JP2003128585A - Composition for external use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a safe and antiseptic composition for external use, to provide a method for enhancing an antiseptic effect of the composition containing sorbic acid and/or EDTA, and to provide a method for producing the composition. SOLUTION: This composition for external use, which has a highly antiseptic effect, is obtained by including (a) a xanthine, (b) a buffering agent, (c) sorbic acid or a salt thereof and/or EDTA or a salt thereof.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a composition having antiseptic ability. More specifically, the present invention relates to a composition having high safety and an excellent antiseptic effect. Furthermore, the present invention relates to a method for enhancing the antiseptic effect of sorbic acid, ethylenediaminetetraacetic acid, or salts thereof, which have been conventionally known to have antiseptic effects.

[0002]

BACKGROUND OF THE INVENTION Ophthalmic solutions and ophthalmic ointments are usually prepared as a sterile composition in the manufacturing process, but after opening, they can be opened and closed several times until they are used up for 1 to several months. Since it is used, it is exposed to the risk of contamination by microorganisms that are normally present in the environment or the human body.
In addition, compositions such as foods, cosmetics, or quasi-drugs,
It is not always manufactured completely as a sterile composition in the manufacturing process. Therefore, in preparation of the composition, it is necessary to treat or devise it so as to prevent microbial contamination after opening and enhance the preservation effect of the composition to prevent the growth of microorganisms in the composition.

Therefore, various preservatives are generally added to compositions such as foods, cosmetics, pharmaceuticals or quasi-drugs to maintain the preservation effect of the products.
For example, ophthalmic aqueous compositions such as eye drops and liquids for contact lenses include benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, p-aminobenzoic acid ester, polyalkylaminoethylglycine, sorbic acid. , Or these salts and the like, which are used alone or in combination of two or more as a preservative. Among these preservatives, especially sorbic acid or a salt thereof is higher in safety than cationic preservatives such as benzalkonium chloride, and since there are few problems such as adsorbability to contact lenses, it is a food product. It has been widely used as an antiseptic for contact lenses and contact lens agents, and in recent years, as an antiseptic agent for a wide range of product compositions such as cosmetics, quasi-drugs, and pharmaceuticals as well as such foods and contact lens agents. Is also frequently used.

However, it is needless to say that even with such a preservative which is said to be relatively safe, it is desirable to reduce the compounding amount as much as possible from the viewpoint of requiring higher safety.

Therefore, recently, as a unit dose (a sealed and aseptic preparation, which can be used once after opening), pharmaceuticals (eg eye drops) and cosmetics which do not contain a preservative have become known. However, unit doses are expensive to manufacture and cannot be provided to consumers at low cost.

On the other hand, sorbic acid or its salt is highly safe, but has a weaker preservation effect than other preservatives such as cationic surfactant type preservatives (benzalkonium chloride, benzethonium chloride) and the like. The current situation is that sufficient preservation is not obtained. Therefore, various studies have been made so far to enhance the preservation effect of sorbic acid and / or its salt. For example, Japanese Patent Application Laid-Open No. 11-292793 describes that the antiseptic activity of sorbic acid is enhanced by adding a flavoring agent and sodium edetate to sorbic acid. However, the antiseptic power is not yet sufficient.

[0007]

An object of the present invention is to provide a composition (external composition, antiseptic composition) having high safety and excellent antiseptic property. Another object of the present invention is to provide a preservative composition containing sorbic acid or ethylenediaminetetraacetic acid, a method for enhancing its antiseptic power, and a method for producing an antiseptic composition having an excellent antiseptic effect.

[0008]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies in order to achieve the above-mentioned objects, and found that sorbic acid, ethylenediaminetetraacetic acid or salts thereof having a conventionally known antiseptic activity, By adding a mixture of xanthines represented by caffeine and the like and a buffer, it was found that these antiseptic effects were further enhanced, and sorbic acid, ethylenediaminetetraacetic acid or their salts were added to the xanthines and the buffer. It was confirmed that the composition prepared by combining the above was useful as a preservative.
The present invention was developed based on such findings.

That is, the present invention is a composition for external use listed in the following (1) to (5): (1) a) The following formula (I):

[0010]

[Chemical 6]

(Wherein R ¹ , R ² and R ^{3, which} may be the same or different, each represents a hydrogen atom or an optionally substituted alkyl group) or a salt thereof, b ) A buffer, and c) sorbic acid or a salt thereof, and / or ethylenediaminetetraacetic acid or a salt thereof, for external use. (2) The external composition according to (1), wherein the buffer is a borate buffer or a phosphate buffer. (3) The compound (I) is at least one selected from the group consisting of caffeine, pentoxifylline, theophylline, diprophylline, theobromine and proxyphylline.
The external composition according to (1) or (2), which is one compound. (4) The composition for external use according to any one of (1) to (3), which is an aqueous composition. (5) The external composition according to any one of (1) to (4), which is applied to a mucous membrane.

Further, the present invention is an antiseptic composition listed in the following (6) to (7): (6) The following formula (I):

[0013]

[Chemical 7]

(Wherein R ¹ , R ² and R ³ are the same as above), or a salt thereof, a buffer, and sorbic acid or a salt thereof, and / or ethylenediaminetetraacetic acid or a salt thereof. An antiseptic composition containing salt. (7) The antiseptic composition according to (6), wherein the buffer is a phosphate buffer or a borate buffer.

The term "preservative composition" as used herein includes two meanings: a composition used for the purpose of antiseptic (use) such as an antiseptic, and a composition having antiseptic property and preservative effect. .

Further, the present invention is a method for enhancing the antiseptic activity of sorbic acid, ethylenediaminetetraacetic acid or salts thereof listed in (8) below: (8) a) The following formula (I):

[0017]

[Chemical 8]

(Wherein R ¹ , R ² and R ³ may be the same or different and each represents a hydrogen atom or an optionally substituted alkyl group) or a salt thereof, b) a buffer and c) sorbic acid or a salt thereof, and / or ethylenediaminetetraacetic acid or a salt thereof, which are used in combination to enhance the antiseptic activity of sorbic acid, ethylenediaminetetraacetic acid or a salt thereof Method.

Further, the present invention is a method for enhancing the antiseptic activity of a composition containing sorbic acid and the like listed in (9) below: (9) A buffer, sorbic acid or a salt thereof, and / or ethylenediamine tetra A composition containing acetic acid or a salt thereof has the following formula (I):

[0020]

[Chemical 9]

A method for enhancing the preservative power of the above composition, which comprises using a compound represented by the formula (wherein R ¹ , R ² and R ³ are the same as above) or a salt thereof in combination. .

