JP2018087180A - 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

Description

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

  In an ophthalmic composition such as an eye drop, confirmation of dissolution at the time of manufacture is important for safe application to the eye.

  In addition, among ophthalmic compositions, in the case of pharmaceuticals such as eye drops and eye wash, foreign matter inspection in the production process is essential. However, during the manufacturing process, when bubbles are generated in the ophthalmic composition and the speed at which the bubbles disappear is slow, it is difficult to distinguish between the blended components or the foreign material and the foam. 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 antifoaming technology that can cope with the variety of formulations is desired.

WO2012 / 090985

  The objective of this invention is providing the ophthalmic composition excellent in the antifoaming effect.

  According to the study by the present inventors, at least one 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. (C) One or more selected from the group consisting of chlorpheniramine and salts thereof, and (D) an ophthalmic composition with excellent antifoaming properties can be obtained by containing a combination of antiallergic agents. I found it.

  In addition, according to the study by the present inventors, an ophthalmic composition such as an eye drop recognizes unpleasant bitter taste and sweetness, causes precipitation (crystallization) and turbidity of components over time, and a production line. There are various new problems such as adhesion and precipitation (for example, adhesion of liquid droplets and precipitation at the tip of a filling tube), but such problems can be overcome by selecting specific components. The present invention has been completed by finding that it can be solved and by further studying it.

That is, the composition (ophthalmic composition) of the present invention provides the following invention, for example.
[1]
(A) one or more selected from the group consisting of pranoprofen and a salt thereof,
(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 salts thereof, and (D) an antiallergic agent,
An ophthalmic composition containing
[2]
(D) The ophthalmic composition according to [1], wherein the antiallergic agent comprises one or more selected from the group consisting of cromoglycic acid, tranilast, and salts thereof.
[3]
(A) The ophthalmic composition according to [1] or [2], comprising 0.0001 to 1 w / v% of one or more selected from the group consisting of pranoprofen and a salt thereof.
[4]
(B) The ophthalmic composition according to any one of [1] to [3], containing 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], containing 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 comprising (E) a fat-soluble antioxidant.
[8]
Furthermore, the ophthalmic composition in any one of [1]-[7] containing 1 or more types selected from the group which consists of (F) chondroitin sulfate and its salt.
[9]
The ophthalmic composition according to any one of [1] to [8], further comprising (G) a cooling 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 used 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 ophthalmic solution having 4 eye drops per day.
[13]
The ophthalmic composition according to any one of [1] to [12], which is not an eye drop for instilling while wearing a contact lens.

  In the present invention, an ophthalmic composition having excellent antifoaming properties (high defoaming speed) can be provided. The present inventor newly found a problem that the generated foam is likely to be stabilized particularly in the composition containing pranoprofen and / or a salt thereof, and a composition containing such pranoprofen and / or a salt thereof. Even if it is a thing, according to the specific composition of this invention, the high defoaming effect can be acquired.

  Moreover, such an antifoaming property surprisingly varies greatly depending on the material of the container filled with the ophthalmic composition, and in particular, in a specific plastic container, the antifoaming time is increased. Therefore, even in such a plastic container, the speed at which the bubbles disappear can be remarkably improved.

  Thus, 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”. 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) Planoprofen and / or a salt thereof (component (A))

  The salt of pranoprofen may be a pharmaceutically or physiologically acceptable salt, such as 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 and metal salts (aluminum salts, etc.), organic amine salts (methylamine salts, triethylamine salts, diethylamine salts, triethanolamine salts, morpholine salts, piperazine salts, pyrrolidine salts, tripyridine salts And salts with organic bases such as picoline salts).

  In addition, pranoprofen and its salt may be in the form of a hydrate.

  A preferred pranoprofen and / or salt thereof is pranoprofen.

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

  The content of the component (A) in the composition is, for example, 0.0001 w / v% or more, preferably 0.001-1 w / v%, more preferably 0.005-0 with respect to the total amount of the composition. 0.5 w / v%, more preferably 0.007 to 0.2 w / v%, even more preferably 0.01 to 0.1 w / v%, particularly preferably 0.03 to 0.1 w / v%, most preferably Preferably, it may be about 0.045 to 0.06 w / v%. Among these, 0.05 w / v% is particularly preferable.

(B) Glycyrrhizic acid and / or its salt (component (B))

  As a salt of glycyrrhizic acid, any salt that is pharmaceutically or physiologically acceptable may be used. 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, And salts with organic bases such as picoline salts).

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

  A preferred glycyrrhizic acid and / or 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 with respect to 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%. Among these, 0.25 w / v% is particularly preferable.

  When the component (A) and the component (B) are contained, the proportion 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). 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 (component (C)) and / or (D) an antiallergic agent (component (D)). In particular, the composition of the present invention may contain all the components (A) to (D).

(C) Chlorpheniramine and / or its salt (component (C))

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

  Note that chlorpheniramine and a salt thereof may be in the form of a hydrate, and may be any of d-form, l-form, and 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.

  Content of (C) component in a composition is 0.0001 w / v% or more, 0.001-1 w / v% with respect to the whole quantity of a composition, Preferably 0.005-0.5 w / v%, more preferably 0.01 to 0.3 w / v%, still more preferably 0.05 to 0.1 w / v%, still more preferably 0.01 to 0.05 w / v%, particularly preferably 0. 0.02 to 0.04 w / v%, most preferably about 0.025 to 0.035 w / v%, 0.015 w / v% or more (for example, 0.018 w / v% or more, preferably 0.02 w / v% or more). Among these, 0.03 w / v% is particularly preferable.

  Moreover, when using together with (A) component, the ratio of (C) component is 0.01-100 weight part with respect to 1 weight part of (A) component, Preferably it is 0.03-50 weight part, More preferably 0.05 to 30 parts by weight, still more preferably 0.1 to 10 parts by weight, still more preferably 0.2 to 5 parts by weight, particularly preferably 0.3 to 3 parts by weight, and particularly preferably 0. .35 to 1 part by weight, particularly preferably 0.4 to 0.8 part by weight, and most preferably about 0.5 to 0.7 part by weight. Among them, the proportion of the component (C) is particularly preferably 0.6 parts by weight with respect to 1 part by weight of the component (A).

