JP2003104870A - Aqueous composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a safe aqueous composition having stable, high antiseptic activities. SOLUTION: This water-based composition contains sorbic acid or a salt thereof, and a zinc salt such as zinc sulfate and zinc hydroxycarboxylate. This method for improving antiseptic activities of the water-based composition comprises making the zinc salt such as the zinc sulfate and the zinc hydroxycarboxylate coexist with the water-based composition containing the sorbic acid or the salt thereof.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an aqueous composition having improved antibacterial activity.

[0002]

2. Description of the Related Art Preservatives (bactericidal agents, bacteriostatic agents) are added to aqueous compositions applied to living bodies such as pharmaceuticals and cosmetics in order to prevent contamination by microorganisms. The type of preservative used is appropriately selected in consideration of the presence or absence of irritation and the degree of antibacterial effect according to the type of composition. For example, in ophthalmic aqueous compositions such as eye drops (agents), as preservatives, cationic surfactants such as benzalkonium chloride, benzethonium chloride, and chlorhexidine gluconate, and amphoteric surfactants such as alkylpolyaminoethylglycine are used. , Parabens, chlorobutanol and sorbic acid are 1 or 2
Used in combination of more than one species. Among these,
Sorbic acid or a salt thereof is used in various fields because it is less toxic to cells such as corneal epithelial cells as compared with other preservatives such as benzalkonium chloride. It is also widely used in things. However, there is a problem that the antiseptic action is low. Further, there is a problem that the antiseptic action is weak especially at high pH, and stable antiseptic power cannot be obtained.

Conventionally, in order to solve such problems, a buffer having a high antiseptic property such as boric acid is blended at the same time, and a fragrance and ethylenediaminetetraacetic acid or a salt thereof is blended (Japanese Patent Laid-Open No. 11- 292793) and the like have been devised in preparation, but the effect is not sufficient, and a method for stably improving the antiseptic effect of sorbic acid or a salt thereof has been strongly demanded. Such a method expands the use of sorbic acid or a salt thereof as a preservative for a wide range of aqueous compositions, and is useful not only in medicine but also in the fields of cosmetics and the like, and the antiseptic effect is stably enhanced. It is possible to provide the aqueous composition thus obtained.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide an aqueous composition containing sorbic acid or a salt thereof, which stably exhibits a high antiseptic effect and is highly safe.

[0005]

Means for Solving the Problems As a result of intensive studies for achieving the above object, the present inventors have found that sorbic acid or a salt thereof and a zinc salt such as zinc sulfate or zinc oxycarboxylate are added to an aqueous composition. It has been found that, when properly compounded, the composition exhibits an unexpectedly high antiseptic effect, and the present invention has been completed.

That is, the present invention provides (1) an aqueous composition containing sorbic acid or a salt thereof and a zinc salt, and (2) the zinc salt is selected from oxycarboxylic acid zinc salt and zinc sulfate. (1) The aqueous composition according to (1), further comprising a monoterpene (3), the aqueous composition according to (1) or (2),
(4) The aqueous composition according to any one of (1) to (3), which is a composition for mucosal application, (5)
A zinc salt is added to the aqueous composition according to any one of (1) to (4), which is an ophthalmic composition, and (6) an aqueous composition containing sorbic acid or a salt thereof. And a method for enhancing antibacterial activity of an aqueous composition.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION In this specification, unless otherwise specified,% means w / v%. The term contact lens (CL) is used to include all types of contact lenses such as hard, oxygen permeable hard, and soft, unless otherwise specified.

As sorbic acid or a salt thereof, sorbic acid or a pharmacologically or physiologically acceptable salt can be used. As the pharmacologically or physiologically acceptable salt,
For example, salts with organic bases (eg, methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, amino acids, salts with organic amines such as tripyridine, picoline, etc.), salts with inorganic bases (eg, ammonium salt) , An alkali metal such as sodium and potassium, an alkaline earth metal such as calcium and magnesium, and a salt with a metal such as aluminum). Specific examples include sorbic acid, potassium sorbate, sodium sorbate, and triclocarban sorbate. Preferably, a salt with an inorganic base,
It is sorbic acid, and sorbic acid, potassium sorbate, sodium sorbate and the like are particularly preferable. Sorbic acid or its salt can be used individually or in combination of 2 or more types.

