JP2022082697A - Ophthalmic composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an ophthalmic composition having improved defoaming properties and the like.

SOLUTION: An ophthalmic composition at least contains (A) at least one selected from the group consisting of pranoprofen and a salt thereof, (B) at least one selected from the group consisting of glycyrrhizinic acid and a salt thereof, (C) at least one selected from the group consisting of chlorpheniramine and a salt thereof, and (D) antiallergic agent. Such a composition also may contain (E) at least one selected from the group consisting of lipid-soluble antioxidant and (F) chondroitin sulfate and a salt thereof, or may be stored in a plastic container (for example, PET container).

SELECTED DRAWING: None

COPYRIGHT: (C)2022,JPO&INPIT

Description

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

In ophthalmic compositions such as eye drops, confirmation of dissolution at the time of manufacture is emphasized in order to safely apply to the eye.

Further, among ophthalmic compositions, foreign matter inspection in the manufacturing process is indispensable for pharmaceuticals such as eye drops and eye wash. However, if bubbles are generated in the ophthalmic composition during the manufacturing process and the rate at which the bubbles disappear is slow, it is difficult to distinguish between the compounding components or foreign substances and the bubbles. The current situation is that manufacturing cannot be performed efficiently.

Conventionally, terpenoids and the like have been used for the purpose of improving the speed at which bubbles disappear (see Patent Document 1).

However, further defoaming technology that can handle a variety of formulations is desired.

WO2012 / 090985

An object of the present invention is to provide an ophthalmic composition having an excellent defoaming effect.

According to the studies by the present inventors, at least one selected from the group consisting of (A) pranoprofen and its salt, and one or more selected from the group consisting of (B) glycyrrhizinic acid and its salt. , (C) One or more selected from the group consisting of chlorpheniramine and a salt thereof, and (D) an antiallergic agent in combination to obtain an ophthalmic composition having excellent antifoaming properties. I found it.

Further, according to the study by the present inventors, in ophthalmic compositions such as eye drops, unpleasant bitterness and miscellaneous taste and sweetness may be recognized, and precipitation (crystallization) or turbidity of components may occur over time, or a production line. Various new problems have been found, such as the adhesion and precipitation of droplets (for example, the adhesion and precipitation of droplets at the tip of the filling tube). We have found that it can be solved, and after further studies, we have completed the present invention.

That is, the composition of the present invention (ophthalmic composition) provides, for example, the following invention.
[1]
(A) One or more selected from the group consisting of pranoprofen and its salts,
(B) One or more selected from the group consisting of glycyrrhizic acid and salts thereof,
(C) One or more selected from the group consisting of chlorpheniramine and its salts, and (D) antiallergic agents,
An ophthalmic composition containing.
[2]
(D) The ophthalmic composition according to [1], wherein the antiallergic agent comprises at least one selected from the group consisting of cromoglycic acid, tranilast, and salts thereof.
[3]
(A) The ophthalmic composition according to [1] or [2], which contains 0.0001 to 1 w / v% of one or more selected from the group consisting of pranoprofen and salts thereof.
[4]
(B) The ophthalmic composition according to any one of [1] to [3], which contains 0.01 to 3 w / v% of one or more selected from the group consisting of glycyrrhizic acid and a salt thereof.
[5]
(C) The ophthalmic composition according to any one of [1] to [4], which contains 0.0001 to 1 w / v% of one or more selected from the group consisting of chlorpheniramine and a salt thereof.
[6]
(D) The ophthalmic composition according to any one of [1] to [5], which contains 0.1 to 10 w / v% of an antiallergic agent.
[7]
The ophthalmic composition according to any one of [1] to [6], further containing (E) a fat-soluble antioxidant.
[8]
The ophthalmic composition according to any one of [1] to [7], further containing (F) one or more selected from the group consisting of chondroitin sulfate and a salt thereof.
[9]
The ophthalmic composition according to any one of [1] to [8], further containing (G) a refreshing agent.
[10]
The ophthalmic composition according to any one of [1] to [9], which is contained in a plastic container.
[11]
The ophthalmic composition according to any one of [1] to [10], which is for alleviating, improving, suppressing and / or treating allergic symptoms caused by pollen and / or house dust.
[12]
The ophthalmic composition according to any one of [1] to [11], which is an eye drop having four eye drops per day.
[13]
The ophthalmic composition according to any one of [1] to [12], which is not an eye drop for instillation while wearing contact lenses.

INDUSTRIAL APPLICABILITY The present invention can provide an ophthalmic composition having excellent defoaming property (fast defoaming speed). The present inventor has newly found a problem that generated bubbles are likely to be stabilized in a composition containing pranoprofen and / or a salt thereof, and a composition containing such pranoprofen and / or a salt thereof. Even if it is a product, a high defoaming effect can be obtained according to the specific composition of the present invention.

Moreover, such defoaming property is surprisingly greatly different depending on the material of the container filled with the ophthalmic composition, and in particular, the defoaming time is increased in a specific plastic container. According to this, even in such a plastic container, the rate at which bubbles disappear can be significantly improved.

As described above, the composition of the present invention is extremely practical.

In the present specification, the unit of content "w / v%" is synonymous with "g / 100 mL". Further, 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 contains at least (A) pranoprofen and / or a salt thereof, and / or (B) glycyrrhizic acid and / or a salt thereof.

(A) Pranoprofen and / or a salt thereof (component (A))

The salt of planoprofen may be any pharmaceutically or physiologically acceptable salt, for example, an alkali metal salt (sodium salt, potassium salt, etc.), an alkaline earth metal salt (calcium salt, magnesium salt, etc.). , Ammonium salt, salt with inorganic base such as metal salt (aluminum salt, etc.), organic amine salt (methylamine salt, triethylamine salt, diethylamine salt, triethanolamine salt, morpholine salt, piperazine salt, pyrrolidine salt, tripyridine salt) , Salts with organic bases such as picolin salts).

The pranoprofen and its salt may be in the form of a hydrate.

A preferred pranoprofen and / or a salt thereof is pranoprofen.

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

The content of the component (A) in the composition is, for example, 0.0001 w / v% or more, preferably 0.001 to 1 w / v%, more preferably 0.005 to 0, based on the total amount of the composition. .5w / v%, more preferably 0.007 to 0.2w / v%, even more preferably 0.01 to 0.1w / v%, particularly preferably 0.03 to 0.1w / v%, most It may be preferably about 0.045 to 0.06 w / v%. Of these, 0.05 w / v% is particularly preferable.

(B) Glycyrrhizic acid and / or a salt thereof (component (B))

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

Glycyrrhizic acid and its salt may be in the form of a hydrate.

A preferred glycyrrhizic acid and / or a salt thereof is dipotassium glycyrrhizinate.

Glycyrrhizic acid 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, 0.01 w / v% or more, preferably 0.02 to 3 w / v%, more preferably 0.05 to 1 w, based on the total amount of the composition. / V%, more preferably 0.1 to 0.5 w / v%, even more preferably 0.15 to 0.4 w / v%, particularly preferably 0.2 to 0.3 w / v%, most preferably. It may be about 0.22 to 0.28 w / v%. Of these, 0.25 w / v% is particularly preferable.

When the component (A) and the component (B) are contained, the ratio of the component (B) is, for example, 0.01 to 100 parts by weight, preferably 0.1 to 50 parts by weight with respect to 1 part by weight of the component (A). It may be parts by weight, more preferably 1 to 30 parts by weight, particularly preferably 2 to 20 parts by weight, more particularly preferably 3 to 10 parts by weight, and most preferably 4 to 6 parts by weight. Among them, the ratio of the component (B) is particularly preferably 5 parts by weight with respect to 1 part by weight of the component (A).

The composition of the present invention may contain (C) chlorpheniramine and / or a salt thereof ((C) component) and / or (D) an antiallergic agent ((D) component). In particular, the composition of the present invention may contain all the components (A) to (D).

(C) Chlorpheniramine and / or a salt thereof (component (C))

The salt of chlorpheniramine may be any pharmaceutically or physiologically acceptable salt, for example, an organic acid salt (for example, maleate, fumarate, etc.), an inorganic acid salt (for example, hydrochloride, etc.). Sulfate, etc.), metal salts (eg, metal salts exemplified in the section of (A) component and (B) component, etc.) and the like.

The chlorpheniramine and its salt may be in the form of a hydrate, and may be d-form, l-form, or dl-form.

A preferred chlorpheniramine and / or salt thereof is chlorpheniramine maleate.

