Ophthalmic composition and allergic disease therapeutic

Abstract

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

Description

[Technical Field]

[0001] The present invention relates to an ophthalmic composition and an allergic reaction product used to suppress the aggravation of allergic symptoms. It relates to a drug for treating gastrointestinal diseases. [Background technology]

[0002] Allergic symptoms are caused by contact with allergens, which activate mast cells or basophils. This causes the release (degranulation) of chemical mediators such as histamine. It is known that allergic reactions are caused by the histamine. It is effective to inhibit the release of ATP itself.

[0003] Previously, drugs have been developed that inhibit histamine release by inhibiting the degranulation of mast cells. and is being used (for example, Patent Document 1). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Laid-Open No. 2001-97865 Summary of the Invention [Problem to be solved by the invention]

[0005] However, research into the aggravation of allergic symptoms has not yet progressed sufficiently. [Means for solving the problem]

[0006] Inflammatory cells such as mast cells are deeply involved in the aggravation of allergic symptoms. Some chemical mediators released from inflammatory cells promote the migration of inflammatory cells. In the conjunctiva of patients with allergic conjunctivitis, migrated mast cells Accumulates at the site of inflammation.

[0007] As a result of extensive research, the present inventors have discovered that anti-allergic drugs inhibit the migration of inflammatory cells. The present invention is based on this new finding. It is based on this.

[0008] That is, the present invention provides the following [1] to [5]. [1] An ophthalmic composition containing an antiallergic drug that suppresses the aggravation of allergic symptoms. . [2] The antiallergic drug is tranilast, ibudilast, pemirolast, ashitaba Zanolast, amlexanox, ketotifen, levocabastine, olopatadine, Epina at least one selected from the group consisting of cromolyn, cromolyn acid, and salts thereof; The ophthalmic composition according to [1]. [3] The aggravation of the allergic symptoms is due to the migration of inflammatory cells. The ophthalmic composition according to [1] or [2], which is an ophthalmic composition for treating eye diseases. [4] The ophthalmic composition described in [3], wherein the inflammatory cells are mast cells. [5] Tranilast, ibudilast, pemirolast, ashitazanolast, amlexa Nox, ketotifen, levocabastine, olopatadine, epinastine, cromoglycate and salts thereof. A drug for treating allergic diseases caused by running. [Effects of the Invention]

[0009] According to the present invention, an ophthalmic solution that inhibits the migration of inflammatory cells and prevents the aggravation of allergic symptoms is provided. A composition for use can be provided. [Brief explanation of the drawings]

[0010] [Figure 1] FIG. 1 is a graph showing the results of Test 1. [Figure 2] FIG. 2 is a graph showing the results of Test 2. [Figure 3] FIG. 3 is a graph showing the results of Test 3. DETAILED DESCRIPTION OF THE INVENTION

[0011] Hereinafter, the embodiments of the present invention will be described in detail. It is not limited to the embodiment.

[0012] In this specification, the content unit "w / v%" is synonymous with "g / 100 mL."

[0013] [Ophthalmic composition] The ophthalmic composition according to an embodiment of the present invention contains an antiallergic drug and is effective for treating allergic symptoms. It is an ophthalmic composition for suppressing the aggravation of the condition.

[0014] The antiallergic drug contained in the ophthalmic composition according to this embodiment inhibits the migration of inflammatory cells. Examples of antiallergic drugs include tranilast and ibudi. Last, pemirolast, ashitazanolast, amlexanox, ketotifen, levocaba Examples of such antihistamines include phenytoin, olopatadine, epinastine, cromoglycate, and salts thereof.

[0015] The salts of antiallergic drugs are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Any suitable salt may be used, for example, an alkali metal or alkaline earth metal salt (e.g., permirolastokine). Cromoglycate sodium, cromoglycate potassium, cromoglycate magnesium Calcium cromoglycate, etc.), inorganic acid salts (olopatadine hydrochloride, epinastine hydrochloride salts, levocabastine hydrochloride, etc.), organic acid salts [e.g., tosylate, fumarate (fumaric acid Ketotifen, etc.), etc. Hydrates of each salt may also be used.

[0016] These antiallergic drugs can be used singly or in appropriate combination of two or more. Among these, tranilast or a salt thereof, chromo Glycic acid or a salt thereof, pemirolast or a salt thereof are preferred, and tranilast, cromoglycol These anti-allergic drugs inhibit the migration of inflammatory cells. It can also be used as a treatment for allergic diseases caused by running.

[0017] The content of the antiallergic drug in the ophthalmic composition according to this embodiment is The amount is determined appropriately depending on the type and content, the formulation form of the ophthalmic composition, etc. The total content is, for example, 0.001 w / v% or more, preferably 0.001 w / v% or more, based on the total amount of the ophthalmic composition. The content is preferably 0.01 to 5 w / v%, more preferably 0.01 to 1 w / v%.

[0018] The antiallergic drug contains at least one selected from tranilast and its salts. When the ophthalmic composition contains the component, the total content of the component is, for example, 0.001 w / v% or more, preferably 0.01 to 10 w / v%, more preferably 0.05 to 5 w / v%, More preferably, it is 0.07 to 2 w / v%, even more preferably, it is 0.1 to 1 w / v%, and particularly preferably, it is 0.1 to 1 w / v%. Preferably, it is 0.2 to 1 w / v%, and most preferably, it is about 0.25 to 0.8 w / v%. Among these, 0.3 to 0.7 w / v% is preferable, and 0.4 to 0.6 w / v% is more preferable. Preferably, 0.45 to 0.55 w / v % (eg, 0.5 w / v %) is particularly preferred.

