WO2020080316A1 - Ecm cycle normalizer - Google Patents

Abstract

[Problem] The purpose of the present invention is to provide a novel ECM cycle normalizer. [Solution] The technical features of the present invention for solving the above problem are as follows. 1. A normalizer of the collagen production and uptake cycle in skin fibroblasts, the normalizer having lycoperoside A as an active ingredient. 2. A normalizer of the elastin production and uptake cycle in skin fibroblasts, the normalizer having lycoperoside A as an active ingredient. 3. A normalizer of the ECM cycle in skin fibroblasts, the normalizer having lycoperoside A as an active ingredient.

Description

ECM cycle normalizer

The present invention relates to a normalizing agent for the production and uptake cycle of extracellular matrix components. INDUSTRIAL APPLICABILITY The present invention is widely used for foods, drugs, external preparations for skin and the like.

Tomato (Solanum lycopersicum) is a plant that is eaten daily in the world, and it is sold as a juice or supplement because it contains abundant ingredients such as vitamin C, lycopene, and GABA. As the functionality of tomato, a blood pressure lowering action and a cholesterol lowering action have been reported. In 2004, a new saponin esculeoside was identified from tomato (Non-patent Document 1 and Non-patent Document 2). Among them, esculeoside A was found to improve hyperlipidemia and arteriosclerosis in mice. (Non-Patent Document 3). However, these are all findings in tomato fruits, and there are few reports limited to tomato seeds.

On the other hand, collagen is a major constituent of the extracellular matrix in the skin and plays an important role in maintaining the elasticity and firmness of the skin. Elastin is mentioned as a major constituent factor of extracellular matrix other than collagen, and elastin is an important factor for maintaining skin elasticity like collagen. It is known that collagen and elastin are produced by fibroblasts, and their degradation products undergo a cycle of being absorbed again by fibroblasts. However, it is known that abnormalities occur in this cycle and accumulation of degradation products causes alteration of cell morphology and increase of oxidative stress in skin. Therefore, it is considered that maintaining normal production / degradation cycles of collagen and elastin constituting extracellular matrix is very important for maintaining normal skin condition.

Therefore, in order to maintain the normal production / degradation cycle of collagen and elastin constituting the extracellular matrix, lysosome is an organelle that has the action of absorbing the degradation product again into fibroblasts (Patent Document 1).
Lysosomes are one of the organelles of eukaryotes, and are the sites of intracellular digestion with hydrolases inside. Biopolymers taken into the membrane by endocytosis or autophagy are decomposed in lysosomes, useful ones of the decomposed substances are absorbed into the cytoplasm and reused, and unnecessary substances are discarded to the outside by exocytosis. Or, they remain in the cell as residual bodies.

It is known that the activity of lysosome is involved in various diseases. A lysosomal storage disease is known as a typical disease. The lysosomal storage disease is often caused by a deficiency or mutation of a hydrolase that acts in the lysosome, and the substrate of the enzyme is not decomposed but accumulates in the cell as a deposit. Lysosomal storage diseases have a wide range of clinical heterogeneity and biological diversity and include lipid storage diseases, mucopolysaccharidosis, mucolipidosis, and glycoprotein storage diseases (see Patent Documents 2 and 3). .

On the other hand, it is known that a whitening effect can be obtained by improving the lysosomal activity in keratinocytes and promoting the degradation of melanosomal proteins (Patent Document 4, Non-Patent Documents 4 and 5).

Further, cathepsin B1 and D, which are enzymes in lysosome, decompose collagen (Non-patent document 6), hyaluronic acid is taken into and decomposed in lysosome (Non-patent document 7), and it is compared with the skin of young people. It is known that the amount of fragmented collagen is significantly large in the skin of the elderly (Non-patent document 8).
Lysosomes are composed of more than 100 kinds of lysosomal membrane proteins, and most of them are highly glycosylated toward the lumen side. These sugar chain modifications are considered to be important in order to escape the action of hydrolases. Major lysosomal membrane proteins include LAMP-1, LAMP-2, and LIMP-2, which account for 50% or more of the total lysosomal membrane protein amount (Non-Patent Document 9).
Therefore, by evaluating the amount of these lysosomal membrane proteins in the cell, the amount of lysosome in the cell can be known. Thus, the amount of LAMP-1 in the cell serves as an indicator of the amount of lysosome.

JP 2017-206468 JP Japanese Patent Publication No. 2014-517015 Japanese Patent Publication No. 2014-523881 JP, 2015-10071, A

However, little research has been done on the cycle of production, degradation, and uptake of extracellular matrix components (ECM) such as collagen and elastin.
Under the above background, the present inventor relates to genes relating to the production of collagen and elastin, which are the main components of ECM, and the intracellular uptake of degraded collagen and elastin for tomato seed extract and saponin contained therein. It has been found that it has the function of promoting the expression of both genes.
Moreover, as a result of promoting collagen production in skin fibroblasts and evaluating the amount of lysosomes in skin fibroblasts using LAMP-1 as an index, it was found that it has an action of increasing lysosomes in skin fibroblasts. .
It was found that this has the effect of normalizing the cycle of ECM production and uptake (hereinafter referred to as "ECM cycle"), and finally maintaining homeostasis of extracellular matrix, and completed the present invention.
That is, the present invention aims to provide a novel ECM cycle normalizing agent.

