Compositions

Abstract

To provide novel means capable of reducing an amount of decomposition products of active ingredients in a composition containing one or more selected from brimonidine and salts thereof and one or more selected from timolol and salts thereof.SOLUTION: Provided is a composition comprising one or more selected from brimonidine and salts thereof, one or more selected from timolol and salts thereof, and one or more selected from citric acid, salts of citric acid, and solvates of citric acid and salts of citric acid.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a composition comprising one or more selected from brimonidine and salts thereof, and one or more selected from timolol and salts thereof. [Background technology]

[0002] Brimonidine and timolol are known as therapeutic agents for glaucoma and ocular hypertension, respectively, and a combination eye drop solution containing both of them as active ingredients has been approved (Non-Patent Document 1). Patent Document 1 shows that instillation of a combination drug containing brimonidine and timolol exhibits a superior intraocular pressure-lowering effect in patients with glaucoma or ocular hypertension compared to instillation of brimonidine alone or timolol alone, and also has an equivalent or superior safety profile, including adverse events.

[0003] On the other hand, a problem is known in that preparations containing brimonidine and timolol generate decomposition products over time or during storage at high temperatures, etc. To address this problem, for example, Patent Document 2 describes an ophthalmic composition containing brimonidine and / or a salt thereof, timolol and / or a salt thereof, phosphoric acid and / or a salt thereof, and edetic acid and / or a salt thereof, in which the concentration of phosphoric acid and / or a salt thereof is 32 mM or less, and shows that this composition can suppress the generation of decomposition products during storage. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Special Publication No. 2005-523316 [Patent Document 2] Patent No. 7378959 [Non-patent literature]

[0005] [Non-Patent Document 1] Eyebeta (registered trademark) combination eye drops pharmaceutical interview form Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention aims to find a new means for reducing the amount of decomposition products of the active ingredients in a composition containing one or more selected from brimonidine and salts thereof and one or more selected from timolol and salts thereof. [Means for solving the problem]

[0007] The present inventors have conducted extensive research to solve the above problems and have found that in a composition containing one or more selected from brimonidine and salts thereof, one or more selected from timolol and salts thereof, and a specified ingredient, the amount of decomposition products of the active ingredients is reduced, leading to the completion of the present invention.

[0008] That is, the present invention relates to the following. [1] One or more selected from brimonidine and its salts, one or more selected from timolol and salts thereof; one or more selected from citric acid, salts of citric acid, and solvates of citric acid and salts of citric acid; A composition comprising: [2] The composition according to [1], further comprising one or more selected from edetic acid, salts of edetic acid, and solvates of edetic acid and salts of edetic acid. [3] The composition described in [1] or [2], further comprising an isotonicity agent. [4] The composition described in [3], wherein the tonicity agent comprises sodium chloride. [5] The composition according to any one of [1] to [4], which does not contain phosphoric acid, salts of phosphoric acid, or solvates of phosphoric acid and salts of phosphoric acid. [6] The composition according to any one of [1] to [5], wherein the concentration of citric acid, a salt of citric acid, and a solvate of citric acid and a salt of citric acid relative to the total concentration of the composition is 0.001 mg / mL or more. [7] The composition according to any one of [1] to [6], which is contained in a container that satisfies one or more of (i) and (ii): (i) The maximum light transmittance of wavelengths between 280 and 330 nm is 25% or less; (ii) The maximum light transmittance of the wavelength of 380 to 460 nm is 50% or less. [8] The composition according to any one of [1] to [7], which contains water. [9] The composition according to any one of [1] to [8], which contains a quaternary ammonium salt.

[10] The composition according to any one of [1] to [9], which is for eye drops. [Effects of the Invention]

[0009] According to the present invention, the amount of decomposition products of the active ingredients is reduced in a composition containing one or more selected from brimonidine and salts thereof and one or more selected from timolol and salts thereof. [Brief explanation of the drawings]

[0010] [Figure 1] FIG. 1 shows the calculation results of cell viability in Test Example 2-1. DETAILED DESCRIPTION OF THE INVENTION

[0011] The present invention will be described below. The features of the present invention described below do not limit the invention described in the claims. Furthermore, the features of the present invention described below can be combined in any manner.

[0012] [Composition] One embodiment of the present invention relates to a composition comprising one or more selected from brimonidine and salts thereof, and one or more selected from timolol and salts thereof (hereinafter referred to as the composition of the present invention).

[0013] (Brimonidine) Brimonidine (5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)quinoxalin-6-amine) is a compound known to have adrenergic α2 receptor agonism. The salt of brimonidine may be any salt within a pharmaceutically acceptable range, such as tartrate, hydrochloride, sulfate, nitrate, hydrofluoride, hydrobromide, phosphate, acetate, etc. Brimonidine or a salt thereof may also be in the form of a solvate. The solvate may contain any solvent molecules, such as a hydrate containing water molecules. The number of solvent molecules in the solvate is not particularly limited. Either brimonidine or a salt thereof may be used alone, or they may be used in combination.

