Aqueous composition containing epinastine or salt thereof

Abstract

To provide an aqueous composition for enhancing transferability into ocular tissue, the aqueous composition containing epinastine or salt thereof as an active ingredient.SOLUTION: The present disclosure provides an aqueous composition containing epinastine or salt thereof and a quaternary ammonium compound, where the content ratio of the quaternary ammonium compound with respect to the epinastine or salt thereof is 0.1 pt.wt. or less with respect to 1 pt.wt. of the content of the epinastine or salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an aqueous composition containing epinastine or a salt thereof, more particularly to an aqueous composition containing epinastine or a salt thereof and a quaternary ammonium compound (hereinafter also referred to as "the aqueous composition of the present invention"). [Background technology]

[0002] Aqueous compositions containing a solvent such as water, intended for repeated use, require a certain level of preservative measures to prevent the growth of bacteria and other microorganisms. Therefore, such compositions typically contain a preservative. For example, benzalkonium chloride is commonly used in eye drops. It is water-soluble, chemically stable, and has a higher preservative effect than other preservatives. However, benzalkonium chloride is cytotoxic, and increased exposure increases the likelihood of corneal epithelial damage, so it is recommended that its use be avoided whenever possible.

[0003] Alesion, currently on the market in Japan (登録商標) The 0.05% eye drops contain epinastine hydrochloride as an active ingredient, and instead of adding benzalkonium chloride as a preservative, boric acid is added (Non-Patent Document 1). Furthermore, it is known that by setting the concentration of epinastine or a salt thereof in the eye drops to more than 0.075% (w / v), a sufficient preservative effect can be obtained without substantially containing any preservative or component having preservative action (Patent Document 1). Thus, in recent years, efforts have been made to develop eye drops that do not use benzalkonium chloride, and there is a trend to avoid using benzalkonium chloride in aqueous compositions.

[0004]

[0003] In addition, from the viewpoint of medication adherence, it is desirable to administer the medication less frequently per day. However, reducing the number of administrations may result in the inability to maintain the effective concentration in biological tissues, which may reduce the efficacy of the medication. Therefore, in order to exert the efficacy of the medication, it is necessary to maintain the effective concentration in biological tissues. In the case of eye drops, methods for maintaining the effective concentration in ocular tissues include increasing the concentration of the active ingredient, using an absorption enhancer, and incorporating a thickener to improve retention in ocular tissues.

[0005] For example, Patent Document 2 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. Furthermore, Patent Document 3 describes that adding a sugar alcohol to a β-blocker improves the intraocular penetration of the drug.

[0006] On the other hand, it has been reported that a topically administrable aqueous solution containing epinastine inhibits the influx of neutrophils and eosinophils into the tissues of the conjunctiva of the eyeball and the nasal mucosa, thereby reducing or preventing the occurrence of delayed phase reactions, and a certain amount of benzalkonium chloride is added to the aqueous solution as a preservative (Patent Document 4).

[0007] There have been no reports that the addition of a quaternary ammonium compound such as benzalkonium chloride to an aqueous composition containing epinastine or a salt thereof improves the transfer of epinastine or a salt thereof to ocular tissues and maintains an effective concentration in the ocular tissues. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Patent No. 6134853 [Patent Document 2] Special Publication No. 2002-511430 [Patent Document 3] International Publication No. 2012 / 026609 Brochure [Patent Document 4] Special Publication No. 2003-514021 [Non-patent literature]

[0009] [Non-Patent Document 1] Alesion (registered trademark) eye drops 0.05% package insert Summary of the Invention [Problem to be solved by the invention]

[0010] Therefore, it is very useful to improve the transferability of active ingredients to tissues, particularly ocular tissues, in order to achieve excellent medicinal effects, and it is an interesting challenge to provide an aqueous composition containing epinastine or a salt thereof as an active ingredient and having improved transferability to tissues, particularly ocular tissues. [Means for solving the problem]

[0011] The present inventors have conducted extensive research into aqueous compositions containing epinastine or a salt thereof and have found that when an aqueous composition containing epinastine or a salt thereof and a quaternary ammonium compound adjusted to a specific content is administered by instillation into the eye, the transfer of epinastine to ocular tissues is improved, leading to the completion of the present invention.

