Ophthalmic components

Abstract

To provide an ophthalmic composition with excellent photostability and thermal stability of brimonidine and / or its salts. [Solution] An ophthalmic composition contained in a container, comprising (A) brimonidine and / or a salt thereof, and (B) a cooling agent, wherein the filling rate of the ophthalmic composition in the container is 70% or more.

Description

Technical Field

[0001] The present invention relates to an ophthalmic composition.

Background Art

[0002] Conventionally, ophthalmic drops for the treatment of glaucoma and ocular hypertension are known as ophthalmic compositions containing brimonidine and / or its salts as an active ingredient. In addition, the use of brimonidine and / or its salts as an active ingredient for improving conjunctival congestion has also been studied (for example, Patent Document 1), and products claiming such efficacy are sold overseas.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] In such an ophthalmic composition, it is required to enhance the stability of brimonidine and / or its salts. For example, when the ophthalmic composition is exposed to light or heat for a long time, the content of brimonidine and / or its salts may decrease over time.

[0005] Therefore, an object of the present invention is to provide an ophthalmic composition having excellent photo-stability and thermal stability of brimonidine and / or its salts.

Means for Solving the Problems

[0006] As a result of intensive studies by the present inventors, by adding a cooling agent to an ophthalmic composition containing brimonidine and / or its salts and further storing the ophthalmic composition in a container at a predetermined filling ratio, it has been found that the stability of brimonidine and / or its salts can be enhanced, and the present invention has been completed.

[0007] The present invention provides, for example, the following [1] to

[11] . [1] An ophthalmic composition contained in a container, comprising (A) brimonidine and / or a salt thereof, and (B) a cooling agent, wherein the filling rate of the ophthalmic composition in the container is 70% or more. [2] The ophthalmic composition according to [1], wherein the content of component (A) is 0.005 to 0.02 w / v% based on the total amount of the ophthalmic composition. [3] The ophthalmic composition according to [1] or [2], wherein the content of component (B) is 0.001 to 0.5 w / v% based on the total amount of the ophthalmic composition. [4] The ophthalmic composition according to any one of [1] to [3], wherein the mass ratio of the content of component (B) to the content of component (A) is 0.1 to 50. [5](B) An ophthalmic composition according to any one of [1] to [4], wherein the component is menthol. [6] The ophthalmic composition according to any one of [1] to [5], wherein the filling rate of the ophthalmic composition in the container is 90% or more. [7](C) An ophthalmic composition according to any one of [1] to [6], further containing a surfactant. [8] For ophthalmic compositions, irradiance of 765 w / m 2 An ophthalmic composition according to any one of [1] to [7], wherein, when irradiated with light for 8 hours, the ratio of the content of component (A) after irradiation to the content of component (A) before irradiation is 80% or more. [9] An ophthalmic composition according to any one of [1] to [8], wherein, when the ophthalmic composition is left standing for 3 weeks in an environment of 60°C, the ratio of the content of component (A) after standing to the content of component (A) before standing is 80% or more.

[10] An ophthalmic composition according to any one of [1] to [9], wherein, when the ophthalmic composition is left standing at room temperature for 3 years, the ratio of the content of component (A) after standing to the content of component (A) before standing is 80% or more.

[11] A method for stabilizing brimonidine and / or a salt thereof in an ophthalmic composition, comprising placing an ophthalmic composition containing (A) brimonidine and / or a salt thereof and (B) a cooling agent in a container such that the filling rate is 70% or more. [Effects of the Invention]

[0008] According to the present invention, it is possible to provide an ophthalmic composition with excellent photostability and thermal stability of brimonidine and / or its salts. Furthermore, according to the present invention, it is possible to provide a novel method for stabilizing brimonidine and / or its salts in an ophthalmic composition containing brimonidine and / or its salts. [Modes for carrying out the invention]

[0009] The embodiments for carrying out the present invention will be described in detail below. However, the present invention is not limited to the following embodiments.

[0010] In the numerical ranges described stepwise in this specification, the upper or lower limit of one step in the numerical range may be arbitrarily combined with the upper or lower limit of another step in the numerical range. In the numerical ranges described in this specification, the upper or lower limit of that numerical range may be replaced with the values ​​shown in the examples. Unless otherwise specified, the components or materials exemplified in this specification may be used individually or in combination of two or more.

[0011] The ophthalmic composition according to this embodiment contains (A) brimonidine and / or a salt thereof, and (B) a cooling agent. The ophthalmic composition is contained in a container, and the filling rate of the ophthalmic composition in the container is 70% or more.

[0012] The ophthalmic composition according to this embodiment has the above-described structure and therefore exhibits excellent stability (photostable and thermal stable) of brimonidine and / or its salts. More specifically, this ophthalmic composition suppresses the decrease in the content of brimonidine and / or its salts over time. The decrease in the content of brimonidine and / or its salts over time includes not only the decrease in content that occurs when left standing in a natural environment for a long period of time, but also the decrease in content that occurs when exposed to harsh environments such as light or heat.

