JP2020180050A - Melanocyte activator production inhibitor - Google Patents

Abstract

To provide techniques of inhibiting production of a melanocyte activator.SOLUTION: A melanocyte activator production inhibitor contains D-pantothenyl alcohol as an active ingredient. Preferably, the melanocyte activator is adrenomedullin, endothelin, interleukin 1α, and interleukin 6.SELECTED DRAWING: None

Description

The present invention relates to a component that suppresses the production of a melanocyte activator.

In addition to sunburn caused by exposure to ultraviolet rays, skin symptoms caused by pigmentation such as spots, freckles, chloasma, and skin blackening caused by drugs are caused by the melanin pigment produced after the melanin production of pigment cells (melanocytes) is enhanced. It is known that it is caused by depositing on the skin due to abnormal turnover or the like.
Such skin symptoms associated with pigmentation are easily observed from the appearance and therefore greatly affect the impression of the face. Therefore, interest in the prevention and improvement of skin pigmentation is very high, especially for those who have a desire to make the skin look beautiful, and the demand for whitening agents and whitening cosmetics has been increasing in recent years.

Ascorbic acid, hydroquinone, and the like have long been known as whitening agents for the purpose of preventing or improving skin pigmentation, and external preparations containing these have been widely used for preventing or improving skin pigmentation. Has been used. Further, in recent years, by elucidating the mechanism of action that causes pigmentation, the development of a whitening agent having a mechanism of action different from that of conventional whitening agents has been actively carried out.
One of such mechanisms of action is a mechanism in which melanin produced by melanocytes is transported to keratinocytes by dendrites (tentacles) of melanocytes, and a dendrite elongation inhibitor having this as an action point is used as an active ingredient of a whitening agent. It has been proposed to do so (Patent Document 1). It is also disclosed that a pigmentation inhibitor can be screened using the activity of a regulator of a melanocyte activator as an index. (Patent Document 2).

By the way, D-pantothenic alcohol is an alcohol-type derivative of pantothenic acid, which is a substance that is converted into vitamin B5 (pantothenic acid) in the body. Further, it has been used for a long time as a compounding component of an external preparation for skin, and various external preparations for skin containing D-pantothenyl alcohol have been proposed.
Patent Document 3 describes that a skin cosmetic containing D-pantothenyl alcohol improves rough skin, particularly dryness of the skin, and prepares the skin quality.
Patent Document 4 describes that a whitening effect can be obtained quickly according to a composition in which D-pantothenyl alcohol and another whitening ingredient are combined.

Japanese Unexamined Patent Publication No. 2013-236579 JP-A-2019-004746 Japanese Unexamined Patent Publication No. 2012-41302 International Publication 2015/152384

An object of the present invention is to provide a technique for suppressing the production of a melanocyte activator.

As a result of diligent research to solve the above problems, the present inventors have found that D-pantothenyl alcohol exerts an excellent inhibitory effect on the production of melanocyte activator, and have completed the present invention. It was.

That is, the present invention is as follows.
[1] An agent for suppressing the production of melanocyte activator, which contains D-pantothenyl alcohol.
[2] The production inhibitor according to [1], wherein the melanocyte activator is selected from the group consisting of adrenomedulin, endothelin, interleukin 1α, and interleukin 6.
[3] A composition for suppressing pigmentation, which contains the production inhibitor according to [1] or [2].
[4] The composition according to [3], which is an external preparation for skin.
[5] The composition according to [4], which is a cosmetic.

INDUSTRIAL APPLICABILITY The present invention provides an agent for suppressing the production of a melanocyte activator. Such inhibitors are suitable for compositions for suppressing skin pigmentation.

The graph which shows the amount of endothelin in the keratinocyte culture supernatant of the control group which did not irradiate UVB, and the group and the control group which added D-pantothenyl alcohol of UVB irradiation.

The melanocyte activator production inhibitor of the present invention contains D-pantothenyl alcohol.
D-pantothenyl alcohol is an alcohol-type derivative of pantothenic acid and has the structure shown below.
D-pantothenyl alcohol is used as a material for external preparations for skin such as cosmetics, and there is no difficulty in obtaining it, and a commercially available product can be used as appropriate.

D-pantothenyl alcohol has an action of suppressing the production of melanocyte activator.
Here, the melanocyte activating factor refers to a factor that stimulates and activates melanocytes, and is preferably selected from the group consisting of adrenomedulin, endothelin, interleukin 1α, and interleukin 6, according to the agent of the present invention. The production of one or more of these is suppressed. Of these factors, adrenomedulin is particularly preferred.
Adrenomedulin has the effect of activating melanocytes to increase or extend the number of dendrites. Increased and elongated dendrites are involved in the transport of melanin from melanocytes to keratinocytes, leading to increased pigmentation.