[0012] Specifically, the present invention provides the following: (1) An aqueous composition containing epinastine or a salt thereof and a quaternary ammonium compound, wherein the content ratio of the quaternary ammonium compound to epinastine or a salt thereof is 0.1 parts by weight or less per 1 part by weight of the epinastine or a salt thereof. (2) The aqueous composition according to (1), wherein the epinastine or a salt thereof is epinastine hydrochloride. (3) The aqueous 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 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 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 composition according to any one of (1) to (5), wherein the quaternary ammonium compound is one or more selected from the group consisting of benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, and polydronium chloride. (7) The aqueous composition according to any one of (1) to (6), wherein the quaternary ammonium compound is benzalkonium chloride. (8) An aqueous composition according to any one of (1) to (7), wherein the content ratio of the quaternary ammonium compound to epinastine or a salt thereof is 0.05 parts by weight or less per 1 part by weight of the epinastine or a salt thereof. (9) The aqueous composition according to any one of (1) to (8), which is for ophthalmic use. (10) The aqueous composition according to any one of (1) to (9), which is an eye drop. (11) A method for improving the transferability of epinastine or a salt thereof into ocular tissues by incorporating a quaternary ammonium compound into an aqueous composition containing epinastine or a salt thereof as an active ingredient. (12) The method according to (11), wherein the quaternary ammonium compound is at least one selected from the group consisting of benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, and polidronium chloride. (13) The method according to (11) or (12), wherein the quaternary ammonium compound is benzalkonium chloride. (14) An eye drop containing epinastine hydrochloride at a concentration of 0.1% (w / v) and benzalkonium chloride, wherein the ratio of benzalkonium chloride to epinastine hydrochloride is 0.0001 parts by weight or more and less than 0.1 parts by weight per part by weight of epinastine hydrochloride. It should be noted that any two or more of the above configurations (1) to (14) can be selected and combined.

[0013] Furthermore, the present invention also provides the following: (15) A method for treating an allergic disease, comprising administering a therapeutically effective amount of the aqueous composition according to any one of (1) to (10) to a patient in need of treatment. (16) The aqueous composition according to any one of (1) to (10), which is used for treating an allergic disease. (17) Use of the aqueous composition according to any one of (1) to (10) for producing a medicament for treating an allergic disease. [Effects of the Invention]

[0014] The present invention provides an aqueous composition containing epinastine or a salt thereof, which can improve the transfer of epinastine or a salt thereof to ocular tissues and thereby provide excellent medicinal effects by incorporating a quaternary ammonium compound into the aqueous composition. DETAILED DESCRIPTION OF THE INVENTION

[0015] The present invention will be described in detail below.

[0016] 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: [ka] It is a compound represented by the formula:

[0017] In the aqueous composition of the present invention, the epinastine contained therein may be a racemate or an optical isomer.

[0018] In the aqueous composition of the present invention, epinastine may be contained in the form of a salt, and there are no particular limitations on the salt as long as it is a pharmaceutically 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, 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, and sulfosalicylic acid. As a salt of epinastine, the monohydrochloride salt (epinastine hydrochloride) is particularly preferred.

[0019] In the aqueous composition of the present invention, epinastine or a salt thereof may be in the form of a hydrate or solvate.

[0020] In the aqueous 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 ophthalmic preparations, for example, 5% (w / v). The content of epinastine or a salt thereof is preferably 0.01 to 5% (w / v), more preferably 0.05 to 1% (w / v), even more preferably 0.05 to 0.2% (w / v), and particularly preferably 0.05 to 0.1% (w / v). For example, the content is 0.1% (w / v).

[0021] In the present invention, "% (w / v)" means the mass (g) of the target ingredient contained in 100 mL of the aqueous 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] In the present invention, the "quaternary ammonium compound" refers to a salt of a quaternary ammonium cation with another anion, and is also called a quaternary ammonium salt.

[0023] In the aqueous composition of the present invention, examples of the quaternary ammonium compound contained include benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, polidronium chloride, cetylpyridinium chloride, benzalkonium bromide, benzethonium bromide, methylbenzethonium bromide, and cetrimide, of which benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, and polidronium chloride are preferred, and benzalkonium chloride is more preferred.

[0024] In the aqueous composition of the present invention, the quaternary ammonium compound also functions as a pharmaceutical additive, for example, a preservative, a surfactant, a stabilizer, a tonicity agent, a buffer, etc. Therefore, the quaternary ammonium compound can also be used as a pharmaceutical additive. In the aqueous composition of the present invention, one or more quaternary ammonium compounds may be used in combination.