[0014] The concentration of brimonidine and its salts relative to the total composition of the present invention may be, for example, 0.01 mg / mL or more, 0.05 mg / mL or more, 0.1 mg / mL or more, 0.3 mg / mL or more, 0.5 mg / mL or more, 0.8 mg / mL or more, or 1 mg / mL or more, or, for example, 10 mg / mL or less, 8 mg / mL or less, 7 mg / mL or less, 6 mg / mL or less, 5 mg / mL or less, 4 mg / mL or less, 3 mg / mL or less, or 2 mg / mL or less. The above-mentioned concentration values may be arbitrarily combined to represent a concentration range. In addition, in the present invention, "the concentration of brimonidine and its salts" refers to the concentration of brimonidine and its salts contained in the composition when the composition contains only brimonidine or its salts.

[0015] (Timolol) Timolol ((2S)-1-(tert-butylamino)-3-(4-morpholino-1,2,5-thiadiazol-3-yloxy)-2-propanol) is a compound known to have β-receptor blocking activity. The salt of timolol may be any salt within the pharmaceutically acceptable range, such as maleate, fumarate, citrate, succinate, mesylate, besylate, tosylate, tartrate, hydrochloride, sulfate, nitrate, hydrofluoride, hydrobromide, hydroiodide, phosphate, acetate, etc. Timolol or a salt thereof may also be in the form of a solvate. The solvate may contain any solvent molecules, such as a hydrate containing water molecules. The number of solvent molecules in the solvate is not particularly limited. Timolol or a salt thereof may be used alone or in combination.

[0016] The concentration of timolol and its salts in the entire composition of the present invention may be, for example, 0.05 mg / mL or more, 0.1 mg / mL or more, 0.5 mg / mL or more, 1 mg / mL or more, 3 mg / mL or more, 5 mg / mL or more, or 6.8 mg / mL or more, or may be, for example, 20 mg / mL or less, 15 mg / mL or less, 14 mg / mL or less, 13 mg / mL or less, 12 mg / mL or less, 11 mg / mL or less, or 10 mg / mL or less. The above-mentioned concentrations may be arbitrarily combined to represent a concentration range. In the present invention, "the concentration of timolol and its salts" refers to the concentration of timolol and its salts contained in the composition when the composition contains only one of timolol and its salts.

[0017] (citric acid) The composition of the present invention contains one or more selected from citric acid, citric acid salts, and solvates of citric acid and citric acid salts. The citric acid salt may be any salt, for example, an alkali metal salt such as a sodium salt or a potassium salt, or an alkaline earth metal salt such as a calcium salt or a magnesium salt. The solvate of citric acid or a salt thereof may contain any solvent molecule, for example, a hydrate containing water molecules. The number of solvent molecules in the solvate is not particularly limited, and the solvate may be, for example, a dihydrate containing two water molecules. In the present invention, the term "solvate" also includes an anhydrate (anhydrous product) obtained by removing water molecules from a hydrate. In one embodiment, the solvate of citric acid or a citric acid salt is sodium citrate hydrate.

[0018] The concentration of citric acid, citric acid salts, and solvates of citric acid and citric acid salts relative to the total composition of the present invention may be, for example, 0.001 mg / mL or more, 0.01 mg / mL or more, 0.05 mg / mL or more, 0.1 mg / mL or more, 0.5 mg / mL or more, 1 mg / mL or more, 3 mg / mL or more, 5 mg / mL, 10 mg / mL or more, or 30 mg / mL or more, or, for example, 500 mg / mL or less, 400 mg / mL or less, 300 mg / mL or less, 200 mg / mL or less, 100 mg / mL or less, 80 mg / mL or less, or 50 mg / mL or less. Any combination of the above concentrations may be used to express a concentration range. In the present invention, the "concentration of citric acid, salts of citric acid, and solvates of citric acid and salts of citric acid" refers to the concentration of citric acid, salts of citric acid, and solvates of citric acid and salts of citric acid contained in the composition when the composition does not contain all of citric acid, salts of citric acid, and solvates of citric acid and salts of citric acid.

[0019] In the composition of the present invention, the ratio of the concentration of citric acid, citric acid salts, and solvates of citric acid and citric acid salts to the concentration of brimonidine and salts thereof (concentration of citric acid, citric acid salts, and solvates of citric acid and citric acid salts (mg / mL) / concentration of brimonidine and salts thereof (mg / mL)) may be, for example, 0.001 or more, 0.01 or more, 0.1 or more, 0.25 or more, 0.5 or more, 1 or more, 3 or more, 5 or more, 10 or more, or 30 or more, while it may be, for example, 50,000 or less, 10,000 or less, 5,000 or less, 500 or less, 200 or less, 100 or less, 80 or less, or 50 or less. The above-mentioned lower and upper limits may be arbitrarily combined to represent a numerical range.

[0020] The ratio of the concentration of citric acid, citric acid salts, and solvates of citric acid and citric acid salts to the concentration of timolol and its salts in the composition of the present invention (concentration of citric acid, citric acid salts, and solvates of citric acid and citric acid salts (mg / mL) / concentration of timolol and its salts (mg / mL)) may be, for example, 0.0005 or more, 0.001 or more, 0.005 or more, 0.01 or more, 0.015 or more, 0.074 or more, 0.15 or more, 0.44 or more, 0.5 or more, 0.74 or more, 1 or more, 1.5 or more, 4.4 or more, 5 or more, 7.4 or more, 10 or more, or 14.5 or more, while it may be, for example, 10,000 or less, 5,000 or less, 1,000 or less, 200 or less, 30 or less, or 15 or less. The above-mentioned lower limits or upper limits may be arbitrarily combined to form a numerical range.

