JP2021054805A - Ophthalmic composition and allergic disease therapeutic - Google Patents

Abstract

To provide an ophthalmic composition that can suppress an allergy symptom from becoming serious.SOLUTION: The present disclosure provides an ophthalmic composition that can suppress an allergy symptom from becoming serious, which contains an antiallergic.SELECTED DRAWING: Figure 1

Description

The present invention relates to an ophthalmic composition used to suppress the aggravation of allergic symptoms and a therapeutic agent for allergic diseases.

It is known that allergic symptoms are caused by the release (degranulation) of chemical mediators such as histamine from mast cells (mast cells) or basophils upon contact with allergens. In order to prevent or improve allergic symptoms, it is effective to suppress the release of histamine itself.

Conventionally, a drug that suppresses histamine release by suppressing degranulation of mast cells and the like has been developed and used (for example, Patent Document 1).

Japanese Unexamined Patent Publication No. 2001-97865

However, research on the aggravation of allergic symptoms has not yet progressed sufficiently.

Inflammatory cells such as mast cells are deeply involved in the aggravation of allergic symptoms. For example, among the chemical mediators released from inflammatory cells and the like, there are substances that promote the migration of inflammatory cells, and in the conjunctiva of patients with allergic conjunctivitis, the migrated mast cells accumulate locally in the inflammation. ing.

As a result of intensive studies, the present inventors have newly found an action of suppressing the migration of inflammatory cells with respect to an antiallergic drug, and have completed the present invention. The present invention is based on this novel finding.

That is, the present invention provides the following [1] to [5].
[1] An ophthalmic composition containing an antiallergic agent and suppressing the aggravation of allergic symptoms.
[2] The antiallergic agent is at least one selected from the group consisting of tranilast, ibudilast, pemirolast, acitazanolast, amlexanox, ketotifen, levocabastine, olopatadine, epinastine, cromoglycic acid, and salts thereof. The ophthalmic composition according to [1].
[3] The ophthalmic composition according to [1] or [2], wherein the aggravation of the allergic symptom is the aggravation of the allergic symptom due to the migration of inflammatory cells.
[4] The ophthalmic composition according to [3], wherein the inflammatory cells are mast cells.
[5] Migration of inflammatory cells containing at least one selected from the group consisting of tranilast, ibudilast, pemirolast, acitazanolast, amlexanox, ketotifen, levocabastine, olopatadine, epinastine, cromoglycic acid, and salts thereof. A remedy for allergic diseases caused by.

According to the present invention, it is possible to provide an ophthalmic composition that suppresses the migration of inflammatory cells and suppresses the aggravation of allergic symptoms.

FIG. 1 is a graph showing the results of Test 1. FIG. 2 is a graph showing the results of Test 2. FIG. 3 is a graph showing the results of Test 3.

Hereinafter, embodiments for carrying out the present invention will be described in detail. However, the present invention is not limited to the following embodiments.

In the present specification, the unit of content "w / v%" is synonymous with "g / 100 mL".

[Ophthalmic composition]
The ophthalmic composition according to the embodiment of the present invention is an ophthalmic composition containing an antiallergic agent and suppressing the aggravation of allergic symptoms.

The antiallergic agent contained in the ophthalmic composition according to the present embodiment has an effect of suppressing the migration of inflammatory cells. Antiallergic agents include, for example, tranilast, ibudilast, pemirolast, acitazanolast, amlexanox, ketotifen, levocabastine, olopatadine, epinastine, cromoglycic acid, and salts thereof.

The salt of the antiallergic drug may be any pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable salt, for example, an alkali metal or alkaline earth metal salt (pemirolast potassium, chromogric acid). Sodium, potassium cromoglycate, magnesium cromoglycate, calcium cromoglycate, etc.), inorganic acid salts (olopatazine hydrochloride, epinastine hydrochloride, levocabastine hydrochloride, etc.), organic acid salts [for example, tosilate, fumarate (fumaric acid) Ketotiphen, etc.)], etc. Moreover, you may use the hydrate of each salt.

These antiallergic agents can be used alone or in combination of two or more. Among these, tranilast or a salt thereof, cromoglycic acid or a salt thereof, pemirolast or a salt thereof is preferable, and tranilast, sodium cromoglycate, and pemirolast are more preferable, from the viewpoint of remarkably exerting the effect of the present invention. These antiallergic agents can also be used as therapeutic agents for allergic diseases caused by the migration of inflammatory cells.

The content of the antiallergic agent in the ophthalmic composition according to the present embodiment is appropriately set according to the type and content of other compounding ingredients, the formulation form of the ophthalmic composition, and the like. The total content of the antiallergic agent is, for example, 0.001 w / v% or more, preferably 0.01 to 5 w / v%, and 0.01 to 1 w / v% with respect to the total amount of the ophthalmic composition. preferable.

When at least one selected from tranilast and a salt thereof is contained as a component of the antiallergic drug, the total content of the component is preferably 0.001 w / v% or more, for example, with respect to the total amount of the ophthalmic composition. Is 0.01 to 10 w / v%, more preferably 0.05 to 5 w / v%, still more preferably 0.07 to 2 w / v%, even more preferably 0.1 to 1 w / v%, particularly preferably. It may be about 0.2 to 1 w / v%, most preferably about 0.25 to 0.8 w / v%. Among them, 0.3 to 0.7 w / v% is preferable, 0.4 to 0.6 w / v% is more preferable, and 0.45 to 0.55 w / v% (0.5 w / v%, etc.) is preferable. Especially preferable.

