JP2021104968A - Autophagy inducer - Google Patents

Abstract

To provide useful agents for inducing autophagy.SOLUTION: The agent is composed of a quercetin glycoside or a safflower component (safflower extract, and the like).SELECTED DRAWING: None

Description

The present invention relates to agents and the like useful for inducing autophagy.

Autophagy is a cell metabolic function that plays a role in breaking down unwanted proteins and organelles in cells.

Then, an effective component for such autophagy induction is being searched for. For example, Patent Document 1 discloses an autophagy inducer containing a cyclic glucooligosaccharide as an active ingredient.

International Publication No. 2018-173653 Pamphlet

An object of the present invention is to provide a novel agent useful for inducing autophagy and the like.

As a result of diligent studies to achieve the above object, the present inventor has induced (improved, improved, improved) autophagy by quercetin glycosides (particularly, glycosides containing quercetin-7-glucoside) and safflower extract. We have found that it is useful for expression) and anti-aging (for example, prevention and improvement of skin aging), and have completed the present invention.

That is, the present invention relates to the following inventions and the like.
[1]
An autophagy inducer (autophagy activator, autophagy-expressing agent) containing a quercetin glycoside (included as an active ingredient).
[2]
An anti-aging agent containing a quercetin glycoside (included as an active ingredient).
[3]
An autophagy inducer (autophagy activator, autophagy-expressing agent) containing a safflower component (included as an active ingredient).
[4]
An anti-aging agent containing a safflower ingredient (included as an active ingredient).
[5]
The agent according to [3] or [4], wherein the safflower component is a safflower extract containing a quercetin glycoside.
[6]
The agent according to any one of [1] to [5], wherein the quercetin glycoside or safflower component contains quercetin-7-glucoside.
[7]
The agent according to any one of [3] to [6], wherein the safflower component is a safflower extract containing at least safflower leaves.
[8]
The agent according to any one of [3] to [7], wherein the safflower component is a safflower extract (extract) of a solvent containing at least alcohol (ethanol or the like).
[9]
The agent according to any one of [3] to [8], wherein the safflower component contains quercetin-7-glucoside in a proportion of 0.03% by mass or more.
[10]
The agent according to any one of [1] to [9], which is used for preventing and / or improving skin aging.
[11]
A composition containing the agent (quercetin glycoside, safflower component) according to any one of [1] to [10].
[12]
The composition according to [11], which is used for preventing and / or ameliorating skin aging.
[13]
The composition according to [11] or [12], which contains quercetin-7-glucoside in a proportion of 0.00003% by mass or more.
[14]
The composition according to any one of [11] to [13], which is for cosmetics.
[15]
The agent or composition according to any one of [1] to [14] for inducing autophagy on epidermal keratinized cells and / or fibroblasts.

According to the present invention, it is possible to provide a novel agent or the like useful for inducing autophagy.

FIG. 1 is a diagram (graph) showing the results obtained in Example 1. FIG. 2 is a diagram (graph) showing the results obtained in Example 2. FIG. 3 is a diagram (graph) showing the results obtained in Example 3.

[Agent]
(First aspect)
In the first aspect of the present invention, an agent containing (containing as an active ingredient) a quercetin glycoside (a quercetin glycoside) is provided.

Quercetin is the following compound, and the quercetin glycoside is a hydroxy group of quercetin (this compound) with a sugar substituted (bonded).

In the quercetin glycoside, the sugar is not particularly limited, but may be, for example, a monosaccharide (monosaccharide), an oligosaccharide, a polysaccharide (polysaccharide), or the like. The sugar (oligosaccharide or polysaccharide) may be either a homopolysaccharide or a heteropolysaccharide.

In the monosaccharide, the number of carbon atoms is not particularly limited, and for example, pentose or hexose may be used. Further, the monosaccharide may be, for example, furanose or pyranose.

Specific sugars include monosaccharides [eg, pentoses (eg, ribose, arabinose, xylose, deoxyribose, etc.), hexoses (eg, fructose, tagatos, allose, altrose, glucose, mannose, galactose, lambnorse, glucosamine, etc.) (Galactosamine, glucuronic acid), etc.], oligosaccharides or polysaccharides to which these monosaccharides are bound [for example, disaccharides (eg, maltose, kojibiose, cellobiose, isomaltose, gentobiose, lactose, rutinose, neoheseridos, etc.)], etc. Can be mentioned.

Among these, typical sugars include monosaccharides (for example, hexoses such as glucose and galactose).

The sugar may be D-form, L-form, or a mixture thereof.

In the quercetin glycoside, the sugar substitution (binding) position is not particularly limited and may be any of the hydroxyl groups of quercetin. Further, in the quercetin glycoside, the number of sugars (quercetin or hydroxyl group of quercetin) [number of substitutions (bonds)] is not particularly limited and may be 1, 2 or more (for example, 2 to 5, 2 to 2). 4, 2-3, 2 etc.) may be used.

When the number of sugars is 2 or more, the sugars may be the same or different.

Further, the quercetin glycoside may be any of α-form (α-anomer, α-glycoside (O-glycoside)), β-form (β-anomer, β-glycoside (O-glycoside)), and a mixture thereof. ..

