Combination of antiallergic agent and pharmaceutical composition for transdermal administration containing epinastine or salt thereof

Abstract

The present invention provides a pharmaceutical composition for transdermal administration containing epinastine or a salt thereof, the pharmaceutical composition being characterized by being administered in combination with an antiallergic agent.

Description

Combination of a pharmaceutical composition for transdermal administration containing epinastine or a salt thereof with an antiallergic drug

[0001] The present invention relates to a combination of a pharmaceutical composition for transdermal administration containing epinastine or a salt thereof and an antiallergic drug. More specifically, the present invention relates to a pharmaceutical composition for transdermal administration containing epinastine or a salt thereof (hereinafter also referred to as the "pharmaceutical composition of the present invention"), which is administered in combination with an antiallergic drug.

[0002] Allergic diseases are diseases caused by allergies, and typical allergic diseases include hay fever, allergic conjunctivitis, allergic rhinitis, atopic dermatitis, food allergies, and bronchial asthma. Hay fever is a general term for seasonal allergic diseases caused by pollen from plants such as cedar and cypress, and is said to affect a large number of people every year, regardless of age. Treatments for hay fever include avoiding pollen, which is an allergen, medication to suppress allergic symptoms such as itching and inflammation, and immunotherapy, which reduces reactivity to allergens by administering very small amounts of the allergen that causes the allergy.

[0003] Treatment of allergic conjunctival diseases, such as allergic conjunctivitis caused by pollen, mainly involves eye drops, and antiallergic eye drops, steroid eye drops, or immunosuppressant eye drops are selected depending on the type of disease. If the condition is mild, only antiallergic eye drops are used, but depending on the severity, antiallergic eye drops are used in combination with steroid eye drops or immunosuppressant eye drops (Non-Patent Document 1).

[0004] As an example of a drug for treating allergic conjunctivitis, there is "Alesion," which contains epinastine hydrochloride as an active ingredient and is usually administered as one drop at a time, four times a day. （登録商標） "0.05% Eye Drops" and "Allegion," which is usually administered one drop at a time, twice a day. （登録商標）Eye drops such as "LX eye drops 0.1%" are known (Non-Patent Documents 2 and 3). Regarding epinastine or its salts, ophthalmic transdermal formulations (hereinafter also referred to as epinastine transdermal formulations) have been reported as formulations other than eye drops (Patent Documents 1 to 3). Patent Document 1 reports that a patch containing a high concentration of epinastine hydrochloride (10% w / w) exhibits a prolonged antiallergic effect compared to eye drops containing 0.05% (w / v) epinastine hydrochloride. Patent Document 2 reports that a cream containing epinastine or a salt thereof exhibits a therapeutic effect as a therapeutic agent for allergic conjunctivitis even when administered to the eyelid skin once a day. Patent Document 3 reports a pharmaceutical composition for transdermal administration containing epinastine or a salt thereof, which has sufficient stability. However, none of the documents describe or suggest the combined use of an epinastine transdermal formulation and an antiallergic drug, or what effects may be expected when they are used in combination.

[0005] WO2007 / 007851 Patent No. 7124248 Patent No. 7171971

[0006] "Guidelines for the Treatment of Allergic Conjunctival Diseases - Key Points in Diagnosis and Treatment" Allergy, 2018 (Heisei 30), 67 (2), 103-107 Alesion (registered trademark) eye drops 0.05% package insert Alesion (registered trademark) LX eye drops 0.1% package insert

[0007] Non-Patent Document 1 describes that, for example, steroid eye drops used for severe allergic symptoms can cause an increase in intraocular pressure if administered in the eye continuously, which can lead to dangerous side effects such as glaucoma, and that this is more likely to occur with local administration such as eye drops than with systemic administration. Furthermore, Patent Document 2 describes that when a composition containing epinastine or a salt thereof is administered to the eyelid skin, the higher the concentration of epinastine or a salt thereof, the more likely it is to cause skin irritation, and that from a safety perspective, the concentration of epinastine or a salt thereof is preferably less than 1% (w / w), suggesting that it is difficult to further increase the concentration of epinastine or a salt thereof to enhance the efficacy. On the other hand, neither document describes or suggests the combined use of an epinastine transdermal formulation and an antiallergic drug, or what effects would be expected from such combined use.

[0008] Therefore, it is an extremely interesting task to provide a new therapeutic agent for allergic diseases (particularly allergic conjunctival diseases) that is highly effective, safe, and convenient, particularly a new pharmaceutical composition containing epinastine or a salt thereof as an active ingredient.

[0009] The present inventors have conducted extensive research into means for enhancing the antiallergic effect of a transdermal formulation containing epinastine or a salt thereof, even when the formulation is used at a low concentration. In the process, they discovered that by combining an epinastine transdermal formulation with an antiallergic drug, the antiallergic effect of the drug is significantly enhanced compared to when each drug is used alone, which led to the completion of the present invention.

[0010] Specifically, the present invention provides the following: (1) A pharmaceutical composition for transdermal administration containing epinastine or a salt thereof, characterized in that it is administered in combination with an antiallergic drug. (2) The pharmaceutical composition according to (1), for treating an allergic disease. (3) The pharmaceutical composition according to (2), wherein the allergic disease is an allergic conjunctival disease. (4) The pharmaceutical composition according to (3), wherein the allergic conjunctival disease is allergic conjunctivitis. (5) The pharmaceutical composition according to any one of (1) to (4), characterized in that it is administered in combination with an antiallergic drug. (6) The pharmaceutical composition according to any one of (1) to (5), characterized in that it is administered at a different time from or simultaneously with the antiallergic drug. (7) The pharmaceutical composition according to any one of (1) to (6), characterized in that it is administered to a site different from the site of administration of the antiallergic drug. (8) The pharmaceutical composition according to any one of (1) to (7), wherein the pharmaceutical composition is administered to the eyelid skin. (9) The pharmaceutical composition according to any one of (1) to (8), wherein the pharmaceutical composition is an ointment, cream, or gel. (10) The pharmaceutical composition according to any one of (1) to (8), wherein the pharmaceutical composition is a cream. (11) The pharmaceutical composition according to any one of (1) to (10), wherein the antiallergic drug is an eye drop or eye ointment. (12) The pharmaceutical composition according to any one of (1) to (11), wherein the antiallergic drug comprises one or more drugs selected from the group consisting of ashitazanolast, amlexanox, ibudilast, cromoglycate, tranilast, pemirolast, epinastine, olopatadine, ketotifen, levocabastine, cyclosporine, tacrolimus, azulene sulfonic acid, indomethacin, glycyrrhizinic acid, diclofenac, nevafenac, pranoprofen, bromfenac, dexamethasone, dexamethasone sulfobenzoate, hydrocortisone, fluorometholone, prednisolone, betamethasone, betamethasone phosphate, methylprednisolone, salts thereof, and hydrates thereof. (13) The pharmaceutical composition according to any one of (1) to (12), wherein the antiallergic drug comprises epinastine or a salt thereof. (14) The pharmaceutical composition according to any one of (1) to (13), wherein the concentration of epinastine or a salt thereof is 0.05 to 1% (w / w).(15) The pharmaceutical composition according to any one of (1) to (14), characterized in that the pharmaceutical composition is administered to a patient once a day. (16) The pharmaceutical composition according to any one of (1) to (15), characterized in that the antiallergic drug is administered to a patient 1 to 4 times a day. (17) A therapeutic agent for allergic diseases for transdermal administration containing epinastine or a salt thereof, characterized in that the therapeutic agent for allergic diseases is used in combination with an antiallergic drug. (18) The therapeutic agent according to (17), characterized in that it is administered in combination with an antiallergic drug. (19) The therapeutic agent according to (17) or (18), characterized in that it is administered at a different time from or simultaneously with the antiallergic drug. (20) The therapeutic agent according to (17), which is a combination drug contained in combination with an antiallergic drug.

