JP2016027033A - Composition for external application, ophthalmic composition, antibacterial agent, and antibacterial method - Google Patents

Abstract

（式中、Ｒは、水素原子又は―Ｃ（Ｏ）Ｒ^１で表される基である。Ｒ^１は、炭素数９〜１９の、飽和脂肪族基又は1個の不飽和結合を有する脂肪族基である。ｍは、０又は１である。）で表される化合物又はその薬学的に許容される塩を含む、抗菌用の外用組成物。
【選択図】なしThe present invention provides a composition for external use having sufficient antibacterial properties and low irritation, an antibacterial agent used therefor, an antibacterial method using such a new type of antibacterial component, and the like. Objective.
(A) The following formula (1);

(In the formula, R is a hydrogen atom or a group represented by —C (O) R ^1. R ¹ is a saturated aliphatic group having 9 to 19 carbon atoms or a fatty acid having one unsaturated bond. And m is 0 or 1.) An antibacterial composition for external use comprising a compound represented by the formula: or a pharmaceutically acceptable salt thereof.
[Selection figure] None

Description

  The present invention relates to an external composition, an ophthalmic composition, an antibacterial agent, and an antibacterial method.

  In cosmetics, pharmaceuticals, etc., antibacterial agents and preservatives are widely used to prevent product contamination and alteration caused by microorganisms and to ensure the storage stability of products (patent documents) 1). Similarly, antibacterial agents and antiseptics are also used in cosmetics and pharmaceuticals having antibacterial effects such as anti-acne and antifungal. For example, in the field of cosmetics, benzoic acid, salicylic acid, sorbic acid, dehydroacetic acid, and salts thereof, paraoxybenzoic acid esters, parachlorometacresol, etc., and in the pharmaceutical field, benzoic acid, sodium benzoate, chloride Benzalkonium, benzethonium chloride, cresol, chlorobutanol, thymol and the like are used as antibacterial agents and preservatives. However, many of these substances are generally highly irritating and some are toxic. There are also allergens that cause allergies to the skin or the whole body.

  Therefore, attempts have been made to prepare cosmetics, pharmaceuticals and the like having sufficient antibacterial activity without blending such conventional antibacterial agents and preservatives. For example, a method of blending alcohol, a method of blending phenoxyethanol, a method using an antibacterial polyol, a method using components and extracts derived from antibacterial animals and plants, and the like are known. However, with these methods, sufficient antibacterial activity cannot be obtained, and at room temperature, it may rot during use or mold may grow.

  Patent Document 2 describes a gelling agent composed of a specific lipid peptide, but there is no specific description of a composition for external use using this gelling agent. There is no description or suggestion that the peptide has an antibacterial effect.

JP 2005-170854 A International Publication No. 2010/013555

  Under such circumstances, the present invention provides a composition for external use having sufficient antibacterial and hypoallergenic properties, an antibacterial agent used therefor, an antibacterial method using such a new type of antibacterial component, It is an object of the present invention to provide an ophthalmic composition comprising such a new type of ingredient.

（式中、Ｒは、水素原子又は―Ｃ（Ｏ）Ｒ^１で表される基である。Ｒ^１は、炭素数９〜１９の、飽和脂肪族基又は1個の不飽和結合を有する脂肪族基である。ｍは、０又は１である。）で表される化合物又はその薬学的に許容される塩（以下、「（Ａ）成分」ともいう）を含む、抗菌用の外用組成物。
＜２＞アクネ菌に対する抗菌用である、＜１＞記載の外用組成物。
＜３＞真菌に対する抗菌用である、＜１＞記載の外用組成物。
＜４＞体臭の原因菌に対する抗菌用である、＜１＞記載の外用組成物。
＜５＞口腔内の抗菌用又は殺菌用である、＜１＞記載の外用組成物。
＜６＞う歯及び歯周病からなる群より選択される少なくとも１種を抑制、改善又は予防するための、＜５＞記載の外用組成物。
＜７＞アトピー性皮膚炎を抑制、改善又は予防するための、＜１＞記載の外用組成物。
＜８＞眼科用である、＜１＞記載の外用組成物。
＜９＞（Ａ）成分以外の抗菌成分をさらに含む、＜１＞〜＜８＞のいずれか記載の外用組成物。
＜１０＞（Ａ）下記式（１）

（式中、Ｒは、水素原子又は―Ｃ（Ｏ）Ｒ^１で表される基である。Ｒ^１は、炭素数９〜１９の、飽和脂肪族基又は1個の不飽和結合を有する脂肪族基である。ｍは、０又は１である。）で表される化合物又はその薬学的に許容される塩を含む、抗菌剤。
＜１１＞（Ａ）下記式（１）

（式中、Ｒは、水素原子又は―Ｃ（Ｏ）Ｒ^１で表される基である。Ｒ^１は、炭素数９〜１９の、飽和脂肪族基又は1個の不飽和結合を有する脂肪族基である。ｍは、０又は１である。）で表される化合物又はその薬学的に許容される塩を抗菌成分として用いることを特徴とする、抗菌方法。
＜１２＞（Ａ）下記式（１）

（式中、Ｒは、水素原子又は―Ｃ（Ｏ）Ｒ^１で表される基である。Ｒ^１は、炭素数９〜１９の、飽和脂肪族基又は1個の不飽和結合を有する脂肪族基である。ｍは、０又は１である。）で表される化合物又はその薬学的に許容される塩を含む、眼科用組成物。 The invention for solving the above-mentioned problem, that is, the gist of the present invention is as follows.
<1> (A) The following formula (1)

(In the formula, R is a hydrogen atom or a group represented by —C (O) R ^1. R ¹ is a saturated aliphatic group having 9 to 19 carbon atoms or a fatty acid having one unsaturated bond. M is 0 or 1) or a pharmaceutically acceptable salt thereof (hereinafter also referred to as “component (A)”). .
<2> The composition for external use according to <1>, which is for antibacterial against acne bacteria.
<3> The composition for external use according to <1>, which is for antibacterial activity against fungi.
<4> The composition for external use according to <1>, wherein the composition is for antibacterial against causative bacteria of body odor.
<5> The composition for external use according to <1>, which is used for antibacterial or sterilization in the oral cavity.
<6> The composition for external use according to <5>, for suppressing, improving or preventing at least one selected from the group consisting of caries and periodontal disease.
<7> The composition for external use according to <1>, for suppressing, improving or preventing atopic dermatitis.
<8> The composition for external use according to <1>, which is for ophthalmology.
<9> The composition for external use according to any one of <1> to <8>, further comprising an antibacterial component other than the component (A).
<10> (A) Formula (1) below

(In the formula, R is a hydrogen atom or a group represented by —C (O) R ^1. R ¹ is a saturated aliphatic group having 9 to 19 carbon atoms or a fatty acid having one unsaturated bond. M is 0 or 1), or an antibacterial agent comprising a pharmaceutically acceptable salt thereof.
<11> (A) The following formula (1)

(In the formula, R is a hydrogen atom or a group represented by —C (O) R ^1. R ¹ is a saturated aliphatic group having 9 to 19 carbon atoms or a fatty acid having one unsaturated bond. An antibacterial method characterized by using a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an antibacterial component.
<12> (A) The following formula (1)

(In the formula, R is a hydrogen atom or a group represented by —C (O) R ^1. R ¹ is a saturated aliphatic group having 9 to 19 carbon atoms or a fatty acid having one unsaturated bond. An ophthalmic composition comprising a compound represented by the formula: or a pharmaceutically acceptable salt thereof.

  The composition for external use of the present invention has sufficient antibacterial properties even when the conventional antibacterial agent or preservative is not used or the blending amount is reduced by including the component (A). Since the composition for external use of the present invention has such characteristics, skin diseases (acne, scalp eczema, eczema on the back, atopic dermatitis, etc.), oral diseases (such as caries, periodontal disease, gum inflammation, etc.), body odor It can also be widely used as cosmetics, quasi-drugs and / or pharmaceuticals having antibacterial effects and antiseptic sterilization effects on bacteria and fungi involved in

FIG. 1 is a diagram showing the anti-acne bacterium effect of an external composition which is one of the embodiments of the present invention. FIG. 2 is a diagram showing the anti-S. Aureus effect of the composition for external use which is one of the embodiments of the present invention. FIG. 3 is a diagram showing the anti-mutans bacterium effect of the composition for external use which is one of the embodiments of the present invention. FIG. 4 is a diagram showing the anti-E. Coli effect of the composition for external use which is one embodiment of the present invention. FIG. 5 is a diagram showing the anti-Pseudomonas aeruginosa effect of the composition for external use which is one of the embodiments of the present invention. FIG. 6 is a diagram showing the anti-malassezia effect of the composition for external use which is one of the embodiments of the present invention. FIG. 7 is a diagram showing an anti-Candida effect of an external composition that is one embodiment of the present invention.

