JP6963651B2 - Aqueous composition containing epinastine or a salt thereof - Google Patents

Description

The present invention is an aqueous composition containing epinastine or a salt thereof, more specifically, an aqueous composition containing epinastine or a salt thereof and a quaternary ammonium compound (hereinafter, also referred to as "aqueous composition of the present invention"). Regarding.

An aqueous composition containing a solvent such as water, which is intended for repeated use, is required to have a certain level of antiseptic measures in order to prevent the growth of fungi and the like. Therefore, such compositions are usually formulated with preservatives. For example, in the case of eye drops, benzalkonium chloride is generally used. Benzalkonium chloride is water-soluble, chemically stable, and has a high antiseptic effect compared to other preservatives. However, benzalkonium chloride is cytotoxic, and as the exposure increases, the possibility of causing corneal epithelial damage increases, so it is desirable not to use it as much as possible.

Currently, Alesion ^{(registered trademark)} ophthalmic solution 0.05% marketed in Japan is an ophthalmic solution containing epinastine hydrochloride as an active ingredient, and boric acid is used instead of adding benzalkonium chloride as a preservative. It has been added (Non-Patent Document 1).
Furthermore, by setting the concentration of epinastine or a salt thereof in the eye drops to more than 0.075% (w / v), a sufficient antiseptic effect can be obtained without substantially containing a preservative or a component having an antiseptic action. It is also known that it can be obtained (Patent Document 1).
As described above, in recent years, eye drops that do not use benzalkonium chloride have been developed, and there is a tendency to avoid using benzalkonium chloride in the aqueous composition.

In addition, from the viewpoint of medication adherence, it is desirable that the number of medications per day is small. However, if the number of doses is reduced, the effective concentration in the living tissue cannot be maintained and the drug effect may be reduced, and it is necessary to maintain the effective concentration in the living tissue in order to exert the drug effect. In the case of eye drops, as a method of maintaining the effective concentration in the eye tissue, a method of increasing the concentration of the active ingredient, a method of using an absorption promoter, or a method of adding a thickener is used to retain the active ingredient in the eye tissue. There are known methods for improving.

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 an effect of prolonging the action time after administration. Further, Patent Document 3 describes that by adding a sugar alcohol to a β-blocker, the transferability of the drug into the eye is improved.

On the other hand, in a locally administrable aqueous solution containing epinastine, the influx of neutrophils and eosinophils into the conjunctiva and nasal mucosa tissues is suppressed to reduce or prevent the occurrence of delayed phase reactions. Has been reported, and a certain amount of benzalkonium chloride is added as an antiseptic to the aqueous solution (Patent Document 4).

In an aqueous composition containing epinastine or a salt thereof, the addition of a quaternary ammonium compound such as benzalkonium chloride improves the transfer of epinastine or its salt to the ocular tissue and maintains the effective concentration in the ocular tissue. There is no report.

Japanese Patent No. 6134853 Special Table 2002-511430 International Publication No. 2012/026609 Pamphlet Special Table 2003-514021

Alesion® ophthalmic solution 0.05% package insert

Therefore, it is very useful to improve the transferability of the active ingredient to tissues, especially eye tissues, in order to bring about excellent medicinal properties, and to tissues containing epinastine or a salt thereof as active ingredients, especially to eye tissues. Providing an aqueous composition with improved migration is an interesting subject.

The present inventors have conducted intensive studies on an aqueous composition containing epinastine or a salt thereof, and found that an aqueous composition containing epinastine or a salt thereof and a quaternary ammonium compound adjusted to a specific content. The present invention was completed by finding that the transferability of epinastine to the ocular tissue is improved when the epinastine is instilled into the eye.