Here, "production of a melanocyte activator" may include both a production amount and a production rate, but usually refers to a production amount and is represented by an expression level of a protein of the factor or a gene encoding the same. To. The expression level of a protein or gene (usually mRNA) can be measured by a conventional method. Alternatively, the amount of the factor produced may be expressed as a measured value of the reaction activity of the factor. For example, for the adrenomedulin activity, even if the activity of morphologically changing the dendrite is measured by an arbitrary method. Good (see Patent Document 1). Since the melanocyte activator is usually expressed in keratinocytes, the amount of activity can be a value measured in keratinocytes.

"Suppression of production" means that the production of melanocyte activator when D-pantothenyl alcohol is added is smaller than the production when D-pantothenyl alcohol is not added, and is usually 95% or less, preferably 85% or less. , More preferably 80% or less, which can be confirmed.

It is generally known that melanin production is enhanced by tyrosinase when melanocytes are activated. Therefore, the production of melanocyte activator is suppressed, so that the production of melanin is suppressed, so that D-pantothenyl alcohol exerts a whitening effect.
In the present specification, whitening refers to suppression (prevention and / or improvement) of pigmentation, and more specifically, enhancement of melanin production such as dark spots, dullness, freckles, sunburn, and darkening due to skin inflammation and irritation. , Excessive accumulation, pigmentation symptoms caused by abnormal deposition, etc., and pigmentation symptoms caused by diseases that cause pigmentation such as skin blackening caused by drugs such as steroids, etc., are prevented and / or improved. That is, the agent for suppressing the production of the melanocyte activator of the present invention can be suitably contained in the composition for suppressing pigmentation.

In the composition for suppressing pigmentation of the present invention, the content of the production inhibitor of the melanocyte activator of the present invention is the total amount with respect to the total amount of D-pantothenyl alcohol, preferably the total amount. It is 0.01 to 20% by mass, more preferably 0.1 to 10% by mass, and further preferably 0.1 to 5% by mass. Within such a range, the desired effect can be easily obtained, and the degree of freedom in formulation design can be ensured.

Examples of the dosage form of the composition for suppressing pigmentation of the present invention include lotion type, emulsifier type such as milky lotion and cream, oil type, oil gel type, gel type, pack, cleaning agent and the like.
In addition, the composition for suppressing pigmentation of the present invention is preferably in the form of an external preparation for skin, and more preferably in the form of cosmetics and quasi-drugs.

In the composition for suppressing pigmentation of the present invention, in addition to D-pantothenyl alcohol, any component used in ordinary external preparations for skin can be arbitrarily contained as long as the effect of the present invention is not impaired. Examples of such an optional ingredient include various active ingredients, oily ingredients, surfactants, polyhydric alcohols, thickeners, powders, ultraviolet absorbers and the like.

Examples of the active ingredient include other whitening ingredients, wrinkle improving ingredients, anti-inflammatory ingredients, extracts derived from animals and plants, and the like.
The other whitening ingredients are not particularly limited as long as they are generally used in cosmetics. For example, 4-n-butyl resorcinol, ascorbic acid glucoside, 3-О-ethylascorbic acid, arbutin, ellagic acid, kojic acid, linoleic acid, nicotinamide, 5,5'-dipropylbiphenyl-2,2'- Examples thereof include diol, disodium 5'-adenylate, potassium 4-methoxysalicylate salt, hydroquinone and the like.

The wrinkle improving ingredient is not particularly limited as long as it is generally used in cosmetics. For example, isopropyloxopropylaminocarbonylpyrrolidin carbonylmethylpropylaminocarbonylbenzoylaminoacetate sodium, nicotinic acid amide, vitamin A or derivatives thereof (retinol, retinal, retinoic acid, tretinoin, isotretinoin, tocopherol retinoate, retinol palmitate) , Retinol acetate, etc.), ursolic acid benzyl ester, ursolic acid phosphate ester, bethuric acid benzyl ester, benzylic acid phosphate ester.

Anti-inflammatory components include glycyrrhetinic acid, glycyrrhetinic acid, allantin, isopropylmethylphenol, clarinone, glabridin, salicylic acid, tocopherol acetate, tocopherol nicotinic acid ester, nicotinamide, pantothenic acid, pantothenyl alcohol, and salts or derivatives thereof. And the like, preferably glycyrrhetinic acid and its salt, glycyrrhetinic acid and its salt, pantothenyl alcohol and pantothenic acid and its salt.