The amount of sorbic acid or a salt thereof used in the aqueous composition of the present invention varies depending on the mode of the composition, the method of application, the type of compound, etc., but is usually in the range of 0.0001 to 10%. Specifically, in the case of an aqueous composition for internal use, 0.
001 to 10%, preferably 0.01 to 5%, more preferably 0.05 to 1%, and in the case of an aqueous composition for outer skin, 0.0001 to 2%, preferably 0.001 to 1%, more preferably Is in the range of 0.005 to 0.5%, and in the case of an aqueous composition for mucosal application, 0.0001 to 10%, preferably 0.001 to 5%,
More preferably, it is in the range of 0.01 to 1%.

As the zinc salt, zinc oxycarboxylic acid salts such as zinc lactate, zinc glycolate, zinc hydroxybutyrate, zinc glycerin, zinc malate, zinc tartrate and zinc citrate, and zinc sulfate can be used. Preferred salts are zinc lactate, zinc sulfate and the like. Zinc lactate and zinc sulfate also act as astringents and have little irritation when administered to mucous membranes that are sensitive to irritation such as ocular mucosa, so use in aqueous compositions for mucous membranes such as eye drops and nasal drops In particular, it is preferable because of its high safety especially when used in an ophthalmic composition.

The amount of the zinc salt used in the aqueous composition of the present invention varies depending on the aspect of the composition, the method of application, the type of compound, etc., but is usually in the range of 0.0001 to 5%. Specifically, in the case of an aqueous composition for internal use, 0.0001 to 5%, preferably 0.0005 to 1%, more preferably 0.002 to 0.5%.
% In the range of 0.0005,
~ 5%, preferably 0.001-2%, more preferably 0.0
It is in the range of 1 to 0.5%, and in the case of an aqueous composition for application to mucous membrane (aqueous solution), 0.0001 to 5%, preferably 0.001 to 2
%, And more preferably 0.005 to 0.5%. The zinc salt can be used alone or in combination of two or more kinds.

The ratio of sorbic acid or its salt to zinc salt varies depending on the mode of composition, application method, kind of compound, etc., but normally, zinc salt is added to 1 part by weight of sorbic acid or its salt. , 0.0001 to 1000 parts by weight, preferably 0.0005
˜500 parts by weight, more preferably 0.001 to 50 parts by weight, and particularly preferably 0.005 to 10 parts by weight.

The present invention is based on the finding that coexistence of sorbic acid or a salt thereof and a zinc salt in an aqueous composition exerts an antibacterial effect which is unpredictably high when used alone. ing. The composition of the present invention can be applied to all fields as long as it requires such an antibacterial action, and can be used in a wide range of fields such as pharmaceuticals, quasi drugs, cosmetics and foods.

The aqueous composition of the present invention may have any form as long as it is a composition containing water, and may take various forms depending on the purpose. For example, jelly, liquid,
It may be semi-solid (eg ointment). Specifically, it can be formulated into a dosage form such as an orally administrable composition such as a jelly, a liquid or a soft capsule, or a mucosal composition such as a liquid or a semisolid (ointment). Since the aqueous composition of the present invention has high and stable antiseptic properties and excellent safety, it is useful as an aqueous composition for internal use, outer skin, application to mucous membranes, and contact lenses. In particular, it is suitable for use as a preparation for mucosal application to ocular mucosa, nasal mucosa, oral mucosa, large intestine mucosa, etc., and especially for use as a preparation for ocular mucosa. In addition, since sorbic acid has almost no adsorptivity for contact lenses, it is not only a formulation that is applied directly to the ocular mucosa during or while wearing contact lenses, but also any contact lens solution that is indirectly applicable. It is also effective as a liquid agent for lenses.

