Aqueous pharmaceutical composition

Abstract

To provide an aqueous pharmaceutical composition containing brimonidine or a salt thereof, where the aqueous pharmaceutical composition realizes higher preservation of quality and safety by enhancing photostability and / or thermostability of the brimonidine or salt thereof.SOLUTION: The aqueous pharmaceutical composition contains brimonidine or a salt thereof, and is substantially free from iron.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an aqueous pharmaceutical composition containing brimonidine or a salt thereof, which is substantially free of iron.The present invention also relates to an aqueous pharmaceutical composition containing brimonidine or a salt thereof and chlorous acid or a salt thereof, which is substantially free of iron, and further relates to a method for light stabilization and / or heat stabilization of these aqueous pharmaceutical compositions. [Background technology]

[0002] In the production of an aqueous pharmaceutical composition, extremely small amounts of metals may be contained in the aqueous pharmaceutical composition from the raw materials and production equipment used in the production. Furthermore, these metals may have a physicochemical effect on the aqueous pharmaceutical composition. Therefore, it is extremely important to identify the type of metal and control the amount of the contained trace amounts of metal in order to produce the aqueous pharmaceutical composition and maintain the quality and safety of the aqueous pharmaceutical composition to a higher degree.

[0003] Known aqueous pharmaceutical compositions containing brimonidine or a salt thereof include Aiphagan (registered trademark) ophthalmic solution 0.1% (Non-Patent Document 1), which contains brimonidine tartrate as an active ingredient; Aibeta (registered trademark) combination ophthalmic solution, which is a combination ophthalmic solution of brimonidine tartrate and timolol maleate (Non-Patent Document 2); and Ailamid (registered trademark) combination ophthalmic suspension, which is a combination ophthalmic solution of brimonidine tartrate and brinzolamide (Non-Patent Document 3), and these compositions have been approved or marketed in Japan as therapeutic agents for glaucoma and ocular hypertension. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] AIPHAGAN (registered trademark) eye drops 0.1% package insert [Non-patent document 2] Eyebeta (registered trademark) combination eye drops package insert [Non-patent document 3] Ilamid (registered trademark) eye drop suspension package insert Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention aims to provide an aqueous pharmaceutical composition that maintains a higher level of quality and safety by improving the photostability and / or thermal stability of brimonidine or a salt thereof in an aqueous pharmaceutical composition containing brimonidine or a salt thereof, or more preferably by improving the photostability and / or thermal stability of brimonidine or a salt thereof and chlorous acid or a salt thereof in an aqueous pharmaceutical composition containing brimonidine or a salt thereof and chlorous acid or a salt thereof. [Means for solving the problem]

[0006] The present inventors have conducted extensive research into what types of metals may be contained in the preparation of aqueous pharmaceutical compositions containing brimonidine or a salt thereof, and what amount (concentration) of such metals will affect the quality of the aqueous pharmaceutical composition. As a result, they have found that the preparation of aqueous pharmaceutical compositions containing brimonidine or a salt thereof may contain extremely small amounts of iron, i.e., on the order of ppb (μg / L), and that the presence of such iron affects the photostability and thermal stability of brimonidine or a salt thereof. Furthermore, in aqueous pharmaceutical compositions containing brimonidine or a salt thereof and chlorous acid or a salt thereof, the presence of such iron affects not only the photostability and thermal stability of brimonidine or a salt thereof, but also the photostability and thermal stability of chlorous acid or a salt thereof. Therefore, the present inventors have discovered that controlling the iron content to a level that is substantially free, more specifically, controlling the iron content so that the iron content is not 154 ppb or more, can inhibit the photolysis and / or thermal decomposition of brimonidine or a salt thereof in an aqueous pharmaceutical composition, and that in an aqueous pharmaceutical composition containing brimonidine or a salt thereof and chlorous acid or a salt thereof, the photolysis and / or thermal decomposition of chlorous acid or a salt thereof can be inhibited, thereby completing the present invention. More specifically, the present invention provides the following:

[0007] (1) An aqueous pharmaceutical composition containing brimonidine or a salt thereof, which is substantially free of iron. (2) The aqueous pharmaceutical composition according to (1), further comprising chlorous acid or a salt thereof. (3) The aqueous pharmaceutical composition according to (1) or (2), which does not contain 154 ppb or more of iron. (4) The aqueous pharmaceutical composition according to any one of (1) to (3), wherein the brimonidine or a salt thereof is 0.1 to 0.2% (w / v). (5) The aqueous pharmaceutical composition according to any one of (1) to (3), wherein the brimonidine or a salt thereof is 0.1% (w / v). (6) The aqueous pharmaceutical composition according to any one of (2) to (5), wherein the concentration of chlorous acid or a salt thereof is 0.001 to 0.01% (w / v). (7) The aqueous pharmaceutical composition according to any one of (2) to (5), wherein the concentration of chlorous acid or a salt thereof is 0.005 to 0.008% (w / v). (8) The aqueous pharmaceutical composition according to any one of (1) to (7), wherein the brimonidine or a salt thereof is brimonidine tartrate. (9) The aqueous pharmaceutical composition according to any one of (2) to (8), wherein the chlorous acid or a salt thereof is sodium chlorite. (10) The aqueous pharmaceutical composition according to any one of (1) to (9), further comprising at least one selected from the group consisting of a buffering agent, an isotonicity agent, a thickening agent, a preservative, a pH adjusting agent, and a solubilizing agent. (11) The aqueous pharmaceutical composition according to any one of (1) to (9), further comprising at least one selected from the group consisting of boric acid, borax, sodium chloride, potassium chloride, magnesium chloride, calcium chloride hydrate, carmellose sodium, sodium hydroxide, dilute hydrochloric acid, and purified water. (12) An aqueous pharmaceutical composition containing only 0.1% (w / v) brimonidine tartrate, sodium chlorite, boric acid, borax, sodium chloride, potassium chloride, magnesium chloride, calcium chloride hydrate, carmellose sodium, sodium hydroxide, dilute hydrochloric acid, and purified water, which is substantially free of iron. (13) The aqueous pharmaceutical composition according to any one of (1) to (12), which is an aqueous eye drop. (14) A method for improving the photostability of brimonidine or a salt thereof in an aqueous pharmaceutical composition containing brimonidine or a salt thereof, by controlling the amount of iron in the aqueous pharmaceutical composition so that the composition is substantially free of iron. (15) A method for improving the thermal stability of brimonidine or a salt thereof in an aqueous pharmaceutical composition containing brimonidine or a salt thereof, by controlling the amount of iron in the aqueous pharmaceutical composition so that the composition contains substantially no iron. (16) A method for improving both the photostability and the thermal stability of brimonidine or a salt thereof in an aqueous pharmaceutical composition containing brimonidine or a salt thereof by controlling the amount of iron in the aqueous pharmaceutical composition so that the composition is substantially free of iron.

