CN115397430A - Aqueous composition containing epinastine or its salt - Google Patents

Abstract

The present invention provides an aqueous composition having improved migration to an eye tissue, comprising epinastine or a salt thereof and a quaternary ammonium compound, wherein the content of the quaternary ammonium compound is 0.1 part by weight or less relative to epinastine or a salt thereof per 1 part by weight of the epinastine or a salt thereof.

Description

Aqueous composition containing epinastine or its salt

technical field

The present invention relates to an aqueous composition containing epinastine or a salt thereof, and more specifically, to 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") things").

Background technique

Aqueous compositions containing solvents such as water require more than a certain level of antiseptic measures in consideration of repeated use in order to prevent the growth of fungi and the like. Therefore, preservatives are usually blended in such compositions. For example, in the case of eye drops, benzalkonium chloride is commonly used. Benzalkonium chloride is water-soluble, chemically stable, and has higher antiseptic efficacy than other preservatives. However, benzalkonium chloride has cell damage, and if the exposure amount increases, the possibility of causing damage to the corneal epithelium increases, so it is desirable not to use it as much as possible.

Alesion ^{(registered trademark)} eye drops 0.05% on the market in Japan is the eye drops with epinastine hydrochloride as active ingredient at present, does not add benzalkonium chloride as an additive, what replaces is to add boric acid (non-patented Literature 1).

In addition, it is also known that by making the concentration of epinastine or its salt in the eye drops more than 0.075% (w/v), it is possible to obtain sufficient antiseptic or antiseptic ingredients substantially. anti-corrosion effect (Patent Document 1).

In this way, in recent years, the development of ophthalmic solutions not using benzalkonium chloride has been progressing, and there is a tendency to avoid the use of benzalkonium chloride in aqueous compositions.

In addition, from the viewpoint of medication compliance, it is desirable to reduce the frequency of daily drug administration. However, if the frequency of administration is reduced, there is a possibility that the effective concentration in the living tissue cannot be maintained and the efficacy of the drug may be reduced. In order to exert the drug effect, it is necessary to maintain the effective concentration in the living tissue. In the case of eye drops, as a method of maintaining the effective concentration in the eye tissue, there are known methods of increasing the compounding concentration of the active ingredient, using an absorption enhancer, and increasing the concentration in the eye tissue by compounding a thickener. The retention method, etc.

For example, Patent Document 2 describes that adding a β receptor blocker to an aqueous solution containing alginic acid and adjusting the pH to 6-8 has the effect of prolonging the action time after administration. In addition, Patent Document 3 describes that intraocular migration of a drug can be improved by adding a sugar alcohol to a β-receptor blocking drug.

On the other hand, it has been reported that a locally administrable aqueous solution comprising epinastine can inhibit the influx of neutrophils and eosinophils to the conjunctiva of the eyeball and the tissues of the nasal mucosa, thereby reducing or preventing the progression of the delayed phase reaction. Occurred, added a certain amount of benzalkonium chloride in its aqueous solution as preservative (patent document 4).

In the aqueous composition containing epinastine or its salt, there is no report that adding a quaternary ammonium compound such as benzalkonium chloride improves the migration of epinastine or its salt to ocular tissue so as to maintain an effective concentration in the ocular tissue.

Prior art literature

patent documents

Patent Document 1: Japanese Patent No. 6134853

Patent Document 2: Japanese PCT Publication No. 2002-511430

Patent Document 3: International Publication No. 2012/026609 Handbook

Patent Document 4: Japanese PCT Publication No. 2003-514021

non-patent literature

Non-Patent Document 1: Alesion ^{(registered trademark)} eye drops 0.05% instructions

Contents of the invention

The problem to be solved by the invention

Therefore, in order to bring about excellent drug effects, it is very useful to improve the migration of active ingredients to tissues, especially eye tissues. Aqueous compositions for tissue migration are the subject of interest.

means to solve the problem

After the inventors of the present application conducted in-depth studies on aqueous compositions containing epinastine or its salts, it was found that the aqueous composition containing epinastine or its salts and a quaternary ammonium compound adjusted to a specific content The inventors have completed the present invention by improving the migration of epinastine to ocular tissues when administered as eye drops.

