JP5826075B2 - Cosmetics - Google Patents

Description

The present application relates to a cosmetic in which a specific component is combined with a production promoter for the amount of clock gene BMAL-1 protein.

For rough skin caused by normal seasonal fluctuations, prevention, improvement, and healing can be achieved by using cosmetics that contain polymers such as hyaluronic acid and moisturizers such as proteins such as collagen and their degradation products. I have been.

However, in recent years, pathological rough skin caused by atopic dermatitis or lack of sleep or circadian rhythms can be improved with cosmetics that simply apply moisturizing ingredients from outside the skin. Few.
This is because the rough skin caused by seasonal changes is due to a temporary decline in skin function, and if this is supplemented with something like cosmetics, the rough skin caused by atopic dermatitis is the surface of the skin. This is because it is not caused by a change in the state of the skin, but is caused by an abnormal function of the epidermal cells.
Therefore, atopic dermatitis and the like had to be improved from the inside of the skin.

In recent years, genetic analysis results have revealed that patients with atopic dermatitis often have abnormalities in the filaggrin gene. In Europe, it has been reported that filaggrin gene abnormality was observed in about 40% of patients with atopic dermatitis. Filaggrin is a protein produced in epidermal cells and is degraded by an enzyme called caspase-14. The degradation product plays an important role in retaining moisture in the skin as a natural moisturizing factor.

In patients with atopic dermatitis, filaggrin is not sufficiently produced, so that the natural moisturizing factor is not produced and the moisture retention of the skin cannot be maintained. Moreover, since the barrier function of the skin is not sufficient, a skin condition in which rough skin and inflammation are likely to occur is exhibited.

On the other hand, the clock center that controls the circadian rhythm of the living body exists in the suprachiasmatic nucleus of the hypothalamus. However, it has been clarified that in each tissue of the living body, for example, there are peripheral clocks in the heart, liver, lungs, and skin, and they are controlled by the central clock.
Recently, it has been clarified that there is a time zone that is likely to cause illness due to the expression rhythm of the clock gene. For example, it is known that myocardial infarction occurs frequently in the morning, and itching of atopic dermatitis worsens at night. It has been found that this is due to a diurnal rhythm in the enzyme activity related to the blood coagulation system, and because the sensitivity of hormones and histamine in the cells increases at night by the action of clock genes.

Until now, JP 2009-84192 A (Patent Document 1) is intended to contain cryptoxanthin and / or an ester thereof as normalizing the biological clock or exhibiting the sleep improvement effect by normalizing the biological clock. There is a description of a composition in which the characterized composition, preferably cryptoxanthin and / or an ester thereof, is composed of Wenzhou mandarin oranges, processed products of mandarin oranges, enzyme processed products of citrus mandarin oranges, and solvent extracts of citrus mandarin oranges.

JP-A-2005-247740 (Patent Document 2) provides a drug capable of preventing and treating lifestyle-related diseases (such as obesity) by inhibiting BMAL-1 which controls lipid metabolism. A protein BMAL-1 having a gene regulating function and a method for inhibiting BMAL-1 by administering a thiazolidine compound having an inhibitory action to the BMAL-1 to a living body are described.

Further, JP 2008-266319 (Patent Document 3) discloses a flavonoid selected from the group consisting of flavone, flavonol, isoflavone, flavanone, anthocyanin and flavanol, and steroidal saponin, sesquiterpenoid, And derivatives of monacolin K, and resveratrol, scopoletin, eugenol, silymarin, forskolin, and products extracted from celery seeds with ethanol or glycerin.

On the other hand, JP 2010-90037 (Patent Document 4) discloses filaggrin production promoting action in order to effectively improve and prevent dry skin, wrinkles, rough skin, and atopic dermatitis by exerting a skin moisturizing effect. A composition containing rosmarinic acid having the following and eriodictyol 7-O-rutinoside is described.

JP-A-2008-285423 (Patent Document 5) describes a composition containing an extract from Agez as a substance having a profilaggrin production promoting action and a filaggrin production promoting action and having a pore conspicuous inhibiting effect.

JP 2008-88075 (Patent Document 6) discloses profilaggrin / filaggrin production promoter, epidermal keratinocyte proliferation promoter, stratum corneum normalization and / or skin external preparation excellent in epidermal normalization effect as a human lysizuka extract A composition containing as an active ingredient is described.

