Aqueous pharmaceutical composition containing epinastine or a salt thereof

Abstract

To provide an aqueous pharmaceutical composition that has improved migration to eye tissue, and contains as an active ingredient epinastine or a salt thereof.SOLUTION: An aqueous pharmaceutical composition contains epinastine or a salt thereof, and a lower aliphatic carboxylic acid.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an aqueous pharmaceutical composition containing epinastine or a salt thereof, more specifically, to an aqueous pharmaceutical composition containing epinastine or a salt thereof and a lower aliphatic carboxylic acid (hereinafter also referred to as "the aqueous pharmaceutical composition of the present invention"). [Background technology]

[0002] Allergyon, which contains epinastine hydrochloride as an active ingredient, is currently on the market in Japan as a treatment for allergic conjunctivitis. (登録商標) The usual dosage of 0.05% eye drops is one drop administered at a time, four times a day (Non-Patent Document 1).

[0003] From the viewpoint of medication adherence, it is desirable to instill eye drops four times a day, because there may be situations in daily life where eye drops cannot be instilled for several hours. However, reducing the number of instillations may reduce the efficacy of the drug because the effective concentration in the ocular tissue cannot be maintained, and it is necessary to maintain the effective concentration in the ocular tissue in order to exert the drug's efficacy. Methods for maintaining the effective concentration in the ocular tissue include increasing the concentration of the active ingredient, using an absorption enhancer, and improving tissue retention by adding a thickener. For example, Patent Document 1 describes that adding a β-blocker to an aqueous solution containing alginic acid and adjusting the pH to 6 to 8 has the effect of extending the duration of action after administration. Patent Document 2 describes that adding a sugar alcohol to a β-blocker improves the intraocular transfer of the drug. However, there is no report that the addition of a lower aliphatic carboxylic acid improves the transfer of epinastine or a salt thereof to ocular tissues and maintains the effective concentration in ocular tissues. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Special Publication No. 2002-511430 [Patent Document 2] International Publication No. 2012 / 026609 Brochure [Non-patent literature]

[0005] [Non-Patent Document 1] Alesion (registered trademark) eye drops 0.05% package insert Summary of the Invention [Problem to be solved by the invention]

[0006] Therefore, in order to achieve excellent medicinal efficacy, it is very useful to improve the transferability of an active ingredient to tissues, particularly to ocular tissues, and it is an interesting task to provide an aqueous pharmaceutical composition containing epinastine or a salt thereof as an active ingredient and having improved transferability to tissues, particularly to ocular tissues. [Means for solving the problem]

[0007] The present inventors have conducted extensive research into aqueous pharmaceutical compositions containing epinastine or a salt thereof and have discovered that when an aqueous pharmaceutical composition containing epinastine or a salt thereof and a lower aliphatic carboxylic acid is administered by instillation into the eye, the transfer of epinastine into ocular tissue is improved, leading to the completion of the present invention.