  Hereinafter, the present invention will be described in detail.

<External composition>
The composition for external use of this invention contains the compound or its pharmaceutically acceptable salt ((A) component) represented by following formula (1). The composition for external use of this invention is excellent in antibacterial property by containing (A) component. In addition, the composition for external use of this invention may contain various arbitrary components for the purpose of improving the effect of this invention other than (A) component. Hereinafter, (A) component, a solvent, and arbitrary components are demonstrated.

  Here, the term “antibacterial” refers to the growth of pathogenic bacteria, not only against bacteria such as acne, mutans, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa, but also fungi such as candida and malassezia. It means the property of inhibiting and / or reducing the number of bacteria. For example, in the antibacterial evaluation, the increase in the number of bacteria after a certain time is prevented and / or the number of bacteria is reduced as compared with the control. It refers to the characteristics to be made.

[(A) component]
Component (A) is a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof, and includes a peptide moiety. Furthermore, the peptide moiety is composed of histidine or glycinyl histidine.

In the above formula, R is a hydrogen atom or a group represented by —C (O) R ¹ . R ¹ is a saturated aliphatic group having 9 to 19 carbon atoms or an aliphatic group having one unsaturated bond. m is 0 or 1.

  When R is a hydrogen atom, the compound represented by the formula (1) is histidine or glycinyl histidine.

When R is —C (O) R ¹ , R ¹ has a saturated aliphatic group having 11 to 17 carbon atoms or one unsaturated bond from the viewpoint of the antibacterial effect of the composition for external use of the present invention. It is preferably an aliphatic group, more preferably a saturated aliphatic group having 11 to 17 carbon atoms, and even more preferably a linear saturated aliphatic group having 11 to 17 carbon atoms.

Examples of R ¹ include a nonyl group, a decanyl group (capryl group), an undecanyl group, a dodecanyl group (lauryl group), a tridecanyl group, a tetradecanyl group (mistyl group), a pentadecanyl group, a hexadecanyl group (palmityl group), and a heptadecanyl group. , Octadecanyl group (stearyl group), nonadecanyl group, nonenyl group, decenyl group, undecenyl group, dodecenyl group, tridecenyl group, tetradecenyl group, pentadecenyl group, hexadecenyl group, heptadecenyl group, octadecenyl group, nanodecenyl group and the like. Among these, from the viewpoint of the antibacterial effect of the external composition of the present invention, a tetradecanyl group (mistyl group), a hexadecanyl group (palmityl group), and an octadecanyl group (stearyl group) are preferable.

  As the preferred component (A) in the composition for external use of the present invention, when m is 0, N-nonyloyl histidine, N-decanoyl histidine, N-undecanoyl histidine, N-lauroyl histidine, N-tri Decanoyl histidine, N-mistoyl histidine, N-pentadecanoyl histidine, N-palmitoyl histidine, N-heptadecanoyl histidine, N-stearoyl histidine, N-nonadecanoyl histidine, N-icosanoyl histidine, etc. Can be mentioned.

  In the case where m is 1, dipeptides glycinyl histidine, N-nonyl glycinyl histidine, N-decanoyl glycinyl histidine, N-undecanoyl glycinyl histidine, N-lauroyl glycinyl histidine, N- Tridecanoyl glycinyl histidine, N-mistoyl glycinyl histidine, N-pentadecanoyl glycinyl histidine, N-palmitoyl glycinyl histidine, N-heptadecanoyl glycinyl histidine, N-stearoyl glycinyl histidine, N-nona Decanoyl glycinyl histidine, N-icosanoyl glycinyl histidine, etc. are mentioned.

  In addition, as a histidine part in (A) component, either L or R optically active histidine can be used. Since the composition for external use of the present invention is suitably used for cosmetics, medicines, quasi drugs and the like, it is particularly preferable to use a compound having L-form histidine present in the living body.

  Examples of the pharmaceutically acceptable salt of the compound represented by the above formula (1) include alkali metal salts such as lithium salt, sodium salt, potassium salt and calcium salt as salts corresponding to the carboxyl group of histidine. Examples of the salt corresponding to the imidazole group of histidine include inorganic acid salts such as hydrochloride, sulfate and phosphate, and organic acid salts such as acetate, carbonate, citrate and succinate.

  The component (A) described above can be produced by methods known to those skilled in the art. For example, by the peptide solid phase synthesis method, necessary amino acids are linked, and the N-terminal of the amino acid at the terminal position when viewed from the solid phase is reacted with the fatty acid serving as the lipid portion, and if necessary, the salt form Can be manufactured. Moreover, (A) component can be manufactured by starting from a fatty acid by a liquid phase method, connecting an amino acid to this, and making it into the salt form as needed.

  In this invention, (A) component may be used individually by 1 type, and may be used in combination of 2 or more types arbitrarily. The content of the component (A) in the entire external composition of the present invention (in 100% by weight) is usually 0.0001 to 5% by weight and 0.0005 to 3% by weight from the viewpoint of antibacterial properties and the like. It is preferable that it is 0.001-1.5 weight%.

[solvent]
The composition for external use of the present invention contains water, alcohol, hydrophilic organic solvent, fatty acid, higher fatty acid ester, glyceride or hydrophobic organic solvent, or a miscible mixed solvent thereof. When the component (A) is added to these solvents at a specific ratio, gelation occurs, and an external composition having an appropriate viscosity and good skin compatibility can be obtained.

  The solvent preferably functions as a base or carrier in the composition for external use, and is an aqueous solvent such as water, liquid paraffin, squalane, petrolatum, gelled hydrocarbon (plasty base, etc.), ozokerite, α-olefin oligomer, light liquid paraffin. Hydrocarbons such as: methylpolysiloxanes such as polymethylsilsesquioxane, cross-linked methylpolysiloxane, highly polymerized methylpolysiloxane, cyclic silicone, alkyl-modified silicone, cross-linked alkyl-modified silicone, amino-modified silicone, polyether-modified Silicone, polyglycerin-modified silicone such as lauryl dimethicone polyglycerin-3 cross-polymer, cross-linked polyether-modified silicone, cross-linked alkyl polyether-modified silicone, silicone-alkyl chain co-modified polyether-modified Silicone oil such as ricone, silicone-alkyl chain co-modified polyglycerin-modified silicone, polyether-modified branched silicone, polyglycerin-modified branched silicone, acrylic silicone, phenyl-modified silicone, silicone resin; cetanol, cetostearyl alcohol, stearyl alcohol, behenyl alcohol Higher alcohols such as; cellulose derivatives such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose; polyvinylpyrrolidone; carrageenan; polyvinyl butyrate; polyethylene glycol; dioxane; butylene glycol adipic acid polyester; isopropyl myristate, octyldodecyl myristate, Isopropyl palmitate, cetyl palmitate, Esters such as octyl mytinate, isononyl isononanoate, pentaerythritol tetra-2-ethylhexanoate, glyceryl tri-2-ethylhexanoate, jojoba oil; polysaccharides such as dextrin, maltodextrin; ethanol, isopropanol, etc. Alcohol etc. are mentioned. Of these, aqueous solvents are preferred, with water being particularly preferred. When the external composition of the present invention contains water, the amount of the composition can be appropriately selected in consideration of the feeling on the skin and the effects of the present invention. 0.001 to 99.99% by weight, preferably 0.01 to 99.9% by weight, more preferably 0.1 to 30% by weight, and most preferably 1 to 20% by weight.

[Optional ingredients]
The composition for external use of the present invention comprises vitamins, 1,2-alkanediol, bactericides, polyhydric alcohols, glycol ethers, and thickeners in addition to the component (A) for the purpose of improving the effects of the present invention. It can further comprise at least one component selected from the group. Each of these compounds may be used alone or in any combination of two or more. In addition to these, other components may be used as long as the effects of the present invention are not impaired. In addition, when the compound specifically illustrated as each component overlaps, it should just be contained as any component.

