JP2023107940A - Acne bacteria biofilm destructive composition - Google Patents

Abstract

To provide agents of improving acne by inhibiting proliferation of acne bacteria, namely, biofilm destructive compositions.SOLUTION: An acne bacteria biofilm destructive composition contains at least one acne bacteria biofilm destructive component (A) selected from the group consisting of isopropyl methylphenol, salicylic acid, glycyrrhizinic acid, ibuprofen piconol, sulfadiazine and salts thereof, ethanol, resorcin, sulfur, and benzoyl peroxide.SELECTED DRAWING: Figure 2

Description

TECHNICAL FIELD The present invention relates to an acnes biofilm-disrupting composition, and more particularly to an acnes-bacteria biofilm-disrupting composition that inhibits propagation of P. acnes and fundamentally improves acne.

Acne is a skin disease that causes comedones, papules, nodules, and pustules, and may be accompanied by inflammation of hair follicles, and is mainly found on the face, chest, and back. It is known that the main causative bacterium of acne is Propionibacterium acnes (P. acnes), which is a resident bacterium of the skin.

P. acnes, an anaerobic bacterium, lives deep in the hair follicles and multiplies by using sebum accumulated in the follicles as nutrients, causing inflammation. . In order to treat such symptoms, various external preparations and oral preparations have been developed for the purpose of suppressing sebum production, preventing infection, suppressing inflammation, normalizing keratinization, and the like.

By the way, some bacteria form an accumulation of bacterial secretions (polysaccharides, etc.) called a biofilm and adhere to an adherend with viscosity. For example, sink slime is known to be a biofilm formed by bacteria. In addition, plaque that forms between teeth and between teeth and gums is considered to be a kind of biofilm.

P. acnes is also known to form biofilms. Since polysaccharides and the like secreted by P. acnes are accumulated in the biofilm, it is difficult for drugs such as antibacterial agents to penetrate into the biofilm, and the bactericidal effect is weakened. Therefore, since the presence or absence of biofilm formation affects the pathogenicity of various bacterial infections (Non-Patent Document 1), the development of antibacterial agents that are highly effective against biofilms is also underway. , Streptococcus mutans, and Escherichia coli have already been disclosed (Patent Document 1).
In addition, an amino sugar derivative is known to remove or destroy Pseudomonas aeruginosa biofilms, and is known as a therapeutic agent for bifilm infections presenting intractable infections (Patent Document 2).

Japanese Patent No. 3717960 Japanese Patent No. 3769040

Tom Coenye et al., Infectious Disorders-Drug Targets, 2008, 8, P.156-159

However, the development of biofilm-destroying preparations against P. acnes, which forms biofilms deep in hair follicles, has not yet been sufficiently accomplished. Therefore, an object of the present invention is to provide a formulation that is highly effective in destroying such biofilms.

To achieve the above objects, the present invention provides at least one selected from the group consisting of isopropylmethylphenol, salicylic acid, glycyrrhizic acid, ibuprofenpiconol, sulfadiazine and salts thereof, ethanol, resorcinol, sulfur, and benzoyl peroxide. A first aspect is a biofilm-disrupting composition containing a biofilm-disrupting component (A) of P. acnes.

Further, in the present invention, the P. acnes biofilm disrupting component (A) is at least one selected from the group consisting of isopropylmethylphenol, sulfadiazine and salts thereof, ethanol, resorcinol, and benzoyl peroxide. This is the second gist. Furthermore, in addition to the component (A), the third gist is to contain at least one destruction-assisting component (B) selected from the group consisting of chlorobutanol, propyl gallate, sodium lactate, and orange oil. .

And the acnes biofilm-disrupting component (A) is at least one selected from the group consisting of isopropylmethylphenol, salicylic acid, glycyrrhizic acid, ibuprofenpiconol, sulfadiazine and salts thereof, resorcinol, sulfur, and benzoyl peroxide. The fourth gist is that the content of the component (A) is 0.05 to 8% by weight of the entire acne biofilm-disrupting composition, and the acne biofilm-disrupting component (A) is The fifth gist is that it is ethanol, and the content of the ethanol is 2.5 to 50% by weight of the entire P. acnes biofilm-disrupting composition.
A sixth aspect is the acnes biofilm-disrupting composition according to any one of the first to fifth aspects, which is applied to the skin.

That is, the present inventors have conducted repeated studies on biofilms formed by P. acnes, and as a result, even if it is a component that has a bactericidal effect on P. acnes, while confirming a component that does not have an effect of destroying P. acnes biofilms. , discovered a biofilm-disrupting composition having an effect of destroying P. acnes biofilms, and found that the use of this biofilm-disrupting composition destroys the biofilm of P. acnes to fundamentally improve acne, and arrived at the present invention. .

That is, the biofilm disrupting composition of the present invention contains at least one selected from the group consisting of isopropylmethylphenol, salicylic acid, glycyrrhizic acid, ibuprofenpiconol, sulfadiazine and salts thereof, ethanol, resorcinol, sulfur, and benzoyl peroxide. Since it contains the biofilm disrupting component (A) of P. acnes, it has an excellent effect in destroying the biofilm of P. acnes.

In addition, the P. acnes biofilm-disrupting component (A) in the biofilm-disrupting composition is at least one selected from the group consisting of isopropylmethylphenol, sulfadiazine and salts thereof, ethanol, resorcin, and benzoyl peroxide. When there is, while having a so-called bactericidal effect, it also has a biofilm destruction effect of P. acnes different from the bactericidal effect.

Acne bacteria biofilm disrupting composition, in addition to component (A), further contains at least one destruction-assisting component (B) selected from the group consisting of chlorobutanol, propyl gallate, sodium lactate, and orange oil. If it does, the effect of destroying the biofilm of P. acnes is further improved, and even if the content of the biofilm-destroying component (A) is low, a sufficient effect of destroying the biofilm can be observed.

