JP6894223B2 - Topical composition - Google Patents

Description

The present invention relates to an external composition useful for preventing or ameliorating UV damage to the skin.

Ultraviolet rays are known to have various effects on the skin. For example, ultraviolet A wave (UVA, 315-400 nm) reaches deep into the skin due to its long wavelength, and easily causes collagen denaturation and the like in the dermis. In addition, ultraviolet B waves (UVB, 280 to 315 nm), which have a short wavelength among ultraviolet rays, have strong energy and are likely to cause inflammation of cells on the skin surface, which may trigger pigmentation. Are known.

Pigmentation such as stains on the skin occurs due to various causes. For example, delayed pigmentation due to allergic reactions such as drugs and atopic dermatitis is caused by activation of melanocytes by GROα, which is a type of CXC chemokine induced by allergic reactions. On the other hand, in the skin exposed to ultraviolet rays (UVB), the keratinocytes on the surface of the skin are damaged, and the keratinocytes cause inflammation such as prostaglandin E2 (PGE2) and interleukin-1α (IL-1α). It is known that the production of sex cytokines is promoted, thereby activating the production of melanin in melanocytes and causing pigmentation (Non-Patent Documents 1 and 2).

Conventionally, in order to minimize the influence of such ultraviolet rays on the skin, sunscreens and the like containing an ultraviolet absorber, an ultraviolet scattering agent and the like have been widely used. However, in some cases, improper use such as improper repainting may not produce sufficient effects, and it is a means to prevent and / or improve damage to the skin when exposed to ultraviolet rays. Development is required.

By the way, hyaluronic acid has been used in many external preparations for skin in anticipation of a moisturizing effect on the skin. It has also been proposed to use hyaluronic acid for suppressing the occurrence of skin inflammation (Patent Document 1). However, Patent Document 1 confirms the effect of orally ingesting hyaluronic acid as a food, and discloses at all the effect of exposure to ultraviolet rays on the production of inflammatory cytokines such as PGE2 and IL-1α in the skin. It has not been.

Japanese Unexamined Patent Publication No. 2015-013852

Hitoshi Masaki, Journal of the Japan Cosmetic Engineers Association, Special Review 47 (3), 2013, 197-201 Fumi Kusuda et al., FUJIFILM RESEARCH & DEVELOPMENT (No. 55-2010), 33-37

The present invention has been made in view of the above prior art, and an object of the present invention is to provide an external composition useful for preventing or ameliorating ultraviolet damage to the skin.

As a result of diligent studies to solve the above problems, the present inventors have used at least one selected from the group consisting of hyaluronic acid, its derivatives, and salts thereof as an active ingredient, thereby causing ultraviolet rays to the skin. We found that damage can be effectively suppressed. Furthermore, the present inventors have proceeded with studies, and when using hyaluronic acids having a specific average molecular weight, when at least one selected from the group consisting of tranexamic acid, its derivatives, and salts thereof is used in combination, It was also found that the effect of suppressing UV damage can be exerted even more effectively. The present invention has been completed by further making improvements based on such findings.

That is, the present invention provides the following external composition.
[Item 1] An external composition for preventing or ameliorating ultraviolet damage to the skin, which contains at least one selected from the group consisting of hyaluronic acid, its derivatives, and salts thereof as an active ingredient.
[Item 2] The external composition according to Item 1, wherein prevention or improvement of ultraviolet damage to the skin prevents or ameliorates skin inflammation due to exposure to ultraviolet rays.
[Item 3] The external composition according to Item 1 or 2, wherein the ultraviolet rays are ultraviolet B waves.
[Item 4] The external composition according to any one of Items 1 to 3, wherein prevention or improvement of ultraviolet damage to the skin prevents or ameliorates induction of melanin production due to inflammation of the skin due to exposure to ultraviolet rays. ..
[Item 5] The prevention or improvement of UV damage to the skin is due to the suppression of the production of at least one selected from the group consisting of PGE2 and IL-1α in epidermal keratinized cells due to UV exposure. The external composition according to any one of 1 to 4.
[Item 6] The external composition according to any one of Items 1 to 5, wherein the average molecular weight of hyaluronic acid is 0.1 to 700 kDa.
[Item 7] The external composition according to any one of Items 1 to 6, further comprising at least one selected from the group consisting of tranexamic acid, a derivative thereof, and a salt thereof as an active ingredient.
[Item 8] Selected from the group consisting of tranexamic acid, its derivatives, and salts thereof with respect to 1 part by weight of the total amount of at least one component selected from the group consisting of hyaluronic acid, its derivatives, and salts thereof. Item 2. The external composition according to Item 7, wherein the total amount of at least one component to be added is 0.05 to 4000 parts by weight.

