JP2003055221A - Stabilized composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a composition containing amlexanox stabilized at a high level even in an aqueous solution. SOLUTION: The stability of the amlexanox to the light is improved by adding 0.01-100,000 pts.wt. xanthines (caffeine, theophylline or the like) based on 1 pts.wt. amlexanox. The composition is useful as an aqueous composition, e.g. a topically applied composition such as an eye drop, and a composition applied to the mucous membrane.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a composition having improved long-term stability even if it contains amlexanox having photolability (for example, a composition for topical application such as eye drops, an aqueous composition). Pharmaceutical composition).

[0002]

BACKGROUND OF THE INVENTION Amlexanox is widely used as an anti-allergic agent for the treatment of allergic diseases.
However, since this compound is gradually decomposed and colored by light, when amlexanox is added to the composition, the color tone of the product is changed and the drug efficacy is lowered. Since it becomes unstable to light in an aqueous solution, it is very important to ensure stability in the manufacturing process of the aqueous composition, market distribution process, and long-term stability after opening.

In order to stably hold a formulation containing a pharmacologically active substance which is unstable to light, a light-shielding means by a packaging material containing the formulation, for example, an auxiliary light-shielding for shielding a container containing the formulation. Light-shielding means such as using a bag as an accessory and using a brown container or an aluminum container as a container for containing the drug product has been adopted. However, when the user does not use the auxiliary light-shielding bag or 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. Further, in the manufacturing process of the aqueous composition, it is necessary to inspect foreign substances after filling the formulation from the outside of the container,
Opaque containers such as aluminum and transparent but dark brown containers cannot be used, and the light-shielding means by the packaging material can be used only in a limited manner.

Furthermore, it is almost impossible to use the preparation under shading even when applying the preparation. In particular, when a drug for topical administration is taken out of a container and applied to the skin or mucous membrane, the drug is usually exposed to light, and photolysis at the application site is unavoidable.

From this point of view, for example, eye drops containing amlexanox use a transparent plastic container which has a good squeeze property, is easy to be instilled, and is easy to carry. It is placed in a paper box and protected from light. Further, since the user may continue to use it for one month to several months after opening the package, we are trying to maintain the light stability by recommending the auxiliary use of a plastic light-shielding bag. However, the light-shielding means using such a packaging material cannot not only ensure stability in the manufacturing process, but also photodegradation at the formulation application site after opening, and there is a possibility that the user's light-shielding bag will not be used or lost. , Not necessarily an effective method.

On the other hand, since caffeine has a central excitatory action, it is mainly used as a composition for internal use in medicines and food compositions for improving drowsiness, and is also compounded in an external preparation. Regarding caffeine, JP-A-10-279
Japanese Patent No. 503 discloses the use of purine bases (caffeine, theobromine, theophylline) to stabilize an arylcarboxylic acid having an anti-inflammatory effect. JP-A-7-228532 and JP-A-7-2
Japanese Patent No. 58083 discloses that in order to improve the solubility and photostability of argininamides in water and to alleviate eye irritation,
The use of caffeine or cyclodextrin is disclosed. Japanese Patent Publication No. 5-51568 discloses a non-irritating aqueous ophthalmic composition containing suprofen and a xanthine derivative (theophylline, caffeine, theobromine), which eliminates or relieves discomfort of suprofen when applied topically to the eye. The thing is disclosed. JP 2000-2
Japanese Patent No. 47885 discloses an eye drop for improving eye strain that contains caffeine as an active ingredient.

However, the action of xanthine compounds on amlexanox is unknown.

[0008]

Therefore, it is an object of the present invention to provide a composition (or pharmaceutical composition) capable of stabilizing amlexanox at a high level. Another object of the present invention is to provide an aqueous composition (aqueous pharmaceutical composition) which has improved stability to light even in an aqueous solution and is stable for a long period of time.

[0009]

Means for Solving the Problems The inventors of the present invention have made extensive studies as a result of achieving the above object. As a result, when coexisting with a xanthine derivative, amlexanox is exposed to light for a long time even in an aqueous composition. They have found that they can be stabilized, and have completed the present invention.

That is, the stabilized composition of the present invention comprises a compound represented by the following formula (1) or a salt thereof (hereinafter sometimes simply referred to as xanthines) and amlexanox. contains.

[Chemical 2] (In the formula, R ¹ , R ² and R ³ may be the same or different and each represents a hydrogen atom or an alkyl group which may be substituted.) The present invention is represented by the formula (1). Also disclosed are aqueous compositions containing xanthines and amlexanox.

Further, examples of the compound represented by the formula (1) include caffeine, theophylline, theobromine, diprophylline, proxyphylline, pentoxifylline and salts thereof, preferably caffeine and salts thereof. it can. The ratio of xanthines in the composition is not particularly limited as long as it is an effective amount, and is, for example, about 0.001 to 1000 parts by weight with respect to 1 part by weight of amlexanox. The composition of the present invention can be used as various compositions or formulations based on the activity of xanthines and amlexanox, and may be, for example, a composition for topical application or a composition for mucosal application. In addition, the composition of the present invention can improve light stability and the like, and thus is suitable for packaging in a reusable form. For example, it is suitable for being housed in a light transmissive container, particularly a plastic container.

The present invention is not limited to the above composition, but also includes a method for improving the stability of amlexanox by blending the xanthines.