The P. acnes biofilm-disrupting component (A) is at least one selected from the group consisting of isopropylmethylphenol, salicylic acid, glycyrrhizic acid, ibuprofenpiconol, sulfadiazine and salts thereof, resorcinol, sulfur, and benzoyl peroxide. In some cases, the content is preferably 0.05 to 8% by weight of the entire P. acnes biofilm disrupting composition from the viewpoint of biofilm disrupting effect.

When the P. acnes biofilm disrupting component (A) is ethanol, the content of the ethanol is 2.5 to 50% by weight of the entire P. acnes biofilm disrupting composition from the viewpoint of the biofilm disrupting effect. is preferred.

The acnes biofilm-disrupting composition is preferably applied to the skin.

FIG. 1(a) is a graph showing the results of the biofilm survival rate of the P. acnes biofilm destruction test of Example 1 product and Comparative Example 1 product, and FIG. 1(b) is Example 1 product and Comparative Example 1 product. is a graph showing the results of bacterial viability. FIG. 2(a) shows an optical micrograph of Reference Example 1 product (acne bacteria biofilm formation in control), and FIG. 2(b) shows an optical micrograph of Example 1 product. FIG. 3 is a graph showing the results of P. acnes biofilm destruction test of Examples 2 to 9 and Comparative Example 2. FIG. 4 is a graph showing the results of P. acnes biofilm destruction test for the products of Examples 1-1 to 1-4 with varying isopropylmethylphenol concentrations. FIG. 5 is a graph showing the results of P. acnes biofilm destruction test with varying ethanol concentrations for the products of Examples 2-1 to 2-5. FIG. 6 is a graph showing the results of P. acnes biofilm destruction test for the products of Examples 3-1 to 3-5 with varying resorcin concentrations. FIG. 7 is a graph showing the results of the P. acnes biofilm disruption test of Examples 10 to 13 containing the P. acnes biofilm-disrupting component (A) and the P. acnes biofilm-disrupting component (B). FIG. 8 is a graph showing the results of the P. acnes biofilm disruption test of Examples 14 to 16 containing the P. acnes biofilm-disrupting component (A) and the P. acnes biofilm-disrupting component (B).

Next, embodiments of the present invention will be described in detail. However, the present invention is not limited to the following embodiments.

Acne bacteria biofilm disruption composition of the present invention, at least one selected from the group consisting of isopropylmethylphenol, salicylic acid, glycyrrhizic acid, ibuprofenpiconol, sulfadiazine and salts thereof, ethanol, resorcinol, sulfur, and benzoyl peroxide It contains the P. acnes biofilm disrupting component (A) of the species. P. acnes biofilm destruction means the reduction of biofilms formed by microorganisms (acne bacteria). The reduction in biofilm is detected by a known method, but if it is the method described in the test examples described later, it is desirable that the biofilm survival rate is reduced to 80% or less, further 60% or less, Especially 50% or less, especially 40% or less is preferable. Hereinafter, P. acnes biofilm disruption may be abbreviated as “BF disruption”.

The BF-destroying component (A), which is an essential component of the BF-destroying composition, will be described in detail below.

<BF destruction component (A)>
BF-disrupting component (A) refers to isopropylmethylphenol, salicylic acid, glycyrrhizic acid, ibuprofenpiconol, sulfadiazine and their salts, ethanol, resorcinol, sulfur, and benzoyl peroxide. Methylphenol and its salts, ethanol and resorcinol are preferred, and isopropylmethylphenol and its salts are more preferred.
These BF-destroying components (A) can be used alone or in combination of two or more.

(I) Among the components (A), isopropylmethylphenol, sulfadiazine and their salts, ethanol, resorcinol, and benzoyl peroxide have been conventionally known as bactericidal components, and have not only a bactericidal effect but also a bactericidal effect. It is preferably used because it has a biofilm destruction effect different from.

(II) Among components (A), salicylic acid and its salts, and sulfur are conventionally known as keratin-softening components, and have a keratin-softening effect that is different from the biofilm-breaking effect together with the biofilm-breaking effect. Therefore, it is preferably used.

(III) Among components (A), glycyrrhizic acid, ibuprofen piconol, and salts thereof are conventionally known as anti-inflammatory components, and are preferred because they have anti-inflammatory effects and biofilm destruction effects. Used.

Various positional isomers of isopropylmethylphenol (A) are known, and any of them may be used in the present invention. Specifically, positional isomers of isopropylmethylphenol include 3-methyl-4-isopropylphenol [also called biosol], 2-isopropyl-5-methylphenol [also called thymol], or 2-methyl-5-isopropylphenol. Examples include, but are not limited to, phenol (also called carvacrol). 3-Methyl-4-isopropylphenol is preferred from the viewpoint of exhibiting the effects of the present invention.

The salt of isopropylmethylphenol as component (A) may be any pharmacologically acceptable salt, for example, salts of mineral acids such as sulfuric acid, hydrochloric acid or phosphoric acid, organic acids such as maleic acid or methanesulfonic acid Acid salts, alkali metal salts such as sodium or potassium, alkaline earth metal salts, and the like.

Also, the salicylic acid salt of component (A) may be any pharmaceutically acceptable salt, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth salts such as calcium salts and magnesium salts; zinc salts; iron salts; ammonium salts; salts with basic amino acids such as arginine, lysine, histidine and ornithine; salts with amines such as monoethanolamine, diethanolamine and triethanolamine.

Further, the salt of glycyrrhizic acid as component (A) may be any pharmacologically acceptable salt, and examples thereof include alkali metal salts such as sodium salts and potassium salts; alkali metal salts such as calcium salts and magnesium salts; Earth metal salts; salts with amines such as tilamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine and picoline. Among these, an alkali metal salt of glycyrrhizic acid, and more preferably dipotassium glycyrrhizinate are preferred from the viewpoint of exhibiting the effects of the present invention.

