Agent for adjusting Th1 / Th2 cytokine balance and agent for improving atopic dermatitis using the same

Abstract

To provide a novel Th1 / Th2 cytokine balance regulator and an atopic dermatitis-improving agent using the same.SOLUTION: 1. A Th1 / Th2 cytokine balance regulator contains tomato seeds and / or extract thereof as active ingredient. 2. A Th1 / Th2 cytokine balance regulator contains lycoperoside H as active ingredient. 3. A reduction agent of total IgE amount contains tomato seeds and / or extract thereof as active ingredient. 4. A reduction agent of total IgE amount contains lycoperoside H as active ingredient. 5. An atopic dermatitis-improving agent contains one of aforementioned 1-4 as active ingredient.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a Th1 / Th2 cytokine balance regulator and an atopic dermatitis improving agent using the same. The present invention is widely used in foods, medicines, cosmetics, etc. [Background technology]

[0002] Tomatoes (Solanum lycopersicum) are a plant that is eaten daily around the world, and are sold as juice and supplements due to their rich content of vitamin C, lycopene, GABA, and other ingredients. The reported functionality of tomatoes is that they have blood pressure-lowering and cholesterol-lowering effects. In addition, in 2004, esculeosides, which are new saponins, were identified from tomatoes (Non-Patent Documents 1 and 2), and esculeoside A was found to have the effect of improving hyperlipidemia and arteriosclerosis in mice (Non-Patent Document 3). However, these findings are all from tomato fruit, and there are few reports that are specific to tomato seeds.

[0003] On the other hand, helper T cells (hereinafter abbreviated as Th) are functionally divided into type I helper T cells (hereinafter abbreviated as Th1) and type II helper T cells (hereinafter abbreviated as Th2).

[0004] Th1 produces Th1 type cytokines such as IFN-γ and IL-12 (interleukin-12), which attack and destroy foreign substances such as bacteria and viruses to defend against infection and also activate macrophages. IL-12 is a cytokine secreted from antigen-presenting cells such as dendritic cells and macrophages, and is known as a very powerful immune activator that activates natural killer cells (NK cells), LAK cells, and killer T cells (CTL cells) that directly attack cancer cells, and enhances the production of interferon-γ (IFN-γ).

[0005] In addition, Th2 is known to be involved in humoral immunity by producing Th2-type cytokines such as IL-4, IL-5, and IL-10, and by inducing B cells to produce IgE antibodies in response to mold, mites, and the like.

[0006] Furthermore, Th1 type cytokines suppress Th2, and conversely, Th2 type cytokines suppress Th1; these two are interrelated in order to maintain the overall balance of the immune system.

[0007] In recent years, with the progress of immunology research, it has been speculated that the balance between Th1 and Th2 plays an important role in the onset and progression of diseases. Recently, there has been a strong tendency for Th2 to be promoted by the living environment, and it is believed that the onset of cancer, immunodeficiency, asthma, dermatitis, allergic diseases, nephritis, infectious diseases, etc. is related to the promotion of Th2 function (see Non-Patent Document 4 and Patent Document 1).

[0008] In order to treat or prevent such diseases, it is believed that control of Th2 activation, and therefore regulation of Th-produced cytokines, is extremely important.

[0009] [Non-Patent Document 1] Fujiwara S. et al., Tetrahedron, 60, 4915-4920 (2004). [Non-Patent Document 2] Ono M. et al., Chem. Pharm. Bull., 54(2), 237-239 (2006). [Non-Patent Document 3] Nohara T., J. Trad. Med., 27, 217-224 (2010). [Non-Patent Document 4] Springer Seminars in Immunopathology Vol.21(3), 1999 and Latest Medicine "Clinical Studies of Autoimmune Diseases 1998", 32, 1998 [Patent Document 1] JP 2008-195631 A DISCLOSURE OF THEINVENTION [Problem to be solved by the invention]

[0010] Against the above background, tomato seeds and / or extracts thereof, and its component lycoperoside H were used in tests on model mice that naturally develop atopic dermatitis, and it was found that these have the effect of improving the Th1 / Th2 cytokine balance in the skin, thereby improving atopic dermatitis, thereby completing the present invention. The present invention provides a Th1 / Th2 cytokine balance regulator containing a novel ingredient as an active ingredient, and an atopic dermatitis ameliorating agent using the same. [Means for solving the problem]

[0011] The technical features of the present invention for solving the above problems are as follows. 1. An agent for improving Th1 / Th2 cytokine balance, comprising tomato seeds and / or tomato seed extracts as active ingredients. 2. A Th1 / Th2 cytokine balance improver containing lycoperoside H as an active ingredient. 3. A total IgE reducer containing tomato seeds and / or their extracts as active ingredients. 4. A total IgE reducer containing lycoperoside H as the active ingredient. 5. An agent for improving atopic dermatitis, comprising any one of the agents listed in 1. to 4. above as an active ingredient. [Brief description of the drawings]

