Aqueous composition, and method for stabilizing the aqueous composition

Abstract

This invention provides a novel means for improving the thermal and light stability of an aqueous composition comprising one or more substances selected from brimonidine and its salts, and one or more substances selected from timolol and its salts. [Solution] The present invention provides an aqueous composition contained in a container comprising one or more substances selected from brimonidine and its salts, and one or more substances selected from timolol and its salts, wherein the maximum transmittance of light with wavelengths of 280 nm to 330 nm is 15% or less, and the maximum transmittance of light with wavelengths of 380 nm to 460 nm is 20% or less, and a method for stabilizing the aqueous composition.

Description

Technical Field

[0001] The present invention relates to an aqueous composition and a method for stabilizing the aqueous composition.

Background Art

[0002] Brimonidine and timolol are each known as therapeutic agents for glaucoma or ocular hypertension, and an ophthalmic drop containing both as active ingredients has been approved (Non-Patent Document 1). In Patent Document 1, it is shown that instillation of a combined drug containing brimonidine and timolol exhibits an excellent intraocular pressure-lowering effect on patients with glaucoma or ocular hypertension as compared with instillation of brimonidine alone or timolol alone, and is equivalent or superior in terms of a safety profile such as adverse events.

[0003] On the other hand, in a preparation containing brimonidine and timolol, there is a known problem that decomposition products are generated by storage under high temperature, exposure to light, etc. In response to this problem, for example, Patent Document 2 describes an ophthalmic composition containing brimonidine and / or its salt, timolol and / or its salt, phosphoric acid and / or its salt, and edetic acid and / or its salt, and having a concentration of phosphoric acid and / or its salt of 32 mM or less, and it is shown that formation of decomposition products by storage can be suppressed by using this composition.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Non-Patent Documents

[0005]

Non-Patent Document 1

Summary of the Invention

[0006] The present invention aims to provide a novel means for improving the stability against heat and light in an aqueous composition comprising one or more substances selected from brimonidine and its salts, and one or more substances selected from timolol and its salts. [Means for solving the problem]

[0007] The following inventions are provided. [1] An aqueous composition comprising one or more selected from brimonidine and its salts, and one or more selected from timolol and its salts, An aqueous composition contained in a container having a maximum transmittance of 15% or less for light with wavelengths of 280 nm to 330 nm, and a maximum transmittance of 20% or less for light with wavelengths of 380 nm to 460 nm. [2] The aqueous composition according to [1], further comprising one or more selected from citric acid, salts thereof, and solvates thereof. [3] The aqueous composition according to [2], comprising 5 parts by weight or more of one or more selected from citric acid, its salts, and solvates thereof, per 1 part by weight of brimonidine and its salt. [4] The aqueous composition according to any one of [1] to [3], further comprising one or more selected from edetic acid, salts thereof, and solvates thereof. [5] The aqueous composition according to any one of [1] to [4], wherein the container is made of a resin containing a polyolefin resin. [6] A method for stabilizing an aqueous composition comprising one or more selected from brimonidine and its salts and one or more selected from timolol and its salts, A method comprising encapsulating an aqueous composition in a container having a maximum transmittance of 15% or less for light with a wavelength of 280 nm to 330 nm and a maximum transmittance of 20% or less for light with a wavelength of 380 nm to 460 nm. [Effects of the Invention]

[0008] The present invention provides an aqueous composition comprising one or more substances selected from brimonidine and its salts, and one or more substances selected from timolol and its salts, which can improve stability against heat and light. [Modes for carrying out the invention]

[0009] The present invention will be described in detail below. The features of the present invention described below can be combined in any way.

[0010] [Aqueous composition] One embodiment of the present invention relates to an aqueous composition. In the present invention, an aqueous composition means a composition containing water. The water content in the aqueous composition may be, for example, 80% (w / v) or more, 90% (w / v) or more, 95% (w / v) or more, or more. The water may be purified water, sterile purified water, water for injection, etc.

[0011] (Brimonidine) The aqueous composition of the present invention contains one or more selected from brimonidine and its salts as an active ingredient. Brimonidine is represented by the chemical formula: 5-bromo-N-(4,5-dihydro-1H-imidazo-l-2-yl)quinoxaline-6-amine and is a compound known to have adrenergic α2 receptor agonist activity.

