JP2020033290A - Aqueous composition - Google Patents

Abstract

To provide a technique that improves the stability of brimonidine in an aqueous composition.SOLUTION: An aqueous composition contains following components (A) and (B): (A) brimonidine or a salt thereof or their solvates; and (B) an amino compound.SELECTED DRAWING: None

Description

  The present invention relates to an aqueous composition and the like.

  Brimonidine such as brimonidine tartrate (chemical name: 5-Bromo-N- (4,5-dihydro-1H-imidazol-2-yl) quinoxaline-6-amine mono- (2R, 3R) -tartrate) is adrenaline α2 It is a type of receptor agonist and has an aqueous humor production inhibitory action and an aqueous humor outflow promoting action from the uveoscleral outflow tract, and exhibits an excellent intraocular pressure lowering effect. It is used as an active ingredient of ophthalmic preparations such as glaucoma drugs (Non-Patent Document 1). An ophthalmic agent is usually a composition containing water (aqueous composition), and various studies have been made on an aqueous composition containing brimonidine (for example, Patent Documents 1 and 2).

JP-T-2004-504279 JP 2012-246304 A

Aifagan (registered trademark) Ophthalmic Solution 0.1% Pharmaceutical Interview Form, Senju Pharmaceutical Co., Ltd. May 2013 (Revised 4th Edition)

The aqueous composition is water-friendly because it contains water and is excellent in safety for living organisms such as ocular tissues, and has the advantage of being easy to handle at the time of production and use. Easy to destabilize. Even in an aqueous composition containing brimonidine, by improving the stability, it is possible to provide pharmaceuticals and the like with higher quality.
Accordingly, an object of the present invention is to provide a technique for improving the stability of brimonidine in an aqueous composition.

  Therefore, the present inventors have conducted intensive studies to solve the above-mentioned problems, and surprisingly, the aqueous composition containing brimonidine, further containing an amino compound represented by chlorhexidine, the aqueous composition The present inventors have found that reduction in the content of brimonidine therein during high-temperature storage is suppressed, and completed the present invention.

That is, the present invention provides the following components (A) and (B):
(A) brimonidine or a salt thereof or a solvate thereof;
(B) an amino compound;
The present invention provides an aqueous composition containing

Further, the present invention provides the following component (A):
(A) brimonidine or a salt thereof or a solvate thereof;
The following component (B) is added to the aqueous composition containing
(B) an amino compound;
And a method for stabilizing brimonidine or a salt thereof or a solvate thereof in an aqueous composition.

  ADVANTAGE OF THE INVENTION According to this invention, the fall of the content at the time of high temperature preservation | save of brimonidine in an aqueous composition can be suppressed, and the aqueous composition excellent in stability can be provided.

<Brimonidine or a salt thereof or a solvate thereof>
In the present specification, `` brimonidine or a salt thereof or a solvate thereof '' includes not only brimonidine, but also a pharmacologically acceptable salt of brimonidine, further, brimonidine or a pharmacologically acceptable salt thereof, and water or Solvates with alcohols and the like are also included. The pharmacologically acceptable salt is not particularly limited, but specifically includes, for example, inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrofluoride, hydrobromide; acetate, tartaric acid Salt, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, naphthalenesulfonate, camphorsulfonate And the like, and among them, tartrate is preferable.

Examples of brimonidine or a salt thereof or a solvate thereof include brimonidine, brimonidine tartrate (brimonidine monotartrate) (chemical name: 5-Bromo-N- (4,5-dihydro-1H-imidazol-2-yl) quinoxaline) -6-amine mono- (2R, 3R) -tartrate) is preferred.
Brimonidine or a salt thereof or a solvate thereof is known, and may be produced by a known method, or a commercially available product may be used.

  The content of brimonidine or a salt thereof or a solvate thereof in the aqueous composition is not particularly limited, and may be determined by appropriately examining according to the applicable disease or the sex of the patient, age, symptoms, etc. From the viewpoint of obtaining a pharmacological action, the content is preferably 0.01 to 10 w / v%, more preferably 0.02 to 1 w / v%, more preferably 0.06 to 0. It is particularly preferred to contain 5 w / v%.

