JP2003055223A - Stabilized composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a composition containing ketotifen or a salt thereof stabilized at a high level even in an aqueous solution. SOLUTION: The stability of the ketotifen or the salt thereof to the light is improved by adding 0.01-100,000 pts.wt. xanthines (caffeine, theophylline or the like) based on 1 pts.wt. ketotifen or the salt thereof. 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 stability over a long period of time even when it contains photolabile ketotifen or a salt thereof (for example, a composition for topical application such as eye drops, Pharmaceutical compositions, such as aqueous compositions).

[0002]

2. Description of the Related Art Ketotifen or a salt thereof 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 ketotifen or a salt thereof 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 these points, in the case of ketotifen-containing eye drops, for example, a transparent plastic container having a good squeeze property, easy to instill, and easy to carry is used. It is placed in a paper box and protected from light. After opening, the user will be
Since it may be used continuously for several months, we try to maintain the light stability by recommending the auxiliary use of a plastic shading 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 ketotifen or its salts is not known.

[0007]

Therefore, it is an object of the present invention to provide a composition (or pharmaceutical composition) capable of stabilizing ketotifen or a salt thereof 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.

[0008]

Means for Solving the Problems As a result of intensive studies to achieve the above-mentioned object, the present inventors have found that when coexisting with a xanthine derivative, ketotifen or its salt is exposed to light or the like even in an aqueous composition. They have found that they can be stabilized for a long period of time 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 referred to simply as xanthines), ketotifen or a salt thereof. And salt.

[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 provides xanthines and ketotifen or a salt thereof. Aqueous compositions containing the same are also disclosed.

Further, examples of the compound represented by the formula (1) include caffeine, theophylline, theobromine, diprophylline, proxyphylline and pentoxifylline, and caffeine is particularly preferable. The proportion of xanthines in the composition is not particularly limited as long as it is an effective amount,
For example, for 1 part by weight of ketotifen or a salt thereof,
It is about 001 to 1000 parts by weight. The composition of the present invention can be used as various compositions or formulations based on the activity of xanthines and ketotifen or a salt thereof, 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, and also includes a method for improving the stability of ketotifen or a salt thereof by incorporating the above xanthines.

In the present specification, the term "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 ketotifen) can be used in the form of pharmaceutically acceptable salts or hydrates.

[0013]

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) include xanthine derivatives such as caffeine, theophylline, oxtriphylline, daphylline, diisobutylaminobenzoyloxypropyl theophylline, theobromine, diprophylline, proxyphylline, pentoxy. Examples include filin. 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%.

Ketotifen (4,9-dihydro-4- (1-methyl-4-piperidylidene) -10H-benzo [4,5] cyclohepta [1,2-b] thiophene- used in the compositions of the present invention. 10-on) is a known anti-allergic agent, and ketotifen or a salt thereof can be obtained as a commercial product. The salt of ketotifen is not particularly limited, and the salts similar to those described for the compound of formula (1) can be exemplified. Of these, fumarate is particularly preferable. The amount of ketotifen or a salt thereof used in the present invention varies depending on the type and dosage form of the compound, for example,
In the case of a composition applied systemically, the daily dose is 0.5 to
The formulation can be designed in the range of about 2 mg, and a daily application amount of a composition for topical application of about 0.001 to 0.5 mg. For example, when used as an aqueous composition, the amount of ketotifen or a salt thereof used is 0.00001 to 1%, preferably 0.00
001-0.5%, particularly preferably 0.0001-0.
It can be selected from the range of about 1%, and usually 0.001 to 0.
It is about 05% (for example, 0.01 to 0.05%).

The ratio of xanthines to ketotifen or a salt thereof varies depending on the kind of the compound, and usually 0.
01 to 100,000 parts by weight (for example, 0.05 to 500
00 parts by weight), preferably 0.1 to 10000 parts by weight (e.g. 0.5 to 5000 parts by weight), more preferably 0.1 to 100 parts by weight (e.g. 0.5 to 100 parts by weight). The amount is usually 1 to 100 parts by weight (for example, 1 to 75 parts by weight).

In the composition of the present invention, ketotifen or a salt thereof may be incorporated into clear eye drops, eye washes or nasal drops because the solubility of ketotifen or a salt thereof in an aqueous solution is extremely low. It is desirable to further incorporate a solubilizer.