[0012] The salt of brimonidine may be any salt within a pharmaceutically acceptable range, such as tartrate, hydrochloride, sulfate, nitrate, hydrofluoride, hydrobromide, phosphate, acetate, etc. The salt of brimonidine is preferably tartrate of brimonidine.

[0013] The content of brimonidine and its salts in the aqueous composition 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, while on the other hand, it may be, 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. Any combination of the above concentrations may be used to express a concentration range.

[0014] (Timoroll) The aqueous composition of the present invention contains one or more selected from timolol and its salts as an active ingredient. Timolol is represented by the chemical formula (2S)-1-(tert-butylamino)-3-(4-morpholino-1,2,5-thiadiazo-3-yloxy)-2-propanol and is a compound known to have β-receptor blocking activity.

[0015] The salt of timolol may be any salt within a pharmaceutically acceptable range, such as maleate, fumarate, citrate, succinate, mesylate, besylate, tosylate, tartrate, hydrochloride, sulfate, nitrate, hydrofluoride, hydrobromide, hydroiodide, phosphate, acetate, etc. The salt of timolol is preferably maleate of timolol.

[0016] The content of timolol and its salts in the aqueous composition 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, while on the other hand, it 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 numerical values ​​of the above concentrations may be arbitrarily combined to express a range of concentrations.

[0017] Also, the content of timolol and its salts may be, as timolol, 0.05 mg / mL or more, 0.1 mg / mL or more, 0.5 mg / mL or more, 1 mg / mL or more, 2.5 mg / mL or more, or 5 mg / mL or more in the aqueous composition. On the other hand, for example, it may be 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. Each numerical value of the above-mentioned concentrations may be arbitrarily combined to represent a concentration range. When referring to "as timolol" for the salt of timolol, it represents the content of timolol itself among the salts of timolol. The content of timolol itself among the salts of timolol can be calculated from the content of the salt of timolol, for example, based on the molecular weight ratio of the counter ion to timolol.

[0018] (Citric acid) In one aspect, the aqueous composition of the present invention may contain one or more selected from citric acid, its salts, and their solvates. The salt of citric acid may be any salt, for example, an alkali metal salt such as sodium salt, potassium salt, etc., an alkaline earth metal salt such as calcium salt, magnesium salt, etc. The solvate of citric acid or its salt may contain any solvent molecule, for example, a hydrate containing water molecules. Also, the number of solvent molecules in the solvate is not particularly limited. For example, the solvate may be a monohydrate containing one water molecule (hereinafter, the monohydrate may be referred to as a hydrate in some cases), a dihydrate containing two water molecules, etc. Note that the salts of citric acid also include anhydrides (anhydrous compounds) obtained by removing water molecules from hydrates.

[0019] One or more contents selected from citric acid, its salts, and their solvates may be, for example, 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, or 3 mg / mL or more in the aqueous composition, and it is preferably 5 mg / mL or more from the viewpoint of stabilizing the aqueous composition. On the other hand, it may be, for example, 500 mg / mL or less, 300 mg / mL or less, 200 mg / mL or less, 100 mg / mL or less, 50 mg / mL or less, or 30 mg / mL or less.

[0020] In addition, the aqueous composition of the present invention may contain one or more selected from citric acid, its salts, and their solvates, for example, 0.01 part by weight or more, 0.05 part by weight or more, 0.1 part by weight or more, 0.5 part by weight or more, 1 part by weight or more, 2 parts by weight or more, 3 parts by weight or more, or 4 parts by weight or more with respect to 1 part by weight of brimonidine and its salts, and preferably contains 5 parts by weight or more.

[0021] In addition, the aqueous composition of the present invention may contain one or more selected from citric acid, its salts, and their solvates, for example, 0.0014 part by weight or more, 0.0073 part by weight or more, 0.014 part by weight or more, 0.05 part by weight or more, 0.073 part by weight or more, 0.1 part by weight or more, 0.14 part by weight or more, 0.2 part by weight or more, 0.3 part by weight or more, 0.4 part by weight or more, 0.5 part by weight or more, 0.6 part by weight or more, or 0.7 part by weight or more with respect to 1 part by weight of timolol and its salts, and preferably contains 0.73 part by weight or more.

