JP2013129617A - Tryptase activity inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a safe tryptase activity inhibitor that is effective for treatment or prevention to diseases of itching, wrinkle, rough dry skin, whole body anaphylaxis, asthma, a stromal lung disease, stromal cystitis, atopy, pain, gingivitis, chronicity indirect rheumatism, arthritis, a periodontal disease, pollinosis or the like.SOLUTION: The tryptase activity inhibitor contains a flower head extract of (Paeoniaceae) (Paeonia) Paeonia lactiflora Pallas(=P. albiflora Pallas) as an active ingredient.

Description

  The present invention relates to a tryptase activity inhibitor. More specifically, the present invention provides a safe tryptase activity inhibitor containing a flower head extract of the genus Buttonaceae as an active ingredient.

Tryptase is an intracellular trypsin-type protease isolated and purified from human lungs in 1984 by Smith et al.

TJSmith, MW Hougland, DAJohnson, J. Biol. Chem. 259, P11046 (1984) Tryptase 1) cleaves the C-terminus of basic amino acids (especially arginine) in the same way as trypsin. It is considered to belong to a trypsin type protease because it decomposes and 3) the protease activity is inhibited by the trypsin inhibitor group. However, tryptase is not capable of decomposing 1) Arg-MCA (arginine-methylcoumarinamide) and Arg-bNA (arginine-β-naphthylamide), which are artificial substrates that trypsin degrades very well. 2) Degraded by trypsin. Degrading Boc-Ile-Gly-Arg-MCA (t-butoxycarbonyl-isoleucine-glycine-arginine-methylcoumarinamide) which is an artificial substrate of blood coagulation factor Xa which is difficult to be treated 3) Trypsin is prothrombin However, trypsin is classified as a family with different properties because it restricts prothrombin to generate thrombin. Also, tryptase and other proteases (for example, plasmin, thrombin, kallikrein, elastase, etc.) are completely different in terms of structure, localized cells and physiological action.

  Tryptase is a natural anti-protease that modulates the activity of other trypsin-like serine proteinases, such as mucus protease inhibitors (= anti-leucoprotease or HUSI-I), antithrombin III, α1-proteinase inhibitors, α2-macroglobulin, Or it is said that it is not inhibited by C1-esterase inhibitor.

Although tryptase is known to exist in the following cells, the structure differs depending on the localized cells.
(1) Mast cell tryptase (tryptase M)
Tryptase M is localized in a soluble state in histamine granules of typical (connective tissue) mast cells, atypical (mucosal) mast cells and basophils. Human tryptase M was isolated and purified by Schwartz et al.

LBSchwartz, RALewis, KFAnsten: J. Biol. Chem. 256, P11939 (1981) This enzyme is a heterotetramer with a molecular weight of 144,000 composed of two subunit molecules with a molecular weight of 37,000 and two subunit molecules with a molecular weight of 35,000. (2) Tryptase of T4 lymphocytes (tryptase TL1, TL2, TL3) Tryptases TL1, TL2, and TL3 were isolated and purified by Kido and Katsunuma et al. From a large-scale cultured cell of Molt4, clone 8 strain, which is a kind of T4 lymphocytes. H. Kido, A. Fukutomi, N. Katunuma: J. Biol. Chem. 265, P21979 (1991) Tryptase TL1 and tryptase TL2 were purified from the cell membrane, and tryptase TL3 was purified from the Golgi apparatus. (3) Clara Cell Tryptase (Tryptase Clara) Tryptase Clara was isolated and purified from bronchial mucosal secretory cells (Clara cells) by Kido, Katsunuma et al. H. Kido, Y. Yokogoshi, K. Sakai, M. Tashiro, Y. Kishino, A. Fukutomi, N. Katunuma: J. Biol. Chem. 267, P13573 (1992) The molecular weight of this enzyme is in the presence of a reducing agent. It is 30,000 by SDS-PAGE (SDS-polyacrylamide gel electrophoresis) and 180,000 by gel filtration.

Regarding the relationship between tryptase and various diseases, it has been reported that the tryptase concentration is higher than usual in the following patients.
• Patients with mastocytosis, and patients after systemic anaphylaxis (Schwartz Metcalfe, 1987; Schwartz Yunginger, 1989).

• Patients with a systemic response after aspirin challenge in patients with aspirin-sensitive asthma (especially in their plasma) (Bosso Schwartz, 1991).

• Patients with asthma (Broide Gleich, 1991; Bousquet Chanez, 1991, WenzelFowler, 1988).

• Patients with interstitial lung disease (Walls Bennett, 1991).

• Patients with interstitial cystitis (Theoharides TC, Kempuraj D, Sant GR., 2001).

• Patients with irritable bowel syndrome (Pang X, Boucher W, Triadafilopoulos G, Sant GR, Theoharides TC, 1996).

-Allergic patients after antigenic challenge infection (especially in their bronchoalveolar lavage fluid) (Castells, 1988; Butrus, 1990).
• Patients with atopic and allergic skin (especially in skin blister fluid after skin antigen challenge) (Shalit Schwartz, 1990; Atkins Schw-artz, 1990).

• Patients with seasonal allergic rhinitis (especially in nasal lavage after topical antigen challenge) (Juliusson Holmberg, 1991).

• Patients with gingivitis and periodontitis (especially in their gingival exudates) (Cox Eley, 1989, J Period Res; Eley Cox, 1992, J Dent).

• Patients with psoriasis (especially in their diseased skin) (Harvima Naukkarinen, 1989).

Furthermore, it has also been confirmed in vitro that tryptase is directly related to the pathogenesis of mast cell-related diseases, according to which tryptase increases airway smooth muscle contractility (Sekizawa, 1989), it is known to destroy the bronchodilating action by inactivating vasoactive intestinal peptides (TamCaughey, 1990; TamFranconi, 1990; Franconi, 1989). Thus, it was proposed that tryptase is a pathogenic mediator of asthma. Tryptase has also been shown to be a potent fibroblast mitogen and has been reported to be associated with pulmonary fibrosis in asthma and interstitial lung disease (Ruoss Hartmann, 1991; Hartmann Ruoss, 1992). It is known that tryptase released from mast cells found in chronic indirect rheumatic sites enhances collagenase activity. (Non-Patent Document 5)

Gruber BL: J.Immunol 140, P3936-3942 (1988)

Tryptase activates prostromelysin (= MMP-3), which in turn activates collagenase to initiate destruction of cartilage and periodontal connective tissue. It is also related to the etiology.
Gruber Marchese, 1989; Gruber Schwartz, 1990; Cox Eley, 1989, J. Period Res; Eley Cox, 1992, J Dent). And it can also promote blood coagulation disorders by inactivating the procoagulant (coagulant precursor) function of high molecular weight kininogen (Maier Spragg, 1983) and cleaving fibrinogen (Schwartz Bradford Littman, 1985) Is also known.

It has also been reported that tryptase is inhibited by common inhibitors of trypsin-like proteinases such as diisopropylfluorophosphate, phenylmethylsulfonyl fluoride and tosyl-L-lysine chloromethyl ketone (Smith Hougland, 1984; Harvima Schechter, 1988). However, these compounds are said to be unsuitable for in vivo use because of their high toxicity and poor stability, and even unsuitable for in vitro testing. Furthermore, the peptide-arginine aldehydes leupeptin and antipain (Cromlish Seidah, 1987) and (Caughey, 1993), which are known to have tryptase inhibitory action, have weak tryptase inhibitory effects and have limited usefulness. .

There are also references describing purified human tryptase inhibitor molecules that are polypeptides, and tryptase inhibitors obtained from extracts of leech.
Special table hei 9-500532

The relationship between tryptase and various diseases is as described above, but the following is also known. For example, mast cells are involved in renal interstitial fibrosis, and it has been reported that tryptase, the main proteolytic enzyme, is involved in fibroblast proliferation and promotion of extracellular matrix synthesis. .
J.Am.Soc.Nephrol 12, P1668-1676 (2001)

  There are the following reports about hay fever. First, when pollen (antigen) in the air sticks to the mucous membrane of the nose and eyes and enters the body, the living body regards the antigen as a foreign substance and produces IgE antibodies. Especially in people with hay fever, this IgE antibody is produced excessively. IgE antibodies first attach to the cell surface. When an antigen further enters there, it binds to the antibody and causes an “antigen-antibody reaction”, and chemical mediators such as histamine, heparin, and tryptase are released from the inside of the cell. These chemical mediators have the effect of stimulating sensory nerve endings, causing mucosal edema, and severe mucus secretion. This causes excessive runny nose, itchy eyes, and nasal congestion.

  In addition, the following reports have been made on the relationship between inflammation and side effects caused by X-ray contrast agents and tryptase. Regarding inflammatory cells, multilateral studies have been conducted on the activation mechanisms of mast cells, basophils, eosinophils and airway epithelial cells. First, regarding the onset mechanism of side effects of X-ray contrast agents, hyperosmotic X-ray contrast agents cause histamine release from human basophils, and this release rate is significantly correlated with that caused by immunological stimulation. Became clear. It is well known that immunologic histamine release capacity is enhanced in allergic patients, and this is the reason why the frequency of side effects of X-ray contrast media is high in allergic patients. The possibility was suggested. There is also a report that IgE antibody was detected in about 30% of patients who showed side effects as a result of detection of IgE antibody against isoxaglic acid, which is a typical X-ray contrast agent. However, since the amount is very small, the significance of this specific IgE antibody should be examined. Since the tryptase concentration was increased in the serum of patients who had shock symptoms with X-ray contrast media, mediators may be released from mast cells during severe side effects.

  Next, regarding the onset mechanism of aspirin asthma, a load test of aspirin was conducted on such patients, and when urine was collected over time and metabolites of various mediators were measured, leukotriene E4, 11b There are also reports that significant increases in pGF2a and methylhistamine were observed. From these results, it is considered that in aspirin asthmatic patients, at least mediator release from mast cells is caused by aspirin, and it is considered to contribute to the treatment of aspirin asthma.

  Based on the above findings, drugs that inhibit tryptase are systemic anaphylaxis disease, aspirin-sensitive asthma, asthma, interstitial lung disease, allergic disease, atopic disease, skin blister symptoms, gingivitis, psoriasis, lung fiber It is considered to be effective as a therapeutic agent for various diseases caused by tryptase such as rheumatoid arthritis, rheumatoid arthritis, arthritis, periodontal disease, blood coagulation disorder, renal interstitial fibrosis, side effects of X-ray contrast media, hay fever.

In the basal membrane of the skin, the basal cells do not endure and repeat division, and the divided basal cells are sequentially pushed upward to form a stratum corneum at the top layer of the epidermis. Since the stratum corneum is extremely related to the properties of the cosmetic skin, the influence of the basement membrane on the skin is also great. The basement membrane is a kind of extracellular matrix (described later), and includes type IV collagen, proteoglycan, laminin, fibronectin and the like. The dermis is composed of connective tissue, and the extracellular space is mainly filled with a macromolecular network called extracellular matrix (ECM). The extracellular matrix (ECM) consists of fibrous proteins (collagen, elastin, etc.) and cell adhesion proteins (glycosaminoglycan, proteoglycan, fibronectin, laminin, etc.). And so on.