[0021] (edetic acid) The composition of the present invention may further contain one or more selected from edetic acid, salts of edetic acid, and solvates of edetic acid and salts of edetic acid. The salt of edetic acid may be any salt, for example, an alkali metal salt such as a sodium salt or a potassium salt, or an alkaline earth metal salt such as a calcium salt or a magnesium salt. The solvate of edetic acid or a salt thereof may contain any solvent molecule, for example, a hydrate containing water molecules. The number of solvent molecules in the solvate is not particularly limited, and the solvate may be, for example, a dihydrate containing two water molecules. In the present invention, the term "solvate" also includes an anhydrate (anhydrate) obtained by removing water molecules from a hydrate. In one embodiment, the solvate of edetic acid or a salt of edetic acid is sodium edetate hydrate.

[0022] The concentration of edetic acid, edetic acid salts, and solvates of edetic acid and edetic acid salts relative to the total composition of the present invention may be 0.001 mg / mL or more, 0.003 mg / mL or more, 0.005 mg / mL or more, 0.01 mg / mL or more, 0.03 mg / mL or more, 0.05 mg / mL or more, 0.1 mg / mL or more, 0.3 mg / mL or more, 0.5 mg / mL or more, or 1 mL or more, or may be, for example, 20 mg / mL or less, 15 mg / mL or less, 10 mg / mL or less, 5 mg / mL or less, 3 mg / mL or less, or 1.27 mg / mL or less. Any combination of the above concentrations may be used to express a concentration range. In the present invention, the term "concentration of edetic acid, salts of edetic acid, and solvates of edetic acid and salts of edetic acid" refers to the concentration of edetic acid, salts of edetic acid, and solvates of edetic acid and salts of edetic acid contained in the composition when the composition does not contain all of edetic acid, salts of edetic acid, and solvates of edetic acid and salts of edetic acid.

[0023] In the composition of the present invention, the ratio of the concentration of edetic acid, edetic acid salts, and solvates of edetic acid and edetic acid salts to the concentration of brimonidine and salts thereof (concentration of edetic acid, edetic acid salts, and solvates of edetic acid and edetic acid salts (mg / mL) / concentration of brimonidine and salts (mg / mL)) may be, for example, 0.001 or more, 0.003 or more, 0.005 or more, 0.01 or more, 0.03 or more, 0.05 or more, 0.1 or more, 0.3 or more, 0.5 or more, or 1 or more, or, for example, 2000 or less, 300 or less, 100 or less, 20 or less, 10 or less, 5 or less, or 2 or less. The above-mentioned lower and upper limits may be arbitrarily combined to represent a numerical range.

[0024] In the composition of the present invention, the ratio of the concentration of edetic acid, salts of edetic acid, and solvates of edetic acid and salts of edetic acid to the concentration of timolol and salts thereof (concentration of edetic acid, salts of edetic acid, and solvates of edetic acid and salts of edetic acid (mg / mL) / concentration of timolol and salts thereof (mg / mL)) is, for example, 0.00005 or more, 0.0001 or more, 0.00015 or more, 0.0 The range may be, for example, 400 or less, 150 or less, 20 or less, 5 or less, 2.95 or less, 2.2 or less, 2 or less, 1.5 or less, 1 or less, 0.4 or less, 0.2 or less, or 0.1 or less. The above-mentioned lower limits or upper limits may be combined in any manner to represent a numerical range.

[0025] (Tonicity agent) The composition of the present invention may further comprise an isotonicity agent. The isotonicity agent may be one commonly used in the pharmaceutical (preferably ophthalmic) field, and may be, for example, one or more selected from sodium chloride, potassium chloride, calcium chloride, magnesium chloride, glycerin, concentrated glycerin, propylene glycol, polyethylene glycol, glucose, sorbitol, mannitol, trehalose, maltose, sucrose, and butylene glycol. In one embodiment, the isotonicity agent is one or more agents including sodium chloride.

[0026] The concentration of the isotonic agent in the entire composition of the present invention may be, for example, 0.1 mg / mL or more, 0.5 mg / mL or more, 1 mg / mL or more, 2 mg / mL or more, 3 mg / mL or more, 5 mg / mL or more, 6 mg / mL or more, 6.2 mg / mL or more, or 10 mg / mL or more, or may be, for example, 50 mg / mL or less, 45 mg / mL or less, 40 mg / mL or less, 35 mg / mL or less, 30 mg / mL or less, 25 mg / mL or less, or 20 mg / mL or less. Any combination of the above concentrations may be used to express a concentration range.