[0012] [Figure 1] 1 shows a photograph of an IL33-Tg mouse used in this example. [Diagram 2] 1 is a graph showing the effects of tomato seed extract and lycoperoside H on skin inflammation. [Diagram 3] 1 is a graph showing the change in wheel activity due to tomato seed extract and lycoperoside H. [Figure 4] 1 is a graph showing changes in TEWL due to tomato seed extract and lycoperoside H. [Diagram 5] 1 is a graph showing changes in serum IgE levels in response to tomato seed extract and lycoperoside H. [Figure 6] 1 is a graph showing changes in cutaneous Th1 / Th2 cytokine balance in tomato seed extract and lycoperoside H. [Figure 7] 13 shows micrographs of HE stained specimens of mouse paw skin treated with tomato seed extract and lycoperoside H. BEST MODE FOR CARRYING OUT THEINVENTION

[0013] The present invention will be described in detail below. The present invention is characterized in that tomato seeds and / or extracts thereof are used as active ingredients. Tomato (Solanum lycopersicum, English: Tomato) is a plant of the Solanaceae family, native to the Andean highlands of South America (Peru, Ecuador). It is a perennial plant, and its fruit is edible. It is a type of green-yellow vegetable. In Japanese, it is also known by other names such as toushi (karaku persimmon), akanasu (akanasu), banka (banka), koganeuuri (koganeuuri), and sangojunasu (sango tree eggplant). Another feature of the present invention is that the seeds are used as the part of the tomato. This is because the seeds contain lycoperosides, which are saponin components unique to the seeds. Examples of lycoperosides include lycoperoside A and lycoperoside H. The above-mentioned lycoperoside A is a compound represented by the following chemical formula (1), and lycoperoside H is a compound represented by the following chemical formula (2). In the present invention, tomato seeds may be used as they are, but it is preferable to use a tomato seed extract, since this allows for obtaining active ingredients such as lycoperosides at high concentrations.

[0014] [ka]

[0015] [ka]

[0016] In addition, any method such as stirring extraction, continuous extraction, immersion extraction, and countercurrent extraction can be adopted as a method for extracting the active ingredient from the tomato seeds, and any device can be used at room temperature or under reflux heating. In this case, examples of the extraction solvent for obtaining the extract include water, lower monohydric alcohols (methyl alcohol, ethyl alcohol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, etc.), liquid polyhydric alcohols (glycerin, propylene glycol, 1,3-butylene glycol, etc.), lower esters (ethyl acetate, etc.), hydrocarbons (benzene, hexane, pentane, etc.), ketones (acetone, methyl ethyl ketone, etc.), ethers (diethyl ether, tetrahydrofuran, dipropyl ether, etc.), acetonitrile, etc., and one or more of these can be used. This is because lycoperosides, which are inherent components contained in tomato seeds, can be contained in high concentrations.

[0017] A preferred example of the extraction method is a method in which extraction is performed using aqueous ethanol or aqueous methanol at a concentration of 0 to 100% (v / v) for 1 to 10 hours at room temperature or with heating, followed by filtration, etc. This is because an extract containing active ingredients such as lycoperosides at a higher concentration can be obtained.

[0018] The tomato seed extract may be a commercially available product, in which case it is preferable to use one that contains the above-mentioned lycoperosides. Examples of such commercially available products include "Tomato Seed Extract-P" manufactured by Oryza Oil & Fat Chemical Co., Ltd.

[0019] The present invention is also characterized in that it contains lycoperoside H as an active ingredient.

[0020] The method for obtaining lycoperoside H is not particularly limited, but a method of extracting and purifying it from plants is particularly preferred. When lycoperoside H is extracted from a plant, the raw material is not particularly limited, but it is particularly preferable to use tomatoes, since they contain a high concentration of lycoperoside H. When extracting lycoperoside H from tomatoes, the tomato seeds are used because lycoperoside H is not found in the flesh or skin of tomatoes, but only in the seeds.

[0021] Furthermore, when solvent extraction is used as the extraction method, examples of the extraction solvent for obtaining the extract include water, lower monohydric alcohols (methyl alcohol, ethyl alcohol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, etc.), liquid polyhydric alcohols (glycerin, propylene glycol, 1,3-butylene glycol, etc.), lower esters (ethyl acetate, etc.), hydrocarbons (benzene, hexane, pentane, etc.), ketones (acetone, methyl ethyl ketone, etc.), ethers (diethyl ether, tetrahydrofuran, dipropyl ether, etc.), acetonitrile, etc., and one or more of these can be used.

[0022] A preferred example of the extraction method is a method in which extraction is performed using aqueous ethanol or aqueous methanol at a concentration of 0 to 100% (v / v) at room temperature or with heating for 1 to 10 hours, followed by filtration, etc. Specifically, for example, it can be obtained by the method described in the Examples of the present specification.

