JP2015063509A - Eye drop - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an eye drop for IL-33 production inhibition.SOLUTION: An eye drop for IL-33 production inhibition comprises (A) tranilast or salt thereof.

Description

  The present invention relates to eye drops.

  Tranilast is clinically used as a therapeutic agent for allergic diseases. For example, eye drops containing tranilast are clinically used as a therapeutic agent for allergic conjunctivitis in the ophthalmic field (Non-patent Document 1).

  Interleukin-33 (IL-33) is a cytokine belonging to the IL-1 superfamily and is known to promote mast cell degranulation, which is an early reaction of allergy. IL-33 is also known to be produced by conjunctival cells upon stimulation with inflammatory cytokines such as TNF-α.

  Thus, once an allergic reaction has begun, IL-33 causes degranulation of mast cells, releasing inflammatory cytokines, thereby producing IL-33, and the produced IL-33 reduces degranulation of mast cells. A vicious circle of promotion occurs. That is, suppressing the production of mast cells by suppressing the production of IL-33 is important from the viewpoint of preventing the onset of allergic symptoms.

  However, the mechanism of action of tranilast is “to exhibit antiallergic action by inhibiting the release of chemical mediators (histamine, leukotriene, etc.) from mast cells and various inflammatory cells by antigen stimulation” (Non-patent Document 1). Although it is known that tranilast acts on mast cells, not only the influence of tranilast on conjunctival cells but also the influence on IL-33 production is not known at all.

Rizaben (registered trademark) ophthalmic solution 0.5% (Kissei Pharmaceutical) package insert

  An object of the present invention is to provide an eye drop for inhibiting IL-33 production.

  As a result of intensive studies to solve the above problems, the present inventors have found that (A) tranilast or a salt thereof (hereinafter also referred to as “(A) component”) suppresses IL-33 production of conjunctival cells. I found. In addition, the present inventors have reported that at least one selected from the group consisting of (B) an antihistamine, an anti-inflammatory agent, an amino acid and a refreshing agent (IL) It has also been found that it can be exerted and enhanced by combining with (B) component). Furthermore, it has been found that when an eye drop containing the component (A) and the component (B) is administered to an allergic patient before allergen contact, allergic symptoms are more alleviated than when administered to an allergic patient. Based on these findings, the present inventors have completed the present invention.

That is, the present invention provides the following [1] to [10].
[1] An eye drop for inhibiting IL-33 production, comprising (A) tranilast or a salt thereof.
[2] An eye drop for inhibiting IL-33 production, comprising (A) tranilast or a salt thereof and (B) at least one selected from the group consisting of an antihistamine, an anti-inflammatory agent, amino acids and a refreshing agent. .
[3] At least selected from the group consisting of (A) tranilast or a salt thereof, and (B) an antihistamine, an anti-inflammatory agent, an amino acid, and a cooling agent, which are applied from 1 to 2 weeks before contact with the allergen An ophthalmic solution for preventing allergic symptoms, comprising one kind.
[4] The eye drop according to [3], which is applied from 1 to 2 weeks before the start of pollen scattering.
[5] The allergic symptom is at least one selected from the group consisting of redness of eyes, itching of eyes, sloppy eyes, blurred vision of eyes, and a foreign body sensation of eyes, according to [3] or [4] Eye drops.
[6] The eye drop according to any one of [3] to [5], which is applied without wearing a silicone hydrogel contact lens.
[7] The eye drop according to any one of [3] to [6], which contains at least one antihistamine selected from the group consisting of chlorpheniramine maleate, iproheptin and diphenhydramine hydrochloride as the component (B).
[8] The component (B) is selected from the group consisting of ε-aminocaproic acid, allantoin, berberine sulfate, berberine chloride, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme chloride, pranoprofen and sodium azulenesulfonate. The eye drop according to any one of [3] to [7], comprising at least one anti-inflammatory agent.
[9] Any of [3] to [8], wherein the component (B) includes at least one amino acid selected from the group consisting of sodium chondroitin sulfate, potassium aspartate, aminoethylsulfonic acid, and epsilon aminocaproic acid An ophthalmic solution according to the above.
[10] The ophthalmic solution according to any one of [3] to [9], comprising as component (B) at least one refreshing agent selected from the group consisting of menthol, camphor, borneol, geraniol and mint oil. Agent.

  Since the eye drop of the present invention has an IL-33 production inhibitory action, it can be used for prevention of allergic symptoms. Specifically, the eye drops of the present invention are effective in preventing allergic symptoms such as redness of the eyes, itching of the eyes, soothing eyes, blurred vision of the eyes, and a feeling of foreign objects in the eyes.

  In addition, IL-33 is also known to be involved in hyperalgesia, and the eye drop of the present invention is useful for preventing a sense of foreign body sensation (a tingling sensation, a sensation of grooving) that is hyperalgesia caused by hay fever. It is particularly effective.

In the evaluation of animal allergic symptoms, relative values of various VAS scores when using the eye drop of Example 6 with respect to various VAS scores when using the eye drop of Comparative Example 3 are shown. In the evaluation of animal allergic symptoms, relative values of various VAS scores when using the eye drops of Example 7 with respect to various VAS scores when using the eye drops of Comparative Example 3 are shown. In the evaluation of pollen allergy symptoms, relative values of various VAS scores when using the eye drops of Example 8 with respect to various VAS scores when using the eye drops of Comparative Example 4 are shown. In the evaluation of pollen allergy symptoms, relative values of various VAS scores when using the eye drops of Example 9 with respect to various VAS scores when using the eye drops of Comparative Example 4 are shown.

  In the present specification, the unit of content “%” means “w / v%” and is synonymous with “g / 100 mL”.

  In this specification, the abbreviation “POE” means polyoxyethylene, and the abbreviation “POP” means polyoxypropylene.

  The eye drop according to this embodiment contains (A) tranilast or a salt thereof and (B) at least one selected from the group consisting of an antihistamine, an anti-inflammatory agent, amino acids, and a refreshing agent.

Component (A) Tranilast is a known compound also referred to as N- (3,4-dimethoxycinnamoyl) anthranilic acid, and may be synthesized by a known method or obtained as a commercial product.

