JP6161500B2 - 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 compositions with significantly improved photostability while containing terpenoids with bromfenac and / or its salts. The present invention further relates to a method for improving the photostability of bromfenac, which is deteriorated by the combined use with terpenoids.

  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 ophthalmic compositions so far (Patent Document 1).

  On the other hand, terpenoids have been used in ophthalmic compositions so far as a cooling agent for imparting a refreshing sensation or cooling sensation.

  Nonionic surfactants are widely used in pharmaceuticals such as eye drops and internal preparations, cosmetics, foods and the like for the purpose of assisting in dissolving components. So far, a technology relating to an aqueous solution that does not cause precipitation has been provided for a preparation containing sodium bromfenac [also known as sodium 2-amino-3- (4-bromobenzoyl) phenylacetate] and a specific antibiotic. (Patent Document 2).

  However, the stability of bromfenac sodium combined with terpenoids, especially the stability when irradiated with light, is not known at all, and the effect of adding a nonionic surfactant is easy. The current situation cannot even be guessed. And when bromfenac decomposes | disassembles by light irradiation, pharmacological effects, such as an anti-inflammatory effect | action of bromfenac, will attenuate, and the quality of a bromfenac containing composition will fall.

  In general, as a means for stably holding a preparation containing a pharmacologically active substance that is unstable to light, a light shielding means by a packaging material containing the preparation, for example, an auxiliary light shielding means for shielding a container containing the preparation. Light shielding means such as a method of using a light shielding bag incidentally and a method of using a brown container or an aluminum container as a container for storing the preparation are employed. However, there are many cases where the user does not use the auxiliary light shielding bag, and in the manufacturing process in which the container or the packaging material cannot be used, there is a high risk of the substance being decomposed by light. Furthermore, in the manufacturing process of the preparation, when an opaque or low-transparency container such as an aluminum container or a dark brown container is used, it is difficult to inspect for contamination from the outside of the container after filling the container with the preparation. .

JP 2002-307664 A International Publication No. 2005/046700 Pamphlet

  An object of the present invention is to provide a composition having improved formulation stability, particularly light stability, while containing bromfenac and / or a salt thereof and a terpenoid. .

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have significantly promoted the decomposition of bromfenac when a composition containing both bromfenac and / or a salt thereof and a terpenoid is exposed to light. I found out. Therefore, when a composition containing both bromofenac and / or a salt thereof and a terpenoid is used in combination with a nonionic surfactant, surprisingly, decomposition of bromofenac during light irradiation is remarkable. It was found that it can be suppressed. 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.
(1) (A) Bromfenac and / or its salt;
(B) a terpenoid,
(C) A composition containing a nonionic surfactant.
(2) As component (C), selected from the group consisting of polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene-polyoxypropylene block copolymer, and polyethylene glycol monostearate The composition according to (1) above, comprising at least one of the above.
(3) As component (C), polysorbate 80, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil 10, polyoxyethylene castor oil 35, poloxamer 407, and polyoxyl 40 stearate The composition according to (1) above, comprising at least one selected from the group consisting of:
(4) The component (B) contains at least one selected from the group consisting of menthol, camphor, borneol, geraniol, cool mint oil, peppermint oil, peppermint oil, camphor oil, eucalyptus oil, and bergamot oil, The composition according to any one of (1) to (3).
(5) In any one of the above (1) to (4), the total content of the component (B) is 0.0002 to 10 parts by weight with respect to 1 part by weight of the total content of the component (A). The composition as described.
(6) In any one of the above (1) to (5), the total content of component (C) is 0.01 to 10000 parts by weight with respect to 1 part by weight of the total content of component (B) The composition as described.
(7) The composition according to any one of (1) to (6), which is an aqueous liquid composition.
(8) The composition according to any one of (1) to (7), which is an ophthalmic composition.
(9) The composition according to any one of (1) to (8), which is an eye drop.
(10) The composition according to any one of (1) to (9), which is contained in a light transmissive container.
(11) The composition according to (10) above, wherein the material of the light transmissive container contains a polyester resin.
(12) A method for improving the photostability of bromfenac and / or a salt thereof, comprising (B) a terpenoid and (C) a nonionic surfactant in (A) bromfenac and / or a salt thereof.

