JP2010195695A - PREPARATION FOR ACTIVATING Akt-mTOR-p70S6K OF MUSCLE STRENGTHENING SYSTEM AND METHOD THEREOF - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a novel preparation for activating Akt-mTOR-p70S6K signaling which has not been found and an activation method. <P>SOLUTION: The preparation for activating Akt-mTOR-p70S6K signaling in muscles has, as an active ingredient, a specific compound, for example, cardamonin having excellent activation of transmission of each signal of Akt signal, mTYOR signal, and p70S6K signal in muscles. A preparation to activate Akt-mTOR-p70S6K signalling in muscles is described. A muscle strengthening method and a method of preventing muscular atrophy use the preparation. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

The present invention improves Akt, mammalian target of rapamycin (hereinafter referred to as mTOR) and p70S6K, which are important factors known as muscle augmentation reactions, in order to improve the state in which muscle strength declines and muscle protein synthesis is reduced. It relates to a novel formulation to be activated and a method to activate (FIG. 1).

  To increase muscle strength, it is necessary to increase protein synthesis of muscle cells. It has been found from recent studies that if the signaling parameters of Akt, mTOR and p70S6K among the parameters controlling the protein synthesis of muscle cells can be activated, they will work for muscle enhancement (Non-Patent Documents 1 to 3). These cells work by muscle cells to synthesize proteins and strengthen muscles, and are considered to be an indicator of muscle enhancement when Akt, mTOR and p70S6K signaling parameters are activated.

The medical foundation of physical therapy Vol8, No.1, P8 (2004) Medical Basics of Physical Therapy Vol9, No.1, P15 (2005) Physiotherapy Vol31, P409 (2004)

  Based on the above findings, when each signal transmission of Akt-mTOR-p70S6K is activated, protein synthesis of muscle cells is promoted and progressed to muscle strength enhancement. Therefore, it is possible to prevent or improve muscle strength increase or maintenance of muscle strength of athletes, or muscle strength decrease due to aging caused by aging, thus making important contribution in various fields such as sports field and nursing field. Expected.

  Each signal cascade of Akt-mTOR-p70S6K is involved in the control of protein synthesis for improving muscle atrophy and muscle growth, and a substance that activates this signal transduction is required to increase muscle strength. In order to increase muscle strength, it is important to activate each signaling of Akt-mTOR-p70S6K. However, the components that activate these muscle signal cascades are still unclear.

  Therefore, the present inventors have found that the Akt-mTOR-p70S6K signal cascade of muscle cells, which is a muscle enhancement reaction, is activated by compounds centered on cardamonin, and found that it is effective for increasing muscle strength. It is.

  To date, training and protein intake have been known as muscle enhancement methods, and muscle enhancement effects have also been observed with intake of steroids and the like. However, it is not known that chalcones, which are plant-derived flavonoid-like substances, have a muscle enhancing action.

  Therefore, an object of the present invention is to develop a preparation that activates Akt-mTOR-p70S6K signaling in muscle, which has hardly been found in the past, or a method for activating Akt-mTOR-p70S6K signaling in muscle. Development.

  The present inventors have found that a specific compound has an effect of activating the transmission of each of the Akt signal, mTOR signal and p70S6K signal in an excellent muscle. Therefore, the present invention provides a muscle enhancement effect using a preparation that activates Akt-mTOR-p70S6K signal transduction in muscle and a preparation that activates Akt-mTOR-p70S6K signal transduction in muscle. And a method for preventing muscle atrophy.

  The preparation of the present invention has an effect of activating Akt-mTOR-p70S6K signaling in muscle. In addition, this activation action can also provide a new method that can prevent a variety of muscle strength disorders such as reduction of bedridden elderly people, or prevention of muscle atrophy, reduction of muscle atrophy, etc. is there.

It is a figure showing the signal pathway of a muscle augmentation system.

It is a figure which shows the cardamomon of this invention activating the signal of Akt.

It is a figure which shows the cardamomonin of this invention to activate the signal of mTOR.

It is a figure which shows the cardamomonin of this invention to activate the signal of p70S6K.

  The compound used as an active ingredient in the preparation of the present invention is a compound represented by the following formula 1.

：式１

: Formula 1

Each R ¹ to R ³ of the formula 1 of the formula 1 are independently hydrogen, a hydroxyl group, a straight-chain alkoxy group having 1 to 5 carbon atoms. R ^{4 in} Formula 1 independently represents a hydroxyl group, a linear alkyl group having 1 to 3 carbon atoms, or a linear alkoxy group having 1 to 3 carbon atoms, and n in Formula 1 is an arbitrary number of 0 to 5 Indicates an integer. Specific examples of the linear alkoxy group having 1 to 5 carbon atoms include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, and a pentoxy group. Specific examples of the linear alkyl group having 1 to 3 carbon atoms include a methyl group, an ethyl group, and a propyl group. Preferably, R ^{1 to} R ^{2 in} Formula 1 are a hydroxyl group, R ³ is a methoxy group, and Cardamonin, which is a compound set by a parameter of n = 0.

The compound represented by the above formula 1 can be produced and obtained by a known method such as a chemical synthesis method. Alpinia plants, such as Alpinia katsumadai H., Alpinia speciosa K. Schum, Alpinia blepharocalyx, Gingidae Zingiberaceae Boesenbergia, also known as Krachai, Karchai (Boesenbergia) pandurata, Boesenbergia rotunda (L.) Mansf), as well as Elettaria cardamomum, Piper dilatatum, Vitex leptobotrys, Kaempferia angustifolia or other plants of Kaempferia angustifolia It is also possible to obtain it by extracting and purifying it. In the case of an extract and purified product from a plant, when the extract contains an amount of the above-mentioned compound as a main component or sufficient to activate each Akt-mTOR-p70S6 signal transduction, As an alternative to using the above compound, it is possible to use it in the form of a plant extract equivalent to the above compound.

  The content of the compound in the preparation of the present invention is not particularly limited as long as activation of each signal transduction of Akt-mTOR-p70S6 can be confirmed, but generally 0.001 μg / g to 200 mg / g g (denominator indicates the weight of the formulation). The range is preferably 0.02 μg / g to 20 mg / g, and most preferably 0.2 μg / g to 10 mg / g.

As an application method as a medicine, either oral administration or parenteral administration can be adopted. In administration, the active ingredient can be mixed with a solid or liquid nontoxic pharmaceutical carrier suitable for administration methods such as oral administration, rectal administration and injection, and administered in the form of a conventional pharmaceutical preparation. Examples of such preparations include solid preparations such as tablets, granules, powders and capsules, liquid preparations such as solutions, suspensions and emulsions, freeze-dried preparations, and the like. It can be prepared by conventional means. Examples of the non-toxic pharmaceutical carrier include glucose, lactose, sucrose, starch, mannitol, dextrin, fatty acid glyceride, polyethylene glycol, hydroxyethyl starch, ethylene glycol, polyoxyethylene sorbitan fatty acid ester, amino acid, gelatin, Examples include albumin, water, and physiological saline. If necessary, conventional additives such as stabilizers, wetting agents, emulsifiers, binders, tonicity agents and the like can be added as appropriate.

  Moreover, as food / beverage products, as it is or it adds various nutrient components, it is made to contain in food / beverage products, and is eaten as a health food or health food, a supplement, and a food material. For example, after adding the above-mentioned appropriate auxiliaries, it may be used for edible by using conventional means, and forming into an edible form, for example, granular, granular, tablet, capsule, paste, etc. In addition, various foods such as processed marine products such as kamaboko and chikuwa, livestock products such as sausage and ham, Western confectionery, Japanese confectionery, raw noodles, Chinese noodles, boiled noodles, buckwheat noodles, sauce, soy sauce, sauce, Seasonings such as sugar, honey, powdered candy, syrup, etc., spices such as curry powder, mustard powder, pepper powder, jam, marmalade, chocolate spread, pickles, red vegetables, sprinkles, canned and bottled vegetables and fruits Processed vegetables and fruits, dairy products such as cheese, butter, yogurt, miso soup, soup, fruit juice, vegetable juice, whey beverage, soft drink, alcoholic beverages, liquid food, etc. Addition to can be used, also, pet food, can also be used for animals and plants for feed and the like.

  As a cosmetic composition, for example, it can be used in various external preparations (including preparations used for animals) in general, specifically, ampoules, capsules, pills, tablets, powders, granules, solids, liquids 1) Pharmaceuticals, 2) Quasi-drugs, 3) Topical or systemic skin cosmetics (eg lotion) , Basic cosmetics such as emulsion, cream, ointment, lotion, oil, pack, facial cleanser and skin cleanser, massage agent, cleansing agent, hair remover, hair remover, shaving treatment, after shave lotion, pre-shave Makeup cosmetics such as lotion, shaving cream, foundation, lipstick, blusher, eye shadow, eyeliner, mascara, perfume, beauty nail, beauty nail enamel, beauty nail Mel removers, poultices, plasters, tapes, sheets, patches, aerosols, etc.), 4) medicinal and / or cosmetic preparations applied to the scalp and hair (eg shampoos, rinses, Hair treatment agent, pre-hair treatment agent, permanent solution, hair dye, hair styling agent, hair styling agent, hair growth / hair nourishing agent, poultice agent, plaster agent, tape agent, sheet agent, patch, aerosol agent, etc.), 5) bath Bathing agents used in hot water, 6) Other anti-smell and deodorants, deodorants, antiperspirants, hygiene products, sanitary cotton, wet tissue, toothpaste, mouth freshener, gargle, dishwashing It can also be used for agents.

  In addition to the above-mentioned compounds that are essential active ingredients, the preparations of the present invention can be further added with various functions by arbitrarily selecting and using various components exemplified below as additives. Is possible. Although content in a formulation is not specifically limited, Usually, the density | concentration range of 0.0001 to 50 weight% is common.

Calcium supplement formulation An additive that promotes calcium absorption can be added to the formulation of the present invention. Raw materials containing calcium, vitamin D and vitamin D derivatives that promote calcium absorption, tocopherol or its salts and derivatives thereof (α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, ε-tocopherol, α-tocopherol Ferryl retinoate, aminomethylated tocopherol, hydroxymethylated tocopherol, tocopheryl phosphate, tocopherol acetate, tocopherol nicotinate, tocopherol succinate, tocopherol linoleate, tocopherol orotate, DL-α-tocopheryl glucoside, DL-α -Tocopheryl maltoside, DL-β-tocopheryl glucoside, DL-β-tocopheryl maltoside, DL-γ-tocopheryl glucoside, DL-γ-tocopheryl maltoside, DL-δ-tocopheryl glucoside, DL- δ-G Ferryl maltoside, D-α-tocopheryl glucoside, D-α-tocopheryl maltoside, D-β-tocopheryl glucoside, D-β-tocopheryl maltoside, D-γ-tocopheryl glucoside, D-γ- Tocopheryl maltoside, D-δ-tocopheryl glucoside, D-δ-tocopheryl maltoside, L-α-tocopheryl glucoside, L-α-tocopheryl maltoside, L-β-tocopheryl glucoside, L-β -Tocopheryl maltoside, L-γ-tocopheryl glucoside, L-γ-tocopheryl maltoside, L-δ-tocopheryl glucoside, L-δ-tocopheryl maltoside, 1- (sulfoethylamino) -3- (α-Tocopheryl-6-iroxy) propan-2-ol, 1- (carboxypropylamino) -3- (α-tocopheryl-6-iroxy) propan-2-ol hydrochloride, S- [3 -(α-Tocopheryl-6-Iroxy) -2-hydroxypropyl] system , S- [3- (α-tocopheryl-6-iroxy) -2-hydroxypropyl] -γ-glutamylcystenylglycine, N- [3- (α-tocopheryl-6-iroxy) -2 -Hydroxypropyl] aspartic acid, N- [3- (α-tocopheryl-6-yloxy) -2-hydroxypropyl] glutamic acid, etc.), tocotrienol or a salt thereof and derivatives thereof (α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, tocotrienol acetate, tocotrienol nicotinate, tocotrienol succinate, tocotrienol linoleate, tocotrienol orotate, etc., ascorbic acid or a salt thereof and derivatives thereof (phosphoric acid-magnesium magnesium ascorbate, palmitic acid) Ascorbyl, Ascorbyl dipalmitate, Ascorbic acid hydroxypro Phosphorus phosphate, 5-o-α-D-glucopyranosyl-L-ascorbic acid, L-ascorbic acid phosphate sodium salt, L-ascorbic acid phosphate potassium salt, L-ascorbic acid phosphate magnesium salt, L -Ascorbic acid phosphate calcium salt, L-ascorbic acid phosphate aluminum salt, L-ascorbic acid sulfate sodium salt, L-ascorbic acid sulfate potassium salt, L-ascorbic acid sulfate magnesium salt, L-ascorbic acid Sulfate calcium salt, L-ascorbic acid sulfate aluminum salt, L-ascorbic acid sodium salt, L-ascorbic acid potassium salt, L-ascorbic acid magnesium salt, L-ascorbic acid calcium salt, L-ascorbic acid aluminum salt, 6 -o-α-D-Galactopyranosyl-L-As Corbic acid, 2-o-β-D-galactopyranosyl-L-ascorbic acid, L-ascorbic acid phosphate magnesium salt, L-ascorbic acid phosphate sodium salt, L-ascorbic acid sulfate sodium salt, 6-o-acyl ascorbic acid phosphate sodium salt, 6-o-acyl ascorbic acid phosphate ammonium salt, 6-o-acyl ascorbic acid phosphate isopropanolamine salt, 3-o-isopropyl-L-ascorbic acid 6-o-alkylascorbic acid phosphate potassium salt, 6-o-alkylascorbic acid phosphate calcium salt, 6-o-alkylascorbic acid phosphate barium salt, 6-o-alkylascorbic acid phosphate Ammonium salt, 6-o-alkyl ascorbic acid phosphate monoethanolamine salt, 6-o-alkyl amine Scorbic acid phosphate diethanolamine salt, 6-o-alkylascorbic acid phosphate triethanolamine salt, 6-o-alkylascorbic acid phosphate monoisopropanolamine salt, 6-o-alkylascorbic acid phosphate diisopropanol Amine salt, 6-o-alkylascorbic acid phosphate triisopropanolamine salt, 3-o-glycosyl-L-ascorbic acid, 6-o-β-D-galactopyranosyl-L-ascorbic acid, phosphorus ascorbate Acid cholesterol ester, palmitic acid-L-ascorbyl, isopalmitic acid-L-ascorbyl, dipalmitic acid-L-ascorbyl, diisopalmitic acid-L-ascorbyl, stearic acid-L-ascorbyl, isostearic acid-L-ascorbyl, Distearic acid-L-ascorbyl, diisostearic acid-L- Scorbyl, myristic acid-L-ascorbyl, isomyristic acid-L-ascorbyl, dimyristic acid-L-ascorbyl, diisomyristic acid-L-ascorbyl, 2-ethylhexanoic acid-L-ascorbyl, di-2-ethylhexane Acid-L-ascorbyl, oleic acid-L-ascorbic acid, 2-o-α-D-glucosyl-L-ascorbic acid, 2-o-α-D-maltosyl-L-ascorbic acid, 2-o-α- D-maltotriosyl-L-ascorbic acid, 3-o-α-D-glucosyl-L-ascorbic acid, 2-o-α-D-maltosyl-L-ascorbic acid, 2-o-α-D-malto Triosyl-L-ascorbic acid, L-ascorbic acid tetraisopalmitic acid ester, L-ascorbic acid tetralauric acid ester, L-ascorbic acid tetra-2-ethylhexanoic acid ester, L-ascorbic acid tetraoleic acid ester, 5 , 6-Isopropylidene-L-ascorbic acid, L-ascorbic acid retinol ester, L-ascorbic acid-DL-tocopherol phosphate ester, L-3-o-ethylascorbic acid, L-ascorbic acid tristearate, L-ascorbic acid tripalmitate, L-ascorbic acid trio Rate, L-ascorbic acid triphosphate, 2-o-ascorbyl cinnamate, 2-o-ascorbyl ferrate, 2-o-ascorbyl caffeate, 2-o-ascorbyl synapate, 2-o- [6-palmitoyl Ascorbyl] -4'-acetoxyferrate, DL-α-tocopherol-2-L-ascorbic acid phosphate diester, ascorbic acid inositol-conjugated derivative, ascorbic acid phosphoramide derivative, ascorbyl arbutin conjugate, ascorbyl phosphoryl cholesterol, chromanyl ascorbine Acid derivatives, ascorbic acid sialic acid derivatives ), Silk extract, citrus extract, especially Hyuga Summer Extract, Souzok Extract, Ghetto Extract, Alpinia Belfaro Calix Extract, Ginger Extract, Obanjutsu Extract, Shozukku Extract, Hidakamitsutsu Azalea Extract, Vitex Leptobotris Extract, Kaempferia -Angastifolia extract, cultured natto metabolite, natto extract and the like.

Cell activating agent / metabolic activator A cell activating agent / metabolic activator can be added to the preparation of the present invention. Specific examples of cell activators and metabolic activators include vitamin A group: retinol or its salts and derivatives thereof (retinyl unsaturated fatty acid esters such as retinyl linoleate, retinyl linolenate, retinyl oleate, retinyl arachidate, etc.) ), Retinal or a salt thereof and derivatives thereof, dehydroretinal or a salt thereof and derivatives thereof, retinoic acid or a salt thereof and derivatives thereof, retinoic acid analog (4-[[[8- (3,5-dimethylphenyl ) -2-Naphthalenyl] carbonyl] amino] benzoic acid, 4-[[[8- (3-methylphenyl) -2-naphthalenyl) carbonyl] amino] benzoic acid, 4-[[[8- (4-methylphenyl) ) -2-Naphthalenyl] carbonyl] amino] benzoic acid, 4-[[[8- (2-methylphenyl) -2-naphthalenyl] carbonyl] amino] benzoic acid, 4-[[[8- (3,4- Dimethylphenyl) -2-naphthaleni ] Carbonyl] amino] benzoic acid, 4-[[[8- (2,4-dimethylphenyl) -2-naphthalenyl] carbonyl] amino] benzoic acid, 4-[[[8- (2-isopropylphenyl) -2 -Naphthalenyl] carbonyl] amino] benzoic acid, 4-[[[8- (2-ethylphenyl) -2-naphthalenyl] carbonyl] amino] benzoic acid, 4-[[[8- (2-fluorophenyl) -2 -Naphthalenyl] carbonyl] amino] benzoic acid, 4-[[[8- (2-methoxyphenyl) -2-naphthalenyl] carbonyl] amino] benzoic acid, 4-[[(8-benzyl-2-naphthalenyl) carbonyl] Amino] benzoic acid, 4-[(E) -2- (8-phenyl-2-naphthalenyl) propenyl] benzoic acid), retinoic acid derivative (4-hydroxyphenylretinamide), retinoid analogue (4-[[( 5,6-dihydro-5,5-dimethyl-8-ethyl-2-naphthalenyl) amino] carbonyl] benzoic acid, 4-[[((5,6-dihydro-5,5,8-trimethyl-2-naphthalenyl) Amino] Kerr Bonyl] benzoic acid, 4-[[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthalenyl) amino] carbonyl] benzoic acid, 4-[[((5,6-dihydro-5, 5-dimethyl-8-ethyl-2-naphthalenyl) carbonyl] amino] benzoic acid, 4-[[(5,6-dihydro-5,5,8-trimethyl-2-naphthalenyl) -carbonyl] amino] benzoic acid, 4- (E)-[2- (5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthalenyl) -1-propenyl] benzoic acid, 4-[[((5,6-dihydro-5 , 5-Dimethyl-8-phenyl-2-naphthalenyl) oxy] carbonyl] benzoic acid, 4-[[(5,6-dihydro-5,5-dimethyl-8-phenyl-2- (naphthalenyl) carbonyl] amino] Benzoic acid, 4-[[(5,6-dihydro-5,5-dimethyl-8-phenyl-2- (naphthalenyl) carbonyl] oxy] benzoic acid, 4-[[5,6-dihydro-5,5- Dimethyl-8- (2-fluorophenyl) -naphthalenyl] carbonyl] amino] benzoic acid, 4-[[((5,6-dihydro-5,5,6-trimethyl) ] -8-phenyl-2- (naphthalenyl) carbonyl] amino] benzoic acid, 4-[[(5,6-dihydro-5,5,7-trimethyl-8-phenyl-2-naphthalenyl) carbonyl] benzoic acid, 4-[[((E)-(5,6-dihydro-5,5-dimethyl-8-phenyl) -2-naphthalenyl] vinyl] benzoic acid, 4-[[[((5,6-dihydro-5,5 -Dimethyl-8-phenyl) -2-naphthalenyl] carbonyl] sulfamyl] benzoic acid, 4-[[[[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthalenyl] sulfamyl] carbonyl] benzoic acid Acid, 4-[[(5,6-dihydro-5,5-dimethyl-8-phenyl) -2-naphthalenyl] ethyl] benzoic acid, 4-[[[(5,6-dihydro-5,5-dimethyl -8-phenyl) -2-naphthalenyl] thiocarbonyl] amino] benzoic acid, 4-[[[[(5,6-dihydro-5,5-dimethyl-8-phenyl) -2-naphthalenyl] carbonyl] methyl] benzoic acid Acid, 4-[[[((5,6-Dihydro-5,5-dimethyl-8-phenyl) -2-naphthalenyl] methyl] oxy] benzoic acid Acid 4-[[[(5,6-dihydro-5,5-dimethyl-8-phenyl) -2-naphthenyl] oxy] methyl] benzoic acid, 4-[[[((5,6-dihydro-5, 5-dimethyl-8- (2,4-dimethylphenyl)]-2-naphthalenyl] carbonyl] amino] benzoic acid, 4-[[[[(5,6-dihydro-5,5-dimethyl-8- (4- Methylphenyl)]-2-naphthalenyl] carbonyl] amino] benzoic acid, 4-[[(5,6-dihydro-5,5-dimethyl-8-phenyl) -2-naphthalenyl] ethyl] benzoic acid, 4- [ [[(5,6-dihydro-5,5-dimethyl-8-phenyl) -2-naphthalenyl] sulfamyl] methyl] benzoic acid, 4-[[((5,6-dihydro-5,5-dimethyl-8- Phenyl) -2-naphthalenyl] methyl] amino] benzoic acid, 4-[[[((5,6-dihydro-5,5-dimethyl-8-phenyl) -2-naphthalenyl] amino] thiocarbonyl] benzoic acid, 4 -[[[((5,6-Dihydro-5,5-dimethyl-8-phenyl) -2-naphthalenyl] methyl] sulfamyl] benzoic acid, 4-[[[((5,6-dihydro-5,5-dimethyl - 8-phenyl-2-naphthalenyl] amino] methyl] benzoic acid, 4-[[[[(5,6-dihydro-5,5-dimethyl-8-phenyl) -2-naphthalenyl] carbonyl] amino] -2-hydroxy Benzoic acid, 4-[[[(5,6-dihydro-5,5-dimethyl-8-phenyl) -2-naphthalenyl] carbonyl] amino] -2-nitrobenzoic acid, 4-[[[((5,6 -Dihydro-5,5-dimethyl-8-phenyl) -2-naphthalenyl] carbonyl] amino] -2-fluorobenzoic acid, 4-[[[((5,6-dihydro-5,5-dimethyl-8-phenyl) -2-Naphthalenyl] carbonyl] amino] -2-methoxybenzoic acid, 4-[[[[(5,6-dihydro-5,5-dimethyl-8- (2-naphthalene)]-2-naphthalenyl] carbonyl] amino ] Benzoic acid, 4-[[(5,6-dihydro-8-phenyl-2-naphthalenyl) carbonyl] aminobenzoic acid, 4-[[((5,6-dihydro-5,5-dimethyl-8-phenyl- 2-Naphthalenyl) carbonyl] amino] -3-fluorobenzoic acid, 4-[[((5,6-dihydro-5,5-dimethyl-8-phenyl) Enyl-2-naphthalenyl) carbonyl] amino] -3-methylbenzoic acid, 4-[[((5,8,10,10a-tetrahydro-10,10-dimethyl-9-phenyl-2-anthracenyl) carbonyl] amino] Benzoic acid, 4-[[(1,1-dimethyl-3-phenyl-1H1-inden-5-yl) amino] carbonyl] benzoic acid, 4-[(1,1-dimethyl-3-phenyl-1H-indene -5-yl-oxymethyl) benzoic acid, 4- [2- (1,1-dimethyl-3-phenyl-1H-inden-5-yl) vinyl] benzoic acid, 4-[(1,1-dimethyl- 3-phenyl-1H-indene-5-carbonyl) amino] benzoic acid), carotene or salts thereof and derivatives thereof (α-carotene, β-carotene, γ-carotene, lycopene, cryptoxanthine, lutein, zeaxanthin, isoseaxanthin, rhodoxanthine , Carotenoids such as capsanthin and crocetin), lycopene or its salts and derivatives thereof, vitamin B group: thiami Or salts thereof and derivatives thereof (thiamine hydrochloride, thiamine disulfide, bisbenchamine, bisbutiamine, thiamine monophosphate disulfide, benfotiamine, chicotiamine, octothiamine, discetiamine, fursultiamine, prosultiamine, astaxanthin Thiamine phosphate diester, etc.), thiamine sulfate, riboflavin or its salts and derivatives thereof (flavin adenine dinucleotide, flavin mononucleotide, riboflavin phosphate diester, 1-β-D-ribofuranosylnicotinamide pyrophosphate diester, 1 -β-D-ribofuranosylnicotinic acid, etc.), pyridoxine or its salts and derivatives thereof (pyridoxine 3,4-dipalmitate, pyridoxine 3,4-dicaprylate, pyridoxine sulfate diester, etc.), pyridoxer Or salts thereof and derivatives thereof, pyridoxamine or salts thereof and derivatives thereof, cyanocobalamin or salts thereof and derivatives thereof, cobalamines (such as methylcobalamin, adenosylcobalamin, hydroxocobalamin, aquacobalamin), folic acid or salts thereof, and Derivatives thereof, nicotinic acid or salts thereof and derivatives thereof, pantothenic acid or salts thereof and derivatives thereof, biotin or salts thereof and derivatives thereof, choline or salts thereof and derivatives thereof, inositol or salts thereof and derivatives thereof , Vitamin C group: ascorbic acid or a salt thereof and derivatives thereof, vitamin D group: ergocalciferol or a salt thereof and derivatives thereof, cholecalciferol and a salt thereof and derivatives thereof (1α-hydroxy-22-[(1 -Hide Xyl-1-methyl) -2-cyclopenten-4-yl-oxy] -23,24,25,26,27-pentanorolecalciferol, [1R, 4R] -1α-hydroxy-22-[(1- Hydroxy-1-methyl) -2-cyclopenten-4-yl-oxy] -23,24,25,26,27-pentanorolecalciferol, [1R, 4S] -1α-hydroxy-22-[(1- Hydroxy-1-methyl) -2-cyclopenten-4-yl-oxy] -23,24,25,26,27-pentanorolecalciferol, [1S, 4R] -1α-hydroxy-22-[(1- Hydroxy-1-methyl) -2-cyclopenten-4-yl-oxy] -23,24,25,26,27-pentanorolecalciferol, [1S, 4S] -1α-hydroxy-22-[(1- Hydroxy-1-methyl) -2-cyclopenten-4-yl-oxy] -23,24,25,26,27-pentanorolecalciferol, etc.), dihydrotaxosterol or a salt thereof and derivatives thereof, vitamin E group : Tocopherol or a salt thereof and derivatives thereof, Tocotrie Nord or a salt thereof and derivatives thereof, ubiquinone or a salt thereof and derivatives thereof, vitamin K group: phytonadione or a salt thereof and derivatives thereof, menaquinone or a salt thereof and derivatives thereof, menadione or a salt thereof and derivatives thereof, menadiol Or salts thereof and derivatives thereof, vitamin F group: linoleic acid or salts thereof and derivatives thereof, linolenic acid or salts thereof and derivatives thereof, arachidonic acid or salts thereof and derivatives thereof, carnitine or salts thereof and Derivatives, ferulic acid or a salt thereof and derivatives thereof, γ-oryzanol or a salt thereof and derivatives thereof, orotic acid or a salt thereof and derivatives thereof, vitamin P group: rutin or a salt thereof and derivatives thereof, eriocitrin or a derivative thereof Salt and it Derivatives, hesperidin or salts thereof and derivatives thereof, vitamin L group: anthranilic acid or salts thereof and derivatives thereof, adenylthiomethylpentose or salts thereof and derivatives thereof, vitamin U group: methylmethionine sulfonium chloride or derivatives thereof , Valine, leucine, isoleucine, threonine, methionine, phenylalanine, tryptophan, lysine, glycine, alanine, asparagine, glutamine, serine, cysteine, cystine, tyrosine, proline, hydroxyproline, aspartic acid, glutamic acid, hydroxylysine, arginine, ornithine, Histidine or its derivatives (N-octyloxycarbonyl-β-alanyl-L-histidine, N-dodecyloxycarbonyl-β-alanyl-L-histidine, N- (12-amino-1-oxo Dodecyl) -L-histidine, N-2-ethylhexyloxycarbonyl-β-alanyl-L-histidine hydrochloride, N-hexadecyloxycarbonyl-β-alanyl-L-histidine, N-octylaminocarbonyl-β-alanyl- L-histidine, N-dodecylaminocarbonyl-β-alanyl-L-histidine, N-dodecylsulfonyl-β-alanyl-L-histidine, N-dodecylamino-oxalyl-β-alanyl-L-histidine, etc.) Amino acids such as sulfates, phosphates, nitrates, citrates, or amino acid derivatives such as pyrrolidone carboxylic acid, α-hydroxy acids such as glycolic acid, citric acid, malic acid, tartaric acid, lactic acid, succinic acid, 2-hydroxycarboxylic acids (methyl lactic acid, 2-hydroxybutanoic acid, 2-hydroxypentanoic acid, 2-hydroxyhexanoic acid, 2-hydroxyheptanoic acid, 2-hydroxyiodic acid Tanic acid, 2-hydroxynonanoic acid, 2-hydroxydecanoic acid, 2-hydroxyundecanoic acid, α-hydroxylauric acid, α-hydroxymyristic acid, α-hydroxypalmitic acid, α-hydroxystearic acid, α-hydroxyarachidonic acid , Cerebronic acid, α-hydroxynervonic acid, mandelic acid, benzylic acid, phenyllactic acid, atrolactic acid, 2- (4'-hydroxyphenyl) -2-hydroxyethanoic acid, 2- (4'-chlorophenyl) -2-hydroxy Ethanoic acid, 2- (3′-hydroxy-4′-methoxyphenyl) -2-hydroxyethanoic acid, 2- (4′-hydroxy-3′-methoxyphenyl) -2-hydroxyethanoic acid, 3- (2 ′ -Hydroxyphenyl) -2-hydroxypropanoic acid, 3- (4'-hydroxyphenyl) -2-hydroxypropanoic acid, 2- (3 ', 4'-dihydroxyphenyl) -2-hydroxyethanoic acid, glyceric acid, erythrone Acid, ribbon Arabinonic acid, xylonic acid, lyxonic acid, aronic acid, altronic acid, gluconic acid, mannonic acid, gulonic acid, idonic acid, galactonic acid, taronic acid, glucoheptonic acid, galactoheptonic acid, tartronic acid, mucinic acid, etc.), polyhydroxy Carboxylic acid or hydroxypolycarboxylic acid (gluconolactone, galactonolactone, glucuronolactone, galacturonolactone, gulonolactone, ribonolactone, sugar lactone, pantoyl lactone, glucoheptonolactone, mannonolactone, galactoheptonolactone 2-keto acids (glyoxylic acid, methyl 2-ketoethanoate, benzoylformic acid, methyl benzoylformate, ethyl benzoylformate, phenylpyruvic acid, methyl phenylpyruvate, ethyl phenylpyruvate, 2-ketobutanoic acid, 2-ketobutanoic acid, etc. Topanoic acid, 2-ketohexanoic acid, 2-ketoheptanoic acid, 2-ketooctanoic acid, 2-ketododecanoic acid, methyl 2-ketooctanoate, etc.), quinic acid, isocitric acid, tropic acid, tretocanic acid, 3-chlorolactic acid, cerebronic acid , Citramalic acid, agaricinic acid, aleuricinic acid, pantoic acid, lactobionic acid, hexulosonic acid, photosensitizer 301, hinokitiol, pantothenic acid or derivatives thereof, allantoin, pentadecanoic acid glyceride, linolenic acid or derivatives thereof, eicosapentaenoic acid or derivatives thereof Docosahexaenoic acid or a derivative thereof, estradiol, etenyl estradiol, antialol or a glycoside thereof, lionilesinol or a glycoside thereof, rhododendrol or a glycoside thereof, platyphyronol or a glycoside thereof, a lactone compound (D -Gurukuro -6,3-lactone, α-D-glucoheptonic-γ-lactone, δ-glucuronolactone, α, β-glucooctonic-γ-lactone, L-glonic-γ-lactone, γ-D- Galactonolactone, D-saccharide-1,4-lactone, D-saccharide-3,6-lactone, D-ribonic-γ-lactone, α-butyrolactone, γ-butyrolactone, α-octanoic lactone, γ-octa Neutic lactone, Nonanoic lactone, γ-valerolactone, D-manninoic-δ-lactone, D-xyleuic-δ-lactone, D-arabinoic-δ-lactone, stearoyl-δ-gluconolactone, DL-pantolactone, Palmitoyl-DL-pantolactone, etc.), 3-hydroxy-3,4-dicarboxy-1,4-butanolide or derivatives thereof, 6-benzylaminopurine or derivatives thereof, 1,4-diazadicyclooctane, 2,5 -Dimethylfuran, 2- Tilfuran, 2,5-diphenylfuran, 1,3-diphenylisobenzofuran, rutin, tectrigenin 7-xylosyl glucoside, captopril, alacepril, lisinopril, enalapril, delapril, benazepril, cilazapril, imidapril, quinapril, trandlapril, perindopril , Temocapril, losartan, endothelin, galactomannan saccharide polymer, mucin, trimethylglycine, proteoglycan, lactic acid bacteria extract, lactic acid bacteria culture extract, lactic acid bacteria fermented milk extract, bifidobacteria extract, bifidobacteria culture extract, bifidobacteria fermented milk extract, placenta extract , Ganoderma extract, Spleen extract, Thymus extract, Yeast extract, Yeast culture extract, Yeast fermentation extract, Filamentous fungus extract, Filamentous fungus culture extract, Basidiomycetes extract, Basidiomycetes Nutrient solution extract, Bacterial cell disruption extract, Bacterial culture fluid extract, Cultured human dermal cell disruption extract, Red gecko (ground yellow) extract, Fennel (cage) extract, Ekokogi (Tomogoka) extract, Barley (barley) extract, O Kururi Higotai (Zhengzhou Leopard) Extract, Root-knotweed Extract, Hypericum perforatum Extract, Dutch Jelly Extract, Dutch Honeybee Extract, Silkworm Extract, Roman Chamomile Extract, Garcinia Extract, Kawaran Ginseng (Blue Panax) Extract, Kakiran Extract, Kiraya Extract, Ginkgo biloba extract, Ginkgo biloba extract, Calendula extract, Sakaneran (Ezosa kaneran) extract, Sababagin orchid extract, Sawagurumi extract (Plum walnut extract), Prunus serrata extract, Shajin (San ginseng) extract, Plum extract, Gurumi extract, Sugina extract, Pineapple Leopard extract, Chinese cabbage extract, Japanese cypress extract, beech extract, physalis (Torone) extract, maitake (maiko) extract, misohagi (chikuma) extract, mugwort (mushroom) extract, mukuroji (prolonged skin) extract, sprout Extract, Eucalyptus extract, Yukinoshita (tiger ear grass) extract, Suabisimus (cool) extract, Lettuce (Chisha) extract, Aloe extract, Ogon extract, Tonka bean extract, Gentianana extract, Burdock extract, Shikon extract, Carrot extract, Hamamelis extract, Hop extract, Yokuinin extract, Odorikosou extract, Senburi extract, Toki extract, Toki-senka extract, Achacha extract, Hypericum extract, Cucumber extract, Pepper extract, Rosemary extract, Parsley extract, Sanadagusa extract, Fukurinamiji extract, Gatsuga Kombu extract, Oyster comb extract, Oni kombu extract, Gohei kombu extract, Naga kumbu extract, Pea kumbu extract, Ojimikombu extract, Rattle extract, Rattle extract, Beni mozuku extract, Hoso Beni mozuku extract, Kagekinori extract, Ezotosaka extract , Silamo extract, birch extract and the like.

Blood flow promoting agent and blood vessel stimulating agent A blood flow promoting agent and blood vessel stimulating agent can be added to the preparation of the present invention. Specific examples of blood flow promoters and vascular stimulants include tocopherol or salts thereof and derivatives thereof, tocotrienol or salts thereof and derivatives thereof, cephalanthin, carpronium chloride, eugenol derivatives (acetyleugenol, methyleugenol, methylisoeugenol, ethyl (Eugenol, ethylisoeugenol, eugenol salicylate, etc.), minoxidil, pepper tincture, nonyl acid vanillamide, cantalis tincture, ginger tincture, peppermint oil, L-menthol, camphor, benzyl nicotinate, cinnarizine, trazoline, acetylcholine, verapamil, ectamol , Α-borneol, cyclandelate, nonyl acid wallenylamide, capsaicin, gingerone, assembly extract, garlic extract, carrot extract , Aloe extract, Gentian extract, Toki extract, Ashitaba (Tomorrow) extract, Arnica extract, Ukiyagara (Sanryo) extract, Himewiku extract, Citrus unshiu (Chest) extract, Toucan beetle (coconut) extract, Oyster extract, Persimmon extract, Kina extract, goldfish extract, pine moth (horse whip grass) extract, gubijinsou extract, kohone (river bone) extract, burdock (beef bowl, beef coconut) extract, scallop (Yamabachi) extract, syringen extract, ginger (ginger) extract, Shobu (bamboo root, radish) extract, hawthorn extract, sea bream (Otaku) extract, Daidai (orange peel) extract, tanjin (dansang) extract, thyme extract, chiketsu carrot (bamboo ginseng) extract, tsurudokudami (what neck crab) extract , Garlic extract , Scotchworm extract (Sadako), Natsumikan extract, elderberry (bone graft) extract, hazelnut (coconut) extract, Hashiridokoro (roth root) extract, mint (light load, thin load leaf) extract, Hamabou Fu (beach wind) extract, Higotai extract , Fujimodoki (Chojizakura, Camellia) extract, Black currant extract, Bodaiju (Aoki tree) extract, Merirot extract, Yuzu extract, Loquat extract, Japanese jelly extract, Hibiscus extract, Rosehip extract and the like.

Structural protein synthesis promoter A structural protein synthesis promoter can be added to the preparation of the present invention. Specific examples of structural protein synthesis promoters include ethanolamine derivatives, pentoxyphyllin, serine derivatives, geraniol, crocetin, methyl 4- (2-ethylhexyloxy) -2-hydroxybenzoate, 2-hydroxy-4- (3, 5,5-Trimethylhexyloxy) methyl benzoate, methyl 4-cyclohexylmethoxy-2-hydroxybenzoate, methyl 4- (2-cyclohexylethoxy) -2-hydroxybenzoate, 4- (3,7-dimethyl-6 -Octenyloxy) methyl 2-hydroxybenzoate, ethyl 3- (2-ethylhexyloxy) -5-hydroxybenzoate, methyl 5- (2-ethylhexyloxy) -2-hydroxybenzoate, 2-hydroxy-5 -(3,5,5-trimethylhexyloxy) methyl benzoate, methyl 5- (2-cyclohexylethoxy) -2-hydroxybenzoate, methyl 4-N-hexyloxy-2-hydroxybenzoate, 2-hydride Methyl xyl-4-N-octyloxybenzoate, methyl 4-N-decyloxy-2-hydroxybenzoate, methyl 5-N-hexyloxy-2-hydroxybenzoate, 4- (2-ethylhexyloxy) -2- Hydroxybenzoic acid, 2-hydroxy-4- (2,5,5-trimethylhexyloxy) benzoic acid, 4-cyclohexylmethoxy-2-hydroxybenzoic acid, 4- (2-cyclohexylethoxy) -2-hydroxybenzoic acid, 4- (3,7-dimethyl-6-octenyloxy) -2-hydroxybenzoic acid, 3- (2-ethylhexyloxy) -5-hydroxybenzoic acid, 5- (2-ethylhexyloxy) -2-hydroxybenzoic acid Acid, 5- (2-ethylhexyloxy) -2-hydroxybenzoic acid, 2-hydroxy-5- (3,5,5-trimethylhexyloxy) benzoic acid, 5- (2-cyclohexylethoxy) -2-hydroxybenzoic acid Acid, 4-N-hexyloxy-2-hydroxybenzoic acid, 5-N-hexyloxy-2 -Hydroxybenzoic acid, 2-hydroxy-4-N-octyloxybenzoic acid, 4-N-decyloxy-2-hydroxybenzoic acid, N- (2-hydroxyethyl) -4- (2-ethylhexyloxy) -2- Hydroxybenzamide, N-ethyl-4- (2-ethylhexyloxy) -2-hydroxybenzamide, 2-acetoxy-4-cyclohexylmethoxybenzoic acid, 4- (2-ethylhexyloxy) -2-hydroxybenzoic acid sodium, 4- [(2E) -3,7-dimethyl-2,6-octadienyloxy] -2-hydroxybenzoate methyl, 4-[(2E) -3,7-dimethyl-2,6-octadienyloxy] Ethyl-2-hydroxybenzoate, 5-[(2E) -3,7 dimethyl-2,6-octadienyloxy] -2-hydroxyethyl benzoate, 3-[(2E) -3,7-dimethyl- Ethyl 2,6-octadienyloxy] -2-hydroxybenzoate, ethyl 3-[(2E) -3,7-dimethyl-2,6-octadienyloxy] -5-hydroxybenzoate, 4- [(2E) -3,7-dimethyl-2,6-octadienyloxy] -3-methoxybenzoate, 4-[(2E, 6E) -3,7,11-trimethyl-2,6,10 -Dodecatrienyloxy] -2-hydroxybenzoic acid methyl, 4-[(2E) -3,7-dimethyl-2,6-octadienyloxy] -2-hydroxybenzoic acid (2E) -3,7- Dimethyl-2,6-octadienyl, 4-[(2E) -3,7-dimethyl-2,6-octadienyloxy] -2-hydroxybenzoic acid, 5-[(2E) -3,7-dimethyl- 2,6-octadienyloxy] -2-hydroxybenzoic acid, 3-[(2E) -3,7-dimethyl-2,6-octadienyloxy] -2-hydroxybenzoic acid, 3-[(2E ) -3,7-dimethyl-2,6-octadienyloxy] -5-hydroxybenzoic acid, 2-hydroxy-4-[(2E, 6E) -3,7,11-trimethyl-2,6,10 -Dodecatrienyloxy] benzoic acid, 4-[(2E) -3,7-dimethyl-2,6-octadienyloxy] -3-methoxybenzoic acid, 2-acetoxy-4-[(2E) -3 , 7-Dimethyl-2,6-octadienyloxy ] Benzoic acid, N- (2-hydroxyethyl) -4-[(2E) -3,7-dimethyl-2,6-octadienyloxy] -2-hydroxybenzamide, 4-[(2E) -3, 7-dimethyl-2,6-octadienylamino] -2-hydroxybenzoic acid, dimethyl-2,6-octadienyloxybenzoic acid, N- (2-hydroxyethyl) -4-[(2E) -3 , 7-dimethyl-2,6-octadienyloxy] -2-hydroxybenzamide, 4-[(2E) -3,7-dimethyl-2,6-octadienylamino] -2-hydroxybenzoic acid, 3 -Dodecyloxybenzoic acid, 3- (12-hydroxydodecyloxy) benzoic acid, 4-dodecyloxybenzoic acid, 4- (12-hydroxydodecyloxy) benzoic acid, 3- (12-hydroxyoctadecyloxy) benzoic acid, 4 -(12-hydroxyoctadecyloxy) benzoic acid, 3- (11-hydroxyundecyloxy) benzoic acid, 4- (11-hydroxyundecyloxy) benzoic acid, 3-[(2E) -3,7-dimethyl- 2,6- Tadienyloxy] benzoic acid, 4-[(2E) -3,7-dimethyl-2,6-octadienyloxy] benzoic acid, 3-[(2E, 6E) -3,7,11-trimethyl-2,6 , 10-Dodecatrienyloxy] benzoic acid, 4-[(2E, 6E) -3,7,11-trimethyl-2,6,10-dodecatrienyloxy] benzoic acid, 4- [3,7-dimethyl -9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2,4,6,8-nonatetraenyloxy] benzoic acid, 4- [3,4-dihydro-2,5, 7,8-Tetramethyl-2- (4,8,12-trimethyltridecyl) -2H-1-benzopyran-6-oxy] benzoic acid, 4-[(2E, 6E) -3,7,11-trimethyl -2,6,10-dodecatrienyloxy] benzamide, 4-[(2E) -3,7-dimethyl-2,6-octadienyloxy] benzamide, 4- (2-methyl-2-butenyloxy) benzamide 4- (2-ethylhexyloxy) benzamide, 4-dodecyloxybenzamide, 4- (12-hydroxydodecyloxy) benzamide, 4- (12-hydroxyoxy) Tadecyloxy) benzamide, 4- (11-hydroxyundecyloxy) benzamide, 4- (10-hydroxydecyloxy) benzamide, 4-isostearyloxybenzamide, N- (2-hydroxyethyl) -4-[(2E, 6E ) -3,7,11-trimethyl-2,6,10-dodecatrienyloxy] benzamide, N, N-dimethyl-4-[(2E, 6E) -3,7,11-trimethyl-2,6, 10-dodecatrienyloxy] benzamide, N, N-di [(2E) -3,7-dimethyl-2,6-octadienyl] -4-aminobenzamide, 4- [N'-methoxycarbonyl-N-[( 2E) -3,7-dimethyl-2,6-octadienylamino] benzamide, 4- [N-acetyl-N-[(2E) -3,7-dimethyl-2,6-octadienyl]] aminobenzamide, N- (2-hydroxyethyl) -4-[(2E, 6E) -3,7,11-trimethyl-2,6,10-dodecatrienyloxy] -2-hydroxybenzamide, N, N-diethyl-4 -[(2E, 6E) -3,7,11-Trimethyl-2,6,10-dodecatrienyl Xy] -2-hydroxybenzamide, pea extract, red pepper extract, scots reed extract, hosobonori extract, bonito extract, igisu extract, keigi extract, harii squirrel extract, honey beet extract, euglena extract, moly rush extract, Willow extract, Willow extract, Motsuyurena extract, Venetian extract, Moth willow extract, Sabaya willow extract, Wasabi extract, Merbow extract and the like.

Mucopolysaccharide synthesis promoter A mucopolysaccharide synthesis promoter can be added to the preparation of the present invention. Specific examples of the mucopolysaccharide synthesis accelerator include stilbene derivatives or salts thereof, morgin or salts thereof and derivatives thereof, N-acetylglucosamine, flax extract, cinnamon extract, mulberry extract, scotch extract, breadfruit extract, hirakotoji extract , Kotojitsu no Mata Extract, Yaleus Banori Extract, Kagiosu Banori Extract, Susius Banori Extract, Amiaosa Extract, Nagaaosa Extract, Hosobanosakamodoki Extract, Hirohatosakamodoki Extract, Yatsudegatatosakamodoki Extract, Kurotosakamodoki Examples include extract, nematode salamander extract, Yusora extract, Echikinosa salamander extract, nankaitosakamodoki extract, Himetosakamodoki extract, and the like.

Other Additive Ingredients Specific examples of ingredients derived from plant-based materials used as additives to the formulation of the present invention include Aokazura (Seifuto) extract, Aotenma extract, Akasuguri extract, Aquine (crustacean) extract, Aguay Guasu extract, Abiu extract, Abiurana extract, Yellow sapote extract, Ylang ylang extract, Uranium orchid extract, Uba tea extract, Ezo lily extract, Eun Boku extract, Elderberry extract, Prunus extract Extract, Onoelan extract, Crab extract (Kinshato) extract, Karaya extract, Galyu extract, Kawaratake extract, Candelilla extract, Canna extract, Kidachi pepper extract, Kimenkaku extract, Cave extract, Kiraja saponaria extract, Ginsekai Kiss, Kimbusen Extract, Guapeba Vermela Extract, Kugenuma Maran Extract, Gooseberry Extract, Curitiba River Extract, Curkurigo Latifolia Extract, Black Ganechi (Rescuer) Extract, Kourian Extract, Sapotea Marillo Extract, Salmon Berry Extract, Salamander Extract , Cactus Cactus Extract, Cranberry Extract, Shunran Extract, Shozuk Extract, Shirobanatsuta Extract, Cinchona Sacylbra Extract, Swimberry Extract, Star Apple Extract, Sulgaran Extract Japanese butterfly extract, mistletoe extract, sennin cactus extract, senboku extract, elephant weevil extract, cinnamon wax extract, potato mono potato extract, da Couture Cherry Extract, Prickly Pear Extract, Choco Nostay Extract, Datura Artemisia Extract, Vulgaris Extract, Tuxiabi Extract, Duckweed (Duckweed) Extract, Duberry Extract, Papilio Kazura Extract, Tragacanth Extract, Triacanthus Extract , Neiseria berry extract, Rapeseed extract, Plover-dough extract, Pau doce extract, Hakuru berry extract, Batata extract, Hamakakiran extract, Balata extract, Harcan orchid extract, Pecan nut extract, Hinori duck extract, Himemuyoran extract, Brazil Carrot extract, Branjen extract, Frucereria extract, Blond psyllium extract, Hetsukaran extract, Heneken extract, Berry extract, Persair extract, Pervianburg extract, Pereschia gura Ndofria extract, Boysenberry extract, Hausairan extract, Pouteria sapota extract, Pouteria rukuma extract, Hosobabarengiku extract, White berry extract, Masaransuba extract, Masheira de Boyi extract, Matta auryo extract, Mulberry extract, Midori Sapote extract, purple corn extract, megacansa opuntica extract, mokukirin extract, Japanese maple extract, Morero cherry extract, Yakawa purple potato extract, cornflower extract, Ruritama thisami (Vultures), red currant extract, red pitaya Examples include plant extracts such as extract, lemongrass extract, wax palm extract, and logan berry extract.

  In addition, as specific examples of components derived from plant-based raw materials used as additives to the preparation of the present invention, Dunaliella genus Dunaliella extract, Kuwanomi genus Kuwanomimo extract, Volbox genus genus sunflower extract, Volbox genus Volbox extract, Palmera extract, Yotsumemo extract, Aomydra spp. , Pseudomonas genus blackberry extract, Casanori genus Casanori extract, Mika Kakimo extract, Collecaete extract, Tatsumi potato extract, Kakinogusa genus Kakakugusa extract, Sayamidro extract, Kunshomo Green algae extracts such as kiss, Sumiremo violet extract, Hosimidro extract, Fuchinashimidoru extract, Cyanobacteria genus Suizinori extract, Blue-green algae extract such as Aoko extract, Yuremo extract, Piraella genus Piraela extract, Shiomidomo Nagamisiomidro extract, Isovine genus isovine extract , Isogawala genus Isogawara extract, Black moth genus Black moth moth extract, Kashirazaki genus Kashirazaki essence, Muchimo genus Muchimo extract, Muchimo genus Hiramachimo extract, Muchimo genus Quercus crisposa extract, Amygusa genus Sakibiro amiji extract, Common genus genus Common genus extract, Jigamigusa genus digigagus Nami-makura genus Hirami-makura extract, Someraceae genus Someraceae extract, Navaimo genus Navarimo extract, Chasommen genus Mocha-chaumen extract, Na Matsumo spp.Natsufumo sp. Genus Composita extract, genus Camellia spp. Nori extract, genus Cyprus extract, genus genus genus extract, cranula genus extract, cactus genus extract, kikui Brown sorghum extract, Brown spruce burdock extract, etc. Milnobeni extract, Konahada spp. Sodegarami Sodegarami Extract, Hirohatamitaki Hirohatamitaki Extract, Tengusa Nambugusa Extract, Tengusa Kohira Extract, Tengusa Yohira Extract, Tengusa Kinukusae , Hibiro spp., Hibiro spp. , Okitsubara Okibutsubara Extract, Sangomoda Ragarodoku Extract, Shiogusagoromo Shiogusagoromo Extract, Iwanokawa Etsukiiwakawa Extract, Kainokawa Kainokawa Extract, Kaninote Kaninote Extract, Sangomo Sangomo Extract Genus Hiram Cadet Extract, Centipede Cyprus Extract, Centacum Nikumukade Extract, Centacum Tsurut Extract, Centacum Fudarak Extract, Muca Bamboo genus extract, Astragalus edulis extract, Amaranthus edulis extract, Astragalus japonicum extract, A quinaceae quintox extract, A quince genus rice extract, A quince genus Tosaka pine extract, A quince genus H. Genus centipede extract, Kintoki genus Nagakintoki extract, Kintoki sp. Tsukasanori genus Kalymenia extract, Honoho genus Hounoo extract, genus genus genus genus extract, genus genus Usuginu extract, d Honoco genus Honoo extract, Venetian genus Venus nago extract, Susca venus Susca veni extract, Okamuragusa genus extract, Isomokka genus Isomokka extract, Kizino genus Kizino essence extract, Isodantsu genus Isodantsu extract, Atsubanori genus Atsubanori extract Mizoogonori extract, Ogonori genus Beniogonori extract, Ogonori sp. Ogonori genus Ogonori extract, Ogonori genus tsutsuginu extract, Ogonori genus Ogonori extract, Ogonori Kubireogonori extract, Ogonori genus Mosaogonori extract, Ogono Rhizopus genus extract, Namiiwatake namiitake extract, Saimi cypress extract, Saimi genus extract, Lotus japonica extract Extract Extract, Weibusa genus Bugaxa extract, Benifukuronori genus Benifukuronori extract, Virginella spp. , Egonori Egonori Extract, Egonori Futogigi Extract, Saeda Saeda Extract, Chirimomiji Chilli Momiji Extract, Habutaenori Extract, Conanus Extract, Swan White Extract, Usbeni Usbeni Extract, Hasujiginu Hasujiginu Extract, Nagakonohanoori Naga Sugiginus Sugiginu Extract, Sugiginu Atsubasujiginu Extract, Haius Banori Kagious Banori Extract, Haius Banori Yareus Banori Extract, Haius Banori Susius Banori Extract, Haius Banori Genus Huis Banori Extract, Usbanorimodoki Extract Genus Ayanishiki extract, Ayaginu genus Ayaginu extract, Dada genus Enashidadia extract, Shimadadia genus Isohagi extract, Shimadadia genus Shimadadia extract, Dajimodoki Dajimomodoki extract, Makuri genus Extract, Hanegusa genus extract, Hanegusa genus extract, Kozanemo genus extract, Kozanemo genus Isomurasaki extract, Kozanemo genus Hosocozanemo extract, Himego genus Himegoke extract, Himegoke genus Extract Red algae extract such as Chisujinori extract, Shajikumo extract, Shiratamamo extract, Hoshitsurimo Hoshitsurimo extract, Likunnotumusu extract, Flaskamo spp. Examples thereof include axle algae extracts such as extracts, chabo flask extract and tripella extract, and yellow algae extracts such as Hikarimo Hikarimo extract.

  Specific examples of ingredients derived from animal materials used as an additive to the preparation of the present invention include chicken crown extract, cow, pig or human placenta extract, pig or cow stomach, duodenum, intestine, spleen extract or decomposition products thereof , Bovine or porcine brain tissue extract, water-soluble collagen, collagen derivatives such as acylated collagen, collagen hydrolysate, elastin, elastin hydrolysate, water-soluble elastin derivative, keratin and its degradation product or derivatives thereof, silk Proteins and degradation products thereof or derivatives thereof, porcine or bovine blood cell protein degradation products (globin peptides), cattle or porcine hemoglobin degradation products (hemin, hematin, heme, protoheme, heme iron, etc.), milk, casein and degradation thereof Products or derivatives thereof, skim milk powder and degradation products thereof or derivatives thereof, lactoferrin or degradation products thereof, egg components, fish meat Examples include degradation products, nucleic acid-related substances (ribonucleic acid, deoxyribonucleic acid), and the like.

  Specific examples of components derived from microbial raw materials used as additives to the preparation of the present invention include yeast metabolites, yeast extract, bacterial metabolites, bacterial extract, metabolites such as fungi or mushrooms, actinomycetes metabolites , Extracts such as fungi or mushrooms, actinomycetes extract, natto metabolite, natto extract, rice fermented extract, rice bran (red rice bran, birch) fermented extract, euglena extract or a decomposed product thereof or a water-soluble derivative thereof, raw milk Or the lactic acid fermented product of skim milk powder etc. are mentioned.

  The plant, animal, or microbial raw material may be any site, cell, tissue, organ, metabolite, etc. derived from a transgenic or cell fusion. Furthermore, it can be obtained by culturing cells of any site, cell, tissue, organ, etc., for example, cultured cells derived from each tissue (cultures derived from animals such as fibroblasts, Langerhans cells, macrophages, epidermal cells, hepatocytes, etc.) Cells, etc.), undifferentiated cells, cells in the middle of differentiation, metabolites thereof, and the like can also be used.

  Specific examples of the ingredients of the natural product raw materials used as additives include seawater such as deep sea water, for example, sea salt, dried sea water, dead sea or Atlantic or Pacific sea water (sodium chloride, chloride). Magnesium, potassium chloride, etc.), sea mud or mud (Fango), for example, sea mud or mud in various places such as Italian Fango, German Fango, Eifel Fango, Freiburg Fango (Containing components: silicon dioxide, titanium dioxide, aluminum oxide, Iron oxide, manganese oxide, sodium oxide, potassium oxide, magnesium oxide, calcium oxide, strontium oxide, sodium, potassium, magnesium, calcium, chromium, iron, copper, nickel, zinc, lead, manganese, arsenic, water), saintoku stone Natural smectite, bentonite, hectorite and the like.

  Extracts derived from plant raw materials, animal raw materials, microbial raw materials, and other natural product raw materials used as additives are processed in a conventional manner according to the product type and form to be added (for example, pulverization, milling, Treatment, extraction, decomposition, fermentation or metabolic conversion by microorganisms, fractionation, purification, pressing, filtration, drying, pulverization, granulation, dissolution, sterilization, pH adjustment, deodorization, decolorization, etc. ) And any one of various materials may be selected for use.

  The solvent used for extraction may be selected in consideration of the intended purpose and type of the product to be provided or the processing to be performed later. Usually, water, methanol, ethanol, propyl alcohol, isopropyl alcohol, butanol, isopropanol are used. Lower alcohol such as butanol or hydrous lower alcohol, propylene glycol, 1,3-butylene glycol, 1,2-butylene glycol, 1,4-butylene glycol, 1,5-pentanediol, 1,2-pentanediol, 1, 3-pentanediol, 1,4-pentanediol, 1,3,5-pentanetriol, 1,2-hexanediol, 1,5-hexanediol, 1,6-hexanediol, pentylene glycol, hexylene glycol, Polyhydric alcohols such as glycerin and polyethylene glycol (molecular weight 100 to 100,000) or hydrous polyhydric alcohols, aceto Various organic solvents such as ethyl acetate, diethyl ether, dimethyl ether, ethyl methyl ether, dioxane, acetonitrile, xylene, benzene, chloroform, carbon tetrachloride, phenol, toluene, and acids (hydrochloric acid, sulfuric acid, nitric acid) , Phosphoric acid, formic acid, acetic acid, etc.) and alkalis (sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia, etc.) are preferably used. However, when it is not preferable to contain a solvent depending on the application, it is sufficient to use only water or ethanol which can be easily removed after extraction and used alone or in any mixed solution with water. It may be extracted after squeezing.

  Regarding the extraction method, the temperature of the solvent, the weight ratio of the solvent to the raw material, or the extraction time can be arbitrarily set for various raw materials and the solvent used. The temperature of the solvent can be arbitrarily set in the range of −4 ° C. to 100 ° C., but is preferably around 10 to 40 ° C. from the viewpoint of the stability of the components contained in the raw material. Further, the weight ratio of the solvent to the raw material can be arbitrarily set within the range of, for example, raw material: solvent 4: 1 to 1: 100, and a weight ratio of 1: 1 to 1:10 is particularly preferable.

  Decomposition mainly includes acid decomposition, alkali decomposition, enzyme decomposition, and high-temperature and high-pressure decomposition. In the decomposition with an acid, for example, it is preferable to use an inorganic acid or an organic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, formic acid, oxalic acid, hydrogen bromide, perchloric acid, and periodic acid. In the decomposition by alkali, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, barium hydroxide, sodium carbonate, ammonium carbonate, calcium carbonate, magnesium hydroxide, sodium silicate, etc. are preferably used. In the decomposition with acid or alkali, the concentration, reaction time, reaction temperature, and the like can be arbitrarily set for the target raw material. In the enzymatic degradation, it is preferable to use an enzyme having a function of degrading proteins, polysaccharides, lipids or complexes thereof having an important function particularly with respect to cell structure, tissue structure, etc., for example, aminopeptidase, dipeptidase, dipeptide Peptidyl peptidase, tripeptidyl peptidase, carboxypeptidase, serine protease, trypsin, chymotrypsin, cysteine protease, thiol protease, papain, aspartate endopeptidase, metalloendopeptidase, bromelain, thermolysin, pronase, pepsin, rennin, pan Proteolytic enzymes (proteases) such as creatine, chymopapain, ficin, collagenase, elastase, amylase, takaamylase, cellulase, hemicellular Polysaccharide-degrading enzymes such as pectinase, polygalacturonase, dextranase, planarase, chicken egg white lysozyme, human lysozyme, papaya lysozyme, turnip lysozyme, barley lysozyme, zymolyce, lysozyme chloride, glucanase, chitinase, etc. Cell wall lytic enzyme. In the degradation with an enzyme, the concentration, reaction time, reaction temperature, pH of the solution, etc. can be set arbitrarily, but it is particularly preferable to set the optimum value for the enzyme used.

  Fermentation or metabolic conversion by microorganisms can be performed by inoculating and growing at least one kind of microorganism on a raw material used as a substrate. Inoculation of microorganisms to the substrate can be done by adding microorganisms directly into the substrate, or by adsorbing them on a carrier such as alginic acid, polyvinyl, gelatin, etc., for example, in the form of fine beads composed of microorganisms and carrier. Further, it can be used by being fixed to the tube wall of the bioreactor. Fermentation or metabolic conversion by microorganisms is not particularly defined as a microorganism to be used, but can generally be defined as microorganisms other than pathogenic microorganisms that exhibit significant toxicity to living bodies. As the microorganism to be used, for example, as microorganisms classified into yeast, the genus Aciculoconidium, Actonia, Aessosporon, Ambrosiozyma, Anthomyces, Apiotrichum, Arthroascus, Arxula, Ashbia, Ashbya, Asporomyces, Atelosaccharomyces Genus, Azymoprocandida, Babjevia, Ballistosporomyces, Bensingtonia, Blastobotrys, Blastodendrion, Blastoderma, Blastoschizomyces, Botryoascus, Botryozyma, Brettanomyces, Brettanomyces bruno, Cullus Genus (Candida albicans, Candida amylolenta, Candida anomala, Candida boidinii, Candida entomaea, Candida etchellsii, Candida famata, Candida fermentati, Candida guilliermondii, Candida halophila, Candida krusei, Candida krusei, Candida krusei, Candida krusei, Candida krusei Candida sake, Candida tropicalis, Candida versatilis, Candida vulgaris, etc.), Castellani Genus a, Chlamydozyma, Chromotorula, Citeromyces, Cladosporium, Clavispora, Crebrothecium, Cryptococcus, Debaryomyces (Debaryomyces delbrueckii, Debaryomyces halotolerans, Debaryomyces hansenii etc.), Deberoozyma, Debaryozyma, Dipodascus, Eeniella, Endomyces, Endomycopsis, Eremascus, Eremothecium, Eutorulopsis, Fabospora, Fellomyces, Filobasidium, Galactomyces, Geotrichoides, Geotrichum, Guilliermondella, anomala, Hansenula kluyveri, Hansenula miso, Hansenula polymorpha, Hansenula wickerhamii etc.), Hypomyces, Issatchenkia, Kloeckera (Kloeckera brevis, Kloeckera fluoresceny, Kloeckera Etc.), Kockovaella genus, Kurtzmanomyces genus, Leucosporidium genus, Lipomyces genus, Metschnikowia , Microanthomyces genus, Monilia genus, Monospora genus, Monosporella genus, Mrakia genus, Myceloblastanon genus, Mycocandida genus, Mycoderma genus, Mycotorula genus, Mycotoruloides genus, Myxozyma genus, Nadsonia sp Genus, Oospora, Oosporidium, Pachysolen, Parasaccharomyces, Paratorulopsis, Parendomyces, Petasopsora, Pichia (Pichia amylophila, Pichia farinosa, Pichia guilliermondii, Pichia membranifaciens, Pichia moc Genus, Proteomyces genus, Pseudomonilia genus, Pseudosaccharomyces genus, Pseudozyma genus, Rhodomyces genus, Rhodosporidium genus, Rhodotorula genus, Saccharomyces genus (Saccharomyces aceti, Saccharomyces cerasi, Saccharomyces cerevisiae Genus, Saturnispora, Schizoblastosporion, Schizosaccharomyces, Schwanniomyces Selenotila genus, Selenozyma genus, Smithiozyma genus, Sporidiobolus genus, Sporobolomyces genus, Sporothrix genus, Stephanoascus genus, Sterigmatomyces genus, Sympodiomyces genus, Symingospora genus, Tetrapisispora genus, Torulaspora genus, Tordenpostomy genus, Torulopsiron genus, Torulopsisces genus Genus William, genus Williamopsis, genus Wingea, genus Xanthophyllomyces, genus Yamadazyma, genus Zendera, genus Zygofabospora, genus Zygopichia, genus Zygosaccharomyces, genus Zymodebaryomyces and the like. The microorganisms classified as bacteria include the genus Acetobacter (Acetobacter aceti, etc.), Achromobacter genus, Acidianus genus, Acidobacterium genus, Acidithiobacillus genus, Acrocarpospora genus, Actinoalloteichus genus, Actinocorallia genus, Actinokineospora genus, Actinomadospura genus, Actinomadspura Actinosynnema genus, Aerococcus genus, Aeromicrobium genus, Agrobacterium genus, Agromyces genus, Ahrensia genus, Alcaligenes genus, Alicyclobacillus genus, Alloiococcus spp. Aureobacterium genus, Azotobacter genus, Bacillus genus (Bacillus brevis, Bacillus subtilis etc.), Bacteroides genus, Beneckea genus, Bifidobacterium genus (Bifidobacterium bifidum, Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium infantis etc.), Brachybacterium genus, Brevicillus genus, Brevicillus, Brevundimonas, Burkholderia, Carnobacterium, Catellatospora, Cellulomonas sp Enterobacter sp Genus, Halobacterium genus, Halococcus genus, Herbidospora genus, Hydrogenophilus genus, Hyphomicrobium genus, Hyphomonas genus, Intrasporangium genus, Janibacter genus, Kinesia spp. Kocuria, Kurthia, Lactobacillus (Lactobacillus rimae, Lactobacillus divergens, Lactob acillus carnis, Lactobacillus piscicola, Lactobacillus acidophilus, Lactobacillus amylophilus, Lactobacillus animalis, Lactobacillus brevis, Lactobacillus casei, Lactobacillus curvatus, Lactobacillus bulgaricus, Lactobacillus delbrueckii, Lactobacillus fermentum, Lactobacillus fructivorans, Lactobacillus fructosus, Lactobacillus helveticus, Lactobacillus hilgardii, Lactobacillus homohiochii, Lactobacillus kefiri , Lactobacillus malefermentans, Lactobacillus murinus, Lactobacillus paracasei, Lactobacillus paracasei subsp. tolerans, Lactobacillus parakefiri, Lactobacillus pentosus, Lactobacillus plantarum, Lactobacillus reuteri, Lactobacillus rhamnosus, Lactobacillus sakei, Lactobacillus confusus, Lactobacillus viridescens, Lactobacillus johnsonii, Lactobacillus viscosus, Lactobacillus fermentatae, Lactobacillus acidophil-aerogenes, Lactobacillus leichmannii, Lactobacillus gasseri, Lactobacillus bifidus, Lactobacillus jugurt, Lactobacillus caucasicus Lactobacillus arabinosus, Lactobacillus kunkeei, Lactobacillus nagelii, Lactobacillus fornicalis, Lactobacillus pentoaceticus, Lactobacillus xylosus, Lactobacillus minutus, etc.), Leuconostoc genus (Leuconostoc lactis, Leuconostoc dextranicum, Leuconostoc mesenteroides, Leuconostoc oenos, Leuconostoc paramesenteroides, Leuconostoc cremoris, such as Leuconostoc citrovorum), Listonella Genus, Lucibacterium genus, Luteococcus genus, Magnetospirillum genus, Marinilabilia genus, Marinospirillum genus Mesorhizobium genus, Metallosphaera genus, Methylobacterium genus, Microbispora genus, Micrococcus genus, Microellobosporia genus, Micromonospora genus, Mycobacterium genus, Nocoides genus, Noiaides Genus, Nonomuria, Oceanospirillum, Ochrobactrum, Oerskovia, Oligella, Paenibacillus, Pediococcus (Pediococcus cerevisiae, Pediococcus pentosaceus, Pediococcus urinae-equi etc.), Pedobacterto, Pedobacterto , Planobispora, Planococcus, Planomonospora, Prevotella, Propionibacterium, Proteus, Protomonas, Pseudomonas, Pseudonocardia, Rahnella, Rarobacter, Rathayibacter, Rhizobium, Rhizomonas , Rhodospirillum genus, Rothia genus, Rubrobacter genus, Ruegeria genus, Saccharomonospora genus, Saccharothrix genus, Serratia genus, Sinorhizobium genus, Sphingobacterium genus, Sphingomonas genus, Sporolactobacillus genus, Stenotrophomonas genus, Streptoalloteococ genus Streptoalloteococ faecium, Streptococcus bovis, Streptococcus equinus, Streptococcus mutans, Streptococcus salivarius, Streptococcus thermophilus, Streptococcus agalactiae, Streptococcus mitis, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus lactisdy uberis, Streptococcus cremoris, Streptococcus diacetilactis, etc.), Streptomyces genus, Streptosporangium genus, Streptoverticillium genus, Terrabacter genus, Thermoactinomyces genus, Thermobifida genus, Thermobispora genus, Thermohispera genus, Thermohispa genus, Thermopispa genus, Thermopispa genus, Thermopispa genus Genus, Xanthobacter genus, Xanthomonas genus, Zymomonas genus and the like. Microorganisms classified as ascomycetes, basidiomycetes or incomplete fungi other than yeast include Allomyces, Amoebidium, Amorphotheca, Arthroderma, Ascoidea, Ascobolus, Ascodesmis, Aspergillus, Aureobasidium, Botryosphaeria Botryotinia sp Genus, Dothidea genus, Endogone genus, Entomophthora genus, Emericella genus, Eupenicillium genus, Eurotium genus, Exobasidium genus, Gibberella genus, Glomus genus, Graphiola genus, Gymnoascus genus, Harpella genus, Helicomyces genus, Helvella genus, Hemicarpenteles genus, Hyphochytrium genus, Hyphochytrium Hypocrea, Laboulbenia, Labyrinthula, Leptosphaeria, Leptosphaerulina, Lophodermium, Melanotaenium, Microascus, Microstroma, Medeololaria, Melampsora , Melamsporella, Morchella, Monascus, Monilinia, Mycospharella, Nannizzia, Nectria, Neolecta, Neurospora, Nodulosphaeria, Olpidium, Peziza, Penicillium, Perenospora, Pestopolisis Genus, Pneumocystis genus, Preussia genus, Pleospora genus, Puccinia genus, Pythium genus, Ravenelia genus, Rickia genus, Rhinocladiella genus, Rhizidiomyces genus, Rhizoctonia genus, Sclerocleista genus, Saprolegnia genus, Sclerotinia genus, Sclerotum genus, Septobasidium genus, Septobasidium genus Sporidiobolus genus, Stigmatomyces genus, Sydowiella genus, Talaromyces genus, Taphrina genus, Thraustochytrium genus, Tolyposporium genus, Trichoglossum genus, Trichoma genus, Ustilago genus, Verticillium genus, Xylaria genus and the like.

