Epinastine-containing aqueous composition for improving tissue mobility and preservative efficacy

Abstract

The present invention provides an aqueous composition which contains epinastine or a salt thereof at a concentration of 0.1% (w / v), boric acid and / or a salt thereof, and an isotonic agent, has a pH of 6.0-7.7, and has a concentration of boric acid and / or a salt thereof of 150-500 mM in terms of boron concentration, and which improves migration into ocular tissue and preservative efficacy.

Description

Technical Field

[0001] The present invention relates to an aqueous composition containing epinastine, which improves tissue migratability and antiseptic efficacy. Specifically, it is the following aqueous composition (hereinafter, also referred to as "the aqueous composition of the present invention"), which contains epinastine or its salt at a concentration of 0.1% (w / v), boric acid and / or its salt, and an isotonic agent, and has a pH of 6.0 to 7.7. In the aqueous composition, the concentration of boric acid and / or its salt, converted to boron concentration, is 150 to 500 mM. Background Art

[0002] Currently, as a therapeutic agent for allergic conjunctivitis, there is Alesion (注册商标) eye drops 0.05% containing epinastine hydrochloride, which is usually used at a dosage of 1 drop once and 4 times a day (Non-Patent Document 1). In addition, there is Alesion (注册商标) LX eye drops 0.1% containing epinastine hydrochloride, which is usually used at a dosage of 1 drop once and 2 times a day (Non-Patent Document 2).

[0003] From the viewpoint of medication compliance, it is desirable to minimize the number of eye drops. However, if the number of eye drops is reduced, it may not be possible to maintain the effective concentration in the eye tissue, resulting in a decrease in drug efficacy. To exert the drug efficacy, it is necessary to maintain the effective concentration in the eye tissue. As a method for maintaining the effective concentration in the eye tissue, the following methods are known: a method of increasing the compounding concentration of the active ingredient; a method of using an absorption promoter; a method of increasing tissue retention by compounding a thickening agent; a method of compounding a specific additive; and so on.

[0004] For example, Patent Document 1 describes that the migratability of epinastine into eye tissue is improved when an aqueous pharmaceutical composition containing epinastine or its salt and lower aliphatic carboxylic acids is instilled into the eye, and Patent Document 2 describes that the migratability of epinastine into eye tissue is improved when an aqueous pharmaceutical composition containing epinastine or its salt and a quaternary ammonium compound is instilled into the eye.

[0005] However, there is no report of maintaining the effective concentration in the eye tissue by adding boric acid and / or its salt to an aqueous composition containing epinastine or its salt to improve the migration of epinastine or its salt into the eye tissue.

[0006] In Patent Document 3, the following ophthalmic composition is described, which is an ophthalmic composition containing boric acid or its salt and inhibiting the deterioration of soft contact lenses. The ophthalmic composition contains epinastine or its salt, and the aforementioned soft contact lenses are soft contact lenses that can be worn for up to 1 month. However, Patent Document 3 does not describe or teach that the migratability of epinastine into eye tissues is improved when an aqueous composition containing epinastine or its salt, boric acid and / or its salt, and an isotonic agent is instilled into the eye.

[0007] Prior Art Documents

[0008] Patent Documents

[0009] Patent Document 1: Japanese Patent Application Laid-Open No. 2020-172486

[0010] Patent Document 2: Japanese Patent Application Laid-Open No. 2021-169431

[0011] Patent Document 3: Japanese Patent Application Laid-Open No. 2019-108320

[0012] Non-Patent Documents

[0013] Non-Patent Document 1: Alesion (注册商标) Instructions attached to 0.05% eye drops

[0014] Non-Patent Document 2: Alesion (注册商标) Instructions attached to 0.1% LX eye drops Summary of the Invention

[0015] Problems to be Solved by the Invention

[0016] Therefore, in order to obtain excellent drug efficacy, it is very useful to improve the migratability of the active ingredient into tissues, especially eye tissues. It is an interesting subject to provide an aqueous composition containing epinastine or its salt as an active ingredient and having improved migratability into tissues, especially eye tissues.

[0017] Means for Solving the Problems

[0018] The inventors of the present application have conducted in-depth research on an aqueous composition containing epinastine or a salt thereof, and as a result, it has been found that when an aqueous composition containing epinastine or a salt thereof at a concentration of 0.1% (w / v), boric acid and / or a salt thereof adjusted to a specific content, and an isotonic agent, and having a pH of 6.0 to 7.7 is instilled into the eye, the migratability of epinastine into eye tissues is improved. Furthermore, it has been found that by adding boric acid and / or a salt thereof adjusted to a specific content, the excellent antiseptic efficacy of the aqueous composition containing epinastine or a salt thereof is further enhanced. In particular, it has been found that these effects can be more significantly exerted in an aqueous composition containing epinastine or a salt thereof at a concentration of 0.1% (w / v), boric acid and / or a salt thereof adjusted to a boron concentration of 200 to 300 mM, and an isotonic agent, and having a pH of 6.8 to 7.5, and thus the present invention has been completed.

[0019] Specifically, the present invention provides the following aspects.

[0020] (1) An aqueous composition containing epinastine or a salt thereof at a concentration of 0.1% (w / v), boric acid and / or a salt thereof, and an isotonic agent, and having a pH of 6.0 to 7.7, wherein the concentration of boric acid and / or a salt thereof in the aqueous composition is 150 to 500 mM in terms of boron concentration.

[0021] (2) The aqueous composition according to (1), wherein the boric acid and / or a salt thereof is at least one selected from the group consisting of boric acid, sodium borate, potassium borate, and hydrates thereof.

[0022] (3) The aqueous composition according to (1) or (2), wherein the concentration of boric acid and / or a salt thereof is 200 to 300 mM in terms of boron concentration.

[0023] (4) The aqueous composition according to any one of (1) to (3), wherein the pH of the aqueous composition is 6.8 to 7.5.

[0024] (5) The aqueous composition according to any one of (1) to (4), wherein the boric acid and / or a salt thereof is boric acid and borax.