[0008] Specifically, the present invention provides the following: (1) An aqueous pharmaceutical composition comprising epinastine or a salt thereof and a lower aliphatic carboxylic acid. (2) The aqueous pharmaceutical composition according to (1), wherein the epinastine or a salt thereof is epinastine hydrochloride. (3) The aqueous pharmaceutical composition according to (1) or (2), wherein the concentration of epinastine or a salt thereof is 0.01 to 5% (w / v). (4) The aqueous pharmaceutical composition according to (1) or (2), wherein the concentration of epinastine or a salt thereof is 0.05% (w / v) or more. (5) The aqueous pharmaceutical composition according to any one of (1) to (4), wherein the concentration of epinastine or a salt thereof is 0.1% (w / v). (6) The aqueous pharmaceutical composition according to any one of (1) to (5), wherein the lower aliphatic carboxylic acids are one or more selected from the group consisting of acetic acid, citric acid, edetic acid, sorbic acid, ε-aminocaproic acid, and salts thereof. (7) The aqueous pharmaceutical composition according to any one of (1) to (6), wherein the lower aliphatic carboxylic acid is sorbic acid or a salt thereof. (8) The aqueous pharmaceutical composition according to (6) or (7), wherein the concentration of sorbic acid or a salt thereof is 0.01 to 2% (w / v). (9) The liquid pharmaceutical composition according to any one of (1) to (6), wherein the lower aliphatic carboxylic acid is citric acid or a salt thereof. (10) The aqueous pharmaceutical composition according to (6) or (9), wherein the concentration of citric acid or a salt thereof is 0.01 to 3.5% (w / v). (11) The aqueous pharmaceutical composition according to any one of (1) to (6), wherein the lower aliphatic carboxylic acid is ε-aminocaproic acid or a salt thereof. (12) The aqueous pharmaceutical composition according to (6) or (11), wherein the concentration of ε-aminocaproic acid or a salt thereof is 0.01 to 1% (w / v). (13) The liquid pharmaceutical composition according to any one of (1) to (12), further comprising an isotonicity agent. (14) The aqueous pharmaceutical composition according to any one of (1) to (13), which is for ophthalmic use. (15) The aqueous pharmaceutical composition according to any one of (1) to (14), which is an eye drop. (16) A method for improving the transferability of epinastine or a salt thereof into ocular tissues by incorporating a lower aliphatic carboxylic acid into an aqueous pharmaceutical composition containing epinastine or a salt thereof as an active ingredient. (17) The method according to (16), wherein the lower aliphatic carboxylic acids are one or more selected from the group consisting of acetic acid, citric acid, edetic acid, sorbic acid, ε-aminocaproic acid, and salts thereof. (18) The method according to (16) or (17), wherein the lower aliphatic carboxylic acid is sorbic acid or a salt thereof. (19) The method according to (16) or (17), wherein the lower aliphatic carboxylic acid is citric acid or a salt thereof. (20) The method according to (16) or (17), wherein the lower aliphatic carboxylic acid is ε-aminocaproic acid or a salt thereof. (21) The method according to any one of (16) to (20), wherein the ocular tissue is the conjunctiva. In addition, any two or more of the configurations (1) to (21) above can be selected and combined.

[0009] In addition, the present invention also provides the following: (22) A method for treating an allergic disease, comprising administering to a patient in need of treatment a therapeutically effective amount of the aqueous pharmaceutical composition according to any one of (1) to (15). (23) The aqueous pharmaceutical composition according to any one of (1) to (15), which is used for the treatment of an allergic disease. (24) Use of the aqueous pharmaceutical composition according to any one of (1) to (15) for producing a medicament for treating an allergic disease. Effect of the Invention

[0010] The present invention provides an aqueous pharmaceutical composition containing epinastine or a salt thereof, which, by incorporating lower aliphatic carboxylic acids into the aqueous pharmaceutical composition, improves the migration of epinastine or a salt thereof into ocular tissue, thereby providing excellent medicinal efficacy. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The present invention will be described in detail below.

[0012] 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 represented by the following formula: [ka] It is a compound represented by the formula:

[0013] In the aqueous pharmaceutical composition of the present invention, the epinastine contained therein may be a racemate or an optical isomer.

[0014] In the aqueous pharmaceutical composition of the present invention, epinastine may be in the form of a salt, and there is no particular limitation as long as it is a medicamentously acceptable salt. 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, and the like. 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, glucoheptic 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, and sulfosalicylic acid. As a salt of epinastine, the monohydrochloride salt (epinastine hydrochloride) is particularly preferred.

[0015] In the aqueous pharmaceutical composition of the present invention, epinastine or a salt thereof may be in the form of a hydrate or solvate.

[0016] In the aqueous pharmaceutical composition of the present invention, the content of epinastine or a salt thereof is preferably 0.01% (w / v) or more, more preferably 0.05% (w / v) or more, and even more preferably 0.1% (w / v) or more, with the upper limit being any concentration acceptable for an ophthalmic preparation, for example, 5% (w / v). The content of epinastine or a salt thereof is preferably 0.01-5% (w / v), more preferably 0.05-1% (w / v), even more preferably 0.05-0.2% (w / v), and particularly preferably 0.05-0.1% (w / v). For example, the content is 0.1% (w / v).