[0025] In the aqueous composition of the present invention, the content of the quaternary ammonium compound can be adjusted appropriately depending on the type, but is, for example, 0.0001 to 1% (w / v), preferably 0.0001 to 0.1% (w / v), more preferably 0.0001 to 0.01% (w / v), and even more preferably 0.0001 to 0.005% (w / v). For example, when the quaternary ammonium compound is benzalkonium chloride, the upper limit of its content is preferably 0.01% (w / v) or less or less than 0.01% (w / v), and more preferably 0.005% (w / v). The lower limit of its content is preferably 0.0001% (w / v) or more, more preferably 0.001% (w / v) or more, and even more preferably 0.003% (w / v) or more. More specifically, the content is preferably 0.0001 to 0.01% (w / v), more preferably 0.001 to 0.005% (w / v), and even more preferably 0.001 to 0.003% (w / v) or 0.003 to 0.005% (w / v).

[0026] In the aqueous composition of the present invention, the content of the quaternary ammonium compound can be adjusted appropriately depending on the type, but for example, the upper limit of the content is 0.1 part by weight or less or less than 0.1 part by weight, preferably 0.05 part by weight or less, per part by weight of epinastine or a salt thereof. The lower limit of the content is 0.0001 part by weight or more, preferably 0.001 part by weight or more, more preferably 0.003 part by weight or more, 0.005 part by weight or more, or 0.01 part by weight or more, per part by weight of epinastine or a salt thereof. More specifically, the content is 0.0001 to 0.1 part by weight, preferably 0.001 to 0.1 part by weight, more preferably 0.003 to 0.1 part by weight, even more preferably 0.005 to 0.05 part by weight, and particularly preferably 0.01 to 0.05 part by weight. For example, when the quaternary ammonium compound is benzalkonium chloride, the possibility of causing corneal epithelial damage increases with increased exposure, so the content ratio is 0.1 part by weight or less or less than 0.1 part by weight, and preferably 0.05 part by weight or less or 0.03 part by weight or less, per part by weight of epinastine or a salt thereof. More specifically, the content ratio is 0.0001 to 0.1 part by weight, preferably 0.001 to 0.1 part by weight, more preferably 0.003 to 0.1 part by weight, even more preferably 0.005 to 0.05 part by weight, particularly preferably 0.01 to 0.05 part by weight, and particularly preferably 0.03 to 0.05 part by weight.

[0027] Aqueous compositions containing epinastine or its salts at a certain concentration or higher can obtain sufficient preservative effect without substantially containing any preservative or component having preservative action.For example, in the aqueous composition of the present invention, when the quaternary ammonium compound is benzalkonium chloride, which is commonly used as a preservative, the content of benzalkonium chloride may not be sufficient to exert the effect as a preservative, and may be contained in an amount that exerts the effect of the present invention.On the other hand, as long as the effect of the present invention is exerted, the content of benzalkonium chloride may be sufficient to exert the effect as a preservative.

[0028] In the present invention, ocular tissues include, for example, the conjunctiva, cornea, tears, aqueous humor, anterior chamber, etc. When the aqueous composition of the present invention is administered to the eye, it is possible to increase (or also improve) the amount of epinastine or a salt thereof transferred to ocular tissues.

[0029] In the present invention, the term "aqueous composition" refers to a composition containing water. The content of water in the aqueous composition of the present invention is not particularly limited, 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 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.

[0030] 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 produces a therapeutic effect on a disease and its symptoms, or an amount that delays the progression of a disease and its symptoms, compared to an untreated subject.

[0031] Pharmaceutical additives may be used in the aqueous composition of the present invention as needed, such as buffers, thickeners, surfactants, isotonicity agents, stabilizers, preservatives, antioxidants, pH adjusters, etc. These may be used alone or in appropriate combinations of two or more, and may be blended in appropriate amounts.

