyaluronic acid, alginic acid, and salts thereof.

Specific amino acids and mucopolysaccharides include glycine, alanine, γ-aminobutyric acid, γ-aminovaleric acid, epsilon aminocaproic acid, aspartic acid, glutamic acid, arginine, aminoethyl sulfonic acid, chondroitin sulfate, hyaluronic acid, alginic acid, or the like. Examples include salt.

Note that chondroitin sulfate is a product in which sulfuric acid is ester-bonded to all or part of the hydroxyl groups of a sugar chain in which D-glucuronic acid and N-acetylglucosamine repeat. The bonding position and number of sulfuric acid are diverse, and chondroitin sulfate also includes derivatives (for example, those in which all or part of N-acetylglucosamine is substituted with iduronic acid).
Such chondroitin sulfate may have any structure. Examples include chondroitin 4-sulfate (chondroitin sulfate A), chondroitin 6-sulfate (chondroitin sulfate C), and chondroitin sulfate E in which the 4- and 6-positions of N-acetylglucosamine are sulfated. Furthermore, chondroitin sulfate may be extracted from animals.

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

Specific salts include salts of aspartic acid (sodium aspartate, potassium aspartate, magnesium aspartate, magnesium/potassium aspartate mixture, etc.), salts of glutamic acid (sodium glutamate, magnesium glutamate, etc.), sodium chondroitin sulfate, hyaluronic acid, etc. Examples include sodium acid.

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

Preferred amino acids include aminoethyl sulfonic acid (taurine) or its salt, sodium chondroitin sulfate, aspartate (e.g., potassium L-aspartate, magnesium/potassium L-aspartate), epsilon aminocaproic acid or its salt, hyaluronic acid. Acids or salts thereof (sodium hyaluronate, etc.) are included, and among these, hyaluronic acid or salts thereof (sodium hyaluronate, etc.), aminoethylsulfonic acid (taurine) and/or salts thereof, and sodium chondroitin sulfate are preferred.

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

When the composition contains amino acids, the content of the amino acids in the composition is, for example, 0.001 w/v% or more, preferably 0.01 to 20 w/v%, or more, based on the total amount of the composition. Preferably 0.03 to 10 w/v%, more preferably 0.05 to 5 w/v%, even more preferably 0.1 to 3 w/v%, particularly preferably about 0.15 to 2 w/v%. Usually 0.001 to 10 w/v% [for example, 0.005 to 10 w/v%, preferably 0.01 to 5 w/v%, more preferably 0.05 to 3 w/v% (for example, 0.1 to 1 w/v%)].

Cooling Agent The composition of the present invention may include a cooling agent.
Combining component (A), component (B), and component (C) may reduce or impair the feeling of use, but such a feeling of use may 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 solubility, etc., the higher the pH of the composition, the stronger the discomfort may be and the feeling of use may be impaired. By using the agent, such discomfort can be alleviated and the feeling of use can be efficiently improved.

Examples of the cooling agent include, but are not particularly limited to, terpenoids such as menthol, anethole, eugenol, camphor, geraniol, cineole, borneol, limonene, and rhubarb. These may be d-, l-, or dl-forms. Also included are essential oils such as peppermint oil, coolmint oil, spearmint oil, peppermint oil, fennel oil, cinnamon bark oil, bergamot oil, eucalyptus oil, and rose oil.

Among these, terpenoids are preferred, and among them, menthol, camphor, geraniol, cineole, borneol, and rhubarb are preferred, menthol, camphor, and borneol are more preferred, menthol and borneol are even more preferred, and menthol is most preferred.

The cooling agents may be used alone or in combination of two or more. In particular, the cooling agent preferably contains one or more selected from the group consisting of menthol, borneol, and camphor, and even when two or more types are combined, at least a combination of these (for example, a combination of menthol, borneol, and camphor) is preferred. is preferred.

When the composition contains a refreshing agent, the proportion of the refreshing agent is, for example, 0.00001 w/v% or more, 0.00005 w/v% or more, 0.0001 w/v% or more with respect to the total amount of the composition. , 0.0003 w/v% or more, 0.0005 w/v% or more, 0.0007 w/v% or more, 0.0008 w/v% or more, 0.0009 w/v% or more, 0.001 w/v% or more. You can.