[0019] At least one antiallergic drug selected from cromoglycic acid and its salts When the ophthalmic composition contains the above components, the total content of the components is, for example, 0.1 to 10 w / v%, preferably 0.2 to 8 w / v%, more preferably 0.3 to 5 w / v%, and even more preferably Preferably 0.4 to 4 w / v%, even more preferably 0.5 to 3 w / v%, particularly preferably 0.7 to 2.0 w / v%, more particularly preferably 0.8 to 1.5 w / v%, most preferably It may be about 0.9 to 1.2 w / v %, with 1.0 w / v % being particularly preferred. .

[0020] At least one selected from pemirolast and its salts is used as an antiallergic drug ingredient. When the ophthalmic composition contains the component, the total content of the component is, for example, 0.0001wt% based on the total amount of the ophthalmic composition. / v% or more, preferably 0.0001 to 1 w / v%, more preferably 0.001 to 0.5 It may be about 0.005 to 0.2 w / v%, more preferably about 0.005 to 0.2 w / v%. 0.1 w / v % is particularly preferred.

[0021] The ophthalmic composition according to this embodiment further contains a nonionic surfactant in addition to the antiallergic drug. The nonionic surfactant may be any of those having medicinal, pharmacological (pharmaceutical) or There are no particular limitations as long as it is physiologically acceptable.

[0022] Specifically, nonionic surfactants include polyoxyethylene (hereinafter referred to as "POE"). (hereinafter also referred to as "POP")-polyoxypropylene glycol (e.g., poly Poloxamers such as Poloxamer 407, Poloxamer 235, and Poloxamer 188; Poloxamers POE-POP block copolymer adducts of ethylenediamine such as oxamine; monolaurate Polysorbate 20, Sorbitan (Polysorbate 20), Monooleate POE(20) Sorbitan (Polysorbate 80), POE Sorbitan Monostearate (Polysorbate POE sorbitan tristearate (Polysorbate 60), POE sorbitan tristearate (Polysorbate 65), etc. Tan fatty acid esters; POE(5) hydrogenated castor oil, POE(10) hydrogenated castor oil, PO E(20) hydrogenated castor oil, POE(40) hydrogenated castor oil, POE(50) hydrogenated castor oil, POE hydrogenated castor oils such as POE(60) hydrogenated castor oil and POE(100) hydrogenated castor oil; POE castor oil such as POE(3) castor oil, POE(10) castor oil, POE(35) castor oil, etc. Mulberry oil; POE(9) lauryl ether and other POE alkyl ethers; POE(20) POE·POP alkyl ethers such as POP(4) cetyl ether; POE(10) POE alkyl phenyl ethers such as phenyl ether; polyoxy stearate Examples include polyethylene glycol monostearate such as PEG-40. The numbers indicate the average number of moles of POP or POE added.

[0023] Among these nonionic surfactants, POE-POP glycol, POE sorbitan Fatty acid esters, POE hydrogenated castor oil, POE castor oil, and polyethylene monostearate Ethylene glycols are preferred, and poloxamer 407, monooleic acid POE(20) soybean oil, Rubitan (Polysorbate 80), POE (60) hydrogenated castor oil (polyoxyethylene hardener) Hydrogenated Castor Oil 60), POE(40) Hydrogenated Castor Oil (Polyoxyethylene Hydrogenated Castor Oil 40) ), POE(3) Castor Oil (Polyoxyethylene Castor Oil 3), POE(10) Castor Oil (Polyoxyethylene Castor Oil 10), POE(35) Castor Oil (Polyoxyethylene Castor Oil Malus oil 35), polyoxyl stearate 40 is more preferred, POE monooleate ( 20) Sorbitan and POE(60) hydrogenated castor oil are particularly preferred.

[0024] These nonionic surfactants may be synthesized by known methods or may be commercially available. The nonionic surfactants may be used alone or in any combination of two or more. may be used in combination with

[0025] When the ophthalmic composition according to this embodiment contains a nonionic surfactant, The content of nonionic surfactants depends on the type of nonionic surfactant, the type and amount of other ingredients, etc. The total content of the nonionic surfactants relative to the total amount of the ophthalmic composition can be set appropriately according to the requirements. Although not limited, it is preferably 0.0001 to 10 w / v%, more preferably 0.001 Up to 5 w / v%, more preferably 0.005 to 1 w / v%, and particularly preferably 0.01 to 0. It is 5 w / v%.

[0026] The ophthalmic composition according to this embodiment further contains a thickener in addition to the antiallergic drug. Specific examples of the thickener include methyl cellulose, ethyl cellulose, hydroxy cellulose, Ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxy hydroxypropyl methylcellulose (hypromellose), carboxymethylcellulose and cellulose-based polymer compounds such as carboxyethyl cellulose and its salts, Glycosaminoglycans such as leutin sulfate and its salts, hyaluronic acid and its salts, poly Vinyl alcohol (fully or partially saponified), polyvinylpyrrolidone (K17, K25, K30, K90, etc.), vinyl polymers such as carboxyvinyl polymers and their salts, dextromethorphan Macrogol such as Tran, Macrogol 6000, Macrogol 4000, Macrogol 400 Examples include gall (polyethylene glycol), gellan gum, and alginic acid and its salts. Here, the salt is not particularly limited, but sodium salt is preferred. From the viewpoint of significantly achieving the above, glycosaminoglycan, cellulose-based polymer, or vinyl-based polymer is used. Glycosaminoglycans are preferred, and chondroitin sulfate, hyaluronan, etc. are more preferred. More preferred are chondroitin acids and their salts, and sodium chondroitin sulfate (chondroitin sulfate More preferred are sodium hyaluronate and sodium hyaluronate.