Specifically, the present invention provides the following solutions.

(1) An aqueous composition, which is an aqueous composition containing epinastine or a salt thereof, and a quaternary ammonium compound, relative to 1 part by weight of the content of epinastine or a salt thereof, relative to epinastine The content ratio of the quaternary ammonium compound or its salt is 0.1 weight part or less.

(2) The aqueous composition as described in (1) whose epinastine or its salt is epinastine hydrochloride.

(3) The aqueous composition according to (1) or (2), wherein the concentration of epinastine or a salt thereof is 0.01 to 5% (w/v).

(4) The aqueous composition according to (1) or (2), wherein the concentration of epinastine or a salt thereof is 0.05% (w/v) or more.

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

(6) The aqueous composition as described in any one of (1) to (5), wherein the quaternary ammonium compound is selected from benzalkonium chloride, benzethonium chloride, methyl benzethonium chloride and polychloride One or more of the group consisting of ammonium.

(7) The aqueous composition according to any one of (1) to (6), wherein the quaternary ammonium compound is benzalkonium chloride.

(8) The aqueous composition according to any one of (1) to (7), wherein, relative to 1 part by weight of the content of epinastine or its salt, relative to epinastine or its salt The content ratio of the quaternary ammonium compound is 0.05 parts by weight or less.

(9) The aqueous composition according to any one of (1) to (8), which is for ophthalmic use.

(10) The aqueous composition according to any one of (1) to (9), which is an eye drop.

(11) A method of improving migration of epinastine or a salt thereof to ocular tissues by blending a quaternary ammonium compound into an aqueous composition containing epinastine or a salt thereof as an active ingredient.

(12) The method according to (11), wherein the quaternary ammonium compound is at least one selected from the group consisting of benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, and polimonium chloride.

(13) The method according to (11) or (12), wherein the quaternary ammonium compound is benzalkonium chloride.

(14) Eye drops, which are eye drops containing benzalkonium chloride and epinastine hydrochloride at a concentration of 0.1% (w/v), relative to the content of epinastine hydrochloride by 1 weight In terms of parts, the content ratio of benzalkonium chloride relative to epinastine hydrochloride is 0.0001 parts by weight or more and less than 0.1 parts by weight.

In addition, each structure of said (1)-(14) can select arbitrarily 2 or more types, and can combine them.

In addition, the present invention also provides the following solutions.

(15) A method for treating allergic diseases, comprising administering a therapeutically effective amount of the aqueous composition described in 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 the treatment of allergic diseases.

(17) Use of the aqueous composition according to any one of (1) to (10) for the manufacture of a medicament for treating allergic diseases.

The effect of the invention

The present invention provides an aqueous composition capable of improving migration of epinastine or a salt thereof to ocular tissues by adding a quaternary ammonium compound to an aqueous composition containing epinastine or a salt thereof, thereby bringing excellent efficacy.

Detailed ways

Hereinafter, the present invention will be described in detail.

In the present invention, "epistine" refers to a compound represented by the chemical name (±)-3-Amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine, In addition, it refers to a compound represented by the following formula,

[chemical formula 1]

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

The epinastine contained in the aqueous composition of the present invention may be a salt, and there is no particular limitation as long as it is a pharmaceutically acceptable salt. As a salt, the salt formed with an inorganic acid, the salt formed with an organic acid, etc. are mentioned, for example.

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

Examples of 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, glucoheptonic acid, glucuronic acid, 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, dimethyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid, etc. Salt.

As the salt of epinastine, monohydrochloride (epinastine hydrochloride) is particularly preferable.

In the aqueous composition of the present invention, epinastine or a salt thereof contained may be in 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, still more preferably 0.1% (w/v) As mentioned above, the upper limit should just be the concentration allowable as 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), still more preferably 0.05 to 0.2% (w/v), especially Preferably it is 0.05 to 0.1% (w/v). For example, its content is 0.1% (w/v).