Specific examples of the quercetin glycoside include quercetin glucoside (eg, quercetin-3-glucoside, quercetin-7-glucoside), quercetin galactoside (eg, quercetin-3-galactoside), and quercetin ramnoside (eg, quercetin). -3-ramnoside), quercetin lucronide (eg, quercetin-3-glucuronide), quercetin lucinoside (eg, quercetin-3-lucinoside) and the like.

The quercetin glycoside may be used alone or in combination of two or more.

Among these, quercetin glucoside and / or quercetin-7-glycoside are preferable, and quercetin-7-glucoside is particularly preferable. Therefore, the quercetin glycoside may contain at least such a glycoside (for example, quercetin-7-glucoside).

In such a case, the quercetin glycoside contains quercetin glucoside and / or quercetin-7-glycoside with respect to the whole quercetin glycoside, for example, 10% by mass or more, 30% by mass or more, 50% by mass or more, 60. It may be contained in a proportion of mass% or more, 70% by mass or more, 80% by mass or more, 90% by mass or more, or substantially 100% by mass.

In particular, when the quercetin glycoside contains quercetin-7-glucoside, the ratio of quercetin-7-glucoside to the entire quercetin glycoside is, for example, 1% by mass or more (for example, 5% by mass or more), preferably. May be 10% by mass or more (for example, 15% by mass or more), more preferably 20% by mass or more, particularly 30% by mass or more.

The quercetin glycoside may be a commercially available product or may be synthesized by a conventional method. Further, like the safflower component described later, it may be derived from a plant (the plant itself or one separated or extracted from the plant).

(Second aspect)
In the second aspect of the present invention, an agent containing a safflower component (containing as an active ingredient) is provided.
Examples of the safflower component include safflower, safflower extract, and the like, and these may be combined. As a safflower component, a safflower extract is typically used in many cases.

As the safflower, for example, parts such as flowers, leaves, seeds (seed, seed coat), stems, roots, etc. may be used, these may be used in combination, or whole plants may be used.

As the safflower, in particular, safflower containing at least leaves may be used.

The safflower extract may be a commercially available product, or can be obtained by extracting the safflower.

In the extraction, the solvent (extraction solvent) can be selected depending on the part of the red flower to be used, for example, water, alcohols [for example, C _{1 such as alkanol (for example, methanol, ethanol, isopropanol, n-butanol, etc.). -4} Alcanol), polyols (eg ethylene glycol, propylene glycol, 1,3-butylene glycol, glycerin, etc.)], ketones (eg, acetone, methyl ethyl ketone, etc.), ethers (eg, diethyl ether, etc.), esters (For example, ethyl acetate, etc.) and the like.
The extraction solvent may be used alone or in combination of two or more.

Typical extraction solvents include water, alcohols (ethanol, etc.), and a mixture thereof.

In particular, as the solvent, a solvent containing at least a polar solvent (for example, alcohols), particularly a solvent containing ethanol [for example, 30% by mass or more of ethanol, preferably 50% by mass or more, still more preferably 70% by mass or more ( For example, a solvent containing 90% by mass or more) may be preferably used. By using such a solvent, it is easy to efficiently obtain a safflower extract containing a quercetin glycoside (for example, quercetin-7-glucoside).

The extraction temperature and extraction time are not particularly limited, and can be appropriately selected depending on the extraction solvent, extraction method, and the like.

At the time of extraction, the safflower may be subjected to an appropriate treatment (crushing treatment, heat treatment, drying treatment, etc.), if necessary. In addition, the extract may be further subjected to concentration and drying (normal temperature drying, freeze drying, etc.).

The form of the safflower component is not particularly limited, and may be, for example, liquid (for example, an extract containing an extraction solvent), powder (or powdery granules), or the like.

The safflower component may specifically contain a quercetin glycoside. The safflower component containing such a quercetin glycoside can be efficiently obtained by selecting the safflower portion to be used and the extraction conditions of the extract.

Examples of the quercetin glycoside include glycosides similar to those exemplified in the first aspect, and preferred embodiments thereof are also the same.

For example, the safflower component may contain at least quercetin glucoside and / or quercetin-7-glycoside, in particular quercetin-7-glucoside.

The safflower component containing the quercetin glycoside may contain other components (components other than the quercetin glycoside). Examples of such other components include quercetin, luteolin, luteolin glycosides (for example, luteolin-7-glucoside), etc., depending on the site of safflower, extraction conditions, and the like.

Other components may be contained in the safflower component alone or in combination of two or more.

When the safflower component (for example, safflower extract) contains a quercetin glycoside, the ratio of the quercetin glycoside in the safflower component (the ratio to the total solid content when containing a solvent) is, for example, 0.01% by mass. The above (for example, 0.03% by mass or more), preferably 0.1% by mass or more (for example, 0.3% by mass or more), more preferably 1% by mass or more (for example, 3% by mass or more), and the like. May be good.
The upper limit of the ratio of quercetin glycosides in the safflower component (ratio to the total solid content when a solvent is contained) is not particularly limited, but for example, 0.3% by mass, 1% by mass, 3% by mass, 5 It may be mass%, 10 mass%, 20 mass%, 30 mass% and the like.