[0027] These thickeners may be synthesized by known methods or may be commercially available products. These thickeners may be used alone or in any combination of two or more. It's fine.

[0028] When a thickener is blended in the ophthalmic composition according to this embodiment, the total content of the thickener is The amount of the thickener to be used and the amount and type of other ingredients to be added can be appropriately determined. 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%, and even more preferably 0.001 to 1 w / v%, even more preferably 0.005 to 0.5 w / v%, particularly preferably 0.0 The concentration is 1 to 0.5 w / v%, and most preferably 0.05 to 0.3 w / v%.

[0029] The ophthalmic composition according to this embodiment may further contain a buffering agent in addition to the antiallergic drug. Buffers that can be incorporated into the ophthalmic composition include those that are medicinally, pharmacologically (pharmaceutical) or biocompatible. There are no particular limitations on the buffering agent as long as it is physiologically acceptable. Borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, Tris buffer , aspartic acid, aspartate, epsilon-aminocaproic acid, etc. As the buffer, borate buffer, phosphate buffer, carbonate buffer, and citrate buffer are preferred. .

[0030] Examples of borate buffers include boric acid, alkali metal borates, and alkali borates. Examples of phosphate buffers include, for example, phosphoric acid or phosphate buffers. Examples of suitable phosphates include alkali metal phosphates and alkaline earth metal phosphates. Examples of the carbonate include carbonic acid, alkali metal carbonate, and alkaline earth metal carbonate. Examples of citrate buffers include citric acid and alkali metal citrate. salts, alkaline earth metal citrates, etc.

[0031] Hydrates of the respective salts may also be used as buffering agents. However, boric acid or its salts (sodium borate, tetraborate, etc.) are used as borate buffers. potassium, potassium metaborate, ammonium borate, borax, etc.); as a phosphate buffer , phosphoric acid or its salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, dihydrogen phosphate) Potassium, trisodium phosphate, dipotassium phosphate, monobasic calcium phosphate, dibasic calcium phosphate Calcium hydrogen carbonate, etc.); Carbonic acid or its salts (sodium bicarbonate, sodium carbonate, etc.) as a carbonate buffer Thorium, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, carbonate magnesium, etc.); citric acid buffers, such as citric acid or its salts (sodium citrate, Potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate acetic acid buffers, such as acetic acid or its salts (ammonium acetate, potassium acetate, acetic acid calcium, sodium acetate, etc.); aspartic acid or its salts (sodium aspartate Aspartic acid, magnesium aspartate, potassium aspartate, magnesium aspartate Examples include hydrates of each salt as raw materials for the production of buffers. It may be used.

[0032] Among the buffers, borate buffers and phosphate buffers are particularly preferred, and borate buffers are more preferred. Preferred examples of the borate buffer include boric acid, a combination of boric acid and a salt thereof ( For example, boric acid and borax can be mentioned, and preferably boric acid or a combination of boric acid and borax. A more preferred example is boric acid.

[0033] These buffers may be synthesized by known methods or may be commercially available products. These buffers may be used alone or in any combination of two or more. It's fine.

[0034] When a buffering agent is contained in the ophthalmic composition according to this embodiment, the content of the buffering agent is The amount of the solution can be appropriately determined depending on the type of buffer used, the types and amounts of other ingredients, etc. The total content of the buffering agent relative to the total amount of the composition is not limited, but is preferably 0.01 to 1.00. 10 w / v%, more preferably 0.05 to 5 w / v%, and even more preferably 0.1 to 3 w / v %, and particularly preferably 0.3 to 2 w / v %.

[0035] The ophthalmic composition according to this embodiment may further contain a cooling agent in addition to the antiallergic agent. The cooling agent is not particularly limited, but examples thereof include menthol, anethole, and eugenol. Nol, camphor, geraniol, cineole, borneol, limonene, ryunou, etc. These may be in the d-, l- or dl-form. , peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon Also included are essential oils such as bergamot oil, eucalyptus oil, and rose oil.

[0036] Among these, terpenoids are preferred, and particularly menthol, camphor, and geraniol. , cineole, borneol, and ryuno are preferred, and menthol, camphor, and borneol are preferred. More preferred is menthol, and even more preferred is menthol.

[0037] These cooling agents may be synthesized by known methods or may be commercially available products. These cooling agents may be used alone or in combination of two or more.

[0038] The total content of the cooling agent is, for example, 0.0001 w / v% relative to the total amount of the ophthalmic composition. or more, 0.0005w / v% or more, 0.001w / v% or more, 0.002w / v% or more, 0.003w / v% or more, 0.004w / v% or more, 0.005w / v% or more, 0.00 6w / v% or more, 0.007w / v% or more, 0.008w / v% or more, 0.009w / v % or more, or 0.01 w / v% or more.

[0039] The total content of the cooling agent is 1 w / v% or less, 0.1 w / v% or less, based on the total amount of the ophthalmic composition. w / v% or less, 0.09w / v% or less, 0.08w / v% or less, 0.07w / v% or less, 0.06w / v% or less, 0.05w / v% or less, 0.04w / v% or less, 0.03w / v % or less, or 0.02 w / v% or less.