Specific examples of the aqueous composition of the present invention include internal medicines, external preparations, pharmaceuticals such as aqueous preparations for ophthalmology and otolaryngology, foods and cosmetics. Further specific examples, eye drops (including eye drops that can also be used while wearing contact lenses), eye washes (agents) (including eye drops that can be used while wearing contact lenses), Eye ointment (agent), contact lens mounting solution,
Agent for contact lenses (cleaning solution, preservative, cleaning preservative,
Disinfectant (eg, multi-purpose solution),
Examples include nasal drops and nasal washes. The aqueous composition of the present invention is particularly useful as an ophthalmic composition such as an eye drop, an eye wash, an agent for contact lenses and the like.

The aqueous composition of the present invention may contain at least one monoterpene for enhancing antibacterial activity. Examples of the monoterpene contained in the aqueous composition of the present invention include menthol, camphor, borneol,
Examples thereof include geraniol, cineol, anethole, limonene, eugenol and the like. These monoterpenes are
Although it may be a d-form, an l-form or a dl-form, 1-menthol, d
-Menthol, dl-menthol, d-camphor, dl
-Camphor, d-borneol and dl-borneol are preferred. Geraniol, 1-menthol, d-camphor and d-borneol are particularly preferred. Further, the monoterpene can also be used in a state of being contained in an essential oil, preferred essential oils are eucalyptus oil, bergamot oil,
Examples include peppermint oil, cool mint oil, and spearmint oil. These monoterpenes may be used alone or in combination of two or more.

The concentration of the monoterpene in the aqueous composition of the present invention varies depending on the mode of application of the composition, the method of application, the type of compound, etc., but is usually in the range of 0.00001 to 0.1% by weight, preferably 0.0001 to 0.05% by weight. Is. Especially in the case of an aqueous composition for mucosal application, the concentration range is appropriately adjusted. However, it is preferably 0.1% by weight or less from the viewpoint of avoiding eye damage, and is preferably 0.00001% by weight or more from the viewpoint of obtaining a sufficient antibacterial activity enhancing effect. A suitable range would be 0.0003 to 0.05% by weight for eye drops or contact lens mounting solutions, and 0.0001 to 0.03% by weight for contact lens care compositions or eye washes.

The ratio of sorbic acid or a salt thereof to the monoterpene varies depending on the mode of the composition, the method of application, the type of compound, etc., but usually the monoterpene is added to 1 part by weight of sorbic acid or a salt thereof. , 0.0001 to 100 parts by weight, preferably 0.0005 to 50 parts by weight, more preferably 0.002 to 10 parts by weight
It may be used in an amount of about 0.02 to 5 parts by weight, particularly preferably 0.02 to 5 parts by weight.

The aqueous composition of the present invention may contain boric acid and / or borax not only as a usual component but also for enhancing antibacterial activity. Also, citric acid and /
Alternatively, it is also preferably used for its salt. When boric acid and borax are blended in the aqueous composition of the present invention, the amount used varies depending on the aspect of the composition, application method, etc., but usually the concentration of boric acid is 0.1 to 2%, particularly, 0.2 to 1% is preferable, and the concentration of borax is 0.01 to 1%, and especially 0.1.
02-0.5% is preferable. When citric acid and / or a salt thereof is added to the aqueous composition of the present invention, the amount used varies depending on the aspect of the composition, the application method, etc., but usually the concentration of citric acid is 0.0005 to 2 %, Especially 0.001-0.
5% is preferable, and the concentration of citrate is 0.001 to 5
%, Particularly 0.005 to 2% is preferable. As the citrate, sodium citrate is particularly preferable. Even when these are used in combination, it is preferable to mix them in the above preferable range.

The aqueous composition of the present invention is, for example, a combination of various components (including a pharmacologically active ingredient and a physiologically active ingredient) in addition to sorbic acid or a salt thereof and a zinc salt, as long as the effects of the present invention are not impaired. May be included. The type of such components is not particularly limited, and examples include decongestant components, α-adrenergic agonist components, anti-inflammatory drug components, vitamins, amino acids, saccharides, local anesthetic components, steroid components, antihistamine drug components. Alternatively, an antiallergic drug component, cellulose or a derivative thereof or a salt thereof, a polysaccharide or a derivative thereof, and the like can be exemplified. Examples of suitable components in the present invention include the following components.