The technical features of the present invention for solving the above problems are as follows.
1. A smad gene expression promoter in skin fibroblasts containing lycoperoside A as an active ingredient.
2. An agent for promoting endo180 gene expression in skin fibroblasts containing lycoperoside A as an active ingredient.
3. An agent for promoting endo180 gene expression in skin fibroblasts, which comprises a tomato seed extract as an active ingredient.
4. Above 1. ~ Above 3. A collagen production / uptake cycle normalizing agent in dermal fibroblasts, which comprises the agent of any one of 1.
5. A fiblin gene expression promoter in skin fibroblasts containing lycoperoside A as an active ingredient.
6. A neuraminidase-1 gene expression promoter in dermal fibroblasts containing lycoperoside A as an active ingredient.
7. The above 5. Alternatively, the above 6. Elastin production / uptake cycle normalizing agent in dermal fibroblasts containing the agent as an active ingredient.
8. An agent for promoting collagen production in skin fibroblasts, which comprises a tomato seed extract as an active ingredient.
9. A lysosome-increasing agent in skin fibroblasts containing tomato seed extract as an active ingredient.
10. A lysosomal enhancer in skin fibroblasts containing lycoperoside A as an active ingredient.
11. A lysosome-increasing agent in skin fibroblasts containing lycoperoside H as an active ingredient.
12. Above 1. ~ Above 11. An agent for normalizing ECM cycle in dermal fibroblasts, which comprises the agent of any one item selected from:
13. ECM cycle normalizing agent in dermal fibroblasts containing lycoperoside A as an active ingredient.
14. An ECM cycle normalizing agent in dermal fibroblasts containing a tomato seed extract as an active ingredient.
15. A method for normalizing the ECM cycle in human dermal fibroblasts by administering to a human an effective amount of one or more members selected from the group consisting of tomato seed extract, lycoperoside A and lycoperoside H.
16. A method for increasing lysosomes in human dermal fibroblasts by administering to a human an effective amount of one or more members selected from the group consisting of tomato seed extract, lycoperoside A and lycoperoside H.

The smad gene expression promoter of the present invention is not contained in the pulp, but lycoperoside A, which is a saponin contained only in tomato seeds, promotes the expression of the smad gene involved in collagen production. Lycoperoside A which is a component of lycoperoside has an action of promoting the production of collagen.
Further, the endo180 gene expression promoter of the present invention, lycoperoside A promotes the expression of the endo180 gene involved in the uptake of degraded collagen into cells, so that lycoperoside A is degraded into intracellular cells of collagen. It has the effect of promoting uptake.
As a result, lycoperoside A promotes both the smad gene, which is involved in collagen production, and the endo180 gene, which is involved in intracellular uptake of degraded collagen, and thus normalizes the collagen production / uptake cycle. Have an effect. Therefore, lycoperoside A has an excellent effect as a collagen production / uptake cycle normalizing agent.
Further, the fiblin gene expression promoting agent of the present invention, lycoperoside A, because it promotes the expression of the fiblin gene involved in the production of elastin, a component specific to tomato seeds, lycoperoside A has the action of promoting the production of elastin. Have.
And, the neuraminidase-1 gene expression promoter of the present invention, lycoperoside A promotes the expression of the neuraminidase-1 gene involved in the uptake of decomposed elastin into cells, so that lycoperoside A is decomposed elastin It has the effect of promoting uptake into cells.
As a result, lycoperoside A promotes both the fiblin gene, which is involved in the production of elastin, and the neuraminidase-1 gene, which is involved in the uptake of degraded elastin into the cell, and therefore the elastin production / uptake cycle is normal. Has the effect of Therefore, lycoperoside A has an excellent effect as an elastin production / uptake cycle normalizing agent.
Further, in the present invention, lycoperoside A and tomato seed extract have excellent effects as a collagen production promoter.
In addition, lycoperoside A, lycoperoside H, and tomato seed extract have an action of increasing LAMP-1, which is one of the membrane proteins constituting lysosomes in skin dermal fibroblasts. As a result, lycoperoside A, lycoperoside H, and tomato seed extract have the effect of increasing lysosomes in skin dermal fibroblasts.
This has the effect of promoting the uptake of intracellular matrix components.
As described above, lycoperoside A has the effect of normalizing both the production and uptake cycles of collagen and elastin, and therefore has the effect of normalizing the production and uptake of extracellular matrix components. Has excellent effect.

It is a graph which shows the effect of the tomato seed extract and saponin of this Example on the collagen production. It is a graph which shows the effect on the smad gene expression level of the tomato seed extract and saponin of this Example. It is a graph which shows the effect of the tomato seed extract and saponin of this example on the endo180 gene expression level. 3 is a graph showing the effects of the tomato seed extract and saponin of this Example on the expression level of fiblin-4 gene. 3 is a graph showing the effects of the tomato seed extract and saponin of this Example on the expression level of neuraminidase-1 gene. 3 is a photograph showing the effects of tomato seed extract and seed saponin on LAMP-1 levels in skin fibroblasts. White represents LAMP-1. It is a fluorescent immunostaining image (3D image) of the extracellular matrix degradation product accumulated in the cell sheet. Cylindrical or rounded ones are cell nuclei, and haze-like ones between them are extracellular matrix degradation products. It is a graph which shows the effect on the Endo180 gene expression in the cell sheet of a tomato seed extract and a lycoperoside. 2 is a graph showing the effects of tomato seed extract and lycoperosides on the expression of Neuraminidase-1 gene in cell sheets.

