JP5909152B2 - Aqueous composition containing tranilast - Google Patents

Description

  The present invention relates to an aqueous composition.

  Tranilast (N- (3,4-dimethoxycinnamoyl) anthranilic acid) is used as an active ingredient for oral administration, eye drops and the like as a therapeutic agent for allergic diseases. However, it is known that an aqueous composition containing tranilast and / or a salt thereof tends to precipitate crystals during storage.

  As a technique for suppressing such crystal precipitation, for example, Patent Document 1 discloses (A) tranilast, a salt thereof, or a mixture thereof, (B) sorbic acid, a salt thereof, or a mixture thereof, and (C). An aqueous preparation containing ethylenediaminetetraacetic acid, a salt thereof, or a mixture thereof, having a pH of 6.8 to 9, and filled in a plastic container is disclosed.

JP 2006-169193 A

  The present invention provides an aqueous composition that is superior in terms of formulation because it is an aqueous composition containing tranilast and / or a salt thereof, and even when stored for a long period of time, crystal precipitation is suppressed. For the purpose.

  The present invention includes (A) at least one selected from the group consisting of tranilast and its salt, (B) at least one selected from the group consisting of pranoprofen and its salt, (C) pyridoxine and its Provided is an aqueous composition containing at least one selected from the group consisting of salts and (D) at least one selected from the group consisting of dibutylhydroxytoluene and salts thereof.

  Even when the aqueous composition of the present invention is a composition containing tranilast and / or a salt thereof, particularly when it is stored for a long time at a low temperature at which crystal precipitation is likely to occur, the component (B) The presence of the components (C) and (D) significantly suppresses crystal precipitation (hereinafter, this effect is also referred to as “crystal precipitation suppression effect”). In addition, the aqueous composition of the present invention has a crystal precipitation inhibitory effect as described above, is stable, and is excellent in terms of formulation.

  The aqueous composition of the present invention can be used for ophthalmology and is preferably applied as an eye drop.

  In ophthalmic aqueous compositions and eye drops, the concentration of the compounding components is often very low. For example, if the content is slightly reduced due to crystal precipitation, the composition is greatly affected. Further, when crystal precipitation occurs, the quality and safety of the product including the safety as a preparation applied to the ocular mucosa may be reduced. However, according to the present invention, the stability of the aqueous composition containing tranilast and / or a salt thereof is improved, and the decrease in the content of compounding ingredients and crystal precipitation are remarkably suppressed. Therefore, it is possible to obtain an aqueous composition having high quality and commercial value including safety as a preparation to be applied to the ocular mucosa. Therefore, it can be suitably used for ophthalmic use and eye drop use.

  According to the present invention, even if it is an aqueous composition containing tranilast and / or a salt thereof, it may be stored for a long period of time (in particular, it may be stored at a low temperature for a long period of time). ), Crystal precipitation is remarkably suppressed and stable, and even if it is distributed and stored in a cold region, an aqueous composition excellent in formulation is provided.

(A) In Test Example 1, it is a photograph showing a state after each test solution has been stored for a long time at a low temperature. (B) It is the trace figure which traced the photograph of (A). In Experiment 1, it is a graph which shows the tranilast density | concentration after storing each test liquid for a long time under low temperature.

  The aqueous composition of the present invention contains (A) tranilast and / or a salt thereof (also referred to as “component (A)”).

  Tranilast is a known compound also referred to as N- (3,4-dimethoxycinnamoyl) anthranilic acid, which may be synthesized by a known method or obtained as a commercial product.

  Among the components (A) used in the present invention, the salt of tranilast is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Is an organic acid salt [eg, monocarboxylate (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylate (fumarate, maleate, succinic acid, etc. Salt, malonate, etc.), oxycarboxylate (lactate, tartrate, citrate, etc.), organic sulfonate (methanesulfonate, toluenesulfonate, tosylate, etc.)], inorganic acid salt (E.g., hydrochloride, sulfate, nitrate, hydrobromide, phosphate), salts with organic bases (e.g., methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, Salts with organic amines such as choline), salts with inorganic bases [for example, ammonium salts; salts with alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), metals such as aluminum], etc. And various salts. These tranilast salts may be used alone or in any combination of two or more.