  ADVANTAGE OF THE INVENTION According to this invention, the composition stable to light can be provided, containing a terpenoid with bromfenac and / or its salt.

In the present specification, the unit “%” of content means “w / v%” and is synonymous with “g / 100 mL”.
In the present specification, unless otherwise specified, the abbreviation “POE” means polyoxyethylene.
In this specification, unless otherwise specified, the abbreviation “POP” means polyoxypropylene.

  The present invention relates to a composition comprising (A) bromfenac and / or a salt thereof, (B) a terpenoid, and (C) a nonionic surfactant.

The composition of the present invention comprises bromfenac and / or a salt thereof (hereinafter also simply referred to as component (A)).
Containing.

  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 that a higher light stabilizing effect can be obtained, preferably bromfenac, a salt thereof with an inorganic base, and / or a solvate thereof, more preferably bromfenac, an alkali metal salt thereof, an alkaline earth metal salt thereof. And / or solvates thereof, more preferably bromfenac, alkali metal salts thereof, and / or solvates thereof, particularly preferably bromfenac, sodium salts thereof, and / or hydrates thereof.

  In the composition of the present invention, the content of the component (A) is not particularly limited, depending on the type of component (A), the type and content of other components, the use of the composition, the formulation form, the method of use, etc. Is set as appropriate. For example, based on the total amount of the composition of the present invention, the total content of the component (A) is preferably 0.001 to 1.0 w / v%, and preferably 0.002 to 0.5 w / v%. It is more preferable that it is 0.005-0.2 w / v%, and it is especially preferable that it is 0.01-0.1 w / v%.

  The composition of the present invention needs to contain a terpenoid (hereinafter sometimes referred to as component (B)) in addition to the component (A). By causing the (A) component and the (B) component to coexist, decomposition of the (A) component is remarkably induced.

  The terpenoid used as the component (B) is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such terpenoids include menthol, camphor, borneol, geraniol, cineole, citronellol, menthone, carvone, anethole, eugenol, limonene, linalool, linalyl acetate, and derivatives thereof. These compounds may be d-form, l-form or dl-form. In the present invention, an essential oil containing the above compound may be used as a terpenoid. Examples of such essential oils include eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, and rose oil.

  In the composition of the present invention, as the component (B), one of terpenoids may be used alone, or two or more may be used in any combination. From the viewpoint of obtaining a higher light stabilizing effect with respect to the component (A) when the component (B) coexists, menthol, camphor, geraniol, borneol and the like are preferable, and these are preferably contained. Examples of the essential oil include cool mint oil, peppermint oil, mint oil, camphor oil, eucalyptus oil, bergamot oil and the like. More preferably, mention may be made of menthol, camphor, geraniol, borneol, eucalyptus oil and bergamot oil, more preferably l-menthol, dl-menthol, d-camphor, dl-camphor, geraniol, d-borneol, eucalyptus oil and Bergamot oil, particularly preferably l-menthol and dl-menthol.

  In the composition of the present invention, the content of the component (B) is not particularly limited, depending on the type of component (B), the type and content of other components, the use of the composition, the formulation form, the method of use, etc. Set as appropriate. For example, based on the total amount of the composition of the present invention, the total content of the component (B) is preferably 0.0001 to 0.2 w / v%, and 0.0005 to 0.1 w / v%. Is more preferably 0.001 to 0.07 w / v%, and particularly preferably 0.002 to 0.05 w / v%. In addition, when using the essential oil containing a terpenoid, it can set so that the terpenoid in the essential oil contained in a composition may satisfy | fill the said content.

  In the composition of the present invention, the content ratio of the component (B) to the component (A) is not particularly limited, and the types of the component (A) and the component (B), the use of the aqueous composition, the formulation form, the method of use, etc. It is set appropriately according to As the content ratio of the component (B) to the component (A), for example, the total content of the component (B) is 0 with respect to 1 part by weight of the total content of the component (A) contained in the composition of the present invention. .0002 to 10 parts by weight, more preferably 0.001 to 5 parts by weight, still more preferably 0.005 to 2 parts by weight, and 0.02 to 0.5 parts by weight. It is particularly preferred. The content ratio of the component (B) to the component (A) is suitable from the viewpoint of the effect of improving the light stability of the component (A) when the component (B) coexists in the composition.