[0011] The present invention further provides the following: (21) Use of a combination of a transdermal pharmaceutical composition containing epinastine or a salt thereof and an antiallergic drug for the manufacture of a medicament for the treatment of an allergic disease. (22) A combination of a transdermal pharmaceutical composition containing epinastine or a salt thereof and an antiallergic drug for use in the treatment of an allergic disease. (23) A combination of a transdermal pharmaceutical composition containing epinastine or a salt thereof and an eye drop containing epinastine or a salt thereof for use in the treatment of an allergic conjunctival disease. (24) A method for treating an allergic disease, comprising administering to a subject in need thereof a therapeutically effective amount of a transdermal pharmaceutical composition containing epinastine or a salt thereof and a therapeutically effective amount of an antiallergic drug. (25) A method for treating an allergic disease, comprising administering to a subject in need thereof a therapeutically effective amount of a transdermal pharmaceutical composition containing epinastine or a salt thereof, followed by administering a therapeutically effective amount of an antiallergic drug. (26) A method for treating an allergic disease, comprising administering to a subject in need of treatment a therapeutically effective amount of an antiallergic drug, and then administering a therapeutically effective amount of a pharmaceutical composition for transdermal administration containing epinastine or a salt thereof. (27) The method of treatment according to any one of (24) to (26), wherein the antiallergic drug is administered to a site different from that of the pharmaceutical composition for transdermal administration.

[0012] It should be noted that any two or more of the above configurations (1) to (27) can be selected and combined.

[0013] According to the present invention, by administering a pharmaceutical composition for transdermal administration containing epinastine or a salt thereof in combination with an antiallergic drug, the antiallergic effect of the drug is significantly enhanced compared to when each drug is used alone. Therefore, the present invention is useful as a therapeutic agent for allergic diseases. Furthermore, the pharmaceutical composition of the present invention is sufficiently safe as a pharmaceutical product.

[0014] The present invention will be described in detail below.

[0015] In the present invention, "epinastine" refers to a compound represented by the chemical name (±)-3-Amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine, and also has the following formula: It is a compound represented by the formula:

[0016] In the pharmaceutical composition of the present invention, the epinastine contained therein may be a racemate or an optical isomer.

[0017] In the pharmaceutical composition of the present invention, epinastine may be present in the form of a salt, and there are no particular limitations on the salt as long as it is pharmaceutically acceptable. Examples of salts include salts with inorganic acids and salts with organic acids. Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Examples of salts with organic acids include salts with acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptoic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid, etc. As a salt of epinastine, the monohydrochloride salt (epinastine hydrochloride) is particularly preferred.

[0018] In the pharmaceutical composition of the present invention, epinastine or a salt thereof may be in the form of a hydrate or solvate.

[0019] When preparing the pharmaceutical composition of the present invention, the form of epinastine in the pharmaceutical composition may be a salt of epinastine, but in order to more efficiently improve transdermal absorption, it is more preferable that epinastine is in free form.In the manufacturing process of the pharmaceutical composition of the present invention, the pharmaceutical composition may be prepared using free form epinastine, or a salt of epinastine (e.g., epinastine hydrochloride) and an appropriate amount of base (e.g., sodium hydroxide) may be used to desalt during the process, thereby producing free form epinastine in the pharmaceutical composition.

[0020] In the pharmaceutical composition of the present invention, the content of epinastine or a salt thereof is not particularly limited as long as it is an amount sufficient to achieve the desired therapeutic effect as a pharmaceutical, but is preferably 0.01 to 5% (w / w), more preferably 0.03 to 3% (w / w), even more preferably 0.05 to 1% (w / w), and particularly preferably 0.05 to 0.5% (w / w) or 0.1 to 1% (w / w). Furthermore, the content of epinastine or a salt thereof is also preferably 0.01% (w / w), 0.03% (w / w), 0.05% (w / w), 0.1% (w / w), 0.2% (w / w), 0.25% (w / w), 0.3% (w / w), 0.4% (w / w), 0.5% (w / w), 0.6% (w / w), 0.7% (w / w), 0.75% (w / w), 0.8% (w / w), 0.9% (w / w), 1% (w / w), 1.5% (w / w), 2% (w / w), 3% (w / w), or 5% (w / w).

[0021] In the present invention, "% (w / w)" means the mass (g) of the target ingredient contained in 100 g of the pharmaceutical composition of the present invention. When a salt of epinastine is contained in the present invention, the value is the content of the epinastine salt. Furthermore, when epinastine or a salt thereof is formulated in the form of a hydrate or solvate in the present invention, the value is the content of the hydrate or solvate of epinastine or a salt thereof. The same applies hereinafter unless otherwise specified.

[0022] The pharmaceutical composition of the present invention can be applied topically for transdermal administration and can be prepared for, for example, ophthalmic, otolaryngological, or dermatological use. The pharmaceutical composition of the present invention is particularly preferably a transdermal formulation for ophthalmic use.

[0023] The dosage form of the pharmaceutical composition of the present invention is not particularly limited as long as it is usable as a pharmaceutical, and examples thereof include ointments, creams, gels, patches (tapes, poultices), sprays (e.g., pump sprays, aerosols for external use), liquids for external use (e.g., lotions, liniments), and solids for external use (e.g., powders for external use). The pharmaceutical composition of the present invention is preferably an ointment, cream, gel, patch, spray, or liquid for external use, more preferably an ointment, cream, or gel, and particularly preferably a cream. These can be manufactured according to conventional methods in the art.

[0024] When the pharmaceutical composition of the present invention is used as an ophthalmic transdermal preparation, it is preferably administered near the eye. "Near the eye" refers to the eyelids, such as the upper and lower eyelids, and their vicinity, or the area around the orbit, including the eyelid skin and the skin in the vicinity, or the skin around the orbit. Administration near the eye includes, for example, application or attachment to the eyelid skin and its vicinity of the upper and lower eyelids, or both, or application or attachment to the skin around the orbit. While the eyelid margin may be included in the vicinity of the eye, it is more preferable not to administer the pharmaceutical composition to the eyelid margin, since blinking can cause eye irritation by bringing part of the pharmaceutical composition administered to the eyelid margin into contact with the sensitive ocular surface.