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

The content of the component (C) in the composition is, for example, 0.0001 w / v% or more, 0.001 to 1 w / v%, preferably 0.005 to 0.5 w /, based on the total amount of the composition. v%, more preferably 0.01 to 0.3 w / v%, even more preferably 0.05 to 0.1 w / v%, even more preferably 0.01 to 0.05 w / v%, particularly preferably 0. It may be about 0.02 to 0.04 w / v%, most preferably about 0.025 to 0.035 w / v%, and is 0.015 w / v% or more (for example, 0.018 w / v% or more, preferably 0.018 w / v% or more). It may be 0.02 w / v% or more). Of these, 0.03 w / v% is particularly preferable.

When used in combination with the component (A), the ratio of the component (C) is, for example, 0.01 to 100 parts by weight, preferably 0.03 to 50 parts by weight, based on 1 part by weight of the component (A). More preferably 0.05 to 30 parts by weight, still more preferably 0.1 to 10 parts by weight, even more preferably 0.2 to 5 parts by weight, particularly preferably 0.3 to 3 parts by weight, and particularly more preferably 0. It may be about 35 to 1 part by weight, more preferably 0.4 to 0.8 part by weight, and most preferably about 0.5 to 0.7 part by weight. Above all, the ratio of the component (C) is particularly preferably 0.6 parts by weight with respect to 1 part by weight of the component (A).

Further, when used in combination with the component (B), the ratio of the component (C) is, for example, 0.001 to 30 parts by weight, preferably 0.003 to 10 parts by weight, based on 1 part by weight of the component (B). More preferably 0.005 to 5 parts by weight, still more preferably 0.01 to 1 part by weight, particularly preferably 0.03 to 0.5 part by weight, more particularly preferably 0.05 to 0.2 part by weight, most preferably. It may be preferably about 0.1 to 0.15 parts by weight. Above all, the ratio of the component (C) is particularly preferably 0.12 parts by weight with respect to 1 part by weight of the component (B).

(D) Anti-allergic agent ((D) component)
Examples of the antiallergic agent include cromoglycic acid, tranilast, ibudilast, acitazanolast, tazanolast, spratast, pemirolast, levocabastine, olopatadine, ketotifen, anlexanox, oxatomid and salts thereof.

Examples of the salt of the antiallergic agent include the salts exemplified in the sections (A) to (C) above, and for example, alkali metal or alkaline earth metal salt (sodium cromoglycate, cromoglycic acid). Examples include potassium, magnesium cromoglycate, calcium cromoglycate, etc.), inorganic acid salts (eg, olopatadine hydrochloride, etc.), organic acid salts [eg, tosilate, fumarate (ketotiphen fumarate, etc.), etc.].

Of these, cromoglycic acid, tranilast and salts thereof are preferable, cromoglycic acid and its salts and tranilast are more preferable, and sodium cromoglycate is further preferable.

The antiallergic agent may be used alone or in combination of two or more.

The content of the component (D) in the composition is, for example, 0.1 to 10 w / v%, preferably 0.2 to 8 w / v%, more preferably 0.3 to 0.3, based on the total amount of the composition. 5w / v% (eg 0.4-4w / v%), even more preferably 0.5-3w / v%, particularly preferably 0.7-2w / v%, even more preferably 0.8-. It may be about 1.5 w / v%, most preferably about 0.9 to 1.2 w / v%. Above all, 1.0 w / v% is particularly preferable.
When the component (D) contains at least one selected from tranilast and a salt thereof, the content of the component (D) in the composition is, for example, 0.1 to 1 w / v with respect to the total amount of the composition. % Is preferable, 0.3 to 0.75 w / v% is more preferable, 0.4 to 0.6 w / v% is even more preferable, and 0.5 w / v% is particularly preferable.

When used in combination with the component (A), the ratio of the component (D) is, for example, 0.1 to 1000 parts by weight, preferably 0.2 to 500 parts by weight, more preferably 1 part by weight of the component (A). Is 0.3 to 300 parts by weight, more preferably 0.5 to 200 parts by weight, still more preferably 0.7 to 100 parts by weight, particularly preferably 1 to 50 parts by weight, and particularly preferably 3 to 40 parts by weight. In particular, it may be more preferably about 5 to 30 parts by weight, and most preferably about 10 to 25 parts by weight. Above all, the ratio of the component (D) is particularly preferably 20 parts by weight with respect to 1 part by weight of the component (A).

When used in combination with the component (B), the ratio of the component (D) is, for example, 0.001 to 50 parts by weight, preferably 0.01 to 30 parts by weight, more preferably 1 part by weight with respect to 1 part by weight of the component (B). Is 0.1 to 20 parts by weight, more preferably 0.3 to 15 parts by weight, still more preferably 0.5 to 10 parts by weight, particularly preferably 1 to 8 parts by weight, and most preferably about 3 to 5 parts by weight. May be. Above all, the ratio of the component (D) is particularly preferably 4 parts by weight with respect to 1 part by weight of the component (B).

When used in combination with the component (C), the ratio of the component (D) is, for example, 0.1 to 1000 parts by weight, preferably 0.2 to 500 parts by weight, more preferably 1 part by weight of the component (C). Is 0.5 to 300 parts by weight, more preferably 1 to 200 parts by weight, even more preferably 2 to 100 parts by weight), particularly preferably 3 to 70 parts by weight, particularly more preferably 5 to 60 parts by weight, and particularly further. It may be preferably 10 to 50 parts by weight, particularly more preferably 15 to 45 parts by weight, most preferably about 20 to 40 parts by weight, or 30 to 35 parts by weight. Above all, the ratio of the component (D) is particularly preferably 33.3 parts by weight with respect to 1 part by weight of the component (C).

[Other ingredients]
From the viewpoint of exerting the effect of the present invention more remarkably, the composition of the present invention preferably further contains (E) a fat-soluble antioxidant in addition to the components (A) to (D).

(E) Fat-soluble antioxidant (component (E))
Fat-soluble antioxidants include, for example, butyl group-containing phenols such as dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA); nordihydroguayaletic acid (NDGA); ascorbic acid palmitate, ascorbic acid stearate, Ascorbic acid esters such as aminopropyl ascorbate, tocopherol ascorbate, triphosphate ascorbate, palmitate ascorbate; and octylic acid such as ethyl gallate, propyl acid, octyl acid, dodecyl acid. Esters; propyl gallate; 3-butyl-4-hydroxyquinoline-2 on; carotenoids such as lutein and astaxanthin; polyphenols such as anthocyanins, catechins, tannins, curcumin; CoQ10 and the like.

Of these, dibutylhydroxytoluene is preferable.

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

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

When used in combination with the component (A), the ratio of the component (E) is, for example, 0.001 to 20 parts by weight, preferably 0.005 to 10 parts by weight, more preferably 1 part by weight with respect to 1 part by weight of the component (A). Is 0.01 to 5 parts by weight, more preferably 0.02 to 3 parts by weight, still more preferably 0.03 to 1 part by weight, particularly preferably 0.05 to 0.5 part by weight, and most preferably 0. It may be about 07 to 0.2 parts by weight.

When used in combination with the component (B), the ratio of the component (E) is, for example, 0.0001 to 10 parts by weight, preferably 0.0005 to 5 parts by weight, more preferably to 1 part by weight of the component (B). Is 0.001 to 3 parts by weight, more preferably 0.005 to 1 part by weight, still more preferably 0.008 to 0.5 part by weight, particularly preferably 0.01 to 0.1 part by weight, and particularly more preferably. May be about 0.015 to 0.05 parts by weight.

From the viewpoint of exerting the effect of the present invention more remarkably, the composition of the present invention preferably further contains (F) chondroitin sulfate and / or a salt thereof in addition to the components (A) to (D).

(F) Chondroitin sulfate and / or a salt thereof (component (F))
Chondroitin sulfate is obtained by ester-bonding sulfuric acid to all or part of the hydroxyl groups of the sugar chain in which D-glucuronic acid and N-acetylglucosamine are repeated. The binding positions and numbers of sulfuric acid are diverse, and there are also derivatives of chondroitin sulfate (for example, those in which all or part of N-acetylglucosamine is replaced with iduronic acid).

The chondroitin sulfate used in the present invention may have any structure. For example, chondroitin 4-sulfate (chondroitin sulfate A), chondroitin 6-sulfate (chondroitin sulfate C), chondroitin sulfate E in which the 4-position and 6-position of N-acetylglucosamine are sulfated can be mentioned. Moreover, chondroitin sulfate may be extracted from an animal.

The salt of chondroitin sulfate may be any pharmaceutically or physiologically acceptable salt, for example, alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, etc.), ammonium. Salts, salts with inorganic bases such as metal salts (aluminum salts, etc.), organic amine salts (methylamine salt, triethylamine salt, diethylamine salt, triethanolamine salt, morpholinic salt, piperazine salt, pyrrolidine salt, tripyridine salt, picolin Examples include salts with organic bases such as (salts, etc.).