Decongestant components: epinephrine, ephedrine, tetrahydrozoline, naphazoline, phenylephrine, methylephedrine and salts thereof. α-adrenergic agonists: for example, imidazoline derivatives (naphazoline, 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).

Anti-inflammatory drug component: celecoxib
b), rofecoxib, indomethacin,
Diclofenac, diclofenac sodium, pranoprofen, piroxicam, meloxica
m), epsilon-aminocaproic acid, berberine and pharmacologically acceptable salts (for example, berberine chloride, berberine sulfate), lysozyme, lysozyme chloride, methyl salicylate, allantoin, glycyrrhizinic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, etc. )Such.

Antihistamine or antiallergic ingredients: For example, chlorpheniramine, diphenhydramine, iproheptin, ketotifen, emedastine, clemastine, azelastine, levocabastine, olopatadine, cromoglic acid, tranilast, amlexanox, mequitazine, loratadine (loratadine), loratadine, loratadine. Fexofenadine, cetirizin
e), ibudilast, splatast, pemirolast or salts thereof (for example, chlorpheniramine maleate, diphenhydramine hydrochloride, iproheptin hydrochloride, ketotifen fumarate, emedastine fumarate, clemastine fumarate, azelastine hydrochloride, levocabastine hydrochloride, olopatadine hydrochloride, clomoglitan hydrochloride). etc.

Vitamin: For example, vitamin A [eg, retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene and pharmacologically acceptable salts thereof (eg, retinol acetate, retinol palmitate, etc.)] , Vitamin Bs [thiamine hydrochloride, thiamine nitrate, bisthiamine nitrate, thiamine disulfide, thiamine dicetyl nitrate ester salt, dicetiamine hydrochloride, fursultiamine hydrochloride, octotiamine, shicothiamine, bis-ibutyamine, bisbentiamine, fursultiamine, pro Sultiamine, benfotiamine,
Flavin adenine dinucleotide sodium, riboflavin, sodium riboflavin phosphate, riboflavin butyrate, pyridoxine hydrochloride, pyridoxal phosphate, hydroxocobalamin hydrochloride, hydroxocobalamin acetate, cyanocobalamin, hydroxocobalamin, nicotinic acid, nicotinic acid amide, panthenol, calcium pantothenate, Sodium pantothenate, biotin, 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, cholecalciferol, hydroxycholecalciferol, dihydroxycholecalciferol, dihydrotaki Sterols and pharmaceutically acceptable salts thereof, etc.], vitamin Es [eg tocopherol and its derivatives, ubiquinone derivatives and pharmaceutically acceptable salts thereof (tocopherol acetate, tocopherol nicotinate, tocopherol succinate) , Tocopherol calcium succinate, etc.), and other vitamins [eg, carnitine, ferulic acid, γ-
Oryzanol, orotic acid, 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) or salts thereof (eg potassium aspartate, magnesium aspartate, cysteine hydrochloride, etc.) and the like.

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

Local anesthetic components: lidocaine, oxyprocaine, dipcaine, procaine, ethyl aminobenzoate, meprilukaine, and salts thereof (lidocaine hydrochloride, oxybuprocaine hydrochloride, etc.) and the like. Steroid ingredients: hydrocortisone, prednisolone,
And their salts etc.

Cellulose or derivatives thereof or salts thereof: methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, cellulose and the like.

Polysaccharides or derivatives thereof: 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 (alginic acid), chitin and its derivatives, chitosan and its derivatives, elastin, heparin, heparinoid, heparin sulfate, heparan sulfate, hyaluronic acid, chondroitin sulfate or its salts (sodium alginate, sodium hyaluronate, sodium chondroitin sulfate) Etc.) and other components: polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, etc.