When at least one selected from cromoglycic acid and a salt thereof is contained as a component of the antiallergic drug, the total content of the component is, for example, 0.1 to 10 w / v% with respect to the total amount of the ophthalmic composition. , Preferably 0.2 to 8 w / v%, more preferably 0.3 to 5 w / v%, even more preferably 0.4 to 4 w / v%, even more preferably 0.5 to 3 w / v%, in particular. It may be preferably 0.7 to 2.0 w / v%, more particularly preferably 0.8 to 1.5 w / v%, and most preferably about 0.9 to 1.2 w / v%. Of these, 1.0 w / v% is particularly preferable.

When at least one selected from pemirolast and a salt thereof is contained as a component of the antiallergic drug, the total content of the component is preferably 0.0001 w / v% or more, for example, with respect to the total amount of the ophthalmic composition. May be 0.0001 to 1 w / v%, more preferably 0.001 to 0.5 w / v%, still more preferably about 0.005 to 0.2 w / v%. Of these, 0.1 w / v% is particularly preferable.

The ophthalmic composition according to the present embodiment may further contain a nonionic surfactant in addition to the antiallergic agent. The nonionic surfactant is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

Specific examples of the nonionic surfactant include polyoxyethylene (hereinafter, also referred to as "POE")-polyoxypropylene (hereinafter, also referred to as "POP") glycol (for example, Poroxummer 407, Poroxummer 235, Poroxumer 188, etc.). Poroxummers); POE-POP block copolymer adducts of ethylenediamine such as poroxamine; POE monolaurate (20) sorbitan (polysorbate 20), POE monooleate (20) sorbitan (polysorbate 80), POE sorbitan monostearate ( POE sorbitan fatty acid esters such as polysorbate 60) and POE sorbitan tristearate (polysorbate 65); POE (5) cured castor oil, POE (10) cured castor oil, POE (20) cured castor oil, POE (40) cured POE cured castor oil such as castor oil, POE (50) cured castor oil, POE (60) cured castor oil, POE (100) cured castor oil; POE (3) castor oil, POE (10) castor oil, POE (35) ) POE castor oil such as castor oil; POE (9) POE alkyl ethers such as lauryl ether; POE (20) POP (4) POE / POP alkyl ethers such as cetyl ether; POE (10) nonylphenyl ether and the like POE alkylphenyl ethers; polyethylene glycols monostearate such as polyoxyl 40 stearate and the like can be mentioned. The numbers in parentheses indicate the average number of moles of POP or POE added.

Among these nonionic surfactants, POE-POP glycol, POE sorbitan fatty acid esters, POE-hardened castor oil, POE castor oil, and polyethylene glycol monostearate are preferable, and Poroxummer 407 and POE monooleate (20). Solbitan (polysolvate 80), POE (60) hardened castor oil (polyoxyethylene hydrogenated castor oil 60), POE (40) cured castor oil (polyoxyethylene hydrogenated castor oil 40), POE (3) castor oil (polyoxyethylene) Himasi oil 3), POE (10) Himasi oil (polyoxyethylene glycol oil 10), POE (35) Glycol oil (polyoxyethylene glycol oil 35), polyoxyl 40 stearate are more preferable, and monooleic acid POE (20) Sorbitane, POE (60) hardened castor oil is particularly preferred.

These nonionic surfactants may be synthesized and used by a known method, or commercially available products may be obtained and used. The nonionic surfactant may be used alone or in any combination of two or more.

When a nonionic surfactant is contained in the ophthalmic composition according to the present embodiment, the content of the nonionic surfactant depends on the type of the nonionic surfactant, the type and amount of other components, and the like. Can be set as appropriate. The total content of the nonionic surfactant with respect to the total amount of the ophthalmic composition is not limited, but is preferably 0.0001 to 10 w / v%, more preferably 0.001 to 5 w / v%, still more preferably 0. It is .005 to 1 w / v%, particularly preferably 0.01 to 0.5 w / v%.

The ophthalmic composition according to the present embodiment may further contain a thickener in addition to the antiallergic agent. Specific examples of the thickener include methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (hypromellose), carboxymethyl cellulose and its salts, and cellulose-based polymer compounds such as carboxyethyl cellulose and its salts. Vinyl such as chondroitin sulfate and its salt, glycosaminoglycan such as hypromellose and its salt, polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone (K17, K25, K30, K90, etc.), carboxyvinyl polymer and its salt, etc. Examples thereof include macromolecules, dextran, macrogol 6000, macrogol 4000, macrogol (polyethylene glycol) such as macrogol 400, gellan gum, alginic acid and salts thereof. Here, the salt is not particularly limited, but a sodium salt is preferable. From the viewpoint of remarkably exerting the effect of the present invention, glycosaminoglycan, cellulose-based polymer, or vinyl-based polymer is preferable, glucosaminoglycan is more preferable, chondroitin sulfate, hyaluronic acid, and salts thereof are more preferable. Sodium chondroitin sulfate (sodium chondroitin sulfate) and sodium hyaluronate are more preferable.