[0025] (4) The aqueous composition according to (5), wherein the content ratio of borax to boric acid is 0.05 to 0.5 parts by weight relative to 1 part by weight of the content of boric acid.

[0026] (7) The aqueous composition according to (5), wherein the content ratio of borax to boric acid is 0.1 part by weight relative to 1 part by weight of the content of boric acid.

[0027] (8) The aqueous composition according to any one of (1) to (7), wherein only epinastine or a salt thereof is contained as an active ingredient.

[0028] (9) The aqueous composition according to any one of (1) to (8), wherein epinastine or a salt thereof is epinastine hydrochloride.

[0029] (10) An aqueous composition that contains only epinastine or a salt thereof at a concentration of 0.1% (w / v), boric acid, borax, an isosmotic agent, a pH adjuster, and water, and has a pH of 6.0 to 7.7. In the aqueous composition, the concentration of boric acid and borax in terms of boron concentration is 150 to 500 mM.

[0030] (11) The aqueous composition according to (10), wherein the concentration of boric acid and borax in terms of boron concentration is 200 to 300 mM.

[0031] (12) The aqueous composition according to (10) or (11), wherein the pH of the aqueous composition is 6.8 to 7.5.

[0032] (13) An aqueous composition that contains epinastine hydrochloride at a concentration of 0.1% (w / v), boric acid at a concentration of 1.4% (w / v), borax at a concentration of 0.14% (w / v), and sodium chloride, and has a pH of 6.0 to 7.7.

[0033] (14) An aqueous composition that contains only epinastine hydrochloride at a concentration of 0.1% (w / v), boric acid at a concentration of 1.4% (w / v), borax at a concentration of 0.14% (w / v), an isosmotic agent, a pH adjuster, and water, and has a pH of 6.0 to 7.7.

[0034] (15) The aqueous composition according to (13) or (14), wherein the pH of the aqueous composition is 6.8 to 7.5.

[0035] (16) An aqueous composition that contains epinastine hydrochloride at a concentration of 0.1% (w / v), boric acid at a concentration of 1.68% (w / v), borax at a concentration of 0.168% (w / v), and sodium chloride, and has a pH of 6.0 to 7.7.

[0036] (17) An aqueous composition that contains only epinastine hydrochloride at a concentration of 0.1% (w / v), boric acid at a concentration of 1.68% (w / v), borax at a concentration of 0.168% (w / v), an isosmotic agent, a pH adjuster, and water, and has a pH of 6.0 to 7.7.

[0037] (18) The aqueous composition according to (16) or (17), wherein the pH of the aqueous composition is 6.8 to 7.5.

[0038] (19) The aqueous composition according to any one of (1) to (18), which is an eye drop.

[0039] (20) The aqueous composition according to any one of (1) to (19), which does not contain benzalkonium chloride.

[0040] (21) The aqueous composition according to any one of (1) to (20), which does not contain a preservative.

[0041] (22) A method for increasing the migration of epinastine or a salt thereof into eye tissues by adjusting the concentration of boric acid and / or a salt thereof to a boron concentration of 150 to 500 mM in terms of conversion in an aqueous composition containing epinastine or a salt thereof at a concentration of 0.1% (w / v), boric acid and / or a salt thereof, and an isotonic agent, and having a pH of 6.0 to 7.7.

[0042] (23) The method according to (22), wherein the eye tissue is conjunctiva and / or aqueous humor.

[0043] (24) A method, which is a method for imparting preservative efficacy to an aqueous composition containing epinastine or a salt thereof at a concentration of 0.1% (w / v), boric acid and / or a salt thereof, and an isotonic agent, and having a pH of 6.0 to 7.7, and in this method, the concentration of boric acid and / or a salt thereof is adjusted to a boron concentration of 150 to 500 mM in terms of conversion.

[0044] (25) A method, which is a method for maintaining the preservative efficacy of an aqueous composition containing epinastine or a salt thereof at a concentration of 0.1% (w / v), boric acid and / or a salt thereof, and an isotonic agent, and having a pH of 6.0 to 7.7, and in this method, the concentration of boric acid and / or a salt thereof is adjusted to a boron concentration of 150 to 500 mM in terms of conversion.

[0045] (26) The method according to (24) or (25), wherein the preservative efficacy is the preservative efficacy conforming to the preservative efficacy test method described in the tenth edition of the European Pharmacopoeia and / or the 2020 edition of the Chinese Pharmacopoeia.

[0046] It should be noted that two or more of the foregoing components (1) to (26) can be arbitrarily selected and combined.

[0047] In addition, the present invention also provides the following solutions.

[0048] (27) A method for treating an allergic disease, which is characterized by administering a therapeutically effective amount of the aqueous composition according to any one of (1) to (21) to a patient in need of treatment.

[0049] (28) The aqueous composition according to any one of (1) to (21), which is used for the treatment of allergic diseases.

[0050] (29) Use of the aqueous composition according to any one of (1) to (21) for manufacturing a medicament for treating allergic diseases.

[0051] Advantages of the Invention

[0052] The present invention provides an aqueous composition which can improve the migration of epinastine or its salt into ocular tissues and achieve excellent drug efficacy by adjusting the concentration of boric acid and / or its salt to a specific amount in an aqueous composition containing epinastine or its salt at a concentration of 0.1% (w / v), boric acid and / or its salt, and an isotonic agent and having a pH of 6.0 to 7.7. In addition, according to the present invention, the excellent antiseptic efficacy of the aqueous composition can be further improved or maintained. Detailed Description of the Invention

[0053] Hereinafter, the present invention will be described in detail.

[0054] In the present invention, "epinastine" refers to the compound represented by the chemical name (±)-3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine, and is also the compound represented by the following formula. ((±)-3-Amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine), and is also the compound represented by the following formula.

[0055] [Chemical Formula 1]

[0056]

[0057] In the aqueous composition of the present invention, the epinastine contained may be a racemate or an optical isomer.