In addition, in this invention, "% (w/v)" means the mass (g) of the object component contained in 100 mL of aqueous compositions of this invention. In the present invention, when the salt of epinastine is included, the value is the content of the salt of epinastine. In addition, in the present invention, when epinastine or a salt thereof is blended in the form of a hydrate or a solvate, the value is the content of the hydrate or solvate of epinastine or a salt thereof. Hereinafter, unless otherwise specified, it has the same meaning.

In the present invention, "quaternary ammonium compound" refers to a salt formed of quaternary ammonium cations and other anions, also called quaternary ammonium salts.

In the aqueous composition of the present invention, the quaternary ammonium compound contained for example can enumerate benzalkonium chloride, benzethonium chloride, methyl benzethonium chloride, polimonium chloride, cetylpyridinium chloride, benzalkonium bromide, Benzethonium bromide, methyl benzethonium bromide, cetrimonium bromide, etc., preferably benzalkonium chloride, benzethonium chloride, methyl benzethonium chloride, polimonium chloride, more preferably benzalkonium chloride.

In the aqueous composition of the present invention, the quaternary ammonium compound also functions as an additive of pharmaceuticals, such as a preservative, a surfactant, a stabilizer, an isotonic agent, a buffer, and the like. Therefore, quaternary ammonium compounds can also be used as additives of pharmaceuticals.

Moreover, in the aqueous composition of this invention, a quaternary ammonium compound can be used 1 type or 2 or more types together.

In the aqueous composition of the present invention, the content of the quaternary ammonium compound can be appropriately adjusted depending on the type, for example, 0.0001 to 1% (w/v), preferably 0.0001 to 0.1% (w/v), more preferably 0.0001 to 0.01% (w/v), more preferably 0.0001 to 0.005% (w/v). For example, when the quaternary ammonium compound is benzalkonium chloride, if the exposure amount increases, the possibility of causing corneal epithelial damage increases, so the upper limit of the content is preferably 0.01% (w/v) or less. (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, still more preferably 0.003% (w/v) or more. More specifically, its content is preferably 0.0001 to 0.01% (w/v), more preferably 0.001 to 0.005% (w/v), still more preferably 0.001 to 0.003% (w/v) or 0.003 to 0.005% ( w/v).

In the aqueous composition of the present invention, the content ratio of the quaternary ammonium compound can be appropriately adjusted depending on the type, for example, with respect to 1 part by weight of the content of epinastine or a salt thereof, the upper limit of the content ratio is 0.1 parts by weight or less or Less than 0.1 part by weight, preferably 0.05 part by weight or less. With respect to 1 part by weight of the content of epinastine or a salt thereof, the lower limit of the content ratio is 0.0001 parts by weight or more, preferably 0.001 parts by weight or more, more preferably 0.003 parts by weight or more, 0.005 parts by weight or more, or 0.01 parts by weight servings or more. More specifically, the content ratio thereof 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, still more preferably 0.005 to 0.05 parts by weight, and especially preferably 0.01 to 0.05 parts by weight. For example, when the quaternary ammonium compound is benzalkonium chloride, if the amount of exposure increases, the possibility of causing corneal epithelial damage increases, so relative to 1 part by weight of the content of epinastine or its salt, its The content ratio is 0.1 weight part or less or less than 0.1 weight part, Preferably it is 0.05 weight part or less or 0.03 weight part or less. More specifically, its 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, even more preferably 0.005 to 0.05 parts by weight, especially preferably 0.01 to 0.05 parts by weight, Particularly preferably, it is 0.03 to 0.05 parts by weight.

An aqueous composition containing epinastine or a salt thereof at a certain concentration or more can obtain a sufficient preservative effect without substantially containing a preservative or a component having a preservative effect. In the aqueous composition of the present invention, for example, in the case where the quaternary ammonium compound is benzalkonium chloride commonly used as a preservative, the content of benzalkonium chloride may be less than the amount that exerts its function as a preservative, or it may contain amount of effect. On the other hand, as long as the effects of the present invention are exhibited, the content of benzalkonium chloride may be such that it functions as a preservative.

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

In the present invention, "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 even more preferably 50% (w/v) or more. In particular, it is preferably 70% (w/v) or more, more preferably 90% (w/v) or more, and still more preferably 95% (w/v) or more.