[0013] Brimonidine and / or its salts (hereinafter also referred to as component (A)) are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of brimonidine salts include hydrochloride, sulfate, phosphate, acetate, citrate, oxalate, malonate, salicylate, malate, fumarate, succinate, ascorbate, maleate, methanesulfonate, and tartrate. Brimonidine salts are preferably tartrate.

[0014] The content of component (A) may be 0.005 w / v% or more, 0.007 w / v% or more, or 0.01 w / v% or more, based on the total amount of the ophthalmic composition, and may be 0.02 w / v% or less, 0.017 w / v% or less, or 0.015 w / v% or less. The content of component (A) may be 0.005 to 0.02 w / v%, 0.007 to 0.017 w / v%, or 0.01 to 0.015 w / v%, based on the total amount of the ophthalmic composition, and may be 0.01 w / v%.

[0015] The cooling agent (hereinafter also referred to as component (B)) is a compound having an action of imparting a cooling sensation or a cold sensation to the eyes, and its salts. Examples of component (B) include terpenoids and essential oils containing terpenoids. Examples of terpenoids include menthol, mentone, camphor, borneol, geraniol, cineol, citronellol, carvone, anethole, eugenol, limonene, linalool and linalyl acetate. Examples of essential oils containing terpenoids include eucalyptus oil, bergamot oil, peppermint oil, star anise oil, rose oil, cinnamon oil, spearmint oil and camphor oil. The terpenoid may be any of the d-form, l-form and dl-form. From the viewpoint of further enhancing the effects of the present invention, component (B) is preferably menthol.

[0016] (B) From the viewpoint of further enhancing the effects of the present invention, the content of component (B) is preferably 0.0001 w / v% or more, 0.0005 w / v% or more, 0.0008 w / v% or more, 0.001 w / v% or more, 0.002 w / v% or more, 0.003 w / v% or more, 0.005 w / v% or more, or 0.007 w / v% or more based on the total amount of the ophthalmic composition. Also, from the same viewpoint, the content of component (B) is preferably 0.5 w / v% or less, 0.3 w / v% or less, 0.2 w / v% or less, 0.15 w / v% or less, 0.1 w / v% or less, 0.05 w / v% or less, 0.03 w / v% or less, or 0.01 w / v% or less based on the total amount of the ophthalmic composition.

[0017] (B) From the viewpoint of further enhancing the effects of the present invention, the mass ratio of the content of component (B) to the content of component (A) ((content of component (B) / content of component (A))) is preferably 0.1 or more, more preferably 0.5 or more, still more preferably 1 or more, and is also preferably 50 or less, more preferably 30 or less, still more preferably 10 or less, and particularly preferably 5 or less. The mass ratio of the content of component (B) to the content of component (A) may be 0.1 to 50.

[0018] The ophthalmic composition of this embodiment may further contain (C) a surfactant (hereinafter also referred to as (C) component) from the viewpoint of solubilizing the cooling agent. Component (C) is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, or capable of solubilizing the cooling agent, and may be, for example, a nonionic surfactant, anionic surfactant, amphoteric surfactant, or cationic surfactant.

[0019] Examples of nonionic surfactants include POE(20) sorbitan fatty acid esters such as POE(20) sorbitan monolaurate (polysorbate 20), POE(20) sorbitan monopalmitate (polysorbate 40), POE(20) sorbitan monostearate (polysorbate 60), POE(20) sorbitan tristearate (polysorbate 65), and POE(20) sorbitan monooleate (polysorbate 80); poloxamer 407, poloxamer 235, poloxamer 188, poloxamer 403, POE·POP glycols such as poloxamer 237 and poloxamer 124; POE hydrogenated castor oils such as POE hydrogenated castor oil 40, POE hydrogenated castor oil 50, POE hydrogenated castor oil 60, and POE hydrogenated castor oil 80; POE castor oils such as POE castor oil 3, POE castor oil 4, POE castor oil 6, POE castor oil 7, POE castor oil 10, POE castor oil 13.5, POE castor oil 17, POE castor oil 20, POE castor oil 25, POE castor oil 30, POE castor oil 35, and POE castor oil 50; polyethylene monostearate Polyethylene glycol (2 E.O.), polyethylene glycol monostearate (4 E.O.), polyethylene glycol monostearate (9 E.O.), polyethylene glycol monostearate (10 E.O.), polyethylene glycol monostearate (23 E.O.), polyethylene glycol monostearate (25 E.O.), polyethylene glycol monostearate (32 E.O.), polyethylene glycol monostearate (40 E.O., polyoxyl 40 stearate), polyoxyl monostearate Examples include polyethylene glycol monostearate such as ethylene glycol (45 E.O.), polyethylene glycol monostearate (55 E.O.), polyethylene glycol monostearate (75 E.O.), and polyethylene glycol monostearate (140 E.O.); POE alkyl ethers such as POE(9) lauryl ether; POE-POP alkyl ethers such as POE(20)POP(4) cetyl ether; and POE alkylphenyl ethers such as POE(10) nonylphenyl ether. In the compounds exemplified above, POE stands for polyoxyethylene, POP stands for polyoxypropylene, and the number in parentheses indicates the number of moles added.