As described above, various methods have been proposed. However, in the case where a moisturizing effect is directly provided, although there is a temporary effect, a long-term effect cannot be expected at present. On the other hand, when moisturizing-related components are produced inside cells, a fundamental improvement can be expected, but the actual effect cannot be expected unless the effective components reach the skin. Therefore, in atopic dermatitis that cannot be improved by simply applying a moisturizer or the like directly to the skin, it is important how to penetrate into the cell a component that can even produce a moisturizing related component in the cell. come.

Although menthol is known as a component that enhances the transdermal absorption effect, menthol has a unique odor and is also irritated even in small amounts, especially for those with skin diseases such as atopic dermatitis with weak skin irritation. Could not be used.

JP 2009-84192 A JP 2005-247740 A JP 2008-266319 A JP 2010-90037 A JP 2008-285423 A JP 2008-88075 A

An object is to infiltrate cells with an effective component that promotes the production of BMAL-1 protein in the cell, and to ensure that the effect is exerted in the cell.

As a result of diligent studies to achieve the above-mentioned problems, an effective ingredient (A) that promotes production of the clock gene BMAL-1 protein, fatty acid menthol ester (B), diisopropyl sebacate, menthoxypropanediol, The problem was solved by using in combination the component (C) for promoting percutaneous absorption with cyclohexane-1,4-dicarboxylic acid bisethoxydiglycol.
Hereinafter, in the present application, when BMAL-1 represents a gene, it is denoted as Bmal-1, and when it represents a protein, it is denoted as BMAL-1.

The barrier function of the skin can be enhanced and the amount of skin moisture transpiration can be drastically suppressed. Thereby, it can be expected to improve skin diseases such as atopic dermatitis that required fundamental improvement from the inside of the cells.

Hereinafter, the present invention will be described in detail.
Sage (Salvia
officinalis) is a perennial plant belonging to the genus Akigiri, which is also called medicinal salvia. The plant height is about 50-70 cm, and purple or white lip-shaped flowers bloom in May-July. Some say that the leaves are dried and used as herbal teas, or used to remove the smell of meat and are well-matched with pork. Around 900 species are distributed around the world, mainly in Latin America and Europe, including salvia and sage. There are various types of Japanese origin such as Akinotamuraso and Kibanaakigiri (Huangka Aki Tung), but any type can be used.

Nicotinic acid amide has nicotinic acid as a related compound, and is essential for metabolism of carbohydrates, lipids, and proteins in vivo. It works to promote the work of the circulatory system, digestive system, nervous system, and when deficient, symptoms such as dermatitis, stomatitis, neuritis and diarrhea occur. In addition, nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate play an important role as a coenzyme of oxidoreductase during energy metabolism, and any compound can be used.

Calcium pantothenate includes pantothenic acid, panthenol, and panthenyl ethyl ether as related compounds. Pantothenic acid, also called vitamin B5, is a substance involved in important reactions in sugar metabolism and fatty acid metabolism as a constituent of CoA (coenzyme A). The foods that are included in most foods, especially those that are abundant, include dried yeast, eggs, milk, liver, natto, peanuts, dried shiitake mushrooms, salmon, and sardines.

For the nicotinic acid amide and calcium pantothenate of the above compounds, commercially available reagents may be used, and those extracted and purified from microorganisms such as yeast, cells of animals, plants, etc. are also used in the present invention. it can. In the present invention, one or more of the aforementioned compounds can be used in combination.

Although the preparation method of the sage extract used for this invention is not specifically limited, For example, it can extract under low temperature from heating using various suitable organic solvents. Examples of the extraction solvent include water; lower monohydric alcohols such as methyl alcohol and ethyl alcohol; liquid polyhydric alcohols such as glycerin, propylene glycol, and 1,3-butylene glycol; ketones such as acetone and methyl ethyl ketone; and ethyl acetate. One kind or two or more kinds of alkyl esters; hydrocarbons such as benzene and hexane; ethers such as diethyl ether; halogenated alkanes such as dichloromethane and chloroform can be used. Among them, water, ethyl alcohol, and one or more mixed solvents of 1,3-butylene glycol are particularly preferable.

As the extraction method, for sage, a leaf or whole plant can be used as it is, or a pulverized solvent can be used in a mass ratio of 2 to 1000 times, particularly 5 to 100 times the amount of solvent. In the case of normal temperature extraction, it is preferable to carry out at 0 ° C. or higher, particularly 20 ° C. to 40 ° C. for 1 hour or longer, particularly 3 to 7 days. Moreover, you may heat-extract at 60-100 degreeC for 0.5 to 24 hours.