  The salt of tranilast is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such salts include organic acid salts [for example, monocarboxylates (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylate (fumarate , Maleate, succinate, malonate, etc.), oxycarboxylate (lactate, tartrate, citrate, etc.), organic sulfonate (methanesulfonate, toluenesulfonate, tosylate) Etc.)], inorganic acid salts (eg, hydrochloride, sulfate, nitrate, hydrobromide, phosphate), salts with organic bases (eg, methylamine, triethylamine, triethanolamine, morpholine, piperazine, Salts with organic amines such as pyrrolidine, tripyridine, picoline), salts with inorganic bases [eg ammonium salts; alkali metals (sodium, potassium, etc.), alkaline earth metals] Calcium, magnesium, etc.), include various salts of salt], etc. with a metal such as aluminum.

  These tranilast salts may be used alone or in any combination of two or more. From the viewpoint of the effects of allergy prevention and IL-33 production suppression, the component (A) is preferably tranilast.

  The content of the component (A) in the eye drop according to the present embodiment is not particularly limited, and is appropriately set according to the type of the component (A), the type and content of the component (B) to be used together. As content of (A) component, it is preferable that the total content of (A) component is 0.0001-5 w / v% on the basis of the total amount of the eye drop which concerns on this embodiment, for example, 0 0.001 to 1 w / v% is more preferable, 0.01 to 0.5 w / v% is still more preferable, and 0.05 to 0.5 w / v% is particularly preferable. The content of the component (A) is suitable from the viewpoints of allergy prevention and IL-33 production suppression.

(B) component (B) component is at least 1 sort (s) selected from the group which consists of an antihistamine, an anti-inflammatory agent, amino acids, and a refreshing agent. You may use individually by 1 type and may use it in combination of 2 or more types arbitrarily.

  The antihistamine is not particularly limited as long as it is a substance having an antihistamine action. Examples of the antihistamine include chlorpheniramine, iproheptin, diphenhydramine, and salts thereof. Examples of such salts include hydrochloride and maleate, and specific examples include chlorpheniramine maleate and diphenhydramine hydrochloride. From the viewpoint of the effect of inhibiting IL-33 production, chlorpheniramine maleate and diphenhydramine hydrochloride are preferred, and chlorpheniramine maleate is particularly preferred.

  The content of the antihistamine in the eye drop according to the present embodiment is not particularly limited, and is appropriately set according to the type of antihistamine, the type and content of the component (A) to be used together. As content of an antihistamine, it is preferable that the total content of an antihistamine is 0.001-1 w / v% on the basis of the total amount of the eyedrops based on this embodiment, for example, 0.003-0.5 w / V% is more preferable, 0.005 to 0.2 w / v% is still more preferable, and 0.01 to 0.1 w / v% is particularly preferable. The content of the antihistamine is preferable from the viewpoints of preventing allergies and suppressing IL-33 production.

  Further, the content ratio of the antihistamine to the component (A) in the eye drop according to the present embodiment is not particularly limited, and is appropriately set according to the type of the component (A) and the antihistamine. As the content ratio of the antihistamine to the component (A), for example, the total content of the antihistamine is 0.0005 to 1 part by mass of the total content of the component (A) contained in the eye drop according to this embodiment. It is preferably 20 parts by mass, more preferably 0.001 to 10 parts by mass, still more preferably 0.003 to 5 parts by mass, and particularly preferably 0.01 to 2 parts by mass. . The content ratio of the antihistamine with respect to the component (A) is preferable from the viewpoint of the effects of allergy prevention and IL-33 production suppression.

  The anti-inflammatory agent is not particularly limited as long as it is a substance having an anti-inflammatory action. Examples of the anti-inflammatory agent include ε-aminocaproic acid, allantoin, berberine, glycyrrhizic acid, azulene sulfonic acid, zinc, tranexamic acid, lysozyme, and pranoprofen and salts thereof. Such salts include salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, sulfates, lactates, hydrochlorides, chloride salts, sodium salts, Examples include potassium salts. Specific examples include berberine sulfate, berberine chloride, dipotassium glycyrrhizinate, sodium azulenesulfonate, zinc sulfate, zinc lactate, lysozyme chloride and the like. From the viewpoint of the effect of inhibiting IL-33 production, ε-aminocaproic acid, allantoin, berberine sulfate, berberine chloride, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme chloride, pranoprofen and sodium azulenesulfonate are preferred. Particularly preferred is dipotassium glycyrrhizinate.

  The content of the anti-inflammatory agent in the eye drop according to this embodiment is not particularly limited, and is appropriately set according to the type of the anti-inflammatory agent, the type and content of the component (A) to be used together. As the content of the anti-inflammatory agent, for example, the total content of the anti-inflammatory agent is preferably 0.001 to 7.5 w / v% based on the total amount of the eye drop according to the present embodiment, and 0 It is more preferably 0.005 to 5 w / v%, still more preferably 0.01 to 1 w / v%, and particularly preferably 0.02 to 0.5 w / v%. The content of the anti-inflammatory agent is suitable from the viewpoint of preventing allergies and suppressing IL-33 production.

  Further, the content ratio of the anti-inflammatory agent to the component (A) in the eye drop according to the present embodiment is not particularly limited, and is appropriately set according to the type of the component (A) and the anti-inflammatory agent. As the content ratio of the anti-inflammatory agent to the component (A), for example, the total content of the anti-inflammatory agent is 1 part by mass of the total content of the component (A) contained in the eye drop according to the present embodiment. It is preferably 0.001 to 500 parts by mass, more preferably 0.01 to 200 parts by mass, still more preferably 0.02 to 100 parts by mass, and 0.04 to 80 parts by mass. It is particularly preferred. The content ratio of the anti-inflammatory agent with respect to the component (A) is preferable from the viewpoint of the effects of allergy prevention and IL-33 production suppression.