In addition, the proportion of the refreshing agent 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% or less with respect to the total amount of the composition. , 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 proportion of menthol is, for example, 0.00001 w/v% or more (for example, 0.00005 to 2 w/v%), preferably 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 %) may be sufficient.

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 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.

In particular, when the composition of the present invention contains camphor, the proportion of camphor is, for example, 0.00001 w/v% or more (for example, 0.00005 to 1 w/v%), preferably 0.0001 to 0.1 w/v% (for example, 0.0003 to 0.05 w/v%), more preferably 0.0005 to 0.02 w/v% (for example, 0.001 to 0.01 w/v %) may be sufficient.

Fat-Soluble Antioxidants The compositions of the present invention may include fat-soluble antioxidants.

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

Among these, dibutylhydroxytoluene is preferred.

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

When the composition contains a fat-soluble antioxidant, the content of the fat-soluble antioxidant in the composition is, for example, 0.0001 to 0.1 w/v%, preferably 0. .0005 to 0.01 w/v%, more preferably 0.0007 to 0.009 w/v%, even more preferably 0.001 to 0.008 w/v%, even more preferably 0.003 to 0.007 w/v%. v%, most preferably about 0.0045 to 0.006 w/v%.

Antiallergic Agents The compositions of the present invention may also include antiallergic agents.

Examples of antiallergic agents include tranilast, cromoglylic acid, ibudilast, acitazanolast, tazanolast, suplatast, pemirolast, amlexanox, oxatomide, and salts thereof.

Examples of the salt include the salts listed above, such as alkali metal or alkaline earth metal salts (sodium cromolycate, potassium cromolycate, magnesium cromolycate, calcium cromolycate, etc.), inorganic acid salts (e.g., hydrochloride) , sulfate, etc.), organic acid salts (eg, tosylate, fumarate, etc.), and the like.

Among these, tranilast, cromoglylic acid, and salts thereof are preferred, and tranilast and sodium cromoglycate are more preferred.

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

When the composition contains an anti-allergic agent, the content of the anti-allergic agent in the composition is, for example, 0.1 to 10 w/v%, preferably 0.2 to 8 w/v, based on the total amount of the composition. %, more preferably 0.3 to 5 w/v%, even more preferably 0.5 to 3 w/v%, particularly preferably 0.7 to 2 w/v%, even more particularly preferably 0.8 to 1.5 w /v%, most preferably about 0.9 to 1.2 w/v%.

Antihistamines The compositions of the present invention may include antihistamines.
Antihistamines (antihistamines other than epinastine and its salts) are not particularly limited as long as they have an antihistamine effect, and examples include chlorpheniramine, diphenhydramine, ketotifen, olopatadine, levocabastine, iproheptine, and salts thereof. .

The salt may be any pharmaceutically or physiologically acceptable salt, such as inorganic acid salts (e.g., hydrochloride, sulfate, etc.), organic acid salts (e.g., tosylate, fumarate, etc.)

Specific examples of the salt include diphenhydramine hydrochloride, iproheptine hydrochloride, and chlorpheniramine maleate.

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

When the composition contains an antihistamine, the content of the antihistamine in the composition is, for example, 0.0001 w/v% or more, preferably 0.001 to 10 w/v%, more preferably 0.003 to 5 w/v%, 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, it may be about 0.02 to 0.1 w/v%), most preferably about 0.025 to 0.05 w/v% (for example, 0.03 w/v%), and usually 0.01 to 0 It may be about .05 w/v%.

Anti-inflammatory agents The compositions of the present invention may include anti-inflammatory agents.
Anti-inflammatory agents (anti-inflammatory agents other than pranoprofen and its salts) are not particularly limited as long as they have anti-inflammatory effects, such as indomethacin, allantoin, berberine, azulene sulfonic acid, diclofenac, bromfenac, Examples include glycyrrhizic acid, zinc, silver, tranexamic acid, lysozyme and salts thereof.

Examples of the salts include the above-mentioned salts such as salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases, such as sulfates, lactates, hydrochlorides, and chlorides. Examples include salts, sodium salts, and potassium salts.

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

Anti-inflammatory agents may be used alone or in combination of two or more.