In the present specification, "salt" means a pharmacologically or physiologically acceptable salt. In addition, a composition for external use, a preparation or a preparation composition, a composition for mucosal application (or a preparation for mucosal application) may be simply referred to as “composition” or “formulation”. The compounds (xanthines and amlexanox) can be used in the form of pharmaceutically acceptable salts or hydrates.

[0014]

DETAILED DESCRIPTION OF THE INVENTION In the compound represented by the formula (1), the alkyl group, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, C _1-6 alkyl group such as a t- butyl group (especially C _1-4 alkyl group)
Can be illustrated. Preferred alkyl groups include methyl and ethyl groups. These alkyl groups are substituents,
For example, halogen atom (chlorine, bromine, fluorine atom, etc.), hydroxyl group, alkoxy group (C _1-4 alkoxy group such as methoxy, ethoxy, butoxy group, etc.),
Aryloxy group, a carboxyl group, an alkoxycarbonyl group (C _1-4 alkoxy - carbonyl group), an aryloxycarbonyl group, an acyl group (formyl, acetyl, C _1-4 alkyl, such as propionyl group - carbonyl group, a benzoyl group Aryl-carbonyl group), nitro group, amino group, N-substituted amino group (mono- or di-C _1-4 alkylamino group etc.), cyano group and the like.

The compound represented by the formula (1) can be used as a pharmacologically (pharmaceutically) or physiologically acceptable salt. Examples of the pharmacologically or physiologically acceptable salt include, for example, organic acid salts (for example, lactate, acetate, butyric acid, trifluoroacetate, fumarate, maleate, tartrate, citrate, succinate). Acid salts, malonates, methanesulfonates, toluenesulfonates, tosylate salts, palmitic acid, stearic acid, etc., inorganic acid salts (eg, hydrochlorides, sulfates, nitrates, hydrobromides, phosphorus) Acid salt),
Salts with organic bases (for example, methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, amino acids, salts with organic amines such as tripyridine and picoline), salts with inorganic bases (for example, ammonium salt, sodium) , An alkali metal such as potassium, an alkaline earth metal such as calcium and magnesium, a salt with a metal such as aluminum), and the like.

Specific compounds represented by the formula (1) (xanthines) include xanthine derivatives such as caffeine, theophylline, oxtriphylline, daphylline, diisobutylaminobenzoyloxypropyltheophylline, theobromine, diprophylline and proxy. Examples include filin and pentoxifylline. These compounds can be used alone or in combination of two or more kinds. Preferred compounds are methylxanthine derivatives such as caffeine, theophylline and theobromine; diprophylline, proxyphylline, pentoxifylline and the like, and caffeine is particularly preferable. Caffeine also includes anhydrous caffeine.

Further, the xanthines may be contained in the composition of the present invention in the form of a mixture with other substances.
Examples of such a mixture include, for example, sodium caffeine benzoate, which is a mixture of caffeine and sodium benzoate, caffeine citrate, which is a mixture of caffeine and citric acid, and a mixture of theophylline and ethylenediamine. Examples include aminophylline, bufilin, which is a mixture of theophylline and aminoisobutanol, calcium theobromine salicylate, which is a mixture of theobromine and salicylate, sodium theobromine salicylate, and sodium theobromine acetate, which is a mixture of theobromine and sodium acetate.

The amount of xanthines used in the composition of the present invention varies depending on the type and dosage form of compound (1),
For example, in the case of a composition applied systemically, the daily application amount is about 10 to 500 mg, and in the case of a composition applied topically, the formulation amount can be designed in the range of about 0.001 to 50 mg. For example, in an aqueous composition, the concentration of the compound represented by the above formula (1) or a salt thereof in the composition is 0.
It can be selected from the range of about 0001 to 10 W / V% (hereinafter, "W / V%" is simply represented by "%" unless otherwise specified), and is usually 0.001 to 10%, preferably 0.01.
It is about 5 (for example, 0.01 to 3%), and particularly about 0.1 to 3%.

The amlexanox used in the composition of the present invention is a known representative agent for treating allergic diseases, and can be produced by a known method or can be obtained as a commercial product. The amount of amlexanox used in the composition of the present invention varies depending on the type and dosage form of the compound,
For example, for a composition to be applied systemically, the daily dosage may be about 50 to 150 mg, and for a composition to be applied topically, the daily dosage may be about 0.1 to 5 mg. For example, when used as an aqueous composition, the amount of amlexanox used is 0.00001 to 1%, preferably 0.0000, based on the entire composition.
1 to 0.5%, particularly preferably 0.0001 to 0.5%
It can be selected from a range of about 0.03 to 0.25%
(For example, 0.1 to 0.25%). The ratio of xanthines to amlexanox varies depending on the type of compound, and usually 0.01 to 100000 parts by weight of xanthines (for example, 0.05 to 50000 parts by weight), preferably 0. 1
1 to 10,000 parts by weight (for example, 0.5 to 5000 parts by weight), and more preferably 0.1 to 100 parts by weight (for example, 0.5 to 100 parts by weight).
Usually, it is about 1 to 100 parts by weight (for example, 1 to 75 parts by weight).