  In the aqueous composition of the present invention, as component (A), one type of tranilast and a salt thereof may be used alone, or two or more types may be used in any combination. Also good. Of these, tranilast is preferably used.

  In the aqueous composition of the present invention, the blending ratio of the component (A) is appropriately set according to the type of the component (A), the type of the other blending component, the formulation form of the aqueous composition, etc. Compound (A) is a total amount of 0.001 to 10 w / v%, preferably 0.01 to 5 w / v%, more preferably 0.1 to 1 w / v%, based on the total amount of the aqueous composition The ratio is illustrated.

  The aqueous composition of the present invention contains (B) pranoprofen and / or a salt thereof (also referred to as “component (B)”).

  Planoprofen is a known compound also called α-methyl-5H- [1] benzopyrano [2,3-b] pyridine-7-acetic acid, which may be synthesized by a known method and obtained as a commercial product. You can also.

  The salt of pranoprofen is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and specifically, a salt that can be taken by component (A) The thing of the same form is illustrated. These pranoprofen salts may be used alone or in any combination of two or more.

  Further, pranoprofen and / or a salt thereof may be any of d-form, l-form, and dl-form.

  Of the pranoprofen and its salt, pranoprofen is preferable from the viewpoint of obtaining a higher crystal precipitation suppressing effect.

  In the aqueous composition of the present invention, the blending ratio of the component (B) is appropriately set according to the type of the component (B), the type of the other blending components, the formulation form of the aqueous composition, etc. With respect to the total amount of the aqueous composition, the total amount of component (B) is 0.001 to 1 w / v%, preferably 0.005 to 0.5 w / v%, more preferably 0.01 to 0.1 w / v. A blending ratio of% is exemplified.

  Moreover, in the aqueous composition of the present invention, the ratio of the component (B) to the component (A) is not particularly limited, but as an example, per 100 parts by mass of the total amount of the component (A), (B) Examples include a range in which the total amount of components is 0.2 to 200 parts by mass, preferably 1 to 100 parts by mass, and more preferably 2 to 20 parts by mass.

  The aqueous composition of the present invention contains (C) pyridoxine and / or a salt thereof (also referred to as “component (C)”).

  Pyridoxine is a compound also called 5-hydroxy-6-methylpyridine-3,4-dimethanol. Pyridoxine and its salt are known compounds as vitamin B6, which is a water-soluble vitamin, and may be synthesized by a known method or obtained as a commercial product.

  The salt of pyridoxine is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable, and specifically, the same form as the salt that component (A) can take. Are exemplified. Among these salts, preferred are inorganic acid salts and / or organic acid salts, more preferred are inorganic acid salts, still more preferred are hydrochlorides and / or phosphates, and particularly preferred are hydrochlorides. These pyridoxine salts may be used alone or in any combination of two or more.

  Among the pyridoxines and salts thereof, from the viewpoint that a higher crystal precipitation suppression effect is obtained, pyridoxine and / or an inorganic acid salt thereof is preferable, more preferably pyridoxine, pyridoxine hydrochloride, and / or pyridoxine phosphate, Pyridoxine hydrochloride and / or pyridoxine phosphate are preferable, and pyridoxine hydrochloride (pyridoxine hydrochloride) is particularly preferable.

  In the aqueous composition of the present invention, the blending ratio of the component (C) is appropriately set according to the type of the component (C), the type of other blending components, the formulation form of the aqueous composition, etc. The total amount of component (C) is 0.0001 to 1 w / v%, preferably 0.001 to 0.5 w / v%, more preferably 0.01 to 0.2 w / v, based on the total amount of the aqueous composition. A blending ratio of% is exemplified.

  Further, in the aqueous composition of the present invention, the ratio of the component (C) to the component (A) is not particularly limited, but as an example, per 100 parts by mass of the total amount of the component (A), (C) Examples include a range in which the total amount of components is 0.02 to 200 parts by mass, preferably 0.2 to 100 parts by mass, and more preferably 2 to 40 parts by mass.

  The aqueous composition of the present invention contains (D) dibutylhydroxytoluene and / or a salt thereof (also referred to as “(D) component”).