[0025] If necessary, pharmaceutical additives can be added to the pharmaceutical composition of the present invention, such as pH adjusters, buffers, isotonicity agents, thickeners, stabilizers, antioxidants, preservatives, surfactants, cooling agents, oil components, etc. These may be used alone or in appropriate combinations of two or more, and can be blended in appropriate amounts.

[0026] When a pH adjuster is added to the pharmaceutical composition of the present invention, the pH adjuster may be any pH adjuster that can be used as an additive for pharmaceuticals. Examples of the pH adjuster include acids and bases. Examples of acids include hydrochloric acid, phosphoric acid, acetic acid, and citric acid, and examples of bases include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate.

[0027] The pH of the pharmaceutical composition of the present invention may be within a pharmaceutically acceptable range, for example, 4.0 to 8.5 or 4.0 to 8.0, preferably 6.0 to 8.0, and more preferably 6.5 to 7.5. A particularly preferred pH is 6.7 to 7.3, with 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, and 7.3 being even more preferred.

[0028] When a buffer is added to the pharmaceutical composition of the present invention, any buffer usable as an additive for pharmaceuticals can be appropriately added. Examples of the buffer include phosphoric acid or a salt thereof, boric acid, borax, trometamol, organic acids or salts thereof, and hydrates or solvates thereof.

[0029] Examples of phosphoric acid or a salt thereof include phosphoric acid, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate.

[0030] Examples of organic acids include citric acid, acetic acid, ε-aminocaproic acid, gluconic acid, fumaric acid, lactic acid, ascorbic acid, succinic acid, maleic acid, malic acid, and amino acids, and examples of salts thereof include sodium salts and potassium salts.

[0031] When a buffer is incorporated into the pharmaceutical composition of the present invention, the content of the buffer can be appropriately adjusted depending on the type of buffer, etc., and is, for example, 0.01 to 5% (w / w), although this is not limited thereto if the buffer also has an effect other than that of a buffer. Furthermore, when a buffer is incorporated into the pharmaceutical composition of the present invention, one type of buffer may be used, or two or more types of buffers may be used together.

[0032] When an isotonicity agent is added to the pharmaceutical composition of the present invention, the isotonicity agent may be any agent that can be used as an additive for pharmaceuticals. Examples of the isotonicity agent include ionic isotonicity agents and nonionic isotonicity agents.

[0033] Examples of ionic tonicity agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and the like.

[0034] Examples of non-ionic tonicity agents include glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose, and xylitol.

[0035] When an isotonicity agent is incorporated into the pharmaceutical composition of the present invention, the content of the isotonicity agent can be adjusted appropriately depending on the type of the isotonicity agent, and is, for example, 0.01 to 5% (w / w), preferably 0.05 to 3% (w / w), more preferably 0.1 to 2% (w / w), and even more preferably 0.1 to 1% (w / w), although this does not apply when the isotonicity agent also has an effect other than that of an isotonicity agent. Furthermore, when an isotonicity agent is incorporated into the pharmaceutical composition of the present invention, one or more isotonicity agents may be used together.

[0036] When thickening agent is incorporated into the pharmaceutical composition of the present invention, the thickening agent can be appropriately incorporated as the thickening agent that can be used as an additive for pharmaceuticals.As thickening agent, for example, methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, sodium hyaluronate etc. can also be their hydrate or solvate.

[0037] When a thickener is incorporated into the pharmaceutical composition of the present invention, the content of the thickener can be adjusted appropriately depending on the type of thickener, for example, 0.01 to 20% (w / w), preferably 0.1 to 10% (w / w), and more preferably 1 to 10% (w / w), although this does not apply if the thickener also has an effect other than that of a thickener. Furthermore, if the pharmaceutical composition of the present invention is in the form of a gel, the thickener may be contained in an amount of, for example, 20% (w / w) or more. Furthermore, when a thickener is incorporated into the pharmaceutical composition of the present invention, one or more thickeners may be used together.

[0038] When a stabilizer is added to the pharmaceutical composition of the present invention, any stabilizer that can be used as an additive for pharmaceuticals can be appropriately added. Examples of the stabilizer include edetic acid or a salt thereof, cyclodextrin, and the like, and may further include hydrates or solvates thereof.

[0039] Examples of edetic acid or salts thereof include edetic acid, disodium edetate, and tetrasodium edetate.

[0040] When a stabilizer is incorporated into the pharmaceutical composition of the present invention, the content of the stabilizer can be adjusted appropriately depending on the type of stabilizer, etc., and is, for example, 0.01 to 5% (w / w), preferably 0.01 to 3% (w / w), and more preferably 0.01 to 1% (w / w), although this does not apply when the stabilizer also has an effect other than that of a stabilizing agent. Furthermore, when a stabilizer is incorporated into the pharmaceutical composition of the present invention, one type of stabilizer may be used, or two or more types of stabilizers may be used together.

[0041] When an antioxidant is incorporated into the pharmaceutical composition of the present invention, an antioxidant that can be used as an additive for pharmaceuticals can be appropriately incorporated. Examples of antioxidants include ascorbic acid, tocopherol or derivatives thereof, propyl gallate, dibutylhydroxytoluene, cysteine, N-acetylcysteine, methionine, glutathione, 2-mercaptobenzimidazole, sodium thiomalate, thioglycerol, sodium thioglycolate, sodium thiosulfate, sodium bisulfite, sodium sulfite, and the like, and further include hydrates or solvates thereof.

[0042] When an antioxidant is incorporated into the pharmaceutical composition of the present invention, the content of the antioxidant can be adjusted appropriately depending on the type of antioxidant, etc., and is, for example, 0.01 to 2% (w / w), preferably 0.03 to 1.5% (w / w), and more preferably 0.05 to 1% (w / w), although this does not apply when the antioxidant also has an effect other than that of an antioxidant. Furthermore, when an antioxidant is incorporated into the pharmaceutical composition of the present invention, one type of antioxidant may be used, or two or more types of antioxidants may be used together.

[0043] When a preservative is added to the pharmaceutical composition of the present invention, the preservative can be any preservative that can be used as an additive in pharmaceuticals, and examples thereof include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine gluconate, chlorhexidine hydrochloride, paraben, sodium chlorite, phenoxyethanol, thymol, sorbic acid, and chlorobutanol.

[0044] Examples of parabens include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, and propyl parahydroxybenzoate.

[0045] When a preservative is incorporated into the pharmaceutical composition of the present invention, the content of the preservative can be appropriately adjusted depending on the type of preservative, and is, for example, 0.001 to 1% (w / w). When a preservative is incorporated into the pharmaceutical composition of the present invention, one type of preservative or two or more types of preservatives may be used together.