It is known that in the skin, tryptase in the skin is increased by ultraviolet rays.
Bosset S et al .: British J Dermatol 149, P826-835 (2003)

Tryptase degrades type 4 collagen (Non-patent document 9) and fibronectin (Non-patent document 10) and damages the basement membrane (Non-patent document 11).
Lohi et al .: J Cell Biochem 50, P337-349 (1992) J. Invest. Dermatol 113 (4), P567-573 (1999 Oct.) J. Clin. Invest 88, P493 (1991)

Furthermore, it causes degradation of type 1 collagen (Non-patent Document 12), and further causes migration of neutrophils by enhancing permeability of peripheral blood vessels, thereby promoting the degradation of elastin by neutrophil-derived elastase (Non-patent Document 13). Has also been reported.
Fajardo et al .: J immumol 171, P1493 (2003) He S et al .: Eur. J. harmacol 328, P89 (1997)

Tryptase causes keratinization delay in wound healing (Non-Patent Document 12). Therefore, from these findings, tryptase is used to reduce or denature extracellular matrix components (ECM) such as collagen and elastin in the dermis due to ultraviolet rays, as well as aging of the skin due to basement membrane damage and epidermal thickening, ie wrinkles, disappearance of texture, It is thought that it is related to a decrease in elasticity. Further, degranulation promoting action of mast cells has been reported (Non-patent Document 13), and is considered to play a major role in inflammation caused by ultraviolet rays.
Exp dermatol. 9, P258 (2000) Shaogeng HE: J Pharmacol Exp Therapeutics 286, P289-297 (1998) Thus, inhibition of tryptase seems to be useful for the prevention and improvement of skin inflammation, itching, rough skin, sagging, wrinkles, etc. caused by ultraviolet rays.

On the other hand, it has recently been clarified that tryptase has a specific stimulating effect on preteinase activated receptor-2 (PAR-2). Proteinase-activated receptor (PAR) is a kind of G protein-coupled receptor. The agonist proteinase cleaves the N-terminal extracellular peptide chain of the receptor molecule at a specific site, and the exposed receptor activation sequence It is activated by binding to another site on the receptor molecule. In 1991, PAR-1 was cloned as the thrombin receptor of human platelets, revealing its unique activation mechanism, and then PAR-2, PAR-3, and PAR-4 have been cloned to date. . Of the four PARs, PAR-1, PAR-3, and PAR-4 are thrombin receptors, whereas PAR-2 is not activated at all by thrombin, and some proteinases such as trypsin and tryptase are endogenous. Identified as an agonist enzyme candidate. PAR-1 plays an important role in the activation of human platelets, is widely distributed in the nervous system, digestive system, respiratory system, vascular system and others, and is involved in the control of various functions. PAR-2, like PAR-1, is widely distributed in the living body and modifies various functions different from PAR-1.

Furthermore, according to the “Japanese Journal of Pharmacology” (Okayama Univ./Medical/Pharmacy Masahiro Nishibori), the following report has been made. Along with platelets, important PARs-expressing cells are vascular endothelial cells and vascular smooth muscle. PAR-1 or PAR-2 stimulation elicits an endothelium (NO) -dependent vasodilator response. PAR-2 expression in vascular endothelial cells is markedly increased by LPS, IL-1β, and TNF-α (Non-patent Document 14), suggesting that PAR-2 is involved in septicshock (Non-patent Document 15). ing. PAR-1 stimulation of vascular endothelium and neutrophils enhances selectin expression in both cells. Thus, the generation of thrombin accompanying vascular failure causes vasodilation and neutrophil accumulation infiltration via PAR-1 stimulation, and is closely involved in the progression of the inflammatory reaction. In the coronary balloon restenosis model, the PAR-2 receptor is strongly expressed in the intima and media layers, while the cultured vascular endothelial cells and smooth muscle cells are stimulated by PAR-1 and PAR-2 stimulation. It was suggested that PAR-2 receptor stimulation is involved in proliferative thickening of the intima. In addition to trypsin, mast cell tryptase has been identified as a PAR-2 receptor-stimulated proteinase.
J Biol Chem 271, P14910-14915 (1996) Circulation 99, P2590-2597 (1999)

  Furthermore, with regard to the physiological role of PAR-2, PAR-2 present in respiratory epithelium transmits information via inositol phospholipid metabolism, particularly modifies LPS action in airway epithelial cells and favors in pulmonary epithelial cells. Various physiological actions such as promoting the adhesion of neutrophils are induced, and PAR-2 present in the sensory nervous system is involved in the expression of inflammatory pain, while mucus secretion in the gastric mucosa through the release of CGRP and tachykinins There is also a report that it acts to protect the gastric mucosa.

Thus, it is well known that PAR-2 is involved in various pathophysiology such as hyperalgesia, pain, airway contraction, and edema, and has a specific stimulating action on PAR-2. If tryptase can be effectively inhibited, it can be applied to various diseases involving PAR-2 receptor, ie, suppression of hypersensitivity, analgesic action, anti-pruritic action (PAR-2 is at sensory nerve endings, tryptase CGRP and substance P are released by the stimulation of the substance, and various effects such as anti-edema action and anti-asthma action (tracheal contraction by PAR-2 stimulation in the respiratory tract) can be expected, such as tryptase and PAR-2 agonist peptide. In particular, application as an anti-pruritic agent in the case of atopic dermatitis as an ointment and application as an inhibitor against hypersensitivity such as neuralgia and postherpetic pain can be greatly expected.

  As described above, diisopropyl fluorophosphate, phenylmethylsulfonyl fluoride, tosyl-L-lysine chloromethyl ketone and the like are already known as compounds having tryptase inhibitory activity, but the activity is still insufficient and more powerful. A compound having an inhibitory action is desired.

  In view of the above, the present invention provides a tryptase activity inhibitor excellent in safety and effect, particularly a tryptase activity inhibitor that can reliably inhibit the enzyme activity of tryptase.

The tryptase activity inhibitor of the present invention contains a flower head extract of Paeonia lactiflora Pallas (= P. albiflora Pallas) as an active ingredient.

  The active ingredient according to the present invention is evaluated as a highly safe tryptase activity inhibitor that can reliably inhibit the enzyme activity of tryptase. Therefore, itching, wrinkles, sagging, external preparations for improving rough skin, systemic anaphylaxis disease, aspirin-sensitive asthma, asthma, interstitial lung disease, interstitial cystitis, irritable bowel syndrome, allergic disease, atopy Sexual illness, skin blistering, hypersensitivity, pain, pruritus, gingivitis, edema, psoriasis, pulmonary fibrosis, rheumatoid arthritis, arthritis, periodontal disease, blood coagulation disorder, renal interstitial fibrosis, radiography Increased vascular permeability or pulmonary edema as a side effect of the agent, and can be used as an external preparation, medication or food / beverage composition for treatment or prevention of a disease selected from the group consisting of hay fever, and improvement of those diseases , Effective for mitigation and prevention.

It supplements about the plant used as a tryptase activity inhibitor by this invention.
Peonies use Paeoniaceae Paeonia lactiflora Pallas (= P. albiflora Pallas) and related plants. The active ingredient of the present invention is an extract obtained from the flower heads of these plants.

  These plants are preferably used as they are or after processing the dried product into small pieces, pulverization or the like. Extraction from plants is performed with a solvent at room temperature to the boiling point of the solvent. Usable solvents are water, alcohols (for example, lower alcohols such as methanol, ethanol and butanol, polyhydric alcohols such as propylene glycol, 1,3-butylene glycol and glycerin), ketones such as acetone, ethyl ether, Esters such as dioxane, acetonitrile, and ethyl acetate, and organic solvents such as xylene, benzene, and chloroform can be used alone or in any combination of two or more.

  The extraction method usually uses a solvent 1 to 20 with respect to the plant 1 and performs dip extraction at room temperature to the boiling point of the solvent for 1 hour to 1 week under normal pressure. Further, not only normal pressure but also high pressure or supercritical fluid can be used. After extraction, the solution is recovered by filtration, and purification such as deodorization and decolorization is performed as necessary. The extract thus obtained can be used as a tryptase activity inhibitor as it is. However, it can be used as a paste or dried (extract) by diluting or distilling off the solvent depending on the purpose of use. It may be processed.

  The tryptase inhibitor according to the present invention includes 1) topical or systemic topical preparations, skin cleansing agents, skin cosmetics, 2) medicinal or cosmetic preparations applied to the scalp and hair, and 3) throwing in bath water. Medicinal or cosmetic bath agents, 4) deodorant and deodorant for human body, 5) medicated or cosmetic oral agents such as dentifrice, mouthwash, mouthwash, 6) sheet for skin application , Cosmetic sheets, cosmetic cotton, sanitary products, sanitary cotton, wet tissue, and the like can be used as appropriate. Ampules, capsules, powders, granules, solids, solutions, gels, bubbles, emulsions, sheets, mists, sprays, etc.

  Specifically, basic cosmetics such as creams, gels, ointments and liquids, lotions, emulsions, creams, ointments, gels, lotions, oils, packs, mists, facial cosmetic sheets, shavings, etc. Cosmetics, facial cleansers, skin cleansers (including soaps), shampoos, rinses, hair treatments, hair styling agents, permanents, hair nickings, hair dyes, hair restorers, hair conditioners, foundations, Examples include makeup cosmetics such as lipstick, blusher, eye shadow, eyeliner and mascara, perfumes, deodorants for skin, antiperspirants, bath preparations, mouthwashes, toothpastes, and mouth fresheners.

  The tryptase inhibitor according to the present invention is a systemic anaphylaxis disease, aspirin-sensitive asthma, asthma, interstitial lung disease, interstitial cystitis, irritable bowel syndrome, allergic disease, atopic disease, cutaneous blistering, perception Hypersensitivity, pain, pruritus, gingivitis, edema, psoriasis, pulmonary fibrosis, rheumatoid arthritis, arthritis, periodontal disease, blood coagulation disorder, renal interstitial fibrosis, vascular permeability as a side effect of X-ray contrast media It can be used by appropriately blending it with cosmetics and health-oriented foods and drinks, as well as internal medicines and drugs for the treatment or prevention of diseases selected from the group consisting of hypersensitivity or pulmonary edema and hay fever. In terms of form, ampules, capsules, pills, tablets (tablets), powders, granules, solids, liquids, jellies (gels), bubbles, and the like can be used.

  Specific examples of beauty and health-oriented foods and beverages include nutritional supplementation, nourishing tonic, fatigue recovery, constitution improvement, whitening, beautiful skin, beautiful hair, hair growth / hair growth, slimming, mental stability, and other beauty / health-oriented processed foods In addition to nutritional supplements and drinks, preference foods or beverages such as gums, candy, yogurt, tablets, soft drinks, etc. are raised.

  When the tryptase activity inhibitor according to the present invention is added to an external preparation, the active ingredient concentration is about 0.0001 to 5% as an active ingredient concentration, and when it is added to a medication or a food or drink composition, the active ingredient per day It is preferable to adjust so that the amount of intake is about 5 mg to 20 g.

[Production of tryptase activity inhibitor]
After the plant (100 g) is pulverized, a solvent (1 Kg) is added, and immersion extraction is performed at room temperature to under heating, and then filtered through a filter paper to obtain an extract (about 1 Kg). By this operation, a tryptase activity inhibitor was obtained.