(Vitamins)
Examples of the vitamins include retinol derivatives such as retinol, retinol acetate, and retinol palmitate, retinal, retinoic acid, methyl retinoic acid, ethyl retinoic acid, retinol retinoic acid, d-δ-tocopheryl retinoate, and α-tocotic acid. Vitamin A such as ferryl retinoate and β-tocopheryl retinoate; provitamin A such as β-carotene, α-carotene, γ-carotene, δ-carotene, lycopene, zeaxanthin, cryptoxanthin and echinone; δ-tocopherol , Α-tocopherol, β-tocopherol, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, δ-tocopherol, tocopherol nicotinate, etc .; Riboflavin, flavin mononucleoti Vitamin B2 such as flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, sodium riboflavin 5'-phosphate, riboflavin tetranicotinate; nicotinic acids such as methyl nicotinate, nicotinic acid, nicotinamide; Ascorbyl stearate, L-ascorbyl dipalmitate, ascorbyl tetraisopalmitate (ascorbyl tetra-2-hexyldecanoate), ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate, magnesium ascorbate phosphate, Vitamin Cs such as ascorbic acid glucoside and 3-O-ethylascorbic acid; methyl hesperidin, ergocalciferol, cholecalci Vitamin Ds such as erol; Vitamin Ks such as phylloquinone and farnoquinone; dibenzoylthiamine, dibenzoylthiamine hydrochloride, thiamine hydrochloride, thiaminecetyl hydrochloride, thiamine thiocyanate, thiamine lauryl hydrochloride, thiamine nitrate, thiamine monolin Acid salt, thiamine lysine salt, thiamine triphosphate, thiamine monophosphate phosphate, thiamine monophosphate, thiamine diphosphate, thiamine diphosphate hydrochloride, thiamine triphosphate, thiamine triphosphate monophosphate, etc. Vitamin B1 of vitamin B6 such as pyridoxine hydrochloride, pyridoxine acetate, pyridoxal hydrochloride, 5'-phosphate pyridoxal, pyridoxamine hydrochloride, cyanocobalamin, hydroxocobalamin, deoxya Vitamin B12 such as nosylcobalamin; folic acid such as folic acid, pteroylglutamic acid; pantothenic acid, calcium pantothenate, pantothenyl alcohol (panthenol), D-pantethein, D-panthetin, coenzyme A, pantothenyl ether Pantothenic acids such as biotin; biotins such as biotin and biocytin; and other vitamin-like agents such as carnitine, ferulic acid, α-lipoic acid, orotic acid, and γ-oryzanol. Among these, vitamin Cs are preferable from the viewpoint that the antibacterial effect of the external composition of the present invention is high. In addition, among vitamin Cs, a part of vitamin C derivative is converted into vitamin C by an enzyme and acts in vivo. For example, ascorbic acid glucoside is considered to be decomposed into ascorbic acid and glucose in vivo, and ascorbic acid has an antibacterial effect.

  When blending vitamins, the amount used can be appropriately selected in consideration of the feeling of use, but for example, 0.001 to 30% by weight, preferably 0.1 to 0.1% by weight with respect to the total composition for external use of the present invention. 25% by weight, more preferably 0.5 to 20% by weight.

(1,2-alkanediol)
The composition for external use of this invention can stabilize the antimicrobial property by including a 1, 2- alkanediol. The 1,2-alkanediol used in the present invention includes the following formula (2):

R ² —CH (OH) —CH ₂ —OH (2)

1,2-alkanediol represented by the following formula.

In the above formula, R ² is an alkyl group having 2 to 8 carbon atoms. This alkyl group may be linear or branched.

  Examples of the 1,2-alkanediol contained in the composition for external use of the present invention include 1,2-butanediol, 1,2-pentanediol, 1,2-hexanediol, 1,2-heptanediol, 1, Examples include 2-octanediol and 1,2-decanediol. Of these, 1,2-hexanediol and 1,2-octanediol are preferable, and 1,2-octanediol is more preferable.

  The content of 1,2-alkanediol in the entire external composition of the present invention (in 100% by weight) is preferably 0.01 to 15% by weight from the viewpoint of stabilizing antibacterial properties, More preferably, it is 1 to 10% by weight.

(Fungicide)
The composition for external use of this invention can improve the antibacterial property by further including antibacterial agents other than (A) component as antibacterial components other than (A) component. The bactericidal agent is not particularly limited. For example, as a quaternary ammonium salt type bactericidal agent, the following formula (3);

で表される第４級アンモニウム塩を用いることができる。

The quaternary ammonium salt represented by these can be used.

In the above formula (3), ^{R 3} and ^{R 4} are each independently an alkyl group having 1 to 3 carbon atoms. R ⁵ is a group represented by the following formula (4). R ⁶ is an alkyl group or alkenyl group having 1 to 4 carbon atoms. X ⁻ is a chloride ion or a bromide ion.

In the above formula (4), ^{R 7} is an alkyl group having 1 to 4 carbon atoms. n is an integer of 3 to 60.

R ⁷ is preferably a methyl group, and n is preferably an integer of 9 to 41. As the quaternary ammonium salt type bactericide contained in the composition for external use of the present invention, R ⁵ in the formula (3) is a polyoxypropylene group which is a polymer of 9 units to 41 units of oxypropylene, For example, polyoxypropylene chloride (9) methyldiethylammonium chloride, polyoxypropylene chloride (25) methyldiethylammonium chloride, polyoxypropylene chloride (40) methyldiethylammonium chloride and the like are preferable. Examples of these commercially available products include Emcol CC-9, 36, 42 manufactured by Witco Chemical Company and Adeka Coal EC-CC-9, 36, 42 manufactured by Asahi Denka Kogyo Co., Ltd. In addition to these, cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride and the like can also be mentioned as preferable examples.

  Of these quaternary ammonium salt fungicides, cetylpyridinium chloride, benzalkonium chloride, and benzethonium chloride are preferred from the viewpoint of antibacterial properties and safety.

  In addition, since the composition for external use of the present invention has an excellent antibacterial property by including the component (A), it is sufficient to add a small amount of the quaternary ammonium salt type bactericide as needed, but there is no particular limitation. . It is used at a concentration of 0.001 wt% to 0.5 wt% in the entire external composition of the present invention (in 100 wt%).

  The composition for external use of the present invention can contain a slightly water-soluble active fungicide as a fungicide as an antibacterial component other than the component (A). Here, the slightly water-soluble active fungicide means a substance having a disinfecting / antibacterial ability, which has a solubility in water at 25 ° C. of less than 1% by weight (w / v). This sparingly water-soluble active disinfectant is roughly classified into phenolic substances and alcoholic substances.

  Examples of the phenolic substance include triclosan, triclocarbanilide, methyl paraben, ethyl paraben, propyl paraben, isopropyl methyl phenol, and the like. Examples of alcohol-based substances include dodecyl alcohol and decyl alcohol.

  The slightly water-soluble active fungicide may be composed of a single substance, may be composed of a mixture of a plurality of phenolic substances, or may be composed of a mixture of a plurality of alcoholic substances. It may be configured such that a phenolic substance and an alcoholic substance are mixed.

  In addition, since the composition for external use of the present invention has an excellent antibacterial property by including the component (A), it is sufficient to add a small amount of the poorly water-soluble active fungicide as necessary, and the entire composition for external use of the present invention. Medium (100% by weight), used at a concentration of 0.001 to 0.5% by weight.

  As other germicides, those used as germicides for cosmetics, quasi drugs or pharmaceuticals can be used without limitation. For example, sulconazole nitrate, luliconazole, miconazole, amorolfine hydrochloride, clotrimazole, ketoconazole, bifonazole, neticonazole hydrochloride, lanconazole, rylanaphthalate, efinaconazole, decalinium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, alkyldiaminoethylglycine chloride, Cetylpyridinium, sodium benzoate, chlorobutanol, salicylic acid, gluconic acid, thymol, hexachlorophene, berberine, terbinafine hydrochloride, butenafine hydrochloride, lysozyme chloride, salicylic acid, salicylate, sulfur or sulfur compounds, hinokitiol, triclosan, trichlorocarbani Lido, halocarban, chlorophenesin, sorbic acid, potassium sorbate, dehydrovinegar Sodium, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds, and the like.

  Among these other bactericides, from the viewpoint of antibacterial properties and safety, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, decalinium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, Cetylpyridinium chloride and thymol are preferred. In addition, since the composition for external use of the present invention has an excellent antibacterial property by including the component (A), it is sufficient to add a small amount of a bactericidal agent as needed, and the total composition for external use of the present invention (100 weight) %)), At a concentration of 0.0001 to 1% by weight.