The salt of ibuprofen piconol as the component (A) may be any pharmacologically acceptable salt, for example, salts of mineral acids such as sulfuric acid, hydrochloric acid or phosphoric acid, maleic acid or methanesulfonic acid, and the like. organic acid salts, alkali metal salts such as sodium or potassium, and alkaline earth metal salts.

Also, the salt of sulfadiazine as the component (A) may be any pharmacologically acceptable salt, for example, salts of mineral acids such as sulfuric acid, hydrochloric acid or phosphoric acid, Salts of acids, salts of metals such as sodium, potassium or silver are included.

[(A) component content]
(I) Among the BF-destroying components (A), the content of the poorly water-soluble component and the water-soluble solid component is preferably 0.05 to 8% by weight of the entire BF-destroying composition from the viewpoint of effect. . Among the BF-destroying components (A), poorly water-soluble components include isopropylmethylphenol, salicylic acid, ibuprofenpiconol, sulfadiazine and salts thereof, resorcinol, sulfur, and benzoyl peroxide. Water-soluble solid components include Examples include glycyrrhizic acid and salts thereof. These can be used alone or in combination of two or more.

Among them, the content of at least one of isopropylmethylphenol and its salt is preferably 0.05 to 1.5% by weight, particularly preferably 0.3 to 1% by weight, of the entire BF-destroying composition. . If it is within these ranges, it exhibits an excellent biofilm destruction effect, while if it is less than 0.05% by weight, the biofilm destruction effect tends to be relatively low, and if it exceeds 1.5% by weight, the odor intensity of the formulation is high and tends to be unsuitable for practical use.

Moreover, it is particularly preferable that the content of resorcin is 0.5 to 4% by weight of the entire BF-destroying composition. If it is within this range, it exhibits an excellent biofilm destruction effect, but if it is less than 0.5% by weight, the biofilm destruction effect tends to be insufficient. tend to be unsuitable for sex.

(II) Among the BF-destroying components (A), the content of the water-soluble liquid component is preferably 2.5 to 50% by weight of the entire BF-destroying composition from the viewpoint of effect, particularly 2.5 ~30% by weight is preferred. If it is within these ranges, an excellent biofilm destruction effect is exhibited, but if it is less than 2.5% by weight, the biofilm destruction effect tends to be insufficient, and if it exceeds 30% by weight, the odor intensity is high and practical. tend to be unsuitable for sex. Among the BF-destroying components (A), examples of water-soluble liquid components include ethanol.

<Destruction aid component (B)>
Next, the biofilm disrupting composition of the present invention preferably contains not only the above component (A) but also a disruption assisting component (B). Here, the destruction-assisting component refers to a component for assisting the destruction of P. acnes biofilm.

Examples of the breaking-assisting ingredient (B) include chlorobutanol, propyl gallate, sodium lactate, and orange oil, among which chlorobutanol, propyl gallate, and sodium lactate are more preferred. These destruction-assisting components (B) can be used alone or in combination of two or more.

The chlorobutanol is used as a preservative, the propyl gallate as an antioxidant for foods, the sodium lactate as a moisturizing ingredient, and the orange oil as an additive added to foods and beverages, perfumes, detergents, etc. used so far. The destruction-assisting component (B) is thus a completely different component from the BF-destroying component (A), but when used in combination with the component (A), it effectively reinforces the biofilm destruction effect. . Furthermore, since the reinforcing effect is high, even when the content of the component (A) is low and tends to be insufficient, the biofilm destruction effect can be sufficiently obtained.

The content of the breakage assisting component (B) is preferably 0.001 to 10% by weight of the entire BF breakage composition from the viewpoint of effect and practicality, and further preferably 0.01 to 5% by weight. preferable.

<Other ingredients>
In addition, according to various purposes, moisturizing ingredients, polyhydric alcohols, scrubbing agents, ultraviolet absorbing ingredients, ultraviolet scattering ingredients, anti-inflammatory agents other than component (A), astringent ingredients, vitamins, peptides or derivatives thereof, amino acids or Other ingredients such as derivatives thereof, cleansing ingredients, bactericidal ingredients other than ingredient (A), keratin softening ingredients, cell activating ingredients, anti-aging ingredients, blood circulation promoting ingredients, whitening ingredients, etc., are added to the extent that the effects of the present invention are not impaired. may be included in Among them, it is preferable to contain polyhydric alcohols, vitamins, and anti-inflammatory agents other than the component (A). In addition, these other components may be used individually by 1 type, and may use 2 or more types together.

Examples of the moisturizing ingredients include diglycerin trehalose; sodium hyaluronate, heparin analogues, sodium chondroitin sulfate, collagen, elastin, keratin, chitin, chitosan and other high-molecular compounds; glycine, aspartic acid, arginine and other amino acids; urea , natural moisturizing factors such as sodium pyrrolidonecarboxylate; lipids such as ceramide, cholesterol and phospholipid; plant extracts such as chamomile extract, hamamelis extract, tea extract and perilla extract.

As the polyhydric alcohol, those having 2 to 10 carbon atoms are preferable, and examples thereof include glycerin, diglycerin, triglycerin, propylene glycol, dipropylene glycol, 1,3-butanediol, ethylene glycol, diethylene glycol, isoprene glycol, 1 , 3-butylene glycol, sorbitol, xylitol, erythritol, mannitol, pentanediol, hexanediol, octanediol, decanediol, neopentyl glycol and the like.

Among these, glycerin, diglycerin, triglycerin, propylene glycol, dipropylene glycol, 1,3-butanediol, ethylene glycol, diethylene glycol, isoprene glycol, sorbitol, xylitol, erythritol, mannitol, pentanediol, hexanediol, octanediol are preferred, and glycerin, diglycerin, propylene glycol, dipropylene glycol, 1,3-butanediol, diethylene glycol, isoprene glycol, sorbitol, xylitol, erythritol, mannitol, pentanediol and hexanediol are more preferred.