Specifically, the present invention provides:
(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 1 part by weight of the content of epinastine or a salt thereof. An aqueous composition which is 0.1 part by weight or less based on the amount.
(2) The aqueous composition according to (1), wherein 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 quaternary ammonium compound is at least one selected from the group consisting of benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride and polydronium chloride, to any one of (1) to (5). The aqueous composition described.
(7) The aqueous composition according to any one of (1) to (6), wherein the quaternary ammonium compound is benzalkonium chloride.
(8) Any 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 with respect to 1 part by weight of the content of epinastine or a salt thereof. The aqueous composition according to one.
(9) The aqueous composition according to any one of (1) to (8), which is for ophthalmology.
(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 to eye tissue by blending a quaternary ammonium compound with 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 polydronium chloride.
(13) The method according to (11) or (12), wherein the quaternary ammonium compound is benzalkonium chloride.
(14) An eye drop containing epinastine hydrochloride having a concentration of 0.1% (w / v) and benzalkonium chloride, wherein the content ratio of benzalkonium chloride to epinastine hydrochloride is epinastine hydrochloride. An eye drop having a content of 0.0001 parts by weight or more and less than 0.1 parts by weight with respect to 1 part by weight.
It should be noted that each of the configurations (1) to (14) can be arbitrarily selected and combined with two or more.

Furthermore, the present invention also provides:
(15) A method for treating an allergic disease, which comprises 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 drug for treating an allergic disease.

The present invention is an aqueous composition containing epinastine or a salt thereof, which can improve the transferability of epinastine or a salt thereof to an ocular tissue and bring about an excellent medicinal effect by blending a quaternary ammonium compound. The composition is provided.

Hereinafter, the present invention will be described in detail.

で表される化合物である。 In the present invention, "epinastine" is a compound represented by the chemical name (±) -3-Amino-9,13b-dihydro-1H-divenz [c, f] imidazo [1,5-a] azepine. , And the following formula:

It is a compound represented by.

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

In the aqueous composition of the present invention, the epinastine contained may be a salt, and is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples of the salt include a salt with an inorganic acid, a salt with an organic acid, and the like.
Examples of the salt with the inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
Salts with organic acids include 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, and alanine. , Lactic acid, horse uric acid, 1,2-ethanedisulfonic acid, isetioic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- Examples thereof include salts with toluene sulfonic acid, lauryl sulfate, methyl sulfate, naphthalene sulfonic acid, sulfosalicylic acid and the like.
As the salt of epinastine, monohydrochloride (epinastine hydrochloride) is particularly preferable.

In the aqueous composition of the present invention, the contained epinastine or a salt thereof may take the form of a hydrate or a solvate.

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 0.1% (w). / V) or more is more preferable, and the upper limit thereof may be any concentration acceptable for an ophthalmic preparation, 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), and more preferably 0.05 to 0.2% (w / v). v) is more preferable, and 0.05 to 0.1% (w / v) is particularly preferable. For example, its content is 0.1% (w / v).

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 a salt of epinastine is contained in the present invention, the value is the content of the salt of epinastine. When epinastine or a salt thereof is blended in the form of a hydrate or a solvate in the present invention, the value is the content of the hydrate or the solvate of the epinastine or a salt thereof. Hereinafter, the same shall apply unless otherwise specified.

In the present invention, the "quaternary ammonium compound" is a salt of a quaternary ammonium cation and another anion, and is also referred to as a quaternary ammonium salt.

In the aqueous composition of the present invention, the quaternary ammonium compound contained is, for example, benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, polydronium chloride, cetylpyridinium chloride, benzalkonium bromide, benzethonium bromide, odor. Examples thereof include methylbenzethonium chloride and cetrimid, preferably benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, polydronium chloride, and more preferably benzalkonium chloride.

In the aqueous composition of the present invention, the quaternary ammonium compound also acts as an additive for pharmaceuticals, for example, a preservative, a surfactant, a stabilizer, an isotonic agent, a buffer, and the like. Therefore, the quaternary ammonium compound can also be used as an additive for pharmaceutical products.
Further, in the aqueous composition of the present invention, one or more quaternary ammonium compounds may be used together.

