JP7623822B2 - External Composition - Google Patents

Description

The present invention relates to a topical composition, and more specifically to a topical composition containing bactiol and glycyrrhizic acid or a derivative thereof, or a salt thereof.

Bakuchiol is a type of meroterpene, a naturally occurring terpenophenolic compound, and is an oily hydrophobic compound at room temperature. In recent years, it has been revealed that bakuchiol has a retinol-like effect (Non-Patent Document 1), and its anti-aging effect on the skin has attracted attention. To date, bakuchiol has been used in cosmetics, for example, as a skin-whitening agent (Patent Document 1).

Glycyrrhizic acid is also a type of triterpene glycoside and is used in medicines and cosmetics because it has anti-inflammatory properties.

On the other hand, it is known that inflammatory cytokines are involved in skin inflammation. For example, IL-6 is one of the major inflammatory cytokines known to be associated with various inflammatory diseases, and it is known that there is a correlation between increased serum IL-6 concentrations and psoriasis (Non-Patent Document 2). IL-6 also induces the proliferation of keratinocytes and is involved in the thickening of the skin seen in psoriasis and other conditions (Non-Patent Document 3). Furthermore, IL-6 has the effect of promoting collagen production by fibroblasts, but when IL-6 acts on fibroblasts, the fibroblasts themselves produce IL-6, resulting in excessive secretion of IL-6 through positive feedback, which causes fibrosis (Non-Patent Document 4).

Japanese Patent Application Publication No. 11-71231

International Journal of Cosmetic Science, 2014, Vol.36, Issue 3, p.221-230 Mediators of Inflammation, 2005, 2005:5, Article ID 201561 Proc. Natl Acad. Sci. USA, 1989, Vol.86, No.16, pp.6367-6371 Biomedicines, 2020, Vol.8, No.5, 101

The objective of the present invention is to provide a composition for external use that suppresses the production of IL-6, which is involved in skin inflammation and fibrosis.

As a result of intensive research aimed at solving the above problems, the inventors discovered that a composition containing (A) bactiol and (B) glycyrrhizic acid or a derivative thereof, or a salt thereof, has an inhibitory effect on IL-6 production in macrophages, and thus completed the present invention.

That is, the present invention provides the following topical composition.
Item 1.
A composition for topical use comprising (A) bactiol and (B) glycyrrhizic acid or a derivative thereof, or a salt thereof.
Item 2.
Item 2. The composition for external use according to item 1, wherein the mass ratio of the component (B) to the component (A) [(B)/(A)] is 0.01 to 5,000.
Item 3.
The composition for external use according to claim 1 or 2, further comprising (C-1) a surfactant having an HLB of 12 to 15.
Item 4.
Item 4. The composition for external use according to Item 3, wherein the component (C-1) is one or more selected from the group consisting of PPG-6-decyltetradeceth-30, polyglyceryl-10 stearate, PEG-40 hydrogenated castor oil, ceteth-10, PEG-60 hydrogenated castor oil, PEG-20 sorbitan isostearate, and PEG-80 hydrogenated castor oil.

The topical composition of the present invention contains (A) bactiol and (B) glycyrrhizic acid or its derivatives or salts thereof, thereby suppressing the production of IL-6 in macrophages.

FIG. 1 is a graph showing the amount of IL-6 produced in each group in Test Example 1, with the amount of IL-6 produced in treatment group 1 taken as 100.

The topical composition of the present invention contains (A) bactiol and (B) glycyrrhizic acid or a derivative thereof, or a salt thereof.

(A) Bactiol
In this specification, bactiol is a compound also represented as 4-[(1E,3S)-3-Ethenyl-3,7-dimethyl-1,6-octadien-1-yl]phenol, and has the CAS number 10309-37-2.

There are no particular limitations on the bactiol, so long as it can be incorporated into cosmetics, quasi-drugs, or pharmaceuticals; for example, natural or synthetic bactiol can be used.

In the topical composition of the present invention, the content of the (A) component is appropriately set according to the type and content of other components, the formulation form, the method of use, etc. Although not limited, for example, the total content of the (A) component is preferably 0.00001% by mass or more, more preferably 0.00005% by mass or more, even more preferably 0.0001% by mass or more, particularly preferably 0.0002% by mass or more, even more particularly preferably 0.0004% by mass or more, and most preferably 0.0006% by mass or more, based on the total amount of the topical composition. In addition, the content of the (A) component is preferably 0.5% by mass or less, for example, 0.4% by mass or less, 0.2% by mass or less, 0.1% by mass or less, 0.05% by mass or less, or 0.045% by mass or less, based on the total amount of the topical composition, from the viewpoint of improving the stability of the topical composition.
The content of component (A) is preferably 0.00001 to 0.5 mass%, more preferably 0.00005 to 0.4 mass%, even more preferably 0.0001 to 0.2 mass%, particularly preferably 0.0002 to 0.1 mass%, and even more particularly preferably 0.0004 to 0.05 mass% or 0.0006 to 0.045 mass%, based on the total amount of the topical composition.