  An amino acid includes an amino acid or a salt thereof, and an amino acid analog, and means a compound having an amino group and a carboxyl group or a sulfone group in the molecule or a derivative thereof. Specific examples include amino acids or salts thereof, mucopolysaccharides or salts thereof. Among amino acids, examples of amino acids or salts thereof include monoamino monocarboxylic acids such as glycine, alanine, aminobutyric acid, aminovaleric acid, and aminocaproic acid; monoaminodicarboxylic acids such as aspartic acid and glutamic acid; Examples thereof include diaminomonocarboxylic acids such as arginine and lysine or salts thereof; derivatives such as aminoethylsulfonic acid (taurine) or salts thereof. Among amino acids, examples of the mucopolysaccharide or a derivative thereof or a salt thereof include, for example, a derivative such as chondroitin sulfate, hyaluronic acid, or alginic acid or a salt thereof as an acidic mucopolysaccharide. Specific examples include glycine, alanine, γ-aminobutyric acid, γ-aminovaleric acid, epsilon aminocaproic acid, aspartic acid, glutamic acid, arginine, aminoethylsulfonic acid, chondroitin sulfate, hyaluronic acid, alginic acid, and salts thereof. . Amino acid salts or mucopolysaccharide salts include pharmaceutically, pharmacologically or physiologically acceptable salts. Examples of such salts include salts with organic acids [for example, monocarboxylates (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylate (fumarate , Maleate, etc.), oxycarboxylate (lactate, tartrate, citrate, succinate, malonate, etc.), organic sulfonate (methanesulfonate, toluenesulfonate, tosylate) Etc.), salts with inorganic acids (eg, hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), salts with organic bases (eg, methylamine, triethylamine, triethanolamine, Salts with organic amines such as morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc.), salts with inorganic bases [eg ammonium salts; alkali metals (sodium, potassium, etc.), alkaline earths Metal (calcium, magnesium etc.), salts with metals such as aluminum, etc.] or the like can be illustrated, it is appropriately selected depending on the compound. For example, in the case of monoaminodicarboxylic acid, a salt with an inorganic base is preferable, and an alkali metal salt or an alkaline earth metal salt is particularly preferable. The amino acids of the present invention may be any of D-form, L-form and DL-form. From the viewpoint of the effect of inhibiting IL-33 production, aspartic acid, aminocaproic acid, aminoethylsulfonic acid, chondroitin sulfate, hyaluronic acid, alginic acid or a salt thereof are preferable, among which potassium aspartate, magnesium aspartate, epsilon aminocaproic acid, Aminoethylsulfonic acid, sodium chondroitin sulfate, sodium hyaluronate, alginic acid, and sodium alginate are preferred. More preferred is chondroitin sulfate or a salt thereof, and particularly chondroitin sulfate sodium is preferred.

  The content of amino acids in the eye drop according to this embodiment is not particularly limited, and is appropriately set according to the type of amino acids, the type and content of the component (A) to be used in combination. As the content of amino acids, for example, the total content of amino acids is preferably 0.001 to 10 w / v% based on the total amount of eye drops according to this embodiment, and 0.005 to 8 w. / V% is more preferable, 0.02 to 5 w / v% is further preferable, and 0.05 to 2 w / v% is particularly preferable. The content of the amino acids is suitable from the viewpoint of the effects of allergy prevention and IL-33 production suppression.

  Moreover, the content ratio of the amino acids with respect to the component (A) in the eye drop according to this embodiment is not particularly limited, and is appropriately set according to the type of the component (A) and the amino acids. As the content ratio of the amino acids to the component (A), for example, the total content of amino acids is 0. It is preferably 001 to 500 parts by mass, more preferably 0.005 to 200 parts by mass, still more preferably 0.01 to 100 parts by mass, and 0.05 to 70 parts by mass. Particularly preferred. The content ratio of amino acids to the component (A) is preferable from the viewpoints of allergy prevention and IL-33 production suppression.

  The refreshing agent is not particularly limited as long as it is a substance that imparts a refreshing feeling to the eye drop. Examples of the refreshing agent include terpenoids and essential oils containing terpenoids (for example, eucalyptus oil, bergamot oil, peppermint oil, fennel oil, rose oil, cinnamon oil, spearmint oil, camphor oil, cool mint and mint oil). It is done. Examples of terpenoids include menthol, menthone, camphor, borneol (Ruuno), geraniol, cineol, citronellol, carvone, anethole, eugenol, limonene, linalool and linalyl acetate. The terpenoid may be any of d-form, l-form and dl-form, and examples thereof include l-menthol, d-menthol, dl-menthol, dl-camphor, d-camphor, dl-borneol, and d-borneol. However, optical isomers may not exist depending on terpenoids such as geraniol and cineol. From the viewpoint of the effect of suppressing IL-33 production, menthol, camphor, borneol, geraniol and mint oil are preferred, and l-menthol is particularly preferred.

  Content of the refreshing agent in the eye drop which concerns on this embodiment is not specifically limited, It sets suitably according to the kind of cooling agent, the kind and content of (A) component to use together. The content of the refreshing agent can be measured as a terpenoid. For example, the total content of the refreshing agent (as a terpenoid) is 0.00005 to 0 on the basis of the total amount of eye drops according to the present embodiment. 0.5 w / v% is preferable, 0.0005 to 0.05 w / v% is more preferable, 0.001 to 0.05 w / v% is further preferable, and 0.004 to 0 is preferable. Particularly preferred is 0.02 w / v%. The content of the refreshing agent is suitable from the viewpoints of preventing allergies and suppressing IL-33 production.

  Moreover, the content rate of the refreshing agent with respect to (A) component in the eye drop which concerns on this embodiment is not specifically limited, It sets suitably according to the kind etc. of (A) component and a refreshing agent. (A) As a content rate of the refreshing agent with respect to a component, for example, with respect to 1 mass part of total content of the (A) component contained in the eye drop which concerns on this embodiment, the total content of a refreshing agent is, It is preferably 0.0001 to 100 parts by mass, more preferably 0.0005 to 50 parts by mass, still more preferably 0.001 to 10 parts by mass, and 0.005 to 5 parts by mass. It is particularly preferred. The content ratio of the refreshing agent with respect to the component (A) is preferable from the viewpoints of the effects of allergy prevention and IL-33 production suppression.