When the red flower component (for example, red flower extract) contains quercetin-7-glucoside, the ratio of quercetin-7-glucoside in the red flower component (ratio to the total solid mass when containing a solvent) is, for example, 0.001. Mass% or more (for example, 0.003 mass% or more, 0.005 mass% or more, 0.01 mass% or more), preferably 0.01 mass% or more (for example, 0.03 mass% or more, 0.05 mass% or more) % Or more, 0.1% by mass or more), more preferably 0.1% by mass or more (for example, 0.3% by mass or more, 0.5% by mass or more, 1% by mass or more) and the like.
The upper limit of the ratio of quercetin-7-glucoside in the red flower component (ratio to the total solid content when a solvent is contained) is not particularly limited, but for example, 0.1% by mass, 1% by mass, 3% by mass, etc. It may be 5% by mass, 10% by mass, or the like.

When the safflower component (for example, safflower extract) contains luteolin-7-glucoside, the ratio of luteolin-7-glucoside in the safflower component (ratio to the total solid content when containing a solvent) is, for example, 0.01. It may be mass% or more, preferably 0.1 mass% or more, more preferably 1 mass% or more, and the like.
The upper limit of the ratio of luteolin-7-glucoside in the safflower component (ratio to the total solid content when a solvent is contained) is not particularly limited, but for example, 0.1% by mass, 1% by mass, 3% by mass, etc. It may be 5% by mass, 10% by mass, or the like.

(Use of agent)
The agent of the present invention (agent of the first aspect, agent of the second aspect) can be used for a specific application.

First, the agent of the present invention can be used as an autophagy inducer [an agent for inducing (expressing, improving, improving, activating) autophagy].
As described above, autophagy (function) plays a role of decomposing unnecessary proteins and organelles in cells, for example, and according to the agent of the present invention, such autophagy (function). Can be induced (expression, improvement, improvement, activation).
Such agents may induce autophagy on skin cells. Examples of skin cells include epidermal keratinocytes and fibroblasts. In particular, the agent of the present invention can induce autophagy on epidermal keratinocytes and fibroblasts, and can efficiently exert an autophagy function (furthermore, a skin prevention or improvement function associated therewith). ..

In addition, the agent of the present invention can be used as an anti-aging agent.

In particular, the agent of the present invention may be an agent for preventing and / or ameliorating skin aging.

In addition, in the anti-aging agent (furthermore, the agent for preventing and / or improving the aging of the skin), the anti-aging action / function (further, the preventing / / or improving action / function of the skin aging) is autophagy ( It may be accompanied by induction of function).

In addition, the agent of the present invention may be used as an agent for a specific application target, for example, for pharmaceuticals, foods and drinks, cosmetics, and the like.

[Composition]
The present invention also includes a composition containing the agent (first aspect or second aspect).

In addition, such a composition can also be used for the same function and application as the above-mentioned agent. For example, it can be used for autophagy induction, anti-aging, prevention and / or improvement of skin aging). Further, it may be used for medicine, food and drink, cosmetics and the like.

In particular, the composition of the present invention may be suitably used for cosmetics (composition for cosmetics) from the viewpoint of having an autophagy-inducing action and an anti-aging action. The cosmetic composition is not particularly limited, and may be classified as a quasi-drug in the definition of medicated cosmetics and the like in the Pharmaceutical Affairs Law.

The composition of the present invention may contain the above-mentioned agent (quercetin glycoside or safflower component), and may contain other components depending on its use, form and the like.

Examples of such other components include bases or carriers, additives, other active ingredients, and the like. In addition, such other components and their ratios can be appropriately selected depending on the form, properties and the like of the composition.