[0017] In the present invention, "% (w / v)" means the mass (g) of the target component contained in 100 mL of the aqueous 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. In addition, when epinastine or a salt thereof is formulated in the present invention in the form of a hydrate or solvate, the value is the content of the hydrate or solvate of epinastine or a salt thereof. The same applies hereinafter unless otherwise specified.

[0018] In the present invention, the term "lower aliphatic carboxylic acids" refers to carboxylic acids having 15 or less carbon atoms and one or more carboxyl groups. The number of carboxyl groups in the lower aliphatic carboxylic acids is not particularly limited, but is preferably 1 to 4, and more preferably 1 to 3. The number of carbon atoms in the lower aliphatic carboxylic acids may be 15 or less, preferably 2 to 12, and more preferably 4 to 10.

[0019] The carbon chains in the lower aliphatic carboxylic acids may be straight or branched, saturated or unsaturated. The lower aliphatic carboxylic acids may have a substituent other than the carboxyl group, and the number and type of the substituent are not particularly limited. Examples of the substituent include an amino group and a hydroxyl group.

[0020] In the aqueous pharmaceutical composition of the present invention, the lower aliphatic carboxylic acid contained may be in the form of a salt, and there is no particular limitation as long as it is a medicamentously acceptable salt. Examples of the salt include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as magnesium and calcium. In addition, when the lower aliphatic carboxylic acid contained has, for example, an amino group as a substituent, examples of the salt include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid.

[0021] In the aqueous pharmaceutical composition of the present invention, examples of lower aliphatic carboxylic acids contained include acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, lactic acid, malic acid, citric acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, maleic acid, pyruvic acid, tartaric acid, sorbic acid, edetic acid, ε-aminocaproic acid (ε-aminocaproic acid), glycine, alanine, leucine, isoleucine, valine, serine, aspartic acid, glutamic acid, or salts thereof, and may be hydrates or solvates thereof. Preferred are acetic acid, citric acid, edetic acid, sorbic acid, ε-aminocaproic acid, or salts thereof, more preferred are sorbic acid or a salt thereof, citric acid or a salt thereof, ε-aminocaproic acid or a salt thereof, and even more preferred is sorbic acid or a salt thereof. Examples of sorbic acid or its salts include sorbic acid, sodium sorbate, and potassium sorbate. Examples of citric acid or its salts include citric acid, monosodium citrate, disodium citrate, trisodium citrate, monopotassium citrate, dipotassium citrate, tripotassium citrate, magnesium citrate, and calcium citrate. Examples of ε-aminocaproic acid or its salts include ε-aminocaproic acid, sodium ε-aminocaproate, potassium ε-aminocaproate, ε-aminocaproic acid hydrochloride, ε-aminocaproic acid hydrobromide, ε-aminocaproic acid hydroiodide, ε-aminocaproic acid nitrate, ε-aminocaproic acid sulfate, and ε-aminocaproic acid phosphate.

[0022] In the aqueous pharmaceutical composition of the present invention, the lower aliphatic carboxylic acids also act as pharmaceutical additives, such as buffers, stabilizers, preservatives, pH regulators, etc. Therefore, the lower aliphatic carboxylic acids can also be used as pharmaceutical additives. For example, the lower aliphatic carboxylic acids may be acetic acid or a salt thereof, which acts as a buffer, pH regulator, etc.; citric acid or a salt thereof, which acts as a buffer, pH regulator, etc.; edetic acid or a salt thereof, which acts as a stabilizer, etc.; sorbic acid or a salt thereof, which acts as a preservative, etc.; and ε-aminocaproic acid or a salt thereof, which acts as a buffer, etc. In the aqueous pharmaceutical composition of the present invention, the lower aliphatic carboxylic acids may be used alone or in combination of two or more kinds.