When the composition contains an anti-inflammatory agent, the content of the anti-inflammatory agent in the composition is, for example, 0.001 w/v% or more (for example, 0.02 w/v%), based on the total amount of the composition. Preferably 0.005 to 10 w/v% (eg 5 w/v%), more preferably 0.01 to 1 w/v%, even more preferably 0.1 to 0.5 w/v% (eg 0. 3 w/v%), particularly preferably about 0.2 to 0.3 w/v% (for example, 0.25 w/v%).

The composition of the present invention may contain various components (for example, components that do not belong to the above-mentioned categories). Such components (additives) include, for example, surfactants, preservatives, buffers, pH adjusters, tonicity agents, thickeners or viscosity agents, stabilizers, oils, sugars, and Examples include molecular compounds, polyhydric alcohols, inorganic salts, non-fat-soluble antioxidants (or water-soluble antioxidants), and the like.

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

Specific examples of the additive are shown below.

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

Nonionic surfactants include monolauric acid POE (20) sorbitan (polysorbate 20), monopalmitic acid POE (20) sorbitan (polysorbate 40), monostearic acid POE (20) sorbitan (polysorbate 60), tristearic acid POE (20) Polysorbates (POE sorbitan fatty acid esters) such as sorbitan (polysorbate 65), monooleic acid POE (20) sorbitan (polysorbate 80); POE hydrogenated castor oil 40, POE hydrogenated castor oil 50, POE hydrogenated castor oil 60 , POE hydrogenated castor oil such as POE hydrogenated castor oil 80; POE castor oil 3, POE castor oil 4, POE castor oil 6, POE castor oil 7, POE castor oil 10, POE castor oil 13.5, POE castor oil 17, POE castor oil such as POE castor oil 20, POE castor oil 25, POE castor oil 30, POE castor oil 35, POE castor oil 50; POE alkyl ethers such as POE (9) lauryl ether; POE (20) POP (4) ) POE-POP alkyl ethers such as cetyl ether; POE alkyl phenyl ethers such as POE (10) nonylphenyl ether; In addition, in the compounds exemplified above, POE represents polyoxyethylene, POP represents polyoxypropylene, and the number in parentheses represents the number of moles added.

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

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

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

Further, the proportion of the surfactant may be, for example, 5 w/v % or less, preferably 1 w/v % or less, based on the total amount of the composition.

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

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

When the composition contains a preservative, the proportion of the preservative in the composition is, for example, 0.000001 w/v% or more, especially 0.00001 w/v% or more, especially 0.00005w, based on the total amount of the composition. /v% or more, especially 0.001 w/v% or more, especially 0.005 w/v% or more. In addition, the total amount of preservatives, based on the total amount of the composition, is 1 w/v% or less, especially 0.1 w/v% or less, especially 0.05 w/v% or less, especially 0.03 w/v% or less, especially Examples include 0.025 w/v% or less.

Buffers The compositions of the present invention may include buffers.
Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, and the like.

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

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

Components of the carbonate buffer include carbonic acid, carbonates (potassium carbonate, sodium carbonate, calcium carbonate, potassium bicarbonate, sodium bicarbonate, magnesium carbonate, etc.). The carbonate may be a hydrate.

Components of the citric acid buffer include citric acid, citrates (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.). Citrate may be a hydrate.

Components of the acetate buffer include acetic acid, acetate salts (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.). Acetate may be a hydrate.

Among these, boric acid buffers are preferred from the viewpoint of preservative efficacy, phosphate buffers are preferred from the viewpoint of low cytotoxicity, and boric acid buffers are more preferred. The boric acid buffer is preferably a combination of boric acid and a salt thereof, more preferably a combination of boric acid and an alkali metal salt and/or an alkaline earth metal salt of boric acid, and a combination of boric acid and an alkali metal salt of boric acid is more preferable. Even more preferred is a combination with a salt, and even more preferred is a combination of boric acid and borax.

When a buffering agent is added to the composition of the present invention, the amount of the buffering agent varies depending on the type of buffering agent and the types and amounts of other ingredients, and cannot be uniformly specified. Based on the total amount of the composition, the total amount of buffering agent is 0.001 w/v% or more, especially 0.01 w/v% or more, especially 0.05 w/v% or more, especially 0.1 w/v% or more. It will be done. In addition, the total amount of buffering agent is 10 w/v% or less, especially 5 w/v% or less, especially 3 w/v% or less, especially 2.5 w/v% or less, especially 2 w/v%, based on the total amount of the composition. The following may be mentioned.