[0027] In the composition of the present invention, the ratio of the concentration of the isotonic agent to the concentration of brimonidine and salts thereof (concentration of isotonic agent (mg / mL) / concentration of brimonidine and salts thereof (mg / mL)) may be, for example, 0.01 or more, 0.05 or more, 0.1 or more, 0.3 or more, 0.5 or more, 1 or more, 2 or more, 3 or more, 5 or more, 6 or more, 6.2 or more, or 10 or more, or may be, for example, 2000 or less, 300 or less, 150 or less, 50 or less, 45 or less, 40 or less, 35 or less, 30 or less, 25 or less, or 20 or less. The above-mentioned lower and upper limits may be arbitrarily combined to represent a numerical range.

[0028] The ratio of the concentration of the isotonic agent to the concentration of timolol and its salts (concentration of isotonic agent (mg / mL) / concentration of timolol and its salts (mg / mL)) in the composition of the present invention may be, for example, 0.005 or more, 0.02 or more, 0.05 or more, 0.07 or more, 0.1 or more, 0.15 or more, 0.3 or more, 0.4 or more, 0.7 or more, 0.9 or more, 1 or more, or 1.5 or more, while it may be, for example, 4000 or less, 150 or less, 30 or less, 15 or less, 10 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. The above-mentioned lower and upper limits may be arbitrarily combined to represent a numerical range.

[0029] (water) The composition of the present invention contains water. The water is not particularly limited and may be purified water, sterile purified water, water for injection, etc. The water content in the composition may be, for example, 70% (w / v) or more, 80% (w / v) or more, 90% (w / v) or more, or 95% (w / v) or more.

[0030] (Other ingredients) The composition of the present invention may further contain other ingredients (other ingredients) in addition to those described above. Examples of other ingredients include buffers, stabilizers, pH adjusters, thickeners, surfactants, preservatives, etc. The composition of the present invention may also further contain one or more active ingredients other than brimonidine and timolol.

[0031] The buffering agent may be any buffering agent used in the pharmaceutical (preferably ophthalmic) field, and may be, for example, one or more selected from acetic acid, epsilon-aminocaproic acid, boric acid, tartaric acid, salts thereof, and solvates thereof.

[0032] The stabilizer may be any stabilizer used in the pharmaceutical (preferably ophthalmic) field, and may be, for example, one or more selected from ascorbic acid, tocopherol, dibutylhydroxytoluene, povidone, sulfite, monoethanolamine, cyclodextrin, dextran, and taurine.

[0033] The pH adjuster may be any pH adjuster used in the pharmaceutical (preferably ophthalmic) field, and may be, for example, one or more selected from hydrochloric acid, hydrochloride, hydrochloride hydrate, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate.

[0034] The thickening agent may be any agent used in the pharmaceutical (preferably ophthalmic) field, and may be, for example, one or more selected from carboxyvinyl polymer, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, xanthan gum, sodium chondroitin sulfate, sodium hyaluronate, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and sodium carboxymethyl cellulose.

[0035] The surfactant may be any surfactant used in the pharmaceutical (preferably ophthalmic) field, and may be, for example, one or more selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene glycol monostearate, polysorbate, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, and tyloxapol.

[0036] The preservative may be any preservative used in the pharmaceutical (preferably ophthalmic) field, and may be, for example, one or more selected from quaternary ammonium salts, benzoic acid or its salts, parahydroxybenzoic acid esters, biguanide compounds, chlorobutanol, sorbic acid or its salts, dehydroacetic acid or its salts, benzyl alcohol, parachlormetaxylenol, chlorocresol, phenethyl alcohol, thimerosal, polydronium chloride, zinc chloride, and chlorite.

[0037] The active ingredient other than brimonidine and timolol may be, for example, any ingredient having an intraocular pressure-reducing effect, including, but not limited to, compounds having α1 receptor blocking activity such as bunazosin hydrochloride, compounds having α2 receptor agonism such as apraclonidine, compounds having β receptor blocking activity such as carteolol, compounds having carbonic anhydrase inhibitory activity such as dorzolamide hydrochloride and brinzolamide, prostaglandin-related compounds such as latanoprost, travoprost, tafluprost, bimatoprost and cepetaprost, compounds having Rho kinase inhibitory activity such as ripasudil hydrochloride, and compounds having EP2 receptor agonist activity such as omidenepagisopropyl.

[0038] In some embodiments, the compositions of the present invention do not contain phosphoric acid, salts of phosphoric acid, or solvates of phosphoric acid and salts of phosphoric acid. In some embodiments, the solvates of phosphoric acid or salts of phosphoric acid are one or more selected from sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate hydrate, disodium hydrogen phosphate dodecahydrate, and sodium dihydrogen phosphate dihydrate.

[0039] (pH) The pH of the composition of the present invention is not particularly limited as long as the effects of the present invention are not impaired, and may be, for example, 4 or more, 5 or more, 6 or more, or 7 or more, or may be 10 or less, 9 or less, or 8 or less. The above-mentioned pH values may be appropriately combined to express a pH range.

[0040] (osmotic pressure, osmotic pressure ratio) The osmotic pressure of the composition of the present invention is not particularly limited as long as the effects of the present invention are not impaired, and may be, for example, 100 mOsm or more, 150 mOsm or more, 200 mOsm or more, or 240 mOsm or more, or, for example, 500 mOsm or less, 450 mOsm or less, 400 mOsm or less, or 350 mOsm or less. The osmotic pressure ratio of the composition of the present invention is also not particularly limited as long as the effects of the present invention are not impaired, and may be, for example, 0.35 or more, 0.5 or more, 0.7 or more, or 0.8 or more, or, for example, 1.75 or less, 1.6 or less, 1.4 or less, or 1.2 or less.