Preferred chondroitin sulfate and / or a salt thereof is an alkali metal salt of chondroitin sulfate, more preferably sodium chondroitin sulfate, and more preferably sodium chondroitin sulfate published in Japanese Pharmacopoeia Standard 2002.

The content of the component (F) in the composition is, for example, 0.001 w / v% or more, preferably 0.01 to 10 w / v%, more preferably 0.05 to 1 w, based on the total amount of the composition. / V%, more preferably 0.07 to 0.9 w / v%, even more preferably 0.1 to 0.8 w / v%, particularly preferably 0.3 to 0.7 w / v%, particularly more preferably. May be about 0.45 to 0.6 w / v%. Among them, 0.5 w / v% is the most preferable.

When used in combination with the component (A), the ratio of the component (F) is, for example, 0.05 to 200 parts by weight, preferably 0.2 to 100 parts by weight, more preferably 1 part by weight with respect to 1 part by weight of the component (A). Is 0.5 to 50 parts by weight, more preferably 1 to 40 parts by weight, still more preferably 3 to 30 parts by weight, particularly preferably 5 to 20 parts by weight, and most preferably about 7 to 15 parts by weight. good. Above all, the ratio of the component (F) is particularly preferably 10 parts by weight with respect to 1 part by weight of the component (A).

When used in combination with the component (B), the ratio of the component (F) is, for example, 0.0005 to 30 parts by weight, preferably 0.005 to 20 parts by weight, more preferably 1 part by weight of the component (B). Is 0.05 to 10 parts by weight, more preferably 0.1 to 10 parts by weight, still more preferably 0.2 to 5 parts by weight, particularly preferably 0.5 to 4 parts by weight, and most preferably 1 to 3 parts by weight. It may be about a part. Above all, the ratio of the component (F) is particularly preferably 2 parts by weight with respect to 1 part by weight of the component (B).

The composition of the present invention preferably further contains (G) a refreshing agent from the viewpoint of exerting the effect of the present invention more remarkably.

(G) Cooling agent ((G) component)
The refreshing agent is not particularly limited, and examples thereof include terpenoids such as menthol, anethole, eugenol, camphor, geraniol, cineole, borneol, limonene, and ryuno. These may be d-body, l-body or dl-body. Further, essential oils such as peppermint oil, cool mint oil, spare mint oil, peppermint oil, uikyo oil, keihi oil, bergamot oil, eucalyptus oil and rose oil can also be mentioned.

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

The refreshing agent may be used alone or in combination of two or more.

The proportion of the component (G) is, for example, 0.0001 w / v% or more, 0.0005 w / v% or more, 0.001 w / v% or more, 0.002 w / v% or more, with respect to the total amount of the composition. 0.003w / v% or more, 0.004w / v% or more, 0.005w / v% or more, 0.006w / v% or more, 0.007w / v% or more, 0.008w / v% or more, 0. It may be 009 w / v% or more and 0.01 w / v% or more.

The ratio of the component (G) is 1 w / v% or less, 0.1 w / v% or less, 0.09 w / v% or less, 0. 08w / v% or less, 0.07w / v% or less, 0.06w / v% or less, 0.05w / v% or less, 0.04w / v% or less, 0.03w / v% or less, 0.02w / It may be v% or less.

When used in combination with the component (A), the ratio of the component (G) is preferably 0.005 to 10 parts by weight, more preferably 0.01 to 5 parts by weight, based on 1 part by weight of the component (G). It may be more preferably about 0.05 to 1 part by weight, and even more preferably about 0.1 to 0.5 part by weight.

When used in combination with the component (B), the ratio of the component (G) is preferably 0.0005 to 5 parts by weight, more preferably 0.001 to 1 part by weight, based on 1 part by weight of the component (G). It may be more preferably 0.005 to 0.5 parts by weight, and even more preferably about 0.01 to 0.1 parts by weight.

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

Additives can be used alone or in combination of two or more. In addition, each additive can be used alone or in combination of two or more.

Specific examples of additives are illustrated below.

(H) Nonionic Surfactant (Component (H))
The composition of the present invention preferably contains (H) a nonionic surfactant from the viewpoint of exerting the effect of the present invention more remarkably.

Examples of the nonionic surfactant include monolaurate POE (20) sorbitan (polysorbate 20), monopalmitate POE (20) sorbitan (polysorbate 40), monostearate POE (20) sorbitan (polysorbate 60), and tristearate POE. (20) Polysorbates (POE sorbitan fatty acid esters) such as sorbitan (polysorbate 65), monooleic acid POE (20) sorbitan (polysorbate 80); POE / POP glycols such as POE cured castor oil 40, POE cured castor oil 50, POE cured castor oil 60, POE cured castor oil 80 and the like; POE castor oil 3, POE castor oil 4, POE castor Oil 6, POE Himashima Oil 7, POE Himashima Oil 10, POE Himashima Oil 13.5, POE Himashima Oil 17, POE Himashima Oil 20, POE Himashima Oil 25, POE Himashima Oil 30, POE Himashima Oil 35, POE Himashima Oil 50, etc. POE castor oil; polyethylene glycol monostearate (2EO), polyethylene glycol monostearate (4EO), polyethylene glycol monostearate (9EO), polyethylene glycol monostearate (10EO). ), Polyethylene Glycol Monostearate (23EO), Polyethylene Glycol Monostearate (25EO), Polyethylene Glycol Monostearate (32EO), Polyethylene Glycol Monostearate (40EO, Polyoxyl 40) monostearate, polyethylene glycol monostearate (45EO), polyethylene glycol monostearate (55EO), polyethylene glycol monostearate (75EO), polyethylene glycol monostearate (140E.O.). Polyethylene glycol monostearate such as O.); POE alkyl ethers such as POE (9) lauryl ether; POE-POP alkyl ethers such as POE (20) POP (4) cetyl ether; POE (10) nonylphenyl ether Examples thereof include POE alkylphenyl ethers and the like. In the above-exemplified compounds, POE is polyoxyethylene, POP is polyoxypropylene, and the numbers in parentheses indicate the number of added moles.

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

When the component (H) is blended in the composition of the present invention, the ratio of the component (H) is, for example, 0.001 w / v% or more, preferably 0.005 w / v% or more, based on the total amount of the composition. , More preferably 0.01 w / v% or more, and particularly preferably 0.05 w / v% or more.
The ratio of the component (H) is, for example, 5 w / v% or less, preferably 1 w / v% or less, more preferably 0.5 w / v% or less, and particularly 0.3 w / v% or less, based on the total amount of the composition. V% or less can be mentioned.

Preservatives Examples of preservatives include polydronium chloride, alkylpolyaminoethylglycines (eg, alkyldiaminoethylglycine hydrochloride, etc.), sodium benzoate, ethanol, quaternary ammonium salts (eg, benzalconium chloride, benzethonium chloride, etc.). ), Chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxybenzoic acid ester (eg, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc.), sulfuric acid Examples thereof include oxyquinoline, phenethyl alcohol, benzyl alcohol, biguanide compounds (for example, polyhexanide hydrochloride, etc.), and glokill (manufactured by Rhodia).

Among them, alkylpolyaminoethylglycines (for example, alkyldiaminoethylglycine hydrochloride), sodium benzoate, ethanol, quaternary ammonium salt, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, paraoxybenzoic acid ester, biguanide compounds. Is preferred, quaternary ammonium salts, chlorhexidine gluconate, chlorobutanol, and biguanide compounds are more preferred, and benzalconium chloride and polyhexanide hydrochloride are even more preferred.

When a preservative is blended in the composition of the present invention, as an example of the blending amount, the total amount of the preservative is 0.000001w / v% or more, particularly 0.00001w / v% or more, based on the total amount of the composition. Above all, 0.00005w / v% or more, particularly 0.001w / v% or more, and above all, 0.005w / v% or more can be mentioned. Further, the total amount of the preservative is 1 w / v% or less, particularly 0.1 w / v% or less, particularly 0.05 w / v% or less, particularly 0.02 w / v% or less, and above all, with respect to the total amount of the composition. 0.01 w / v% or less can be mentioned.

Buffering Agent The composition of the present invention preferably further contains a buffering agent from the viewpoint of exerting the effect of the present invention more remarkably.
Examples of the buffering agent include borate buffering agent, phosphoric acid buffering agent, carbon dioxide buffering agent, citric acid buffering agent, acetate buffering agent and the like.

Examples of the component of the boric acid buffer include boric acid and borate (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borate sand and the like). The borate may be a hydrate.

The components of the phosphoric acid buffer include phosphoric acid, phosphate (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, (Calcium dihydrogen phosphate, etc.) and the like. The phosphate may be a hydrate.

