JP6012231B2 - Bromfenac-containing composition - Google Patents

Description

  The present invention relates to a composition containing bromfenac and / or a salt thereof having excellent pharmaceutical stability. More particularly, the present invention relates to a composition with significantly improved stability while including a nonionic surfactant with bromfenac and / or its salts. Furthermore, the present invention relates to a method for improving the stability of bromfenac, which deteriorates when used in combination with a nonionic surfactant.

  Bromfenac and / or its salts are excellent for inflammatory diseases of the external and anterior segments (eg blepharitis, conjunctivitis, scleritis (including episcleral inflammation), postoperative inflammation, etc.) As a drug capable of exerting an anti-inflammatory action, it has been used in eye drops so far.

  In addition, nonionic surfactants are widely used in pharmaceuticals such as eye drops and internal preparations, cosmetics, foods, and the like for the purpose of assisting dissolution of poorly soluble drugs. Further, nonionic surfactants are often used as stabilizers for stabilizing other components to be blended.

  Furthermore, chlorpheniramine, pyridoxine, aspartic acid, and / or their salts are widely used in various pharmaceuticals, cosmetics, and foods for the purpose of exerting antihistamine action, promoting metabolism, and enhancing nutrition.

  And so far, stability at 60 ° C. was evaluated by combining bromfenac sodium [alias: sodium 2-amino-3- (4-bromobenzoyl) phenylacetate] and a specific nonionic surfactant. It is known (Patent Document 1). Specifically, in Patent Document 1, when polysorbate 80 was used as a specific nonionic surfactant, the residual ratio of bromfenac sodium after storage at 60 ° C. for 4 weeks was 51.3%. Have been described. In addition, Patent Document 1 does not describe or suggest any combination of chlorpheniramine, pyridoxine, aspartic acid, and / or a salt thereof.

International Publication No. 2004/064828 Pamphlet

  In view of the above-described conventional technology, an object of the present invention is to provide a composition having improved formulation stability while containing a nonionic surfactant together with bromfenac and / or a salt thereof.

  As a result of intensive studies to solve the above problems, the present inventors have found that (A) bromfenac and / or a salt thereof, (B) a nonionic surfactant, (C) chlorpheniramine, pyridoxine, and asparagine. It has been found that by further combining the acids and / or their salts, the composition (A) and the component (B) can coexist and a very stable composition can be obtained. Furthermore, the present inventors have proceeded with studies, and the composition containing the three components (A) to (C) is very stable not only against heat but also against light. I also found. Therefore, according to the present invention, it is possible to provide a composition containing bromofenac and / or a salt thereof which is very excellent in terms of formulation.

Accordingly, the present invention provides the following.
Item 1. (A) at least one selected from the group consisting of bromfenac and salts thereof; (B) a nonionic surfactant; and (C) selected from the group consisting of chlorpheniramine, pyridoxine, aspartic acid and salts thereof. A composition comprising at least one selected from the group consisting of:
Item 2. As component (B), at least one selected from the group consisting of polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, and polyoxyethylene-polyoxypropylene block copolymers The composition of claim | item 1 containing.
Item 3. Item 3. The composition according to Item 1 or 2, which is an aqueous liquid composition.
Item 4. Item 4. The composition according to any one of Items 1 to 3, wherein the pH is 6.0 to 9.0.
Item 5. Item 5. The composition according to any one of Items 1 to 4, further comprising boric acid or a salt thereof.
Item 6. Item 6. The composition according to any one of Items 1 to 5, which is an ophthalmic composition.
Item 7. Item 7. The composition according to any one of Items 1 to 6, which is an eye drop.

Furthermore, the present invention includes the following.
(1) (A) at least one selected from the group consisting of bromfenac and salts thereof, (B) a nonionic surfactant, and (C) chlorpheniramine, pyridoxine, aspartic acid and salts thereof The stabilization method of the said (A) component which coexists with the said (B) component including mixing at least 1 sort (s) selected from a group.
(2) Stability for stabilizing the component (A) in a composition comprising (A) at least one selected from the group consisting of bromofenac and a salt thereof and (B) a nonionic surfactant A stabilizing agent comprising (C) at least one selected from the group consisting of chlorpheniramine, pyridoxine, aspartic acid and salts thereof.

