JP4942336B2 - Aqueous composition containing flavin adenine dinucleotide - Google Patents

Description

  The present invention relates to an aqueous composition having improved flavin adenine dinucleotide (hereinafter referred to as “FAD”) stability. Furthermore, the present invention relates to a method for stabilizing an aqueous composition containing FAD.

FAD is a coenzyme-type vitamin B ₂ and is a substance involved in oxidative degradation of sugars, lipids, amino acids and the like in vivo. Conventionally, FAD is conjunctivitis, eye strain, angular cheilitis, stomatitis, glossitis, cheilitis, are formulated in various pharmaceutical formulations for the treatment or prevention of vitamin B ₂ deficiency, such as seborrheic dermatitis. In ophthalmic preparations, FAD is also blended for the purpose of improving resilience during fatigue by promoting energy metabolism of cells. On the other hand, FAD has a drawback that it tends to be unstable in the presence of water. Therefore, when FAD is blended in an aqueous composition to prepare a formulation, the desired effect is reduced or disappeared with the time-dependent degradation of FAD, and a constant quality cannot be guaranteed. Under such circumstances, when FAD is blended in an aqueous composition, it is considered important to formulate the FAD so that it is stably maintained.

  Conventionally, as a technique for stabilizing FAD in an aqueous composition, for example, a method in which a xanthine derivative such as caffeine coexists with FAD has been reported (see Patent Document 1). However, at present, it is impossible to infer what kind of structure and action compounds are useful for stabilizing FAD, except for compounds already reported to contribute to stabilization of FAD.

On the other hand, acitazanolast has pharmacological actions such as antiallergy and intraocular pressure reduction against allergic conjunctivitis through the inhibitory action of histamine, platelet activating factor (PAF) and leukotriene B4 / D4 from mast cells. It has been found useful as an active ingredient of topical preparations such as eye drops (see, for example, Patent Document 2). On the other hand, there is no report on the effect of acitazanolast on the stabilization of FAD in aqueous compositions.
JP 2003-55225 A Japanese Patent Laid-Open No. 9-30968

  An object of the present invention is to provide an aqueous composition containing FAD and / or a salt thereof in a stable state. Furthermore, this invention aims at providing the method of stabilizing FAD and / or its salt in the aqueous composition containing FAD and / or its salt.

  The present inventor has intensively studied to solve the above-mentioned problems, and as a result, by preparing an aqueous composition in which agitazanolast and / or a salt thereof coexist with FAD and / or a salt thereof, FAD and / or a salt thereof is prepared. It has been found that stability over time can be imparted to the salt. The present invention has been completed by making further improvements based on such findings.

That is, the present invention provides the following aqueous compositions:
Item 1. An aqueous composition comprising (i) flavin adenine dinucleotide and / or a salt thereof, and (ii) acitazanolast and / or a salt thereof.
Item 2. Item 2. The aqueous composition according to Item 1, which is a topical mucosa application agent.

Furthermore, the present invention provides the stabilization methods listed below:
Item 3. (i) A method for stabilizing an aqueous composition containing flavin adenine dinucleotide and / or a salt thereof, characterized in that (ii) acitazanolast and / or a salt thereof is added to the aqueous composition. , Stabilization method.

  Hereinafter, the present invention will be described in detail. In addition, in this specification, an aqueous composition is a composition containing water. Examples of the aqueous composition include those containing 1% by weight of water, preferably 5% by weight or more, more preferably 20% by weight or more, and particularly preferably 50% by weight or more in the composition.

1. Aqueous Composition The aqueous composition of the present invention contains FAD and / or a salt thereof as component (i).