  The eye drop according to this embodiment preferably further contains a buffer. Thereby, pH of eyedrops can be adjusted and the effect of this application can be exhibited more notably. The buffer is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such buffers include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, Tris buffer, aspartic acid, aspartate and the like. These buffering agents may be used alone or in any combination of two or more. Examples of the boric acid buffer include boric acid or boric acid salts such as alkali metal borate and alkaline earth metal borate. Examples of the phosphate buffer include phosphoric acid or phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Examples of the carbonate buffer include carbonates or carbonates such as alkali metal carbonates and alkaline earth metal carbonates. Examples of the citrate buffer include citric acid, alkali metal citrate, and alkaline earth metal citrate. Moreover, you may use the borate or the hydrate of a phosphate as a borate buffer or a phosphate buffer. As a more specific example, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); as a phosphate buffer, phosphoric acid or a salt thereof Salt (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); Or a salt thereof (sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.); citric acid or a salt thereof (sodium citrate, potassium citrate, citric acid, etc.) Acid calcium, sodium dihydrogen citrate, disodium citrate, etc.); acetic acid Agents as, acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.); aspartic acid or a salt thereof (sodium aspartate, magnesium aspartate, potassium aspartate, etc.) and the like. Among these buffering agents, boric acid buffering agents (for example, a combination of boric acid and borax) and phosphoric acid buffering agents (for example, a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate) are preferable. An acid buffer is more preferred.

  When the eye drop according to the present embodiment contains a buffering agent, the content thereof is appropriately set according to the type of buffering agent, the type and content of other components, and the like. As content of a buffering agent, it is preferable that the total content of a buffering agent is 0.01-15 w / v% on the basis of the total amount of eyedrops, for example, and is 0.05-10 w / v%. Is more preferable, 0.1 to 7.5 w / v% is further more preferable, and 0.5 to 5 w / v% is particularly preferable.

  The eye drop according to this embodiment preferably further contains a thickening agent. Thereby, the viscosity of the eyedrops according to the present embodiment can be adjusted, and the effects of the present application can be exhibited more remarkably. Examples of thickeners include vinyl thickeners [polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone (K25, K30, K90, etc.), carboxyvinyl polymer, etc.], cellulose derivatives [methylcellulose, ethylcellulose, hydroxyethylcellulose, etc. , Hydroxypropylcellulose, hydroxypropylmethylcellulose (2208, 2906, 2910, etc.), carboxymethylcellulose, carboxyethylcellulose, nitrocellulose or their salts], polyethylene glycol (Macrogol 300, Macrogol 400, Macrogol 1500, Macrogol 4000) , Macrogol 6000, etc.), sodium chondroitin sulfate, sodium hyaluronate, gum arabic, tragacanth, dextran ( 0, 70, etc.), glucose, sorbitol, etc., preferably vinyl thickeners [polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone (K25, K30, K90), carboxyvinyl polymer, etc.], cellulose derivatives (Methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (2208, 2906, 2910), carboxymethylcellulose or a salt thereof), polyethylene glycol (Macrogol 300, Macrogol 400, Macrogol 4000, Macrogol 6000, etc.), Dextran (70), more preferably a vinyl thickener [among others, polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone (K25, K30, K 90), carboxyvinyl polymer], cellulose derivatives [among others, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose (2208, 2906, 2910), carboxymethylcellulose or a salt thereof], polyethylene glycol (Macrogol 300, Macrogol 400, Macrogol 4000) , Macrogol 6000) and Dextran (70). These thickening agents may be used alone or in any combination of two or more. In particular, vinyl thickeners are preferable, and among them, polyvinylpyrrolidone is preferable, and polyvinylpyrrolidone K30 is more preferable.

  When the eye drop which concerns on this embodiment contains a thickener, the content is suitably set according to the kind of thickener, the kind and content, etc. of another content component. As the content of the viscous agent, for example, the total content of the viscous agent is preferably 0.0001 to 5 w / v%, based on the total amount of eye drops, and is preferably 0.0005 to 3 w / v%. It is more preferable that it is 0.001-1 w / v%, and it is especially preferable that it is 0.01-0.2 w / v%.

  The eye drop according to this embodiment preferably further contains a nonionic surfactant. Thereby, the solubility of the component mix | blended with the eyedrops concerning this embodiment can be adjusted, and the effect of this application can be exhibited more notably.

  Here, the nonionic surfactant is appropriately selected from known nonionic surfactants that are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, depending on the components to be dissolved. Can do. The nonionic surfactant used by this invention may be used individually by 1 type, and may be used in combination of 2 or more type.

  Specific examples of the nonionic surfactant include monolauric acid POE (20) sorbitan (polysorbate 20), monopalmitic acid POE (20) sorbitan (polysorbate 40), monostearic acid POE (20) sorbitan (polysorbate 60). POE sorbitan fatty acid esters such as POE (20) sorbitan tristearate (polysorbate 65), POE (20) sorbitan monooleate (polysorbate 80); POE (40) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 40), POE hydrogenated castor oil such as POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60); POE (3) castor oil (polyoxyethylene castor oil 3), POE (10) castor oil (polyoxyethylene castor oil) 10), POE (3 POE castor oil such as castor oil (polyoxyethylene castor oil 35), POE (70) castor oil (polyoxyethylene castor oil 70); POE alkyl ether such as POE (9) lauryl ether; POE (20) POP ( 4) POE-POP alkyl ethers such as cetyl ether; polyoxyethylene / polyoxypropylene block copolymers such as POE (196) POP (67) glycol (poloxamer 407, Pluronic F127), POE (200) POP (70) glycol; Examples thereof include polyethylene glycol monostearate such as polyoxyl stearate 10 and polyoxyl 40 stearate. In the compounds exemplified above, the numbers in parentheses indicate the number of added moles. POE sorbitan fatty acid ester, POE castor oil, polyoxyethylene / polyoxypropylene block copolymer are preferable, POE sorbitan fatty acid ester is more preferable, and monooleic acid POE (20) sorbitan (polysorbate 80) is more preferable. It is.