The sage extract obtained under the above conditions may be used as a solution after filtration or the like. However, if necessary, the sage extract can be used by appropriately using concentrated and powdered products.

Fatty acid menthol ester is a compound in which fatty acid and L-menthol are ester-bonded. Typical fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid,
Palmitoleic acid, myristoleic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid and the like can be used. It is also possible to create menthol esters of mixed fatty acids by enzymatic synthesis from oils such as safflower oil, rapeseed oil, cottonseed oil, and soybean oil.

Diisopropyl sebacate was a cosmetic raw material commercially available from Nikko Chemicals Co., Ltd., Mentoxypropanediol was Takasago Fragrance Co., Ltd., and Cyclohexane-1,4-dicarboxylic acid bisethoxydiglycol was commercially available from Nippon Seika Co., Ltd.

Cosmetics comprising the sage of the present invention, nicotinic acid amide, calcium pantothenate, fatty acid menthol ester, diisopropyl sebacate, menthoxypropanediol, cyclohexane-1,4-dicarboxylic acid bisethoxydiglycol, For example, basic cosmetics such as milky lotion, cream, lotion, essence, pack, face wash, makeup cosmetics such as lipstick, foundation, liquid foundation, makeup pressed powder, cleansing makeup such as face wash, body shampoo, soap However, it is not limited to these.

The amount of sage, nicotinic acid amide and calcium pantothenate in the cosmetic of the present invention is generally 0.001 to 10% by mass, preferably 0.01 to 3% by mass.
The amount of fatty acid menthol ester is generally in the range of 0.001 to 10 mass%, preferably 0.01 to 1.0 mass%.
The blending amount of diisopropyl sebacate, menthoxypropanediol and bisethoxydiglycol of cyclohexane-1,4-dicarboxylate is generally in the range of 0.001 to 10% by mass, preferably 0.01 to 3.0% by mass. It is.

In addition to the above-mentioned essential ingredients, the cosmetics of the present invention include compounding ingredients usually used in cosmetics, such as oily ingredients, surfactants, moisturizers, thickeners, antiseptic / disinfectants, powder ingredients, ultraviolet rays. Absorbers, pigments, fragrances and the like can be appropriately blended as necessary.

Here, as the oil component, for example, olive oil, jojoba oil, castor oil, soybean oil, rice oil, rice germ oil, palm oil, palm oil, cacao oil, meadow foam oil, sheer butter, tea tree oil, avocado oil, Oils derived from plants such as macadamia nut oil and plant-derived squalane; Fats derived from animals such as mink oil and turtle oil; waxes such as beeswax, carnauba wax, rice wax, lanolin; liquid paraffin, petrolatum, paraffin wax, squalane, etc. Hydrocarbons; fatty acids such as myristic acid, palmitic acid, stearic acid, oleic acid, isostearic acid, cis-11-eicosenoic acid; higher alcohols such as lauryl alcohol, cetanol, stearyl alcohol; isopropyl myristate, palmitic acid Isopropyl, me Butyl phosphate, 2-ethylhexyl glycerides, higher fatty acid octyldodecyl (octyl stearate dodecyl and the like), and the synthetic esters and synthetic triglycerides such like.

Examples of the surfactant include polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene Nonionic surfactants such as oxyethylene sorbitol fatty acid esters; fatty acid salts, alkyl sulfates, alkylbenzene sulfonates, polyoxyethylene alkyl ether sulfates, polyoxyethylene fatty acid amine sulfates, polyoxyethylene alkyl phenyl ether sulfates, Polyoxyethylene alkyl ether phosphates, α-sulfonated fatty acid alkyl ester salts, polyoxyethylene alkyl phenyl ether phosphates, etc. ON surfactant: quaternary ammonium salt, primary to tertiary fatty acid amine salt, trialkylbenzylammonium salt, alkylpyridinium salt, 2-alkyl-1-alkyl-1-hydroxyethylimidazolinium salt, N N, N-dimethyl-N-alkyl-N-carboxymethylammoniobetaine, N, N, N-trialkyl-N-, N, N-dimethyl-N-alkyl-N-carboxymethylammoniobetaine Amphoteric surfactants such as alkylene ammoniocarboxybetaine and N-acylamidopropyl-N ′, N′-dimethyl-N′-β-hydroxypropylammoniosulfobetaine can be used.

