JP2003128552A - Composition applicable to mucous - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a composition applicable to mucous, stably maintaining vitamin E for a long time. SOLUTION: The stability of the vitamin E is improved by being compounded with a xanthine (caffeine, theophylline, theobromine, proxyphylline, or pentoxifylline). By the method, compositions applicable to mucous such as collyria, collyrium and collunarium each stably maintaining the vitamin E for a long time are provided.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a composition for application to mucosa, which has improved stability over a long period of time. The present invention also relates to methods of improving the stability of vitamin Es.

[0002]

BACKGROUND OF THE INVENTION Vitamin E has an effect of improving peripheral circulatory disorders, an effect of preventing an increase in lipid peroxide, an effect of improving metabolic abnormality of the retina, an effect of improving focus adjustment ability, and the like, and eye diseases such as asthenopia and cataract treatment. It is included in eye drops for the purpose of treatment. Furthermore, by suppressing nasal mucosal cell damage,
It is known to be effective for nasal inflammation such as allergic rhinitis and vasomotor rhinitis, which has an action of suppressing inflammation of the nasal mucosa, and is incorporated into nasal drops (Japanese Patent Laid-Open No. 10-23124).
3). As described above, vitamin Es are useful for mucosal compositions such as eye drops and nasal drops, but in the case of mucosal compositions, aqueous compositions may be used in order to exhibit safety and immediate effects. Although desirable, vitamin Es have a problem of becoming unstable in an aqueous solution.

Therefore, there has been a demand for a composition for application to mucosa, which retains vitamin Es stably for a long period of time.

[0004]

Therefore, an object of the present invention is to provide a composition for mucosal application which is excellent in long-term stability of vitamin Es. Another object of the present invention is to provide a method for stably holding vitamin Es for a long period of time.

[0005]

Means for Solving the Problems As a result of intensive studies for achieving the above-mentioned object, the inventors of the present invention improved the stability of vitamin Es by coexisting with a xanthine derivative to improve vitamin Es over a long period of time. They have found that they can be stably held, and have completed the present invention.

That is, the present invention includes the following (I) to (VII)
The composition is listed in: (I) Formula (1)

[Chemical 3] (Wherein R ¹ , R ² and R ^{3, which} may be the same or different, each represents a hydrogen atom or an alkyl group which may be substituted) and a salt thereof. At least one compound selected,
A composition for mucosal application containing vitamin Es, (II) The mucosa according to (I), wherein the compound represented by the formula (1) is caffeine, theophylline, theobromine, diprophylline, proxyphylline, pentoxifylline. Application composition, (III) The mucosal application composition according to (I) or (II), wherein the compound represented by the formula (1) is caffeine, (IV) Vitamin E 1 part by weight, Formula (1)
The compound of any one of (I) to (III), which contains at least one compound selected from the group consisting of compounds represented by Composition for mucosal application, (V) Composition for mucosal application according to any one of (I) to (IV), further comprising a solubilizer, (VI) Any of (I) to (V), which is an aqueous composition The composition for applying mucosa according to any one of (I) to (VI), which is an eye drop, an eye wash, a nasal drop, and a nasal lavage solution, and the present invention is described below. It is a method to improve the stability of vitamin E listed below: (VII
I) An aqueous composition containing vitamin Es is prepared according to formula (1)

[Chemical 4] (Wherein R ¹ , R ² and R ^{3, which} may be the same or different, each represents a hydrogen atom or an alkyl group which may be substituted) and a salt thereof. A method for improving the stability of vitamin Es by incorporating at least one selected compound.

Unless otherwise specified in this specification,
% Shall mean w / v%. Further, in the present specification, the contact lens is hard, oxygen permeable hard,
It is meant to include all types of contact lenses such as soft.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION In the compound represented by the above formula (1), the alkyl group is a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl group (particularly, C _1-4 alkyl group) can be exemplified. Preferred alkyl groups include methyl and ethyl groups.

These alkyl groups are substituted, for example, by
Halogen atom (chlorine, bromine, fluorine atom, etc.), hydroxyl group, alkoxy group (C _1-4 alkoxy group such as methoxy, ethoxy, butoxy group), aryloxy group, carboxyl group, alkoxycarbonyl group (C _1-4
Alkoxy-carbonyl group), aryloxycarbonyl group, acyl group (C _1-4 alkyl-carbonyl group such as formyl, acetyl, propionyl group, aryl-carbonyl group such as benzoyl group), nitro group, amino group, N It may have a substituted amino group (mono or di C _1-4 alkylamino group etc.), a cyano group and the like.