The present invention will be described in detail below.
The ECM cycle normalizing agent of the present invention is characterized by containing lycoperoside A as an active ingredient.
Lycoperoside A is a saponin represented by the following chemical formula (1).

A method for obtaining lycoperoside A is not particularly limited, but a method of extracting and purifying from lycoperoside A is particularly preferable.
When lycoperoside A is extracted from a plant, its raw material is not particularly limited, but tomato is particularly preferably used. This is because it contains lycoperoside A in a high concentration.
When obtaining lycoperoside A from tomato, tomato seeds are used as the site. This is because lycoperoside A is not contained in the flesh or skin of tomato, but only in the seeds of tomato.

When solvent extraction is performed as an extraction method, the extraction solvent for obtaining the extract is, for example, water, a lower monohydric alcohol (methyl alcohol, ethyl alcohol, 1-propanol, 2-propanol, 1-butanol, 2- Butanol, etc.), liquid polyhydric alcohol (glycerin, propylene glycol, 1,3-butylene glycol, etc.), lower ester (ethyl acetate, etc.), hydrocarbon (benzene, hexane, pentane, etc.), ketones (acetone, methyl ethyl ketone, etc.) , Ethers (diethyl ether, tetrahydrofuran, dipropyl ether, etc.), acetonitrile and the like, and one or more of them can be used.

An example of a preferable extraction method is a method of using water-containing ethanol or water-containing methanol having a concentration of 0 to 100% (v / v) at room temperature or after heating for 1 to 10 hours for extraction, followed by filtration. Can be mentioned.

As a purification method, the tomato seed extract obtained by the above method was sequentially partitioned and extracted with ethyl acetate and n-butanol, followed by silica gel chromatography, column chromatography, etc. to obtain lycoperoside A (ECM cycle). Normalizing agent) can be obtained.

As a specific method for obtaining lycoperoside A from tomato seeds, the method according to the example of the present specification is preferable.

The collagen production promoter of the present invention is characterized by containing a tomato seed extract or lycoperoside A as an active ingredient.
The above can be manufactured by the method described above.

The ECM cycle normalizing agent of the present invention can be used as a material for various food and drink compositions. Examples of food and drink include confectionery (gum, candy, caramel, chocolate, cookie, snack, jelly, gummy, tablet confectionery), noodles (soba, udon, ramen, etc.), dairy products (milk, ice cream, yogurt). Etc.), seasonings (miso, soy sauce, etc.), soups, beverages (juice, coffee, tea, tea, carbonated drinks, sports drinks, etc.), health foods (tablets, capsules, etc.), nutrition Supplementary foods (nutritive drinks, etc.) Foods with functional claims and foods for specified health use are listed. It is advisable to appropriately add the ECM cycle normalizing agent of the present invention to these foods and drinks.

These food and drink compositions can be blended with various components depending on the type, for example, glucose, fructose, sucrose, maltose, sorbitol, stevioside, corn syrup, lactose, citric acid, tartaric acid, apple. 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, Food materials such as gum arabic, carrageenan, casein, gelatin, pectin, agar, vitamin Bs, nicotinic acid amide, calcium pantothenate, amino acids, calcium salts, pigments, flavors and preservatives can be used.

As a specific production method, an ECM cycle normalizing agent is spray-dried or freeze-dried together with powdered cellulose, and this is made into powder, granules, tablets or a solution, and easily contained in foods and drinks (instant foods, etc.). You can Further, the ECM cycle normalizing agent can be dissolved in, for example, fats and oils, ethanol, glycerin, or a mixture thereof to form a liquid, and then added to a beverage or a solid food. If necessary, it may be mixed with a binder such as gum arabic or dextrin into a powder or granules and added to a beverage or a solid food.

When the ECM cycle normalizing agent of the present invention is applied to foods and drinks, the main purpose is to maintain health and beauty. Therefore, the total amount of active ingredients in foods and drinks should be 1 to 20 wt% or less. Preferably.

The ECM cycle normalizing agent of the present invention may be used as a material for a pharmaceutical composition (including a drug and a quasi drug). The ECM cycle normalizing agent of the present invention can be appropriately added to the raw material for the pharmaceutical preparation to produce the drug. Examples of the drug substance that can be added to the ECM cycle normalizing agent of the present invention include excipients (glucose, lactose, sucrose, sodium chloride, starch, calcium carbonate, kaolin, crystalline cellulose, cocoa butter, hydrogenated vegetable oil, kaolin, Talc, etc.), binder (distilled water, physiological saline, ethanol water, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.), disintegrant (sodium alginate, agar, carbonic acid) Sodium hydrogen, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, gum arabic powder, gelatin, ethanol, etc.), disintegration inhibitor (sucrose, stearin, cacao butter, hydrogenated oil, etc.), absorption enhancer (No. Quaternary ammonium base, sodium lauryl sulfate Um, etc.), adsorbents (glycerin, starch, lactose, kaolin, bentonite, silicic acid, etc.), lubricants (purified talc, stearates, polyethylene glycol, and the like) and the like.

The ECM cycle normalizing agent of the present invention can be generally administered orally in the form of tablets, pills, soft / hard capsules, fine granules, powders, granules, liquids and the like. Alternatively, it may be administered parenterally. When administered as a parenteral agent, it may be administered in a tissue state, intradermally, subcutaneously, intramuscularly or intravenously, or in the form of a solution or a dispersion, suspension, stabilizer, etc. it can. Further, it may be in the form of a suppository or the like.

The dose may vary depending on the administration method, medical condition, age of the patient, etc., but for adults, it is usually 0.5 to 5000 mg as an active ingredient per day, and for children, it is usually about 0.5 to 3000 mg.
The blending ratio of the ECM cycle normalizing agent can be appropriately changed depending on the dosage form. Normally, it is about 0.3 to 15.0 wt% when administered orally or by mucosal absorption, and when parenterally administered. Is preferably 0.01 to 10 wt%. Since the dose varies depending on various conditions, a dose smaller than the above dose may be sufficient in some cases, or a dose exceeding the range may be required in some cases.

The ECM cycle normalizing agent of the present invention can be expected to have an ECM cycle normalizing action even when used as a skin external preparation (including cosmetics, pharmaceuticals and quasi drugs).
The form of the external preparation for skin in which the ECM cycle normalizing agent of the present invention can be mixed is, for example, emulsion, soap, facial cleanser, bath agent, cream, emulsion, lotion, cologne, shaving cream, shaving lotion. , Cosmetic oil, suntan / sunblock lotion, powder, foundation, perfume, pack, nail cream, enamel, enamel remover, eyebrow, blusher, eye cream, eye shadow, mascara, eyeliner, lipstick, lip balm, shampoo, Examples include rinses, hair dyes, dispersions, and cleaning agents. In addition, examples of the form of the drug or quasi drug to which the ECM cycle normalizing agent of the present invention can be added include ointments, creams, external preparations and the like.

The external preparation for skin of the above-mentioned form includes, in addition to the ECM cycle normalizing agent according to the present invention, components and oil components to be added to the external preparation for skin such as cosmetics and quasi drugs within a range not impairing the ECM cycle normalizing action. , Higher alcohols, fatty acids, ultraviolet absorbers, powders, pigments, surfactants, polyhydric alcohols / sugars, polymers, physiologically active ingredients, solvents, antioxidants, fragrances, 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 diisopropylate, neopentanoic acid isoaralkyl, tri (capryl / capric acid) glyceryl, tri-2-ethylhexanoate trimethylolpropane, triisostearate trimethylol Propane, pentaerythritol tetra-2-ethylhexanoate, cetyl caprylate, decyl laurate, hexyl laurate, decyl myristate, myristyl myristate, cetyl myristate, stearyl stearate, decyl oleate, cetyl ricinoleate, isolaurate Stearyl, isotridecyl myristate, isocetyl myristate, isostearyl myristate, isocetyl palmitate, isostearyl palmitate, octyl stearate, isocetyl stearate, isodecyl oleate, octyldodecyl oleate, octyl dodecyl linoleate, isopropyl isostearate, 2-ethylhexanoate cetostearyl, 2-ethylhexanoate stearyl, hexyl isostearate, dioctanoic acid ethylene glycol , 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, triisolate Glyceryl palmitate, glyceryl triisostearate, octyldodecyl neopentanoate, isostearyl octanoate, octyl isononanoate, hexyldecyl neodecanoate, octyldodecyl neodecanoate, isostearyl isostearate, isostearyl isostearate, octyldecyl isostearate, polyglycerin olein Acid ester, polyglycerin isostearic acid ester, dipropyl carbonate, charcoal Dialkyl (C12-18), triisocetyl citrate, triisoaralkyl citrate, triisooctyl citrate, lauryl lactate, myristyl lactate, cetyl lactate, octyl decyl lactate, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, Trioctyl citrate, diisostearyl malate, 2-ethylhexyl hydroxystearate, di2-ethylhexyl succinate, diisobutyl adipate, diisopropyl sebacate, dioctyl sebacate, cholesteryl stearate, cholesteryl hydroxystearate, cholesteryl hydroxystearate, olein. Cholesteryl acidate, dihydrocholesteryl oleate, phytosteryl isostearate, phytosteryl oleate, 12-stearoyl hydroxystearate a Cetyl, 12-stearoyl-hydroxystearic acid stearyl 12-stearoyl-hydroxystearic acid isostearate, and the like.
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 hardened 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 , Vegetable oils such as sunflower oil, grape seed oil, jojoba oil, hydrogenated jojoba oil, macadamia nut oil, medhome oil, cottonseed oil, hydrogenated cottonseed oil, coconut oil, hydrogenated coconut oil and their hardening , Beeswax, high acid value beeswax, lanolin, reduced lanolin, hydrogenated 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 UV 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-paraparamethoxycinnamate Glyceryl ethylhexanoate, isopropyl paramethoxycinnamate, paramethoxyhydrocinnamic acid diethanolamine salt, diisopropyl diisopropylcinnamate Stell 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) can Full, isopropyldibenzoylmethane, 4- (3,4-dimethoxyphenylmethylene) -2, 5-dioxo-1-imidazolidine 2-ethylhexyl propionate and the like, and polymer derivatives and silane derivatives of these are included.