[0023] In the aqueous pharmaceutical composition of the present invention, the content of the lower aliphatic carboxylic acid can be appropriately adjusted depending on the type, and is, for example, 0.01 to 3.5% (w / v). It is preferably 0.01 to 2% (w / v), more preferably 0.05 to 1.5% (w / v), even more preferably 0.05 to 1% (w / v), and even more preferably 0.1 to 1% (w / v). For example, when the lower aliphatic carboxylic acid is sorbic acid or a salt thereof, the content is preferably 0.01 to 2% (w / v), more preferably 0.1 to 1% (w / v), and even more preferably 0.2 to 0.8% (w / v). For example, the content is 0.6% (w / v). For example, when the lower aliphatic carboxylic acid is citric acid or a salt thereof, the content is preferably 0.01 to 3.5% (w / v), more preferably 0.1 to 2.5% (w / v), and even more preferably 0.5 to 2% (w / v). For example, the content is 1.6% (w / v). For example, when the lower aliphatic carboxylic acid is ε-aminocaproic acid or a salt thereof, the content is preferably 0.01 to 1% (w / v), more preferably 0.1 to 1% (w / v), and even more preferably 0.2 to 0.8% (w / v). For example, the content is 0.5% (w / v).

[0024] In the present invention, the term "aqueous pharmaceutical composition" refers to a pharmaceutical composition containing water. The content of water in the aqueous pharmaceutical composition of the present invention is not particularly limited as long as it is an amount usable as a pharmaceutical composition, but is preferably 10% (w / v) or more, more preferably 30% (w / v) or more, and even more preferably 50% (w / v) or more, based on the total weight of the aqueous pharmaceutical composition. In particular, it is preferably 70% (w / v) or more, more preferably 90% (w / v) or more, and even more preferably 95% (w / v) or more.

[0025] In the present invention, ocular tissues include, for example, the conjunctiva, cornea, tears, aqueous humor, anterior chamber, etc. When the aqueous pharmaceutical composition of the present invention is administered to the eye, it is possible to increase (or improve) the amount of epinastine or a salt thereof transferred to ocular tissues, and it is particularly preferable to increase the amount transferred to the conjunctiva.

[0026] 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, and 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.

[0027] Pharmaceutical additives can be used in the aqueous pharmaceutical composition of the present invention as necessary, for example, buffers, thickening agents, surfactants, isotonicity agents, stabilizers, preservatives, antioxidants, pH regulators, etc. These can be used alone or in appropriate combinations of two or more, and can be blended in appropriate amounts.

[0028] When a buffering agent is blended in the aqueous pharmaceutical composition of the present invention, the buffering agent can be any buffering agent that can be used as an additive for pharmaceuticals. Examples of the buffering agent include phosphoric acid or a salt thereof, boric acid or a salt thereof, carbonic acid or a salt thereof, and organic amines, and these may also be hydrates or solvates.

[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, dipotassium hydrogen phosphate, and the like, and hydrates thereof may also be used.

[0030] Examples of boric acid or a salt thereof include boric acid, sodium borate (borax), potassium borate, and the like, and hydrates thereof may also be used.

[0031] Examples of carbonic acid or a salt thereof include sodium carbonate, sodium hydrogen carbonate, and the like, and may also be hydrates thereof.

[0032] The organic amine includes trometamol, etc., and may be a hydrate thereof.

[0033] When a buffering agent is incorporated into the aqueous pharmaceutical composition of the present invention, the content of the buffering agent can be adjusted as appropriate depending on the type of buffering agent, etc., and is preferably 0.001 to 10% (w / v), more preferably 0.01 to 5% (w / v), even more preferably 0.1 to 5% (w / v), and particularly preferably 0.1 to 1% (w / v). When a buffer is added to the liquid pharmaceutical composition of the present invention, one or more kinds of buffers may be used in combination.