[(B): Glycyrrhizic acid, a derivative of glycyrrhizic acid, or a salt thereof]
The topical composition of the present invention contains, as component (B), any one kind alone or a combination of two or more kinds of compounds selected from the group consisting of glycyrrhizinic acid, derivatives of glycyrrhizinic acid, and salts thereof.

There are no particular limitations on glycyrrhizinic acid, derivatives of glycyrrhizinic acid, or salts thereof, so long as they can be incorporated into cosmetics, quasi-drugs, or pharmaceuticals, and for example, natural or synthetic products can be used.

For example, licorice extract can be used to incorporate glycyrrhizinic acid into the topical composition of the present invention. The extract can be used in a liquid state (including fluid, viscous, etc.), or it can be dried and used in a solid state (including semi-solid, gel, etc.), for example in powder form.

Examples of derivatives of glycyrrhizinic acid include methyl glycyrrhizinate and stearyl glycyrrhizinate.

The salt of glycyrrhizinic acid or a derivative thereof may be any pharma- ceutically or physiologically acceptable salt, and examples of such salts include ammonium salts, alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts, magnesium salts, etc.), metal salts (aluminum salts, etc.), salts with inorganic bases such as ammonium salts; and salts with organic bases such as organic amine salts (methylamine salts, triethylamine salts, triethanolamine salts, morpholine salts, piperazine salts, pyrrolidine salts, tripyridine salts, picoline salts, etc.).
The salt of glycyrrhizic acid may be a hydrate, hemihydrate, or anhydrous.

In the topical composition of the present invention, the total content of the (B) component is appropriately set according to the type and content of other blended components, the formulation form, the method of use, etc. Although not limited, for example, the total content of the (B) component is preferably 0.0001% by mass or more, more preferably 0.0005% by mass or more, even more preferably 0.001% by mass or more, particularly preferably 0.005% by mass or more, even more particularly preferably 0.01% by mass or more, and most preferably 0.02% by mass or more, based on the total amount of the topical composition. In addition, the total content of the (B) component is preferably 0.5% by mass or less, and may be, for example, 0.4% by mass or less, 0.3% by mass or less, 0.2% by mass or less, 0.1% by mass or less, 0.05% by mass or less, or 0.01% by mass or less, based on the total amount of the topical composition.
The total content of component (B) is preferably 0.0001 to 0.5 mass%, more preferably 0.0005 to 0.4 mass%, even more preferably 0.001 to 0.3 mass%, and particularly preferably 0.01 to 0.2 mass%, based on the total amount of the topical composition.

In the topical composition of the present invention, from the viewpoint of exhibiting the effects of the present invention more significantly, the mass ratio of component (B) to component (A) [(B)/(A)] may be, for example, 0.01 to 5000 parts by mass, 0.05 to 3000 parts by mass, 0.1 to 1000 parts by mass, or 0.5 to 500 parts by mass.

When component (B) contains a derivative of glycyrrhizinic acid, the mass ratio of component (B) to component (A) of the present invention may be 0.25 to 3000 parts by mass, 1 to 1000 parts by mass, or 2.5 to 500 parts by mass.

[(C) Surfactant]
The composition for external use of the present invention may optionally further contain a surfactant as component (C), which may be one or a combination of two or more of compounds selected from the group consisting of anionic surfactants, amphoteric surfactants, nonionic surfactants, and naturally occurring surfactants such as lecithin, hydrogenated lecithin, saponin, sodium surfactin, cholesterol, and bile acid.