The compound represented by the above formula (1) can be used as a pharmacologically (pharmaceutically) or physiologically acceptable salt. As the pharmacologically or physiologically acceptable salt,
For example, organic acid salts (eg, lactate, acetate, butyric acid, trifluoroacetate, fumarate, maleate, tartrate, citrate, succinate, malonate, methanesulfonate, toluene). Sulfonate, tosylate, palmitic acid, stearic acid, etc.), inorganic acid salt (eg, hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.),
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 above formula (1) include xanthine derivatives such as caffeine, theophylline, oxtriphylline, daphylline, diisobutylaminobenzoyloxypropyltheophylline,
Theobromine, diprophylline, proxyphylline, pentoxifylline and the like can be mentioned. 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.

These compounds represented by the above formula (1) or salts thereof (hereinafter, they may be collectively referred to as "xanthines") may be used alone or in combination of two or more kinds.

Further, the compound represented by the above formula (1) can be used in the form of a mixture with other compounds. 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 for mucosal application of the present invention varies depending on the kind of the compound represented by the above formula (1) and cannot be unconditionally specified, but it is usually
The concentration of the compound represented by the formula (1) or a salt thereof in the mucosal composition can be selected from the range of about 0.0001 to 10 W / V%, preferably 0.001 to 10%, more preferably Is 0.01 to 5 (for example, 0.05 to 4
%), And more preferably about 0.1 to 3%.

In the present invention, as vitamin Es,
Examples include tocopherol and its derivatives or salts thereof. Examples of the salt that can be used include the same salts as those described for the compound of the formula (1), and examples thereof include tocopherol calcium succinate and the like. As the vitamin Es, both natural products and synthetic products can be used, and specifically, d-α-tocopherol and dl-α-
There are tocopherols, β-tocopherols, γ-tocopherols, δ-tocopherols, and the like, and examples of these derivatives include vitamin E acetate ester (tocopherol acetate), vitamin E nicotinate ester, vitamin E.
Examples thereof include succinic acid ester and vitamin E linolenic acid ester. Among them, tocopherol acetate (acetic acid d-α
-Tocopherol, dl-α-tocopherol acetate, etc.)
Is preferred. These vitamin Es can be used alone or in combination of 2
Any combination of two or more species can be used.

The amount of vitamin E compounded in the composition for mucosal application is usually 0.00001 to 10%, preferably 0.
It is 0005 to 5%. For example, in the case of an ophthalmic composition such as eye drops, the amount of vitamin E compounded is 0.0000.
5 to 0.25% can be blended, and preferably 0.
It is in the range of 0005 to 0.05% by weight. In the case of a nasal composition such as nasal drops, the amount of vitamin E compounded is
It is 0.001 to 10% by weight, preferably 0.05 to 1% by weight.

The mixing ratio of xanthines and vitamin Es in the mucosal composition varies depending on the type of compound,
Usually, 0.01 to 5000 parts by weight of vitamin Es, preferably 0.1 to 500 parts by weight, relative to 1 part by weight of xanthines.
The amount is 0 parts by weight, more preferably 1 to 750 parts by weight, and particularly preferably 1 to 500 parts by weight. In the composition of the present invention, when a fat-soluble vitamin such as vitamin E is added to clear eye drops, eye washes or nasal drops, a solubilizer is used because the solubility of vitamin E in an aqueous solution is extremely low. Further blending 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, 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 salt thereof, Examples thereof include lecithin derivatives, preferably polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil or hydrogenated castor oil, sorbitan fatty acid ester, particularly preferably polyoxyethylene 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.
The amount is ˜30 times, preferably about 0.3 to 10 times.