These thickeners may be synthesized and used by a known method, or commercially available products may be obtained and used. These thickeners may be used alone or in any combination of two or more.

When a thickener is added to the ophthalmic composition according to the present embodiment, the total content of the thickener is appropriately set according to the type of thickener to be used, the type and amount of other compounding components, and the like. it can. The total content of the thickener is not limited, but is preferably 0.0001 to 5 w / v%, more preferably 0.0005 to 3 w / v%, still more preferably 0.0005 to 3 w / v%, based on the total amount of the ophthalmic composition. Is 0.001 to 1 w / v%, even more preferably 0.005 to 0.5 w / v%, particularly preferably 0.01 to 0.5 w / v%, and most preferably 0.05 to 0. It is 3 w / v%.

The ophthalmic composition according to the present embodiment may further contain a buffer in addition to the antiallergic agent. The buffer that can be blended in the ophthalmic composition is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such a buffer include borate buffer, phosphoric acid buffer, carbon dioxide buffer, citric acid buffer, acetate buffer, tris buffer, aspartic acid, aspartate, epsilon-aminocaproic acid and the like. Be done. As the buffer, a borate buffer, a phosphate buffer, a carbonic acid buffer, and a citric acid buffer are preferable.

Examples of the boric acid buffer include borate, or borates such as an alkali metal boric acid salt and an alkaline earth metal boric acid salt. Examples of the phosphoric acid buffer include phosphates, or phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Examples of the carbonic acid buffer include carbonic acid, or carbonates such as alkali metal carbonate and alkaline earth metal carbonate. Examples of the citric acid buffer include citric acid, an alkali metal citrate salt, and an alkaline earth metal citrate salt.

Moreover, you may use the hydrate of each salt as a buffering agent. As a more specific example, but not limited to, as a borate buffer, boric acid or a salt thereof (sodium citrate, potassium tetraborate, potassium metaborate, ammonium borate, boar sand, etc.); as a phosphate buffer. , Phosphate or a salt thereof (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); As a buffer, carbonic acid or a salt thereof (sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.); as a citrate buffer, citrate or a salt thereof (sodium citrate, Potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.); acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.) as an acetate buffer; aspartic acid or a salt thereof (Sodium citrate, magnesium aspartate, potassium aspartate, magnesium aspartate / potassium mixture, etc.) can be exemplified. Further, the hydrate of each salt may be used as a raw material for producing the buffer.

Among the buffers, boric acid buffers and phosphate buffers are particularly preferable, and boric acid buffers are even more preferable. Suitable specific examples of the boric acid buffer include boric acid, a combination of boric acid and a salt thereof (for example, boric acid and borax), preferably a combination of boric acid, boric acid and borax, and more preferably. Is exemplified by boric acid.

These buffers may be synthesized and used by a known method, or commercially available products may be obtained and used. These buffers may be used alone or in any combination of two or more.

When the ophthalmic composition according to the present embodiment contains a buffer, the content of the buffer can be appropriately set according to the type of the buffer to be used, the type and amount of other compounding components, and the like. The total content of the buffer relative to the total amount of the ophthalmic composition is not limited, but is preferably 0.01-10 w / v%, more preferably 0.05-5 w / v%, even more preferably 0.1-. It is 3 w / v%, particularly preferably 0.3 to 2 w / v%.

The ophthalmic composition according to the present embodiment may further contain a refreshing agent in addition to the antiallergic agent. The refreshing agent is not particularly limited, and examples thereof include terpenoids such as menthol, anethole, eugenol, camphor, geraniol, cineole, borneol, limonene, and ryuno. These may be d-form, l-form, or dl-form. In addition, essential oils such as peppermint oil, cool mint oil, sparemint oil, peppermint oil, uikyo oil, kehi oil, bergamot oil, eucalyptus oil, and rose oil can also be mentioned.

Among them, terpenoids are preferable, and menthol, camphor, geraniol, cineole, borneol, and ryuno are preferable, menthol, camphor, and borneol are more preferable, and menthol is further preferable.

These refreshing agents may be synthesized and used by a known method, or commercially available products may be obtained and used. These refreshing agents may be used alone or in combination of two or more.

The total content of the refreshing agent 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 with respect to the total amount of the ophthalmic composition. % Or more, 0.003w / v% or more, 0.004w / v% or more, 0.005w / v% or more, 0.006w / v% or more, 0.007w / v% or more, 0.008w / v% or more , 0.009 w / v% or more, 0.01 w / v% or more.

The total content of the refreshing agent is 1 w / v% or less, 0.1 w / v% or less, 0.09 w / v% or less, 0.08 w / v% or less, based on the total amount of the ophthalmic composition. , 0.07w / v% or less, 0.06w / v% or less, 0.05w / v% or less, 0.04w / v% or less, 0.03w / v% or less, 0.02w / v% or less. You may.

The ophthalmic composition according to the present embodiment may further contain an isotonic agent in addition to the antiallergic agent. Specific examples of the tonicity agent that can be blended in the ophthalmic composition of the present invention include sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, sodium thiosulfate, magnesium sulfate, and glycerin. Examples include propylene glycol and the like. Among these tonicity agents, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, glycerin, and propylene glycol are preferably mentioned from the viewpoint of remarkably exerting the effect of the present invention. These isotonic agents may be used alone or in any combination of two or more.