[0058] In the aqueous composition of the present invention, the epinastine contained may be a salt, and there is no particular limitation as long as it is a pharmaceutically acceptable salt. Examples of the salt include salts formed with inorganic acids, salts formed with organic acids, and the like.

[0059] Examples of the salts formed with inorganic acids include salts formed with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.

[0060] Examples of the salts formed with organic acids include salts formed with acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptonic 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, and the like.

[0061] As a salt of epinastine, the monohydrochloride (epinastine hydrochloride) is particularly preferred.

[0062] In the aqueous composition of the present invention, epinastine or its salt contained therein may be in the form of a hydrate or a solvate.

[0063] In the aqueous composition of the present invention, based on various factors such as drug efficacy, number of eye drops, presence or absence of influence on soft contact lenses, and medication compliance, the content of epinastine or its salt is preferably 0.1% (w / v). If the content of epinastine or its salt is less than 0.1% (w / v), it is necessary to increase the amount of eye drops and the number of eye drops to obtain sufficient drug efficacy. In addition, if the content is greater than 0.1% (w / v), although it is theoretically possible to further reduce the number of eye drops, sometimes it may cause the deformation of soft contact lenses and may affect the use when wearing soft contact lenses.

[0064] It should be noted that in the present invention, “% (w / v)” means the mass (g) of the target component contained in 100 mL of the aqueous composition of the present invention. When the aqueous composition of the present invention contains a salt of epinastine, the value is the content of the salt of epinastine. In addition, in the present invention, when epinastine or its salt is contained in the form of a hydrate or a solvate, the value is the content of the hydrate or solvate of epinastine or its salt. Hereinafter, the same applies unless otherwise specified.

[0065] In the aqueous composition of the present invention, boric acid and / or its salt is a substance that improves the migration of epinastine or its salt into eye tissues and further enhances the antiseptic efficacy in the aqueous composition, but also has functions as additives for pharmaceuticals, such as buffers, preservatives, stabilizers, isotonic agents, solubilizers, pH regulators, etc. Therefore, boric acid and / or its salt can also be used as an additive for pharmaceuticals.

[0066] In addition, in the aqueous composition of the present invention, one kind of boric acid and / or its salt can be used, or two or more kinds can be used together.

[0067] Examples of boric acid and / or its salt include boric acid, sodium borate, potassium borate, etc., and they can also be hydrates. Examples of the hydrate of boric acid and / or its salt include borax (sodium tetraborate decahydrate). Boric acid and / or its salt is preferably boric acid and / or borax, more preferably boric acid and borax.

[0068] In the aqueous composition of the present invention, when boric acid and / or its salt is boric acid and borax, the content ratio of borax to boric acid can be appropriately adjusted. The content ratio is preferably 0.05 to 0.5 parts by weight, more preferably 0.1 to 0.2 parts by weight, and particularly preferably 0.1 part by weight, based on 1 part by weight of the content of boric acid.

[0069] In the aqueous composition of the present invention, the concentration of boric acid and / or its salts can be appropriately adjusted according to the type. For example, the concentration in terms of boron concentration is 150 to 500 mM, preferably 170 to 450 mM, more preferably 200 to 400 mM, further preferably 200 to 300 mM, and particularly preferably 240 to 260 mM.

[0070] It should be noted that in the present invention, "M" representing the boron concentration is the amount of substance (mol) of the target component contained in 1 L of the aqueous composition of the present invention, and can also be expressed as "mol / L". In addition, in the present invention, the so-called "converted to boron concentration" means converting the concentration of boric acid and / or its salts to the concentration of boron atoms from boric acid and / or its salts. For example, 1% (w / v) boric acid is equivalent to 161.7 mM when converted to boron concentration, and 0.1% (w / v) borax is equivalent to 10.5 mM when converted to boron concentration. For example, when the aqueous composition of the present invention contains 1% (w / v) boric acid and 0.1% (w / v) borax as boric acid and / or its salts, the concentration of boric acid and / or its salts in the aforementioned aqueous composition becomes 172.2 mM when converted to boron concentration.

[0071] In the aqueous composition of the present invention, when boric acid and / or its salts are boric acid, its content is, for example, 0.93 to 3.1% (w / v), preferably 1.1 to 2.8% (w / v), more preferably 1.2 to 2.5% (w / v), further preferably 1.2 to 1.9% (w / v), and particularly preferably 1.5 to 1.6% (w / v). In addition, in the aqueous composition of the present invention, when boric acid and / or its salts are boric acid and borax, and the content ratio of boric acid to borax is 1:0.1, the content of boric acid is particularly preferably 1.4 to 1.5% (w / v).

[0072] The isotonic agent contained in the aqueous composition of the present invention can appropriately contain an isotonic agent that can be used as an additive for pharmaceuticals. Examples thereof include ionic isotonic agents and non-ionic isotonic agents.

[0073] Examples of the ionic isotonic agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, etc. Examples of the non-ionic isotonic agent include glycerol, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose, xylitol, etc.

[0074] The isotonic agent is preferably an ionic isotonic agent, more preferably sodium chloride. In addition, the isotonic agent is also preferably a non-ionic isotonic agent, more preferably glycerol.

[0075] The content of the isotonic agent contained in the aqueous composition of the present invention can be appropriately adjusted according to the type of the isotonic agent and the like. The content is preferably 0.001 to 5% (w / v), more preferably 0.01 to 3% (w / v), further preferably 0.1 to 1% (w / v), and particularly preferably 0.1 to 0.5% (w / v).

[0076] In addition, one kind of the isotonic agent contained in the aqueous composition of the present invention can be used, or two or more kinds can be used together.

[0077] In the aqueous composition of the present invention, in addition to boric acid and / or its salts and the isotonic agent, pharmaceutical additives such as buffers, thickeners, surfactants, stabilizers, preservatives, antioxidants, pH adjusters, etc. can be added as needed. They can be used alone, and in addition, two or more kinds can be appropriately combined and used, and can be contained in an appropriate amount.