  In fermentation or metabolic conversion by microorganisms, in addition to various raw materials such as plant-based materials, animal-based materials, and other natural product-based materials, the growth and metabolism of microorganisms are regulated or activated, and special biosynthesis or degradation pathways are induced. In order to achieve this, various compounds can be added to the raw material. For example, as a carbon source, sugar, ethane such as glucose, fructose, galactose, sucrose, maltose, mannose, lactose, glycerin, starch, etc. , Hydrocarbons such as methane, propane, butane, formic acid, acetic acid, propionic acid, lauric acid, palmitic acid, fatty acids such as oleic acid, linoleic acid, linolenic acid, etc., nitrogen sources such as ammonium sulfate, ammonium hydrochloride, ammonium phosphate, etc. Ammonium salts, urea, uric acid, amino acids, etc. Vitamins and compounds containing potassium, calcium, magnesium, sodium, sulfur, phosphorus, chlorine, etc., as well as iron, copper, zinc, cobalt, nickel, boron, manganese, molybdenum, tin, selenium, silicon It is possible to further add compounds contained in the composition such as arsenic, vanadium, chromium and fluorine. In addition, the optimum temperature, oxygen supply amount, pH, pressure, etc. that affect the growth and metabolic activities of various microorganisms can be arbitrarily set according to the characteristics inherent to various microorganisms. Can be arbitrarily set within the range of 10 to 50 ° C., and the pH can be arbitrarily set within the range of 1 to 14.

  In fractionation or purification, generally known techniques can be used as appropriate. In addition to solvent extraction, for example, liquid chromatography (ion exchange chromatography, ion exclusion chromatography, affinity chromatography, gel filtration chromatography, size exclusion chromatography, etc.). Chromatography, hydrophilic adsorption chromatography, hydrophobic adsorption chromatography, ligand exchange chromatography, etc.), dialysis with semipermeable membrane, crystallization and recrystallization of components, filter paper, membrane filter, ultra filter, Examples thereof include filtration using activated carbon, filter aids, etc., centrifugal separation and its application, such as fractional precipitation method, density gradient separation method such as density gradient sedimentation equilibrium method, and the like.

Specific examples of other components used as additives in the preparation of the present invention include silica, magnesium silicate, talc, kaolin, bentonite, hectorite, natural or synthetic smectite, stevensite, mica, and mica titanium. , Inorganic pigments such as bismuth oxychloride, zirconium oxide, magnesium oxide, zinc oxide, titanium oxide, calcium carbonate, magnesium carbonate, yellow iron oxide, bengara, black iron oxide, gunjou, chromium oxide, chromium hydroxide, carbon black, calamine Hydrogen peroxide solution, sodium persulfate, ammonium persulfate, sodium perborate, urea peroxide, sodium percarbonate, sodium tripolyphosphate, sodium bromate, potassium bromate, sodium pyrophosphate, ortholine peroxide Sodium acid, Sodium iodate hydrogen peroxide adduct, sodium sulfate hydrogen peroxide adduct, sodium chloride hydrogen peroxide adduct, β-tyrosinase enzyme solution, mushroom extract, strontium sulfate, sodium sulfide, barium sulfide, calcium sulfide, etc. Reducing agents, redox agents such as thioglycolic acid or its salts (calcium thioglycolate, sodium thioglycolate, lithium thioglycolate, magnesium thioglycolate, strontium thioglycolate), 5-aminoorthocresol, 2-amino -4-nitrophenol, 2-amino-5-nitrophenol, 1-amino-4-methylaminoanthraquinone, 3,3'-iminodiphenol, 2,4-diaminophenoxyethanol hydrochloride, 2,4-diaminophenol hydrochloride, Toluene-2,5-diamine hydrochloride, nitroparaphenylene hydrochloride Amine, paraphenylenediamine hydrochloride, N-phenylparaphenylenediamine hydrochloride, metaphenylenediamine hydrochloride, orthoaminophenol, N-phenylparaphenylenediamine acetate, 1,4-diaminoanthraquinone, 2,6-diaminopyridine, 1,5- Dihydroxynaphthalene, toluene-2,5-diamine, toluene-3,4-diamine, nitroparaphenylenediamine, paraaminophenol, paranitroorthophenylenediamine, paraphenylenediamine, paramethylaminophenol, picramic acid, sodium picrate, N N′-bis (4-aminophenyl) -2,5-diamino-1,4-quinonediimine, 5- (2-hydroxyethylamino) -2-methylphenol, N-phenylparaphenylenediamine, metaaminophenol, Metaphenylenediamine, 5-aminoorthocresol sulfate , 2-amino-5-nitrophenol sulfate, orthoaminophenol sulfate, orthochloroparaphenylenediamine sulfate, 4,4'-diaminodiphenylamine sulfate, 2,4-diaminophenol sulfate, toluene-2,5-diamine sulfate, sulfuric acid Nitroparaphenylenediamine, paraaminophenol sulfate, paranitroorthophenylenediamine sulfate, paranitrometaphenylenediamine sulfate, paraphenylenediamine sulfate, paramethylaminophenol sulfate, metaaminophenol sulfate, metaphenylenediamine, catechol, diphenylamine, α- Natural movements such as naphthol, hydroquinone, phloroglucin, 2-hydroxy-5-nitro-2 ', 4'-diaminoazobenzene-5'-sulphonate, hematein and other dyes, musk, civet, castrium and ambergris Physical Flavor, Anise Essential Oil, Angelica Essential Oil, Ylang Ylang Essential Oil, Iris Essential Oil, Fennel Essential Oil, Orange Essential Oil, Kananga Essential Oil, Caraway Essential Oil, Cardamom Essential Oil, Guayak Wood Essential Oil, Cumin Essential Oil, Black Letter Essential Oil, Kei skin Essential Oil, Geranium Essential Oil, Copaiba Balsam Essential Oil , Coriander essential oil, perilla essential oil, cedarwood essential oil, citronella essential oil, jasmine essential oil, gingergrass essential oil, cedar essential oil, spearmint essential oil, western peppermint essential oil, otsuki aroma essential oil, tuberose essential oil, clove essential oil, orange flower essential oil, winter green essential oil, true Balsam essential oil, buttery essential oil, rose essential oil, palmarosa essential oil, cocoon essential oil, hiba essential oil, sandalwood essential oil, petit gren essential oil, bay essential oil, vetiva essential oil, bergamot essential oil, peru balsam essential oil, boadrose essential oil, melamine essential oil, mandarin essential oil, eucalyptus essential oil, Im essential oil, lavender essential oil, linaloe essential oil, lemongrass essential oil, lemon essential oil, rosemary essential oil, vegetable flavors such as Japanese mint essential oil, other synthetic flavors, 5-amino-o-cresol, o-aminophenol, m-aminophenol, p-aminophenol, 2,6-diaminopyridine, 5- (2-hydroxylethylamino) -2-methylphenol, N, N-bis (β-hydroxyl) -p-phenylenediamine sulfate, N, N-bis (2-hydroxyethyl) -p-phenylenediamine, p-nitro-o-phenylenediamine, p-phenylenediamine, m-phenylenediamine, N-phenyl-p-phenylenediamine, 2-hydroxy-5 -Nitro-2 ', 4'-diaminoazobenzenesodium sulfate, toluene-2,5-diamine, 2- (2'-hydroxyethylamino) -5-aminotoluene, N, N-bis (β-hydroxyl) -p -Phenylenediamine, N, N-bi (2-hydroxyethyl) -p-phenylenediamine sulfate, 5-amino-o-cresol sulfate, p-aminophenol sulfate, o-chloro-p-phenylenediamine sulfate, 2- (2'-hydroxy Ethylamino) -5-aminotoluene sulfate, 4,4'-diaminodiphenylamine sulfate, p-methylaminophenol sulfate, p-phenylenediamine sulfate, m-phenylenediamine sulfate, toluene-2,5-diamine Sulfate, 2,4-diaminophenoxyethanol hydrochloride, toluene-2,5-diamine hydrochloride, m-phenylenediamine hydrochloride, 2,4-diaminophenol hydrochloride, 3,3'-iminodiphenol, p-phenylene Diamine hydrochloride, N-phenyl-p-phenylenediamine hydrochloride, N-phenyl-p-phenylenediamine acetate, 1,5-dihydroxynaphthalene, toluene-3,4-diamine, p-methylaminophenol, N, N '-Bis (4- Minophenyl) -2,5-diamino-1,4-quinonediimine, o-aminophenol sulfate, 2,4-diaminophenol sulfate, m-aminophenol sulfate, 2-amino-4-nitrophenol, 2-amino -5-nitrophenol, 1-amino-4-methylaminoanthraquinone, nitro-p-phenylenediamine hydrochloride, 1,4-diaminoanthraquinone, nitro-p-phenylenediamine, picramic acid, sodium picrate, 2-amino- 5-nitrophenol sulfate, resorcinol, nitro-p-phenylenediamine sulfate, p-nitro-o-phenylenediamine sulfate, p-nitro-m-phenylenediamine sulfate, red No. 2, red No. 3, red 102 No., Red 104 (1), Red 105 (1), Red 106, Red 201, Red 227, Red 230 (1), Red 230 (2), Red 231, Red 232, Red 401, Red 502, Red 503, Red 504 , Red 506, yellow 4, yellow 5, yellow 202 (1), yellow 202 (2), yellow 203, yellow 402, yellow 403 (1), yellow 406, yellow 407, orange 205, orange 207, orange 402, green 3, green 204, green 205, green 205, green 401, green 402, brown 201, purple 401, blue 1, blue 2 , Blue 202, Blue 203, Blue 205, Black 401, Red cabbage dye, Red potato dye, Catechol tannin, Red rice dye, Akane dye, Anato dye, Ikumi dye, Turmeric dye, Enju dye, Krill dye, Amber pigment, Caramel, Gold, Silver, Gardenia pigment, Corn pigment, Onion pigment, Tamarind pigment, Spirulina pigment, Cherry pigment, Nori pigment, Hibiscus pigment, Grape juice pigment, Grape skin pigment, Marigold pigment, Purple potato pigment, Purple Dye and colorants such as yam pigment, lac pigment, rutin, avoca Oil, almond oil, fennel oil, sesame oil, olive oil, orange oil, orange raffer oil, sesame oil, cacao butter, chamomile oil, carrot oil, cucumber oil, beef tallow fatty acid, cucumber nut oil, safflower oil, shea butter, liquid shea Fat, soybean oil, camellia oil, corn oil, rapeseed oil, persic oil, castor oil, cottonseed oil, peanut oil, turtle oil, mink oil, egg yolk oil, palm oil, palm kernel oil, owl, coconut oil, beef tallow, lard Or oils and fats such as hydrogenated products (hardened oil, etc.), beeswax, carnauba wax, whale wax, lanolin, liquid lanolin, reduced lanolin, hard lanolin, candelilla wax, montan wax, shellac wax, rice wax, squalene, squalane, pristane Waxes, liquid paraffin, petrolatum, paraffin, ozokelide Mineral oils such as ceresin and microcristan wax, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, linoleic acid, linolenic acid, docosahexaenoic acid, eicosapentaenoic acid, 12-hydroxystearic acid, undecylenic acid, Natural fatty acids such as tall oil, lanolin fatty acid, isononanoic acid, caproic acid, 2-ethylbutanoic acid, isopentanoic acid, 2-methylpentanoic acid, 2-ethylhexanoic acid, isopentanoic acid and other fatty acids such as ethanol, isopyropanol , Lauryl alcohol, cetanol, stearyl alcohol, oleyl alcohol, lanolin alcohol, cholesterol, phytosterol, phenoxyethanol, and other natural alcohols, 2-hexyldecanol, isostearyl alcohol, 2-octyl Alcohols such as synthetic alcohols such as dodecanol, isopropyl myristate, isopropyl palmitate, butyl stearate, hexyl laurate, myristyl myristate, oleyl oleate, decyl oleate, octyldodecyl myristate, hexyldecyl dimethyloctanoate, adipine Diisobutyl acid, 2-hexyldecyl adipate, diheptylundecyl adipate, N-alkyl glycol monoisostearate, isocetyl isostearate, trimethylolpropane triisostearate, ethylene glycol diethyl hexanoate, neopentyl glycol diethyl hexanoate, 2- Cetyl ethylhexanoate, trimethylolpropane triethylhexanoate, pentaerythritol tetraethylhexanoate, octanoic acid Cetyl, octyldodecyl gum, cetyl lactate, myristyl lactate, diethyl phthalate, dibutyl phthalate, lanolin acetate, ethylene glycol monostearate, propylene glycol monostearate, propylene glycol dioleate, aluminum stearate, stearic acid Magnesium, zinc stearate, calcium stearate, zinc palmitate, magnesium myristate, zinc laurate, zinc undecylenate, etc., anionic surfactants (alkyl carboxylates, alkyl sulfonates, alkyl sulfates, Alkyl phosphate ester salts), alkyl sulfate ester salts (sodium lauryl sulfate, potassium lauryl sulfate, triethanolamine lauryl sulfate, ammonium lauryl sulfate, Sodium sulfate, sodium stearyl sulfate, etc.), secondary alcohol sulfate, alkyl ether sulfate (for example, polyoxyethylene lauryl sulfate triethanolamine, polyoxyethylene lauryl sodium sulfate, etc.), alkyl and alkyl allyl ether sulfates Salt (N-acyl methyl alanine salt, N-acyl glutamate, N-acyl methyl taurate, N-acyl isethionate, N-acyl glycine salt, alkyl phosphate, alkyl ether carboxylate, alkyl sulfonate, Alkylsulfosuccinate, sodium polyoxyethylene lauryl ether sulfate, polyoxyethylene lauryl ether sulfate triethanolamine, polyoxyethylene lauryl ether ammonium sulfate, polyoxyethylene alkyl ether Sodium tersulfate, polyoxyethylene alkyl ether triethanolamine sulfate, polyoxyethylene alkyl ether sulfate diethanolamine, polyoxyethylene alkyl ether ammonium sulfate, etc.), higher fatty acid alkylolamide sulfate, higher fatty acid ester sulfate (cured coconut oil) Fatty acid sodium glycerine sulfate, etc.), polyoxyethylene alkyl ether carboxylic acid, polyoxyethylene alkyl allyl ether carboxylate, sulfated oil such as sulfated castor oil, mono or dialkyl or alkenyl phosphate ester salt, polyoxyethylene mono or Dialkyl or alkenyl phosphate ester salts (sodium monolauryl phosphate, sodium isostearyl phosphate, arginine 2-hexyldecyl phosphate, 2-heptyl u Potassium decyl acid, polyoxyethylene (4-10) la
Sodium uryl ether phosphate, sodium monocetyl phosphate, arginine monomyristyl phosphate, sodium monooleyl phosphate, potassium polyoxyethylene (2-10) potassium lauryl ether, sodium dioctyl phosphate, etc.), polyoxyethylene alkyl ether phosphorus Acid ester salts (polyoxyethylene lauryl ether phosphate, polyoxyethylene oleyl ether phosphate, polyoxyethylene cetyl ether phosphate, polyoxyethylene stearyl ether phosphate, polyoxyethylene alkyl ether phosphate, polyoxyethylene alkyl phenyl ether Phosphoric acid, etc.), sulfonates of higher fatty acid amides or sulfonates of higher fatty acid esters (α-olefin sulfonate, N-myristoyl-N-methyltaurine sodium, coconut oil Fatty acid methyl taurine sodium, lauroyl methyl taurine sodium, etc.), alkylbenzene sulfonate (dodecylbenzenesulfonic acid, dodecylbenzenesulfonic acid monoethanolamine, dodecylbenzenesulfonic acid diethanolamine, dodecylbenzenesulfonic acid triethanolamine, dodecylbenzenesulfonic acid sodium salt) Etc.), sulfosuccinate (sodium diethylhexyl sulfosuccinate, sodium sulfosuccinate, disodium lauryl sulfosuccinate, disodium polyoxyethylene sulfosuccinate, disodium polyoxyethylene sulfosuccinate lauryl, polyoxyethylene lauroyl ethanolamide ester sulfosuccinate Sodium, disodium undecylenoylamidoethylsulfosuccinate, Nolauroyl monoethanolamide polyoxyethylene sodium sulfosuccinate, sodium lauryl polypropylene glycol sulfosuccinate, etc.), N-acyl sarcosine salts (eg, lauroyl sarcosine sodium, palmitoyl sarcosine sodium), condensates of higher fatty acids and amino acids (N-acyl glutamate) , Sodium N-stearoyl glutamate, potassium N-palmitoyl glutamate, sodium N-lauroyl-L-glutamate, disodium N-stearoyl-L-glutamate, sodium N-myristoyl-L-glutamate, sodium myristoyl methyl taurate, sodium palmitoyl methyl taurate , Stearoyl methyl taurine sodium, N-palmitoyl-β-alanine arginine, N-palmitoyl aspartate ditriethanola Anionic surfactants such as fatty acid soaps such as oleate, suarenate, laurate, palmitate, etc. (examples of anionic surfactant salts include alkali salts such as sodium salts and potassium salts). Metal salts, monoethanolamine salts, diethanolamine salts, triethanolamine salts, L-lysine salts, organic ammonium salts such as L-arginine salts, ammonium salts, etc.), quaternary ammonium salts (alkyltrimethylammonium chloride, Cetyl ammonium chloride, cetyl ammonium bromide, lauryl ammonium chloride, lauryl ammonium bromide, stearyl ammonium chloride, stearyl ammonium bromide, cetyl dimethyl ammonium chloride, cetyl dimethyl ammonium bromide, lauryl dimethyl ammonium chloride, stearyl dimethyl chloride Ruammonium, lauryltrimethylammonium chloride, lauryltrimethylammonium bromide, stearyldimethylcetylditallowdimethylammonium chloride, dicetylammonium chloride, dicetylammonium bromide, dilaurylammonium chloride, dilaurylammonium bromide, distearylammonium chloride, Distearylammonium bromide, dicetylmethylammonium chloride, dicetylmethylammonium bromide, dilaurylmethylammonium chloride, dilaurylmethylammonium bromide, distearylmethylammonium chloride, distearylmethylammonium bromide, cetyltrimethylammonium chloride, Cetyltrimethylammonium bromide, stearyltrimethylammonium chloride, stearyltrimethylammonium bromide, bromide Lauryltrimethylammonium chloride, dialkyldimethylammonium chloride, dicetyldimethylammonium chloride, distearyldimethylammonium chloride, dicocoyldimethylammonium chloride, myristyldimethylbenzylammonium chloride, stearyldimethylbenzylammonium chloride, ethyl lanolin sulfate fatty acid aminopropylethyldimethylammonium chloride Cetyltrimethylammonium chloride, stearyltrimethylammonium chloride, behenyltrimethylammonium chloride, behenyldimethylhydroxyethylammonium chloride, stearyldimethylbenzylammonium chloride, distearyldimethylammonium chloride, distearoylethylhydroxyethylmonium metasulfate, dicocoylethylhydroxyethylmolybdate Ummetasulfate, dipalmitoylethylhydroxyethylmonium metasulfate, and cetyltriethylammonium methylsulfate, alkyltrimethylammonium chloride, alkyldimethylbenzylammonium chloride, dialkyldimethylammonium chloride, alkyltrimethylammonium bromide, alkylpentaethoxyammonium chloride, ditallow Dimethyl ammonium chloride, ditallow dimethyl ammonium methyl sulfate, ditallow dipropyl ammonium phosphate, ditallow dimethyl ammonium nitrate, di (coconut alkyl) dimethyl ammonium chloride, di (coconut alkyl) dimethyl ammonium bromide, coconut ammonium chloride, stearamide propyl PG-dimonium chloride, stearua Dopropyl ethyl dimonium esosulphate, stearamide propyl dimethyl (myristyl acetate) ammonium chloride, stearamide propyl dimethyl cetearyl ammonium tosylate, stearamide propyl dimethyl ammonium chloride, stearamide propyl dimethyl ammonium lactate, ethyl lanolin sulfate Fatty acid aminopropylethyldimethylammonium, cationized cellulose, acyldiethylaminoethylamide, acyldimethylaminopropylamide, polyoxyethylene fatty acid amide, myristyldimethylamine oxide, N-lauryldimethylaminoacetic acid betaine, N-myristyldimethylaminoacetic acid betaine, N -Stearyldimethylaminoacetic acid betaine), bis fatty acid ester salts (hydroxypropyl-bis-laur) Amidopropyl-N, N-dimethylammonium chloride, hydroxypropyl-bis-myristate amidopropyl-N, N-dimethylammonium chloride, hydroxypropyl-bis-palmitic acid amidopropyl-N, N-dimethylammonium chloride, hydroxy Propyl-bis-stearic acid amidopropyl-N, N-dimethylammonium chloride, hydroxypropyl-bis-behenic acid amidopropyl-N, N-dimethylammonium chloride, hydroxypropyl-bis-oleic acid amidopropyl-N, N-dimethyl Ammonium chloride, hydroxypropyl-bis-isostearic acid amidopropyl-N, N-dimethylammonium chloride, hydroxypropyl-bis-coconut fatty acid amidopropyl-N, N-dimethylammonium chloride, hydroxypropyl-bis- Fatty acid amidopropyl-N, N-dimethylammonium chloride, hydroxypropyl-bis-tallow fatty acid amidopropyl-N, N-dimethylammonium chloride, hydroxypropyl-bis-lauric acid amidoethyl-N, N-diethylammonium chloride, hydroxy Propyl-bis-myristate amidoethyl-N, N-diethylammonium chloride, hydroxypropyl-bis-palmitamidoethyl-N, N-diethylammonium chloride, hydroxypropyl-bis-amidoethyl stearate-N, N-diethylammonium chloride, Hydroxypropyl-bis-behenamidoethyl-N, N-diethylammonium chloride, hydroxypropyl-bis-oleic acidamidoethylammonium chloride, hydroxypropyl-bis-isostearic acid amide Chill-N, N-diethylammonium chloride, hydroxypropyl-bis-coconut fatty acid amidoethyl-N, N-diethylammonium chloride, hydroxypropyl-bis-palm fatty acid amidoethyl-N, N-diethylammonium chloride, hydroxypropyl-bis-tallow Fatty acid amidoethyl-N, N-diethylammonium chloride, hydroxypropyl-bis-lauric acid amidopropyl-N, N-diethylammonium chloride, hydroxypropyl-bis-myristic amidopropyl-N, N-diethylammonium chloride, hydroxypropyl- Bis-palmitic acid amidopropyl-N, N-diethylammonium chloride, hydroxypropyl-bis-stearic acid amidopropyl-N, N-diethylammonium chloride, hydroxypropyl-bis-behenic acid amidopropyl- N, N-diethylammonium chloride, hydroxypropyl-bis-oleic acid amidopropyl-N, N-diethylammonium chloride, hydroxypropyl-bis-isostearic acid amidopropyl-N, N-diethylammonium chloride, hydroxypropyl-bis-coconut Fatty acid amidopropyl-N, N-diethylammonium chloride, hydroxypropyl-bis-palm fatty acid amidopropyl-N, N-diethylammonium chloride, hydroxypropyl-bis-tallow fatty acid amidopropyl-N, N-diethylammonium chloride), Stearamidepropyl PG-dimonium chloride phosphate, behenamidopropyl PG dimonium chloride, stearamidepropylethyldimonium ethosulphate, stearamidepropyldimethyl (myristyl acetate) chloride Cationic surfactants such as nium, stearamidepropyldimethylcetearylammonium tosylate, stearamidepropyldimethylammonium chloride, stearamidepropyldimethylammonium lactate, glycerin fatty acid esters (glyceryl monoundecylenate, glyceryl diundecylenate) Glyceryl monomyristate, glyceryl dimyristate, glyceryl monopalmitate, glyceryl dipalmitate, glyceryl monostearate, glyceryl distearate, glyceryl monooleate, mono cottonseed oil fatty acid glycerin, glyceryl monoerucate, glyceryl sesquioleate, mono Glyceryl stearate, α, α'-oleic acid pyroglutamate glycerin, glyceryl monostearate malate, etc.), polyglycerin Fatty acid esters (diglyceryl monomyristate, diglyceryl dimyristate, diglyceryl trimyristate, diglyceryl monopalmitate, diglyceryl dipalmitate, diglyceryl tripalmitate, diglyceryl monostearate, diglyceryl distearate) Diglyceryl tristearate, diglyceryl monooleate, diglyceryl dioleate, diglyceryl trioleate, tetraglyceryl monopalmitate, tetraglyceryl dipalmitate, tetraglyceryl tripalmitate, tetraglyceryl tetrapalmitate, pentapalmitin Tetraglyceryl acid, tetraglyceryl monostearate, tetraglyceryl distearate, tetraglyceryl tristearate, tetraglyceryl tetrastearate , Tetraglyceryl pentastearate, tetraglyceryl monooleate, tetraglyceryl dioleate, tetraglyceryl trioleate, tetraglyceryl tetraoleate, tetraglyceryl pentaoleate, hexaglyceryl monopalmitate, hexaglyceryl dipalmitate, tri Hexaglyceryl palmitate, hexaglyceryl tetrapalmitate, hexaglyceryl pentapalmitate, hexaglyceryl monostearate, hexaglyceryl distearate, hexaglyceryl tristearate, hexaglyceryl tetrastearate, hexaglyceryl pentastearate, hexaoleate monooleate Glyceryl, hexaglyceryl dioleate, hexaglyceryl trioleate, hexaglyceryl tetraoleate Lil, penta oleic hexaglyceryl monopalmitate decaglyceryl dipalmitate decaglyceryl, decaglyceryl tripalmitate, Tet
Decaglyceryl lapalmitate, decaglyceryl pentapalmitate, decaglyceryl hexapalmitate, decaglyceryl heptapalmitate, decaglyceryl octapalmitate, decaglyceryl nonapalmitate, decaglyceryl monostearate, decaglyceryl monostearate, distearic acid Decaglyceryl, Decaglyceryl tristearate, Decaglyceryl tetrastearate, Decaglyceryl pentastearate, Decaglyceryl hexastearate, Decaglyceryl heptearate, Decaglyceryl octastearate, Decaglyceryl nonostearate, Decaglyceryl decastearate , Decaglyceryl monooleate, Decaglyceryl dioleate, Decaglyceryl trioleate, Decatetraoleate Lyceryl, decaglyceryl pentaoleate, decaglyceryl hexaoleate, decaglyceryl heptaoleate, decaglyceryl octaoleate, decaglyceryl nonaoleate, decaglyceryl monohydroxystearate, decaglyceryl dihydroxystearate, decaglyceryl dihydroxystearate, tri Decaglyceryl hydroxystearate, decaglyceryl tetrahydroxystearate, decaglyceryl pentahydroxystearate, decaglyceryl hexahydroxystearate, decaglyceryl heptahydroxystearate, decaglyceryl octahydroxystearate, decaglyceryl nonahydroxystearate, decahydroxyl Decaglyceryl stearate, hexaglyceryl polyricinoleate, poly Decaglyceryl synolate, polyoxyethylene glyceryl monostearate, polyoxyethylene glyceryl distearate, polyoxyethylene glyceryl monooleate, polyoxyethylene glyceryl monomyristic acid), polyoxyethylene glycerin fatty acid ester (polyoxyethylene glyceryl monoester) Stearate, polyoxyethylene glycerol monoisostearate, polyoxyethylene glycerol triisostearate, etc.), sorbitan fatty acid ester (sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, sorbitan monopalmitate) Sorbitan monostearate, sorbitan distearate, sorbitan dioleate, sorbitan monopalmitate, Sorbitan ristearate, sorbitan trioleate, diglycerin sorbitan penta-2-ethylhexylate, diglycerin sorbitan tetra-2-ethylhexylate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polypalmitate monopalmitate Oxyethylene sorbitan, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, polyoxyethylene sorbitan pentaoleate, propylene glycol fatty acid ester (propylene glycol monooctanoate, propylene glycol monodecanoate, propylene glycol monostearate) ), Sucrose fatty acid ester (monolauric acid sucrose ester, dilauric acid sucrose ester, monopalmitic acid sucrose Ester, dipalmitic acid sucrose ester, monostearic acid sucrose ester, distearic acid sucrose ester, etc.), dextrin fatty acid ester (such as dextrin palmitate), coconut oil fatty acid alkanolamide, polyoxyethylene castor oil, polyoxyethylene cured Castor oil, polyoxyethylene hydrogenated castor oil monoisostearate, polyoxyethylene hydrogenated castor oil triisostearate, polyoxyethylene hydrogenated castor oil monopyroglutamic acid monoisostearate diester, polyoxyethylene hydrogenated castor oil maleic acid, polyoxy Ethylene alkyl ether (alkyl polyglucoside, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene behenyl ether, polyoxyethylene Rail ether, polyoxyethylene lauryl ether, polyoxyethylene-2-octyldodecyl ether, polyoxyethylene cholestanol ether, etc.), polyoxyethylene alkylphenyl ether (polyoxyethylene nonylphenyl ether, polyoxyethylene octylphenyl ether, etc.) , Polyoxyethylene fatty acid esters (polyethylene glycol monooleate, polyethylene glycol monostearate, polyethylene glycol monolaurate, etc.), lanolin derivatives (polyoxyethylene lanolin, polyoxyethylene lanolin alcohol, polyoxyethylene sorbitol lanolin, etc.), POE POP-alkyl ether (POE / POP-cetyl ether, POE / POP-2-decyltetradecyl ether, POE / POP-monobutyl ether, POE / POP-water Nonionic surfactants such as lanolin, POE / POP-glycerin ether, tetronic, etc.), alkanolamides (coconut oil fatty acid diethanolamide, lauric acid monoethanolamide, fatty acid isopropanolamide, etc.), betaine-type amphoteric surfactants (2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine, lauryldimethylaminoacetic acid betaine, sodium undecylcarboxymethoxyethylcarboxymethylimidazolinium betaine, sodium undecylhydroxyethylimidazolinium betaine, undecyl- N-hydroxyethyl-N-carboxymethylimidazolinium betaine, alkyldiaminoethylglycine hydrochloride, stearyl dihydroxyethyl betaine, stearyldimethylaminoacetic acid betaine, stear Lildimethylbetaine solution, coconut oil alkyl-N-carboxyethyl-N-hydroxyethylimidazolinium betaine sodium, coconut oil alkylbetaine, coconut oil alkyldimethylaminoacetic acid betaine, coconut oil fatty acid amidopropyl betaine, coconut oil fatty acid-N -Carboxymethoxyethyl-N-carboxyethylimidazolinium betaine sodium, N-lauroyl-N'-carboxymethyl-N'-hydroxyethylethylenediamine sodium, N-cocoyl-N'-carboxymethyl-N'-hydroxyethylethylenediamine sodium , Lauryldimethylaminoacetic acid hydroxysulfobetaine, palm oil alkyldimethylaminoacetic acid hydroxysulfobetaine, laurylaminopropionic acid triethanolamine, β-laurylaminopropionic acid sodium salt, Amidopropyl dimethylaminoacetic acid betaine laurate, Amidopropyl dimethylaminoacetate hydroxysulfobetaine, fatty acid amidopropyldimethylaminoacetic acid hydroxysulfobetaine, Palm oil fatty acid amidopropyldimethylaminoacetic acid hydroxysulfobetaine, Palm oil fatty acid amidopropyldimethyl Aminoacetic acid betaine, palm oil fatty acid amidopropyldimethylaminoacetic acid betaine, lauryl-N-carboxymethoxyethyl-N-carboxymethylimidazolinium disodium dodecanoyl sarcosine, sodium lauryldiaminoethylglycine, lauric acid amidopropyl betaine solution, lauryl sulfo Betaine, laurylhydroxysulfobetaine, 2-heptadecyl-N-carboxymethyl-N-hydroxyethylimidazo Nitrobetaine, Cocodimethylcarboxymethylbetaine, Lauryldimethylcarboxymethylbetaine, Lauryldimethylalphacarboxyethylbetaine, Cetyldimethylcarboxymethylbetaine, Cetyldimethylbetaine, Laurylbis- (2-hydroxyethyl) carboxymethylbetaine, Stearylbis- (2- (Hydroxypropyl) carboxymethylbetaine, oleyldimethylgamma-carboxypropylbetaine, laurylbis- (2-hydroxypropyl) alpha-carboxyethylbetaine, cocodimethylsulfopropylbetaine, stearyldimethylsulfopropylbetaine, lauryldimethylsulfoethylbetaine, laurylbis- ( 2-Hydroxyethyl) sulfopropylbetaine, Levon 2000 (Sanyo Kasei), palm oil fatty acid amide pro Pyrdimethylbetaine, palm oil fatty acid amidopropylsulfobetaine, imidazolinium type amphoteric surfactant (bis (stearyl-N-hydroxyethylimidazoline) chloroacetic acid complex, N-alkyl-N-carboxymethyl-N-hydroxyethylimidazo Linium betaine, N-alkyl-N-carboxymethyl-N-hydroxyethylethylenediamine lauryl sulfate and its salts, coconut oil alkyl-N-carboxyethoxyethyl-N-carboxyethylimidazolinium disodium hydroxide, coconut oil alkyl -N-carboxymethoxyethyl-N-carboxyethylimidazolinium disodium hydroxide, palm oil alkyl-N-carboxymethoxyethyl-N-carboxyethylimidazolinium disodium lauryl sulfate, 2-undecyl-N, N, N -(Hydroxyethylcarboxyme 2) -2-imidazoline sodium, 2-cocoyl-2-imidazolinium hydroxide-1-carboxyethyloxy disodium salt, ovazoline 662 (Toho Chemical Co., Ltd.), Swanol AM-101 (Nikko Chemicals Co., Ltd.), aminopropion Acidic amphoteric surfactant (alkylaminopropionic acid such as sodium dodecylaminopropionate, alkylaminodipropionic acid, etc.), sodium dodecylaminopropanesulfonate, N-higher alkylaspartic acid or its salt, coamidopropyl chlorinated polyethylene glycol Dimonium phosphate, cocamidopropyl hydroxysultain, sodium lauroyl sarcosinate, alkylamine oxide (decylamine oxide, cocoamine oxide, myristoylamine oxide, palmitoylamine oxide, alkyldimethylamine oxide) Amphoteric surfactants such as xoxide, alkylamidopropylamine oxide), natural surfactants (lecithin, sodium caseinate, sphingolipid, saponin, mannosyl polyhydric alcohol fatty acid ester, glucosyl polyhydric alcohol fatty acid ester, galactosyl polyhydric alcohol) Monosaccharide polyhydric alcohol fatty acid esters such as fatty acid esters or disaccharide polyhydric alcohol fatty acid esters, oligosaccharide polyhydric alcohol fatty acid esters, etc.) and amino acid surfactants (capric acid chloride, lauric acid chloride, myristic acid chloride, palmitic acid) Fatty acid chlorides such as chloride, stearic acid chloride, oleic acid chloride, behenic acid chloride, coconut oil fatty acid chloride and glycine, sarcosine, β-alanine, N-methyl-β-alanine, taurine, N- Reactants with amino acids in a broad sense such as tiltaurine), silicone surfactants (silicon KF-6011 (manufactured by Shin-Etsu Chemical Co., Ltd.), KF-6012 (manufactured by Shin-Etsu Chemical Co., Ltd.), KF-6013 (manufactured by Shin-Etsu Chemical Co., Ltd.) ), KF-6015 (Shin-Etsu Chemical Co., Ltd.), KF-6016 (Shin-Etsu Chemical Co., Ltd.), KF-6017 (Shin-Etsu Chemical Co., Ltd.), X-22-4991 (Shin-Etsu Chemical Co., Ltd.), NUC Silicon Polyoxyalkylene-modified organopolysiloxanes such as L7002 (Nippon Unicar), SH-3772C (Toray Dow Corning Silicone), SH-3775C (Toray Dow Corning Silicone), ABIL EM-90 (Gold Schmidt) ), ABIL B9806 (manufactured by Goldschmidt), silicone KF-6026 (manufactured by Shin-Etsu Chemical Co., Ltd.), etc., long-chain alkyl-containing polyoxyalkylene-modified organopolysiloxane), polyether-modified silicone (polyoxyethylene, methylpoly) Siloxane copolymer, poly (oxyethylene Oxypropylene) methylpolysiloxane copolymer, etc.), oxazoline-modified organopolysiloxane, alkyl-modified organopolysiloxane, styryl ketone silicone derivatives, dimethylpolysiloxane, methylphenylpolysiloxane, epoxy-modified silicone, fluorine-modified silicone, alcohol-modified Silicone, alkyl-modified silicone, alkoxy-modified silicone, amino-modified silicone, ammonium-modified polymer silicone, organopolysiloxane, methylphenylpolysiloxane, polysiloxane, poly (N-acylalkyleneimine) -modified silicone, dimethylpolysiloxane, nitrogen-containing acrylic -Silicone-based graft copolymer, decamethylcyclopentasiloxane, fluorine-substituted alkyl-modified silicone, organopolysiloxane Kisa alkenyl silyl alkyl-modified silicone, tricyclic Jiteru Bae Nkarubon acid-modified silicone, trifluoroalkyl-modified silica
Corn, divinylpolydimethylsiloxane, dihydrogenpolydimethylsiloxane, dihydrogenpolydimethylsiloxane divinylpolydimethylsiloxane polymer, trimethylsiloxysilicate, polyoxypropylene / methylpolysiloxane copolymer, ethylpolysiloxane, ethylmethylpolysiloxane, Ethylphenyl polysiloxane, octamethylcyclotetrasiloxane, diorganopolysiloxane, octamethylcyclotetrasiloxane, tetramethyltetraphenyltetracyclosiloxane, polyether modified polysiloxane, amino modified polysiloxane, epoxy modified polysiloxane, fluorine modified poly Siloxane, alcohol-modified polysiloxane, alkyl-modified polysiloxane, dodecamethylcyclohexasiloxane, lauric Methicone copolyol, aminoethylaminopropylsiloxane / dimethylsiloxane copolymer, silicone compounds such as eugenol-modified silicone, selenium disulfide, alkylisoquinolinium bromide, zinc pyrithione, biphenamine, thianthol, quinine hydrochloride, strong ammonia water, etc. And the like.