[0020] Examples of the anionic surfactant include polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl ether sulfates, alkylbenzene sulfonates, alkyl sulfates, and N-acyltaurine salts.

[0021] Examples of the amphoteric surfactant include lauryldimethylaminoacetic acid betaine and alkyldiaminoethyl glycine hydrochloride.

[0022] Examples of the cationic surfactant include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine gluconate, polydronium hydrochloride, and cetylpyridinium chloride.

[0023] As the component (C), a nonionic surfactant is preferred. Examples of the nonionic surfactant include POE sorbitan fatty acid esters; POE·POP glycols; POE hydrogenated castor oil; POE castor oil; and polyethylene glycol monostearate. Among them, polysorbate 80, poloxamer 407, POE hydrogenated castor oil 40, POE hydrogenated castor oil 60, POE castor oil 3, POE castor oil 10, POE castor oil 35, and polyoxyl 40 stearate are more preferred, polysorbate 80, poloxamer 407, POE hydrogenated castor oil 60, POE castor oil 10, and polyoxyl 40 stearate are still more preferred, and polysorbate 80 and POE hydrogenated castor oil 60 are particularly preferred. The nonionic surfactant may be used alone or in combination of two or more.

[0024] From the viewpoint of further enhancing the effects of the present invention, the content of the component (C) is preferably 0.001 w / v% or more, 0.005 w / v% or more, 0.01 w / v% or more, or 0.1 w / v% or more, and preferably 5 w / v% or less, 3 w / v% or less, 1 w / v% or less, or 0.5 w / v% or less, based on the total amount of the ophthalmic composition.

[0025] The mass ratio of the content of component (C) to the content of component (A) (content of component (C) / content of component (A)) is preferably 0.1 or more, 0.5 or more, 5 or more, or 10 or more, and also preferably 200 or less, 100 or less, 70 or less, or 50 or less.

[0026] The ophthalmic composition of this embodiment may further contain a buffering agent. The buffering agent is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and examples include inorganic buffering agents derived from inorganic acids, and organic buffering agents derived from organic acids or organic bases. Commercially available buffering agents may be used.

[0027] Examples of inorganic buffers include borate buffers, phosphate buffers, and carbonate buffers. Examples of borate buffers include boric acid or its salts (alkali metal borate, alkaline earth metal borate, etc.). Examples of phosphate buffers include phosphoric acid or its salts (alkali metal phosphate, alkaline earth metal phosphate, etc.). Examples of carbonate buffers include carbonic acid or its salts (alkali metal carbonate, alkaline earth metal carbonate, etc.). In addition, hydrates of borates, phosphates, or carbonates may be used as borate buffers, phosphate buffers, or carbonate buffers. More specific examples include boric acid buffers such as boric acid or its salts (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); phosphoric acid buffers such as phosphoric acid or its salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); and carbonate buffers such as carbonate or its salts (sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.).

[0028] Examples of organic buffers include citrate buffers, acetate buffers, lactic acid buffers, succinate buffers, Tris buffers, and AMPD buffers. Examples of citrate buffers include citric acid or its salts (alkali metal citrate, alkaline earth metal citrate, etc.). Examples of acetate buffers include acetic acid or its salts (alkali metal acetate, alkaline earth metal acetate, etc.). Examples of lactic acid buffers include lactic acid or its salts (alkali metal lactate, alkaline earth metal lactate, etc.). Examples of succinate buffers include succinic acid or its salts (alkali metal succinate, etc.). In addition, citrate, acetate, lactate, or succinate hydrates may be used as citrate buffers, acetate buffers, lactic acid buffers, or succinate buffers. More specific examples include citric acid or its salts (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.) as citrate buffers; acetic acid or its salts (ammonium acetate, sodium acetate, potassium acetate, calcium acetate, etc.) as acetic acid buffers; lactic acid or its salts (sodium lactate, potassium lactate, calcium lactate, etc.) as lactic acid buffers; and succinic acid or its salts (monosodium succinate, disodium succinate, etc.) as succinic acid buffers. Examples of Tris buffers include trometamol or its salts (trometamol hydrochloride, etc.). Examples of AMPD buffers include 2-amino-2-methyl-1,3-propanediol or its salts.

[0029] Preferred buffering agents include boric acid buffers (e.g., a combination of boric acid and borax), phosphate buffers (e.g., a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate), citrate buffers, and Tris buffers (e.g., trometamol), with boric acid buffers being more preferred, boric acid and its salts being even more preferred, and a combination of boric acid and borax being even more preferred.

[0030] The buffering agent content is not particularly limited and is set appropriately depending on the type of buffering agent, the types and content of other components, the use of the ophthalmic composition, and the formulation form. From the viewpoint of further enhancing the effects of the present invention, the buffering agent content is preferably 0.01 to 10 w / v%, more preferably 0.05 to 5 w / v%, and even more preferably 0.1 to 3 w / v%, based on the total amount of the ophthalmic composition.