In particular, when a borate buffer is used, the proportion of the buffer in the composition is 0.01 to 10 w/v%, preferably 0.05 to 5 w/v%, more preferably 0.05 to 5 w/v%, based on the entire composition. may be about 0.1 to 4 w/v%, more preferably about 0.2 to 3 w/v%.

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

Isotonic agent Examples of the tonicity agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, potassium acetate, sodium acetate, magnesium sulfate, glycerin, and propylene glycol.
The tonicity agents may be used alone or in combination of two or more.

Thickener or Thickener The ophthalmic composition of the present invention may contain a thickener or thickener.

Thickeners or thickeners include guar gum, hydroxypropyl guar gum, cellulose-based polymer compounds (for example, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, etc.), gum arabic, karaya gum, xanthan gum, agar , alginic acid, α-cyclodextrin, dextrin, dextran, mucopolysaccharides (e.g., heparin analogues, 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, carboxyvinyl polymer, etc.), alkali metal salts of polyacrylic acid (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 (sodium salt, etc.) ), alginate esters (such as propylene glycol esters), tragacanth powder, and triisopropanolamine.
Thickeners or thickeners may be used alone or in combination of two or more.

Stabilizers As stabilizers, for example, hydroxyalkylamines (or aminoalkanols or alkanolamines, such as monoethanolamine, diethanolamine, triethanolamine, trometamol, etc.), sodium formaldehyde sulfoxylate (Rongalit), Examples include aluminum monostearate and glyceryl monostearate.
The stabilizers may be used alone or in combination of two or more.

Examples of the oil component include animal oils such as squalane and refined lanolin, mineral oils such as liquid paraffin, white petrolatum, and vegetable oils such as castor oil and sesame oil.

Examples of sugars include monosaccharides, oligosaccharides (disaccharides, etc.), and specific examples include glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, sorbitol, mannitol, and the like.

Polyhydric alcohol Examples of the polyhydric alcohol include polyethylene glycol, glycerin, propylene glycol, xylitol, diethylene glycol, mannitol, sorbitol, polyvinyl alcohol, and the like.

Inorganic salts Examples of inorganic salts include potassium chloride, sodium chloride, calcium chloride, magnesium chloride, sodium hydrogen carbonate, sodium carbonate (including dry sodium carbonate), potassium hydrogen carbonate, potassium carbonate, magnesium sulfate, sodium hydrogen phosphate, Examples 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, and sodium thiosulfate.
Among these, potassium chloride, sodium chloride, calcium chloride, sodium hydrogen carbonate, sodium carbonate (including dry sodium carbonate), magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate are preferred; potassium chloride, Sodium chloride, calcium chloride, sodium hydrogen phosphate, and sodium dihydrogen phosphate are more preferred, and potassium chloride and sodium chloride are even more preferred.

Water-soluble antioxidants Examples of water-soluble antioxidants include ascorbic acid, ascorbic acid derivatives (disodium ascorbic acid-2-sulfate, sodium ascorbate, magnesium ascorbic acid-2-phosphate, ascorbic acid-2- sodium phosphate, etc.), sodium bisulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, edetate or its salts (disodium edetate, tetrasodium edetate, etc.).

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

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

Examples of such pharmacologically active ingredients and physiologically active ingredients include active ingredients in various pharmaceuticals listed in the 2017 edition of the OTC Drug Manufacturing and Sales Approval Standards and Application Practice Guide (supervised by the Society of Regulatory Science) that requires guidance. For example, decongestants, ocular muscle regulators, astringents, vitamins, amino acids, antibacterial or bactericidal agents, local anesthetic components, analgesics, sulfa drugs, etc. Specific examples of these drugs are: Examples are shown below.

Decongestants (vasoconstrictors)
Examples of decongestants include α-adrenergic agonists, specifically imidazoline decongestants such as oxymetazoline, tetrahydrozoline, naphazoline, or salts thereof such as hydrochloride and nitrate, epinephrine, epinephrine hydrochloride, and hydrochloric acid. Examples include ephedrine, phenylephrine hydrochloride, methylephedrine hydrochloride, and epinephrine bitartrate. These may be d-, l-, or dl-forms.