  Further, the composition of the present invention contains a nonionic surfactant (hereinafter also simply referred to as component (C)). In this way, by combining the (C) component with the (A) component and the (B) component, the decomposition of the (A) component promoted by the coexistence of the (B) component during light irradiation is effectively suppressed. Effect.

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)
), POE sorbitan fatty acid esters such as POE (20) sorbitan (20) sorbitan (polysorbate 65), monooleic acid POE (20) sorbitan (polysorbate 80); POE / POP block copolymers such as 124; POE hydrogenated castor oil such as POE (40) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 40), POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60); POE (10) POE castor oil such as castor oil (polyoxyethylene castor oil 10), POE (35) castor oil (polyoxyethylene castor oil 35); POE alkyl ethers such as POE (9) lauryl ether; POE (20) POE-POP alkyl ethers such as POP (4) cetyl ether; POE alkylphenyl ethers such as POE (10) nonylphenyl ether; polyoxystearate Polyethylene glycol monostearate such as 40 and the like. In the compounds exemplified above, the numbers in parentheses indicate the number of added moles.

  In the composition of the present invention, as the component (C), one kind of nonionic surfactant may be used alone, or two or more kinds may be used in any combination. From the viewpoint that a higher light stabilization effect can be obtained, preferably, POE sorbitan fatty acid ester, POE hydrogenated castor oil, POE castor oil, POE / POP block copolymer, polyethylene glycol monostearate, more preferably polysorbate 80, poly Oxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil 10, polyoxyethylene castor oil 35, poloxamer 407 (polyoxyethylene (196) polyoxypropylene (67) glycol), and stearic acid Polyoxyl 40 is used.

  In the composition of the present invention, the content of the component (C) is not particularly limited, depending on the type of component (C), the type and content of other components, the use of the composition, the formulation form, the method of use, etc. Set as appropriate. For example, based on the total amount of the composition of the present invention, the total content of the component (C) is preferably 0.0005 to 5 w / v%, and preferably 0.001 to 3 w / v%. More preferably, it is 0.005 to 2 w / v%, further preferably 0.01 to 1 w / v%. The content of the component (C) is preferable from the viewpoint of the effect of improving the photostability of bromfenac in the composition.

  In the composition of the present invention, the content ratio of the component (C) to the component (A) is not particularly limited, and the types of the components (A) and (C), the use of the aqueous composition, the formulation form, and the use It is set appropriately according to the method and the like. As the content ratio of the component (C) to the component (A), for example, the total content of the component (C) is 0 with respect to 1 part by weight of the total content of the component (A) contained in the composition of the present invention. .0005 to 5000 parts by weight, preferably 0.005 to 1000 parts by weight, more preferably 0.02 to 200 parts by weight, and 0.1 to 100 parts by weight. Is particularly preferred. The content ratio of the component (C) to the component (A) is preferable from the viewpoint of the effect of improving the light stability of the component (A) in the composition.

  Furthermore, in the composition of the present invention, the content ratio of the (C) component to the (B) component is not particularly limited, and the types of the (B) component and (C) component, the use of the aqueous composition, the formulation form, and the use It is set appropriately according to the method and the like. As the content ratio of the component (C) to the component (B), for example, the total content of the component (C) is 0 with respect to 1 part by weight of the total content of the component (B) contained in the composition of the present invention. 0.01 to 10000 parts by weight, more preferably 0.05 to 2000 parts by weight, still more preferably 0.2 to 500 parts by weight, and particularly preferably 1 to 200 parts by weight. The amount is preferably 1 to 70 parts by weight, more preferably 2 to 40 parts by weight, and still more preferably 2 to 30 parts by weight. The content ratio of the component (C) to the component (B) is suitable from the viewpoint of the effect of improving the light stability of the component (A) when the component (B) coexists in the composition.