The amounts of these components to be incorporated in the aqueous composition are appropriately selected according to the type of formulation, the type of active ingredient, etc.
The blending amounts of various components in the preparations for internal use, outer skin, mucous membranes, etc. are known in the art. For example, 0.0001 to 30%, preferably 0.001 based on the whole preparation.
It can be selected from the range of about 10%. More specifically,
The content of each component in the aqueous composition for ocular mucosa application 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%. Anti-inflammatory drug component or astringent drug component: For example, 0.0001 to 10%, preferably 0.0001 to
5%. Antihistamine drug component or antiallergic drug component: For example, 0.0001 to 10%, preferably 0.001 to
5%. Vitamins: For example, 0.0001 to 1%, preferably 0.0001 to 0.5%. Amino acids: For example, 0.0001 to 10%, preferably 0.001 to 3
%. Sugar: For example, 0.0001 to 5%, preferably 0.001 to 5%, and more preferably 0.01 to 2%.
Local anesthetic component: For example, 0.001 to 1%, preferably 0.01 to 1%. Cellulose or a derivative thereof or a salt thereof: for example, 0.001 to 5%, preferably 0.0
1-1%. Polysaccharide or its derivative: For example, 0.000
1-2%, preferably 0.01-2%, 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%.

Further, the aqueous composition of the present invention may contain an antibacterial agent component or a bactericidal agent component, if desired. Specifically, examples of the antibacterial or bactericidal component include, for example, sulfonamides (eg, sulfamethoxazole, sulfisoxazole, sulfisomidine, and pharmacologically acceptable salts (sulfamethoxazole). Sodium, sodium sulfisomidine, etc., acrinol, quaternary ammonium compounds (eg, benzalkonium, benzethonium, cetylpyridinium), and pharmacologically acceptable salts (benzalkonium chloride, benzethonium chloride, cetyl chloride) Pyridinium, cetylpyridinium bromide, etc., alkylpolyaminoethylglycine, new quinolone agents (lomefloxacin, levofloxacin, ciprofloxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride, etc.), biguanides (polyhexamethylene) Guanide, chlorhexidine or a salt thereof, berberine or a salt thereof, polydronium chloride, Glokill (trade name, manufactured by Rhodia), polydiallyldimethylammonium chloride, poly [oxyethylene (dimethyliminio) ethylene- (dimethyliminio) ethrene Dichloride], parabens (such as methyl benzoate and ethyl aminobenzoate) can be used.

These antibacterial or bactericidal components are added to the aqueous composition of the present invention in an amount of 0.001 to 10%, preferably 0.
It may be contained at a concentration of 01 to 10%.

The ophthalmic aqueous composition of the present invention is not limited to a specific form, provided that excellent antibacterial activity is maintained, and various carriers (aqueous carrier, hydrophilic carrier, oily carrier,
It can be formulated into various dosage forms such as a semisolid agent (ointment) and a liquid agent depending on the purpose by combining with a liquid carrier). However, it is preferable that it is a liquid agent from the viewpoint of ease of use.

Further, in the aqueous composition of the present invention, various components and additives are appropriately selected according to a conventional method depending on the application and form thereof, as long as the effects of the invention are not impaired, and one or You may make it contain more than that together. As their components or additives, for example, carriers (water, aqueous solvents, aqueous or oily bases, etc.) generally used for the preparation of semisolid agents, liquid agents, etc., thickeners, surfactants, preservatives , Bactericides, antibacterial agents, pH regulators, isotonic agents, inorganic salts, chelating agents, buffers, solubilizers, suspending agents, emulsifiers, antioxidants, and various additives such as fragrances. it can.

The typical components used in the aqueous composition of the present invention are illustrated below, but the invention is not limited thereto.

Thickening agents: For example, polysaccharides or derivatives thereof (arabic gum, 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.

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. Such as pharmacologically acceptable salts.

Surfactant: For example, polyoxyethylene (POE) -polyoxypropylene (POP) block copolymer (for example, poloxamer 407, poloxamer)
235, poloxamer 188, etc.), polyoxyethylene-polyoxypropylene block copolymer adduct of ethylenediamine (for example, poloxamine), POE (20) sorbitan monolaurate (polysorbate 20), POE (20) sorbitan monooleate (polysorbate 80). ) And other POE 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, nonionic surfactants such as POE alkylphenyl ethers such as POE (10) nonylphenyl ether; glycine type such as alkyldiaminoethylglycine, Amphoteric surfactants such as betaine acetate type such as betayl lauryldimethylaminoacetate and imidazoline type; POE (10) POE alkyl ether phosphates such as sodium lauryl ether phosphate and salts thereof, N-acyl amino acids such as sodium lauroyl methylalanine Salts, alkyl ether carboxylates, N-acyl taurine salts such as sodium N-cocoyl methyl taurine,
Sulfonates such as sodium tetradecene sulfonate, alkyl sulfates such as sodium lauryl sulfate, P
OE (3) POE such as sodium lauryl ether sulfate
Anionic surfactants such as alkyl ether sulfates and α-olefin sulfonates; alkylamine salts, alkyl quaternary ammonium salts (benzalkonium chloride, benzethonium chloride, etc.), alkylpyridinium salts (cetylpyridinium chloride, cetyl bromide) (Eg, pyridinium) and other cationic surfactants. The numbers in parentheses indicate the number of added moles.

Preservatives, fungicides 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, zirconium phosphate Silver carrier, thimerosal, dehydroacetic acid, chlorxylenol, chlorophene, resorcin, thymol, hinokitiol, sulfamine, lysozyme, lactoferrin, triclosan, 8
-Hydroxyquinoline, undecylenic acid, caprylic acid,
Propionic acid, benzoic acid, propionic acid, 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 such as G
lokill PQ, manufactured by Rhodia), polydiallyldimethylammonium chloride, poly [oxyethylene (dimethyliminio) ethylene- (dimethyliminio) etrendichloride, polyethylene polyamine, dimethylamine epichlorohydrin polycondensate (trade name, for example, Busan1
157, manufactured by Backman Laboratories).

PH adjusters: For example, inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, boric acid, etc.), organic acids (lactic acid, acetic acid, citric acid, tartaric acid, malic acid, succinic acid, oxalic acid, gluconic acid) , Fumaric acid, propionic acid, acetic acid,
Aspartic acid, epsilon-aminocaproic acid, glutamic acid, 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.

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

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

Fragrances or cooling agents: eg menthol,
Camphor, borneol, geraniol, eucalyptus oil,
Bergamot oil, fennel oil, peppermint oil, cinnamon oil,
Rose oil, peppermint oil, etc.

The aqueous composition of the present invention needs to be adjusted to a pH and / or an osmotic pressure within a range acceptable to the living body, if necessary. The appropriate pH and osmotic pressure will differ depending on the site of application, dosage form, etc., but are generally pH 3.0 to 10.0, preferably 4.0 to 8.5, and particularly preferably 4.0 to 7.0. The osmotic pressure is 100 to 1200 mOsm, preferably 100 to 600 mOsm, and particularly preferably 150 to 4
It is about 50 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. Especially when the aqueous composition is an ophthalmic composition, the pH is usually 4.0 to 9.0, preferably 4.0 to reduce irritation.
8.0, particularly preferably 4.0-7.0; osmotic pressure is 10
0 to 1200 mOsm, preferably 100 to 600 mO
sm, particularly preferably 150 to 400 mOsm; the osmotic pressure ratio to physiological saline is usually 0.4 to 4.0, preferably 0.6 to 2.5, particularly preferably 0.8 to 1.6.
Is the range. The pH can be adjusted by using a buffer,
It can be carried out using a regulator, the above-mentioned tonicity agent, the above-mentioned inorganic salts and the like.

Here, as the buffer, a borate buffer,
Examples thereof include phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, epsilon-aminocaproic acid, aspartate and the like. These buffer agents may be used in combination. Preferred buffers are borate buffers, phosphate buffers, carbonate buffers and citrate buffers. Particularly preferred buffering agents are borate buffers, citrate 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 citrate buffer include citrate alkali metal salts and the like. As a phosphate buffer,
Examples thereof include phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Further, a borate, citrate or phosphate hydrate may be used as the borate buffer, citrate buffer or phosphate buffer. More specifically, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, etc.), phosphoric acid or a salt thereof (sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc.) , Carbonic acid or salts thereof (sodium hydrogen carbonate, sodium carbonate, etc.), citric acid or salts thereof (sodium citrate, potassium citrate, etc.). When a borate buffer, a citrate 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,
It is about 0.0001 to 10.0% by weight.