Examples of the components of the carbon dioxide buffer include carbonic acid and carbonates (potassium carbonate, sodium carbonate, calcium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, magnesium carbonate, etc.). The carbonate may be a hydrate.

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

Examples of the components of the acetic acid buffer include acetic acid and acetic acid salts (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.). The acetate salt may be a hydrate.

Of these, boric acid buffers and phosphate buffers are preferable, and boric acid buffers are more preferable. As the boric acid buffer, a combination of boric acid and its salt is preferable, a combination of boric acid and an alkali metal salt of boric acid and / or an alkaline earth metal salt is more preferable, and a combination of boric acid and an alkali metal of boric acid is more preferable. The combination with salt is even more preferable, and the combination of boric acid and boric acid is even more preferable.

When a buffer is added to the composition of the present invention, the amount of the buffer is different depending on the type of the buffer, the type and amount of other compounding components, and the like, and cannot be uniformly specified. The total amount of the buffer is 0.001 w / v% or more, particularly 0.01 w / v% or more, particularly 0.05 w / v% or more, and 0.1 w / v% or more, particularly with respect to the total amount of the composition. Be done. Further, the total amount of the buffer is 10 w / v% or less, particularly 5 w / v% or less, particularly 3 w / v% or less, particularly 2.5 w / v% or less, and particularly 2 w / v% with respect to the total amount of the composition. The following can be mentioned.

In particular, when a boric acid buffer is used, the proportion of the buffer in the composition is 0.1 to 10 w / v%, preferably 0.2 to 5 w / v%, more preferably 0.2 to 5 w / v% with respect to the entire composition. May be 0.5 to 4 w / v%, more preferably 1 to 3 w / v%, and even more preferably about 1.5 to 2.5 w / v%.

pH regulator Examples of the pH regulator include hydrochloric acid, sulfuric acid, polyphosphate, organic acids (propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, tartrate acid, malic acid, succinic acid, etc.), sodium hydroxide, and water. Examples thereof include potassium oxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diisopropanolamine and the like.

Isotonic agent Examples of the isotonic agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, potassium acetate, sodium acetate, magnesium sulfate, glycerin, and propylene glycol.

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

Examples of the thickener or thickener include guar gum, hydroxypropyl guar gum, cellulose-based polymer compounds (for example, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, etc.), arabic rubber, karaya gum, xanthan gum, and agar. , Arginic acid, α-cyclodextrin, dextrin, dextran, mucopolysaccharides (eg, heparin analogs, heparin, heparin sulfate, heparan sulfate, heparinoids, hyaluronic acid, hyaluronate (sodium salt, etc.), etc.), starch, chitin and Derivatives thereof, chitosan and its derivatives, carrageenan, sorbitol, polyvinyl-based polymer compounds (polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, etc.), alkali metal salts of polyacrylic acid (sodium salt, potassium salt, etc.), polyacrylic acid. Amin 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.) ), Arginic acid ester (propylene glycol ester, etc.), tragant powder, triisopropanolamine and the like.

Stabilizers Stabilizers include, for example, tromethamole, sodium formaldehyde sulfoxylate (longalit), monoethanolamine, aluminum monostearate, glycerin monostearate and the like.

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

Sugars Examples of saccharides include monosaccharides and disaccharides, specifically 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, and polyvinyl alcohol.

Inorganic salts Examples of inorganic salts include potassium chloride, sodium chloride, calcium chloride, magnesium chloride, sodium hydrogencarbonate, sodium carbonate (including dry sodium carbonate), potassium hydrogencarbonate, potassium carbonate, magnesium sulfate, sodium hydrogenphosphate, and the like. 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 and sodium thiosulfate.
Among them, potassium chloride, sodium chloride, calcium chloride, sodium hydrogencarbonate, sodium carbonate (including dry sodium carbonate), magnesium sulfate, sodium hydrogenphosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate are preferable, and potassium chloride, Sodium chloride, calcium chloride, sodium hydrogen phosphate, sodium dihydrogen phosphate are more preferable, and potassium chloride and sodium chloride are even more preferable.

Water-soluble antioxidants Examples of water-soluble antioxidants include ascorbic acid, ascorbic acid derivatives (ascorbic acid-2-sodium sulfate, sodium ascorbate, ascorbic acid-2-magnesium phosphate, ascorbic acid-2-. (Sodium phosphate, etc.), sodium hydrogen sulfite, sodium sulfite, sodium pyrosulfate, sodium thiosulfate, edetonic acid or a salt thereof (disodium edetate, tetrasodium edetate, etc.) and the like.

Dissolution aid The solubilizer is not particularly limited, but is, for example, polyvinylpyrrolidone (PVP, PVPK25, K30, K90, etc.), hydroxyalkylamines (or aminoalkanols or alkanolamines, for example, monoethanolamine, diethanolamine, etc.). , Triethanolamine, tromethamole, etc.), alcohols (eg, polyols such as propylene glycol), caffeine and the like.
The lysis aid may be used alone or in combination of two or more.

When the composition contains a solubilizing agent, the content of the solubilizing agent in the composition is, for example, 0.001 w / v% or more, preferably 0.005 to 20 w / v%, based on the total amount of the composition. , More preferably 0.01 to 10 w / v%, still more preferably 0.03 to 5 w / v%, even more preferably about 0.05 to 3 w / v%, 0.1 to 10 w / v. It may be about v%.

When the component (D) contains at least one selected from tranilast and a salt thereof, a solubilizing agent (monoethanolamine or the like) may be preferably used.
When the composition of the present invention comprises at least one selected from tranilast and salts thereof, the proportion of solubilizing agent is 0, for example, relative to 1 part by weight of at least one selected from tranilast and salts thereof. 001 to 30 parts by weight, preferably 0.005 to 20 parts by weight, still more preferably 0.01 to 15 parts by weight, particularly preferably 0.02 to 10 parts by weight, and more particularly preferably 0.05 to 8 parts by weight. It may be 0.1 to 15 parts by weight (for example, 0.2 to 10 parts by weight, 0.3 to 8 parts by weight, 0.5 to 5 parts by weight, etc.).

Base or Carrier The composition of the 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 components with a pharmaceutically acceptable base or carrier, for example, as described in the 16th revised Japanese Pharmacopoeia Manual. It can be prepared by the method of.

Examples of the base or carrier include water, polar solvents such as ethanol (particularly water-soluble solvents), oil-based bases, and the like. The base or carrier may be used alone or in combination of two or more.

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).

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

The pharmacologically active ingredient or the physiologically active ingredient may be used alone or in combination of two or more.

As such pharmacologically active ingredients and physiologically active ingredients, active ingredients in various pharmaceutical products described in the 2012 edition of the OTC drug manufacturing and marketing approval standard (supervised by the Society of Regulatory Science) can be exemplified. For example, decongestant, ocular muscle regulator, anti-inflammatory agent other than (A) and (B) component, anti-histamine agent other than (C) component, astringent, vitamins, amino acids, antibacterial or bactericidal agent, topical Examples include anesthetic components, painkillers, and sulfa drugs. Specific examples of these drugs are illustrated below.

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

To elaborate on the imidazoline vasoconstrictor, the salt of the imidazoline vasoconstrictor may be any pharmaceutically or physiologically acceptable salt, for example, an organic acid salt such as maleate, fumarate; hydrochloric acid. Inorganic acid salts such as salts and sulfates; salts such as metal salts can be mentioned. Among the salts, an inorganic acid salt is preferable, a hydrochloride salt or a nitrate salt is more preferable, and a hydrochloride salt salt (tetrahydrozoline hydrochloride or the like) is particularly preferable.

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

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

Anti-inflammatory agents other than component (A) and component (B)
As an anti-inflammatory agent or astringent agent other than the component (A) and the component (B), for example, zinc sulfate, zinc lactate, allantin, epsilon-aminocaproic acid, indomethacin, lysozyme chloride, silver nitrate, sodium azulene sulfonate, diclofenac sodium, brom. Examples include fenac sodium, berberine chloride, berberine sulfate and the like.

Antihistamines other than (C) ingredient
Examples of the antihistamine other than the component (C) include diphenhydramine, iproheptine and salts thereof (for example, diphenhydramine hydrochloride, iproheptine hydrochloride, etc.).

Vitamins Examples of vitamins include flavin adenin dinucleotide or a salt thereof (for example, flavin adenin dinucleotide sodium), cobalamine or a salt thereof (for example, cyanocobalamine, methylcobalamine), retinol, a salt thereof or a derivative thereof (for example, acetic acid). Retinol, retinol palmitate), pyridoxin or a salt thereof (eg, pyridoxin hydrochloride), pantenol, pantothenic acid or a salt thereof (eg, sodium pantothenate, potassium pantothenate, calcium pantothenate, magnesium pantothenate), tocopherol, a salt thereof. Or derivatives thereof (for example, tocopherol acetate, tocopherol succinate, tocopherol nicotinate), pyridoxal or a salt thereof (for example, pyridoxal phosphate), ascorbic acid or a salt thereof (for example, sodium ascorbate, calcium ascorbate) and the like.