  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 and / or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); boric acid buffer, phosphoric acid as phosphate buffer And / or a salt thereof (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); carbonate buffer Carbonic acid and / or salt thereof (sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.); Citric acid and / or salt thereof (citrate) Acid sodium, potassium citrate, calcium citrate, sodium dihydrogen citrate, dinatrate citrate Acetic acid and / or salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.); tris (hydroxymethyl) aminomethane and / or salt thereof (hydrochloride) , Acetate, sulfonate, etc.). 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 content 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, etc., and is uniform. 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 3 w / v%, particularly preferably 0.5 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 6.0 to 8.5, and particularly preferably. The range which becomes 6.5-8.0 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 0.8 to 3.0, and particularly preferably 0.9 to 1.4. 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 or antiallergic agents, decongestants, bactericides, vitamins, amino acids, anti-inflammatory agents, astringents, and the like. Specifically, the following components are listed as components used in ophthalmic drugs.
Antihistamine or antiallergic agent: for example, iproheptin, diphenhydramine hydrochloride chlorpheniramine maleate, ketotifen fumarate, pemirolast potassium, cromoglycate sodium, tranilast, olopatadine hydrochloride 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, pyridoxine hydrochloride and the like.
Amino acids: for example, aminoethylsulfonic acid, potassium aspartate, magnesium aspartate, sodium chondroitin sulfate, sodium hyaluronate and the like.
Anti-inflammatory agents: for example, dipotassium glycyrrhizinate, allantoin, azulene, sodium azulenesulfonate, guaiazulene, ε-aminocaproic acid, berberine chloride, berberine sulfate, lysozyme chloride, licorice, pranoprofen and the like.
Astringent: For example, zinc white, zinc lactate, zinc sulfate and the like.
Other: For example, neostigmine methyl sulfate, sulfamethoxazole, sulfamethoxazole sodium, etc.

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. Such carriers and additives include, for example, isotonic agents, thickeners, sugars, sugar alcohols, preservatives, bactericides or antibacterial agents, pH regulators, stabilizers, chelating agents, fragrances or refreshing agents. Although a chemical agent etc. are mentioned, it is not limited to these. Examples of typical components include the following carriers and additives.
Carrier: An aqueous carrier such as water or hydrous ethanol.
Isotonizing agents (inorganic salts): For example, sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like.
Polyhydric alcohol: glycerin, propylene glycol, polyethylene glycol 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, cyclodextrin, glucose 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, trometamol, sodium dehydroacetate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexanide hydrochloride ( Polyhexamethylene biguanide), etc.), Glow Kill (trade name, manufactured by Rhodia), 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, monoethanolamine, diisopropanolamine, sulfuric acid, magnesium sulfate, 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, 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), disodium ethylenediaminetetraacetic acid (sodium edetate), N- (2-hydroxyethyl) ethylenediaminetriacetic acid (HEDTA) ), Diethylenetriaminepentaacetic acid (DTPA) and the like.

  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 order of addition of each component is not particularly limited as long as the effects of the present invention are not hindered, but it is preferable to add (C) a nonionic surfactant, (A) bromfenac and / or a salt thereof, and (B) a terpenoid. .

  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 16th revised 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-mentioned uses, ophthalmic compositions often have a very low content of compounding components compared to compositions for other uses such as oral compositions, and even if there is a slight decrease in content. It can be a 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. In addition, eye wash and contact lens care products are often stored at room temperature or in dark places such as washstands, while eye drops are placed on the dashboard of a car during the day. It is easy to be exposed to light such as sunlight and lighting by being carried outdoors. Furthermore, it can be said that the eye drop is a preparation form that is easily affected by light from the outside because it is generally individually packaged in a small amount. According to the composition of the present invention, a light stabilizing effect can be effectively exhibited even for an ophthalmic composition (particularly an eye drop) that is easily affected by light. 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 has high light stability and can maintain high light stability over a long period of time. Therefore, it is excellent in light-transmitting containers, glass or plastic containers, particularly squeeze and portability. It can be packaged or accommodated in a plastic container or the like in a form that can be used repeatedly. Furthermore, since the composition of the present invention can be packaged or accommodated in a container having high light transmittance such as a plastic container, foreign matter contamination can be reliably determined from the outside of the container, and a foreign matter confirmation test is easily performed. In addition, it is possible to reliably perform process control and quality control of the composition (eye drops, eye wash, injection, infusion solution, beverage, food, cosmetic preparation, etc.).