(Polyhydric alcohol)
The composition for external use of the present invention may further contain a polyhydric alcohol. As a polyhydric alcohol used for the external composition of this invention, what is used as a polyhydric alcohol of cosmetics, a quasi-drug, or a pharmaceutical can be used without a restriction | limiting. For example, glycols (ethylene glycol, diethylene glycol, propylene glycol, isopropylene glycol, dipropylene glycol, polypropylene glycol, polyethylene glycol, 1,3-butylene glycol, pentylene glycol, etc.), glycerin, diglycerin, triglycerin, polyglycerin Sorbitol, alkanediol (propanediol, 3-methyl-1,3-butanediol, pentanediol, etc.) and the like. Among these, from the viewpoint of formulation considering the feeling of use and the like, propylene glycol, dipropylene glycol, 1,3-butylene glycol, pentylene glycol, glycerin, diglycerin, sorbitol, alkanediol (propanediol, pentanediol, Hexanediol) and the like, and dipropylene glycol, 1,3-butylene glycol, and pentylene glycol are more preferable. These polyhydric alcohols can be used alone or in combination of two or more.

  The content of the polyhydric alcohol is preferably 0.01% by weight or more, more preferably 0.1% by weight or more, and further preferably 0.5% by weight or more in the entire external composition (100% by weight) of the present invention. More preferred. Moreover, 99.9 weight% or less is preferable in the whole external composition of this invention (in 100 weight%), 75 weight% or less is more preferable, and 50 weight% or less is still more preferable. If it is the said range, in addition to the effect of this invention, a moisturizing force and a favorable usability | use_condition can be provided to an external composition.

(Glycol ether)
The composition for external use of the present invention may further contain a glycol ether. As a glycol ether used for the composition for external use of this invention, what is used as a glycol ether of cosmetics, a quasi-drug, or a pharmaceutical can be used without a restriction | limiting. For example, ethylene glycol based glycol ethers such as ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, and ethylene glycol monopropyl ether; diethylene glycol based glycols such as diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, and diethylene glycol monopropyl ether Ethers; propylene glycol-based glycol ethers such as propylene glycol monoethyl ether and propylene glycol monopropyl ether; and dipropylene glycol-based glycol ethers such as dipropylene glycol monoethyl ether and dipropylene glycol monopropyl ether Is mentioned. Among these, ethylene glycol and diethylene glycol glycol ethers are preferred, ethylene glycol monomethyl ether and diethylene glycol monoethyl ether are more preferred, and diethylene glycol monoethyl ether is particularly preferred. These glycol ethers can be used alone or in combination of two or more.

  The content of glycol ether is preferably 0.01% by weight or more, more preferably 0.1% by weight or more, and even more preferably 0.5% by weight or more in the entire external composition (100% by weight) of the present invention. preferable. Moreover, 97 weight% or less is preferable in the whole external composition (100 weight%) of this invention, 50 weight% or less is more preferable, and 30 weight% or less is still more preferable. If it is the said range, in addition to the effect of this invention, a moisturizing force and a favorable usability | use_condition can be provided to an external composition.

(Thickener)
The external composition of the present invention can further contain a thickener. Thereby, it can be set as the external composition which is familiar with skin and excellent in a usability | use_condition.

  As such thickeners, those used as thickeners for cosmetics, quasi drugs or pharmaceuticals can be used without limitation. For example, agar, gellan gum, guar gum, locust bean gum, carrageenan, xanthan gum, dextran, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose, sodium alginate, propylene alginate Glycol ester, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, carboxyvinyl polymer, acrylic acid alkyl methacrylate copolymer, sodium polyacrylate, polyethylene glycol, bentonite, dextrin fatty acid ester, pectin, (A Hydroxyethyl silylate / acryloyldimethyltaurine Na) copolymer, dimethyldistearylammonium hectorite, (acryloyldimethyltaurine ammonium / vinylpyrrolidone) copolymer, (acryloyldimethyltaurine ammonium methacrylate behenes-25) cross copolymer, (acryloyldimethyltaurine ammonium / Stearless methacrylate-25) crosspolymer, polyethylene glycol distearate, ethylene glycol triisostearate, polyoxyethylene (20) methylglucoside triisostearate, and the like. Among these, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose, xanthan gum, alkyl methacrylate methacrylate copolymer (hydroxyethyl acrylate / acryloyldimethyltaurine Na) More preferred are copolymers and (acryloyldimethyltaurate ammonium / vinylpyrrolidone) copolymers. These thickeners may be used alone or in any combination of two or more.

  The content of the thickener is preferably 0.0001 to 20% by weight, more preferably 0.001 to 10% by weight, more preferably 0.05 to 5% by weight in the entire external composition of the present invention (in 100% by weight). % Is more preferable. If content of a thickener is the said range, it can be set as the composition for external use which is familiar with skin and excellent in a usability | use_condition.

(Other ingredients)
In addition to the above-mentioned components as optional components, the composition for external use of the present invention, in addition to the above-mentioned components, has an ultraviolet scattering component, an ultraviolet absorbing component, a component having a DNA damage preventing and / or repairing action, Whitening component, anti-inflammatory component, cell activation component, astringent component, antioxidant component, anti-aging component, moisturizing component, keratin softening component, blood circulation promoting component, sebum adsorbing component, hair growth component, antihistamine component, anti-inflammatory analgesic component, antipruritic agent You may mix | blend various components, such as a component and a local anesthetic component, by combining 1 type (s) or 2 or more types. These components are not particularly limited as long as they can be used in the fields of pharmaceuticals, quasi drugs, cosmetics, and the like, and arbitrary components can be appropriately selected and used. Moreover, what corresponds to the following several components shall be added as a component of arbitrary efficacy among them.

  Examples of the ultraviolet scattering component include inorganic compounds such as zinc oxide, titanium oxide, iron oxide, cerium oxide, zirconium oxide, titanium silicate, zinc silicate, anhydrous silicic acid, cerium silicate, hydrous silicic acid, and the like. These inorganic compounds are coated with inorganic powders such as hydrous silicic acid, aluminum hydroxide, mica and talc, or compounded with resin powders such as polyamide, polyethylene, polyester, polystyrene, nylon, and silicon oil and fatty acids. The thing etc. which processed with aluminum salt etc. are mentioned. Of these, inorganic compounds such as zinc oxide, titanium oxide and iron oxide, and those inorganic compounds coated with inorganic powder such as aluminum hydroxide, hydrous silicic acid, mica and talc, and silicon oil are preferable. In the case of blending an ultraviolet scattering component, the amount used can be appropriately selected in consideration of the feeling of use and effects on the skin, but is preferably 0.001 to 35% by weight, for example, based on the total amount of the external composition of the present invention. Is 0.1 to 25% by weight.

  Examples of the ultraviolet absorbing component include 2-methoxyhexyl paramethoxycinnamate, 2- [4- (diethylamino) -2-hydroxybenzoyl] benzoic acid hexyl ester, 2,4,6-tris [4- (2- Ethylhexyloxycarbonyl) anilino] -1,3,5-triazine, dimethoxybenzylideneoxoimidazolidinepropionate 2-ethylhexyl, 2,4-bis-[{4- (2-ethylhexyloxy) -2-hydroxy} -phenyl] -6- (4-methoxyphenyl) -1,3,5-triazine and the like. When the ultraviolet absorbing component is blended, the amount used can be appropriately selected in consideration of the feeling of use and effects on the skin, but it is preferably 0.01 to 20% by weight, for example, with respect to the total composition for external use of the present invention. Is 0.1 to 15% by weight.