[0032] When a buffering agent is added to the aqueous composition of the present invention, the buffering agent can be any buffering agent that can be used as an additive for pharmaceuticals, and examples thereof include phosphoric acid or a salt thereof, boric acid or a salt thereof, carbonic acid or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, tartaric acid or a salt thereof, ε-aminocaproic acid or a salt thereof, glutamic acid or a salt thereof, or an organic amine, and hydrates or solvates of these may also be used. Examples of phosphoric acid or a salt thereof include phosphoric acid, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate (hereinafter also referred to as sodium hydrogen phosphate), potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, etc., and hydrates thereof may also be used. Examples of boric acid or salts thereof include boric acid, sodium borate (borax), potassium borate, and the like, and hydrates thereof may also be used. Examples of carbonic acid or a salt thereof include sodium carbonate and sodium hydrogen carbonate, and hydrates thereof may also be used. Examples of citric acid or salts thereof include citric acid, monosodium citrate, disodium citrate, trisodium citrate, and the like, and hydrates thereof may also be used. Examples of acetic acid or a salt thereof include acetic acid, sodium acetate, and the like, and hydrates thereof may also be used. Examples of tartaric acid or salts thereof include tartaric acid, monosodium tartrate, disodium tartrate, and the like, and hydrates thereof may also be used. Examples of ε-aminocaproic acid or a salt thereof include ε-aminocaproic acid, sodium ε-aminocaproate, ε-aminocaproic acid hydrochloride, and the like, and hydrates thereof may also be used. Examples of glutamic acid or a salt thereof include glutamic acid, monosodium glutamate, disodium glutamate, and glutamic acid hydrochloride, and hydrates thereof may also be used. Examples of organic amines include trometamol, and hydrates thereof may also be used.

[0033] When a buffering agent is incorporated into the aqueous composition of the present invention, the content of the buffering agent can be adjusted as appropriate depending on the type of buffering agent, etc., but 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 2% (w / v). When a buffering agent is added to the aqueous composition of the present invention, one or more buffering agents may be used in combination.

[0034] When a thickener is blended into the aqueous composition of the present invention, the thickener can be any thickener that can be used as an additive for pharmaceuticals, and examples thereof 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, etc.

[0035] When a thickener is blended into the aqueous composition of the present invention, the content of the thickener can be adjusted appropriately depending on the type of thickener, etc., but 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 thickener is added to the aqueous composition of the present invention, one or more thickeners may be used in combination.

[0036] When a surfactant is blended into the aqueous composition of the present invention, the surfactant may be any surfactant that can be used as an additive for pharmaceuticals, such as a cationic surfactant, an anionic surfactant, or a nonionic surfactant. 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. Examples of anionic surfactants include phospholipids such as lecithin. 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 Examples of suitable oleic acid esters include 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).

[0037] When a surfactant is blended into the aqueous composition of the present invention, the content of the surfactant can be adjusted appropriately 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 composition of the present invention, one or more surfactants may be used in combination.

[0038] When an isotonicity agent is incorporated into the aqueous composition of the present invention, the isotonicity agent may be any isotonicity agent that can be used as an additive in pharmaceuticals, and examples thereof include ionic isotonicity agents and non-ionic isotonicity agents. Examples of ionic tonicity agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and the like. Examples of non-ionic tonicity agents include glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose, and xylitol. When an isotonic agent is incorporated into the aqueous composition of the present invention, the content of the isotonic agent can be adjusted as appropriate depending on the type of isotonic agent, etc., but 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 aqueous composition of the present invention, one or more isotonicity agents may be used in combination.

[0039] When a stabilizer is incorporated into the aqueous composition of the present invention, the stabilizer may be any stabilizer that can be used as an additive for pharmaceuticals, such as edetic acid or a salt thereof, cyclodextrin, sodium thiosulfate, etc. Examples of edetic acid or a salt thereof include edetic acid, monosodium edetate, disodium edetate (hereinafter also referred to as sodium edetate), trisodium edetate, tetrasodium edetate, and the like, and hydrates thereof may also be used. When a stabilizer is blended into the aqueous composition of the present invention, the content of the stabilizer can be adjusted appropriately depending on the type of stabilizer, etc., but is preferably 0.001 to 5% (w / v), more preferably 0.01 to 3% (w / v), and even more preferably 0.01 to 1% (w / v). When a stabilizer is added to the aqueous composition of the present invention, one type of stabilizer may be used, or two or more types of stabilizers may be used in combination.