[0078] When the aqueous composition of the present invention contains a buffer, the buffer can appropriately contain a buffer that can be used as a pharmaceutical additive. Examples thereof include phosphoric acid or its salts, carbonic acid or its salts, citric acid or its salts, acetic acid or its salts, tartaric acid or its salts, ε-aminocaproic acid or its salts, glutamic acid or its salts, organic amines, etc., and they can also be hydrates or solvates.

[0079] Examples of phosphoric acid or its salts 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 they can also be hydrates. In addition, the aqueous composition of the present invention preferably does not contain phosphoric acid or its salts.

[0080] Examples of carbonic acid or its salts include sodium carbonate, sodium bicarbonate, etc., and they can also be hydrates.

[0081] Examples of citric acid or its salts include citric acid, sodium citrate monohydrate, sodium citrate dihydrate, sodium citrate tribasic, etc., and they can also be hydrates.

[0082] Examples of acetic acid or its salts include acetic acid, sodium acetate, etc., and they can also be hydrates.

[0083] Examples of tartaric acid or its salts include tartaric acid, sodium tartrate monohydrate, sodium tartrate dihydrate, etc., and they can also be hydrates.

[0084] Examples of ε-aminocaproic acid or its salts include ε-aminocaproic acid, sodium ε-aminocaproate, ε-aminocaproic acid hydrochloride, etc., and they can also be hydrates.

[0085] Examples of glutamic acid or its salts include glutamic acid, monosodium glutamate, disodium glutamate, glutamic acid hydrochloride, etc., and they can also be hydrates.

[0086] Examples of the organic amine include tromethamine and the like, and they may also be hydrates.

[0087] When the aqueous composition of the present invention contains a buffering agent, the content of the buffering agent can be appropriately adjusted according to the type of the buffering agent and the like. The content is preferably 0.001 to 10% (w / v), more preferably 0.01 to 5% (w / v), still more preferably 0.1 to 5% (w / v), and particularly preferably 0.1 to 2% (w / v).

[0088] In addition, when the aqueous composition of the present invention contains a buffering agent, one kind of buffering agent can be used, or two or more kinds can be used together.

[0089] It should be noted that the aqueous composition of the present invention contains boric acid and / or its salt in a specified amount. Specifically, it contains boric acid and / or its salt in an amount such that the boron concentration in terms of the concentration of boric acid and / or its salt is 150 to 500 mM. Depending on the combination of additives of the added pharmaceutical, it can exert a sufficient buffering effect even without a buffering agent. Therefore, it is also preferred that the aqueous composition of the present invention does not contain a buffering agent other than boric acid and / or its salt.

[0090] When the aqueous composition of the present invention contains a thickening agent, the thickening agent can appropriately contain a thickening agent that can be used as an additive for pharmaceuticals. Examples thereof include 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, and the like.

[0091] When the aqueous composition of the present invention contains a thickening agent, the content of the thickening agent can be appropriately adjusted according to the type of the thickening agent and the like. The content is preferably 0.001 to 5% (w / v), more preferably 0.01 to 3% (w / v), still more preferably 0.1 to 2% (w / v).

[0092] In addition, when the aqueous composition of the present invention contains a thickening agent, one kind of thickening agent can be used, or two or more kinds can be used together.

[0093] When the aqueous composition of the present invention contains a surfactant, the surfactant can appropriately contain a surfactant that can be used as an additive for pharmaceuticals. Examples thereof include cationic surfactants, anionic surfactants, nonionic surfactants, and the like.

[0094] Examples of the cationic surfactant include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoesters, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkylimidazolines, 1-acylaminoethyl-2-alkylimidazolines, 1-hydroxyethyl-2-alkylimidazolines, and the like. It should be noted that 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.

[0095] Examples of the anionic surfactant include phospholipids such as lecithin.

[0096] Examples of the nonionic surfactant include polyoxyethylene fatty acid esters such as polyoxyethylene 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; castor oil polyoxyethylene esters such as castor oil polyoxyethylene ester 5, castor oil polyoxyethylene ester 9, castor oil polyoxyethylene ester 15, castor oil polyoxyethylene ester 35, and castor oil polyoxyethylene ester 40; 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; tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS), and the like.

[0097] When the aqueous composition of the present invention contains a surfactant, the content of the surfactant can be appropriately adjusted according to the type of the surfactant and the like. The content is preferably 0.01 to 1% (w / v), more preferably 0.05 to 0.5% (w / v), and further preferably 0.05 to 0.2% (w / v).

[0098] In addition, when the aqueous composition of the present invention contains a surfactant, one type of surfactant can be used, or two or more types can be used together.

[0099] When the aqueous composition of the present invention contains a stabilizer, the stabilizer can suitably contain stabilizers that can be used as additives for pharmaceuticals. Examples thereof include ethylenediaminetetraacetic acid or its salts, cyclodextrins, sodium thiosulfate, and the like.

[0100] Examples of ethylenediaminetetraacetic acid or its salts include ethylenediaminetetraacetic acid, sodium ethylenediaminetetraacetate monohydrate, disodium ethylenediaminetetraacetate (hereinafter also referred to as sodium ethylenediaminetetraacetate), trisodium ethylenediaminetetraacetate, and tetrasodium ethylenediaminetetraacetate. These may also be hydrates.

[0101] When the aqueous composition of the present invention contains a stabilizer, the content of the stabilizer can be appropriately adjusted according to the type of the stabilizer and the like. The content is preferably 0.001 to 5% (w / v), more preferably 0.01 to 3% (w / v), and still more preferably 0.01 to 1% (w / v).

[0102] In addition, when the aqueous composition of the present invention contains a stabilizer, one type of stabilizer can be used, or two or more types can be used together.