Among them, flavin adenin dinucleotide or a salt thereof (particularly, flavin adenin dinucleotide sodium), cobalamin or a salt thereof (particularly cyanocobalamin), retinol, a salt thereof or a derivative thereof (particularly retinol acetate, retinol palmitate), pyridoxin or a substance thereof. Salts (particularly pyridoxin hydrochloride), pantenol, pantothenic acid or salts thereof (particularly sodium pantothenate, calcium pantothenate), tocopherols, salts thereof or derivatives thereof (particularly tocopherol acetate) are preferred, pyridoxine hydrochloride, tocopherol acetate More preferred.

Amino acids Amino acids (amino acids that are not chondroitin sulfate and its salts) include, for example, aminoethylsulfonic acid (taurine), aspartic acid or a salt thereof (sodium aspartate, potassium aspartate, magnesium aspartate, magnesium aspartate). (Potassium mixture, etc.), glutamate or a salt thereof (sodium glutamate, magnesium glutamate, etc.), creatinine, epsilon-aminocaproic acid, glycine, alanine, arginine, lysine, γ-aminobutyric acid, γ-aminovaleric acid, etc. These may be d-form, l-form or dl-form.

Among them, aminoethylsulfonic acid, aspartic acid or a salt thereof (potassium aspartate, magnesium aspartate, magnesium aspartate / potassium mixture, etc.), epsilon-aminocaproic acid, arginine are preferable, and aminoethylsulfonic acid, aspartic acid or a salt thereof (aminoethylsulfonic acid, aspartic acid or a salt thereof (preferably. Potassium aspartate, magnesium aspartate, magnesium aspartate / potassium equal amount mixture, etc.) are more preferable.

Antibacterial agent or bactericidal agent Examples of the antibacterial agent or bactericidal agent include sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxazole monoethanolamine, and the like. Sulfafurazole agents such as sulfisomezole sodium, sulfisomidin sodium, alkylpolyaminoethylglycine, chloramphenicol, offloxacin, norfloxacin, levofloxacin, and romefloxacin hydrochloride can be mentioned.

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

Painless agent Examples of the painless agent include procaine hydrochloride and the like.

Sulfa agent Examples of the sulfa agent include sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulfisomidin sodium and the like.

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. It also includes those that have become liquid, fluid, gel, or semi-solid by preparation at the time of use. The semi-solid state refers to a property having plasticity that can be deformed by applying a force, such as an ointment.

Further, as described above, the composition may be an aqueous composition (mainly containing an aqueous or hydrophilic composition as a base or a carrier), or an oily composition (an oily or hydrophobic composition as a base or a carrier). (Mainly including those).

The water content in the case of the aqueous composition is preferably 50% by weight or more, more preferably 75% by weight or more, still more preferably 90% by weight or more, based on the total amount of the composition (or the preparation). Further, it may be 95% by weight or more, or 98% by weight or more. Further, the base or carrier may consist only of water.

The water content in the case of an oily composition is preferably less than 50% by weight, more preferably 30% by weight or less, still more preferably 20% by weight or less, based on the total amount of the composition (or formulation).

pH
The pH of the composition of the present invention is preferably 3 or more, more preferably 4 or more, even more preferably 5 or more, and even more preferably 6 or more. Further, 10 or less is preferable, 9 or less is more preferable, 8.5 or less is even more preferable, and 8 or less is even more preferable.

The pH of the composition of the present invention may be, for example, 4 to 10, preferably 5 to 9, and more preferably 6 to 8 (for example, 6.5 to 7.5).

Osmotic pressure The osmotic pressure ratio of the composition of the present invention is, for example, preferably 0.4 or more, more preferably 0.6 or more, and even more preferably 0.8 or more. Further, 5 or less is preferable, 3 or less is more preferable, and 2 or less is even more preferable.

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 16th revised Japanese Pharmacopoeia. The osmotic pressure is measured according to the osmotic pressure measurement method (freezing point drop method) described in the 16th revised Japanese Pharmacopoeia. The standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) is prepared by drying sodium chloride (standard reagent according to the Japanese Pharmacopoeia) at 500 to 650 ° C. for 40 to 50 minutes and then in a desiccator (silica). Allow to cool, weigh accurately 0.900 g, dissolve in purified water to prepare exactly 100 mL, or use a commercially available standard solution for measuring osmotic pressure ratio (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, an eye drop (also referred to as an eye drop or an eye drop. The eye drop can be instilled while wearing a contact lens. (Including eye drops), eye wash, eye ointment (water-soluble eye ointment, oil-soluble eye ointment), contact lens wearing solution, intraocular injection (for example, intravitreous injection), contact lens solution (cleaning solution, storage) Liquids, disinfectants, multipurpose solutions, package solutions), preservatives for removed eye drops such as corneal membranes for transplantation, perfusate during surgery, etc. Eye drops, eye wash agents, and eye ointments include those used when wearing contact lenses.

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

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 wearing solution, contact lens solution (cleaning solution, preservative solution, disinfectant solution). , Multi-purpose solution, package solution), and more preferably, eye drops, eye wash, contact lens wearing solution, contact lens solution (cleaning solution, preservative solution, disinfectant solution, multi-purpose solution) and the like. Eye drops and eye wash are more preferable, and eye drops are particularly preferable.

Such a composition of the present invention is an ophthalmic composition (when worn) or used or applied while wearing (wearing) or while wearing (wearing) contact lenses (hard contact lenses, soft contact lenses, especially silicone hydrogel contact lenses). In particular, eye drops, eye wash agents, or eye ointments) can be excluded.

The composition of the present invention may be a single-use unit dose or a multi-dose that can be used repeatedly, but it is preferably contained and used in the form of a multi-dose because of its excellent preservative effect.

Container The composition of the present invention may be contained (filled, injected, sealed) in a container.
The container may be a package having a portion (surface) in contact with the composition (formulation), for example, a container main body portion for accommodating the composition (for example, a liquid composition) and a portion including an extraction port of the container. It may be composed of (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 a part or all of the contact portion with the composition is plastic [for example, olefin resin, styrene resin, acrylic resin, polyester resin, polycarbonate. Based 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-based resins that may be substituted with halogen atoms, etc.], metals (aluminum, etc.), etc.

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

Examples of the olefin resin include polyethylene resins [for example, polyethylene (including high-density polyethylene, low-density polyethylene, ultra-low-density polyethylene, linear low-density polyethylene, ultra-high molecular weight polyethylene, etc.), ethylene-propylene copolymer, etc. ], Polyethylene-based resin [for example, polypropylene (PP) (including isotactic polypropylene, syndiotactic polypropylene, atactic polypropylene, etc.), propylene-ethylene copolymer, etc.], Methylpentene-based resin (for example, polymethylpentene). Etc.) and so on.

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

Examples of the acrylic resin include a resin containing an acrylic ester such as methyl acrylate, a methacrylic acid ester such as methyl methacrylate, cyclohexyl methacrylate, and t-butylcyclohexyl methacrylate as a polymerization component.

Examples of the polyester-based resin include aromatic polyester-based resins [for example, resins having an alkylene terephthalate unit (alkylene terephthalate-based resins: for example, polyethylene terephthalate (PET), polytrimethylene terephthalate, polybutylene terephthalate (PBT), etc.). Resins having an alkylene naphthalate unit (for example, polyethylene terephthalate (PEN), polybutylene naphthalate, etc.)] and the like can be mentioned.

Fluororesin includes fluorine-substituted polyethylene (polytetrafluoroethylene, polychlorotrifluoroethylene, etc.), polyvinylidene fluoride, vinyl fluoride, perfluoroalkoxyfluororesin, ethylene tetrafluoride / propylene hexafluoride copolymer, ethylene / 4 Examples thereof include a fluoroethylene copolymer and an ethylene / chlorotrifluoroethylene copolymer.

Examples of the polyacetal resin include those consisting only of oxymethylene units and those containing some oxyethylene units.

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

Examples of polyarylate include amorphous polyarylate.

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

Examples of cellulose acetate include cellulose diacetate and cellulose triacetate.

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

The container may be a polymer blend with a polymer other than the polymer as the container material. When the container material of the container containing the ophthalmic composition of the present invention is a polymer blend with the polymer, the mixing ratio of the polymer with 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, still more preferably 65 w / w% or more, based on the total amount of the constituent materials. , 80 w / w% or more is particularly preferable.

The container may be made of the above-mentioned material at least a part of the surface in contact with the composition of the present invention. For example, a layer or film made of the above material may be formed on the inner surface of the container, or the container itself may be molded from the above material. From the viewpoint of significantly exerting the effect of the present invention, it is preferable that the container itself is molded from the above material.

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

Target disease (use)
The target disease (use) of the composition of the present invention is not particularly limited as long as it is for ophthalmology, but for example, allergic symptoms, foreign body sensation (rolling sensation, etc.), corneal barrier function, and epiphora (flow). It is useful for alleviation, improvement, suppression, or treatment of epiphora).

Lacrimal punctum is a symptom that occurs when the tear discharge path from the lacrimal punctum to the lacrimal canaliculi, lacrimal sac, and nasolacrimal duct is obstructed by the eyes or the like, or when tears are excessively produced by stimulation. ..

In the present specification, "alleviation" includes symptom relief and symptom progression suppression, and "improvement", "suppression", and "treatment" include symptom relief, symptom progression suppression, cure or complete recovery. Include.

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

The allergen for allergic symptoms is not particularly limited, but may be pollen (sugi pollen, cypress pollen, etc.), house dust (indoor dust, etc.) and the like.

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 and the like.

For example, when the composition of the present invention is an eye drop, an eye wash, an eye ointment, or the like, the usage thereof varies depending on the target symptom, but for example, once or more or twice a day. It can be 3 times or more, 4 times or more, 5 times or more, or 6 times or more. Further, 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 preferable 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 instilled at a time, and 1 to 2 drops or 2 to 3 drops may be applied. It is preferable to instill 1 to 2 drops. It can be one drop.

When the composition of the present invention is an eye wash, for example, the eye may be washed with 1 to 30 mL at a 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 at a time.

When the composition of the present invention is a contact lens mounting solution, when the contact lens is attached or detached, for example, 1 to 3 drops, preferably 1 to 2 drops, may be applied to one side of the contact lens and / or when the contact lens is attached or detached. It may be worn after being drip-dried on both sides and wet, preferably after wetting both sides of the contact lens.

[2. Improvement of defoaming speed]
The ophthalmic composition according to the present embodiment has an effect that the defoaming rate in the ophthalmic composition can be improved.
Therefore, as one embodiment of the present invention, one or more selected from the group consisting of (A) pranoprofen and a salt thereof, and one or more selected from the group consisting of (B) glycyrrhizinic acid and a salt thereof. , (C) One or more selected from the group consisting of chlorpheniramine and salts thereof, and (D) compounding an antiallergic agent into the ophthalmic composition to improve the defoaming rate in the ophthalmic composition. The method is provided.
Further, as one embodiment of the present invention, an ophthalmic composition containing at least one selected from the group consisting of (A) pranoprofen and a salt thereof is selected from the group consisting of (B) glycyrrhizinic acid and a salt thereof. A defoaming rate improving agent is provided, which comprises blending (C) one or more selected from the group consisting of chlorpheniramine and a salt thereof, and (D) an antiallergic agent. ..
Regarding the types and contents of the components (A) to (D), the types and contents of other components, the formulation form and use of the ophthalmic composition, etc. in each of the above embodiments, [1. Ophthalmic Composition] as described.

[3. Improvement of unpleasant taste after administration]
The ophthalmic composition according to the present embodiment has the effect of being able to improve the unpleasant taste after administration of the ophthalmic composition.
Therefore, as one embodiment of the present invention, one or more selected from the group consisting of (A) pranoprofen and a salt thereof, and one or more selected from the group consisting of (B) glycyrrhizinic acid and a salt thereof. , (C) One or more selected from the group consisting of chlorpheniramine and salts thereof, and (D) an unpleasant taste after administration in the ophthalmic composition, which comprises blending an antiallergic agent into the ophthalmic composition. Is provided with a way to improve.
Further, as one embodiment of the present invention, an ophthalmic composition containing at least one selected from the group consisting of (B) glycyrrhizinic acid and a salt thereof is selected from the group consisting of (A) pranoprofen and a salt thereof. An agent for improving unpleasant taste after administration, which comprises blending (C) one or more selected from the group consisting of chlorpheniramine and a salt thereof, and (D) an antiallergic agent. Is provided.
Regarding the types and contents of the components (A) to (D), the types and contents of other components, the formulation form and use of the ophthalmic composition, etc. in each of the above embodiments, [1. Ophthalmic Composition] as described.

[4. Suppression of precipitation and cloudiness]
The ophthalmic composition according to the present embodiment has the effect of suppressing precipitation and clouding in the ophthalmic composition.
Therefore, as one embodiment of the present invention, one or more selected from the group consisting of (A) pranoprofen and a salt thereof, and one or more selected from the group consisting of (B) glycyrrhizinic acid and a salt thereof. , (C) One or more selected from the group consisting of chlorpheniramine and salts thereof, and (D) suppression of precipitation and cloudiness in the ophthalmic composition, which comprises blending an antiallergic agent into the ophthalmic composition. A method of suppressing is provided.
Further, as an embodiment of the present invention, an ophthalmic composition containing at least one selected from the group consisting of (A) pranoprofen and a salt thereof is selected from the group consisting of (B) glycyrrhizinic acid and a salt thereof. Provided is an agent for suppressing precipitation / white turbidity, which comprises blending (C) one or more selected from the group consisting of chlorpheniramine and a salt thereof, and (D) an antiallergic agent. To.
Regarding the types and contents of the components (A) to (D), the types and contents of other components, the formulation form and use of the ophthalmic composition, etc. in each of the above embodiments, [1. Ophthalmic Composition] as described.

[5. Method for reducing and suppressing affinity for production lines and containers]
The ophthalmic composition according to the present embodiment has the effect of reducing or suppressing the affinity (parental liquidity) of the ophthalmic composition with respect to the production line or the container.
Therefore, as one embodiment of the present invention, one or more selected from the group consisting of (A) pranoprofen and a salt thereof, and one or more selected from the group consisting of (B) glycyrrhizinic acid and a salt thereof. , (C) One or more selected from the group consisting of chlorpheniramine and salts thereof, and (D) Affinity for production lines and containers in the ophthalmic composition, which comprises blending an antiallergic agent into the ophthalmic composition. A method for reducing or suppressing sex (parental fluid) is provided.
Further, as one embodiment of the present invention, an ophthalmic composition containing at least one selected from the group consisting of (B) glycyrrhizinic acid and a salt thereof is selected from the group consisting of (A) pranoprofen and a salt thereof. Affinity for production lines and containers, including (C) one or more selected from the group consisting of chlorpheniramine and salts thereof, and (D) an antiallergic agent. Liquid) reduction, inhibitors are provided.
Regarding the types and contents of the components (A) to (D), the types and contents of other components, the formulation form and use of the ophthalmic composition, etc. in each of the above embodiments, [1. Ophthalmic Composition] as described.

[6. Sustained suppression of allergic inflammatory reaction]
The ophthalmic composition according to the present embodiment has an effect that inflammation caused by allergies and the like can be effectively and continuously reduced and suppressed.
For example, the ophthalmic composition according to the present embodiment can reduce or suppress an immediate phase reaction and a delayed phase reaction in an allergic inflammatory reaction. That is, it is possible to suppress both "immediate inflammation" that occurs immediately after the antigen invades the conjunctiva and "persistent inflammation" that occurs following the immediate inflammation. Therefore, the inflammatory reaction can be rapidly suppressed and not prolonged, and can be effectively effective for subjective symptoms such as swelling and hyperemia of the eyelids.
Therefore, as one embodiment of the present invention, one or more selected from the group consisting of (A) pranoprofen and a salt thereof, and one or more selected from the group consisting of (B) glycyrrhizic acid and a salt thereof ( Further, if necessary, inflammation caused by allergies and the like, including the addition of (C) component, (D) component and other components) into the ophthalmic composition, is effectively and continuously reduced and suppressed. A way to make it is provided.
Further, as one embodiment of the present invention, the ophthalmic composition is selected from one or more selected from the group consisting of (A) pranoprofen and a salt thereof, and (B) selected from the group consisting of glycyrrhizic acid and a salt thereof1. Effective and long-lasting reducing and suppressing agents for inflammation caused by allergies, etc., including blending more than seeds (and other components such as (C) component and (D) component as needed) Provided.
Further, as one embodiment of the present invention, one or more selected from the group consisting of (A) planoprofen and a salt thereof, and one or more selected from the group consisting of (B) glycyrrhizinic acid and a salt thereof (B) Further, if necessary, a persistent ophthalmic composition (persistent) having an anti-allergic inflammatory effect (reduction or suppression of inflammatory symptoms due to allergies, etc.) containing (C) component, (D) component and other components). Eye drops) are provided.
Regarding the types and contents of the components (A) and (B), the types and contents of other components, the formulation form and use of the ophthalmic composition in each of the above embodiments, [1. Ophthalmic Composition] as described.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples, and many modifications are made in the art within the technical idea of the present invention. It is possible by someone with normal knowledge.