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 poly. Oxyethylene 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, polyoxy Ethylene polyoxypropylene alkyl ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene Alkyl ether phosphoric acid or salts thereof, lecithin derivatives and the like, preferably polyoxyethylene sorbitan fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene castor oil or hydrogenated castor oil, sorbitan fatty acid ester, particularly preferably polyoxy Ethylene sorbitan 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, and is usually 0.1 to 30 with respect to the amount of ketotifen or a salt thereof. Double the amount, preferably 0.
The amount is about 3 to 10 times.

In the present invention, by adding the xanthines, the photostability of the ketotifen or its salt can be greatly improved and the safety is high. Therefore, the composition (or formulation composition) of the present invention can be formulated by combining with various carriers (aqueous carrier, hydrophilic carrier, oily carrier, liquid carrier, granular carrier, etc.) and is a non-aqueous composition. 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 has various forms depending on the purpose, for example, a solid agent,
It can be provided in various dosage forms such as a semi-solid preparation and a liquid preparation.

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, injections (including pre-prepared injections), aerosols, soft capsules, drinks, etc.) As an aqueous composition, such as an aqueous solution,
It may be an aqueous semisolid agent such as 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 almost no 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 for contact lenses), contact lens agents (cleansing solution, preservative, sterilizing solution, multipurpose solution, etc.), otolaryngological composition (drops, ear drops, nasal wash, etc.) ), Oral compositions (oropharyngeal agents, gargles, etc.) and the like. 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 contains, for example, xanthines and ketotifen or a salt thereof, as well as various components (including pharmacologically active ingredients and physiologically active ingredients) in combination unless stability and the like are impaired. You may. The type of such components is not particularly limited, for example, decongestant component, anti-inflammatory drug component, antihistamine drug component or antiallergic drug component, astringent drug component, antipyretic analgesic drug component, stomachic drug component, digestive drug component, Examples include ulcer therapeutic drug components, antibacterial or bactericidal drug components, antitumor drug components, hormones, proteins or peptides, vitamins, amino acids and the like. Examples of suitable components in the present invention include the following components.

Decongestant components: α-adrenergic agonists such as epinephrine, ephedrine, tetrahydrozoline, naphazoline, phenylephrine, methylephedrine and salts thereof, for example imidazoline derivatives (nafazoline, tetrahydrozoline, etc.), β-phenylethylamine derivatives (phenylephrine, epinephrine). , Ephedrine, methylephedrine, etc.) and pharmaceutically or physiologically acceptable salts thereof (eg, naphazoline hydrochloride, naphazoline nitrate, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, phenylephrine hydrochloride,
Inorganic acid salts such as epinephrine hydrochloride, ephedrine hydrochloride, and methylephedrine hydrochloride; organic acid salts such as epinephrine hydrogen tartrate) Ocular muscle regulator component: Cholinesterase inhibitor having an active center similar to acetylcholine, such as neostigmine methylsulfate Anti-inflammatory drug components such as quaternary ammonium compounds and their salts: celecoxib,
Rofecoxib, indomethacin, diclofenac, pranoprofen, piroxicam, meloxicam, epsilon-aminocaproic acid, berberine, glycyrrhizic acid,
Astringent drug components such as lysozyme, methyl salicylate, allantoin, azulene, azulene sulfonic acid and pharmacologically acceptable salts (for example, berberine chloride, berberine sulfate, diclofenac sodium, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, lysozyme chloride, etc.): Zinc and salts thereof (eg, zinc sulfate,
Zinc lactate) etc.

Antihistamine or antiallergic ingredients: For example, chlorpheniramine, diphenhydramine, iproheptin, emedastine, clemastine, azelastine, levocabastine, olopatadine, cromoglic acid, tranilast, amlexanox, mequitazine, loratadine (loratadine), loratadine, loratadine. (Fexofenadine), cetirizine, 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,
Antibacterial or antiseptic components such as sodium cromoglycate: For example, sulfonamides (eg, sulfamethoxazole, sulfisoxazole, sulfisomidine and pharmacologically acceptable salts (sulfamethoxazole sodium). , Sodium sulfisomidine), acrinol, quaternary ammonium compounds (eg, benzalkonium, benzethonium, cetylpyridinium), and pharmacologically acceptable salts (benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride). , Cetylpyridinium bromide), alkylpolyaminoethylglycine, new quinolone agents (lomefloxacin, levofloxacin, ciprofloxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride, etc.), biguanides (poly Xamethylene biguanide, polyaminopropyl biguanide, chlorhexidine or a salt thereof, berberine or a salt thereof, polydronium chloride, Glokill (trade name, manufactured by Rhodia, for example, Glokill PQ), polydiallyl dimethyl ammonium chloride, poly [oxyethylene (dimethyl ethylene) (Minio) ethylene- (dimethyliminio) etylene dichloride), parabens (methyl aminobenzoate, ethyl aminobenzoate, etc.) and the like.