[0103] When the aqueous composition of the present invention contains a preservative, the preservative can suitably contain a preservative that can be used as an additive for pharmaceuticals. Examples thereof include benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, polidocanol, cetylpyridinium chloride, benzalkonium bromide, benzethonium bromide, methylbenzethonium bromide, trimethylammonium bromide, chlorhexidine gluconate, chlorhexidine hydrochloride, methyl paraben, propyl paraben, sodium chlorite, or chlorobutanol. In addition, benzalkonium chloride has cell-damaging properties, and if the exposure amount increases, the possibility of causing corneal epithelial damage increases. Therefore, it is also preferred not to contain benzalkonium chloride.

[0104] When the aqueous composition of the present invention contains a preservative, the content of the preservative can be appropriately adjusted according to the type of the preservative and the like. The content is preferably 0.0001 to 0.1% (w / v), more preferably 0.001 to 0.05% (w / v). In addition, since the aqueous composition of the present invention can exhibit an antiseptic effect substantially without containing a preservative, the aqueous composition of the present invention may also not contain a preservative.

[0105] In addition, when the aqueous composition of the present invention contains a preservative, one type of preservative can be used, or two or more types can be used together.

[0106] When the aqueous composition of the present invention contains an antioxidant, the antioxidant can suitably contain an antioxidant that can be used as an additive for pharmaceuticals. Examples thereof include ascorbic acid, tocopherol, dibutylhydroxytoluene, and sodium sulfite.

[0107] When the aqueous composition of the present invention contains an antioxidant, the content of the antioxidant can be appropriately adjusted according to the type of the antioxidant and the like. The content is preferably 0.001 to 5% (w / v), more preferably 0.01 to 3% (w / v), and still more preferably 0.1 to 2% (w / v).

[0108] In addition, when the aqueous composition of the present invention contains an antioxidant, one kind of antioxidant can be used, or two or more kinds can be used together.

[0109] When the aqueous composition of the present invention contains a pH regulator, the pH regulator can suitably contain a pH regulator that can be used as an additive for pharmaceuticals, such as an acid or a base. Examples of the acid include hydrochloric acid, phosphoric acid, etc., and examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, etc.

[0110] In the aqueous composition of the present invention, the pH only needs to be within the range allowable for pharmaceuticals, for example, within the range of 4.0 to 8.5 or 4.0 to 8.0, preferably 6.0 to 7.7, more preferably 6.8 to 7.5, still more preferably 6.8 to 7.3, and particularly preferably 7.0 to 7.3. In order for the aqueous composition of the present invention to exhibit sufficient antiseptic efficacy, the pH is preferably 6.8 to 7.0 or 7.0 to 7.5, and may also be 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4 or 7.5.

[0111] The osmotic pressure ratio of the aqueous composition of the present invention only needs to be within the range allowable for pharmaceuticals, for example, 0.5 to 2.0, preferably 0.7 to 1.6, more preferably 0.8 to 1.4, and still more preferably 0.9 to 1.2.

[0112] In the present invention, the so-called "eye tissue" includes, for example, conjunctiva, cornea, tear fluid, aqueous humor, anterior chamber, etc. When the aqueous composition of the present invention is administered to the eye, it can increase (or also referred to as improve) the migration amount of epinastine or its salt into the eye tissue, and particularly preferably increase the migration amount of epinastine or its salt into the conjunctiva and / or aqueous humor.

[0113] In the present invention, the so-called "aqueous composition" refers to a composition containing water. The content of water contained in the aqueous composition of the present invention is not particularly limited, and is preferably 10% (w / v) or more, more preferably 30% (w / v) or more, and still more preferably 50% (w / v) or more, based on the total weight of the aqueous composition. Furthermore, based on the total weight of the aqueous composition, the content of water is preferably 70% (w / v) or more, more preferably 90% (w / v) or more, and still more preferably 95% (w / v) or more.

[0114] In the present invention, the so-called "allergic disease" refers to a disease or its symptoms caused by an immune response to an antigen from the outside. The antigen from the outside is, for example, pollen. Examples of allergic diseases include, but are not limited to, allergic conjunctivitis. In the present invention, the treatment of allergic diseases refers to all treatments (such as cure, improvement, alleviation, inhibition of progression, etc.) of allergic diseases or their symptoms and their prevention. In addition, it also includes prevention of recurrence of allergic diseases.

[0115] In the present invention, the so-called "patient" is not limited to humans, but also represents other animals, such as dogs, cats, horses, etc. The patient is preferably a mammal, and more preferably a human. In the present invention, the so-called "therapeutically effective amount" refers to an amount that brings a therapeutic effect on a disease and its symptoms or causes a delay in the progression of a disease and its symptoms as compared with an untreated subject.

[0116] The aqueous composition of the present invention is particularly preferably used as a medicine and is suitable for parenteral (e.g., topical) administration. As the parenteral administration routes of the aqueous composition of the present invention, there can be mentioned topical administration routes admissible as pharmaceuticals, such as topical administration to the eye (e.g., eye drop administration), nasal drop (intranasal) administration, topical administration to the ear (e.g., ear drop administration), inhalation administration, spray administration, transdermal administration, skin application, injection administration, etc. Topical administration to the eye is preferred.

[0117] The aqueous composition of the present invention can be used as an ophthalmic preparation, an otorhinolaryngological preparation, an inhalation preparation, a transdermal absorption preparation. There is no particular limitation on its dosage form as long as it can be used as a medicine. As the dosage form, for example, there can be mentioned eye drops, nasal drops, ear drops, inhalants (inhalation powders, inhalation liquid preparations, inhalation aerosols), ointments, creams, gels, transdermal absorption type preparations, patches (tape preparations, cataplasms), external liquid preparations (lotions, liniments), external solid preparations (external powders), sprays (pump sprays, external aerosols), injections (infusion solutions, implantable injections, sustained-release injections), etc., which are topical administration agents. Eye drops, ophthalmic transdermal absorption type preparations or ophthalmic injections are preferred, and eye drops are more preferred. They can be manufactured according to the usual methods in the technical field.