Examples of the scrubbing agent include apricot kernel powder, almond shell powder, apricot kernel powder, sodium chloride grains, olive kernel powder, seawater dried grains, candelilla wax, walnut shell powder, cherry kernel powder, coral powder, and charcoal powder. , husk powder, polyethylene powder, silicic anhydride, and the like.

Examples of the ultraviolet absorbing component include octyltriazone, dimethoxybenzylidenedioxoimidazolidinepropionate, 2-ethylhexyl paramethoxycinnamate, and phenylbenzimidazole sulfonic acid.

Examples of the ultraviolet scattering component include inorganic compounds such as hydrous silicic acid, zinc silicate, cerium silicate, titanium silicate, zirconium oxide, cerium oxide, titanium oxide, iron oxide, and silicic anhydride, and these inorganic compounds. Coated with inorganic powder such as hydrated silicic acid, aluminum hydroxide, mica and talc, compounded with resin powder such as polyamide, polyethylene, polyester, polystyrene, nylon, silicone oil and fatty acid aluminum salt etc. processed ones, and the like.

Anti-inflammatory agents other than the component (A) include allantoin and its derivatives, glycyrrhetinic acid and its derivatives, azulene and its derivatives, components derived from plants (eg, comfrey), zinc oxide, tocopherol acetate, aminocaproic acid, hydrocortisone, prednisolone and salts thereof; Among them, allantoin and its derivatives, glycyrrhetic acid and its derivatives, azulene and its derivatives, and aminocaproic acid are preferred, and allantoin, allantoin chlorohydroxyaluminum, allantoin dihydroxyaluminum, glycyrrhetinic acid, stearyl glycyrrhetinate, epsilon aminocaproic acid, azulene, guaiazulene and Salts thereof are more preferred, and allantoin is particularly preferred. The term "derivatives" refers to esters, ethers, alkylates, glycosides, etc. of the described compounds.

Examples of the astringent component include zinc sulfate, zinc oxide, aluminum chloride, zinc sulfonate, and tannic acid.

Examples of the above vitamins include vitamin E such as dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate; riboflavin, flavin mononucleotide, flavin Vitamin B2s such as adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5′-phosphate sodium, riboflavin tetranicotinate; nicotinic acid, dl-α-tocopherol nicotinate, benzyl nicotinate, nicotinic acid nicotinic acids such as methyl, β-butoxyethyl nicotinate, 1-(4-methylphenyl)ethyl nicotinate, nicotinamide; ascorbigen-A, ascorbyl stearate, ascorbyl palmitate, dipalmitate L- vitamin Cs such as ascorbyl; vitamin Ds such as methylhesperidin, ergocalciferol, cholecalciferol; vitamin Ks such as phylloquinone and farnoquinone; γ-oryzanol, dibenzoylthiamine, dibenzoylthiamine hydrochloride, thiamine hydrochloride, Thiamine cetyl hydrochloride, thiamine thiocyanate, thiamine lauryl hydrochloride, thiamine nitrate, thiamine monophosphate, thiamine lysine salt, thiamine triphosphate, thiamine monophosphate phosphate, thiamine monophosphate, thiamine diphosphate, Vitamin B1s such as thiamine diphosphate hydrochloride, thiamine triphosphate, thiamine triphosphate monophosphate; vitamin B6s such as pyridoxine hydrochloride, pyridoxine acetate, pyridoxal hydrochloride, 5′-pyridoxal phosphate, pyridoxamine hydrochloride; cyanocobalamin , hydroxocobalamin, deoxyadenosylcobalamin and other vitamin B12s; folic acid, pteroylglutamic acid and other folic acids; pantothenic acid, calcium pantothenate, pantothenyl alcohol (panthenol), D-panthesaine, D-pantethine, coenzymes A, pantothenic acids such as pantothenyl ethyl ether; biotins such as biotin and biocytin; ascorbic acid derivatives such as ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate, and magnesium ascorbate phosphate. vitamin Cs; vitamin-like acting factors such as carnitine, ferulic acid, α-lipoic acid and orotic acid;

Examples of the peptides or derivatives thereof include keratin-degrading peptides, hydrolyzed keratin, collagen, fish-derived collagen, atelocollagen, gelatin, elastin, elastin-degrading peptides, collagen-degrading peptides, hydrolyzed collagen, hydroxypropylammonium chloride hydrolyzed collagen, Elastin-degrading peptide, conchiolin-degrading peptide, hydrolyzed conchiolin, silk proteolytic peptide, hydrolyzed silk, lauroyl hydrolyzed silk sodium, soybean proteolytic peptide, hydrolyzed soybean protein, wheat protein, wheat proteolytic peptide, hydrolyzed wheat protein, Examples include casein-degraded peptides, acylated peptides (palmitoyl oligopeptide, palmitoyl pentapeptide, palmitoyl tetrapeptide, etc.).

Examples of the above amino acids or derivatives thereof include betaine (trimethylglycine), proline, hydroxyproline, arginine, lysine, serine, glycine, alanine, phenylalanine, β-alanine, threonine, glutamic acid, glutamine, asparagine, aspartic acid, cysteine, Cystine, methionine, leucine, isoleucine, valine, histidine, taurine, γ-aminobutyric acid, γ-amino-β-hydroxybutyric acid, carnitine, carnosine, creatine and the like.

Examples of the cleaning component include soaps selected from alkaline metal salts such as potassium laurate, potassium myristate, potassium palmitate or potassium stearate, alkanolamide salts or amino acid salts; sodium cocoyl glutamate, sodium cocoyl methyltaurate. Amino acid-based surfactants such as amino acid-based surfactants; ether sulfate salts such as sodium laureth sulfate; ether carboxylates such as sodium lauryl ether acetate; sulfosuccinate salts such as alkyl sulfosuccinate Na; coconut oil fatty acid monoethanolamide, coconut oil Fatty acid alkanolamides such as fatty acid diethanolamide; monoalkyl phosphate ester salts such as sodium lauryl phosphate and sodium polyoxyethylene lauryl ether phosphate; coconut oil fatty acid amidopropyl dimethylamino acetate betaine, lauryl dimethylamino acetate betaine, 2-alkyl -N-carboxymethyl-N-hydroxyethylimidazolinium betaine, lauryl hydroxysulfobetaine and lauroylamidoethyl hydroxyethyl carboxymethyl betaine betaine-type amphoteric surfactants such as sodium hydroxypropyl phosphate; amino acids such as sodium laurylaminopropionate type amphoteric surfactants, and the like.