FAD and salts thereof are known as a coenzyme type vitamin _{B 2.} The salt of FAD is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specifically, an organic acid salt (for example, lactate salt, acetate salt) , Butyrate, trifluoroacetate, fumarate, maleate, tartrate, citrate, succinate, malonate, methanesulfonate, toluenesulfonate, tosylate, palmitate, Stearates, etc .; inorganic acid salts (eg, hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.); salts with organic bases (eg, methylamine, triethylamine, triethanolamine, morpholine) , Piperazine, pyrrolidine, amino acids, salts with organic amines such as tripyridine, picoline, etc.); alkali metal salts (for example, sodium salts, potassium salts, etc.); alkaline earth metal salts (for example, Calcium salt, magnesium salt, etc.); other metal salts (aluminum salt) and the like. Among these, an alkali metal salt is preferable, and a sodium salt is more preferable. These FAD and its salt may be used individually by 1 type, and may be used in combination of 2 or more types arbitrarily.

  In the aqueous composition of the present invention, a sodium salt of FAD is preferably used as component (i).

  The blending ratio of the component (i) in the aqueous composition of the present invention is appropriately set according to the use and form of the composition. Usually, the blending ratio of the component (i) in the composition is 0.0005 to 0.5% by weight, preferably 0.001 to 0.1% by weight, more preferably 0.005 to 0 in terms of the total amount of the components. 0.05% by weight is exemplified.

  The aqueous composition of the present invention contains acitazanolast and / or a salt thereof as the component (ii) in addition to the component (i). By containing the component (ii), it is possible to impart stability to the FAD and / or a salt thereof in the aqueous composition.

Acitazanolast is a known compound represented by 3- (1H-tetrazol-5-yl) oxanilic acid (IUPAC name), molecular formula C ₉ H ₇ N ₅ O ₃ . The compound is synthesized by a known method.

  The salt of acitazanolast is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such salts include salts with organic bases (salts with organic amines such as methylamine, triethylamine, diethylamine, and triethanolamine); alkali metal salts (for example, sodium salts and potassium salts) An inorganic earth salt such as an alkaline earth metal salt (calcium salt, magnesium salt, etc.) and another metal salt (aluminum salt, etc.). These acitazanolasts and salts thereof may be used alone or in any combination of two or more.

  Acitazanolast and a salt thereof used in the present invention may be in the form of a hydrate such as a half hydrate or a monohydrate.

  In the aqueous composition of the present invention, agitazanolast monohydrate is preferably used as the component (ii).

  The blending ratio of the component (ii) in the aqueous composition of the present invention varies depending on the form and use of the aqueous composition, but as an example, the component (ii) is added to the total amount of the aqueous composition. 0.0005 to 2% by weight, preferably 0.001 to 1% by weight, and more preferably 0.005 to 0.11% by weight.

  In addition, in the aqueous composition of the present invention, from the viewpoint of providing further stability to FAD and / or a salt thereof, the component (ii) is added to 100 parts by weight of the component (i). It is desirable to satisfy the ratio of 1 to 100000 parts by weight, preferably 2 to 20000 parts by weight, and more preferably 10 to 2200 parts by weight.

  In addition, the water contained in the aqueous composition of the present invention may be any pharmaceutical, 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 14th revised Japanese Pharmacopoeia.

  The aqueous composition of the present invention can further contain a buffer. The buffer that can be incorporated into the aqueous composition of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such buffers include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, epsilon-aminocaproic acid, aspartic acid, aspartate, glutamate and the like. These buffering agents may be used alone or in any combination of two or more. Among the above buffers, borate buffer, phosphate buffer, and epsilon-aminocaproic acid are preferable. When blending a buffering agent in the aqueous composition of the present invention, the blending ratio of the buffering agent varies depending on the type of buffering agent used and the expected effect, and cannot be defined uniformly, for example, In the aqueous composition, the ratio of the buffering agent is 0.1 to 5% by weight, preferably 0.3 to 4% by weight, and more preferably 0.5 to 3% by weight.

  In addition, the aqueous composition of the present invention can be adjusted to a pH within a range acceptable for a living body. The appropriate pH varies depending on the application site, dosage form and the like of the aqueous composition, but is usually 3.5 to 9, preferably 4 to 8, and more preferably about 4.5 to 7.5. The pH and osmotic pressure can be adjusted by a method known in the art using the buffer, the pH adjuster, tonicity agent, salts, etc. described later.