[0046] If the pharmaceutical composition of the present invention can exhibit the preservative effectiveness required for pharmaceuticals without containing a preservative, it is preferable to not include a preservative, for example, it is preferable to not include a paraben. The preservative effectiveness required for pharmaceuticals is determined by the criteria for each formulation classification, for example, in the Japanese Pharmacopoeia, 18th Edition, and each formulation is recognized as having preservative effectiveness if it meets these criteria. Since epinastine or a salt thereof exhibits preservative effectiveness depending on the formulation concentration, the pharmaceutical composition of the present invention can exhibit the desired preservative effectiveness without the addition of a preservative, depending on the type of formulation. The desired preservative effectiveness refers, for example, to compliance with the preservative effectiveness test method described in the Japanese Pharmacopoeia, 18th Edition. Furthermore, the absence of a preservative can reduce irritation when the pharmaceutical composition of the present invention is administered transdermally.

[0047] When a surfactant is added to the pharmaceutical composition of the present invention, any surfactant that can be used as an additive for pharmaceuticals can be appropriately added. Examples of surfactants include cationic surfactants, anionic surfactants, and nonionic surfactants.

[0048] Examples of cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkylimidazolines, 1-acylaminoethyl-2-alkylimidazolines, and 1-hydroxylethyl-2-alkylimidazolines.

[0049] Examples of anionic surfactants include sodium alkylbenzenesulfonate, sodium dodecyl sulfate, and phospholipids such as lecithin.

[0050] Examples of nonionic surfactants include polyoxyethylene fatty acid esters such as polyoxyl 40 stearate; sorbitan fatty acid esters such as sorbitan stearate; polyoxyethylene sorbitan fatty acid esters such as polysorbate 80; polyoxyethylene hydrogenated castor oils such as polyoxyethylene hydrogenated castor oil 60; polyoxyl castor oils such as polyoxyl 35 castor oil; polyoxyethylene polyoxypropylene glycols such as polyoxyethylene (20) polyoxypropylene (20); polyoxyethylene polyoxypropylene cetyl ethers such as polyoxyethylene (20) polyoxypropylene (4) cetyl ether; and polyoxyethylene cetyl ethers. polyoxyethylene behenyl ether; glycerin fatty acid esters such as glyceryl laurate, polyglyceryl laurate, glyceryl palmitate, polyglyceryl palmitate, glyceryl stearate, polyglyceryl stearate, glyceryl oleate, polyglyceryl oleate, glyceryl linoleate, polyglyceryl linolenate, glyceryl linolenate, polyglyceryl linolenate, glyceryl ricinoleate, polyglyceryl ricinoleate, and condensed polyglyceryl ricinoleate (condensed polyglyceryl ricinoleate); and sucrose fatty acid esters such as sucrose stearate.

[0051] When a surfactant is incorporated into the pharmaceutical composition of the present invention, the content of the surfactant can be adjusted appropriately depending on the type of surfactant, etc., and is, for example, 0.1 to 20% (w / w), preferably 0.5 to 10% (w / w), and more preferably 1 to 5% (w / w), although this does not apply if the surfactant also has an effect other than that of a surfactant. Furthermore, when a surfactant is incorporated into the pharmaceutical composition of the present invention, one type of surfactant or two or more types of surfactants may be used together, or a mixture of two or more types of surfactants may be used.

[0052] Surfactants are characterized by the balance between the hydrophilic and lipophilic portions of their molecule and have a hydrophilic-lipophilic balance (HLB) number. HLB increases with increasing hydrophilicity, and the HLB of different manufacturers may vary even for the same ingredient name.

[0053] When a surfactant is incorporated into the pharmaceutical composition of the present invention, the HLB of the surfactant is not particularly limited as long as it can be prepared as a preparation for topical administration, and is, for example, 1 to 20, preferably 1.0 to 10.0, more preferably 2.0 to 8.0, and even more preferably 3.0 to 6.0.

[0054] When a cooling agent is added to the pharmaceutical composition of the present invention, any cooling agent that can be used as an additive for pharmaceuticals can be appropriately added. Examples of cooling agents include terpenoids and essential oils containing terpenoids.

[0055] Examples of terpenoids include menthol, camphor, borneol, geraniol, nerol, cineole, citronellol, carvone, anethole, eugenol, limonene, linalool, linalyl acetate, etc., and may be in the d-, l-, or dl-form. Examples of essential oils containing terpenoids include eucalyptus oil, bergamot oil, peppermint oil, fennel oil, rose oil, cinnamon oil, spearmint oil, camphor oil, cool mint, peppermint oil, etc.

[0056] When a cooling agent is incorporated into the pharmaceutical composition of the present invention, the content of the cooling agent can be appropriately adjusted depending on the type of cooling agent, etc., and is, for example, 0.001 to 1% (w / w). When a cooling agent is incorporated into the pharmaceutical composition of the present invention, one type of cooling agent or two or more types of cooling agents may be used together.

[0057] When an oil component is incorporated into the pharmaceutical composition of the present invention, the content of the oil component may be any oil component that can be used as an additive for pharmaceuticals. Examples of oil components include hydrocarbons, waxes, fats and oils, aliphatic carboxylic acids or salts thereof, fatty acid esters, medium-chain fatty acid triglycerides (MCTs), and higher alcohols.

[0058] Examples of hydrocarbons include petrolatum, white petrolatum, paraffin, liquid paraffin (light liquid paraffin, heavy liquid paraffin), solid paraffin, squalene, squalane, ceresin, microcrystalline wax, etc., and mixtures thereof may also be used, such as a mixture of paraffin and microcrystalline wax.

[0059] Examples of waxes include beeswax, white beeswax, and lanolin.

[0060] Examples of fats and oils include olive oil, castor oil, sesame oil, and soybean oil.

[0061] Examples of aliphatic carboxylic acids include short-chain fatty acids such as butyric acid, valeric acid, and caproic acid, medium-chain fatty acids such as caprylic acid and capric acid, long-chain fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, linoleic acid, linolenic acid, ricinoleic acid (ricinoleic acid), and arachidonic acid, and aliphatic dicarboxylic acids such as succinic acid, glutaric acid, adipic acid, and sebacic acid, including branched aliphatic carboxylic acids. Examples of salts of aliphatic carboxylic acids include sodium salts of these.

[0062] In the present invention, the term "fatty acid ester" refers to a compound in which an alcohol is ester-bonded to the carboxyl group of an aliphatic carboxylic acid. Examples of the alcohol that may be ester-bonded to the carboxyl group of the aliphatic carboxylic acid include monohydric alcohols such as methanol, ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol, n-heptanol, n-octanol, isopropanol, isobutanol, sec-butanol, and isopentanol; polyhydric alcohols such as ethylene glycol, diethylene glycol, propylene glycol, butylene glycol, and glycerin; and polyhydric alcohol multimers (polymers) such as dipolyethylene glycol, polyethylene glycol, dipropylene glycol, polypropylene glycol, diglycerin, triglycerin, and polyglycerin. Examples include polyethylene glycol laurate, octyl myristate, glycol palmitate, polyethylene glycol stearate, isopropyl oleate, propylene glycol linoleate, ethyl linoleate, and ethylene glycol ricinoleate (ricinoleate). When the aliphatic ester has two or more ester bonds, the alcohols constituting the ester bonds may be the same or different.