Examples of bactericidal components other than the above component (A) include chlorhexidine, benzalkonium chloride, acrinol, benzethonium chloride, cresol, gluconic acid and its derivatives, povidone iodine, potassium iodide, iodine, triclocarban, triclosan, and photosensitizer 101. No. 201, paraben, phenoxyethanol, 1,2-pentanediol, alkyldiaminoglycine hydrochloride, pyroctoolamine, miconazole and the like.

Examples of the keratin softening component include lactic acid, gluconic acid, citric acid, malic acid, fruit acid, phytic acid, urea, and sulfur.

Examples of the cell activating components include amino acids such as γ-aminobutyric acid and ε-aminocaproic acid; vitamins such as retinol, thiamine, riboflavin, pyridoxine hydrochloride and pantothenic acids; α-hydroxy acids such as glycolic acid and lactic acid. tannins, flavonoids, saponins, photosensitizer No. 301 and the like.

Examples of the antiaging component include pangamic acid, kinetin, ursolic acid, turmeric extract, sphingosine derivatives, silicon, silicic acid, N-methyl-L-serine, and mevalonolactone.

Examples of the blood circulation-promoting ingredients include plants (e.g., Panax ginseng, Angelica keiskei, Arnica, Ginkgo biloba, Fennel, Trichophyllum japonicum, Holland oak, Chamomile, Roman chamomile, Carrot, Gentian, Burdock, Rice, Hawthorn, Shiitake mushroom, Ginger, Hawthorn, Juniperus juniper). , Cnidium, Senburi, Thyme, Clove, Chimp, Pepper, Angelica, Tonin, Spruce, Carrot, Garlic, Butcher Bloom, Grape, Button, Horse Chestnut, Melissa, Yuzu, Yokuinin, Ryokucha, Rosemary, Rosehip, Peach, Apricot, walnuts, corn, etc.); acetylcholine, ictamol, cantharis tincture, gamma oryzanol, cepharanthine, tolazoline, tocopherol nicotinate, glucosyl hesperidin, and the like.

Examples of the whitening ingredients include tocopherol and tranexamic acid.

<Method for producing BF destruction composition>
The method for producing the BF-destroyed composition of the present invention is not particularly limited. Various components (above-mentioned other components, bases or carriers described later, additives, etc.) can be appropriately selected and blended, and can be produced by a conventional method.

The BF-destroying composition of the present invention may be an emulsified composition or a solubilized composition. In that case, it may be either an oil-in-water type or a water-in-oil type, but from the viewpoint of expressing the effects of the present invention and the feeling of use of the BF-destroying composition (stickiness, spreadability, moist feeling, etc.), an oil-in-water composition is used. is preferably

<Application of BF destruction composition>
As described above, since the BF-disrupting composition of the present invention contains the BF-disrupting component (A), it destroys P. acnes biofilms and is used as a pharmaceutical composition that is particularly effective for fundamental treatment of acne. In particular, it can be suitably used as an external preparation applied to the skin. External preparations can be formulated by known methods in the form of liquids, suspensions, emulsions, creams, ointments, gels, liniments, lotions, aerosols, powders, sheets, and the like. can. Preferred are solutions, suspensions, emulsions and creams, more preferred are solutions, emulsions and creams.

The usage, dosage, etc. of the BF-disrupting composition of the present invention are not particularly limited, and vary depending on the age of the subject to be used, the degree of symptoms, etc., but usually several times a day (for example, about twice a day in the morning and evening) ), an appropriate amount (for example, about 0.01 to 1 g) is applied (for example, applied, sprayed, or pasted) to the outer skin of the skin (especially, the affected area where symptoms are worrisome, such as the area where acne occurs). can be used Specifically, it can be used for topical administration to skin surfaces such as the face, around the lips, scalp, neck, chest, back, abdomen, arm, oral cavity, armpit, buttocks and genitals. It can be administered topically to various acne conditions, for example, microcomedones (keratotic plug formation, initial keratotic plugging), so-called pimples (adult acne), white acne (white papules), blackheads (open It can be used as a prophylactic and/or therapeutic agent for red acne (red papules) or yellow acne (suppurative acne) accompanied by inflammation. It is effectively used when P. acnes proliferates in or around hair follicles and forms a biofilm.

Dry skin, which is often seen in adult acne, is prone to excessive sebum secretion and blockage of keratin plugs, and such changes in the surrounding environment and stress may increase biofilm formation by P. acnes. In addition, there is concern that when biofilm formation increases, P. acnes protected by the biofilm becomes more likely to repeatedly develop acne symptoms. It is known that increased biofilm formation leads to increased lipase activity, and lipase decomposes triglycerides in sebum to produce free fatty acids, causing inflammation in hair follicles. Therefore, the biofilm formation inhibitor of the present invention, more specifically the BF-disrupting composition of the present invention, is used for treating or preventing acne, and more specifically treating acne in dry skin. Alternatively, it can be used for prophylaxis, for the treatment or prevention of recurrent acne, or for the treatment or prevention of acne associated with inflammation in hair follicles.

<Formulation>
The BF-destroying composition of the present invention contains the essential ingredients and other ingredients described above, etc., a base or carrier commonly used in pharmaceuticals, etc., and, if necessary, additives described later. Then, emulsification or solubilization is performed as necessary, and BF-disrupting compositions in various formulations can be obtained.