In the composition of the present invention, in order to mix amlexanox with clear eye drops, eye washes and nasal drops, the solubility of amlexanox in an aqueous solution is extremely low, and therefore a solubilizer is further added. That is desirable.
The type of the solubilizer is not particularly limited, and examples thereof include polyoxyethylene alkyl ether, polyoxyethylene castor oil or hydrogenated castor oil, sorbitan fatty acid ester, propylene glycol fatty acid ester, glycerin fatty acid ester, and polyoxyethylene glycerin. Fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester,
Polyoxyethylene sorbit fatty acid ester, polyoxyethylene alkylphenyl formaldehyde condensate, polyoxyethylene sterol / hydrogenated sterol, polyethylene glycol fatty acid ester, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene alkylphenyl ether, polyoxyethylene alkyl Ether phosphoric acid or a salt thereof, a lecithin derivative and the like can be mentioned, preferably polyoxyethylene sorbitan fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene castor oil or hydrogenated castor oil, sorbitan fatty acid ester, particularly preferably polyoxyethylene sorbitan. It is a fatty acid ester, polyoxyethylene castor oil or hydrogenated castor oil. These can be used alone or in appropriate combination of two or more. When a solubilizer is used in a composition for application to mucous membranes, its amount is preferably a solubilizing effective amount that does not impair the effects of the present invention.
The amount is 0 times, preferably about 0.3 to 10 times.

In the present invention, by adding the xanthines, the photostability of the amlexanox can be greatly improved and the safety is high. Therefore, the composition (or pharmaceutical composition) of the present invention can be formulated by combining with various carriers (aqueous carrier, hydrophilic carrier, oil carrier, liquid carrier, granular carrier, etc.), and a non-aqueous composition It may be. In particular, the composition of the present invention is useful as an aqueous composition because it has high photostability even in an aqueous medium. The composition of the present invention can be provided in various forms depending on the purpose, for example, various dosage forms such as solid agents, semi-solid agents, and liquid agents.

For example, the composition of the present invention comprises solid agents (tablets, powders, granules, capsules, etc.), semisolid agents [ointments (hard ointments, ointments, etc.), creams], liquid agents. (Lotions, extracts, suspensions, emulsions, syrups, dry syrups (prepared before use), injections (including pre-prepared injections), aerosols, soft capsules, drinks, etc. Available in the form of
It may be an aqueous composition, for example, an aqueous semisolid agent such as an aqueous solution, an aqueous ointment or an aqueous cream. Furthermore, the composition of the present invention is not limited to a pharmaceutical composition, and can be used as a non-pharmaceutical composition such as a cleaning agent, a contact lens solution, food, and cosmetics.

The compositions of the present invention are useful as topically applied compositions (topically applied compositions or topically applied formulations) that are susceptible to light exposure. Examples of such a composition for topical application include, for example, ointment for outer skin, cream for outer skin, liquid for outer skin, eye drops, eyewash, eye ointment, contact lens mounting liquid, liquid for contact lens (washing liquid, preservative, disinfection). Liquids, multi-purpose solutions, etc.), nasal drops, nasal washes, oropharyngeal drugs, gargles, ear drops, cosmetics and the like.

Furthermore, since the aqueous composition of the present invention is safe with no or little irritation, it is a mucous membrane that is susceptible to irritation (ocular mucosa such as cornea and conjunctiva, gums, tongue, lip, oral mucosa, nasal mucosa). , Mucous membrane of the pharynx, etc.) is useful. Examples of such a composition for applying mucosa (or a preparation for applying mucosa) include an ophthalmic composition (eye drops (including eye drops that can be used during contact lens wearing), contact lens mounting liquid, eye wash (contact lens wearing) (Including eye wash that can be used inside), contact lens agent (washing solution, preservative solution, sterilizing solution, multi-purpose solution, etc.), otolaryngological composition (nasal drops, ear drops,
Examples include nasal washes and the like) and oral compositions (oropharyngeal agents, gargles, etc.). In the present specification, the contact lens includes all types of contact lenses such as hard and soft.

Furthermore, since it is highly stable to light,
Compositions (especially aqueous compositions) packaged in a multiple dose form and continuously used by the user, eg
It is also useful as an outer ointment, an outer skin cream, an outer skin liquid, an eye drop, an eye wash, a nasal drop, a mouthwash, a contact lens liquid (a cleaning liquid, a preservative, an antiseptic).

The aqueous composition of the present invention may contain various components (including pharmacologically active ingredients and physiologically active ingredients) in combination with, for example, xanthines and amlexanox, as long as stability and the like are not impaired. Good. The type of such a component is not particularly limited, and for example, a decongestant component,
Anti-inflammatory drug component, anti-histamine drug component or anti-allergic drug component, astringent drug component, antipyretic analgesic drug component, stomach medicine drug component, digestive drug component, ulcer treatment drug component, antibacterial or bactericidal drug component, antitumor drug component, hormone Examples thereof include proteins, peptides or peptides, vitamins, amino acids and the like. Examples of suitable components in the present invention include the following components.

Decongestant components: epinephrine, ephedrine, tetrahydrozoline, naphazoline, phenylephrine, methylephedrine and salts thereof.

Α-adrenergic agonists: imidazoline derivatives (naphazoline, tetrahydrozoline, etc.), β-
Phenylethylamine derivatives (phenylephrine, epinephrine, ephedrine, methylephedrine, etc.), and pharmaceutically or physiologically acceptable salts thereof (for example,
Inorganic acid salts such as naphazoline hydrochloride, naphazoline nitrate, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, phenylephrine hydrochloride, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride; organic acid salts such as epinephrine hydrogen tartrate).

Ocular muscle regulator component: A cholinesterase inhibitor having an active center similar to acetylcholine, for example, quaternary ammonium compounds such as neostigmine methylsulfate and salts thereof.