  If necessary, the aqueous composition of the present invention can be adjusted to an osmotic pressure ratio within a range acceptable for a living body. The appropriate osmotic pressure ratio varies depending on the application site, dosage form and the like, but is usually about 0.4 to 2, preferably about 0.5 to 1.8, and more preferably about 0.6 to 1.6. The osmotic pressure can be adjusted by adding an inorganic salt, a polyhydric alcohol, a sugar alcohol, a saccharide or the like.

  In the aqueous composition of the present invention, the osmotic pressure ratio is the ratio of the osmotic pressure of the sample to the osmotic pressure of the 0.9 w / v% aqueous sodium chloride solution based on the 14th revised Japanese pharmacopoeia, and the osmotic pressure is the osmotic pressure described in the Japanese pharmacopoeia. Measure using the pressure measurement method (freezing point depression method).

  The aqueous composition of the present invention may contain a combination of various pharmacologically active components and physiologically active components in addition to the above components as long as the effects of the present invention are not hindered. The type of such component is not particularly limited, and examples thereof include a decongestant component, an eye muscle modulator component, an anti-inflammatory component or an astringent component, an antihistamine component or an antiallergic component, vitamins, amino acids, antibacterial agents. Examples of the drug component or bactericidal component, sugars, polymer compounds or derivatives thereof, cellulose or derivatives thereof, water-soluble polymers other than those described above, local anesthetic components, steroid components, glaucoma treatment components, and cataract treatment components. Examples of suitable components in the present invention include the following components.

  Decongestant: For example, α-adrenergic agonists, specifically epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine hydrogen tartrate, naphazoline nitrate. These may be d-form, l-form or dl-form.

  Ocular muscle modulator component: For example, cholinesterase inhibitor having an active center similar to acetylcholine, specifically, neostigmine methyl sulfate, tropicamide, helenien, atropine sulfate and the like.

  Anti-inflammatory component or astringent component: for example, zinc sulfate, zinc lactate, allantoin, epsilon-aminocaproic acid, indomethacin, lysozyme chloride, silver nitrate, pranoprofen, sodium azulenesulfonate, dipotassium glycyrrhizinate, diammonium glycyrrhizinate, Diclofenac sodium, bromfenac sodium, berberine chloride, berberine sulfate, etc.

  Antihistamine component or antiallergic agent component: for example, amlexanox, ibudilast, tazanolast, tranilast, isothipentyl, dipheterol, diphenylpyraline, triprolidine, tripelenamine, tondilamine, mebhydroline, phenetazine, oxatomide, mequitazine, terfenadine, espinastine, azoestine, astemistatin Cetirizine, loratadine, fexofenadine, suplatast, diphenhydramine hydrochloride, levocabastine hydrochloride, ketotifen fumarate, sodium cromoglycate, pemirolast potassium, chlorpheniramine maleate, emedastine fumarate Clemastine, azelastine hydrochloride, iproheptin hydrochloride, olopatadine hydrochloride, etc.

  Vitamins: for example, retinol acetate, retinol palmitate, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate, ascorbic acid, tocopherol acetate, tocopherol nicotinate, tocopherol succinate, tocopherol calcium succinate , Ubiquinone derivatives and the like.

  Amino acids: for example, aminoethylsulfonic acid (taurine), glutamic acid, creatinine, sodium aspartate, potassium aspartate, magnesium aspartate, magnesium aspartate / potassium mixture, glutamic acid, sodium glutamate, magnesium glutamate, epsilon-aminocaproic acid, glycine , Alanine, arginine, lysine, γ-aminobutyric acid, γ-aminovaleric acid, sodium chondroitin sulfate and the like. These may be d-form, l-form or dl-form.