The animal and plant-derived extracts are not particularly limited as long as they are generally used in cosmetics and the like. For example, akebi extract, asunaro extract, asparagus extract, avocado extract, amacha extract, almond extract, arnica extract, aloe extract, aronia extract, apricot extract, ginkgo extract, indokino extract, uikyo extract, udo extract, agetsu extract, elephant kogi extract. , Enmeisou extract, Ogon extract, Oubaku extract, Ouren extract, Otaneninjin extract, Otogirisou extract, Odorikosou extract, Orange extract, Kakyoku extract, Kakon extract, Chamomile extract, Carrot extract, Kawarayomogi extract, Kiwi extract, Cucumber extract, Guava extract, Kujin extract, Kuchinashi extract, Kumazasa extract, Clara extract, Walnut extract, Grapefruit extract, Black rice extract, Chlorella extract, Kuwa extract, Keiketto extract, Gettoyo extract, Gentiana extract, Gennoshoco extract, Tea extract, Gobo extract, Rice extract, Fermented rice extract , Rice bran extract, rice germ oil, moss peach extract, salvia extract, sabonsou extract, sasa extract, sansha extract, sansho extract, shiitake extract, dioe extract, shikon extract, shiso extract, shinanoki extract, shimotsukesou extract, shakuyaku extract, shokyo extract, Shobu root extract, white birch extract, sugina extract, stevia extract, stevia fermented product, sardine extract, sardine extract, sardine extract, sardine extract, sardine extract, sage extract, zenia oyster extract, senkyu extract, senburi extract, sohakuhi Extract, Daiou extract, Soybean extract, Taisou extract, Thyme extract, Dandelion extract, Tea extract, Chouji extract, Chinpi extract, Jincha extract, Togarashi extract, Touki extract, Tokinsenka extract, Tounin extract, Tohi extract, Dokudami extract, Tomato extract, Natto extract , Carrot extract, garlic extract, Novara extract, Hibiscus extract, Bakumondou extract, Hass extract, Parsley extract, Birch extract, Hamamelis extract, Hikiokoshi extract, Hinoki extract, Biwa extract, Fukitanpopo extract, Fukinoto extract, Bukuryo extract, Butcher bloom extract, Grape Extract, grape seed extract, hechima extract, benibana extract, peppermint extract, bodaiju extract, button extract, ho Pup extract, pine extract, mayonara extract, marronnier extract, mizubasho extract, mukuroji extract, melissa extract, mozuku extract, peach extract, yagurumagiku extract, eucalyptus extract, yukinoshita extract, yuzu extract, lily extract, yokunin extract, yomogi extract, lavender extract, green tea extract, apple extract , Louis Boss tea extract, Reishi extract, lettuce extract, lemon extract, lotus extract, lotus extract, rose extract, rosemary extract, roman chamomile extract, royal jelly extract, crackle extract and the like are preferable.

Examples of the oily component include polar oils and volatile hydrocarbon oils.
Polar oils include synthetic ester oils such as isopropyl myristate, cetyl octanate, octyldodecyl myristate, isopropyl palmitate, and butyl stearate.
Hexyl laurate, myristyl myristate, decyl oleate, hexyldecyl dimethyloctanate, cetyl lactate, myristyl lactate, lanolin acetate, 2-ethylhexyl isononanoate, isosetyl stearate, isosetyl isostearate, cholesteryl 12-hydroxystearate, di- Ethylene glycol 2-ethylhexanoate, dipentaerythritol fatty acid ester, N-alkyl glycol monoisostearate, neopentyl glycol dicaprate, diisostearyl malate, glyceryl di-2-heptyl undecanoate, tri-2-ethylhexanoic acid Examples thereof include trimethylolpropane, trimethylolpropane triisostearate, pentaneerythritol tetra-2-ethylhexanoate, glyceryl tri-2-ethylhexanoate, and trimethylolpropane triisostearate.

In addition, cetyl 2-ethylhexanoate, 2-ethylhexyl palmitate, glyceryl trimyristate, glyceride tri-2-heptyl undecanoate, castor oil fatty acid methyl ester, oleic acid oil, cetostearyl alcohol, acetoglyceride, palmitic acid 2 -Heptylundecyl, diisobutyl adipate, N-lauroyl-L-glutamic acid-2-octyldodecyl ester, di-2-heptylundecyl adipate, ethyllaurate, di-2-ethylhexyl sebatate, 2-hexyl myristate Examples thereof include decyl, 2-hexyldecyl palmitate, 2-hexyldecyl adipate, diisopropyl sebatate, 2-ethylhexyl succinate, ethyl acetate, butyl acetate, amyl acetate, triethyl citrate, and octylmethoxycinnamate.