[0008] It should be noted that any two or more of the above configurations (1) to (16) can be selected and combined.

[0009] The present invention further relates to the following: (17) A method for improving the photostability of brimonidine or a salt thereof and / or chlorous acid or a salt thereof in an aqueous pharmaceutical composition containing brimonidine or a salt thereof and chlorous acid or a salt thereof, by controlling the amount of iron so that the aqueous pharmaceutical composition contains substantially no iron. (18) A method for improving the thermal stability of brimonidine or a salt thereof and / or chlorous acid or a salt thereof in an aqueous pharmaceutical composition containing brimonidine or a salt thereof and chlorous acid or a salt thereof, by controlling the amount of iron so that the aqueous pharmaceutical composition contains substantially no iron. (19) A method for improving both the photostability and thermal stability of brimonidine or a salt thereof and / or chlorous acid or a salt thereof in an aqueous pharmaceutical composition containing brimonidine or a salt thereof and chlorous acid or a salt thereof, by controlling the amount of iron so that the aqueous pharmaceutical composition contains substantially no iron. (20) An aqueous pharmaceutical composition containing brimonidine or a salt thereof and timolol maleate, which is substantially free of iron. (21) The aqueous pharmaceutical composition according to (20), further comprising at least one selected from the group consisting of sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate hydrate, sodium edetate hydrate, benzalkonium chloride, an isotonic agent, and a pH adjuster. (22) An aqueous pharmaceutical composition containing brimonidine tartrate and brinzolamide, which is substantially free of iron. (23) The aqueous pharmaceutical composition according to (22), further comprising at least one selected from the group consisting of tyloxapol, concentrated glycerin, boric acid, carboxyvinyl polymer, sodium edetate hydrate, benzalkonium chloride, an isotonic agent, and a pH adjuster. (24) The aqueous pharmaceutical composition according to (1), further comprising at least one selected from the group consisting of boric acid, borax, sodium chloride, potassium chloride, magnesium chloride, calcium chloride hydrate, polyvinylpyrrolidone, and a pH adjuster.

[0010] It should be noted that any two or more of the above configurations (1) to (24) can be selected and combined. [Effects of the Invention]

[0011] According to the present invention, photolysis and / or thermal decomposition of brimonidine or a salt thereof in an aqueous pharmaceutical composition containing brimonidine or a salt thereof is inhibited, and preferably, in an aqueous pharmaceutical composition containing brimonidine or a salt thereof and chlorous acid or a salt thereof, photolysis and / or thermal decomposition of chlorous acid or a salt thereof in the aqueous pharmaceutical composition is inhibited, thereby making it possible to provide an aqueous pharmaceutical composition that maintains quality and safety to a higher degree. [Brief explanation of the drawings]

[0012] [Figure 1] FIG. 1 is a graph showing the results of a photostability test of brimonidine tartrate. [Figure 2] FIG. 2 is a graph showing the results of a photostability test of sodium chlorite. [Figure 3] FIG. 3 is a graph showing the results of a thermal stability test of brimonidine tartrate. [Figure 4] FIG. 4 is a graph showing the results of a thermal stability test of sodium chlorite. DETAILED DESCRIPTION OF THE INVENTION

[0013] The present invention will be described in detail below.

[0014] In the present invention, "brimonidine" refers to a compound represented by the chemical name 5-Bromo-N-(4,5-dihydro-1H-imidazol-2-yl)quinoxaline-6-amine, and the following chemical structural formula: [ka] It is a compound represented by the formula:

[0015] Brimonidine contained in the aqueous pharmaceutical composition of the present invention may be in the form of a salt, and the salt is not particularly limited as long as it is a pharmaceutically acceptable salt, such as a salt with an inorganic acid or a salt with an organic acid.

[0016] Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.

[0017] Examples of salts with organic acids include salts with acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptoic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, and sulfosalicylic acid.

[0018] The tartrate salt of brimonidine is more preferred.

[0019] Brimonidine or a salt thereof contained in the aqueous pharmaceutical composition of the present invention may be in the form of a hydrate or solvate.

[0020] In the aqueous pharmaceutical composition of the present invention, the content of brimonidine or a salt thereof is not particularly limited as long as it is a pharmaceutically acceptable concentration. For example, the content is preferably 0.05 to 0.35% (w / v), more preferably 0.05 to 0.15% (w / v), 0.1 to 0.15% (w / v), 0.15 to 0.25% (w / v), 0.2 to 0.3% (w / v), or 0.25 to 0.35% (w / v), and even more preferably 0.1% (w / v), 0.15% (w / v), 0.2% (w / v), 0.25% (w / v), or 0.3% (w / v).

[0021] In the present invention, when the brimonidine contained is a salt, these values ​​refer to the content of the brimonidine salt. In the present invention, when brimonidine or a salt thereof is formulated in the form of a hydrate or solvate, these values ​​refer to the content of the hydrate or solvate of brimonidine or a salt thereof. "% (w / v)" refers to the mass (g) of the target ingredient (here, brimonidine or a salt thereof) contained in 100 mL of the aqueous pharmaceutical composition of the present invention. The same applies hereinafter unless otherwise specified.

[0022] In the aqueous pharmaceutical composition of the present invention, "substantially free of iron" means that the aqueous pharmaceutical composition contains no iron at all, or contains iron in an amount sufficient to ensure the stability of brimonidine or a salt thereof, chlorous acid or a salt thereof, and the preservative effectiveness of the aqueous pharmaceutical composition as a pharmaceutical. Specifically, the aqueous pharmaceutical composition preferably contains no more than 154 ppb (μg / L) of iron (may contain less than 154 ppb of iron), more preferably no more than 116 ppb of iron (may contain no more than 116 ppb of iron), even more preferably no more than 67 ppb of iron (may contain no more than 67 ppb of iron), even more preferably no more than 23 ppb of iron (may contain no more than 23 ppb of iron), and particularly preferably no iron at all. The range of iron content is greater than 0 ppb to less than 154 ppb, preferably greater than 0 ppb to 116 ppb, more preferably greater than 0 ppb to 67 ppb, and particularly preferably greater than 0 ppb to 23 ppb. By controlling the iron content in this way, it is possible to ensure the stability of brimonidine or a salt thereof and chlorous acid or a salt thereof in the aqueous pharmaceutical composition of the present invention and / or the preservative effectiveness of the aqueous pharmaceutical composition, even if the composition contains iron. Note that, in the present invention, ppb means "μg / L."