[0031] The ophthalmic composition according to this embodiment may contain, in addition to the above-mentioned components, a combination of components selected from various pharmacologically active and physiologically active components in appropriate amounts, as long as the effects of the present invention are not impaired. The components are not particularly limited, and examples include the active ingredients in ophthalmic drugs described in the 2017 edition of the Standards for Approval of Manufacturing and Marketing of Over-the-Counter Drugs (supervised by the Japanese Society of Regulatory Science). Specifically, examples of components used in ophthalmic drugs include the following components. Antiallergic agents: For example, cromoglycic acid or its salts (e.g., sodium cromoglycate), tranilast, pemirolast potassium, acitazanolest, anlexanox, ibudilast, etc. Antihistamines: For example, chlorpheniramine or its salts, diphenhydramine or its salts (e.g., diphenhydramine hydrochloride), iproheptine or its salts (e.g., iproheptine hydrochloride), levocabastine or its salts (e.g., levocabastine hydrochloride), ketotifen or its salts (e.g., ketotifen fumarate), pemirolast potassium, olopatadine or its salts (e.g., olopatadine hydrochloride), epinastine or its salts (e.g., epinastine hydrochloride), etc. Steroids: For example, fluticasone propionate, fluticasone furoate, mometasone furoate, beclomethasone propionate, flunisolide, etc. Decongestants: For example, tetrahydrozoline hydrochloride, naphazoline hydrochloride, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, etc. Ocular muscle modulating agents: For example, cholinesterase inhibitors that have an active site similar to acetylcholine, specifically neostigmine methylsulfate, tropicamide, helenien, atropine sulfate, pilocarpine hydrochloride, etc. Anti-inflammatory agents: For example, azulene sulfonic acid or its salts, methyl salicylate, glycol salicylate, allantoin, tranexamic acid, lysozyme, lysozyme chloride, indomethacin, pranoprofen, ibuprofen, ibuprofen piconol, ketoprofen, felbinac, bendazac, piroxicam, bufexamac, flufenamate butyl, epsilon-aminocaproic acid, berberine chloride, berberine sulfate, glycyrrhizic acid or its salts (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate), zinc sulfate, zinc lactate, etc. Vitamins: For example, retinol or its derivatives, tocopherol or its derivatives, flavin adenine dinucleotide sodium, pyridoxine hydrochloride, panthenol, calcium pantothenate, cyanocobalamin, ascorbic acid, sodium ascorbate, etc. Amino acids: For example, L-arginine, glutamic acid, glycine, alanine, lysine, gamma-aminobutyric acid, gamma-aminovaleric acid, trimethylglycine, taurine, aspartic acid, or salts thereof. Astringent agents: For example, zinc oxide. Others: For example, sulfamethoxazole, sulfisoxazole, sulfisomidine and their salts, chondroitin sulfate and its salts (sodium salt, etc.).

[0032] The ophthalmic composition according to this embodiment may contain, in accordance with conventional methods, various additives selected appropriately and used in combination in appropriate amounts, one or more types, depending on the formulation, as long as the effects of the present invention are not impaired. Examples of such additives include the various additives listed in the 2021 Dictionary of Pharmaceutical Additives (edited by the Japan Pharmaceutical Additives Association). Representative components include the following additives. Carrier: For example, an aqueous solvent such as water or aqueous ethanol. Chelating agents: For example, ethylenediaminetetraacetic acid (EDTA), ethylenediaminetriacetic acid, ethylenediaminediacetic acid (EDDA), N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), etc. Base: For example, octyldodecanol, titanium dioxide, potassium bromide, Plastibase, etc. pH adjusters: For example, hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, diisopropanolamine, etc. Stabilizers: For example, sodium formaldehyde sulfoxylate (Longalit), sodium sulfite, sodium bisulfite, sodium pyrosulfite, aluminum monostearate, glyceryl monostearate, cyclodextrin, monoethanolamine, butylhydroxyanisole, dibutylhydroxytoluene, sodium thiosulfate, potassium iodide, etc. Preservatives, disinfectants, or antibacterial agents: for example, sodium benzoate, ethanol, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexanide hydrochloride (polyhexamethylene biguanide), etc.), Glokill (a trade name of Rhodia Corporation), etc. Thickeners: For example, cellulosic polymer compounds such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose; guar gum; hydroxypropyl guar gum; gum arabic; karaya gum; xanthan gum; agar; alginic acid and its salts (sodium salt, etc.); mucopolysaccharides such as heparinoids, heparin, heparin sulfate, heparan sulfate, heparinoids, hyaluronic acid and its salts (sodium salt, etc.), chondroitin sulfate and its salts (sodium salt, etc.); starch; chitin and its derivatives; chitosan and its derivatives; carrageenan; monosaccharides such as glucose, etc. Sugar alcohols: For example, xylitol, sorbitol, mannitol, glycerin, etc. Glycols: For example, propylene glycol, ethylene glycol, etc. Oils: For example, vegetable oils such as sesame oil, castor oil, soybean oil, and olive oil; animal oils such as squalane; mineral oils such as liquid paraffin and petrolatum.

[0033] From the viewpoint of further enhancing the effects of the present invention, the ophthalmic composition according to this embodiment may not contain benzalkonium chloride, chlorhexidine gluconate, dibutylhydroxytoluene, propylene glycol, allantoin, or chlorpheniramine maleate.