(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 blue and dark blue, white pigments such as zinc oxide, titanium oxide and cerium oxide, body pigments such as talc, mica, sericite, kaolin and barium sulphate, titanium mica. Pearl pigments such as, barium sulfate, calcium carbonate, magnesium carbonate, aluminum silicate, metal salts such as magnesium silicate, Rica, inorganic powder such as alumina, aluminum stearate, magnesium stearate, zinc palmitate, zinc myristate, magnesium myristate, zinc laurate, zinc undecylenate, and other metal soaps, bentonite, smectite, boron nitride and the like. To be 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 diameter 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 and the like.

(6) Examples of surfactants Anionic surfactants: fatty acid soap, α-acylsulfonate, alkylsulfonate, alkylallylsulfonate, alkylnaphthalenesulfonate, 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 Sodium, acylated hydrolyzed collagen peptide salt, perfluoroalkyl phosphate ester and the like can be mentioned.
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 surfactants: lecithin, saponin, sugar-based surfactants 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, NSC), methyl vinyl ether maleic acid half ester (Gantrez ES, ISP), T-butyl acrylate / ethyl acrylate / methacrylic acid copolymer (Rubimer , BASF), vinylpyrrolidone / vinyl acetate / vinyl propionate copolymer (Rubiscol 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, BA SF), acrylate / acrylamide copolymer (Ultrahold, BASF), vinyl acetate / butyl maleate / isobornyl acrylate copolymer (Advantage, ISP), carboxyvinyl polymer (Carbopol, BF Goodrich), an acrylic acid / alkyl methacrylate copolymer (Pemulene, manufactured by BF Goodrich), an anionic polymer compound, an acetic acid amphoteric dialkylaminoethyl methacrylate polymer (Yukaformer, manufactured by Mitsubishi Chemical), Amphoteric polymer compounds such as octyl acrylamide acrylate / hydroxypropyl acrylate / butylaminoethyl methacrylate copolymer (AMPHOMER, NSC), quaternary vinylpyrrolidone / dimethylaminoethyl methacrylate (GAFQUAT, ISP) , Methyl vinyl imidazolium chloride Cationic polymer compounds such as de / vinylpyrrolidone copolymer (Rubicoat, manufactured by BASF), polyvinylpyrrolidone (Rubiscor K, manufactured by BASF), vinylpyrrolidone / vinyl acetate copolymer (Rubiscor VA, manufactured by BASF) ), Vinylpyrrolidone / dimethylaminoethylmethacrylate copolymer (Copolymer 937, ISP), vinylcaprolactam / vinylpyrrolidone / dimethylaminoethylmethacrylate copolymer (Copolymer VC713, ISP), etc. There is. In addition, 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, gum arabic, 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 activating agent, an enzyme component and the like are included. 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, sagebrush extract, licorice extract, karkade extract, oyster extract, kina extract, cucumber extract, guanosine, gardenia extract, kumazasa extract, clarae Kiss, walnut extract, grapefruit extract, clematis extract, chlorella extract, mulberry extract, gentian extract, tea extract, yeast extract, burdock extract, rice bran extract, rice germ oil, comfrey extract, collagen, cowberry extract, cinnamon extract, psycho extract. , Saitai extract, salvia extract, sapon extract, sasa extract, hawthorn extract, hawthorn extract, shiitake extract, dio extract, shikon extract, perilla extract, linden extract, spirea extract, peony extract, ginger root extract, birch extract, horse mackerel extract, horseradish extract. Witch extract, hawthorn extract, Sambucus nigra extract, yarrow extract, mint extract, sage extract, mallow extract, senki Ginseng extract, senburi extract, soybean extract, turmeric extract, thyme extract, tea extract, clove extract, chigaya extract, chimpi extract, touki extract, quince extract, tonin extract, spruce extract, dokudami extract, tomato extract, natto extract, carrot extract, garlic extract, Novara extract, Hibiscus extract, Bakumondo extract, Parsley extract, Honey, Hamamelis extract, Parietaria extract, Hikikoshi extract, Bisabolol, Loquat extract, Fukitampo extract, Fukinoto extract, Bukurou extract, Butcher bloom extract, Grape extract, Propolis, Loofah extract, Safflower extract, peppermint extract, bodaiju extract, button extract, hop extract, pine extract, horse chestnut extract, hornbill Kiss, Mucrose extract, Melissa extract, Peach extract, Cornflower extract, Eucalyptus extract, Yukinoshita extract, Yokuinin extract, Artemisia extract, Lavender extract, Apple extract, Lettuce extract, Lemon extract, Forsythia extract, Rose extract, Rosemary extract, Roman chamomile extract , Royal jelly extract and the like.
In addition, biopolymers such as deoxyribonucleic acid, mucopolysaccharide, sodium hyaluronate, sodium chondroitin sulfate, collagen, elastin, chitin, chitosan, hydrolyzed egg shell membrane, amino acids, hydrolyzed peptides, sodium lactate, urea, sodium pyrrolidonecarboxylate. , Betaine, whey, moisturizing components such as trimethylglycine, sphingolipids, ceramides, phytosphingosine, cholesterol, cholesterol derivatives, oil components 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, nicotinamide, vitamin C ester Vitamins, allantoin, diisopropylamine dichloroacetate, active ingredients such as 4-aminomethylcyclohexanecarboxylic acid, tocopherols, carotenoids, flavonoids, tannins, lignans, saponins and other antioxidants, α-hydroxy acids, β-hydroxy acids, etc. Cell enhancer, γ-oryzanol, blood circulation promoter such as vitamin E derivative, retinol, wound healing agent such as retinol derivative, arbutin, kojic acid, placenta extract, sulfur, ellagic acid, linoleic acid, tranexamic acid, glutathione, etc. Whitening agent, 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-pan Totenyl alcohol, acetylpantothenyl ethyl ether, biotin, allantoin, isopropylmethylphenol, estradiol, ethinyl estradiol, capronium chloride, benzalkonium chloride, diphenhydramine hydrochloride, tacanal, camphor, salicylic acid, nonyl acid vanillyl amide, nonanoic acid 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, monostearate Examples include hair-growing agents such as polyoxyethylene sorbitan, peppermint oil, and Sasanishiki extract.