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

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

Eye muscle regulators Examples of eye muscle regulators include cholinesterase inhibitors having an active center similar to acetylcholine, specifically neostigmine methyl sulfate, tropicamide, helenien, and atropine sulfate.

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

Among them, flavin adenine dinucleotide or its salt (especially sodium flavin adenine dinucleotide), cobalamin or its salt (especially cyanocobalamin), retinol, its salt or its derivative (especially retinol acetate, retinol palmitate), pyridoxine or its Salts (especially pyridoxine hydrochloride), panthenol, pantothenic acid or its salts (especially sodium pantothenate, calcium pantothenate), tocopherol, its salts or derivatives thereof (especially tocopherol acetate) are preferable, and pyridoxine hydrochloride and tocopherol acetate are preferable. More preferred.
Note that the composition of the present invention does not need to contain pyridoxine and its salt.

Antibacterial agents or bactericidal agents Examples of antibacterial agents or bactericidal agents include sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxazole monoethanolamine, Examples include sulfa drugs such as sulfisomezole sodium and sulfisomidine sodium, alkyl polyaminoethylglycine, chloramphenicol, ofloxacin, norfloxacin, levofloxacin, and lomefloxacin hydrochloride.

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

Base or Carrier The compositions of the present invention may include a base or carrier.
A composition containing such a base or carrier can be prepared, for example, by mixing each of the above-mentioned components with a pharmaceutically acceptable base or carrier. It can be prepared by the following method.

Examples of the base or carrier include water, polar solvents such as ethanol (especially water-soluble solvents), oil bases, and the like. One type of base or carrier can be used alone or two or more types can be used in combination.

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

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

Further, as mentioned above, the composition may be an aqueous composition (mainly containing an aqueous or hydrophilic base or carrier) or an oil-based composition (mainly containing an oily or hydrophobic base or carrier). ), and in particular may be an aqueous composition.

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

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

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

The pH of the composition of the present invention may be, for example, 4 to 9, preferably 4.5 to 8.5, more preferably 5 to 8, 5.5 to 8, 6 to 8, 6 to 7. It may be .5, 6.5 to 7.5, etc.
In the present invention, the effects of the present invention (precipitation suppressing effect, etc.) can be efficiently achieved even at the above pH.

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

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

Dosage form The dosage form (dosage form, shape, structure) of the composition of the present invention is not particularly limited, and for example, eye drops (also referred to as eye drops or eye drops). eye drops), eye wash, eye ointment (water-soluble eye ointment, oil-soluble eye ointment), contact lens fitting solution, intraocular injection (e.g. intravitreal injection), contact lens solution (cleaning solution, storage solution) liquid, disinfectant, multi-purpose solution, packaged solution), preservatives for removed eye tissues such as corneas for transplantation, and surgical irrigation fluids. Eye drops, eye washes, and eye ointments also include those used when wearing contact lenses.

Note that "contact lenses" include hard contact lenses and soft contact lenses (including both ionic and nonionic lenses, and includes 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 washes, eye ointments (water-soluble eye ointments, oil-soluble eye ointments), contact lens fitting solutions, contact lens solutions (cleaning solutions, preservative solutions, disinfectant solutions). , multipurpose solutions, packaged solutions), and more preferably eye drops, eyewashes, contact lens fitting solutions, contact lens solutions (cleaning solutions, preservation solutions, disinfectants, multipurpose solutions), and more. More preferred are eye drops and eye washes, and particularly preferred are eye drops.

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

Container The composition of the present invention may be housed (filled, poured, enclosed) in a container.
The container may be any packaging body that has a part (surface) that comes into contact with the composition (preparation), such as a main part of the container that contains the composition (for example, a liquid composition), a part of the container that includes an extraction port, etc. (nozzle, inner plug), suction tube, cap, etc.

The material constituting the container can be selected from a wide range. For example, at least part or all of the part that comes into contact with the composition may be made of plastic (e.g., olefin resin, styrene resin, acrylic resin, polyester resin, polycarbonate). resins, fluororesins, chlorine resins (polyvinyl chloride, etc.), polyamide resins, polyacetal resins, polyphenylene ether resins (modified polyphenylene ether, etc.), polyarylates, polysulfones, polyimide resins, cellulose resins (cellulose acetate) etc.), hydrocarbon resins which may be substituted with halogen atoms), metals (aluminum etc.), and the like.