Examples of humectants include glycols such as glycerin, propylene glycol, dipropylene glycol, 1,3-butylene glycol, and polyethylene glycol, sugars such as maltitol, sorbitol, xylitol, trehalose, glucose, sodium pyrrolidonecarboxylate, and lactic acid bacteria fermentation. Rice, mucopolysaccharide (eg, hyaluronic acid and its derivatives, chondroitin and its derivatives, heparin and its derivatives), elastin and its derivatives, collagen and its derivatives, hydrolyzed silk protein, lactic acid, urea, higher fatty acid octyldodecyl, Examples include phytosterol, soybean phospholipid, cholesteryl isostearate, seaweed extract, various amino acids, and derivatives thereof. In addition, belode oyster extract, Yokuinin extract, Giant extract, Taiso extract, Kidachi aloe extract, Burdock extract, Mannen wax extract, Arnica extract, Tomato extract, Toki extract, Toki root extract, Soybean extract, Asparagus extract, Ashitaba extract, Amatya extract, Altea extract, Plant extracts such as aloe vera extract and melissa extract can be used.

Examples of thickeners include, for example, brown algae such as alginic acid, agar, carrageenan, fucoidan, and fartheraran, green algae or red algae-derived components, beech extract, pectin, locust bean gum, polysaccharides such as aloe polysaccharide, xanthan gum, tragacanth gum, guar gum Synthetic polymers such as gums such as carboxymethylcellulose, hydroxyethylcellulose, etc., polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, acrylic acid / methacrylic acid copolymer; hyaluronic acid and its derivatives, polyglutamic acid and its Examples thereof include sugar compounds mainly composed of derivatives, glucosyl trehalose and hydrolyzed hydrogenated starch.

Examples of the antiseptic / bactericidal agent include urea; paraoxybenzoates such as methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate; phenoxyethanol, dichlorophene, hexachlorophene, chlorhexidine hydrochloride, benzaza chloride Extracts of Arachnium plants such as Luconium, Salicylic acid, Ethanol, Undecylenic acid, Phenols, Jamal (Imidazodenyl urea), 1,2-pentanediol, Udo, various essential oils, bark dry matter, propolis extract, etc. is there.

Examples of the powder component include sericite, titanium oxide, talc, kaolin, bentonite, zinc oxide, magnesium carbonate, magnesium oxide, zirconium oxide, barium sulfate, silicic anhydride, mica, 6- or 12-nylon powder, polyethylene powder. , Silk powder, cellulosic powder and the like.

Examples of the ultraviolet absorber include ethyl paraaminobenzoate, ethylhexyl paradimethylaminobenzoate, amyl salicylate and derivatives thereof, 2-ethylhexyl paramethoxycinnamate, octyl cinnamate, oxybenzone, 2,4-dihydroxybenzophenone, 2-hydroxy-4 -Methoxybenzophenone-5-sulfonate, 4-tertiarybutyl-4-methoxybenzoylmethane, 2- (2-hydroxy-5-methylphenyl) benzotriazole, urocanic acid, ethyl urocanate, aloe extract, etc. .

Antioxidants include, for example, superoxide dismutase, bioactive oxygen-degrading enzymes such as catalase, vitamins such as vitamin E and vitamin D and derivatives thereof, butylhydroxyanisole, butylhydroxytoluene, propyl gallate, There are ubidecaquinone (ubiquinone), rutin, rutin glucoside, γ-oryzanol and the like.