<Amino compound>
As used herein, the term "amino compound" means one or more compounds selected from the group consisting of compounds having one or more amino groups, salts thereof, and solvates thereof. Here, the salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and specifically, for example, inorganic acids such as hydrochloride, sulfate, nitrate, hydrofluoride, hydrobromide and the like Salts: acetate, tartrate, lactate, citrate, gluconate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate And organic salts such as naphthalenesulfonate and camphorsulfonate; and metal salts such as sodium salt, potassium salt, lithium salt, calcium salt and magnesium salt. Further, the amino compound may be a solvate such as a hydrate or an alcoholate.

  Examples of the amino compound include, for example, one or more aromatic amines which may have a substituent selected from the group consisting of aliphatic amines which may have a substituent, salts thereof, and solvates thereof. And one or more compounds selected from the group consisting of a carbamoyl group which may have a substituent, a salt thereof, and a solvate thereof, and at least one member selected from the group consisting of a salt thereof and a solvate thereof. The above are mentioned. In addition, such a substituent is not particularly limited, and examples thereof include a halogeno group, a carboxyl group, a hydroxyl group, a sulfonic acid group, a guanidino group, a carbamoyl group, a mercapto group, an imidazolyl group, a methylthio group, a phenyl group, an indolyl group, and ethoxycarbonyl. And the like, and one or more of these may be substituted in combination.

  Specific examples of one or more selected from the group consisting of an aliphatic amine which may have a substituent, a salt thereof, and a solvate thereof include, for example, an aliphatic which may have a substituent. One or more selected from the group consisting of primary amines and salts thereof and solvates thereof, and the group consisting of aliphatic secondary amines which may have a substituent, salts thereof and solvates thereof And at least one selected from the group consisting of aliphatic tertiary amines which may have a substituent, salts thereof, and solvates thereof. In this case, the aliphatic group is not particularly limited, but from the viewpoint of suppressing the reduction in the content of brimonidine or a salt thereof or a solvate thereof, a linear or branched aliphatic group having 1 to 12 carbon atoms. A group is preferable, a linear or branched aliphatic group having 2 to 10 carbon atoms is more preferable, and a linear or branched aliphatic group having 2 to 6 carbon atoms is particularly preferable.

Specific examples of one or more selected from the group consisting of an aliphatic primary amine optionally having a substituent, a salt thereof, and a solvate thereof include, for example, L-aspartic acid, L-asparagine Sodium, potassium L-aspartate, magnesium L-aspartate, DL-alanine, L-alanine, L-arginine, L-arginine hydrochloride, epsilon-aminocaproic acid, glycine, L-glutamine, L-glutamic acid, L- Glutamate hydrochloride, potassium L-glutamate, sodium L-glutamate, L-cystine, L-cysteine, L-cysteine hydrochloride hydrate, L-histidine, L-histidine hydrochloride hydrate, L-phenylalanine, DL-methionine, L-methionine, L-lysine, L-lysine hydrochloride, dl-leucine, -An aliphatic primary amine (amino acid) having at least a carboxyl group as a substituent, such as leucine; an aliphatic primary amine having a hydroxyl group as a substituent, such as trometamol or monoethanolamine; a substituent such as taurine. An aliphatic primary amine having a sulfonic acid group as a substituent; at least a phenyl group as a substituent such as a netethersyl mesylate salt (preferably a 2-mesylate salt) or a salt thereof or a solvate thereof; Aliphatic primary amines; and unsubstituted aliphatic primary amines such as ethylenediamine.
Specific examples of one or more selected from the group consisting of an aliphatic secondary amine which may have a substituent, a salt thereof, and a solvate thereof include, for example, carteolol hydrochloride (preferably, At least as a substituent such as carteolol or a salt thereof such as monohydrochloride) or a solvate thereof, or timolol or a salt thereof or a solvate thereof such as timolol maleate (preferably monomaleate). Aliphatic secondary amine having a hydroxyl group; chlorhexidine such as chlorhexidine hydrochloride (preferably dihydrochloride), chlorhexidine gluconate (preferably digluconate), and chlorhexidine acetate (preferably diacetate) Or an aliphatic secondary amine having at least a guanidino group as a substituent, such as a salt thereof or a solvate thereof; omidenepag Such Omi Dene Pag isopropyl or a salt or solvate thereof, such as an isopropyl, aliphatic secondary amines such as having at least isopropoxycarbonyl group as a substituent.
Specific examples of one or more selected from the group consisting of aliphatic tertiary amines which may have a substituent, salts thereof, and solvates thereof include, for example, calcium disodium edetate, edetate Examples include aliphatic tertiary amines having a carboxyl group as a substituent, such as sodium hydrate and tetrasodium edetate.
In addition, specific examples of one or more selected from the group consisting of an aromatic amine which may have a substituent, a salt thereof, and a solvate thereof include, for example, ethyl aminobenzoate and the like.
Further, as one or more selected from the group consisting of compounds having a carbamoyl group which may have a substituent and salts thereof and solvates thereof, specifically, for example, ethyl urea, urea, fenproba Mate and the like.
In addition, all of these amino compounds are known, and may be produced by a known method, or a commercially available product may be used. Further, as the amino compound, a compound which forms a salt or a complex with another component may be used.

  As the amino compound, from the viewpoint of suppressing the reduction in the content of brimonidine or a salt thereof or a solvate thereof, from the group consisting of an aliphatic amine which may have a substituent, a salt thereof, and a solvate thereof. One or more selected is preferable, and one or more selected from the group consisting of an aliphatic tertiary to tertiary (preferably secondary) amine which may have a substituent, a salt thereof, and a solvate thereof The above are more preferable, and as the substituent, a carboxyl group, a hydroxyl group, a sulfonic acid group, a guanidino group, a carbamoyl group, a mercapto group, an imidazolyl group, a methylthio group and a phenyl group (preferably a carboxyl group, a hydroxyl group, a sulfonic acid group, a guanidino group and 1 to 12 (preferably 2 to 10) carbon atoms which may have (preferably 1 to 4) one or more selected from the group consisting of imidazolyl groups). Particularly preferably, at least one selected from the group consisting of 2 to 6) aliphatic tertiary to tertiary (preferably secondary) amines and salts thereof and solvates thereof is more preferable, and aspartic acid, Alanine, arginine, epsilon-aminocaproic acid, edetic acid, glycine, glutamine, glutamic acid, cystine, cysteine, histidine, phenylalanine, methionine, lysine, leucine, tromethamol, monoethanolamine, taurine, ethylenediamine, chlorhexidine, edetic acid and the like. And more preferably one or more selected from the group consisting of salts and solvates thereof, arginine, epsilon-aminocaproic acid, glutamic acid, taurine, histidine, lysine, tromethamol, monoethanolamine, ethylenediamine, One or more selected from the group consisting of hexidine, edetic acid and salts thereof and solvates thereof are even more preferable, and one selected from the group consisting of chlorhexidine, edetic acid and salts thereof and solvates thereof The above is still more preferred, and one or more selected from the group consisting of chlorhexidine and salts thereof and solvates thereof is still more preferred, and chlorhexidine, chlorhexidine hydrochloride, chlorhexidine gluconate and chlorhexidine acetic acid are preferred. One or more selected from the group consisting of salts and solvates thereof are even more preferable, and one or more selected from the group consisting of chlorhexidine hydrochloride and chlorhexidine gluconate solution listed in the 17th Revised Japanese Pharmacopoeia. Even more preferably, the black pigment listed in the 17th Japanese Pharmacopoeia Luhexidine gluconate solution is particularly preferred.

  The content of the amino compound in the aqueous composition is not particularly limited, but from the viewpoint of suppressing the reduction in the content of brimonidine or a salt thereof or a solvate thereof, the total amount of the amino compound is 0.00001 with respect to the total volume of the aqueous composition. The content is preferably from 10 to 10 w / v%, more preferably from 0.00005 to 5 w / v%, and particularly preferably from 0.0001 to 1 w / v%. In particular, when using one or more selected from the group consisting of chlorhexidine and its salts and solvates thereof as the amino compound, from the viewpoint of suppressing the reduction in the content of brimonidine or its salts or their solvates. It is preferably contained in a total of 0.0001 to 0.1 w / v%, more preferably 0.0005 to 0.05 w / v%, more preferably 0.001 to 0 w / v%, based on the total volume of the aqueous composition. It is particularly preferable to contain 0.11 w / v%.

  In addition, the content mass ratio of brimonidine or a salt thereof or a solvate thereof and the amino compound in the aqueous composition is not particularly limited, but from the viewpoint of an effect of suppressing a decrease in the content of brimonidine or a salt thereof or a solvate thereof, Brimonidine or a salt thereof or a solvate thereof is preferably contained in an amount of 0.00005 to 100 parts by mass, preferably 0.0005 to 50 parts by mass, based on 1 part by mass of the free form thereof. More preferably, the content is particularly preferably 0.005 to 5 parts by mass. Among them, when the amino compound is at least one selected from the group consisting of chlorhexidine and salts thereof and solvates thereof, from the viewpoint of suppressing the decrease in the content of brimonidine or salts thereof or solvates thereof, Brimonidine or a salt thereof or a solvate thereof is converted into a free form thereof and 1 part by mass of chlorhexidine or a salt thereof or a solvate thereof is added in a total amount of 0.1% or more. The content is preferably 0001 to 10 parts by mass, more preferably 0.001 to 1 part by mass, and particularly preferably 0.01 to 0.1 part by mass.

In the present specification, the “aqueous composition” means a composition containing at least water, and its properties include liquid (solution or suspension) and semi-solid (ointment), and liquid is preferable. . As the water in the composition, for example, purified water, water for injection, sterilized purified water and the like can be used.
The content of water contained in the aqueous composition is not particularly limited, but is preferably 5% by mass or more, more preferably 20% by mass or more, still more preferably 50% by mass or more, even more preferably 90% by mass or more, and 90 to 90% by mass. 99.9% by weight is particularly preferred.

  The aqueous composition can be made into various dosage forms according to a known method described in, for example, the 16th revised edition of the Pharmacopoeia of Japan. Dosage forms include, for example, injections, inhalation solutions, eye drops, eye ointments, ear drops, nasal drops, enemas, external preparations, sprays, ointments, gels, oral solutions, syrups, etc. Is mentioned. The dosage form is preferably an ophthalmic agent, specifically an eye drop or an ointment, and particularly preferably an eye drop, from the viewpoint of advantageously utilizing the pharmacological action of brimonidine.

The aqueous composition may contain additives used in pharmaceuticals, quasi-drugs, and the like, depending on the dosage form. Examples of such additives include inorganic salts, isotonic agents, chelating agents, stabilizers, pH regulators, preservatives, antioxidants, thickeners, surfactants, solubilizers, Examples include a turbidity agent, a cooling agent, a dispersant, a preservative, an oily base, an emulsion base, and a water-soluble base. In addition, you may further use said "amino compound" as such an additive.
As such additives, specifically, for example, ascorbic acid, sodium bisulfite, alginic acid, sodium benzoate, benzyl benzoate, fennel oil, ethanol, ethylene-vinyl acetate copolymer, potassium chloride, calcium chloride hydrate , Sodium chloride, magnesium chloride, hydrochloric acid, carboxyvinyl polymer, dried sodium sulfite, dried sodium carbonate, d-camphor, dl-camphor, xylitol, citric acid hydrate, sodium citrate hydrate, glycerin, gluconic acid, chloro Butanol, crystalline sodium dihydrogen phosphate, geraniol, chondroitin sulfate, acetic acid, potassium acetate, sodium acetate hydrate, titanium oxide, gellan gum, dibutylhydroxytoluene, potassium bromide, benzododecinium bromide, liquor Acid, sodium hydroxide, polyoxyl 45 stearate, purified lanolin, D-sorbitol, sorbitol solution, sodium bicarbonate, sodium carbonate hydrate, sodium thiosulfate hydrate, thimerosal, tyloxapol, sodium dehydroacetate, concentrated glycerin, concentrated Mixed tocopherol, white petrolatum, peppermint water, peppermint oil, concentrated benzalkonium chloride liquid 50, ethyl parahydroxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, methyl paraoxybenzoate, sodium hyaluronate, human serum albumin, hydroxy Ethyl cellulose, hydroxypropyl cellulose, hypromellose, glacial acetic acid, sodium pyrosulfite, phenylethyl alcohol, glucose, propylene glycol, bergamot oil, benzalkoni Chloride, benzalkonium chloride solution, benzyl alcohol, benzethonium chloride solution, benzethonium chloride solution, borax, boric acid, povidone, polyoxyethylene (200) polyoxypropylene glycol (70), sodium polystyrene sulfonate, Polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyvinyl alcohol (partially saponified product), d-borneol, macrogol 4000, macrogol 6000, D-mannitol, anhydrous citric acid, anhydrous sodium hydrogen phosphate, anhydrous phosphoric acid Sodium hydrogen, methanesulfonic acid, methylcellulose, 1-menthol, aluminum monostearate, polyethylene glycol monostearate, eucalyptus oil, potassium iodide, sulfuric acid, oxyquinoline sulfate, liquid paraffin, Ryunow, phosphoric acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, sodium dihydrogen phosphate dihydrate, malic acid, petrolatum, etc. Is exemplified.

  As an additive, for example, potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, hydrochloric acid, glycerin, acetic acid, potassium acetate, sodium acetate hydrate, tartaric acid, sodium hydroxide, sodium hydrogen carbonate, aqueous sodium carbonate Japanese product, concentrated glycerin, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, borax, boric acid, povidone, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol monostearate, polyvinyl alcohol (partially saponified product), macrogol 4000, macrogol 6000, anhydrous citric acid, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methylcellulose, phosphoric acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, phosphoric acid Sodium hydrogen sodium phosphate monobasic monohydrate, sodium phosphate monobasic dihydrate, sodium hyaluronate, glucose, l-menthol is preferable.

The aqueous composition may further contain, other than the above, other medicinal ingredients depending on the indications and the like. Examples of such medicinal components include bunazosin such as bunazosin hydrochloride or a salt thereof or an α1 receptor blocker containing a solvate thereof; apraclonidine or a salt thereof or an α2 receptor agonist containing a solvate thereof Drug: nipradilol or a salt thereof or a solvate thereof, betaxolol or a salt thereof such as betaxolol hydrochloride or a solvate thereof, levobunolol or a salt thereof such as levobunolol hydrochloride or a solvate thereof, befnolol or a salt thereof, or Β-blockers containing solvates thereof, metipranolol or salts thereof or solvates thereof; dorzolamide or salts thereof such as dorzolamide hydrochloride or solvates thereof, brinzolamide or salts thereof or solvates thereof , Acetazolamide or a salt thereof Carbonyl anhydrase inhibitors including solvates thereof, dichlorphenamide or salts thereof or solvates thereof, methazolamide or salts thereof or solvates thereof; isopropyl unoprostone or salts thereof or solvates thereof , Tafluprost or a salt thereof or a solvate thereof, travoprost or a salt thereof or a solvate thereof, bimatoprost or a salt thereof or a solvate thereof, latanoprost or a salt thereof or a solvate thereof, cloprostenol Or a salt thereof or a solvate thereof, prostaglandins including fluprostenol or a salt thereof or a solvate thereof; dipivefrin such as dipivefrin hydrochloride or a salt thereof or a solvate thereof, epinephrine or epinephrine boric acid Salt, epinephrine hydrochloride Sympathomimetics including epinephrine or a salt thereof or a solvate thereof; distigmine bromide or a salt thereof or a solvate thereof, pilocarpine such as pilocarpine, pilocarpine hydrochloride, pilocarpine nitrate or a salt thereof or a solvate thereof Drug, carbachol or a salt thereof or a solvate thereof; a parasympathetic agent; lomerizine such as lomerizine hydrochloride or a salt thereof or a calcium antagonist containing a solvate thereof; demepotassium or a salt thereof or a solvate thereof , Chothiosterase inhibitors containing physostigmine or a salt thereof or a solvate thereof, and the like, and one or more of these may be blended. In addition, the aqueous composition may not contain lipasil such as lipasil hydrochloride hydrate or a salt thereof, or a solvate thereof.
As the other medicinal component, at least one selected from the group consisting of latanoprost, nipradilol, dorzolamide, brinzolamide and salts thereof is preferable.

  The pH (25 ° C.) of the aqueous composition is not particularly limited, but is preferably from 4 to 8.5, more preferably from 5 to 8, and particularly preferably from 6 to 7.5. Further, the osmotic pressure ratio to the physiological saline is not particularly limited, but is preferably 0.6 to 3, and more preferably 0.6 to 2.

  The aqueous composition is preferably contained in a container from the viewpoint of storage stability, portability, and the like. The form of the container is not particularly limited as long as it can accommodate the aqueous composition, and may be appropriately selected and set according to the dosage form and the like. Specific examples of the form of such a container include, for example, a container for an injection, a container for an inhalant, a container for a spray, a bottle-shaped container, a tube-shaped container, a container for eye drops, a container for nasal drops, Ear container, bag container and the like can be mentioned. Further, these containers may be further packaged by boxes, bags, or the like.

  The material (material) of the container is not particularly limited, and may be appropriately selected according to the form of the container. Specific examples include glass, plastic, cellulose, pulp, rubber, metal, and the like. From the viewpoints of workability, squeezability, and durability, it is preferable to be made of plastic. The resin for the plastic container is preferably a thermoplastic resin, for example, polyolefin resins such as low-density polyethylene (including linear low-density polyethylene), high-density polyethylene, medium-density polyethylene, polypropylene, and cyclic polyolefin. A polyester resin such as polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, polybutylene naphthalate, poly (1,4-cyclohexylene dimethylene terephthalate); a polyphenylene ether resin; a polycarbonate resin; a polysulfone resin; Resin; polyvinyl chloride resin; styrene resin, and the like, and a mixture thereof (polymer alloy) may be used.

The disease to which the aqueous composition is applied is not particularly limited, and may be appropriately selected depending on the pharmacological action of brimonidine and the like.
Specifically, for example, it can be used as a prophylactic or therapeutic agent for ocular hypertension and glaucoma based on the adrenergic α2 receptor activating action and intraocular pressure lowering action of brimonidine. Here, as glaucoma, more specifically, for example, primary open-angle glaucoma, normal-tension glaucoma, excessive aqueous glaucoma, acute angle-closure glaucoma, chronic angle-closure glaucoma, plateau iris syndrome, mixed glaucoma Steroid glaucoma, capsular glaucoma of the lens, pigmented glaucoma, amyloid glaucoma, neovascular glaucoma, and malignant glaucoma.

  The aqueous composition is used as a prophylactic and / or therapeutic agent for ocular diseases (preferably, diseases selected from ocular hypertension, glaucoma, and fundus diseases: particularly preferably, diseases selected from ocular hypertension, and glaucoma). In the case of use, an appropriate amount (for example, about one drop in the case of eye drops) is administered about 1 to 3 times a day, preferably about 1 to 2 times a day, depending on the degree of expected drug effect. I just need.

The present specification discloses, but is not limited to, the following embodiments, for example.
[1A] The following components (A) and (B):
(A) brimonidine or a salt thereof or a solvate thereof;
(B) an amino compound;
An aqueous composition comprising:
[2A] The aqueous composition according to [1A], wherein the component (A) is brimonidine tartrate.
[3A] The description of [1A] or [2A], wherein the component (B) is at least one selected from the group consisting of an aliphatic amine which may have a substituent, a salt thereof, and a solvate thereof. Aqueous composition.
[4A] Component (B) has a carboxyl group, a hydroxyl group, a sulfonic acid group, a guanidino group, a carbamoyl group, a mercapto group, an imidazolyl group, a methylthio group and a phenyl group (preferably a carboxyl group, a hydroxyl group, a sulfonic acid group) , A guanidino group and an imidazolyl group), which may have one or more (preferably 1 to 4) carbon atoms having 1 to 12 (preferably 2 to 10, particularly preferably 2 to 4) carbon atoms. Any one of [1A] to [3A], which is at least one member selected from the group consisting of aliphatic primary to tertiary (preferably secondary) amines and their salts and solvates thereof. Aqueous composition according to any one of the preceding claims.
[5A] Component (B) is aspartic acid, alanine, arginine, epsilon-aminocaproic acid, edetic acid, glycine, glutamine, glutamic acid, cystine, cysteine, histidine, phenylalanine, methionine, lysine, leucine, trometamol, monoethanolamine, The aqueous composition according to any one of [1A] to [4A], which is at least one selected from the group consisting of taurine, ethylenediamine, chlorhexidine, edetic acid, and salts and solvates thereof.
[6A] The component (B) is at least one selected from the group consisting of chlorhexidine, chlorhexidine hydrochloride, chlorhexidine gluconate, chlorhexidine acetate and solvates thereof, [1A] to The aqueous composition according to any one of [5A].
[7A] The aqueous composition according to any one of [1A] to [6A], which is an ophthalmic agent.
[8A] The aqueous composition according to [7A], which is an eye drop.
[9A] The aqueous composition according to any one of [1A] to [8A], which is an agent for preventing and / or treating a disease selected from the group consisting of ocular hypertension and glaucoma.
[10A] The aqueous composition according to any one of [1A] to [9A], which does not contain ripasudil, a salt thereof, or a solvate thereof.
[11A] A pharmaceutical product comprising the aqueous composition according to any one of [1A] to [10A] contained in a container.

[1B] The following component (A):
(A) brimonidine or a salt thereof or a solvate thereof;
The following component (B) is added to the aqueous composition containing
(B) an amino compound;
A method for stabilizing brimonidine or a salt thereof or a solvate thereof in an aqueous composition (preferably, a method for suppressing a decrease in content).
[2B] The method of [1B], wherein the component (A) is brimonidine tartrate.
[3B] The component [B] or [2B], wherein the component (B) is at least one selected from the group consisting of an aliphatic amine which may have a substituent, a salt thereof, and a solvate thereof. the method of.
[4B] Component (B) has a carboxyl group, a hydroxyl group, a sulfonic acid group, a guanidino group, a carbamoyl group, a mercapto group, an imidazolyl group, a methylthio group and a phenyl group (preferably a carboxyl group, a hydroxyl group, a sulfonic acid group) , A guanidino group and an imidazolyl group), which may have one or more (preferably 1 to 4) carbon atoms having 1 to 12 (preferably 2 to 10, particularly preferably 2 to 4) carbon atoms. Any one of [1B] to [3B], which is one or more selected from the group consisting of aliphatic primary to tertiary (preferably secondary) amines and their salts and solvates thereof. Or the method described.
[5B] Component (B) is aspartic acid, alanine, arginine, epsilon-aminocaproic acid, edetic acid, glycine, glutamine, glutamic acid, cystine, cysteine, histidine, phenylalanine, methionine, lysine, leucine, trometamol, monoethanolamine, The method according to any one of [1B] to [4B], which is at least one selected from the group consisting of taurine, ethylenediamine, chlorhexidine, edetic acid, and salts and solvates thereof.
[6B] The component (B) is at least one selected from the group consisting of chlorhexidine, chlorhexidine hydrochloride, chlorhexidine gluconate, chlorhexidine acetate and solvates thereof, [1B] to The method according to any one of [5B].
[7B] The method according to any one of [1B] to [6B], wherein the aqueous composition is an ophthalmic agent.
[8B] The method of [7B], wherein the ophthalmic agent is an eye drop.
[9B] The method according to any one of [1B] to [8B], wherein the aqueous composition is an agent for preventing and / or treating a disease selected from the group consisting of ocular hypertension and glaucoma.
[10B] The method according to any one of [1B] to [9B], wherein the aqueous composition does not contain ripasudil, a salt thereof, or a solvate thereof.

  Next, the present invention will be further described with reference to examples, but the present invention is not limited thereto.

[Test Example 1] Storage test (evaluation of stability of brimonidine)
In order to evaluate the stability of brimonidine in the aqueous composition, the aqueous compositions of Example 1 and Comparative Example 1 containing the components and amounts shown in Table 1 per 100 mL were prepared by a conventional method.
Each of the obtained aqueous compositions was stored at 80 ° C. for one day, and the remaining ratio of brimonidine after storage was measured as follows.
That is, for each aqueous composition before the start of storage and after storage for one day, the peak height was measured using an HPLC apparatus, and the remaining ratio (%) of brimonidine was calculated according to the following formula, and an index of the decrease in content was calculated. And

Brimonidine residual rate (%) = Brimonidine peak height after storage / Brimonidine peak height before storage start x 100

  Table 1 shows the results.

  From the results shown in Table 1, in the aqueous composition containing only brimonidine (Comparative Example 1), when stored at 80 ° C. for 1 day, the residual ratio of brimonidine became about 96.5%, and the content was reduced. On the other hand, in the aqueous composition (Example 1) further containing chlorhexidine gluconate in addition to brimonidine, even after storage at 80 ° C. for 1 day, a substantial decrease in brimonidine content was not observed.

  From the results of Test Example 1 described above, the aqueous composition containing brimonidine or a salt thereof or a solvate thereof is further represented by one or more selected from the group consisting of chlorhexidine and a salt thereof and a solvate thereof. It has been clarified that by containing an amino compound, a decrease in the content of brimonidine can be suppressed.

[Production Examples 1 to 27]
An aqueous composition containing the components and amounts (amount (g) per 100 mL of the aqueous composition) described in Tables 2 to 4 can be produced by a conventional method.

  According to the present invention, an aqueous composition having excellent stability can be provided, and can be suitably used in the pharmaceutical industry and the like.

Claims (6)

The following components (A) and (B):
(A) brimonidine or a salt thereof or a solvate thereof;
(B) an amino compound;
An aqueous composition comprising:   Component (B) is selected from the group consisting of arginine, epsilon-aminocaproic acid, glutamic acid, taurine, histidine, lysine, trometamol, monoethanolamine, ethylenediamine, chlorhexidine, edetic acid, salts thereof, and solvates thereof. 2. The aqueous composition of claim 1, which is at least one species.   The aqueous composition according to claim 1 or 2, wherein the component (B) is at least one selected from the group consisting of chlorhexidine, a salt thereof, and a solvate thereof. The following components (A):
(A) brimonidine or a salt thereof or a solvate thereof;
The following component (B) is added to the aqueous composition containing
(B) an amino compound;
A method for stabilizing brimonidine or a salt thereof or a solvate thereof in an aqueous composition, the method comprising:   Component (B) is selected from the group consisting of arginine, epsilon-aminocaproic acid, glutamic acid, taurine, histidine, lysine, trometamol, monoethanolamine, ethylenediamine, chlorhexidine, edetic acid, salts thereof, and solvates thereof. 5. The method of claim 4, wherein the method is at least one species.   The method according to claim 4 or 5, wherein the component (B) is at least one selected from the group consisting of chlorhexidine and salts thereof and solvates thereof.