From a different point of view, the method of enhancing the antiseptic property is as follows (10) Buffering agent, sorbic acid or salt thereof, and / or
Alternatively, in a composition containing ethylenediaminetetraacetic acid or a salt thereof, the following formula (I):

[0023]

[Chemical 10]

(In the formula, R ¹ , R ² and R ³ are the same as the above.) A method for producing an antiseptic composition, characterized in that the compound or a salt thereof is combined and prepared. be able to.

Furthermore, the present invention is a method for enhancing the preservative power of the composition listed in (11) below: (11) Sorbic acid or a salt thereof, and / or
A composition containing ethylenediaminetetraacetic acid or a salt thereof has the following formula (I):

[0026]

[Chemical 11]

The antiseptic activity of the above composition, characterized in that a compound represented by the formula (wherein R ¹ , R ² and R ³ are the same as above) or a salt thereof and a buffering agent are used in combination. How to enhance.

The method for enhancing the antiseptic property is, from another viewpoint, the following (12) sorbic acid or a salt thereof, and / or
A composition containing ethylenediaminetetraacetic acid or a salt thereof has the following formula (I):

[0029]

[Chemical 12]

Preparation of an antiseptic composition, which is prepared by combining a compound represented by the formula (wherein R ¹ , R ² and R ³ are the same as above) or a salt thereof and a buffering agent. Method: Can be paraphrased as:

In this specification, unless otherwise specified,% means W / V%. Further, in the present specification, the contact lens is soft, hard,
It is used to include all types of contact lenses, regardless of whether they are oxygen-permeable contact lenses or the like.

[0032]

BEST MODE FOR CARRYING OUT THE INVENTION (1) External composition The composition for external use of the present invention comprises a) the following formula (I):

[0033]

[Chemical 13]

A compound represented by: or a salt thereof, b) a buffer, and c) sorbic acid or a salt thereof, and / or
It contains ethylenediaminetetraacetic acid or a salt thereof. By combining these components in combination, it is possible to obtain a composition having a further enhanced antiseptic action.

In the compound represented by the formula (I) which is the component (a), R ¹ , R ² and R ³ are hydrogen atoms or optionally substituted alkyl groups, and these are the same groups as each other. Alternatively, they may be different groups.

The alkyl group represented by R ^{1 to} R ³ is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group or the like having 1 to 6 carbon atoms, preferably Is a lower alkyl group having 1 to 4 carbon atoms. Preferred alkyl groups include methyl and ethyl groups.

These alkyl groups may have a substituent, and examples of such a substituent include a halogen atom (eg, chlorine atom, bromine atom or fluorine atom); a hydroxyl group; an alkoxy group (eg, A lower alkoxy group having 1 to 4 carbon atoms such as a methoxy, ethoxy or butoxy group); an aryloxy group; a carboxyl group; an alkoxy-carbonyl group (for example, 1 to 4 carbon atoms)
An alkoxycarbonyl group having a lower alkoxy group), an aryloxycarbonyl group; an acyl group (eg, a carbonyl group having a lower alkyl group having 1 to 4 carbon atoms such as formyl, acetyl, and propionyl groups, an aryl group such as a benzoyl group) A carbonyl group having);
Examples thereof include nitro group; amino group; N-substituted amino group (for example, mono- or di-C _1-4 alkylamino group), cyano group and the like.

Specific compounds represented by the formula (I) include, for example, caffeine, theophylline, oxtriphylline, daphylline, diisobutylaminobenzoyloxypropyl theophylline, theobromine, diprophylline, proxyphylline, pentoxifylline and the like. The xanthine derivative can be mentioned. Preferred 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.

The compound (I) can be used in the form of a salt, preferably a pharmacologically (pharmaceutically) or physiologically acceptable salt. Here, as the pharmacologically or physiologically acceptable salt, for example, an organic acid salt (for example,
Lactate, acetate, butyric acid, trifluoroacetate, fumarate, maleate, tartrate, citrate, succinate, malonate, methanesulfonate, toluenesulfonate, tosylate, Palmitic acid, stearic acid, etc.), inorganic acid salts (eg, hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), salts with organic bases (eg, methylamine, triethylamine, triethanolamine) , Morpholine, piperazine, pyrrolidine, amino acids, salts with organic amines such as tripyridine and picoline), salts with inorganic bases (eg ammonium salts; alkali metals such as sodium or potassium; alkaline earth metals such as calcium or magnesium) A salt with a metal such as aluminum).

In the composition for external use of the present invention, one of these compounds (I) or salts thereof (hereinafter, these may be collectively referred to as "xanthines") may be used alone or optionally. It is also possible to use two or more kinds in combination. In addition, compound (I) can also be used in the form of a mixture with other compounds. Examples of such mixtures 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 aminophylline, which is a mixture of theophylline and ethylenediamine. Examples include bufilin, which is a mixture of theophylline and aminoisobutanol, calcium theobromine salicylate, which is a mixture of theobromine and salicylate, sodium theobromine sodium salicylate, and sodium theobromine acetate, which is a mixture of theobromine and sodium acetate.

The proportion of these xanthines contained in the composition for external use of the present invention varies depending on the kind of xanthines specifically used and cannot be unconditionally specified, but is usually
It can be appropriately selected and adjusted according to the type so as to be in the range of 0.0001 to 10%. Preferably 0.00
1 to 10%, more preferably 0.01 to 5%, further preferably 0.01 to 3%, particularly preferably 0.1 to 3%
Is the ratio.

Further, the buffering agent which is the component (b) can be used without particular limitation as long as it has a buffering action. Specific examples include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer and the like. Preferred are borate buffer, phosphate buffer, carbonate buffer and citrate buffer, more preferred are borate buffer and phosphate buffer, and particularly preferred is phosphate buffer.

As the borate buffer, borate, such as boric acid, boric acid alkali metal salt (sodium salt, potassium salt) or boric acid alkaline earth metal salt (calcium salt, magnesium salt), etc., Examples thereof include a combination of boric acid and salts of these boric acids. Specific examples of the salt of boric acid include sodium borate.

Examples of the phosphate buffer include phosphates such as phosphoric acid, alkali metal phosphates (sodium salt, potassium salt) or alkaline earth metal phosphates (calcium salt, magnesium salt), and hydrogen phosphate. Examples thereof include hydrogen phosphates such as alkali metal salts or alkaline earth metal salts, and combinations of phosphoric acid with these phosphates or hydrogen phosphates. As the hydrogen phosphate, specifically, sodium hydrogen phosphate, sodium dihydrogen phosphate,
Alternatively, potassium dihydrogen phosphate and the like can be exemplified.

Examples of the carbonic acid buffering agent include carbonates such as alkali metal carbonates (sodium salt, potassium salt) and alkaline earth metal carbonates (calcium salt, magnesium salt), alkali metal hydrogen carbonates or alkaline earth metals. Examples thereof include hydrogen carbonates such as salts, and combinations of carbonic acid with these carbonates or hydrogen carbonates. Specific examples of the hydrogen carbonate include sodium hydrogen carbonate and sodium carbonate.