  Others, hormones, sequestering agents, pH adjusters, chelating agents, antiseptic / antibacterial agents, refreshing agents, stabilizers, emulsifiers, animal / plant proteins and their degradation products, animal / plant polysaccharides and their Degradation products, animal / plant glycoproteins and their degradation products, anti-inflammatory agents, antiallergic agents, wound treatment agents, foaming agents, thickeners, enzymes, purified water (electronic water, small clustering, etc.), deodorant / A deodorant etc. can be used in combination.

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

[Production Example 1]
A 50% EtOH extract (500 mL) of rhubarb rhizome was adsorbed on a synthetic adsorption resin (Diaion HP20, manufactured by Mitsubishi Chemical Corporation), washed with an EtOH aqueous solution, and then eluted with EtOH. The EtOH elution fraction was subjected to silica gel column chromatography and eluted with a chloroform-methanol solvent while changing the mixing ratio. Further, among the fractions with the highest activity, fractionation was performed for each peak using HPLC with absorption wavelengths of UV 280 nm and 330 nm as indices. The activity of these fractions was evaluated, and the strongest fraction was selected. As a result, 3 mg of cardamonin yellow crystals were obtained.
Identification result of the above cardamonin
MS spectrum (JMS-DX300 (JEOL)), EIMS m / z (rel.int.): 270 (48, M ⁺ ), 193 (100), 167 (45)

NMR spectrum (JNM-AL-400 (JEOL))
¹ H-NMR (400 MHz, acetone-d ₆ ): 3.92 (3H, s, C6′-OCH ₃ ), 5.87 (1H, d, J = 2 Hz, C3′-H), 5.95 (1H, d, J = 2Hz, C5'-H), 7.39-7.45, 7.66-7.70, (5H, m, C2-C6-H), 7.68, 8.05 (1H, d, J = 16Hz, CH = CH), 14.10 (1H, brs , C2'-OH)

[Example 1]
Undifferentiated C2C12, a cultured cell derived from mouse white muscle, was used. Culture in DMEM medium containing fetal bovine serum (FBS). After 12 hours of pre-culture, cardamonin obtained in Production Example 1 was added. Cells were harvested after 8 hours incubation. The final concentrations of cardamonin added after preculture were 0.2 μg / ml, 1 μg / ml, 5 μg / ml, and 25 μg / ml. The activation signal is based on the activation (phosphorylation) levels of Akt, mTOR and p70S6K in order to see the signal pathway upstream and downstream of mTOR activation. Each phosphorylation level was expressed by obtaining a value of [phosphorylated form / total protein] from a band detected by Western blotting using an antibody against each total protein and phosphorylated form. The control [phosphorylated form / total protein amount] was 1.

[Results of Examples]
As a result of examining the effect of cardamonin on muscle cells, it was confirmed that all signals of Akt, mTOR, and p70S6K had an activating effect as compared with the case where cardamonin was not added. The results are shown in FIGS. Thus, it was found that the muscle strengthening system is activated.

  The present invention relates to a preparation used to activate Akt-mTOR-p70S6K of the muscle strengthening system, for example, in the form of internal use or external use for preventing muscle strength increase or maintenance, or muscle strength decrease due to aging. To provide a preparation that is applied to the human body. Moreover, it can provide to a pharmaceutical, food-drinks, and also cosmetics composition.

Claims (6)

A formulation used to activate Akt-mTOR-p70S6K, a muscle-enhancing system, which comprises a compound represented by the following formula 1 as an active ingredient.

: Formula 1
[R ^{1 to} R ^{3 in} Formula 1 each independently represents a hydrogen atom, a hydroxyl group, or a linear alkoxy group having 1 to 5 carbon atoms. R ^{4 in} Formula 1 independently represents a hydroxyl group, a linear alkyl group having 1 to 3 carbon atoms, or a linear alkoxy group having 1 to 3 carbon atoms, and n in Formula 1 is an arbitrary number of 0 to 5 Indicates an integer. ]   The preparation according to claim 1, which is used for preventing muscle strength reduction or muscle strength maintenance due to muscular strength enhancement or muscular strength maintenance or aging.   3. The preparation according to claim 1, wherein the compound represented by Formula 1 is cardamonin.   4. The preparation according to claim 1, wherein the dosage form of the preparation is an internal or external form.   Akt characterized by applying a preparation containing the compound represented by formula 1 as an active ingredient to a human body in an internal or external form in order to increase or maintain muscle strength or prevent muscle strength decrease due to aging. -Method of activating the muscle enhancement response of mTOR-p70S6K.   6. The method for activating a muscle enhancing reaction according to claim 5, wherein the compound represented by Formula 1 is cardamonin.

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