[0023] Furthermore, the form or type of iron is not particularly limited, as long as it is iron that can be contained in the aqueous pharmaceutical composition during the pharmaceutical manufacturing process.

[0024] For example, the iron may be pure iron, oxidized or ionized iron, ultrafine iron in solid form, or iron dissolved in an aqueous pharmaceutical composition. Furthermore, the iron may be encapsulated or complexed with an additive or the like.

[0025] In the aqueous pharmaceutical composition of the present invention, the form or type of chlorous acid contained therein is not particularly limited as long as it is acceptable as an additive for pharmaceuticals, but the type is preferably a preservative.

[0026] When chlorous acid is in the form of a salt, there are no particular limitations as long as the salt is acceptable as an additive for pharmaceuticals.

[0027] Examples of salts of chlorite include sodium chlorite and magnesium chlorite, with sodium chlorite being preferred.

[0028] Furthermore, chlorous acid may be in the ionic or molecular form, or may be in the form of chlorous acid water.

[0029] When chlorous acid or a salt thereof is added to the aqueous pharmaceutical composition of the present invention, the content of chlorous acid or a salt thereof can be adjusted appropriately depending on the type of chlorous acid or a salt thereof, etc. For example, the content is preferably 0.000001 to 10% (w / v), more preferably 0.00001 to 5% (w / v), even more preferably 0.0001 to 0.1% (w / v), still more preferably 0.001 to 0.01% (w / v), and particularly preferably 0.005 to 0.008% (w / v).

[0030] When chlorous acid or a salt thereof is blended in the aqueous pharmaceutical composition of the present invention, one or more types of chlorous acid or a salt thereof may be blended together as needed, and it is preferable that the total content thereof falls within the above-mentioned range of the content of chlorous acid or a salt thereof.

[0031] Pharmaceutical additives can be used in the aqueous pharmaceutical composition of the present invention as needed, and any additive usable as a pharmaceutical additive can be used without particular limitation. For example, additives that satisfy the requirements for use in ophthalmic compositions can be preferably used, and additives that satisfy the requirements for use in eye drops can be more preferably used.

[0032] Specifically, buffering agents, isotonicity agents, thickening agents (thickeners), preservatives (antiseptics), stabilizers, surfactants, antioxidants, pH adjusters, etc. These additives can be blended in appropriate amounts, and may be used alone or in combination of two or more types as needed.

[0033] When a buffer is added to the aqueous pharmaceutical composition of the present invention, any buffer usable as an additive for pharmaceuticals can be added as needed without particular limitation. Examples of the buffer include boric acid or a salt thereof, borax, phosphoric acid or a salt thereof, carbonic acid or a salt thereof, and organic acids or salts thereof, and may be hydrates or solvates thereof.

[0034] Examples of boric acid or salts thereof include boric acid, sodium borate, potassium borate, and the like, and hydrates thereof may also be used.

[0035] Examples of phosphoric acid or a salt thereof include phosphoric acid, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate, and hydrates thereof may also be used.

[0036] Examples of carbonic acid or salts thereof include sodium carbonate and sodium hydrogen carbonate, and hydrates thereof may also be used.

[0037] Examples of organic acids or salts thereof include citric acid, acetic acid, ε-aminocaproic acid, gluconic acid, fumaric acid, lactic acid, ascorbic acid, succinic acid, maleic acid, malic acid, amino acids, and sodium salts and potassium salts thereof, and hydrates thereof may also be used.

[0038] When a buffering agent is incorporated into the aqueous pharmaceutical composition of the present invention, the content of the buffering agent can be adjusted as appropriate depending on the type of buffering agent, etc. For example, the content is preferably 0.001 to 10% (w / v), more preferably 0.005 to 5% (w / v), even more preferably 0.05 to 3% (w / v), even more preferably 0.1 to 2% (w / v), and particularly preferably 0.1 to 1% (w / v).

[0039] When a buffering agent is incorporated into the aqueous pharmaceutical composition of the present invention, one or more buffering agents may be incorporated together as needed, and the total content thereof preferably falls within the range of the buffering agent content described above.

[0040] When an isotonicity agent is added to the aqueous pharmaceutical composition of the present invention, any isotonicity agent that can be used as an additive for pharmaceuticals can be added as needed without particular limitation. Examples of such agents include ionic isotonicity agents and nonionic isotonicity agents, and these may also be hydrates or solvates.

[0041] Examples of ionic tonicity agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and the like, and hydrates thereof may also be used.

[0042] Examples of non-ionic tonicity agents include glycerin (including concentrated glycerin), propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose, and xylitol, with glycerin (including concentrated glycerin) being preferred.

[0043] When an isotonic agent is incorporated into the aqueous pharmaceutical composition of the present invention, the content of the isotonic agent can be adjusted as appropriate depending on the type of isotonic agent, etc. For example, the content is preferably 0.001 to 10% (w / v), more preferably 0.005 to 5% (w / v), even more preferably 0.1 to 2% (w / v), and even more preferably 0.1 to 1% (w / v).

[0044] When an isotonic agent is incorporated into the aqueous pharmaceutical composition of the present invention, one or more isotonic agents may be incorporated together as needed, and it is preferable that the total content thereof falls within the range of the content of the isotonic agent described above.

[0045] When a thickening agent (thickener) is added to the aqueous pharmaceutical composition of the present invention, any thickening agent that can be used as an additive for pharmaceuticals can be added as needed without any particular limitation. Examples of the thickening agent include polysaccharides, cellulose polymers, synthetic polymers, etc., and hydrates or solvates thereof may also be used.

[0046] Examples of polysaccharides include alginic acid, chondroitin sulfate, hyaluronic acid, xanthan gum, and salts thereof.