When the ophthalmic composition according to the present embodiment contains an isotonic agent, the content of the isotonic agent depends on the type of isotonic agent used, the type and amount of other compounding components, and the like. Can be set as appropriate. The total content of the buffer relative to the total amount of the ophthalmic composition is not limited, but is preferably 0.01-10 w / v%, preferably 0.05-5 w / v%, more preferably 0.1 to 3 w. / V%.

In addition to the antiallergic agent, the ophthalmic composition according to the present embodiment can usually contain any component that can be used in the ophthalmic composition. Such an ingredient is not particularly limited, and examples thereof include active ingredients (pharmacological active ingredients, physiologically active ingredients, etc.) described in the 2012 edition of the OTC drug manufacturing and marketing approval standard (supervised by the Regulatory Science Society). Specifically, the following components can be mentioned.

Antihistamines: for example, iproheptine, diphenhydramine hydrochloride, chlorpheniramine maleate and the like.

Decongestant: for example, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline sulfate, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, phenylephrine hydrochloride and the like.

Eye muscle regulators: For example, cholinesterase inhibitors having an active center similar to acetylcholine, specifically neostigmine methylsulfate, tropicamide, helenien, atropine sulfate and the like.

Vitamins: For example, flavin adenine dinucleotide sodium, pyridoxine hydrochloride, cyanocobalamin, retinol acetate, retinol palmitate, tocopherol acetate, panthenol, calcium pantothenate, sodium pantothenate and the like.

Amino acids: For example, aminoethylsulfonic acid (taurine), potassium L-aspartate, magnesium L-aspartate, magnesium / potassium L-aspartate and the like.

Anti-inflammatory agents: for example, glycyrrhizinic acid, dipotassium glycyrrhizinate, glycyrrhetinic acid, methyl salicylate, glycol salicylate, azulene sulfonic acid, sodium azulene sulfonate, allantin, tranexamic acid, berberine, lysoteam, lysoteam chloride, berberine chloride, berberine sulfate, epsilon -Aminocaproic acid, indomethacin, pranoprofen, ibprofen, ibprofen piconol, ketoprofen, diclofenac sodium, bromfenac sodium, felbinac, bendazac, piroxicam, bufexamac, butyl flufenamic acid, etc.

Astringent: For example, zinc oxide, zinc lactate, zinc sulfate, etc. These may be hydrates.

Local anesthetic component: For example, procaine hydrochloride, lidocaine hydrochloride, etc.

Others: For example, sulfamethoxazole, sodium sulfamethoxazole, sulfisoxazole, sodium sulfisomidin, purple root, horse chestnut, and salts thereof.

The blending ratio of various active ingredients is known in the field of ophthalmic compositions, and the blending ratio of the above components in the ophthalmic composition according to the present embodiment is the dosage form, pharmacologically active ingredient or physiological activity of the ophthalmic composition. It is appropriately set according to the type of component and the like. For example, the blending ratio of the pharmacologically active ingredient or the physiologically active ingredient can be usually 0.0001 to 30 w / v%, preferably about 0.001 to 10 w / v, based on the total amount of the ophthalmic composition. Can be%.

The above active ingredients may be used alone or in any combination of two or more.

Further, for the ophthalmic composition according to the present embodiment, additives such as carriers, pH regulators, general sugars, general chelating agents, stabilizers, preservatives and the like are selected, and at least one of them is used in combination. It may be contained in an appropriate amount. Examples of these additives include various additives described in the Encyclopedia of Pharmaceutical Additives 2007 (edited by the Japan Pharmaceutical Additives Association). The following additives can be mentioned as typical components.

Carrier: An aqueous carrier such as hydrous ethanol.

Sugars: For example, monosaccharides, disaccharides, specifically glucose, cyclodextrin, alpha-cyclodextrin and the like.
Sugar alcohols: For example, maltose, trehalose, sucrose, xylitol, sorbitol, mannitol, glycerin and the like.

pH adjuster: For example, hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, diisopanolamine and the like.

Stabilizers: for example, tromethamole, sodium formaldehyde sulfoxylate (longalit), sodium metabisulfite, monoethanolamine, aluminum monostearate, glycerin monostearate, dibutylhydroxytoluene (BHT), cyclodextrin and the like.

Chelating agents: for example, ethylenediamine diacetic acid (EDDA), ethylenediamine triacetic acid, ethylenediaminetetraacetic acid (edetic acid, EDTA), N- (2-hydroxyethyl) ethylenediaminetriacetic acid (HEDTA), diethylenetriamine pentaacetic acid (DTPA), ascorbic acid. , Tetrasodium edetate, sodium edetate, etc.

Preservatives, bactericides or antibacterial agents: for example, alkyl quaternary ammonium salts (benzalconium chloride, benzethonium chloride, etc.), biguanide compounds (specifically, polyhexanide hydrochloride, etc.), chlorhexidine hydrochloride, chlorhexidine gluconate, sodium benzoate. , Ethanol, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, glowkill, acrinol , Cetylpyridinium, zinc chloride, alkyldiaminoethylglycine, lauryldimethylaminoacetate betaine, etc.

Anionic surfactants: for example, alkylbenzene sulfonates, alkyl sulfates, polyoxyethylene alkyl sulfates, aliphatic α-sulfomethyl esters, α-olefin sulfonic acids and the like.