[0034] The ophthalmic compositions according to this embodiment can be used, for example, as eye drops (also called eye solutions or eye medicines; eye drops include artificial tears; eye drops also include eye drops that can be administered while wearing contact lenses), eye washes (also called eye wash solutions or eye medicines; eye washes also include eye washes that can be administered while wearing contact lenses), and contact lens compositions [contact lens insertion solutions, contact lens care compositions (contact lens disinfectants, contact lens preservatives, contact lens cleaning agents, contact lens cleaning and preservation agents), contact lens insertion eye drops used for both contact lens insertion solutions and eye drops during contact lens wear, etc.]. Note that "contact lenses" include hard contact lenses and soft contact lenses (including both ionic and nonionic types, and including both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses). A preferred example of the ophthalmic composition according to this embodiment is an eye drop, an eye wash, or a contact lens composition, and a more preferred example is an eye drop, particularly an artificial tear solution.

[0035] The pH of the ophthalmic composition according to this embodiment is not particularly limited as long as it is within a range that is pharmaceutically, pharmacologically (pharmaceutically), or physiologically acceptable. The pH of the ophthalmic composition may be, for example, 4.0 to 9.5, 5.0 to 9.0, 5.5 to 8.5, 6.0 to 8.0, 6.5 to 7.5, 6.8 to 7.4, 6.9 to 7.3, or 7.0 to 7.2.

[0036] The ophthalmic composition according to this embodiment can be adjusted to an osmotic pressure ratio within a range acceptable to the body, as needed. An appropriate osmotic pressure ratio can be set as appropriate depending on the use, formulation form, and method of use of the ophthalmic composition, but may be, for example, 0.5 to 5.0, 0.6 to 3.0, 0.7 to 2.2, 0.8 to 2.0, 0.85 to 1.5, 0.9 to 1.4, 0.9 to 1.3, or 1.0 to 1.2. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (osmotic pressure of 0.9 w / v% sodium chloride aqueous solution) based on the 18th edition of the Japanese Pharmacopoeia, and the osmotic pressure is measured with reference to the osmotic pressure measurement method (freezing point depression method) described in the Japanese Pharmacopoeia. The standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution) can be prepared by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650°C for 40-50 minutes, then allowing it to cool in a desiccator (silica gel), accurately weighing 0.900 g of it, dissolving it in purified water to make exactly 100 mL, or by using a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution).

[0037] The viscosity of the ophthalmic composition according to this embodiment is not particularly limited, as long as it is within a range that is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. For example, the viscosity of the ophthalmic composition according to this embodiment may be 0.5 to 120 mPa·s, 0.6 to 100 mPa·s, 0.7 to 70 mPa·s, 0.8 to 40 mPa·s, 0.9 to 30 mPa·s, 1 to 20 mPa·s, 1 to 10 mPa·s, 1 to 5 mPa·s, 1 to 3 mPa·s, or 1 to 1.5 mPa·s, as measured at 20°C using a rotational viscometer (RE550 viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34' × R24).

[0038] The ophthalmic composition according to this embodiment is housed in a container. The container may be made of glass, resin, or, for example, resin. Examples of resins used to form the container include polyethylene terephthalate, polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, polyimide, cyclic olefin copolymers and copolymers of monomers constituting these, and mixtures of two or more of these. Preferably, it is polypropylene, polyethylene, or polyethylene terephthalate, and more preferably, polyethylene terephthalate. The container housing the ophthalmic composition according to this embodiment may be a transparent container that allows visibility of the contents, or an opaque container that makes it difficult to see the contents. Here, "transparent container" includes both colorless transparent containers and colored transparent containers.

[0039] A nozzle may be attached to the container for containing the ophthalmic composition according to this embodiment. The material of the nozzle is not particularly limited; for example, it may be made of glass or resin, but resin is preferred. Examples of resins for forming the nozzle include polybutylene terephthalate, polyethylene, polypropylene, polyethylene naphthalate and copolymers of monomers constituting these, and mixtures of two or more of these. From the viewpoint of further enhancing the effects of the present invention, polypropylene, polyethylene, polyethylene terephthalate, and polyethylene naphthalate are preferred as the material of the nozzle, and polyethylene terephthalate is more preferred.

[0040] The container may be a multi-dose type that holds multiple doses, or a unit-dose type that holds a single dose, but a multi-dose type is preferred.

[0041] The diameter of the hole in the liquid-contacting surface of the container according to this embodiment may be, for example, φ0.1 to 2 mm, 0.3 to 1.5 mm, or 0.3 to 1 mm.

[0042] The diameter of the tip of the container according to this embodiment may be, for example, φ1 to 4 mm, 1.5 to 3 mm, or 2 to 2.5 mm.

[0043] If the container according to this embodiment has a perforated inner stopper (nozzle), the diameter of the tip of the nozzle may be, for example, φ1 to 4 mm, 1.5 to 3 mm, or 2 to 2.5 mm.