In the aqueous composition of the present invention, the content of the quaternary ammonium compound can be appropriately adjusted depending on the type, and is, for example, 0.0001 to 1% (w / v) and 0.0001 to 0.1% (w / v). w / v) is preferable, 0.0001 to 0.01% (w / v) is more preferable, and 0.0001 to 0.005% (w / v) is even more preferable. For example, when the quaternary ammonium compound is benzalkonium chloride, the upper limit of its content is 0.01% (w / v) or less because the possibility of causing corneal epithelial damage increases as the exposure amount increases. Alternatively, it is preferably less than 0.01% (w / v), more preferably 0.005% (w / v). The lower limit of the content is preferably 0.0001% (w / v) or more, more preferably 0.001% (w / v) or more, and further preferably 0.003% (w / v) or more. More specifically, the content thereof is preferably 0.0001 to 0.01% (w / v), more preferably 0.001 to 0.005% (w / v), and 0.001 to 0.003%. (W / v) or 0.003 to 0.005% (w / v) is more preferable.

In the aqueous composition of the present invention, the content ratio of the quaternary ammonium compound can be appropriately adjusted depending on the type, but for example, the upper limit of the content ratio is 0.1 per 1 part by weight of the content of epinastine or a salt thereof. It is less than a part by weight or less than 0.1 part by weight, preferably 0.05 part by weight or less. The lower limit of the content ratio is 0.0001 parts by weight or more, preferably 0.001 parts by weight or more, and 0.003 parts by weight or more and 0.005 parts by weight with respect to 1 part by weight of the content of epinastine or a salt thereof. More preferably, more than 0.01 parts by weight or more. More specifically, the content ratio is 0.0001 to 0.1 parts by weight, preferably 0.001 to 0.1 parts by weight, more preferably 0.003 to 0.1 parts by weight, and 0.005 parts by weight. ~ 0.05 parts by weight is more preferable, and 0.01 to 0.05 parts by weight is particularly preferable. For example, when the quaternary ammonium compound is benzalkonium chloride, the possibility of causing corneal epithelial damage increases as the exposure amount increases, so the content ratio is based on 1 part by weight of the content of epinastine or a salt thereof. It is 0.1 part by weight or less or less than 0.1 part by weight, preferably 0.05 part by weight or less or 0.03 part by weight or less. More specifically, the content ratio is 0.0001 to 0.1 parts by weight, preferably 0.001 to 0.1 parts by weight, more preferably 0.003 to 0.1 parts by weight, and 0.005 to 0.005 parts by weight. 0.05 parts by weight is more preferable, 0.01 to 0.05 parts by weight is particularly preferable, and 0.03 to 0.05 parts by weight is particularly preferable.

An aqueous composition containing epinastine or a salt thereof at a certain concentration or higher can obtain a sufficient antiseptic effect without substantially containing a preservative or a component having an antiseptic action. In the aqueous composition of the present invention, for example, when the quaternary ammonium compound is benzalkonium chloride commonly used as a preservative, the content of benzalkonium chloride is sufficient to exert an action as a preservative. It does not have to be, and may contain an amount that exerts the effect of the present invention. On the other hand, the content of benzalkonium chloride may be an amount that exerts an action as a preservative as long as the effect of the present invention is exhibited.

In the present invention, the eye tissue includes, for example, conjunctiva, cornea, tears, aqueous humor, anterior chamber and the like. When the aqueous composition of the present invention is administered to the eye, the amount of epinastine or a salt thereof transferred to the eye tissue can be increased (or also referred to as improvement).

In the present invention, the "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, but is preferably 10% (w / v) or more, preferably 30% (w / v) or more, based on the total weight of the aqueous composition. More preferably, 50% (w / v) or more is further preferable. In particular, it is preferably 70% (w / v) or more, more preferably 90% (w / v) or more, and further preferably 95% (w / v) or more.