[0023] The Th1 / Th2 cytokine balance regulator of the present invention and the atopic dermatitis improving agent using the same (hereinafter simply referred to as the "agent of the present invention") can be used as ingredients for various food and beverage compositions. Examples of food and beverage include general foods such as confectionery (gum, candy, caramel, chocolate, cookies, snacks, jellies, gummies, tablet candies, etc.), noodles (soba, udon, ramen, etc.), dairy products (milk, ice cream, yogurt, etc.), seasonings (miso, soy sauce, etc.), soups, beverages (juice, coffee, black tea, tea, carbonated drinks, sports drinks, etc.), health foods (tablets, capsules, etc.), nutritional supplements (nutritional drinks, etc.), functional foods, and foods for specified health uses. The agent of the present invention may be appropriately blended into these foods and beverages.

[0024] These food and beverage compositions can contain various ingredients depending on their type, and food ingredients such as glucose, fructose, sucrose, maltose, sorbitol, stevioside, corn syrup, lactose, citric acid, tartaric acid, malic acid, succinic acid, lactic acid, L-ascorbic acid, dl-α-tocopherol, sodium erythorbate, glycerin, propylene glycol, glycerin fatty acid esters, polyglycerin fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, propylene glycol fatty acid esters, gum arabic, carrageenan, casein, gelatin, pectin, agar, B vitamins, nicotinamide, calcium pantothenate, amino acids, calcium salts, colorants, flavorings, preservatives, etc. can be used.

[0025] As a specific manufacturing method, the agent of the present invention can be easily incorporated into food and beverages (instant foods, etc.) by spray-drying or freeze-drying the agent together with powdered cellulose and forming it into a powder, granules, tablets, or solution. The agent of the present invention can also be dissolved in, for example, fats and oils, ethanol, glycerin, or a mixture of these to form a liquid, which can then be added to beverages or solid foods. If necessary, it can also be mixed with a binder such as gum arabic or dextrin to form a powder or granules, which can then be added to beverages or solid foods.

[0026] When the agent of the present invention is applied to food and drink, the amount of active ingredient added is preferably 1 to 20 wt% in total, since the main purpose is maintaining health and beauty.

[0027] The agent of the present invention may be used as a material for pharmaceutical compositions (including medicines and quasi-drugs). Pharmaceutical compositions can be produced by appropriately mixing the agent of the present invention with raw materials for pharmaceutical preparations. Examples of pharmaceutical raw materials that can be incorporated into the agent of the present invention include excipients (glucose, lactose, sucrose, sodium chloride, starch, calcium carbonate, kaolin, crystalline cellulose, cocoa butter, hardened vegetable oil, kaolin, talc, etc.), binders (distilled water, saline, ethanol water, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.), disintegrants (sodium alginate, agar, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearate monoglyceride, starch, lactose, powdered gum arabic, gelatin, ethanol, etc.), disintegration inhibitors (sucrose, stearin, cocoa butter, hydrogenated oil, etc.), absorption enhancers (quaternary ammonium bases, sodium lauryl sulfate, etc.), adsorbents (glycerin, starch, lactose, kaolin, bentonite, silicic acid, etc.), lubricants (purified talc, stearates, polyethylene glycol, etc.), etc.

[0028] The agent of the present invention can generally be administered orally in the form of tablets, pills, soft or hard capsules, fine granules, powders, granules, liquids, etc., but may also be administered parenterally. When administered parenterally, it may be administered in the form of a solution or with the addition of a dispersant, suspending agent, stabilizer, etc., by local tissue administration, intradermal, subcutaneous, intramuscular, or intravenous injection. It may also be in the form of a suppository, etc.

[0029] The dosage may vary depending on the method of administration, the condition, the patient's age, etc., but adults can usually be given 0.5 to 5,000 mg of active ingredient per day, and children can usually be given 0.5 to 3,000 mg. The compounding ratio of the agent of the present invention can be appropriately changed depending on the dosage form, but it is usually about 0.3 to 15.0 wt% when administered orally or via mucosal absorption, and about 0.01 to 10 wt% when administered parenterally. Note that the dosage varies depending on various conditions, so in some cases a smaller dosage than the above is sufficient, and in other cases it is necessary to administer more than the range.

[0030] The agent of the present invention can be expected to have the same effect as the agent of the present invention even when used as an external skin preparation (including cosmetics, pharmaceuticals and quasi-drugs). Examples of the forms of external skin preparations that can be blended with the agent of the present invention include milky lotion, soap, facial cleanser, bath additive, cream, milky lotion, skin lotion, cologne, shaving cream, shaving lotion, cosmetic oil, suntan / sunscreen lotion, face powder, foundation, perfume, pack, nail cream, enamel, enamel remover, eyebrow ink, blusher, eye cream, eye shadow, mascara, eyeliner, lipstick, lip balm, shampoo, rinse, hair dye, dispersion, cleanser, etc. Examples of the forms of pharmaceuticals or quasi-drugs that can be blended with the agent of the present invention include ointments, creams, external liquids, etc.