Examples of anionic surfactants include fatty acid soaps (e.g., sodium laurate, sodium palmitate, potassium laurate, potassium myristate, potassium palmitate, potassium stearate, etc.); alkyl sulfate ester salts (e.g., sodium lauryl sulfate, potassium lauryl sulfate, etc.); alkyl ether sulfate ester salts (e.g., POE-triethanolamine lauryl sulfate, sodium POE-lauryl sulfate, sodium laureth sulfate, etc.); N-acylsarcosinic acid (e.g., sodium lauroyl sarcosinate, etc.); fatty acid alkanolamides (e.g., coconut oil fatty acid monoethanolamide ... fatty acid diethanolamide, lauroyl monoethanolamide, lauric acid diethanolamide, etc.); higher fatty acid amide sulfonate salts (e.g., sodium N-myristoyl-N-methyl taurate, sodium coconut oil fatty acid methyl taurate, sodium lauryl methyl taurate, etc.); phosphate salts (sodium POE-oleyl ether phosphate, POE-stearyl ether phosphate, sodium lauryl phosphate, sodium polyoxyethylene lauryl ether phosphate, etc.); sulfosuccinate salts (e.g., sodium alkyl sulfosuccinate, sodium di-2-ethylhexyl sulfosuccinate, polyoxyethylene stearate, sodium lauryl ether phosphate, etc.); sodium sulfosuccinate, sodium lauryl polypropylene glycol sulfosuccinate, etc.); alkylbenzene sulfonates (for example, sodium linear dodecylbenzene sulfonate, triethanolamine linear dodecylbenzene sulfonate, linear dodecylbenzene sulfonic acid, etc.); amino acid surfactants (for example, sodium cocoyl glutamate, N-acyl glutamate, etc.); N-acyl glutamate (for example, potassium lauroyl glutamate, monosodium N-lauroyl glutamate, disodium N-stearoyl glutamate, monosodium N-myristoyl-L-glutamate, etc.); higher fatty acids Examples include ester sulfate salts (e.g., sodium hydrogenated coconut oil fatty acid glycerin sulfate, etc.); sulfated oils (e.g., turmeric oil, etc.); ether carboxylate salts (e.g., polyoxyethylene alkyl ether carboxylic acid, polyoxyethylene alkyl allyl ether carboxylate, sodium polyoxyethylene lauryl ether acetate, etc.); α-olefin sulfonate salts; higher fatty acid ester sulfonate salts; secondary alcohol sulfate salts; higher fatty acid alkylolamide sulfate salts; sodium lauroyl monoethanolamide succinate; ditriethanolamine N-palmitoyl aspartate; and sodium caseinate.

Examples of amphoteric surfactants include imidazoline-based amphoteric surfactants (e.g., 2-undecyl-N,N,N-(hydroxyethylcarboxymethyl)-2-imidazoline sodium, 2-cocoyl-2-imidazolinium hydroxide-1-carboxyethyloxy disodium salt, etc.); betaine-based surfactants (e.g., 2-heptadecyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine, lauryl dimethylamino acetate betaine, alkyl betaine, amido betaine, sulfobetaine, coconut oil fatty acid amidopropyl betaine, lauryl dimethylamino acetate betaine, 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine, lauryl hydroxysulfobetaine, lauroyl amidoethyl hydroxyethyl carboxymethyl betaine, sodium hydroxypropyl phosphate, etc.); and amino acid-based amphoteric surfactants (sodium lauryl aminopropionate).

Examples of nonionic surfactants include sorbitan fatty acid esters (e.g., sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, diglycerol sorbitan penta-2-ethylhexyl acid, diglycerol sorbitan tetra-2-ethylhexyl acid, etc.); propylene glycol fatty acid esters (e.g., propylene glycol monostearate, etc.); hydrogenated castor oil derivatives (e.g., 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, etc.); polyoxyethylene sorbitan fatty acid esters (e.g., monolauric acid Polyoxyethylene (20) sorbitan (polysorbate 20), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), polyoxyethylene (20) sorbitan monooleate (polysorbate 80), polyoxyethylene (20) sorbitan isostearate, etc.); glycerin derivatives (e.g., polyoxyethylene monococoate glyceryl, glycerin alkyl ether); polyoxyalkylene alkyl ethers (e.g., polyoxyethylene cetyl ether, etc.); silicone surfactants (e.g., polyoxyethylene-methylpolysiloxane copolymer, lauryl PEG-9 polydimethylsiloxyethyl dimethicone, PEG-9 polydimethylsiloxyethyl dimethicone, etc.); alkyl glucosides; and the like.

(Component (C-1): Surfactant with HLB of 12 to 15)
In one embodiment, the topical composition of the present invention contains (C-1) a surfactant having an HLB value of 12 to 15. A surfactant having an HLB value of 12 to 15 is preferred because it provides better emulsion stability to the composition when components (A) and (B) are combined, compared to surfactants having an HLB value outside that range.

Examples of surfactants with an HLB of 12 to 15 include compounds selected from the group consisting of PPG-6 decyltetradeceth-30, polyglyceryl-10 stearate, PEG-40 hydrogenated castor oil, ceteth-10, PEG-60 hydrogenated castor oil, PEG-20 sorbitan isostearate, and PEG-80 hydrogenated castor oil, either alone or in combination.

In this specification, the HLB value is not particularly limited and may be a calculated value or an experimentally determined value. The calculated value may be, for example, a calculated value based on the Griffin method (20 x sum of formula weights of hydrophilic moieties/molecular weight).