[0040] The ophthalmic composition according to this embodiment further contains an isotonic agent in addition to the antiallergic agent. Specific examples of the tonicity agent that can be incorporated into the ophthalmic composition of the present invention include bisulfite. Sodium, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, chloride Magnesium, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol Among these isotonicity agents, the following are particularly effective in achieving the effects of the present invention: From this viewpoint, sodium chloride, potassium chloride, calcium chloride, magnesium chloride are preferable. These tonicity agents include cereals, glycerin, and propylene glycol. They may be used alone or in any combination of two or more.

[0041] When an isotonic agent is contained in the ophthalmic composition according to this embodiment, the content of the isotonic agent is The amount of the isotonic agent used can be determined appropriately depending on the type and amount of other ingredients used. The total content of the buffering agent relative to the total amount of the ophthalmic composition is not limited, but is preferably 0. 0.01 to 10 w / v%, preferably 0.05 to 5 w / v%, more preferably 0.1 to 3 w / v%.

[0042] In addition to the antiallergic drug, the ophthalmic composition according to this embodiment may contain other ingredients that are usually used in ophthalmic compositions. Any component that can be contained in the composition may be contained. Such components are not particularly limited, and For example, the 2012 edition of the OTC Drug Manufacturing and Sales Approval Standards (Regulatory Agency of Japan) Examples of active ingredients (pharmacologically active ingredients, physiologically active ingredients, etc.) listed in the "Medicine and Pharmaceutical Sciences Association" are listed. Specifically, the following ingredients are included:

[0043] Antihistamines: e.g., iproheptine, diphenhydramine hydrochloride, chloromaleate rupheniramine and the like.

[0044] Decongestants: e.g., tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline sulfate , epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, hydrochloric acid phenylephrine and the like.

[0045] Ocular muscle regulating drugs: for example, cholinesterases with an active center similar to that of acetylcholine enzyme inhibitors, specifically neostigmine methylsulfate, tropicamide, helenien, and acetaminophen Lopin et al.

[0046] Vitamins: e.g., flavin adenine dinucleotide sodium, pyridoxine hydrochloride , Cyanocobalamin, Retinol Acetate, Retinol Palmitate, Tocopherol Acetate, Panthenol, calcium pantothenate, sodium pantothenate, etc.

[0047] Amino acids: e.g., aminoethylsulfonic acid (taurine), potassium L-aspartate L-aspartic acid magnesium, L-aspartic acid magnesium potassium, etc. .

[0048] Anti-inflammatory agents: for example, glycyrrhizinic acid, dipotassium glycyrrhizinate, glycyrrhetinic acid , methyl salicylate, glycol salicylate, azulene sulfonic acid, azulene sulfonic acid Sodium, allantoin, tranexamic acid, berberine, lysozyme, lysozyme chloride , berberine chloride, berberine sulfate, epsilon-aminocaproic acid, indomethacin, Pranoprofen, Ibuprofen, Ibuprofen Piconol, Ketoprofen, Zyk Lofenac sodium, bromfenac sodium, felbinac, bendazac, pyro xicam, bufexamac, butyl flufenamate and the like.

[0049] Astringents: for example, zinc oxide, zinc lactate, zinc sulfate, etc. These may be hydrated.

[0050] Local anesthetic ingredients: for example, procaine hydrochloride, lidocaine hydrochloride, etc.

[0051] Others: For example, sulfamethoxazole, sulfamethoxazole sodium, sulfamethoxazole Fisoxazole, sulfisomidine sodium, purple root, horse chestnut, and Salt, etc.

[0052] The blending ratios of various active ingredients are known in the field of ophthalmic compositions, and The blending ratio of the above-mentioned components in the ophthalmic composition depends on the dosage form of the ophthalmic composition, the pharmacologically active component or physiologically active component. For example, the formulation of pharmacologically active ingredients or physiologically active ingredients The ratio is usually 0.0001 to 30 w / v% of the total amount of the ophthalmic composition. The concentration can be adjusted to preferably about 0.001 to 10 w / v %.

[0053] The above active ingredients can be used alone or in any combination of two or more.

[0054] Furthermore, the ophthalmic composition according to this embodiment may contain a carrier, a pH adjuster, a common sugar, a common Select additives such as chelating agents, stabilizers, and preservatives, and use at least one of them in combination as appropriate. These additives may be contained in an amount of, for example, the Pharmaceutical Additives Encyclopedia 2007 (Japan Examples of additives are listed in the Pharmaceutical Additives Association (ed.). Additives can be mentioned.

[0055] Carrier: For example, an aqueous carrier such as aqueous ethanol.

[0056] Sugars: for example, monosaccharides, disaccharides, specifically glucose, cyclodextrin, alpha -cyclodextrin, etc. Sugar alcohols: e.g., maltose, trehalose, sucrose, xylitol, sorbitol, mannitol, glycerin, etc.

[0057] pH adjusters: for example, hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide ammonium, magnesium hydroxide, triethanolamine, diisopropylamine, etc.

[0058] Stabilizers: e.g., trometamol, sodium formaldehyde sulfoxylate ( Rongalit), sodium pyrosulfite, monoethanolamine, aluminum monostearate Aluminum, glycerin monostearate, dibutylhydroxytoluene (BHT), cyclohexyl palmitate Rodextrin etc.

[0059] Chelating agents: e.g., ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid , ethylenediaminetetraacetic acid (edetic acid, EDTA), N-(2-hydroxyethyl)ethyl Diethylenetriaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), Asco edetate, tetrasodium edetate, sodium edetate, etc.

[0060] Antiseptics, disinfectants or antibacterial agents: For example, alkyl quaternary ammonium salts (benzalkonium chloride) ium, benzethonium chloride, etc.), biguanide compounds (specifically, polyhexanide hydrochloride, etc. ), chlorhexidine hydrochloride, chlorhexidine gluconate, sodium benzoate, ethanol alcohol, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, Methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, Butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol Cole, Gloquil, Acrinol, Cetylpyridinium, Zinc Chloride, Alkyldiamino Ethylglycine, lauryldimethylaminoacetic acid betaine, etc.

[0061] Anionic surfactants: e.g., alkylbenzene sulfonates, alkyl sulfates, poly Oxyethylene alkyl sulfate, aliphatic α-sulfomethyl ester, α-olefin sulfonate Phononic acid etc.

[0062] Oils: For example, vegetable oils such as sesame oil, castor oil, soybean oil, olive oil, squalane, Animal oils such as nolin, mineral oils such as liquid paraffin and vaseline, etc.

[0063] Other: Lipidure-PMB (2-methacryloyloxyethyl phosphorylcholine methyl Butyl acrylate copolymer), Lipidure-HM, caffeine, etc.

[0064] [Physical Properties] The pH of the ophthalmic composition according to this embodiment is determined based on pharmaceutical, pharmacological (pharmaceutical) or There are no particular limitations as long as it is within a physiologically acceptable range. From the viewpoint of enhancing the stability of the pharmaceutical composition, the pH is 4.0 to 9.0, preferably 4.5 to 8. 5, more preferably 5.0 to 8.0, even more preferably 6.0 to 8.0, and particularly preferably The range is 6.5 to 8.0.

[0065] The ophthalmic composition according to the present embodiment may further contain, as necessary, a substance capable of permeating the ophthalmic composition within a range acceptable to the living body. The appropriate osmotic pressure ratio varies depending on the application site, dosage form, etc., but is usually , 0.5 to 5.0, more preferably 0.6 to 3.0, and even more preferably 0.7 to 2.0. The osmolality ratio is 286 mOsm (0. The osmotic pressure is the ratio of the osmotic pressure of the sample to the osmotic pressure of a 9 w / v% sodium chloride aqueous solution. The measurement is carried out according to the osmotic pressure measurement method (freezing point depression method) described in this Pharmacopoeia. The standard solution (0.9 w / v% sodium chloride aqueous solution) is sodium chloride (Japanese Pharmacopoeia standard reagent ) was dried at 500-650°C for 40-50 minutes, and then placed in a desiccator (silica gel). Cool, accurately measure 0.900 g, dissolve in purified water and make exactly 100 mL. Alternatively, use a commercially available standard solution for measuring osmotic pressure ratios (0.9 w / v% sodium chloride solution). The osmotic pressure can be adjusted by using inorganic salts, polyhydric alcohols, sugar alcohols, sugars, etc., as known in the art. This can be done by known methods.

[0066] The viscosity of the ophthalmic composition according to this embodiment is within a physiologically or pharmacologically acceptable range. If so, it will be set appropriately depending on the type and content of the compounded ingredients, the formulation form, the method of use, etc. Measured using a rotating viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34' x R24) The viscosity at 20°C is preferably 1 to 10,000 mPa·s, and more preferably 1 to 100 It is more preferable to set it to 0 mPa·s, and even more preferable to set it to 1 to 100 mPa·s. It is even more preferable that the viscosity is 1 to 10 mPa·s.

[0067] The ophthalmic composition according to this embodiment may contain, for example, an antiallergic agent and, if necessary, other ingredients. The composition can be prepared by adding and mixing the ingredients so as to obtain the desired content. Specifically, for example, the above components are dissolved or suspended in purified water, and the pH and osmotic pressure are adjusted to a predetermined level. The solution can be prepared by adjusting the amount of the solution and sterilizing it by filtration sterilization or the like.

[0068] The ophthalmic composition according to this embodiment can be in various dosage forms depending on the purpose, for example, Examples of such preparations include liquid preparations, gel preparations, semi-solid preparations (ointments, etc.), and gel ointments. The ophthalmic composition according to this embodiment is preferably an aqueous solution. When the above is made into an aqueous solution, the content of water is, for example, 50 w / v relative to the total amount of the ophthalmic composition. % or more, preferably 70 w / v% or more, and more preferably 80 w / v% or more. It is more preferable that the content is 90 w / v % or more, and even more preferable that the content is 90 w / v % or more. The water used in the composition is medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable. Water may be used, and examples of such water include distilled water, tap water, purified water, and sterilized purified water. , water for injection, distilled water for injection, etc.

[0069] The ophthalmic composition according to this embodiment is used in the ophthalmic field and is effective in preventing eye damage when it comes into contact with the eye. There are no restrictions on the formulation form as long as it is used as described above. For example, eye drops (However, eye drops include those that can be used while wearing contact lenses), artificial tears, eye drops, Ointments, eyewashes (including eyewashes that can be used while wearing contact lenses) , contact lens compositions [contact lens wetting solution, contact lens care composition (Contact lens disinfectant, contact lens preservative, contact lens cleaner, Cleansing and preservative agents for contact lenses, etc. Among these, eye drops are preferred. Please note that "contact lenses" are classified into hard contact lenses and soft contact lenses (Ion This includes both ionic and nonionic contact lenses, and is suitable for silicone hydrogel contact lenses and non-silicone hydrogel contact lenses. This includes both acrylic and hydrogel contact lenses.