[0031] In addition to the agent of the present invention, the skin topical agent in the above form may contain, within the scope of not impairing the effect of the agent of the present invention, ingredients that are contained in skin topical agents such as cosmetics and quasi-drugs, oils, higher alcohols, fatty acids, ultraviolet absorbers, powders, pigments, surfactants, polyhydric alcohols, sugars, polymers, physiologically active ingredients, solvents, antioxidants, fragrances, preservatives, etc. Examples are listed below, but the present invention is not limited to these examples.

[0032] (1) Example of oil Ester-based oil phase components: glyceryl tri-2-ethylhexanoate, cetyl 2-ethylhexanoate, isopropyl myristate, butyl myristate, isopropyl palmitate, ethyl stearate, octyl palmitate, isocetyl isostearate, butyl stearate, butyl myristate, ethyl linoleate, isopropyl linoleate, ethyl oleate, isocetyl myristate, isostearyl myristate, isostearyl palmitate, octyldodecyl myristate, isocetyl isostearate, diethyl sebacate, diisopropyl adipate isopropyl, isoarachyl neopentanoate, tri(caprylic / capric)glyceryl, trimethylolpropane tri-2-ethylhexanoate, trimethylolpropane triisostearate, pentaerythritol tetra-2-ethylhexanoate, cetyl caprylate, decyl laurate, hexyl laurate, decyl myristate, myristyl myristate, cetyl myristate, stearyl stearate, decyl oleate, cetyl ricinoleate, isostearyl laurate, isotridecyl myristate, isocetyl myristate, isostearate Tearyl, isocetyl palmitate, isostearyl palmitate, octyl stearate, isocetyl stearate, isodecyl oleate, octyldodecyl oleate, octyldodecyl linoleate, isopropyl isostearate, cetostearyl 2-ethylhexanoate, stearyl 2-ethylhexanoate, hexyl isostearate, ethylene glycol dioctanoate, ethylene glycol dioleate, propylene glycol dicaprate, propylene glycol dicaprylate, propylene glycol dicaprylate, dicaprin Neopentyl glycol acid, neopentyl glycol dioctanoate, glyceryl tricaprylate, glyceryl triundecylate, glyceryl triisopalmitate, glyceryl triisostearate, octyldodecyl neopentanoate, isostearyl octanoate, octyl isononanoate, hexyldecyl neodecanoate, octyldodecyl neodecanoate, isocetyl isostearate, isostearyl isostearate, octyldecyl isostearate, polyglycerin oleate, polyglycerin isostearate, dipropyl carbonate,Dialkyl carbonate (C12-18), triisocetyl citrate, triisoarachyl citrate, triisooctyl citrate, lauryl lactate, myristyl lactate, cetyl lactate, octyldecyl lactate, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, trioctyl citrate, diisostearyl malate, 2-ethylhexyl hydroxystearate, di-2-ethylhexyl succinate, diisobutyl adipate, diisopropyl sebacate propyl, dioctyl sebacate, cholesteryl stearate, cholesteryl isostearate, cholesteryl hydroxystearate, cholesteryl oleate, dihydrocholesteryl oleate, phytosteryl isostearate, phytosteryl oleate, isocetyl 12-stearoylhydroxystearate, stearyl 12-stearoylhydroxystearate, isostearyl 12-stearoylhydroxystearate, and the like. Hydrocarbon-based oil phase components: squalane, liquid paraffin, α-olefin oligomer, isoparaffin, ceresin, paraffin, liquid isoparaffin, polybutene, microcrystalline wax, petrolatum, etc. Animal and vegetable oils and their hydrogenated oils, and naturally derived waxes: beef tallow, hydrogenated beef tallow, lard, hydrogenated lard, horse oil, hydrogenated horse oil, mink oil, orange roughy oil, fish oil, hydrogenated fish oil, egg yolk oil, and other animal oils and their hydrogenated oils, avocado oil, almond oil, olive oil, cocoa butter, kiwi seed oil, apricot kernel oil, kukui nut oil, sesame oil, wheat germ oil, rice germ oil, rice bran oil, safflower oil, shea butter, soybean oil, evening primrose oil, perilla oil, tea seed oil, camellia oil, corn oil, rapeseed oil, Examples of such oils include vegetable oils and their hydrogenated oils such as hydrogenated rapeseed oil, palm kernel oil, hydrogenated palm kernel oil, palm oil, hydrogenated palm oil, peanut oil, hydrogenated peanut oil, castor oil, hydrogenated castor oil, sunflower oil, grape seed oil, jojoba oil, hydrogenated jojoba oil, macadamia nut oil, medicamentoil, cottonseed oil, hydrogenated cottonseed oil, coconut oil, and hydrogenated coconut oil; and waxes such as beeswax, high acid value beeswax, lanolin, reduced lanolin, hydrogenated lanolin, liquid lanolin, carnauba wax, and montan wax. Silicone-based oil phase components: dimethylpolysiloxane, methylphenylpolysiloxane, methylcyclopolysiloxane, octamethylpolysiloxane, decamethylpolysiloxane, dodecamethylcyclosiloxane, methylhydrogenpolysiloxane, polyether-modified organopolysiloxane, dimethylsiloxane-methylcetyloxysiloxane copolymer, dimethylsiloxane-methylstearoxysiloxane copolymer, alkyl-modified organopolysiloxane, terminal-modified organopolysiloxane, amino-modified silicone oil, amino-modified organopolysiloxane, dimethiconol, silicone gel, acrylic silicone, trimethylsiloxysilicate, silicone RTV rubber, etc. Fluorine-based oil phase components: Perfluoropolyether, fluorine-modified organopolysiloxane, fluorinated pitch, fluorocarbon, fluoroalcohol, fluoroalkyl-polyoxyalkylene-co-modified organopolysiloxane, etc.