[0041] Osmolality can be measured, for example, according to the osmolality measurement method specified in the Japanese Pharmacopoeia, 18th Edition. The osmolality ratio can be calculated, for example, as specified in the Japanese Pharmacopoeia, 18th Edition, as the ratio of osmolality to the osmolality of 286 mOsm (0.900 g / 100 mL) physiological saline.

[0042] (Preparation method) The composition of the present invention can be prepared by any method.For example, the composition of the present invention can be prepared by dissolving each component in water and adjusting pH.The preparation may include a filtration sterilization step.The filtration sterilization step may, for example, include passing the composition through a filter.

[0043] (properties, form) In some embodiments, the composition of the present invention is an aqueous composition. In the present invention, an aqueous composition refers to a composition in which the water content is 70% (w / v) or more, 80% (w / v) or more, 90% (w / v) or more, or 95% (w / v) or more. The aqueous composition may be in any form, such as an aqueous solution, an aqueous suspension, or an emulsion.

[0044] In one embodiment, the composition of the present invention is an ophthalmic composition. An ophthalmic composition refers to a composition that can be used for treatment (including therapy, examination, etc.) in the ophthalmic field. In another embodiment, the composition of the present invention is an eye drop composition.

[0045] [container] The composition of the present invention may be contained in an appropriate container. A container refers to anything that can hold the composition. The container may be any of a "sealed container," an "airtight container," and a "sealed container" as defined in the general rules of the Japanese Pharmacopoeia (18th revision).

[0046] (Material) The material of the container may be any material that can be appropriately selected as long as the effects of the present invention are not impaired. The material of the container may include, for example, glass, plastic, cellulose, pulp, rubber, metal, etc., and in one embodiment, may be glass or plastic.

[0047] The resin used for the plastic container is a thermoplastic resin. Thermoplastic resins include, for example, polyolefin-based resins, polyester-based resins, polyphenylene ether-based resins, polycarbonate-based resins, polysulfone-based resins, polyamide-based resins, polyvinyl chloride resins, and styrene-based resins. A plastic container containing a thermoplastic resin also includes a container having, for example, a thermoplastic resin layer such as a polyolefin layer provided as an inner layer that comes into contact with the composition, and a resin of another material laminated on the outer surface.

[0048] The polyolefin resin may be, for example, a resin containing polyethylene (including low-density polyethylene (including linear low-density polyethylene), high-density polyethylene, and medium-density polyethylene), polypropylene, cyclic polyolefin, or the like, and in one embodiment, is a resin containing at least one selected from polyethylene and polypropylene. Furthermore, the polyolefin resin may be a polymer (homopolymer) of a single type of monomer, or a copolymer (copolymer) of multiple types of monomers. Furthermore, when it is a copolymer, the polymerization mode is not particularly limited, and may be random polymerization or block polymerization, and further, the stereoregularity (tacticity) is not particularly limited.

[0049] The polyester-based resin may be, for example, a resin containing polyethylene terephthalate, and in one embodiment, a resin containing polybutylene terephthalate, polyethylene naphthalate, polybutylene naphthalate, poly(1,4-cyclohexylene dimethylene terenaphthalate), or the like.

[0050] The resin used for the plastic container may be a mixture (polymer alloy) of two or more of the above resins.

[0051] (light transmittance) In one embodiment, the container has a predetermined maximum light transmittance at a predetermined wavelength. The maximum light transmittance refers to the maximum rate at which light (incident light) passes through the container. (i) The container may have a maximum light transmittance of 25% or less at wavelengths of 280 to 330 nm, preferably 20% or less, more preferably 15% or less, even more preferably 10% or less, and particularly preferably 5% or less. Alternatively, (ii) the container may have a maximum light transmittance of 50% or less at wavelengths of 380 to 460 nm, preferably 40% or less, more preferably 20% or less, even more preferably 15% or less, and particularly preferably 10% or less. In a preferred embodiment, the container satisfies both (i) and (ii). By containing the composition in a container having such a light transmittance, the amount of decomposition products of the active ingredient in the composition can be reduced, or a decrease in the content can be suppressed.

[0052] In the present invention, the maximum transmittance of light having a wavelength of 280 to 330 nm is a value obtained by measuring the transmittance of light having a wavelength of 280 to 330 nm at wavelength intervals of 0.5 nm using a UV-visible spectrophotometer and calculating the maximum value of the measured transmittance values. The same applies to the maximum transmittance of light having a wavelength of 380 to 460 nm.

[0053] (Other ingredients) The container may contain a substance that prevents transmission of ultraviolet light, such as an ultraviolet absorber or an ultraviolet scattering agent.

[0054] The ultraviolet absorber may be, for example, 2-(2H-benzotriazol-2-yl)-p-cresol (e.g., Tinuvin P, manufactured by BASF), or 2-(2H-benzotriazol-2-yl)-4,6-bis(1-methyl-1-phenylethyl)phenol (e.g., Tinuvin 234, manufactured by BASF).