[0070] The ophthalmic composition according to this embodiment is used according to the method of use that corresponds to the formulation. For example, when the ophthalmic composition is an eye drop (including an eye drop for contact lenses), it is Alternatively, an appropriate amount of eye drops may be instilled into the eye wearing a contact lens. Even if the composition is an eyewash (including eyewash for contact lenses), it should not be used on naked eyes or contact lenses. An appropriate amount of eyewash may be used to wash the eyes wearing the lenses. If you are using contact lens solution, please use the contact lens and solution when wearing the contact lenses. The compound is used by contacting an appropriate amount of the compound.

[0071] [container] The container into which the ophthalmic composition according to the present embodiment is filled is not particularly limited. Polyethylene terephthalate, polyarylate, polycarbonate, polyethylene, polypropylene Containers made of polyethylene terephthalate are particularly preferred. The composition may be filled in a light-shielding container. By placing the composition in a light-shielding container, the composition according to this embodiment can be The container can keep the ophthalmic composition stable for a long period of time. By mixing, you can block out light, or shrink film, polypropylene The light may be blocked by covering the container with a case or outer box such as the one shown.

[0072] [Application] The ophthalmic composition according to this embodiment contains an antiallergic drug, thereby preventing allergic reactions. It is intended for a new use in preventing the aggravation of symptoms.

[0073] In this embodiment, the aggravation of allergic symptoms refers to the progression of various allergic symptoms to a severe state. For example, itching of the eyes may worsen, the frequency of itching may increase, redness may worsen, or abnormalities may occur. These include worsening of sensation of substance, eye discharge, and watery eyes. From this viewpoint, the ophthalmic composition according to this embodiment is effective in preventing the worsening of eye itching (itching) and the increase in the frequency of itching. It is preferable that the product be used for the purpose of suppressing allergic reactions. It is recommended to use this medicine when sufficient effect has not been obtained after using the eye drops for about two days.

[0074] In this embodiment, factors that may aggravate allergic symptoms include, but are not limited to, the following: For example, migration of inflammatory cells such as mast cells, basophils, eosinophils, neutrophils, and macrophages. In order to more significantly exhibit the effects of the present invention, the ophthalmic composition according to this embodiment is The product is intended to be used to suppress the aggravation of allergic symptoms caused by mast cell migration. It is preferable that:

[0075] In this embodiment, the chemical mediator that promotes the migration of inflammatory cells is, in particular, For example, but not limited to, prostaglandin D2 (PGD2), prostaglandin E 2 (PGE2), leukotriene B4 (LTB4), interleukin 15 (IL-15), Inhibits the migration of inflammatory cells, such as CCL2 chemokine (MCP-1) and stem cell factor (SCF). From the viewpoint of more significantly exhibiting the effects of the present invention, The ophthalmic composition according to this embodiment is a composition comprising a compound selected from the group consisting of PGD2, PGE2, LTB4, and SCF. The present invention relates to a method for treating mast cell migration caused by at least one chemical mediator selected from the group consisting of: It is preferable that the compound be used to suppress the aggravation of allergic symptoms caused by PGD2, PGE2 and LTB4. It is more preferable that the composition be used for suppressing the aggravation of allergic symptoms caused by cell migration. stomach.

[0076] The ophthalmic composition according to one embodiment of the present invention contains an antiallergic drug and an anti-inflammatory agent. The present invention is provided as an ophthalmic composition containing the anti-migration agent as an anti-migration agent. From the viewpoint of being particularly advantageous, the ophthalmic composition according to this embodiment is an ophthalmic composition containing an antiallergic agent, It is preferable that the ophthalmic composition contains the compound as a migration inhibitor to inhibit the migration of the compound.

[0077] One embodiment of the present invention is a composition for inhibiting the migration of inflammatory cells, which contains an antiallergic drug. From the viewpoint of more significantly exhibiting the effects of the present invention, The ophthalmic migration inhibitor according to the present embodiment contains an antiallergic drug and inhibits the migration of mast cells. It is preferable that the ophthalmic migration inhibitor is an ophthalmic antimigration agent.

[0078] The new use provided by the ophthalmic composition according to this embodiment is to release inflammatory cells. Unlike the conventional mechanism of action that suppresses histamine, which stimulates the proliferation of inflammatory cells such as mast cells, It is based on a new mechanism of action that suppresses eye irritation and It can suppress the migration and accumulation of inflammatory cells, which can cause an increase in the frequency of itching. The present invention is based on this novel finding. This may lead to the worsening of allergic symptoms such as itching of the eyes and an increase in the frequency of itching. It is extremely effective as an ophthalmic treatment for

[0079] [A drug for the treatment of allergic diseases caused by migration of inflammatory cells] One embodiment of the present invention is a pharmaceutical composition containing an anti-allergic drug, which is used to treat inflammation caused by the migration of inflammatory cells. From the viewpoint of more significantly exhibiting the effects of the present invention, A therapeutic drug for allergic diseases caused by migration of mast cells, containing an antiallergic drug. It is preferable to set the following.

[0080] Allergens for allergic symptoms or diseases are not particularly limited, but include, for example, pollen (cedar pollen, cypress pollen, etc.), house dust (indoor dust), PM2.5, yellow sand, etc. do.

[0081] [Method for imparting an inhibitory effect on migration of inflammatory cells to an ophthalmic composition] The eye drops according to this embodiment contain an antiallergic drug, which inhibits the migration of inflammatory cells. Therefore, in one embodiment of the present invention, the ophthalmic composition contains the above-mentioned By incorporating an allergy drug, the ophthalmic composition is endowed with an inflammatory cell migration effect. We can provide a method.