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

In the aqueous composition of the present invention, pharmaceutical additives such as buffers, thickeners, surfactants, isotonic agents, stabilizers, preservatives, antioxidants, pH regulators, etc. can be added as needed. These can be used individually, respectively, and can also be used in combination of 2 or more types suitably, and can mix|blend an appropriate amount.

The buffer in the case of adding a buffer to the aqueous composition of the present invention can be appropriately mixed with a buffer that can be used as an additive for pharmaceuticals, for example, phosphoric acid or a salt thereof, boric acid or a salt thereof, carbonic acid or a salt thereof, 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. may also be hydrates or solvates of these.

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. Hydrates of these.

Examples of boric acid or its salt include boric acid, sodium borate (borax), potassium borate, and the like, and these hydrates may also be used.

Examples of carbonic acid or salts thereof include carbonic acid, sodium carbonate, sodium bicarbonate, and the like, and these hydrates may also be used.

Examples of citric acid or salts thereof include citric acid, monosodium citrate, disodium citrate, and trisodium citrate, and hydrates of these may be used.

Acetic acid, sodium acetate, etc. are mentioned as acetic acid or its salt, and these hydrates may be sufficient.

Examples of tartaric acid or its salt include tartaric acid, monosodium tartrate, disodium tartrate, and the like, and these hydrates may also be used.

Examples of ε-aminocaproic acid or salts thereof include ε-aminocaproic acid, sodium ε-aminocaproate, and ε-aminocaproic acid hydrochloride, and hydrates of these may be used.

Examples of glutamic acid or its salt include glutamic acid, monosodium glutamate, disodium glutamate, glutamic acid hydrochloride, and the like, and these hydrates may also be used.

Tromethamine etc. are mentioned as an organic amine, and these hydrates may be sufficient.

The content of the buffer in the case of adding a buffer to the aqueous composition of the present invention can be appropriately adjusted according to the type of buffer, and is preferably 0.001 to 10% (w/v), more preferably 0.01 to 5% (w /v), more preferably 0.1 to 5% (w/v), particularly preferably 0.1 to 2% (w/v).

In addition, when a buffer is blended in the aqueous composition of the present invention, the buffer may be used alone or in combination of two or more.

The thickener in the case of adding a thickener to the aqueous composition of the present invention can be appropriately mixed with a thickener that can be used as an additive for pharmaceuticals, for example, methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, etc. Hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose Cellulose Acetate Succinate, Hydroxypropylmethylcellulose Phthalate, Carboxymethylethylcellulose, Cellulose Acetate Phthalate, Polyvinylpyrrolidone, Polyvinyl Alcohol, Carboxyvinyl Polymers, polyethylene glycol, sodium hyaluronate, etc.

When a thickener is added to the aqueous composition of the present invention, the content of the thickener can be appropriately adjusted depending on the type of thickener, and is preferably 0.001 to 5% (w/v), more preferably 0.01 to 3%. % (w/v), more preferably 0.1 to 2% (w/v).

Moreover, when a thickener is mix|blended with the aqueous composition of this invention, a thickener can be used 1 type or 2 or more types together.

The surfactant in the case of adding a surfactant to the aqueous composition of the present invention can be appropriately mixed with a surfactant that can be used as an additive for pharmaceuticals, for example, cationic surfactants, anionic surfactants, Nonionic surfactants, etc.

Examples of cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyldiethylamine salts, fatty acid polyamine condensates, alkyl imidazoline, 1-acylaminoethyl-2-alkylimidazoline, 1-hydroxyethyl-2-alkylimidazoline, and the like. In addition, quaternary ammonium cations, such as benzalkonium chloride, have the property of a cationic surfactant, However, These are not included in the cationic surfactant in this invention.

Phospholipids, such as lecithin, etc. are mentioned as anionic surfactant.