(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, apple extracts, and plant extracts having an antioxidant effect.

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

The collagen production promoter of the present invention can be used as a raw material for food and drink compositions, pharmaceutical compositions, and external skin preparations.
As the drug substance which can be added to these, the same ones as those used for the above-mentioned ECM cycle normalizing agent can be used, and the manufacturing method and administration method can be the same as those for the ECM cycle normalizing agent. it can.

Hereinafter, the present invention will be described based on examples.
Example 1: Preparation of tomato seed extract and isolation and identification of saponin component from tomato seed 367.7 g of dried tomato seed was extracted with methanol (70 ° C, 2 hours) to obtain a methanol extract. The obtained methanol extract was dispersed in water, and partitioned and extracted sequentially with ethyl acetate and n-butanol. Ethyl acetate-soluble part (ethyl acetate fraction) 0.63 g, n-butanol-soluble part (butanol fraction) 2.41 g and 5.05 g of water-soluble part (water fraction) were obtained. Then, of these, the butanol fraction was used as the tomato seed extract of this example. Then, the butanol fraction was subjected to silica gel chromatography (chloroform: methanol = 9: 1 → 7: 3 → chloroform: methanol: water = 6: 4: 1 → methanol) to obtain Fr. 1 to 6. Fr. 3 (1.1 g) was subjected to reverse phase ODS column chromatography (methanol concentration 20% → 50% → 80% → 100%) to obtain Fr.3-1 to Fr.3-4. A saponin compound, lycoperoside A (above chemical formula (1)) (7.0 mg) and H (following chemical formula (2), from Fr.3-3 (mg) by reverse phase HPLC preparative (Inertsil ODS-SP, 70% methanol) ) (7.5 mg) was isolated. Each compound was identified by comparing its 1 H-NMR (600 MHz) and 13 C-NMR (150 MHz) spectra with literature values.

Test Example 1-1: Effect of tomato seed extract and saponin on collagen production Human skin fibroblasts (TIG-103) were seeded in a 24-well plate at a cell concentration of 1.0 × 10 ⁴ cells / well and cultured for 2 days. did. The butanol fraction (1, 3 and 10 μg / mL) of the methanol extract of tomato seed extract and lycoperoside A and H (0.1, 0.3 and 1.0 μg / mL) were added to the cells after culturing, and the cells were cultured for 1 day. After the addition culture, the medium from which the medium was removed was homogenized with PBS, and the amount of collagen in the cell layer was measured using the obtained cell suspension using a Collagen assay kit (Cosmo Bio). In addition, toxicity evaluation by MTT assay was also performed. The result is shown in FIG.

Results and Effect of Example in Test Example 1-1 As shown in FIG. 1, the amount of collagen produced was significantly increased in cells to which butanol fraction (3 μg / mL) and lycoperoside A (0.3 and 1 μg / mL) were added. Was found to be increasing. Further, no cytotoxicity due to addition of the sample was observed. From this, it was confirmed that tomato seed extract and lycoperoside A are useful as collagen production promoters.

Test Example 1-2: Effect of tomato seed extract and seed saponin on intracellular lysosome amount Human skin fibroblasts (TIG-103) were seeded in a 48-well plate at a cell concentration of 1.0 × 10 ⁵ cells / well, and 1 Cultured for a day. The n-butanol fraction (3 μg / mL) of the methanol extract of tomato seed extract, lycoperoside A and H (10 μM) were added to the cultured cells, and the cells were cultured for 2 days. After the addition culture, the cells from which the medium was removed were fixed with 4% paraformaldehyde / PBS, and the localization and abundance of LAMP-1 in the cells were confirmed by a microscope by a fluorescent immunostaining method.

Results and effects relating to Test Example 1-2 As a result, compared to the control without addition of sample, LAMP-in the cells by addition of n-butanol fraction (3 μg / mL), lycoperoside A and H (10 μM). It was found that the amount of 1 increased (Fig. 6). The increase due to the addition of lycoperoside A was particularly remarkable. In addition, in FIG. 6, white indicates LAMP-1.
From these results, it was confirmed that tomato seed extract and lycoperoside A and H contained in it increased the amount of lysosomes that take up and decompose waste products in the extracellular matrix of skin dermis.