[0063] Examples of higher alcohols include lauryl alcohol, myristyl alcohol, palmityl alcohol (cetyl alcohol), stearyl alcohol, behenyl alcohol, oleyl alcohol, linolyl alcohol, linolenyl alcohol, and octyldodecanol.

[0064] When an oil component is incorporated into the pharmaceutical composition of the present invention, the content of the oil component can be adjusted appropriately depending on the type of oil component, etc., and is, for example, 0.1 to 50% (w / w), preferably 1 to 40% (w / w), and more preferably 10 to 30% (w / w). However, if the pharmaceutical composition of the present invention is in the form of an ointment, the content may be, for example, 50% (w / w) or more. Furthermore, when an oil component is incorporated into the pharmaceutical composition of the present invention, one type of oil component or two or more types of oil components may be used together.

[0065] When the oil component incorporated in the pharmaceutical composition of the present invention acts as a surfactant, the oil component may be read as a surfactant.

[0066] The oil component incorporated in the pharmaceutical composition of the present invention may also serve as a solubilizer to increase the solubility of other components contained in the pharmaceutical composition.

[0067] The oil component incorporated in the pharmaceutical composition of the present invention may be used as a permeation enhancer or absorption enhancer to enhance the skin permeability of the active ingredient contained in the pharmaceutical composition.

[0068] The pharmaceutical composition of the present invention may further contain a solvent and / or dispersion medium. The pharmaceutical composition of the present invention containing a solvent and / or dispersion medium may have all of its components dissolved or partially suspended, or may be in the form of an emulsion or semi-solid. Examples of solvents and / or dispersion mediums include, but are not limited to, water, ethanol, polyols (e.g., glycerin (glycerol), propylene glycol, liquid polyethylene glycol, macrogol, etc.), etc.

[0069] When a solvent and / or dispersion medium is blended into the pharmaceutical composition of the present invention, the content of the solvent and / or dispersion medium can be appropriately adjusted depending on the type of the solvent and / or dispersion medium, but is preferably 10% (w / v) or more, and more preferably 30% (w / v) or more, based on the total weight of the pharmaceutical composition. Furthermore, when a solvent and / or dispersion medium is blended into the pharmaceutical composition of the present invention, one type of solvent and / or dispersion medium may be used, or two or more types of solvents and / or dispersion mediums may be used together.

[0070] When the pharmaceutical composition of the present invention is used as an emulsion, the pharmaceutical composition of the present invention may be an oil-in-water emulsion (an emulsion consisting of oily droplets dispersed in an aqueous phase with an aqueous phase as the continuous phase) or a water-in-oil emulsion (an emulsion consisting of aqueous droplets dispersed in an oil with an oil phase as the continuous phase). The pharmaceutical composition of the present invention is preferably a water-in-oil emulsion.

[0071] The average size of the oily or aqueous droplets is, for example, 20 to 3000 nm, preferably 50 to 2000 nm, more preferably 100 to 1000 nm, and even more preferably 200 to 800 nm.

[0072] The pharmaceutical composition of the present invention can be produced according to conventional methods commonly used in the art. For example, it can be produced by mixing the active ingredient with additives such as stabilizers, antioxidants, preservatives, surfactants, oil components, and solvents or dispersion media such as water. If necessary, it can also be produced as a sterile preparation according to conventional sterilization methods commonly used in the art. The sterilization method is not particularly limited as long as it is a method that can be used during the manufacturing process, and examples include autoclaving, filtration sterilization, dry heat sterilization, electron beam (EB) sterilization, gamma ray sterilization, ethylene oxide gas (EOG) sterilization, and hydrogen peroxide gas sterilization.

[0073] Unless otherwise specified, the pharmaceutical composition of the present invention may contain a pharmaceutical active ingredient other than epinastine or a salt thereof. Therefore, the pharmaceutical composition of the present invention may be a single transdermal formulation (combination) containing epinastine or a salt thereof and other pharmaceutical active ingredients. The pharmaceutical composition of the present invention may also be a single transdermal formulation (combination) containing epinastine or a salt thereof and an antiallergic drug pharmaceutical active ingredient, or a single transdermal formulation (combination) containing epinastine or a salt thereof, an antiallergic drug pharmaceutical active ingredient, and other pharmaceutical active ingredients. For example, when the pharmaceutical composition of the present invention is an ophthalmic pharmaceutical composition, it may contain other pharmaceutical active ingredients used in eye drops other than epinastine or a salt thereof. Examples of other pharmaceutical active ingredients include anti-inflammatory agents, antibacterial agents, antiviral agents, vitamins, vasoconstrictors, mydriatics, miotics, intraocular pressure-reducing agents, dry eye treatments, and local anesthetics. The pharmaceutical composition of the present invention may also contain epinastine or a salt thereof as the sole active ingredient.

[0074] In the present invention, examples of antiallergic drugs used in combination include mediator release inhibitors such as azatazanolast, amlexanox, cromoglycate, tazanolast, tranilast, nedocromil, pemirolast, and repirinast, acrivastine, azatadine, astemizole, azelastine, alimemazine, alcaftadine, antazoline, icotidine, isothipendyl, ebastine, emedastine, epinastine, oxatomide, opipramol, olanzapine, olopatadine, carbinoxamine, quetiapine, and clemastine. acid, chlorphenamine, chlorpheniramine, chlorphenoxamine, chlorpromazine, chloropyramine, ketanserin, ketotifen, dioxopromethazine, cyclizine, diphenylpyraline, diphenhydramine, cyproheptadine, dimethindene, dimethothazine, cinnarizine, cetirizine, tecastemizole, dexbrompheniramine, dexchlorpheniramine, desloratadine, deptropine, temelastine, terfenadine, doxylamine, triprolidine, tripelennamine, thonzylamine, nobelastine, bamipyramine H1 receptor antagonists such as benzodiazepine, hydroxyzine, pimethixene, bilastine, fexofenadine, pheniramine, phenindamine, buclizine, bromodiphenhydramine, brompheniramine, promethazine, bepotastine, homochlorcyclizine, mizolastine, mequitazine, meclozine, mepyramine, mebhydroline, rupatadine, levocabastine, levocetirizine, locastine and loratadine, ifetroban, imitrodast, ozagrel, surotroban, seratrodast, daltroban, bapiprost, picotamide, ramatroban and thromboxane A2 receptor antagonists such as ridogrel, leukotriene antagonists such as abulukast, ibudilast, etalosib, zafirlukast, sinalukast, sulukast, ticorubant, tipelukast, tomerukast, pranlukast, berlukast, povilukast, moxilbant, montelukast and litorukast, Th2 cytokine inhibitors such as suplatast, non-steroidal anti-inflammatory drugs (NSAIDs) such as azulene sulfonic acid, indomethacin, glycyrrhizinic acid, diclofenac, nevafenac, pranoprofen and bromfenac,Examples of the antiallergic agent used in combination with the pharmaceutical composition of the present invention include immunosuppressants such as tacrolimus and cyclosporine, and steroidal anti-inflammatory agents such as dexamethasone, dexamethasone sulfobenzoate, hydrocortisone, fluorometholone, prednisolone, and betamethasone. The antiallergic agent used in combination with the pharmaceutical composition of the present invention may be in the form of a salt or a hydrate. The antiallergic agent used in combination with the pharmaceutical composition of the present invention also includes an antihistamine.