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

Pharmaceutical additives can be used in the aqueous composition of the present invention, if necessary, for example, buffers, thickeners, surfactants, tonicity agents, stabilizers, preservatives, etc. Antioxidants, pH regulators and the like can be added. These may be used alone or in combination of two or more as appropriate, and an appropriate amount may be blended.

When a buffer is added to the aqueous composition of the present invention, a buffer that can be used as an additive for pharmaceuticals can be appropriately added, and for example, citric acid or a salt thereof, boric acid or a salt thereof, etc. Examples thereof include carbonic acid or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, tartrate 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 buffers thereof. It may be.
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, and hydrogen phosphate. Examples thereof include dipotassium, and these hydrates may be used.
Examples of boric acid or a salt thereof include boric acid, sodium borate (borax), potassium borate and the like, and hydrates thereof may be used.
Examples of carbonic acid or a salt thereof include sodium carbonate, sodium hydrogencarbonate and the like, and hydrates thereof may be used.
Examples of citric acid or a salt thereof include citric acid, monosodium citrate, disodium citrate, trisodium citrate and the like, and hydrates thereof may be used.
Examples of acetic acid or a salt thereof include acetic acid, sodium acetate and the like, and hydrates thereof may be used.
Examples of tartaric acid or a salt thereof include tartaric acid, monosodium tartaric acid, disodium tartrate and the like, and hydrates thereof may be used.
Examples of ε-aminocaproic acid or a salt thereof include ε-aminocaproic acid, sodium ε-aminocaproate, ε-aminocapronate salt and the like, and hydrates thereof may be used.
Examples of glutamic acid or a salt thereof include glutamic acid, monosodium glutamic acid, disodium glutamic acid, glutamic acid salt and the like, and hydrates thereof may be used.
Examples of the organic amine include tromethamole and the like, and these hydrates may be used.

The content of the buffer when the buffer is added to the aqueous composition of the present invention can be appropriately adjusted depending on the type of the buffer and the like, but is preferably 0.001 to 10% (w / v), and is 0. 0.01 to 5% (w / v) is more preferable, 0.1 to 5% (w / v) is further preferable, and 0.1 to 2% (w / v) is particularly preferable.
When a buffer is added to the aqueous composition of the present invention, one or more buffers may be used together.

When the thickening agent is blended in the aqueous composition of the present invention, the thickening agent that can be used as an additive for pharmaceuticals can be appropriately blended, and for example, methyl cellulose, ethyl cellulose, and hydroxymethyl cellulose can be blended. , 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, polyvinyl pyrrolidone, polyvinyl alcohol, Examples thereof include carboxyvinyl polymer, polyethylene glycol, sodium hyaluronate and the like.

The content of the thickening agent when the thickening agent is added to the aqueous composition of the present invention can be appropriately adjusted depending on the type of the thickening agent and the like, but is 0.001 to 5% (w / w /). v) is preferable, 0.01 to 3% (w / v) is more preferable, and 0.1 to 2% (w / v) is further preferable.
Further, when the thickening agent is blended in the aqueous composition of the present invention, one kind or two or more kinds of thickening agents may be used together.

When the surfactant is blended in the aqueous composition of the present invention, the surfactant that can be used as an additive for pharmaceuticals can be appropriately blended, for example, a cationic surfactant. , Anionic surfactants, nonionic surfactants and the like.
Cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkylimidazolines, 1-acylaminoethyl-2. -Alkyl imidazoline, 1-hydroxyl ethyl-2-alkyl imidazoline and the like can be mentioned. Although quaternary ammonium cations such as benzalkonium chloride have the properties of a cationic surfactant, they are not included in the cationic surfactant in the present invention.
Examples of the anionic surfactant include phospholipids such as lecithin.
Examples of the nonionic surfactant include polyoxyethylene fatty acid esters such as polyoxyl 40 stearate; polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan triolate, and polysorbate 65. Polyoxyethylene sorbitan fatty acid ester; polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, etc. Polyoxyethylene hydrogenated castor oil; polyoxyl 5 castor Polyoxyl castor oil such as oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil; polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxy Poly such as propylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol, etc. Oxyethylene polyoxypropylene glycol; sucrose fatty acid ester such as sucrose stearic acid ester; tocopherol polyethylene glycol 1000 succinic acid ester (vitamin E TPGS) and the like.