In the topical composition of the present invention, the total content of the (C) component is appropriately set according to the type and content of other blended components, the formulation form, the method of use, etc. Although not limited, for example, the total content of the (C) component is preferably 0.001% by mass or more, more preferably 0.005% by mass or more, even more preferably 0.01% by mass or more, particularly preferably 0.02% by mass or more, even more particularly preferably 0.05% by mass or more, and most preferably 0.1% by mass or more, based on the total amount of the topical composition. In addition, the total content of the (C) component is preferably 10% by mass or less, and may be, for example, 8% by mass or less, 6% by mass or less, 5% by mass or less, 4% by mass or less, or 3% by mass or less, based on the total amount of the topical composition.
The total content of component (C) is preferably 0.001 to 10 mass%, more preferably 0.005 to 8 mass%, even more preferably 0.01 to 6 mass%, and particularly preferably 0.1 to 3 mass%, based on the total amount of the topical composition.

[Other ingredients]
The topical composition of the present invention optionally contains, in addition to the above-mentioned components, at least one selected from the group consisting of another anti-inflammatory agent, a germicidal disinfectant (antibacterial agent), vitamins, an anti-wrinkle agent, a skin-whitening agent, an anti-glycation component, a cell activating component, an antioxidant component, an anti-aging component, and a moisturizing component.

(Anti-inflammatory agent)
Examples of the other anti-inflammatory agents include allantoin and derivatives thereof (e.g., alcloxa, allantoin, etc.), tranexamic acid, glycyrrhetinic acid or derivatives thereof, or salts thereof (e.g., glycyrrhetinic acid, stearyl glycyrrhetinate, etc.), zinc oxide, aminocaproic acid, azulene and derivatives thereof (e.g., guaiazulene, azulene, etc.), salicylic acid or derivatives thereof, steroids or derivatives thereof, or salts thereof (e.g., hydrocortisone, prednisolone, etc.), ufenamate, bufexamac, ibuprofen piconol, azelaic acid, diphenhydramine, nicotinamide, etc.

When an anti-inflammatory agent is included, its content is preferably 0.0001 to 10% by mass, more preferably 0.001 to 8% by mass, even more preferably 0.01 to 5% by mass, and even more preferably 0.01 to 2% by mass, based on the total amount of the topical composition.

(Disinfectant (antibacterial agent))
Examples of the germicide disinfectant (antibacterial agent) include chlorhexidine, salicylic acid, benzalkonium chloride, acrinol, benzethonium chloride, cetyltrimethylammonium chloride, cresol, gluconic acid and its derivatives, povidone-iodine, potassium iodide, iodine, isopropylmethylphenol, triclocarban, triclosan, zinc pyrithione, photosensitizer No. 101, photosensitizer No. 201, alkyldiaminoglycine hydrochloride, cetylpyridinium chloride, piroctone olamine, miconazole or a salt thereof, resorcinol, sulfur, homosulfamine, sulfadiazine, and the like.

When a bactericidal disinfectant is added, its content is preferably 0.00001 to 10% by mass, more preferably 0.001 to 5% by mass, and even more preferably 0.01 to 2% by mass, based on the total amount of the composition for external use.

(Vitamins)
The vitamins may be either water-soluble or oil-soluble vitamins, and examples thereof include vitamin B6; pantothenic acids; nicotinic acids; vitamin B1; vitamin B2; vitamin B12; vitamin C; vitamin E (tocopherol acetate, etc.); vitamin A; and vitamin-like factors such as pyrroloquinoline quinone or a salt thereof, hesperidins, ubiquinone, and α-lipoic acid.

When vitamins are included, the content is preferably 0.00001 to 10% by mass, more preferably 0.001 to 5% by mass, even more preferably 0.005 to 3% by mass, and even more preferably 0.01 to 2% by mass, based on the total amount of the topical composition.

(Anti-wrinkle agent)
Examples of the anti-wrinkle agent include hydrolyzed soy protein, nicotinic acid amide, retinol, retinal, retinoic acid, 3-dehydroretinol, 3-dehydroretinal, 3-dehydroretinoic acid, hydrogenated retinol, tocopheryl retinoate, and other vitamin A derivatives thereof such as retinol palmitate, retinol propionate, retinol linoleate, and retinol acetate, provitamin A derivatives such as α-carotene, β-carotene, γ-carotene, and cryptoxanthin, glycolic acid, acylated glucosamine, kinetin, vitamin C and its derivatives, vitamin E and its derivatives, aloe, collagen, hydrolyzed collagen, water-soluble collagen, hyaluronic acid, sodium hyaluronate, acetylated hyaluronic acid, and peptides (caproyl tetrapeptide-3, oligopeptide-24, etc.).

When nicotinamide is used as the anti-wrinkle agent, the content is preferably 0.001 to 10% by mass, more preferably 0.01 to 8% by mass, even more preferably 0.1 to 6% by mass, and even more preferably 0.5 to 5% by mass, based on the total amount of the topical composition.