  According to the present invention, a pharmaceutically stable composition can be provided while containing a nonionic surfactant together with bromfenac and / or a salt thereof.

In Test Example 1, it is a figure which shows the result of having evaluated the thermal stability of each test liquid (Comparative Example 1-4 and Example 1-9). In Test Example 2, it is a figure which shows the result of having evaluated the thermal stability of each test liquid (Comparative Examples 5 and 6 and Examples 10 and 11). In Test Example 3, it is a figure which shows the result of having evaluated the thermal stability of each test liquid (Comparative Examples 7 and 8 and Examples 12 and 13). In Test Example 4, it is a figure which shows the result of having evaluated the photostability of each test liquid (Comparative Examples 9, 10 and Example 14). In Test Example 5, it is a figure which shows the result of having evaluated the light stability of each test liquid (Comparative Examples 5 and 6 and Examples 10, 11, and 15). In Test Example 5, it is a figure which shows the result of having evaluated the light stability of each test liquid (Comparative Examples 7 and 8 and Examples 12, 13, and 16).

The present invention includes (A) at least one selected from the group consisting of bromfenac and salts thereof, (B) a nonionic surfactant, and (C) chlorpheniramine, pyridoxine, aspartic acid and salts thereof. The present invention relates to a composition containing at least one selected from the group consisting of:
The composition of the present invention contains bromfenac and / or a salt thereof (hereinafter also simply referred to as component (A)).

  Bromfenac is a known compound also referred to as 2-amino-3- (4-bromobenzoyl) phenylacetic acid, and it 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 bromfenac 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 (eg, hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), salt with organic base (eg, methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine) Salts with organic amines such as picoline), salts with inorganic bases [eg ammonium salts; alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.), salts with metals such as aluminum, etc. And various salts. Among these salts, preferably a salt with an organic base and / or a salt with an inorganic base, more preferably a salt with an inorganic base, still more preferably an alkali metal salt and / or an alkaline earth metal salt, still more preferably. Alkali metal salts, particularly preferably sodium salts are used. These bromfenac salts may be used alone or in any combination of two or more.

  The bromfenac and salts thereof of the present invention also include solvate (for example, hydrate) forms. Examples of the solvate include, but are not limited to, 1/2 hydrate, monohydrate, 3/2 hydrate, and the like. Preferable is 3/2 hydrate.

  In the composition of the present invention, as component (A), among bromofenac and salts thereof, one kind may be used alone, or two or more kinds may be used in any combination. From the viewpoint of obtaining a higher preparation stabilizing effect, bromfenac, its salt with an inorganic base, and / or solvate thereof, more preferably bromfenac, its alkali metal salt, its alkaline earth metal salt And / or their solvates, more preferably bromfenac, its alkali metal salts, and / or their solvates, even more preferably bromfenac, its sodium salts, and / or their hydrates, particularly preferred Is bromfenac sodium 3/2 hydrate.

  In the 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 other blending components, etc., for example, relative to the total amount of the composition Thus, the total amount of the component (A) is 0.001 to 1.0 w / v%, preferably 0.005 to 0.5 w / v%, more preferably 0.01 to 0.2 w / v%.

  Furthermore, the composition of the present invention contains a nonionic surfactant (hereinafter also simply referred to as component (B)).