Oils: For example, vegetable oils such as sesame oil, castor oil, soybean oil and olive oil, animal oils such as squalane and lanolin, and mineral oils such as liquid paraffin and petrolatum.

Others: Lipidure-PMB (2-methacryloyloxyethyl phosphorylcholine / butyl methacrylate copolymer), Lipidure-HM, caffeine, etc.

[Physical characteristics]
The pH of the ophthalmic composition according to the present embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable range, but as an example, From the viewpoint of enhancing the stability of the ophthalmic composition, the pH is 4.0 to 9.0, preferably 4.5 to 8.5, more preferably 5.0 to 8.0, and even more preferably 6.0. The range is ~ 8.0, particularly preferably 6.5 to 8.0.

The ophthalmic composition according to the present embodiment can be further adjusted to an osmotic pressure ratio within a range acceptable to the living body, if necessary. The appropriate osmotic pressure ratio varies depending on the application site, dosage form, etc., but is usually in the range of 0.5 to 5.0, more preferably 0.6 to 3.0, and further preferably 0.7 to 2.0. Can be mentioned. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to the osmotic pressure of 286 mOsm (0.9 w / v% sodium chloride aqueous solution) based on the 17th revised Japanese Pharmacy, and the osmotic pressure is the osmotic pressure measurement method described in the Japanese Pharmacy. Measure according to the freezing point descent method). The standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) is prepared by drying sodium chloride (standard reagent of the Japanese Pharmacopoeia) at 500 to 650 ° C. for 40 to 50 minutes and then in a desiccator (silica). Allow to cool, weigh accurately 0.900 g, dissolve in purified water to prepare exactly 100 mL, or use a commercially available standard solution for measuring osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution). The osmotic pressure can be adjusted by a method known in the art using inorganic salts, polyhydric alcohols, sugar alcohols, sugars and the like.

The viscosity of the ophthalmic composition according to the present embodiment is appropriately set according to the type and content of the compounding ingredients, the formulation form, the method of use, etc., as long as it is within the physiologically or pharmacologically acceptable range. .. The viscosity at 20 ° C. measured with a rotary viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1 ° 34'x R24) is preferably 1 to 10000 mPa · s, preferably 1 to 1000 mPa · s. It is more preferably 1 to 100 mPa · s, further preferably 1 to 10 mPa · s.

The ophthalmic composition according to the present embodiment can be prepared, for example, by adding and mixing an antiallergic agent and, if necessary, other contained components so as to have a desired content. Specifically, for example, it can be prepared by dissolving or suspending the above components in purified water, adjusting the pH and osmotic pressure to a predetermined value, and sterilizing by filtration sterilization or the like.

The ophthalmic composition according to the present embodiment can take various dosage forms depending on the purpose, and examples thereof include liquid preparations, gel preparations, semi-solid preparations (ointments and the like), gel ointments and the like. Among these, liquid preparations are preferable. Further, among the liquid preparations, an aqueous liquid preparation is preferable. When the ophthalmic composition according to the present embodiment is used as an aqueous solution, for example, the water content may be 50 w / v% or more and 70 w / v% or more with respect to the total amount of the ophthalmic composition. It is more preferably 80 w / v% or more, and even more preferably 90 w / v% or more. As the water used in the ophthalmic composition according to the present embodiment, pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable water may be used, and such water may be, for example, distilled water. Examples thereof include water, normal water, purified water, sterilized purified water, water for injection, distilled water for injection and the like.

The ophthalmic composition according to the present embodiment is used in the field of ophthalmology, and its formulation form is not limited as long as it is used so as to come into contact with the eye. For example, eye drops (however, eye drops include eye drops that can be instilled while wearing contact lenses), artificial tears, eye ointment, eye wash (however, eye drops can be washed while wearing contact lenses). Compositions for contact lenses (including eye drops) [contact lens mounting solutions, contact lens care compositions (contact lens disinfectants, contact lens preservatives, contact lens cleaners, contact lens wash preservatives), etc.] Can be mentioned. Among these, eye drops are preferable. The "contact lens" includes a hard contact lens and a soft contact lens (including both ionic and non-ionic, and both a silicone hydrogel contact lens and a non-silicone hydrogel contact lens).

The ophthalmic composition according to the present embodiment is used according to the usage method according to the formulation form. For example, when the ophthalmic composition is an eye drop (including an eye drop for contact lenses), an appropriate amount of the eye drop may be instilled into the naked eye or the eye wearing the contact lens. Further, when the ophthalmic composition is an eye wash (including a contact lens eye wash), an appropriate amount of the eye wash may be used for the naked eye or the eye wearing contact lenses. When the ophthalmic composition is a contact lens mounting solution, it is used by bringing an appropriate amount of the contact lens and the mounting solution into contact with each other when the contact lens is worn.

[container]
The container filled with the ophthalmic composition according to the present embodiment is not particularly limited, and examples thereof include containers containing materials such as polyethylene terephthalate, polyarylate, polycarbonate, polyethylene, and polypropylene. In particular, a container made of polyethylene terephthalate is preferable. It may be filled in a light-shielded container. By putting it in a light-shielding container, the ophthalmic composition according to this embodiment can be kept stable for a long period of time. The container may be shielded from light by, for example, mixing the above material with a colorant or the like, or may be covered with a case made of shrink film, polypropylene or the like, an outer box, or the like to shield the container from light.