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

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

Examples of the styrene resin include polystyrene, acrylonitrile-containing styrene resin (eg, acrylonitrile-styrene copolymer (AS resin), acrylonitrile-butadiene-styrene copolymer (ABS resin), etc.).

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

Examples of the polyester resin 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.); Examples include resins having alkylene naphthalate units (eg, polyethylene naphthalate (PEN), polybutylene naphthalate, etc.).

Examples of fluororesins include fluorine-substituted polyethylene (polytetrafluoroethylene, polychlorotrifluoroethylene, etc.), polyvinylidene fluoride, polyvinyl fluoride, perfluoroalkoxy fluororesin, tetrafluoroethylene/hexafluoropropylene copolymer, and ethylene/tetrafluoropropylene copolymer. Examples include fluorinated ethylene copolymer and ethylene/chlorotrifluoroethylene copolymer.

Examples of polyacetal resins include those consisting only of oxymethylene units and those partially containing oxyethylene units.

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

Examples of the 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.

As for the material of the container, plastics such as olefin resins, styrene resins, and polyester resins (i.e., plastic containers) are preferable, and ethylene resins, propylene resins, alkylene terephthalate resins, and polystyrene are more preferable, and polypropylene, Polyethylene terephthalate and polystyrene are more preferred, and polyethylene terephthalate is even more preferred.

Note that the material of the container may be a polymer blend with a polymer other than the above-mentioned polymer. When the container material of the container containing the ophthalmic composition of the present invention is a blend polymer with the above-mentioned polymer, the mixing ratio of the above-mentioned polymer and a polymer other than the above-mentioned 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 all the constituent materials. , 80 w/w% or more is particularly preferred.

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

Further, the parts constituting the container (container body, part including the extraction port (nozzle, inner stopper), suction tube, cap, etc.) may be made of the above material, and all parts of the container may be made of the above material. It may be composed of. In particular, from the viewpoint of achieving remarkable effects of the present invention, it is preferable that the container body portion be made of the above-mentioned material, and that the entire container body portion be made of the above-mentioned material (a part of the container body It is more preferable that the layer is not made of the above material.

Target disease (use)
The target diseases (uses) of the composition of the present invention are not particularly limited as long as they are for ophthalmology, but include, for example, allergic symptoms, itchy eyes, pain in the eyes, inflammation of the eyes, blepharitis, and Alleviation, improvement, suppression, or treatment of blurred vision, hyperemia, foreign body sensation (rolling sensation, etc.), corneal damage, corneal damage, watery eyes (lacrimation), follicles in the palpebral conjunctiva, eye discharge (eye mucus), etc. It is useful for enhancing and normalizing barrier function, protecting the cornea, etc.

Watery eyes are a symptom that occurs when the tear drainage path from the lacrimal punctum to the lacrimal canaliculi, lacrimal sac, and nasolacrimal duct becomes blocked by mucus, or when excessive tears are produced due to irritation. .

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

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

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

In another aspect, the composition of the present invention can be used to treat eye itching, eye pain, eye inflammation, blepharitis, blurred vision, bloodshot eyes, watery eyes, foreign body sensation, corneal damage, corneal damage, watery eyes ( It is suitable for alleviating, improving, suppressing, or treating symptoms such as epiphora), follicles of the palpebral conjunctiva, and eye discharge (eye mucus). These symptoms may or may not be derived from allergic symptoms.

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

For example, when the composition of the present invention is a preparation to be applied to the eyes such as eye drops, eye wash, eye ointment, etc., the usage thereof varies depending on the target symptom, but for example, once or more times a day, or twice a day. The number of times can be 3 or more, 4 or more, 5 or more, or 6 or more times. Further, the number of times per day may be 9 times or less, 8 or less, 7 or less, 6 or less, 5 or less, or 4 or less. Particularly preferred is administration four times a day.

When the composition of the present invention is an eye drop, for example, 1 to 3 drops may be instilled into the eye at a time, and 1 to 2 drops, or 2 to 3 drops may be used. Preferably, 1 to 2 drops may be instilled into the eye. It can also be one drop. Further, the amount of one drop in the eye may preferably be 30 to 50 μL.