Anti-inflammatory drug component: celecoxib
oxib), rofecoxib,
Indomethacin, diclofenac, pranoprofen,
Piroxicam, meloxicam,
Epsilon-aminocaproic acid, berberine, glycyrrhizic acid, lysozyme, methyl salicylate, allantoin, azulene, azulenesulfonic acid and pharmacologically acceptable salts (for example, berberine chloride, berberine sulfate, diclofenac sodium, dipotassium glycyrrhizinate, ammonium glycyrrhizinate). , Lysozyme chloride, etc.) etc.

Astringent drug components: zinc and salts thereof (eg, zinc sulfate, zinc lactate) and the like.

Antihistamine or antiallergic ingredients: For example, chlorpheniramine, diphenhydramine, iproheptin, ketotifen, emedastine, clemastine, azelastine, levocabastine, olopatadine, cromoglic acid, tranilast, mequitazine, loratadine (loratadine), (Fexofenadine), cetirizine (cet
irizine), ibudilast, suplatast, pemirolast, and pharmacologically acceptable salts (eg, chlorpheniramine maleate, diphenhydramine hydrochloride,
Iproheptin hydrochloride, ketotifen fumarate, emedastine fumarate, clemastine fumarate, azelastine hydrochloride, levocabastine hydrochloride, olopatadine hydrochloride, sodium cromoglycate etc.) etc.

Antibacterial or bactericidal components: For example, sulfonamides (eg sulfamethoxazole, sulfisoxazole, sulfisomidine and pharmacologically acceptable salts (sulfamethoxazole sodium, sulfone). Isomidine sodium, etc., acrinol, quaternary ammonium compounds (for example, benzalkonium, benzethonium, cetylpyridinium), and pharmacologically acceptable salts (benzalkonium chloride, benzethonium chloride, etc.)
Cetylpyridinium chloride, cetylpyridinium bromide, etc., alkylpolyaminoethylglycine, new quinolone agents (lomefloxacin, levofloxacin, ciprofloxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride, etc.), biguanides (polyhexamethylene biguanide, polyaminopropyl) Biguanide, chlorhexidine or a salt thereof, berberine or a salt thereof, polydronium chloride, Glokill (trade name, manufactured by Rhodia, such as Glokill PQ), polydiallyldimethylammonium chloride,
Poly [oxyethylene (dimethyliminio) ethylene-
(Dimethyliminio) Ethylene dichloride), parabens (methyl aminobenzoate, ethyl aminobenzoate, etc.), etc.

Vitamin: For example, vitamin A [eg, retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene and pharmacologically acceptable salts thereof (eg, retinol acetate, retinol palmitate, etc.)] , Vitamins B [eg, thiamine, thiamine disulfide, dicethiamine, octothiamine, shicotiamine, bisbutyamine, bisbentiamine, prosultiamine, benfotiamine, fursultiamine, riboflavin, flavin adenine dinucleotide, pyridoxine, pyridoxal, Hydroxocobalamin, Cyanocobalamin, Methylcobalamin, Deoxyadenocobalamin, Folic acid, Tetrahydrofolic acid, Dihydrofolic acid, Nicotinic acid, Nicotinamide, Nicotinic alcohol, Pa Tothenic acid, panthenol, biotin, choline, inositol and their pharmaceutically acceptable salts (for example, thiamine hydrochloride, thiamine nitrate, dicetiamine hydrochloride, fursultiamine hydrochloride, riboflavin butyrate, flavin adenine dinucleotide sodium, hydrochloric acid) Pyridoxine, pyridoxal phosphate, calcium pyridoxal phosphate, hydroxocobalamin hydrochloride, hydroxocobalamin acetate, calcium pantothenate, sodium pantothenate, etc.], vitamin C
[Ascorbic acid and its derivatives, erythorbic acid and its derivatives and pharmacologically acceptable salts thereof (eg, sodium ascorbate, sodium erythorbate, etc.]], Vitamin D [eg, ergocalciferol, cholecalci] Ferrol, hydroxycholecalciferol, dihydroxycholecalciferol, dihydrotachysterol and pharmacologically acceptable salts thereof, etc.], vitamin E [eg tocopherol and its derivatives, ubiquinone derivative and its pharmacologically acceptable salts] Salts (tocopherol acetate, tocopherol nicotinate, tocopherol succinate, tocopherol succinate calcium, etc.), and other vitamins [eg, carnitine, ferulic acid, γ-oryzanol, orotene , Rutin, eriocitrin, hesperidin and its pharmacologically acceptable salts (carnitine chloride, etc.), etc.].

Amino acids: for example, leucine, isoleucine, valine, methionine, threonine, alanine,
Phenylalanine, tryptophan, lysine, glycine, asparagine, aspartic acid, serine, glutamine, glutamic acid, proline, tyrosine, cysteine,
Histidine, ornithine, hydroxyproline, hydroxylysine, glycylglycine, aminoethyl sulfonic acid (taurine) and pharmaceutically acceptable salts thereof (eg potassium aspartate, magnesium aspartate, cysteine hydrochloride, etc.) and the like.

Sugars: monosaccharides (eg glucose), disaccharides (eg trehalose, lactose, fructose etc.), oligosaccharides (eg lactulose, raffinose, pullulan etc.), cellulose or its derivatives (eg methylcellulose, ethylcellulose). , Hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, etc.), high molecular sugars (eg chondroitin sulfate, hyaluronic acid etc.) and their pharmacologically acceptable salts (eg sodium chondroitin sulfate, sodium hyaluronate etc.) ), Sugar alcohols (eg, mannitol, xylitol, sorbitol, etc.) and the like.