According to the external composition of the present invention, UV damage to the skin can be effectively prevented and / or ameliorated.

FIG. 1 is a graph showing the results of the PGE2 production suppression test of Test Example 1.

Hereinafter, the present invention will be described in detail. It should be understood that the terms used herein are used in the meaning commonly used in the art unless otherwise specified.

(1. External composition)
The external composition for preventing or ameliorating ultraviolet damage to the skin of the present invention is effective at least one selected from the group consisting of hyaluronic acid, its derivatives, and salts thereof (hereinafter, also referred to as hyaluronic acids). It is characterized by being contained as an ingredient.

(A) Hyaluronic acid, its derivatives, and salts thereof:
Hyaluronic acid is a kind of acidic mucopolysaccharide, and is a polysaccharide containing a disaccharide of glucuronic acid and N-acetylglucosamine as a constituent unit. Hyaluronic acid can be extracted and recovered from chicken crowns, animal tissues such as shark skin, umbilical cord, eyeball, skin, and cartilage, hyaluronic acid-producing microorganisms such as Streptococcus microorganisms, and cultures of animal cells or plant cells. .. You can also purchase a commercial product.

As described above, hyaluronic acid obtained by extracting from animal tissues, microorganisms, etc. is generally said to have an average molecular weight of about 1000 kDa or more, and is known to be extremely high molecular weight. In the present invention, such high molecular weight hyaluronic acid may be used, or low molecular weight hyaluronic acid obtained by decomposing high molecular weight hyaluronic acid may be used. Low-molecular-weight hyaluronic acid is a method of hydrolyzing high-molecular-weight hyaluronic acid in the presence of an acid such as hydrochloric acid or an alkali, a method of treating with an enzyme such as hyaluronidase, or a method of physically cutting by ultrasonic waves or shearing. Can be obtained by In addition, low-molecular-weight hyaluronic acid can be used by purchasing a commercially available product. In the external composition of the present invention, low molecular weight hyaluronic acid is preferably used, but not limited to.

The average molecular weight of the hyaluronic acid of the present invention is not particularly limited as long as the effects of the present invention are exhibited, and may be, for example, about 0.1 to 1800 kDa. From the viewpoint that the effects of the present invention can be exerted even more effectively, the average molecular weight of the hyaluronic acid of the present invention is preferably about 0.1 to 700 kDa, more preferably about 0.2 to 600 kDa. It is even more preferably about 4 to 500 kDa, even more preferably about 5 to 400 kDa, and particularly preferably about 8 to 350 kDa.

As used herein, the average molecular weight means a weight average molecular weight. The weight average molecular weight can be determined by a known measuring method. Specifically, it can be measured by size exclusion chromatography. The conditions are (column: TSKgel GMPWXL 7.8 mm × 30 cm (manufactured by Showa Denko KK), column temperature: constant temperature around 40 ° C., detector: differential refractometer, mobile phase: 0.2 mol / L NaCl, Flow rate: 0.3 mL / min, injection volume: 100 μL, standard substance: Pulran standard product (STANDARD P-82, manufactured by Showa Denko KK).

The derivative of hyaluronic acid is not particularly limited as long as it is pharmacologically or physiologically acceptable. For example, acetylated hyaluronic acid having an acetylated hydroxyl group, sulfated hyaluronic acid having a sulfated hydroxyl group, and cationization. Examples thereof include cationized hyaluronic acid, hydrolyzed alkyl hyaluronate (C12-13) glyceryl, and the like. Preferably, acetylated hyaluronic acid is used.

The salt of hyaluronic acid or a derivative thereof is also not particularly limited as long as it is pharmacologically or physiologically acceptable, for example, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, aluminum and the like. Examples include salt with metal. Preferably, a sodium salt or a potassium salt is used as the salt of hyaluronic acid or a derivative thereof.

In the external composition of the present invention, hyaluronic acid, a derivative thereof, and a salt thereof may be used alone or in combination of two or more.