[0044] The shape and capacity (internal volume) of the container according to this embodiment are not particularly limited and can be set as appropriate depending on the application. For example, if the container is for containing eye drops, the internal volume of the container is preferably 0.1 mL or more, 0.2 mL or more, 4 mL or more, 5 mL or more, 10 mL or more, or 13 mL or more. Alternatively, the internal volume of the container is preferably 25 mL or less, 20 mL or less, 18 mL or less, 3 mL or less, or 1 mL or less. The internal volume of the container may also be 5 to 25 mL, 10 to 20 mL, 13 to 18 mL, 0.1 to 3 mL, or 0.2 to 1 mL. Note that the internal volume of the container refers to the maximum volume of ophthalmic composition that can be contained in the container when a nozzle is attached.

[0045] The container may have an overall height of 50-70 mm, a width of 20-40 mm, and a body thickness of 10-20 mm.

[0046] The ophthalmic composition according to this embodiment has a filling rate of 70% or more in the container according to this embodiment. From the viewpoint of further enhancing the effects of the present invention, the filling rate is preferably 75% or more, 77% or more, 80% or more, 85% or more, or 90% or more. The upper limit of the filling rate is not particularly limited and may be 100% or less, or 95% or less. In this specification, the filling rate means the ratio (%) of the amount of ophthalmic composition filled (mL) to the internal volume (mL) of the container in which the ophthalmic composition is contained, and is calculated by the following formula (A). Note that the internal volume of the container refers to the maximum volume of ophthalmic composition that can be contained in the container in the state at the time of sale of the containerized ophthalmic composition, and not the sales volume indicated on the product, etc. Here, the state at the time of sale of the containerized ophthalmic composition means the state in which all parts (e.g., nozzles) that are attached to the container at the time of sale are attached. Filling rate (%) = Amount of ophthalmic composition filled (mL) / Volume of the container (mL) × 100 ... (A)

[0047] In the ophthalmic composition according to this embodiment, the ophthalmic composition is given an irradiance of 765 w / m². 2 When irradiated with light for 8 hours, it is preferable that the ratio of the content of component (A) after irradiation to the content of component (A) before irradiation is 70% or more. When this ratio is 70% or more, the photostability of the ophthalmic composition according to this embodiment is particularly excellent. Irradiance 765 w / m 2 Methods of irradiating light under these conditions include irradiating the ophthalmic composition, while it is contained in a container, with a light irradiation device (for example, SUNTEST XLS+, Toyo Seiki Seisakusho Co., Ltd.).

[0048] For ophthalmic compositions, irradiance of 765 w / m² 2 When light is irradiated for 8 hours, the ratio of the content of component (A) after irradiation to the content of component (A) before irradiation may be 72% or more, 75% or more, 80% or more, 82% or more, 85% or more, 87% or more, or 90% or more.

[0049] In the ophthalmic composition according to this embodiment, it is preferable that when the ophthalmic composition is left to stand in a 60°C environment for 3 weeks, the ratio of the content of component (A) after standing to the content of component (A) before standing is 70% or more. When this ratio is 70% or more, the thermal stability of the ophthalmic composition according to this embodiment is said to be particularly excellent.

[0050] When an ophthalmic composition is left to stand for three weeks in an environment of 60°C, the ratio of the content of component (A) after standing to the content of component (A) before standing may be 72% or more, 75% or more, 80% or more, 82% or more, 85% or more, 87% or more, or 90% or more. Furthermore, it is preferable that the ratio is 95% or more or 97% or more.

[0051] When an ophthalmic composition is left standing at 60°C for 3 weeks, if the content of component (A) described above is 70% or more, it is expected that it will exhibit excellent thermal stability when left standing at 40°C for 6 months and when left standing at room temperature for 3 years. When an ophthalmic composition is left standing at 40°C for 6 months or at room temperature for 3 years, the preferred ratio of the content of component (A) after standing to the content of component (A) before standing is the same as the preferred range for when it is left standing at 60°C for 3 weeks.

[0052] The present invention described above can also be understood as a method for stabilizing brimonidine and / or its salts in an ophthalmic composition, comprising placing an ophthalmic composition containing (A) brimonidine and / or its salts and (B) a cooling agent in a container such that the filling rate is 70% or more. Stabilization of brimonidine and / or its salts includes suppressing the decrease in the content of brimonidine and / or its salts contained in the ophthalmic composition over time (including the decrease in content caused by exposure to light or heat, etc.). The present invention can also be described as a method for improving the photostability and thermal stability of brimonidine and / or its salts, including the above-described configuration. Specific embodiments of the method can be applied without particular limitation to the specific embodiments described above. [Examples]

[0053] The present invention will be described in more detail below using examples and comparative examples, but the present invention is not limited to the following examples.

[0054] The ophthalmic compositions of the formulation examples shown in Tables 1 and 2 were prepared by conventional methods. The prepared ophthalmic compositions were filled into eye drop bottles (internal volume: 8 mL, material: PET, body thickness: 13 mm, total height: 61 mm) to a filling rate of 50%, 80%, or 90%, respectively, and the caps were attached to obtain the ophthalmic compositions (ophthalmic compositions contained in containers) according to the examples and comparative examples.