[0033] (2) Examples of higher alcohols Examples of the alcohol include lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, behenyl alcohol, 2-ethylhexanol, hexadecyl alcohol, and octyldodecanol.

[0034] (3) Examples of fatty acids Examples of the acid include caprylic acid, capric acid, undecylenic acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, arachidic acid, arachidonic acid, behenic acid, erucic acid, and 2-ethylhexanoic acid.

[0035] (4) Examples of UV absorbers Para-aminobenzoic acid, amyl para-aminobenzoate, dihydroxypropyl ethyl para-aminobenzoate, glyceryl para-aminobenzoate, ethyl para-aminobenzoate, octyl para-aminobenzoate, octyldimethyl para-aminobenzoate, ethylene glycol salicylate, octyl salicylate, triethanolamine salicylate, phenyl salicylate, butylphenyl salicylate, benzyl salicylate, homomenthyl salicylate, benzyl cinnamate, octyl para-methoxycinnamate, 2-ethylhexyl para-methoxycinnamate, glyceryl di-para-methoxycinnamate mono-2-ethylhexanoate, isopropyl para-methoxycinnamate, diethanolamine salt of para-methoxyhydrocinnamate, mixture of diisopropyl and diisopropyl cinnamate, urocanic acid, ethyl urocanate, hydroxymethoxybenzophenone, hydroxymethoxybenzophenone sulfonic acid and its salts, di Hydroxymethoxybenzophenone, dihydroxymethoxybenzophenone sodium disulfonate, dihydroxybenzophenone, dihydroxydimethoxybenzophenone, hydroxyoctoxybenzophenone, tetrahydroxybenzophenone, butylmethoxydibenzoylmethane, 2,4,6-trianilino-p-(carbo-2-ethylhexyl-1-oxy)-1,3,5-triazine, 2-(2-hydroxy-5-methylphenyl)benzotriazole, methyl-O-aminobenzoate, 2-ethylhexyl-2-cyano-3,3-diphenylacrylate, phenylbenzimidazole sulfate, 3-(4-methylbenzylidene)camphor, isopropyldibenzoylmethane, 4-(3,4-dimethoxyphenylmethylene)-2,5-dioxo-1-imidazolidinepropionate 2-ethylhexyl, and the like, as well as polymer derivatives and silane derivatives thereof.

[0036] (5) Examples of powders and pigments Dyes such as Red No. 104, Red No. 201, Yellow No. 4, Blue No. 1, Black No. 401, lake dyes such as Yellow No. 4 AL Lake, Yellow No. 203 BA Lake, nylon powder, silk powder, urethane powder, Teflon (registered trademark) powder, silicone powder, polymethyl methacrylate powder, cellulose powder, starch, silicone elastomer spherical powder, polyethylene powder and other polymers, yellow iron oxide, red iron oxide, black iron oxide, chromium oxide, carbon black, ultramarine, Prussian blue and other colored pigments, zinc oxide, titanium oxide, acid Examples of such pigments include white pigments such as cerium chloride, extender pigments such as talc, mica, sericite, kaolin, and plate-like barium sulfate, pearl pigments such as titanium mica, metal salts such as barium sulfate, calcium carbonate, magnesium carbonate, aluminum silicate, and magnesium silicate, inorganic powders such as silica and alumina, metal soaps such as aluminum stearate, magnesium stearate, zinc palmitate, zinc myristate, magnesium myristate, zinc laurate, and zinc undecylenate, bentonite, smectite, and boron nitride. There are no particular limitations on the shape (spherical, rod-like, needle-like, plate-like, irregular, flaky, spindle-like, etc.) and particle size of these powders. These powders may or may not have been previously surface-treated by a conventionally known surface treatment, such as a fluorine compound treatment, a silicone treatment, a silicone resin treatment, a pendant treatment, a silane coupling agent treatment, a titanium coupling agent treatment, an oil treatment, an N-acylated lysine treatment, a polyacrylic acid treatment, a metal soap treatment, an amino acid treatment, a lecithin treatment, an inorganic compound treatment, a plasma treatment, or a mechanochemical treatment.