  When the eye drop according to the present embodiment contains a nonionic surfactant, the content thereof is appropriately set according to the type of nonionic surfactant, the type and content of other components, and the like. As content of nonionic surfactant, for example, the total content of nonionic surfactant is 0.0001 to 5 w / v%, preferably 0.001 to 2 w / v, based on the total amount of eye drops. %, More preferably 0.005 to 0.5 w / v%.

  The eye drop according to this embodiment preferably further contains a chelating agent. Thereby, the solubility and stability of the component mix | blended with the eye drop which concern on this embodiment can be adjusted, and the effect of this application can be exhibited more notably.

  Here, the chelating agent can be appropriately selected from known surfactants that are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, depending on the components to be dissolved or stabilized. . As the chelating agent used in the present invention, one kind may be used alone, or two or more kinds may be used in combination.

  Specific examples of chelating agents include ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (edetic acid, EDTA), N- (2-hydroxyethyl) ethylenediaminetriacetic acid (HEDTA), and diethylenetriaminepentaacetic acid (DTPA). Etc.) or a salt thereof or a hydrate thereof. Sodium edetate or a hydrate thereof is preferable, sodium edetate hydrate is more preferable, and sodium edetate hydrate (16th revised Japanese Pharmacopoeia compatible product) is particularly preferable.

  When the eye drop according to the present embodiment contains a chelating agent, the content is appropriately set according to the type of chelating agent, the type and content of other components, and the like. As the content of the chelating agent, for example, based on the total amount of eye drops, the total content of the chelating agent is 0.0001 to 1 w / v%, preferably 0.0005 to 0.5 w / v%, more preferably Is 0.001 to 0.1 w / v%.

  The eye drop according to this embodiment preferably further contains ethanolamine. Thereby, the solubility and stability of the component mix | blended with the eye drop which concern on this embodiment can be adjusted, and the effect of this application can be exhibited more notably.

  Here, ethanolamine can be appropriately selected from known surfactants that are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, depending on the component to be dissolved or stabilized. . The ethanolamine used in the present invention may be used alone or in combination of two or more.

  Specific examples of ethanolamine include monoethanolamine (MEA), diethanolamine (DEA), and triethanolamine (TEA). More preferred is monoethanolamine.

When the eye drop according to the present embodiment contains ethanolamine, the content thereof is appropriately set according to the type of ethanolamine, the type and content of other components, and the like. As the content of ethanolamine, for example, the total content of ethanolamine is 0.001 to 2 w / v%, preferably 0.01 to 1 w / v%, more preferably 0, based on the total amount of eye drops. 0.05 to 0.5 w / v%.
In order to exhibit the effects of the present application more remarkably, it is more preferable to contain both ethanolamine and a thickener in the eye drop. A preferred combination of ethanolamine and a thickener is, for example, monoethanolamine and a vinyl thickener, more preferably monoethanolamine and polyvinylpyrrolidone, and even more preferably a combination of monoethanolamine and polyvinylpyrrolidone K30. . Furthermore, it is more preferable to combine ethanolamine, a thickener, and a nonionic surfactant.

  The eye drop according to this embodiment preferably further contains a polymer antibacterial agent. Thereby, the preservation | save effect of the eyedrop which concerns on this embodiment can be adjusted, and the effect of this application can be exhibited more notably.

  Here, the polymer antibacterial agent can be appropriately selected from known pharmaceutical antibacterial agents that are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. The polymer antibacterial agent used in the present invention may be used alone or in combination of two or more.

  Specific examples of the polymer antibacterial agent include biguanide compounds (specifically, polyhexamethylene biguanide, polyhexanide hydrochloride, etc.), polyquaternium, glowkill (trade name, manufactured by Rhodia), and the like.

  When the eye drop according to this embodiment contains a polymer antibacterial agent, the content thereof is appropriately set according to the type of polymer antibacterial agent, the type and content of other components, and the like. The content of the polymer antibacterial agent is, for example, based on the total amount of eye drops, and the total content of the polymer antibacterial agent is 0.000001 to 0.1 w / v%, preferably 0.000005 to 0.05 w. / V%, more preferably 0.00001 to 0.01 w / v%.

  Moreover, the eye drop according to the present embodiment can further contain an isotonic agent. The isotonic agent is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such isotonic agents include, for example, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride Potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol, polyethylene glycol, glucose, mannitol, sorbitol and the like. Among these isotonic agents, glycerin, propylene glycol, polyethylene glycol, glucose, sodium chloride, potassium chloride, calcium chloride, or magnesium chloride is preferable, sodium chloride, potassium chloride, or polyethylene glycol is more preferable, and sodium chloride is particularly preferable. preferable. These isotonic agents may be used alone or in any combination of two or more.

  When the eye drop according to the present embodiment contains an isotonic agent, the content is appropriately set according to the type of tonicity agent, the type and content of other components. As the content of the tonicity agent, for example, the total content of the tonicity agent is preferably 0.01 to 10 w / v%, based on the total amount of eye drops, and 0.05 to 5 w / v. It is more preferable that it is v%, and it is still more preferable that it is 0.1-3 w / v%.

  The pH of the eyedrops according to the present embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable range. As pH of eyedrops, it is preferable that it is 4.0-9.5, for example, it is more preferable that it is 5.0-9.0, and it is still more preferable that it is 5.5-8.5.

  In addition, the osmotic pressure of the eye drop according to the present embodiment is not particularly limited as long as it is within the range allowed by the living body. The osmotic pressure ratio of the eye drop is, for example, preferably 0.5 to 5.0, more preferably 0.6 to 3.0, and still more preferably 0.7 to 2.0. 0.9 to 1.55 is particularly preferable. The osmotic pressure can be adjusted by a method known in the art using an inorganic salt, a polyhydric alcohol, a sugar alcohol, a sugar, or the like. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (0.9 w / v% sodium chloride aqueous solution) based on the 16th revised Japanese Pharmacopoeia. Measure with reference to (freezing point depression method). In addition, about the standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution), after drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650 degreeC for 40-50 minutes, it is in a desiccator (silica gel). It is allowed to cool, and 0.900 g is accurately weighed and dissolved in purified water to prepare exactly 100 mL, or a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution) can be used. .