  Examples of the plastic container resin that can contain the composition include olefin resins (polyethylene, polypropylene, etc.), polyester resins, polyphenylene ether resins, polycarbonate resins, polysulfone resins, polyamide resins, polyimide resins, Examples thereof include hard vinyl chloride resin, styrene resin (polystyrene, acrylonitrile-styrene copolymer (AS resin), etc.), cellulose acetates, and the like. Preferred resins for the container containing the composition having light stability are polyethylene, polypropylene, polyester resins, and polycarbonate resins, and particularly preferred resins are polyester resins.

As the polyester resin, a resin composed of a dicarboxylic acid component (such as an aromatic dicarboxylic acid component such as phthalic acid, terephthalic acid, or naphthalenedicarboxylic acid) and a diol component can be used. Specifically, aromatic polyester resins such as polyalkylene terephthalate [poly C _2-4 alkylene terephthalate such as polyethylene terephthalate (PET) and polybutylene terephthalate (PBT)], polyalkylene naphthalate [polyethylene naphthalate ( PEN), poly C _2-4 alkylene naphthalate such as polybutylene naphthalate, etc.], polycycloalkylene terephthalate [poly (1,4-cyclohexylenedimethylene terephthalate) (PCT) etc.], polyarylates (bisphenols ( Homopolyesters such as bisphenol-A and the like) and phthalic acids (resins composed of phthalic acid and terephthalic acid). The polyester resin also includes a copolyester containing the homopolyester unit as a main component (for example, 50% by weight or more), a copolymer of the homopolyester (such as a copolymer of PET and PCT), and the like. . In the present invention, for example, when described as a polyester-based resin container, it is sufficient that a polyester-based resin is included as a constituent material of the container, and the ratio is not particularly limited. For example, it means that the polyester resin is 10 to 100 w / w%, preferably 30 w / w% or more, particularly preferably 50 w / w% or more, based on the weight of the entire material constituting the container.

  Of these, olefin resins (polyethylene, etc.), aromatic polyester resins (polyethylene terephthalate, polyethylene naphthalate, polyarylate, etc.) and polycarbonate resins are preferred.

  The polycarbonate-based resin is, for example, an aromatic polycarbonate based on bisphenols (such as bisphenol-A).

  The plastic container may be a polymer alloy (polymer blend or the like) as long as there is no real harm in cost performance, strength, light transmittance, gas or water vapor barrier property (moisture permeability), or the like. Preferred polymer alloys include a polymer blend of a plurality of synthetic resins (such as a polymer blend of PET and PEN).

  Especially, it is preferable to use the container made from PET from a viewpoint that it is widely used as a container for an over-the-counter medicine (for example, an eye drop container). In addition, when describing as a container made from PET in this invention, for example, PET should just be included as a constituent material of a container, The ratio is not specifically limited. For example, it means that the polyethylene terephthalate is 10 to 100 w / w%, preferably 30 w / w% or more, particularly preferably 50 w / w% or more, based on the weight of the entire material constituting the container.

  The resin is preferably a resin having good squeeze properties and durability against repeated pressing, and a transparent or translucent resin, and may be colored as necessary. Then, by incorporating a component that can inhibit light transmission (such as an ultraviolet absorber or an infrared absorber) into the resin, or by applying a coating agent containing the component to the resin surface, the effect of the present invention is achieved. Thus, the light stability may be further improved.

  Thus, the composition of the present invention is a high-quality composition that is unlikely to decompose bromfenac by light and that can stably exhibit the performance of the contained components over a long period of time.

  The stability of the composition of the present invention can be evaluated by methods well known to those skilled in the art. The stability test of the composition can be performed from the viewpoint of temperature, humidity and light. For example, the pharmaceutical production and sales guideline 2010 (Jiho) describes that verification is performed in a severe test in which the above three conditions are set as separate conditions (page 249, 4. severe test).