Also, as natural oils, avocado oil, camellia oil, turtle oil, macadamia nut oil, corn oil, mink oil, olive oil, rapeseed oil, egg yolk oil, sesame oil, persic oil, wheat germ oil, southern ka oil, castor oil, flaxseed oil, Saflower oil, cotton seed oil, eno oil, soybean oil, peanut oil, tea seed oil, kaya oil, rice bran oil, cinnamon oil, Japanese millet oil, jojoba oil, germ oil, triglycerin, glyceryl trioctanoate, glyceryl triisopalmitate And so on.

Examples of the volatile hydrocarbon oil include isododecane and isohexadecane.

Examples of the surfactant include anionic surfactants such as fatty acid sucrose (sodium laurate, sodium palmitate, etc.), potassium lauryl sulfate, triethanolamine alkyl sulfate ether, stearyltrimethylammonium chloride, benzalconium chloride, laurylamine oxide. Cationic surfactants such as, betaine-based surfactants (alkylbetaine, amide betaine, sulfobetaine, etc.), imidazoline-based amphoteric surfactants (2-cocoyl-2-imidazolinium hydroxide-1-carboxyethyloxy 2) (Sodium salt, etc.), amphoteric surfactants such as acylmethyltaurine, sorbitan fatty acid esters (sorbitan monostearate, sorbitan sesquioleate, etc.), glycerin fatty acid esters (glyceryl monostearate, etc.), propylene glycol fatty acid esters (Polyethylene glycol monostearate, etc.), hardened castor oil derivative, glycerin alkyl ether, POE sorbitan fatty acid esters (POE sorbitan monooleate, polyoxyethylene sorbitan monostearate, etc.), POE sorbit fatty acid esters (POE-sorbit mono) Laurate, etc.), POE glycerin fatty acid esters (POE-glycerin monoisostearate, etc.), POE fatty acid esters (polyethylene glycol monoolate, POE distearate, etc.), POE alkyl ethers (POE2-octyldodecyl ether, etc.), POE Alkylphenyl ethers (POE nonylphenyl ether, etc.), Pluronic types, POE / POP alkyl ethers (POE / POP2-decyltetradecyl ether, etc.), Tetronics, POE castor oil / cured castor oil derivative (POE castor oil, etc.) , POE cured castor oil, etc.), nonionic surfactants such as sucrose fatty acid ester, alkyl glucoside, etc.

Polyhydric alcohols include polyethylene glycol, glycerin, 1,3-butylene glycol, erythritol, sorbitol, xylitol, martitol, propylene glycol, dipropylene glycol, diglycerin, isoprene glycol, 1,2-pentanediol, 2,4. -Hexylene glycol, 1,2-hexanediol, 1,2-octanediol and the like can be mentioned.

As thickeners, guar gum, quince seed, carrageenan, galactan, arabic gum, pectin, mannan, starch, xanthan gum, curdlan, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methyl hydroxypropyl cellulose, chondroitin sulfate, dermatan sulfate, glycogen, Heparan sulfate, hyaluronic acid, sodium hyaluronate, traganth gum, keratane sulfate, chondroitin, mucoitin sulfate, hydroxyethyl guar gum, carboxymethyl guar gum, dextran, keratosulfate, locust bean gum, succinoglucan, caronic acid, chitin, chitosan, carboxymethyl Examples thereof include chitin, agar, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, alkyl-modified carboxyvinyl polymer, sodium polyacrylate, polyethylene glycol, bentonite and the like.

As the powders, the surface may be treated, such as mica, talc, kaolin, synthetic mica, calcium carbonate, magnesium carbonate, silicic acid anhydride (silica), aluminum oxide, barium sulfate and the like, and the surface. May be treated, red iron oxide, black iron oxide, cobalt oxide, ultramarine, dark blue, titanium oxide, zinc oxide inorganic pigments, surface may be treated, mica titanium, fish phosphorus foil, Pearl agents such as bismuth oxychloride, red 202, red 228, red 226, yellow 4, blue 404, yellow 5, red 505, red 230, red 223, which may be raked. Organic pigments such as No., Orange No. 201, Red No. 213, Yellow No. 204, Yellow No. 203, Blue No. 1, Green No. 201, Purple No. 201, Red No. 204, Polyethylene powder, Polymethyl methacrylate, Nylon powder, Examples thereof include organic powders such as organopolysiloxane elastomers.