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 their pharmacologically acceptable salts (eg potassium aspartate, magnesium aspartate, cysteine hydrochloride, etc.) Sugars: monosaccharides (Eg glucose), disaccharides (eg trehalose, lactose, fructose etc.), oligosaccharides (eg lactulose, raffinose, pullulan etc.), cellulose or its derivatives (eg methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose). , Carboxymethyl cellulose, carboxyethyl cellulose, etc.), high molecular sugars (eg chondroitin sulfate,
Hyaluronic acid, etc. and pharmacologically acceptable salts thereof (eg, sodium chondroitin sulfate, sodium hyaluronate, etc.), sugar alcohols (eg, mannitol, xylitol, sorbitol, etc.), local anesthetic ingredients: lidocaine, oxyprocaine, etc. , Dipcaine, procaine, ethyl aminobenzoate, meprilukaine, and their salts (lidocaine hydrochloride, oxybuprocaine hydrochloride, etc.) Steroid components: hydrocortisone, prednisolone,
And other components such as salts thereof: 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): eg 0.0001-0.5%, preferably 0.000
5 to 0.3%, more preferably 0.001 to 0.1% Ocular muscle modulator component: For example, 0.0001 to 0.5%, preferably 0.001 to 0.1% Anti-inflammatory drug component or Astringent drug component: For example, 0.0001-
10%, preferably 0.0001 to 5% Antihistamine drug component: For example, 0.0001 to 10%,
Preferably 0.001-5% Bactericidal ingredient: For example, 0.001-10%, preferably 0.01-10% Vitamins: For example, 0.0001-1%, preferably 0.0001-0 0.5% Amino acids: for example, 0.0001 to 10%, preferably 0.001 to 3% Sugars: for example, 0.0001 to 5%, preferably 0.0
01-5%, more preferably 0.01-2% Cellulose or its derivative or salt thereof: For example,
0.001-5%, preferably 0.01-1% Polymeric saccharides or salts thereof: for example, 0.0001-2%,
Preferably 0.01 to 2%, more preferably 0.01
˜1% Polyvinylpyrrolidone, polyvinyl alcohol: for example, 0.001 to 10%, preferably 0.001 to 5
%, More preferably 0.01 to 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 will be described below in the form of an aqueous composition (in particular, eye drops, eye washes, contact lens mounting solutions, contact lens preparations, 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, and their pharmacological properties. Thickeners such as acceptable salts: polysaccharides or derivatives thereof (eg gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac butter, quince seed, dalman 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, heparinoid, heparin sulfate, heparan sulfate, hyaluronic acid, chondroitin Sulfuric acid, etc., ceramide, cellulose derivatives (methyl cellulose, ethyl cellulose,
Hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose,
Cellulose, etc.), polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, macrogol, polyvinylmethacrylate, polyacrylic acid, carboxyvinyl polymer, polyethyleneimine, ribonucleic acid, deoxyribonucleic acid, etc. and their pharmacologically acceptable Surfactants such as salts to be used: polyoxyethylene (POE)-
Polyoxypropylene (POP) block copolymers (eg, Poloxamer 407, Poloxamer 235,
Poloxamer 188), monolauric acid POE (2
0) POE sorbitan fatty acid esters such as sorbitan (polysorbate 20), POE (20) sorbitan (polysorbate 80) monooleate, POE (6
0) POE such as hydrogenated castor oil, hydrogenated castor oil, POE
(9) POE alkyl ethers such as lauryl ether, POE (20) POP (4) non-ionic POE / POP alkyl ethers such as cetyl ether, and POE alkyl phenyl ethers such as POE (10) nonyl phenyl ether Surfactants; amphoteric surfactants such as glycine type such as alkyldiaminoethylglycine, betaine acetate such as lauryl dimethylamino acetic acid betaine, imidazoline type; POE (10) POE alkyl ether phosphate such as sodium lauryl ether phosphate and Its salts, N-acyl amino acid salts such as sodium lauroylmethylalanine, alkyl ether carboxylates, N-acyl taurine salts such as sodium N-cocoylmethyl taurine, and sodium tetradecene sulfonate. Down salts, alkyl sulfates such as sodium lauryl sulfate, POE (3) POE alkyl ether sulfates such as sodium lauryl ether sulfate, alpha
Anionic surfactants such as olefin sulfonates;
Examples thereof include cationic surfactants such as alkylamine salts, alkyl quaternary ammonium salts (benzalkonium chloride, benzethonium chloride, etc.), alkylpyridinium salts (cetylpyridinium chloride, cetylpyridinium bromide, etc.) and the like. 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 And its pharmacologically acceptable salts such as pH adjusting agents: 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, apple) Acid, succinic acid, oxalic acid, gluconic acid, fumaric acid, propionic acid, acetic acid, aspartic acid,
Epsilon aminocaproic acid, glutamic acid, aminoethylsulfonic 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 pharmacologically acceptable salts thereof, etc. Isotonizing agents: for example, glycerin, propylene glycol, etc. Inorganic salts such as alcohols and sugars (but sugar, mannitol, sorbitol, etc.): 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. In that case, the amount of the chelating agent used in the aqueous composition is, for example, the entire composition. To 0.001-1.0%, preferably 0.001-0.5
%, 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.) can be added if necessary. .