When a vitamin A derivative is used as the anti-wrinkle agent, its content is preferably 0.0001 to 1% by mass, more preferably 0.001 to 0.8% by mass, and even more preferably 0.01 to 0.5% by mass, based on the total amount of the topical composition.

When an anti-wrinkle agent other than nicotinamide or a vitamin A derivative is used, the content is, for example, 0.0001 to 10% by mass, preferably 0.0005 to 5% by mass, more preferably 0.001 to 4% by mass, and even more preferably 0.005 to 3% by mass, based on the total amount of the topical composition.

(skin whitening agent)
Examples of whitening agents include nicotinamide, placenta; arbutin; kojic acid; ellagic acid; phytic acid; tranexamic acid; rucinol; chamomilla ET; hydroquinone, 4-methoxysalicylic acid potassium salt; linoleic acid and its derivatives; ascorbic acid and its salts, vitamin C such as ascorbic acid derivatives (sodium ascorbic acid phosphate, magnesium ascorbic acid phosphate, ascorbyl tetra-2-hexyldecanoate, 2-O-ethyl ascorbic acid, 3-O-ethyl ascorbic acid, ascorbyl glucoside, disodium isostearyl ascorbyl phosphate, L-ascorbyl dipalmitate, trisodium ascorbyl palmitate phosphate, glyceryl ascorbic acid, bisglyceryl ascorbic acid, alkylglyceryl ascorbic acid, etc.), vitamin A or its derivatives, and vitamins such as pantothenic acid or its derivatives. Furthermore, plant ingredients having a whitening effect may be used as the whitening agent. Examples of such plant ingredients include iris, almond, aloe, acerola, oolong tea, Chinese laurel, coptis, seaweed, gardenia, sophora jasmine, chlorella, rice, rice bran, oryzanol, rice bran, saishin, Japanese pepper, peony, cnidium, sophora jasmine, natto, tea, angelica tree, calendula, hamamelis, safflower, moutan pea, coix seed, acacia, persimmon (Diospyros kaki), and the like. Examples of plant ingredients include those derived from kaki, kiwi, black bean, gentian, gentiana, radish, azalea, parsley, holly, hops, clove, tangerine, chamomile, prune, meadowsweet, hawkweed, grapefruit, thorn pear, lemon, kiwi, pine, neem, artichoke, horsetail, Chinese laurel, evening primrose, bilberry, gelatin, Salicornia herb, white willow, saxifrage, Centella asiatica, devil's claw, etc. When using such plant ingredients in the external composition of the present invention, the form of the plant ingredient is not particularly limited, but it can usually be used in the form of a plant extract (plant extract) or essential oil. The parentheses in the above-mentioned plant ingredients indicate the scientific name, alternative name, or herbal medicine name of the plant.

When a whitening agent is used, the content is, for example, about 0.0003 to 10% by mass, preferably about 0.01 to 5% by mass, based on the total amount of the topical composition. When a plant extract is used, the content is, for example, about 0.00001 to 20% by mass, preferably about 0.0001 to 15% by mass, more preferably 0.001 to 10% by mass, based on the total amount of the topical composition, calculated as the amount of the extract.

Examples of anti-glycation ingredients include plant extracts such as Budreja axillaris leaf extract, plum fruit extract, and edelweiss extract, evening primrose oil, amla fruit, fruit juice or extracts thereof, L-arginine, L-lysine, hydrolyzed casein, hydrolyzable tannin, and carnosine.

Examples of cell activation components include amino acids such as γ-aminobutyric acid and ε-aminocaproic acid; vitamins such as retinol, thiamine, riboflavin, pyridoxine hydrochloride, and pantothenic acid pyrroloquinoline quinones; α-hydroxy acids such as gluconic acid, phytic acid, glycolic acid, and lactic acid; tannins, flavonoids, saponin, allantoin, photosensitizer No. 301, and components derived from plants (such as bilberry leaves).

Examples of antioxidant components include butyl hydroxyanisole, dibutyl hydroxytoluene, sodium bisulfite, sodium pyrosulfite, erythorbic acid and its salts, ascorbic acid and its salts, flavonoids, glutathione, glutathione peroxidase, glutathione-S-transferase, catalase, superoxide dismutase, thioredoxin, taurine, thiotaurine, hypotaurine, and plant extracts (such as honeysuckle flower extract).

Examples of anti-aging ingredients include hydrolyzed soy protein, retinoids (retinol, retinoic acid, retinal, etc.), pangamic acid, ursolic acid, turmeric extract, sphingosine derivatives, silicon, silicic acid, N-methyl-L-serine, mevalonolactone, peptides (caproyl tetrapeptide-3, oligopeptide-24, etc.), etc.