  Examples of the whitening component include hydroquinone, placenta, arbutin, kojic acid, ellagic acid, phytic acid, tranexamic acid, 4-n-butylresorcinol, chamomile extract, vitamin A or a derivative thereof, pantothenic acid or a derivative thereof, and the like. And the like. Furthermore, a plant component having a whitening effect may be used as a whitening component. Examples of such plant components include Iris (Iris), Almond, Aloe, Ginkgo, Oolong Tea, Ages, Ogon, Ouren, Hypericum, Adriatic, Seaweed, Cuckoo, Gardenia, kujin, chlorella, goby wheat, rice, rice haiga, oryzanol, rice bran, saishin, salamander, perilla, peonies, senkyu, sakuhakuhi, soybeans, natto, tea, touki, daikinsen, garlic, hamamelis, safflower, safflower, buttonpi, yokui Toki, Amethyst, Acaciatic, Acebi Warabi, Inohaki, Enoki, Oyster (Diospyros kaki), Cattle, Black Bean, Gentian, Genzin, Salsa, Sweet Bean Shouma, Juju, Sage, Zenko, Daikon, Azalea, Tsu Ingredients derived from horsetail, tocin, nigaki, parsley, holly, hops, malbahagi, clove, licorice, grapefruit and the like. Preferably, Iris (Iris), Aloe, Ginkgo, Oolong tea, Ages, Ogon, Oulen, Hypericum, Olysam, Seaweed, Cuckoo, Gardenia, Kujin, Gobaishi, Wheat, Rice, Rice bran, Saishin, Salamander, Perilla, Peonies, Senkyu , Sakuhakuhi, Tea, Toki, Toki-Senka, Hamelis, Safflower, Buttonpi, Yokuinin, Amethyst, Acalysia, Enoki, Oyster (Diospyros kaki), Cattle, Black Bean, Gentian, Salsa, Soyagen, Juju, Sage, Zenko, Daikon, Tsuji It is a component derived from Tsukuhashigi, Toshin, Nigaki, Parsley, Holly, Hop, Clove, Licorice, Grapefruit, and Toki, and more preferably Iris (Iris), Aloe, Ginkgo, Ages, Ogon, Oure , Hypericum, gardenia, cucumber, rice, rice bran, saishin, peony, senkyu, sakuhakuhi, tea, touki, kansen, hamamelis, safflower, buttonpi, amethyst, asenyaku, enoki, oyster (Diospyros kaki), sage, daikon , Parsley, hops, licorice, grapefruit and yokuinin-derived components. Among these, Iris root extract, which is a component derived from Iris (iris), brown algae extract, Calaf comb extract, and aloe extract, which are components derived from seaweed, are more preferable. When these plant components are used in the composition for external use of the present invention, the form of the plant component is not particularly limited, but can be usually used in the form of a plant extract (plant extract), an essential oil or the like. In addition, the inside of () described in the said plant component is the scientific name of the plant, an alias, or a crude drug name. When the whitening component described above is blended in the external composition of the present invention, the amount used can be appropriately selected in consideration of the feeling of use and effects on the skin, but for example 0.0003 relative to the entire external composition. -10 wt%, preferably 0.01-5 wt%. When the plant extract is used, the amount used is 0.00001 to 20% by weight, preferably 0.0001 to 15% by weight, more preferably 0. 001 to 10% by weight.

  Examples of the anti-inflammatory component include allantoin, calamine, tranexamic acid, glycyrrhizic acid or a derivative thereof or a salt thereof, glycyrrhetinic acid or a derivative thereof or a salt thereof, zinc oxide, guaiazulene, tocopherol acetate, pyridoxine hydrochloride, menthol, camphor , Turpentine oil, indomethacin, salicylic acid or a derivative thereof. Preferred is glycyrrhizic acid or a derivative thereof or a salt thereof (for example, dipotassium glycyrrhizinate), glycyrrhetinic acid or a derivative thereof or a salt thereof, or zinc oxide. When an anti-inflammatory component is blended, the amount used can be appropriately selected in consideration of the feeling of use and effects on the skin, but it is, for example, 0.0003 to 10% by weight, preferably with respect to the entire external composition of the present invention. Is 0.01 to 5% by weight.

  Examples of the cell activation component include amino acids such as γ-aminobutyric acid and ε-aminocaproic acid: α-hydroxy acids such as glycolic acid and lactic acid: tannin, flavonoids, saponins, allantoin, and photosensitizer 301. It is done. When the cell activating component is blended, the amount used can be appropriately selected in consideration of the feeling of use and effects on the skin. For example, 0.0003 to 10% by weight relative to the total composition for external use of the present invention, Preferably it is 0.01 to 5 weight%.

  Examples of the astringent component include metal salts such as alum, chlorohydroxyaluminum, aluminum chloride, allantoin aluminum salt, zinc sulfate, and potassium aluminum sulfate; organic acids such as tannic acid, citric acid, lactic acid, and succinic acid. it can. When blending an astringent component, the amount used can be appropriately selected in consideration of the feeling of use and effects on the skin, but for example 0.0003 to 10% by weight, preferably based on the total composition for external use of the present invention. 0.01 to 5% by weight.

  Examples of the antioxidant component include butylhydroxyanisole, dibutylhydroxytoluene, sodium hydrogensulfite, sodium pyrosulfite, flavonoid, glutathione, glutathione peroxidase, glutathione-S-transferase, catalase, superoxide dismutase, thioredoxin, taurine, thiotaurine, Examples include hypotaurine, L-cysteine hydrochloride, astaxanthin and the like. When the antioxidant component is blended, the amount used can be appropriately selected in consideration of the feeling of use and effects on the skin, but it is preferably, for example, 0.00001 to 10% by weight, preferably based on the total composition for external use of the present invention. Is 0.0001 to 5 wt%, more preferably 0.001 to 5 wt%.

  Examples of the anti-aging component include pangamic acid, ursolic acid, turmeric extract, sphingosine derivative, silicon, silicic acid, N-methyl-L-serine, mevalonolactone, and the like. When blending an anti-aging component, the amount used can be appropriately selected in consideration of the feeling of use and effects on the skin, but for example 0.0003 to 10% by weight, preferably with respect to the total composition for external use of the present invention. Is 0.01 to 5% by weight.

  Examples of the moisturizing component include amino acids such as alanine, serine, leucine, isoleucine, threonine, glycine, trimethylglycine, proline, hydroxyproline, glucosamine, and theanine; polyhydric alcohols such as glycerin; sugar alcohols such as sorbitol Phospholipids such as lecithin and hydrogenated lecithin; NMF-derived components such as lactic acid, sodium pyrrolidonecarboxylate, and urea; plant-derived components such as lavender oil and red ginseng extract. When the moisturizing component is blended, the amount used can be appropriately selected in consideration of the feeling of use and effects on the skin, but it is, for example, 0.1 to 10% by weight, preferably, based on the total composition for external use of the present invention. 0.5 to 5% by weight.

  Examples of the keratin soft component include lanolin, urea, phytic acid, lactic acid, lactate, glycolic acid, salicylic acid, malic acid, citric acid, and the like. When the keratin soft component is blended, the amount used can be appropriately selected in consideration of the feeling of use and effects on the skin, but for example 0.0001 to 50% by weight relative to the total composition for external use of the present invention, Preferably it is 0.001 to 50 weight%, More preferably, it is 0.05 to 25 weight%.

  Examples of the blood circulation promoting component include plants (e.g., ginseng, ashitaba, arnica, ginkgo, fennel, entomop, dutch oak, chamomile, roman chamomile, carrot, gentian, burdock, rice, hawthorn, shitake, hawthorn, cherries, Senkyu, assembly, thyme, clove, chimpi, spruce, spruce, spruce, carrot, garlic, butcher bloom, grapes, buttons, maronier, melissa, yuzu, yokuinin, rosemary, rosehip, chimpi, spruce, spruce, peach, apricot , Walnuts, corn); tocopherol nicotinate, glucosyl hesperidin, hesperidin. When the blood circulation promoting component is blended, the amount used can be appropriately selected in consideration of the feeling of use and effects on the skin, but is preferably, for example, 0.00001 to 10% by weight, preferably based on the total composition for external use of the present invention. Is 0.0001 to 5 wt%, more preferably 0.001 to 5 wt%. The amount used in the case of using a plant-derived component is 0.00001 to 20% by weight, preferably 0.0001 to 15% by weight, and more preferably 0, in terms of an extract such as an extract, based on the whole composition for external use. 0.001 to 10% by weight.

  Examples of the sebum adsorbing component include talc, mica, hydroxyapatite, zinc oxide, aluminum silicate, and the like. Of these, mica, hydroxyapatite, and zinc oxide are preferable, and mica is particularly preferable. When the sebum adsorbing component is blended, the amount used can be appropriately selected in consideration of the feeling of use and effects on the skin, but for example, 0.001 to 35% by weight, preferably with respect to the total composition for external use of the present invention. Is 0.1 to 25% by weight.