[0037] (6) Examples of surfactants Anionic surfactants: fatty acid soaps, α-acylsulfonates, alkylsulfonates, alkylarylsulfonates, alkylnaphthalenesulfonates, alkyl sulfates, POE alkyl ether sulfates, alkylamide sulfates, alkyl phosphates, POE alkyl phosphates, alkylamide phosphates, alkyloylalkyl taurine salts, N-acylamino acid salts, POE alkyl ether carboxylates, alkylsulfosuccinates, sodium alkylsulfoacetates, acylated hydrolyzed collagen peptide salts, perfluoroalkyl phosphate esters, and the like. Cationic surfactants: alkyltrimethylammonium chloride, stearyltrimethylammonium chloride, stearyltrimethylammonium bromide, cetostearyltrimethylammonium chloride, distearyldimethylammonium chloride, stearyldimethylbenzylammonium chloride, behenyltrimethylammonium bromide, benzalkonium chloride, behenic acid amidopropyldimethylhydroxypropylammonium chloride, stearate diethylaminoethylamide, stearate dimethylaminopropylamide, lanolin derivative quaternary ammonium salts, etc. Amphoteric surfactants: Examples of amphoteric surfactants include carboxybetaine type, amidobetaine type, sulfobetaine type, hydroxysulfobetaine type, amidosulfobetaine type, phosphobetaine type, aminocarboxylate type, imidazoline derivative type, and amidoamine type. Nonionic surfactants: Propylene glycol fatty acid esters, glycerin fatty acid esters, polyglycerin fatty acid esters, sorbitan fatty acid esters, POE sorbitan fatty acid esters, POE sorbit fatty acid esters, POE glycerin fatty acid esters, POE alkyl ethers, POE fatty acid esters, POE hydrogenated castor oil, POE castor oil, POE·POP copolymers, POE·POP alkyl ethers, polyether modified silicone lauric acid alkanolamide, alkylamine oxide, hydrogenated soybean phospholipids, etc. Natural surfactants: Examples include lecithin, saponin, sugar-based surfactants, etc.

[0038] (7) Examples of polyhydric alcohols and sugars Examples of suitable sugars include ethylene glycol, diethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, glycerin, diglycerin, polyglycerin, 3-methyl-1,3-butanediol, 1,3-butylene glycol, sorbitol, mannitol, raffinose, erythritol, glucose, sucrose, fructose, xylitol, lactose, maltose, maltitol, trehalose, alkylated trehalose, mixed isomerized sugar, sulfated trehalose, pullulan, etc. Chemically modified versions of these sugars may also be used.

[0039] (8) Examples of polymers Acrylic acid ester / methacrylic acid ester copolymer (Plussize, manufactured by GOO Chemical Co., Ltd.), vinyl acetate / crotonic acid copolymer (Resin 28-1310, manufactured by NSC Co., Ltd.), vinyl acetate / crotonic acid / vinyl neodecanoate copolymer (28-2930, manufactured by NSC Co., Ltd.), methyl vinyl ether maleic acid half ester (Gantrez ES, manufactured by ISP Co., Ltd.), t-butyl acrylate / ethyl acrylate / methacrylic acid copolymer (Rubymer, manufactured by BASF Co., Ltd.), vinyl pyrrolidone / vinyl acetate / vinyl propionate copolymer (Ruviscol VAP, manufactured by BASF Co., Ltd.), vinyl acetate Vinyl acetate / crotonic acid copolymer (Rubyset CA, BASF), vinyl acetate / crotonic acid / vinyl pyrrolidone copolymer (Rubyset CAP, BASF), vinyl pyrrolidone / acrylate copolymer (Rubyflex, BASF), acrylate / acrylamide copolymer (Ultrahold, BASF), vinyl acetate / butyl maleate / isobornyl acrylate copolymer (Advantage, ISP), carboxyvinyl polymer (Carbopol, BFGoodrich), acrylic acid / alkyl methacrylate copolymer (Pemulen, BF Examples of such polymers include anionic polymers such as acetic acid amphoteric product of dialkylaminoethyl methacrylate polymer (Yukaformer, manufactured by Mitsubishi Chemical Corporation) and amphoteric polymers such as octylacrylamide acrylate / hydroxypropyl acrylate / butylaminoethyl methacrylate copolymer (AMPHOMER, manufactured by NSC Corporation); cationic polymers such as quaternary product of vinylpyrrolidone / dimethylaminoethyl methacrylate (GAFQUAT, manufactured by ISP Corporation) and methylvinylimidazolium chloride / vinylpyrrolidone copolymer (Rubycoat, manufactured by BASF Corporation); and nonionic polymers such as polyvinylpyrrolidone (Ruviscol K, manufactured by BASF Corporation), vinylpyrrolidone / vinyl acetate copolymer (Ruviscol VA, manufactured by BASF Corporation), vinylpyrrolidone / dimethylaminoethyl methacrylate copolymer (copolymer 937, manufactured by ISP Corporation), and vinylcaprolactam / vinylpyrrolidone / dimethylaminoethyl methacrylate copolymer (copolymer VC713, manufactured by ISP Corporation).Also suitable for use are naturally occurring polymeric compounds such as cellulose or derivatives thereof, keratin and collagen or derivatives thereof, calcium alginate, pullulan, agar, gelatin, tamarind seed polysaccharides, xanthan gum, carrageenan, high methoxyl pectin, low methoxyl pectin, guar gum, gum arabic, crystalline cellulose, arabinogalactan, karaya gum, tragacanth gum, alginic acid, albumin, casein, curdlan, gellan gum, and dextran.

[0040] (9) Examples of physiologically active ingredients Examples of the physiologically active ingredient include substances that impart some physiological activity to the skin when applied to the skin. For example, they include whitening ingredients, immune activators, anti-aging agents, UV protection agents, slimming agents, tightening agents, antioxidants, hair growth agents, hair restorers, moisturizers, blood circulation promoters, antibacterial agents, bactericides, drying agents, cooling agents, warming agents, vitamins, amino acids, wound healing promoters, irritation relievers, analgesics, cell activators, enzyme ingredients, etc. Examples of suitable ingredients include angelica extract, avocado extract, amacha extract, althea extract, arnica extract, aloe extract, apricot extract, apricot kernel extract, ginkgo extract, fennel extract, turmeric extract, oolong tea extract, eijitsu extract, echinacea leaf extract, scutellaria extract, phellodendron bark extract, coptis japonica extract, barley extract, hypericum extract, white nettle extract, watercress extract, orange extract, Dried seawater, seaweed extract, hydrolyzed elastin, hydrolyzed wheat powder, hydrolyzed silk, chamomile extract, carrot extract, artemisia capillaris extract, licorice extract, kalkade extract, kakyoku extract, cinchona extract, cucumber extract, guanosine, gardenia extract, kumazasa extract, sophora flavescens extract, walnut extract, grapefruit extract, clematis extract, chlorella extract, mulberry extract, gentiana extract, black tea extract, yeast extract, burdock extract, coix seed extract, Fermented rice bran extract, rice germ oil, comfrey extract, collagen, lingonberry extract, Chinese ivy extract, Chinese rhizome extract, umbilical cord extract, salvia extract, soapwort extract, bamboo extract, hawthorn extract, Japanese pepper extract, shiitake mushroom extract, rehmannia extract, lithospermum extract, perilla extract, linden extract, meadowsweet extract, peony extract, calamus root extract, white birch extract, horsetail extract, ivy extract, hawthorn extract, se Elderberry extract, yarrow extract, peppermint extract, sage extract, mallow extract, cnidium extract, swertia britannica extract, soybean extract, tsinga extract, thyme extract, tea extract, clove extract, imperata cylindrica extract, tangerine peel extract, angelica extract, calendula extract, peach kernel extract, spruce extract, houttuynia cordata extract, tomato extract, natto extract, carrot extract, garlic extract, wild rose extract, hibiscus extract,Examples of such extracts include burdock root extract, parsley extract, honey, witch hazel extract, parietaria extract, burdock root extract, bisabolol, loquat extract, coltsfoot extract, butterbur bud extract, poria extract, butcher's broom extract, grape extract, propolis, loofah extract, safflower extract, peppermint extract, linden extract, peony extract, hop extract, pine extract, horse chestnut extract, skunk cabbage extract, soapberry extract, melissa extract, peach extract, cornflower extract, eucalyptus extract, saxifrage extract, coix seed extract, mugwort extract, lavender extract, apple extract, lettuce extract, lemon extract, astragalus extract, rose extract, rosemary extract, Roman chamomile extract, and royal jelly extract. In addition, it contains biopolymers such as deoxyribonucleic acid, mucopolysaccharides, sodium hyaluronate, sodium chondroitin sulfate, collagen, elastin, chitin, chitosan, and hydrolyzed eggshell membrane, moisturizing ingredients such as amino acids, hydrolyzed peptides, sodium lactate, urea, sodium pyrrolidone carboxylate, betaine, whey, and trimethylglycine, oily ingredients such as sphingolipids, ceramides, phytosphingosine, cholesterol, cholesterol derivatives, and phospholipids, ε-aminocaproic acid, glycyrrhizic acid, β-glycyrrhetinic acid, lysozyme chloride, and guaiazure. immune stimulants such as glycerin, hydrocortisone, etc.; vitamins such as vitamin A, vitamin B2, vitamin B6, vitamin C, vitamin D, vitamin E, calcium pantothenate, biotin, nicotinamide, vitamin C ester, etc.; active ingredients such as allantoin, diisopropylamine dichloroacetate, 4-aminomethylcyclohexanecarboxylic acid, etc.; antioxidants such as tocopherol, carotenoids, flavonoids, tannins, lignans, saponins, etc.; cell stimulants such as alpha-hydroxy acids, beta-hydroxy acids, etc.; blood circulation promoters such as gamma-oryzanol, vitamin E derivatives, etc. Wound healing agents such as retinol and retinol derivatives, skin whitening agents such as arbutin, kojic acid, placenta extract, sulfur, ellagic acid, linoleic acid, tranexamic acid, and glutathione, cepharanthine, licorice extract, capsicum tincture, hinokitiol, iodized garlic extract, pyridoxine hydrochloride, DL-α-tocopherol, DL-α-tocopherol acetate, nicotinic acid, nicotinic acid derivatives, calcium pantothenate, D-pantothenyl alcohol, acetyl pantothenyl ethyl ether, biotin, allantoin, isopropyl methylphenol, estradiol, All, ethinyl estradiol, capronium chloride, benzalkonium chloride, diphenhydramine hydrochloride, tacanal, camphor, salicylic acid, vanillylamide nonylate, vanillylamide nonanoate, piroctone olamine, glyceryl pentadecanoate, L-menthol, mononitroguaiacol, resorcinol, gamma-aminobutyric acid, benzethonium chloride, mexiletine hydrochloride, auxin, female hormones, cantharides tincture, cyclosporine, zinc pyrithione, hydrocortisone, minoxidil, polyoxyethylene sorbitan monostearate, peppermint oil,Examples include hair growth agents such as Sasanishiki extract.