[0118] For the aqueous composition of the present invention, the constituent components can all be dissolved or partially suspended, and can also be in the form of an emulsion or a semi-solid state. The aqueous composition of the present invention is more preferably in a solution state in which all the constituent components are dissolved, and most preferably an aqueous solution. For example, if used for ophthalmology, eye drops (eye drop solutions) are particularly preferred.

[0119] When the aqueous composition of the present invention is an emulsion, it can be an oil-in-water emulsion (an emulsion having an aqueous phase as the continuous phase and composed of an aqueous phase and dispersed oil droplets), or it can be a water-in-oil emulsion (an emulsion having an oil phase as the continuous phase and composed of oil and dispersed aqueous droplets).

[0120] 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. In addition, unless otherwise specified, the aqueous composition of the present invention may contain pharmaceutical active ingredients other than epinastine or its salt, such as active ingredients used in other eye drops, or may contain only epinastine or its salt as the sole active ingredient.

[0121] When the aqueous composition of the present invention is administered to the eye as an eye drop, there is no particular limitation on the dosage form and dosage as long as it is sufficient to exhibit the desired drug effect. The aqueous composition of the present invention can be instilled into the eye once or twice at a time, divided into 1 to 10 times a day, preferably 1 to 6 times a day, more preferably 1 to 4 times a day, further preferably once or twice a day, and particularly preferably twice a day.

[0122] When the aqueous composition of the present invention is used as an eye drop, the aqueous composition of the present invention can be stored in any container such as a multi-dose container, a single-dose container for single use, or a PFMD (Preservative Free MultiDose) container. It should be noted that there is no particular limitation on the raw material of the container as long as it is a generally used container for eye drops, but a resin container is preferred. As the resin container, for example, containers 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. For example, when the material of the resin container is polyethylene, polyethylene is classified according to its density, so as the resin container, containers made of low density polyethylene (LDPE), medium density polyethylene (MDPE), high density polyethylene (HDPE), etc. can be used.

[0123] The present invention provides a method for improving the migratability of epinastine or its salt into eye tissues. The detailed description of the above aqueous composition of the present invention is also applicable to the method for improving the migratability of epinastine or its salt into eye tissues of the present invention.

[0124] In the present invention, the method for enhancing the migration of epinastine or its salt into ocular tissues is preferably the following method, which enhances the migration of epinastine or its salt into ocular tissues by adjusting the concentration of boric acid and / or its salt to a boron concentration of 150 to 500 mM in terms of conversion in an aqueous composition containing epinastine or its salt at a concentration of 0.1% (w / v), boric acid and / or its salt, and an isosmotic agent, and having a pH of 6.0 to 7.7.

[0125] The present invention provides a method for imparting antiseptic efficacy to an aqueous composition containing epinastine or its salt at a concentration of 0.1% (w / v). The detailed description of the aqueous composition of the present invention above also applies to the method for imparting antiseptic efficacy to an aqueous composition of the present invention.

[0126] In the present invention, the method for imparting antiseptic efficacy to an aqueous composition is preferably the following method, which imparts antiseptic efficacy to the aqueous composition by adjusting the concentration of boric acid and / or its salt to a boron concentration of 150 to 500 mM in terms of conversion in an aqueous composition containing epinastine or its salt at a concentration of 0.1% (w / v), boric acid and / or its salt, and an isosmotic agent, and having a pH of 6.0 to 7.7.

[0127] The present invention provides a method for maintaining the antiseptic efficacy of an aqueous composition containing epinastine or its salt at a concentration of 0.1% (w / v). The detailed description of the aqueous composition of the present invention above also applies to the method for maintaining the antiseptic efficacy of an aqueous composition of the present invention.

[0128] In the present invention, the method for maintaining the antiseptic efficacy of an aqueous composition is preferably the following method, which maintains the antiseptic efficacy of the aqueous composition by adjusting the concentration of boric acid and / or its salt to a boron concentration of 150 to 500 mM in terms of conversion in an aqueous composition containing epinastine or its salt at a concentration of 0.1% (w / v), boric acid and / or its salt, and an isosmotic agent, and having a pH of 6.0 to 7.7.

[0129] In the present invention, the so-called "preservative efficacy" refers to the efficacy of inhibiting the increase in the number of viable bacteria in an aqueous composition over time, and is also referred to as preservation efficacy. The evaluation of the preservative efficacy can be carried out in accordance with, for example, the preservative efficacy test methods described in the pharmacopoeias established in various countries. The aqueous composition of the present invention preferably has a preservative efficacy that conforms to the preservative efficacy test methods described in the pharmacopoeias of various countries, more preferably has a preservative efficacy that conforms to the preservative efficacy test methods of the Japanese Pharmacopoeia, the United States Pharmacopeia (also referred to as "USP"), the European Pharmacopoeia, the British Pharmacopoeia, and / or the Pharmacopoeia of the People's Republic of China, and further preferably has a preservative efficacy that conforms to the preservative efficacy test methods of the European Pharmacopoeia and / or the Pharmacopoeia of the People's Republic of China. In the preservative efficacy test methods of the European Pharmacopoeia and / or the Pharmacopoeia of the People's Republic of China, Standard A (A criteria, also referred to as "meeting A"), which is the recommended achievement criterion, and Standard B (B criteria, also referred to as "meeting B"), which is the criterion that should be achieved at least in the case where Standard A cannot be achieved due to the risk of side effects, etc., are specified. When the aqueous composition of the present invention is used as an eye drop, the aqueous composition of the present invention preferably meets Standard B, and more preferably meets Standard A.

[0130] Since the pharmacopoeias of various countries are updated, it is preferable to refer to the latest edition as much as possible. For example, the latest edition of the Pharmacopoeia of the People's Republic of China is the 2020 edition of the Pharmacopoeia of the People's Republic of China (also referred to as "CP2020"), and the latest edition of the Japanese Pharmacopoeia is the 18th revised edition of the Japanese Pharmacopoeia. Examples

[0131] The following shows formulation examples and test examples, but these are for better understanding of the present invention and do not limit the scope of the present invention.