Local anesthetic components: lidocaine, oxyprocaine, dipcaine, procaine, ethyl aminobenzoate, meprilukaine, and salts thereof (lidocaine hydrochloride, oxybuprocaine hydrochloride, etc.), etc.

Steroid components: hydrocortisone, prednisolone, and salts thereof, etc.

Other components: polyvinyl alcohol (fully or partially saponified product), polyvinylpyrrolidone and the like.

The content of these components can be selected according to the type of formulation, the type of active ingredient, etc., and is, for example, 0.0001 to 30%, preferably 0.00
It can be selected from the range of about 1 to 10%. More specifically, in the preferred aqueous composition of the present invention, the content of each component is, for example, as follows.

Decongestant component (vasoconstrictor or sympathomimetic): For example, 0.0001 to 0.5%, preferably 0.0005 to 0.3%, more preferably 0.0.
01-0.1%

Ocular muscle regulator component: For example, 0.0001-
0.5%, preferably 0.001-0.1%

Anti-inflammatory or astringent components: eg
0.0001 to 10%, preferably 0.0001 to 5%

Antihistamine drug component: For example, 0.000
1-10%, preferably 0.001-5%

Bactericidal ingredient: For example, 0.001-10
%, Preferably 0.01-10%

Vitamins: For example, 0.0001 to 1
%, Preferably 0.0001 to 0.5%

Amino acids: For example, 0.0001 to 10
%, Preferably 0.001 to 3%

Sugars: For example, 0.0001 to 5%, preferably 0.001 to 5%, more preferably 0.01 to
2%

Cellulose or a derivative thereof or a salt thereof: for example, 0.001 to 5%, preferably 0.01 to
1%

High molecular saccharides or salts thereof: For example, 0.00
01 to 2%, preferably 0.01 to 2%, more preferably 0.01 to 1%

Polyvinylpyrrolidone, polyvinyl alcohol: for example, 0.001 to 10%, preferably 0.0
01-5%, more preferably 0.01-3%.

The composition of the present invention may optionally contain various components and additives used in pharmaceuticals, quasi drugs, etc., depending on the form of the preparation, as long as the effects of the invention are not impaired. It is possible to formulate it in combination with.
For example, in solid preparations, binders (hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, etc.), excipients (sucrose, lactose, starch, corn starch, crystalline cellulose, light anhydrous) Silicic acid etc.), lubricants (magnesium stearate etc.), disintegrating agents (croscarmellose sodium etc.) and the like can be used. In the case of semi-solid preparations, a base depending on the type of formulation, for example,
Ointment base (for example, hydrocarbon base such as petrolatum, liquid paraffin, wax, cetanol, higher fatty acid ester, etc.), gel base (for example, carboxyvinyl polymer, polyoxyethylene polyoxypropylene block copolymer, gum, etc.) ), An oily base (vegetable oil such as olive oil, soybean oil, sesame oil, cottonseed oil, propylene glycol, etc.) and the like can be used. Further, in the liquid agent, a solvent or water as a base, an oily base, a solubilizing agent, a suspending agent or an emulsifying agent, an isotonicity agent, a buffering agent and the like can be used. Also,
Preservatives, antioxidants, sweeteners, acidulants, colorants, fragrances and the like may be added to these compositions, if necessary. When the composition of the present invention is used as an aqueous composition, a solubilizing agent can be used in order to improve the solubility of the xanthines in an aqueous solution and make a stable aqueous composition. Examples of such solubilizing agents include benzoic acid, citric acid, aminoisobutanol, taurine and salts thereof, surfactants, and polyhydric alcohols such as propylene glycol.

The present invention is described below in the form of an aqueous composition (in particular, eye drops, eye washes, contact lens mounting solutions, contact lens solutions, nasal drops, nasal washes, oropharyngeal drugs, gargles, ear drops, etc.). However, the components of the aqueous composition are not limited to these components.

Sugars: for example, glucose, fructose, galactose, mannose, ribose, ribulose, arabinose, xylose, lyxose, deoxyribose, maltose, trehalose, sucrose, cellobiose, lactose, pullulan, lactulose, raffinose, maltitol, and the like. Pharmacologically acceptable salts, etc.

Thickeners: For example, polysaccharides or derivatives thereof (gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac butter, quince seed, darman gum, tragacanth, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin. , Dextran, carrageenan, gelatin, collagen, pectin, starch, polygalacturonic acid, chitin and its derivatives, chitosan and its derivatives, elastin, heparin, heparinoids, heparin sulfate, heparan sulfate, hyaluronic acid, chondroitin sulfate, etc.), ceramide, cellulose Derivatives (methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethyl Cellulose, carboxyethyl cellulose, cellulose), polyvinyl alcohol (completely or partially saponified), polyvinyl pyrrolidone,
Macrogol, polyvinyl methacrylate, polyacrylic acid, carboxyvinyl polymer, polyethyleneimine, ribonucleic acid, deoxyribonucleic acid, etc., and their pharmacologically acceptable salts, etc.