The content of the surfactant when the surfactant is blended in the aqueous composition of the present invention can be appropriately adjusted depending on the type of the surfactant and the like, but is 0.01 to 1% (w / w /). v) is preferable, 0.05 to 0.5% (w / v) is more preferable, and 0.05 to 0.2% (w / v) is even more preferable.
Further, when a surfactant is blended in the aqueous composition of the present invention, one or more surfactants may be used together.

When the isotonic agent is blended in the aqueous composition of the present invention, the isotonic agent that can be used as an additive of a pharmaceutical product can be appropriately blended, and for example, an ionic isotonic agent. , Non-ionic tonicity agent and the like.
Examples of the ionic isotonic agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like.
Examples of the nonionic isotonic agent include glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose, xylitol and the like.
The content of the tonicity agent when the tonicity agent is blended in the aqueous composition of the present invention can be appropriately adjusted depending on the type of the tonicity agent and the like, but is 0.001 to 10% (w / w /). v) is preferable, 0.01 to 5% (w / v) is more preferable, 0.1 to 3% (w / v) is further preferable, and 0.2 to 1% (w / v) is particularly preferable.
When the isotonic agent is blended in the aqueous composition of the present invention, one or two or more isotonic agents may be used together.

When the stabilizer is added to the aqueous composition of the present invention, a stabilizer that can be used as an additive for pharmaceutical products can be appropriately added, and for example, edetic acid or a salt thereof, cyclodextrin, etc. Examples thereof include sodium thiosulfate.
Examples of edetonic 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 these hydrates There may be.
The content of the stabilizer when the stabilizer is added to the aqueous composition of the present invention can be appropriately adjusted depending on the type of the stabilizer and the like, but is 0.001 to 5% (w / v). Preferably, 0.01 to 3% (w / v) is more preferable, and 0.01 to 1% (w / v) is further preferable.
Further, when a stabilizer is blended in the aqueous composition of the present invention, one or more stabilizers may be used together.

When the preservative is blended in the aqueous composition of the present invention, a preservative that can be used as an additive for pharmaceuticals can be appropriately blended. For example, chlorhexidine gluconate, chlorhexidine hydrochloride, methyl paraoxybenzoate, etc. Examples thereof include propyl paraoxybenzoate, sodium chlorite or chlorobutanol.
The content of the preservative when the preservative is added to the aqueous composition of the present invention can be appropriately adjusted depending on the type of the preservative and the like, but the amount is preferably such that it does not adversely affect the safety, for example. It is preferably 0.0001 to 0.1% (w / v), more preferably 0.001 to 0.05% (w / v).
When a preservative is added to the aqueous composition of the present invention, one or two or more preservatives may be used together.

When an antioxidant is added to the aqueous composition of the present invention, an antioxidant that can be used as an additive for pharmaceutical products can be appropriately added. For example, ascorbic acid, tocopherol, dibutylhydroxytoluene, etc. Examples thereof include sodium sulfite.
The content of the antioxidant when the antioxidant is added to the aqueous composition of the present invention can be appropriately adjusted depending on the type of the antioxidant and the like, but is 0.001 to 5% (w / v). Preferably, 0.01 to 3% (w / v) is more preferable, and 0.1 to 2% (w / v) is even more preferable.
When an antioxidant is added to the aqueous composition of the present invention, one or more antioxidants may be used together.