The base or carrier is not particularly limited, but for example, paraffin, liquid paraffin, squalane, white wax, gelled hydrocarbon (plastibase, etc.), ozokelite, selecin, vaseline, hard fat, microcrystalin wax, α-olefin oligomer. , Hydrocarbons such as light liquid paraffin; fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, isostearic acid; glyceryl tri2-ethylhexaneate (trioctanoin), tri (caprylic acid / capric acid) ) Tri-fatty acid glycerides such as glyceryl; higher alcohols such as cetanol, stearyl alcohol, behenyl alcohol; methylpolysiloxane, highly polymerized methylpolysiloxane, dimethylsiloxane / methyl (polyoxyethylene) siloxane / methyl (polyoxypropylene) siloxane copolymer , Dimethylsiloxane / methyl (polyoxyethylene) siloxane copolymer, dimethylsiloxane / methyl (polyoxypropylene) siloxane copolymer, polyoxyethylene / methylpolysiloxane copolymer, poly (oxyethylene / oxypropylene) / methyl Polysiloxane copolymer, dimethylsiloxane / methylcetyloxysiloxane copolymer, dimethylsiloxane / methylstealoxysiloxane copolymer, alkyl acrylate copolymer methylpolysiloxane ester, crosslinked methylpolysiloxane, crosslinked methylphenylpoly Siloxane, cross-linked polyether-modified silicone, cross-linked alkyl polyether-modified silicone, cross-linked alkyl-modified silicone, decamethylcyclopentasiloxane, ethyltrisiloxane, methyltrimethicone, methylsiloxane reticulated polymer, polyoxyethylene / methylpolysiloxane Silicone oils such as copolymers, methylhydrogenpolysiloxane, triethoxysilylethyl polydimethylsiloxyethylhexyl dimethicone, dimethylpolysiloxane; ethylene glycol monoacetylate, ethylene glycol diacetate, triethylene glycol diacetate, hexylene glycol Glycolacetates such as diacetate and 2-methyl-2-propen-1,1-diol diacetate; triethylene glycol divalerate, 2,2,4-trimethyl-1,3-pentanediol monoiso Butyrate, 2,2,4-trimethyl-1,3-pentanediol diiso Glycolesters such as butyrate; glycolacrytes such as ethylene glycol diacrylate, diethylene glycol diacrylate, propylene glycol monoacrylate, 2,2-dimethyl-trimethylethylene glycol diacrylate, and 1,3-butylene glycol diacrylate. Lattes; glycol dinitlates such as ethylene glycol dinitrate, diethylene glycol dinitrate, triethylene glycol dinitrate, and propylene glycol dinitrate; 2,2'-[1,4-phenylenedioxy] diethanol; ethyl cellulose, hydroxypropyl cellulose, Cellulous derivatives such as hydroxypropylmethylcellulose; polyvinylpyrrolidone; carrageenan; polyvinylbutyrate; polyethylene glycol; dioxane; butylene glycol adipate polyester; isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isononyl isononanoate, tetra Esters such as pentaerytherit 2-ethylhexanoic acid; polysaccharides such as dextrin and maltodextrin; lower alcohols such as ethanol and isopropanol; ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, diethylene glycol monomethyl ether , Diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monobutyl ether, propylene glycol monoethyl ether, propylene glycol monopropyl ether, dipropylene glycol monoethyl ether, glycol ether such as dipropylene glycol monopropyl ether; aqueous groups such as water Agents and the like can be mentioned. These bases or carriers can be used alone or in combination of two or more.

Additives are not particularly limited, and examples thereof include antioxidants, surfactants, thickeners, preservatives, pH adjusters, stabilizers, preservatives, colorants, and fragrances. These additives may be used alone or in combination of two or more.

Examples of the antioxidant include dibutylhydroxytoluene, butylhydroxyanisole, sorbic acid, sodium sulfite, ascorbic acid, ascorbic acid derivative (ascorbic acid phosphate, etc.), tocopherol, tocopherol derivative, erythorbic acid, L-cysteine hydrochloride. And so on.

Examples of the surfactant include sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, penta-2-ethylhexylate diglycerol sorbitan, tetra-2-ethylhexylate diglycerol sorbitan and the like. Polysorbate fatty acid esters; propylene glycol fatty acid esters such as propylene glycol monostearate; glycerin alkyl ethers; alkyl glucosides; amines such as stearylamine and oleylamine; polyoxyethylene / methylpolysiloxane copolymers, lauryl PEG-9 poly Examples thereof include silicone-based surfactants such as dimethylsiloxyethyl dimethicone and PEG-9 polydimethylsiloxyethyl dimethicone.

Examples of thickeners include guar gum, locust bean gum, carrageenan, xanthan gum, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, alkyl methacrylate copolymer, polyethylene glycol, bentonite, alginic acid, macrogol, and cellulose-based thickeners. Examples thereof include thickeners (methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, etc.) and salts thereof.

Examples of preservatives and preservatives include benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, butyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and paraoxy. Examples thereof include benzyl benzoate, methyl paraoxybenzoate, phenoxyethanol, benzyl alcohol, chlorobutanol, sorbic acid and salts thereof, chlorhexidine gluconate, alcandiol, and glycerin fatty acid ester.

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

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

Other active ingredients are not particularly limited, but are, for example, moisturizing ingredients, anti-inflammatory ingredients, antibacterial or bactericidal ingredients, vitamins, peptides or derivatives thereof (esters, amides, etc.), cell activating ingredients, antiaging ingredients, blood circulation. Examples include an accelerating component, a keratin softening component, a whitening component, and a converging component. These active ingredients may be used alone or in combination of two or more.

Examples of the moisturizing component include high molecular compounds such as collagen, elastin, keratin, chitin and chitosan; natural moisturizing factors such as sodium lactate, urea and sodium pyrrolidone carboxylate; lipids such as ceramide, cholesterol and phospholipid; chamomile extract, Examples thereof include plant extracts such as hamamelis extract, cha extract, and perilla extract.

Examples of the anti-inflammatory component include components derived from plants (for example, comfrey), allantoin, glycyrrhizinic acid or a derivative thereof, zinc oxide, pyridoxine hydrochloride, tocopherol acetate, salicylic acid or a derivative thereof, ε-aminocaproic acid and the like. ..

Examples of antibacterial or bactericidal components include ethanol, chlorhexidine, salicylic acid, benzalkonium chloride, acrinol, sulfur, resorcin, benzethonium chloride, adaparene, benzoyl peroxide, clindamycin, cresol, gluconic acid and its derivatives, povidone iodine, and iodine. Potassium chloride, iodine, isopropylmethylphenol, triclosan, triclosan, photosensitizer 101, photosensitizer 201, paraben, phenoxyethanol, 1,2-pentanediol, alkyldiaminoglycine hydrochloride, chlorhexidine gluconate, zinc paraphenolsulfonate, etc. Can be mentioned.