  The nonionic surfactant that can be incorporated into the composition of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. , Monolauric acid POE (20) sorbitan (polysorbate 20), monopalmitic acid POE (20) sorbitan (polysorbate 40), monostearic acid POE (20) sorbitan (polysorbate 60), tristearic acid POE (20) sorbitan (polysorbate 65) POE sorbitan fatty acid esters such as POE (20) sorbitan monooleate (polysorbate 80); POE / POP block copolymers such as Poloxamer 407, Poloxamer 235, Poloxamer 188, Poloxamer 403, Poloxamer 237, Poloxamer 124; POE ( 60) POE hydrogenated castor oil such as hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60); POE castor oil; POE (9) POE alkyl ethers such as Uri ether; POE (20) POP (4) POE-POP alkyl ethers such as cetyl ether; POE (10) POE alkylphenyl ethers such as nonylphenyl ether. In the compounds exemplified above, POE is polyoxyethylene, POP is polyoxypropylene, and the numbers in parentheses indicate the number of moles added. In the composition of this invention, these nonionic surfactants may be used individually by 1 type, and may be used in combination of 2 or more type.

  In the composition of the present invention, the component (B) is preferably 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 hydrogenated castor oil, and / or POE / POP block copolymers, more preferably polysorbate 80, polyoxyethylene hydrogenated castor oil 60, and / or poloxamer 407 are used. Among them, polysorbate 80 tends to cause destabilization of bromfenac and / or its salt as compared to other nonionic surfactants. However, according to the present invention, the stability can be remarkably improved even when the polysorbate 80 that easily causes destabilization is used. In view of this viewpoint, in the present invention, polysorbate 80 can be suitably used as the component (B).

  In the 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 other blending components, etc., for example, relative to the total amount of the composition The total amount of the component (B) is 0.001 to 3.0 w / v%, preferably 0.005 to 2.5 w / v%, more preferably 0.02 to 2.0 w / v%, still more preferably 0.05 to 2.0 w / v%. Illustrated.

  In the 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 weight of the total amount of the component (A), Examples include a range in which the total amount of component (B) is 2 to 6000 parts by weight, preferably 10 to 5000 parts by weight, and more preferably 40 to 4000 parts by weight.

  Furthermore, the composition of the present invention contains chlorpheniramine, pyridoxine, aspartic acid and / or a salt thereof (hereinafter also simply referred to as component (C)). Thus, by using the component (C) together with the components (A) to (B), the thermal stability of the component (A) that is easily destabilized by the coexistence of the component (B) can be effectively improved, Furthermore, the light stability of the component (A) can also be improved to a high degree.

  Among the components (C), chlorpheniramine is a known compound also called 3- (4-chlorophenyl) -N, N-dimethyl-3-pyridin-2-yl-propylamine.

  The salt of chlorpheniramine is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and specifically, a salt that can be taken by the component (A). The same form is illustrated. Among these salts, preferably an organic acid salt and / or an inorganic acid salt, more preferably an organic acid salt, still more preferably a polyvalent carboxylate, still more preferably a maleate and / or a fumarate, particularly preferably May include maleate. These chlorpheniramine salts may be used alone or in any combination of two or more.

  Further, chlorpheniramine and a salt thereof may be in the form of a solvate (for example, hydrate), and may be any of d-form, l-form, and dl-form.

  Among chlorpheniramines and salts thereof, from the viewpoint that a higher preparation stabilizing effect can be obtained, chlorpheniramine and / or an organic acid salt thereof is preferable, more preferably chlorpheniramine and / or a polyvalent carboxylic acid thereof. Salts, more preferably chlorpheniramine, its maleate and / or its fumarate, particularly preferably maleate of chlorpheniramine (chlorpheniramine maleate).

  Among the components (C), pyridoxine is a known compound that is 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. Specifically, it is the same as the salt that can be taken by the component (A). The thing of a form is illustrated. 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 these pyridoxines and salts thereof, from the viewpoint of obtaining a higher preparation stabilizing effect, preferably pyridoxine and its inorganic acid salt, more preferably pyridoxine, pyridoxine hydrochloride, and pyridoxine phosphate, more preferably Examples include pyridoxine hydrochloride and pyridoxine phosphate, particularly preferably pyridoxine hydrochloride (pyridoxine hydrochloride).