[Evaluation of inhibitory activity of tryptase activity]
(Test sample)
The tryptase activity inhibitor produced in the above Example was further diluted to 0.1% and 1.0% with purified water to obtain a test sample. As a control, purified water alone was used as a test sample. A Leupeptin (100 μg / mL) solution was used as a positive control. Tryptase was obtained from Wako Pure Chemicals, and the substrate was obtained from Peptide Institute.
(Test method)
To a 96-well plate, 20 μL of a test sample and 20 μL of tryptase (50 ng / mL) were added and incubated at 37 ° C. for 20 minutes. As a control, 20 μL of purified water was added instead of the test sample. As a positive control, Leupeptin (100 μg / mL) was used. Boc-Phe-Ser-Arg-MCA (Peptide Institute) was dissolved to a concentration of 10 μM using 100 mM Tris-HCl buffer (pH 8.0) containing 150 mM NaCl and 1% DMSO, and 160 μL in 96 wells. In addition to the plate, it was incubated at 37 ° C. for 60 minutes. The fluorescence intensity after the reaction (Ex 360 nm, Em 450 nm) was measured, and the tryptase inhibition rate (%) was calculated by the following formula (Equation 1).

(Equation 1)
Tryptase inhibition rate (%) = 100 × (1-sample fluorescence intensity / control fluorescence intensity)

Table 1 shows the evaluation results of the tryptase activity inhibitory action. The peony flower head extract showed tryptase inhibitory activity in a concentration-dependent manner. On the other hand, peony root extract was not highly active.

  When applying the tryptase activity inhibitor of the present invention to an external preparation, a medication or a food or drink composition, the components and additives exemplified below can be arbitrarily selected and blended as necessary.

(1) Various fats and oils Avocado oil, almond oil, fennel oil, sesame oil, olive oil, orange oil, orange rafa oil, sesame oil, cocoa butter, chamomile oil, carrot oil, cucumber oil, beef tallow fatty acid, cucumber oil, safflower oil , Shea fat, 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, palm Oil, beef tallow, pork tallow, squalene, squalane, pristane or hydrogenated products of these oils (hardened oil, etc.).

(2) Waxes Beeswax, carnauba wax, whale wax, lanolin, liquid lanolin, reduced lanolin, hard lanolin, candelilla wax, montan wax, shellac wax, rice wax and the like.

(3) Mineral oils Liquid paraffin, petrolatum, paraffin, ozokelide, ceresin, microcrystalline wax, etc.

(4) Fatty acids 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, tall oil, lanolin fatty acid Synthetic fatty acids such as natural fatty acids such as isononanoic acid, caproic acid, 2-ethylbutanoic acid, isopentanoic acid, 2-methylpentanoic acid, 2-ethylhexanoic acid and isopentanoic acid.

(5) Alcohols: natural alcohols such as ethanol, isopyropanol, lauryl alcohol, cetanol, stearyl alcohol, oleyl alcohol, lanolin alcohol, cholesterol, phytosterol, phenoxyethanol, and synthetic alcohols such as 2-hexyldecanol, isostearyl alcohol, 2-octyldodecanol .

(6) Polyhydric alcohols Ethylene oxide, ethylene glycol, diethylene glycol, triethylene glycol, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, polyethylene glycol, propylene oxide, propylene glycol, polypropylene glycol 1,3-butylene glycol, pentyl glycol, glycerin, pentaerythritol, threitol, arabitol, xylitol, ribitol, galactitol, sorbitol, mannitol, lactitol, maltitol and the like.

(7) Esters Isopropyl myristate, isopropyl palmitate, butyl stearate, hexyl laurate, myristyl myristate, oleyl oleate, decyl oleate, octyldodecyl myristate, hexyl decyl dimethyloctanoate, cetyl lactate, myristyl lactate, Diethyl phthalate, dibutyl phthalate, lanolin acetate, ethylene glycol monostearate, propylene glycol monostearate, propylene glycol dioleate, and the like.

(8) Metal soaps Aluminum stearate, magnesium stearate, zinc stearate, calcium stearate, zinc palmitate, magnesium myristate, zinc laurate, zinc undecylenate and the like.

(9) gum, sugar or water-soluble polymer compound gum arabic, benzoin rubber, dammar gum, guaiac oil, Irish moss, karaya gum, tragacanth gum, carob gum, quinseed, agar, casein, lactose, fructose, sucrose or ester thereof, Trehalose or its derivatives, dextrin, gelatin, pectin, starch, carrageenan, carboxymethyl chitin or chitosan, hydroxyalkyl (C ₂ -C ₄ ) chitin or chitosan to which alkylene (C ₂ -C ₄ ) oxide such as ethylene oxide is added Low molecular chitin or chitosan, chitosan salt, sulfated chitin or chitosan, phosphorylated chitin or chitosan, alginic acid or salt thereof, hyaluronic acid or salt thereof, chondroitin sulfate or salt thereof, heparin, ethylcellulose, methylcellulose, cal Polymethyl cellulose, carboxyethyl cellulose, sodium carboxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, nitrocellulose, crystalline cellulose, polyvinyl alcohol, polyvinyl methyl ether, polyvinyl pyrrolidone, polyvinyl methacrylate, polyacrylate, polyethylene oxide, polypropylene oxide, etc. Alkylene oxide or its crosslinked polymer, carboxyvinyl polymer, polyethyleneimine and the like.

(10) Surfactant Anionic surfactant (alkyl carboxylate, alkyl sulfonate, alkyl sulfate ester salt, alkyl phosphate ester salt), cationic surfactant (alkyl amine salt, alkyl quaternary ammonium salt), amphoteric Surfactant: Carboxylic acid type amphoteric surfactant (amino type, betaine type), sulfate ester type amphoteric surfactant, sulfonic acid type amphoteric surfactant, phosphate ester type amphoteric surfactant, nonionic surfactant ( Ether type nonionic surfactant, ether ester type nonionic surfactant, ester type nonionic surfactant, block polymer type nonionic surfactant, nitrogen-containing type nonionic surfactant), other surfactants ( Natural surfactants, protein hydrolyzate derivatives, polymer surfactants, surfactants containing titanium and silicon, fluorocarbons System surfactant), and the like.

(11) Various vitamins Vitamin A group: retinol, retinal (vitamin A1), dehydroretinal (vitamin A2), carotene, lycopene (provitamin A), vitamin B group: thiamine hydrochloride, thiamine sulfate (vitamin B1), Riboflavin (vitamin B2), pyridoxine (vitamin B6),
Cyanocobalamin (vitamin B12), folic acids, nicotinic acids, pantothenic acids, biotins, choline, inositols, vitamin C group: vitamin C acid or derivatives thereof, vitamin D group: ergocalciferol (vitamin D2), cholecalciferol ( Vitamin D3), dihydrotaxol, vitamin E group: vitamin E or derivatives thereof, ubiquinones, vitamin K group: phytonadione (vitamin K1), menaquinone (vitamin K2), menadione (vitamin K3), menadiol (vitamin K4), others Essential fatty acids (vitamin F), carnitine, ferulic acid, γ-oryzanol, orotic acid, vitamin Ps (rutin, eriocitrin, hesperidin), vitamin U and the like.

(12) Various amino acids 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 and the like, and their amino acid derivatives such as sulfate, phosphate, nitrate, citrate or pyrrolidone carboxylic acid.

(13) Various additives derived from plant or animal raw materials These are processed in a conventional manner according to the type and form of the product to be added (for example, grinding, milling, washing, hydrolysis, fermentation, purification) , Compression, extraction, fractionation, filtration, drying, pulverization, granulation, dissolution, sterilization, pH adjustment, deodorization, decolorization, etc., arbitrarily selected and combined), arbitrarily selected from various materials You can use it.

  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 1 type selected from various organic solvents such as lower alcohols such as isobutanol or hydrous lower alcohols, polyhydric alcohols such as propylene glycol, 1,3-butylene glycol and glycerin or hydrous polyhydric alcohols, acetone and ethyl acetate Alternatively, it is desirable to use a mixture of two or more. However, when it is not preferable to contain an organic solvent depending on the application, it is sufficient to use only water or ethanol that can be easily removed after extraction, and it may be used alone or in any mixture with water. The thing extracted and extracted may be sufficient.

  In addition, when using additives derived from plant or animal-based ingredients for systemic or topical external preparations and cosmetics, it protects skin and hair, moisturizes, improves touch and texture, imparts flexibility, and stimulates Relaxation, stress relief by fragrance, cell activation (cell aging prevention), suppression of inflammation, improvement of skin and hair quality, prevention of rough skin and its improvement, hair growth, hair growth, hair loss prevention, imparting gloss, cleansing effect, In addition to cosmetic effects such as fatigue relief, blood flow promotion, and warm bath effects, effects such as flavoring, deodorization, thickening, antiseptic, and buffering can also be expected.

  In addition, in food and drink, nutritional supplementation, fatigue recovery, tonicity, cell activation (cell aging prevention) and other healthy and cosmetic effects, as well as improved taste, color tone, aroma, gloss, stabilization, thickening, It can be used for antiseptic purposes. In addition to this, we expect various cosmetic and pharmaceutical effects of each of the raw materials known so far, and by combining these, we aim to enhance the target effect or to have a multifunctional effect It is also possible to make a product that expects