Examples of vitamins include retinol derivatives such as retinol, retinol acetate, and retinol palmitate, retinal, retinoic acid, methyl retinoate, ethyl retinoate, retinol retinoate, d-δ-tocopheryl retinoate, and α-tocopheryl. Vitamin A such as retinoate and β-tocopheryl retinoate; Vitamin E such as dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate; Vitamin B2s such as riboflavin, flavin mononucleotide, flavin adenin dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5'-phosphate sodium, riboflavin tetranicotinic acid ester; dl-α-tocopherol nicotinate, nicotinic acid Nicotinic acids such as benzyl, methyl nicotinate, β-butoxyethyl nicotinate, 1- (4-methylphenyl) ethyl nicotinate; ascorbigen-A, ascorbic acid stearate, ascorbic acid palmitate, dipalmitate L- Vitamin Cs such as ascorbyl; Vitamin Ds such as methylhesperidine, ergocalciferol, cholecalciferol; Vitamin Ks such as phylloquinone and farnoquinone, γ-orizanol, dibenzoylthiamine, dibenzoylthiamine hydrochloride; thiamine hydrochloride, Thiamine cetyl hydrochloride, thiamine thiocyanate, thiamine lauryl hydrochloride, thiamine nitrate, thiamine monophosphate, thiamine lysine salt, thiamine triphosphate, thiamine monophosphate ester phosphate, thiamine monophosphate, thiamine diphosphate, Vitamin B1s such as thiamine diphosphate ester hydrochloride, thiamine triphosphate ester, thiamine triphosphate monophosphate; pyridoxin hydrochloride, pyridoxin acetate, pyridoxal hydrochloride, 5'-pyridoxal phosphate, vitamin B6 such as pyridoxamine hydrochloride; cyanocobalamine , Vitamin B12s such as hydroxocobalamine, deoxyadenosylcobalamine; folic acids such as folic acid and pteroylglutamic acid; nicotinic acids such as nicotinic acid and nicotinic acid amide; D-pantesin, D-pantetin, coenzyme A, pantothenyl ethyl ether, etc. Pantothenic acids; biotins such as biotin and biotisin; vitamin Cs which are ascorbic acid derivatives such as ascorbic acid, sodium ascorbic acid, dehydroascorbic acid, sodium ascorbic acid phosphate, magnesium ascorbic acid phosphate; carnitine, ferula Examples thereof include vitamin-like acting factors such as acid, α-lipoic acid, and ollotic acid.

Examples of the peptide or its derivative include keratin-degrading peptide, hydrolyzed keratin, collagen, fish-derived collagen, atelocollagen, gelatin, elastin, elastin-degrading peptide, collagen-degrading peptide, hydrolyzed collagen, hydroxypropylammonium chloride hydrolyzed collagen, and elastin. Degrading Peptide, Conchiolin Degrading Peptide, Hydrolyzed Conchiolin, Silk Proteolytic Peptide, Hydrolyzed Silk, Lauroyl Hydrolyzed Silk Sodium, Soy Proteolytic Peptide, Hydrolyzed Soy Protein, Wheat Protein, Wheat Proteolytic Peptide, Hydrolyzed Wheat Protein, Casein Degrading peptides, acylated peptides (palmitoyl oligopeptide, palmitoyl pentapeptide, palmitoyl tetrapeptide, etc.) and the like can be mentioned.

Examples of the cell activating component include vitamins such as retinol, thiamine, riboflavin, pyridoxine hydrochloride, and pantothenic acids; α-hydroxy acids such as glycolic acid and lactic acid; tannins, flavonoids, saponins, allantin, and photosensitizer No. 301. Can be mentioned.

Examples of the anti-aging component include pangamic acid, kinetin, ursolic acid, turmeric extract, sphingosine derivative, silicon, silicic acid, N-methyl-L-serine, mevalonolactone and the like.

Examples of blood circulation promoting components include plants (eg, ginseng, shiitake mushroom, arnica, ginkgo, uikyo, enmeisou, Dutch oak, chamomile, roman chamomile, carrot, gentiana, gobo, rice, hawthorn, shiitake mushroom, hawthorn, hawthorn, and senkyu. , Senburi, thyme, chow, chimpi, touki, tounin, touhi, carrot, garlic, butcher bloom, grape, button, marronnier, melissa, yuzu, yokunin, rosemary, rosehip, peach, apricot, walnut, corn) Ingredients; glucosyl hesperidin and the like.

Examples of the keratin softening component include salicylic acid, glycolic acid, fruit acid, phytic acid, sulfur and the like.

Examples of the whitening component include ascorbic acid and its derivatives (phosphoric acid ester, etc.), arbutin, tocopherol, and the like.

Examples of the astringent component include zinc paraphenol sulfonate, zinc oxide, menthol, ethanol and the like.

The shape of the composition of the present invention is not particularly limited and can be appropriately selected depending on the intended use and the like, and examples thereof include a liquid state, a fluid state and a semi-solid state.
The form of the composition of the present invention (composition for cosmetics, etc.) is not particularly limited, and for example, a liquid agent, a suspension agent, an emulsion, a cream agent, an ointment agent, a gel agent, a liniment agent, a lotion agent, or an aerosol. Examples thereof include agents and sheet agents obtained by impregnating a non-woven fabric with a chemical solution. Among these, liquids, suspensions, emulsions, creams and the like are preferable.

Specific uses of the composition of the present invention are not particularly limited, but for example, cosmetics, cosmetic emulsions, cosmetic oils, gels, creams, beauty liquids, sunscreen cosmetics, packs, masks, hand creams, etc. Basic cosmetics such as body lotion and body cream; Cleaning cosmetics such as wash pigment, makeup remover, body shampoo, shampoo, conditioner, treatment; makeup base, foundation, face powder, water stain, whitening, dolan, eye shadow base, eye Makeup cosmetics such as shadow, nose shadow, lip pencil, lipstick, lip gloss, cheek red, various colors; shampoo, dry shampoo, conditioner, rinse, rinse-in shampoo, treatment, hair tonic, hair conditioner, hair oil, pomade, hair Hair care products such as coloring agents; dentifrices, lip creams, soaps, body soaps and the like.
Among these, cosmetics, cosmetic emulsions, cosmetic oils, gels, creams, beauty essences, sunscreen cosmetics and the like are preferable, and cosmetics, cosmetic emulsions, creams, beauty essences and the like are more preferable. Is.

When the composition of the present invention is a quasi-drug, its specific use is not particularly limited, but for example, medicated cosmetics, medicated soap, medicated dentifrice, antiperspirant, medicated cream, hair restorer, hair dye. , Mouthwash, energy drink, mouth refreshing agent, contact lens wearing agent, sterilizing and disinfecting agent, toothpaste, digestive agent, quasi-drug containing health medicine, vitamin-containing health medicine, bath salt and the like. Among these, cosmeceuticals, cosmeceutical creams, hair restorers and the like are preferable.

The method for producing the composition of the present invention is not particularly limited as long as it is a method using the agent of the present invention (quercetin glycoside, safflower component), and conventionally known methods are used depending on the use and properties of the composition. Can be used. For example, the agent of the present invention can be produced by a conventional method as it is at the time of producing the composition, or by emulsifying, solubilizing, dispersing and blending.

In the composition of the present invention, the proportion of the agent of the present invention can be appropriately selected depending on the type of composition, the compounding components and the like, and is not particularly limited. For example, the proportion of quercetin glycoside (solid content when a solvent is contained). The ratio to the whole) may be, for example, 0.00003% by mass or more, preferably 0.0003% by mass or more, still more preferably 0.003% by mass or more.
The upper limit of the ratio of the quercetin glycoside in the composition (the ratio to the total solid content when the solvent is contained) is not particularly limited, but is, for example, 0.0001% by mass, 0.0003% by mass, 0.001. It may be mass%, 0.003 mass%, 0.01 mass%, 0.03 mass% and the like.

When the composition of the present invention contains quercetin-7-glucoside, the proportion of quercetin-7-glucoside in the composition (ratio to the total solid content when containing a solvent) is, for example, 0.00001% by mass or more. , It may be preferably 0.0001% by mass or more, more preferably 0.001% by mass or more, and the like.
The upper limit of the ratio of quercetin-7-glucoside (ratio to the total solid content when a solvent is contained) in the composition is not particularly limited, but is, for example, 0.0001% by mass, 0.0003% by mass, 0.001. It may be mass%, 0.003 mass%, 0.01 mass%, 0.03 mass% and the like.

When the composition of the present invention contains a safflower component (for example, safflower extract), the ratio of the safflower component in the composition (the ratio to the total solid content when containing a solvent) is, for example, 0.01 mass. % Or more, preferably 0.1% by mass or more, more preferably 1% by mass or more.
The upper limit of the ratio of the safflower component in the composition (the ratio to the total solid content when the solvent is contained) is not particularly limited, but is, for example, 0.1% by mass, 1% by mass, 10% by mass, or the like. May be good.

[Usage mode, etc.]
The present invention includes various methods using the above-mentioned agents or compositions.
Such a method may be, for example, a method of using the agent or composition as an object of use (application).

And such a method may be accompanied by the said function / action (for example, autophagy induction, anti-aging, prevention and / or improvement of skin aging).

The method of using (applying) the agent or composition of the present invention is not particularly limited, and can be appropriately selected depending on the object of use (application) and the like. For example, when it is used for cosmetics, it can be appropriately selected depending on the skin condition, age, gender, etc. For example, several times a day (for example, 1 to 5 times a day, preferably 1 to 1 a day). 3 times), an appropriate amount (for example, about 0.005 to 0.5 g) may be applied to the skin (application, spraying, application, etc.). It can also be applied to any skin such as face, neck, hands, feet, fingers, torso, scalp and the like.

The amount of the agent or composition of the present invention used (applied) is also not particularly limited and may be appropriately changed depending on the type and component of the composition. For example, a quercetin glycoside (particularly, quercetin-7-glucoside) may be used. as quercetin glycoside) or safflower component comprises, per day per adult, and preferably from about 0.001 to 10 mg / cm ² (area of skin), and more preferably, from about 0.01 to 1 mg / cm ² (area of skin) It may be.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto.

[Quantification of quercetin-7-glucoside and quercetin glycoside]
The sample was analyzed according to known high performance liquid chromatography (HPLC method) and calculated by comparing the peak area of quercetin-7-glucoside with the peak area of the standard product.
In addition, quercetin glycosides other than quercetin-7-glucoside were also calculated in the same manner.

Synthesis example (safflower extract)
10 g of safflower leaf powder was suspended in 100 mL of a 90 mass% ethanol aqueous solution, and the mixture was stirred at room temperature for 1 hour. The extract was separated by filtration, distilled off under reduced pressure, and then freeze-dried to obtain 1 g of safflower extract.

Example 1
Human epidermal fibroblasts (derived from a 51-year-old white woman) (hereinafter referred to as NHDF) were seeded in a 6-well plate, and DMEM medium (thermo) supplemented with 10% fetal bovine serum, 1% penicillin / streptomycin, and 1% L-glutamine. The cells were cultured overnight at 37 ° C. and 5% CO _{2 in Fisher Scientific (manufactured by Fisher Scientific).}
Safflower extract was added to the medium to a concentration of 10,100 μg / mL, and the cells were cultured for 24 hours. At the same time, for autophagy flux analysis, the safflower extract was similarly added and cultured for 8 hours, then chloroquine (hereinafter, CQ), which is a lysosome inhibitor, was added to a concentration of 5 μM, and the cells were further cultured for 16 hours. The cultured cells were collected with RIPA buffer (manufactured by Millipore), and a sample for SDS-PAGE was prepared using SDS sample buffer.
The amount of LC3-II, which is a marker protein for autophagy, was measured by Western blotting using an LC3 antibody (manufactured by Cell Signaling Technology). Image analysis software ImageJ was used to measure the band intensity.
When the band intensity of LC3-II was comparatively quantified, GAPDH having a constant production amount in vivo was used as an internal standard, and the ratio of the band intensity of LC3-II to the band intensity of GAPDH was calculated and standardized. In the autophagy flux analysis, the test substance exerts an autophagy-inducing effect when the two conditions of increasing the band intensity of LC3-II and further increasing the band intensity by the treatment with the addition of a lysosomal inhibitor are satisfied in the treatment of the test substance. Judge to have.
FIG. 1 shows the expression level of LC3-II standardized by the internal standard GAPDH. The LC3-II expression level in the non-additive cells was set to "1", and the relative values of various cells with respect to this were determined.
From FIG. 1, the LC3-II band intensity increased in the group to which 10,100 μg / mL safflower extract was added, as compared with the group to which no addition was added. Moreover, it was confirmed that the band strength was further increased by the addition of CQ.

Example 2
Normal human epidermal keratinocytes (derived from a 47-year-old white woman) (hereinafter referred to as NHEK) were seeded in a 6-well plate and added with human keratinocyte growth factor (HKGS) in Epilife medium (manufactured by Thermofisher Scientific). Incubated overnight at 37 ° C. _{under 5% CO 2.}
Safflower extract was added to the medium at 1, 10, 100 μg / mL and cultured for 24 hours. At the same time, for autophagy flux analysis, the safflower extract was similarly added and cultured for 8 hours, then chloroquine (hereinafter, CQ), which is a lysosome inhibitor, was added to a concentration of 5 μM, and the cells were further cultured for 16 hours. The cultured cells were collected with RIPA buffer (manufactured by Millipore), and a sample for SDS-PAGE was prepared using SDS sample buffer.
The amount of LC3-II, which is a marker protein for autophagy, was measured by Western blotting using an LC3 antibody (manufactured by Cell Signaling Technology). Image analysis software ImageJ was used to measure the band intensity. When the band intensity of LC3-II was comparatively quantified, GAPDH having a constant production amount in vivo was used as an internal standard, and the ratio of the band intensity of LC3-II to the band intensity of GAPDH was calculated and standardized.
FIG. 2 shows the expression level of LC3-II standardized by the internal standard GAPDH. The LC3-II expression level in the non-additive cells was set to "1", and the relative values of various cells with respect to this were determined.
From FIG. 2, the LC3-II band intensity increased in the group to which 1, 10, 100 μg / mL safflower extract was added, as compared with the group to which no addition was added. Moreover, it was confirmed that the band strength was further increased by the addition of CQ.