  Among the components (C), aspartic acid is a compound known as an acidic amino acid, also called 2-aminobutanedioic acid.

  The salt of aspartic acid is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and specifically, a salt that can be taken by the above component (A) The thing of the same form is illustrated. Among these salts, preferably a salt with an inorganic base and / or a salt with an organic base, more preferably a salt with an inorganic base, still more preferably an alkali metal salt and an alkaline earth metal salt, still more preferably asparagine. Potassium acid, magnesium aspartate, and magnesium and potassium aspartate, particularly preferably potassium aspartate. These aspartic acid salts may be used alone or in any combination of two or more.

  In addition, aspartic acid and its salt may be any of l-form, d-form, and dl-form, but is preferably l-form.

  Among the aspartic acids and salts thereof, from the viewpoint that a higher preparation stabilizing effect can be obtained, preferably aspartic acid and / or a salt thereof with an inorganic base, more preferably aspartic acid, an alkali metal salt thereof, and / or Or an alkaline earth metal salt thereof, more preferably potassium aspartate, magnesium aspartate, and magnesium potassium aspartate, particularly preferably potassium aspartate.

  In the composition of the present invention, the component (C) may be used alone or in combination of two or more of chlorpheniramine, pyridoxine, aspartic acid, and / or their salts. May be used in any combination. Preferable examples of the component (C) used in the present invention include chlorpheniramine maleate, pyridoxine hydrochloride, and / or potassium aspartate. Particularly preferred is chlorpheniramine maleate.

When the component (C) is blended in the composition of the present invention, the blending ratio of the component (C) depends on the type of the component (C), the type of the component (A) or the component (B) used in combination Although it sets suitably, as an example, (C) component is 0.01-4.5 w / v% by total amount with respect to the total amount of this composition, Preferably 0.03-2.3 w / v% is illustrated. More specifically, the following ranges are exemplified as the blending ratio of each component (C) with respect to the total amount of the composition of the present invention.
When component (C) is chlorpheniramine and / or a salt thereof: these are generally in a total amount of 0.0005 to 0.5 w / v%, preferably 0.001 to 0.1 w / v%, more preferably 0.005 to 0.06 w / v%. ;
When component (C) is pyridoxine and / or a salt thereof: these are generally in a total amount of 0.0005 to 0.6 w / v%, preferably 0.001 to 0.4 w / v%, more preferably 0.005 to 0.2 w / v%;
When component (C) is aspartic acid and / or a salt thereof: These are generally in a total amount of 0.01 to 3.0 w / v%, preferably 0.1 to 2.5 w / v%, more preferably 0.5 to 2 w / v%.

Further, the ratio of the component (C) to the component (A) in the composition of the present invention is not particularly limited, but the component (A) that is destabilized by the coexistence of the component (B). From the viewpoint of more effectively improving the thermal stability and / or from the viewpoint of further improving the light stability of the component (A), the above (C) per 100 parts by weight of the total amount of the component (A) Examples include a range in which the total amount of components is 1 to 8200 parts by weight, preferably 10 to 4550 parts by weight. More specifically, the following ranges are exemplified as the ratio of each component (C) per 100 parts by weight of the total amount of component (A):
When component (C) is chlorpheniramine and / or a salt thereof: These are total amounts, usually 1 to 1000 parts by weight, preferably 2 to 200 parts by weight, more preferably 5 to 150 parts by weight, particularly preferably 10 to 120 parts by weight;
When component (C) is pyridoxine and / or a salt thereof: these are total amounts, usually 1 to 1200 parts by weight, preferably 2 to 800 parts by weight, more preferably 5 to 500 parts by weight, particularly preferably 10 to 400 parts by weight. Part;
When component (C) is aspartic acid and / or a salt thereof: These are total amounts, usually 20 to 6000 parts by weight, preferably 200 to 5000 parts by weight, more preferably 500 to 4500 parts by weight, particularly preferably 1000 to 4000. Parts by weight.