Specific plants (herbal medicines) as raw materials include, for example, almonds (toen), ai (indigo leaves), aokazura (Keifu Fuji), Aoki (Aoki), Aogiri or Kenashia Ogiri (Ao Tung), Aotsu Samurai (wooden candy) , Aotenma, acacia, red ginseng, red spruce `` fruit '', red clover, red grapes, red ginseng (logwood), red wrinkles (red buds), red crested or red crested or reddish (root), red crested or reddish (ground yellow), Agi (Aki), Aki larch, Akinire (crusted skin), Aguay Guassou, Aguahe (Omiten coconut palm), Akebi (Kitsu), Asa (Asakojin), Maruba morning glory or morning glory (Chicken), Hydrangea (hydrangea), Ashitaba (Tomorrow), Azuki (Red Azuki), Asunaro, Acerola, Asenyaku (Asenyaku), Athira (Shokuyokanna), Anise, Abiyu, A Biurana, oilseed rape, Abemaki `` fruit '', avocado, ama, achacha (Amacha), Achacharu, Amadokoro (Jade bamboo), Amana (a light-hearted), amaranth (Hyuyu, Hagatetou, Himogeito, Senninkoku, Sugimorigateto, Hosoaogeito, Hasoagoito Aozulan, Amaranthus hypochondriacus), Amigasayuri or Baimo (shellfish mother), Aristolomeria (Yurizuisen), Arcana (Alcanna), Algarrobo (Cabe), Altea, Arnica, Alpinia or Katsumadai (Suzukuku), Aloe (蘆薈), Aloe vera, angelica, apricot or honanzu (Anzujin), Ansokkou (benzoic incense), yellow support, igakozolina (geo-biliary head), licorice or gecko licorice (indian oyster), rush (light heart grass), itadori (tiger cane root), yew (one Place), Strawberry, fig (no flower `` fruit, leaf ''), Ichihatsu (first), Ichibi (winter lion), Ichiyakusou (one medicinal herb), ginkgo (Ginkgo `` seed, leaves ''), Japanese yellow peas (distant), carob, Japanese beetle ( Taillexi), Inubiyu (Honagainubiyu), Rice `` Seeds, Seed coat '', Inondo `` Seeds '', Ibuki-so-sou, Nettle, Ylang-ylang, Iwa-tobacco (Iwabuchi), Iwahiba or Iwamatsu (rolling mushroom), kidney beans, oolong tea, fennel (mustard) , Wheat (Chibusanoki), Ukiyara (Sanryo), Uguisukagura `` Fruit '', Himewikyo, Turmeric (Urban), Duckweed, Usubasaishin or Keirinsaishin or Oshusaishin (spicy), Usvenia Oy, Usbeni Hollyhock, phalaenopsis, weevil (summer hay), udo or shishiudo (gung, alone, tangy), unyadegato (unkari) A, Cat's Claw), Uba tea, Ume (Japanese apricot `` seed, pulp ''), Japanese white beetle, Uwaurushi (Kusako-kemomo), Unshuumika (Chen), Unboku, Estragon, Ezoukogi (Tomogoka), Ezo-suzuran, Echinashi (Hosobamurasaki Barengiku) , Enishida, Enokitake (榎 茸), Ebisugusa or Cassia Tora (Keiko), El Campre, Elderberry “fruit”, Elemi, Elingi or Pre-Lotus Elinji, Enju (Safflower, Camellia rice), Pea, Ogi or Kibanaogi (Yellow Twilight), Naruko Yuri or Kagura-mabanaru Koyuri (Yellow), Ohisasa Yuki or Sasano Yuki, Ouren (Yo Ren), Ogata Houken, Okarasuri (Karokon), Oguruma (Civil Works Incense), Otsu Samurai (Prevention), Psyllium , Car forage), toucan thistle (Zhengzhou leakage, bald eagle), toucan Mi (coconut palm), Toucan cactus, Ovana okera or okera (white moth), Osara squirrel (Banaba), Ooyabaya shabushi "fruit", Oohashigusa (cereal sperm), Omia catechu, Oomihasa or hawthorn (Mountain vegetation), Omiyashi, Omiji Barley), Oka, Okazeri (snake bed), Okra `` fruit '', Oguruma (overturn), Oguri higotai (Zhengzhou leakage, indigo head), Panax ginseng or Tochibaninjin (Ginseng), Hypericum pertussis or Pterotus pertussis or Hypericum perforatum (Brother cut grass), Odorikosou (continuous), Onamomi (Circle ear), Onigomi, Onikoro or Tokoro or Nagadokoro (Hikai), Oninoyara (Tempa), Onyuri or Sasayuri or Hakatayuri (Yuri), Onoelan, Ononis, Halibut楡), Ominae (losing sauce), Yuuko, Dutch mustard (watercress), Ora Dazelli, Dutch beech, Dutch bees, olives `` fruit, seeds, leaves '', oregano, orange `` fruits, peels '', silkworm (ripe yellow), cacao `` fruits, peels, seeds '', oysters (bamboo `` leaves ''), Kagi-Kazura (Katsufuji), Kakidooshi or Kantorisou (Lotus), Kakiran, Gaku Hydrangea, Cassia, Casinoki (fruit berries), Gadju (Kashiwa), Kashiwa (Kashiwagi, Kashiwa), Cascarilla, Cascala Sagrada, gypsophila, gypsophila, cynomolgus (Kinshato), kaniwa, carnation, valerian (valerian), hippopotamus, birch or fern birch (white birch), gerbera, pumpkin, kapokoki `` seed '', kahoku salamander (蜀椒), gama Yellow), chamomile or roman chamomile, chamomile (weed), cam cam (camo duck), collar, chrysanthemum, calla or cinnamon , Oat biscak (half summer), oats, guarana `` seed '', carahoo (kokubaku), karaya, galyu, karin (garden), garcinia, kawamidori, kawara-saiko (reeled rape, white millet), kawajisha, kawaratake, kawaranadeshiko ( (Stone bamboo) or Ezokawaranadeshiko (buckwheat noodles, buckwheat), Chinese carrot (blue potatoes), Chinese mugwort (bamboo chin mackerel), kansui (kansui), licorice (licorice), kantarasa, candelilla, kanto, canna, kanran, raspberry (ezo strawberry) , Dutch Strawberry, Shrimp Strawberry, Nawashiro Strawberry, Momiji Strawberry, European Raspberry Strawberry), Kiwi `` Fruits, Leaves '', Kikarasuuri (Gurone), Chrysanthemum (Kikyo, Kikyo-root), Chrysanthemum (Chrysanthemum, Chrysanthemum, Datura), Kikutanigiku, Kisage (Salmon), Gigigishi (sheep hooves), pheasant (salmon), Kizuta, Kidachi aloe, Kidachi mint , Quina, linden (shinkona, red linden), quinoa (quinoa), yellowfin (yellow tuna), bean, gymnema sylvester, kimenkaku, cabbage, cabbage `` unripe fruit '', caraway, cucumber, gyory (Nishikawa willow, tail willow), Kiraja saponaria, Kiraya, Kiransou (Kinza small grass), Kumquat `` fruit '', Kinkiju, Ginseikai, Kimbusen, Kinma, Kinkihiki (Sentsukusa), Kinlan, Ginlan, Ginryohen, Guapeba Vermela, Guava `` Fruit '', Guayule, Quercus・ Infectria (garlic pods), kukui nuts, kugenumaran, wolfberry (bamboo shoots, coconut palm leaves, cocoon leaves, ground bone skin), cedar casserole (Tenmon winter), kudu (kudzu), camphor tree, gooseberry `` fruit '', ginseng (yellow flower candy) ), Kutiti River, Gardenia (Yamako), Kunigi (Kusou), Kupu , Kubeba, Kumazasa, Kuma-tsutsura (horse whip grass), Clara (bitter), cranberry `` fruit '', chestnut `` seed, fruit, astringent skin '', curcumigo latifolia `` fruit '', grapefruit `` fruit and leaf '', buckthorn, kuroganemochi ( Rescue), Kamehiba Kokoshi or Kurobana Hikikoshi or Hikiokoshi (prolonging grass), Clove (clove, clove), Gumbai Tuna (Sekimei, Sekimeishi), Keigai (Kashiwa, Hakuho), Celosia (Chicken flower, Chicken crown), Gekkavidin, Gecko (Laurel Tree), Kenashi Sartoribaira (Dogo, Mountain Return), Gentiana, Gennoshouko (Old Grass), Kemponashi (Kigushi), Kokisekoku, Kishimizukan (Koji, Tachibana, Obenimikan, Fukurimikan, Sagamikouji, Ponkan, Santara Skin) ), Koshinbara (monthly flower), Koiusui mint, Kozo `` Fruit '', kocha (tea), kohone (river bone), koh hong (Tsubakimoto, Karamotomoto), Kouriang, Kouryokyo (Koryo), cilantro `` fruit '', Koouren (Huo Ren), Koganebana (Yellow Gon), cowberry (Etsu) Tachibana), Coco `` fruit '', Goshuyu (Kurei), Gosho strawberry (Golden bonsai), Pepper (Pepper), Cosmos, Copaiba balsam, Coffee `` Seeds, leaves '', Kobushi or magnolia (hot pepper), Burdock (Beef bowl, Gyudon) ), Coconut lees, sesame (sesame seeds), sesame seeds (genus ginseng), trash (goji), saneka or binankazura or pine bush, wheat (wheat), rice or rice bran `` red potato, white birch '', rice oil, cola acminata `` seed '' , Cola Bella "Seeds", Colony Lilla, Koroha "Fruits", Colombo, Conzurango, Kombu, Konjac, Comfrey (Chang Zhang grass), Sisal (Sisal Asa), Cy Hailan Sakaneran (Ezosakaneran), Sasima button eel or Sina button eel or Cinnamon ginseng (weikensen), Sakura (Ooshima cherry, Yamazakura, Oyamazakura, Edhigashi, Mamezakura, Miyazakura, Someiyoshino, Takanezakura, Kasamikan, Sakura, Sakura, Sakura Fruit, bark (cherry bark) ''), cherry, pomegranate, sasa, sababagin orchid, sasanqua, sardine sardine (salmon), sweet potato, sugar cane, sugar beet, sunflower jujube (saccharin), saffron (bancho flower, west safflower), sapodilla, sapotea mariyo , Pomelo `` fruit '', savonso, salmon berry `` fruit '', salamander (sasma), salamander (sand indigo sashimi), salvia (sage), scallops (bamboo rape), sawagurumi (wild walnuts), sankaku cactus, sangre Degrad ( Loton), Salamander, Sansino Ginseng (37 ginseng), Sanshuyu (Yamamuro), Sansho (Yamamuro), Sandskon (Yamazune), Shea (Kalite), Cyano `` fruit '', Shiitake mushroom (Shitake), Sion (Purple spider), deer bear, jikitarisu, shikunshi (messy prince), perilla or ajizo or chimmentiso or catamenzo (purple leaf, shisocho), rosewood, linden tree, red-faced syringae, renilla (ream), shrimp Shimeji, beech shimeji, honjimeshi, shirotamogitake, shimokren (hot pepper), shimotsuso, potato, shajin (shasan), jasmine (matsurika), janohi (barley winter), jury scorpion, shrimp swordfish, sand , Shredded sand), juzudama, palm "fruit", shung lan, jujuu palm, show (Ginger), Zodiac hydrangea (Tsuneyama), Shobu (bamboo shoot, Sone), Shozu `` fruit '', Shirakashi `` Seeds '', Silane (Bikkyu), Shirogori `` Seeds '', White clover (Clover), White clover (chicken bone grass) , White squirrels (smoke squirrels), Shirobanatsuta "flowers", Shirobana Lupine, Shirominanten (southern Tenmi), Cinconacylbra, Ginkgo biloba (Mizuka, Suzuka, Senncho), Cinnamon, Cinnamomum cassia (Kaishin), Suika , Honeysuckle (gold and silver flowers, Shinobu winter), sorrel (acid model), swim berry `` fruit '', star apple, stevia, strawberry `` fruit '', succulent (Xu Longan), sugina (question), purslane (horse tooth soap, horse tooth soap Child), plum "fruit", sulgaran (oran), Japanese red pine "ball cone", Japanese larch, Japanese kizuta, Japanese seiyo Walnut, hawthorn, cypress, dandelion, horse chestnut (maronier), pear `` fruit '', sunflower, elder, scallop (juniper, pine), yarrow (milfoil), rose, antelope Japanese butterfly, Japanese mistletoe, American mint or Atlantic mint Sarcophagus), cedron (Boushuboku), mallow, hirohasenega, senega, seri, celery, nematode (river cucumber), senshinren (pure ream), sendan, sennin cactus, Nanna `` fruit, leaf '', ginseng (daikon), sea bream (medicated), senboku, soka (grass), elephant chrysanthemum, prawns, buckwheat `` seed '', potato monogram, broad bean, daiou (daihuang), radish, soybean, daidai (Orange peel, fruit), Takasago Gurihigotai (Southeast Indigo Sashimi), Takasaburo (Cirrus Lotus), Takatodai (Oyodo), Takarabi (Cirrus spine), Dark Sweet Cherry `` Fruit '', Japanese hollyhock, Tachikoso (Time, Hundred incense), Tachidokoro (Hikai), Tachiyanagi, Tamarind `` Seeds '', Onion, Tamshiba (hot pepper), Taranoki `` Fruits, leaves, root bark '', Tarayo (Large winter blue, Ichiha tea, bitter tea, bitter tea), Dahlia (Tenjiku button), Tarwi, Tankimi, Tanshiwiwa, Tanjin (Tanjin), Dandelion (Shinko), Shirobana Dandelion or Mouko Dandelion, Danmaru, Cherry , Imperata "fruit, roots, buds", the district Seth carrot (Takefushi carrots), chicory, chunker Piedra
(Kidachi Kumiso), Tulip, Chono Stay, Datura Thistle (Artichoke), Datura (Dark Yellow), Datura (Amber), Datura Worm, Choreimaitake (Amber), Chorogi, Azalea, Azalea, Tsukuritake (mushrooms), Tsuchiakebi, camellia, camellia, clover (lacquered grass), camellia (duck-weed), Tsuruzuki (red bean), Tsurutsukikibi, Tsurudokudami (what neck rice cake), Tsuruna (Apricot apricot), Tsuruninjin (four leaf ginseng), Tsuruma, Tsuwabuki, Deiko, Teuchigurumi, Duberry `` Fruit '', Tengusa, Tencha (bamboo tea), Tendai-yaku (glaze), Toga (winter coconut), Tokagi quail, Capsicum (banban), Toki (toll), Tokinsenka (Tokinsenka) Marigold), red croaker, touna bena (river cut), corn or corn hair (Southern lashes), horned potato (Sadako), Torindo or Ginseng (Dragon gall), Tokusa (wood band), Dokudami (10 medicines), Tokushi (Nippaku), Toshishi or Mamedaoshi or Nekazura, Tochu (bark, bark, Leaves, roots ''), ash (crusts), tomatoes, tragacanth, triacanthos `` seed '', Turkish almonds, tormentilla, dronoki, troro mallow, tonka bean, nigerian berries `` fruit '', Chinese yam or wild yam (wild boar), nagii kada (butcher bloom) ), Naginata Koju, Nazuna, Rapeseed, Natsume or Vertical Spider (Sword Bean), Natsumikan, Jujube (Otsugi), Naniwaibara (Golden Cherry), Navena (Suspended), Nameko, Nankin Bean (Peanut), Nanten (Southern Fruit), Namban Karamushi (Sesame), Niosumire, Nigaki (Nakiki), Nigamugi (Sweetness), Nikuzuku, Kei or Nikkei or Seika Ronnikei or Yabunikei (Cinnamon) or Keishi (Keishi branch), Flying tiger plover, leek (lion), elderberry (bone, `` fruit, flower, stem, leaf ''), garlic (large persimmon), Nurde (penta), leek, nemonoki Or Nebu or Nebi or Nemurino or Digokubana (community), Noazami (Daisetsu), Nobara (fruit), Nozenkazura (Lingen flower), Nogateto, Yarrow, Nodake (former cucumber), Novara, Peach, Pineapple `` fruit '', Hibiscus (Busouge) , Fulinbussouge, Roselle), Hailindo, Hauchiwa, Pau Dorse, Hakama Labosi (osteostomy), Hakukayumatou, Chinese cabbage, Chinese cabbage (white tinea), Hakulberry `` fruit '', Japanese crocodile (breeding), Habami (coconut), Hasidorokoro (Roof root), basil, lotus (lotus, lotus meat, lotus), parsley (holland jellies), hadakamugi, batata, bee or maize Ke (bamboo shoots), patchouli, mint (thin-load, thin-leaves), yellow peas, pearl barley (Yokuinin), Hanasuge (my mother), bananas, hanahakka, Hanabishi (Sitoshiri, Shitsutsuri), vanilla bins, papaya, scallop , Pahalobobo, hub `` whole grass, stem, leaf '', paprika, oysters, hamago or honey bee (Vulgaris), hamasge (Katsukiko), Hamabishi (Shitsuko), Hamanasu (Maikai flower), hamabofu (hamafufu), Hamamelis, palm, rose (rose), balata, balata rubber tree, agaric (agaric, white-faced agaric, quince) (Skin, maple leaves), Barbasco, Harlindow, Handaikai (Taiho Sea), breadfruit, hinoki Sea urchin (hiboshi), lizard carrot (participant), pecan nuts, ganbanana (stone urchin, vine pearl shahua), higurmadaria, higotai, hishi (hishimi), pistachio, beet, human lizard (hisarium), human winged fern, daisies (Daisy), Hinata Taikozuchi (cow knee), chickweed, cypress, hiba, castor, sunflower, bell pepper, Himezu (Tengu), Himamatsu (Kaori), Himematsutake (Kawariharatake, Hiromatsutake), Himemuyoran, Pimenta `` fruit '', Beakshi, beakkyu, jade "fruit", chickpea, lentil, bellowed oyster, hirohaokinagusa (bald eagle), loquat "fruit, leaf, stem", betel nut (large clothes skin, coconut), puer tea (common tea), sweet pod (Southern rattan), Japanese cypress, Japanese cypress poppo (Japanese winter flower, Japanese winter leaf), Fujibakama (Orchid), Japanese bean (Japanese peas), Japanese red bean (Chujizakura, strawberry) ), Grapes `` fruit, pericarp, seeds, leaves '', beech, Fuyumushinatsusatake (Cycium Cordyceps), Brazilian licorice, Brazilian carrot, Brazilian palm, Brazilian elephant coconut, black currant `` fruit '', blackberry, Branjen, plum `` Fruit '', Fruceraria, Blueberry (Prunus serrata), Prunes, Floral Blanca, Blond Psyllium, Bundow (Mung Beans), Hazelnut, Loofah, Hetsukaran, Safflower (Safflower), Heneken, Belladonna, Berry `` Fruits '', Percea, Pervianberg , Pereschia grandifolia, red beetle or squirrel (scenic sky), boysenberry `` fruit '', scallop or narcissus or nendo or hahagigi kokia (silk), horsiran, scallop (saccharus, acute pupa, pelagic grass), pouteria・ Supporters, Po Terrier Lucuma, Spinach, Bow Fu (Windproof), Spinach, Japanese physalis (Torune), Japanese cypress (Japanese folk magnolia, Park), Bokeh (Kiso), Hosoba-Aragiku (Kayoyoku), Hosoba-oguruma, Hosobanaokera (Samurai), Hosobakirinso (Keitenzochi), Hosobabarengiku, Bodaiju (bamboo tree), button (peony `` flowers, leaves, stems, bark ''), button pi (peony skin), hop, jojoba, borage (Lurichisha), Bordeaux, howtle berry `` `` Fruit '', Hononiku (meat jutsu, large art), Honsecek (iron skin stone shark, sparrow mountain stone shark), myzurutennansho (Tennan star), Maitake (maiko), maou (mao), maca, macadamia nut, margaret (mok) (Shungiku), Makri (marine grass), Magwa (mulberry bark `` bark, leaf ''), Magnolia splengeri, Mazaran euba, Masalanzuba de Searer, Masheira de Boi Mashua (Tamanowenhalen, Kyukonkinrenka), Matatabi (wood tengu), Matsukasa, pine `` leaves, bark, root '', Matta Orillo, Matsuhodo (茯苓), Matico (Cordon sillo), Mayoram (Hanahakka), Malvano jardin (Bitter), Mulberry `` Fruit '', Quince, Malene (Biloud Mouse Squid), Mango, Mangosteen, Manzanya (Andesuka Mitsuru), Manshugurumi, Mandarin `` Fruit '', Mannentake (Ganoderma biloba), Pheasant (fruit berry `` Fruit '') , Mishimasaiko (Saihu), Mizusobako or Mizuasagao (Dongweed), Mizokakushi (Half-sided lotus), Misohagi (Chinese green), Japanese willow or Japanese willow (Henpo), Mitsugasiwa, Mitsuba, Midorisapote, Mirimaza, Mimosa, Myoga, Miracle fruit “fruit”, myrrh, mirobalan, wheat straw, mugweed (mushroom), muk Japanese cypress, mugwort (life-prolonging skin), munya, purple (purple), purple or yellow purple corn, purple corn, purple corn (Kunming chicken blood), megakansa opuntika, pheasant (maranthus), mebougi, melaroika, Melissa, Melilot, Melon `` Fruit '', Moukomomogi, Mosouchiku, Mokkirin, Mogi (Pepper), Mochinoki, Mokko (woody incense), Momijidaio, Peach (peach `` leaves, seeds, flowers, fruit ''), coconut, Morello Cherry `` fruit '', Morohaya (burlap), Yakawamura potato, Yakuchi (Michichi), cornflower (cornflower), cornflower mint, yacon, Yashabushi (Yagari) or Himeyashabushi `` Fruit, pericarp, fruit ear '', Yachiyanagi, Millet (octagonal gold plate), mistletoe (willow infestation), willow (kawayanagi, tachiyana) , Weeping willow, red willow, cat willow, dog willow, gold willow, koryanagi, unryu willow, miyagi willow, palm, willow, beech, goldfish, beef, stalk (Crane, Tenmeisei), pokeweed (commercial land), Japanese alder (Yamamuro), Japanese yam (Plum skin), Japanese mugwort, eucalyptus, Yukinoshita (tiger ear grass), yucca or flevifolia, yuzu `` fruit '', lily, yorogusa, Mugwort (Leaf), Ligan (Raimaru), Lime `` fruit '', Rye, Lacanca `` Fruit '', Raspberry `` Leaf, fruit '', Latania (Klamelia), Lackey or Shallot (Lady), Lavender, Longan (long-eyed meat), Agave (Aono Agave, Fuclin Agave) Ryokucha (green tea), apple `` fruits, seeds, leaves, roots '', gentian, lubas or suabishimusu (Suzu Ryo), Ruritama thistle (bladder tiger tai, Xinjiang indigo sashimi), litchi (toothpick, toothpick core), lettuce (chisha) , Red currant `` fruit '', red pitaya, lemon `` fruit '', lemongrass, forsythia or Chinese forsythia (ream), forsythia, wintersweet, wax palm, locon (reed, root), loganberry `` fruit '', rose Examples thereof include marie (mannenrou), rose hips (nobara), wasabi, cotton wisteria (Ming Mongolia), and bituminous (ground).