[0055] The ultraviolet scattering agent may be, for example, titanium oxide or zinc oxide.

[0056] (Form, etc.) The shape of the container may be any shape that can accommodate the composition, and may be appropriately selected depending on the dosage form, etc. Examples of the container shape include a container for injections, a container for inhalants, a container for sprays, a bottle-shaped container, a tube-shaped container, a container for eye drops, a container for nasal drops, a container for ear drops, and a bag-shaped container. Containers that accommodate the composition may be further packaged in boxes, bags, etc. The size of the container may be appropriately selected depending on the purpose, and may be, for example, a size suitable for an individual formulation or a size suitable for industrial production, storage, etc.

[0057] The container may be a multi-dose container. A multi-dose container is a container that holds multiple doses of a composition and can be reused. For example, multi-dose containers include preservative-free multi-dose containers and regular multi-dose containers.

[0058] The multi-dose preservative-free container has a mechanism for preventing the composition that has seeped out of the multi-dose container from flowing back into the multi-dose container and a mechanism for preventing foreign matter from entering the multi-dose container, such as a one-way valve, a microfilter, and a special double-walled container.

[0059] A typical multi-dose container is a multi-dose container that does not have the above-mentioned mechanism. When a composition is contained in a typical multi-dose container, the composition needs to be passed through a filter in the filtration sterilization step during the production of the composition.

[0060] The composition of the present invention may be contained in a unit-dose container, which is a container that holds a single dose of the composition and is used up after one administration.

[0061] When the composition of the present invention is contained in a container, the container may be the container itself, or the container may be partially or entirely covered with a covering material.

[0062] The composition of the present invention may be delivered to the affected area via a filter-passing step. That is, the container may have a filter, and the composition may pass through the filter to leave the container. Here, the term "filter" refers to a porous membrane that allows the composition to pass through but does not allow bacteria or fungi to pass through. The pore size of the filter is usually 5 μm or less, preferably 0.1 to 2.5 μm, and more preferably 0.1 to 1 μm. The material of the filter is not particularly limited, and examples thereof include polyethersulfone, polyvinylidene fluoride, polycarbonate, polytetrafluoroethylene, mixed cellulose esters, and polyamides.

[0063] The container may be sterilized with a gas such as ethylene oxide gas or hydrogen peroxide. The type of gas used in the gas sterilization is not particularly limited, and examples include ethylene oxide gas, hydrogen peroxide gas, and mixed gases of these with carbon dioxide, etc. The container may also be sterilized with radiation such as gamma ray irradiation or electron beam irradiation.

[0064] [Reduction of the amount of decomposition products] According to the composition of the present invention, the amount of decomposition products of the active ingredient can be reduced. According to some embodiments of the composition of the present invention, the amount of decomposition products of brimonidine or a salt thereof is reduced. Examples of the decomposition products of brimonidine or a salt thereof include decomposition product 1, decomposition product 2, decomposition product 3, decomposition product 4, and decomposition product 5.

[0065] The decomposition products of brimonidine or a salt thereof or timolol or a salt thereof can be measured by a method known to those skilled in the art. For example, the method may involve analyzing the amount of decomposition products by high-performance liquid chromatography (HPLC) after storage for a predetermined period under predetermined conditions (such as a given temperature and humidity, open, protected from light, or airtight). A reduction in the amount of decomposition products of an active ingredient may refer to a reduction in the amount of one or more decomposition products of the active ingredient, or a reduction in the total amount of decomposition products of the active ingredient, after storage for a predetermined period, compared to a control (such as a control that does not contain citric acid, a citric acid salt, or a solvate of citric acid or a citric acid salt). The total amount of decomposition products refers to all decomposition products of a specific active ingredient.

[0066] According to the composition of the present invention, when stored in a dark place at 60°C for one week, the ratio of the total amount of degradation products in the composition of the present invention to the total amount of degradation products in a case where citric acid, citric acid salts, and solvates of citric acid and citric acid salts are not contained (total amount of degradation products in the composition of the present invention / total amount of degradation products in a case where citric acid, citric acid salts, and solvates of citric acid and citric acid salts are not contained × 100) (%) is 87% or less in some embodiments, 80% or less in some embodiments, 75% or less in some embodiments, 70% or less in some embodiments, 65% or less in some embodiments, and 60% or less in some embodiments. Furthermore, the inclusion of edetic acid reduces the amount of degradation products in the composition. In this invention, a dark place refers to a state where the composition is not exposed to direct sunlight, preferably a state where there is no human visible light (electromagnetic waves with a wavelength of 350 to 830 nm).

[0067] [Methods for reducing the formation of decomposition products] One embodiment of the present invention relates to a method for reducing the production of decomposition products in a composition containing one or more selected from brimonidine and its salts and one or more selected from timolol and its salts, comprising blending one or more selected from brimonidine and its salts, one or more selected from timolol and its salts, and one or more selected from citric acid, citric acid salts, and solvates of citric acid and citric acid salts. Regarding the reduction in the production of decomposition products, the explanation in the above section "Reducing the amount of decomposition products" can be referred to. In some embodiments, the decomposition products are decomposition products of brimonidine or its salts. Furthermore, blending can typically be referred to as mixing.