[0047] Examples of cellulose polymers include nonionic cellulose and anionic cellulose.

[0048] Examples of nonionic cellulose include methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, and hydroxypropyl methyl cellulose, with hydroxyethyl cellulose or hydroxypropyl methyl cellulose being preferred.

[0049] Examples of anionic cellulose include carboxymethyl cellulose (carmellose), hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, carboxymethyl ethyl cellulose, and cellulose acetate phthalate, with carboxymethyl cellulose (carmellose) being preferred, and sodium salts thereof may also be used.

[0050] Examples of synthetic polymers include carboxyvinyl polymers, polyacrylic acid, polyethylene glycol, polyvinylpyrrolidone, and polyvinyl alcohol, with carboxyvinyl polymers, polyvinylpyrrolidone, and polyethylene glycol being preferred.

[0051] Polyvinylpyrrolidone is further classified according to its viscosity characteristic value (K value), and any polyvinylpyrrolidone can be blended as needed without any particular restrictions. Examples include polyvinylpyrrolidone K-10, polyvinylpyrrolidone K-15, polyvinylpyrrolidone K-30, polyvinylpyrrolidone K-60, polyvinylpyrrolidone K-85, polyvinylpyrrolidone K-90, and polyvinylpyrrolidone K-120, with polyvinylpyrrolidone K-90 being preferred. Furthermore, one or more polyvinylpyrrolidones with different K values ​​may be blended together as needed.

[0052] When a thickening agent is incorporated into the aqueous pharmaceutical composition of the present invention, the content of the thickening agent can be adjusted appropriately depending on the type of thickening agent, etc. For example, the content is preferably 0.001 to 10% (w / v), more preferably 0.01 to 5% (w / v), even more preferably 0.05 to 2% (w / v), still more preferably 0.01 to 2% (w / v), and particularly preferably 0.1 to 1% (w / v).

[0053] When a thickening agent is added to the aqueous pharmaceutical composition of the present invention, one or more types of thickening agents may be added together as needed, and it is preferable that the total content thereof falls within the range of the above-mentioned thickening agent content.

[0054] When a preservative (antiseptic) is added to the aqueous pharmaceutical composition of the present invention, the preservative can be added as needed without any particular limitation, as long as it is usable as an additive for pharmaceuticals.

[0055] Examples include benzalkonium chloride (benzalkonium chloride), benzalkonium bromide, benzethonium chloride, chlorhexidine or a salt thereof, sorbic acid or a salt thereof, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, sodium chlorite, etc., with benzalkonium chloride or sodium chlorite being preferred, and sodium chlorite being more preferred.

[0056] When a preservative is incorporated into the aqueous pharmaceutical composition of the present invention, the content of the preservative can be adjusted appropriately depending on the type of preservative, and is not particularly limited as long as it does not adversely affect the safety of the aqueous pharmaceutical composition. For example, the content is preferably 0.00001 to 1% (w / v), more preferably 0.0001 to 0.5% (w / v), even more preferably 0.0005 to 0.1% (w / v), and even more preferably 0.001 to 0.01% (w / v).

[0057] When a preservative is added to the aqueous pharmaceutical composition of the present invention, one or more preservatives may be added together as needed, and it is preferable that the total content thereof falls within the range of the preservative content.

[0058] When a stabilizer is added to the aqueous pharmaceutical composition of the present invention, any stabilizer that can be used as an additive for pharmaceuticals can be added as needed without particular limitation, such as edetic acid or a salt thereof.

[0059] Examples of edetic acid or salts thereof include edetic acid, disodium edetate, tetrasodium edetate, etc., with disodium edetate being preferred, and hydrates thereof may also be used.

[0060] When a stabilizer is incorporated into the liquid pharmaceutical composition of the present invention, the content of the stabilizer can be adjusted as appropriate depending on the type of stabilizer, etc. For example, the content is preferably 0.001 to 5% (w / v), more preferably 0.01 to 3% (w / v), and even more preferably 0.1 to 2% (w / v).

[0061] When a stabilizer is incorporated into the aqueous pharmaceutical composition of the present invention, one or more stabilizers may be incorporated together as needed, and the total content thereof preferably falls within the range of the stabilizer content.

[0062] When a surfactant is added to the aqueous pharmaceutical composition of the present invention, any surfactant that can be used as an additive for pharmaceuticals can be added as needed without any particular limitation, such as cationic surfactants, anionic surfactants, and nonionic surfactants.

[0063] Examples of cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkylimidazolines, 1-acylaminoethyl-2-alkylimidazolines, and 1-hydroxylethyl-2-alkylimidazolines.

[0064] Examples of anionic surfactants include phospholipids such as lecithin.

[0065] Examples of nonionic surfactants include polyoxyethylene fatty acid esters such as polyoxyl 40 stearate; polyoxyethylene sorbitan fatty acid esters such as polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, and polysorbate 65; polyoxyethylene hydrogenated castor oils such as polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60; polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, and polyoxyethylene hydrogenated castor oil. Examples of suitable oleic acid esters include polyoxyl castor oils such as Sil 35 castor oil and Polyoxyl 40 castor oil; polyoxyethylene polyoxypropylene glycols such as polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, and polyoxyethylene (20) polyoxypropylene (20) glycol; sucrose fatty acid esters such as sucrose stearate; tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS), and tyloxapol, with tyloxapol being preferred.

[0066] When a surfactant is added to the aqueous pharmaceutical composition of the present invention, the content of the surfactant can be adjusted appropriately depending on the type of surfactant, etc. For example, the content is preferably 0.001 to 1% (w / v), more preferably 0.005 to 0.5% (w / v), even more preferably 0.01 to 0.2% (w / v), still more preferably 0.02 to 0.05% (w / v), and particularly preferably 0.02 to 0.03% (w / v).

[0067] When a surfactant is added to the aqueous pharmaceutical composition of the present invention, one or more surfactants may be added together as needed, and it is preferable that the total content thereof falls within the range of the surfactant content described above.

[0068] When an antioxidant is added to the aqueous pharmaceutical composition of the present invention, any antioxidant that can be used as an additive in pharmaceuticals can be added as needed without particular limitation, such as ascorbic acid, tocopherol, dibutylhydroxytoluene, sodium sulfite, etc.