[0132] Formulation Example

[0133] The following shows representative formulation examples of the present invention. It should be noted that in the following formulation examples, the content of each component is the content in 1 mL of the preparation.

[0134] Formulation Example 1

[0135]

[0136] Formulation Example 2

[0137]

[0138] Formulation Example 3

[0139]

[0140]

[0141] Formulation Example 4

[0142]

[0143] Formulation Example 5

[0144]

[0145] Formulation Example 6

[0146]

[0147]

[0148] Formulation Example 7

[0149]

[0150] Formulation Example 8

[0151]

[0152] Test Example

[0153] 1. Antiseptic Efficacy Test

[0154] This test was carried out in accordance with the method for examining bacteriostatic efficacy recorded in the Chinese Pharmacopoeia 2020 Edition.

[0155] (1) Preparation of Tested Preparations

[0156] Epinastine hydrochloride, boric acid, borax, and sodium chloride were dissolved in water to obtain the concentrations shown in Table 1 below, and pH regulators (dilute hydrochloric acid and / or sodium hydroxide) and water were added to make the total volume 10 mL, followed by filtration sterilization to prepare Preparations 1 to 6.

[0157] In addition, "Alesion (registered trademark) LX Eye Drops 0.1%", which is marketed as a therapeutic agent for allergic conjunctivitis in Japan, was used as Preparation 7 (control). It should be noted that Preparation 7 contains 0.1% of epinastine hydrochloride as the active ingredient, and the additives contained in the preparation are sodium dihydrogen phosphate hydrate, disodium hydrogen phosphate hydrate, sodium chloride, and a pH regulator, and the pH is 6.7 - 7.3.

[0158] [Table 1]

[0159]

[0160] (2) Test Method

[0161] As the inoculating bacteria, the following strains are used.

[0162] Bacterial species:

[0163] Staphylococcus aureus, Staphylococcus aureus CMCC(B)26003 (also known as S. aureus)

[0164] Pseudomonas aeruginosa, Pseudomonas aeruginosa CMCC(B)10104 (also known as P. aeruginosa)

[0165] Fungal species:

[0166] Candida, Candida albicans CMCC(F)98001 (also known as C. albicans) Aspergillus niger, Aspergillus niger CMCC(F)98003 (also known as A. niger)

[0167] Prepare each inoculum solution in such a way that it becomes approximately 10 8 cfu / mL, so that the inoculum solution becomes 10 5 ~10 6 cfu / mL and inoculate each inoculum solution into the test preparations of Formulations 1 to 7, and mix evenly to prepare specimens. Store these specimens in the dark at 20 - 25°C. At each sampling point (after 6 hours, 24 hours, 7 days, or 28 days), use a micropipette to take out 1 mL from each specimen and measure the viable cell count. After sampling by opening the lid of the specimen solution and then closing the lid at each sampling point.

[0168] (3) Test results and discussion

[0169] The test results are shown in Table 2. The test results in Table 2 are expressed as the common logarithm of the ratio (B / A) of the number of bacteria at the time of inoculation (B) to the number of viable bacteria at the time of measurement. For example, when the value is "1", it means that the viable bacteria count at the time of inspection has decreased to 10% of the inoculated bacteria count.

[0170] Regarding the determination of whether the test is qualified or not, it is determined as "meeting A" when all of the following conditions are met: For bacterial species (P. aeruginosa, S. aureus), it is 2.0 or more after 6 hours of inoculation, 3.0 or more after 24 hours, and no test bacteria can be recovered after 28 days (denoted as NR); and for fungal species (C. albicans, A. niger), it is 2.0 or more after 7 days of inoculation, and the number of bacteria after 28 days has not increased compared to that after 7 days (denoted as NI). Additionally, as the criterion for the minimum required antiseptic efficacy, it is determined as "meeting B" when all of the following conditions are met: For bacterial species (P. aeruginosa, S. aureus), it is 1.0 or more after 24 hours of inoculation, 3.0 or more after 7 days, and the number of bacteria after 28 days has not increased compared to that after 7 days (NI); and for fungal species (C. albicans, A. niger), it is 1.0 or more after 14 days of inoculation, and the number of bacteria after 28 days has not increased compared to that after 7 days (NI).

[0171] [Table 2]

[0172]

[0173] As shown in Table 2, for Preparation 1 and Preparation 7 that do not contain boric acid and / or its salts, and Preparation 2 with a boron concentration less than 150 mM, although antiseptic efficacy can be obtained, it is only limited to meeting B. In contrast, Preparation 3, Preparation 5, and Preparation 6 containing 150 mM or more of boric acid exhibit sufficient antiseptic efficacy and are shown to meet A. Additionally, among Preparation 4 and Preparation 5 with the same boron concentration, Preparation 4 with a pH of 6.7 is only limited to meeting B, while Preparation 5 with a pH of 7.3 is shown to meet A.

[0174] 2. Intraocular dynamic test

[0175] (1) Preparation of the test preparation

[0176] Epinastine hydrochloride, boric acid, and sodium chloride were dissolved in water to achieve the concentrations shown in Table 3 below, and a pH regulator (dilute hydrochloric acid and / or sodium hydroxide) and water were added to make the total volume 10 mL, followed by filtration sterilization to prepare Preparations 8 - 11. It should be noted that for Preparations 8 - 10, the addition amount of sodium chloride was appropriately adjusted to achieve the same osmotic pressure as Preparation 7 in the aforementioned "1. Antiseptic efficacy test". Additionally, since the osmotic pressure of Preparation 11 is higher than that of Preparation 7, Preparation 7-1 was prepared by adjusting the addition amount of sodium chloride in Preparation 7 to achieve the same osmotic pressure as Preparation 11.