  Furthermore, when using together with (B) component, the ratio of (C) component is 0.001-30 weight part with respect to 1 weight part of (B) component, Preferably 0.003-10 weight part, 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 parts by weight, more particularly preferably 0.05 to 0.2 parts by weight, most preferably Preferably, it may be about 0.1 to 0.15 parts by weight. Especially, it is especially preferable that the ratio of (C) component is 0.12 weight part with respect to 1 weight part of (B) component.

(D) Antiallergic agent (component (D))
Examples of the antiallergic agent include cromoglycic acid, tranilast, ibudilast, acitazanolast, tazanolast, suplatast, pemirolast, levocabastine, olopatadine, ketotifen, amlexanox, oxatomide and salts thereof.

  Examples of the salt of the antiallergic agent include salts exemplified in the above-mentioned items (A) to (C), and examples thereof include alkali metal or alkaline earth metal salts (sodium cromoglycate, cromoglycic acid). Potassium, magnesium cromoglycate, calcium cromoglycate, etc.), inorganic acid salts (eg, olopatadine hydrochloride), organic acid salts [eg, tosylate, fumarate (eg, ketotifen fumarate), etc.] and the like.

  Of these, cromoglycic acid, tranilast and salts thereof are preferred, cromoglycic acid and salts thereof and tranilast are more preferred, and sodium cromoglycate is still more preferred.

  Antiallergic agents 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 the total amount of the composition. 5 w / v% (for example, 0.4 to 4 w / v%), even more preferably 0.5 to 3 w / v%, particularly preferably 0.7 to 2 w / v%, still more preferably 0.8 to It may be about 1.5 w / v%, most preferably about 0.9 to 1.2 w / v%. Among these, 1.0 w / v% is particularly preferable.
When (D) component contains at least 1 sort (s) selected from tranilast and its salt, content of (D) component in a composition is 0.1-1 w / v with respect to the whole quantity of a composition, for example. % Is preferred, 0.3 to 0.75 w / v% is more preferred, 0.4 to 0.6 w / v% is even more preferred, and 0.5 w / v% is particularly preferred.

  When used together with the component (A), the proportion 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, even 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. More preferably, it may be 5 to 30 parts by weight, and most preferably about 10 to 25 parts by weight. Especially, it is especially preferable that the ratio of (D) component is 20 weight part with respect to 1 weight part of (A) component.

  When used in combination with component (B), the proportion of 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 of component (B). Is 0.1-20 parts by weight, more preferably 0.3-15 parts by weight, still more preferably 0.5-10 parts by weight, particularly preferably 1-8 parts by weight, most preferably about 3-5 parts by weight. It may be. Especially, it is especially preferable that the ratio of (D) component is 4 weight part with respect to 1 weight part of (B) component.

  When used together with the component (C), the proportion 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). 0.5 to 300 parts by weight, more preferably 1 to 200 parts by weight, still 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, particularly further Preferably, it may be 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. Especially, it is especially preferable that the ratio of (D) component is 33.3 weight part with respect to 1 weight part of (C) component.

[Other ingredients]
The composition of the present invention preferably further contains (E) a fat-soluble antioxidant in addition to the components (A) to (D) from the viewpoint of more prominently achieving the effects of the present invention.

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

  Of these, dibutylhydroxytoluene is preferred.

  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 based on the total amount of the composition. 0.0007-0.009 w / v%, more preferably 0.001-0.008 w / v%, even more preferably 0.003-0.007 w / v%, most preferably 0.0045-0.006 w It may be about / v%.

  When used together with the component (A), the proportion 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 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 parts by weight, and most preferably 0.0. It may be about 07 to 0.2 parts by weight.

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

  It is preferable that the composition of the present invention further contains (F) chondroitin sulfate and / or a salt thereof in addition to the components (A) to (D) from the viewpoint of more prominently achieving the effects of the present invention.

(F) Chondroitin sulfate and / or salt thereof (component (F))
Chondroitin sulfate is a compound in which sulfuric acid is ester-bonded to all or part of the hydroxyl groups of sugar chains in which D-glucuronic acid and N-acetylglucosamine repeat. The binding position and number of sulfuric acid are various, and there are derivatives of chondroitin sulfate (for example, those in which all or part of N-acetylglucosamine is substituted with iduronic acid).

  The chondroitin sulfate used in the present invention may have any structure. Examples thereof include chondroitin sulfate sulfate (chondroitin sulfate A), chondroitin hexasulfate (chondroitin sulfate C), chondroitin sulfate E in which the 4th and 6th positions of N-acetylglucosamine are sulfated. In addition, chondroitin sulfate may be extracted from animals.

  The salt of chondroitin sulfate may be any salt that is pharmaceutically or physiologically acceptable. 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, morpholine salt, piperazine salt, pyrrolidine salt, tripyridine salt, picoline salt And a salt with an organic base such as a salt).

  A preferable chondroitin sulfate and / or salt thereof is an alkali metal salt of chondroitin sulfate, more preferably sodium chondroitin sulfate, and sodium chondroitin sulfate described in Japanese Pharmacopoeia Standard 2002 is more preferable.

  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 with respect to 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%. Of these, 0.5 w / v% is most preferable.

  When used together with the component (A), the proportion 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 of the component (A). Is 0.5 to 50 parts by weight, more preferably 1 to 40 parts by weight, even 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. Especially, it is especially preferable that the ratio of (F) component is 10 weight part with respect to 1 weight part of (A) component.

  When used in combination with the component (B), the proportion 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, even 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. Especially, it is especially preferable that the ratio of (F) component is 2 weight part with respect to 1 weight part of (B) component.

  The composition of the present invention preferably further contains (G) a cooling agent from the viewpoint of more prominently achieving the effects of the present invention.