The aqueous composition (or aqueous solution) is adjusted to pH and / or osmotic pressure within a range acceptable for the living body while maintaining the solubility and stability of ketotifen or a salt thereof, if necessary. There is a need to. 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 outer skin, pH 6
-9, preferably pH 6.5-8.5, particularly preferably pH 7.0-8.5 is preferred. In the case of a composition for application to mucous membranes such as eye drops and eye washes, the pH is usually 3.
The pH is 0 to 6.5, preferably 3.5 to 6.0, and particularly preferably 3.8 to 6.0. Osmotic pressure is 100-12
00 mOsm, preferably 100 to 600 Osm, particularly preferably 150 to 400 Osm, and the osmotic pressure ratio to physiological saline is usually 0.3 to 4.1, preferably 0.3 to 2.1, and particularly preferably 0. It is about 0.5 to 1.4. The pH and osmotic pressure can be adjusted by using a buffering agent, the pH adjusting agent, an isotonicity agent, salts and the like.

A buffer is preferably added to the composition of the present invention in order to further maintain stability. Examples of such a buffer include borate buffer, phosphate buffer, carbonate buffer and citric acid. Buffers, acetate buffers, epsilon aminocaproic acid, aspartates and the like can be mentioned. Preferred buffers are borate buffers, phosphate buffers, carbonate buffers and citrate buffers. A particularly preferred buffer is
A borate buffer or a phosphate buffer. Examples of the borate buffer include borate salts such as alkali metal borate and alkaline earth metal borate. Examples of the phosphate buffer 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 its salt (sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc.), carbonic acid or its salt (sodium hydrogen carbonate, carbonic acid) Sodium) and 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 agent and the liquid agent can be produced by mixing the base and each component. More specifically, if it is an eye drop of an aqueous composition, for example, ketotifen and xanthines are dissolved using distilled water or purified water and an additive, and 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 ketotifen or its salt. Therefore, it can be used in various packaging forms and can stabilize ketotifen or its salt for a long period of time even if it is stored in a transparent or light-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) Aqueous preparations such as agents, infusions, foods, cosmetics, etc.)
The process control and quality control can be surely performed.

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 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), polycycloalkyl terephthalate (poly 1,4
-Cyclohexyl dimethylene terephthalate (PCT)
Etc.), homopolyesters such as polyarylates (resins composed of bisphenols (bisphenol-A, etc.) and phthalic acids (phthalic acid, terephthalic acid), etc.). The polyester resin also includes a copolyester containing the homopolyester unit as a main component (for example, 50% by weight or more), a homopolyester copolymer (such as a PET / PCT copolymer), and the like. . Of these, olefin resins (polyethylene, etc.), aromatic polyester resins (polyethylene terephthalate, polyethylene naphthalate, polyarylate, etc.), and polycarbonate are preferable. The polycarbonate-based resin is, for example, an aromatic polycarbonate based on bisphenols (bisphenol-A and the like).