[0034] When a thickening agent is blended into the aqueous pharmaceutical composition of the present invention, the thickening agent can be any thickening agent that can be used as an additive for pharmaceuticals, and examples of the thickening agent include methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, sodium hyaluronate, and the like.

[0035] When a thickener is incorporated into the aqueous pharmaceutical composition of the present invention, the content of the thickener can be adjusted as appropriate depending on the type of thickener, and is preferably 0.001 to 5% (w / v), more preferably 0.01 to 3% (w / v), and even more preferably 0.1 to 2% (w / v). When a thickening agent is added to the aqueous pharmaceutical composition of the present invention, one or more types of thickening agents may be used in combination.

[0036] When a surfactant is blended in the aqueous pharmaceutical composition of the present invention, the surfactant may be any surfactant that can be used as an additive in pharmaceuticals, and examples of the surfactant include cationic surfactants, anionic surfactants, and nonionic surfactants.

[0037] 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, 1-hydroxyethyl-2-alkylimidazolines, etc. Although quaternary ammonium cations such as benzalkonium chloride have the properties of cationic surfactants, they are not included in the cationic surfactants of the present invention.

[0038] Anionic surfactants include phospholipids such as lecithin.

[0039] Nonionic surfactants include polyoxyethylene fatty acid esters such as polyoxyl 40 stearate; polyoxyethylene sorbitan fatty acid esters such as polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, and polysorbate 65; polyoxyethylene hydrogenated castor oils such as polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60; polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, and polyoxyl polyoxyl castor oils such as polyoxyl 35 castor oil and polyoxyl 40 castor oil; polyoxyethylene polyoxypropylene glycols such as polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, and polyoxyethylene (20) polyoxypropylene (20) glycol; sucrose fatty acid esters such as sucrose stearate; and tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS).

[0040] When a surfactant is incorporated into the aqueous pharmaceutical composition of the present invention, the content of the surfactant can be appropriately adjusted depending on the type of surfactant, etc., but is preferably 0.01 to 1% (w / v), more preferably 0.05 to 0.5% (w / v), and even more preferably 0.05 to 0.2% (w / v). When a surfactant is added to the aqueous pharmaceutical composition of the present invention, one or more types of surfactants may be used in combination.

[0041] When an isotonicity agent is blended into the aqueous pharmaceutical composition of the present invention, the isotonicity agent can be appropriately blended with an isotonicity agent that can be used as an additive for pharmaceuticals, and examples of the isotonicity agent include ionic isotonicity agents and non-ionic isotonicity agents.

[0042] Ionic tonicity agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and the like.

[0043] Non-ionic tonicity agents include glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose, xylitol, and the like.

[0044] When an isotonicity agent is incorporated into the aqueous pharmaceutical composition of the present invention, the isotonicity agent is preferably an ionic isotonicity agent, and particularly preferably sodium chloride.

[0045] When an isotonicity agent is blended in the aqueous pharmaceutical composition of the present invention, the content of the isotonicity agent can be appropriately adjusted depending on the type of the isotonicity agent, and is preferably 0.001 to 10% (w / v), more preferably 0.01 to 5% (w / v), even more preferably 0.1 to 3% (w / v), and particularly preferably 0.2 to 1% (w / v). When an isotonicity agent is added to the liquid pharmaceutical composition of the present invention, one or more types of isotonicity agents may be used together.

[0046] When a stabilizer is added to the aqueous pharmaceutical composition of the present invention, the stabilizer can be appropriately selected from those that can be used as additives for pharmaceuticals, and examples of the stabilizer include cyclodextrin, sodium thiosulfate, etc.

[0047] When a stabilizer is blended in the aqueous pharmaceutical composition of the present invention, the content of the stabilizer can be appropriately adjusted depending on the type of stabilizer, etc., and is preferably 0.001 to 5% (w / v), more preferably 0.01 to 3% (w / v), and even more preferably 0.05 to 1% (w / v). When a stabilizer is added to the liquid pharmaceutical composition of the present invention, one type of stabilizer may be used, or two or more types of stabilizers may be used together.

[0048] When a preservative is added to the aqueous pharmaceutical composition of the present invention, the preservative can be appropriately selected from preservatives that can be used as an additive in pharmaceuticals, and examples of the preservative include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine gluconate, chlorhexidine hydrochloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate, sodium chlorite, and chlorobutanol.

[0049] When a preservative is incorporated into the aqueous pharmaceutical composition of the present invention, the content of the preservative can be appropriately adjusted depending on the type of preservative, etc., but it is preferable that the amount is an amount that does not adversely affect safety, and for example, 0.0001 to 0.1% (w / v) is preferable, and 0.001 to 0.05% (w / v) is more preferable.

[0050] When an antioxidant is incorporated into the aqueous pharmaceutical composition of the present invention, the antioxidant may be any antioxidant that can be used as an additive in pharmaceuticals, and examples of the antioxidant include ascorbic acid, tocopherol, dibutylhydroxytoluene, sodium sulfite, etc.

[0051] When an antioxidant is incorporated into the aqueous pharmaceutical composition of the present invention, the content of the antioxidant can be adjusted as appropriate depending on the type of antioxidant, etc., and is preferably 0.001 to 5% (w / v), more preferably 0.01 to 3% (w / v), and even more preferably 0.1 to 2% (w / v). When an antioxidant is added to the liquid pharmaceutical composition of the present invention, one or more antioxidants may be used in combination.

[0052] When a pH adjuster is added to the aqueous pharmaceutical composition of the present invention, the pH adjuster can be any pH adjuster that can be used as an additive for pharmaceuticals, and is, for example, an acid or a base. Examples of the acid include hydrochloric acid and phosphoric acid, and examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate.

[0053] The pH of the aqueous pharmaceutical composition of the present invention may be within a medicament 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.

[0054] The osmotic pressure ratio of the aqueous pharmaceutical composition of the present invention may be within a medicament acceptable range, for example, 0.5 to 2.0, preferably 0.7 to 1.6, more preferably 0.8 to 1.4, and even more preferably 0.9 to 1.2.

[0055] The aqueous pharmaceutical composition of the present invention is suitable for parenteral (e.g., topical) administration. The parenteral administration route of the aqueous pharmaceutical composition of the present invention includes medicamentously acceptable local administration routes, such as local administration to the eye (e.g., eye drop administration), nasal (transnasal) administration, local administration to the ear (e.g., ear drop administration), inhalation administration, spray administration, transdermal administration, epicutaneous administration, injection administration, etc. Topical administration to the eye is preferred. The aqueous pharmaceutical composition of the present invention can also be administered orally.

[0056] The aqueous pharmaceutical composition of the present invention can be used as an ophthalmic preparation, an otolaryngological preparation, an inhalation preparation, or a transdermal preparation, and the dosage form is not particularly limited as long as it can be used as a pharmaceutical. Examples of dosage forms include oral 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 liquids (lotions, liniments), external solids (external powders), sprays (pump sprays, external aerosols), and injections (infusions, implant injections, sustained release injections). Eye drops, ophthalmic transdermal preparations, or ophthalmic injections are preferred, and eye drops are more preferred. These can be produced according to conventional methods in the art.

[0057] The aqueous pharmaceutical composition of the present invention may be in the form of an emulsion or semi-solid, in which all of the components are dissolved or partially suspended. The aqueous pharmaceutical composition of the present invention is more preferably in the form of a solution in which all of the components are dissolved, and most preferably in the form of an aqueous solution. For example, for ophthalmic use, eye drops (eye drops) are particularly preferred.

[0058] When the aqueous pharmaceutical composition of the present invention is an emulsion, it may be an oil-in-water emulsion (an emulsion in which the aqueous phase is the continuous phase and is composed of oily droplets dispersed in the aqueous phase) or a water-in-oil emulsion (an emulsion in which the oil phase is the continuous phase and is composed of aqueous droplets dispersed in oil).