  As seaweeds, seaweed [Green algae: Chlorella vulgaris, Chlorella pyrenoidosa, Chlorella ellipsoidia, Aonori (Usba aonori, Sugiaonori, Hiraaoori, Boaonori, Hosoeda Aonori), Anaaoosa (Aosa)] (Macombu, Resilibu, Hosocome, Mitsuishi Kombu), Wakame, Hirome, Aowakame, Giant Kelp (Macrocystis Integrifolia, Neocitus Ruetkeana), Hijiki, Hibamata, Umiuchiwa, Usubaumiuchiwa Umiuchiwa, Akaba Umiuchiwa, Konami Uchiwa, Okinawa Uchiwa, Usuki Uchiwa, Etsumi Uchiwa], seaweed [Red algae: Hijirimen, Maca (Tengusa), Hiraksa, Syria, Oaxa Caterpillar, Yatabegusa, Yuukiri, Shimatengusa, Tosakanori, Togekirinsai, Amakusakirinsai, Giraffe, Juniper ginkgo rhinoceros, Tsunomata, Totsuka (Yahazutsu notamata), Ezotsunotamata, Togetu no Takita , Yaleus banori, Kagius banori, Susius banori, Haius banori, Akamo mizunori] and the like.

  In addition, other algae such as green algae (Chlamydomonas: Chlamydomonas, Akayukimo, Dunaliella: Dunaliella, Chlorococcus: Chlorococcus, Kuwanomimo: Kuwanomimo, Volboxa: Ougemawari, Volbox, Palmera, Yotsumeo, Aomido: Chrysanthemum, Aoumidro, Tirguimidro, Hibidoro: Hibidoro, Aosa: Anaaaosa, Amiaosa, Nagaaosa, Kawanori: Kawanori, Friccella, Shiogusa Magama genus: Magamata, Iwagata: Fusaikawa, Surichogata, Heraiwata, Kurokita, Hanemo, Genus: Mill, Chromel, Sakibutimil, Nagamil, Hira Lemon, Casanori genus: Casanori, Jusmo genus: Jujusmo, Tamajusmo, Mizojuzumo, Mika ヅ kimo, Korekaete, Tsutsumimo genus: Kyukougusa, Hitogususa genus: Humanegusa, Hirohatohigususa, Umushihimoe, Sakikimoe Sumiremo: Sumiremo, Hoshimamidro, Fushinashimidoro etc.).

  Cyanobacteria (Suizenjinori: Suizinori, Aoko, Nenju: Kawatake, Ishijelly, Hassai, Yuremo, Rasenmo (Spirulina): Spirulina, Trichodesmium (Iaciasio), etc.

  Brown alga Sanadagusa: Sanadagusa, Fukurimamiji, Commongusa: Commongusa, Yahazugusa: Ezoyahaz, Yahazugusa, Uraboshiyahaz, Jigamusa: Jigmygusa, Umichiwagusa, Umamisakugakua, Hakusou : Navarimo, Chasomen genus: Motsuki Chasomen, Matsumo genus: Matsumo, Nagamatsumo genus: Nagamatsumo, Okinawa mozuku: Okinawa mozuku, fake Tomozuku: Niseft Mozuku, Futomozuku: Futomozuku, Ishimozuku: Ishimozuku, Kuromo: Kuromo, Nisemozuku: Nisemozuku, Mozuku: Mozuku, Ishige: Ishige, Iroro, Ichimegasa: Ichimegasa Umibosu, Urushigusu: Urushigusa, Keurushigusa, Tobaccogusa, Composita: Composita, Haberodomo: Haberodoki, Havanori: Habanori, Habanori: Habanori, Commonbukuro, Ezobukuro, Ezobukuro Chishima fukuronori genus: Chishima fukuronori, Kagomenori genus: Kagomenori, Muraridori genus: Murachidori, shark genus: shark zusa, genus genus: lobster, genus genus: yokojimamanori, Ganoderma genus: cynomolgus, fennel spider: fennel spider, vine genus: turmo, turtle genus: sea turtle, scorpion genus: sujime, misji kumbu genus: misji kumbu, atsuba misji kumbu, kumbu genus: tsutsugara kumbu, oyster kumbu, onikombu, gakonbubu Barracuda, Trollocombu: Trollocombu, Antokume: Antokume, Kajime: Kajime, Tsuruarame, Kurome, Kikuishikombu: Kikuishicombu, Nejikcombu: Nejicombu, Kuroshiome: Kuroshiome, Nekoshikonbu, Aramei Genus: Ainuwakame, Chigaiso, Oniwakame Ezoi Shige: Ezoi Shige, Yabane Moku: Yabane Moku, Rappa Moku: Rappa Moku, Joromoku: Ugano Moku, Jo Lomoku, Hiemoku, Honda Walla: Tamanashimoku, Isomoku, Nagashimamoku, Akamoku, Shidamoku, Honda Walla, Nejimoku, Narasamo, Mametawala, Tatsukuri, Yatsumata Moku, Umitora no Moku, Fushishimoku, Mohmokumoku, Hahamokumoku , Ukimo: Ouokimo, Burukimo: Burukimo, Kayamonori: Kayamonori, etc.).

Red algae Genus: Sea urchins, Tsukumonori, Anemone crickets, Astragalus, Amaranthus, Amaranthus, Agaricata Genus: Tamaitadaki, Kaikekenori Genus: Kaginori, Kaikekenori, Tengusa: Himetengususa, Hytengususa, Oobusa, Nambugu , Kohira, Yohira, Kinukusa, Hibirodo: Hibirodo, Himebiro, Isomumedo: Isommedo, Aedes: Rhizome, Ryumons: Ryumon, Ranunculaceae, Nisekare Naminohana: Hosobanaminohana, Naminohana, Sangomodoki: Ragaramomodoki, Shiogusagoromo: Shiogusagoromo, Iwanokawa: Etsukiiwanawa, Kinokawa: Kinokawa, Kanonote, Sangori Kyono Shiro, Sakuranori, Nikumukade, Tambanori, Tsurutsuru, Fudarak, Marubahdarak, Isonohana: Nurakusa, Ronulaksa, Oomkadenori, Hirakintoki: Hirakintoki, Matabou: Matabou, Kintoki: Chabokintoki, Kintoki, Matsunori, Rice, Tokamatsu, Hitomatsu, Fushikintoki, Tsunomude, Nagakinito, Crayfish Nagaobane: Naganobane, Funori genus: Hanafonori, Fukurofunori, Mafunori, Karekigusa: Karekigusa, Tosakamodoki: Hosobanatosakamodoki, Hironotosakamodoki, Yatsudegatatosakamodoki, Kurotosakamodokisane, Zotosofomoza Tosakamodoki, Nankaitosakamodoki, Himetosakamodoki, Kinuhada: Kinuhada, Ezotosaka: Ezotosaka, Tsukasanori: Enashikarimenia, Otsukasanori, Hana Tacarimenia, Hoonoo: Honoo, Hikagenoit: Hikagenoit, Usuginu, Nikuhounoo: Nikuhounoo, Venus nago, Venus nago, Susca veni: Suscabeni, Okarugusa: Yamadagusa, Mirin: Mirin, Hosokamiso , Isomocca genus: Isomocca, Yukari genus: Yukari, Hosoyukari, Ibaranori genus: Ibaranori, Saidaibara, Tachiibara, Kagibaranori, Kojinoo: Kizino-o, Isodantsu: Isodantsu, Atsubanori: Atsubanori, Ogonori, Ogonori, Ogori Mizo-okonori, birch, beniogonori, fukureshinori, purple birch, shinkaibanori, spruce birch, kataogonori, ryukyuogono Li, Atlantic scorpion, Ivy genus, Yumigataonori, Kubireogonori, Mosagogonori, Kinubanori, Amanita genus: Hachijotensamodoki, Fushikenori genus: Fushikenori, Namiiwatake, Nymphalanthus Itagususa, Saimi, Hari, Lotus Jigusa: Lotus Jigusa, Sugi nori: Ikanoashi, Hosoibonori, Nobonori, Black Haginansou Genus: gourd, cherries, octopus: octopus, sedge, genus: genus, genus: goat, dals : Dulse, Scorpionus, Anadalus, Weibusa: Uebusca, Benifronori: Benifuronori, Fusunagi: Futsutsunagi, Himefusunagi, Hirohafushitsugi, Otsunagisou, Hirawatagigi, Usuwasugi , Egonori: Egonori, Futogigi, Saeda: Saeda, Chirimomiji: Chirimomiji, Konohori family: Habutaenori, Konohori, Suzuronori, Usubeni: Genus: Kagios banori, Yareus banori, Susius banori, Heius banori, Usubanorimodoki: Usubanorimodoki, Ayanishiki genus: Ayani Genus: Aeginu, Dadia: Enasidadia, Shimadadia: Isohagi, Shimadadia, Dajimodoki: Dajimodoki, Euglena: Morayogusa, Fuyugusa, Makuri: Makri, Yanaginogi, Yuna, Yukinagina , Sasabayanaginori, Sozo genus: Kurosozo, Kobsozo, Hanesozo, Sozonohana, Hanegusa genus: Hananegusa, Hananegusa, Kozanemo genus: Kozanemo, Isomurasaki, Hosozozanemo, Himegoshigusu, Giant genus Isomagusa, Suginasugusa: Suginasusa, Isobashou: Isobasho, Fujimatsumo: Fujimatsumo, Sawweed: Haeshinosakiba, Kawamoku : Kawamoku, Aokawa Mozuku, Himekawa Mozuku, Ideyugogome: Ideyugogome, Okichimozuku: Okimozu, Otosa, Chinomo: Chinomo, Chisujinori, Chisujinori, etc.).

  Axial algae (Shajikumo, Shiratamamo, Hoshitsurimo: Hoshitsurimo, Rikunotumusu, Flaskmo: Himebumo, Chaboflasmo, Tripera, etc.), yellow algae (Hikarimo: Hikarimo, etc.), etc.

  In addition, the materials derived from animal materials include chicken crown extract, cow or pig, human placenta extract, cow or pig stomach, duodenum, intestine, spleen extract or decomposition product thereof, cow or pig brain tissue Extracts, cattle / pig or fish collagen hydrolyzate (acid, alkali, enzyme etc.) degradation products, water-soluble collagen or collagen derivatives such as acylated collagen, cow or pig elastin or elastin hydrolyzate (acid, alkali, Enzymes etc.) or water-soluble elastin derivatives, keratin and its degradation products or their derivatives, silk proteins and their degradation products or their derivatives, 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 its degradation products or their derivatives, skim milk powder and their degradation products or their inducements Body, lactoferrin or decomposed product thereof, egg ingredients, fish hydrolyzate, nucleic acid-related substance (ribonucleic acid, deoxyribonucleic acid), or the like.

  In addition, as a material derived from a plant or animal material, any site, cell, tissue, organ, metabolite, etc. derived from a gene recombinant or a cell fusion can be used. Furthermore, for example, an undifferentiated cell group, a cell group in the middle of differentiation, or the like obtained by culturing an arbitrary site, cell, tissue, organ or the like can also be used.

(14) Marine components Seawater such as deep seawater, for example, sea salt, dried seawater, inorganic salt (sodium chloride, magnesium chloride, potassium chloride, etc.), sea mud or mud (from the Dead Sea or Atlantic Ocean) Fango), for example, Italian mud, German fungo, Eifelfango, Freiburg fungo, etc. Sea mud or mud from various locations (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, etc.

(15) Microbial culture metabolite Yeast metabolite, yeast extract, bacterial metabolite, bacterial extract, mold or actinomycete metabolite, mold or actinomycete extract, natto metabolite, natto extract, rice fermentation extract , Fermented rice bran (red rice bran, white birch) extract, Euglena extract or decomposition product thereof or water-soluble derivative thereof, trehalose or derivative thereof, lactic acid fermentation product of raw milk or skim milk powder, fermented lactic acid bacteria of legumes, coconut plant Lactic acid bacteria fermented products.

(16) α-hydroxy acids Glycolic acid, citric acid, malic acid, tartaric acid, lactic acid and the like.

(17) Inorganic pigments Silicic anhydride, magnesium silicate, talc, kaolin, bentonite, mica, titanium mica, bismuth oxychloride, zirconium oxide, magnesium oxide, zinc oxide, titanium oxide, calcium carbonate, magnesium carbonate, yellow iron oxide, Bengala, black iron oxide, gunjo, chromium oxide, chromium hydroxide, carbon black, calamine, etc.