[0082] In the above method, the type and content of anti-allergic drugs, the type and content of other ingredients, etc. The dosage, formulation and use of the ophthalmic composition are the same as those described above for the ophthalmic composition. be. [Example]

[0083] The present invention will be described in detail below based on examples, but the present invention is not limited to these. The "%" in each test below is "w / v%."

[0084] <Test 1: Evaluation of the inhibitory effect of tranilast on mast cell migration (1)> [Example 1] Bone marrow cells collected from mice (C57BL / 6J, 8 weeks old) were cultured in the presence of IL-3 and SCF( PEPROTECH, product number 250-03) was added to the basal medium. The medium was then induced to produce BMMC-derived mast cells (BMMCs) and BMMC-containing medium was obtained. Pre-treated with RPMI (Gibco, product number 61870-036) containing FBS. The treated BMMCs were resuspended in pretreatment medium supplemented with tranilast (0.01% of the medium volume). After 6 hours, the cells were resuspended in 1 μg / mL of Calcein-A (see "Pretreatment" in Table 1 below). BMMCs were stained using 1% M (Invitrogen). Antibiotic-Antimycotic, 1% Sodium Pyruvate, 1% No n-Essential Amino Acid Slution, 10% Fetal Bovine Serum RPMI (Gibco, product number 61870-036) medium containing fetal bovine serum (FBS) was used. The treatment medium was RPMI (Gibco, product number 61) containing 10% fetal bovine serum (FBS). 870-036) medium was used. Then, the cells were placed in a Transwell (Transwell®, 24-well, Por e size: 5 μm, Corning, product number 3421) bar), BMMC is 3 × 10 5 Tranilast (0. The cells were inoculated with 100 μL of a suspension of medium containing 0.1% of the 200 μL of 1 ... The lower layer contained 500 μL of medium containing tranilast (0.01%) and PGD2 (Ca After 4 hours, 50 μM of 12010 (manufactured by Yman Chemical Co.) was added. BMMCs that migrated from the upper layer to the lower layer of the insert were collected and analyzed using ImageXpress Microscopy. Fluorescence observation was performed using cro confocal (Molecular Devices). The number of cells was counted (cells / field of view). The medium used for the Transwell was 0.2% Dimethyl sulfoxide (DMSO), RPMI containing 10% FBS (Gibco, product code: No. 61870-036) medium was used.

[0085] [Control 1] No tranilast was added to the pretreatment medium, and tranilast and PGD2 were added to the lower layer. Control 1 was prepared in the same manner as in Example 1 except that no addition was made.

[0086] [Test Example 1-1] Do not add tranilast to the pretreatment medium, and do not add tranilast to the lower layer. Other than that, the same treatment as in Example 1 was carried out as Test Example 1-1.

[0087] [Test Example 1-2] Test Example 1-1 was prepared in the same manner as in Example 1, except that PGD2 was not added to the lower layer. I chose 2.

[0088] The outline of the above examples and test examples is shown in Table 1 below, and the results are shown in FIG.

[0089] [Table 1]

[0090] As shown in Figure 1, in Test Example 1-1, the number of viable cells was significantly increased compared to Control 1. The addition of PGD2 confirmed the effect of promoting the migration of bone marrow-derived mast cells. In Example 1, the number of viable cells was significantly reduced compared to Test Example 1-1. The inhibitory effect of LAST on the migration of bone marrow-derived mast cells was confirmed. In Test Example 1-2, no significant change in the number of viable cells was confirmed compared to Control 1. However, the migration-promoting and migration-inhibiting effects of tranilast itself on bone marrow-derived mast cells have not been confirmed. It wasn't done.

[0091] <Test 2: Evaluation of the inhibitory effect of tranilast on mast cell migration (2)> [Example 2-1] Bone marrow cells collected from mice (C57BL / 6J, 8 weeks old) were cultured in the presence of IL-3 and SCF( PEPROTECH, product number 250-03) was added to the basal medium. The medium was then induced to produce BMMC-derived mast cells (BMMCs) and BMMC-containing medium was obtained. Pre-treated with RPMI (Gibco, product number 61870-036) containing FBS. The treated BMMCs were placed in a pretreatment medium containing tranilast (0.0025% of the medium volume). After 6 hours, the cells were resuspended in 1 μg / mL of Calcein- BMMCs were stained using AM (Invitrogen). %Antibiotic-Antimycotic, 1% Sodium Pyruvate, 1% N on-Essential Amino Acid Slution, 10% fetal bovine blood RPMI (Gibco, product number 61870-036) medium containing supernatant (FBS) was used. The pretreatment medium was RPMI (Gibco, product number 6) containing 10% fetal bovine serum (FBS). 1870-036) medium was used. Then, the cells were placed in a Transwell (Transwell®, 24-well, Por e size: 5 μm, Corning, product number 3421) bar), BMMC is 3 × 10 5 Tranilast (0. A suspension of 100 μL of medium containing 0.25% of the 25% ethanol was inoculated (see "Chamber" in Table 2 below). The lower layer contained 500 μL of medium containing tranilast (0.0025%) and SCF After 4 hours, BMMCs migrated from the upper layer to the lower layer of the insert. The samples were collected and analyzed using ImageXpress Micro confocal (Molecular Device). Fluorescence observation was performed using a microscope (manufactured by Isuzu) and the number of living cells was counted (cells / field of view). The medium used for the Transwell was RPMI (Gi The medium used was BCO (product number 61870-036).