[0059] When the aqueous pharmaceutical composition of the present invention is used as an ophthalmic preparation, it is particularly useful as a therapeutic agent for allergic conjunctivitis. Furthermore, unless otherwise specified, the aqueous pharmaceutical composition of the present invention may contain a pharmaceutical active ingredient other than epinastine or a salt thereof, for example, an active ingredient used in other eye drops.

[0060] When the aqueous pharmaceutical composition of the present invention is administered to the eye as an eye drop, there is no particular limitation on the dosage and administration as long as it is sufficient to achieve the desired medicinal effect, but it can be administered as one drop at a time, 1 to 10 times a day, preferably 1 to 6 times a day, more preferably 2 to 4 times a day, even more preferably twice a day or 4 times a day, and particularly preferably twice a day. It can also be used when wearing contact lenses.

[0061] When the aqueous pharmaceutical composition of the present invention is used as an eye drop, it may be contained in any of a multi-dose type container, a single-use unit dose type container, or a PFMD (Preservative Free Multi Dose) container. The material of the container is not particularly limited, and any commonly used eye drop container may be used, but a resin container is preferable, and for example, a container made of polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic, polystyrene, polycyclic olefin copolymer, etc. can be used. In addition, if the material of the resin container is, for example, polyethylene, polyethylene is classified according to its density, and a container made of low density polyethylene (LDPE), medium density polyethylene (MDPE), high density polyethylene (HDPE), etc. can be used. EXAMPLES

[0062] The following formulation examples and test examples are provided to aid in better understanding of the present invention and are not intended to limit the scope of the present invention.

[0063] Formulation examples Representative formulation examples of the present invention are shown below. Note that the amount of each ingredient in the following formulation examples is the content per 1 mL of the formulation.

[0064] Formulation Example 1 Epinastine hydrochloride 1mg Sorbic acid 5mg Sodium chloride 5mg Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) pH 7.0

[0065] Formulation Example 2 Epinastine hydrochloride 0.5mg Sorbic acid 5mg Sodium chloride 5mg Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) pH 7.0

[0066] Formulation Example 3 Epinastine hydrochloride 0.5mg Sorbic acid 1mg Boric acid 1mg Sodium chloride 5mg Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) pH 7.0

[0067] Formulation Example 4 Epinastine hydrochloride 1mg Sodium edetate hydrate 1mg Boric acid 0.5mg Sodium citrate 1mg Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) pH 7.0

[0068] Formulation Example 5 Epinastine hydrochloride 1mg Sodium edetate hydrate 0.5mg ε-aminocaproic acid 2mg Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) pH 7.0

[0069] Formulation Example 6 Epinastine hydrochloride 1mg ε-aminocaproic acid 3mg Sodium chloride 9mg Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) pH 7.0

[0070] Formulation Example 7 Epinastine hydrochloride 1mg Sodium citrate hydrate 10mg Sodium chloride 5mg Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) pH 7.0

[0071] Formulation Example 8 Epinastine hydrochloride 1mg Sodium edetate hydrate 1mg Sodium chloride 8mg Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) pH 7.0

[0072] Test Example 1. Ocular dynamics test (1) (1) Preparation of test formulations Epinastine hydrochloride, sorbic acid, and sodium chloride were dissolved in water to the concentrations shown in Table 1 below, a pH adjuster (dilute hydrochloric acid and / or sodium hydroxide) and water were added to make the total volume 10 mL, and the solution was sterilized by filtration to prepare the formulation of Example 1 (pH 7.0). In addition, the preparations of Comparative Example 1 and Comparative Example 2 in Table 1 below were prepared in the same manner as the preparation method of Example 1. The sodium chloride contents of Comparative Example 1 and Comparative Example 2 were appropriately adjusted to match the osmotic pressure of Example 1. [Table 1]

[0073] (2) Test method 5 μL of each test formulation was instilled into the eyes of rats (n=4-6) once, and the rats were sacrificed and their eyeballs were removed 1 and 4 hours after administration. The epinastine concentration in the conjunctiva was measured and the average value was calculated.