  The viscosity of the eye drop according to the present embodiment is not particularly limited as long as it is within a range acceptable for a living body. The viscosity at 25 ° C. measured with a rotational viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1 ° 34 ′ × R24) is preferably 0.1 to 1000 mPa · s, for example, 0.5 More preferably, it is -100 mPa * s, and it is still more preferable that it is 1-10 mPa * s.

In addition, the eye drop according to the present embodiment may contain an appropriate amount of various pharmacologically active components and physiologically active components in addition to the above components, as long as the effects of the present invention are not hindered. Such an ingredient is not particularly limited, and examples thereof include active ingredients in various medicines described in the Occupational Drug Manufacturing and Sales Approval Standard 2012 Edition (supervised by the Japan Society for Regulatory Science). Specifically, the following components are listed as components used in ophthalmic drugs.
Antiallergic agents: for example, ketotifen fumarate, pemirolast potassium, cromoglycate sodium and the like. Decongestant: Tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, naphazoline hydrochloride, naphazoline nitrate, epinephrine, epinephrine hydrochloride, ephedrine, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, and the like.
Eye muscle modulating agent: for example, cholinesterase inhibitor having an active center similar to acetylcholine, specifically, neostigmine methyl sulfate, tropicamide, helenien, atropine sulfate, etc.
Vitamins: For example, flavin adenine dinucleotide sodium, cyanocobalamin, retinol palmitate, retinol acetate, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, tocopherol acetate, etc.
Amino acids: potassium aspartate, magnesium aspartate, magnesium / potassium aspartate, aminoethylsulfonic acid and the like.
Bactericides: for example, acrinol, cetylpyridinium, benzalkonium chloride, benzethonium chloride, chlorhexidine, polyhexamethylene biguanide, alkyldiaminoethylglycine hydrochloride, etc.
Other: For example, sulfamethoxazole, sulfamethoxazole sodium and salts thereof.

In addition, for the eye drops according to the present embodiment, various additives are appropriately selected according to a conventional method according to the use or formulation form, as long as the effects of the invention are not impaired, and one or more kinds thereof are used. And may be contained in an appropriate amount. Examples of these additives include various additives described in Pharmaceutical Additives Encyclopedia 2007 (edited by Japan Pharmaceutical Additives Association). Typical additives include the following additives.
Carrier: An aqueous carrier such as water or hydrous ethanol.
Sugars: for example, glucose, cyclodextrin and the like.
Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like. These may be any of D-form, L-form and DL-form.
Antiseptics, bactericides or antibacterials: for example, zinc chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, dehydroacetic acid Sodium, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol and the like.
Stabilizers: trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate, etc.

  The eye drop according to the present embodiment is prepared by adding the above components (A) and (B) and other components as necessary to the carrier so as to have a desired content. Specifically, for example, the components can be dissolved or suspended in purified water, adjusted to a predetermined pH and osmotic pressure, and sterilized by filtration sterilization or the like.

  In the eye drop according to the present embodiment, the water content is 85 w / v% or more, preferably 90 w / v% or more, and preferably 92 w / v% or more with respect to the total amount of eye drops. Is more preferably 94 w / v% or more, and particularly preferably 96 w / v% or more. As the water used in the eye drop according to the present embodiment, water that is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable may be used. Specifically, as such water, Examples include distilled water, ordinary water, purified water, sterilized purified water, water for injection, distilled water for injection, and the like.

  The eye drop according to this embodiment is provided by being accommodated in an arbitrary container. The container for storing the eye drops according to this embodiment is not particularly limited, and may be made of glass or plastic, for example. Preferably it is made of plastic. Examples of the plastic include polyethylene terephthalate, polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, polyimide, a copolymer of monomers constituting these, and a mixture of these two or more. Polyethylene terephthalate is preferable. In addition, the container for storing the eye drop according to the present embodiment may be a transparent container that can visually recognize the inside of the container, or an opaque container that is difficult to visually recognize the inside of the container. A transparent container is preferable. Here, the “transparent container” includes both a colorless transparent container and a colored transparent container. The eye drops according to the present embodiment can be used by being housed in a multi-dose form that can be used repeatedly, for example, in a colored transparent plastic container.

  The ophthalmic solution according to the present embodiment can be applied in a state where a contact lens is worn, but from the viewpoint of the effects of allergy prevention and IL-33 production suppression, it may be applied without wearing a contact lens. Is preferred.

  The ophthalmic solution according to the present embodiment can be applied in a state of wearing on any contact lens including a hard contact lens and a soft contact lens, but from the viewpoint of allergy prevention and IL-33 production suppression. Is preferably applied without wearing a contact lens, especially a soft contact lens, particularly a silicone hydrogel contact lens. Silicone hydrogel contact lenses are both ionic and non-ionic, but ionic silicone contact lenses are known to have the property of adsorbing proteins that are allergens. In addition, the silicone hydrogel contact lens is harder than other soft contact lenses and is likely to cause physical damage to the corneal epithelium, so the influence on the effect of preventing allergic symptoms is immeasurable. However, it is not recommended that the eye drop according to the present embodiment be instilled while wearing the silicone hydrogel contact lens.

  The eye drops according to the present embodiment are effective in preventing various allergic symptoms such as food allergy, animal allergy, hay fever, house dust (indoor dust) and the like. Above all, it is suitable for the prevention of allergic symptoms of the eyes due to pollen and house dust (indoor dust). Specifically, such allergic symptoms include redness of the eyes, itchy eyes, blurred eyes, and a lot of eyes. It is used for prevention of slickness, foreign body feeling (feeling groggy).

  In addition, the usage and dosage of the eye drop according to the present embodiment is not particularly limited as long as it is effective and has few side effects. For example, in the case of an adult (15 years old or older) and a child 7 years or older, A method of instilling 1 to 2 drops at a time, 4 times a day (for example, morning, noon, evening, and before going to bed) is preferable.