Moisturizing ingredients include, for example, amino acids and derivatives thereof such as alanine, serine, aspartic acid, glycine, proline, hydroxyproline, glucosamine, theanine, and arginine; polyhydric alcohols such as glycerin, dipropylene glycol, and 1,3-butanediol; polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene polyoxypropylene glycol, polyoxyethylene alkyl glucoside, polyoxybutylene polyoxyethylene polyoxypropylene glyceryl ether (3B.O.) (8E.O.) (5P.O.), polyoxypropylene diglyceryl ether, and the like. polyhydric alcohol derivatives such as sorbitol, xylitol, erythritol, maltose-sucrose condensates (glucooligosaccharides), hydrolyzed xylan (xylooligosaccharides), and other sugar alcohols; glycosyltrehalose, trehalose; ceramide, glucosylceramide, cholesterol, phytosterol, cholesterol derivatives, phytosterol derivatives; phospholipids such as lecithin and hydrogenated lecithin; NMF-derived components such as lactic acid, sodium lactate, sodium pyrrolidone carboxylate, and urea; hyaluronic acid (including hydrolyzed hyaluronic acid, low molecular weight hyaluronic acid, and the like); salts of hyaluronic acid (for example, hyaluronic acid, sodium hyaluronate, zinc hyaluronate, low molecular weight zinc hyaluronate, etc.); hyaluronic acid derivatives (acetylated hyaluronic acid or its salts (e.g., sodium acetylated hyaluronate, zinc acetylated hyaluronate, etc.), crosslinked hyaluronic acid derivatives (sodium hyaluronate crosspolymer, etc.), sodium carboxymethyl hyaluronate, unsaturated hyaluronic acid or its salts, hydrolyzed alkyl (C12-13) glyceryl hyaluronate, cationized hyaluronic acid derivatives (hydroxypropyltrimonium hyaluronate, etc.), dimethylsilanol hyaluronate, etc.); collagen, elastin, keratin, chitin, chitosan, etc., These include hydrolysates thereof; hydroxyethyl urea; phosphorylcholine-containing polymers such as 2-methacryloyloxyethyl phosphorylcholine/butyl methacrylate copolymer and polymethacryloyloxyethyl phosphorylcholine; divalent carboxylate esters such as polyglyceryl-10 (eicosandioic acid/tetradecanedioic acid), bisethoxydiglycol cyclohexanedicarboxylate, diethoxyethyl succinate, and diethylhexyl succinate; and ingredients derived from plants (for example, aloe, seaweed, chlorella, lemongrass, chamomile, witch hazel, tea, grapefruit, and Gynostemma pentaphyllum).

When a phosphorylcholine-containing polymer is blended as the moisturizing component, its content is preferably 0.001 to 20% by mass, more preferably 0.01 to 15% by mass, and even more preferably 0.1 to 10% by mass, based on the total amount of the topical composition.

The topical composition of the present invention can contain various ingredients that are generally used as ingredients in topical preparations in cosmetics, quasi-drugs, or pharmaceuticals, such as irritation reducers, thickeners, preservatives, UV protection agents, colorants, dispersants, pH adjusters, and fragrances. These ingredients can be used alone or in any combination of two or more.

In addition to the above-mentioned components, the topical composition of the present invention may contain one or more of a combination of various components such as ultraviolet scattering agents, ultraviolet absorbing agents, components having the effect of preventing and/or repairing DNA damage, organic acids, astringent components, antioxidant components, polyhydric alcohols, keratin softening components, blood circulation promoting components, sebum adsorbing components, peptides or derivatives thereof, and amino acids or derivatives thereof. There are no particular limitations on these components as long as they can be used in the fields of pharmaceuticals, quasi-drugs, cosmetics, etc., and any components may be appropriately selected and used.

[Additives, etc.]
In addition to the above-mentioned components, the topical composition of the present invention may be appropriately blended with components that are commonly used in the fields of medicines, quasi-drugs, cosmetics, etc., depending on the application or dosage form. The components that can be blended are not particularly limited, and may include additives such as bases or carriers, surfactants, thickeners, antioxidants, preservatives, preservatives, pH adjusters, chelating agents, stabilizers, irritation reducers, solubilizers, suspending agents, isotonicity agents, buffers, colorants, dispersants, colorants, and fragrances. These components may be blended alone or in any combination of two or more. The content of these components may be appropriately determined within the range known in the art without impairing the effects of the present invention. Furthermore, when a specific component falls into multiple categories, it may be added as a component with any of the functions.

[Use and application area]
As shown in the Examples, the topical composition of the present invention has an effect of suppressing the production of IL-6, a major inflammatory cytokine in macrophages, and thus has an effect of preventing or ameliorating, for example, inflammation of the skin or mucous membrane, or excessive thickening or fibrosis of the skin or mucous membrane.