Examples of nonionic surfactants include polyoxyethylene fatty acid esters such as polyoxyethylene 40 stearate; polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan mono Polyoxyethylene sorbitan fatty acid esters such as laurate, polyoxyethylene sorbitan trioleate, polysorbate 65; polyoxyethylene 10 hydrogenated castor oil, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene Ethylene 50 hydrogenated castor oil, polyoxyethylene 60 hydrogenated castor oil and other polyoxyethylene hydrogenated castor oil; polyoxyethylene 5 castor oil, polyoxyethylene 9 castor oil, polyoxyethylene 15 castor oil, polyoxyethylene 35 castor oil, polyoxyethylene castor oil Polyoxyethylene castor oil such as oxyethylene 40 castor oil; polyoxyethylene (160) polyoxypropylene (30) diol, polyoxyethylene (42) polyoxypropylene (67) diol, polyoxyethylene (54) polyoxyethylene Polyoxyethylene polyoxypropylene glycol such as propylene (39) diol, polyoxyethylene (196) polyoxypropylene (67) diol, polyoxyethylene (20) polyoxypropylene (20) diol; sucrose stearic acid Sucrose fatty acid esters such as esters; tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS), etc.

When a surfactant is blended into the aqueous composition of the present invention, the content of the surfactant can be appropriately adjusted depending on the type of surfactant, etc., and is preferably 0.01 to 1% (w/v), more preferably 0.05 to 0.5% % (w/v), more preferably 0.05 to 0.2% (w/v).

Moreover, when surfactant is mix|blended with the aqueous composition of this invention, surfactant can be used 1 type or 2 or more types together.

When the isotonizing agent is blended into the aqueous composition of the present invention, the isotonizing agent that can be used as an additive for pharmaceuticals can be appropriately blended, and examples thereof include ionic isotonizing agents and nonionic isotonizing agents. Wait.

Sodium chloride, potassium chloride, calcium chloride, magnesium chloride etc. are mentioned as an ionic isotonizing agent.

Glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose, xylitol etc. are mentioned as a nonionic isotonizing agent.

When the isotonic agent is mixed with the aqueous composition of the present invention, the content of the isotonic agent can be appropriately adjusted according to the type of the isotonic agent, and is preferably 0.001 to 10% (w/v), more preferably 0.01 to 5%. % (w/v), more preferably 0.1 to 3% (w/v), particularly preferably 0.2 to 1% (w/v).

Moreover, when an isotonizing agent is mix|blended with the aqueous composition of this invention, it can use 1 type or 2 or more types together.

In the case of adding a stabilizer to the aqueous composition of the present invention, the stabilizer can be appropriately mixed with a stabilizer that can be used as an additive for pharmaceuticals, for example, ethylenediaminetetraacetic acid or its salt, cyclodextrin, thio Sodium Sulfate etc.

Examples of EDTA or salts thereof include EDTA, monosodium EDTA, disodium EDTA (hereinafter also referred to as sodium EDTA), ethylenediamine Trisodium tetraacetate, tetrasodium ethylenediaminetetraacetate, and the like may also be hydrates of these.

When the stabilizer is added to the aqueous composition of the present invention, the content of the stabilizer can be appropriately adjusted according to the type of stabilizer, and is preferably 0.001 to 5% (w/v), more preferably 0.01 to 3% (w /v), more preferably 0.01 to 1% (w/v).

Moreover, when a stabilizer is mix|blended with the aqueous composition of this invention, a stabilizer can be used 1 type or 2 or more types together.

The preservative in the case of adding a preservative to the aqueous composition of the present invention can be appropriately mixed with a preservative that can be used as an additive for pharmaceuticals, for example, chlorhexidine gluconate, chlorhexidine hydrochloride, p-hydroxybenzoic acid Methylparaben, propylparaben, sodium chlorite or chlorobutanol, etc.

When a preservative is added to the aqueous composition of the present invention, the content of the preservative can be appropriately adjusted depending on the type of preservative, and it is only necessary to have an amount that does not adversely affect safety. For example, it is preferably 0.0001 to 0.1 % (w/v), more preferably 0.001 to 0.05% (w/v).

In addition, when a preservative is blended in the aqueous composition of the present invention, the preservative may be used alone or in combination of two or more.

When an antioxidant is added to the aqueous composition of the present invention, an antioxidant that can be used as an additive for pharmaceuticals can be appropriately added, and examples thereof include ascorbic acid, tocopherol, dibutylhydroxytoluene, and sodium sulfite.