Furthermore, if necessary, other active ingredients (whitening agents, skin aging prevention / skin roughening agents, anti-inflammatory agents, etc.) may be blended within the range not impairing the effects and features of the present invention. For example, for whitening agents, tranexamic acid and derivatives thereof, t-cycloamino acid derivatives, kojic acid and derivatives thereof, ascorbic acid and derivatives thereof, hydroquinone derivatives, ellagic acid and derivatives thereof, resorcinol derivatives, placenta extract, cysteine, Sakuhakuhi extract, saxifrage extract, hamameris extract, itadori extract, licorice extract, genus shochu extract, saxifrage extract, jujube extract, peonies extract, peach extract, green algae, red algae or brown algae seaweed If it is an extract, a component for preventing skin aging and improving skin roughness, collagen derived from animal or fish and its inducement Body, elastin and derivatives thereof, intercellular lipids such as ceramide, placenta extract, cultured yeast extract, glycyrrhizic acid and derivatives thereof (dipotassium salt, etc.), t-cycloamino acid derivatives, vitamin A precursor, vitamin A and derivatives thereof Vitamin E and derivatives thereof, allantoin, α-hydroxy acids, diisopropylamine dichloroacetate, γ-amino-β-hydroxybutyric acid, coenzyme Q-10, adenosine, α-lipoic acid, picoline, carnitine and derivatives thereof, gentian extract, Herbal extracts such as licorice extract, pearl barley extract, chamomile extract, carrot extract, aloe extract, fermented rice extract, seaweed extract of green algae, red algae or brown algae, beech extract, beetle aloe extract, mannenrou extract, ginkgo biloba Extract, horsetail extract Safflower extract, Panax ginseng extract, Elderberry extract, Hagoromogusa extract, Astragalus extract, Mango extract, Egg shell membrane extract protein, Deoxyribonucleic acid potassium salt, Purple orchid root extract, Murasakixikibu extract, Rice extract, etc. In addition, if it is an anti-inflammatory component, for example, azulene derivatives such as sodium guaiazulene sulfonate and ethyl guaiazulene sulfonate, glycyrrhizic acid derivatives such as dipotassium glycyrrhizinate and stearyl glycyrrhizinate, allantoin, licorice extract, cucumber extract, button paste extract, Forsythia extract, ryutan extract, ginseng extract, parsley extract, hypericum extract and the like.

Next, an experiment in which mRNA of Bmal-1 was knocked down by RNA interference and the result thereof will be described in detail. The present invention will be described more specifically with reference to formulation examples (cosmetic examples) and test examples, but the present invention is not limited thereto. In the following, all parts are parts by mass, and all% are% by mass.

<Bmal-1 RNA interference test>
The siRNA sequence for RNA interference of Bmal-1 is PNAS August 23, vol.102,
The following sequences described in No. 34, 12071-12076, 2005 were used.
Bmal-1 siRNA sequence
Sense 5'-CCA / CCA / ACC / CAU / ACA / CAG / AAG / CAA / A-3 '
Anti
sense 5'-UGC / UUC / UGU / GUA / UGG / GUU / GGU / GGA / A-3 '
control array
Sense 5'-CCA / CCA / AAU / ACA / CAC / GAA / GCC / CAA / A
Anti
sense 5'-UGG / GCU / UCG / UGU / GUA / UUU / GGU / GGA / A

<Introduction of Bmal-1-siRNA into cells>
The cells were cultured by culturing Hacat cells, which are human epidermal cells. Plus 1 ml of culture solution
After adding 8 μl of Reagent, 4 μl of Lipofectamine, and 30 nmol of Bmal-1-siRNA, it was added to Hacat cells that were about 80% confluent. After 3 hours of incubation, siRNA was introduced into the cells. Thereafter, the culture medium was replaced with D-MEM medium containing 5% FBS, and mRNA was extracted from the cells 21 hours later. mRNA was extracted with RNeasy mini kit (Qiagen).

<Confirmation of mRNA expressed in cells>
CDNA was prepared from mRNA extracted from the cells using Prime Script RT reagent kit (Perfect Real time) Takara. Real time PCR was performed using Primer described in Table-1, the prepared cDNA, and Power SYBR Green PCR Master Mix (Applied biosystem). The expression level of mRNA was corrected by the CPD value of GAPDH as a reference gene and determined by the ΔΔCt method, which is a relative quantification method.

Experimental results Table 2 shows the relative amount of mRNA expression in Hacat cells into which Bmal-1-siRNA was introduced, with the amount of each mRNA in cells into which control sequences were introduced as 100.
In addition, as a result of confirming the gene transfer efficiency into Hacat cells, which are human epidermal cells, by X-gal staining in advance, the amount of siRNA introduced into the cells was 50-60%.
The mRNA expression level of Bmal-1 subjected to RNA interference was 58.2%. Considering the gene transfer efficiency into Hacat cells, which are human epidermal cells, it is considered that Bmal-1 expression was strongly suppressed in cells into which siRNA was introduced. The other mRNA expression levels were 58.9% for claudin 1, 62.1% for filaggrin, and 41.0% for caspase-14. From this result, it was clarified that the mRNA levels of claudin 1, filaggrin, and caspase 14 also decreased in conjunction with a decrease in the Bmal-1 mRNA level.