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

Among these, terpenoids are preferable, and among these, menthol, camphor, geraniol, cineol, borneol, and agate are preferable, menthol, camphor, and borneol are more preferable, and menthol is more preferable.
In addition, eucalyptus oil is also preferable from the viewpoint of more prominently achieving the effects of the present invention.

  The cooling agents 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, 0.003 w / v% or more, 0.004 w / v% or more, 0.005 w / v% or more, 0.006 w / v% or more, 0.007 w / v% or more, 0.008 w / v% or more, 0. 009 w / v% or more, 0.01 w / v% or more may be sufficient.

  Moreover, the ratio of (G) component is 1 w / v% or less, 0.1 w / v% or less, 0.09 w / v% or less, and 0.0. 08 w / v% or less, 0.07 w / v% or less, 0.06 w / v% or less, 0.05 w / v% or less, 0.04 w / v% or less, 0.03 w / v% or less, 0.02 w / It may be v% or less.

  When used together with the component (A), the proportion of the component (G) is, for example, preferably 0.005 to 10 parts by weight, more preferably 0.01 to 5 parts by weight with respect to 1 part by weight of the component (G). More preferably, it may be about 0.05 to 1 part by weight, and more preferably about 0.1 to 0.5 part by weight.

  When used together with the component (B), the proportion of the component (G) is, for example, preferably 0.0005 to 5 parts by weight, more preferably 0.001 to 1 part by weight with respect to 1 part by weight of the component (G). More preferably, it may be about 0.005 to 0.5 parts by weight, and still more preferably about 0.01 to 0.1 parts by weight.

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

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

  Specific examples of the additive are exemplified below.

(H) Nonionic surfactant (component (H))
The composition of the present invention preferably contains (H) a nonionic surfactant from the viewpoint of more prominently achieving the effects of the present invention.

  Nonionic surfactants include monolauric acid POE (20) sorbitan (polysorbate 20), monopalmitic acid POE (20) sorbitan (polysorbate 40), monostearic acid POE (20) sorbitan (polysorbate 60), and tristearic acid POE. (20) Polysorbates (POE sorbitan fatty acid esters) such as sorbitan (polysorbate 65) and monooleic acid POE (20) sorbitan (polysorbate 80); Poloxamer 407, Poloxamer 235, Poloxamer 188, Poloxamer 403, Poloxamer 237, Poloxamer 124 POE hardened castor oil such as POE hardened castor oil 40, POE hardened castor oil 50, POE hardened castor oil 60, POE hardened castor oil 80, etc. POE castor oil 3, POE castor oil 4, POE castor oil 6, POE castor oil 7, POE castor oil 10, POE castor oil 13.5, POE castor oil 17, POE castor oil 20, POE castor oil 25, POE castor oil 30, POE castor oil such as POE castor oil 35, POE castor oil 50; polyethylene glycol monostearate (2E.O.), polyethylene glycol monostearate (4E.O.), polyethylene glycol monostearate (9E.O. .), Polyethylene glycol monostearate (10E.O.), polyethylene glycol monostearate (23E.O.), polyethylene glycol monostearate (25E.O.), polyethylene glycol monostearate (32E.O.) , Monostearic acid polyethylene Glycol (40E.O., polyoxyl 40 stearate), polyethylene glycol monostearate (45E.O.), polyethylene glycol monostearate (55E.O.), polyethylene glycol monostearate (75E.O.), Polyethylene glycol monostearate such as polyethylene glycol monostearate (140EO); POE alkyl ethers such as POE (9) lauryl ether; POE-POP alkyl ethers such as POE (20) POP (4) cetyl ether POE alkyl phenyl ethers such as POE (10) nonyl phenyl ether. In the compounds exemplified above, POE is polyoxyethylene, POP is polyoxypropylene, and the numbers in parentheses indicate the number of moles added.

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

When the component (H) is added to the composition of the present invention, the proportion 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, particularly preferably 0.05 w / v% or more.
The proportion 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, particularly 0.3 w / v, based on the total amount of the composition. Examples include v% or less.

Preservatives Preservatives, e.g., Poridoroniumu chloride, alkylpolyaminoethylglycine compound (such as alkyldiaminoethylglycine hydrochloride), sodium benzoate, ethanol, quaternary ammonium salts (e.g., benzalkonium chloride, benzethonium chloride ), Chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxybenzoate (eg, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate), sulfuric acid Examples thereof include oxyquinoline, phenethyl alcohol, benzyl alcohol, biguanide compounds (for example, polyhexanide hydrochloride), glowkill (manufactured by Rhodia), and the like.

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

  When the preservative is blended in the composition of the present invention, as an example of the blending amount, the total amount of the preservative is 0.000001 w / v% or more, particularly 0.00001 w / v% or more, based on the total amount of the composition. In particular, 0.00005 w / v% or more, especially 0.001 w / v% or more, especially 0.005 w / v% or more. The total amount of the preservative is 1 w / v% or less, especially 0.1 w / v% or less, especially 0.05 w / v% or less, especially 0.02 w / v% or less, 0.01 w / v% or less is mentioned.

Buffering agent The composition of the present invention preferably further comprises a buffering agent from the viewpoint of more prominently achieving the effects of the present invention.
Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, and acetate buffer.

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

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

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

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

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

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

  When blending a buffering agent in the composition of the present invention, the blending amount of the buffering agent varies depending on the type of buffering agent, the type and amount of other blending components, and cannot be uniformly defined. The total amount of the buffering agent is 0.001 w / v% or more, particularly 0.01 w / v% or more, especially 0.05 w / v% or more, especially 0.1 w / v% or more with respect to the total amount of the composition. It is done. Further, the total amount of the buffering agent with respect to the total amount of the composition is 10 w / v% or less, especially 5 w / v% or less, especially 3 w / v% or less, especially 2.5 w / v% or less, especially 2 w / v%. The following are mentioned.

