JP6723737B2 - Glucosylceramide production and metabolic gene expression promoter in skin - Google Patents

Description

The present invention relates to a novel skin glucosylceramide production and metabolic gene expression promoter. INDUSTRIAL APPLICABILITY The present invention is widely used for functional foods and external preparations for skin.

Moisturizing is a particularly important factor in the condition of beautiful skin, so-called beautiful skin. Even in today's cosmetics and functional food markets, there are many products that claim to moisturize the skin. The epidermis, which is the outermost layer of the skin, is composed of a basal layer, a spinous layer, a granular layer, and a stratum corneum from the inside, and various molecules involved in moisturizing are localized particularly in the stratum corneum that is in direct contact with the outside. The normal function of these molecules without deficiency allows them to exert a keratin barrier function that prevents foreign substances from invading from the outside and excessive evaporation of water in the body.
Ceramide is ubiquitously present as a biological membrane component of cell membrane tissue, in particular as a major lipid component of the horny layer of skin, and is involved in barrier function and retention of water. Ceramide is a kind of lipid formally called sphingolipid, but it is also used as a broad term that includes compounds partially having a ceramide structure such as glucosylceramide. Further, it has been proved that intake of plant-derived glucosylceramide improves water retention and barrier function of epidermal keratin, and utilization of plant ceramide is widespread (Non-Patent Document 1 and Non-Patent Document 2).

The biosynthetic pathways of sphingolipids are well studied. First, as the first step of sphingolipid synthesis, serine and palmitoyl CoA were used as starting materials, and palmitoyl CoA and the non-essential amino acid L-serine were polycondensed by serine palmitoyl transferase enzyme (SPT). Ceramide is then synthesized in the spinous layer. Then, sphingomyelin synthase transforms it into sphingomyelin and accumulates in the granular layer, and then acid sphingomyelinase synthesizes ceramide again in the stratum corneum (route on the right in FIG. 1).

In addition, ceramide synthesized in the spinous layer is changed to glucosylceramide by glucosylceramide synthase and accumulated in the granular layer, and then cerebromidosidase synthesizes ceramide again in the stratum corneum (Fig. 1, left). Route).

In addition, there are 10 types of ceramides, including ceramides (EOS, NS, NP, EOH, AS, AP, AH, NH, and EOP). Among them, ceramide (EOS) is called acyl ceramide and has a skin barrier function. Have. In addition, in a person suffering from atopic dermatitis, the amount of ceramide (EOS) (acyl ceramide), which is abundant in the intercellular lipids of the skin, is about 1/10 of that in a normal person, so that the barrier function of the skin deteriorates. Therefore, the symptom of atopic dermatitis can be improved by promoting the synthesis of ceramide EOS.

Ceramide (NS) is known to contribute to the water retention function of the skin and is often found in hair. Further, ceramide (NP) is known to contribute to the water retention function. Furthermore, ceramides (EOH) and (AS) are known to be involved in the construction and maintenance of the keratin lipid barrier layer.
Ceramides (AP) I and (AP) II are known to have a water retention function, a promotion of turnover, and a function of reducing wrinkles. Ceramide 7 also controls the proliferation and differentiation of cells and balances the bacteria on the skin. The functions of ceramides (NH) and (EOP) have not been reported yet.
In particular, the lack of ceramides (EOS), (NP), and (AP) is said to have a particularly strong effect on dry skin, sensitive skin, and atopic dermatitis.

Here, ceramides (EOS, NS, NP, EOH, AS, AP) are produced in the left route for obtaining glucosylceramide in FIG.
On the other hand, only ceramides (NS) and (AS) are produced in the right pathway for obtaining sphingomyelin and producing ceramide. Therefore, in order to synthesize ceramides (EOS, NS, NP, EOH, AS, AP) in a well-balanced manner, it is preferable to produce ceramide by the left pathway for obtaining glucosylceramide, which results in the gene for serine palmitoyltransferase. And it is necessary to express the genes for glucosylceramide synthase.

On the other hand, β-sitosterol glycosides such as b-sitosterol glucoside are known to be contained in various plant species such as rice germ (wheat, beet, konjac, corn, etc.) (non-patent document 3 to non-patent document 5).

J. Duan et al., Experimental Dermatol., 21, 448-452 (2012) Shimoda H. et al., J. Med. Food., 15, 1064-1072 (2012) Mira A. et al., Molecules, 20, 4813-4832 (2015) Badria FA et al., Z. Naturforsch C., 62, 656-660 (2007) Chung I. M. et al., J. Chem. Ecol., 2005, 31(6), 1339-1352

Under such a background, the present inventors have found that β-sitosterol glycoside has an action of promoting the expression of serine palmitoyltransferase gene and glucosylceramide synthase (glucosylceramide production and metabolism gene in skin), The present invention has been completed.
That is, an object of the present invention is to provide a novel glucosylceramide production and metabolic gene expression promoter in the skin and a skin barrier function and moisturizing function improving agent using the same.

The technical features of the present invention for solving the above problems are as follows.
1. A serine palmitoyltransferase gene expression promoter comprising β-sitosterol glycoside as an active ingredient.
2. A glucosylceramide synthase gene expression promoter containing β-sitosterol glycoside as an active ingredient.
3. A sphingomyelin synthase gene expression inhibitor containing β-sitosterol glycoside as an active ingredient.
4. The β-sitosterol glycoside is β-sitosterol glucoside. The agent according to 3 above.
5. Above 1. ~4. A skin barrier function-improving agent comprising the agent according to 1. as an active ingredient.
6. Above 1. ~4. A moisturizing function-improving agent comprising the agent according to item 1 as an active ingredient.
7. Above 1. ~4. An atopic dermatitis-improving agent containing the agent according to 1. as an active ingredient.