Surfactants: For example, polyoxyethylene (POE) -polyoxypropylene (POP) block copolymer (for example, poloxamer 407, poloxamer 235, poloxamer 188, etc.), POE (20) sorbitan monolaurate (polysorbate 20). , POE sorbitan fatty acid esters such as POE (20) sorbitan monooleate (polysorbate 80), P
POE hydrogenated castor oil, such as OE (60) hydrogenated castor oil,
POE (9) lauryl ether and other POE alkyl ethers, POE (20) POP (4) cetyl ether and other POE / POP alkyl ethers, POE (1
0) Nonionic surfactants such as POE alkylphenyl ethers such as nonylphenyl ether; glycine type such as alkyldiaminoethylglycine, betaine acetate type such as lauryldimethylaminoacetic acid betaine, and amphoteric surfactants such as imidazoline type; POE (10) POE alkyl ether phosphates such as sodium lauryl ether phosphate and salts thereof, N-acyl amino acid salts such as sodium lauroylmethylalanine, alkyl ether carboxylates, N-acyl taurine such as sodium N-cocoylmethyl taurine Salts, sulfonates such as sodium tetradecene sulfonate, alkyl sulfates such as sodium lauryl sulfate, POE (3) POE alkyl ether sulfates such as sodium lauryl ether sulfate, α-olefin Anionic surfactants such as sulfonates, alkyl amine salts, alkyl quaternary ammonium salt (benzalkonium chloride, benzethonium chloride),
Examples thereof include cationic surfactants such as alkylpyridinium salts (cetylpyridinium chloride, cetylpyridinium bromide, etc.). The numbers in parentheses indicate the number of added moles.

Preservatives, bactericides or antibacterial agents: for example, paraoxybenzoic acid ester (methyl paraoxybenzoate,
Ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc.), acrinol,
Methylrosaniline chloride, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, cetylpyridinium bromide, chlorhexidine, polyhexamethylene biguanide, polyaminopropyl biguanide, alkyl polyaminoethylglycine, benzyl alcohol, phenethyl alcohol, chlorobutanol, isopropanol, ethanol, phenoxyethanol , Sulfur, zirconium phosphate silver, zinc, zinc oxide support, silver zinc aluminosilicate, Mercurochrome, thimerosal, povidone iodine, dehydroacetic acid, chlorxylenol, cresol, chlorophene, phenol, resorcin, orthophenylphenol, isopropyl Methylphenol, thymol, hinokitiol, sulfamine,
Lysozyme, lactoferrin, triclosan, 8-hydroxyquinoline, undecylenic acid, caprylic acid, propionic acid, benzoic acid, propionic acid, sorbic acid, potassium sorbate, sodium sorbate, triclocarban sorbate, halocarban, thiabendazole, polymyxin B, 5-chloro-2-methyl-4-isothiazolin-3-one, 2-methyl-4-isothiazolin-3
-One, polylysine, hydrogen peroxide, polydronium chloride, Glokill (trade name, manufactured by Rhodia, for example, Glokill PQ, etc.), polydiallyldimethylammonium chloride, poly [oxyethylene (dimethyliminio) ethylene- (dimethyliminio) etrenedichloride Etc. and their pharmacologically acceptable salts, etc.

PH adjusters: For example, inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, boric acid, etc.), organic acids (lactic acid, acetic acid, citric acid, tartaric acid, malic acid, succinic acid, oxalic acid, gluconic acid). , Fumaric acid, propionic acid, acetic acid,
Aspartic acid, epsilon aminocaproic acid, glutamic acid, aminoethyl sulfonic acid, etc.), gluconolactone, ammonium acetate, inorganic bases (sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, etc.) , Organic bases (monoethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, lysine, etc.), borax, and their pharmacologically acceptable salts, etc.

Isotonic agents: polyhydric alcohols such as glycerin and propylene glycol, saccharides (but sugar,
Mannitol, sorbitol, etc.)

Inorganic salts: For example, sodium chloride, potassium chloride, sodium carbonate, sodium hydrogen carbonate, calcium chloride, magnesium sulfate, sodium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate,
Sodium thiosulfate, sodium acetate, etc.

Chelating agents: for example, edetic acid (ethylenediaminetetraacetic acid, EDTA), ethylenediaminediacetic acid (EDDA), diethylenetriaminepentaacetic acid (DTP)
A), N- (2-hydroxyethyl) ethylenediamine triacetic acid (HEDTA), N- (2-hydroxyethyl)
Iminodiacetic acid (HIDA), citric acid, tartaric acid, phosphoric acids (polyphosphoric acid, hexametaphosphoric acid, metaphosphoric acid), succinic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1-diphosphonic acid, and A chelating agent such as a pharmacologically acceptable salt thereof is preferably added to the composition of the present invention in order to further improve the stability, and the addition amount in that case is an aqueous composition, for example, the entire composition. To 0.0
It is 01 to 1.0%, preferably 0.001 to 0.5%, and particularly preferably 0.005 to 0.3%. A preferable chelating agent is ethylenediaminetetraacetic acid or a salt thereof, and examples thereof include tetrasodium ethylenediaminetetraacetate, disodium ethylenediaminetetraacetate, disodium ethylenediaminetetraacetate dihydrate (hereinafter, also referred to as sodium edetate). Is mentioned.

Further, a flavoring agent or a cooling agent (eg, menthol, camphor, borneol, geraniol, eucalyptus oil, bergamot oil, fennel oil, peppermint oil, cinnamon oil, rose oil, peppermint oil, etc.) is added if necessary. be able to.

If necessary, the aqueous composition (or aqueous solution) must be adjusted to a pH and / or an osmotic pressure within a range acceptable for the living body while maintaining the solubility and stability of amlexanox. is there. From the viewpoint of low irritation to the skin and mucous membranes and good usability, the acceptable pH is usually preferably acidic to neutral with a pH of 3 to 8 in the case of a drink for internal use. In the case of a composition for the outer skin, usually pH2
-10, preferably pH 3-9, more preferably pH 5-5
It is preferably from weakly acidic to neutral of 8. In the case of a mucosal composition such as eye drops and eye washes, the pH is usually 4.0 to 9.
0, preferably 5.0 to 8.0, particularly preferably 5.5.
Is ~ 8.0.

The osmotic pressure is 100 to 1200 mOsm, preferably 100 to 600 Osm, and particularly preferably 150.
Is about 500 to 500 Osm, and the osmotic pressure ratio to the physiological saline is usually 0.3 to 4.1, preferably 0.3 to 2.
1, particularly preferably about 0.5 to 1.6. The pH and osmotic pressure can be adjusted by buffering agents, the pH adjusting agents, isotonic agents,
It can be performed using salts and the like.

A buffering agent is preferably added to the composition of the present invention in order to further maintain stability. Examples of such buffering agents include borate buffering agents, phosphate buffering agents, carbonate buffering agents,
Examples include citrate buffer, acetate buffer, epsilon aminocaproic acid, aspartate and the like. Preferred buffers are borate buffers, phosphate buffers, carbonate buffers and citrate buffers. Particularly preferred buffering agents are borate buffers or phosphate buffers. Examples of the borate buffer include borate salts such as alkali metal borate and alkaline earth metal borate. As a phosphate buffer,
Examples thereof include phosphates such as alkali metal phosphates and alkaline earth metal phosphates. In addition, a borate or a hydrate of a phosphate may be used as the borate buffer or the phosphate buffer. More specifically, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, etc.), phosphoric acid or a salt thereof (sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc.) , Carbonic acid or salts thereof (sodium hydrogen carbonate, sodium carbonate, etc.), citric acid or salts thereof (sodium citrate, potassium citrate, etc.). When a borate buffer or a phosphate buffer is used as the buffer, the concentration of these buffers in the aqueous composition of the present invention is, for example, about 0.0001 to 10.0% by weight.

The composition of the present invention can be produced by a known method. The solid preparation can be prepared, for example, by kneading or granulating each component, adding an additive if necessary, and tableting. The semi-solid preparation and the liquid preparation can be produced by mixing the base and each component. More specifically, in the case of an eye drop of an aqueous composition, for example, distilled water or purified water and additives are used to dissolve amlexanox and xanthines, and the solution is adjusted to a predetermined osmotic pressure and pH, if necessary. It can be manufactured by filtration sterilization in a sterile environment.

As described above, the composition of the present invention can greatly improve the photostability of amlexanox. Therefore, it can be used in various packaging forms, and the amlexanox can be stabilized for a long period of time even if it is stored in a transparent or thin colored transparent container. The effects of the present invention are effective in a composition that is packaged or contained in a container in a form that can be repeatedly used, such as a plastic container having excellent squeezeability and portability. Furthermore, in the composition of the present invention, it is not always necessary to use a container that can be completely shielded from light such as an aluminum container, and it is possible to reliably discriminate foreign material contamination in a foreign material test, and therefore an aqueous composition (eye drops, eyewash, injection) It is possible to reliably perform process control and quality control of agents, infusions, foods, aqueous preparations such as cosmetics).

Examples of the resin for the plastic container that can be used to contain the composition of the present invention include olefin resins (polyethylene, polypropylene, etc.), polyester resins, polyphenylene ether resins, polycarbonate resins, polysulfone resins. Examples thereof include polyamide resins, hard vinyl chloride resins, styrene resins (polystyrene, acrylonitrile-styrene copolymer (AS resin), etc.), cellulose acetates and the like. Preferred resins are polyethylene, polypropylene,
Polyester resin, polycarbonate resin,
A particularly preferable resin is a polyester resin.

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 and naphthalene dicarboxylic acid) and a diol component can be used. Specifically, aromatic polyester resins, for example, polyalkylene terephthalate (poly C such as polyethylene terephthalate (PET) and polybutylene terephthalate (PBT)).
_2-4 alkylene terephthalate, etc., polyalkylene naphthalate (polyethylene naphthalate (PE
N), poly C _2-4 alkylene naphthalates such as polybutylene naphthalate), polycycloalkyl terephthalates (such as poly 1,4-cyclohexyl dimethylene terephthalate (PCT)), polyarylates (bisphenols (bisphenol-A) Etc.) and phthalic acids (phthalic acid, terephthalic acid) and other resins) and homopolyesters. Further, the polyester resin includes a copolyester containing the homopolyester unit as a main component (for example, 50% by weight or more) and a homopolyester copolymer (PET and PCT).
And copolymers) and the like. Of these, olefin resins (polyethylene, etc.), aromatic polyester resins (polyethylene terephthalate, polyethylene naphthalate, polyarylate, etc.), and polycarbonate are preferable.

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

The plastic container may be a polymer alloy (polymer blend, etc.) as long as the cost performance, strength, light transmittance, gas or water vapor barrier property (moisture permeability), etc. are not damaged. A preferred polymer alloy includes a polymer blend (P
Polymer blends of ET and PEN, etc.) are included.

The resin is preferably a resin having a good squeeze property and having durability against repeated pressing, and a transparent or translucent resin, and may be colored if necessary. By incorporating a component capable of inhibiting the transmission of light (such as an ultraviolet absorber or an infrared absorber) into the resin or applying a coating agent containing the component onto the surface of the resin, the effect of the present invention can be improved. It may be operated to further improve the stability.