[0092] [Example 2-2] The amount of tranilast added to the pretreatment medium was set to 0.01%. The same treatment as in Example 2-1 was carried out except that the amount of added phosphate was set to 0.01%. The score was 2-2.

[0093] [Control 2] No tranilast was added to the pretreatment medium, and tranilast and SCF were added to the lower layer. Control 2 was treated in the same manner as in Example 2-1, except that no treatment was performed.

[0094] [Test Example 2-1] Do not add tranilast to the pretreatment medium, and do not add tranilast to the lower layer. Other than the above, the same treatment as in Example 2-1 was carried out to prepare Test Example 2-1.

[0095] [Test Example 2-2] Test Example 2: The same treatment as in Example 2-2 was carried out except that SCF was not added to the lower layer. I set it to -2.

[0096] The outline of the above examples and test examples is shown in Table 2 below, and the results are shown in FIG.

[0097] [Table 2]

[0098] As shown in Figure 2, in Test Example 2-1, the number of viable cells was significantly increased compared to Control 2. The results confirmed that SCF promotes the migration of bone marrow-derived mast cells. In Examples 2-1 and 2-2, the number of viable cells was significantly reduced compared to Test Example 2-1. This confirmed that tranilast has the effect of inhibiting the migration of bone marrow-derived mast cells. In Test Example 2-2, no significant change in the number of viable cells was confirmed compared to Control 2. However, the migration-promoting and migration-inhibiting effects of tranilast itself on bone marrow-derived mast cells have not been confirmed. It wasn't done.

[0099] <Test 3: Evaluation of the inhibitory effect of pemirolast on mast cell migration> [Example 3] Bone marrow cells collected from mice (C57BL / 6J, 8 weeks old) were cultured in the presence of IL-3 and SCF( PEPROTECH, product number 250-03) was added to the basal medium. The medium was then induced to produce BMMC-derived mast cells (BMMCs) and BMMC-containing medium was obtained. Pre-treated with RPMI (Gibco, product number 61870-036) containing FBS. The treated BMMCs were resuspended in preconditioning medium supplemented with pemirolast (0.01% of the medium volume). After 6 hours, 1 μg / mL of Calcein-AM was added to the medium. BMMCs were stained using a basal medium containing 1% A Antibiotic-Antimycotic, 1% Sodium Pyruvate, 1% Non - Essential Amino Acid Slution, 10% Fetal Bovine Serum ( RPMI (Gibco, product number 61870-036) containing FBS was used. The culture medium was RPMI (Gibco, product number 618) containing 10% fetal bovine serum (FBS). 70-036) medium was used. Then, the cells were placed in a Transwell (Transwell®, 24-well, Por e size: 5 μm, Corning, product number 3421) bar), BMMC is 3 × 10 5 Pemirolast (0. The cells were inoculated with 100 μL of a suspension of medium containing 0.1% of the 200 μL of 1 ... The lower layer contained 500 μL of medium containing pemirolast (0.01%) and SCF (10 nL). After 4 hours, BMMCs that had migrated from the upper layer to the lower layer of the insert were collected. , ImageXpress Micro confocal (Molecular Devices) ) was used for fluorescence observation, and the number of living cells was counted (cells / field of view). The medium used in the wells was RPMI (Gibco, product number 61870) containing 10% FBS. -036) medium was used.

[0100] [Control 3] No pemirolast was added to the pretreatment medium, and pemirolast and SCF were added to the lower layer. Control 3 was treated in the same manner as in Example 3, except that no treatment was performed.

[0101] [Test Example 3-1] Do not add pemirolast to the pre-treatment medium, and do not add pemirolast to the lower layer. Other than the above, the same treatment as in Example 3 was carried out as Test Example 3-1.

[0102] [Test Example 3-2] Test Example 3-2 was prepared in the same manner as in Example 3, except that SCF was not added to the lower layer. It was decided.

[0103] The outline of the above examples and test examples is shown in Table 3 below, and the results are shown in FIG.

[0104] [Table 3]

[0105] As shown in Figure 3, in Test Example 3-1, the number of viable cells was significantly increased compared to Control 3. The results confirmed that SCF promotes the migration of bone marrow-derived mast cells. In Example 3, the number of viable cells was significantly reduced compared to Test Example 3-1. The inhibitory effect of stimuli on the migration of bone marrow-derived mast cells was confirmed. In Test Example 3-2, no significant change in the number of viable cells was confirmed compared to Control 3. However, the migration-promoting and migration-inhibiting effects of pemirolast itself on bone marrow-derived mast cells were not confirmed. It wasn't done.

[0106] In addition, we evaluated the inhibitory effect of sodium cromoglycate on mast cell migration. (b) The inhibitory effect of sodium cromoglycate on the migration of bone marrow-derived mast cells was confirmed.

[0107] The above test results suggest that the anti-allergic drug's inhibitory effect on mast cell migration may contribute to the allergic reaction. It was confirmed that this product can suppress the worsening of allergic symptoms.

[0108] [Formulation example] The formulation examples shown in the table below were prepared and tested to have the effect of inhibiting the migration of inflammatory cells such as mast cells. The blending ratio of each component is based on the total amount of the ophthalmic composition, and the unit is w / v%.

[0109] [Table 4]

[0110] [Table 5]

[0111] [Table 6]

Claims

[Claim 1] An agent for suppressing an increase in the frequency of eye itching, comprising at least one selected from the group consisting of tranilast, ibudilast, pemirolast, ashitazanolast, amlexanox, ketotifen, levocabastine, olopatadine, epinastine, cromoglycic acid, and salts thereof.

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