The composition for mucosal application of the present invention can obtain a more stable composition by combining with a chelating agent. Examples of the chelating agent include edetic acid (ethylenediaminetetraacetic acid, EDTA), ethylenediaminediacetic acid (EDDA), diethylenetriaminepentaacetic acid (DTPA), N- (2-hydroxyethyl) ethylenediaminetriacetic 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,
Examples thereof include 1-diphosphonic acid. These chelating agents may be used alone or in combination of two or more, and may be used as a pharmacologically or physiologically acceptable salt. Preferred chelating agents are ethylenediaminetetraacetic acid, citric acid and salts thereof. Particularly preferred is ethylenediaminetetraacetic acid or a salt thereof, and examples thereof include disodium ethylenediaminetetraacetate and disodium ethylenediaminetetraacetate dihydrate (hereinafter also referred to as sodium edetate).

When the chelating agent is added to the mucosal composition, the concentration in the composition is usually 0.0001 to 1% by weight, 0.001 to 0.5% by weight, 0.005 to 0.3%.
It is about% by weight. The compounding ratio in the composition is usually 0.01 to 10 parts by weight of the chelating agent with respect to 1 part by weight of vitamin Es.
It is 0 part by weight, preferably 0.01 to 10 parts by weight.

The composition for application to mucosa of the present invention is useful in that by incorporating the above-mentioned xanthines, vitamin Es can be stably maintained for a long period of time even in an aqueous composition. The application is not particularly limited as long as it utilizes this effect, and it can be used in various fields such as pharmaceuticals, quasi drugs, and cosmetics. For example, eye drops (including eye drops that can be used while wearing contact lenses (CL)), eye washes (including eye drops that can also be used while wearing contact lenses (CL)), Examples include eye ointments, contact lens (CL) mounting solutions, contact lens agents (cleansing solutions, preservatives, sterilizing solutions, multipurpose solutions, etc.), nasal drops, nasal washes, oropharyngeal agents, and mouth rinses. Among them, it is useful as a composition for application to the mucous membrane of the eye or nasal mucosa such as eye drops, eye washes, and nasal drops, which is an aqueous composition in which the effects of vitamin Es are particularly suitably exerted.

The composition for application to mucosa of the present invention contains, for example, xanthines and vitamin E in combination with various components (including pharmacologically active ingredients and physiologically active ingredients) unless the effects of the present invention are impaired. May be. The type of such components is not particularly limited, for example, decongestant component, α-adrenergic agonist, anti-inflammatory drug component, antihistamine drug component or antiallergic drug component, astringent drug component, antibacterial drug or bactericidal drug component, Examples include high molecular saccharides or salts thereof, vitamins, amino acids and the like. Examples of suitable components in the present invention include the following components.

Decongestant components: For example, epinephrine, ephedrine, tetrahydrozoline, naphazoline, phenylephrine, methylephedrine and salts thereof α-adrenergic agonists: For example, imidazoline derivatives (naphazoline, tetrahydrozoline, etc.), β-phenylethylamine derivatives (phenylephrine). , Epinephrine, ephedrine, methylephedrine, etc.), and pharmaceutically or physiologically acceptable salts thereof (for example, 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 modulator component: Cholinesterase inhibitor having an active center similar to acetylcholine, such as neostigmine methylsulfate Anti-inflammatory drug components such as quaternary ammonium compounds and salts thereof: celecoxib, rofecoxib, indomethacin, diclofenac,
Planoprofen, piroxicam, meloxicam (melo
xicam), epsilon-aminocaproic acid, berberine,
Glycyrrhizic acid, lysozyme, methyl salicylate, allantoin, and pharmacologically acceptable salts (for example,
Astringent drug components such as berberine chloride, berberine sulfate, sodium diclofenac, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, lysozyme chloride, etc .: Zinc and salts thereof (eg, zinc sulfate,
Zinc lactate) and other antihistamine or antiallergic drug components: for example, diphenhydramine, iproheptin,
Ketotifen, emedastine, clemastine, azelastine, levocabastine, olopatadine, cromoglicic acid, tranilast, amlexanox, mequitazine, loratadine, fexofenadine (fexofen)
adine), cetirizine, ibudilast, suplatast, pemirolast, and pharmacologically acceptable salts (for example, diphenhydramine hydrochloride, iproheptin hydrochloride, ketotifen fumarate, emedastine fumarate,
Cremastine fumarate, azelastine hydrochloride, levocabastine hydrochloride, olopatadine hydrochloride, sodium cromoglycate, etc.) antibacterial or bactericidal components: eg sulfonamides (eg sulfamethoxazole, sulfisoxazole, sulfisomidine and pharmacology) Acceptable salts (sulfamethoxazole sodium, sulfisomidine sodium, etc.), acrinol, quaternary ammonium compounds (eg, benzalkonium, benzethonium, cetylpyridinium), and pharmacologically acceptable Salts (benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, cetylpyridinium bromide, etc.), alkylpolyaminoethylglycine, new quinolone agents (lomefloxacin, levofloxacin, ciprofloxacin, off Xacin, norfloxacin, ciprofloxacin hydrochloride, etc., biguanides (polyhexamethylene biguanide, chlorhexidine or its salts, etc.), berberine or its salts, polydronium chloride, Glokill (trade name, Rhodia: eg Glokill PQ), poly Vitamins such as diallyldimethylammonium chloride, poly [oxyethylene (dimethyliminio) ethylene- (dimethyliminio) ethylenedichloride], parabens (methyl benzoate, ethyl aminobenzoate, etc.): For example, vitamins A [eg, Retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene and pharmacologically acceptable salts thereof (eg, retinol acetate, retinol palmitate, etc.)], vitamin B [eg, thiamine, thia Down disulfide, dicethiamine, oct thiamine, Shikochiamin, bis Eve thiamine, 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, pantothenic acid, panthenol, biotin, Choline,
Inositol and its pharmacologically acceptable salts thereof (for example, thiamine hydrochloride, thiamine nitrate, dicetiamine hydrochloride, fursultiamine hydrochloride, riboflavin butyrate, flavin adenine dinucleotide sodium, pyridoxine hydrochloride, pyridoxal phosphate, pyridoxal calcium 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, ascorbine) Acid salts, sodium erythorbate, etc.), vitamin Ds [eg, ergocalciferol, cholecalciferol, hydroxycholecalciferol, dihydroxycohol Calciferol, dihydrotaxosterol and pharmacologically acceptable salts thereof, etc.), and other vitamins [eg, carnitine, ferulic acid, γ-oryzanol, orotate, rutin, eriocitrin, hesperidin and its pharmacology] Acceptable salts (carnitine chloride, 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, aminoethylsulfonic acid (taurine)
And pharmaceutically acceptable salts thereof (eg potassium aspartate, magnesium aspartate, cysteine hydrochloride etc.), saccharides: monosaccharides (eg glucose etc.), disaccharides (eg trehalose, lactose, fructose etc.), oligos Sugars (eg, lactulose, raffinose, pullulan, etc.), cellulose or derivatives thereof (eg, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, etc.), polymeric 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, oxybu Steroid components such as procaine, dibucaine, procaine, ethyl aminobenzoate, meprilcaine, and their salts (lidocaine hydrochloride, oxybuprocaine hydrochloride, etc.): hydrocortisone, prednisolone,
Other components such as salts thereof, polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, etc. The content of these components can be selected according to the type of formulation, the type of active ingredient, etc. On the other hand, 0.
It can be selected from the range of 0001 to 30%, preferably about 0.001 to 10%.

More specifically, the content of each component in the mucosal composition is as follows, for example.

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 modulator component: For example, 0.0001-0.5%, preferably 0.001-0.1% 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%.

Since the composition for mucosal application of the present invention can greatly improve the stability of vitamin Es, its form is not particularly limited as long as it utilizes this effect, and various carriers (aqueous carrier, hydrophilic carrier) are used. Carrier, oil carrier, liquid carrier, etc.)
Can be combined with the formulation, various forms depending on the purpose,
For example, it can be provided in various dosage forms such as a semi-solid preparation and a liquid preparation.

In the present invention, various components and additives may be optionally selected or used in combination according to the usual method according to the application and the form, if necessary, within a range that does not impair the effects of the invention. It is possible. For example, carriers (water, aqueous solvents, aqueous or oily bases, etc.) commonly used to prepare semi-solid agents and liquid agents, solubilizers, suspending agents, emulsifiers, buffers, thickeners, interfaces Activator, antiseptic, bactericide, antibacterial agent,
Examples include various additives such as an isotonicity agent, an antioxidant, a flavoring agent, a sour agent, and a fragrance. Among them, solubilizers are
A stable aqueous composition that improves the solubility of the xanthines of the present invention in an aqueous composition (an aqueous composition in the form of liquid, suspension, emulsion, ointment, cream, etc.)
Is a suitable compounding ingredient. Examples of such solubilizing agents include benzoic acid, citric acid, aminoisobutanol, taurine and salts thereof, surfactants, and polyhydric alcohols such as propylene glycol.

The typical components used in the composition for application to mucosa of the present invention are shown below, but the components are not limited to these components.

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, heparinoid, 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: eg polyoxyethylene (POE) -polyoxypropylene (POP) block copolymers (eg Poloxamer 407, Poloxamer 2)
35, poloxamer 188, etc.), monolauric acid POE (2
0) Sorbitan (polysorbate 20), P monooleate
POE such as OE (20) sorbitan (polysorbate 80)
Sorbitan fatty acid esters, POE (60) hydrogenated castor oil and other POE hydrogenated castor oil, POE (9) lauryl ether and other POE alkyl ethers, POE (20) POP
(4) POE / POP alkyl ethers such as cetyl ether, POE such as POE (10) nonylphenyl ether
E Nonionic surfactants such as alkylphenyl ethers; glycine type such as alkyldiaminoethylglycine, betaine acetate type such as lauryldimethylaminoacetic acid betaine, and amphoteric surfactants such as imidazoline type; PO
E (10) POE such as sodium lauryl ether phosphate
Alkyl ether phosphoric acid 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, sulfonates such as sodium tetradecene sulfonate , Alkyl sulphates such as sodium lauryl sulphate, POE (3) POE alkyl ether sulphates such as sodium lauryl ether sulphate, anionic surfactants such as α-olefin sulfonates; alkyl amine salts, alkyl quaternary ammonium salts ( Examples thereof include cationic surfactants such as benzalkonium chloride and benzethonium chloride) and alkylpyridinium salts (such as cetylpyridinium chloride and cetylpyridinium bromide). 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, alkylpolyaminoethylglycine, benzyl alcohol, phenethyl alcohol, chlorobutanol, isopropanol, ethanol, phenoxyethanol, sulfur, phosphorus Zirconium acid silver, zinc, zinc oxide, and other carriers, silver zinc aluminosilicate, mercury chrome, 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, trichloro sorbate. Calvin, halo Calvin,
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: Glokill PQ, for example), polydiallyldimethylammonium chloride, poly [oxyethylene (dimethyliminio) ethylene- (dimethyl [Iminio) ethylene dichloride] and the like, and pharmacologically acceptable salts thereof, etc. 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, malic 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 Isotonic agents such as bases (monoethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, lysine, etc.), borax, and pharmacologically acceptable salts thereof, such as glycerin, propylene glycol, and the like. Inorganic salts such as polyhydric alcohols and sugars (sugar 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., and if necessary, a fragrance or a cooling agent (for example, menthol, camphor, borneol, geraniol, eucalyptus). Oil, bergamot oil, fennel oil, peppermint oil, cinnamon oil, rose oil, peppermint oil, etc.) and the like can be added.

The composition for application to mucosa of the present invention needs to be adjusted to pH and / or osmotic pressure within a range that is acceptable to the living body, if necessary. The pH is usually 5.0 to 9.0, preferably 5.5 to 9.0, and particularly preferably 5.5 to 8.5.

The osmotic pressure is 100 to 1200 mOsm, preferably 100 to 600 mOsm, and particularly preferably 15
It is about 0 to 400 mOsm, 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 1.4. p
The H and osmotic pressure can be adjusted using a buffering agent, the pH adjusting agent, an isotonicity agent, salts and the like.

Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, 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.
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 its salt (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, sodium carbonate, etc.), citric acid or its salt (sodium citrate, potassium citrate, etc.) Can be mentioned. When a borate buffer or a phosphate buffer is used as the buffer, the concentration of these buffers in the mucosal composition of the present invention is, for example, 0.0001 to 10.
It is about 0% by weight.

The composition for mucosal application of the present invention can be produced by a known method. The semi-solid formulation and the liquid formulation can be prepared by mixing the base with each component. More specifically, for example, in the case of eye drops, vitamin Es and xanthines are dissolved using distilled water or purified water and an additive to give a predetermined osmotic pressure and p
It can be manufactured by adjusting it to H and subjecting it to filtration sterilization in a sterile environment as required. It is more preferable that the container is pillow-wrapped, and an oxygen absorber is enclosed or nitrogen is replaced.

The present invention also relates to an aqueous composition containing vitamin Es, which is a method for improving the stability of the vitamin Es. Such a method can be achieved by blending the xanthines with an aqueous composition containing vitamin Es. In addition, the kind of xanthines to be mixed, the mixing ratio, the mixing method, and the like can be performed according to the above description regarding the composition for mucosal application of the present invention.

[0037]

EFFECTS OF THE INVENTION Since the composition for mucosal application of the present invention combines xanthines and vitamin Es, it has the effect of significantly improving the stability of vitamin Es even in an aqueous composition. Have. Therefore, it is possible to provide a composition for mucosal application in which vitamins E are stably retained for a long period of time. Therefore, the composition for applying mucosa of the present invention includes eye drops, eye drops, eye ointments, contact lens mounting solutions, contact lens agents (cleansing solutions, preservatives, sterilizing solutions, multipurpose solutions, etc.), nasal drops, nasal washes. It can be used for oropharyngeal medicine, gargle, etc.

Further, the method of the present invention in which xanthines stabilize vitamin Es for a long period of time can improve the safety in a wide range of aqueous compositions other than pharmaceuticals and quasi drugs, so that it can be used in various applications. It is useful for preparing various forms of aqueous compositions used.

[0039]

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 39 By the compositions shown in Tables 1 to 6 below, eye drops, eye washes, contact lens preparations, nasal drops or nasal washes were prepared.

[0041]

[Table 1]

[0042]

[Table 2]

[0043]

[Table 3]

[0044]

[Table 4]

[0045]

[Table 5]

[0046]

[Table 6]

Test Example 1 Vitamin Es with caffeine
In order to test the long-term stability of vitamin Es by caffeine, glass ampoules were filled with various test solutions shown in the table and sealed. Then, these test solutions were stored in a thermostatic chamber at 70 ° C. for 14 days. After storage for 14 days, the residual amount of dl-α-tocopherol acetate in each test solution was measured by UV absorption at 288 nm using a high performance liquid chromatography method. The column used for measurement is 150 mm long and 4.6 mm in diameter (brand name CHE
MCOSORB C87μm, manufactured by Chemco Co., Ltd., column temperature is 40
C. and methanol was used as the mobile phase. The residual rate was calculated from the residual amount, and the results are shown in Table 7.

[0048]

[Table 7]

As a result of the test, in the example of the present invention in which caffeine was blended with dl-α-tocopherol acetate, the residual rate after storage at 70 ° C. for 14 hours was increased. Therefore, it was confirmed that the long-term stability of dl-α-tocopherol acetate was remarkably improved. Also, acetic acid
The long-term stabilizing effect of dl-α-tocopherol was observed depending on the concentration of caffeine. Therefore, it was shown that xanthine derivatives such as caffeine significantly improve the long-term stability of vitamin Es.

Claims (8)

[Claims] 1. Formula (1): (Wherein R ¹ , R ² and R ^{3, which} may be the same or different, each represents a hydrogen atom or an alkyl group which may be substituted) and a salt thereof. At least one compound selected,
A mucosal composition containing vitamin Es. 2. The composition for mucosal application according to claim 1, wherein the compound represented by the formula (1) is caffeine, theophylline, theobromine, diprophylline, proxyphylline, pentoxifylline. 3. The composition for mucosal application according to claim 1, wherein the compound represented by the formula (1) is caffeine. 4. 1 to 50 parts by weight of at least one compound selected from the group consisting of compounds represented by formula (1) and salts thereof with respect to 1 part by weight of vitamin Es.
The composition for mucosal application according to any one of claims 1 to 3, which is contained in an amount of 00 parts by weight. 5. The composition for application to mucosa according to claim 1, further comprising a solubilizing agent. 6. The composition for application to mucosa according to any one of claims 1 to 5, which is an aqueous composition. 7. The composition for applying mucosa according to claim 1, which is an eye drop, an eye wash, a nasal drop, or a nasal wash. 8. An aqueous composition containing vitamin Es,
Formula (1) (Wherein R ¹ , R ² and R ^{3, which} may be the same or different, each represents a hydrogen atom or an alkyl group which may be substituted) and a salt thereof. A method of improving the stability of vitamin Es by incorporating at least one compound selected.