Moreover, as a result of confirming the protein amount by Western blotting, the BMAL-1 protein amount was 66%, the FILAGGRIN protein amount was 69%, the CASPASE-14 protein amount was 48%, and CLAUDIN- It was found that the amount of 1 protein decreased to 71%.
From the above, it was revealed for the first time that BMAL-1 protein is involved in the production of filaggrin, caspase-14, and claudin-1 protein.

It is already known that the clock gene BMAL-1 acts as a transcription factor together with CLOCK.
Filaggrin is a high molecular protein produced by the epidermis cells of the skin and is present in the granulosa cells as profilagrin. In epidermal cells, profilagrin is degraded by enzymes to form filaggrin, and is degraded by caspase 14 to become a natural moisturizing factor NMF, which acts as a skin moisturizing component. For this reason, a decrease in BMAL-1 protein leads to a decrease in the protein content of filaggrin and caspase 14, and ultimately results in a decrease in the moisturizing component of the skin. Furthermore, claudin 1 is a protein that forms tight junctions between epidermal cells. Tight junctions connect epidermal cells to each other to prevent moisture in the skin from evaporating and to prevent irritants and foreign substances from the outside world. If these tight junctions are not sufficiently formed, they exhibit an ichthyosis-like skin state, and thus play an important role for the skin moisturizing function. For this reason, it is considered that the improvement of the skin moisturizing function can be expected by promoting the production of BMAL-1 protein.

<BMAL-1 protein production promotion test>
<Adjustment of component A>
The whole sage plant was dried, 100 g of purified water was added to 10 g of the dried product, and heat extraction was performed at 80 ° C. for 2 hours. After cooling, the solid matter was removed to obtain an extract.
For nicotinic acid amide and calcium pantothenate, a Wako Pure Chemical Industries reagent was purchased and dissolved in purified water as an additive sample (concentration is listed in Table 3).
Hacat cells were cultured on a 50 cm ² plate in D-MEM medium supplemented with 5% FBS until they became confluent. After the cells became confluent, the cells were replaced with D-MEM medium containing no FBS, and the above-mentioned component A was added so as to have the concentration shown in Table-3. After the addition, the cells were cultured at 37 ° C. for 48 hours, and the cells were collected and used as a sample for measuring the amount of BMAL-1. The cells were lysed with 200 μl of RIPA buffer, and the amount of BMAL-1 was measured by Western blotting.

The results of Western blotting are shown in Table-3. When the sage extract was added to the medium at 1.25% and 2.5%, the BMAL-1 protein production was 103% and 128% of protein production promoting effect compared to the control group. Similarly, in the nicotinic acid amide addition group, 107% and 142% were shown, respectively. In the calcium pantothenate addition group, it was 116% and 135%, respectively, indicating a strong protein production promoting effect. In addition, when 1.25% and 2.5% of Melissa extract was added to the medium as a substance having no BMAL-1 production promoting effect, the BMAL-1 protein production amount was 100% and 101 compared to the control group. %, And no protein production promoting effect was observed.

<Preparation of B component> Preparation of fatty acid menthol ester L-menthol 140 g, purified water 70 g and lipase 460,000 units were mixed with 250 g of safflower oil, and menthol ester was prepared by stirring at room temperature for 72 hours. The prepared menthol ester was purified to obtain safflower oil menthol ester. Since safflower oil contains multiple fatty acids, the end result is 6.71% palmitic acid menthol ester, 1.28% stearic acid menthol ester, 17.6% oleic acid menthol ester, linole It was confirmed that 73.7% of acid menthol ester was contained.

280 g of linoleic acid was mixed with 156 g of L-menthol, 80 g of purified water and 520,000 units of lipase and stirred at room temperature for 72 hours to prepare menthol ester. The prepared menthol ester was purified to prepare linoleic menthol ester.