Examples of the citric acid buffer include citric acid, citric acid alkali metal salts (sodium salt, potassium salt) and citric acid alkaline earth metal salts (calcium salt, magnesium salt), citric acid and the like. And the combination with citrate. Specific examples of the citrate salt include sodium citrate and potassium citrate.

In the above buffer, boric acid salt,
Acid salts such as phosphates, hydrogen phosphates, carbonates, hydrogen carbonates or citrates can also be used in the form of hydrates.

Even if one type of buffering agent is used alone,
It is also possible to use two or more kinds in any combination.

The mixing ratio of the buffering agent can be set and adjusted by using the ratio of the xanthines mixed in the above composition as a guide. For example, the amount of xanthines contained in the final composition is 0.1 to 500 parts by weight, preferably 0.1 to 500 parts by weight, based on 1 part by weight, as the total amount of the above acids such as boric acid and phosphoric acid or salts thereof. The range may be 1 to 100 parts by weight, more preferably 0.1 to 50 parts by weight.

The proportion of the buffering agent contained in the external composition of the present invention is usually 0.0001 to 10 as the concentration of the total amount of the above acids such as boric acid and phosphoric acid or salts thereof in the external composition. %, Preferably 0.001
It can be about 5%, more preferably about 0.01 to 3%.

The external composition of the present invention contains at least one of sorbic acid or a salt thereof and ethylenediaminetetraacetic acid or a salt thereof as the component c).

Sorbic acid may be used in the form of an acid or in the form of a salt, or a mixture of an acid and a salt may be used. Preferable examples of the sorbic acid salt used here include alkali metal salts such as potassium sorbate and sodium sorbate used as preservatives for ophthalmic compositions and the like.

Ethylenediaminetetraacetic acid (hereinafter simply referred to as "ED
(Also referred to as “TA”), like sorbic acid, may be used in the form of an acid, in the form of a salt, or in the form of a hydrate. It can also be used. Preferable examples of the salt of ethylenediaminetetraacetic acid used here include alkali metal salts such as sodium ethylenediaminetetraacetate, disodium ethylenediaminetetraacetic acid, and tetrasodium ethylenediaminetetraacetic acid. In the present invention, disodium ethylenediaminetetraacetic acid disodium (hereinafter, also referred to as “sodium edetate”) can be preferably used.

Sorbic acid or a salt thereof and ethylenediaminetetraacetic acid or a salt thereof can be used alone or in any combination. From the viewpoint of enhancing antiseptic power, it is preferable to use sorbic acid or a salt thereof in combination with ethylenediaminetetraacetic acid or a salt thereof.

When sorbic acid or a salt thereof is used, the proportion of sorbic acid or a salt thereof is 0.002 to 100 parts by weight, preferably 0.002 to 100 parts by weight, based on the weight of xanthines to be added to the composition for external use. Is 0.01
The proportion may be from 10 to 10 parts by weight, more preferably from 0.01 to 2 parts by weight, still more preferably from 0.02 to 2 parts by weight. The proportion of sorbic acid or a salt thereof to be blended in the composition for external use of the present invention is not particularly limited as long as the above ratio is satisfied, but depending on the use of the composition for external use, a drug, a pharmacy part It can be determined in consideration of laws and regulations in various fields related to external products or cosmetics. For example, when the external composition is used as a pharmaceutical composition, the concentration in the external composition is usually 0.00
About 005-10%, preferably 0.0001-10%
The range is about 0.005 to 5%, more preferably about 0.001 to 5%.

When EDTA or a salt thereof is used, the total amount of EDTA or a salt thereof is 0.001 part by weight with respect to 1 part by weight of xanthines to be added to the composition for external use.
1 to 1000 parts by weight, preferably 0.002 to 100 parts by weight, more preferably 0.002 to 10 parts by weight, and further preferably 0.004 to 1 part by weight. The ratio of EDTA or a salt thereof to be blended in the composition for external use of the present invention is not particularly limited as long as the above ratio is satisfied, but depending on the use of the composition for external use, pharmaceuticals, quasi drugs. It can be determined in consideration of customs in various fields such as cosmetics or cosmetics. For example, the concentration in the composition for external use is usually 0.001
To about 1.0%, preferably about 0.005 to 0.5%, more preferably about 0.01 to 0.3%, and further preferably about 0.01 to 0.2%. You can

When sorbic acid or a salt thereof and EDTA or a salt thereof are used in combination, there is no particular limitation, but the mixing ratio of the two is EDTA or a salt thereof per 1 part by weight of the total amount of sorbic acid or a salt thereof. The total amount of salt is 0.001 to 100 parts by weight, preferably 0.01.
It is preferable to employ a ratio such that it is ˜50 parts by weight, more preferably 0.1 to 5 parts by weight.

The composition for external use of the present invention is characterized by having excellent antiseptic property or storage effect by itself by containing the above components. Therefore, as long as the composition for external use of the present invention has this feature, its form and use are not particularly limited, and it is used for pharmaceuticals, quasi drugs, perfumes and cosmetics, or daily necessities (general goods). Can be used as various types of external compositions in various applications.

For example, the topical composition for external use of the present invention contains various active ingredients or medicinal ingredients (pharmacologically active ingredients or physiologically active ingredients) depending on various uses in addition to the above-mentioned ingredients as long as the effects of the present invention are not impaired. May be contained in combination. The type of such a component is not particularly limited, and examples thereof include a decongestant component (vasoconstrictor or sympathomimetic),
Anti-inflammatory drug component, antihistamine drug or antiallergic drug component, astringent drug component, antibacterial drug or bactericidal drug component, vitamins, amino acids, sugars, local anesthetic drug component, steroid component, α-adrenergic drug component, ocular muscle A regulator drug component, an antipyretic analgesic drug component, etc. can be illustrated. Although not limited, specific examples of such components include the following components.

Decongestant component (vasoconstrictor or sympathetic nerve
Drugs) : epinephrine, ephedrine, tetrahydrozoline, naphazoline, phenylephrine, methylephedrine or pharmacologically acceptable salts thereof.

Anti-inflammatory drug component : celecoxib
b), rofecoxib, indomethacin,
Diclofenac, pranoprofen, piroxicam, meloxicam, epsilon-aminocaproic acid, berberine, glycyrrhizic acid, lysozyme, methyl salicylate, allantoin, or a pharmacologically acceptable salt thereof (for example, berberine chloride, berberine sulfate, Diclofenac sodium, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, lysozyme chloride, etc.) etc.