  Antibacterial component or bactericidal component: for example, aminodeoxykanamycin sulfate, kanamycin sulfate, gentamicin sulfate, sisomycin sulfate, streptomycin sulfate, tobramycin, micronomycin sulfate, alkylpolyaminoethylglycine, chloramphenicol, sulfamethoxazole, Sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxazole monoethanolamine, sulfisomethazole sodium, sulfisomidine sodium, tetracycline hydrochloride, oxytetracycline hydrochloride, ofloxacin, Norfloxacin, Levofloxacin, Lomefloxacin hydrochloride, Sulbenicin sodium, Cefmenoxime hydrochloride, Benzylpenicillin potassium, Verbe sulfate , Berberine chloride, boric acid, sodium colistin metasulfonate, erythromycin, erythromycin lactobionate, kitasamycin, spiramycin, fradiomycin sulfate, polymyxin sulfate, dibekacin, amikacin, amikacin sulfate, acyclovir, iododeoxycytidine, idoxuridine , Cyclocytidine, cytosine arabinoside, trifluorothymidine, bromodeoxyuridine, polyvinyl alcohol iodine, iodine, amphotericin B, isoconazole, econazole, clotrimazole, nystatin, pimaricin, fluorocytosine, miconazole and the like.

  Saccharides: for example monosaccharides, disaccharides, specifically glucose, fructose, galactose, mannose, ribose, allose, ribulose, arabinose, xylose, lyxose, deoxyribose, maltose, trehalose, sucrose, cellobiose, glucobiose, vicyanose, lutinose, Lactose, pullulan, lactulose, raffinose, maltitol, stachyose, cyclodextrin, xylitol, sorbitol, mannitol, etc.

  High molecular compound or derivative thereof: for example, gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac oil, quince seed, dummar gum, tragacanth, benzoin gum, locust bean gum, casein, agar, alginic acid, sodium alginate, dextrin, dextran, Carrageenan, gelatin, collagen, pectin, starch, polygalacturonic acid, chitin and its derivatives, chitosan and its derivatives, elastin, heparin, heparinoid, heparin sulfate, heparan sulfate, sodium hyaluronate, chondroitin sulfate, ceramide, polyvinyl alcohol (complete, Or partially saponified products), polyvinylpyrrolidone, polyvinyl methacrylate, polyacrylic acid, carboxyvinyl polymer, polyethylene N'imin, ribonucleic acid, deoxyribonucleic acid, and the like pharmaceutically acceptable salts.

  Cellulose or derivatives thereof: for example, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, nitrocellulose and the like.

  Local anesthetic components: for example, oxybuprocaine hydrochloride, cocaine hydrochloride, cornecaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, diethylaminoethyl parabutylaminobenzoate, piperocaine hydrochloride, procaine hydrochloride, proparacaine hydrochloride, hexothiocaine hydrochloride, lidocaine hydrochloride.

  Steroid component: for example, dexamethasone, hydrocortisone, fluorometholone, prednisolone, methylprednisolone, hydroxymesterone, hydrocortisone caproate, prednisolone caproate, cortisone acetate, hydrocortisone acetate, prednisolone acetate, sodium dexamethasone metasulfobenzoate, sodium dexamethasone sulfate Dexamethasone sodium phosphate, triamcinolone acetonide, betamethasone sodium phosphate, dexamethasone sodium metasulfobenzoate, methylprednisolone and the like.

  Glaucoma treatment components: for example, isopropyl unoprostone, epinephrine, apraclonidine hydrochloride, carteolol hydrochloride, dipivefrin hydrochloride, dorzolamide hydrochloride, pilocarpine hydrochloride, bunazosin hydrochloride, bupranolol hydrochloride, betaxolol hydrochloride, befnolol hydrochloride, carbachol, levobunolol hydrochloride, epinephrine hydrochloride , Distigmine bromide, nipradilol, timolol maleate, latanoprost and the like.

  Cataract treatment component: for example, glutathione, pirenoxine, sodium 5,12-dihydroazapentacene disulfonate and the like.

  The compounding amounts of the various components in various applications are known in the art, and the compounding amounts of the components in the aqueous composition are appropriately selected according to the dosage form of the aqueous composition, the type of the active ingredient, and the like. . For example, it can be selected from a range of about 0.0001 to 30 w / v%, preferably about 0.001 to 10 w / v% with respect to the entire aqueous composition.