  The composition of the present invention may further contain a buffer. The buffer that can be incorporated into the 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, and the like. These buffering agents may be used in combination. Preferred buffering agents are borate buffer, phosphate buffer, carbonate buffer, and citrate buffer, more preferred buffers are borate buffer and phosphate buffer, and particularly preferred buffers are boron. It is an acid buffer. 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.) Calcium acetate, sodium dihydrogen citrate, disodium citrate, etc.); with acetate buffer Acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.); Tris (hydroxymethyl) aminomethane or a salt thereof (hydrochloride, acetate, sulfonate, etc.) as a Tris buffer Can be illustrated. These buffering agents may be used alone or in any combination of two or more.

  Among the above buffering agents, borate buffering agent is particularly preferable. Preferred 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 and boric acid. Combinations of alkali metal salts of acids; particularly preferably combinations of boric acid and borax.

  When a buffering agent is blended in the 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 composition, and the like. 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. A ratio of 1 to 2 w / v% is exemplified.

  The pH of the composition of the present invention is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable range, but the higher the pH, the higher the formulation stability. There is a tendency to acquire properties (especially high stability to light). In view of this viewpoint, as a suitable example of the pH of the composition of the present invention, the pH is 6.0 or more, preferably 6.0 to 9.0, more preferably 6.5 to 9.0, more preferably The range which becomes 7.0-9.0, Especially preferably, it is 7.5-9.0 is mentioned.

  In addition, the osmotic pressure of the composition of the present invention is not particularly limited as long as it is within a range acceptable for a living body. An example of the osmotic pressure ratio of the composition of the present invention is preferably in the range of 0.7 to 5.0, more preferably 0.9 to 3.0, and particularly preferably 1.0 to 2.0. The osmotic pressure can be adjusted by a method known in the art using inorganic salts, polyhydric alcohols, sugar alcohols, saccharides and 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 with reference to the descent 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 released in a desiccator (silica gel). Cool and accurately measure 0.900 g and dissolve in purified water to make exactly 100 mL, or use a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution).

  The 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 components and physiologically active components include, but are not limited to, antihistamines, decongestants, bactericides, vitamins, amino acids, anti-inflammatory agents, and astringents. Specifically, the following components are listed as components used in ophthalmic drugs.

Antihistamines: for example, iproheptin, diphenhydramine hydrochloride, ketotifen fumarate, pemirolast potassium and the like.
Decongestant: For example, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline sulfate, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, and the like.
Fungicide: For example, cetylpyridinium, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, polyhexamethylene biguanide hydrochloride, and the like.
Vitamins: For example, flavin adenine dinucleotide sodium, cyanocobalamin, retinol acetate, retinol palmitate, panthenol, calcium pantothenate, tocopherol acetate and the like.
Amino acids: For example, aminoethylsulfonic acid and the like.
Anti-inflammatory agent: for example, dipotassium glycyrrhizinate, allantoin, azulene, sodium azulenesulfonate, guaiazulene, ε-aminocaproic acid, berberine chloride, berberine sulfate, lysozyme chloride, licorice and the like.
Astringent: For example, zinc white, zinc lactate, zinc sulfate and the like.
Other: For example, sodium cromoglycate, sodium chondroitin sulfate, sodium hyaluronate, sulfamethoxazole, sodium sulfamethoxazole and the like.

  In addition, the composition of the present invention may contain a pharmaceutically acceptable carrier or additive according to a conventional method according to its use or form as long as the effects of the present invention are not impaired. Examples of such carriers and additives include isotonic agents, thickeners, saccharides, sugar alcohols, preservatives, bactericides or antibacterial agents, pH adjusters, stabilizers, fragrances, or refreshing agents. However, it is not limited to these. As typical components, for example, the following additives may be mentioned.