[0073]

INDUSTRIAL APPLICABILITY Since the aqueous composition of the present invention comprises a combination of xanthines and amlexanox, the stability of amlexanox, particularly light stability, can be significantly improved.
Furthermore, the stability to light can be improved even in an aqueous composition. Therefore, even with an aqueous composition, amlexanox can be stably retained for a long period of time.

[0074]

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

Examples 1 to 16 Using the components shown in the following table, eye drops, eye washes, contact lens preparations, and nasal drops were prepared by a conventional method and filled in plastic resin containers.

[0076]

[Table 1]

[0077]

[Table 2]

[0078]

[Table 3]

Example 17 (Tablets) Amlexanox 75 parts Anhydrous caffeine 125 parts d-Chlorpheniramine maleate 7.5 parts Belladonna total alkaloids 0.5 parts Aspartame 18 parts Mannitol 1169 parts Avicel 75 parts Menthol 15 parts Stearic acid Magnesium 15 parts Total amount 1500 parts Chewable tablets were obtained according to a conventional method. After sufficiently mixing, the mixture was compressed to give a chewable tablet of 500 mg / tablet.

Example 18 (Soft Capsule) Amlexanox 250 g Sodium Benzoate Caffeine 333 g dl-Methylephedrine Hydrochloride 200 g Lysozyme Chloride 290 g (potency) Roth Extract 120 g Medium Chain Fatty Acid Triglyceride 1279 g Salami Beeswax 67 g Polysorbate 80 167 g Glycerin Fatty Acid Ester Total amount: 2773 g A gelatin film was filled according to a conventional method to obtain about 10,000 soft capsules.

Example 19 (Soft Capsule) Amlexanox 500 g Sodium Benzoate Caffeine 333 g dl-Methylephedrine Hydrochloride 200 g Lysozyme Chloride 290 g (potency) Roth Extract 120 g Medium Chain Fatty Acid Triglyceride 1279 g Salami Beeswax 67 g Polysorbate 80 167 g Glycerin Fatty Acid Ester Total amount 3023 g A gelatin film was filled according to a conventional method to obtain about 10,000 soft capsules.

[0082] In accordance with a conventional method, hard capsules were filled to obtain about 1000 hard capsules.

Example 21 (Ointment) Amlexanox 2.5 g Anhydrous caffeine 10 g Glycyrrhizic acid 100 g Stearyl alcohol 100 g Polyoxyethylene hydrogenated castor oil 1 g Glyceryl stearate 1 g White vaseline 400 g Purified water 1000 g Ointment according to a conventional method. Obtained.

Example 22 (Injection) Amlexanox 2.5 g Anhydrous caffeine 10 g Sodium chloride 9 g Purified water Appropriate amount Total amount 1000 g An injection was obtained according to a conventional method.

Test Example 1 Anlexano with caffeine
Stability test of casks (decomposition by UV and visible light
And its inhibition test) Various test liquids shown in Table 4 were filled in a transparent and colorless container made of polyethylene terephthalate and sealed. In addition to these, using a D65 fluorescent lamp as a light source, at room temperature of 25 degrees,
It was irradiated with light of 5000 lux (light stability tester Light-Tron LT-120 D3CJ type, manufactured by Nagano Scientific Co., Ltd.), and the change in color tone was observed with time. The change in color tone is "-":
Colorless and transparent, "+": pale yellow, "++": yellow, "++"
+ ": Evaluated based on dark yellow. The results are shown in Table 4.

[0086]

[Table 4]

According to Comparative Example 1 and Examples 23 to 27,
It has been revealed that amlexanox is colored when exposed to light. Further, in Comparative Example 1, coloring progressed as the cumulative irradiation amount increased, but in Example 23, it was confirmed that addition of only 0.1% of caffeine significantly suppressed coloring, and in Example 25, complete coloring was suppressed. It was

Test Example 2 Anlexano with caffeine
Couscous light severity test Various test liquids shown in Table 5 were filled in a colorless transparent quartz container and sealed. Using a chemical lamp with high energy intensity as a light source, 1000 μW /
Irradiation with light of cm ² (light stability tester Light-Tron LT-120 D3CJ type, manufactured by Nagano Scientific Co., Ltd.) was performed to observe the change in color tone over time. The change in color tone was evaluated based on "-": colorless and transparent, "+": pale yellow, "++": yellow, and "++++": dark yellow. The results are shown in Table 5.

[0089]

[Table 5]

According to Comparative Example 2 and Examples 28 to 32,
It was also confirmed that caffeine suppressed the coloring of amlexanox even in the light severe test.

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Claims (9)

[Claims] 1. The following formula (1): (Wherein R ¹ , R ² and R ³ may be the same or different and each represents a hydrogen atom or an alkyl group which may be substituted) or a compound selected from a salt thereof. And a stabilized composition containing amlexanox. 2. An aqueous composition containing amlexanox and a compound selected from the compound represented by formula (1) according to claim 1 or a salt thereof. 3. The composition according to claim 1, wherein the compound represented by the formula (1) is caffeine, theophylline, theobromine, diprophylline, proxyphylline, pentoxifylline. 4. The compound according to claim 1, which contains 0.001 to 1000 parts by weight of the compound represented by the formula (1) or a compound thereof, relative to 1 part by weight of amlexanox. The composition according to 2. 5. The composition according to claim 1, which is a topical composition. 6. The composition according to claim 1, which is a mucosal composition. 7. The composition according to claim 1, which is packaged in a reusable form. 8. The composition according to claim 1, which is contained in a plastic container. 9. A method for improving the stability of amlexanox by adding a compound selected from the compound represented by formula (1) or the salt thereof according to claim 1.