It is a schematic diagram which shows the synthetic pathway of the ceramide in skin. It is a graph which shows the influence which (beta)-sitosterol glucoside has on SPTLC2 gene. It is a graph which shows the influence which (beta)-sitosterol glucoside has on GCS gene. It is a graph which shows the influence which (beta)-sitosterol glucoside has on SMS gene. It is a graph which shows the effect of β-sitosterol glucoside on ceramide-related gene expression.

The present invention will be described in detail below.
The present invention is characterized by using β-sitosterol glycoside as an active ingredient.

The β-sitosterol glycoside is not particularly limited, and examples thereof include β-sitosterol glucoside, β-sitosterol rutinoid, β-sitosterol sanbubioside, and the like, and β-sitosterol glucoside is particularly preferable.
The method for obtaining β-sitosterol glucoside is not particularly limited, and a commercially available product may be used, or it may be extracted from a plant. As a commercially available product, "sitosterol-3-O-glucoside, β- (AHP Verified)" manufactured by Wako Pure Chemical Industries, Ltd. can be used.

The plant raw material for obtaining β-sitosterol glucoside is not particularly limited, and examples thereof include rice, wheat, beet, konjac, corn and the like. Of these, rice is preferred.
The site used to obtain β-sitosterol glucoside from rice is not particularly limited, but rice bran and rice germ are particularly preferably used.

The method for obtaining β-sitosterol from rice bran or rice germ is not particularly limited, for example, fermented rice bran or rice germ to obtain a fermented product, and then the fermented product is extracted with a nonpolar solvent to obtain a fermented product extract. It can be obtained by obtaining and then distributing this fermented product extract. Further, it can be extracted from "Oriza Ceramide" (registered trademark) manufactured by Oriza Yuka Co., Ltd.

The present invention can be applied to various uses for the above-mentioned effects. Uses include pharmaceuticals, reagents (for research, test kits), orally ingested compositions (for example, health foods, foods for specified health uses, foods with functional claims, supplements, foods for specific purposes, supplements for pets, etc.) To be

The pharmaceutical composition containing the glucosylceramide production and metabolic gene expression promoter in the skin of the present invention may contain an excipient, a carrier or an additive. Excipients, carriers, and additives are not particularly limited as long as they are commonly used and pharmaceutically acceptable, and their types and compositions can be appropriately changed.

Examples of the excipient include sodium chloride, sodium citrate and the like, and examples of the carrier include sterilized water, physiological saline, various buffer solutions and the like. Examples of the additives include thickeners, buffers, preservatives and preservatives.

The dosage form of the pharmaceutical composition is not particularly limited and may be appropriately selected as needed. For example, oral preparations such as tablets, capsules, granules, fine granules and powders; injections , Parenteral agents such as suppositories and coating agents.

Oral preparations such as tablets, capsules, granules, fine granules, powders, etc. are manufactured according to a conventional method using starch, lactose, sucrose, trehalose, mannitol, carboxymethylcellulose, corn starch, inorganic salts, etc., The compounding amount of the compound of the present invention in these preparations is not particularly limited and can be appropriately set. Binders, disintegrants, surfactants, lubricants, fluidity enhancers, corrigents, colorants, fragrances and the like can be appropriately used in this type of preparation.

In the case of a parenteral preparation, the dose is adjusted according to the age, body weight, degree of disease, etc. of the patient, and administered by, for example, intravenous injection, intravenous drip injection, subcutaneous injection, intramuscular injection and the like. This parenteral preparation is manufactured by a conventional method, and distilled water for injection, physiological saline or the like can be generally used as a diluent. Further, if necessary, a bactericidal agent, a preservative, a stabilizer and the like may be added. Further, from the viewpoint of stability, this parenteral preparation may be filled in a vial or the like and then frozen, the water content may be removed by an ordinary freeze-drying treatment, and the liquid preparation may be re-prepared from the freeze-dried product immediately before use. Further, if necessary, a tonicity agent, a stabilizer, a preservative, a soothing agent, etc. may be added. Examples of other parenteral agents include liquid preparations for external use, coating agents such as ointments, suppositories for rectal administration, and the like, which are also manufactured by a conventional method.

When the present invention is used for health foods (including functionally labeled foods, foods for specified health uses, health drinks and supplements), the compound of the present invention may be added to health foods as a raw material for various health foods, or dextrin may be added as necessary. It can be processed into pellets, tablets, granules and the like together with excipients such as lactose, starch and the like, flavors and pigments, or can be coated with gelatin and processed into capsules to produce health foods.

The mixing ratio of the glucosylceramide generation and metabolic gene expression promoter in the skin that is mixed into the health food is not particularly limited as long as the expected effect of the glucosylceramide generation and metabolic gene expression promoter in the skin can be obtained, Usually, the intake amount is about 0.0001 to 2000 mg.