[0055] [Table 1]

[0056] [Table 2]

[0057] <Test Example 1: Photostability Test> The eye drop bottles containing the ophthalmic compositions according to the examples and comparative examples were subjected to irradiation at 765 w / m² using a light irradiation device called Suntest XLS+ (Toyo Seiki Seisakusho Co., Ltd.). 2 The sample was irradiated with light for 8 hours (22032 kJ / m³). 2 (Equivalent to). The brimonidine tartrate content of the ophthalmic composition before and after light irradiation was measured by HPLC under the following conditions. Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm, packed with 3.5 μm high-performance liquid chromatography ODS silica gel (Xbridge C18 column, Waters). Column temperature: Constant temperature around 25°C Mobile phase: 2.3 g of potassium dihydrogen phosphate and 47.5 mg of sodium 1-heptanesulfonate were dissolved in 830 mL of water, and the pH was adjusted to 3.0 using phosphoric acid. 84 mL of acetonitrile and 84 mL of methanol were mixed with this solution, and water was added to make 1 L. Flow rate: approx. 1mL / min

[0058] For each of the examples and comparative examples, the ratio (%) of the brimonidine tartrate content after the test to the brimonidine tartrate content before the test was calculated, and this was defined as the residual rate (%) of brimonidine tartrate after the test. As a result, the residual rate was 70% or more in the ophthalmic compositions of Examples 1 to 3. Furthermore, the rate of reduction in brimonidine tartrate content was calculated for each of the examples and comparative examples based on the following formula (1). Decreased percentage of brimonidine tartrate content (%) = 100 - remaining percentage (%) ... (1)

[0059] Next, using the content reduction rate calculated using formula (1), the degree of improvement (%) in the reduction of brimonidine tartrate content within the same formulation, relative to the example with a 50% fill rate, was calculated based on formula (2) below. This degree of improvement indicates how much the reduction rate of brimonidine tartrate content associated with the test improves when the fill rate is changed from 50% to 80% or 90%. A positive value for this degree of improvement means that the photostability has improved compared to the example with a 50% fill rate, and the larger this value, the better the photostability. The degree of improvement in content reduction (%) based on the example of a 50% filling rate = 100 × (Content reduction rate at a 50% filling rate - Content reduction rate at each filling rate) / Content reduction rate at a 50% filling rate ... (2)

[0060] Table 3 shows the results of the improvement calculated using formula (2). When the fill rate was increased from 50% to 80% or 90% within the same formulation, the decrease in brimonidine tartrate content did not improve in formulation examples 1 and 3, but the decrease in content improved in formulation examples 2 and 4, indicating improved photostability. In other words, it was found that the ophthalmic compositions of Examples 1 to 3, which contain brimonidine and / or its salt, a cooling agent, and have a fill rate of 70% or more, exhibit excellent photostability.

[0061] [Table 3]

[0062] Furthermore, for the 90% fill rate examples in Formulation Example 1 and Formulation Example 2, the degree of improvement (%) in the reduction of brimonidine tartrate content due to the addition of a cooling agent was calculated based on the following formula (3). This degree of improvement indicates how much the reduction in brimonidine tartrate content after testing is improved by the addition of a cooling agent, given the same fill rate. A positive value for this degree of improvement means that the photostability is improved compared to Formulation Example 1, which does not contain a cooling agent, and the larger this value, the better the photostability. Improvement in content reduction due to the addition of a cooling agent (%) = 100 × (Percentage reduction in content in Formula Example 1 - Percentage reduction in content in Formula Example 2) / Percentage reduction in content in Formula Example 1 ... (3)

[0063] In this study, the degree of improvement was calculated according to formula (3), using the content reduction rate of Comparative Example 3 as an example of Formulation Example 1, and the content reduction rate of Example 2 as an example of Formulation Example 2. As a result, the degree of improvement in content reduction for Example 2 was 15.3%. In other words, when the filling rate is the same (90%), the ophthalmic composition of Example 2, which contains menthol as a cooling agent, showed improved reduction in brimonidine tartrate content and improved photostability compared to the ophthalmic composition of Comparative Example 3, which does not contain a cooling agent.

[0064] Furthermore, by replacing Formula Example 1 with Formula Example 3 and Formula Example 2 with Formula Example 4 in the above formula (3), the degree of improvement (%) in the reduction of brimonidine tartrate content due to the addition of a cooling agent was calculated for the example in Formula Example 4 with a filling rate of 90%.

[0065] In calculating the degree of improvement, the content reduction rate of Comparative Example 6 was used as an example for Formulation Example 3, and the content reduction rate of Example 3 was used as an example for Formulation Example 4. As a result, the degree of improvement in content reduction for Example 3 was 25.9%. In other words, when the filling rate is the same (90%), the ophthalmic composition of Example 3, which contains menthol as a cooling agent, showed improved reduction in brimonidine tartrate content and improved photostability compared to the ophthalmic composition of Comparative Example 6, which does not contain a cooling agent.

[0066] <Test Example 2: Thermal Stability Test 1> The eye drop bottles containing the ophthalmic compositions according to the examples and comparative examples were stored in a light-shielded environment at 60°C for 3 weeks. The brimonidine tartrate content of the ophthalmic compositions before and after storage was measured by HPLC under the above conditions.