[0177] [Table 3]

[0178]

[0179] (2) Test method

[0180] In order to compare the intraocular dynamics when instilling a boric acid preparation (Preparations 8 to 11) containing boric acid and / or its salt and a phosphoric acid preparation (Preparations 7, 7-1) containing phosphoric acid or its salt into the eyes, a boric acid preparation was instilled into one eye of a rat, and a phosphoric acid preparation was instilled into the contralateral eye, thereby minimizing the influence caused by individual differences in animals. More specifically, in the group where Preparations 8 to 10 were instilled into one eye respectively, Preparation 7 was instilled into the contralateral eye. In addition, in the group where Preparation 11 was instilled into one eye, Preparation 7-1 was instilled into the contralateral eye.

[0181] 5 μL of each test preparation was instilled into the eyes of rats once (n = 3 to 6), and the eyeballs were removed after sacrifice at the time point of 1 hour after instillation. The epinastine concentration in the conjunctiva and aqueous humor was measured, and the epinastine concentration ratio of the boric acid preparation relative to the phosphoric acid preparation was calculated for each individual as described below, and then its average value was calculated.

[0182] Epinastine concentration ratio = (Epinastine concentration in the tissue after instillation of the boric acid preparation) / (Epinastine concentration in the tissue after instillation of the phosphoric acid preparation)

[0183] (3) Test results and discussion

[0184] The test results are shown in Table 4.

[0185] [Table 4]

[0186] Epinastine Concentration Ratio (Average) Conjunctiva Aqueous Humor Formulation 8 / Formulation 7 1.07 1.56 Formulation 9 / Formulation 7 1.08 1.67 Formulation 10 / Formulation 7 1.55 3.12 Formulation 11 / Formulation 7-1 1.63 1.79

[0187] As shown in Table 4, it was shown that the migratability of epinastine into the conjunctiva and aqueous humor was improved in the boric acid preparation containing boric acid and / or its salt compared with the phosphoric acid preparation containing phosphoric acid or its salt. In particular, it was shown that the concentration of epinastine in the conjunctiva was more than 1.5 times that of the phosphoric acid preparation when the boron concentration in the composition was more than 162 mM, and the concentration of epinastine in the aqueous humor was the largest when the boron concentration in the composition was about 243 mM, being more than 3 times that of the phosphoric acid preparation.

[0188] Industrial applicability

[0189] The present invention provides an aqueous composition containing epinastine or its salt at a concentration of 0.1% (w / v), boric acid and / or its salt, and an isotonic agent, and having a pH of 6.0 to 7.7. In the aqueous composition, the concentration of boric acid and / or its salt is 150 to 500 mM in terms of boron concentration.

Claims

1. An aqueous composition containing epinastine or its salt at a concentration of 0.1% (w / v), boric acid and / or its salt, and an isosmotic agent, with a pH of 6.0 to 7.

7. In the aqueous composition, the concentration of boric acid and / or its salt, converted to boron concentration, is 150 to 500 mM.

2. The aqueous composition according to claim 1, wherein, The boric acid and / or its salt is at least one selected from the group consisting of boric acid, sodium borate, potassium borate, and their hydrates.

3. The aqueous composition according to claim 1 or 2, wherein, The concentration of boric acid and / or its salt, converted to boron concentration, is 200 to 300 mM.

4. The aqueous composition according to claim 1, wherein the pH of the aqueous composition is 6.8 to 7.

5.

5. The aqueous composition according to claim 1, wherein, The boric acid and / or its salt is boric acid and borax.

6. The aqueous composition according to claim 5, wherein, The content ratio of borax to boric acid is 0.05 to 0.5 parts by weight relative to 1 part by weight of the content of boric acid.

7. The aqueous composition according to claim 5, wherein The content ratio of borax to boric acid is 0.1 part by weight relative to 1 part by weight of the content of boric acid.

8. The aqueous composition according to claim 1, wherein, Contains only epinastine or its salt as the active ingredient.

9. The aqueous composition according to claim 1, wherein The epinastine or its salt is epinastine hydrochloride.

10. An aqueous composition containing only epinastine or its salt at a concentration of 0.1% (w / v), boric acid, borax, an isosmotic agent, a pH adjuster, and water, with a pH of 6.0 to 7.

7. In the aqueous composition, the concentration of boric acid and borax, converted to boron concentration, is 150 to 500 mM.

11. The aqueous composition according to claim 10, wherein, The concentration of boric acid and borax, converted to boron concentration, is 200 to 300 mM.

12. The aqueous composition according to claim 10 or 11, wherein the pH of the aqueous composition is 6.8 to 7.

5.

13. An aqueous composition containing epinastine hydrochloride at a concentration of 0.1% (w / v), boric acid at a concentration of 1.4% (w / v), borax at a concentration of 0.14% (w / v), and sodium chloride, with a pH of 6.0 to 7.

7.

14. An aqueous composition containing only epinastine hydrochloride at a concentration of 0.1% (w / v), boric acid at a concentration of 1.4% (w / v), borax at a concentration of 0.14% (w / v), an isosmotic agent, a pH adjuster, and water, with a pH of 6.0 to 7.

7.

15. The aqueous composition according to claim 13 or 14, wherein the pH of the aqueous composition is 6.8 to 7.

5.

16. An aqueous composition containing epinastine hydrochloride at a concentration of 0.1% (w / v), boric acid at a concentration of 1.68% (w / v), borax at a concentration of 0.168% (w / v), and sodium chloride, with a pH of 6.0 to 7.

7.

17. An aqueous composition containing only epinastine hydrochloride at a concentration of 0.1% (w / v), boric acid at a concentration of 1.68% (w / v), borax at a concentration of 0.168% (w / v), an isosmotic agent, a pH adjuster, and water, with a pH of 6.0 to 7.

7.

18. The aqueous composition according to claim 16 or 17, wherein the pH of the aqueous composition is 6.8 to 7.

5.

19. The aqueous composition according to claim 1, which is an eye drop.

20. A method for improving the migratability of epinastine or its salt into ocular tissues by adjusting the concentration of boric acid and / or its salt to a boron concentration of 150 to 500 mM in terms of conversion in an aqueous composition containing 0.1% (w / v) of epinastine or its salt, boric acid and / or its salt, and an isotonic agent, and having a pH of 6.0 to 7.7.

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