[0068] In one embodiment, the method for inhibiting the formation of decomposition products of the present invention comprises combining one or more selected from brimonidine and its salts, one or more selected from timolol and its salts, one or more selected from citric acid, salts of citric acid, and solvates of citric acid and salts of citric acid, and an isotonicity agent.In another embodiment, the method for inhibiting the formation of decomposition products of the present invention comprises combining one or more selected from brimonidine and its salts, one or more selected from timolol and its salts, one or more selected from citric acid, salts of citric acid, and solvates of citric acid and salts of citric acid, an isotonicity agent, and one or more selected from edetic acid, salts of edetic acid, and solvates of edetic acid and salts of edetic acid.

[0069] [Methods for reducing cytotoxicity] According to one aspect of the present invention, the cytotoxicity of a composition comprising one or more selected from brimonidine and its salts and one or more selected from timolol and its salts can be reduced. That is, one embodiment of the present invention relates to a method for reducing the cytotoxicity of a composition comprising one or more selected from brimonidine and its salts and one or more selected from timolol and its salts. Cytotoxicity can be evaluated, for example, by measuring the viability of cells cultured with the composition of the present invention, as shown in this example. Cell viability may be measured using any known appropriate method, such as an ATP assay, an MTT assay, a WST-1 / WST-8 assay, or a colony assay. In one aspect, the cytotoxicity is cytotoxicity to corneal epithelial cells.

[0070] The method for reducing cytotoxicity of the present invention comprises combining one or more selected from brimonidine and salts thereof, one or more selected from timolol and salts thereof, and one or more selected from citric acid, salts of citric acid, and solvates of citric acid and salts of citric acid. [Example]

[0071] The present invention will be described below with reference to examples, but the present invention is not to be construed as being limited to the specific embodiments shown in the examples.

[0072] [Test Example 1. Evaluation of Decomposition Products] Each composition was prepared by dissolving all ingredients except sodium hydroxide and hydrochloric acid in purified water to obtain the compositions shown in Tables 1 to 3, and then adding sodium hydroxide or hydrochloric acid as needed to adjust the pH to 7.1.

[0073] [Table 1]

[0074] [Table 2]

[0075] [Table 3]

[0076] Test example 1. 5 mL of each composition was placed in a polyethylene container, sealed, and stored in the dark at 60°C for 1 week. Each composition before and after storage was measured using an ultraviolet spectrophotometer (measurement wavelength: 264 nm) by HPLC to analyze the amount of decomposition products before and after storage. The amount of decomposition products increased by storage was calculated according to the following formula (I).

[0077] Formula (I) Increase in amount of decomposition product (%) due to storage = {(Peak area of degradation products in sample solution after storage) / (Peak area of brimonidine in standard solution) × 100} - {(Peak area of degradation products in sample solution before storage) / (Peak area of brimonidine in standard solution) × 100}

[0078] Tables 4 to 6 show the analysis results of the amount of decomposition products (%). Decomposition product 1, degradation product 2, degradation product 3, degradation product 4, and degradation product 5 are degradation products generated when a composition containing brimonidine or a salt thereof is stored for a certain period of time. Decomposition product 1 is a known related substance known as a deimidazoline derivative. Decomposition product 2 is a known related substance known as a hydrolyzate. Each degradation product corresponds to a peak observed at a certain retention time when each composition is measured by HPLC after storage. Brimonidine exhibits a peak at a retention time of 19.3 minutes, degradation product 1 at a retention time of 13.9 minutes, degradation product 2 at a retention time of 38.6 minutes, degradation product 3 at a retention time of 3.2 minutes, degradation product 4 at a retention time of 4.2 minutes, and degradation product 5 at a retention time of 25.5 minutes. The values for degradation products 1 to 5 in the table are calculated by applying the individual peak areas obtained by measurement to formula (I) and truncating to the fourth decimal place. The total amount of decomposition products in the table is calculated by applying the sum of the individual peak areas obtained by measurement to formula (I) and truncating to four decimal places.

[0079]

Table 4

[0080]

Table 5

[0081]

Table 6

[0082] The results of Reference Example 1, Comparative Example 1, Comparative Example 11, and Comparative Example 8 show that the amount of degradation products increases when timolol maleate is further added compared to a composition containing only brimonidine tartrate as an active ingredient.On the other hand, the results of Example 1 and Comparative Example 1 show that the amount of degradation products is suppressed by adding citric acid to a composition containing brimonidine tartrate and timolol maleate.Furthermore, the results of Examples 1-13 show that the inhibitory effect of citric acid on the formation of degradation products in a composition containing brimonidine tartrate and timolol maleate increases with the addition of more citric acid.Furthermore, the results of Examples 1-2 and 3-10 show that the inhibitory effect on the formation of degradation products is further enhanced by adding sodium chloride to a composition containing brimonidine tartrate, timolol maleate, and citric acid. The results of Comparative Examples 2 and 7, Comparative Examples 3 and 8, Comparative Examples 5 and 9, Example 1 and Examples 3-6, and Example 2 and Example 7 indicate that the enhancement of the decomposition product formation inhibitory effect by the incorporation of sodium chloride occurs when combined with phosphoric acid or citric acid, and that the enhancement is particularly high when combined with citric acid compared to when combined with phosphoric acid. Furthermore, the results of Examples 5-6 and 11-12 indicate that the incorporation of edetic acid into a composition containing brimonidine tartrate, timolol maleate, and citric acid inhibits the formation of degradation product 5 in particular, further enhancing the decomposition product formation inhibitory effect. Furthermore, the results of Examples 1-2 and Comparative Examples 2-6, and Examples 5-7 and Comparative Examples 7-9 indicate that citric acid has a stronger inhibitory effect on the formation of degradation products than phosphoric acid, boric acid, acetic acid, or tartaric acid.