  Examples of the hair-restoring ingredients include procyanidins, dipotassium glycyrrhizinate, capronium chloride, cephalanthin, menthol, hinokitiol, L-hydroxyproline, acetylhydroxyproline, fucoidan, capsicum tincture, cephalanthin, sultianin, symphunginicin, flavonosteroid, minoxidil, FGF 10, Enmiso extract (extract), assembly extract (extract), beetle extract (extract), amachazuru extract (extract), hypericum extract (extract), gentian extract (extract), sage extract (extract) , Peppermint extract (extract), hop extract (extract), yokuinin extract (extract), persimmon leaf extract (extract), ginger extract (extract), carrot extract (extract), bo Schima wallichii extract (extract), moutan bark extract (extract), and the like Jiyu extract (extract).

  Examples of the antihistamine component include ethanolamine compounds such as diphenhydramine, diphenhydramine hydrochloride and dimenhydrinate; propylamine compounds such as chlorpheniramine maleate; phenothiazine compounds such as promethazine hydrochloride; piperazine compounds such as hydroxyzine; In addition to piperidine compounds such as cyproheptadine hydrochloride, epinastine hydrochloride, loratadine, and fexofenadine hydrochloride are exemplified. In addition to the hydrochloride, pharmaceutically acceptable salts of the respective compounds can also be used. Among these, diphenhydramine, diphenhydramine hydrochloride, and chlorpheniramine maleate are preferable.

  Examples of the anti-inflammatory analgesic component include: indomethacin; felbinac; ibuprofen; ibuprofen piconol; bufexamac; butyl flufenamate; bendazac; piroxicam; ketoprofen and the like.

  Examples of the antipruritic component include crotamiton; chlorpheniramine; chlorpheniramine maleate; diphenhydramine; diphenhydramine hydrochloride; diphenhydramine salicylate; nonyl acid vanillyl amide; mequitazine; camphor; thymol; eugenol: polyoxyethylene lauryl ether;

  Examples of the local anesthetic component include lidocaine, lidocaine hydrochloride, dibucaine, dibucaine hydrochloride, ethyl aminobenzoate, eucalyptus oil; eugenol, and chlorobutanol.

  In addition to the above-described components, the composition for external use of the present invention may be appropriately mixed with components usually used in the fields of pharmaceuticals, quasi drugs, cosmetics, etc., depending on the use or dosage form. . The ingredients that can be blended are not particularly limited, but for example, additives such as surfactants, preservatives, pH adjusters, chelating agents, stabilizers, irritation reducers, colorants, dispersants, fragrances, etc. Can do. In addition, these components can be mix | blended individually by 1 type or in combination of 2 or more types arbitrarily. Moreover, these usage-amounts can be suitably determined in the range which does not impair the effect of this invention from a conventionally well-known range.

Examples of the surfactant include sorbitan esters such as sorbitan stearate, PEG sorbitan stearate, sorbitan monooleate, sorbitan monoisostearate and sorbitan monolaurate; POE-sorbitan monooleate; polyoxyethylene cured castor Oil (HCO-10); glycerin fatty acid esters such as glycerin monooleate, glycerin monostearate, and glycerin monomyristate; glycerin alkyl ethers such as monoisostearyl glyceryl ether and monomyristyl glyceryl ether; stearic acid polyglyceride, isostearin Polyglyceryl-10, diglyceryl monostearate, decaglyceryl decastearate, decaglyceryl decaisostearate, and diglyceride Various nonionic surfactants such as polyglycerol fatty acid esters such as rildiisostearate:
Alternatively, naturally occurring surfactants such as lecithin, hydrogenated lecithin, saponin, surfactin sodium, cholesterol, bile acid and the like can be exemplified.

  Examples of the preservative include benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, butyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and paraoxybenzoic acid. Examples include benzyl, methyl paraoxybenzoate, and phenoxyethanol.

  Examples of the pH adjuster include inorganic acids (hydrochloric acid, sulfuric acid, etc.), organic acids (lactic acid, sodium lactate, citric acid, sodium citrate, succinic acid, sodium succinate, etc.), inorganic bases (potassium hydroxide, water, etc.). Sodium oxide), organic bases (triethanolamine, diisopropanolamine, triisopropanolamine, etc.).

  Examples of the chelating agent include ethylenediaminetetraacetic acid (edetic acid), ethylenediaminetetraacetate (sodium salt (sodium edetate: Japanese Pharmacopoeia, EDTA-2Na, etc.), potassium salt, etc.), phytic acid, gluconic acid, polyphosphorus An acid, metaphosphoric acid, etc. are mentioned. Of these, sodium edetate is preferable.

  Examples of the stabilizer include magnesium sulfate, sodium polyacrylate, dibutylhydroxytoluene, butylhydroxyanisole and the like.

  Examples of the irritation reducing agent include licorice extract, gum arabic, polyvinylpyrrolidone, sodium alginate and the like.

  Examples of the colorant include inorganic pigments and natural pigments.

  Examples of the dispersant include sodium pyrophosphate, sodium hexametaphosphate, polyvinyl alcohol, polyvinyl pyrrolidone, methyl vinyl ether / maleic anhydride crosslinked copolymer, and organic acid.

[pH]
The composition for external use of the present invention may usually have a liquidity of pH 2.0 to 9.0, but preferably has a pH of 3.0 from the viewpoint of low irritation to skin and mucous membranes and good skin feeling. It is -8.5, More preferably, it is pH 3.5-8.0.

[Property / Formulation]
The property of the composition for external use of the present invention is not particularly limited, and may be liquid, fluid, or semi-solid. Examples of the preparation form include liquids, suspensions, emulsions, creams, emulsions, ointments, gels, liniments, lotions, and sheets obtained by impregnating a nonwoven fabric with a chemical. . Of these, emulsions, creams, emulsions, ointments, gels, and lotions are preferred, and creams, emulsions, ointments, and gels are particularly preferred.

  In addition, as a container filled with the external composition of this invention, a well-known container can be used without a restriction | limiting. The material of the container is not particularly limited. For example, the container can be provided by filling a container made of a material such as polyethylene terephthalate, polyethylene naphthalate, polyarylate, polycarbonate, polyethylene, or polypropylene, or glass. As the container, a container made of polyethylene terephthalate, polyethylene naphthalate, or polyarylate is particularly preferable.

<Method for producing composition for external use>
The manufacturing method in particular of the composition for external use of this invention is not restrict | limited, It can manufacture by selecting (A) component, the arbitrary component mentioned above, and another component suitably, and mixing in a solvent. For example, in order to obtain a gel-like composition, it is necessary to heat the mixture once to 60 ° C. to 95 ° C. and then leave it at room temperature or the like.

  The composition for external use of the present invention has sufficient antibacterial properties even when a conventional bactericidal agent or preservative is not used or its blending amount is reduced by including the component (A). Since the composition for external use of the present invention has such properties, it can be suitably used in cosmetics, quasi drugs and pharmaceutical fields. Antibacterial composition for external use, specifically for anti-acne treatment (anti-acne), treatment for atopic dermatitis, treatment for dental caries and periodontal disease, treatment for scalp eczema, suppression of body odor It can be suitably used in the cosmetics, quasi-drugs and pharmaceutical fields as a composition for external use. In addition, it can be suitably used as an ophthalmic external composition such as an eye ointment, especially as an antibacterial ophthalmic composition against Pseudomonas aeruginosa and the like.

<Antimicrobial agent>
The antibacterial agent of the present invention contains the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof (component (A)). In the antibacterial agent of the present invention, components usually used in cosmetics, quasi-drugs, pharmaceuticals and the like can be appropriately arbitrarily blended within the range not impairing the antibacterial effect and for the purpose of improving the antibacterial effect. Thus, as a component which can be mix | blended with the antibacterial agent of this invention, the component described as an arbitrary component of the above-mentioned external composition of this invention is mentioned, for example. In addition, about description about (A) component which the antibacterial agent of this invention contains, description of (A) component in the external composition of this invention is applicable. Moreover, the antibacterial agent of this invention can be manufactured by mix | blending (A) component and another component in accordance with a conventional method. The antibacterial agent of the present invention has an effect on various bacteria, but in particular, bacteria such as acne, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, mutans bacteria that can cause oral cavity and periodontal disease, and malassezia The antibacterial effect on fungi such as fungi and Candida is remarkable.

<Antimicrobial method>
The antibacterial method using the component (A) having excellent antibacterial properties is also included in the present invention. For example, by blending the component (A) into an external composition, cosmetic, or medicine, it is possible to effectively suppress the growth of bacteria in the external composition, cosmetic, or medicine. Further, by applying an external composition containing the component (A) to the skin, the antibacterial effect can be exerted on the skin, and for example, it can be suitably used for acne care and the like. Furthermore, according to the antibacterial method of the present invention, since various items in the living environment can be subjected to antibacterial treatment with various forms of products containing the component (A), the living environment can be kept clean. .