  In particular, when a borate buffer is used, the ratio of the buffer in the composition is 0.1 to 10 w / v%, preferably 0.2 to 5 w / v%, more preferably based on the whole composition. May be about 0.5 to 4 w / v%, more preferably about 1 to 3 w / v%, and still more preferably about 1.5 to 2.5 w / v%.

pH regulators Examples of pH regulators include hydrochloric acid, sulfuric acid, polyphosphoric acid, organic acids (propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, tartaric acid, malic acid, succinic acid, etc.), sodium hydroxide, water Examples include potassium oxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, and diisopropanolamine.

Isotonic agents isotonic agents, such as 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 can contain a thickener or thickener as long as the effects of the present invention are not impaired.

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

Examples of the stabilizer stabilizing agents, for example, trometamol, sodium formaldehyde sulfoxylate (Rongalite), monoethanolamine, aluminum monostearate, and glyceryl monostearate and the like.

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

Examples of the sugar saccharide include monosaccharides and disaccharides, specifically glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, sorbitol, mannitol and the like.

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 bicarbonate, sodium carbonate (including dry sodium carbonate), potassium bicarbonate, potassium carbonate, magnesium sulfate, sodium hydrogen phosphate, Examples thereof include potassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium hydrogen sulfite, sodium sulfite, potassium acetate, sodium acetate, sodium thiosulfate and the like.
Among them, potassium chloride, sodium chloride, calcium chloride, sodium hydrogen carbonate, sodium carbonate (including dry sodium carbonate), magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate are preferable, potassium chloride, Sodium chloride, calcium chloride, sodium hydrogen phosphate, and sodium dihydrogen phosphate are more preferable, and potassium chloride and sodium chloride are still more preferable.

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

Although it does not specifically limit as a solubilizing agent, For example, polyvinylpyrrolidone (PVP, PVPK25, K30, K90 etc.), hydroxyalkylamines (or aminoalkanols or alkanolamines, for example, monoethanolamine, diethanolamine , Triethanolamine, trometamol, etc.), alcohols (for example, polyols such as propylene glycol), caffeine and the like.
You may use a solubilizing agent individually or in combination of 2 or more types.

  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%, still more preferably about 0.05 to 3 w / v%, It may be about v%.

In addition, when (D) component contains at least 1 sort (s) selected from tranilast and its salt, especially a solubilizing agent (monoethanolamine etc.) may be used suitably.
When the composition of the present invention contains at least one selected from tranilast and a salt thereof, the proportion of the solubilizer is, for example, 0 with respect to 1 part by weight of at least one selected from tranilast and a salt thereof. 0.001 to 30 parts by weight, preferably 0.005 to 20 parts by weight, more preferably 0.01 to 15 parts by weight, particularly preferably 0.02 to 10 parts by weight, more particularly preferably 0.05 to 8 parts by weight. 0.1-15 weight part (for example, 0.2-10 weight part, 0.3-8 weight part, 0.5-5 weight part etc.) may be sufficient.

Base or Carrier The composition of the present invention may comprise a base or carrier.
A composition containing such a base or carrier can be prepared, for example, by mixing 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.

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

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

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

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

  Examples of such pharmacologically active ingredients and physiologically active ingredients include active ingredients in various pharmaceuticals described in the General Occupational Drug Manufacturing and Sales Approval Standards 2012 edition (supervised by the Japanese Society for Regulatory Science). For example, decongestants, eye muscle modifiers, anti-inflammatory agents other than (A) and (B) components, antihistamines other than (C) components, astringents, vitamins, amino acids, antibacterial agents or fungicides, topical Anesthetic components, soothing agents, sulfa drugs and the like can be mentioned. Specific examples of these drugs are illustrated below.

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

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

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

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

Anti-inflammatory agents other than (A) component and (B) component
Examples of anti-inflammatory agents or astringents other than the components (A) and (B) include, for example, zinc sulfate, zinc lactate, allantoin, epsilon-aminocaproic acid, indomethacin, lysozyme chloride, silver nitrate, sodium azulenesulfonate, diclofenac sodium, bromine Examples include fenac sodium, berberine chloride, and berberine sulfate.

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

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

  Among them, flavin adenine dinucleotide or a salt thereof (especially flavin adenine dinucleotide sodium), cobalamin or a salt thereof (particularly cyanocobalamin), retinol, a salt thereof or a derivative thereof (particularly retinol acetate, retinol palmitate), pyridoxine or a salt thereof Preferred are salts (especially pyridoxine hydrochloride), panthenol, pantothenic acid or salts thereof (especially sodium pantothenate, calcium pantothenate), tocopherols, salts or derivatives thereof (especially tocopherol acetate), and pyridoxine hydrochloride and tocopherol acetate. More preferred.

Amino acids As amino acids ( amino acids other than chondroitin sulfate and salts thereof), for example, aminoethylsulfonic acid (taurine), aspartic acid or a salt thereof (sodium aspartate, potassium aspartate, magnesium aspartate, magnesium aspartate, Potassium mixtures, etc.), glutamic acid or salts thereof (sodium glutamate, magnesium glutamate, etc.), creatinine, epsilon-aminocaproic acid, glycine, alanine, arginine, lysine, γ-aminobutyric acid, γ-aminovaleric acid and the like. 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 ( More preferred are potassium aspartate, magnesium aspartate, and an equivalent mixture of magnesium and potassium aspartate).

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

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

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

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

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

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

  The content of water in the case of an aqueous composition is preferably 50% by weight or more, more preferably 75% by weight or more, and still more preferably 90% by weight or more based on the total amount of the composition (or formulation). Moreover, 95 weight% or more or 98 weight% or more may be sufficient. In addition, the base or carrier may be composed 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, and even 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, still more preferably 5 or more, and even more preferably 6 or more. Moreover, 10 or less is preferable, 9 or less is more preferable, 8.5 or less is further more preferable, and 8 or less is still 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 ratio of the composition of the osmotic pressure present invention, for example, preferably 0.4 or more, more preferably 0.6 or more, even more preferably 0.8 or more. Moreover, 5 or less is preferable, 3 or less is more preferable, and 2 or less is still more preferable.

  The osmotic pressure ratio is a ratio of the osmotic pressure of the sample to the osmotic pressure of 286 mOsm (0.9 w / v% sodium chloride aqueous solution) based on the 16th revised Japanese Pharmacopoeia. The osmotic pressure is measured according to the osmotic pressure measurement method (freezing point depression method) described in the 16th revision Japanese Pharmacopoeia. The standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) was dried in sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650 ° C. for 40 to 50 minutes, and then in a desiccator (silica gel). The mixture is allowed to cool and 0.900 g is accurately weighed and dissolved in purified water to make exactly 100 mL, or a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution) is used.

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

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

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

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

  The composition of the present invention may be a single-use unit dose or a multi-dose that can be used repeatedly. However, since it has excellent storage efficacy, it is preferably contained and used in a multi-dose form.

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

  The material constituting the container can be selected from a wide range. For example, at least part or all of the contact portion with the composition is plastic [for example, olefin resin, styrene resin, acrylic resin, polyester resin, polycarbonate. Resin, fluororesin, chlorine resin (polyvinyl chloride, etc.), polyamide resin, polyacetal resin, polyphenylene ether resin (modified polyphenylene ether, etc.), polyarylate, polysulfone, polyimide resin, cellulose resin (cellulose acetate) Etc.), hydrocarbon resins which may be substituted with halogen atoms, etc.], metals (aluminum etc.) and the like.

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

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

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

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

  Examples of polyester resins include aromatic polyester resins [for example, resins having an alkylene terephthalate unit (alkylene terephthalate resins: for example, polyethylene terephthalate (PET), polytrimethylene terephthalate, polybutylene terephthalate (PBT), etc.), Resin having an alkylene naphthalate unit (for example, polyethylene naphthalate (PEN), polybutylene naphthalate, etc.)] and the like.

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

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

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

  Examples of polyarylate include amorphous polyarylate.

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

  Examples of cellulose acetate include cellulose diacetate and cellulose triacetate.

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

  The container may be a polymer blend with a polymer other than the polymer as a container material. When the container material of the container containing the ophthalmic composition of the present invention is a polymer blend with the polymer, the mixing ratio of the polymer and the polymer other than the polymer is not particularly limited as long as the effects of the present invention are exhibited. 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 with respect to the total amount of the constituent materials. 80 w / w% or more is particularly preferable.

  As for a container, at least one part of the surface which contacts the composition of this invention may be comprised with the said material. For example, a layer or film made of the above material may be formed on the inner surface of the container, or the container itself may be molded from the above material. From the viewpoint of remarkably exhibiting the effects of the present invention, the container itself is preferably molded from the above-mentioned material.

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

Target disease (use)
The target disease (use) of the composition of the present invention is not particularly limited as long as it is ophthalmic, and includes, for example, allergic symptoms, foreign body sensation (feeling of squeezing, etc.), corneal barrier function, tear eyes (flow) It is useful for the alleviation, improvement, suppression, or treatment of lacrimation.

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

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

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

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

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

  For example, when the composition of the present invention is a preparation to be applied to the eye such as an eye drop, an eye wash, an eye ointment, etc., the usage varies depending on the target symptom, but for example, once or more twice a day. As mentioned above, it can be 3 times or more, 4 times or more, 5 times or more, or 6 times or more. Also, it can be 9 times or less, 8 times or less, 7 times or less, 6 times or less, 5 times or less, or 4 times or less per day. It is particularly preferred to administer 4 times a day.

  When the composition of the present invention is an eye drop, for example, 1 to 3 drops may be applied per time, or 1 to 2 drops or 2 to 3 drops may be used. Preferably, 1 to 2 drops may be instilled. One drop can also be used.

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

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

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

[2. (Improved defoaming speed)
The ophthalmic composition which concerns on this embodiment has an effect that the defoaming speed in an ophthalmic composition can be improved.
Therefore, as one embodiment of the present invention, (A) one or more selected from the group consisting of pranoprofen and a salt thereof, and (B) one or more selected from the group consisting of glycyrrhizic acid and a salt thereof (C) one or more selected from the group consisting of chlorpheniramine and a salt thereof, and (D) adding an antiallergic agent to the ophthalmic composition to improve the defoaming rate in the ophthalmic composition A method is provided.
In one embodiment of the present invention, an ophthalmic composition containing one or more selected from the group consisting of (A) pranoprofen and a salt thereof is selected from the group consisting of (B) glycyrrhizic acid and a salt thereof. There is provided an antifoaming rate improver, comprising: (1) at least one selected from the group consisting of (C) chlorpheniramine and a salt thereof; and (D) an antiallergic agent. .
In addition, about the formulation form of an ophthalmic composition, a use, etc., such as the kind and content of other components, such as the kind and content of (A)-(D) component in said each embodiment, [1. As described in [Ophthalmic composition].

[3. (Improved unpleasant taste after administration)
The ophthalmic composition which concerns on this embodiment has an effect that the unpleasant taste can be improved after administration of an ophthalmic composition.
Therefore, as one embodiment of the present invention, (A) one or more selected from the group consisting of pranoprofen and a salt thereof, and (B) one or more selected from the group consisting of glycyrrhizic acid and a salt thereof (C) one or more selected from the group consisting of chlorpheniramine and a salt thereof, and (D) an unpleasant taste after administration in the ophthalmic composition, comprising blending an antiallergic agent into the ophthalmic composition A method is provided for improving the above.
Further, as one embodiment of the present invention, (B) an ophthalmic composition containing one or more selected from the group consisting of glycyrrhizic acid and a salt thereof is selected from the group consisting of (A) pranoprofen and a salt thereof. 1 or more selected from the group consisting of (C) chlorpheniramine and a salt thereof, and (D) an antiallergic agent after administration, Is provided.
In addition, about the formulation form of an ophthalmic composition, a use, etc., such as the kind and content of other components, such as the kind and content of (A)-(D) component in said each embodiment, [1. As described in [Ophthalmic composition].

[4. Suppression of precipitation and cloudiness)
The ophthalmic composition which concerns on this embodiment has an effect that precipitation and white turbidity in an ophthalmic composition can be suppressed.
Therefore, as one embodiment of the present invention, (A) one or more selected from the group consisting of pranoprofen and a salt thereof, and (B) one or more selected from the group consisting of glycyrrhizic acid and a salt thereof (C) one or more selected from the group consisting of chlorpheniramine and a salt thereof, and (D) suppression of precipitation and cloudiness in the ophthalmic composition, comprising blending an antiallergic agent into the ophthalmic composition. A method of suppressing is provided.
In one embodiment of the present invention, an ophthalmic composition containing one or more selected from the group consisting of (A) pranoprofen and a salt thereof is selected from the group consisting of (B) glycyrrhizic acid and a salt thereof. A precipitation / white turbidity inhibitor comprising: (1) at least one selected from the group consisting of (C) chlorpheniramine and a salt thereof; and (D) an antiallergic agent. The
In addition, about the formulation form of an ophthalmic composition, a use, etc., such as the kind and content of other components, such as the kind and content of (A)-(D) component in said each embodiment, [1. As described in [Ophthalmic composition].

[5. (Reduction and control method for affinity to production lines and containers)
The ophthalmic composition which concerns on this embodiment has an effect that the affinity (lyophilicity) with respect to a manufacturing line or a container in an ophthalmic composition can be reduced and suppressed.
Therefore, as one embodiment of the present invention, (A) one or more selected from the group consisting of pranoprofen and a salt thereof, and (B) one or more selected from the group consisting of glycyrrhizic acid and a salt thereof (C) one or more selected from the group consisting of chlorpheniramine and a salt thereof, and (D) an affinity for the production line or container in the ophthalmic composition, which comprises blending an antiallergic agent into the ophthalmic composition. Provided is a method for reducing or suppressing sex (lyophilicity).
Further, as one embodiment of the present invention, (B) an ophthalmic composition containing one or more selected from the group consisting of glycyrrhizic acid and a salt thereof is selected from the group consisting of (A) pranoprofen and a salt thereof. One or more selected from the group consisting of (C) chlorpheniramine and a salt thereof, and (D) an anti-allergic agent (A) (Liquid) reduction and inhibitor are provided.
In addition, about the formulation form of an ophthalmic composition, a use, etc., such as the kind and content of other components, such as the kind and content of (A)-(D) component in said each embodiment, [1. As described in [Ophthalmic composition].

[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 late phase reaction in an allergic inflammatory reaction. That is, both “immediate inflammation” that occurs immediately after the antigen enters the conjunctiva and “persistent inflammation” that occurs following immediate inflammation can be suppressed. Therefore, it is possible to effectively suppress subjective symptoms such as swelling of the eyelids and hyperemia without promptly suppressing and prolonging the inflammatory reaction.
Therefore, as one embodiment of the present invention, (A) one or more selected from the group consisting of pranoprofen and a salt thereof, and (B) one or more selected from the group consisting of glycyrrhizic acid and a salt thereof ( In addition, if necessary, it is possible to effectively and continuously reduce and suppress inflammation caused by allergies, including blending (C) component, (D) component, etc.) into ophthalmic compositions. A method is provided.
In one embodiment of the present invention, the ophthalmic composition is selected from the group consisting of (A) pranoprofen and a salt thereof and (B) glycyrrhizic acid and a salt thereof. An effective and sustained reducing agent and inhibitor for inflammation caused by allergies and the like, including blending more than one species (and, if necessary, other components such as component (C) and component (D)) Provided.
Furthermore, as one embodiment of the present invention, (A) one or more selected from the group consisting of pranoprofen and a salt thereof, and (B) one or more selected from the group consisting of glycyrrhizic acid and a salt thereof ( Further, if necessary, a sustained ophthalmic composition (anti-persistent) of anti-allergic inflammatory action (reducing or suppressing inflammatory symptoms due to allergies, etc.) including (C) component, (D) other component) Eye drops).
In addition, about the formulation form of an ophthalmic composition, a use, etc., such as the kind and content, etc. of other components, such as the kind and content of (A) and (B) component in said each embodiment, [1. As described in [Ophthalmic composition].

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

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 speed at which the foam disappeared was evaluated as follows.

That is, 30 mL of each aqueous ophthalmic composition was filled into a polyethylene terephthalate (PET) container (capacity 50 mL, centrifuge tube, Corning No. 430304) or glass container (centrifuge tube) (capacity 50 mL). The sample was shaken 1500 times using RECIPAD SHAKER SR-2w (TAITEC). Immediately after the end of shaking, the foam part and the aqueous solution part were visually confirmed, and the volume of the foam part was measured. Next, they were allowed to stand, the volume of the foam portion was measured over time, and the time required until the initial foam was halved (n = 3) was evaluated.
Moreover, using the measured “required time (minutes) until foam is halved”, “defoaming improvement rate (%)” for 1C was calculated by the following formula.
Defoaming improvement rate (%) = (Required time until 1C foam is halved (minutes) -Required time until each foam is halved (minutes)) / Required until 1C foam is halved Time (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 of Table 1 above, even when pranoprofen is contained (Test Example 1D) by blending dipotassium glycyrrhizinate (Test Example 1E), the defoaming time tends to be shortened, In particular, such an antifoaming effect is obtained when a combination of dipotassium glycyrrhizinate, sodium cromoglycate and chlorpheniramine maleate (further sodium chondroitin sulfate, dibutylhydroxytoluene) (Test Examples 1A and 1B), It was remarkable.

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

  Therefore, it is considered that the foaming problem associated with the blending of pranoprofen should be particularly solved in a plastic container such as PET. However, as shown in Table 1, dipotassium glycyrrhizinate also in such a plastic container. (Test Example 1E), and further, the combination (Test Examples 1A and 1B) in which dipotassium glycyrrhizinate, sodium cromoglycate, and chlorpheniramine maleate (further sodium chondroitin sulfate and dibutylhydroxytoluene) are combined. 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 speed at which the foam disappeared was evaluated as follows.