Examples of the base or carrier include liquid paraffin, squalane, vaseline, gelling hydrocarbons (Plastibase, etc.), ozokerite, α-olefin oligomers, hydrocarbons such as light liquid paraffin; methylpolysiloxane, highly polymerized methylpolysiloxane. , cyclic silicone, alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, silicone/alkyl chain co-modified polyether-modified silicone, silicone/alkyl chain co-modified polyglycerin-modified silicone, polyether-modified branched silicone, Silicone oils such as polyglycerin-modified branched silicones, acrylic silicones, phenyl-modified silicones, and silicone resins; oils and fats such as coconut oil, olive oil, rice bran oil, and shea butter; waxes such as jojoba oil, beeswax, candelilla wax, and lanolin; cetanol , cetostearyl alcohol, stearyl alcohol, behenyl alcohol, octyldodecanol, isostearyl alcohol, phytosterol, higher alcohols such as cholesterol; cellulose derivatives such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose; polyvinylpyrrolidone; carrageenan; polyvinyl butyrate; polyethylene glycol; dioxane; butylene glycol adipate polyester; polysaccharides such as dextrin and maltodextrin; vinyl polymers such as carboxyvinyl polymer and alkyl-modified carboxyvinyl polymer; lower alcohols such as ethanol and isopropanol; ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, Glycol ethers such as diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monobutyl ether, propylene glycol monoethyl ether, propylene glycol monopropyl ether, dipropylene glycol monoethyl ether, dipropylene glycol monopropyl ether; water, etc.; is mentioned. When the BF-disrupting composition of the present invention contains a polyhydric alcohol, the polyhydric alcohol may also serve as a base or carrier. Above all, the BF-destroying composition of the present invention preferably contains water and/or a lower alcohol, and more preferably contains water.

When the BF-destroying composition of the present invention contains a base or carrier other than water and a lower alcohol, examples of the base or carrier include higher alcohols, hydrocarbons, fats and oils, esters, silicone oils, waxes, vinyl system polymers are preferred, and higher alcohols, ester oils, silicone oils and vinyl polymers are more preferred. Among these components, cetanol, cetostearyl alcohol, stearyl alcohol, behenyl alcohol, glyceryl tri-2-ethylhexanoate, dimethicone, cyclomethicone, polyether-modified silicone, polyglycerin-modified silicone, and carboxyvinyl polymer are more preferred.

One of the bases or carriers described above may be used alone, or two or more thereof may be used in combination. In addition, the amount to be used of them is appropriately selected from the range known to those skilled in the art.

<Formulation form>
The formulation form of the BF-disrupting composition of the present invention is not particularly limited. agents and the like. Among these, liquid to semi-solid formulations are preferred, and are particularly useful when applied to liquids, lotions, ointments, gels, and emulsifiers. These formulations can be produced according to a conventional method, for example, the method described in the Japanese Pharmacopoeia General Rules for Preparations, 16th Edition.

<Additive>
The BF-destroying composition of the present invention contains known additives that are added to pharmaceuticals, such as surfactants, stabilizers, antioxidants, coloring agents, and imparting pearl luster, to the extent that the effects of the present invention are not impaired. Agents, dispersants, chelating agents, pH adjusters, cooling agents, preservatives, thickeners, irritation reducing agents and the like can be added. Among them, it is preferable to add a cooling agent and a thickening agent. These additives may be used singly or in combination of two or more.

Examples of the surfactant include nonionic surfactants, cationic surfactants, anionic surfactants, amphoteric surfactants, and the like. Examples include sorbitan monoisostearate and sorbitan monolaurate. , sorbitan monopalmitate, sorbitan monostearate, diglycerol sorbitan penta-2-ethylhexylate, and diglycerol sorbitan tetra-2-ethylhexylate; propylene glycol fatty acid esters such as propylene glycol monostearate; Hydrogenated castor such as polyoxyethylene hydrogenated castor oil 40 (HCO-40), polyoxyethylene hydrogenated castor oil 50 (HCO-50), polyoxyethylene hydrogenated castor oil 60 (HCO-60), polyoxyethylene hydrogenated castor oil 80 Oil derivatives; polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), polyoxyethylene (20) sorbitan monooleate (polysorbate 80), isostearic acid Polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene (20) sorbitan; polyoxyethylene monococonut oil fatty acid glyceryl; glycerin alkyl ether; alkyl glucoside; polyoxyalkylene alkyl ether such as polyoxyethylene cetyl ether; amines such as polyoxyethylene/methylpolysiloxane copolymer, lauryl PEG-9 polydimethylsiloxyethyl dimethicone, PEG-9 polydimethylsiloxyethyl dimethicone and other silicone surfactants. Among these, nonionic surfactants are preferred, and hydrogenated castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, and polyoxyalkylene alkyl ethers are more preferred.

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

Examples of the antioxidant include dibutylhydroxytoluene, butylhydroxyanisole, sorbic acid, sodium sulfite, ascorbic acid, erythorbic acid, L-cysteine hydrochloride and the like.

Examples of the coloring agent include inorganic pigments and natural pigments.

Examples of the pearl luster imparting agent include ethylene glycol distearate, ethylene glycol monostearate, and triethylene glycol distearate.

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

Examples of the chelating agent include EDTA.disodium salt, EDTA.calcium.disodium salt, and the like.

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 sodium oxide, etc.), organic bases (triethanolamine, diisopropanolamine, triisopropanolamine, etc.), and the like. Among them, inorganic bases and/or organic bases are preferred, and potassium hydroxide and triethanolamine are more preferred.

Examples of the cooling agent include terpenes such as menthol, camphor, borneol, geraniol, cineol, anethole, limonene, and eugenol (these may be d-, l-, or dl-forms); eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, fennel oil, peppermint oil, cinnamon oil, rose oil, and turpentine oil.