[0075] In the present invention, the antiallergic drug used in combination can be administered either orally or parenterally, and preferably parenterally.The parenteral administration route of the antiallergic drug can include pharmaceutically acceptable local administration routes, such as local administration to the eye (for example, eye drop administration), nasal (intranasal) administration, local administration to the ear (for example, ear drop administration), inhalation administration, spray administration, transdermal administration, epicutaneous administration, injection administration, etc.The administration route of the antiallergic drug is preferably local administration to the eye, more preferably eye drop administration to the ocular surface (ocular surface) or instillation into the conjunctival sac.

[0076] In the present invention, the dosage form of the antiallergic drug used in combination is not particularly limited as long as it can be used as a pharmaceutical. Examples of dosage forms include oral administration preparations such as liquids and suspensions, eye drops, nasal drops, ear drops, inhalants (inhalation powders, inhalation liquids, inhalation aerosols), ointments, creams, gels, transdermal preparations, patches (tapes, poultices), external liquid preparations (lotions, liniments), external solid preparations (external powders), sprays (pump sprays, external aerosols), and topical preparations such as injections (infusions, implant injections, sustained-release injections). The dosage form of the antiallergic drug is preferably a topical preparation, more preferably eye drops or eye ointment. These can be prepared according to conventional methods in the art.

[0077] In the present invention, when an antiallergic drug is used as an eye drop, examples of the antiallergic drug to be used in combination include mediator release inhibitors such as ashitazanolast hydrate, amlexanox, ibudilast, sodium cromoglycate, tranilast, and pemirolast potassium, H1 receptor antagonists such as epinastine hydrochloride, olopatadine hydrochloride, ketotifen fumarate, and levocabastine hydrochloride, sodium azulene sulfonate, indomethacin, dipotassium glycyrrhizinate, diclofenac The eye drops preferably contain, as an active ingredient, a nonsteroidal anti-inflammatory drug (NSAID) such as thorium, nevafenac, pranoprofen, or bromfenac sodium hydrate; an immunosuppressant such as tacrolimus hydrate or cyclosporine; or a steroidal anti-inflammatory drug such as dexamethasone sodium phosphate, dexamethasone sodium sulfobenzoate, hydrocortisone acetate, fluorometholone, prednisolone acetate, or betamethasone sodium phosphate.

[0078] In the present invention, when an antiallergic drug is used as an eye ointment, the antiallergic drug to be used in combination is preferably an eye ointment containing, as an active ingredient, an immunosuppressant such as tacrolimus hydrate, or a steroidal anti-inflammatory drug such as dexamethasone, prednisolone acetate, betamethasone sodium phosphate, or methylprednisolone.

[0079] The phrase "combining" or "being combined" the pharmaceutical composition of the present invention with an antiallergic drug means that the pharmaceutical composition of the present invention and the antiallergic drug are administered separately (concomitant administration), or that the pharmaceutical composition of the present invention and the antiallergic drug are administered as a preparation (combined drug) in a single dosage form. In the present invention, the pharmaceutical composition and the antiallergic drug are preferably administered in combination.

[0080] When the pharmaceutical composition of the present invention and an antiallergic drug are administered separately (combined administration), the pharmaceutical composition of the present invention may be administered before, simultaneously with, or after the administration of the antiallergic drug.The antiallergic drug may be administered at the same or different site as the pharmaceutical composition of the present invention.For example, when the antiallergic drug is used as an eye drop, the pharmaceutical composition of the present invention may be administered transdermally to the eyelid skin, followed by instillation of the antiallergic drug onto the ocular surface, or the antiallergic drug may be administered transdermally to the ocular surface, followed by instillation of the pharmaceutical composition of the present invention onto the eyelid skin.When the antiallergic drug is used as an eye ointment, the pharmaceutical composition of the present invention may be administered transdermally to the eyelid skin, followed by administration of the antiallergic drug onto the inside of the lower eyelid (conjunctival sac), or the antiallergic drug may be administered onto the inside of the lower eyelid (conjunctival sac), followed by administration of the pharmaceutical composition of the present invention onto the eyelid skin. When multiple eye drops are administered at once, the interval between administrations must be at least 5 minutes. However, when the pharmaceutical composition of the present invention is used in combination with an antiallergic drug, the administration sites are different, allowing for continuous administration without an interval between administrations, thereby improving medication adherence and convenience for patients.

[0081] The pharmaceutical composition of the present invention is useful as a therapeutic agent for allergic diseases, including, but not limited to, hay fever, allergic conjunctivitis, allergic rhinitis, atopic dermatitis, food allergies, and bronchial asthma.

[0082] When the pharmaceutical composition of the present invention is used as an ophthalmic pharmaceutical composition, it is useful as a therapeutic agent for allergic conjunctival diseases. Allergic conjunctival diseases include, for example, allergic conjunctivitis (seasonal and / or perennial), atopic keratoconjunctivitis, vernal conjunctivitis, and giant papillary conjunctivitis, and the pharmaceutical composition of the present invention is particularly preferred as a therapeutic agent for allergic conjunctivitis. In the present invention, "treatment of allergic conjunctivitis" includes any treatment (e.g., improvement, alleviation, inhibition of progression, etc.) and prevention of allergic conjunctivitis and its symptoms.

[0083] When the pharmaceutical composition of the present invention is used as an otorhinolaryngeal pharmaceutical composition, the pharmaceutical composition of the present invention is particularly useful as a therapeutic agent for allergic rhinitis. In the present invention, "treatment of allergic rhinitis" includes any treatment (e.g., improvement, alleviation, inhibition of progression, etc.) and prevention of allergic rhinitis and its symptoms.

[0084] When the pharmaceutical composition of the present invention is used as a dermatological pharmaceutical composition, it is particularly useful as a therapeutic agent for allergic dermatitis such as contact dermatitis, eczema dermatitis, pollen dermatitis, atopic dermatitis, drug eruption, urticaria, etc. In the present invention, "treatment of allergic dermatitis" includes any treatment of allergic dermatitis and its symptoms (e.g., improvement, alleviation, inhibition of progression, etc.) and prevention thereof.