[0069] When an antioxidant is incorporated into the aqueous pharmaceutical composition of the present invention, the content of the antioxidant can be adjusted as appropriate depending on the type of antioxidant, etc. For example, the content is preferably 0.001 to 5% (w / v), more preferably 0.01 to 3% (w / v), and even more preferably 0.1 to 2% (w / v).

[0070] When an antioxidant is incorporated into the aqueous pharmaceutical composition of the present invention, one or more antioxidants may be incorporated together as needed, and the total content thereof preferably falls within the range of the antioxidant content described above.

[0071] When a pH adjuster is added to the aqueous pharmaceutical composition of the present invention, any pH adjuster can be added as needed without particular limitation, as long as it is usable as an additive for pharmaceuticals, such as an acid or a base.

[0072] Examples of the acid include hydrochloric acid (including diluted hydrochloric acid), phosphoric acid, citric acid, acetic acid, etc., with hydrochloric acid (including diluted hydrochloric acid) being preferred.

[0073] Examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, etc., with sodium hydroxide being preferred.

[0074] The pH of the aqueous pharmaceutical composition of the present invention is not particularly limited, as long as it is within the range acceptable for pharmaceuticals, preferably the range acceptable for ophthalmic compositions, and more preferably the range acceptable for eye drops. For example, it is preferably 8 or less, more preferably 4 to 8, more preferably 6.0 to 7.5, even more preferably 6.3 to 7.5, even more preferably 6.3 to 6.8, 6.6 to 7.4, 6.7 to 7.5, 6.9 to 7.5, or 6.9 to 7.3, and among these, 6.6 to 7.4 or 6.9 to 7.5 is even more preferably, and 6.9 to 7.5 is particularly preferably.

[0075] When a pH adjuster is added to the aqueous pharmaceutical composition of the present invention, one or more pH adjusters may be added together, and it is preferable to add the pH adjusters so that the pH falls within the above-mentioned range.

[0076] The solubilizer for the aqueous pharmaceutical composition of the present invention may be, for example, purified water, but ethanol or the like may also be added to the composition to aid in the dissolution of various additives.

[0077] The osmotic pressure ratio of the aqueous pharmaceutical composition of the present invention may be within a pharmaceutically acceptable range, for example, 0.5 to 2.0, preferably 0.7 to 1.6, more preferably 0.8 to 1.4, even more preferably 0.8 to 1.2 or 0.9 to 1.2, and particularly preferably 0.9 to 1.1.

[0078] The form of the aqueous pharmaceutical composition of the present invention is not particularly limited as long as it is an aqueous pharmaceutical composition, and may be a dissolved formulation or a suspended formulation.

[0079] The aqueous pharmaceutical composition of the present invention is preferably an aqueous ophthalmic composition, and more preferably an aqueous eye drop (ophthalmic composition).

[0080] The aqueous pharmaceutical composition of the present invention is particularly useful as a therapeutic agent for glaucoma and ocular hypertension, since it contains brimonidine or a salt thereof, which is an α2 agonist, as an active ingredient.

[0081] The aqueous pharmaceutical composition of the present invention may also contain an active ingredient used in aqueous pharmaceutical compositions other than brimonidine or a salt thereof, preferably an active ingredient used in the treatment of glaucoma or ocular hypertension, and may be formulated with, for example, one or more of β-blockers, carbonic anhydrase inhibitors, α2 agonists, EP2 receptor agonists, prostaglandin-related drugs, ROCK inhibitors, etc. together with brimonidine or a salt thereof (preferably the tartrate salt).The aqueous pharmaceutical composition of the present invention may also contain brimonidine or a salt thereof as the only active ingredient.

[0082] Examples of the β-blocker include timolol, carteolol, betaxol, nipradilol, and salts thereof, with timolol and salts thereof being preferred, and timolol maleate being more preferred.

[0083] Furthermore, when the aqueous pharmaceutical composition of the present invention contains timolol maleate as a β-blocker in addition to brimonidine or a salt thereof, the aqueous pharmaceutical composition preferably contains sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate hydrate, sodium edetate hydrate, benzalkonium chloride, an isotonic agent, and a pH adjuster as additives, and has a pH of 6.9 to 7.3 and an osmotic pressure ratio of 0.9 to 1.1.

[0084] Examples of carbonic anhydrase inhibitors include brinzolamide, acetazolamide, dorzolamide, and salts thereof, with brinzolamide being preferred.

[0085] Furthermore, when the aqueous pharmaceutical composition of the present invention contains brinzolamide as a carbonic anhydrase inhibitor in addition to brimonidine or a salt thereof, the aqueous pharmaceutical composition preferably contains, as additives, tyloxapol, concentrated glycerin, boric acid, carboxyvinyl polymer, sodium edetate hydrate, benzalkonium chloride, an isotonic agent, and a pH adjuster, and has a pH of 6.3 to 6.8 and an osmotic pressure ratio of 0.9 to 1.2.

[0086] Examples of prostaglandin-related drugs include latanoprost, bimatoprost, travoprost, unoprostone, and the like.

[0087] Examples of ROCK inhibitors include ripasudil or a salt thereof (preferably the hydrochloride salt).

[0088] When the aqueous pharmaceutical composition of the present invention is administered to the eye, there are no particular limitations on the dosage and administration as long as it is sufficient to achieve the desired medicinal effect. For example, one to two drops, preferably one drop, can be instilled into the eye one to four times a day, preferably two or three times a day, more preferably twice a day.

[0089] The aqueous pharmaceutical composition of the present invention can be used when wearing hard or soft contact lenses, such as contact lenses containing hydroxyethyl methacrylate as a main component or silicone hydrogel contact lenses.

[0090] The type of soft contact lens to which the present invention is applicable is not particularly limited, and may be ionic or nonionic, or hydrous or non-hydrous. For example, the present invention can be applied to all commercially available soft contact lenses, including soft contact lenses that are used repeatedly, daily disposable soft contact lenses, weekly disposable soft contact lenses, and biweekly disposable soft contact lenses.

[0091] The aqueous pharmaceutical composition of the present invention may be contained (filled), for example, in any of a multi-dose container, a single-use unit-dose container (unit-volume container), or a PFMD (Preservative-Free Multi-Dose) container.

[0092] The material of the container for containing the aqueous pharmaceutical composition of the present invention is not particularly limited, and examples thereof include polyethylene, polypropylene, polyethylene terephthalate, polybutylene terephthalate, polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic resin, polystyrene, and polycyclic olefin copolymer.