Commercially available hyaluronic acid, derivatives thereof, and salts thereof can be used in the present invention. For example, as hyaluronic acid, the product name "sodium hyaluronate HA12N" (Shiseido Co., Ltd.) has an average molecular weight of 1,100 to 1,600 kDa, and the product name "hyaluronic acid FCH-150" (Kikkoman Biochemifa Co., Ltd.) has an average molecular weight of 1,400 to 1800 kDa. "Sodium biohyaluronate SZE" (Shiseido Co., Ltd.) average molecular weight 1100 to 1600 kDa, trade name "hyaluronic acid FCH-120" (Kikkoman Biochemifa Co., Ltd.) average molecular weight 1000 to 1400 kDa, trade name "hyaluronic acid HA-LQ" (KYUPI) (Co., Ltd.) Average molecular weight 600-1200 kDa, trade name "Hyaluronic acid FCH-SU" (Kikkoman Biochemifa Co., Ltd.) Average molecular weight 50-110 kDa, trade name "Hyaluronic acid (L)" (FAP Japan Co., Ltd.) Average molecular weight 50 kDa or less , Product name "Hyaluronic acid" (KUP Co., Ltd.) with an average molecular weight of 10 kDa or less, and product name "Hyaluronic acid (SL)" (FAP Japan Co., Ltd.) with an average molecular weight of 10 kDa or less. As a derivative of hyaluronic acid, the trade name "acetylated sodium hyaluronate" (Shiseido Co., Ltd.) has an average molecular weight of 10 to 100 kDa, the trade name "Hyarobert" (Cupy Co., Ltd.) has an average molecular weight of 500 to 800 kDa, and the trade name "Hyaro Repair" (Cupy) (Co., Ltd.) Examples of commercially available products having an average molecular weight of 10 kDa or less can be exemplified. For the external composition of the present invention, for example, hyaluronic acids having a particularly small average molecular weight, such as nano-sized hyaluronic acid or osmotic hyaluronic acid, may be used.

The content of hyaluronic acids in the external composition of the present invention is not particularly limited as long as the effects of the present invention are exhibited, but is usually 0.0001 to 2% by weight, 0.0005 to 1% by weight, based on the entire composition. It is preferably 0.001 to 0.5% by weight, more preferably 0.001 to 0.5% by weight.

(B) Tranexamic acid, its derivatives, and salts thereof:
In the external composition of the present invention, in addition to the above hyaluronic acids, at least one selected from the group consisting of tranexamic acid, its derivatives, and salts thereof (hereinafter, also referred to as tranexamic acids) is further used as an active ingredient. It may be blended. In particular, when low-molecular-weight hyaluronic acids having an average molecular weight of hyaluronic acid of 350 kDa or less are used, the combined use of tranexamic acids combines the actions of both components to further enhance the effect of suppressing UV damage to the skin. Is known to be obtained.

Tranexamic acid is a compound also called trans-4- (aminomethyl) cyclohexane-1-carboxylic acid, which may be synthesized by a known method or can be obtained as a commercially available product.

The derivative of tranexamic acid is not particularly limited as long as it is pharmacologically or physiologically acceptable. For example, a tranexamic acid ester derivative such as cetyl tranexamic acid; a tranexamic acid amide derivative such as methyl tranexamic acid or ethyl amide tranexamic acid, etc. Can be exemplified. These tranexamic acid derivatives may be synthesized by a known method or can be obtained as a commercially available product.

The salt of tranexamic acid or a derivative thereof is also not particularly limited as long as it is pharmacologically or physiologically acceptable, for example, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, aluminum and the like. Salts with metals; zinc salts; iron salts; ammonium salts; salts with basic amino acids such as arginine, lysine, histidine, ornithine; salts with amines such as monoethanolamine, diethanolamine, triethanolamine; hydrochlorides, sulfates Salts with inorganic acids such as salts, nitrates, hydrobromates, phosphates; salts with organic acids such as acetates, butyrates, fumarates, maleates and the like can be mentioned. Preferably, a sodium salt, a potassium salt, a calcium salt, a magnesium salt, or a hydrochloride salt is used as the salt of tranexamic acid or a derivative thereof.

When tranexamic acids are blended in the external composition of the present invention, one selected from tranexamic acid, its derivatives, and salts thereof may be used, or two or more kinds of tranexamic acids may be used in combination. May be good.

When tranexamic acids are blended in the external composition of the present invention, the content thereof is not particularly limited as long as the effects of the present invention are exhibited, but is usually 0.001 to 4% by weight based on the entire composition. It is preferably 05 to 3.5% by weight, more preferably 0.1 to 3% by weight.

When tranexamic acids are blended in the external composition of the present invention, the blending ratio with respect to hyaluronic acids is not particularly limited. For example, the total amount of tranexamic acids is 0.05 to 4000 with respect to 1 part by weight of the total amount of hyaluronic acids. It can be parts by weight, preferably 0.1 to 3500 parts by weight, more preferably 0.2 to 3000 parts by weight. From the viewpoint of obtaining a higher effect of suppressing UV damage to the skin, it is preferable that the total amount of tranexamic acid is 7 parts by weight to 4000 parts by weight with respect to 1 part by weight of the total amount of hyaluronic acid. , 8 to 3500 parts by weight, and particularly preferably 10 to 3000 parts by weight.