  Dibutylhydroxytoluene (sometimes abbreviated as BHT) is a known compound that is also called 2,6-di-tert-butyl-4-methylphenol, and may be synthesized by a known method. Can also be obtained as

  The salt of dibutylhydroxytoluene is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. The thing of the same form is illustrated. These dibutylhydroxytoluene salts may be used alone or in any combination of two or more.

  Of the dibutylhydroxytoluenes and salts thereof, dibutylhydroxytoluene is preferably used from the viewpoint of obtaining a higher crystal precipitation suppressing effect.

  In the aqueous composition of the present invention, the blending ratio of the component (D) is appropriately set according to the type of the component (D), the type of the other blending components, the formulation form of the aqueous composition, etc. The total amount of component (D) is 0.0001 to 0.05 w / v%, preferably 0.0005 to 0.03 w / v%, more preferably 0.001 to 0.01 w, based on the total amount of the aqueous composition. A blending ratio of / v% is exemplified.

  Moreover, in the aqueous composition of the present invention, the ratio of the component (D) to the component (A) is not particularly limited, but, as an example, per 100 parts by mass of the total amount of the component (A), (D) Examples include a range in which the total amount of components is 0.02 to 20 parts by mass, preferably 0.1 to 10 parts by mass, and more preferably 0.2 to 2 parts by mass.

  The combination of the components (B), (C) and (D) according to the present invention is effective for crystal precipitation in an aqueous composition containing the component (A) (particularly during long-term storage and long-term low-temperature storage). ) Can be effectively suppressed. Therefore, the combination of the components (B), (C) and (D) according to the present invention can be used for suppressing crystal precipitation in an aqueous composition containing tranilast and / or a salt thereof. The combination of the components (B), (C) and (D) according to the present invention can also be used as a crystal precipitation inhibitor in an aqueous composition containing tranilast and / or a salt thereof.

  The aqueous composition of the present invention contains at least the components (A) to (D) described above. In the aqueous composition of the present invention, the compounds described as specific examples of the components (A) to (D) can be used in any combination.

  The aqueous composition of the present invention may further contain a solubilizing agent. The solubilizing agent that can be blended in the aqueous composition of the present invention may be any component that has an action of assisting the dissolution of tranilast and / or a salt thereof, which is extremely hardly soluble in water, in an aqueous solution. For example, polyvinylpyrrolidone , Trometamol, monoethanolamine, diethanolamine, triethanolamine, propylene glycol, caffeine and the like. These solubilizers may be used alone or in any combination of two or more.

  Among these solubilizing agents, polyvinyl pyrrolidone and / or monoethanolamine are preferable, and polyvinyl pyrrolidone is more preferable. The molecular weight of polyvinylpyrrolidone is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable, but in general, the K value by the Fikencher method is 15 to 100, preferably 20 to 99, more preferably about 22 to 98 can be used.

  When the above-mentioned solubilizing agent is blended in the aqueous composition of the present invention, the blending ratio differs depending on the type of solubilizing agent used, the type and blending amount of other components, the use of the aqueous composition, etc. However, for example, the total amount of the solubilizing agent is 0.001 to 10 w / v%, preferably 0.005 to 7 w / v%, more preferably, based on the total amount of the aqueous composition. The compounding ratio which will be 0.01-5 w / v% is illustrated.

  The aqueous composition of the present invention may further contain a buffer. The buffer that can be incorporated into the aqueous composition of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such buffers include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, tris buffer, epsilon-aminocaproic acid, aspartic acid, aspartate and the like. These buffering agents may be used in combination. As the buffer, a borate buffer, a phosphate buffer, a carbonate buffer, and a citrate buffer are preferable.

  Examples of the boric acid buffer include boric acid or boric acid salts such as alkali metal borate and alkaline earth metal borate. Examples of the phosphate buffer include phosphoric acid or phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Examples of the carbonate buffer include carbonates or carbonates such as alkali metal carbonates and alkaline earth metal carbonates. Examples of the citrate buffer include citric acid, alkali metal citrate, and alkaline earth metal citrate. Moreover, you may use the borate or the hydrate of a phosphate as a borate buffer or a phosphate buffer. As a more specific example, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); as a phosphate buffer, phosphoric acid or a salt thereof Salt (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); Or a salt thereof (sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.); citric acid or a salt thereof (sodium citrate, potassium citrate, citric acid, etc.) Acid calcium, sodium dihydrogen citrate, disodium citrate, etc.); acetic acid As an agent, acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.); As a Tris buffer, tris (hydroxymethyl) aminomethane or a salt thereof (hydrochloride, acetate, sulfonate, etc.); Examples include aspartic acid or a salt thereof (sodium aspartate, magnesium aspartate, potassium aspartate, etc.). These buffering agents may be used alone or in any combination of two or more.