Based on the cosmetics of Formulation Example 3 comprising the following (A), (B), and (C) of the present invention, the cosmetics based on the blending amounts of Comparative Examples and Examples were used, and the skin Moisture transpiration was measured.
(A) Any one or more of nicotinic acid amide, calcium pantothenate, sage extract and Melissa extract that does not promote BMAL-1 production but has a moisturizing effect.
(B) Menthol ester of safflower oil, menthol ester of linoleic acid, and isopropyl linoleate as a comparative product of menthol ester of fatty acid.
(C) Dioctyl succinate as a control of diisopropyl sebacate, mentoxypropanediol, bisethoxydiglycol cyclohexane-1,4-dicarboxylate and diisopropyl sebacate, bisethoxydiglycol cyclohexane-1,4-dicarboxylate, ment One or more of menthol as a control for xylpropanediol.
Components other than (A), (B), and (C) are glycerin; 5.0, polyoxyethylene sorbitan monolaurate (20E.O.); 1.0, ethanol; 6.0, perfume; appropriate amount , Preservatives / antioxidants; appropriate amount, purified water; the remainder. When the blending amount increased or decreased in the components (A), (B), (C), it was adjusted with purified water.
No. 2 filter paper cut to a size of 10 mmφ is impregnated with 20 μl of 5% SDS aqueous solution, and occlusion is applied to the human upper arm and lower arm inner skin for 4 hours, and then the filter paper is peeled off and washed. Thereafter, the lotion of Formulation Example 3 was applied. On the next day, the same operation was repeated on the same site, and the treatment was performed for 4 days to obtain a skin site where the barrier function was destroyed. The skin site was repeated application of SDS, Tewa value was 30-35g / ^{m 2} h, TEWA value untreated sites exhibited 5-10g / ^{m 2} h. The TEWA value was measured using VAPO METER (Delfintech).
The average of 10 subjects was shown as the skin moisture transpiration rank.

The results are shown in Table-4 and Table-5. In addition, the evaluation criteria for the skin moisture transpiration rate rank, which is a measure of the barrier function, are shown in Table-6.
In Comparative Example 2-4, the TEWA value was shown when a lotion containing any two groups from the groups (A), (B), and (C) was applied. 3. Compared with Example 8, Example 12, all had a large TEWA value and the improvement effect of the skin barrier function was weak. In Comparative Example 5-7, the TEWA value was shown when a lotion containing any one of the groups (A), (B), and (C) was applied. 3, Compared with Example 8 and Example 12, all had a large TEWA value, and showed that the improvement effect of the skin barrier function was still weaker. On the other hand, in Comparative Example 8 in which Melissa extract having no BMAL-1 protein production promoting effect but having a moisturizing effect was added as a comparative control of Example 3 of group (A), the TEWA value was large and the skin barrier function was improved. Was even weaker. Moreover, in Comparative Example 9 in which isopropyl linoleate was added as a comparative control of safflower oil menthol ester of Example 6 of Group (B), the TEWA value was large, indicating that the effect of improving the skin barrier function was further weak. . Further, dioctyl succinate, which is the same dicarboxylic acid ester, was added as a comparative control of Example 1 and Example 12 in which (C) group diisopropyl sebacate and cyclohexane-1,4-dicarboxylic acid bisethoxydiglycol were blended. In Comparative Example 10, the TEWA value was large, indicating that the effect of improving the skin barrier function was weaker. Similarly, in Comparative Example 11 in which menthol was added as a comparative control of Example 8 containing the (C) group menthoxypropanediol, the TEWA value was large, indicating that the effect of improving the skin barrier function was even weaker.
Moreover, compared with Example 1, in Example 6, the cosmetics in which the addition amount of diisopropyl sebacate was increased, and in Example 7, the addition amount of safflower oil menthol ester was increased. It was recognized that the effect of improving the skin barrier function was high. This effect was also observed in menthoxypropanediol as shown in Examples 8 and 11. Furthermore, as shown in Examples 12 and 13, it was also observed in cyclohexane-1,4-dicarboxylic acid bisethoxydiglycol.
In addition, there was nothing that appealed to the person who used this example.

Next, although the formulation example of this invention is shown, this invention is not limited to this.
Examples of cosmetic formulations

Formulation Example 1
(1) Cosmetic cream (mass%)
a) Beeswax 2.0
b) Stearyl alcohol ... 5.0
c) Stearic acid ... 8.0
d) Squalane ... 10.0
e) Self-emulsifying glyceryl monostearate 3.0
f) Polyoxyethylene cetyl ether (20E.O.) ... 1.0
g) Saflower oil menthol ester 0.5
h) Menthoxypropanediol ... 1.0
i) Sage extract ... 1.0
j) 1,3-butylene glycol ... 5.0
k) Potassium hydroxide ... 0.3
l) Preservatives / antioxidants: appropriate amount m) Purified water: Remaining production methods a) to g) are heated and dissolved and kept at 80 ° C. Heat up to h) to m), keep at 80 ° C., add to a) to g), emulsify, and cool to 40 ° C. with stirring.