  The composition of the present invention exhibits a remarkable histamine release inhibitory effect that cannot be found alone by combining the components (A) to (C), particularly using the concentrations and ratios described above. 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 useful as an ameliorating agent for inflammatory diseases. It is particularly useful for the treatment of allergic diseases because of its inhibitory effect on histamine release.

  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 has various symptoms caused by these inflammatory diseases (for example, a foreign body sensation in the eyes (feeling of tingling and tingling), a throat, redness, itchy eyes, blurred eyes, etc.) Can be used to relax. The composition of the present invention is particularly useful for inflammatory diseases accompanied by allergies, and is suitable for itching of eyes and feeling of foreign bodies (feeling of tingling and tingling).

  Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples, but the present invention is not limited to these Examples and the like.

Test Example 1: Test on light stability (1)
A test solution was prepared according to the formulation shown in Table 1 below, and the photostability of bromfenac sodium was evaluated. Specific experimental methods and results are shown below.

First, each test solution shown in Table 1 was prepared. Next, 7 ml of each test solution was filled into a 10 ml glass headspace vial. The filled container was irradiated with light having an energy of 30000 kJ / m ² using a sun tester (SUNTEST XLS +; Toyo Seiki Seisakusho) as a solar irradiation device. Before and after exposure, the content of bromfenac sodium in each test solution was measured by an HPLC method according to a conventional method, and the residual ratio was calculated according to the following formula [Formula 1]. The calculation results are also shown in Table 1.
[Formula 1]
Residual rate (%) = (bromfenac sodium content after light irradiation / bromfenac sodium content before light irradiation) × 100

  As shown in Table 1, the residual rate of bromfenac sodium decreased after light irradiation, and decomposition of bromfenac sodium by exposure was observed (Comparative Example 1). In the composition containing l-menthol together with bromfenac sodium, this decomposition was further accelerated, and the residual ratio of bromfenac sodium was further reduced (Comparative Example 2). On the other hand, in the composition containing nonionic surfactants such as polyoxyethylene hydrogenated castor oil 60 (Example 1) and poloxamer 407 (Example 2) together with bromfenac sodium and l-menthol. It was confirmed that the residual rate of bromfenac sodium was improved at once and the photostability was improved.

Test Example 2: Test on light stability (2)
A test solution was prepared according to the formulation shown in Table 2 below, and the stability of bromfenac sodium was evaluated. Specific experimental methods and results are shown below.

First, each test solution shown in Table 2 was prepared. Next, each test solution was irradiated with light having an energy of 60000 kJ / m ^{2 in} the same manner as in Test Example 1, and the residual rate of bromfenac sodium was calculated according to the above formula [Formula 1]. The calculation results are also shown in Table 2.

  As shown in Table 2, in the composition containing l-menthol together with bromfenac sodium (Comparative Example 3), the residual ratio of bromfenac sodium significantly decreased after light irradiation. Degradation was observed. On the other hand, polyoxyethylene hydrogenated castor oil 60 (Example 3), polysorbate 80 (Example 4), polyoxyl 40 stearate (Example 5), polyoxy, together with bromfenac sodium and l-menthol. In a composition containing a nonionic surfactant such as ethylene hydrogenated castor oil 40 (Example 6) and polyoxyethylene castor oil 35 (Example 7), the residual ratio of bromfenac sodium is improved at once. It was confirmed that the photostability was improved.

Test Example 3: Test concerning inhibitory effect on histamine release The inhibitory action on histamine release when sodium bromfenac, l-menthol and polyoxyl 40 stearate which is a nonionic surfactant were combined was evaluated. Specific experimental methods and results are shown below.

RBL-2T3 cells were seeded on a 96-well plate at a density of 25 × 10 ⁴ cells / well and cultured at 37 ° C. under 5% CO _{2 for} 24 hours. After removing the medium, it was replaced with PIPES (+) Buffer in which components were dissolved according to the formulation shown in Table 3. After culturing for 1.5 hours under the same conditions, the above Buffer was replaced with PIPES (+) Buffer containing a calcium ionophore reagent and each test drug. The reaction was further performed under the same conditions for 30 minutes, and the supernatant was collected, and the amount of released histamine contained in the test solution was quantified using the Histamine-EIA Kit as each test solution. The histamine release rate was calculated according to the following [Equation 2] by comparison with a standard sample (supernatant after addition of PIPES (+) Buffer not containing the components shown in Table 3). The calculation results are also shown in Table 3.
[Formula 2]
Histamine release rate (%) = (histamine content of each test solution / histamine content of standard sample) × 100