When the pH adjuster is added to the aqueous composition of the present invention, the pH adjuster that can be used as an additive for pharmaceuticals can be appropriately added, and is, for example, an acid or a base, as an acid. For example, hydrochloric acid, phosphoric acid and the like, and examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like.
The pH of the aqueous composition of the present invention may be in the range acceptable for pharmaceutical products, for example, in the range of 4.0 to 8.5 or 4.0 to 8.0, and 6.0 to 8.0. 0 is preferable, and 6.5 to 7.5 is more preferable. Particularly preferred pH is 6.7 to 7.3, but 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3 are even more preferred.

The osmotic pressure ratio of the aqueous composition of the present invention may be within the range acceptable for pharmaceutical products, for example, 0.5 to 2.0, preferably 0.7 to 1.6, and 0.8 to 1. 4 is more preferable, and 0.9 to 1.2 is even more preferable.

The aqueous composition of the present invention is particularly preferably used as a pharmaceutical and is suitable for parenteral (eg, topical) administration. The parenteral route of administration of the aqueous composition of the present invention includes a locally acceptable route of administration as a pharmaceutical product, for example, local administration to the eye (for example, eye drop administration), nasal drop (nasal) administration, and local administration to the ear. (For example, ear drop administration), inhalation administration, spray administration, transdermal administration, skin administration, injection administration and the like can be mentioned. It is preferably topical administration to the eye. The aqueous composition of the present invention can also be orally administered.

The aqueous composition of the present invention can be used as an ophthalmic preparation, an otolaryngological preparation, an inhalation preparation, and a transdermal absorption preparation, and the dosage form thereof is particularly limited as long as it can be used as a pharmaceutical product. It's not a thing. Dosage forms include, for example, oral administrations such as liquids and suspensions, eye drops, nasal drops, ear drops, inhalants, (inhalation powders, inhalation solutions, inhalation aerosols), ointments, creams. , Gel, transdermal absorption type preparation, patch (tape, poultice), external solution (lotion, liniment), external solid (external powder), spray (pump spray, external aerosol), Topical administration agents such as injections (infusions, implantable injections, continuous injections) can be mentioned. It is preferably an eye drop, a transdermal preparation for ophthalmology, or an injection for ophthalmology, and more preferably an eye drop. These can be manufactured according to the usual methods in the art.

The aqueous composition of the present invention may have all the constituents dissolved or partially suspended, or may be in the form of an emulsion or a semi-solid. 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, eye drops (eye drops) are particularly preferable for ophthalmology.
When the aqueous composition of the present invention is an emulsion, even an oil-in-water emulsion (an emulsion composed of oily droplets dispersed in an aqueous phase with the aqueous phase as a continuous phase) is an aqueous emulsion in oil (oil). It may be an emulsion composed of aqueous droplets dispersed with oil, with the phase as a continuous phase).

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. Further, 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.

When the aqueous composition of the present invention is administered to the eye as an eye drop, the dosage is not particularly limited as long as it is sufficient to achieve the desired medicinal effect, but one drop at a time, preferably 1 to 10 times a day. The eye drops can be instilled 1 to 6 times a day, more preferably 2 to 4 times a day, more preferably 2 times a day or 4 times a day, and particularly preferably 2 times a day.

When the aqueous composition of the present invention is used as an eye drop, it may be contained in either 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 container for eye drops that is generally used may be used, but a resin container is preferable, and for example, polyethylene (PE), polypropylene (PP), or polyethylene terephthalate ( Containers made of PET), polybutylene terephthalate (PBT), polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic, polystyrene, polycyclic olefin copolymer and the like can be used. If the material of the resin container is, for example, polyethylene, polyethylene is classified according to its density, and containers made of low-density polyethylene (LDPE), medium-density polyethylene (MDPE), high-density polyethylene (HDPE), etc. are used. Can be used.

Examples of formulations and test examples are shown below, but these are for a better understanding of the present invention and do not limit the scope of the present invention.

Examples of preparations Typical examples of preparations of the present invention are shown below. In the following formulation example, the blending amount of each component is the content in 1 mL of the formulation.