(18) UV absorber / blocker benzophenone derivatives (2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid, sodium 2-hydroxy-4-methoxybenzophenone-5-sulfonate, dihydroxy Dimethoxybenzophenone, dihydroxydimethoxybenzophenone-sodium sulfonate, 2,4-dihydroxybenzophenone, tetrahydroxybenzophenone, etc.), paraaminobenzoic acid derivatives (paraaminobenzoic acid, ethyl paraaminobenzoate, glyceryl paraaminobenzoate, amyl paradimethylaminobenzoate, Octyl paradimethylaminobenzoate), methoxycinnamate derivatives (ethyl paramethoxycinnamate, isopropyl paramethoxycinnamate, octyl paramethoxycinnamate, 2-ethoxycinnamic acid cinnamate) Til, sodium paramethoxycinnamate, potassium paramethoxycinnamate, diparamethoxycinnamate mono-2-ethylhexanoate glyceryl, etc.), salicylic acid derivatives (octyl salicylate, phenyl salicylate, homomenthyl salicylate, dipropylene glycol salicylate, ethylene glycol salicylate, myristyl salicylate, Methyl salicylate, etc.), anthranilic acid derivatives (methyl anthranilate, etc.), urocanic acid derivatives (urocanic acid, ethyl urocanate, etc.), coumarin derivatives, amino acid compounds, benzotriazole derivatives, tetrazole derivatives, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives , Camphor derivative, furan derivative, pyrone derivative, nucleic acid derivative, allantoin derivative, nicotinic acid derivative, vitamin B6 derivative Body, umbelliferone, esculin, benzyl cinnamate, cinoxalate, oxybenzone, dioxybenzone, octabenzone, thrisobenzone, benzoresorcinol, arbutin, guaiazulene, shikonin, baicalin, baicalein, berberine, neoheliopan, escalol, zinc oxide, talc, kaolin etc.

(19) Whitening agent Paraaminobenzoic acid derivative, salicylic acid derivative, anthranilic acid derivative, coumarin derivative, amino acid compound, benzotriazole derivative, tetrazole derivative, imidazoline derivative, pyrimidine derivative, dioxane derivative, camphor derivative, furan derivative, pyrone derivative, Nucleic acid derivatives, allantoin derivatives, nicotinic acid derivatives, vitamin C or derivatives thereof (vitamin C phosphate magnesium salt, vitamin C glucoside, etc.), vitamin E or derivatives thereof, kojic acid or derivatives thereof, oxybenzone, benzophenone, arbutin, guaiazulene, Shikonin, baicalin, baicalein, berberine, placenta extract, ellagic acid, lucinol, etc.

(20) Tyrosinase activity inhibitor Vitamin C or a derivative thereof (vitamin C phosphate magnesium salt, vitamin C glucoside, etc.), hydroquinone or a derivative thereof (hydroquinone benzyl ether, etc.), kojic acid or a derivative thereof, vitamin E or a derivative thereof, N-acetyltyrosine or derivatives thereof, glutathione, hydrogen peroxide, zinc peroxide, placenta extract, ellagic acid, arbutin, lucinol, silk extract, plant extract (camille, mulberry, gardenia, pearl oyster, clam, clam, mugwort, honeysuckle) , Kihada, dokudami, matsuhod, pearl barley, mussel, hops, hawthorn, eucalyptus, yarrow, altea, keihi, mankaishi, hamamelis, yamagwa, lifelong grass, bellflower, toshishi, zetsugo, gyu, mao, senkyu, dod Tsu, Psycho, storm, littoralis, Scutellaria, peony bark, cranesbill, kudzu root, licorice, Fushi aloe, Cimicifuga, safflower, green tea, black tea, Ali elixir), and the like.

(21) Melanin pigment reduction / decomposition substance Phenylmercury hexachlorophene, mercuric oxide, mercuric chloride, hydrogen peroxide, zinc peroxide, hydroquinone or its derivative (hydroquinone benzyl ether).

(22) Turnover promoting action / cell activator hydroquinone, lactic acid bacteria extract, placenta extract, ganoderma extract, vitamin A, vitamin E, allantoin, spleen extract, thymus extract, yeast extract, fermented milk extract, plant extract (aloe, Ogon, Japanese horsetail, Gentian, Burdock, Shikon, Carrot, Camelis, Hop, Yokuinin, Odori, Semburi, Japanese cypress, Japanese red snapper, Achacha, Hypericum, Cucumber, Necklace, Rosemary, Parsley).

(23) Astringents Succinic acid, allantoin, zinc chloride, zinc sulfate, zinc oxide, calamine, zinc paraphenolsulfonate, potassium aluminum sulfate, resorcin, ferric chloride, tannic acid (including catechin compounds) and the like.

(24) Active oxygen scavenger
SOD, catalase, glutathione peroxidase and the like.

(25) Antioxidants Vitamin C or salts thereof, stearic acid ester, vitamin E or derivatives thereof, nordihydrogua cetelenic acid, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), hydroxytyrosol, parahydroxyanisole , Propyl gallate, sesamol, sesamorin, gossypol, propolis, etc.

(26) Lipid peroxide production inhibitor β-carotene, plant extract (sesame culture cell, hamcha, hypericum, hamamelis, clove, melissa, birch, birch, salvia, rosemary, minamitenji, jitsu, ginkgo, green tea).

(27) Anti-inflammatory agent Ictamol, indomethacin, kaolin, salicylic acid, sodium salicylate, methyl salicylate, acetylsalicylic acid, diphenhydramine hydrochloride, d-camphor, dl-camphor, hydrocortisone, guaiazulene, camazulene, chlorpheniramine maleate, glycyrrhizic acid or its Salt, glycyrrhetinic acid or a salt thereof, licorice extract, sicon extract, age extract, propolis, etc.

(28) Antibacterial / bactericidal / disinfectant Acrinol, sulfur, calcium gluconate, chlorhexidine gluconate, sulfamine, mercurochrome, lactoferrin or hydrolyzate thereof, alkyldiaminoethylglycine chloride solution, triclosan, sodium hypochlorite, chloramine T, Sarashi powder, iodine compound, iodoform, sorbic acid or its salt, propionic acid or its salt, salicylic acid, dehydroacetic acid, parahydroxybenzoic acid esters, undecylenic acid, thiamine lauryl sulfate, thiamine lauryl nitrate, phenol, cresol, p -Chlorophenol, p-chloro-m-xylenol, p-chloro-m-cresol, thymol, phenethyl alcohol, O-phenylphenol, Irgasan CH3565, halocarban, hexachlorophene, chlorohexidine, ester Tanol, methanol, isopropyl alcohol, benzyl alcohol, ethylene glycol, propylene glycol, 2-phenoxyethanol, 1,2-pentanediol, zinc pyridione, chlorobutanol, isopropylmethylphenol, nonionic surfactant (polyoxyethylene lauryl ether, Polyoxyethylene nonyl phenyl ether, polyoxyethylene octyl phenyl ether, etc.), amphoteric surfactant, anionic surfactant (sodium lauryl sulfate, lauroyl sarcosine potassium, etc.), cationic surfactant (cetyltrimethylammonium bromide, benzalkco chloride) Nium, benzethonium chloride, methyl rosaniline chloride), formaldehyde, hexamine, brilliant green, malachite green, crystal bio Tsu DOO, Jamaru photosensitive No. 101-containing, photosensitizer No. 201, photosensitizer No. 401, N- long chain acyl basic amino acid derivative and its acid shark salts, zinc oxide, hinokitiol, Sophora root, propolis, and the like.

(29) Moisturizer Glycerin, propylene glycol, 1,3-butylene glycol, hyaluronic acid or its salt, polyethylene glycol, chondroitin sulfate or its salt, water-soluble chitin or its derivative or chitosan derivative, pyrrolidone carboxylic acid or its salt, lactic acid Sodium, mini Sasanishiki extract, natto metabolite, natto extract, loofah water, birch (white birch) or red pine sap

(30) Elastase activity inhibitor diisopropyl fluorophosphate, plant extract (eg, gongoid, hypericum, clara, mulberry leaves, keihi, genokosho, comfrey, salvia, elderberry, bodaiju, button pie), seaweed extract and the like.

(31) Hair preparations Selenium disulfide, alkylisoquinolinium bromide solution, zinc pyrithione, biphenamine, thianthol, castari tincture, pepper tincture, pepper tincture, quinine hydrochloride, strong ammonia water, potassium bromate, sodium bromate, thio Glycolic acid and the like.

(32) Antiandrogens Follicular hormones (estrone, estradiol, ethinyl estradiol, etc.), isoflavones, oxendrone, etc.

(33) Peripheral vascular blood flow promoter Vitamin E or derivatives thereof, assembly extract, garlic extract, carrot extract, aloe extract, gentian extract, toki extract, cephalanthin, carpronium chloride, minoxidil and the like.

(34) Stimulants Pepper tincture, nonyl acid vanillamide, cantalis tincture, ginger tincture, peppermint oil, l-menthol, camphor, benzyl nicotinate and the like.

(35) Metabolic activator Photosensitive element 301, hinokitiol, pantothenic acid or derivatives thereof, allantoin, placenta extract, biotin, pentadecanoic acid glyceride and the like.

(36) Antiseborrheic agent Pyridoxine or a derivative thereof, sulfur, vitamin B6 and the like.

(37) Keratolytic agent Resorcin, salicylic acid, lactic acid, urea and the like.

(38) Oxidizing agent Hydrogen peroxide water, sodium persulfate, ammonium persulfate, sodium perborate, urea peroxide, sodium percarbonate, sodium tripolyphosphate, sodium bromate, potassium bromate, sodium pyrophosphate, Sodium orthophosphate, sodium silicate hydrogen peroxide adduct, sodium sulfate hydrogen peroxide adduct, sodium chloride hydrogen peroxide adduct, β-tyrosinase enzyme solution, mushroom extract, etc.

(39) Hair remover Inorganic reducing agents such as strontium sulfate, sodium sulfide, barium sulfide, calcium sulfide, thioglycolic acid or its salts (calcium thioglycolate, sodium thioglycolate, lithium thioglycolate, magnesium thioglycolate) Strontium thioglycolate) and the like.

(40) Hair swelling agents such as ethanolamine, urea and guanidine.

(41) Dye agent
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, nitroparaphenylenediamine hydrochloride, paraphenylenediamine hydrochloride, N-phenylparaphenylenediamine hydrochloride, metaphenylenediamine hydrochloride, orthoaminophenol, N-phenyl acetate Paraphenylenediamine, 1,4-diaminoanthraquinone, 2,6-diaminopyridine, 1,5-dihydroxynaphthalene, toluene-2,5-diamine, toluene-3,4-diamine, nitroparaphenylenediamine, paraaminophenol, para Nitroorthophenylenediamine, paraphenylenediamine, paramethylamino Phenol, picramic acid, sodium picramate, 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'-diamino sulfate Diphenylamine, 2,4-diaminophenol sulfate, toluene-2,5-diamine sulfate, nitroparaphenylenediamine sulfate, paraaminophenol sulfate, paranitroorthophenylenediamine sulfate, paranitrometaphenylenediamine sulfate, paraphenylenediamine sulfate, parasulfate sulfate Methylaminophenol, metaaminosulfate Diol, metaphenylenediamine sulfate, catechol, diphenylamine, α-naphthol, hydroquinone, pyrogallol, phloroglucin, gallic acid, resorcin, tannic acid, 2-hydroxy-5-nitro-2 ', 4'-diaminoazobenzene-5'-sulfone Sodium acid, hematein, etc.