Antihistamine or antiallergic ingredients :
Chlorpheniramine, diphenhydramine, iproheptin, ketotifen, emedastine, clemastine, azelastine, levocabastine, olopatadine, cromoglicic acid, tranilast, amlexanox, mequitadine, loratadine (loratadine), fexofenadine, etirizastine, frisefenadine, frisefenadine, frisefenadine, frisefenadine, frisefenadine. Pemirolast, or a pharmacologically acceptable salt thereof (for example, chlorpheniramine maleate, diphenhydramine hydrochloride, iproheptin hydrochloride, ketotifen fumarate, emedastine fumarate,
Clemastine fumarate, azelastine hydrochloride, levocabastine hydrochloride, olopatadine hydrochloride, sodium cromoglycate etc.) etc.

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

Antibacterial or bactericidal ingredient : sulfonamides [eg sulfamethoxazole, sulfisoxazole, sulfisomidine and their pharmacologically acceptable salts (sulfamethoxazole sodium, sulfone Isomidine sodium, etc.)], acrinol, a quaternary ammonium compound (eg, benzalkonium, benzethonium, cetylpyridinium) and a pharmacologically acceptable salt thereof (benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, odor) Cetylpyridinium chloride), alkylpolyaminoethylglycine, new quinolones (lomefloxacin, levofloxacin, ciprofloxacin, ofloxacin, norfloxacin,
Ciprofloxacin hydrochloride, etc.), biguanides (polyhexamethylene biguanide, chlorhexidine or salts thereof, etc.), berberine or its salts, polydronium chloride, Glokill (trade name, manufactured by Rhodia), polydiallyldimethylammonium chloride, poly [ Oxyethylene (dimethyliminio) ethylene- (dimethyliminio) ethylene dichloride], parabens (methylparaben, ethylparaben, or salts thereof, etc.) and the like.

[0065] Vitamins: vitamin A [e.g., retinal, retinol, retinoic acid, carotene, dehydroepiandrosterone retinal, lycopene and their pharmacologically acceptable salts (e.g., retinol acetate and retinol palmitate), etc.], Vitamin B [for example, thiamine, thiamine disulfide, dicetiamine, octothiamine, shicothiamine, bisbutyamine, bisbenchamine, prosultiamine, benfotiamine, fursultiamine, riboflavin, flavin adenine dinucleotide, pyridoxine, pyridoxal, hydroxo. Cobalamin, cyanocobalamin, methylcobalamin, deoxyadenocobalamin, folic acid, tetrahydrofolic acid, dihydrofolic acid, nicotinic acid, nicotinic acid amide, nicotinic alcohol, panto Phosphate, panthenol, biotin,
Choline, inositol and their pharmacologically acceptable salts thereof (for example, thiamine hydrochloride, thiamine nitrate, dicetiamine hydrochloride, fursultiamine hydrochloride, riboflavin butyrate, flavin adenine dinucleotide sodium, pyridoxine hydrochloride, pyridoxal phosphate, phosphorus Acid pyridoxal calcium, hydroxocobalamin hydrochloride, hydroxocobalamin acetate, calcium pantothenate, sodium pantothenate, etc.)], vitamin C
[Ascorbic acid and its derivatives, erythorbic acid and its derivatives and pharmacologically acceptable salts thereof (eg, sodium ascorbate, sodium erysorbate, etc.]], vitamin Ds [eg, ergocalciferol, cholesterol Calciferol, hydroxycholecalciferol, dihydroxycholecalciferol, dihydrotaxosterol and their pharmacologically acceptable salts, etc.], vitamin Es [eg tocopherol and its derivatives, ubiquinone derivatives and their pharmacology] Acceptable salts (tocopherol acetate, tocopherol nicotinate, tocopherol succinate, tocopherol calcium succinate, etc.), and other vitamins [eg, carnitine, ferulic acid, γ-oryzano] , Orotic acid, rutin, eriocitrin, (such as carnitine chloride) hesperidin and their pharmacologically acceptable salts, etc.] and the like.

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 pharmacologically acceptable salts thereof (for example, 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, nitrocellulose, etc.), high molecular sugars (eg chondroitin sulfate, hyaluronic acid) and their pharmacologically acceptable salts (eg sodium chondroitin sulfate, hyaluronic acid). Sodium)), sugar alcohols (eg, mannitol, xylitol, sorbitol, etc.) and the like.

Local anesthetic ingredients : lidocaine, oxyprocaine, dibucaine, procaine, ethyl aminobenzoate, meprilukaine, and salts thereof (lidocaine hydrochloride, oxybuprocaine hydrochloride, etc.) and the like.

Steroid components : hydrocortisone, prednisolone, and salts thereof.

Α-adrenergic agonist component : imidazoline derivative (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, epinephrine hydrochloride). , Ephedrine hydrochloride,
Inorganic acid salts such as methylephedrine hydrochloride; organic acid salts such as epinephrine hydrogen tartrate).

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

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

The proportions of these components that can be incorporated in the composition for external use can be selected depending on the use of the composition for external use, the type of active ingredient to be incorporated, and the like. I can not specify,
Specifically, it is usually 0.0001 with respect to the entire composition for external use.
Can be appropriately selected from the range of about -30%, preferably about 0.001-10%. More specifically, the following ratio can be preferably exemplified as the mixing ratio of each component that can be mixed in the aqueous composition for external use of the present invention.

Decongestant component (vasoconstrictor or sympathetic nerve
Stimulant) : 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-
10%, preferably 0.0001-5% antihistamine or antiallergic ingredient :
0.0001 to 10%, preferably 0.001 to 5% astringent component : eg 0.0001 to 10%, preferably 0.005 to 2.5% antibacterial or bactericidal component : eg 0.001 -10
%, Preferably 0.01 to 10% vitamins : for example 0.0001 to 1%, preferably 0.0001 to 0.5% amino acids : for example 0.0001 to 10%, preferably 0. 001-3% saccharides (monosaccharides, disaccharides, oligosaccharides, or sugar alcohols
Kind ) : For example, 0.0001 to 5%, preferably 0.0
01-5%, more preferably 0.01-2% high molecular saccharides or salts thereof : for example, 0.0001-2%,
Preferably 0.01 to 2%, more preferably 0.01
~ 1% cellulose or its derivatives or salts thereof :
0.001-5%, preferably 0.01-1% Local anesthetic component: for example 0.0001-2%, preferably 0.001-1% steroid component: for example 0.0001-10%, preferably Is 0.001 to 3% α adrenergic agonist component: for example, 0.0001 to 2
%, Preferably 0.001 to 1% Ophthalmic muscle modulator component : For example, 0.0001 to 0.5%, preferably 0.001 to 0.1% Polyvinylpyrrolidone, polyvinyl alcohol : For example, 0.001 to 10% %, Preferably 0.001-5
%, More preferably 0.01 to 3%.