These health foods can be blended with various components depending on their types, for example, glucose, fructose, sucrose, maltose, sorbitol, stevioside, corn syrup, lactose, citric acid, tartaric acid, malic acid, Succinic acid, lactic acid, L-ascorbic acid, dl-α-tocopherol, sodium erythorbate, glycerin, propylene glycol, glycerin fatty acid ester, polyglycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, gum arabic Food materials such as carrageenan, casein, gelatin, pectin, agar, vitamins B, nicotinic acid amide, calcium pantothenate, amino acids, calcium salts, pigments, flavors and preservatives can be used. Furthermore, for the glucosylceramide generation and metabolic gene expression promoter in the skin having a health maintenance function, other antioxidants and health food materials and the like are distributed, for example, antioxidants (reduced ascorbic acid (vitamin C), Vitamin E, reduced glutatin, tocotrienols, vitamin A derivatives, lycopene, lutein, astaxanthin, zeaxanthin, fucoxanthin, uric acid, ubiquinone, coenzyme Q10, folic acid, garlic extract, allicin, sesamin, lignans, catechin, isoflavone, chalcone, tannin , Flavonoids, coumarin, isocoumarins, blueberry extract, health food materials (V. (vitamin) A, V.B1, V.B2, V.B6, V.B12, VC, VD, VE, VP, choline, Niacin, Pantothenic Acid, Calcium Folate, EPA, Oligosaccharides, Dietary Fiber, Squalene, Soy Lecithin, Taurine, Donariella, Protein, Octacosanol, DHA, Yolk Lecithin, Linoleic Acid, Lactoferrin, Magnesium, Zinc, Chromium, Selenium, Potassium, Heme Iron, oyster meat extract, chitosan, chitin oligosaccharide, collagen, chondroitin, turmeric, licorice, kokushi, keihi, hawthorn, ginger, ganoderma lucidum, clam extract, soft-shelled turtle, chamomile, chamomile, dandelion, hibiscus, honey, boren, royal jelly, Lime, lavender, rosehip, rosemary, bifidobacteria, faecalis, lacris, wheat germ oil, sesame oil, perilla oil, soybean oil, medium chain fatty acid, agarix, ginkgo leaf extract, turmeric, chondroitin, brown rice germ extract, litchi, Onion, beetroot tea, caterpillar, garlic, bee pup, papaya, puer, propolis, megusuri tree, yab mushroom, saw palmetto, hyaluronic acid, collagen, gaba, harp seal oil, shark cartilage, glucosamine, lecithin, phosphatidylserine, field carrot. , Mulberry leaf, Soybean extract, Echinacea, Eleuthero, Barley extract, Olive leaf, Olive seed, Gymnema, Banaba, Salacia, Garcinia, Chitosan, St. John's wort, Date, Carrot, Passionflower, Broccoli, Placenta, Adlay, Grape seed , Peanut seed coat, bilberry, black cohosh, thistle, laurel, sage, rafuma, black vinegar, bitter melon, maca, safflower, flax, oolong tea, flower spines, caffeine, capsaicin, xylori Gosu sugar, glucosamine, buckwheat, citrus, dietary fiber, protein, prune, spirulina, barley leaf, nucleic acid, yeast, shiitake mushroom, plum meat, amino acid, deep sea shark extract, noni, oyster meat, champignon, psyllium, acerola, pineapple, Bananas, peaches, apricots, melons, strawberries, raspberries, oranges, fucoidan, meshimakobu, cranberries, chondroitin sulfate, zinc, iron, ceramide, silk peptides, glycine, niacin, chest tree, L-cysteine, red wine leaves, millet, horsetail , Biotin, centella asiatica, haskap, pycnogenol, butterbur, rhubarb, clove, catechin, puer, citric acid, brewer's yeast, meliroat, black zinger, ginger, gadget, nattokinase, benikouji, tocotrienol, lactoferrin, cinnamon, 韃靼, Cocoa, yuzu seed extract, perilla seed extract, litchi seed extract, evening primrose extract, black rice extract, α-lipoic acid, green coffee bean extract, Satsuma mandarin orange extract, triterpenoid, kiwi seed extract, red ginger extract, astaxanthin, walnut extract, Resveratrol, red rice extract, white jellyfish polysaccharides, strawberry seed extract, leek seed extract, lingonberry extract, cherry blossom extract, Sasacrehit mushroom extract, maquiberry extract, rice polyamine, wheat polyamine) and the like can also be added. ..

The present invention can be used as an external preparation for skin (including cosmetics, pharmaceuticals, and quasi drugs).
As the form of the present invention, for example, emulsion, soap, face wash, bath agent, cream, emulsion, lotion, cologne, shaving cream, shaving lotion, cosmetic oil, sunscreen lotion, powder, foundation, Perfumes, packs, nail cream, enamel, enamel remover, eyebrow, blusher, eye cream, eye shadow, mascara, eyeliner, lipstick, lip balm, shampoo, rinse, hair dye, dispersion, cleaning agent and the like.
In addition, examples of the form of the drug or quasi drug to which the present invention can be incorporated include ointments, creams, external preparations and the like.

In the external preparation for skin of the above-mentioned form, in addition to the present invention, cosmetics, components to be added to the external preparation for skin such as quasi drugs, oils, higher alcohols, fatty acids, and ultraviolet absorption within a range not impairing the function of the present invention Agents, powders, pigments, surfactants, polyhydric alcohols/sugars, polymers, physiologically active ingredients, solvents, antioxidants, perfumes, preservatives and the like can be added.
Examples are listed below, but the present invention is not limited to these examples.