Pharmaceutical example 1
Epinastine hydrochloride 1 mg
Benzalkonium chloride 0.09 mg
Disodium hydrogen phosphate 5 mg
Sodium chloride 5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0

Pharmaceutical example 2
Epinastine hydrochloride 0.5 mg
Benzalkonium chloride 0.05 mg
Sodium dihydrogen phosphate 4.5 mg
Sodium chloride 5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0

Pharmaceutical example 3
Epinastine hydrochloride 1 mg
Benzalkonium chloride 0.05 mg
Boric acid 1 mg
Sodium chloride 5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0

Pharmaceutical example 4
Epinastine hydrochloride 1 mg
Benzalkonium chloride 0.02 mg
Boric acid 0.2mg
Sodium edetate hydrate 1 mg
Sodium chloride 4.5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0

Pharmaceutical example 5
Epinastine hydrochloride 1 mg
Polidronium chloride 0.05 mg
Disodium hydrogen phosphate 3 mg
Sodium chloride 4.5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0

Test example 1. Intraocular dynamics test (1) Preparation of test preparation Epinastine hydrochloride, benzalconium chloride, sodium chloride, sodium dihydrogen phosphate, sodium hydrogen phosphate hydrate are dissolved in water so as to have the concentrations shown in Table 1 below. Then, a pH adjuster (dilute hydrochloric acid and / or sodium hydroxide) and water were added to make the total volume 10 mL, and filtration sterilization was performed to prepare the preparation 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 the formulation of Example 1.

(2) Test method 50 μL of each test preparation was instilled into the eyes of rabbits three times at 15-minute intervals, 0.25 hours, 0.5 hours, 1 hour, 2 hours and 4 hours after the final instillation. At that time, the eye drops after slaughter were removed. At each time point, the epinastine concentration in the cornea and in the aqueous humor was measured, and the AUC (area under the blood concentration-time curve) was calculated. The AUC was calculated by a Sparse sampling analysis using ^{Phoenix WinNonlin (registered trademark) v8.1.}

(3) Test results and discussion Table 2 shows the test results. In the table, "Mean" is the average value, "SE" is the standard error, and "N" is the number of samples, which are calculated by general-purpose statistical processing.

As shown in Table 2, Examples 1 and 2 containing benzalkonium chloride, which is a quaternary ammonium compound, are in the cornea and aqueous humor as compared with Comparative Example 1 not containing benzalkonium chloride. It was confirmed that the amount of epinastine transferred was increased. Therefore, it was shown that the aqueous composition of the present invention remarkably improves the transferability to the ocular tissue.

The present invention is 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 1 weight by weight of the content of epinastine or a salt thereof. Provided is an aqueous composition having an amount of 0.1 parts by weight or less based on parts.

Claims (6)

0.1% as an active ingredient and (w / v) epinastine or a salt thereof at a concentration of only contains a quaternary ammonium compound, in an ophthalmic aqueous composition containing no preservative other than quaternary ammonium compounds there are, epinastine or the content ratio of the quaternary ammonium compound to the salt thereof is less than or equal 0.05 part by weight relative to the content 1 part by weight of epinastine or a salt thereof, ophthalmic aqueous composition. Epinastine or a salt thereof, is epinastine hydrochloride, ophthalmic aqueous composition according to claim 1. Quaternary ammonium compounds, benzalkonium chloride, benzethonium chloride, at least one selected from the group consisting of methyl chloride benzethonium chloride and Poridoroniumu, ophthalmic aqueous composition according to claim 1 or 2. Quaternary ammonium compound is benzalkonium chloride, ophthalmic aqueous composition according to any one of claims 1 to 3. Is eye drops, ophthalmic aqueous composition according to any one of claims 1 to 4. An eye drop containing only 0.1% (w / v) concentration of epinastine hydrochloride as an active ingredient and benzalkonium chloride and no preservative other than benzalkonium chloride. An eye drop in which the content ratio of benzalkonium chloride to 1 part by weight of epinastine hydrochloride is 0.0001 to 0.05 part by weight.