The content of the antioxidant in the case of adding an antioxidant to the aqueous composition of the present invention can be appropriately adjusted according to the type of antioxidant, and is preferably 0.001 to 5% (w/v), more preferably 0.01 to 3% (w /v), more preferably 0.1 to 2% (w/v).

Moreover, when an antioxidant is mix|blended with the aqueous composition of this invention, it can use 1 type or 2 or more types of antioxidants together.

The pH adjuster in the case of adding a pH adjuster to the aqueous composition of the present invention can be appropriately mixed with a pH adjuster that can be used as an additive for pharmaceuticals, such as an acid or a base, and examples of the acid include hydrochloric acid and phosphoric acid. etc., and examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and the like.

The pH of the aqueous composition of the present invention may be within a range acceptable as a pharmaceutical, for example, within a range of 4.0 to 8.5 or 4.0 to 8.0, preferably 6.0 to 8.0, more preferably 6.5 to 7.5. The pH is particularly preferably 6.7 to 7.3, and even more preferably 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, or 7.3.

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

The aqueous composition of the present invention is particularly preferably used as a medicament, and is suitable for parenteral (eg, topical) administration. As the route of parenteral administration of the aqueous composition of the present invention, local administration routes acceptable as pharmaceuticals are mentioned, for example, local administration to the eye (for example, eye drop administration), nasal drop (transnasal administration), etc. ) administration, topical administration to the ear (for example, ear drop administration), inhalation administration, spray administration, transdermal administration, epidermal administration, injection administration, and the like. Topical administration to the eye is preferred. In addition, the aqueous composition of the present invention can also be administered orally.

The aqueous composition of the present invention can be used as ophthalmic preparations, otolinological preparations, inhalation preparations, and percutaneous absorption preparations, and its dosage form is not particularly limited as long as it can be used as a pharmaceutical. Examples of dosage forms include liquids, suspensions, and other oral preparations, eye drops, nose drops, ear drops, inhalants, (inhalation powder, inhalation liquid, inhalation aerosol), Ointments, creams, gels, transdermal preparations, patches (patches, cataplasms), liquids for external use (lotions, liniments), solid preparations for external use (powders for external use) , Sprays (spray pumps, external aerosols), injections (infusions, implant injections, continuous injections) and other local administration agents. Eye drops, ophthalmic percutaneous absorption type preparations or ophthalmic injections are preferred, and eye drops are more preferred. These can be produced according to usual methods in this technical field.

The aqueous composition of the present invention may be in the form of all dissolved or partially suspended components, or may be in the form of an emulsion or a semisolid. The aqueous composition of the present invention is more preferably in a solution state in which all constituent components are dissolved, and is most preferably an aqueous solution. For example, eye drops (eye drops) are particularly preferred as long as they are used in ophthalmology.

When the aqueous composition of the present invention is an emulsion, it may be an oil-in-water emulsion (a water phase is used as a continuous phase, and an emulsion composed of a water phase and dispersed oil droplets), or an oil-in-water emulsion may be used. Aqueous emulsions (emulsions composed of oil and dispersed aqueous droplets with the oil phase as the 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. In addition, unless otherwise specified, the aqueous composition of the present invention may contain pharmaceutical active ingredients other than epinastine or a salt thereof, such as active ingredients used in other eye drops.

When the aqueous composition of the present invention is administered to the eye as eye drops, the dosage is not particularly limited as long as the desired drug effect is sufficiently achieved, and it can be 1 drop at a time, 1 to 1 drop per day. 10 times, preferably 1 to 6 times a day, more preferably 2 to 4 times a day, even more preferably 2 times a day or 4 times a day, especially preferably 2 times a day .

When the aqueous composition of the present invention is used as eye drops, it may be contained in any container among multi-dose containers, disposable single-dose containers, and PFMD (Preservative Free Multi Dose) containers. It should be noted that the raw material of the container is not particularly limited, as long as it is a commonly used eye drop container, it is preferably a container made of resin, for example, polyethylene (PE), polypropylene (PP), polypropylene Polyethylene phthalate (PET), polybutylene terephthalate (PBT), polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic, polystyrene, polycyclic Containers made of olefin copolymers, etc. In addition, when the material of the resin container is, for example, polyethylene, polyethylene is classified according to its density, and products made of low-density polyethylene (LDPE), medium-density polyethylene (MDPE), and high-density polyethylene (HDPE) can be used. container.