Carrier: An aqueous carrier such as water or hydrous ethanol.
Isotonizing agents: for example, sodium chloride, potassium chloride and the like.
Thickeners: for example, carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, alginic acid, polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, macrogol and the like.
Sugars: For example, cyclodextrins and the like.
Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like. These may be d-form, l-form or dl-form.
Antiseptics, bactericides or antibacterials: for example, dibutylhydroxytoluene, butylhydroxyanisole, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, sorbine Potassium acid, sodium dehydroacetate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide, etc. ), Glow Kill (trade name, manufactured by Rhodia).
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, monoethanolamine, 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 etc.
Stabilizers: for example, dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate, sodium bisulfite, sodium sulfite 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.

  The composition of the present invention is prepared by adding a desired amount of the above-mentioned components (A) to (C) and, if necessary, other blending components to a desired concentration.

  The composition of the present invention can take various preparation forms depending on the purpose. For example, the form of the composition of the present invention includes liquid, semi-solid (such as ointment), solid and the like. Preferably it is a liquid, More preferably, it is an aqueous liquid composition. Here, the aqueous liquid composition means a liquid composition containing water, and usually 1% by weight or more of water in the composition, preferably 5% by weight or more, more preferably 20% by weight or more, More preferably, it means 50% by weight or more, particularly preferably 90% by weight or more. The water contained in the aqueous liquid composition 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 1st 5th Japanese Pharmacopoeia.

  In addition, the 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 a composition for external use on the skin. Here, ophthalmic compositions include eye drops, artificial tears, eyewashes, eye ointments, contact lens mounting liquids, contact lens care agents (contact lens disinfectants, contact lens preservatives, contact lens cleaners). , Contact lens cleaning preservatives, etc.). In addition, nasal compositions include nasal drops, nasal washings, and the like. Oral compositions include internal medicines (eg, liquids, syrups, extracts, etc.), oropharyngeal drugs, mouthwashes, and the like. The eardrop composition includes eardrops. The composition for subcutaneous administration includes injections and the like.

  Among the above uses, ophthalmic compositions are often much lower in concentration of compounding components than compositions for other uses such as oral compositions, and even a slight decrease in content is a major problem. It can be. 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 or in the dark, such as a wash basin, while eye drops are often carried around. Because it may be placed on the dashboard or stored in a bag and carried outdoors, it may be subjected to high temperatures, so it is very susceptible to differences in temperature and is also exposed to light. easy. Furthermore, it can be said that the eye drop is a preparation form that is easily affected by an external temperature change or light because it is generally individually packaged in a small amount. According to the composition of the present invention, it is possible to effectively exhibit the effect of improving the thermal stability even for the ophthalmic composition (particularly eye drops) that is easily affected by the influence of temperature change and light. An effect of improving light stability can also be achieved. In view of such an effect of the present invention, a preferred example of the composition of the present invention is an ophthalmic composition, and a particularly preferred example is an eye drop.

  The composition of the present invention is provided by being contained in any container. The container for storing the composition of the present invention is not particularly limited, and may be made of, for example, glass, or plastic (eg, polyethylene terephthalate, polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, polyimide) Or a copolymer thereof, or a mixture of two or more thereof. Moreover, the transparent container which can visually recognize the inside of a container may be sufficient as the container which accommodates the composition of this invention, and the opaque container which is difficult to visually recognize the inside of a container may be sufficient as it. Here, the “transparent container” includes both a colorless transparent container and a colored transparent container. In the present invention, high light stability is also obtained, so that it can be accommodated in a transparent container.

  Since the composition of the present invention can exhibit an anti-inflammatory action or the like based on the component (A), it is effective for the treatment or prevention of inflammatory diseases and is also useful as an ameliorating agent for inflammatory diseases. Here, as an example of the target inflammatory disease, inflammatory eye disease (for example, blepharitis, conjunctivitis, keratitis, scleritis, superior scleritis, anterior uveitis, postoperative inflammation, lacrimal adenitis Lacrimal cystitis, lacrimal canalitis, etc.). Therefore, the composition of the present invention can be used to alleviate various symptoms (for example, sensation of foreign bodies in the eyes, sullen eyes, redness, itchy eyes, blurred eyes, etc.) caused by these inflammatory diseases. obtain. The composition of the present invention can also exhibit an antihistamine action, a metabolism promoting action, a nutrition enhancing action and the like 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: Thermal stability evaluation 1
Test solutions were prepared according to the formulations shown in Tables 1 and 2 below, and the stability of bromfenac sodium was evaluated. Specific experimental methods and results are shown below.

  First, each test solution (Comparative Example 1-4 and Example 1-9) shown in Tables 1 and 2 was prepared. Each test solution was then filled in a 10 ml glass headspace vial, sealed and stored in a thermostat at 70 ° C., protected from light. Seven days and 14 days after the start of storage, each test solution was taken out, the content of bromfenac sodium was measured by an HPLC method according to a conventional method, and the residual ratio was calculated according to the following formula. Incidentally, 14 days at 70 ° C. corresponds to about 3 years at room temperature.

[Equation 1]
Residual rate (%) = (content of bromfenac sodium in each test solution after storage at 70 ° C./content of bromfenac sodium in each test solution before storage) × 100

  The result is shown in FIG. As is apparent from FIG. 1, it can be seen that bromfenac sodium itself is a very stable component (Comparative Example 1). However, when polysorbate 80, polyoxyethylene hydrogenated castor oil 60, or poloxamer 407, which is a nonionic surfactant, is combined with bromfenac sodium, the stability is extremely lowered unexpectedly. (Comparative Example 2-4). On the other hand, with respect to the significant decrease in stability of bromfenac sodium caused by coexistence with such a nonionic surfactant, by further combining chlorpheniramine maleate, pyridoxine hydrochloride, or potassium aspartate, It became clear that the stability could be greatly improved. In particular, significant improvement was observed when chlorpheniramine maleate was added.

Test Example 2: Thermal stability evaluation 2
A test solution was prepared according to the formulation shown in Table 3 below, and the thermal stability of bromfenac sodium was evaluated. Specific experimental methods and results are shown below.

  First, each test solution shown in Table 3 (Comparative Examples 5 and 6 and Examples 10 and 11) was prepared. Next, each test solution was filled in a glass headspace vial having a capacity of 10 ml, sealed in 5 ml, and stored in a thermostat at 70 ° C. under light shielding. 14 days after the start of storage, each test solution was taken out, and bromofenac sodium was quantified (measurement of content) by an HPLC method according to a conventional method, and the residual rate was calculated according to the above [Equation 1].

  The result is shown in FIG. As is clear from FIG. 2, the same effects as those of Test Example 1 were obtained with the test solutions shown in Table 3. In other words, in contrast to the significant decrease in thermal stability of bromfenac sodium caused by coexistence with a nonionic surfactant, the thermal stability of bromfenac sodium can be further increased by combining chlorpheniramine maleate or pyridoxine hydrochloride. It became clear that the sex could be greatly improved.

Test Example 3: Thermal stability evaluation 3
A test solution was prepared according to the formulation shown in Table 4 below, and the stability of bromfenac sodium was evaluated. Specific experimental methods and results are shown below.

  First, each test solution shown in Table 4 (Comparative Examples 7 and 8 and Examples 12 and 13) was prepared. Next, each test solution was filled in a glass headspace vial having a capacity of 10 ml, sealed in 5 ml, and stored in a thermostat at 70 ° C. under light shielding. Seven days after the start of storage, each test solution was taken out, and bromfenac sodium was quantified by an HPLC method according to a conventional method, and the residual rate was calculated according to the above [Equation 1].

  The result is shown in FIG. As is clear from FIG. 3, the same effects as those of Test Example 1 were obtained with the test solutions shown in Table 4. In other words, compared with the stability of bromfenac sodium in the presence of nonionic surfactant, it is clear that the stability of bromfenac sodium can be greatly improved by further combining pyridoxine hydrochloride or potassium aspartate. It became.