(1) Examples of oils Ester-based oil phase components: glyceryl tri-2-ethylhexanoate, cetyl 2-ethylhexanoate, isopropyl myristate, butyl myristate, isopropyl palmitate, ethyl stearate, octyl palmitate, isostearic acid Isocetyl, Butyl stearate, Butyl myristate, Ethyl linoleate, Isopropyl linoleate, Ethyl oleate, Isocetyl myristate, Isostearyl myristate, Isostearyl palmitate, Octyldodecyl myristate, Isocetyl isostearate, Diethyl sebacate, Adipine Acid diisopropyl, isopentayl neopentanoate, glyceryl tri(capryl/capric acid), trimethylolpropane tri-2-ethylhexanoate, trimethylolpropane triisostearate, pentaerythritol tetra-2-ethylhexanoate, cetyl caprylate, decyl laurate, Hexyl laurate, decyl myristate, myristyl myristate, cetyl myristate, stearyl stearate, decyl oleate, cetyl ricinoleate, isostearyl laurate, isotridecyl myristate, isocetyl myristate, isostearyl myristate, isocetyl palmitate, Isostearyl palmitate, octyl stearate, isocetyl stearate, isodecyl oleate, octyldodecyl oleate, octyldodecyl linoleate, isopropyl isostearate, cetostearyl 2-ethylhexanoate, stearyl 2-ethylhexanoate, hexyl isostearate, Ethylene glycol dioctanoate, ethylene glycol dioleate, propylene glycol dicaprate, propylene glycol di(capryl/capric acid), propylene glycol dicaprylate, neopentyl glycol dicaprate, neopentyl glycol dioctanoate, glyceryl tricaprylate, glyceryl triundecylate, Glyceryl triisopalmitate, glyceryl triisostearate, octyldodecyl neopentanoate, isostearyl octanoate, octyl isononanoate, hexyldecyl neodecanoate, octyldodecyl neodecanoate, isostearyl isostearate, isostearyl isostearate, octyldecyl isostearate, poly Glycerin oleate, polyglycerin isostearate, charcoal Dipropyl acid, dialkyl carbonate (C12-18), triisocetyl citrate, triisoaralkyl citrate, triisooctyl citrate, lauryl lactate, myristyl lactate, cetyl lactate, octyldecyl lactate, triethyl citrate, acetyltriethyl citrate, citrate Acetyltributyl acid, trioctyl citrate, diisostearyl malate, 2-ethylhexyl hydroxystearate, di2-ethylhexyl succinate, diisobutyl adipate, diisopropyl sebacate, dioctyl sebacate, cholesteryl stearate, cholesteryl isostearate, hydroxystearin Examples include cholesteryl acid ester, cholesteryl oleate, dihydrocholesteryl oleate, phytosteryl isostearate, phytosteryl oleate, isocetyl 12-stearoylhydroxystearate, stearyl 12-stearoylhydroxystearate, and isostearyl 12-stearoylhydroxystearate.
Hydrocarbon-based oil phase components: squalane, liquid paraffin, α-olefin oligomer, isoparaffin, ceresin, paraffin, liquid isoparaffin, polybutene, microcrystalline wax, vaseline and the like.
Animal and vegetable oils and hydrogenated oils thereof, and naturally derived waxes: animal oils such as beef tallow, hydrogenated beef tallow, lard, hydrogenated lard, horse oil, hydrogenated horse oil, mink oil, orange laffy oil, fish oil, hydrogenated fish oil, egg yolk oil, and the like. Its hydrogenated oil, avocado oil, almond oil, olive oil, cacao butter, kiwi seed oil, apricot kernel oil, kukui nut oil, sesame oil, wheat germ oil, rice germ oil, rice bran oil, safflower oil, shea butter, soybean oil, evening primrose oil , Perilla oil, tea seed oil, camellia oil, corn oil, rapeseed oil, hydrogenated rapeseed oil, palm kernel oil, hydrogenated palm kernel oil, palm oil, hydrogenated palm oil, peanut oil, hydrogenated peanut oil, castor oil, hydrogenated castor oil , Sunflower oil, grape seed oil, jojoba oil, hardened jojoba oil, macadamia nut oil, medhome oil, cottonseed oil, hardened cottonseed oil, coconut oil, hardened coconut oil and other vegetable oils and hardened oils, beeswax, high acid value beeswax, lanolin, reduced Examples thereof include waxes such as lanolin, hardened lanolin, liquid lanolin, carnauba wax, and montan wax.
Silicone oil phase components: dimethylpolysiloxane, methylphenylpolysiloxane, methylcyclopolysiloxane, octamethylpolysiloxane, decamethylpolysiloxane, dodecamethylcyclosiloxane, methylhydrogenpolysiloxane, polyether-modified organopolysiloxane, dimethyl Siloxane/methylcetyloxysiloxane copolymer, dimethylsiloxane/methylstearoxysiloxane copolymer, alkyl-modified organopolysiloxane, terminal-modified organopolysiloxane, amino-modified silicone oil, amino-modified organopolysiloxane, dimethiconol, silicone gel, acrylic Silicone, trimethylsiloxysilicic acid, silicone RTV rubber and the like can be mentioned.
Fluorine-based oil phase components: perfluoropolyether, fluorine-modified organopolysiloxane, fluorinated pitch, fluorocarbon, fluoroalcohol, fluoroalkyl/polyoxyalkylene co-modified organopolysiloxane, and the like.

(2) Examples of higher alcohols Lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, behenyl alcohol, 2-ethylhexanol, hexadecyl alcohol, octyldodecanol and the like can be mentioned.

(3) Examples of fatty acids Caprylic acid, capric acid, undecylenic acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, arachidic acid, arachidonic acid, behenic acid , Erucic acid, 2-ethylhexanoic acid and the like.

(4) Examples of ultraviolet absorbers Paraaminobenzoic acid, amyl paraaminobenzoate, ethyldihydroxypropyl paraaminobenzoate, glyceryl paraaminobenzoate, ethyl paraaminobenzoate, octyl paraaminobenzoate, octyldimethyl paraaminobenzoate, ethylene glycol salicylate, salicylate Octyl, triethanolamine salicylate, phenyl salicylate, butylphenyl salicylate, benzyl salicylate, homomenthyl salicylate, benzyl cinnamate, octyl paramethoxycinnamate, 2-ethylhexyl paramethoxycinnamate, mono-2-diparamethoxycinnamate. Glyceryl ethylhexanoate, isopropyl paramethoxycinnamate, paramethoxyhydrocinnamic acid diethanolamine salt, diisopropyl-diisopropylcinnamate mixture, urocanic acid, ethyl urocanate, hydroxymethoxybenzophenone, hydroxymethoxybenzophenone sulfonic acid and salts thereof, Dihydroxymethoxybenzophenone, dihydroxymethoxybenzophenone sodium disulfonate, dihydroxybenzophenone, dihydroxydimethoxybenzophenone, hydroxyoctoxybenzophenone, tetrahydroxybenzophenone, butylmethoxydibenzoylmethane, 2,4,6-trianilino-p-(carbo-2-ethylhexyl- 1-oxy)-1,3,5-triazine, 2-(2-hydroxy-5-methylphenyl)benzotriazole, methyl-O-aminobenzoate, 2-ethylhexyl-2-cyano-3,3-diphenylacrylate, Phenylbenzimidazole sulfate, 3-(4-methylbenzylidene)camphor, isopropyldibenzoylmethane, 4-(3,4-dimethoxyphenylmethylene)-2,5-dioxo-1-imidazolidine propionate 2-ethylhexyl, and the like, and These polymer derivatives, silane derivatives and the like can be mentioned.