  Containers filled with aqueous ophthalmic compositions are polypropylene (PP) containers (capacity 50 mL, centrifuge tubes, Corning No. 430829), polystyrene (PS) containers (capacity 50 mL, centrifuge tubes, IWAKI Cat. No. 2434-050) A test was conducted in the same manner as in Test Example 1-1 except that.

  The results are 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 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, bitter taste and sweetness indexes were measured using a taste recognition device (TS-5000Z, manufactured by Intelligent Sensor Technology Co., Ltd.).

  In addition, the measuring method followed the instruction manual of TS-5000Z.

Using the obtained values, the following values were calculated.
-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 apparent from Table 3 above, pranoprofen, sodium cromoglycate, chlorpheniramine maleate (and dibutylhydroxytoluene) were compared with eye drops containing dipotassium glycyrrhizinate (Test Example 2A). By containing, it has confirmed that the parameter | index regarding the sweet taste and bitter taste of an eye drop fell remarkably.

  In addition, the sweetness index was significantly reduced by adding sodium chondroitin sulfate (Test Example 2C). By setting it as these compositions, the unpleasant taste after instillation can be improved notably.

  In addition, it is known that, in general, 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 human taste.

  Therefore, although it is clear from the above result that far exceeds the difference of 0.5, it is clear that the difference can be recognized by human taste, but this was actually confirmed in the following 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 carried out by three subjects who had a sensitive taste. Specifically, the eye drop of Test Example 3A was instilled into both eyes, and the unpleasant sweetness felt up to 6 hours later was evaluated.

Thereafter, the eye drop of Test Example 3B was instilled in the same manner and evaluated in the same manner (Day 1).
On the next day, the same subject evaluated the degree of unpleasant sweetness of Example 1 and Comparative Example 1 in the same procedure except that the order of evaluation of Example 1 and Comparative Example 1 was reversed (second day). ).

  The results are shown in Table 5 below.

  The above results clearly show that even when actually instilled, in addition to dipotassium glycyrrhizinate, in addition to dipotassium glycyrrhizinate, sodium cromoglycate, pranoprofen, chlorpheniramine maleate ( Furthermore, it was confirmed that unpleasant sweetness was less likely to be felt when the eye drops containing BHT) were used.

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

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

A: There is no crystal B: Crystal is confirmed when viewed from a distance of 10 cm, but cannot be confirmed from a location 50 cm or more away C: The crystal can be confirmed even from a location 50 cm or more away, and the bottom of the sample bottle D: Precipitated on one side. D: Crystal is deposited 5mm or more from the bottom of the sample bottle.

  Moreover, 200 microliters of test solutions were added to the 96 well plate from the sample after irradiation, the light absorbency (wavelength 660nm) was measured, and the white turbidity improvement rate with respect to Test Example 4G was computed according to the following formula.

White turbidity improvement rate (%) =
(Turbidity of Test Example 4G−Turbidity of each Test Example) / Turbidity of Test Example 4G × 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 apparent from the results in the above table, by including sodium cromoglycate as compared with the eye drop containing pranoprofen (Test Example 4G), precipitation of crystals and clouding can be suppressed, and in particular, glycyrrhizin Despite containing a combination of dipotassium acid, sodium cromoglycate, and chlorpheniramine maleate (and dibutylhydroxytoluene and sodium chondroitin sulfate), it was possible to remarkably suppress or prevent crystal precipitation and cloudiness. (Test Examples 4A to 4D).

Test Example 5 (Contact angle test)
Ophthalmic compositions (eye drops) having the compositions shown in Table 7 below were prepared, and contact angles (static contact angles) with respect to various materials were measured using an automatic contact angle meter (Drop Master, DM-A501).

  In addition, the droplet angle was 2 μL, and the contact angle 5 seconds after the dropping was evaluated.

  Moreover, the contact angle with respect to polyethylene terephthalate (PET) was measured using a PET eye drop container (manufactured by ROHTO PHARMACEUTICAL CO., LTD., Rotoji b container). ).

  Furthermore, 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, the contact angle with respect to plastic (PET) and metal (stainless steel) is further compared to the case containing dipotassium glycyrrhizinate (Test Example 5C), and pranoprofen, sodium cromoglycate, It was confirmed that when chlorpheniramine maleate, BHT, or the like was blended (particularly when these were blended in combination), the tendency to become high, that is, difficult to wet.

  From this result, when filled in a plastic container such as a PET container, since the affinity between the liquid and the container is low, it is easy to maintain the uniformity of the eye drop, and the components in the eye drop are difficult to adsorb to the container. I understand that

  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 eye drop container, and the filling amount is uniform. It turns out that it becomes easy.

Test Example 6 (Evaluation for immediate phase of allergic inflammation)
BMMC (bone marrow cultured mast cells) are cultured, and 10% FBS, AA, Na pyruvate, NEAA, 2-ME, SCF, IL− are added to RPMI glutamax medium (GIBCO) so as to be 1 × 10 ⁶ cells / mL. It was prepared in a medium supplemented with 3. Then, after moving to 60 mm dish, anti-DNP IgE (manufactured by Sigma-Aldrich) was added to a final concentration of 0.1 μg / mL (antibody sensitization) and incubated at 37 ° C. overnight.
After collecting in a 15 mL tube and centrifuging at 1500 rpm for 5 minutes and recovering the supernatant, the cells were washed twice with 5 mL of PIPES buffer. Then, it was made to suspend with a PIPES buffer so that it might become 2 * 10 < ⁶ > cells / mL. 50 μL of this cell suspension was seeded in a round bottom 96-well plate (1 × 10 ⁵ cells / well).
100 μL of a drug prepared to double the concentration described in Table 8 was added and incubated at 37 ° C. for 10 minutes. Thereafter, 50 μL of DNP-BSA (LSL) prepared to 40 ng / mL was added (antigen induction, total volume 200 μL / well). The plate was incubated at 37 ° C. under 5% CO _{2 for} 30 minutes, and then centrifuged at 2400 rpm for 3 minutes.
The supernatant of each well was put in 50 μL of a flat bottom 96-well plate for assay, and β-hex activity in the sample was measured according to the following method.
In a flat bottom 96-well plate containing the sample, p-nitrophenyl N-acetyl-β-D-glucosaminide (Sigma-Aldrich) was dissolved in 0.04 M citrate solution (pH 4.5) to 10 mM. Substrate buffer was added at 100 μL / well. After incubation for 1 hour at 37 ° C. under 5% CO ₂ , stop buffer (3.0028 g of glycine dissolved in 80 mL of MillQ water and adjusted to pH 10.7 with NaOH) was added at 50 μL / well. did. The fluorescence wavelength was measured at 405/655 nm.
Separately, using a sample in which cells were lysed with TritonX (Sigma-Aldrich) (Lysis sample) and a PIPES buffer not containing cells (blank), and using the value obtained by measuring β-hex activity in the same manner, The β-hex release rate (%) was calculated for the samples shown in Table 8.