[0083] [Test Example 2-1. Evaluation of cytotoxicity] Each composition was prepared by dissolving all ingredients except sodium hydroxide and hydrochloric acid in purified water to obtain the composition shown in Table 7, and then adding sodium hydroxide or hydrochloric acid as needed to adjust the pH to 7.1.

[0084] [Table 7]

[0085] Test Example 2-1. The viability of immortalized human corneal epithelial cells (HCE-T, RIKEN BioResource Research Center, cell number: RCB2280) was measured, and cytotoxicity was evaluated by calculating the cell viability. Corneal epithelial cells were seeded in a 96-well plate (1.3 × 10 4 The cells were cultured in a medium containing 1000 cells / well (1000 cells / well) and cultured for one day in a conventional manner. After one day, the medium was removed and each composition shown in Table 7 or medium was added. The corneal epithelial cells were then cultured for 25 minutes, and after the culture, viability was measured using a Cell Viability Assay Kit (Promega). The cell viability when the corneal epithelial cells were cultured with each composition was calculated using the control (100%) when the cells were cultured with medium added.

[0086] The calculation results of the cell viability when corneal epithelial cells were cultured in each composition are shown in Figure 1. The results of Comparative Example 12 and Comparative Examples 13-16 showed that when phosphoric acid, boric acid, acetic acid, or tartaric acid was added to a composition containing brimonidine tartrate and timolol maleate, the cell viability of corneal epithelial cells was equivalent to or lower than that when no acid was added, and no effect of suppressing cytotoxicity against corneal epithelial cells was observed. On the other hand, the results of Examples 14-15 and Comparative Examples 12-16 showed that when citric acid was added, the cell viability of corneal epithelial cells was improved compared to when no acid was added or when an acid other than citric acid (phosphoric acid, boric acid, acetic acid, or tartaric acid) was added, demonstrating low cytotoxicity against corneal epithelial cells.

[0087] [Test Example 2-2. Evaluation of cytotoxicity] Each composition was prepared by dissolving all ingredients except sodium hydroxide and hydrochloric acid in purified water to obtain the composition shown in Table 8, and then adding sodium hydroxide or hydrochloric acid to adjust the pH to 7.1.

[0088] [Table 8]

[0089] Test Example 2-2. For each of the compositions shown in Table 8, cytotoxicity against immortalized human corneal epithelial cells was evaluated in the same manner as in Test Example 2-1.

[0090] The test results showed that when citric acid was added to an aqueous composition containing brimonidine tartrate and timolol maleate, the cell viability of corneal epithelial cells was higher and cytotoxicity to corneal epithelial cells was lower than when different concentrations of phosphoric acid were added.

[0091] (References cited in the detailed description of the invention) Non-Patent Document 2: Doungdaw Chantasart et al., Evaluation of Skin Permeation of β-blockers for Topical Drug Delivery. Pharm Res. 2013 Mar; 30(3): 10.1007 / s11095-012-0928-9.

Claims

1. One or more selected from brimonidine and its salts, One or more selected from timolol and its salts, One or more selected from citric acid, salts of citric acid, and solvates of citric acid and salts of citric acid, A composition containing the following:

2. The composition according to claim 1, further comprising one or more selected from edetate, salts of edetate, and solvates of edetate and salts of edetate.

3. The composition according to claim 1, further comprising an isotonic agent.

4. The composition according to claim 3, wherein the isotonic agent comprises sodium chloride.

5. The composition according to claim 1, which does not contain phosphoric acid, a salt of phosphoric acid, or a solvate of phosphoric acid or a salt of phosphoric acid.

6. The composition according to claim 1, wherein the concentration of citric acid, a salt of citric acid, and a solvate of citric acid and a salt of citric acid, relative to the entire composition, is 0.001 mg / mL or more.

7. A composition according to any one of claims 1 to 6, comprising water.

8. The composition according to any one of claims 1 to 6, comprising a preservative.

9. A composition according to any one of claims 1 to 6, comprising one or more selected from quaternary ammonium salts, benzoic acid or a salt thereof, parahydroxybenzoic acid esters, biguanide compounds, chlorobutanol, sorbic acid or a salt thereof, dehydroacetic acid or a salt thereof, benzyl alcohol, parachlormetaxylenol, chlorocresol, phenethyl alcohol, thimerosal, polydronium chloride, zinc chloride, and chlorite.

10. A composition for use as eye drops, according to any one of claims 1 to 6.

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