(5) Examples of powders and pigments Red 104, Red 201, Yellow 4, Blue 1, Black 401 and other pigments, Yellow 4 AL lake, Yellow 203 BA lake and other lake pigments, nylon powder , Silk powder, Urethane powder, Teflon (registered trademark) powder, Silicone powder, Polymethylmethacrylate powder, Cellulose powder, Starch, Silicone elastomer spherical powder, Polyethylene powder and other polymers, Yellow iron oxide, Red iron oxide, Black Colored pigments such as iron oxide, chromium oxide, carbon black, ultramarine and dark blue, white pigments such as zinc oxide, titanium oxide and cerium oxide, body pigments such as talc, mica, sericite, kaolin and barium sulfate in plate form, titanium mica. Pearl pigments such as, barium sulfate, calcium carbonate, magnesium carbonate, aluminum silicate, magnesium silicate and other metal salts, silica, alumina and other inorganic powders, aluminum stearate, magnesium stearate, zinc palmitate, zinc myristate, myristin Examples thereof include metal soaps such as magnesium acidate, zinc laurate, and zinc undecylenate, bentonite, smectite, and boron nitride. There is no particular limitation on the shape (spherical shape, rod shape, needle shape, plate shape, irregular shape, flake shape, spindle shape, etc.) and particle size of these powders. These powders are conventionally known surface treatments, for example, fluorine compound treatment, silicone treatment, silicone resin treatment, pendant treatment, silane coupling agent treatment, titanium coupling agent treatment, oil agent treatment, N-acylated lysine treatment, It may or may not be surface-treated in advance by polyacrylic acid treatment, metal soap treatment, amino acid treatment, lecithin treatment, inorganic compound treatment, plasma treatment, mechanochemical treatment, or the like.

(6) Examples of surfactants Anionic surfactants: fatty acid soap, α-acyl sulfonate, alkyl sulfonate, alkyl allyl sulfonate, alkyl naphthalene sulfonate, alkyl sulfate, POE alkyl ether sulfate , Alkylamide sulfate, alkylphosphate, POE alkylphosphate, alkylamidephosphate, alkyloylalkyltaurine salt, N-acylamino acid salt, POE alkyl ether carboxylate, alkylsulfosuccinate, alkylsulfoacetic acid Examples thereof include sodium, acylated hydrolyzed collagen peptide salt, perfluoroalkyl phosphate ester and the like.
Cationic surfactant: alkyl trimethyl ammonium chloride, stearyl trimethyl ammonium chloride, stearyl trimethyl ammonium bromide, cetostearyl trimethyl ammonium chloride, distearyl dimethyl ammonium chloride, stearyl dimethyl benzyl ammonium chloride, behenyl trimethyl ammonium bromide, benzalkonium chloride , Behenic acid chloride amidopropyldimethylhydroxypropylammonium, stearic acid diethylaminoethylamide, stearic acid dimethylaminopropylamide, lanolin derivative quaternary ammonium salt and the like.
Amphoteric surfactants: carboxybetaine type, amidobetaine type, sulfobetaine type, hydroxysulfobetaine type, amidosulfobetaine type, phosphobetaine type, aminocarboxylic acid salt type, imidazoline derivative type, amidoamine type and the like.
Nonionic surfactant: propylene glycol fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, POE sorbitan fatty acid ester, POE sorbit fatty acid ester, POE glycerin fatty acid ester, POE alkyl ether, POE fatty acid ester, POE hardened castor Oil, POE castor oil, POE/POP copolymer, POE/POP alkyl ether, polyether modified silicone lauric acid alkanolamide, alkylamine oxide, hydrogenated soybean phospholipid and the like can be mentioned.
Natural surfactant: lecithin, saponin, sugar-based surfactant and the like.

(7) Examples of polyhydric alcohols and sugars Ethylene glycol, diethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, glycerin, diglycerin, polyglycerin, 3-methyl-1,3-butanediol, 1, 3 -Butylene glycol, sorbitol, mannitol, raffinose, erythritol, glucose, sucrose, fructose, xylitol, lactose, maltose, maltitol, trehalose, alkylated trehalose, mixed isomerized sugar, sulfated trehalose, pullulan and the like. Further, these chemically modified products and the like can also be used.