The external composition of the present invention may further contain various components and additives in accordance with a conventional method, if necessary, and according to its use and form, as long as the effects of the present invention are not impaired. Can be selected and used in combination. For example, in the case of semi-solid preparations, bases depending on the type of formulation, for example, ointment bases (for example, petroleum jelly, liquid paraffin, hydrocarbon bases such as wax, cetanol, higher fatty acid ester, etc.), gel bases ( For example, carboxyvinyl polymer,
Polyoxyethylene polyoxypropylene block copolymers, gums, etc.), oily bases (vegetable oils such as olive oil, soybean oil, sesame oil, cottonseed oil, propylene glycol, etc.) can be used. In the case of liquid preparations, carriers (water or aqueous solvents), aqueous or oily bases, solubilizers, suspending agents, emulsifiers, isotonic agents, buffers, thickeners, pH adjusters, chelating agents or inorganic agents. Salts can be used. In addition, various additives such as an antioxidant, a sweetener, a sour agent, a coloring agent, a fragrance or a cooling agent can be added to these preparations. Among them, the solubilizing agent is a preferable blending component because it improves the dissolution stability of the xanthines to be blended in the composition for external use of the present invention and makes it a stable composition for external use. Examples of such a solubilizing agent include benzoic acid, citric acid, aminoisobutanol, taurine or salts thereof, various surfactants, and polyhydric alcohols such as propylene glycol.

The composition for external use of the present invention is not particularly limited by its form and physical properties, and can have any form of solid, semi-solid or liquid, and physical properties of oily and aqueous. Are preferably aqueous compositions having a semi-solid or liquid form.

That is, the external composition of the present invention includes, for example, pharmaceuticals, quasi drugs, cosmetics, and daily necessities (general goods).
And various forms of aqueous compositions in various fields of external application such as liquid, lotion, cream, ointment, gel, suspension, emulsion, emulsion, extract and aerosol.

Although sorbic acid or a salt thereof is conventionally used as a relatively safe preservative as compared with a cationic preservative such as benzalkonium chloride, it has a problem that it is irritating. The present invention includes an external composition containing sorbic acid or a salt thereof, and the external composition further contains xanthines, thereby alleviating the irritation of sorbic acid or a salt thereof. Therefore, the external composition of the present invention is a skin composition, particularly a composition applied to the lips or mucous membranes (eye mucosa such as cornea and conjunctiva, oral mucosa, nasal mucosa, pharyngeal mucosa, etc.) where irritation may be a problem. Can be suitably used as. Here, the mucosal composition is applied directly to the mucous membrane, for example, an ophthalmic composition (including eye drops (including eye drops that can be used during contact lens (CL) wearing), contact lens mounting liquid, eye wash. Drugs (including CL eyewashes that can be used even when wearing contact lenses (CL)), otolaryngological compositions (nasal drops, ear drops, nasal washes, etc.), oral compositions (oropharyngeal drugs, gargles) In addition to drugs, etc., it is not a direct administration form to the mucous membrane, but may be administered or contact with the mucous membrane depending on the usage form, for example, contact lens agents (cleansing solution, preservative solution, sterilizing solution, multipurpose solution, etc.) ), Or cosmetics (eyeliner, lip balm, etc.) and the like.

Examples of typical components that can be incorporated into such an aqueous composition for external use for mucosal application 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, nitrocellulose), polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone, macrogol, polyvinyl methacrylate, polyacrylic acid, carboxyvinyl polymer,
Polyethyleneimine, ribonucleic acid, deoxyribonucleic acid and the like, and pharmacologically acceptable salts thereof.

Surfactant : For example, polyoxyethylene (POE) -polyoxypropylene (POP) block copolymer (for example, poloxamer 407, poloxamer)
235, Poloxamer 188, etc.), POE monolaurate
P such as (20) sorbitan (polysorbate 20) and POE monooleate (20) sorbitan (polysorbate 80)
OE 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) P
OP (4) POE / POP alkyl ethers such as cetyl ether, non-ionic surfactants such as POE alkylphenyl ethers such as POE (10) nonylphenyl ether; glycine type such as alkyldiaminoethylglycine, lauryldimethylamino Amphoteric surfactants such as betaine acetate type such as betaine acetate and imidazoline type;
POE (10) P such as sodium lauryl ether phosphate
OE alkyl ether phosphate and its salts, N-acyl amino acid salts such as sodium lauroylmethylalanine,
Alkyl ether carboxylates, N-acyl taurine salts such as sodium N-cocoylmethyl taurine, sulfonates such as sodium tetradecene sulfonate, alkyl sulfates such as sodium lauryl sulfate, POE (3)
POE alkyl ether sulfate such as sodium lauryl ether sulfate, anionic surfactant such as α-olefin sulfonate; alkylamine salt, alkyl quaternary ammonium salt (benzalkonium chloride, benzethonium chloride, etc.), alkylpyridinium salt ( Cationic surface active agents such as cetylpyridinium chloride and cetylpyridinium bromide) (the numbers in parentheses indicate the number of moles added).

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,
Isopropylmethylphenol, thymol, hinokitiol, sulfamine, lysozyme, lactoferrin, triclosan, 8-hydroxyquinoline, undecylenic acid, caprylic acid, propionic acid, benzoic acid, propionic acid, sorbic acid, triclocarban sorbate, halocarban, thiabendazole, polymyxin B, 5-chloro-2-methyl-4-isothiazolin-3-one, 2-
Methyl-4-isothiazolin-3-one, polylysine,
Hydrogen peroxide, polydronium chloride, Glokill (trade name,
Manufactured by Rhodia, such as Glokill PQ), polydiallyldimethylammonium chloride, poly [oxyethylene (dimethyliminio) ethylene- (dimethyliminio) ethyne dichloride] and the like, and pharmacologically acceptable salts thereof.

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

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

Chelating agents : for example, edetic acid (ethylenediaminetetraacetic acid, EDTA), ethylenediaminediacetic acid (EDDA), diethylenetriaminepentaacetic acid (DTP)
A), N- (2-hydroxyethyl) ethylenediamine triacetic acid (HEDTA), N- (2-hydroxyethyl)
Iminodiacetic acid (HIDA), citric acid, tartaric acid, phosphoric acids (polyphosphoric acid, hexametaphosphoric acid, metaphosphoric acid), succinic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1-diphosphonic acid and the like.

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 composition for external use of the present invention may be adjusted so as to have a pH and / or an osmotic pressure within a range that is acceptable to the living body, if necessary, and depending on its form, use and administration method. it can.

In the case of a composition for skin, the pH is usually pH.
From the viewpoint of the range of 2 to 10, the low irritation to the skin, and the good feeling of use on the skin, the pH is preferably in the range of 3 to 9, and more preferably in the weakly acidic to neutral range of pH 5 to 8. In the case of a composition for application to mucous membranes such as eye drops and eye washes, it is usually pH 4 to
9, preferably pH 5 to 8.5, particularly preferably pH
The area is 5.5 to 8.5.