The preferred use start time of the eye drop according to this embodiment is 1 to 2 weeks before contact with the allergen. For example, when the eye drop according to this embodiment is used for the prevention of symptoms caused by allergic substances such as proteins such as lysozyme, it is used from 1 to 2 weeks before the scheduled date of contact with these substances. When the eye drop according to this embodiment is used for prevention of symptoms due to animal allergy, it is used from 1 to 2 weeks before the scheduled date of contact with the animal. Examples of animals include dogs, cats, rabbits, hamsters, guinea pigs, rats and mice. In addition, for example, when the eye drop according to this embodiment is used to prevent symptoms due to seasonal allergies such as hay fever, it is used from 1 to 2 weeks before the start of pollen scattering. Examples of the pollen include cedar, cypress, birch, quercus, chestnut, olive, alder, zelkova, ginkgo, red pine, rat, camoline, blue whale, mugwort and ragweed. Since the scattering start time is known for each type of pollen, it is possible to determine 1 to 2 weeks before the start of pollen scattering, which is the use start time, based on the pollen causing allergy. In particular, cedar pollen starts to scatter from February every year, and cedar pollinosis is the most common among hay fever. Therefore, pollen scattering start time is predicted every year by organizations such as the Ministry of the Environment and the Japan Meteorological Association, and it is possible to determine 1 to 2 weeks before the start of pollen scattering, which is the use start time, based on the prediction. Therefore, in this specification, “pollen scattering start” means an actual pollen scattering start date defined as the first day when 1 or more pollen per 1 cm ² is observed continuously for 2 days or more in a pollen measuring instrument. It does not mean, but it means the expected start date or time of pollen scattering. The pollen scattering start predicted date or time may be predicted by any institution. Moreover, although the pollen scattering start date or time may be announced several times depending on the institution, any date or time may be used. The use start time can be determined by the user at his / her own discretion, and can also be determined in consultation with medical personnel such as doctors and pharmacists.

  Since the eye drop according to the present embodiment has an effect of suppressing IL-33 production, it is used from 1 to 2 weeks before the onset of allergic symptoms, particularly contact with allergen, so that mast cells by IL-33 are used. It is possible to effectively prevent the initial reaction of allergies, such as degranulation, and effectively prevent the onset of allergic symptoms.

  From another viewpoint, this embodiment provides an IL-33 production inhibitor containing (A) tranilast or a salt thereof, and (A) tranilast or a salt thereof and (B) an antihistamine, The present invention provides an IL-33 production inhibitor containing at least one selected from the group consisting of an inflammatory agent, amino acids and a refreshing agent.

  This embodiment contains, from another viewpoint, at least one selected from the group consisting of (A) tranilast or a salt thereof and (B) an antihistamine, an anti-inflammatory agent, an amino acid, and a cooling agent. The present invention provides an agent for preventing hyperemia of eyes caused by an allergic reaction.

  This embodiment contains, from another viewpoint, at least one selected from the group consisting of (A) tranilast or a salt thereof and (B) an antihistamine, an anti-inflammatory agent, an amino acid, and a cooling agent. Used to prevent eye itch caused by allergic reaction, eye caused by allergic reaction, excessive prophylactic agent for eye, allergic eye preventive agent caused by allergic reaction or eye caused by allergic reaction The present invention provides a foreign body sensation preventive agent.

  (A) component and / or (B) component may be contained as an active ingredient.

  Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples, but the present invention is not limited to these Examples and the like.

Test Example 1: Evaluation of IL-33 production inhibitory action in conjunctival fibroblasts Sample preparation Each reagent was dissolved in a culture medium. Tranilast (Cayman Chemical) was dissolved in DMSO to make a 500 mM stock solution, and then diluted with a culture medium. TNFα was prepared using human recombinant TNFα (R & D Systems), and IL-4 was used using human recombinant IL-4 (R & D Systems) so that the final concentration was 100 ng / mL. As the chlorpheniramine maleate, dipotassium glycyrrhizinate, sodium chondroitin sulfate and l-menthol, 15th revised Japanese Pharmacopoeia compatible products were used.

Evaluation of IL-33 production inhibitory effect Conjunctival fibroblasts (ScienCell Research Laboratories) were seeded at 6 × 10 ⁵ plate (Corning) at 1.5 × 10 ⁵ cells / well, 37 ° C., 5% CO ₂ , humidity 90% The culture was continued until confluent under the conditions of After the culture medium is replaced with a serum-free medium and cultured overnight, tranilast alone or a drug combining tranilast with each component of chlorpheniramine maleate, dipotassium glycyrrhizinate, sodium chondroitin sulfate or l-menthol is added, and 1 Time pretreated. Thereafter, allergic reaction was induced by adding TNFα and IL-4. The mRNA expression level of IL-33 was quantified by a quantitative real-time PCR method using ABI PRISM7000 Sequence Detection System (Applied Biosystems).

Results Table 1 shows the test results. The expression level of IL-33 is increased by stimulating the conjunctival fibroblasts with TNFα and IL-4 to induce an allergic reaction (Comparative Example 2), but the expression of IL-33 is pretreated with tranilast. The amount was suppressed (Example 1). Moreover, the expression level of IL-33 was remarkably suppressed by pretreating tranilast in combination with chlorpheniramine maleate, dipotassium glycyrrhizinate, sodium chondroitin sulfate or l-menthol (Examples 2 to 5). . Not only tranilast but also chlorpheniramine maleate, dipotassium glycyrrhizinate, sodium chondroitin sulfate, and l-menthol are not known to have IL-33 production inhibitory effects. Nevertheless, it was unexpected that the remarkable IL-33 production inhibitory effect as shown in Table 1 was obtained, and it is clear that the eye drop of the present invention has a particularly remarkable effect on allergy prevention. is there.

Test Example 2: Evaluation of animal allergic symptoms by human monitor test Sample preparation Eye drops of Comparative Example 3 and Examples 6 and 7 were prepared with the compositions shown in Table 2 below.