(8) Examples of polymers Acrylic ester/methacrylic acid ester copolymer (plus size, manufactured by Kyoo Kagaku), vinyl acetate/crotonic acid copolymer (resin 28-1310, manufactured by NSC), vinyl acetate/croton Acid/vinyl neodecanoate copolymer (28-2930, manufactured by NSC), methyl vinyl ether maleic acid half ester (Gantrez ES, manufactured by ISP), T-butyl acrylate/ethyl acrylate/methacrylic acid copolymer (rubimer , BASF), vinylpyrrolidone/vinyl acetate/vinyl propionate copolymer (Rubiscor VAP, BASF), vinyl acetate/crotonic acid copolymer (Rubiset CA, BASF), vinyl acetate/croton Acid/vinylpyrrolidone copolymer (Rubiset CAP, manufactured by BASF), vinylpyrrolidone/acrylate copolymer (Rubiflex, manufactured by BASF), acrylate/acrylamide copolymer (Ultrahold, manufactured by BASF), vinyl acetate/ Butyl maleate/isobornyl acrylate copolymer (Advantage, ISP), carboxyvinyl polymer (Carbopol, BF Goodrich), acrylic acid/alkyl methacrylate copolymer (Pemulene, BF Goodrich), etc. Anionic polymer compound, acetic acid amphoteric compound of dialkylaminoethylmethacrylate polymer (Yukaformer, manufactured by Mitsubishi Chemical Corporation), octylacrylamide acrylate/hydroxypropyl acrylate/butylaminoethyl methacrylate copolymer (AMPHOMER, NSC) Polymeric compounds such as vinyl pyrrolidone/dimethylaminoethyl methacrylate quaternary compound (GAFQUAT, ISP), methyl vinyl imidazolium chloride/vinyl pyrrolidone copolymer (Rubicoat, BASF) Polymer compounds, polyvinylpyrrolidone (Luviscor K, BASF), vinylpyrrolidone/vinyl acetate copolymer (Luviscor VA, BASF), vinylpyrrolidone/dimethylaminoethylmethacrylate copolymer (Copolymer 937, ISP) Non-polymeric compounds such as vinylcaprolactam/vinylpyrrolidone/dimethylaminoethylmethacrylate copolymer (Copolymer VC713, manufactured by ISP). Further, cellulose or its derivative, keratin and collagen or its derivative, calcium alginate, pullulan, agar, gelatin, tamarind seed polysaccharide, xanthan gum, carrageenan, high methoxyl pectin, low methoxyl pectin, guar gum, acacia, crystalline cellulose, arabino. Naturally-derived polymer compounds such as galactan, karaya gum, tragacanth gum, alginic acid, albumin, casein, curdlan, gellan gum and dextran can also be preferably used.

(9) Examples of physiologically active ingredients Examples of physiologically active ingredients include substances that give some kind of physiological activity to the skin when applied to the skin. For example, whitening ingredients, immunostimulants, anti-aging agents, UV protection agents, slimming agents, tightening agents, antioxidants, hair growth agents, hair growth agents, moisturizers, blood circulation promoters, antibacterial agents, bactericides, drying agents, A cooling sensation, a warming sensation, vitamins, amino acids, a wound healing promoter, a stimulant alleviation agent, an analgesic, a cell activator, an enzyme component and the like can be mentioned. Examples of these suitable components include, for example, ashitaba extract, avocado extract, armature extract, altea extract, arnica extract, aloe extract, apricot extract, apricot kernel extract, ginkgo biloba extract, fennel extract, turmeric extract, oolong tea extract, agets. Extract, Chinese cabbage leaf extract, sardine extract, psyllium extract, scutellaria extract, barley extract, St. John's wort extract, sardine extract, Dutch mustard extract, orange extract, seawater dried product, seaweed extract, hydrolyzed elastin, hydrolyzed wheat powder, hydrolyzed silk , Chamomile extract, carrot extract, kawara wormwood extract, licorice extract, karkade extract, oyster extract, kina extract, cucumber extract, guanosine, gardenia extract, kumazasa extract, clara extract, walnut extract, grapefruit extract, clematis extract, chlorella extract, mulberry extract, Gentiana extract, black tea extract, yeast extract, burdock extract, rice bran extract, rice germ oil, comfrey extract, collagen, cowberry extract, cinnamon extract, psyche extract, saitai extract, salvia extract, savanna extract, sasa extract, hawthorn extract , Salamander extract, shiitake extract, dioxin extract, shikon extract, perilla extract, linden extract, sycamore extract, peony extract, ginger root extract, white birch extract, horsetail extract, quince extract, hawthorn extract, elderflower extract, yarrow millet extract, western extract. Mint extract, sage extract, mallow extract, senkyu extract, senburi extract, soybean extract, turmeric extract, thyme extract, tea extract, clove extract, chigaya extract, chimpi extract, touki extract, daffodil extract, tounin extract, spruce extract, dokudami extract, tomato. Extract, Natto extract, Carrot extract, Garlic extract, Novara extract, Hibiscus extract, Bacmond extract, Parsley extract, Honey, Hamamelis extract, Parietaria extract, Hikiokoshi extract, bisabolol, loquat extract, coltsfoot extract, butterbur extract, butcher extract, butcher Bloom Extract, Grape Extract, Propolis, Loofah Extract, Safflower Extract, Peppermint Extract, Bodaiju Extract, Button Extract, Hop Extract, Pine Extract, Horse Chestnut Extract, Water Crab Cormorant extract, sucrose extract, melissa extract, peach extract, cornflower extract, eucalyptus extract, Yukinoshita extract, Yokuinin extract, wormwood extract, lavender extract, apple extract, lettuce extract, lemon extract, lotus root extract, rose extract, rosemary extract, Roman chamomile extract. , Royal jelly extract and the like.
Also, deoxyribonucleic acid, mucopolysaccharide, sodium hyaluronate, sodium chondroitin sulfate, collagen, elastin, chitin, chitosan, biopolymer such as hydrolyzed eggshell membrane, amino acid, hydrolyzed peptide, sodium lactate, urea, sodium pyrrolidonecarboxylate. , Betaine, whey, moisturizing ingredients such as trimethylglycine, sphingolipids, ceramides, phytosphingosine, cholesterol, cholesterol derivatives, oily ingredients such as phospholipids, ε-aminocaproic acid, glycyrrhizic acid, β-glycyrrhetinic acid, lysozyme chloride, guaiazulene, Immunostimulants such as hydrocortisone, vitamin A, vitamin B2, vitamin B6, vitamin C, vitamin D, vitamin E, calcium pantothenate, biotin, nicotinic acid amide, vitamin C ester and other vitamins, allantoin, diisopropylamine dichloro Acetate, active ingredients such as 4-aminomethylcyclohexanecarboxylic acid, tocopherols, carotenoids, flavonoids, tannins, lignans, antioxidants such as saponins, α-hydroxy acids, cell activating agents such as β-hydroxy acids, γ-oryzanol, Blood circulation promoting agents such as vitamin E derivatives, retinol, wound healing agents such as retinol derivatives, arbutin, kojic acid, placenta extract, sulfur, ellagic acid, linoleic acid, tranexamic acid, whitening agents such as glutathione, cepharanthin, licorice extract, Capsicum tincture, hinokitiol, garlic iodide extract, pyridoxine hydrochloride, DL-α-tocopherol, DL-α-tocopherol acetate, nicotinic acid, nicotinic acid derivative, calcium pantothenate, D-pantothenyl alcohol, acetylpantothenyl ethyl ether, biotin , Allantoin, isopropylmethylphenol, estradiol, ethinyl estradiol, capronium chloride, benzalkonium chloride, diphenhydramine hydrochloride, tacanal, camphor, salicylic acid, nonyl vanillyl amide, nonanoic vanillyl amide, piroctone olamine, glyceryl pentadecanoate, L-menthol, Mononitroguaiacol, resorcin, γ-aminobutyric acid, benzethonium chloride, mexiletine hydrochloride, auxin, female hormone, cantharitin tincture, cyclosporine, zinc pyrithione, hydrocortisone, minoxidil, polyoxyethylene sorbitan monostearate, peppermint oil, sasani Hair growth agents such as shiki extract, placenta, yuzu seed extract, blueberry extract, lingonberry extract, canca salix extract, black rice extract, green coffee bean extract, resveratrol, kiwi seed extract, strawberry seed extract, cherry extract, etc. To be