Example 3
Human epidermal fibroblasts (derived from newborns) (hereinafter referred to as NHDF) were seeded in a 6-well plate, and DMEM medium (Thermo Fisher Scientific) supplemented with 10% fetal bovine serum, 1% penicillin / streptomycin, and 1% L-glutamine. Incubated overnight at 37 ° C. _{under 5% CO 2 (manufactured by FIC).}
Quercetin-7-glucoside was added to the medium at 0.05, 0.5, 5 μg / mL, and the cells were cultured for 24 hours. At the same time, for autophagy flux analysis, the safflower extract was similarly added and cultured for 8 hours, then chloroquine (hereinafter, CQ), which is a lysosome inhibitor, was added to a concentration of 5 μM, and the cells were further cultured for 16 hours. The cultured cells were collected with RIPA buffer (manufactured by Millipore), and a sample for SDS-PAGE was prepared using SDS sample buffer.
The amount of LC3-II, which is a marker protein for autophagy, was measured by Western blotting using an LC3 antibody (manufactured by Cell Signaling Technology). Image analysis software ImageJ was used to measure the band intensity. When the band intensity of LC3-II was comparatively quantified, GAPDH having a constant production amount in vivo was used as an internal standard, and the ratio of the band intensity of LC3-II to the band intensity of GAPDH was calculated and standardized.
FIG. 3 shows the expression level of LC3-II standardized by the internal standard GAPDH. The LC3-II expression level in the non-additive cells was set to "1", and the relative values of various cells with respect to this were determined.
From FIG. 3, the LC3-II band intensity increased in the group to which 0.05, 0.5, 5 μg / mL of quercetin-7-glucoside was added, as compared with the group to which no addition was added. Moreover, it was confirmed that the band strength was further increased by the addition of CQ.

Hereinafter, specific formulations of the composition containing the agent of the present invention will be illustrated.

Formulation Example 1: Toner A lotion having the following composition is produced according to the following preparation method.
The following ingredients are prescribed so that the total is 100% by weight. All the ingredients are mixed and stirred at room temperature to make a uniform solution, and the pH is adjusted to 5.5 to obtain a lotion.
Ingredient weight%
Concentrated glycerin 4.0
Sorbitol 4.0
Sodium citrate 0.3
Polyoxyethylene hydrogenated castor oil 0.5
Safflower extract 0.1
Ethanol 15.0
Fragrance 0.005
Citric acid Appropriate amount of purified water Remaining

Formulation Example 2: Facial cleansing cream A facial cleansing cream having the following composition is produced according to the following preparation method.
Each component A to C is formulated in the following proportions so that the total of component A, component B and component C is 100% by weight. First, the mixture of component A is heated and dissolved and kept at 80 ° C. Then, a mixture of component B separately heated and dissolved at 80 ° C. is added to the mixture of component A, and the mixture is sufficiently stirred. Then, the mixture is cooled with stirring, and a mixture of component C is added at 50 ° C. to obtain a facial cleansing cream.
"Ingredient A"
Ingredient weight%
Myristic acid 14.0
Stearic acid 12.0
Lauric acid 3.5
Oleyl alcohol 1.5
Palm fat fatty acid amide propyl betaine 10.5
"Ingredient B"
Ingredient weight%
Concentrated glycerin 18.0
Potassium hydroxide 7.0
Paraoxybenzoic acid ester Appropriate amount of purified water Remaining "Component C"
Ingredient weight%
Safflower extract 0.1
Appropriate amount of fragrance

Formulation Example 3: Emulsion An emulsion having the following composition is produced according to the following preparation method.
Each component D to F is formulated in the following proportions so that the total of component D, component E and component F is 100% by weight. First, the mixture of component D is heated and dissolved and kept at 80 ° C. Then, the mixture of the component E separately heated and dissolved at 80 ° C. is added to the mixture of the component D, and the mixture is sufficiently stirred. Then, cooling is performed with stirring, and a mixture of component F is added at 50 ° C. to obtain a milky lotion.
"Component D"
Ingredient weight%
Sucrose fatty acid ester 1.0
Carboxyvinyl polymer 0.06
Potassium hydroxide 0.028
Paraoxybenzoic acid ester Appropriate amount of purified water Remaining "Component E"
Ingredient weight%
Olive oil 4.0
Jojoba oil 4.0
Myristyl Lactate 2.0
Self-emulsifying glycerin monostearate 1.5
Lipophilic glycerin monostearate 1.5
"Component F"
Ingredient weight%
Safflower extract 0.1
Fragrance 0.2

The agent of the present invention can be used as an autophagy inducer or the like.

Claims (15)

An autophagy inducer containing a quercetin glycoside. An anti-aging agent containing a quercetin glycoside. An autophagy inducer containing safflower ingredients. An anti-aging agent containing safflower ingredients. The agent according to claim 3 or 4, wherein the safflower component is a safflower extract containing a quercetin glycoside. The agent according to any one of claims 1 to 5, wherein the quercetin glycoside or safflower component contains quercetin-7-glucoside. The agent according to any one of claims 3 to 6, wherein the safflower component is an extract of safflower containing at least safflower leaves. The agent according to any one of claims 3 to 7, wherein the safflower component is a safflower extract of a solvent containing at least alcohol. The agent according to any one of claims 3 to 8, wherein the safflower component contains quercetin-7-glucoside in a proportion of 0.03% by mass or more. The agent according to any one of claims 1 to 9, which is used for preventing and / or improving skin aging. A composition containing the agent according to any one of claims 1 to 10. The composition according to claim 11, which is used for preventing and / or ameliorating skin aging. The composition according to claim 11 or 12, which contains quercetin-7-glucoside in a proportion of 0.00003% by mass or more. The composition according to any one of claims 11 to 13, which is for cosmetics. The agent or composition according to any one of claims 1 to 14, for inducing autophagy on epidermal keratinized cells and / or fibroblasts.

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