  Among the above buffering agents, boric acid buffering agents and phosphate buffering agents, particularly boric acid buffering agents are particularly suitable. Preferred specific examples of the boric acid buffer include a combination of boric acid and a salt thereof; preferably a combination of boric acid and an alkali metal salt and / or an alkaline earth metal salt of boric acid; more preferably boric acid. , A combination with an alkali metal salt of boric acid; particularly preferably a combination of boric acid and borax. Further, as a preferable specific example of the phosphate buffer, a combination of a primary phosphate and a secondary phosphate; preferably, an alkali metal salt of a primary phosphate and an alkali metal salt of a secondary phosphate Combination; More preferably, a combination of sodium dihydrogen phosphate and disodium hydrogen phosphate is exemplified.

  When a buffering agent is blended in the aqueous composition of the present invention, the blending ratio of the buffering agent varies depending on the type of buffering agent used, the type and amount of other blending components, the use of the aqueous composition, etc. For example, the total amount of the buffer is 0.01 to 10 w / v%, preferably 0.05 to 5 w / v%, more preferably 0.1 to the total amount of the aqueous composition. Examples of the blending ratio are ˜3 w / v%.

  The aqueous composition of the present invention may further contain a surfactant. The surfactant that can be incorporated into the aqueous composition of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and is a nonionic surfactant or amphoteric. Any of a surfactant, an anionic surfactant, and a cationic surfactant may be used.

  Specific examples of the nonionic surfactant that can be blended in the aqueous composition of the present invention include POE (20) sorbitan monolaurate (polysorbate 20), POE (20) sorbitan monopalmitate (polysorbate 40), and monostearin. POE sorbitan fatty acid esters such as acid POE (20) sorbitan (polysorbate 60), tristearic acid POE (20) sorbitan (polysorbate 65), monooleic acid POE (20) sorbitan (polysorbate 80); poloxamer 407, poloxamer 235, POE / POP block copolymers such as Poloxamer 188, Poloxamer 403, Poloxamer 237, Poloxamer 124; POE cured castor oil such as POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60) POE castor oil; POE alkyl ethers such as POE (9) lauryl ether; POE-POP alkyl ethers such as POE (20) POP (4) cetyl ether; POE alkyl phenyl such as POE (10) nonyl phenyl ether; And ethers. In the compounds exemplified above, POE is polyoxyethylene, POP is polyoxypropylene, and the numbers in parentheses indicate the number of moles added. Specific examples of the amphoteric surfactant that can be incorporated into the aqueous composition of the present invention include alkyldiaminoethylglycine. Specific examples of the cationic surfactant that can be blended in the aqueous composition of the present invention include benzalkonium chloride and benzethonium chloride. Specific examples of the anionic surfactant that can be incorporated into the aqueous composition of the present invention include alkylbenzene sulfonate, alkyl sulfate, polyoxyethylene alkyl sulfate, aliphatic α-sulfomethyl ester, α -Olefin sulfonic acid etc. are illustrated. In the aqueous composition of the present invention, these surfactants may be used alone or in combination of two or more.

  Of these surfactants, nonionic surfactants are preferred. Preferable examples of nonionic surfactants include POE sorbitan fatty acid esters, POE hydrogenated castor oil, POE castor oil and / or POE / POP block copolymers, more preferably POE sorbitan fatty acid esters, POE cured Castor oils and / or POE / POP block copolymers, more preferably POE sorbitan fatty acid esters and / or POE hydrogenated castor oils, particularly preferably POE sorbitan fatty acid esters.

  When a surfactant is blended in the aqueous composition of the present invention, the blending ratio of the surfactant can be appropriately set according to the type of surfactant, the type and amount of other components, the use of the aqueous composition, and the like. . As an example of the blending ratio of the surfactant, the total amount of the surfactant is 0.001 to 1.0 w / v%, preferably 0.005 to 0.5 w / v%, based on the total amount of the aqueous composition. More preferably, a blending ratio of 0.01 to 0.3 w / v% is exemplified.