[0040] When a preservative is incorporated into the aqueous composition of the present invention, the preservative may be any preservative that can be used as an additive in pharmaceuticals, such as chlorhexidine gluconate, chlorhexidine hydrochloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate, sodium chlorite, or chlorobutanol. When a preservative is incorporated into the aqueous composition of the present invention, the content of the preservative can be adjusted as appropriate depending on the type of preservative, etc., but it is preferable that the amount be an amount that does not adversely affect safety, for example, 0.0001 to 0.1% (w / v) is preferred, and 0.001 to 0.05% (w / v) is more preferred. When a preservative is added to the aqueous composition of the present invention, one or more preservatives may be used in combination.

[0041] When an antioxidant is incorporated into the aqueous composition of the present invention, the antioxidant may be any antioxidant that can be used as an additive in pharmaceuticals, such as ascorbic acid, tocopherol, dibutylhydroxytoluene, sodium sulfite, etc. When an antioxidant is incorporated into the aqueous composition of the present invention, the content of the antioxidant can be adjusted as appropriate depending on the type of antioxidant, etc., but 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 aqueous composition of the present invention, one or more antioxidants may be used in combination.

[0042] When a pH adjuster is incorporated into the aqueous 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 acids include hydrochloric acid and phosphoric acid, and examples of bases include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate. The pH of the aqueous 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.

[0043] The osmotic pressure ratio of the aqueous composition of the present invention may be within a pharmaceutically 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.

[0044] The aqueous composition of the present invention is particularly preferably used as a pharmaceutical and is suitable for parenteral (e.g., topical) administration. Examples of parenteral administration routes for the aqueous composition of the present invention include pharmaceutically acceptable topical administration routes, such as topical administration to the eye (e.g., eye drops), nasal (intranasal) administration, topical administration to the ear (e.g., ear drops), inhalation administration, spray administration, transdermal administration, epicutaneous administration, and injection administration. Topical administration to the eye is preferred. The aqueous composition of the present invention can also be administered orally.

[0045] The aqueous composition of the present invention can be used as an ophthalmic preparation, an otolaryngological preparation, an inhalation preparation, or a transdermal preparation. The dosage form is not particularly limited as long as it is suitable for use 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, and inhalation aerosols), ointments, creams, gels, transdermal preparations, patches (tapes and poultices), topical liquid preparations (lotions and liniments), topical solid preparations (topical powders), sprays (pump sprays and topical aerosols), and topical preparations (infusions, implantable injections, and sustained-release injections). Eye drops, ophthalmic transdermal preparations, and ophthalmic injections are preferred, and eye drops are more preferred. These can be prepared according to conventional methods in the art.

[0046] The aqueous composition of the present invention may be in the form of a solution in which all of the components are dissolved or partially suspended, or may be in the form of an emulsion or semi-solid. The aqueous 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. When the aqueous composition of the present invention is an emulsion, it may be an oil-in-water emulsion (an emulsion in which an aqueous phase is the continuous phase and oily droplets are dispersed in the aqueous phase) or a water-in-oil emulsion (an emulsion in which an oil phase is the continuous phase and aqueous droplets are dispersed in oil).

[0047] When the aqueous 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 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.

[0048] When the aqueous composition of the present invention is administered to the eye as eye drops, there are no particular limitations 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 four times a day, and particularly preferably twice a day.

[0049] When the aqueous composition of the present invention is used as an eye drop, it may be contained in any of a multi-dose container, a single-use unit-dose 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. Preferably, the container is made of a resin, such as polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic, polystyrene, or polycyclic olefin copolymer. Furthermore, if the resin container is made of polyethylene, polyethylene is classified by its density, and containers made of low-density polyethylene (LDPE), medium-density polyethylene (MDPE), high-density polyethylene (HDPE), or the like may be used. [Example]

[0050] 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.

[0051] Formulation example Representative formulation examples of the present invention are shown below. Note that the amount of each ingredient in the formulation examples below is the content per 1 mL of the formulation.