(42) Fragrance Natural animal fragrance such as musk, civet, castorium, ambergris, anise essential oil, angelica essential oil, ylang ylang essential oil, iris essential oil, fennel essential oil, orange essential oil, cananga essential oil, caraway essential oil, cardamom essential oil, guayakwood essential oil, Cumin essential oil, black letter essential oil, cinnamon essential oil, cinnamon essential oil, geranium essential oil, copaiba balsam essential oil, coriandel 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, Otsuka perfume essential oil, tuberose essential oil, clove essential oil, orange flower essential oil, winter green essential oil, trout balsam essential oil, buttery essential oil, rose essential oil, palmarosa essential oil, persimmon essential oil, hiba essential oil, sandalwood essential oil, petit gren essential oil, bay essential oil, vetiva essential oil, bergamot Spirit , Peru balsam essential oil, boad rose essential oil, melamine essential oil, mandarin essential oil, eucalyptus essential oil, lime essential oil, lavender essential oil, linaloe essential oil, lemongrass essential oil, lemon essential oil, rosemary essential oil, Japanese mint essential oil, and other synthetic flavors Fragrance etc.

(43) Dye and Colorant Red Cabbage Dye, Red Rice Dye, Akane Dye, Anato Dye, Ikumi Dye, Turmeric Dye, Enju Dye, Krill Dye, Amber Dye, Caramel, Gold, Silver, Gardenia Dye, Corn Dye, Onion Dye , Tamarind pigment, spirulina pigment, buckwheat whole plant pigment, cherry pigment, laver pigment, hibiscus pigment, grape juice pigment, marigold pigment, purple potato pigment, purple yam pigment, lac pigment, rutin etc.

(44) Sweeteners Sugar, sweet tea, fructose, arabinose, galactose, xylose, stevia, mannose, maltose, honey, glucose, miraculin, monelin, licorice extract and the like.

(45) Nutrient enhancer Shell calcined calcium, cyanocobalamin, yeast, wheat germ, egg yolk powder, hemicellulose, heme iron and the like.

(46) Dairy products Milk, cheese, fresh cream, butter, margarine, powdered milk, whey, condensed milk, etc.

(47) Others Hormones, sequestering agents, pH adjusters, chelating agents, antiseptic and antifungal agents, cooling agents, stabilizers, emulsifiers, animal and vegetable proteins and their degradation products, animal and vegetable polysaccharides And its degradation products, animal and plant glycoproteins and their degradation products, blood flow promoters, anti-inflammatory agents, anti-inflammatory agents, anti-allergic agents, wound treatment agents, foam increasing agents, thickeners, enzymes, purified water (electronic Water, small clustering, etc.), oral preparations, deodorants / deodorants, bittering agents, seasonings, etc. are raised, and in combination with these, the effects of the present invention or other cosmetic effects are added Or a synergistic improvement can be expected.

[Safety test (cumulative skin irritation test)]
A Hartley system in which an aqueous solution of the tryptase inhibitor (50% ethanol extract) of Example 1 prepared so that the solid content concentration is about 1.0% was used as a sample, and this was shaved (2 × 2 cm ² ) on the flank. 0.03 mL was applied to each animal once a day, 5 times a week, per 2 × 2 cm ² of skin of guinea pigs (female, 3 mice per group, body weight around 320 g). Application was performed over 2 weeks, and shaving was performed in a timely manner. Judgment was made on the day of each application and the day after the last application by the scoring method of primary irritation using erythema and edema as indices. As a result, in all the animals, no erythema and edema were observed for 2 weeks after application, and the animals were judged negative.

[Safety study (single dose toxicity study)]
A ddy system in which an aqueous solution of the tryptase inhibitor (50% ethanol extract) of Example 1 was prepared so that the solid content concentration was about 1.0%, and the amount of 16 mL / kg per animal was fasted for 16 hours before the test. Mice (male and female, 1 group, 5 animals, 5 weeks of age) were orally administered with a sonde, and the onset, degree, etc. of toxic symptoms were observed over time. As a result, no abnormalities were observed in all mice for 14 days, and no abnormalities were found in the anatomical results. LD ₅₀ was 2,000 mg / kg or more, and judged to be a safe substance.

[Manufacture of various preparations]
Using the tryptase activity inhibitor according to the present invention, various preparations for external use, medications or food / beverage products were produced. The prescription example is as follows. Ethanol is abbreviated as EtOH, and 1,3-butylene glycol is abbreviated as 1,3-BG.

1) Production Example of Lotion A whitening lotion was produced according to the following formulation.
weight%
1. Sorbit
2
2. 1,3-BG
2
3. Polyoxyethylene oleyl ether (25E.O.)
2
4). EtOH
20

5. Ascorbic acid-2-glucoside
0.2

6). Peony flower head 30% -EtOH extract (solid content 1.0%)
1

7). Apigenin
0.01
8). pH adjuster
Appropriate amount 9. Preservative (phenoxyethanol)
Appropriate amount 10. Residue with 100 purified water

2) Example of production of emulsion An emollient emulsion was produced according to the following formulation.
weight%
1. Squalane 3
2. Vaseline 1
3. Stearyl alcohol
0.3
4). Sorbitan monostearate
1.5
5. Polyoxyethylene (20) sorbitan monooleate 3
6. 1,3-BG
Ten
7). Luteolin
0.01
8). Peony flower head 30% -1,3-BG extract (solid content 0.9%) 5
9. Proteoglycan solution (Ichimaru Falcos) 0.1
10. Sodium hyaluronate 0.0005

11. Preservative (Methylparaben)
Appropriate amount 12. Residue with 100 purified water

3) Production Example of Hair Shampoo A hair shampoo was produced according to the following formulation.
weight%
1. Lauryl sulfate triethanolamine 5
2. Polyoxyethylene lauryl ether sulfate Na 12

3. 1,3-BG
Four

4). Lauric acid diethanolamide 2
5. Quercetin
0.05
6. 2-Phenylchromone
0.01

7). Peonies flower head 50% -EtOH extract (solid content 1.1%) 5
8). Arginine or its salt 0.2
9. Preservative (Ethylparaben)
Appropriate amount 10. Residue with 100 purified water

4) Production Example of Body Soap A body soap was produced according to the following formulation.
weight%
1. Potassium laurate 15

2. Potassium myristate 5
3. Propylene glycol 5
4). Peony flower head 70% -EtOH extract (solid content 1.1%) 5
5. Hydrolyzed collagen solution 3
6). Hesperidin 0.001
7). Sodium lactate 0.1
8). pH adjuster
Appropriate amount 9. Preservative
Appropriate amount 10. Residue with 100 purified water

5) Production example of hair rinse A hair rinse was produced according to the following formulation.

weight%
1. Stearyltrimethylammonium chloride
2

2. Cetostearyl alcohol
2

3. Polyoxyethylene lanolin ether
Three

4). Propylene glycol
Five

5. Peonies flower head 50% -1,3-BG extract (solid content 1.1%)
Five

6). pH adjuster
Appropriate amount

7). Residue with 100 purified water

6) Examples of hair liquid production

A hair liquid was produced according to the following formulation.

weight%
1. EtOH
30
2. Polyoxypropylene butyl ether phosphate
Ten
3. Polyoxypropylene monobutyl ether
Five

4). Triethanolamine
1

5. Peonies flower head 50% -EtOH extract (solid content 1.1%)
Five

6). Melissa 30% -EtOH extract
Five

7). Catechin
0.01
8). Residue with 100 purified water

7) Granule bath preparation
weight%
1. sodium hydrogen carbonate
60

2. Anhydrous sodium sulfate
32
3. Borax
Three

4). Peonies flower head 50% -EtOH extraction powder
Five

8) Health foods (tablets)
The composition containing the following additives was compressed into tablets.
weight%
1. Peonies flower head 50% -EtOH extraction powder
twenty five

2. Proteoglycan (Ichimaru Falcos)
Ten

3. Artichoke leaf extraction powder
Five

4). Royal jelly powder
Five
5. Collagen powder
Five
6). lactose
twenty five
7). Corn starch
20
8). Hydroxypropyl cellulose
Four
9. Magnesium stearate
1

9) Health drinks Health drinks were made according to the following prescription.
weight%
1. Proteoglycan solution (Ichimaru Falcos)
20
2. Peony flower head 30% -EtOH extract (solid content 0.9%)
20
3. Honey 15

4). citric acid
0.1
5. dl-malic acid
0.1

6). D-sorbitol solution (70%)
Ten

7). Sodium benzoate
0.05

8). Fragrance
Appropriate amount 9. Residue with 100 purified water

10) Dentifrice A dentifrice was made according to the following prescription.

weight%
1. Silicic anhydride
20.0
2. Sorbit liquid
50.0
3. Glycerin
10.0
4). Peonies flower head 50% -BG extract (solid content 0.9%)
15.0
5. Sodium lauryl sulfate
2.0
6). Saccharin sodium
0.05
7). Carboxymethylcellulose sodium
1.5
8). Fragrance (cardamon water)
Appropriate amount 9. Residue with 100 purified water

[Use test]
Using the emulsions, granule bath preparations, health foods (tablets), health drinks, and dentifrices produced in the examples, a use test with a monitor was carried out.
(monitor)
・ 10 men and women with psoriasis symptoms on atopic skin, elbows, knees, etc. ・ 9 men and women who suffer from hay fever ・ 5 men with gingivitis and periodontal disease (test method)
(1) For 10 men and women with psoriasis symptoms on atopic skin, elbows, knees, etc., use of the emulsion produced in the example twice a day for 14 consecutive days in the morning and before bedtime, A questionnaire was conducted by using the granule bath preparation (40 g per serving) produced in the Examples in combination for 14 consecutive days during bathing.
(2) Nine men and women who suffer from hay fever take health foods (tablets, 2 g each) and health beverages (100 ml, once) for 14 consecutive days after meals. A questionnaire was conducted.
(3) For five men with gingivitis and periodontal disease, the brushing agent manufactured in the example was used, and brushing was performed three times a day, morning, noon, and evening (before going to bed) for 14 consecutive days. A questionnaire was conducted.
(result)
For each monitor, the results of the questionnaire conducted after use were as shown in Table 2.

  The tryptase activity inhibitor according to the present invention is highly safe and can reliably inhibit the enzyme activity of tryptase. Combining or formulating daily use forms such as external preparations, medications or food and beverage compositions, etc., itching, wrinkles, sagging, rough skin improvement, or general anaphylaxis disease, aspirin-sensitive asthma, asthma, interstitial Lung disease, interstitial cystitis, irritable bowel syndrome, allergic disease, atopic disease, skin blistering, hypersensitivity, pain, pruritus, gingivitis, edema, psoriasis, pulmonary fibrosis, rheumatoid arthritis, It can be applied to the treatment or prevention of diseases such as arthritis, periodontal disease, blood coagulation disorder, renal interstitial fibrosis, increased vascular permeability or pulmonary edema as a side effect of X-ray contrast media.

Claims (1)

A tryptase activity inhibitor comprising, as an active ingredient, a flower head extract of Paeoniaceae Paeonia peonies Paeonia lactiflora Pallas (= P. albiflora Pallas).