  Further, in the aqueous composition of the present invention, various components and additives are appropriately selected according to a conventional method according to the use and form as long as the effects of the invention are not impaired. You may contain together. As those components or additives, for example, carriers (aqueous solvents, aqueous or oily bases, etc.) commonly used in the preparation of semi-solids and liquids, thickeners, sugars, sugar alcohols, surfactants And various additives such as agents, preservatives, bactericides or antibacterial agents, pH adjusters, tonicity agents, fragrances or refreshing agents, chelating agents, buffering agents, stabilizers, bases and the like.

  Although the typical component used for the aqueous composition of this invention is illustrated below, it is not limited to these.

  Thickeners: for example, carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, alginic acid, sodium alginate, polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone, macrogol, sodium chondroitin sulfate and the like.

  Sugars: for example, glucose, cyclodextrin and the like.

Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like.
These may be d-form, l-form or dl-form.

  Surfactant: For example, polyoxyethylene (hereinafter abbreviated as POE) -polyoxypropylene (hereinafter abbreviated as POP) block copolymer (specifically, poloxamer 407, etc.), ethylenediamine POE-POP block copolymer adduct ( Specifically, non-ionic surfactants such as poloxamine), POE sorbitan monooleate, POE hydrogenated castor oil (specifically, POE (60) hydrogenated castor oil), polyoxyl stearate; alkyldiaminoethyl Glycine-type amphoteric surfactants such as glycine; alkyl quaternary ammonium salts (specifically, cationic surfactants such as benzalkonium chloride and benzethonium chloride. The numbers in parentheses indicate the number of moles added.

  Preservatives, bactericides or antibacterials: for example, alkyldiaminoethylglycine hydrochloride, sodium benzoate, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxybenzoic acid Methyl, 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) Such.

  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 ,Such.

  Isotonizing agents: for example, sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, dihydrogen phosphate Sodium, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerin, propylene glycol and the like.

  A fragrance or a refreshing agent: for example, camphor, geraniol, borneol, menthol, leopard, fennel oil, cinnamon oil, cool mint oil, spearmint oil, peppermint water, peppermint oil, peppermint oil, bergamot oil, eucalyptus oil, rose oil and the like. These may be d-form, l-form or dl-form.

  Chelating agent: for example, ascorbic acid, tetrasodium edetate, sodium edetate, citric acid and the like.

  Stabilizer: Dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, etc.

  Base: Octyldodecanol, olive oil, sesame oil, titanium oxide, potassium bromide, soybean oil, camellia oil, corn oil, rapeseed oil, cottonseed oil, paraffin, castor oil, plastibase, peanut oil, lanolin, petrolatum, propylene glycol, etc.

  Solubilizer or solubilizer: ethanol, glycerin, hydrochloric acid, sodium hydroxide, trometamol, macrogol 4000, monoethanolamine and the like.

  The aqueous composition of the present invention can take various forms depending on the purpose. For example, the form of the aqueous composition of the present invention includes a liquid agent, a semisolid agent (ointment etc.) and the like. A liquid agent is preferable.

  Specific examples of liquid preparations include eye drops [however, eye drops include eye drops that can be applied while wearing contact lenses], artificial tears, eye wash [however, eye drops can be washed while wearing contact lenses. Contact lens composition, contact lens mounting fluid, contact lens care composition (contact lens disinfectant, contact lens preservative, contact lens cleaning agent, contact lens cleaning preservative), etc. ], Nasal drops, nasal rinses, oropharyngeal drugs, gargles (harvesting agents), ear drops and the like. Moreover, an eye ointment is illustrated as a specific example of a semisolid agent.

  The contact lens composition can be applied to all contact lenses including hard contact lenses and soft contact lenses. Moreover, since the said composition for contact lenses is comprised from the component which is hard to adsorb | suck with respect to especially an oxygen-permeable hard contact lens or a soft contact lens, it is used more suitably with respect to these contact lenses.