The aqueous composition of the present invention can be produced by a known method. The semi-solid agent and the liquid agent can be prepared by mixing the base and each component. Furthermore, if necessary, a filter sterilization treatment step, a container filling step, and the like can be added. The ophthalmic composition of the present invention can also be produced by the above-mentioned known method, but more specifically, for example, in the case of eye drops, eye washes or contact lens agents, sorbic acid or a salt thereof, and a zinc salt. And other compounding ingredients are dissolved in purified water, adjusted to a predetermined osmotic pressure and pH, filtered and sterilized in a sterile environment, and aseptically filled in a container that has been washed and sterilized.

[0048]

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

Test Example 1 Antibacterial activity test (1) Reference information on the 14th revision Japanese Pharmacopoeia "Preservation efficacy test method"
For reference, the preservative efficacy of the aqueous compositions according to the examples and comparative examples of the present invention shown in Table 1 below was tested using Escherichia coli as a test bacterium.

[0050]

[Table 1]

(2) Results of antibacterial activity test Table 2 below shows the test results after 24 hours, 48 hours and 1 week in the case of pH 4.

[Table 2]

Table 3 below shows the test results after 24 hours, 48 hours, 1 week and 2 weeks in the case of pH 6.

[Table 3] The above-mentioned test results show that by adding a zinc salt to potassium sorbate, the viable cell count is reduced at both pH 4.0 and pH 6.0, and the aqueous composition of the present invention is It was confirmed to have enhanced antibacterial activity.

Example 4-35 Aqueous Ophthalmic Composition According to the formulations shown in Tables 4 to 9 below, each component was dissolved in sterilized purified water to adjust the osmotic pressure and pH, and the total amount was adjusted to 100 mL, followed by sterilization. The solution was filtered and filled in a container to prepare eye drops (agent), eye washes (agent), and contact lens solution.

[0054]

[Table 4]

[0055]

[Table 5]

[0056]

[Table 6]

[0057]

[Table 7]

[0058]

[Table 8]

[0059]

[Table 9]

Examples 36-38 Aqueous Compositions for Internal Use According to the formulations shown in Table 10 below, aqueous compositions for internal use of each Example were produced.

[0061]

[Table 10]

Examples 39-41 Aqueous hull composition for outer skin An aqueous hull composition for each example was prepared according to a conventional method according to the formulation shown in Table 11 below.

[0063]

[Table 11]

Examples 42-59 Ophthalmic Aqueous Composition According to the formulations shown in Tables 12 to 14 below, each formulation component was dissolved in sterilized purified water to adjust the osmotic pressure and pH, and the total amount was adjusted to 100 mL, followed by sterilization. The solution was filtered and filled in a container to prepare eye drops (agent), eye washes (agent), and contact lens solution (CL agent).

[0065]

[Table 12]

[0066]

[Table 13]

[0067]

[Table 14]

[0068]

INDUSTRIAL APPLICABILITY The aqueous composition of the present invention contains sorbic acid or a salt thereof and zinc sulfate or a zinc oxycarboxylic acid salt at the same time, and thus is significantly superior to the case where each of them is used alone. Shows antibacterial activity. Since sorbic acid is highly safe and can be safely used in a preparation for application to mucous membranes such as ocular mucous membranes, the aqueous composition of the present invention is not only an aqueous composition for integument or internal use, but also eye drops, eye wash, eye ointment. It is also extremely useful as a composition for application to mucous membranes such as medicines, contact lens mounting solutions, contact lens agents (cleansing solutions, preservatives, cleaning preservatives, disinfectants, etc.), nasal drops and nasal washes.

Claims (6)

[Claims] 1. An aqueous composition comprising sorbic acid or a salt thereof and a zinc salt. 2. Aqueous composition according to claim 1, characterized in that the zinc salt is selected from zinc oxycarboxylic acid salts and zinc sulphate. 3. The aqueous composition according to claim 1, further comprising a monoterpene. 4. The aqueous composition according to claim 1, which is a composition for mucosal application. 5. The aqueous composition according to any one of claims 1 to 4, which is an ophthalmic composition. 6. A method for enhancing the antibacterial activity of an aqueous composition by adding a zinc salt to the aqueous composition containing sorbic acid or a salt thereof.