The external composition of the present invention may further contain other active ingredients as long as the effects of the present invention are not impaired. Specific examples of the active ingredient include vitamin Cs such as vitamins (specifically, ascorbic acid or a derivative thereof (for example, L-ascorbic magnesium phosphate, etc.); tocopherol or a derivative thereof (for example, tocopherol acetate). Vitamin E), moisturizing ingredients, anti-inflammatory ingredients, antibacterial ingredients, peptides or derivatives thereof, amino acids or derivatives thereof, cell activating ingredients, antiaging ingredients, blood circulation promoting ingredients, keratin softening ingredients, whitening ingredients, astringent ingredients, etc. Examples include ultraviolet protective components (ultraviolet absorbers, ultraviolet scatterers) and the like. Among them, the external composition of the present invention preferably contains vitamins, and preferably contains vitamins C and E. These other active ingredients may be blended alone or in any combination of two or more.

When the external composition of the present invention is blended with other active ingredients as described above, the content thereof is not particularly limited, but is usually 0.00001 to 15% by weight, preferably 0. It is preferably about 0001 to 10% by weight, more preferably about 0.001 to 5% by weight.

Further, the external composition of the present invention can be prepared by appropriately blending in addition to each of the above active ingredients, ingredients usually used in the fields of cosmetics, quasi-drugs, pharmaceuticals, etc., depending on the intended use or dosage form. .. The components that can be blended are not particularly limited, but are, for example, bases or carriers, fragrances, antioxidants, preservatives, pH adjusters, chelating agents, stabilizers, irritation reducing agents, preservatives, coloring agents, and dispersants. Additives such as and the like can be blended. In addition, these components can be blended individually by 1 type or in any combination of 2 or more types.

As the base or carrier, water; lower alcohols such as ethanol and isopropanol; ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol. Glycol ethers such as monobutyl ether, propylene glycol monoethyl ether, propylene glycol monopropyl ether, dipropylene glycol monoethyl ether, dipropylene glycol monopropyl ether; polyethylene glycol, propylene glycol, 1,3-butylene glycol, glycerin, isoprene Polyhydric alcohols such as glycol, diglycerin, dipropylene glycol; hydrocarbons such as liquid paraffin, squalane, vaseline, gelled hydrocarbons (such as plastibase), ozokelite, α-olefin oligomers, light liquid paraffins; methylpolysiloxane, Cross-linked methyl polysiloxane, highly polymerized methyl polysiloxane, cyclic silicone, alkyl-modified silicone, cross-linked alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, cross-linked polyether-modified silicone, cross-linked alkyl poly Ether-modified silicone, silicone-alkyl chain co-modified polyether-modified silicone, silicone-alkyl chain co-modified polyglycerin-modified silicone, polyether-modified branched silicone, polyglycerin-modified branched silicone, acrylic silicon, phenyl-modified silicone, silicone resin, etc. Silicone oil; higher alcohols such as setanol, cetostearyl alcohol, stearyl alcohol, behenyl alcohol; cellulose derivatives such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose; polyvinylpyrrolidone; carrageenan; polyvinylbutyrate; polyethylene glycol; dioxane; butylene glycol Polyester adipate; isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isononyl isononanoate, pentaerythlit tetra2-ethylhexanoate, esters such as jojoba oil; dextrin, maltode Polysaccharides such as kistrin; and the like. Water and lower alcohols are preferred, and water is more preferred.

Examples of the surfactant include polyoxyethylene (hereinafter referred to as POE) -POE-branched alkyl ether such as octyldodecyl alcohol and POE-2-decyltetradecyl alcohol; POE-oleyl alcohol ether, POE-cetyl alcohol ether and the like. POE-alkyl ethers; sorbitan esters such as sorbitan monooleate, sorbitan monoisostearate and sorbitan monolaurate; POE-sorbitan ester; glycerin fatty acid ester such as glycerin monooleate, glycerin monostearate, and glycerin monomillistate; POE such as POE-glycerin monooleate, POE-glycerin monostearate, and POE-glycerin monomillistate. -Glycerin fatty acid ester; POE-dihydrocholesterol ester, POE-hardened castor oil, and POE-hardened castor oil fatty acid ester such as isostearate; POE-alkylaryl ether such as POE-octylphenyl ether; mono Glycerin alkyl ethers such as isostearyl glyceryl ether and monomyristyl glyceryl ether; POE-glycerin alkyl ethers such as POE-monostearyl glyceryl ether, POE-monomyristyl glyceryl ether; diglyceryl monostearate, decaglyceryl decasterate, decaglyceryl Various non-ionic surfactants such as decaisostearate and polyglycerin fatty acid esters such as diglyceryl diisostearate: or naturally occurring interfaces such as lecithin, hydrogenated lecithin, saponin, surfactin sodium, cholesterol, bile acid Activators and the like can be exemplified.