Aqueous compositions of the present invention, FAD and / or with fatigue resilience improving effect and vitamin B2 ₂ deficiency improving action of promoting energy metabolism of cells based on a salt, Ya antiallergic action based on acitazanolast and / or a salt thereof Since it can exert an intraocular pressure lowering effect, it is particularly useful as a topical mucosa-applied preparation (for example, eye drops, eye washes, eye ointments, nasal drops, nasal washes, etc.) applied topically to the mucous membranes. Of these, eye drops, eye washes, and nasal drops are preferable, and eye drops are more preferable.

  The aqueous composition of the present invention can be produced by a known method.

  Although it does not restrict | limit especially as a container filled with the aqueous composition of this invention, From a viewpoint of improving the stability with respect to the light of a formulation, it is preferable to fill with the following plastic container.

  The plastic container is not particularly limited as long as it can be used as a container for an aqueous composition, but preferably has a low moisture permeability, and more preferably does not easily adsorb each component. Specific examples of the plastic container include a container made of hard plastic. Specific examples of constituent materials for rigid plastic containers include olefin resins, polyester resins, polyphenylene ether resins, polycarbonate resins, polysulfone resins, polyamide resins, rigid vinyl chloride resins, styrene resins, and cellulose. Acetate resin etc. can be illustrated.

  Examples of the olefin resin include polymers such as polyethylene (PE) and polypropylene (PP).

  Examples of the polyester-based resin include a resin composed of a dicarboxylic acid component (such as an aromatic dicarboxylic acid component such as phthalic acid, terephthalic acid, and naphthalenedicarboxylic acid) and a diol component. Specifically, aromatic polyester resins, for example, polyalkylene terephthalates such as poly C2-4 alkylene terephthalates such as polyethylene terephthalate (PET) and polybutylene terephthalate (PBT); polyethylene naphthalate (PEN) and polybutylene naphthalate Such as poly C2-4 alkylene naphthalate; poly (1,4-cyclohexylenedimethylene terephthalate) (PCT) and other polycycloalkylene terephthalates; bisphenols (such as bisphenol-A) and phthalic acids ( And homopolyesters such as polyarylate such as resin composed of phthalic acid and terephthalic acid. The polyester resin 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.

  Examples of the polycarbonate-based resin include aromatic polycarbonates based on bisphenols such as bisphenol-A.

  Examples of the styrene resin include polystyrene, acrylonitrile-styrene copolymer (AS resin), and the like.

  The plastic container used in the present invention is made of a polymer alloy (polymer blend, etc.) as a constituent material unless there is any actual harm in cost performance, strength, light transmission, gas or water vapor barrier properties (moisture permeability), etc. May be. Preferred polymer alloys include a polymer blend of a plurality of synthetic resins (eg, a polymer blend of PET and PEN).

  The resin is preferably a resin having good squeeze properties and durability against repeated pressing, and a transparent or translucent resin, and is colored yellow, orange, brown or the like as necessary. May be. 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 above component to the resin surface, the effect of the present invention is achieved. The stability may be further improved by working.

  The shape of the plastic container is not particularly limited, and can be appropriately set according to the dosage form and application of the aqueous composition.

2. Method for Stabilizing Aqueous Composition As described above, in the aqueous composition containing (i) FAD and / or its salt, destabilization of FAD and / or its salt It can suppress by mix | blending zanolast and / or its salt. Accordingly, the present invention provides, from another viewpoint, a method for stabilizing the following aqueous composition: (i) an aqueous composition containing FAD and / or a salt thereof, and (ii) agitazanolast and / or A method for stabilizing the aqueous composition, comprising blending the salt.

  In the stabilization method, the components (i) and (ii) to be used, the respective blending ratios in these aqueous compositions, optional additional components that can be blended in the aqueous composition, the form of the aqueous composition, etc. 1. As described in the column “Aqueous composition”.