[0022] (Edetic acid) In some embodiments, the aqueous composition of the present invention may contain one or more selected from EDTA, its salts, and their solvates. The salt of EDTA 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 EDTA or its salt may contain any solvent molecule, for example, a hydrate containing a water molecule. Furthermore, the number of solvent molecules in the solvate is not particularly limited; for example, the solvate may be a dihydrate containing two water molecules.

[0023] The content of one or more edetic acid, its salts, and their solvates in the aqueous composition may be, for example, 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 mg / mL or more, while on the other hand, it 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.

[0024] Furthermore, the aqueous composition of the present invention may contain one or more selected from edetic acid, its salts, and solvates thereof in, for example, 0.001 parts by weight or more, 0.003 parts by weight or more, 0.005 parts by weight or more, 0.01 parts by weight or more, 0.03 parts by weight or more, or 0.05 parts by weight or more, per 1 part by weight of brimonidine and its salt, preferably 0.1 parts by weight or more.

[0025] Furthermore, the aqueous composition of the present invention may contain, for example, 0.001 parts by weight or more, 0.0014 parts by weight or more, 0.0044 parts by weight or more, 0.005 parts by weight or more, 0.0073 parts by weight or more, or 0.01 parts by weight or more, per 1 part by weight of timolol and its salt, preferably 0.014 parts by weight or more.

[0026] (Other ingredients) The aqueous composition of the present invention may further contain one or more components such as a solubilizer, buffer, isotonic agent, preservative, pH adjuster, stabilizer, and viscosity modifier.

[0027] Examples of solubilators include polyoxyethylene hydrogenated castor oil derivatives, polyoxyethylene glycol monostearate, polysorbate, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid esters, and tyroxapol, but are not particularly limited as long as they are commonly used in the pharmaceutical (preferably ophthalmic) field. The aqueous composition of the present invention may contain two or more solubilators.

[0028] Examples of buffering agents include Tris buffering agents such as phosphoric acid, acetic acid, epsilon-aminocaproic acid, tartaric acid, boric acid, and trometamol; amino acid buffering agents such as aspartic acid and glutamic acid; salts thereof; and solvates thereof. However, they are not particularly limited as long as they are commonly used in the pharmaceutical (preferably ophthalmic) field. The aqueous composition of the present invention may contain two or more buffering agents.

[0029] Examples of isotonic agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, propylene glycol, polyethylene glycol, glucose, sorbitol, mannitol, trehalose, maltose, sucrose, butylene glycol, glycerin, concentrated glycerin, etc., but are not particularly limited as long as they are commonly used in the pharmaceutical (preferably ophthalmic) field. The aqueous composition of the present invention may contain two or more isotonic agents.

[0030] Examples of preservatives include quaternary ammonium salts (e.g., benzalkonium chloride, benzethonium chloride), biguanide compounds, benzoic acid and its salts, parahydroxybenzoic acid esters, chlorobutanol, sorbic acid and its salts, dehydroacetic acid and its salts, benzyl alcohol, parachlormetaxylenol, chlorocresol, phenethyl alcohol, thimerosal, polydronium chloride, zinc chloride, chlorites, etc., but are not particularly limited as long as they are commonly used in the pharmaceutical (preferably ophthalmic) field. The aqueous composition of the present invention may contain two or more preservatives.

[0031] Examples of pH adjusting agents include hydrochloric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate, but are not particularly limited as long as they are commonly used in the pharmaceutical (preferably ophthalmic) field. The pH adjusting agent may be one or more types, as long as it can adjust the pH of the aqueous composition of the present invention to the desired range.

[0032] Examples of stabilizers include ascorbic acid, tocopherol, dibutylhydroxytoluene, povidone, sulfites, monoethanolamine, cyclodextrin, dextran, and taurine, but are not particularly limited as long as they are commonly used in the pharmaceutical (preferably ophthalmic) field. The aqueous composition of the present invention may contain two or more stabilizers.

[0033] Examples of thickening agents include carboxyvinyl polymer, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, xanthan gum, sodium chondroitin sulfate, sodium hyaluronate, hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose, but are not particularly limited as long as they are commonly used in the pharmaceutical (preferably ophthalmic) field. The aqueous composition of the present invention may contain two or more thickening agents.