Example

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

Preparation example

Representative formulation examples of the present invention are shown below. In addition, in the following formulation examples, the compounding quantity of each component is the content in 1 mL of formulations.

Preparation Example 1

Preparation example 2

Preparation example 3

Preparation Example 4

Preparation Example 5

Test case

1. Intraocular pharmacokinetic test

(1) Preparation of test preparations

Dissolve epinastine hydrochloride, benzalkonium chloride, sodium chloride, sodium dihydrogen phosphate, sodium hydrogen phosphate hydrate in water so as to become the concentration in Table 1 below, and add a pH adjuster (dilute hydrochloric acid and / or sodium hydroxide) and water so that the total amount was 10 mL, and filter-sterilized 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 by the same method as the preparation method of the formulation of Example 1.

Table 1

(2) Test method

50 μL of each test preparation was administered to the rabbit's eyes three times in total at 15-minute intervals, at 0.25 hours, 0.5 hours, 1 hour, 2 hours, and 4 hours from the last eye drop Click to remove the eyeball after death. The concentration of epinastine in the cornea and aqueous humor was measured at each time point, and the AUC (area under the plasma concentration-time curve) was calculated. In addition, AUC is calculated by the sparse sampling (Sparse sampling) analysis using Phoenix WinNonlin ^{(registered trademark)} V8.1.

(3) Test results and discussion

The test results are shown in Table 2. It should be noted that "Mean" in the table indicates the mean value, "SE" indicates the standard error, and "N" indicates the number of samples, which are calculated through common statistical processing.

Table 2

As shown in Table 2, compared with Example 1 and Example 2 containing benzalkonium chloride as a quaternary ammonium compound, compared with Comparative Example 1 not containing benzalkonium chloride, the concentration of epinastine in the cornea and aqueous humor was confirmed. The amount of migration increases. Therefore, it was shown that the aqueous composition of the present invention significantly improves migration to ocular tissues.

Industrial availability

The present invention provides an aqueous composition, which is an aqueous composition containing epinastine or a salt thereof, and a quaternary ammonium compound. The content ratio of the quaternary ammonium compound or its salt is 0.1 weight part or less.

Claims (14)

1. An aqueous composition comprising epinastine or a salt thereof and a quaternary ammonium compound, wherein the content of the quaternary ammonium compound is 0.1 part by weight or less relative to epinastine or a salt thereof per 1 part by weight of the epinastine or a salt thereof.

2. The aqueous composition as claimed in claim 1, wherein epinastine or the salt thereof is epinastine hydrochloride.

3. The aqueous composition as claimed in claim 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 claim 1 or 2, wherein the concentration of epinastine or a salt thereof is 0.05% (w/v) or more.

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

6. The aqueous composition according to any one of claims 1 to 5, wherein the quaternary ammonium compound is at least 1 selected from the group consisting of benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride and porilium chloride.

7. The aqueous composition of any one of claims 1-6, wherein the quaternary ammonium compound is benzalkonium chloride.

8. The aqueous composition as claimed in any one of claims 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.

9. Aqueous composition according to any one of claims 1 to 8, which is for ophthalmic use.

10. The aqueous composition according to any one of claims 1 to 9, which is an eye drop.

11. A method for improving the migration of epinastine or a salt thereof into an ocular tissue, which comprises adding a quaternary ammonium compound to an aqueous composition containing epinastine or a salt thereof as an active ingredient.

12. The method according to claim 11, wherein the quaternary ammonium compound is at least one selected from the group consisting of benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride and porilium chloride.

13. The method of claim 11 or 12, wherein the quaternary ammonium compound is benzalkonium chloride.

14. An eye drop comprising benzalkonium chloride and epinastine hydrochloride at a concentration of 0.1% (w/v), wherein the content of benzalkonium chloride relative to epinastine hydrochloride is 0.0001 parts by weight or more and less than 0.1 part by weight relative to 1 part by weight of the epinastine hydrochloride content.