The osmotic pressure is 100 to 1200 mOsm, preferably 100 to 600 mOsm, and particularly preferably 150 to 40 in the case of a composition for application to mucous membranes such as eye drops and eye washes.
It is about 0 mOsm, and the osmotic pressure ratio to the physiological saline is in the range of 0.3 to 4.1, preferably 0.3 to 2.
1, particularly preferably about 0.5 to 1.4. The pH and osmotic pressure can be adjusted by using a buffering agent, a pH adjusting agent, a tonicity adjusting agent, salts and the like.

The composition for external use of the present invention can be prepared in a desired form according to a conventional method by appropriately mixing the above-mentioned essential components and, if necessary, the above-mentioned optional components. For example, a semi-solid preparation or a liquid preparation can be prepared by mixing a base material and each component, adjusting the osmotic pressure and pH to a predetermined value, if necessary, and filling the container.

(2) Antiseptic composition The present invention also provides an antiseptic composition. The term "antiseptic composition" as used herein means imparting an antiseptic effect to other compositions by itself having a strong antiseptic effect (antibacterial effect).
What is used as a so-called preservative (preservative composition) (hereinafter referred to as "preservative composition"), and by being preserved by itself having desired bacteriostatic property (preservation effect, preservative) The composition (hereinafter, referred to as "preservative composition") used as an active composition (preservative composition, storage-stable composition) is included.

The antiseptic composition of the present invention comprises: a) compound (I) or a salt thereof (hereinafter referred to as "xanthines"), b) a buffer, and c) sorbic acid or a salt thereof, and / or ethylenediamine. It contains tetraacetic acid or a salt thereof. By containing these components in combination, the composition can have more excellent antiseptic properties. Here, as the xanthines, buffer, sorbic acid or salt thereof, and ethylenediaminetetraacetic acid or salt thereof, those mentioned above can be used.

In the case of the antiseptic composition, the proportion of the xanthines as component a) is usually in the range of 0.0001 to 10%, preferably about 0.001 to 10%, more preferably 0.01 to 5%. %, More preferably 0.01 to
The range of about 3%, particularly preferably about 0.1 to 3% is usually 0.0 as the blending ratio of the buffering agent which is the component (b).
001 to 10% by weight, preferably 0.001 to 5% by weight, more preferably 0.01 to 3% by weight; when sorbic acid or a salt thereof is used as the component c), its blending ratio As a ratio, the total amount of sorbic acid or a salt thereof is usually about 0.00005 to 10%, preferably about 0.00001 to 10%, more preferably about 0.0005 to 10%, and further preferably 0.00.
When EDTA or its salt is used as the component c), the total amount of EDTA or its salt is about 0.001 to 1%, preferably 0.005 to 0%. About 0.5%, more preferably 0.01 to
A range of about 0.3%, more preferably about 0.01 to 0.1% can be mentioned.

On the other hand, in the case of the antiseptic composition, the proportion of the xanthines as the component a) is usually 0.01-9.
A range of about 9.9%, preferably about 0.1 to 70%, more preferably about 1 to 50%; Preferably about 0.1 to 50%, more preferably 0.1 to 1
When the sorbic acid or its salt is used as the component c), the total amount of sorbic acid or its salt is about 0.001 to 90%,
It is preferably about 0.01 to 50%, more preferably 0.
When the amount of EDTA or its salt is used as the component c), the total amount of EDTA or its salt is about 0.1 to 90%, preferably 0.1 to 50%. %, And more preferably about 0.1 to 25%.

Further, in each of these compositions, 0.1 to 500 parts by weight, preferably 0.1 to 10 parts by weight of a buffering agent is used with respect to 1 part by weight of the xanthines contained in the final composition.
It may be contained in an amount of 0 parts by weight, more preferably 0.1 to 50 parts by weight. When sorbic acid or its salt is contained, the total amount of the sorbic acid or its salt is 1
Xanthines are 0.01 to 500 parts by weight, preferably 0.1 to 100 parts by weight, more preferably 0.5 to 100 parts by weight, and still more preferably 0.5 to 50 parts by weight.
If EDTA or a salt thereof is further contained, 0.001 to 1000 parts by weight of xanthines are added to 1 part by weight of the total amount of EDTA or a salt thereof, so that the ratio of the parts is by weight.
It can be appropriately adjusted so as to be contained in a proportion of preferably 0.01 to 500 parts by weight, more preferably 0.1 to 500 parts by weight, and further preferably 1 to 250 parts by weight.

When sorbic acid or a salt thereof is used in combination with EDTA or a salt thereof, there is no particular limitation, but the mixing ratio of the two is EDTA or a salt thereof per 1 part by weight of the total amount of sorbic acid or a salt thereof. The total amount of salt is 0.001 to 100 parts by weight, preferably 0.01.
It is preferable to employ a ratio such that it is ˜50 parts by weight, more preferably 0.1 to 5 parts by weight.

In the case of an antiseptic composition, from the viewpoint of safety, it is generally toxic to tissues and cells such as quaternary ammonium salts such as benzalkonium chloride and benzethonium chloride and biguanide compounds such as chlorhexidine. It is preferable not to include a large amount of antiseptic components having a high content. Although the composition of the present invention is not particularly limited to contain such an antiseptic component, it is a composition that is safe and has a desired storage stability in that the composition has a desired storage effect even without containing it. is there. Further, with respect to sorbic acid or a salt thereof, which has a problem of irritation when used alone, the irritation is alleviated by the combined use of xanthines in the antiseptic composition of the present invention. Therefore, the antiseptic composition of the present invention, by utilizing such safe and excellent antiseptic property, not only the external composition described above, but also as a composition for internal use of medicines and quasi drugs, and as a food composition. It can be applied.

The antiseptic composition of the present invention is added as a safe and excellent antiseptic to the above-mentioned external composition, internal medicine composition for pharmaceuticals and quasi drugs, cosmetics and food composition. Can be used. As the usage rate in this case, when the application target is a composition for external use, xanthines are 0.01 to 3% in the composition for external application, and the application target is a composition for internal use such as pharmaceuticals and foods. In the case of, the xanthines are 0.01 to 5% in the composition for oral administration,
The included range can be appropriately selected.

(3) Method for enhancing antiseptic power In the present invention, at least one of a) xanthines, b) buffer, and c) sorbic acid or its salt, or EDTA or its salt is used in combination. Provide a method for further enhancing the antiseptic properties of sorbic acid, EDTA or salts thereof. Here, as the xanthines, buffer, sorbic acid or salt thereof, and ethylenediaminetetraacetic acid or salt thereof, those mentioned above can be used. In the present invention, the method of using the components a), b) and c) in combination is not particularly limited as long as these components are used so as to coexist. Also, the proportions of these components used can be in accordance with the description in the external composition described above.