[0052] Formulation Example 1 Epinastine hydrochloride 1mg Benzalkonium chloride 0.09mg Disodium hydrogen phosphate 5mg Sodium chloride 5mg Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) pH 7.0

[0053] Formulation Example 2 Epinastine hydrochloride 0.5mg Benzalkonium chloride 0.05mg Sodium dihydrogen phosphate 4.5mg Sodium chloride 5mg Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) pH 7.0

[0054] Formulation Example 3 Epinastine hydrochloride 1mg Benzalkonium chloride 0.05mg Boric acid 1mg Sodium chloride 5mg Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) pH 7.0

[0055] Formulation Example 4 Epinastine hydrochloride 1mg Benzalkonium chloride 0.02mg Boric acid 0.2mg Disodium edetate hydrate 1mg Sodium chloride 4.5mg Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) pH 7.0

[0056] Formulation Example 5 Epinastine hydrochloride 1mg Polydronium chloride 0.05mg Disodium hydrogen phosphate 3mg Sodium chloride 4.5mg Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) pH 7.0

[0057] Test Example 1. Intraocular dynamics test (1) Preparation of test formulations Epinastine hydrochloride, benzalkonium chloride, sodium chloride, sodium dihydrogen phosphate, and sodium hydrogen phosphate hydrate were dissolved in water to the concentrations shown in Table 1 below, and a pH adjuster (dilute hydrochloric acid and / or sodium hydroxide) and water were added to make the total volume 10 mL, followed by filtration sterilization to prepare the formulation of Example 1 (pH 7.0). In addition, the formulations of Example 2 and Comparative Example 1 in Table 1 below were prepared in the same manner as the preparation method of Example 1. [Table 1]

[0058] (2) Test method 50 μL of each test formulation was instilled into the eyes of the rabbits three times at 15-minute intervals, and the rabbits were sacrificed and their eyeballs were removed 0.25, 0.5, 1, 2, and 4 hours after the final instillation. The epinastine concentrations in the cornea and aqueous humor were measured at each time point, and the AUC (area under the blood concentration-time curve) was calculated. The AUC was measured using Phoenix WinNonlin (登録商標) The calculation was performed using sparse sampling analysis using v8.1.

[0059] (3) Test results and considerations The test results are shown in Table 2. In the table, "Mean" represents the average value, "SE" represents the standard error, and "N" represents the number of samples, all of which are calculated using general-purpose statistical processing. [Table 2]

[0060] As shown in Table 2, it was confirmed that Examples 1 and 2, which contain the quaternary ammonium compound benzalkonium chloride, exhibited increased amounts of epinastine transferred into the cornea and aqueous humor compared to Comparative Example 1, which does not contain benzalkonium chloride. Thus, it was demonstrated that the aqueous composition of the present invention significantly improves transferability to ocular tissues. [Industrial Applicability]

[0061] The present invention provides an aqueous composition containing epinastine or a salt thereof and a quaternary ammonium compound, wherein the content ratio of the quaternary ammonium compound to epinastine or a salt thereof is 0.1 parts by weight or less per 1 part by weight of the epinastine or a salt thereof.

Claims

1. An aqueous ophthalmic composition for improving the epinastine concentration in ocular tissue, characterized by comprising epinastine or a salt thereof and a quaternary ammonium compound, wherein the content ratio of the quaternary ammonium compound to the epinastine or a salt thereof is 0.005 to 0.05 parts by weight per 1 part by weight of the epinastine or a salt thereof.

2. 2. The aqueous ophthalmic composition according to claim 1, wherein the content ratio of the quaternary ammonium compound to the epinastine or salt thereof is 0.01 to 0.05 parts by weight per 1 part by weight of the epinastine or salt thereof.

3. 2. The aqueous ophthalmic composition according to claim 1, wherein the content ratio of the quaternary ammonium compound to the epinastine or salt thereof is 0.02 to 0.05 parts by weight per 1 part by weight of the epinastine or salt thereof.

4. 2. The aqueous ophthalmic composition according to claim 1, wherein the content ratio of the quaternary ammonium compound to the epinastine or salt thereof is 0.03 to 0.05 parts by weight per 1 part by weight of the epinastine or salt thereof.

5. 5. The aqueous ophthalmic composition according to claim 1, wherein the concentration of epinastine or a salt thereof is 0.05 to 0.1% (w / v).

6. 6. The aqueous ophthalmic composition according to claim 1, wherein the quaternary ammonium compound is benzalkonium chloride.

7. An aqueous ophthalmic composition for improving the epinastine concentration in ocular tissue, characterized by comprising epinastine hydrochloride at a concentration of 0.1% (w / v) and benzalkonium chloride, wherein the concentration of benzalkonium chloride is 0.001 to 0.005% (w / v).

8. 8. The aqueous ophthalmic composition according to claim 7, wherein the concentration of benzalkonium chloride is 0.002 to 0.005% (w / v).

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