Examples of the solubilizing component include polyhydric alcohols such as propylene glycol, 1,3-butylene glycol, glycerin, isoprene glycol, diglycerin, dipropylene glycol, polyethylene glycol, and ethoxydiglycol; hydrogenated soybean phospholipids and polyoxy. Ethylene sorbitan fatty acid ester, polyoxyethylene lanolin alcohol, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sterol, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene alkyl phenyl ether And so on. It is preferably a polyhydric alcohol, more preferably glycerin, diglycerin, 1,3-butylene glycol, and dipropylene glycol.

Examples of the viscosity modifier include guar gum, locust bean gum, carrageenan, xanthan gum, dextran, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, propylene glycol alginate, and polyvinyl. Alcohol, polyvinylpyrrolidone, polyvinylmethyl ether, carboxyvinyl polymer, alkyl methacrylate copolymer, sodium polyacrylate, polyethylene glycol, bentonite, dextrin fatty acid ester, pectin, (hydroxyethyl acrylate / acryloyldimethyltaurine Na) copolymer , Dimethyldistearylammonium hectrite, polyethylene glycol distearate, ethylene glycol triisostearate, polyoxyethylene triisostearate (20) methyl glucoside and the like. Preferred are xanthan gum and carboxyvinyl polymers.

Examples of preservatives or preservatives include benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, and parabens (isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, butyl paraoxybenzoate, ethyl paraoxybenzoate, paraoxybenzoic acid). Propyl, benzyl paraoxybenzoate, methyl paraoxybenzoate), phenoxyethanol, benzyl alcohol, chlorobutanol, sorbic acid and its salts, alcandiol and the like. Parabens are preferred.

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

Examples of the chelating agent include ethylenediaminetetraacetic acid (edetic acid), ethylenediaminetetraacetic acid salt (sodium salt (Japanese Pharmacopoeia, EDTA-2Na, etc.), potassium salt, etc.), phytic acid, and the like. Examples include polyphosphoric acid and metaphosphoric acid.

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

Examples of the irritation reducing agent include licorice extract and sodium alginate.

As the above-mentioned additives, one type can be used alone, or two or more types can be used in combination.

The external composition of the present invention can take a dosage form usually used in a preparation applied to the skin such as cosmetics, quasi-drugs, or pharmaceuticals, and may be, for example, a liquid preparation, a semi-solid preparation, or a solid preparation. .. Specifically, it can take a known form such as a liquid agent, a gel agent, a liposome agent, an extract agent, a tincture agent, an ointment agent, or a jelly agent. In addition, liquid, suspension, emulsion, cream, gel, sheet (base material supported), spray, aerosol, etc. can be added by adding other solvents or commonly used bases as needed. , Paste-like, mousse-like and various desired forms can be prepared. When the external composition of the present invention is an emulsified composition such as a milky liquid or a cream, it may be either a water-in-oil type or an oil-in-water type, but hyaluronic acids and tranexamic acids exert the effect of the present invention. The oil-in-water type is preferable from the viewpoint that it is easy to be stably blended in a formulation so that it can be easily exhibited. In addition, the external composition of the present invention is preferably liquid because it is easy to use on a daily basis when UV damage to the skin is a concern, or it is easy to slowly penetrate the skin to exert its effect. , Emulsion, cream, gel or sheet.

These dosage forms can be produced by conventional methods in the art. For example, by blending and mixing hyaluronic acids, tranexamic acids and other optional components as required, and further blending other solvents and a base of a commonly used external preparation as necessary. It can be prepared in various desired forms such as liquid, suspension, emulsion, cream, gel, sheet (supporting a base material), spray, aerosol, paste, and mousse.

The external composition of the present invention can be at any pH as long as the effects of the present invention can be exhibited. From the viewpoint of low irritation to the skin and good usability, the external composition of the present invention preferably has a pH of about 3 to 9, more preferably about pH 4 to 8.5, and even more preferably about pH 5 to 8. It is desirable to have.

The external composition of the present invention is not particularly limited as long as it is applied to the skin, but may be, for example, a pharmaceutical form such as a cosmetic product, a quasi drug, or a pharmaceutical product. Cosmetics include, for example, basic cosmetics such as lotions, emulsions, creams, gels, oils, masks and facial masks; makeup cosmetics such as foundations, lipsticks, mascara, eye shadows, eyeliners, eyebrows and facial cleansers; Cleaning agents such as cleansing and body cleaning agents; can be used as bathing agents.