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 actually damaged. A preferred polymer alloy includes a polymer blend (P
Polymer blends of ET and PEN, etc.) are included.
Further, the resin is preferably a resin having good squeeze properties and having durability against repeated pressing, and a transparent or translucent resin, and may be colored as 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.

[0044]

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

[0045]

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 18 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 each was filled in a plastic resin container.

[0047]

[Table 1]

[0048]

[Table 2]

[0049]

[Table 3]

Example 17 (tablets) Ketotifen fumarate 4.14 parts Anhydrous caffeine 125 parts d-Chlorpheniramine maleate 7.5 parts Belladonna total alkaloids 0.5 parts Aspartame 18 parts Mannite Avicel 75 parts Menthol 15 Parts Magnesium stearate 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) Ketotifen Fumarate 13.8 g Sodium Benzoate Caffeine 333 g dl-Methylephedrine Hydrochloride 200 g Lysozyme Chloride 290 g (potency) Roth Extract 120 g Medium Chain Triglycerides 1279 g Salami beeswax 67 g Polysorbate 80 167 g Glycerin fatty acid ester 67 g Total amount 2536.8 g According to a conventional method, a gelatin film was filled to obtain about 10,000 soft capsules.

Example 19 (Hard capsule) Ketotifen fumarate 50 g Anhydrous caffeine 300 g Glycyrrhizic acid 200 g Lactose 300 g Potato starch 90 g Magnesium stearate 10 g Total amount 950 g Hard capsules were filled according to a conventional method, and about 1000 hard capsules were prepared. Obtained.

Example 20 (Dry syrup agent) Ketotifen fumarate 0.138 g dl-Chlorpheniramine maleate 0.6 g Thiamine nitrate 2 g Sucrose proper amount 100 g A dry syrup agent was obtained according to a conventional method.

Example 21 (Syrup) Ketotifen fumarate 0.274 g dl-Chlorpheniramine maleate 0.6 g Thiamine nitrate 2 g Methyl paraoxybenzoate 0.1 g Sucrose proper amount ethanol proper amount purified water total amount 100 ml According to a conventional method, A syrup was obtained.

Example 22 (Ointment) Ketotifen fumarate 0.69 g Anhydrous caffeine 10 g Glycyrrhizic acid 100 g Stearyl alcohol 100 g Polyoxyethylene hydrogenated castor oil 1 g Glyceryl stearyl stearate 1 g White petrolatum 400 g Purified water Total amount 1000 g Ointment according to a conventional method I got an agent.

Example 23 (Injection) Ketotifen fumarate 0.276 g Anhydrous caffeine 10 g Sodium chloride 9 g Purified water Appropriate amount 1000 g An injection was obtained according to a conventional method.

Test Example 1 Keto fumarate with caffeine
Light Stabilization Test of Tiphene Various test liquids shown in Table 4 were filled in a transparent and colorless container made of polyethylene terephthalate and sealed. These test solutions were irradiated with 5000 lux light (light stability tester Light-Tron LT-120 D3CJ type, manufactured by Nagano Scientific Co., Ltd.) at room temperature of 25 ° C. using a D65 fluorescent lamp as a light source, and the color tone was changed with time. Was observed. The change in color tone is "-":
Colorless and transparent, "+": pale yellow, "++": yellow, "++"
+ ": Evaluated based on dark yellow. The results are shown in Table 4.

[0058]

[Table 4]

According to Comparative Example 1 and Examples 24 to 28,
Ketotifen fumarate becomes colored when exposed to light. Further, in Comparative Example 1, coloring progressed as the cumulative irradiation amount increased, but in Example 25, it was confirmed that the addition of 0.5% caffeine significantly suppressed the coloring, and in Example 27, the coloring was completely suppressed. .

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 37/08 A61P 37/08

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 optionally substituted alkyl group) or a compound selected from a salt thereof. And a compound selected from ketotifen or a salt thereof, which is stabilized. 2. An aqueous composition containing a compound selected from the compound represented by formula (1) according to claim 1 or a salt thereof and a compound selected from ketotifen 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. A compound selected from the compound represented by formula (1) or a salt thereof in an amount of 0.001 to 1000 parts by weight relative to 1 part by weight of ketotifen or a salt thereof, or 1. The composition according to claim 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 ketotifen or a salt thereof by incorporating the compound represented by the formula (1) according to claim 1 or a salt thereof.