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

  Thereafter, the β-hex release inhibition rate (%) of each test example relative to the control example was calculated according to the following formula.

β-hex release inhibition 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 on the immediate phase of allergic inflammation. From the results in Table 8, it was confirmed that pranoprofen has an inhibitory effect on the immediate phase of allergic inflammation. Moreover, from the result of Test Example 6G, it was found that the effect of such pranoprafen was not impaired even when dipotassium glycyrrhizinate coexists.

Test Example 7 (Evaluation for late phase of allergic inflammation)
Human conjunctival fibroblasts Hconf were seeded on a 96-well plate (200 × 10 ⁴ cells) using a culture medium (MEM (GIBCO) supplemented with 10% FBS, x100 Antibiotic-Antilytic). / Well). The cells were cultured at 37 ° C. under 5% CO ₂ until they became confluent. The culture supernatant was removed, and 200 μL of assay medium (MEM (GIBCO) added with x100 Antibiotic-Antilytic) was added to each well and cultured for 24 hours. Thereafter, the culture supernatant was removed, and 200 μL of the drug listed in Table 9 was added and incubated for 1 hour. After 1 hour, 11 μL each of TNFα and IL-4 was added, and each final concentration was processed to 10 ng / mL. A control supplemented with assay medium instead of TNFα and IL-4 was used as a control. Plates were incubated for 24 h at 37 ° C., 5% CO ₂ . The total amount of the supernatant was collected, and the Eotaxin-1 concentration in each sample shown in Table 9 was calculated using an Eotaxin-1 ELISA according to the attached protocol.

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

Eotaxin release inhibition rate (%) =
(Control Eotaxin concentration−Eotaxin concentration in each test example) / Control Eotaxin concentration × 100

  The results are shown in Table 9.

Eotaxin-1 is an index that reflects the effect on the late phase of allergic inflammation. From the results in Table 9, it was confirmed that dipotassium glycyrrhizinate exerts an inhibitory effect on the late phase of allergic inflammation.
Moreover, from the result of Test Example 7E, it was found that the effect of such dipotassium glycyrrhizinate was not impaired even when pranoprafen coexists.

  From the results of Test Example 7E and the results of Test Example 6G, the composition containing pranoprafen and dipotassium glycyrrhizinate of the present invention maintains an excellent anti-inflammatory effect over the immediate phase to the late phase of allergic inflammation. It can be seen that it can be used as a long-lasting composition (sustained ophthalmic composition, long-lasting eye drop) of anti-allergic inflammatory effect (anti-allergic inflammatory action).

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 the foam 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 improvement rate was calculated using the following formula.
Defoaming improvement rate (%) = (Required time until 1J foam is halved (minutes) −Required time until foam of each test example is halved (minutes)) / Required until 1J foam is halved Time (minutes) x 100

  The results are 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 even when tranilast was used as the antiallergic agent, there was a tendency similar to that when sodium cromoglycate was contained.
Such a tendency was confirmed even when sodium chondroitin sulfate was blended. For example, in Test Example 1I, an aqueous ophthalmic composition having the same composition as Test Example 1I was prepared except that sodium chondroitin sulfate was blended at a concentration of 0.5 w / v%, and the antifoaming improvement rate was calculated. Similarly, it was confirmed that the defoaming improvement rate was excellent (44.2%).

[Formulation example]
Formulation Examples 1-11 filled with polyethylene terephthalate containers, Formulation Examples 1-11, Formulation Examples 1-11 filled with polypropylene containers, Formulation Examples 12-22, Formulation Examples 1-11 Were filled in polystyrene containers as Preparation Examples 23 to 33. In addition, in the prescription example of the following Table 11, the unit of each component is (w / v%).

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

Claims (10)

(A) one or more selected from the group consisting of pranoprofen and a salt thereof,
(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 salts thereof, and (D) an antiallergic agent,
An ophthalmic composition containing   (D) The ophthalmic composition according to claim 1, wherein the antiallergic agent comprises one or more selected from the group consisting of cromoglycic acid, tranilast, and salts thereof.   (A) The ophthalmic composition of Claim 1 or 2 containing 0.0001-1 w / v% of 1 or more types selected from the group which consists of a planoprofen and its salt.   (B) The ophthalmic composition in any one of Claims 1-3 which contains 0.01-3 w / v% of 1 or more types selected from the group which consists of glycyrrhizic acid and its salt.   (C) The ophthalmic composition according to any one of claims 1 to 4, comprising 0.0001 to 1 w / v% of one or more selected from the group consisting of chlorpheniramine and a salt thereof.   (D) The ophthalmic composition in any one of Claims 1-5 which contains 0.1-10 w / v% of antiallergic agents.   The ophthalmic composition according to any one of claims 1 to 6, further comprising (E) a fat-soluble antioxidant.   Furthermore, the ophthalmic composition in any one of Claims 1-7 containing 1 or more types selected from the group which consists of (F) chondroitin sulfate and its salt.   Furthermore, the ophthalmic composition in any one of Claims 1-8 containing a refreshing agent (G).   The ophthalmic composition according to any one of claims 1 to 9, which is contained in a plastic container.