Skin inflammation is known to cause pigmentation, resulting in spots and freckles. In addition, thickening and fibrosis are associated with the formation of wrinkles and sagging and loss of skin firmness through reduced skin elasticity. Therefore, the topical composition of the present invention is expected to have an effect of improving skin aging, a whitening effect, an effect of preventing or improving spots or freckles, an effect of preventing or improving wrinkles or sagging of the skin, or an effect of improving skin firmness or elasticity.

Therefore, the composition for external use of the present invention can be applied to, for example, the skin or mucosa to improve or prevent diseases associated with inflammation. The mucosa is not particularly limited, but is preferably, for example, the mucosa of the eye or the oral cavity.
Examples of diseases associated with skin inflammation include psoriasis, atopic dermatitis, seborrheic dermatitis, allergic contact dermatitis, irritant contact dermatitis, pruritus, acne, eczema, itching, insect bites, rashes, sores, hives, and heat rash.
Examples of diseases associated with inflammation of the ocular mucosa include keratoconjunctivitis such as allergic conjunctivitis (seasonal allergic conjunctivitis, perennial allergic conjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, etc.), dry keratoconjunctivitis, non-infectious keratitis, non-infectious conjunctivitis, infectious keratitis, and infectious conjunctivitis, uveitis, blepharitis, scleritis, episcleritis, postoperative inflammation, dacryoadenitis, dacryocystitis, and lacrimal canaliculitis.
Examples of diseases associated with inflammation of the oral mucosa include periodontal diseases such as gingivitis and periodontitis, and stomatitis.

The topical composition of the present invention can also be used, for example, by application to the skin to improve skin aging (so-called "anti-aging", "anti-aging", etc.), whitening, preventing or improving blemishes or freckles, preventing or improving wrinkles or sagging skin, or improving skin firmness or elasticity.

As used herein, "improvement" refers to the improvement or alleviation of a disease, symptom, or health condition, the prevention or delay of the deterioration of a disease, symptom, or health condition, or the reversal, prevention, or delay of the progression of a disease or symptom.

[Dosage form]
The composition for external use of the present invention is not particularly limited as long as it is in a form known as a pharmaceutical, quasi-drug, or cosmetic, and can be formulated by a known method in the form of, for example, a liquid, suspension, emulsion, cream, ointment, gel, liniment, lotion, aerosol, powder, spray, a sheet in which a sheet such as a nonwoven fabric is impregnated with the composition of the present invention, a stick, etc. Among these, it is preferably used in the form of a liquid, suspension, emulsion, cream, ointment, gel, lotion, or gel.

Specific formulation forms include, for example, basic cosmetics such as lotion, milky lotion, gel, cream, serum, sunscreen cosmetics, packs, masks, hand cream, all-in-one gel, all-in-one cream, body lotion, and body cream; cleansing cosmetics such as face wash, hand soap, makeup remover, body shampoo, shampoo, rinse, and treatment; face makeup cosmetics such as foundation, makeup base, BB cream, and CC cream; lip cosmetics such as lip cream and lip liner; hair cosmetics, etc. Among these, external compositions for skin are particularly preferred.

[Dosage and Administration]
The composition for external use of the present invention can be used in a known or customary manner and dosage, from once to several times a day, depending on the above-mentioned purpose.

[Production method]
The composition for external use of the present invention can be produced by a known method, which may include a sterilization step, if necessary.

Next, the present invention will be specifically explained using examples and test examples, but the present invention is not limited to the following examples and test examples.

[Test Example 1. Confirmation test of anti-inflammatory effect (IL-6 production suppression effect)]
(Reagents used and culture conditions)
The basal medium used was Dulbecco's modified Eagle's medium (DMEM) (product code 11995-073; manufactured by Gibco) supplemented with 10% (v/v) fetal bovine serum (FBS) (product code 35-010-CV; manufactured by Corning) and 1% (v/v) Antibiotics-Antimycotics (product code 15240-062; manufactured by Gibco).
Bactiol (manufactured by Sytheon; trade name: Sytenol A, product code: BK1002) was dissolved in dimethyl sulfoxide (DMSO) and passed through a 0.2 mm filter to prepare a stock solution.
Bactiol (DMSO solution) and dipotassium glycyrrhizinate (GK2) (Maruzen Pharmaceutical Co., Ltd.) were dissolved in the basal medium to a concentration twice the final concentration, and then added to an equal volume of the culture medium.
Staphylococcus aureus-derived peptidoglycan (product code 77140-10MG; manufactured by Sigma) was dissolved in the basal medium to a concentration of 4 mg/mL, and added in an amount of 1/100 of the culture medium (final concentration 40 μg/mL) before use.
Cultivation and incubation were carried out at 37° C. in a CO ₂ incubator (5% CO ₂ ) unless otherwise specified.