Test Example 1-1 (Defoaming test 1)
An aqueous ophthalmic composition (eye drops) having the composition shown in Table 1 below was prepared, and the rate at which bubbles disappeared was evaluated as follows.

That is, a polyethylene terephthalate (PET) container (capacity 50 mL, centrifuge tube, Corning No. 430304) or a glass container (centrifuge tube) (capacity 50 mL) is filled with 30 mL of each aqueous ophthalmic composition, and these are filled. It was shaken 1500 times using RECIPAD SHAKER SR-2w (TAITEC). Immediately after the shaking was completed, the foam portion and the aqueous solution portion were visually confirmed, and the volume of the foam portion was measured. Next, they were allowed to stand, the volume of the foam portion was measured over time, and the time required for the initial foam to be halved (n = 3) was evaluated.
Further, using the measured "time required for the foam to be halved (minutes)", the "defoaming property improvement rate (%)" with respect to 1C was calculated by the following formula.
Defoaming improvement rate (%) = (Time required for 1C foam to be halved (minutes) -Time required for 1C foam to be halved (minute)) / Required for 1C foam to be halved Hours (minutes) x 100

The results are shown in Table 1 below. In the aqueous ophthalmic composition shown in Table 1 below, the unit of each component is (w / v%).

As is clear from the results in Table 1 above, due to the combination of dipotassium glycyrrhizinate (Test Example 1E) and the like, even if planoprofen is contained (Test Example 1D), the defoaming time tends to be shortened. In particular, such an antifoaming effect is exhibited when dipotassium glycyrrhizinate, sodium chromoglycate and chlorpheniramine maleate (further, sodium chondroitin sulfate and dibutylhydroxytoluene) are combined and blended (Test Examples 1A and 1B). It was remarkable.

Surprisingly, the decrease in defoaming property due to pranoprofen differs depending on the type of container, and in PET containers, the defoaming time became longer due to the formulation of pranoprofen ("Test Examples 1C and 1D" in Test Examples 1C and 1D. Comparison of "PET container").

Therefore, it is considered that the problem of foaming associated with the formulation of planoprofen should be solved exceptionally in a plastic container such as PET. However, as shown in Table 1 above, dipotassium glycyrrhizinate also in such a plastic container. (Test Example 1E), and further, a combination of dipotassium glycyrrhizinate, sodium cromoglycate, and chlorpheniramine maleate (further, sodium chondroitin sulfate, dibutyl hydroxytoluene) is higher. It was found that a defoaming effect can be obtained.

Test Example 1-2 (defoaming test 2)
An aqueous ophthalmic composition (eye drops) having the composition shown in Table 2 below was prepared, and the rate at which bubbles disappeared was evaluated as follows.

Containers for filling the aqueous ophthalmic composition are polypropylene (PP) containers (capacity 50 mL, centrifuge tube, Corning No.430829), polystyrene (PS) containers (capacity 50 mL, centrifuge tube, IWAKI Cat.No.2344-050). The test was carried out in the same manner as in Test Example 1-1.

The results are also shown in Table 2 below. In the aqueous ophthalmic composition shown in Table 2 below, the unit of each component is (w / v%).

As is clear from the results in Table 2 above, it was confirmed that even when polypropylene or polystyrene was used as the container, there was a tendency similar to that of polyethylene terephthalate.

Test Example 2 (taste test)
An ophthalmic composition (eye drops) having the composition shown in Table 3 below was prepared, and the effect on the taste after instillation was evaluated.

That is, using the eye drops having the composition shown in Table 3 below, the indexes of bitterness and miscellaneous taste and sweetness were measured using a taste recognition device (TS-5000Z, manufactured by Intelligent Sensor Technology Co., Ltd.).

The measurement method was based on the instruction manual of TS-5000Z.

The following values were calculated using the obtained values.
-Difference from Test Example 2A = Output value of each sample-Output value of Test Example 2A

The results are shown in Table 3 below. In the ophthalmic composition shown in Table 3 below, the unit of each component is (w / v%).

As is clear from Table 3 above, compared to eye drops containing dipotassium glycyrrhizinate (Test Example 2A), planoprofen, sodium cromoglycate, chlorpheniramine maleate (further, dibutylhydroxytoluene) were used. It was confirmed that the content of the eye drops markedly reduced the indexes related to the sweetness and bitter taste of the eye drops.

Further, by further blending sodium chondroitin sulfate, the index of sweetness was more significantly reduced (Test Example 2C). With these compositions, the unpleasant taste after instillation can be remarkably improved.

It is generally known that if there is a difference of 0.5 or more in the index (output value) using the taste recognition device, the difference can be recognized even by the human taste.

Therefore, from the above results far exceeding the difference of 0.5, it is clear that the difference is recognizable by human taste, but this was actually confirmed in the next eye drop test.

Test Example 3 (eye drop test)
An ophthalmic composition (eye drops) having the composition shown in Table 4 below was prepared and filled in an eye drop container (made of polyethylene terephthalate) having a capacity of about 13 mL. In the aqueous ophthalmic composition shown in Table 4 below, the unit of each component is (w / v%).

Then, an unpleasant sweetness evaluation test was conducted by three subjects who seemed to have a sensitive taste. Specifically, the eye drops of Test Example 3A were instilled into both eyes one drop at a time, and the unpleasant sweetness felt up to 6 hours later was evaluated.

Then, the eye drops of Test Example 3B were similarly instilled and evaluated in the same manner (day 1).
The next day, the same subject evaluated the degree of unpleasant sweetness of Example 1 and Comparative Example 1 by the same procedure except that the order of evaluation of Example 1 and Comparative Example 1 was reversed (day 2). ).

The results are shown in Table 5 below.

From the above results, it is clear that even when actually instilled, in addition to dipotassium glycyrrhizinate, sodium cromoglycate, planoprofen, and chlorpheniramine maleate (chlorpheniramine maleate) are compared with eye drops containing dipotassium glycyrrhizinate. Furthermore, it was confirmed that the unpleasant sweetness was less likely to be felt when the eye drops containing BHT) were used.

Test Example 4 (precipitation / cloudiness test)
An ophthalmic composition (eye drops) having the composition shown in Table 6 below was prepared, and precipitation and cloudiness were evaluated.
That is, each ophthalmic composition shown in the table below was filled with 5 mL each in a 13 mL capacity polyethylene terephthalate container, and irradiated with an optical tester (LT120A WCD, 11114 manufactured by NAGANO, white lamp).

Then, the sample after irradiation was visually evaluated for the degree of precipitation of needle-shaped crystals by the following index.

A: No crystals at all B: Crystals can be confirmed from a distance of 10 cm or more, but cannot be confirmed from a distance of 50 cm or more C: Crystals can be confirmed even from a distance of 50 cm or more, and the bottom of the sample bottle Precipitated on one side D: Crystals are precipitated from the bottom of the sample bottle by 5 mm or more.

Further, 200 μL of the test solution was added to the 96-well plate from the sample after irradiation, the absorbance (wavelength 660 nm) was measured, and the white turbidity improvement rate with respect to Test Example 4G was calculated according to the following formula.

White turbidity improvement rate (%) =
(Turbidity of Test Example 4G-Turbidity of each Test Example) / Turbidity of Test Example 4G x 100

The results are shown in Table 6 below. In the ophthalmic composition shown in Table 6 below, the unit of each component is (w / v%).

As is clear from the results in the above table, the precipitation and cloudiness of crystals can be suppressed by containing sodium cromoglycate, etc., as compared with the eye drops containing planoprofene (Test Example 4G), and in particular, glycyrrhitin. Despite the combination of dipotassium acid acid, sodium cromoglycate, and chlorpheniramine maleate (further, dibutylhydroxytoluene and sodium chondroitin sulfate), the precipitation and clouding of crystals could be significantly suppressed or prevented. (Test Examples 4A-4D).

Test Example 5 (contact angle test)
An ophthalmic composition (eye drops) having the composition shown in Table 7 below was prepared, and the contact angle (static contact angle) for various materials was measured using an automatic contact angle meter (Drop Master, DM-A501).

The amount of droplets was 2 μL, and the contact angle 5 seconds after the droplet was evaluated.

The contact angle with respect to polyethylene terephthalate (PET) was measured using a PET eye drop container (Rohto Pharmaceutical Co., Ltd., Rohto G b container), and the contact angle with metal was measured with a stainless metal plate (Ferrule Cap TypeCLF-B). ) Was used for measurement.