Test Example 4: Light stability evaluation 1
A test solution was prepared according to the formulation shown in Table 5 below, and the stability of bromfenac sodium was evaluated. Specific experimental methods and results are shown below.

  First, each test solution shown in Table 5 (Comparative Examples 9, 10 and Example 14) was prepared. Each test solution was then filled into a glass transparent screw vial having a capacity of 10 ml and sealed in an amount of 1 ml, and the test solution (“Light-Tron LT-120 D3CJ”, Nagano) Using a D65 lamp as a light source, light of 0.5000 lx / h was continuously irradiated for 240 hours at 25 ° C., and each test solution was exposed to light having an integrated irradiation amount of 1.2 million lx. In each test solution after light irradiation, the content of bromfenac sodium was measured by an HPLC method according to a conventional method, and the residual rate was calculated according to the following formula.

[Equation 2]
Residual rate (%) = (content of bromfenac sodium in each test solution after light irradiation / content of bromfenac sodium in each test solution before light irradiation) × 100

  The result is shown in FIG. As shown in FIG. 4, by comparing with the test solution of Comparative Example 10 containing bromfenac sodium and a nonionic surfactant (polysorbate 80), and further using potassium aspartate together, bromfena It was found that the stability of sodium hydroxide can be significantly improved (Example 14).

Test Example 5: Light stability evaluation 2
Test solutions were prepared according to the formulations in Tables 3 and 4 and Table 6 below, and the photostability of bromfenac sodium was evaluated. Specific experimental methods and results are shown below.

  First, each test solution (Comparative Examples 5 to 8 and Examples 10-13, 15, and 16) shown in Tables 3 and 4 and Table 6 was prepared. Next, each test solution was filled in a 10 ml glass transparent screw vial in a 5 ml portion and sealed. The test solution (“Light-Tron LT-120 D3CJ”, Nagano) Using a D65 lamp as a light source, light of 0.5000 lx / h was continuously irradiated for 240 hours at 25 ° C., and each test solution was exposed to light having an integrated irradiation amount of 1.2 million lx. In each test solution after light irradiation, bromfenac sodium was quantified by HPLC according to a conventional method, and the residual ratio was calculated according to the above [Equation 2].

  The results are shown in FIGS. 5 and 6, as compared with the test solutions of Comparative Examples 6 and 8 containing bromfenac sodium and a nonionic surfactant (polysorbate 80), chlorpheniramine maleate and hydrochloric acid were further added. It was found that the stability of bromfenac sodium can be significantly improved by the combined use of pyridoxine or potassium aspartate (Examples 10-13, 15, 16).

[Prescription Examples] Formulations shown in Table 7 below were prepared and filled into polyethylene terephthalate containers to prepare eye drops (Prescription Examples 1 to 7) and eyewashes (Prescription Example 8).

Claims (7)

(A) at least one selected from the group consisting of bromfenac and salts thereof;
(B) a nonionic surfactant;
(C) A composition containing at least one selected from the group consisting of chlorpheniramine, pyridoxine, aspartic acid and salts thereof
(However, an aqueous eye drop containing at least one selected from the group consisting of bromfenac and a salt thereof, tyloxapol, and L-aspartic acid is excluded) . For the total amount of the composition,
The total amount of chlorpheniramine and / or its salt is 0.0005 to 0.5 w / v%,
The total amount of pyridoxine and / or its salt is 0.0005 to 0.6 w / v%,
The total amount of aspartic acid and / or salt thereof is 0.01-3.0 w / v%,
The composition of claim 1. As component (B), at least one selected from the group consisting of polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, and polyoxyethylene-polyoxypropylene block copolymers The composition of Claim 1 or 2 containing this. The composition according to any one of claims 1 to 3 , which is an aqueous liquid composition. The composition according to any one of claims 1 to 4 , wherein the pH is 6.0 to 9.0. Furthermore, the composition in any one of Claims 1-5 containing a boric acid or its salt. The composition according to any one of claims 1 to 6 , which is an ophthalmic composition.

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