[Use]
The ophthalmic composition according to the present embodiment is provided for a new purpose of suppressing the aggravation of allergic symptoms by containing an antiallergic agent.

The aggravation of allergic symptoms in the present embodiment means that various allergic symptoms progress severely, for example, exacerbation of itching in the eyes, increase in the number of itching, exacerbation of hyperemia, exacerbation of foreign body sensation, Exacerbation of eye oil, exacerbation of watery eyes, etc. From the viewpoint of exerting the effect of the present invention more remarkably, it is preferable that the ophthalmic composition according to the present embodiment is used for suppressing the exacerbation of itching and the increase in the number of times of itching. In addition, it is preferable to use a conventional general-purpose eye drop for allergies for about 2 days and provide it when a sufficient effect is not obtained.

The factor of aggravation of allergic symptoms in the present embodiment is not particularly limited, and examples thereof include migration of inflammatory cells such as mast cells, basophils, eosinophils, neutrophils, and macrophages. From the viewpoint of exerting the effect of the present invention more remarkably, it is preferable that the ophthalmic composition according to the present embodiment is used for suppressing the aggravation of allergic symptoms caused by the migration of mast cells.

The chemical mediator that promotes the migration of inflammatory cells in the present embodiment is not particularly limited, and is, for example, prostaglandin D ₂ (PGD ₂ ), prostaglandin E ₂ (PGE ₂ ), leukotriene B ₄ (LTB _4). ), Interleukotriene 15 (IL-15), CCL2 chemokine (MCP-1), stem cell growth factor (SCF) and other chemical mediators that promote the migration of inflammatory cells. From the viewpoint of exerting the effect of the present invention more remarkably, the ophthalmic composition according to the present embodiment is a mast cell migration by at least one chemical mediator selected from the group consisting of _{PGD 2} , PGE ₂ , LTD _{4, and SCF.} It is preferable to be used for suppressing the aggravation of allergic symptoms caused by, and allergic symptoms caused by migration of mast cells by at least one lipid mediator selected from the group consisting of _{PGD 2} , PGE ₂ , and LTD _4. It is more preferable that the product is used for suppressing the aggravation of mast cells.

The ophthalmic composition according to an embodiment of the present invention is provided as an ophthalmic composition containing an antiallergic agent as a migration inhibitor that suppresses migration of inflammatory cells. From the viewpoint of exerting the effect of the present invention more remarkably, the ophthalmic composition according to the present embodiment is preferably an ophthalmic composition containing an antiallergic agent as a migration inhibitor that suppresses migration of mast cells. ..

As one embodiment of the present invention, it is provided as an ophthalmic migration inhibitor that suppresses the migration of inflammatory cells, which contains an antiallergic agent. From the viewpoint of exerting the effect of the present invention more remarkably, the ophthalmic migration inhibitor according to the present embodiment is preferably an ophthalmic migration inhibitor containing an antiallergic agent and suppressing the migration of mast cells.

The new use provided by the ophthalmic composition according to the present embodiment suppresses the migration of inflammatory cells such as mast cells, unlike the conventional mechanism of action that suppresses histamine and the like released from inflammatory cells. It is based on this new mechanism of action, and it can suppress the migration or accumulation of inflammatory cells that cause exacerbation of itching in the eyes and increase in the number of itching, resulting in severe allergic symptoms. Inflammation can be suppressed. The present invention is based on such a novel finding, and is extremely effective as an ophthalmic therapeutic agent for aggravation of allergic symptoms such as exacerbation of pruritus (itch) and increase in the number of itching.

[Treatment for allergic diseases caused by migration of inflammatory cells]
As one embodiment of the present invention, it is provided as a therapeutic agent for an allergic disease caused by migration of inflammatory cells, which contains an antiallergic agent. From the viewpoint of exerting the effect of the present invention more remarkably, it is preferable to use it as a therapeutic agent for allergic diseases caused by migration of mast cells, which contains an antiallergic agent.

The allergen of allergic symptoms or diseases is not particularly limited, and examples thereof include pollen (cedar pollen, cypress pollen, etc.), house dust (indoor dust), PM2.5, yellow sand, and the like.

[Method of imparting inflammatory cell migration inhibitory effect to ophthalmic composition]
The eye drops according to the present embodiment exert an action of suppressing migration of inflammatory cells by containing an antiallergic agent. Therefore, as one embodiment of the present invention, it is possible to provide a method for imparting an inflammatory cell migration effect to the ophthalmic composition by blending the allergic agent with the ophthalmic composition.

The formulation form and use of the ophthalmic composition in the above method, such as the type and content of the antiallergic drug, the type and content of other components, etc., are the same as those described in the above ophthalmic composition.

Hereinafter, the present invention will be described in detail based on examples, but the present invention is not limited thereto. The "%" described in each of the following tests is "w / v%".