[0067] For Example 1, Comparative Example 2, and Comparative Example 4, the ratio (%) of the brimonidine tartrate content after the test to the brimonidine tartrate content before the test was calculated, and this was defined as the residual rate (%) of brimonidine tartrate after the test. As a result, the residual rate in the ophthalmic composition of Example 1 was 80% or more. Furthermore, based on the above formula (1), the rate of reduction in brimonidine tartrate content was calculated for Example 1, Comparative Example 2, and Comparative Example 4.

[0068] Next, using the content reduction rate calculated by formula (1), the degree of improvement (%) in the reduction of brimonidine tartrate content within the same formulation, relative to the example with a 50% fill rate, was calculated based on formula (2) above. A positive value for this degree of improvement means that the thermal stability has improved compared to the example with a 50% fill rate, and the larger this value, the better the thermal stability.

[0069] In this study, the degree of improvement was calculated according to formula (2), using the content reduction rate of Comparative Example 4 as an example of a 50% filling rate, and the content reduction rate of Example 1 as an example of an 80% filling rate. As a result, the degree of improvement in content reduction for Example 1 was 53.09%. In other words, even with the same formulation, the ophthalmic composition of Example 1, which has a filling rate of 70% or more, showed improved reduction in brimonidine tartrate content and improved thermal stability compared to the ophthalmic composition of Comparative Example 4, which has a filling rate of less than 70%.

[0070] Furthermore, based on the above formula (3), the degree of improvement (%) in the reduction of brimonidine tartrate content due to the addition of a cooling agent was calculated. A positive value for this degree of improvement means that the thermal stability is improved compared to Formulation Example 1, which does not contain a cooling agent, and the larger this value, the better the thermal stability.

[0071] In this study, the degree of improvement was calculated according to formula (3), using the content reduction rate of Comparative Example 2 as an example of Formulation Example 1, and the content reduction rate of Example 1 as an example of Formulation Example 2. As a result, the degree of improvement in content reduction for Example 1 was 6.3%. In other words, when the filling rate is the same (80%), the ophthalmic composition of Example 1, which contains menthol as a cooling agent, showed improved reduction in brimonidine tartrate content and improved thermal stability compared to the ophthalmic composition of Comparative Example 2, which does not contain a cooling agent.

[0072] <Test Example 3: Thermal Stability Test 2> In the formulation example 2 shown in Table 1 above, ophthalmic compositions were prepared by conventional methods for formulation example 5 (in which polysorbate 80 was replaced with polyoxyethylene hydrogenated castor oil 60) and formulation example 6 (in which polyoxyl stearate 40 was replaced with polysorbate 80). Note that formulation example 5 used in this study is the same formulation as formulation example 4 shown in Table 2 above.

[0073] The prepared ophthalmic composition was filled into eye drop bottles (internal volume: 8 mL, material: PET, body thickness: 13 mm, total height: 61 mm) to a filling rate of 80% or 90%, and the cap was attached to obtain the ophthalmic composition (ophthalmic composition contained in a container). Example 4 was obtained by filling the ophthalmic composition of Formulation Example 5 to a filling rate of 80%, and Example 5 was obtained by filling it to a filling rate of 90%. Similarly, Example 6 was obtained by filling the ophthalmic composition of Formulation Example 6 to a filling rate of 80%, and Example 7 was obtained by filling it to a filling rate of 90%.

[0074] The eye drop bottles containing the ophthalmic compositions according to Examples 4-7 were stored in a light-shielded container at 40°C for 6 months. The residual rate of brimonidine tartrate was calculated for the ophthalmic compositions before and after storage using the HPLC method described above. As a result, the residual rate for all ophthalmic compositions in Examples 4-7 was 95% or higher. In other words, it was found that brimonidine tartrate is stable in ophthalmic compositions containing menthol as a cooling agent and with a filling rate of 80% or higher, under light-shielded containers at 40°C for 6 months.

Claims

1. An ophthalmic composition contained in a container, (A) Contains brimonidine and / or a salt thereof, and (B) a cooling agent. An ophthalmic composition in which the filling rate of the ophthalmic composition in the container is 70% or more.

2. The ophthalmic composition according to claim 1, wherein the content of component (A) is 0.005 to 0.02 w / v% based on the total amount of the ophthalmic composition.

3. The ophthalmic composition according to claim 1 or 2, wherein the content of component (B) is 0.001 to 0.5 w / v% based on the total amount of the ophthalmic composition.

4. The ophthalmic composition according to claim 1 or 2, wherein the mass ratio of the content of component (B) to the content of component (A) is 0.1 to 50.

5. The ophthalmic composition according to claim 1 or 2, wherein component (B) is menthol.

6. The ophthalmic composition according to claim 1 or 2, wherein the filling rate of the ophthalmic composition in the container is 90% or more.

7. (C) The ophthalmic composition according to claim 1 or 2, further comprising a surfactant.

8. A method for stabilizing brimonidine and / or its salts in ophthalmic compositions, A method comprising placing an ophthalmic composition containing (A) brimonidine and / or a salt thereof and (B) a cooling agent into a container such that the filling rate is 70% or more.

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