Further, as one embodiment of a method for enhancing the antiseptic activity of such sorbic acid, EDTA or a salt thereof (hereinafter, also referred to as sorbic acid etc.), sorbin of the following (3-1) and (3-2) A method for enhancing the antiseptic activity of a composition containing an acid or the like. (3-1) In the present invention, at least one of sorbic acid or a salt thereof, or EDTA or a salt thereof is used as a component.
It is a method of enhancing the preservative power of a composition containing one.

The method comprises sorbic acid or a salt thereof,
Alternatively, it can be achieved by using a composition containing at least one of EDTA or a salt thereof and the above-mentioned xanthines and a buffer in combination.

The proportion of sorbic acid or its salt contained in the composition is usually in the range of 0.00005 to 10%, preferably 0.0001 to 10%, more preferably 0.0005 to 5%, and further Preferably 0.001
Can be up to 5%. Also included in the composition
The ratio of EDTA or its salt is usually 0.001 to
The range is 1.0%, preferably 0.005 to 0.5%, more preferably 0.01 to 0.3%, and further preferably 0.01 to 0.2%.

When the composition contains sorbic acid or a salt thereof, the ratio of xanthines to the composition is 0. 01 to 500 parts by weight, preferably 0.1 to 100 parts by weight, more preferably 0.5 to 100 parts by weight, still more preferably 0.5 to 5 parts by weight.
0 parts by weight; EDTA when EDTA or its salt is included
Alternatively, 0.001 to 1000 parts by weight of xanthines, preferably 0.01 to 5 parts, relative to 1 part by weight of the total amount of salts thereof.
The amount can be appropriately adjusted with a ratio of 00 parts by weight, more preferably 0.1 to 500 parts by weight, still more preferably 1 to 250 parts by weight as a guide. The ratio of the buffer can be set and adjusted by using the ratio of xanthines contained in the composition as a guide. For example, the amount of xanthines contained in the final composition is 0.1 part by weight to 50 parts by weight of the buffering agent.
It can be appropriately set within the range of 0 parts by weight, preferably 0.1 to 100 parts by weight, and more preferably 0.1 to 50 parts by weight.

When sorbic acid or a salt thereof and EDTA or a salt thereof are both mixed, there is no particular limitation, but the mixing ratio of both in the final composition is EDTA with respect to 1 part by weight of sorbic acid. Is 0.001 to 100 parts by weight, preferably 0.01 to 50 parts by weight, and more preferably 0.1 to 5 parts by weight.

The method of increasing the antiseptic power is to use the composition containing at least one of sorbic acid or a salt thereof or EDTA or a salt thereof as a component from another angle. It can also be defined as a method of producing a composition having enhanced γ. In particular,
Such a manufacturing method comprises sorbic acid or a salt thereof, or
It is a method for producing a composition having an enhanced antiseptic activity by combining a composition containing at least one of EDTA or a salt thereof as a component with a xanthine compound and a buffer.

(3-2) Furthermore, in the present invention, in addition to the buffer, sorbic acid or a salt thereof, or EDTA is used as a component.
Alternatively, it is a method of imparting antiseptic power to a composition containing at least one of its salts or enhancing the antiseptic power of the composition.

The method comprises sorbic acid or a salt thereof,
Alternatively, it can be achieved by using a composition containing at least one of EDTA or a salt thereof and a buffer in combination with the above-mentioned xanthines.

The proportion of the buffering agent contained in the composition is usually about 0.0001 to 10%, preferably 0.0
The amount can be about 01 to 5%, more preferably 0.01 to 3%. The proportion of sorbic acid or its salt contained in the composition is usually 0.00005-
The range is 10%, preferably 0.0001 to 10%, more preferably 0.0005 to 5%, and further preferably 0.001 to 5%. The ratio of EDTA or its salt contained in the composition is usually in the range of 0.001 to 1.0%, preferably 0.005.
0.5%, more preferably 0.01 to 0.3%, still more preferably 0.01 to 0.2% can be mentioned.

The ratio of xanthines to be used in the composition is such that xanthines are 0.1 parts by weight based on 1 part by weight of the total amount of sorbic acid or a salt thereof contained in the composition.
01 to 500 parts by weight, preferably 0.1 to 100 parts by weight, more preferably 0.5 to 100 parts by weight, still more preferably 0.5 to 50 parts by weight; and also contained in the above composition. Xanthines are 0.001 to 1000 parts by weight, preferably 0.01 to 500 parts by weight, and more preferably 0.1 to 50 parts by weight with respect to 1 part by weight of EDTA or a salt thereof.
The proportion may be 0 parts by weight, more preferably 1 to 250 parts by weight. The mixing ratio of the xanthines to the buffer is, for example, xanthines of 0.1 part by weight per 100 parts by weight of the buffer in the composition.
2 to 1000 parts by weight, preferably 1 to 1000 parts by weight,
More preferably, it is possible to exemplify the range such that the ratio is 2 to 1000 parts by weight.

When both sorbic acid or its salt and EDTA or its salt are used in the composition, there is no particular limitation, but the mixing ratio of both is 1 part by weight of the total amount of sorbic acid or its salt. The total amount of EDTA or a salt thereof is 0.001 to 100 parts by weight, preferably 0.01 to 50 parts by weight, more preferably 0.1 to 5 parts by weight.
The proportion is preferably such that it is part by weight.

The method for enhancing antisepticity is to use a composition containing, as a raw material, at least one of sorbic acid or a salt thereof, or EDTA or a salt thereof, and a buffering agent from different angles. , A method for producing a composition having enhanced antiseptic activity. Specifically, such a production method comprises at least one of sorbic acid or a salt thereof, or EDTA or a salt thereof.
And a xanthine compound in combination with a composition containing a salt and a buffering agent as components, to produce a composition having an enhanced antiseptic activity.

With regard to these methods, the xanthines, the salts of sorbic acid and EDTA, the types of buffering agents, etc. used can be selected according to the above description regarding the external composition of the present invention.

[0114]

The external composition of the present invention comprises xanthines,
Buffering agent, sorbic acid or salt thereof, and / or ED
By containing TA or a salt thereof in combination,
It has the effect of exhibiting safe and excellent antiseptic properties. Therefore, the composition for external use of the present invention is useful as a product for external use, which is safe and has excellent storage stability in various fields such as pharmaceuticals, quasi drugs, and cosmetics.

When the composition for external use of the present invention contains sorbic acid or a salt thereof, the irritation of sorbic acid or a salt contained in the composition is alleviated by the combined use with xanthines. Has the effect of Therefore, the externally applied composition of the present invention has no irritation even when applied to the outer skin, particularly mucous membranes and is excellent in safety, and therefore, eye drops (including eye drops that can be used even during CL wearing) and contact lens wearing. Liquid, eye wash (C that can be used even while wearing CL
L including eye wash) or contact lens agent (cleansing solution, preservative solution, sterilizing solution, multi-purpose solution)
And the like; ophthalmic compositions such as ear drops and nasal washes; oral compositions such as oropharyngeal agents and gargles.