When the composition of the present invention is an eyewash, for example, 1 to 30 mL may be used per time, 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 each time.

When the composition of the present invention is a contact lens wearing solution, when putting on and taking off the contact lens, apply, for example, 1 to 3 drops, preferably 1 to 2 drops, on one side of the contact lens and/or each time. The contact lens may be worn after being dripped onto both sides of the contact lens, and preferably after being wetted on both sides of the contact lens.

[2. Suppression of precipitation and cloudiness]
The ophthalmic composition according to the present embodiment has the effect that precipitation (cloudiness) can be suppressed (or the dissolution stability can be improved or improved) in the ophthalmic composition.

Accordingly, as one embodiment of the present invention, the following method is provided.

An ophthalmic composition containing (A) one or more selected from the group consisting of epinastine and its salts, and (B) one or more selected from the group consisting of pranoprofen and its salts, (C) alcohol, A method (dissolution) for suppressing precipitation (white turbidity) in an ophthalmological composition, which comprises containing one or more selected from the group consisting of water-soluble polymers, sugars, polyoxyethylene polyoxypropylene glycol, and polyethylene glycol fatty acid esters. methods of improving or increasing stability).

Further, as one embodiment of the present invention, the following agents are provided.

Suppressing precipitation (cloudiness) in an ophthalmic composition containing (A) one or more selected from the group consisting of epinastine and its salts, and (B) one or more selected from the group consisting of pranoprofen and its salts (or an agent for improving or improving dissolution stability), which is selected from the group consisting of (C) alcohol, water-soluble polymer, sugar, polyoxyethylene polyoxypropylene glycol, and polyethylene glycol fatty acid ester; An agent containing one or more selected types.

In addition, regarding the types and contents of components (A) to (C), the types and contents of other components, and the formulation form and use of the ophthalmic composition in each of the above embodiments, please refer to [1. Ophthalmic Composition].

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

Aqueous ophthalmic compositions (eye drops) having the composition shown in the table below were prepared, and precipitation was evaluated as follows.

200 g (200 cm ³ ) of the prepared composition was filled into 10 mL glass screw bottles and stored at room temperature for 1 hour, and then the presence and extent of precipitation (white turbidity) was visually confirmed.

Then, the degree of precipitation for Test Example 1 was evaluated based on the following criteria.

〇: No precipitation △: Same degree of precipitation as Test Example 1 ×: More precipitation than Test Example 1

The results are shown in the table below. In addition, in the aqueous ophthalmic compositions shown in the table below, the unit of each component is (w/v%).

As is clear from the results in the table above, surprisingly, precipitation does occur when epinastine hydrochloride and pranoprofen are combined, although precipitation does not occur when only epinastine hydrochloride or pranoprofen is included. was found (Test Examples 1 to 3).

Such precipitation could be effectively suppressed by using specific components (Test Examples 4 to 19). Normally, such precipitation can be suppressed by using a surfactant, but very common surfactants not only have no effect on suppressing precipitation, but also increase precipitation (Test Example 20). These results were extremely surprising.

The properties of the compositions of Test Examples 4 to 19, in which the precipitation suppressing effect was confirmed in this way, were further investigated.

First, all of these compositions could be filled into eye drop containers (made of PET, diameter 6 mm) without any problem, and had excellent filling properties.

In addition, when the composition was dropped from an eyedropper container, the liquid drained well in all cases. Therefore, it was found that all of the obtained compositions were compositions that did not easily cause dripping.

Further, each of the compositions was dropped onto a colorless and transparent plastic film, and the water was evaporated. When the state after evaporation was visually confirmed, no or almost no white residue (whitening phenomenon or precipitation due to nonvolatile matter) was observed in all cases. Thus, it was confirmed that all of the obtained compositions can be formulated efficiently. In fact, none of the compositions caused any white residue on the production line (nozzles, etc.) when filled into the eye drop containers.

Furthermore, each composition effectively exhibited the function of component (c). For example, in Test Example 5, concentrated glycerin was used, and it exhibited its function as an isotonic agent without impairing its function.

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

The present invention can provide an ophthalmological composition useful as eye drops and the like.

Claims (1)

The invention described herein.