[0093] The polyethylene may be low density polyethylene (LDPE), medium density polyethylene (MDPE), high density polyethylene (HDPE), or the like.

[0094] Furthermore, there are no particular limitations on the color of the container that the aqueous pharmaceutical composition of the present invention is stored in. Examples include transparent, translucent, and colored containers, but when a colored container is used, it is preferable that the colored container allows visual confirmation of the precipitation of insoluble matter or decomposition products in the aqueous pharmaceutical composition of the present invention.

[0095] One aspect of the present invention is an aqueous pharmaceutical composition containing brimonidine or a salt thereof and chlorous acid or a salt thereof, wherein the aqueous pharmaceutical composition is substantially free of iron.

[0096] One aspect of the present invention is a method for improving the photostability of brimonidine or a salt thereof in an aqueous pharmaceutical composition containing brimonidine or a salt thereof by controlling the amount of iron in the aqueous pharmaceutical composition so that the composition is substantially free of iron.

[0097] One aspect of the present invention is a method for improving the thermal stability of brimonidine or a salt thereof in an aqueous pharmaceutical composition containing brimonidine or a salt thereof by controlling the amount of iron in the aqueous pharmaceutical composition so that the composition is substantially free of iron.

[0098] One aspect of the present invention is a method for improving both the photostability and the thermal stability of brimonidine or a salt thereof in an aqueous pharmaceutical composition containing brimonidine or a salt thereof by controlling the amount of iron in the aqueous pharmaceutical composition so that the composition is substantially free of iron.

[0099] One aspect of the present invention is a method for improving the photostability of brimonidine or a salt thereof and / or chlorous acid or a salt thereof in an aqueous pharmaceutical composition containing brimonidine or a salt thereof and chlorous acid or a salt thereof, by controlling the amount of iron in the aqueous pharmaceutical composition so that the composition is substantially free of iron.

[0100] One aspect of the present invention is a method for improving the thermal stability of brimonidine or a salt thereof and / or chlorous acid or a salt thereof in an aqueous pharmaceutical composition containing brimonidine or a salt thereof and chlorous acid or a salt thereof, by controlling the amount of iron in the aqueous pharmaceutical composition so that the composition is substantially free of iron.

[0101] One aspect of the present invention is a method for improving both the photostability and the thermal stability of brimonidine or a salt thereof and / or chlorous acid or a salt thereof in an aqueous pharmaceutical composition containing brimonidine or a salt thereof and chlorous acid or a salt thereof, by controlling the amount of iron in the aqueous pharmaceutical composition so that the composition is substantially free of iron.

[0102] Since it is necessary to control the iron content of the aqueous pharmaceutical composition of the present invention, it is necessary to check the iron content of each product or production lot of the active ingredients and additives used in the present invention, and then select the product or production lot. It is also necessary to check the possibility of iron inclusion in the aqueous pharmaceutical composition from each piece of production equipment used in the present invention (there are no particular limitations as long as the production equipment is able to come into contact with the aqueous pharmaceutical composition from the preparation of the aqueous pharmaceutical composition to the filling of the aqueous pharmaceutical composition into containers, etc.); however, other than that, the composition can be produced according to a conventional method in the technical field.

[0103] The iron content in the aqueous pharmaceutical composition of the present invention can be controlled by checking and managing the iron content of the active ingredients and additives used in the present invention for each product and production lot, and selecting an appropriate product and production lot; and / or by checking the possibility of iron inclusion in the aqueous pharmaceutical composition from each piece of production equipment used in the present invention (there are no particular limitations as long as the production equipment is in contact with the aqueous pharmaceutical composition from the time of preparation to the time of filling the aqueous pharmaceutical composition into containers, etc.), and selecting an appropriate production equipment. [Example]

[0104] Formulation examples and the results of stability tests and preservative effectiveness tests are shown below, but these are intended to provide a better understanding of the present invention and are not intended to limit the scope of the present invention in any way.

[0105] [Formulation example] Representative formulation examples of the present invention are shown below. In the following formulation examples 1 to 12, the blending amount of each ingredient is the content in 1000 mL of the formulation, and the content can be changed as appropriate. In the following, "%" means "% (w / v)".

[0106] [Table 1]

[0107] [Stability test and preservative effectiveness test] 1. Preparation of test formulations 1) Preparation of Brimonidine-Containing Aqueous Compositions Brimonidine tartrate (1 g), carboxymethylcellulose sodium (5 g), boric acid (2.29 g), borax (0.95 g), sodium chloride (5.8 g), potassium chloride (1.4 g), magnesium chloride hexahydrate (0.06 g), calcium chloride dihydrate (0.2 g), and 1.34% sodium chlorite aqueous solution (5 mL) were dissolved in purified water, and an appropriate amount of pH adjuster (hydrochloric acid and / or sodium hydroxide) was added to adjust the pH to 7.2. An appropriate amount of purified water was then added to make the total volume 1000 mL, thereby preparing a brimonidine-containing aqueous composition.

[0108] 2) Preparation of 0.005% iron trichloride solution A 0.5% iron trichloride solution was prepared by adding an appropriate amount of purified water to 40% iron trichloride solution (1.25 g) to make a total volume of 100 mL. A 0.05% iron trichloride solution was then prepared by adding an appropriate amount of purified water to 0.5% iron trichloride solution (5 mL) to make a total volume of 50 mL. A 0.005% iron trichloride solution was then prepared by adding an appropriate amount of purified water to 0.05% iron trichloride solution (5 mL) to make a total volume of 50 mL.

[0109] 3) Preparation of test formulations 1 to 5 (Test Formulation 1) The brimonidine-containing aqueous composition prepared in 1.1) above was designated as Test Preparation 1.

[0110] (Test Formulation 2) Test formulation 2 was prepared by adding the 0.005% iron trichloride solution (0.6 mL) prepared in 1.2) to the brimonidine-containing aqueous composition (200 mL) prepared in 1.1) above, and adding an appropriate amount of pH adjuster (hydrochloric acid and / or sodium hydroxide) to adjust the pH to 7.2.

[0111] (Test Formulation 3) Test formulation 3 was prepared by adding the 0.005% iron trichloride solution (1.2 mL) prepared in 1.2) to the brimonidine-containing aqueous composition (200 mL) prepared in 1.1) above, and adjusting the pH to 7.2 by adding an appropriate amount of pH adjuster (hydrochloric acid and / or sodium hydroxide).

[0112] (Test Formulation 4) Test formulation 4 was prepared by adding the 0.005% iron trichloride solution (1.8 mL) prepared in 1.2) to the brimonidine-containing aqueous composition (200 mL) prepared in 1.1) above, and adding an appropriate amount of pH adjuster (hydrochloric acid and / or sodium hydroxide) to adjust the pH to 7.2.

[0113] (Test Formulation 5) Test formulation 5 was prepared by adding 0.005% iron trichloride solution (2.4 mL) prepared in 1.2) to the brimonidine-containing aqueous composition (200 mL) prepared in 1.1) above, and adding an appropriate amount of pH adjuster (hydrochloric acid and / or sodium hydroxide) to adjust the pH to 7.2.

[0114] 4) Creation of test products Test preparations 1 to 5 (5 mL) prepared in 1.3) above were filled into 5 mL green eye dropper bottles, which were then sealed with inner stoppers and caps to give test products 1 to 5.

[0115] 5) Quantitation of iron concentration in the test preparation The total iron content in test preparations 1 to 5 was quantified using an inductively coupled plasma mass spectrometer (ICP-MS, Agilent 7900). The results are shown in Table 2.

[0116] [Table 2]

[0117] 2.Photostability test 1) Test method Test Products 1 to 5 prepared in 1.4) above were stored for 8 days at room temperature under a light source of 3000 lx. In addition, the amounts of brimonidine tartrate and sodium chlorite in Test Products 1 to 5 (Test Formulations 1 to 5) were measured before and on the 8th day of storage according to the quantification methods shown in 2) and 3) below.

[0118] 2) Quantitative method for brimonidine tartrate Brimonidine tartrate in test formulations 1 to 5 was quantified at a wavelength of 264 nm by high performance liquid chromatography (Waters HPLC Alliance (registered trademark) system) using a column (Atlantis, 4.6 mm I.D. x 250 mm, 5 μm (Waters)).

[0119] 3) Quantitative method for sodium chlorite The total content of sodium chlorite in test formulations 1 to 5 was quantified at a wavelength of 210 nm using high-performance liquid chromatography (Waters HPLC Alliance (registered trademark) system) with a column (TSKgel SuperIC-AZ, 4.6 mm I.D. x 15 cm, 4 μm (Tosoh)).

[0120] 4) Calculation method for survival rate The residual rates of brimonidine tartrate and sodium chlorite were calculated using the following formulas (1) and (2).

[0121] Brimonidine tartrate residual rate (%) = (amount of brimonidine tartrate after storage / amount of brimonidine tartrate before storage) × 100 (1)

[0122] Sodium chlorite residual rate (%) = (amount of sodium chlorite after storage / amount of sodium chlorite before storage) × 100 (2)

[0123] 5) Test results The test results are shown in Figures 1 and 2. Figures 1 and 2 clearly show that the iron content in each test formulation affects the photostability of brimonidine tartrate and sodium chlorite. It was also shown that the lower the iron content in the test formulation, the higher the photostability of brimonidine tartrate and sodium chlorite.

[0124] 3. Thermal stability test 1) Test method Test Products 1 to 5 prepared in 1.4) above were stored in a high-temperature, constant-humidity chamber at 60°C for 14 days under light-shielded conditions. Before storage and on the 14th day of storage, the amounts of brimonidine tartrate and sodium chlorite in Test Products 1 to 5 (Test Formulations 1 to 5) were measured using the same method as in the photostability test, and the remaining percentages of brimonidine tartrate and sodium chlorite were calculated.

[0125] 2) Test results The test results are shown in Figures 3 and 4. Figures 3 and 4 clearly show that the iron content in each test preparation affects the thermal stability of brimonidine tartrate and sodium chlorite. It was also shown that the lower the iron content in the test preparation, the higher the thermal stability of brimonidine tartrate and sodium chlorite.

[0126] 4. Preservative effectiveness test 1) Preparation of test formulations 6 to 9 (Test Formulation 6) A brimonidine-containing aqueous composition was prepared in the same manner as in 1.1) above, except that the 1.34% sodium chlorite aqueous solution (5 mL) was replaced with a 1.34% sodium chlorite aqueous solution (2.5 mL). This was designated Test Preparation 6.

[0127] (Test Formulation 7) A brimonidine-containing aqueous composition was prepared in the same manner as in 1.1) above, except that the 1.34% sodium chlorite aqueous solution (5 mL) was changed to 1.34% sodium chlorite aqueous solution (2.5 mL) and the pH was adjusted to 7.5. This was designated test formulation 7.

[0128] (Test Formulation 8) A brimonidine-containing aqueous composition was prepared in the same manner as in 1.1) above, except that the 1.34% sodium chlorite aqueous solution (5 mL) was changed to 1.34% sodium chlorite aqueous solution (2.5 mL) and the pH was adjusted to 6.7. This was designated test formulation 8.

[0129] (Test Formulation 9) A brimonidine-containing aqueous composition was prepared in the same manner as in 1.1) above, except that the 1.34% aqueous sodium chlorite solution (5 mL) was not added. This was designated Test Preparation 9.

[0130] 2) Test method This test was carried out in accordance with the preservative effectiveness test method described in the 17th edition of the Japanese Pharmacopoeia. More details are as follows.

[0131] As an inoculum, Bacteria: Escherichia coli ATCC 8739 (also known as E. coli) Pseudomonas aeruginosa ATCC 9027 (also known as P. aeruginosa) Staphylococcus aureus ATCC 6538 (also known as S. aureus) Yeasts and molds: Candida, Candida albicans ATCC 10231 (also known as C. albicans) The black mold, Aspergillus brasiliensis ATCC16404 (also known as A. brasiliensis), was used.

[0132] For test preparations 6 to 9 prepared in 4.1), the bacterial solution concentration was 10 5 ~10 6 The inoculum was inoculated to a concentration of viable bacteria / mL (for all five bacterial species). Test preparations 6 to 9 after inoculation were stored at 20 to 25°C in the dark, and 1 mL of each test preparation was taken with a micropipette at each sampling point (after 7, 14, or 28 days) to measure the viable bacterial count.

[0133] 3) Test results The test results are shown in Table 3. The test results in Table 3 are expressed as a common logarithm of the ratio (B / A) of the number of bacteria at the time of inoculation (B) to the number of bacteria at the time of measurement (A). For example, a value of "1" indicates that the number of viable bacteria at the time of measurement had decreased to 10% of the number of bacteria inoculated. The pass / fail criteria for the test were in accordance with the 17th edition of the Japanese Pharmacopoeia.

[0134] [Table 3]

[0135] As shown in Table 3, test preparations 6 to 8, which contain 50% of the labeled amount of sodium chlorite (the same as the sodium chlorite content of test preparation 1: 67 ppm (mg / L)), were confirmed to comply with the standards of the 17th edition of the Japanese Pharmacopoeia at all pH levels. On the other hand, test preparation 9, which does not contain sodium chlorite, was confirmed to not comply with the standards of the 17th edition of the Japanese Pharmacopoeia. In other words, it was confirmed that the preservative effectiveness decreases as the sodium chlorite content decreases.

[0136] 5. Discussion of the results of stability tests and preservative effectiveness tests In order to ensure a higher level of stability of brimonidine or its salt in an aqueous pharmaceutical composition containing brimonidine or its salt, a residual rate of brimonidine tartrate of 93% or more is expected in this test. Therefore, as shown in Figure 1, which shows the results of the photostability test, an iron content of 154 ppb does not meet this requirement.

[0137] Next, in order for an aqueous pharmaceutical composition containing brimonidine or a salt thereof and chlorous acid or a salt thereof to be used as a pharmaceutical, it must comply with the preservative effectiveness standards of the Japanese Pharmacopoeia, 17th Edition. Table 3 showing the preservative effectiveness test results shows that an aqueous pharmaceutical composition containing brimonidine or a salt thereof and chlorous acid or a salt thereof containing 50% of the labeled amount of sodium chlorite (the same as the sodium chlorite content of Test Formulation 1: 67 ppm (mg / L)) is not affected by pH and complies with the standards of the Japanese Pharmacopoeia, 17th Edition. In other words, if the residual rate of sodium chlorite is 50% or more, it complies with the standards of the Japanese Pharmacopoeia, 17th Edition.

[0138] Therefore, in Figure 2 of the photostability test results, when the iron content is 208 ppb, the residual rate of sodium chlorite is 50% or less, which may not meet the requirements for use as a pharmaceutical product.

[0139] From the above, in order to use an aqueous pharmaceutical composition containing brimonidine or a salt thereof as a drug, it is desirable that the composition does not contain iron at least 154 ppb or more, and in this case, the stability of chlorous acid or a salt thereof can also be ensured. [Industrial Applicability]

[0140] According to the present invention, photolysis and / or thermal decomposition of brimonidine or a salt thereof in an aqueous pharmaceutical composition containing brimonidine or a salt thereof is inhibited, and preferably, in an aqueous pharmaceutical composition containing brimonidine or a salt thereof and chlorous acid or a salt thereof, photolysis and / or thermal decomposition of chlorous acid or a salt thereof in the aqueous pharmaceutical composition is inhibited, thereby making it possible to provide an aqueous pharmaceutical composition that maintains quality and safety to a higher degree.

Claims

1. An aqueous pharmaceutical composition comprising brimonidine or a salt thereof at a concentration of 0.1% (w / v), chlorous acid or a salt thereof at a concentration of 0.005 to 0.008% (w / v), and carmellose sodium at a concentration of 0.1 to 1% (w / v), wherein the aqueous pharmaceutical composition contains more than 23 ppb and less than 154 ppb of iron.

2. 2. The aqueous pharmaceutical composition of claim 1, wherein the brimonidine or a salt thereof is brimonidine tartrate.

3. 2. The aqueous pharmaceutical composition according to claim 1, wherein the chlorous acid or a salt thereof is sodium chlorite.

4. The aqueous pharmaceutical composition according to any one of claims 1 to 3, further comprising at least one selected from the group consisting of a buffering agent, an isotonicity agent, a preservative, a pH adjusting agent, and a solubilizing agent.

5. The aqueous pharmaceutical composition according to any one of claims 1 to 3, further comprising at least one selected from the group consisting of boric acid, borax, sodium chloride, potassium chloride, magnesium chloride, calcium chloride hydrate, sodium hydroxide, dilute hydrochloric acid, and purified water.

6. An aqueous pharmaceutical composition containing only brimonidine tartrate at a concentration of 0.1% (w / v), sodium chlorite, boric acid, borax, sodium chloride, potassium chloride, magnesium chloride, and calcium chloride hydrate at concentrations of 0.005 to 0.008% (w / v), carmellose sodium at a concentration of 0.1 to 1% (w / v), sodium hydroxide, dilute hydrochloric acid, and purified water, wherein the aqueous pharmaceutical composition contains more than 23 ppb and less than 154 ppb of iron.

7. The aqueous pharmaceutical composition according to any one of claims 1 to 6, which is an aqueous eye drop.

8. A method for improving the photostability of brimonidine or a salt thereof and chlorous acid or a salt thereof in an aqueous pharmaceutical composition comprising brimonidine or a salt thereof at a concentration of 0.1% (w / v), chlorous acid or a salt thereof at a concentration of 0.005 to 0.008% (w / v), and carmellose sodium at a concentration of 0.1 to 1% (w / v), by controlling the amount of iron so that the iron content is more than 23 ppb and less than 154 ppb.

9. A method for improving the thermal stability of brimonidine or a salt thereof and chlorous acid or a salt thereof in an aqueous pharmaceutical composition comprising brimonidine or a salt thereof at a concentration of 0.1% (w / v), chlorous acid or a salt thereof at a concentration of 0.005 to 0.008% (w / v), and carmellose sodium at a concentration of 0.1 to 1% (w / v), by controlling the amount of iron so that the iron content is more than 23 ppb and less than 154 ppb.

10. A method for improving both the light stability and the heat stability of brimonidine or a salt thereof and chlorous acid or a salt thereof in an aqueous pharmaceutical composition comprising brimonidine or a salt thereof at a concentration of 0.1% (w / v), chlorous acid or a salt thereof at a concentration of 0.005 to 0.008% (w / v), and carmellose sodium at a concentration of 0.1 to 1% (w / v), by controlling the amount of iron so that the iron content is more than 23 ppb and less than 154 ppb.

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