[0085] In the present invention, the term "patient" refers not only to humans but also to other animals, such as dogs, cats, and horses. The patient is preferably a mammal, more preferably a human. In the present invention, the term "therapeutically effective amount" refers to an amount that brings about a therapeutic effect for a disease and its symptoms, or an amount that brings about a delay in the progression of a disease and its symptoms, compared to an untreated subject.

[0086] The dosage of the pharmaceutical composition of the present invention is not particularly limited as long as it is sufficient to achieve the desired medicinal effect, and the pharmaceutical composition of the present invention can be administered, for example, 1 to 4 times a day, preferably 1 to 2 times a day, and more preferably once a day.

[0087] When the pharmaceutical composition of the present invention is used in combination with an antiallergic drug, the dosage of the antiallergic drug is not particularly limited as long as it is sufficient to achieve the desired medicinal effect, and the antiallergic drug can be administered, for example, 1 to 4 times a day. Furthermore, the pharmaceutical composition of the present invention and the antiallergic drug may be administered at different times during the day, or may be administered simultaneously.

[0088] When the pharmaceutical composition of the present invention is used as an ointment, cream, or gel, the dosage is not particularly limited as long as it is sufficient to achieve the desired efficacy, and will vary depending on the content of the active ingredient contained and the patient. For example, when the pharmaceutical composition of the present invention is used as a cream, an appropriate amount of the pharmaceutical composition of the present invention can be transdermally administered to an adult in a single dose, for example, 1 mg to 5 g, preferably 5 mg to 1 g, more preferably 10 mg to 500 mg, and particularly preferably 20 mg to 100 mg. For example, the dosage is 30 mg. As an example of administration, when the pharmaceutical composition of the present invention is used as an ophthalmic pharmaceutical composition, the patient himself / herself takes an appropriate amount of the pharmaceutical composition, for example, 20 to 40 mg, on his / her finger, distributes it so that approximately half is applied to the upper eyelid skin and the other eyelid skin, and then applies it in the same way to the other eye. In actual use, the patient may use the pharmaceutical composition by eyeballing it without weighing it, using the above-mentioned dosage per eye as a guide. Furthermore, although it depends on the size and shape of the container in which the pharmaceutical composition of the present invention is stored, as a guideline for the dosage, for example, the length of the drug removed from the container onto a finger is about 5 mm to 20 mm, preferably about 10 mm to 13 mm, or the amount of drug placed on an adult's index finger from the tip to the first joint is defined as 1 FTU (1 fingertip unit), and for example, 0.5 FTU or 1 FTU may be removed and used. There is no limit to the age of patients to whom the pharmaceutical composition of the present invention can be applied, and when administered to pediatric patients under the age of 12, for example, the dosage may be adjusted according to the child's age and physical condition.

[0089] The application time of the pharmaceutical composition of the present invention when applied to the skin is, for example, 24 hours or less, preferably 0.5 to 24 hours, more preferably 2 to 12 hours, and even more preferably 4 to 8 hours. After the application time has elapsed, even if the pharmaceutical composition is removed, a sufficient amount of the active ingredient remains in the skin tissue, and its sustained release is expected to result in sustained efficacy. On the other hand, antiallergic drugs that can be used in combination with the pharmaceutical composition of the present invention, such as eye drops, can be administered directly to the ocular surface where itching occurs, and therefore immediate efficacy can be expected. However, the duration of efficacy is poor, and multiple administrations per day are often required. However, when the pharmaceutical composition of the present invention is used in combination with an antiallergic drug, as an example of a method of administration, the pharmaceutical composition of the present invention is administered to the eyelid skin before bedtime and removed after waking up, thereby expecting sustained efficacy in treating allergic conjunctival diseases without the need for daytime administration. Furthermore, by administering the antiallergic drug 1 to 4 times per day, an enhanced sustained effect can be expected.

[0090] When the pharmaceutical composition of the present invention is used as an ointment, cream, or gel, there is no particular limitation on the container in which it is housed, and it may be housed in any of a tube, bottle, can, or the like. The material of the container is also no particular limitation, and it may be a resin container made of polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic, polystyrene, polycyclic olefin copolymer, or the like; a metal container made of aluminum or the like; or a laminated container made by bonding together multiple materials such as resin, paper, and aluminum foil. Furthermore, if the resin container is made of polyethylene, for example, polyethylene is classified by its density, and containers made of low-density polyethylene (LDPE), linear low-density polyethylene (LLDPE), medium-density polyethylene (MDPE), high-density polyethylene (HDPE), or the like may be used.

[0091] The pharmaceutical composition of the present invention can be used when wearing both hard and soft contact lenses.

[0092] Formulation examples and test results are shown below, but these are intended to provide a better understanding of the present invention and are not intended to limit the scope of the present invention.

[0093] Formulation Examples Representative formulation examples of the pharmaceutical composition of the present invention are shown below. In the formulation examples below, the blending amount of each ingredient is the content per 100 g of the formulation.

[0094] Formulation Example 1 Water-in-oil emulsion Epinastine 1.0 g Squalane 5.0 g Light liquid paraffin 5.0 g Ceresin 3.0 g White petrolatum 12.0 g White beeswax 1.0 g Glycerin fatty acid ester 4.0 g Propyl parahydroxybenzoate 0.1 g Methyl parahydroxybenzoate 0.1 g 2-mercaptobenzimidazole 0.1 g Sodium edetate hydrate 0.5 g Concentrated glycerin 16.0 g Purified water appropriate amount

[0095] Formulation Example 2 Oil-in-water emulsion Epinastine hydrochloride 1.0 g Squalane 12.0 g Glyceryl monostearate 4.0 g Polyoxyethylene behenyl ether 4.0 g Polyoxyethylene hydrogenated castor oil 1.0 g Cetyl alcohol 4.0 g Stearyl alcohol 2.5 g 2-mercaptobenzimidazole 0.1 g Diisopropyl adipate 4.0 g 1,3-butylene glycol 4.0 g Sodium citrate appropriate amount Sodium hydroxide appropriate amount Purified water appropriate amount

[0096] Formulation Example 3 Water-in-oil emulsion Epinastine 1.0 g Pranoprofen 1.0 g Squalane 4.0 g Light liquid paraffin 4.0 g White petrolatum 10.0 g White beeswax 1.0 g Glycerin fatty acid ester 5.0 g Propyl parahydroxybenzoate 0.1 g Methyl parahydroxybenzoate 0.1 g Dibutylhydroxytoluene 0.05 g Sodium edetate hydrate 0.1 g Concentrated glycerin 15.0 g Purified water appropriate amount

[0097] Formulation Example 4 Water-in-oil emulsion Epinastine 0.5 g Betamethasone sodium phosphate 0.1 g Squalane 3.0 g Light liquid paraffin 5.0 g White petrolatum 15.0 g White beeswax 1.0 g Glycerin fatty acid ester 3.0 g Dibutylhydroxytoluene 0.05 g Sodium edetate hydrate 0.2 g Concentrated glycerin 16.0 g Purified water appropriate amount

[0098] Other formulation examples 5 to 20 are shown in Tables 1 and 2.