<Test 1: Evaluation of mast cell migration inhibitory effect by tranilast (1)>
[Example 1]
Bone marrow cells collected from mice (C57BL / 6J, 8 weeks old) were cultured in a basal medium supplemented with IL-3 and SCF (manufactured by PEPROTECH, product number 250-03) into bone marrow-derived mast cells (BMMC). Induction was performed to obtain a BMMC-containing medium. BMMC pretreated with RPMI (manufactured by Gibco, product number 61870-536) containing 10% fetal bovine serum (FBS) was resuspended in pretreatment medium supplemented with tranilast (0.01% of medium volume). (See "Pretreatment" in Table 1 below). After 6 hours, BMMC was stained with 1 μg / mL Calcein-AM (manufactured by Invitrogen). As the basal medium, 1% Antibiotic-Atimycotic, 1% sodium pyruvate, 1% Non-Essential Amino Acid Solution, 10% fetal bovine serum (FBS) -containing RPMI (Gibco, product number 61870-036) medium is used. There was. As the pretreatment medium, RPMI (manufactured by Gibco, product number 61870-536) containing 10% fetal bovine serum (FBS) was used.
Next, in the insert upper layer (chamber) of Transwell (Transwell (registered trademark), 24-well, Poros size: 5 μm, manufactured by Corning, product number 3421), the BMMC was set to 3 × 10 ⁵ cells / well. A suspension of 100 μL of medium containing (0.01%) was seeded (see “Chamber” in Table 1 below). To the lower layer, 500 μL of a medium containing tranilast (0.01%) and PGD ₂ (manufactured by Cayman Chemical Co., Ltd., product number 12010) (50 μM) were added. After 4 hours, the BMMC migrating from the upper layer to the lower layer of the insert was collected, and fluorescence observation was performed using ImageXpress Micro confocal (manufactured by Molecular Device) to measure the number of living cells (cells / visual field). As the medium used for Transwell, RPMI (manufactured by Gibco, product number 61870-536) medium containing 0.2% dimethyl sulfoxide (DMSO) and 10% FBS was used.

[Control 1]
Control 1 was treated in the same manner as in Example 1 except that tranilast was not added to the pretreatment medium and tranilast and PGD _{2 were not added to the lower layer.}

[Test Example 1-1]
Test Example 1-1 was treated in the same manner as in Example 1 except that tranilast was not added to the pretreatment medium and tranilast was not added to the lower layer.

[Test Example 1-2]
Test Example 1-2 was treated in the same manner as in Example 1 except that PGD _{2 was not added to the lower layer.}

The outlines of the above examples and test examples are shown in Table 1 below, and the results are shown in FIG.

As shown in FIG. 1, in Test Example 1-1, the number of living cells was significantly increased as compared with Control 1, confirming the migration promoting effect of bone marrow-derived mast cells by _{PGD 2.} In Example 1, the number of living cells was significantly reduced as compared with Test Example 1-1, confirming that tranilast had an inhibitory effect on the migration of bone marrow-derived mast cells.
In Test Example 1-2, no significant change was confirmed in the number of viable cells as compared with Control 1, and the migration promoting action and migration suppressing action of bone marrow-derived mast cells by tranilast itself were not confirmed.

<Test 2: Evaluation of mast cell migration inhibitory effect by tranilast (2)>
[Example 2-1]
Bone marrow cells collected from mice (C57BL / 6J, 8 weeks old) were cultured in a basal medium supplemented with IL-3 and SCF (manufactured by PEPROTECH, product number 250-03) into bone marrow-derived mast cells (BMMC). Induction was performed to obtain a BMMC-containing medium. BMMC pretreated with RPMI (manufactured by Gibco, product number 61870-536) containing 10% fetal bovine serum (FBS) was resuspended in pretreatment medium supplemented with tranilast (0.0025% of medium volume). (See "Pretreatment" in Table 2 below). After 6 hours, BMMC was stained with 1 μg / mL Calcein-AM (manufactured by Invitrogen). As the basal medium, 1% Antibiotic-Atimycotic, 1% sodium pyruvate, 1% Non-Essential Amino Acid Solution, 10% fetal bovine serum (FBS) -containing RPMI (Gibco, product number 61870-036) medium is used. There was. As the pretreatment medium, RPMI (manufactured by Gibco, product number 61870-536) containing 10% fetal bovine serum (FBS) was used.
Next, in the insert upper layer (chamber) of Transwell (Transwell (registered trademark), 24-well, Poros size: 5 μm, manufactured by Corning, product number 3421), the BMMC was set to 3 × 10 ⁵ cells / well. A suspension of 100 μL of medium containing 0.0025%) was seeded (see “Chamber” in Table 2 below). To the lower layer, 500 μL of medium containing tranilast (0.0025%) and SCF (10 ng / mL) were added. After 4 hours, the BMMC migrating from the upper layer to the lower layer of the insert was collected, and fluorescence observation was performed using ImageXpress Micro confocal (manufactured by Molecular Device) to measure the number of living cells (cells / visual field). As the medium used for Transwell, RPMI (manufactured by Gibco, product number 61870-536) medium containing 0.2% DMSO and 10% FBS was used.

[Example 2-2]
Examples were treated in the same manner as in Example 2-1 except that the amount of tranilast added to the pretreatment medium was 0.01% and the amount of lower tranilast added was 0.01%. It was set to 2-2.

[Control 2]
Control 2 was treated in the same manner as in Example 2-1 except that tranilast was not added to the pretreatment medium and tranilast and SCF were not added to the lower layer.

[Test Example 2-1]
Test Example 2-1 was treated in the same manner as in Example 2-1 except that tranilast was not added to the pretreatment medium and tranilast was not added to the lower layer.