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

Examples of the thickener include vinyl thickeners such as polyvinyl alcohol, polyvinylpyrrolidone and carboxyvinyl polymer, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose, and the like. cellulose thickener, guar gum, pectin, pullulan, gelatin, locust bean gum, carrageenan, agar, xanthan gum, alkyl acrylate methacrylate copolymer, polyethylene glycol, bentonite, alginic acid, propylene glycol alginate, macrogol, chondroitin sulfate. sodium, hyaluronic acid, sodium hyaluronate, (hydroxyethyl acrylate/acryloyldimethyltaurate Na) copolymer, (acryloyldimethyltaurate ammonium/vinylpyrrolidone) copolymer, and the like. Among these, vinyl-based thickeners and cellulose-based thickeners are preferable, and carboxyvinyl polymer, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxy Ethyl cellulose is more preferred.

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

The BF destruction effect of the BF destruction composition of the present invention can be confirmed by measuring the biofilm residual rate (hereinafter sometimes abbreviated as "BF residual rate") by the BF destruction test described later.

EXAMPLES The present invention will be described in more detail below with reference to examples, but the present invention is not limited by these examples.

<Test 1: BF destruction test>
The biofilm destruction effect is confirmed by measuring the BF residual rate after addition of samples such as the example products to the medium in which P. acnes has formed a biofilm.
Specifically, in a 48-well round-bottom well plate, 10 ⁹ (CFU / mL) of P. acnes suspension cultured anaerobicly at 37 ° C. for 3 days in a reinforced Clostridia (RCM) slant medium. Dispense 500 μL of each test solution inoculated so as to be 1 well. Anaerobic culture is performed at 37° C. for 28 hours to allow the bacteria to adhere to the wells and form a biofilm. Discard the bacterial solution and wash each well twice with 500 μL of phosphate buffered saline (PBS).

After 500 μL of each sample is dispensed per well, anaerobic culture is performed for 24 hours. After incubation, each well is washed twice with 500 μL of PBS. 500 μL of methanol (manufactured by Wako Pure Chemical Industries, Ltd.) is dispensed into each well, left to stand for 15 minutes, then methanol is removed, and dried.

Staining was performed for 20 minutes with 100 μL of 0.5% by weight crystal violet (manufactured by Kanto Kagaku Co., Ltd.) per well. The crystal violet solution was removed, each well was washed twice with 500 μL of purified water, and then crystal violet adhering was dissolved with 150 μL of 33% by weight acetic acid (manufactured by Wako Pure Chemical Industries, Ltd.). 300, manufactured by AS ONE), shake at 300 rpm for 5 minutes. Dispense 100 μL of the extract from each well into a 96-well flat plate, and measure the absorbance at 590 nm where crystal violet exhibits absorbance using a microplate reader (Molecular Devices, Versa max). Take the sample OD ₅₉₀ value.

An RCM medium containing 2.5% by weight dimethyl sulfoxide (DMSO, manufactured by Wako Pure Chemical Industries, Ltd.) was prepared as a control, and the ratio of this biofilm formation amount was used to calculate the biofilm remaining in the following formula (1). Calculate the rate.

Formula (1): biofilm survival rate (%) = sample OD ₅₉₀ value / control OD ₅₉₀ value × 100

The Dunnett test was used to test statistical significance, and the P value was calculated. Experiments are performed with an n number of 6.

<Test 2: Bacterial viability measurement>
Bacterial viability is measured using a Cell Titer-Blue Cell Viability Assay kit (manufactured by Promega).
Specifically, a 48-well round-bottom well plate was inoculated with an anaerobic cultured P. acnes suspension at 37 ° C. for 3 days in an RCM slant medium so that 10 ⁹ (CFU / mL) of the bacterial solution was obtained. Dispense 500 μL of the test solution per well. Anaerobic culture is performed at 37° C. for 28 hours to allow the bacteria to adhere to the wells and form a biofilm. Discard the bacterial solution and wash each well twice with 500 μL of PBS.

After 500 μL of each sample is dispensed per well, anaerobic culture is performed for 24 hours. Wash each well twice with 500 μL of PBS. After dispensing 500 μL physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd.) and 100 μL Cell Titer blue (manufactured by Promega) into each well, anaerobic culture at 37 ° C. for 1 hour, fluorescence microplate reader (manufactured by Molecular Devices, Flex station ) to perform fluorescence measurements (Ex: 560 nm, Em: 590 nm).

An RCM medium containing 2.5% by weight DMSO (manufactured by Wako Pure Chemical Industries, Ltd.) is prepared as a control, and the ratio to this fluorescence value is used to calculate the bacterial survival rate according to the following formula (2).

Formula (2): Bacterial survival rate (%) = sample fluorescence value/control fluorescence value x 100

The Dunnett test was used to test statistical significance, and the P value was calculated. Experiments are performed with an n number of 6.

First, prior to the Examples, Reference Example 1 (control) shown below was prepared, and Examples and Comparative Examples containing the component (A) and, if necessary, the component (B) were prepared.

[Reference Example 1]
As a control, 2.5 wt% DMSO was prepared.

[Example 1, Comparative Example 1]
In addition to the control of Reference Example 1, a BF-destroying composition was prepared so that the content of component (A) in Table 1 below was obtained.

The above BF destruction test and bacterial viability measurement were performed on the 1 product of Reference Example, 1 product of Example and 1 product of Comparative Example. The results of their BF disruption tests are shown in Table 1 above and shown in FIG. 1(a), and the results of bacterial viability measurements are shown in FIG. 1(b).

As a result of measuring the bacterial survival rate, from FIG. 1(b), the bacterial survival rate of Example 1 and Comparative Example 1, which have been conventionally known as bactericidal components, is almost 0%. confirmed.