  The pH of the aqueous composition of the present invention is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable range. The range which becomes 0.0-9.5, Preferably it is 5.0-9.0, More preferably, it is 6.0-8.5, More preferably, it is 7.0-8.0.

  If necessary, the aqueous composition of the present invention can be adjusted to an osmotic pressure ratio within a range acceptable for a living body. The appropriate osmotic pressure ratio varies depending on the application site, dosage form, etc., but is usually in the range of 0.5 to 5.0, more preferably 0.6 to 3.0, and even more preferably 0.7 to 2.0. It is done. The osmotic pressure can be adjusted by a known method in the technical field using an inorganic salt, a polyhydric alcohol, or the like. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to the osmotic pressure of 286 mOsm (0.9 w / v% sodium chloride aqueous solution) based on the 15th revised Japanese Pharmacopoeia. Measure according to the freezing point method. The standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) was dried in sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650 ° C. for 40 to 50 minutes, and then in a desiccator (silica gel). The mixture is allowed to cool and 0.900 g is accurately weighed and dissolved in purified water to make exactly 100 mL, or a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution) is used.

The aqueous composition of the present invention may contain an appropriate amount of various pharmacologically active ingredients and physiologically active ingredients in addition to the above-mentioned ingredients as long as the effects of the present invention are not hindered. Examples of such pharmacologically active ingredients and physiologically active ingredients include active ingredients in various pharmaceuticals described in the over-the-counter drug manufacturing (import) approval standard 2000 edition (supervised by the Pharmaceutical Affairs Research Committee). Specific examples include the following components.
Antihistamine or antiallergic agent: for example, ketotifen fumarate, iproheptin, diphenhydramine hydrochloride, pemirolast potassium, chlorpheniramine maleate, sodium cromoglycate and the like.
Decongestant: For example, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline sulfate, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, and the like.
Bactericides: for example, acrinol, cetylpyridinium, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, polyhexamethylene biguanide hydrochloride, etc.
Vitamins: For example, flavin adenine dinucleotide sodium, cyanocobalamin, retinol acetate, retinol palmitate, panthenol, calcium pantothenate, tocopherol acetate and the like.
Amino acids: For example, potassium aspartate, magnesium aspartate, aminoethylsulfonic acid, sodium chondroitin sulfate and the like.
Anti-inflammatory agents: for example, glycyrrhetinic acid, methyl salicylate, glycol salicylate, azulene sulfonic acid, allantoin, tranexamic acid, ε-aminocaproic acid, berberine, lysozyme, dipotassium glycyrrhizinate, etc.
Astringent: For example, zinc white, zinc lactate, zinc sulfate and the like.
Other: for example, neostigmine methyl sulfate, sodium hyaluronate, sulfamethoxazole, sodium sulfamethoxazole, indomethacin, ibuprofen, ibuprofen piconol, bufexamac, butyl fenfenamic acid, bendazac, piroxicam, ketoprofen, felbinac, purple root, Horse chestnut, and salts thereof.

In addition, in the aqueous composition of the present invention, various additives are appropriately selected according to conventional methods according to the use and formulation form within a range that does not impair the effects of the present invention, and one or more are selected. An appropriate amount may be contained in combination. Examples of such additives include various additives described in Pharmaceutical Additives Encyclopedia 2007 (edited by Japan Pharmaceutical Additives Association). Typical additives include the following additives.
Thickeners: for example, carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, alginic acid, polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone, macrogol, sodium chondroitin sulfate, sodium hyaluronate and the like.
Sugars: for example, glucose, cyclodextrin and the like.
Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like. These may be d-form, l-form or dl-form.
Preservatives, bactericides or antibacterial agents: for example, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxy Methyl benzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically polyhexamethylene biguanide hydrochloride, etc.), Glowyl (manufactured by Rhodia) Product name) etc.
pH adjuster: for example, hydrochloric acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, sodium carbonate, boro Sand, triethanolamine, diisopropanolamine, sulfuric acid, phosphoric acid, polyphosphoric acid, propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, tartaric acid, malic acid, succinic acid, gluconolactone, ammonium acetate and the like.
Stabilizers: For example, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, aluminum monostearate, glyceryl monostearate and the like.
Chelating agents: for example, ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (edetic acid, EDTA), N- (2-hydroxyethyl) ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), and the like.
Perfume or refreshing agent: for example, menthol, anethole, eugenol, camphor, geraniol, cineol, borneol, limonene, ryuno and the like. These may be either d-form, l-form or dl-form, and are formulated as essential oils (mint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, bergamot oil, eucalyptus oil, rose oil, etc.) May be.