[0034] The aqueous composition of the present invention may further contain other active ingredients besides brimonidine and its salts and timolol and its salts. The other active ingredients may be, for example, components that have an intraocular pressure-lowering effect, and specific examples include compounds that have α1 receptor blocking activity such as bunazosin hydrochloride; compounds that have carbonic anhydrase inhibitory activity such as dorzolamide hydrochloride and brinzolamide; and prostaglandins such as latanoprost, travoprost, tafluprost and bimatoprost. 2α Examples include derivatives; compounds with Rho kinase inhibitory activity such as lipasudil; and compounds with EP2 receptor agonist activity such as omidenepaguisopropyl.

[0035] (pH) The pH of the aqueous 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 higher, 4.5 or higher, 5 or higher, 5.5 or higher, 6 or higher, 6.5 or higher, or 7 or higher, while on the other hand, it may be, for example, 9 or lower, 8.5 or lower, 8 or lower, or 7.5 or lower. The above upper and lower limit values ​​may be appropriately combined to express the pH range.

[0036] (Method for preparing aqueous compositions) The aqueous composition of the present invention can be prepared according to conventional methods. For example, the composition of the present invention can be prepared by dissolving each component in water. The preparation may include a pH adjustment step, a filtration sterilization step, and so on. The filtration sterilization step may include, for example, passing the aqueous composition through a filter.

[0037] (Containment) The aqueous composition of the present invention is contained in a container having predetermined wavelength characteristics. By containing the aqueous composition in a container having predetermined wavelength characteristics, the aqueous composition can be stabilized. Note that "contained in a container" means that the aqueous composition is present inside the container.

[0038] The container of the present invention is not limited in shape or size, as long as it can contain an aqueous composition. The container may be, for example, an eye drop container. The container may also be, for example, airtight (a state in which solid foreign matter can be prevented from entering and the contents can be prevented from being lost under normal handling, transport, or storage conditions), airtight (a state in which solid or liquid foreign matter cannot enter and the contents can be prevented from being lost, efflorescent, deliquescent, or evaporated under normal handling, transport, or storage conditions).

[0039] If the container is an eye drop container, the container may consist of multiple parts that eye drop containers generally have, such as a cap, stopper, bottle (bottle, body), and filter. If the eye drop container has a filter, the pore size of the filter may be, for example, 5 μm or less, preferably 0.1 to 2.5 μm, and more preferably 0.1 to 1.0 μm.

[0040] In one embodiment, the container of the present invention is a multi-dose container. A multi-dose container is a type of packaging intended for repeated use, in which the cap or other opening mechanism can be freely opened and resealed.

[0041] The present invention is characterized in that the maximum transmittance of light with wavelengths of 280 nm to 330 nm and the maximum transmittance of light with wavelengths of 380 nm to 460 nm are within predetermined ranges. The maximum transmittance of light in a given wavelength range is, for example, in the case of wavelengths from 280 nm to 330 nm, measured using an ultraviolet-visible spectrophotometer at 0.5 nm intervals within the range of 280 nm to 330 nm, and the maximum value among the measured transmittances is represented.

[0042] The maximum transmittance of light with wavelengths of 280 nm to 330 nm in the containment of the present invention is preferably 15% or less, more preferably 10% or less, even more preferably 5% or less, particularly preferably 3% or less, and most preferably 2% or less. On the other hand, the maximum transmittance of light with wavelengths of 280 nm to 330 nm in the containment of the present invention is preferably 0.01% or more.

[0043] Furthermore, the maximum transmittance of light with wavelengths of 380 nm to 460 nm in the containment of the present invention is preferably 20% or less, more preferably 15% or less, even more preferably 10% or less, particularly preferably 8% or less, and most preferably 6% or less. On the other hand, from the viewpoint of maintaining visibility inside the containment, the maximum transmittance of light with wavelengths of 380 nm to 460 nm in the containment of the present invention is preferably 0.3% or more.

[0044] Furthermore, the maximum transmittance of light with wavelengths of 280 nm to 460 nm in the containment of the present invention is preferably 0.3% or more, from the viewpoint of maintaining visibility inside the containment.

[0045] In the container of the present invention, the region having the above-described wavelength characteristics preferably accounts for 30% or more of the total surface area of ​​the container, more preferably 40% or more, and even more preferably 50% or more. Furthermore, if the container of the present invention is an eye drop container, it is preferable that at least the bottle (bottle, body) portion has a region having the above-described wavelength characteristics.