(Test Method)
The amount of IL-6 produced by mouse macrophage cell line RAW264.7 cultured in a medium containing bactiol and GK2 at the concentrations shown in Table 1 after stimulation with peptidoglycan was measured by the method described below.
(1) RAW264.7 cells that had been previously cultured and harvested were diluted with basal medium to a density of 2 × ¹⁰ cells/well, seeded in a 48-well plate (product code 3548; Corning) and cultured for 24 hours.
(2) A basal medium containing bactiol and GK2 was added to the medium so as to give the final concentrations shown in Table 1, and the medium was cultured for 4 hours. The number of samples in the control group and treatment groups 1 to 4 was 3 each.
(3) Next, peptidoglycan was added to the cells at a final concentration of 40 μg/mL except for the untreated group, and the cells were further cultured for 17 to 18 hours to induce an inflammatory response in the RAW264.7 cells.
(4) The culture supernatant was collected, and the amount of IL-6 in the supernatant was quantified using a mIL-6 ELISA Kit (R&D Systems).
(5) The remaining cells were washed once each with DMEM and phosphate-buffered saline (PBS), and the number of viable cells in each well was then measured using AM-Calcein (Thermo Fisher Scientific).
(6) The amount of IL-6 quantified for each sample was normalized by the number of viable cells. The average value of the normalized IL-6 amounts for the samples in each group was defined as the amount of IL-6 produced in each group.

Figure 1 shows the amount of IL-6 produced in each treatment group, with the amount of IL-6 produced in treatment group 1 taken as 100. The amount of IL-6 produced, a major inflammatory cytokine, increased with stimulation of peptidoglycan. In treatment group 2 (0.02% by mass GK2 treatment group) and treatment group 3 (0.0008% by mass bactiol treatment group), the amount of IL-6 produced was reduced by 21% and 13%, respectively, compared to treatment group 1. The difference in the amount of IL-6 produced between treatment group 1 and treatment group 3 was not statistically significant (unpaired t-test, p≧0.05). On the other hand, there was a statistically significant difference (p<0.05) between the amount of IL-6 produced in treatment group 4 and the amount of IL-6 produced in each of treatment groups 1 to 3. Surprisingly, the amount of IL-6 produced in treatment group 4 was reduced by 44% compared to treatment group 1.

From the above, it has become clear that by combining bactiol and GK2 and allowing it to act on macrophages, a significant effect of suppressing IL-6 production can be achieved.

[Test Example 2: Confirmation test of effect on emulsion stability]
(1) The formulations shown in Table 2 were prepared, and each formulation was placed in a glass cell with a thickness of 20 mm. The L value, a value, and b value in the Hunter Lab color system were measured using a spectrophotometer (CM-5; manufactured by Konica Minolta, Inc.), and the color difference ΔE ^* ab value relative to blank purified water was calculated. The smaller the ΔE ^* ab value, the closer the color (appearance) of the formulation is to purified water, which is colorless and transparent, and generally means that the emulsified particles are sufficiently dispersed and the emulsion stability is high.
(2) Then, the improvement rate of ΔE ^* ab value of the formulation (formulation B) containing GK2 in addition to bactiol (formulation A) was calculated using the following formula to evaluate the emulsion stability due to the addition of GK2.
<Improvement rate of ΔE ^* ab value>
ΔE ^* ab value improvement rate (%)=
[{(ΔE ^* ab of preparation A)-(ΔE ^* ab of preparation B)}/(ΔE ^* ab of preparation A)]×100

The results are shown in Table 2. For formulations containing surfactants with an HLB of 12 to 15, the combination of bakuchiol and GK2 improved emulsion stability compared to bakuchiol alone. On the other hand, when a surfactant with an HLB of less than 12 or more than 15 was used, the combination of bakuchiol and GK2 was found to decrease emulsion stability.

[Prescription Example]
The topical compositions shown in Tables 3 to 7 below were prepared by a conventional method. All formulation figures are expressed as % by mass.

Claims (3)

A composition for external use comprising (A) bactiol , (B) glycyrrhizic acid or a derivative thereof or a salt thereof, and (C-1) a surfactant having an HLB of 12 to 15 . The composition for external use according to claim 1, wherein the mass ratio of component (B) to component (A) [(B)/(A)] is 0.01 to 5000. The topical composition according to claim 1 or 2, wherein the component (C-1) is one or more selected from the group consisting of PPG-6-decyltetradeceth-30, polyglyceryl-10 stearate, PEG-40 hydrogenated castor oil, ceteth-10, PEG-60 hydrogenated castor oil, PEG- 20 sorbitan isostearate, and PEG-80 hydrogenated castor oil.