On the other hand, as a result of the BF destruction test, from Table 1 and FIG. 1(a), it was found that the BF residual rate of Example 1 was reduced to 29%, and BF destruction was effectively performed. On the other hand, the product of Comparative Example 1 containing azelaic acid, which is known as an antibacterial agent for P. acnes, had a BF residual rate of 89%, and was found to have almost no BF destruction effect. Thus, even acne bacteria disinfectants include some that are not BF-destroying ingredients (A). It can be seen that the BF-breaking component (A) capable of BF-breaking has been found.

<Test 3: BF destruction state observation>
The results of Reference Example 1 (control) and Example 1 after staining the biofilm with crystal violet used in the BF destruction test of Test 1 above were examined with an optical microscope (manufactured by Carl Zeiss) at a magnification of 50 times. Observation was made under the conditions of (eyepiece × 10, objective lens × 5), the optical microscope photograph of Reference Example 1 is shown in Fig. 2 (a), and the optical microscope photograph of Example 1 is shown in Fig. 2 (b). rice field.

As a result, as can be seen from FIG. 2, in Reference Example 1, biofilms stained with crystal violet were widely present, whereas in Example 1, the amount of crystal violet staining was significantly reduced. It was found that the biofilm had been destroyed.

[Examples 2 to 9, Comparative Example 2]
Next, a BF-destroying composition was prepared by blending the above control with the component (A) content shown in Table 2 below.

The BF destruction test of Test 1 was performed on the products of Examples 2 to 9 and the product of Comparative Example 2. The results are shown in Table 2 above and also in FIG. From Table 2 and FIG. 3, the product of Comparative Example 2 has a BF residual rate of 98% and the biofilm is hardly reduced. It turned out that there was no On the other hand, it was found that the products of Examples 2 to 9 all had a BF residual rate of less than 60%, exhibiting a BF destruction effect.

Next, the effect of changing the concentration of isopropylmethylphenol (IPMP), which is one of the BF-destroying components (A), was studied.

[Examples 1-1 to 1-4]
A BF-destroying composition was prepared by blending the above control with the IPMP (A) content shown in Table 3 below.

The BF destruction test of Test 1 was performed on the products of Examples 1-1 to 1-4. The results are shown in Table 3 above and also in FIG. From Table 3 and FIG. 4, Example 1-1 product to Example 1-4 product have BF residual rates of 30%, 29%, 11%, and 10%, respectively, and exhibit a certain BF destruction effect. I knew there was

In addition, the BF destruction effect of changing ethanol concentration, which is one of the BF destruction components (A), was examined.

[Examples 2-1 to 2-5]
A BF-destroying composition was prepared by blending the above control with the ethanol (A) content shown in Table 4 below.

The BF destruction test of Test 1 was performed on the products of Examples 2-1 to 2-5. The results are shown in Table 4 above and also in FIG. From Table 4 and FIG. 5, it was found that all of the products of Examples 2-1 to 2-5 had a BF residual rate of less than 60% and exhibited a certain BF destruction effect.

Furthermore, the effect of changing the concentration of resorcin, which is one of the BF-disrupting components (A), was examined.

[Examples 3-1 to 3-5]
A BF-destroying composition containing the resorcinol (A) shown in Table 5 below was prepared for each of the above controls.

The BF destruction test of Test 1 was performed on the products of Examples 3-1 to 3-5. The results are shown in Table 5 above and also in FIG. From Table 5 and FIG. 6, it was found that all of the products of Examples 3-1 to 3-5 exhibited a BF residual rate of 40% or less, exhibiting a certain BF destruction effect.

The BF-breaking effect was investigated when the BF-breaking composition contained the BF-breaking component (A) and the break-assisting component (B).

[Examples 10 to 13]
A BF-destroying composition was prepared by blending the above control with the component (A) content and the component (B) content in Table 6 below.

The BF destruction test of Test 1 was performed on the products of Examples 10 to 13. The results are shown in Table 6 above and also in FIG. From Table 6, FIG. 7 and FIG. 4, even with a low-concentration IPMP-containing composition of 0.025% by weight, the combined use of the destruction-assisting component (B) provides an excellent BF destruction effect of 0.1 It was found that the same degree of BF destruction effect as that of the composition containing wt% IPMP was exhibited.

[Examples 14 to 16]
A BF-destroying composition was prepared by blending the above control with the component (A) content and component (B) content in Table 7 below.

The BF destruction test of Test 1 was performed on the products of Examples 14 to 16 above. The results are shown in FIG. 8 together with Table 7 above. From Table 7, FIG. 8 and FIG. 6, even with a low-concentration resorcinol-containing composition of 0.25% by weight, which tends to have insufficient BF-breaking effect, by using the break-assisting component (B) in combination, , BF destruction effect comparable to 0.5% by weight resorcinol-containing composition, etc., which exhibits an excellent BF destruction effect.

(Formulation example)
Formulation examples of the P. acnes biofilm disrupting composition of the present invention are shown in Tables 8 and 9 below.

Since the BF-disrupting composition of the present invention can destroy biofilms, it is very effective as an externally-applied composition such as an externally-applied drug, an externally-applied quasi-drug, and a cosmetic, which is effective for the fundamental treatment of acne.

Claims (5)

It contains at least one biofilm-disrupting component (A) selected from the group consisting of sulfadiazine and salts thereof, and is used in an external composition applied to the skin for the prevention or treatment of eruptions caused by inflammation in hair follicles. Biofilm disrupting composition. 2. The biofilm disrupting composition according to claim 1, further comprising at least one disrupting component (B) selected from the group consisting of chlorobutanol, propyl gallate, sodium lactate, and orange oil. The biofilm disrupting composition according to claim 1 or 2, wherein the content of component (A) is 0.05 to 8% by weight of the entire biofilm disrupting composition. A biofilm disrupting agent for use in an external composition applied to the skin for the prevention or treatment of eruptions caused by inflammation in hair follicles, comprising at least one selected from the group consisting of sulfadiazine and salts thereof. An external composition for treating or preventing eruptions caused by inflammation in hair follicles, comprising the biofilm disrupting agent according to claim 4.