Results and Effects of Examples for Test Examples 1-1 and 1-2 As described above, the tomato seed extract and lycoperoside A promote collagen production and are a lysosome responsible for uptake and degradation of waste products in the extracellular matrix of the skin dermis. It was found that there is an action to normalize the ECM cycle and keep the extracellular matrix normal by increasing the amount of E.

Test Example 2: Effects of tomato seed extract and saponin on extracellular matrix homeostasis Human dermal fibroblasts (TIG-103) were seeded in a 12-well plate at a cell concentration of 1.0 × 10 ⁵ cells / well, and for 1 day. Cultured. The butanol fraction (1, 3 and 10 μg / mL) of the methanol extract of tomato seed extract and lycoperoside A and H (1, 3 and 10 μM) were added to the cells after culturing, and the cells were cultured for 2 days. RNA was extracted from the cultured cells, and the expression level of each gene (smad gene, endo180 gene, fiblin gene, neuraminidase-1 gene) was evaluated by the real-time RT-PCR method.
The results are shown in FIG. 2 (smad gene), FIG. 3 (endo180 gene), FIG. 4 (fiblin-4 gene) and FIG. 5 (neuraminidase-1 gene).

Results and Effect of Example in Test Example 2 As shown in FIG. 2, the expression of the smad gene involved in collagen production was significantly increased by the addition of lycoperoside A (3 and 10 μM), and is shown in FIG. As described above, it was confirmed that the endo180 gene involved in the uptake of degraded collagen was significantly increased in expression by addition of the butanol fraction (1 μg / mL) and addition of lycoperoside A (3 μM). From this, it was confirmed that lycoperoside A is useful as a smad gene expression promoter and an endo180 gene expression promoter, and as a collagen production / uptake cycle normalizing agent.
Moreover, as shown in FIG. 4, the expression of the fiblin gene involved in the production of elastin was significantly increased by the addition of lycoperoside A (10 μM). Then, as shown in FIG. 5, the expression of the neuraminidase-1 gene involved in the incorporation of the elastin degradation product was significantly increased by the addition of lycoperoside A (3 μM). From this, it was confirmed that lycoperoside A is useful as a fiblin gene expression promoter and neuraminidase-1 gene expression promoter, and as a elastin production / uptake cycle normalizing agent.

Test Example 3: Evaluation of ECM cycle normalizing action of tomato seed extract and seed saponin in the state of forming extracellular matrix Human dermal fibroblasts (TIG-103) were used as a temperature-responsive cell culture device (UpCell) for collecting cell sheets. : Registered trademark, manufactured by Cell Seed Co., Ltd.) and cultured for 2 weeks until the cells adhered to each other to form a sheet. After forming the cell sheet, collagen tripeptide (H-Gly-Pro-Hyp-OH) was added as a extracellular matrix degradation product at a final concentration of 200 μM. At the same time, n-butanol fractions (1, 3 and 10 μg / mL) of methanol extract of tomato seed extract, lycoperoside A and H (0.1, 0.3 and 1.0 μM) were added, and the cells were cultured for 2 days. After the addition culture, the cell sheet was collected, and the amount of collagen degradation product accumulated in the cell sheet was examined by fluorescent immunostaining. In addition, RNA in the cell sheet was extracted, and the expression levels of genes involved in the uptake of collagen degradation products and elastin degradation products were evaluated by the real-time RT-PCR method.

Results and effect of Example in Test Example 3 As a result, from the obtained immunostained image, extracellular matrix degradation products accumulated in the cell sheet were added with butanol fraction (10 μg / mL) and seed saponin (1.0 μM). It was found that it was decreased by (Fig. 7). In FIG. 7, cylindrical or rounded ones are cell nuclei, and haze-like ones existing between them are extracellular matrix degradation products.
Moreover, as a result of gene expression analysis, tomato seed extract (10 μg / mL), lycoperoside A (1, 3 μM) and lycoperoside H ( 1 μM) significantly increased (FIG. 8).
Similarly, the expression of Neuraminidase-1 gene involved in the uptake of elastin degradation products was significantly increased by tomato seed extract (10 μg / mL), lycoperoside A (1, 3, 10 μM) and lycoperoside H (10 μM) (FIG. 9). .
In FIGS. 8 and 9, Normal indicates that extracellular matrix degradation products have not accumulated, and Control and sample addition groups have accumulated extracellular matrix degradation products.
From the above results, tomato seed extract and seed saponin promote the expression of genes involved in the uptake of extracellular matrix degradation products even in cells actually forming extracellular matrix, and increase the uptake ability of degradation products. I understood.

Effects of Examples From the above results, lycoperoside A of the tomato seed extract and the saponins contained in tomato promotes the production and degradation of collagen and elastin, and thus is useful as an ECM cycle normalizing agent, and therefore cells It was found to have the effect of maintaining the homeostasis of the outer matrix.