<Quasi-drugs and pharmaceuticals>
The quasi-drug / pharmaceutical of the present invention includes the external composition of the present invention and the antibacterial agent of the present invention. Therefore, the quasi-drug / pharmaceutical product of the present invention has an excellent antibacterial effect, and is particularly excellent for symptoms and diseases related to Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Acne, Candida, Malassezia, and Mutans. Show the effect.

  Symptoms and diseases related to Staphylococcus aureus include, for example, dermatitis such as atopic dermatitis, various body odors such as axillary odor (crab odor), head odor (head odor), blepharitis, tears Examples include diseases in the ophthalmic region such as cystitis, stye, conjunctivitis, keratitis, and corneal ulcer. The quasi-drug / pharmaceutical product of the present invention is suitable as an atopic dermatitis preventive agent or an atopic dermatitis ameliorating agent for preventing the onset of dermatitis such as atopic dermatitis or alleviating / ameliorating symptoms. Can be used. The quasi-drug / pharmaceutical of the present invention can be suitably used for various body odor generation inhibitors and for the treatment or prevention of various diseases in the ophthalmic field. In addition, since the (A) component (for example, Palmitoyl Dipeptide-18 (INCI name)) contained in the quasi-drug / pharmaceutical of the present invention is not an antibiotic, it can be applied to methicillin-resistant Staphylococcus aureus, which is a multidrug-resistant bacterium. Is possible.

  Examples of symptoms and diseases related to Pseudomonas aeruginosa include Pseudomonas aeruginosa corneal ulcer and Pseudomonas aeruginosa keratitis. The quasi-drug / pharmaceutical of the present invention can be suitably used for the treatment or prevention of these Pseudomonas aeruginosa diseases. In addition, since the (A) component (for example, Palmitoyl Deptide-18 (INCI name)) contained in the quasi-drug / pharmaceutical of the present invention is not an antibiotic, application to multidrug-resistant Pseudomonas aeruginosa is also possible.

  Acne etc. are mentioned as a symptom and disease related to acne bacteria. Acne is not particularly limited, for example, acne on dry skin in the face, neck, back, etc., acne that tends to repeat, acne with inflammation in the hair follicle, microcomedones (corn plug generation, Early acne clogging), pimples (adult acne), white acne (white papules), black acne (open comedones), red acne with inflammation (red papules), yellow acne (purulent acne), adolescence, etc. Easy acne vulgaris, pustular acne mainly composed of pustules, cystic acne mainly composed of cysts, concentrated acne that is a severe case of acne vulgaris, electric acne, etc. The quasi-drug / pharmaceutical of the present invention can be suitably used for the treatment or prevention of these acne.

  Examples of symptoms and diseases related to Candida include candidiasis. Candidiasis is not particularly limited, for example, cutaneous candidiasis, vaginal candidiasis, vulvar candidiasis, male genital candidiasis, oral candidiasis, candidal interdigital erosion, candidal nail nail Examples include inflammation, esophageal / intestinal candidiasis, and the like. The quasi-drug / pharmaceutical of the present invention can be suitably used for the treatment or prevention of these candidiasis.

  Examples of the symptoms and diseases related to Malassezia include eczema on the back, scalp eczema, malassezia folliculitis, seborrheic dermatitis, folding screen, dandruff and the like. The quasi-drug / pharmaceutical product of the present invention can be suitably used for the treatment or prevention of back eczema, scalp eczema, malassezia folliculitis, seborrheic dermatitis, folding screen and the like. Further, it is also suitably used as a dandruff preventive or ameliorating agent for preventing the occurrence of dandruff or relieving / improving the symptoms of dandruff.

  Examples of symptoms and diseases related to mutans bacteria include oral caries, periodontal disease, gingivitis, alveolar pyorrhea and the like, and the quasi-drugs and pharmaceuticals of the present invention are those symptoms and diseases. It can be suitably used as a therapeutic or preventive agent.

<Cosmetics>
Since the cosmetic of the present invention contains the component (A) represented by the above formula (1), it is excellent in antibacterial effect, and in particular, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Acne, Candida, Marassezia, and Mutans Has an excellent antibacterial effect. Therefore, in the cosmetics field, cosmetics for suppressing the generation of body odor, which have an excellent antibacterial effect against Staphylococcus aureus, which is a causative bacterium of body odor, and the like, and anti-acne makeup having a therapeutic effect and a preventive effect on various acne as described above It can be widely used for water, milky lotion, beauty serum and the like.

<Ophthalmic composition>
The ophthalmic composition of the present invention contains the component (A) represented by the formula (1). Since the component (A) also has an action as a gelling agent, the ophthalmic composition of the present invention is suitably used as a medicine, quasi drug, and the like. In addition, the ophthalmic composition of the present invention is suitably used as a medicine, quasi-drug, etc. that are particularly excellent in antibacterial properties. Specifically, eye drops (including eye drops and eye drops), eye wash (including eye wash and eye wash), eye ointments, contact lens mounting liquid, contact lens care agents (cleaning liquid, preservative liquid, It can be used as a disinfectant, a multi-purpose solution, etc. The eye drops and eye wash include eye drops and eye wash that can be used while wearing a contact lens. The contact lenses include all types of contact lenses such as hard contact lenses (including oxygen permeable hard contact lenses) and soft contact lenses. In addition, the dosage for use as an ophthalmic medicine varies depending on the use of the composition, and may be used at a dosage generally employed for each use. In addition, about (A) component which the ophthalmic composition of this invention contains, a solvent, an arbitrary component, the property of the ophthalmic composition of this invention, etc., what can be used for an ophthalmic composition is in the external composition of this invention. A description can be applied. Moreover, the description in the manufacturing method of the composition for external use of this invention can apply also about the manufacturing method of the ophthalmic composition of this invention which can be used for an ophthalmic composition.

Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.
[Preparation of composition]
Compositions (test preparations) of Examples and Comparative Examples were prepared by a conventional method according to the formulation described in Table 1 below. The unit of numerical values in each table is weight (%) unless otherwise specified. For each composition, the following tests were conducted and evaluated.

In this example, the sample names in the table indicate the following.
Pal-GH: Palmitoyl Dipeptide-18 (INCI name)
GH: dipeptide of glycine and histidine IPMP: isopropylmethylphenol MP: methylparaben 1,3-BG or BG: 1,3-butylene glycol

[Test example]
<Antimicrobial test (Acne bacteria)>
The sample sample solution was evaluated for the antibacterial effect using a direct inoculation method to bacteria. Specifically, an acne bacterium solution obtained by anaerobic pre-culture of acne bacteria (P. Acnes) on a modified GAM agar medium (Gifanaerobic medium agar medium) at 36 ° C. for 72 hours is about 1.0 × 10 × 10. Inoculated to ⁶ CFU / mL, cultured at 36 ° C. under anaerobic conditions, diluted inoculated sample after a certain time, and measured the number of viable bacteria by agar plate surface smearing method to confirm the antibacterial effect . (5 minutes, 30 minutes, 60 minutes, 90 minutes, 240 minutes). The results are shown in Table 2 below and FIG.

  As shown in Table 2 and FIG. 1, the compositions of Examples 1 and 2 showed superior antibacterial activity against acne bacteria as compared to the compositions of Comparative Examples 1 and 3 containing the existing fungicide. .

<Antimicrobial test (Staphylococcus aureus)>
The sample sample solution was evaluated for the antibacterial effect using a direct inoculation method to bacteria. More specifically, S. aureus was pre-cultured in SCDLP agar medium (Soybean-Casein Digest Agar with Lecithin & Polysorbate 80 agar medium) at 33 ° C. for 24 hours in a sample sample solution. Inoculate to 3.7 × 10 ⁶ CFU / mL, incubate at 33 ° C., dilute the inoculated sample after a certain time, measure the number of viable bacteria by agar plate surface smearing method, antibacterial effect (0.5 hours, 1 hour, 4 hours, 24 hours). The results are shown in Table 3 below and FIG.

  As shown in Table 3 and FIG. 2, the compositions of Examples 1 and 3 were yellow after 24 hours from the inoculation of the bacteria, compared to the compositions of Comparative Examples 1 to 3 containing existing fungicides. Excellent antibacterial activity against staphylococci.