[0046] The color of the container of the present invention is not particularly limited as long as it has wavelength characteristics within the range described above. Furthermore, it is preferable that the container of the present invention has transparency sufficient to allow the inside of the container to be seen, and more preferably that it has transparency sufficient to allow the insoluble foreign body test for eye drops as prescribed in the 18th edition of the Japanese Pharmacopoeia.

[0047] The material of the container of the present invention is not particularly limited as long as it has wavelength characteristics within the above range, and the container may be made of, for example, a resin. The resin is preferably a thermoplastic resin. Examples of thermoplastic resins include polyolefin resins, polyvinyl chloride resins, polystyrene resins, polyamide resins, polyester resins, etc., and the resin may be made of, for example, one of these, or a polymer alloy or polymer blend made of two or more of these. The container of the present invention is preferably made of a resin containing a polyolefin resin.

[0048] Examples of polyolefin resins include polyethylene, polypropylene, cyclic polyolefins, poly(4-methylpentene), polytetrafluoroethylene, ethylene-propylene copolymer, ethylene-α-olefin copolymer, propylene-α-olefin copolymer, ethylene-acrylic acid copolymer, ethylene-methacrylic acid copolymer, ethylene-vinyl acetate copolymer, ethylene-ethyl acrylate copolymer, and polyolefin thermoplastic elastomers. One or more of these can be used. Preferably, the polyolefin resin contains at least one selected from polyethylene and polypropylene. The type of polyethylene is not particularly limited and may be, for example, low-density polyethylene, linear low-density polyethylene, medium-density polyethylene, high-density polyethylene, etc. Polypropylene may be crystalline or amorphous.

[0049] Examples of polyvinyl chloride resins include polyvinyl chloride, vinyl chloride / vinyl acetate copolymer, vinyl chloride / (meth)acrylic acid copolymer, vinyl chloride / methyl (meth)acrylate copolymer, vinyl chloride / (meth)acrylate copolymer, vinyl chloride / ethyl (meth)acrylate copolymer, vinyl chloride / ethylene copolymer, vinyl chloride / propylene copolymer, vinyl chloride / vinylidene chloride copolymer, and others. One or more of these can be used.

[0050] Examples of polystyrene resins include general-purpose polystyrene (GPPS), high-impact polystyrene (HIPS), polystyrene copolymers such as styrene-butadiene copolymer (SBS) and styrene-acrylonitrile copolymer (SAN), and one or more of these can be used.

[0051] Examples of polyamide resins include linear aliphatic-containing polyamides such as nylon 6 (PA6), nylon 66 (PA66), nylon 11 (PA11), and nylon 12 (PA12), and aromatic ring-containing aliphatic polyamides such as nylon MXD6. One or more of these can be used.

[0052] Examples of polyester resins include polyalkylene terephthalates such as polybutylene terephthalate; polyalkylene naphthalates such as polyethylene naphthalate and polybutylene naphthalate; polycycloalkylene terephthalates such as poly(1,4-cyclohexylenedimethylene terephthalate); and polyarylate. One or more of these can be used. Polyethylene terephthalate may be excluded from the polyester resin.

[0053] The container of the present invention is preferably made of a resin containing polyethylene. In some embodiments, the container of the present invention does not contain polyethylene terephthalate.

[0054] The container of the present invention may contain materials other than resin, as long as the effects of the present invention are not impaired. Examples of other materials include ultraviolet absorbers such as 2-(2H-benzotriazol-2-yl)-p-cresol and 2-(2H-benzotriazol-2-yl)-4,6-bis(1-methyl-1-phenylethyl)phenol; ultraviolet scattering agents such as titanium dioxide and zinc oxide; and colorants such as inorganic pigments, organic pigments, and dyes.

[0055] The container of the present invention may be sterilized. The sterilization may be, for example, gas sterilization, and examples of gases used in gas sterilization include ethylene oxide gas, hydrogen peroxide gas, and mixed gases of these with carbon dioxide, etc. Alternatively, the sterilization may be radiation sterilization, including gamma ray irradiation and electron beam irradiation.

[0056] The means of containing the aqueous composition in the container are not particularly limited, and it may be filled by conventional methods according to the shape of the container, etc.

[0057] Part or all of the container of the present invention may be covered with a label. Examples of label forms include shrink labels, shrink tack labels, and tack labels. A shrink label is a label that has heat shrinkability and shrinks when heat is applied, allowing the container to be shrink-wrapped. A shrink tack label is a label that has a tack (adhesive) surface and shrinks to conform to the shape of the container when heat is applied after application. A tack label is a label that has a tack (adhesive) surface and can be applied under pressure to package a container. Among these, the use of a shrink label is preferred, and the use of a shrink tack label is particularly preferred.

[0058] The label material may include commonly used label film substrates. Examples of film substrates include polyesters such as polyethylene terephthalate (PET), polyethylene naphthalate (PEN), polybutylene terephthalate (PBT), and polybutylene naphthalate (PBN); polyamides such as nylon and aramid; polyarylates such as bisphenol A / terephthalic acid condensate and bisphenol A / isophthalic acid condensate; polycarbonate; polyolefins such as polypropylene and polyethylene; and polyvinyl chloride.

[0059] [Method for stabilizing aqueous compositions] One embodiment of the present invention relates to a method for stabilizing an aqueous composition comprising one or more substances selected from brimonidine and its salts, and one or more substances selected from timolol and its salts.

[0060] In the present invention, stabilization of an aqueous composition means, for example, that when stored for a predetermined period under predetermined conditions (e.g., high-temperature conditions such as 40°C or higher, 50°C or higher, or 60°C or higher), the amount of decomposition products in the aqueous composition decreases compared to a suitable control (for example, when the aqueous composition is contained in a container in which the maximum transmittance of light at wavelengths of 280 nm to 330 nm and the maximum transmittance of light at wavelengths of 380 nm to 460 nm does not satisfy the constituent requirements of the present invention). The amount of decomposition products in the aqueous composition may be measured using a suitable method known to those skilled in the art, which may include, for example, determining the peak area of ​​the aqueous composition other than brimonidine and timolol under appropriate measurement conditions using high-performance liquid chromatography (HPLC). Degradation products are peaks other than brimonidine and timolol that are identified by analyzing an aqueous composition containing one or more substances selected from brimonidine and its salts and one or more substances selected from timolol and its salts under appropriate measurement conditions using high-performance liquid chromatography (HPLC) after storage. The amount of degradation products is determined by summing the areas of these peaks. Furthermore, degradation products are generated from either or both of brimonidine and its salts, or timolol and its salts.

[0061] Alternatively, in the present invention, stabilization of the aqueous composition means, for example, that the decrease in the timolol content in the aqueous composition is suppressed when stored for a predetermined period under predetermined conditions (e.g., under light irradiation conditions such as cumulative irradiation doses of 300,000 lx·hr, 600,000 lx·hr, 1,200,000 lx·hr, etc.). The suppression of the decrease in timolol content can be evaluated, for example, by the fact that when stored for a predetermined period under predetermined storage conditions (e.g., under light irradiation conditions such as cumulative irradiation doses of 300,000 lx·hr, 600,000 lx·hr, 1,200,000 lx·hr, etc.), the timolol content in the aqueous composition becomes higher compared to an appropriate control (e.g., when the aqueous composition is contained in a container in which the maximum transmittance of light at wavelengths of 280 nm to 330 nm and the maximum transmittance of light at wavelengths of 380 nm to 460 nm do not satisfy the constituent requirements of the present invention).

[0062] The stabilization method of the present invention includes housing a predetermined aqueous composition in a predetermined container. Housing an aqueous composition in a container means that the aqueous composition is present inside the container, and the means for doing so are not particularly limited. The aqueous composition used in the stabilization method of the present invention can be selected as described in the [Aqueous Composition] section above. The container used in the stabilization method of the present invention can also be selected as described in the (Container) section above.

[0063] In one embodiment, the stabilization method of the present invention is a method for stabilizing an aqueous composition under high temperature conditions of 40°C or higher, 50°C or higher, or 60°C or higher. In one embodiment, the stabilization method of the present invention is a method for stabilizing an aqueous composition under exposure conditions of 300,000 lx·hr, 600,000 lx·hr, or 1,200,000 lx·hr.

[0064] Furthermore, in one embodiment, the stabilization method of the present invention is a method for suppressing the generation of decomposition products in an aqueous composition. Furthermore, in one embodiment, the stabilization method of the present invention is a method for suppressing the decrease in the timolol content in an aqueous composition. [Examples]

[0065] The present invention will be described in more detail below with reference to examples. The following examples are merely illustrative of the present invention and do not limit its scope.

[0066] Test Example 1 Aqueous compositions with the compositions shown in Table 1 were prepared by conventional methods. 5 mL of each aqueous composition was placed in the designated containers shown in Table 1 to form the filled products.

[0067] [Table 1]

[0068] Each pack was stored in the dark at 60°C for 3 weeks. Each aqueous composition before and after storage was measured by HPLC. The column was packed with octadecylsilylated silica gel, the mobile phase was a mixture of sodium 1-heptanesulfonate aqueous solution, triethylamine, and acetic acid, and methanol. A UV spectrophotometer (measurement wavelength: 264 nm) was used as the detector to analyze the amount of decomposition products. The amount of decomposition products increased due to storage was calculated according to the following formula.

[0069] Amount of decomposition products increased by storage (%) = {(Peak area of ​​decomposition products in the sample solution after storage) / (Peak area of ​​brimonidine in the standard solution) × 100} - {(Peak area of ​​decomposition products in the sample solution before storage) / (Peak area of ​​brimonidine in the standard solution) × 100}

[0070] Table 2 shows the evaluation results of the decomposition products. Replacing PET containers with PE containers reduced the amount of decomposition products (Comparative Examples 1-4). Furthermore, no significant difference in the amount of decomposition products was observed between containers with wavelength characteristics A and B, but the amount of decomposition products was lower in containers with wavelength characteristics C compared to containers with wavelength characteristics A or B (Comparative Examples 4, 5, and 1). In addition, the amount of decomposition products was reduced by incorporating EDTA into the aqueous composition (Examples 1 and 2).

[0071] [Table 2]

[0072] Test Example 2 Aqueous compositions with the compositions shown in Table 1 were prepared by conventional methods, and 5 mL of each aqueous composition was placed in the designated containers shown in Table 1 to form the filled products.

[0073] Each packed product was irradiated with a D65 fluorescent lamp as the light source using a photostability tester (LTL-200A-15WCD, manufactured by Nagano Science Co., Ltd.) at 25°C, with an integrated irradiation dose of 600,000 lx·hr. Each aqueous composition before and after storage was measured by HPLC. A column packed with phenylsilylated silica gel was used as the column, a mixture of sodium 1-hexanesulfonate aqueous solution, triethylamine, and formic acid, methanol, and acetonitrile were used as the mobile phase, and an ultraviolet spectrophotometer (measurement wavelength: 296 nm) was used as the detector to analyze the timolol content. From the determined timolol content, the timolol retention rate was calculated according to the following formula.

[0074] Timolol retention rate (%) = (Timolol content after light irradiation) / (Timolol content before light irradiation) × 100

[0075] Table 3 shows the evaluation results for the timolol retention rate. The results in Table 3 indicate that containers with wavelength characteristic C had a higher timolol retention rate compared to containers with wavelength characteristic A or B (Comparative Examples 1-5, Examples 1-2).

[0076] [Table 3]

Claims

1. An aqueous composition comprising one or more selected from brimonidine and its salts, and one or more selected from timolol and its salts, An aqueous composition contained in a container having a maximum transmittance of 15% or less for light with a wavelength of 280 nm to 330 nm, and a maximum transmittance of 20% or less for light with a wavelength of 380 nm to 460 nm.

2. The aqueous composition according to claim 1, further comprising one or more selected from citric acid, its salts, and solvates thereof.

3. The aqueous composition according to claim 2, comprising 5 parts by weight or more of one or more selected from citric acid, its salts, and solvates thereof, per 1 part by weight of brimonidine and its salt.

4. The aqueous composition according to claim 1, further comprising one or more selected from edetic acid, salts thereof, and solvates thereof.

5. The aqueous composition according to claims 1 to 4, wherein the container is made of a resin containing a polyolefin resin.

6. A method for stabilizing an aqueous composition comprising one or more substances selected from brimonidine and its salts, and one or more substances selected from timolol and its salts, A method comprising encapsulating an aqueous composition in a container having a maximum transmittance of 15% or less for light with a wavelength of 280 nm to 330 nm and a maximum transmittance of 20% or less for light with a wavelength of 380 nm to 460 nm.

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