Examples of the ECM cycle normalizing agent of the present invention will be given below, but the following examples do not limit the present invention.
Formulation 1: Chewing gum 52.0 wt% sugar
Gum base 20.0
Glucose 10.0
Starch syrup 16.0
Fragrance 0.5
Cherry blossom extract 0.5
Glucosylceramide 0.5
ECM cycle normalizer 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
Cherry blossom extract 1.0
Glucosylceramide 1.0
ECM cycle normalizer 1.0
100.0 wt%

Formulation 3: Candy sugar 50.0 wt%
Starch syrup 33.0
Water 14.2
Organic acid 2.0
Fragrance 0.2
Cherry blossom extract 0.1
Glucosylceramide 0.1
ECM cycle normalizer 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
Cherry blossom extract 0.1
Glucosylceramide 0.1
ECM cycle normalizer 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
ECM cycle normalizer 0.05
Fragrance suitable amount
Purified water residue
100.0 wt%

Formulation 6: Soft capsule rice germ oil 86.0 wt%
Cherry blossom extract 0.5
Glucosylceramide 0.5
Emulsifier 12.0
ECM cycle normalizer 1.0
100.0 wt%

Formulation 7: Tablets Lactose 53.0 wt%
Crystalline cellulose 30.0
Starch degradation product 10.0
Cherry blossom extract 0.5
Glucosylceramide 0.5
Glycerin fatty acid ester 5.0
ECM cycle normalizer 1.0
100.0 wt%

Combination example 8: oral granule (medicine)
ECM cycle normalizing agent 1.0 wt%
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: Tablet confectionery sugar 75.4 wt%
Glucose 19.0
Sucrose fatty acid ester 0.2
Strawberry seed extract 0.5
Glucosylceramide 0.5
ECM cycle normalizer 0.5
Purified water 3.9
100.0 wt%

Formulation 10: Cat food corn 33.0 wt%
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
ECM cycle normalizer 1.0
Taurine 0.1
Vitamin 0.5
Minerals 0.5
100.0 wt%

Formulation 11: Dog food corn 30.0 wt%
Meat (chicken) 15.0
Defatted soybean 10.0
Flour 24.0
Rice bran 5.0
Cherry blossom extract 0.5
Glucosylceramide 0.5
ECM cycle normalizer 5.0
Animal fats and oils 8.9
Oligosaccharide 0.1
Vitamin 0.5
Mineral 0.5
100.0 wt%

Formulation 12: Cosmetic cream Squalane 20.0 wt%
Beeswax 5.0
Refined jojoba oil 5.0
Glycerin 5.0
Glycerin monostearate 2.0
Polyoxyethylene (20) sorbitan-
Monostearate 2.0
ECM cycle normalizer 2.0
Preservative Suitable amount Perfume Suitable amount
Purified water residue
100.0 wt%

Formulation 13: 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
ECM cycle normalizer 0.1
Purified water residue
100.0 wt%

Formulation 14: Body gel macadamia nut oil 2.0 wt%
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
ECM cycle normalizer 1.0
1,3-butylene glycol 5.0
Purified water residue
100.0 wt%

Formulation 15: Emulsion Squalane 4.0 wt%
Vaseline 2.5
Cetanol 2.0
Glycerin 2.0
Lipophilic type glyceryl monostearate 1.0
Stearic acid 1.0
L-arginine 1.0
ECM cycle normalizer 0.5
Potassium hydroxide 0.1
Fragrance
Purified water residue
100.0 wt%

Formulation 16: Bath agent (liquid)
Propylene glycol 50.0wt%
Ethanol 20.0
Sodium sulfate 5.0
ECM cycle normalizer 0.5
Lanolin 0.5
Avocado oil 0.5
Pigment 1.5
Fragrance 22.0
100.0 wt%

As described above, the present invention can provide a novel ECM cycle normalizing agent.

Claims (14)

1. A smad gene expression promoter in skin fibroblasts containing lycoperoside A as an active ingredient.
2. An endo180 gene expression promoter in dermal fibroblasts containing lycoperoside A as an active ingredient.
3. An agent for promoting endo180 gene expression in skin fibroblasts, which comprises a tomato seed extract as an active ingredient.
4. A normalizing agent for collagen production / uptake cycle in skin fibroblasts, which comprises the agent according to any one of claims 1 to 3 as an active ingredient.
5. A fiblin gene expression promoting agent in dermal fibroblasts containing lycoperoside A as an active ingredient.
6. A neuraminidase-1 gene expression promoter in skin fibroblasts containing lycoperoside A as an active ingredient.
7. A normalizing agent for the elastin production / uptake cycle in skin fibroblasts, which comprises the agent of claim 5 or claim 6 as an active ingredient.
8. An agent for promoting collagen production in skin fibroblasts, which comprises a tomato seed extract as an active ingredient.
9. A lysosome-increasing agent in skin fibroblasts containing tomato seed extract as an active ingredient.
10. A lysosome-increasing agent in skin fibroblasts containing lycoperoside A as an active ingredient.
11. A lysosome-increasing agent in skin fibroblasts containing lycoperoside H as an active ingredient.
12. An ECM cycle normalizing agent for dermal fibroblasts, which comprises the agent according to any one of claims 1 to 11 as an active ingredient.
13. ECM cycle normalizing agent for dermal fibroblasts containing lycoperoside A as an active ingredient.
14. An ECM cycle normalizing agent in dermal fibroblasts containing a tomato seed extract as an active ingredient.

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