The external composition of the present invention may be provided as a containerized external composition. Examples of the material of the container include polyethylene terephthalate, polypropylene, polyethylene (HDPE, LDPE, LLDPE, etc.), ABS resin, ethylene vinyl alcohol resin, polystyrene, glass, metal (aluminum, etc.), and the like. Not limited.

The method of using the external composition of the present invention includes the condition of the skin to be used, age and gender, required high effect, usage environment (for example, intensity of ultraviolet rays at the time of use, large amount of ultraviolet rays), agent. It depends on the shape, but as an example, it is desired to exert the effect of preventing or improving the UV damage to the skin, usually several times a day (for example, about 1 to 5 times, preferably about 1 to 3 times). An appropriate amount (for example, about 0.01 to 5 g) may be applied to or sprayed on a site (for example, face, neck, arm, hand, torso, leg, foot, etc.). From the viewpoint of increasing the permeability to the skin and more effectively obtaining the preventive or improving effect of the present invention, it is particularly particularly applied directly to the washed skin (for example, the facial skin after washing). preferable.

The external composition of the present invention is used for preventing or ameliorating ultraviolet damage to the skin. Here, prevention or improvement of ultraviolet damage to the skin includes promotion of recovery from ultraviolet damage of the skin or early recovery. As shown in the results of the test examples described below, the external composition of the present invention comprises prostaglandin E2 (PGE2) and interleukin-1α (IL-1α) in epidermal keratinized cells exposed to ultraviolet B wave (UVB). ), The overproduction of two inflammatory cytokines can be highly suppressed. Among them, the external composition of the present invention is particularly excellent in the effect of suppressing PGE2 production in epidermal keratinized cells after exposure to ultraviolet rays. Overproduction of PGE2 and IL-1α in epidermal keratinized cells caused by such UVB exposure causes a short-term erythema reaction called sunburn, which is one of the inflammatory reactions, and also induces melanocyte activation. It can produce melanin pigments, cause pigmentation, and cause UV damage such as blethema, dullness, and freckles on the skin. The external composition of the present invention can suppress the overproduction of PGE2 and / or IL-1α in epidermal keratinized cells after UV exposure, thus causing an early cascade of inflammation and subsequent melanin production in the skin after UV exposure. It can be suppressed and UV damage to the skin can be effectively prevented or ameliorated for care. Therefore, the external composition of the present invention is useful for preventing or improving spots, dullness, and freckles caused by exposure to ultraviolet rays, preparing the skin with a transparent feeling, and maintaining or improving the whitening state of the skin. Can be used for.

(2. Use in the production of external composition)
As described above, it has been confirmed that UV damage to the skin can be effectively suppressed by using at least one selected from the group consisting of hyaluronic acid, its derivatives, and salts thereof as an active ingredient.
Therefore, from yet another point of view, the present invention is at least one selected from the group consisting of hyaluronic acid, its derivatives, and salts thereof in the production of external compositions for preventing or ameliorating UV damage to the skin. Also provides the use of. In certain embodiments, it is preferable to use at least one selected from the group consisting of tranexamic acid, derivatives thereof, and salts thereof in combination with the hyaluronic acids in the above-mentioned use.
More specifically, in the above-mentioned mode of use, the types of ingredients used and their blending ratios, other ingredients that can be blended and their blending ratios, usage methods, etc. are described in the above-mentioned "(1. External composition). ) ”.

(3. How to prevent or improve UV damage to the skin)
As described above, it has been confirmed that UV damage to the skin can be effectively suppressed by using at least one selected from the group consisting of hyaluronic acid, its derivatives, and salts thereof as an active ingredient.
Therefore, from yet another point of view, the present invention is a method for preventing or ameliorating ultraviolet damage to the skin by applying at least one selected from the group consisting of hyaluronic acid, its derivatives, and salts thereof to the skin. Also provides. In a specific embodiment, it is preferable to use at least one selected from the group consisting of tranexamic acid, its derivatives, and salts thereof together with hyaluronic acids in the above method.
More specifically, in the embodiment of the above method, the types of components used and their blending ratios, other components that can be blended and their blending ratios, the methods of use, etc. ) ”.