Further, for Test Examples 5A and 5B, the contact angle improvement rate (%) with respect to Test Example 5C represented by the following formula was calculated.

Contact angle improvement rate (%) =
(Contact angle of each test example-contact angle of test example 5C) / contact angle of test example 5C × 100

The results are shown in Table 7 below. In the ophthalmic composition shown in Table 7 below, the unit of each component is (w / v%).

As is clear from the above table, pranoprofen, sodium cromoglycate, as compared to the case where the contact angle with respect to the plastic (PET) and the metal (stainless steel) contains dipotassium glycyrrhizinate (Test Example 5C). It was confirmed that when chlorpheniramine maleate, BHT, etc. were blended (particularly, when these were blended in combination), the temperature increased, that is, it became difficult to get wet.

From this result, when filled in a plastic container such as a PET container, the affinity between the liquid and the container is low, so that the uniformity of the eye drops can be easily maintained, and the components in the eye drops are less likely to be adsorbed on the container. It turns out that it will be.

In addition, since the filling tube of the production line is made of a metal such as stainless steel, it is possible to reduce the number of droplets adhering to the tip of the filling tube when filling the container of eye drops, and the filling amount is uniform. It can be seen that the conversion becomes easy.

Test Example 6 (Evaluation for the immediate phase of allergic inflammation)
BMMC (bone marrow culture mast cells) is cultured and 10% FBS, AA, Na pyruvate, NEAA, 2-ME, SCF, IL- in RPMI glutamax medium (GIBCO) so as to be 1 × 10 ⁶ cells / mL. It was prepared in the medium to which 3 was added. Then, after transferring to a 60 mm dish, anti-DNP IgE (manufactured by Sigma-Aldrich) was added to a final concentration of 0.1 μg / mL (antibody sensitization), and the mixture was incubated overnight at 37 ° C.
The cells were collected in a 15 mL tube, centrifuged at 1500 rpm for 5 minutes, and after collecting the supernatant, the cells were washed twice with 5 mL of PIPES buffer. Then, it was suspended in PIPES buffer so as to be 2 × 10 ⁶ cells / mL. 50 μL of this cell suspension was seeded on a round bottom 96-well plate (1 × 10 ⁵ cells / well).
100 μL of the drug prepared at twice the concentration shown in Table 8 was added, and the mixture was incubated at 37 ° C. for 10 minutes. Then, 50 μL of DNP-BSA (LSL) prepared at 40 ng / mL was added (antigen evoked, total volume 200 μL / well). The plates were incubated for 30 minutes under 37 ° C. and 5% CO ₂ conditions and then centrifuged at 2400 rpm for 3 minutes.
The supernatant of each well was taken in 50 μL, a flat-bottomed 96-well plate for assay, and β-hex activity in the sample was measured according to the following method.
In a flat-bottomed 96-well plate containing a sample, p-nitrophenyl N-acetyl-β-D-glucosaminide (Sigma-Aldrich) was dissolved in 0.04 M citrate solution (pH 4.5) to a concentration of 10 mM. Substrate buffer was added at 100 μL / well. After incubating for 1 hour at 37 ° C. under 5% CO ₂ conditions, 50 μL / well of stop buffer (3.028 g of glycine dissolved in 80 mL of MillQ water and adjusted to pH 10.7 with NaOH) was added. did. The fluorescence wavelength was measured at 405/655 nm.
Using a sample (Lysis sample) in which cells were lysed separately with TritonX (Sigma-Aldrich) and a PIPES buffer (blank) containing no cells, the β-hex activity was measured in the same manner, according to the following formula. For the samples shown in Table 8, the β-hex release rate (%) was calculated.

β-hex release rate (%) =
(Asorbance in each sample-Absorptance of blank) / Absorbance of Lysis sample x 100

Then, according to the following formula, the β-hex release suppression rate (%) of each test example with respect to the control example was calculated.

β-hex release suppression rate (%) =
(Β-hex release amount of control example-β-hex release amount in each test example) / β-hex release amount of control example × 100

The results are shown in Table 8. In Table 8, DMSO means dimethyl sulfoxide.

β-hex is an index that reflects the effect of allergic inflammation on the immediate phase. From the results in Table 8, it was confirmed that pranoprofen has an inhibitory effect on the immediate phase of allergic inflammation. In addition, from the results of Test Example 6G, it was found that the effect of such planopraphen was not impaired even in the presence of dipotassium glycyrrhizinate.

Test Example 7 (Evaluation for the late phase of allergic inflammation)
Human conjunctival fibroblasts Hconf were seeded on 96-well plates in 200 μL increments using a culture medium (MEM (GIBCO) supplemented with 10% FBS, × 100 Antibiotics-Antibiotic) (1.0 × 10 ⁴ cells). / Well). The cells were cultured under 37 ° C. and 5% CO ₂ conditions until they became confident. The culture supernatant was removed, and 200 μL of assay medium (MEM (GIBCO) supplemented with × 100 Antibiotic-Antibiotic) was added to each well and cultured for 24 hours. Then, the culture supernatant was removed, 200 μL of the agent shown in Table 9 was added, and the mixture was incubated for 1 hour. After 1 hour, 11 μL each of TNFα and IL-4 were added and treated so that the final concentration of each was 10 ng / mL. The control was prepared by adding an assay medium instead of TNFα and IL-4. The plates were cultured for 24 hours at 37 ° C. under 5% CO ₂ conditions. The entire supernatant was collected and the Eotaxin-1 concentration in each sample shown in Table 9 was calculated using the Eotaxin-1 ELISA according to the attached protocol.

Then, according to the following formula, the Eotaxin release suppression rate (%) of each test example with respect to the control example (control) was calculated.

Eotaxin release suppression rate (%) =
(Eotaxin concentration of control example-Eotaxin concentration in each test example) / Eotaxin concentration of control example × 100

The results are shown in Table 9.

Eotaxin-1 is an index that reflects the effect of allergic inflammation on the late phase. From the results in Table 9, it was confirmed that dipotassium glycyrrhizinate has an inhibitory effect on the delayed phase of allergic inflammation.
In addition, from the results of Test Example 7E, it was found that the effect of dipotassium glycyrrhizinate was not impaired even in the presence of planopraphen.

From the results of Test Example 7E and the results of Test Example 6G, the composition containing planopraphen and dipotassium glycyrrhizinate of the present invention maintains an excellent anti-inflammatory effect from the immediate phase to the late phase of allergic inflammation. It can be seen that it can be used as a persistent composition (persistent ophthalmic composition, persistent eye drops) having an anti-allergic inflammatory effect (anti-allergic inflammatory effect).

Test Example 1-3 (defoaming test 3)
An aqueous ophthalmic composition (eye drops) having the composition shown in Table 10 below was prepared, and the rate at which bubbles disappeared was evaluated in the same manner as in Test Example 1-1.

The container filled with the aqueous ophthalmic composition was a polyethylene terephthalate (PET) container (capacity 50 mL, centrifuge tube, Corning No. 430304), and the defoaming property improvement rate was calculated using the following formula.
Defoaming improvement rate (%) = (Time required for 1J foam to be halved (minutes) -Time required for each test example to be halved (minutes)) / Required for 1J foam to be halved Hours (minutes) x 100

The results are also shown in Table 11 below. In the aqueous ophthalmic composition shown in Table 10 below, the unit of each component is (w / v%).

As is clear from the results in Table 10 above, it was confirmed that when tranilast is used as an antiallergic agent, there is a tendency similar to that when sodium cromoglycate is contained.
This tendency was also confirmed when chondroitin sodium sulfate was added. For example, in Test Example 1I, an aqueous ophthalmic composition having the same composition as that of Test Example 1I was prepared except that sodium chondroitin sulfate was blended at a concentration of 0.5 w / v%, and the defoaming property improvement rate was calculated. It was confirmed that the defoaming property improvement rate was also excellent (44.2%).

[Example of pharmaceutical product]
Formulation Examples 1 to 11 are filled in a polyethylene terephthalate container, and Formulation Examples 1 to 11 are filled. Formulation Examples 1 to 11 are filled in a polypropylene container, Preparation Examples 12 to 22, and Formulation Examples 1 to 11. The product filled in a polystyrene container was designated as Preparation Examples 23 to 33. In the formulation example shown in Table 11 below, the unit of each component is (w / v%).

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

Claims (1)

(A) One or more selected from the group consisting of pranoprofen and its salts,
(B) One or more selected from the group consisting of glycyrrhizic acid and salts thereof,
(C) One or more selected from the group consisting of chlorpheniramine and its salts, and (D) antiallergic agents,
An ophthalmic composition containing.