(10) Examples of antioxidants Sodium hydrogen sulfite, sodium sulfite, erythorbic acid, sodium erythorbate, dilauryl thiodipropionate, tocopherol, trilubiguanide, nordihydroguaiaretinic acid, parahydroxyanisole, butylhydroxyanisole, dibutylhydroxy. Examples thereof include toluene, ascorbyl stearate, ascorbyl palmitate, octyl gallate, propyl gallate, carotenoids, flavonoids, tannins, lignans, saponins, and plant extracts having an antioxidant effect, such as apple extract and clove extract.

(11) Examples of solvents Purified water, ethanol, lower alcohols, ethers, LPG, fluorocarbons, N-methylpyrrolidone, fluoroalcohols, volatile linear silicones, and next-generation CFCs.

Hereinafter, the present invention will be described based on examples.
Test method A three-dimensional human epidermal culture model (LabCyte EPI-MODEL 6D (manufactured by J-TEC)) was used for the experiment. B-sitosterol glucoside (1, 10 μg/mL) was added to the medium and the cells were cultured while changing the medium every other day, and the tissues were collected on the 2nd and 4th days of the culture. Expression of ceramide synthesis-related genes was examined by quantitative PCR using genes extracted from the collected tissues.

Results and effects of the examples
b-Sitosterol glucoside significantly increased serine palmitoyltransferase 2 (SPTLC2) gene expression (FIG. 2). Moreover, the expression of glucosylceramide synthase (GCS) gene was significantly increased at 10 μg/mL (FIG. 3). On the other hand, the expression of sphingomyelin synthase (SMS) gene was significantly decreased (Fig. 4). From these results, it was confirmed that b-sitosterol glucoside increases ceramide in the skin by increasing the expression of SPCS2 which is the rate-limiting enzyme of ceramide synthesis reaction and GCS that synthesizes glucosylceramide (Fig. 5).
From the above, the present invention was confirmed to be useful as a serine palmitoyl transferase gene expression promoter, a glucosylceramide synthase gene expression promoter, and further useful as a sphingomyelin synthase gene expression inhibitor, β-sitosterol It was confirmed that glucoside produces ceramide via a pathway for producing glucosylceramide (route on the left side of FIG. 5). Therefore, it was found that the production of ceramide (EOS, NS, NP, EOH, AS, AP) was uniformly promoted. From this, it was confirmed that it functions as a skin barrier improving agent and is useful as a preventive or therapeutic agent for atopic dermatitis.

The following is a combination example of the glucosylceramide production and metabolic gene expression promoter (β-sitosterol glucoside) in the skin of the present invention, but the following combination example does not limit the present invention.
Formulation 1: Chewing gum
Sugar 52.0wt%
Gum base 20.0
Glucose 10.0
Starch syrup 16.0
Fragrance 0.5
Strawberry seed extract 0.5
Glucosylceramide 0.5
β-sitosterol glucoside 0.5
100.0 wt%

Formulation 2: Gummy
Reduced starch syrup 38.0 wt%
Granulated sugar 20.0
Glucose 20.0
Gelatin 4.7
Water 9.68
Kiwi juice 4.0
Kiwi flavor 0.6
Pigment 0.02
Strawberry seed extract 1.0
Glucosylceramide 1.0
β-sitosterol glucoside 1.0
100.0 wt%

Formulation 3: Candy
Sugar 50.0wt%
Starch syrup 33.0
Water 14.2
Organic acid 2.0
Fragrance 0.2
Strawberry seed extract 0.1
Glucosylceramide 0.1
β-sitosterol glucoside 0.4
100.0 wt%

Formulation 4: Yogurt (hard/soft)
Milk 41.5wt%
Skim milk powder 5.8
Sugar 8.0
Agar 0.15
Gelatin 0.1
Lactic acid bacteria 0.005
Strawberry seed extract 0.1
Glucosylceramide 0.1
β-sitosterol glucoside 0.4
Fragrance
Water residue
100.0 wt%

Formulation 5: Soft drink
Fructose glucose liquid sugar 30.0 wt%
Emulsifier 0.5
Strawberry seed extract 0.05
Glucosylceramide 0.05
β-sitosterol glucoside 0.05
Fragrance suitable amount
Purified water residue
100.0 wt%

Formulation 6: Soft capsule
Rice germ oil 86.0 wt%
Strawberry seed extract 0.5
Glucosylceramide 0.5
Emulsifier 12.0
β-sitosterol glucoside 1.0
100.0 wt%