[0074] (3) Test results and considerations The test results are shown in Table 2. [Table 2]

[0075] As shown in Table 2, it was confirmed that Example 1, which contains sorbic acid, increased the epinastine concentration in the conjunctival tissue by about three times compared to Comparative Examples 1 and 2, which do not contain sorbic acid. Thus, the aqueous pharmaceutical composition of the present invention showed remarkable transferability to the conjunctival tissue.

[0076] 2. Ocular dynamics test (2) (1) Preparation of test formulations The preparations of Examples 2 and 3 in Table 3 below were prepared in the same manner as the preparation of Example 1. Comparative Example 1 was also prepared again for comparison. The sodium chloride contents of Examples 2 and 3 were appropriately adjusted to match the osmotic pressure of Comparative Example 1. [Table 3]

[0077] (2) Test method 5 μL of each test formulation was instilled once into the eyes of rats (n=6), and the rats were sacrificed one hour after administration and their eyeballs were removed. The epinastine concentration in the conjunctiva was measured and the average value was calculated.

[0078] (3) Test results and considerations The test results are shown in Table 4. [Table 4]

[0079] As shown in Table 4, it was confirmed that the epinastine concentrations in the conjunctival tissue were increased by about 1.2 times and about 1.3 times, respectively, in Example 2 containing sodium citrate hydrate and Example 3 containing ε-aminocaproic acid, compared to Comparative Example 1 containing no lower aliphatic carboxylic acids. This demonstrates that the transfer of epinastine to the conjunctival tissue is improved in the aqueous pharmaceutical composition of the present invention.

[0080] The results of the above tests (1) and (2) demonstrated that the transfer of epinastine into ocular tissues is improved by adding lower aliphatic carboxylic acids to an aqueous pharmaceutical composition containing epinastine or a salt thereof. [Industrial Applicability]

[0081] The present invention provides an aqueous pharmaceutical composition containing epinastine or a salt thereof and a lower aliphatic carboxylic acid.

Claims

1. An aqueous pharmaceutical composition for eye drops containing only epinastine or a salt thereof as an active ingredient and lower aliphatic carboxylic acids as additives for improving migration to the conjunctiva, the aqueous pharmaceutical composition for eye drops being characterized in that the lower aliphatic carboxylic acids are one or more selected from the group consisting of acetic acid, citric acid, sorbic acid and salts thereof, and being administered twice a day.

2. 2. The aqueous pharmaceutical composition for eye drops according to claim 1, wherein the epinastine or a salt thereof is epinastine hydrochloride.

3. 3. The aqueous pharmaceutical composition for ophthalmic administration according to claim 1, wherein the concentration of epinastine or a salt thereof is 0.01 to 5% (w / v).

4. 3. The aqueous pharmaceutical composition for ophthalmic administration according to claim 1, wherein the concentration of epinastine or a salt thereof is 0.05% (w / v) or more.

5. The aqueous pharmaceutical composition for ophthalmic administration according to any one of claims 1 to 4, wherein the concentration of epinastine or a salt thereof is 0.1% (w / v).

6. The aqueous pharmaceutical composition for ophthalmic administration according to any one of claims 1 to 5, wherein the lower aliphatic carboxylic acid is sorbic acid or a salt thereof.

7. The aqueous pharmaceutical composition for ophthalmic administration according to claim 6, wherein the concentration of sorbic acid or a salt thereof is 0.01 to 2% (w / v).

8. The aqueous pharmaceutical composition for ophthalmic administration according to any one of claims 1 to 5, wherein the lower aliphatic carboxylic acid is citric acid or a salt thereof.

9. The aqueous pharmaceutical composition for ophthalmic administration according to claim 8, wherein the concentration of citric acid or a salt thereof is 0.01 to 3.5% (w / v).

10. The aqueous pharmaceutical composition for ophthalmic administration according to any one of claims 1 to 9, further comprising an isotonicity agent.

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