Furthermore, the antiseptic composition of the present invention has excellent antiseptic properties by containing sorbic acid or a salt thereof and / or EDTA or a salt thereof in combination with xanthines and a buffer. The antiseptic composition can be appropriately adjusted in antiseptic power depending on the concentration of each component, and depending on the antiseptic power, as an antiseptic used in various fields such as pharmaceuticals, quasi drugs, cosmetics and foods, As such, it can be used as a preservative composition.

Further, according to the method for enhancing antiseptic ability of the present invention, it is possible to enhance the antiseptic ability of sorbic acid and EDTA which are conventionally known to have antiseptic ability. As a result, the amount of sorbic acid or EDTA used can be reduced, and the preservation effect can be imparted to medicines, quasi drugs, cosmetics, foods, etc. with higher safety.

[0118]

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

Test Example 1 Preservation efficacy test (preservation test) Each test solution having the composition described in Tables 1 and 2 was prepared,
A preservative efficacy test (antiseptic test) was performed on these test solutions according to the method specified in the Japanese Pharmacopoeia (14th revision), and the antiseptic effect of each test solution was comparatively examined.

Specifically,Pseudomonas aeruginosa ATC
C 9027 strain is inoculated on the surface of agar plate medium and cultured
did. Soybean / Casein /
Digest agar medium is used and 3
2 ° C. and 24 hours were adopted. Aseptic culture cells with platinum loops
Sample, suspend it in sterile physiological saline, and ⁸
A suspension containing viable bacteria in the amount of 1 / ml was prepared. This suspension
It was used as an inoculum and used to inoculate a liquid medium. Culture this
After that, centrifuge to remove the medium and sterilize the resulting cells.
Each test of the composition described in Tables 1 to 3 after washing with saline
1.6x10 with liquid ⁶It was prepared so that the number of cells / mL could be obtained.

The test solution containing cells was stored at 25 ° C. for 48 hours, and the number of viable cells per mL was measured to calculate the log reduction of the number of cells before and after storage. The preservation effect of the test solution was confirmed.

The results are shown together in Tables 1 and 2.

(1) Mixture of xanthines, buffer and EDTA

[0124]

[Table 1]

From the above results, it was found that the preservative effect of the composition was further enhanced by using caffeine and a buffer together with EDTA.

(2) Mixture of xanthines and buffer, sorbic acid and / or EDTA

[0127]

[Table 2]

From the above results, the antiseptic effect of the composition is further enhanced by the combined use of caffeine, the buffer, and sorbic acid, and the antiseptic effect is further enhanced by the combined use of EDTA. It turned out to be.

Example 7 Preservative composition Sodium benzoate Caffeine 5.0 g Sodium edetate 0.5 g Potassium sorbate 3.0 g Sodium dihydrogen phosphate 2.0 g Sodium hydrogen phosphate 12.0 g Purified water Suitable amount Total amount 100 ml.

Example 8 Preservative Composition Sodium Benzoate Caffeine 1.0 g Caffeine 0.5 g Sodium edetate 0.05 g Potassium sorbate 0.05 g Sodium dihydrogen phosphate 0.10 g Sodium hydrogen phosphate 0.60 g Purified water Suitable amount Total 100 ml.

Examples 9 to 55 According to the formulations shown in Tables 3 to 10, the mixture was prepared by a conventional method, filtered and sterilized, and then aseptically filled in a container to produce eye drops, eye washes and contact lens preparations. did.

[0132]

[Table 3]

[0133]

[Table 4]

[0134]

[Table 5]

[0135]

[Table 6]

[0136]

[Table 7]

[0137]

[Table 8]

[0138]

[Table 9]

[0139]

[Table 10]

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 47/18 A61K 47/18 (72) Inventor Yasuko Mori 1-8-1, Tatsunishi, Ikuno-ku, Osaka-shi, Osaka No. Rohto Pharmaceutical Co., Ltd. (72) Inventor Yuka Kiyobayashi 1-8-1, Tatsunishi, Ikuno-ku, Osaka, Japan Rohto Pharmaceutical Co., Ltd. (72) Inventor Tetsuo Koike 1-8, Tatsunishi, Ikuno-ku, Osaka-shi, Osaka No. 1 F-term in Rohto Pharmaceutical Co., Ltd. (reference) 4C076 AA12 BB21 DD22 DD26 DD41 DD41R DD49 DD49R DD60 DD60R FF39 4H011 AA02 AA03 BA01 BB09 BC06 BC18 DA13 DD01

Claims (10)

[Claims] 1. a) The following formula (I): (Wherein R ¹ , R ² and R ^{3, which} may be the same or different, each represents a hydrogen atom or an optionally substituted alkyl group) or a salt thereof, b) a buffering agent And c) an external composition containing sorbic acid or a salt thereof and / or ethylenediaminetetraacetic acid or a salt thereof. 2. The composition for external use according to claim 1, wherein the buffer is a borate buffer or a phosphate buffer. 3. The composition for external use according to claim 1 or 2, wherein the compound (I) is at least one compound selected from the group consisting of caffeine, pentoxifylline, theophylline, diprophylline, theobromine and proxyfilin. 4. The composition for external use according to claim 1, which is an aqueous composition. 5. The composition for external use according to any one of claims 1 to 4, which is applied to a mucous membrane. 6. A) the following formula (I): (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) or a salt thereof, b) a buffer And c) an antiseptic composition containing sorbic acid or a salt thereof, and / or ethylenediaminetetraacetic acid or a salt thereof. 7. The antiseptic composition according to claim 6, wherein the buffer is a phosphate buffer or a borate buffer. 8. The following formula (I): (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) or a salt thereof, b) a buffer And c) Sorbic acid or a salt thereof, and / or ethylenediaminetetraacetic acid or a salt thereof are used in combination, and a method for enhancing the antiseptic activity of sorbic acid, ethylenediaminetetraacetic acid or a salt thereof. 9. A composition containing a buffering agent, sorbic acid or a salt thereof, and / or ethylenediaminetetraacetic acid or a salt thereof, and a compound represented by the following formula (I): (Wherein R ¹ , R ² and R ³ may be the same or different and each represents a hydrogen atom or an optionally substituted alkyl group) or a salt thereof is used in combination. A method for enhancing the antiseptic activity of the above composition, which comprises: 10. A buffer, sorbic acid or a salt thereof,
And / or a composition containing ethylenediaminetetraacetic acid or a salt thereof and the following formula (I): (Wherein R ¹ , R ² and R ³ may be the same or different and each represents a hydrogen atom or an alkyl group which may be substituted) or a salt thereof is prepared. A method for producing an antiseptic composition, comprising: