JP2003128549A - Composition applicable to mucous membrane - Google Patents

Abstract

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

[0002]

BACKGROUND OF THE INVENTION Histamine is an H that is widely distributed in the living body.
It acts on ₁ receptors to exert actions such as vascular permeability enhancement, bronchoconstriction, and inflammatory reaction, and plays a role in inflammation caused by allergic reaction and other mechanisms. On the contrary,
A drug having an antihistamine action blocks the H ₁ receptor and competitively inhibits the expression of histamine action.

Among such antihistamines, chlorpheniramine maleate, which is a drug having a strong antihistamine activity, is immediately applied to a mucosa such as inflamed nasal mucosa and ocular mucosa, and has an excellent therapeutic effect. Can be demonstrated. And since it does not bring about the side effect of drowsiness due to the sedative action in the center of the problematic antihistamine action if taken orally, it is suitable for use as a composition to be applied locally to the mucous membrane such as eye drops and nasal drops. It is useful.

Therefore, for example, when it is applied directly to the nasal mucosa, it alleviates various symptoms such as stuffy nose, nasal discharge (excessive nasal discharge), sneezing, heavy head (heavy head), rough eyes, and acute rhinitis and allergic rhinitis. It is used to treat When applied to the ocular mucosa, it is used for alleviating itching in the eyes and improving inflammation such as allergic conjunctivitis.

In the case of using chlorpheniramine maleate as a composition for mucosal application, it is desirable to use an aqueous composition in order to exhibit an antihistamine action immediately and safely. However, chlorpheniramine maleate is preferable. Has the problem of becoming unstable in an aqueous solution.

Therefore, there has been a demand for a composition for application to mucosa in which chlorpheniramine maleate is stably retained for a long period of time.

[0007]

Therefore, an object of the present invention is to provide a composition for mucosal application which is excellent in long-term stability of chlorpheniramine or a salt thereof. Another object of the present invention is to provide a method for stably holding chlorpheniramine or a salt thereof 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 coexistence with a xanthine derivative improves the stability of chlorpheniramine or a salt thereof, resulting in long-term use. 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 chlorpheniramine or a salt thereof. (II) The composition for mucosal application according to (I), wherein the compound represented by the formula (1) is caffeine, theophylline, theobromine, diprophylline, proxyphylline, or pentoxifylline. (III) The composition for mucosal application according to (I) or (II), wherein the compound represented by the formula (1) is caffeine. (IV) 0.01 to 20000 parts by weight of at least one compound selected from the group consisting of the compound represented by the formula (1) and salts thereof, relative to 1 part by weight of chlorpheniramine or a salt thereof. It is contained in the ratio of parts,
The composition for mucosal application according to any one of (I) to (III). (V) The composition for mucosal application according to any one of (I) to (IV), which further comprises a chelating agent. (VI) The composition for mucosal application according to any one of (I) to (V), which is an aqueous composition. (VII) Eye drops, eye washes, and nasal drops (I) to (V
The composition for mucosal application according to any one of I).

Furthermore, the present invention is a method for improving the stability of chlorpheniramine or a salt thereof, which is set forth below: (VIII) An aqueous composition containing chlorpheniramine or a salt thereof is added with the 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 chlorpheniramine or a salt thereof by incorporating at least one selected compound.

In this specification, unless otherwise specified,
% 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.

[0012]

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 also 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.
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, examples of chlorpheniramine or a salt thereof include chlorpheniramine maleate. In addition, pharmacologically or physiologically acceptable salts of chlorpheniramine can be used. Examples of the pharmacologically acceptable salt include the same salts as those described for the compound of formula (1).

The concentration of chlorphemiramine or a salt thereof in the composition for mucosal application of the present invention is usually 0.00001 to 5%, preferably 0.
001 to 3%, more preferably 0.0005 to 2
%, Particularly preferably about 0.001 to 0.5%.

The ratio of xanthines to chlorpheniramine or a salt thereof varies depending on the type of xanthines, but usually 0.01 to 20000 parts by weight of xanthines (1 part by weight of chlorpheniramine or a salt thereof) ( For example, 0.05 to 15,000 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 1000 parts by weight (e.g. 1 to 750 parts by weight), and particularly preferably 0.1 to 1000 parts by weight.
500 (for example, 1 to 250 parts by weight).

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 pharmacologically or physiologically acceptable salts. Preferred chelating agents are ethylenediaminetetraacetic acid, citric acid and salts thereof. Particularly preferred is ethylenediaminetetraacetic acid or a salt thereof, such as disodium ethylenediaminetetraacetate and disodium ethylenediaminetetraacetate dihydrate (hereinafter also referred to as sodium edetate).

When the chelating agent is added to the composition for mucosal application, 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%.
The content of the chelating agent is usually 0.01 to 5000 parts by weight, preferably 0.01 to 5000 parts by weight, based on 1 part by weight of chlorpheniramine or a salt thereof.
The amount is 1000 parts by weight, more preferably 0.01 to 500 parts by weight, and particularly preferably about 0.1 to 10 parts by weight.

The composition for application to mucosa of the present invention is useful in that chlorpheniramine or a salt thereof can be stably retained for a long period of time even in an aqueous composition by incorporating the xanthines. 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), eye washes (including eye drops that can be used while wearing contact lenses), eye ointments, contact lenses Mounting fluid,
Agents for contact lenses (cleansing solution, preservative solution, sterilizing solution, multi-purpose solution, etc.), nasal drops, nasal wash solution,
Oropharyngeal drugs, gargles, etc. can be mentioned. Among them, it is useful as a composition for application to the mucous membranes of the eye or nasal mucosa such as eye drops, eye washes and nasal drops, which is an aqueous composition in which the effect of chlorpheniramine or a salt thereof is particularly suitably exhibited.

The composition for mucosal application of the present invention is, for example, a combination of xanthines and chlorpheniramine or a salt thereof with various components (including pharmacologically active components and physiologically active components), as long as the effects of the present invention are not impaired. May be included. 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, stomach medicine drug component, digestive drug component, ulcer treatment drug component, antibacterial drug or bactericidal drug component, antitumor Examples include medicinal ingredients, hormones, proteins 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, such as α-adrenergic agonists such as 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 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) etc. Antihistamine drug component or antiallergic drug component: For example,
Diphenhydramine, iproheptin, ketotifen,
Emedastine, clemastine, azelastine, levocabastine, olopatadine, cromoglicic acid, tranilast, amlexanox, mequitazine, loratadine (lora
tadine), fexofenadine, cetirizine, ibudilast, suplatast, pemirolast, and pharmacologically acceptable salts (eg diphenhydramine hydrochloride, iproheptine hydrochloride, ketotifen fumarate, emedastine fumarate, clemastine fumarate). , Azelastine hydrochloride, levocabastine hydrochloride, olopatadine hydrochloride, sodium cromoglycate, etc.) antibacterial or bactericidal components: eg, sulfonamides (eg, sulfamethoxazole, sulfisoxazole, sulfisomidine and pharmacologically acceptable) Salts (sulfamethoxazole sodium, sulfisomidine sodium, etc.), acrinol, quaternary ammonium compounds (eg, benzalkonium, benzethonium, cetylpyridinium), and pharmacology Acceptable salts (benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, cetylpyridinium bromide, etc.), alkylpolyaminoethylglycine, new quinolone agents (lomefloxacin, levofloxacin, ciprofloxacin, ofloxacin, norfloxacin, ciprofloxy hydrochloride. Sacin etc.), biguanides (polyhexamethylene biguanide, chlorhexidine or salts thereof, etc.), berberine or salts thereof, polydronium chloride, Glokill (trade name, manufactured by Rhodia: eg Glokill PQ), polydiallyldimethylammonium chloride, poly [oxy] Ethylene (dimethyliminio) ethylene- (dimethyliminio) ethylene dichloride)], parabens (methyl benzoate, ethyl aminobenzoate, etc.) and other vitamins: For example, Tamine A [for example, retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene and its pharmacologically acceptable salts (for example, retinol acetate, retinol palmitate, etc.)], vitamin B [for example, thiamine , Thiamine disulfide, dicethiamine, octothiamine, schiotiamine, bisbutyamine, bisbenchamine, 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, dihydrotachysterol and pharmacologically acceptable salts thereof, etc.], vitamin E [for example, tocopherol and its derivatives, ubiquinone derivatives and pharmacologically acceptable salts thereof (tocopherol acetate, nicotinic acid) Tocopherol, tocopherol succinate, calcium tocopherol succinate, etc.) and other vitamins [eg, carnitine, ferulic acid, γ-oryzanol, orotic acid, rutin, eriocitrin, hesperidin and pharmaceutically acceptable salts thereof. (Carnitine chloride etc.) Amino acids: For example, leucine, isoleucine, valine, methionine, threonine, alanine, phenylalanine, tryptophan, lysine, glycine, asparagine, aspartic acid, serine, glucine. Min, 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.), 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 chlorpheniramine or a salt thereof,
The form is not particularly limited as long as it utilizes this effect, and it can be formulated by combining with various carriers (aqueous carrier, hydrophilic carrier, oily carrier, liquid carrier, etc.), and various forms can be prepared 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 conventional method according to the application and 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 applying to mucosa of the present invention will be exemplified 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 and the like, and pharmacologically acceptable salts thereof 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 (20) sorbitan monooleate (polysorbate 80), sorbitan fatty acid esters, POE (60) ) POE such as hydrogenated castor oil POE such as hydrogenated castor oil and POE (9) lauryl ether
Alkyl ethers, POE (20) POP (4) cetyl ether and other POE / POP alkyl ethers, POE
(10) Nonionic surfactants such as POE alkyl phenyl ethers such as nonyl phenyl ether; glycine type such as alkyldiaminoethylglycine, betaine acetate type such as lauryl dimethylamino acetic 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 such as sodium N-cocoylmethyl taurine Taurine salts, sulfonates such as sodium tetradecenesulfonate, alkyl sulfates such as sodium lauryl sulfate, POE (3) POE alkyl ether sulfates such as sodium lauryl ether sulfate, α
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, 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,
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) Ethanolamine, diisopropanolamine, triisopropanolamine,
Isotonic agents such as lysine), borax, and pharmacologically acceptable salts thereof, and the like: inorganic salts such as polyhydric alcohols such as glycerin and propylene glycol, sugars (butose 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 mucosal application of the present invention needs to be adjusted to a pH and / or an 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, particularly preferably 150 to 40.
The osmotic pressure ratio to physiological saline is usually about 0.
It is 0.3 to 4.1, preferably 0.3 to 2.1, and particularly preferably 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.

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 mucosal composition 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. Furthermore, if necessary, a filter sterilization treatment step, a container filling step, and the like can be added.
More specifically, in the case of eye drops, for example, distilled water or purified water and additives are used to dissolve chlorphemiramine or a salt thereof and xanthines, and a predetermined osmotic pressure and pH are obtained.
And sterilized in a sterile environment, and then aseptically filled in a container that has been washed and sterilized. It is more preferable that the container is pillow-wrapped, and an oxygen absorber is enclosed or nitrogen is replaced.

The present invention is also a method for improving the stability of chlorfemiramine or a salt thereof with respect to an aqueous composition containing chlorfemiramine or a salt thereof. Such a method can be achieved by blending the xanthines with an aqueous composition containing chlorfemiramine or a salt thereof. 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.

[0039]

EFFECTS OF THE INVENTION Since the composition for mucosal application of the present invention comprises a combination of xanthines and chlorpheniramine or a salt thereof, the stability of chlorpheniramine or a salt thereof is remarkable even in an aqueous composition. It has the effect of being improved. Therefore, it is possible to provide a composition for mucosal application in which chlorphemiramine or a salt thereof is 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 stabilizing chlorpheniramine or a salt thereof with xanthines for a long period of time can widely improve the safety in an aqueous composition in addition to pharmaceuticals and quasi-drugs, and therefore has various uses. It is useful for preparing various forms of aqueous compositions used.

[0041]

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 26 By the compositions shown in Tables 1 to 4 below, eye drops, eye washes, liquids for contact lenses, nasal drops or nasal washes were prepared.

[0043]

[Table 1]

[0044]

[Table 2]

[0045]

[Table 3]

[0046]

[Table 4]

Test Example 1 Maleic acid caffeine with caffeine
Stability of Lorpheniramine In order to test the long-term stability of chlorpheniramine maleate with caffeine, various test solutions shown in the table were filled in glass ampoules and sealed. Then, these test solutions were stored in a thermostatic chamber at 70 ° C. for 10 to 30 days.

After the test liquids were stored for 10 to 30 days, the residual amount of chlorpheniramine maleate in each test liquid was measured by 225 nm UV absorbance using a high performance liquid chromatography method. The column used for measurement is 150 mm long and has a diameter
4.6 mm (trade name InertsilPh-35 μm, manufactured by GL Sciences Inc.), column temperature was 40 ° C., and a mobile phase was a mixture of acetonitrile: PIC (C8) / acetic acid solution 25:75. Here, PIC (C8) / acetic acid solution is 1.08 g of sodium 1-octanesulfonate + 2.5 mL of acetic acid + water 770
This is a mixed solution of mL. Calculate the remaining rate from the remaining amount,
The results are shown in Table 5.

[0049]

[Table 5]

As a result of the test, in the example in which caffeine (anhydrous caffeine) was blended with chlorpheniramine maleate, the residual rate after storage at 70 ° C. for 30 days was increased, and the long-term stability was improved. It was shown that Moreover, this effect was observed depending on the concentration of caffeine (anhydrous caffeine). Furthermore, it was confirmed that the long-term stability was further improved by adding sodium edetate (Japanese Pharmacopoeia).

Examples 33 to 38 The eye drops were prepared according to the composition shown in Table 6 below.

[Table 6]

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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 composition for mucosal application containing chlorpheniramine or a salt thereof. 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. 0.01 to 20000 of at least one compound selected from the group consisting of compounds represented by formula (1) and salts thereof, relative to 1 part by weight of chlorpheniramine or a salt thereof. The composition for mucosal application according to any one of claims 1 to 3, which is contained in a ratio of parts by weight. 5. The method according to claim 1, further comprising a chelating agent.
The composition for mucosal application according to any one of 1. 6. The composition for application to mucosa according to any one of claims 1 to 5, which is an aqueous composition. 7. An eye drop, an eye wash, and a nasal drop.
7. The composition for applying to mucous membrane according to any one of 1 to 6. 8. An aqueous composition containing chlorpheniramine or a salt thereof has the 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 for improving the stability of chlorpheniramine or a salt thereof by incorporating at least one compound selected.