Formulation 7: tablets
Lactose 53.0wt%
Crystalline cellulose 30.0
Starch degradation product 10.0
Strawberry seed extract 0.5
Glucosylceramide 0.5
Glycerin fatty acid ester 5.0
β-sitosterol glucoside 1.0
100.0 wt%

Formulation 8: Oral drug (medicine)
β-sitosterol glucoside 1.0wt%
Strawberry seed extract 0.5
Glucosylceramide 0.5
Lactose 30.0
Corn starch 60.0
Crystalline cellulose 7.0
Polyvinylpyrrolidone 1.0
100.0 wt%

Formulation 9: Tablets
75.4wt% sugar
Glucose 19.0
Sucrose fatty acid ester 0.2
Strawberry seed extract 0.5
Glucosylceramide 0.5
β-sitosterol glucoside 0.5
Purified water 3.9
100.0 wt%

Formulation 15: Cat food
Corn 33.0wt%
Flour 35.0
Meat meal 15.0
Beef tallow 8.9
Salt 1.0
Skipjack extract 4.0
Strawberry seed extract 0.5
Glucosylceramide 0.5
β-sitosterol glucoside 1.0
Taurine 0.1
Vitamin 0.5
Minerals 0.5
100.0 wt%

Formulation 16: dog food
Corn 30.0wt%
Meat (chicken) 15.0
Defatted soybean 10.0
Flour 24.0
Rice bran 5.0
Strawberry seed extract 0.5
Glucosylceramide 0.5
β-sitosterol glucoside 5.0
Animal fats and oils 8.9
Oligosaccharide 0.1
Vitamin 0.5
Mineral 0.5
100.0 wt%
Formulation 1: Cosmetic cream
Squalane 20.0wt%
Beeswax 5.0
Refined jojoba oil 5.0
Glycerin 5.0
Glycerin monostearate 2.0
Polyoxyethylene (20) sorbitan-
Monostearate 2.0
Strawberry seed extract 0.1
Glucosylceramide 0.1
β-sitosterol glucoside 2.0
Preservative Suitable amount
Fragrance suitable amount
Purified water residue
100.0 wt%

Formulation 2: Lotion
Ethanol 5.0 wt%
Glycerin 2.0
1,3-butylene glycol 2.0
Polyethylene oleyl ether 0.5
Sodium citrate 0.1
Citric acid 0.1
Strawberry seed extract 0.1
Glucosylceramide 0.1
β-sitosterol glucoside 0.1
Purified water residue
100.0 wt%

Formulation 3: Body gel
Macadamia nut oil 2.0wt%
Octyldodecyl myristate 10.0
Methylphenyl polysiloxane 5.0
Behenyl alcohol 3.0
Stearic acid 3.0
Batyl alcohol 1.0
Glyceryl monostearate 1.0
Tetraoleic acid polyoxyethylene sorbit 2.0
Hydrogenated soybean phospholipid 1.0
Ceramide 0.1
Retinol palmitate 0.1
Preservative Suitable amount
Centella asiatica extract 1.0
Strawberry seed extract 0.1
Glucosylceramide 0.1
β-sitosterol glucoside 1.0
1,3-butylene glycol 5.0
Purified water residue
100.0 wt%

Formulation 4: Emulsion
Squalane 4.0wt%
Vaseline 2.5
Cetanol 2.0
Glycerin 2.0
Lipophilic type glyceryl monostearate 1.0
Stearic acid 1.0
L-arginine 1.0
Strawberry seed extract 0.1
Glucosylceramide 0.1
β-sitosterol glucoside 0.5
Potassium hydroxide 0.1
Fragrance
Purified water residue
100.0 wt%

Formulation 5: Bath agent (liquid)
Propylene glycol 50.0wt%
Ethanol 20.0
Sodium sulfate 5.0
Strawberry seed extract 0.1
Glucosylceramide 0.1
β-sitosterol glucoside 0.5
Lanolin 0.5
Avocado oil 0.5
Pigment 1.5
Fragrance 22.0
100.0 wt%
Formulation 6: shampoo sodium polyoxyethylene alkyl ether sulfate
(E.O2 mol) 15.0
Coconut oil aliphatic diethanolamide 5.0
Glycerin 3.0
Strawberry seed extract 0.1
Glucosylceramide 0.1
β-sitosterol glucoside 0.4
Ethanol 5.0
Fragrances and preservatives
Deionized water residual
Total 100 wt%

Formulation 7: hair cream
Liquid paraffin 20.0wt%
Solid paraffin 3.0
Polyoxyethylene cetyl ether
(E.O 15 mol) 2.0
Sorbitan sesquioleate 1.0
Strawberry seed extract 0.1
Glucosylceramide 0.1
β-sitosterol glucoside 0.2
Ethanol 10.0
Potassium hydroxide 0.1
Glycerin 3.0
Fragrances and preservatives
Total 100 wt%

Formulation 8: Ointment
White beeswax 5.0 wt%
Purified lanolin 5.0
Strawberry seed extract 0.1
Glucosylceramide 0.1
β-sitosterol glucoside 1.0
Perfume 0.1
Vaseline residue
Total 100 wt%

As described above, by using the β-sitosterol glycoside, the present invention can provide a glucosylceramide production and metabolic gene expression promoter in the skin that is safe and has few side effects.

Claims (4)

An oral preparation for promoting serine palmitoyltransferase gene expression, which comprises β-sitosterol glycoside as an active ingredient. An oral preparation for promoting glucosylceramide synthase gene expression, which comprises β-sitosterol glycoside as an active ingredient. An oral preparation for suppressing sphingomyelin synthase gene expression, which comprises β-sitosterol glycoside as an active ingredient. The oral preparation according to any one of claims 1 to 3, wherein the β-sitosterol glycoside is β-sitosterol glucoside.

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