Formulation example 2
(2) Emulsion (mass%)
a) Beeswax 0.5
b) Petrolatum 2.0
c) Squalane ... 8.0
d) Sorbitan sesquioleate ... 0.8
e) Polyoxyethylene oleyl ether (20EO) 1.2
f) Linoleic acid menthol ester: 5.0
g) Cyclohexane-1,4-dicarboxylate bisethoxydiglycol 0.05
h) Nicotinamide ... 0.01
i) 1,3-butylene glycol 7.0
j) Carboxyvinyl polymer ... 0.2
k) Potassium hydroxide ... 0.1
l) Purified water: balance m) antiseptic / antioxidant ... appropriate amount n) ethanol ... 7.0
The production methods a) to g) are dissolved by heating and kept at 80 ° C. Heat up to h) to m), keep at 80 ° C., add to a) to g), emulsify, and cool to 50 ° C. with stirring. Add n) at 50 ° C., stir to 40 ° C. and cool.

Formulation Example 3
(3) Lotion (mass%)
a) Nicotinamide ... 1.0
b) Glycerin ... 5.0
c) Polyoxyethylene sorbitan monolaurate (20EO) ... 1.0
d) Ethanol ... 6.0
e) Fragrance: appropriate amount f) Preservative / antioxidant ... appropriate amount g) Purified water ... balance h) Diisopropyl sebacate ... 0.5
i) Moleitol ester of oleic acid ... 0.1
The production methods a) to i) are mixed and dissolved uniformly.

Formulation Example 4
(4) Face wash (mass%)
a) Stearic acid ... 12. 0
b) Myristic acid 14. 0
c) Lauric acid ... 5.0
d) Jojoba oil ... 3.0
e) Saflower oil menthol ester ... 0.1
f) Diisopropyl sebacate ... 0.05
g) Glycerin ... 10.0
h) Sorbitol ... 15.0
i) 1,3-butylene glycol ... 10.0
j) POE (20) Glycerol monostearic acid 2.0
k) Potassium hydroxide ... 5.0
l) Water ... balance m) perfume ... proper amount n) sage extract ... 1.0
The production methods a) to j) are heated and dissolved and maintained at 70 ° C. After k) is dissolved in l), it is added to a) to j) and saponified. Then, m) and n) are added and cooled with stirring.

Formulation Example 5
(3) Lotion (mass%)
a) Calcium pantothenate ... 1.0
b) Nicotinamide ... 5.0
c) Glycerin ... 5.0
d) Polyoxyethylene sorbitan monolaurate (20EO) ... 1.0
e) Ethanol ... 6.0
f) Linoleic acid menthol ester 0.01
g) Cyclohexane-1,4-dicarboxylic acid bisethoxydiglycol 1.0
h) Fragrance: appropriate amount
i) Preservatives / Antioxidants ...
j) Purified water: Mix the remaining manufacturing methods a) to j) and dissolve uniformly.

As described in detail above, the cosmetic of the present invention acts on skin cells to promote the production of moisturizing ingredients by the cells and enhances the skin barrier function, so that the effect of improving atopic symptoms such as Kayumi and Katsuki Can be expected. Moreover, the cosmetic of the present invention has no odor or irritation peculiar to menthol, has high safety, and can be used with confidence.

Claims (2)

Cosmetics containing the following (A), (B), (C)
(A) One or more selected from nicotinamide, calcium pantothenate, and sage extract
(B) One or more selected from linoleic menthol ester and safflower oil menthol ester
(C) One or more selected from diisopropyl sebacate, menthoxypropanediol, and bisethoxydiglycol cyclohexane-1,4-dicarboxylate Cosmetic for improving skin barrier function, comprising the following (A), (B) and (C)
(A) One or more selected from nicotinamide, calcium pantothenate, and sage extract
(B) One or more selected from linoleic menthol ester and safflower oil menthol ester
(C) One or more selected from diisopropyl sebacate, menthoxypropanediol, and bisethoxydiglycol cyclohexane-1,4-dicarboxylate