  Whether to apply eye drops containing tranilast (comparative example 3) to the right eye and eye drops containing tranilast and a cooling agent (example 6) to the left eye for 6 subjects with animal allergies Allergy symptoms were evaluated by instilling eye drops containing tranilast (Comparative Example 3) into the right eye and eye drops containing tranilast and chlorpheniramine maleate (Example 7) into the left eye. It was. The instillation is 4 times a day after the allergic reaction is initiated, 4 times a day from 2 to 3 days before the onset of the allergic reaction until after the allergic reaction is initiated, or 4 times a day from 1 week before the onset of the allergic reaction. The experiment was performed in three ways, and the amount of eye drops was one drop per eye. The allergic reaction was induced by bringing the subject into contact with the animal. The animal to be contacted is an animal in which each subject is allergic, and specifically, a rabbit, guinea pig, rat, dog or hamster. The degree of allergic symptom is evaluated after each ophthalmic solution administration by Visual Anal Scale Scale method (VAS method) regarding redness of eyes, itching of eyes, blurred eyes (spotted eyes), sloppy eyes, and foreign body sensation (gorologous feeling). I did it. More specifically, the left end of a 11.8 cm long horizontal straight line is 0% (a state in which no animal allergic symptoms are felt at all), and the right end is 100% (a state in which animal allergic symptoms that have been experienced in the past are the strongest). The percentage (VAS score) was evaluated by having a point indicating the strength of the symptom felt in a straight line and measuring the length from the left end to that point.

  The results are shown in Tables 3 and 4. 1 and 2 show relative values of various VAS scores when the eye drops of Example 6 or 7 are used with respect to various VAS scores when the eye drops of Comparative Example 3 are used.

  The eye drop containing tranilast and the refreshing agent further suppressed allergic symptoms as compared with the eye drop containing tranilast. In particular, when an ophthalmic solution containing tranilast and a cooling agent is administered from one week before the induction of an allergic reaction, the effect of suppressing allergic symptoms is particularly remarkable, and an ophthalmic solution containing tranilast is used to induce an allergic reaction. Even when compared with the case of administration for 1 week, the allergy symptoms were clearly improved. Similar effects were observed with eye drops containing tranilast and chlorpheniramine maleate.

Test Example 3: Evaluation of pollen allergy symptoms by human monitor test Reagent preparation Eye drops of Comparative Example 4 and Examples 8 and 9 were prepared with the compositions shown in Table 5 below.

  Whether to apply eye drops containing tranilast (Comparative Example 4) to the right eye and eye drops containing tranilast and a cooling agent (Example 8) to the left eye for 18 subjects with pollen allergy Allergic symptoms were evaluated by instilling eye drops containing tranilast (Comparative Example 4) in the right eye and eye drops containing tranilast and chlorpheniramine maleate (Example 9) in the left eye. It was. The instillation is (1) 4 days a day after pollen start, 9 days, (2) 2 to 3 days before the start of pollen start to pollen start 4 times a day, and 4 days a day after pollen start 9 days Or, (3) Three people were performed for each eye drop method four times a day from one to two weeks before the start of pollen scattering until the start of pollen scattering, and further four times a day for nine days after the start of pollen scattering. The amount of eye drops was one drop per eye. The pollen start date was determined based on the prediction of the start of cedar pollen start by the Ministry of the Environment (Nara Prefecture). The degree of allergic symptom was evaluated after completion of administration of each eye drop by the VAS method with respect to redness of eyes, itching of eyes, blurring of eyes (in the eyes and eyes), and smooth eyes.

  The results are shown in Tables 6 and 7. 3 and 4 show relative values of various VAS scores when the eye drops of Example 8 or 9 are used with respect to various VAS scores when the eye drops of Comparative Example 4 are used.

  The eye drop containing tranilast and the refreshing agent further suppressed allergic symptoms as compared with the eye drop containing tranilast. In particular, when an ophthalmic solution containing tranilast and a refreshing agent is administered from 1 to 2 weeks before the start of pollen scattering, the effect of suppressing allergic symptoms is particularly remarkable, and the ophthalmic solution containing tranilast is used to start pollen scattering. Even when compared with the case of administration from 1 to 2 weeks before, clear improvement of allergic symptoms was observed. Similar effects were observed with eye drops containing tranilast and chlorpheniramine maleate.

Formulation Example Eye drops were prepared according to the following formulation.

Claims (10)

  (A) An eye drop for inhibiting IL-33 production, containing tranilast or a salt thereof.   An eye drop for inhibiting IL-33 production, comprising (A) tranilast or a salt thereof and (B) at least one selected from the group consisting of an antihistamine, an anti-inflammatory agent, amino acids and a refreshing agent.   Applied from 1 to 2 weeks before contact with the allergen, (A) tranilast or a salt thereof, and (B) at least one selected from the group consisting of an antihistamine, an anti-inflammatory agent, amino acids and a cooling agent An ophthalmic solution for preventing allergic symptoms.   The eye drop according to claim 3, which is applied from 1 to 2 weeks before the start of pollen scattering.   The ophthalmic solution according to claim 3 or 4, wherein the allergic symptom is at least one selected from the group consisting of redness of eyes, itching of eyes, soaking eyes, blurring of eyes, and a feeling of foreign objects in eyes.   The eye drop according to any one of claims 3 to 5, which is applied without wearing a silicone hydrogel contact lens.   The ophthalmic solution according to any one of claims 3 to 6, comprising at least one antihistamine selected from the group consisting of chlorpheniramine maleate, iproheptin and diphenhydramine hydrochloride as the component (B).   The component (B) is at least selected from the group consisting of ε-aminocaproic acid, allantoin, berberine sulfate, berberine chloride, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme chloride, pranoprofen and sodium azulenesulfonate. The eye drop according to any one of claims 3 to 7, comprising one type of anti-inflammatory agent.   The component (B) contains at least one amino acid selected from the group consisting of sodium chondroitin sulfate, potassium aspartate, aminoethylsulfonic acid and epsilon aminocaproic acid. The eye drops described.   The ophthalmic solution according to any one of claims 3 to 9, comprising at least one refreshing agent selected from the group consisting of menthol, camphor, borneol, geraniol, and mint oil as the component (B).

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