[0099]

[0100] Example 1. Drug efficacy evaluation test using an allergic conjunctivitis model In order to evaluate the antiallergic effect on allergic conjunctivitis, an allergic conjunctivitis model was prepared using guinea pigs, and the therapeutic effect of a transdermal formulation containing epinastine or a salt thereof in combination with an antiallergic drug was examined.

[0101] (1) Preparation of Test Formulations Test Formulation 1 was prepared as a transdermal formulation containing epinastine or a salt thereof in the form of a water-in-oil emulsion by mixing the active ingredient epinastine hydrochloride, white petrolatum, light liquid paraffin, squalane, a mixture of paraffin and microcrystalline wax, the oil component of white beeswax, condensed polyglyceryl ricinoleate, sodium edetate hydrate, 2-mercaptobenzimidazole, sodium hydroxide, sodium chloride, concentrated glycerin, and purified water using a commonly used method. The amount of epinastine hydrochloride, the active ingredient of Test Formulation 1, was adjusted to 0.5% (w / w). Additionally, Test Formulation 2, a placebo in the form of a water-in-oil emulsion without epinastine hydrochloride or sodium hydroxide, was prepared using the same method as Test Formulation 1, except for the addition of epinastine hydrochloride and sodium hydroxide. The antiallergic drug used was "Alesion (registered trademark) LX eye drops 0.1%," which is normally used as a treatment for allergic conjunctivitis at a dosage of one drop twice daily, and this was designated Test Preparation 3. Physiological saline was also prepared as a placebo and designated Test Preparation 4.

[0102] (2) Preparation of Conjunctivitis Model and Evaluation Test Method Guinea pigs (male, Hartley strain) were randomly divided into groups as shown in Table 3 (multiple animals per group).

[0103] In each test formulation administration group, the hair around the right eyelid of the guinea pigs was shaved with clippers and an electric razor under isoflurane inhalation anesthesia, and an Elizabethan collar was attached. A histamine solution was instilled into the right eye of the guinea pigs in each test formulation administration group to induce conjunctivitis, creating an allergic conjunctivitis model. In each test formulation administration group, 7.5 μL of test formulation 1 or 2 was applied to the upper and lower eyelids of the right eye under isoflurane inhalation anesthesia 16 hours before instillation of the histamine solution. Furthermore, 5 μL of test formulation 3 or 4 was instilled into the right eye of the guinea pigs 8 hours before instillation of the histamine solution. Prior to instillation of the histamine solution, Evans blue solution was administered intravenously to the ear vein of each test formulation administration group under isoflurane inhalation anesthesia. Test formulation group 1 served as a control group; saline was instilled instead of the histamine solution; other procedures were the same as those for the other test formulation groups. After instillation of the histamine solution, guinea pigs from each test formulation group were euthanized under isoflurane inhalation anesthesia, and the right eyeball and eyelid tissue were removed. The weight of each excised tissue was measured, and the excised tissue was immersed in a pigment extract (acetone solution containing sodium sulfate) to extract the pigment. The pigment extract in which the excised tissue was immersed was centrifuged, and the supernatant was used as a sample, and its absorbance at 620 nm was measured using a spectrophotometer. The mean and standard error of the amount of dye leakage (μg / g) per conjunctival tissue weight for each test formulation group were calculated using a commonly used method. For test formulation groups 3 to 5, the inhibition rate of dye leakage was calculated using the following formula: Inhibition rate (%) = 100 - 100 × [(mean amount of dye leakage in the target test formulation administration group) - (mean amount of dye leakage in test formulation administration group 1)] / [(mean amount of dye leakage in test formulation administration group 2) - (mean amount of dye leakage in test formulation administration group 1)]

[0104] (3) Test results and discussion The test results are shown in Table 4.

[0105] Compared with test preparation group 1, in which no histamine solution was instilled, test preparation group 2, in which histamine solution was instilled, showed stronger allergic conjunctivitis. Furthermore, test preparation group 3, in which the active ingredient epinastine hydrochloride was contained only in the pharmaceutical composition for transdermal administration, and test preparation group 4, in which the active ingredient epinastine hydrochloride was contained only in the antiallergic drug, were shown to have a therapeutic effect on allergic conjunctivitis compared to test preparation group 2. Furthermore, test preparation group 5, in which the active ingredient epinastine hydrochloride was contained both in the pharmaceutical composition for transdermal administration and in the antiallergic drug, was shown to have a stronger therapeutic effect compared to test preparation groups 2 and 3.

[0106] The above results demonstrate that the combined use of a transdermal preparation containing epinastine or a salt thereof and an antiallergic drug provides an excellent therapeutic effect for allergic conjunctivitis.

[0107] The present invention provides a pharmaceutical composition for transdermal administration containing epinastine or a salt thereof, which is administered in combination with an antiallergic drug.

Claims

1. A pharmaceutical composition for transdermal administration containing epinastine or a salt thereof, which is administered in combination with an antiallergic drug.

2. The pharmaceutical composition according to claim 1 for treating allergic diseases.

3. The pharmaceutical composition according to claim 2, wherein the allergic disease is an allergic conjunctival disease.

4. The pharmaceutical composition according to claim 3, wherein the allergic conjunctival disease is allergic conjunctivitis.

5. A pharmaceutical composition according to any one of claims 1 to 4, which is administered in combination with an antiallergic drug.

6. A pharmaceutical composition according to any one of claims 1 to 5, which is administered at a different time from or simultaneously with an antiallergic drug.

7. The pharmaceutical composition according to any one of claims 1 to 6, which is administered to a site different from that of an antiallergic drug.

8. A pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition is administered to the eyelid skin.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the pharmaceutical composition is an ointment, cream or gel.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the antiallergic drug is an eye drop or an eye ointment.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the antiallergic drug comprises one or more drugs selected from the group consisting of acitazanolast, amlexanox, ibudilast, cromoglycate, tranilast, pemirolast, epinastine, olopatadine, ketotifen, levocabastine, cyclosporine, tacrolimus, azulene sulfonic acid, indomethacin, glycyrrhizinic acid, diclofenac, nevafenac, pranoprofen, bromfenac, dexamethasone, dexamethasone sulfobenzoate, hydrocortisone, fluorometholone, prednisolone, betamethasone, betamethasone phosphate, methylprednisolone, salts thereof, and hydrates thereof.

12. A therapeutic agent for allergic diseases for transdermal administration containing epinastine or a salt thereof, which is used in combination with an antiallergic drug.

13. The therapeutic agent according to claim 12, which is administered in combination with an antiallergic drug.

14. The therapeutic agent according to claim 12 or 13, which is administered at a different time from or simultaneously with an antiallergic drug.

15. The therapeutic agent according to claim 12, which is a compounded preparation containing an antiallergic drug in combination.

Images