  In the present specification, the aqueous composition means a composition containing water, and usually contains 1% by mass or more, preferably 5% by mass or more, more preferably 20% by mass or more of water in the composition. It means preferably 50% by mass or more, particularly preferably 90% by mass or more. The water contained in the aqueous composition of the present invention only needs to be pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. For example, distilled water, normal water, purified water, sterilized purified water, water for injection, distilled water for injection, and the like can be used. These definitions are based on the 15th revision Japanese Pharmacopoeia.

  The aqueous composition of the present invention is prepared by adding a desired amount of the above components (A) to (D) and, if necessary, other blending components so as to have a desired concentration. Formulation forms can be taken. For example, as a preparation form of the aqueous composition of the present invention, a liquid agent, a semi-solid agent (ointment etc.) and the like can be mentioned. A liquid agent is preferable.

  In addition, the aqueous composition of the present invention can be used as a pharmaceutical preparation, a quasi-drug, and the like. For example, an ophthalmic composition, a nasal composition, an oral composition, an ear composition, a composition for subcutaneous administration. It can be used in various applications such as products and compositions for external use on the skin.

  Here, the ophthalmic composition includes eye drops (including eye drops that can be used even while wearing contact lenses) and artificial tears (artificial tears that can also be used while wearing contact lenses). ), Eye wash, eye ointment, contact lens mounting solution, contact lens care agent (including contact lens disinfectant, contact lens preservative, contact lens cleaner, contact lens cleaner, etc.) It is.

  In addition, nasal compositions include nasal drops, nasal washings, and the like. Oral compositions include internal medicines (eg, liquids, syrups, extracts), oropharyngeal drugs, mouthwashes, and the like. The eardrop composition includes eardrops. The composition for subcutaneous administration includes injections and the like.

  Among the above-mentioned uses, ophthalmic compositions often have a very low concentration (content ratio) of compounding ingredients compared to compositions for other uses such as oral compositions, resulting in a slight decrease in content. But it can be a big problem. In particular, among ophthalmic compositions, eye drops are greatly affected by a decrease in content because the amount of one-time use is extremely small. Eye drops and contact lens care agents are often stored at room temperature such as a washstand, while eye drops may be stored in a refrigerator by the user. It can be said that it is a preparation form that is highly likely to be stored below. In addition, when crystals are precipitated by such storage, the quality of the product including safety as a preparation to be applied to the ocular mucosa and the commercial value are lowered. It is strongly demanded. According to the aqueous composition of the present invention, although it is an aqueous composition containing tranilast and / or a salt thereof, crystal precipitation is remarkably suppressed even when stored for a long period of time at a low temperature. It can be a clear and pharmaceutically very stable aqueous composition. In view of the effects of the present invention, a preferred example of the aqueous composition of the present invention is an ophthalmic composition, and a particularly preferred example is an eye drop.

  The aqueous composition of the present invention is provided by being contained in an arbitrary container. The container for storing the aqueous composition of the present invention is not particularly limited, and may be made of, for example, glass or plastic. Examples of the plastic include polyethylene terephthalate, polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, polyimide, a copolymer of monomers constituting these, and a mixture of these two or more. Moreover, the transparent container which can visually recognize the inside of a container may be sufficient as the container which accommodates the aqueous composition of this invention, and the opaque container in which visual recognition inside a container is difficult may be sufficient. Here, the “transparent container” includes both a colorless transparent container and a colored transparent container.

  Since the aqueous composition of the present invention can exhibit an antiallergic action based on the component (A), it is useful for the treatment or prevention of allergic diseases. For example, the allergy of eyes caused by pollen, house dust (indoor dust), etc. It can be used as a relieving agent for symptoms (for example, redness of eyes, itching of eyes, blurring of eyes (when there is a lot of eyes and eyes), smooth eyes, foreign body feeling (feeling of rolling)). Moreover, an anti-inflammatory action can be exhibited based on the component (B), and further, it can be used for nutritional supplementation based on the component (C).