<Antimicrobial test (M. mutans)>
The mutans bacterium (scientific name: Streptococcus mutans) is a kind of gram-positive and facultative anaerobic streptococci. It is also present in the human oral cavity and is one of the causative bacteria for caries (cavities). The sample sample solution was evaluated for the antibacterial effect using a direct inoculation method against mutans bacteria. More specifically, mutans bacteria (S. mutans, ATCC 25175) precultured at 33 ° C. for 24 hours in a BHI medium (brain heart infusion medium) at about 1.0 × 10 ⁶ Inoculated to CFU / mL, cultured at 33 ° C., the inoculated sample was diluted after a certain time, and the number of viable bacteria was measured by the agar plate surface smearing method to confirm the antibacterial effect. (0.5 hours, 1 hour, 4 hours, 24 hours). The results are shown in Table 4 below and FIG.

  As shown in Table 4 and FIG. 2, the compositions of Examples 1 and 3 were superior to mutans bacteria in a shorter time than the compositions of Comparative Examples 1 to 3 containing an existing fungicide. Showed antibacterial activity.

<Antiseptic sterilization test (E. coli)>
The sample sample solution was evaluated for the antibacterial effect using a diffusion method (perforated plate method). More specifically, Escherichia coli ATCC 8739 was pre-cultured in an SCD (Soybean-Casein Digest) slant medium at 33 ° C. for 24 hours to prepare a bacterial solution. The bacterial solution is diffused into MH agar medium (Mueller-Hinton agar medium) inoculated with about 10 ⁶ CFU / mL, and a hole with a diameter of 8 mm is formed in the agar medium with a sterilized punch cutter (TOYOBO: biopsy punch 8 mm, stainless steel). Opened, inoculated 100 uL of sample solution into the hole, and cultured at 33 ° C. for 48 hours. After incubation, the diameter of the blocking circle that appeared around the hole was measured. The results are shown in Table 5 below and FIG.

  As shown in Table 5 and FIG. 4, the compositions of Examples 1 and 2 showed excellent antiseptic sterilizing power against E. coli as compared with the compositions of Comparative Examples 1 to 3 containing existing fungicides. .

<Bactericidal test (Pseudomonas aeruginosa)>
The sample sample solution was evaluated for the antibacterial effect using a diffusion method (perforated plate method). More specifically, Pseudomonas aeruginosa (ATCC 9027) was pre-cultured in an SCD (Soybean-Casein Digest) slant medium at 33 ° C. for 24 hours to prepare a bacterial solution. The bacterial solution is diffused into MH agar medium (Mueller-Hinton agar medium) inoculated with about 1.0 × 10 ⁶ CFU / mL, and a hole with a diameter of 8 mm is formed with a sterilized perforation cutter (TOYOBO: biopsy punch 8 mm, made of stainless steel). The agar medium was opened, and 100 uL of the sample solution was inoculated into the hole and cultured at 33 ° C. for 48 hours. After incubation, the diameter of the blocking circle that appeared around the hole was measured. The results are shown in Table 6 below and FIG.

  As shown in Table 6 and FIG. 5, the compositions of Examples 1 and 2 showed superior bactericidal power against Pseudomonas aeruginosa as compared to the compositions of Comparative Examples 1 and 3 containing existing bactericides. It was.

<Sterilization test (Malassezia)>
The sample sample solution was evaluated for the antibacterial effect using a direct inoculation method to bacteria. More specifically, a malassezia solution obtained by pre-culturing malassezia (M. furfur ATCC 46266) in Ptyrosporum medium at 33 ° C. for 5 days is inoculated to a sample sample solution so as to be about 1.6 × 10 ⁶ CFU / mL, The sample inoculated after a certain period of time was diluted and the number of viable bacteria was measured by the agar plate surface smearing method to confirm the antibacterial effect (0.5 hours, 1 hour, 4 hours, 24 hours). The results are shown in Table 7 below and FIG.

  As shown in Table 7 and FIG. 6, the compositions of Examples 1 and 3 were superior in antibacterial against Malassezia in a shorter time than the compositions of Comparative Examples 1 to 3 containing existing fungicides. Showed power.

<Sterilization test (candida)>
The sample sample solution was evaluated for the antibacterial effect using a diffusion method (perforated plate method). More specifically, Candida albicans ATCC 10231 was pre-cultured in an SD medium at 24 ° C. for 48 hours to prepare a bacterial solution. Spread the bacterial solution to MH agar medium (Mueller-Hinton agar medium) inoculated with about 10 ⁶ CFU / mL, and make a hole with a diameter of 8 mm in the agar medium with a sterilized punch cutter (TOYOBO: biopsy punch 8 mm, made of stainless steel) The sample solution was inoculated into the well with 100 uL and cultured at 33 ° C. for 48 hours. After incubation, the diameter of the blocking circle that appeared around the hole was measured.
The results are shown in Table 8 below and FIG.

  As shown in Table 8 and FIG. 7, the compositions of Examples 1 and 2 exhibited superior bactericidal power against Candida, compared to the compositions of Comparative Examples 2 and 3 containing existing bactericides. .

  As described above, the compositions of Examples showed excellent antibacterial activity against various bacteria. Therefore, the compositions of the examples are antibacterial external compositions such as skin diseases (acne, scalp eczema, back eczema, atopic dermatitis, etc.), oral diseases (cavities, periodontal diseases, gum inflammation, etc.) They can also be widely used as cosmetics, quasi-drugs and / or pharmaceuticals having antibacterial effects and antiseptic sterilization effects on bacteria, fungi and the like involved in the generation of body odor. Moreover, since it is also excellent in antibacterial activity against Pseudomonas aeruginosa, it can be suitably used as an ophthalmic composition.

  External preparations for skin (prescription examples 1 to 14) having the following composition were prepared by a conventional method.

  Formulation Example 1: Whitening serum

  Formulation example 2: Whitening milky lotion

  Formulation Example 3: Whitening Cream

  Formulation Example 4: Spray cosmetic

  Formulation Example 5: Skin preparation

  Formulation Example 6: Sunscreen

  Formulation Example 7: Whitening emulsion

  Formulation Example 8: Whitening Cream

  Formulation Example 9: Whitening serum

  Formulation Example 10: Aging Care Cream

  Formulation Example 11: Aging Care Essence

  Formulation Example 12: Whitening serum

  Formulation Example 13: External hair restorer

  Formulation Example 14: Antibacterial preparation for external use

Claims (12)

(A) The following formula (1)

(In the formula, R is a hydrogen atom or a group represented by —C (O) R ^1. R ¹ is a saturated aliphatic group having 9 to 19 carbon atoms or a fatty acid having one unsaturated bond. And m is 0 or 1.) An antibacterial composition for external use comprising a compound represented by the formula: or a pharmaceutically acceptable salt thereof.   The composition for external use according to claim 1, which is for antibacterial against acne bacteria.   The composition for external use according to claim 1, which is for antibacterial purposes against fungi.   The composition for external use according to claim 1, which is for antibacterial against causative bacteria of body odor.   The composition for external use according to claim 1, which is used for antibacterial or sterilization in the oral cavity.   The external composition of Claim 5 for suppressing, improving or preventing at least 1 sort (s) selected from the group which consists of a tooth decay and periodontal disease.   The composition for external use of Claim 1 for suppressing, improving or preventing atopic dermatitis.   The composition for external use according to claim 1, which is for ophthalmology.   The external composition according to any one of claims 1 to 8, further comprising an antibacterial component other than the component (A). (A) The following formula (1)

(In the formula, R is a hydrogen atom or a group represented by —C (O) R ^1. R ¹ is a saturated aliphatic group having 9 to 19 carbon atoms or a fatty acid having one unsaturated bond. M is 0 or 1), or an antibacterial agent comprising a pharmaceutically acceptable salt thereof. (A) The following formula (1)

(In the formula, R is a hydrogen atom or a group represented by —C (O) R ^1. R ¹ is a saturated aliphatic group having 9 to 19 carbon atoms or a fatty acid having one unsaturated bond. An antibacterial method characterized by using a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an antibacterial component. (A) The following formula (1)

(In the formula, R is a hydrogen atom or a group represented by —C (O) R ^1. R ¹ is a saturated aliphatic group having 9 to 19 carbon atoms or a fatty acid having one unsaturated bond. An ophthalmic composition comprising a compound represented by the formula: or a pharmaceutically acceptable salt thereof.

Images