[Test Example 2-2]
Test Example 2-2 was treated in the same manner as in Example 2-2 except that SCF was not added to the lower layer.

The outlines of the above examples and test examples are shown in Table 2 below, and the results are shown in FIG.

As shown in FIG. 2, in Test Example 2-1 the number of living cells was significantly increased as compared with Control 2, and thus the migration promoting effect of bone marrow-derived mast cells by SCF was confirmed. In Examples 2-1 and 2-2, the number of viable cells was significantly reduced as compared with Test Example 2-1. Therefore, the effect of tranilast on the migration of bone marrow-derived mast cells was confirmed.
In Test Example 2-2, no significant change was confirmed in the number of viable cells as compared with Control 2, and the migration promoting action and migration suppressing action of bone marrow-derived mast cells by tranilast itself were not confirmed.

<Test 3: Evaluation of mast cell migration inhibitory effect by pemirolast>
[Example 3]
Bone marrow cells collected from mice (C57BL / 6J, 8 weeks old) were cultured in a basal medium supplemented with IL-3 and SCF (manufactured by PEPROTECH, product number 250-03) into bone marrow-derived mast cells (BMMC). Induction was performed to obtain a BMMC-containing medium. BMMC pretreated with RPMI (manufactured by Gibco, product number 61870-536) containing 10% fetal bovine serum (FBS) was resuspended in pretreatment medium supplemented with pemirolast (0.01% of medium volume). (See "Pretreatment" in Table 3 below). After 6 hours, BMMC was stained with 1 μg / mL Calcein-AM (manufactured by Invitrogen). As the basal medium, 1% Antibiotic-Atimycotic, 1% sodium pyruvate, 1% Non-Essential Amino Acid Solution, 10% fetal bovine serum (FBS) -containing RPMI (Gibco, product number 61870-036) medium is used. There was. As the pretreatment medium, RPMI (manufactured by Gibco, product number 61870-536) containing 10% fetal bovine serum (FBS) was used.
Next, in the insert upper layer (chamber) of Transwell (Transwell (registered trademark), 24-well, Poros size: 5 μm, manufactured by Corning, product number 3421), pemirolast ^{(Pemirolast) so that the BMMC is 3 × 10 5} cells / well. A suspension of 100 μL of medium containing (0.01%) was seeded (see “Chamber” in Table 3 below). To the lower layer, 500 μL of medium containing pemirolast (0.01%) and SCF (10 ng / mL) were added. After 4 hours, the BMMC migrating from the upper layer to the lower layer of the insert was collected, and fluorescence observation was performed using ImageXpress Micro confocal (manufactured by Molecular Device) to measure the number of living cells (cells / visual field). As the medium used for Transwell, RPMI (manufactured by Gibco, product No. 61870-036) medium containing 10% FBS was used.

[Control 3]
Control 3 was treated in the same manner as in Example 3 except that pemirolast was not added to the pretreatment medium and pemirolast and SCF were not added to the lower layer.

[Test Example 3-1]
Test Example 3-1 was treated in the same manner as in Example 3 except that pemirolast was not added to the pretreatment medium and pemirolast was not added to the lower layer.

[Test Example 3-2]
Test Example 3-2 was treated in the same manner as in Example 3 except that SCF was not added to the lower layer.

The outlines of the above examples and test examples are shown in Table 3 below, and the results are shown in FIG.

As shown in FIG. 3, in Test Example 3-1 the number of living cells was significantly increased as compared with Control 3, confirming the migration promoting effect of bone marrow-derived mast cells by SCF. In Example 3, the number of living cells was significantly reduced as compared with Test Example 3-1. Therefore, the effect of pemirolast on the migration of bone marrow-derived mast cells was confirmed.
In Test Example 3-2, no significant change was confirmed in the number of living cells as compared with Control 3, and the migration promoting action and migration suppressing action of bone marrow-derived mast cells by pemirolast itself were not confirmed.

Moreover, when the mast cell migration inhibitory effect of sodium cromoglycate was evaluated, the migration inhibitory effect of bone marrow-derived mast cells by sodium cromoglycate was confirmed.

From the above test results, it was confirmed that the mast cell migration inhibitory action of the antiallergic drug can suppress the aggravation of allergic symptoms.

[Formulation example]
The preparation examples shown in the table below were prepared to obtain an ophthalmic composition having an effect of suppressing the migration of inflammatory cells such as mast cells. The blending ratio of each component is based on the total amount of ophthalmic composition, and the unit is w / v%.

Claims (5)

An ophthalmic composition containing an antiallergic drug that suppresses the aggravation of allergic symptoms. Claim 1 The antiallergic agent is at least one selected from the group consisting of tranilast, ibudilast, pemirolast, acitazanolast, amlexanox, ketotifen, levocabastine, olopatadine, epinastine, cromoglycic acid, and salts thereof. The ophthalmic composition according to. The ophthalmic composition according to claim 1 or 2, wherein the aggravation of the allergic symptom is the aggravation of the allergic symptom due to the migration of inflammatory cells. The ophthalmic composition according to claim 3, wherein the inflammatory cells are mast cells. Due to the migration of inflammatory cells containing at least one selected from the group consisting of tranilast, ibudilast, pemirolast, acitazanolast, amlexanox, ketotifen, levocabastine, olopatadine, epinastine, cromoglycic acid, and salts thereof. , A remedy for allergic diseases.

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