  EXAMPLES The present invention will be described in detail below based on examples, but the present invention is not limited to these examples.

[Test Example 1: Stability test]
Each test solution was prepared according to the formulation shown in Table 1 below, and evaluation was made on crystal precipitation when stored for a long time at low temperature. Specific experimental methods and results are shown below.

<Evaluation criteria for crystal precipitation>
Crystal precipitation is intense: ++++++
There is considerable crystal precipitation: +++
There is crystal precipitation: +++
Slight crystal precipitation: ++
Slight crystal precipitation: +
Crystal clear and clear: −

  Each test solution was prepared according to the formulation shown in Table 1. The presence or absence of crystal precipitation immediately after the preparation was visually confirmed and evaluated according to the above evaluation criteria. Next, 5 mL of each test solution was filled in a 10 mL capacity glass vial and stored at 4 ° C. at a low temperature. Nine months later, the state of each test solution was visually confirmed and evaluated according to the above evaluation criteria in the same manner as immediately after the preparation. Moreover, photography was performed about the state of each test liquid.

  The evaluation results of the crystal precipitation amount immediately after preparation and after storage for 9 months at 4 ° C. are also shown in Table 1 above. FIG. 1 (A) is a photograph of each test solution after storage at 4 ° C. for 9 months. FIG. 1B is a trace image obtained by tracing the photograph. In FIG. 1 (A) and (B), the five glass vials are, from the left, Example 1 (reference numeral 1), Comparative Example 1 (reference numeral 2), Comparative Example 2 (reference numeral 3), and Comparative Example 3 (reference numeral). The glass vial bottle containing the test solution of 4) and the comparative example 4 (code | symbol 5) is shown.

  In the test solution of Comparative Example 4 containing no tranilast, no crystal deposition was observed even when stored for a long time at a low temperature (Comparative Example 4). In addition, when two components were selected and combined from pranoprofen, pyridoxine and dibutylhydroxytoluene in an aqueous composition containing tranilast, remarkable crystal precipitation was confirmed, and no crystal precipitation suppression effect was observed ( Comparative Examples 1-3). On the other hand, unexpectedly, when the three components of pranoprofen, pyridoxine and dibutylhydroxytoluene are combined with tranilast, no crystal precipitation is observed even when stored at low temperature for a long period of time. It was revealed that a very stable aqueous composition can be obtained (Example 1).

<Quantitative tranilast>
The concentration (content ratio) of tranilast was measured after storage for 9 months at 4 ° C. for each of the above test solutions. The concentration of tranilast was measured by HPLC according to a conventional method for the supernatant of each test solution. The relative concentration of tranilast in Comparative Examples 1 to 4 when the concentration of tranilast in the test solution of Example 1 is 100 is shown in FIG. As is clear from the quantitative results in FIG. 2, the test solution of Example 1 in which the three components of pranoprofen, pyridoxine and dibutylhydroxytoluene were combined with tranilast contained tranilast even when stored at low temperatures for a long period of time. The rate reduction was suppressed and the formulation was very excellent.

Eye drops (formulation examples 1 to 16) are prepared according to the formulations shown in Table 2 and Table 3 below. In the formulations of Tables 2 and 3, hydrochloric acid and sodium hydroxide are used for pH adjustment, and the aqueous composition is added so as to have the pH described in Tables 2 and 3. Purified water is added so that the total amount of eye drops is 100 ml.

  DESCRIPTION OF SYMBOLS 1 ... Examples 1, 2 ... Comparative example 1, 3 ... Comparative example 2, 4 ... Comparative example 3, 5 ... Comparative example 4. FIG.

Claims (3)

(A) at least one selected from the group consisting of tranilast and salts thereof;
(B) at least one selected from the group consisting of pranoprofen and a salt thereof;
(C) at least one selected from the group consisting of pyridoxine and salts thereof;
(D) At least 1 sort (s) selected from the group which consists of dibutylhydroxytoluene and its salt, The aqueous composition containing.   The aqueous composition according to claim 1, which is ophthalmic.   The aqueous composition according to claim 1 or 2, which is an eye drop.