Examples of UV absorbers include paraaminobenzoic acid-based UV absorbers, anthranilic acid-based UV absorbers, salicylic acid-based UV absorbers, cinnamic acid-based UV absorbers, benzophenone-based UV absorbers, sugar-based UV absorbers, 2- (2). Examples thereof include UV absorbers such as'-hydroxy-5'-t-octylphenyl) benzotriazole and 4-methoxy-4'-t-butyldibenzoylmethane.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the following Examples as long as the gist thereof is not exceeded.

<Example 1> Examination of the effect of D-pantothenyl alcohol on melanocyte activators 1
Normal human keratinocytes (adult, Lot # 00702, manufactured by Kurabo Industries Ltd.) were inoculated in 6-well plates at 7.5 × 10 ⁴ cells / well, in HuMedia-KG2 medium at 37 ° C., and 24 in a 5% CO ₂ environment. Cultured for hours. After culturing, the medium was replaced with a medium containing 100 μg / mL of D-pantothenyl alcohol. In addition, a control group was also provided in which the medium was replaced with a medium containing no D-pantothenyl alcohol. After the medium was exchanged, the cells were further cultured at 37 ° C. in a 5% CO ₂ environment for 24 hours. After culturing, each well was washed with PBS, and then 350 μL / well of RLT buffer was added to detach the cells. The detached cells were collected in an Eppendorf tube, set with a QIAshredder homogenizer (manufactured by Qiagen), and centrifuged at 4 ° C., 15,000 rpm, and 2 minutes to collect mRNA. The recovered mRNA was purified by treatment with a QIAcube spin column system (manufactured by Qiagen). The purified mRNA was subjected to microarray analysis using an analysis array GeneChip Human Genome U133 Plus 2.0 Array (manufactured by Thermo Fisher Scientific), and the expression level of each gene was measured.

Table 1 shows the expression level of each gene in the D-pantothenyl alcohol-added group as a relative value when the expression level in the control group is 100%.
It was confirmed that the gene expression of adrenomedulin, interleukin 1α, and interleukin 6 was suppressed in keratinocytes supplemented with D-pantothenyl alcohol.

<Example 2> Examination of the effect of D-pantothenyl alcohol on melanocyte activators 2
Normal human keratinocytes (adult, Lot # 00702, manufactured by Kurabo Industries Ltd.) were inoculated on a 24-well plate at 4.0 × 10 ⁴ cells / well in a HuMedia-KG2 medium at 37 ° C. under a 5% CO ₂ environment at 24. Cultured for hours. After culturing, the medium was replaced with a medium containing 100 μg / mL of D-pantothenyl alcohol. In addition, a control group was also provided in which the medium was replaced with a medium containing no D-pantothenyl alcohol. After the medium was exchanged, the cells were further cultured at 37 ° C. in a 5% CO ₂ environment for 24 hours. After culturing, the medium was replaced with 500 μL of PBS, irradiated with UVB (irradiation group: 50 mJ / cm ² , non-irradiation group: 0 mJ / cm ² ), and D-pantothenyl alcohol-containing medium (addition group: 100 μg / mL, control group). : 0 μg / mL) was replaced. After the medium was exchanged, the cells were further cultured at 37 ° C. in a 5% CO ₂ environment for 24 hours. The culture supernatant was collected, and the amount of endothelin in the culture supernatant was measured using the Endothelin-1 Quantikine ELISA Kit (manufactured by R & D Systems).

FIG. 1 shows the amount of endothelin in each group.
It was confirmed that the amount of endothelin was increased in UVB-irradiated keratinocytes, but the amount of endothelin was suppressed by the addition of D-pantothenyl alcohol.

INDUSTRIAL APPLICABILITY The present invention provides an excellent component capable of suppressing the production of a melanocyte activator, which is industrially useful.

Claims (5)

An agent for suppressing the production of melanocyte activator, which contains D-pantothenyl alcohol. The production inhibitor according to claim 1, wherein the melanocyte activator is selected from the group consisting of adrenomedulin, endothelin, interleukin 1α, and interleukin 6. A composition for suppressing pigmentation, which comprises the production inhibitor according to claim 1 or 2. The composition according to claim 3, which is an external preparation for skin. The composition according to claim 4, which is a cosmetic.