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

(Test Example 1. PGE2 production suppression test)
The effect of suppressing PGE2 production in epidermal keratinized cells after UVB exposure was evaluated according to the following method.
First, normal human epidermal keratinocytes (NHEK) were cultured in a 6-well culture plate. More specifically, the cells were plated on plates at a density of 3.0 × 10 ⁵ cells / well, at 37 ° C., it was 1 day culture under an environment of 5% carbon dioxide and 95% air. As the culture medium, 2 mL of a medium prepared by adding 10 μg / mL insulin and 0.67 μg / mL hydrocortisone to Humania-KB2 (manufactured by Kurabo Industries Ltd.) was used for each well. Then, the culture solution was removed, the medium was replaced with 2 mL of PBS (−) (manufactured by Kojin Bio Co., Ltd.), and then the epidermal keratinized cells were irradiated with UVB. UVB irradiation was carried out by irradiating the ^{culture plate with UVB at 25 mJ / cm 2} with the lid of the culture plate removed using an ultraviolet irradiation device (Dermaray-200; manufactured by Toshiba Medical Supplies Co., Ltd.). After UVB irradiation, PBS (-) was removed, and various hyaluronic acids shown in Examples 1 to 3 in Table 1 below were added so as to be 0.001 w / v% and replaced with 2 mL of the culture solution dissolved. Then, it was cultured for 3 days. As a control (Comparative Example 1), a culture was prepared by exchanging with 2 mL of the above-mentioned culture solution in the same manner except that hyaluronic acid was not contained. After culturing for 3 days, the culture broth was collected, and the PGE2 concentration secreted in the culture broth was quantified by an enzyme-binding immunoassay (PGE2 high sensitivity ELISA kit; manufactured by Enzo Life Sciences). All of the hyaluronic acids 1 to 3 used in this test example shown in Table 1 below used reagents manufactured by Aldrich. As a result, the average values calculated from the quantitative values of each Example and Comparative Example are shown in Table 1 and FIG.

As is clear from the results of FIGS. 1 and 1, in Examples 1 to 3 using hyaluronic acid of each molecular weight, PGE2 production in epidermal keratinized cells after exposure to ultraviolet rays was observed as compared with Comparative Example 1 of the control. It was confirmed that it can be highly suppressed. From this result, by using the external composition of the present invention, inflammation of the skin due to exposure to ultraviolet rays and the induction of melanin production caused by the inflammation can be effectively suppressed at an early stage, and ultraviolet damage on the skin is highly prevented or improved. I know I can do it.

(Test Example 2. PGE2 production suppression test)
A PGE2 production suppression test in epidermal keratinized cells after UVB exposure was carried out in substantially the same manner as in Test Example 1 above.
In this test example, the test was conducted using the test agents shown in Table 2 below. The hyaluronic acids 1 to 3 used in this test example are the same as those used in test example 1. Examples (Examples 5, 7, 9) in which tranexamic acid is combined with respect to the PGE2 production amount when using Examples (Examples 4, 6, 8) containing only hyaluronic acid having the same average molecular weight are shown. The results are also shown in Table 2 with the percentage of PGE2 production when used as a percentage (%).

As shown in Table 2, according to the results of this test example, even if tranexamic acid is used in combination with high molecular weight hyaluronic acid (hyaluronic acid 3), the effect of suppressing PGE2 production in epidermal keratinized cells after exposure to ultraviolet rays is observed. No improving effect was observed. On the other hand, when hyaluronic acid (hyaluronic acid 1, hyaluronic acid 2) having an average molecular weight of 350 kDa or less was used, it was clarified that the amount of PGE produced was significantly reduced by further using tranexamic acid. From this result, when low-molecular-weight hyaluronic acid is used, by blending it in combination with tranexamic acid, the effect of suppressing PGE2 production in epidermal keratinized cells after exposure to ultraviolet rays is further enhanced, and ultraviolet damage to the skin is prevented or prevented. It was revealed that the improving effect was enhanced.

(Test Example 3. IL-1α production suppression test)
The effect of suppressing IL-1α production in epidermal keratinized cells after UVB exposure was evaluated according to the following method.
First, normal human epidermal keratinocytes (NHEK) were cultured in a 6-well culture plate. More specifically, the cells were plated on plates at a density of 3.0 × 10 ⁵ cells / well, at 37 ° C., it was 1 day culture under an environment of 5% carbon dioxide and 95% air. As the culture medium, 2 mL of a medium prepared by adding 10 μg / mL insulin and 0.67 μg / mL hydrocortisone to Humania-KB2 (manufactured by Kurabo Industries Ltd.) was used for each well. Then, the culture solution was removed, the medium was replaced with 2 mL of PBS (−) (manufactured by Kojin Bio Co., Ltd.), and then the epidermal keratinized cells were irradiated with UVB. UVB irradiation was carried out by irradiating the ^{culture plate with UVB at 25 mJ / cm 2} with the lid of the culture plate removed using an ultraviolet irradiation device (Dermaray-200; manufactured by Toshiba Medical Supplies Co., Ltd.). After UVB irradiation, PBS (-) was removed, and various hyaluronic acids shown in Examples 10 to 12 in Table 3 below were added so as to be 0.001 w / v% and replaced with 2 mL of the culture solution dissolved. Then, it was cultured for 3 days. As a control (Comparative Example 2), a culture was prepared by exchanging with 2 mL of the above-mentioned culture solution in the same manner except that hyaluronic acid was not contained. After culturing for 3 days, the culture broth was collected, and the concentration of IL-1α secreted in the culture broth was quantified by an enzyme-linked immunosorbent assay (Quantikine ELISA Human IL-1α / IL-1F1; manufactured by R & D). The hyaluronic acids 1 to 3 used in this test example shown in Table 3 below are the same as those used in test example 1. As a result, the average value calculated from the quantitative values of each Example and Comparative Example is also shown in Table 3.

As shown in the results of Table 3 above, in Examples 10 to 13 using hyaluronic acid of each molecular weight, IL-1α production in epidermal keratinized cells after exposure to ultraviolet rays was observed as compared with Comparative Example 2 of the control. It was confirmed that it could be suppressed.

(Test Example 4. PGE2 production suppression test using a human skin three-dimensional model)
The effect of suppressing PGE2 production in a three-dimensional model of normal human skin after UVB exposure was evaluated according to the following method.
First, a normal human skin three-dimensional model EPI-200 (manufactured by Kurabo Industries Ltd.) was cultured in a 6-well culture plate. More specifically, 5 mL of EPI-100 NMM (manufactured by Kurabo Industries Ltd.) was used as a culture solution for each well, and the cells were cultured at 37 ° C. in an environment of 5% carbon dioxide gas and 95% air for 1 day. Then, the human skin 3D model was transferred to a 6-well culture plate containing 0.9 mL of PBS (−) (manufactured by Kojin Bio Co., Ltd.) per well, and then irradiated with UVB. UVB irradiation was carried out by irradiating the ^{culture plate with UVB at 120 mJ / cm 2} with the lid of the plate removed using an ultraviolet irradiation device (Dermaray-200; manufactured by Toshiba Medical Supplies Co., Ltd.). Each human skin 3D model after UVB irradiation was then transferred to a new 6-well culture plate containing 5 mL of EPI-100 NMM culture per well. To this stratum corneum side, 200 μL of PBS (+) (manufactured by Aldrich) dissolved by adding various test drugs (Examples 13 to 15) shown in Table 4 below is added, and the test drug solution is changed every day. Then, it was cultured for 3 days. As a control (Comparative Example 3), a medium was prepared by exchanging the solution with 200 μL of PBS (+) every day and culturing for 3 days in the same manner except that the test drug was not contained. After culturing for 3 days, the culture broth was collected, and the PGE2 concentration secreted in the culture broth was quantified by an enzyme-linked immunosorbent assay (PGE2 high sensitivity ELISA kit; manufactured by Enzo Life Sciences). The hyaluronic acid 1 used in this test example is the same as that used in test example 1. Table 4 shows the results of the average values calculated from the quantitative values of each Example and Comparative Example.

As shown in Table 4, the results of this test example show that the combined use of low-molecular-weight hyaluronic acid with an average molecular weight of 8 to 15 kDa and tranexamic acid highly suppresses PGE2 production after exposure to ultraviolet rays in a three-dimensional model of human skin. It was confirmed that it could be done. Therefore, it can be seen that the use of the external composition of the present invention can effectively suppress ultraviolet damage to the skin.

An example of formulation of the external composition of the present invention is shown below.

Claims (6)

Hyaluronic acid, contain a derivative thereof, and at least one member selected from the group consisting of salts, tranexamic acid, a derivative thereof, and at least one member selected from the group consisting of salts, as an active ingredient ,
An external composition for preventing or ameliorating UV damage to the skin, wherein the average molecular weight of hyaluronic acid is 4 to 700 kDa. The external composition according to claim 1, wherein prevention or improvement of ultraviolet damage to the skin prevents or ameliorates skin inflammation due to exposure to ultraviolet rays. The external composition according to claim 1 or 2, wherein the ultraviolet rays are ultraviolet B waves. The external composition according to any one of claims 1 to 3, wherein the prevention or amelioration of UV damage to the skin prevents or ameliorates the induction of melanin production due to skin inflammation due to UV exposure. The prevention or amelioration of UV damage to the skin is by suppressing the production of at least one selected from the group consisting of PGE2 and IL-1α in epidermal keratinized cells due to UV exposure, according to claims 1 to 4. The external composition according to any one of. At least 1 selected from the group consisting of tranexamic acid, its derivatives and salts thereof, based on 1 part by weight of the total amount of at least one component selected from the group consisting of hyaluronic acid, its derivatives and salts thereof. The external composition according to any one of claims 1 to 5, wherein the total amount of the seed components is 0.05 to 4000 parts by weight.

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