  As shown in Table 3, although bromfenac sodium slightly suppressed the histamine release rate (Comparative Example 4), l-menthol (Comparative Example 5) and polyoxyl 40 stearate (Comparative Example 6) showed histamine. No release inhibitory effect was found. Further, in the presence of bromfenac sodium and polyoxyl 40 stearate (Comparative Example 7), the histamine release inhibitory effect was worse than that of Comparative Example 4. However, when l-menthol and polyoxyl 40 stearate coexist with bromfenac sodium (Example 8), it was confirmed that the release of histamine was remarkably suppressed and the antiallergic action was improved.

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

First, each test solution shown in Table 4 was prepared. Next, 7 ml of each test solution was filled into a 15 ml capacity polyethylene terephthalate (PET) tube. Next, each test solution was irradiated with light having an energy of 30000 kJ / m ^{2 in} the same manner as in Test Example 1, and the residual rate of bromfenac sodium was calculated according to the above formula [Formula 1]. The calculation results are also shown in Table 4.

  As shown in Table 4, when a composition containing l-menthol together with bromfenac sodium was stored in a PET container, the residual rate of bromfenac sodium significantly decreased after light irradiation, and bromfenac sodium due to exposure to light. Was significantly decomposed (Comparative Example 8). In contrast, polysorbate 80 (Example 9), polyoxyethylene castor oil 35 (Example 10), polyoxyethylene hydrogenated castor oil 60 (Example 11), and sodium bromfenac and l-menthol. In the composition containing a nonionic surfactant, it was confirmed that the residual ratio of bromfenac sodium was improved at once and the photostability was improved.

Reference Test Example 1: Test Regarding Thermal Stability Each test solution (Reference Examples 1 and 2) shown in Table 5 below was prepared. Next, 7 ml of each test solution was filled in a 10 ml glass headspace vial, sealed, and stored in a 60 ° C. thermostatic chamber under light shielding. Two weeks and four weeks 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 rate was calculated according to the following formula.
[Formula 3]
Residual rate (%) = (content of bromfenac sodium in each test solution after storage at 60 ° C./content of bromfenac sodium in each test solution before storage) × 100

  As shown in Table 5, it was found that bromfenac sodium and a composition containing l-menthol together with bromfenac sodium are extremely stable to heat.

  From the above, it was found that the decomposition of bromfenac sodium when coexisting with l-menthol is significantly promoted by light irradiation but is not caused by heat.

[Formulation example]
An eye drop (Formulation Example 1-17) and an eye wash (Formulation Example 18-20) were prepared according to the formulations shown in Tables 6 and 7.

Claims (10)

(A) bromfenac and / or a salt thereof;
(B) a terpenoid,
(C) A composition containing a nonionic surfactant.   As the component (C), at least selected from the group consisting of polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene-polyoxypropylene block copolymer, and polyethylene glycol monostearate The composition of claim 1 comprising one species.   The component (B) contains at least one selected from the group consisting of menthol, camphor, borneol, geraniol, cool mint oil, peppermint oil, peppermint oil, camphor oil, eucalyptus oil, and bergamot oil. 2. The composition according to 2.   The composition in any one of Claims 1-3 whose total content of (B) component is 0.0002-10 weight part with respect to 1 weight part of total content of (A) component.   The composition in any one of Claims 1-4 whose total content of (C) component is 0.01-10000 weight part with respect to 1 weight part of total content of (B) component.   The composition according to any one of claims 1 to 5, which is an aqueous liquid composition.   The composition according to any one of claims 1 to 6, which is an ophthalmic composition.   The composition in any one of Claims 1-7 accommodated in the light transmissive container.   The composition according to claim 8, wherein the material of the light transmissive container includes a polyester resin.   A method for improving the photostability of bromfenac and / or a salt thereof, comprising (A) bromfenac and / or a salt thereof containing (B) a terpenoid and (C) a nonionic surfactant.