Since the aqueous composition of the present invention contains FAD and / or its salt in a stable state and has excellent temporal stability, the pharmacological action of FAD and / or its salt can be effectively exhibited. Furthermore, acitazanolast and / or a salt thereof contained in the aqueous composition of the present invention not only contributes to stabilization of FAD and / or a salt thereof, but can also exert its own pharmacological action. Therefore, the aqueous composition of the present invention has an effect of improving fatigue recovery ability by promoting energy metabolism of cells based on FAD and / or a salt thereof, or preventing or treating vitamin B ₂ deficiency, and also to agitazanolast and / or a salt thereof. Therefore, the anti-allergic effect and the intraocular pressure-reducing effect can be effectively exhibited, so that it is useful as a pharmaceutical composition, particularly as a preparation for topical mucosa. Among the above forms, the aqueous composition of the present invention is highly useful as an ophthalmic solution having a high anti-inflammatory / anti-allergic action.

Hereinafter, the present invention will be described in detail based on test examples, examples, and the like, but the present invention is not limited thereto.
Test example 1
According to the formulation described in Table 1, FAD-containing aqueous solutions (Example 1 and Comparative Example 1) were prepared. Each FAD-containing aqueous solution was filtered, filled in a polyethylene terephthalate container (capacity 13 mL), and stored in a dark place at 60 ° C. for 30 days. At 0, 15 and 30 days after the start of storage, the FAD concentration in the FAD-containing aqueous solution was measured by HPLC, and the FAD residual rate was calculated according to the following formula. For the FAD-containing aqueous solution of Example 1, 30 days after the start of storage, the acitazanolast concentration in the FAD-containing aqueous solution was measured by HPLC, and the acitazanolast residual rate was calculated according to the following formula.

  The results obtained for the FAD residual rate are shown in FIG. From this result, it was observed that FAD was decomposed over time in the FAD-containing aqueous solution (Comparative Example 1) not containing acitazanolast. On the other hand, in the FAD-containing aqueous solution (Example 1) blended with acitazanolast, the FAD decomposition was remarkably suppressed, and it was confirmed that the FAD was maintained in a stable state. In addition, in the FAD-containing aqueous solution of Example 1, the residual ratio of acitazanolast was 99% or more even after 30 days from the start of storage, and it was confirmed that acitazanolast itself was present in a stable state in the aqueous solution. It was.

  Separately, when a glass container filled with the FAD-containing aqueous solution of Example 1 and Comparative Example 1 was irradiated with light at 600,000 lx at room temperature, in the FAD-containing aqueous solution of Comparative Example 1, the residual rate of FAD was obtained. Was 31%, whereas in the FAD-containing aqueous solution of Example 1, the residual ratio of FAD was 79% or more. From this result, it became clear that the aqueous composition of the present invention also improved the stability of FAD to light.

Example 2-12
An eye drop (Example 2-12) having the composition shown in Table 2 was prepared and contained in a polyethylene terephthalate container. The eye drop of Example 6 can be used even while wearing a soft contact lens.

Examples 13-19
Eye drops (Examples 13-18) and eye washes (Example 19) having the compositions shown in Table 3 were prepared and accommodated in various containers. Specifically, the eye drops of Examples 13, 14, 18 and 19 are in polyethylene terephthalate containers; the eye drops of Example 15 are in polyethylene containers; the eye drops of Example 16 are in polypropylene containers; The eye drop of Example 17 was housed in a mixed polymer container of polyethylene phthalate and polyethylene terephthalate. The eye drop of Example 18 can be used even while wearing a soft contact lens.

In Test Example 1, the change over time in the residual ratio of FAD measured when FAD was stored in an aqueous solution at 60 ° C. in the presence of acitazanolast (Example 1) or in the absence (Comparative Example 1). FIG.

Claims (3)

(i) flavin adenine dinucleotide and / or salt thereof, and
(ii) Acitazanolast and / or a salt thereof,
An aqueous composition comprising:   The aqueous composition according to claim 1, which is a topical mucosa application agent.   (i) A method for stabilizing an aqueous composition containing flavin adenine dinucleotide and / or a salt thereof, characterized in that (ii) acitazanolast and / or a salt thereof is added to the aqueous composition. , Stabilization method.

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