[0041] (10) Examples of antioxidants Examples of antioxidants include sodium bisulfite, sodium sulfite, erythorbic acid, sodium erythorbate, dilauryl thiodipropionate, tocopherol, tolylbiguanide, nordihydroguaiaretic acid, parahydroxyanisole, butylhydroxyanisole, dibutylhydroxytoluene, ascorbyl stearate, ascorbyl palmitate, octyl gallate, propyl gallate, carotenoids, flavonoids, tannins, lignans, saponin, and plant extracts such as apple extract and clove extract that have antioxidant effects.

[0042] (11) Examples of solvents Examples of suitable solvents include purified water, ethanol, lower alcohols, ethers, LPG, fluorocarbons, N-methylpyrrolidone, fluoroalcohols, volatile linear silicones, and next-generation fluorocarbons. EXAMPLES

[0043] The present invention will now be described with reference to examples. Example: Tomato seed extract and isolation of lycoperoside H Dried tomato seeds were extracted with methanol (70°C, 2 hours) to obtain a methanol extract. The resulting methanol extract was dispersed in water and partitioned with ethyl acetate and n-butanol to obtain 0.63 g of ethyl acetate soluble matter, 2.41 g of n-butanol soluble matter, and 5.05 g of water soluble matter. The n-butanol fraction was subjected to silica gel chromatography (chloroform:methanol = 9:1 → 7:3 → chloroform:methanol:water = 6:4:1 → methanol) to obtain Fr. 1~. Fr. 3 (1.1 g) was subjected to reversed-phase ODS column chromatography (methanol concentration 20% → 50% → 80% → 100%) to obtain Fr. 3-1~. Lycoperoside H, a saponin compound, was isolated from Fr. 3-3 (mg) by reversed-phase HPLC fractionation (Inertsil ODS-SP, 70% methanol). Each compound was 1H-NMR (600 MHz) and 13 The C-NMR (150 MHz) spectrum was compared with literature values ​​to identify the compound.

[0044] Test example: Evaluation of effects on atopic dermatitis symptoms Test sample: The above-mentioned n-butanol fraction was used as the tomato seed extract, and lycoperoside H isolated by the above-mentioned method was used. Test Method The effects on atopic dermatitis symptoms were evaluated using a mouse model (IL33-Tg mice: Figure 1) that spontaneously develops atopic dermatitis. The mice were orally administered tomato seed extract (500 mg / kg / day) or lycoperoside H (10 mg / kg / day) every day for 14 weeks, starting before the onset of the disease. After confirming the onset of skin inflammation symptoms, the inflammation score of the limbs, the amount of exercise in a wheel test, and TEWL were measured. The results are shown in Figure 2 (inflammation score), Figure 3 (wheel test), and Figure 4 (TEWL). Next, serum IgE and skin Th1 / Th2 cytokines (IL-2, IFN-γ, IL-4, and IL-5) were quantified, and pathological specimens of the skin were prepared and observed under a microscope. The results are shown in Figure 5 (total IgE in serum), Figure 6 (cytokine balance in the skin), and Figure 7 (microscope photographs of pathological specimens). Serum IgE and skin cytokines were measured using a Mouse IgE, ELISA Kit and a Th1 / Th2 Mouse Uncoated ELISA Kit with Plates, respectively.

[0045] Results and Effects of the Examples As shown in FIG. 2, the inflammation scores of the limbs showed a tendency for skin inflammation to be suppressed in the tomato seed extract-administered group, and inflammation was significantly suppressed in the lycoperoside H-administered group. Furthermore, as shown in Figure 3, in the wheel test, the amount of locomotion that had decreased due to inflammation-induced stress was significantly restored by administration of tomato seed extract and lycoperoside H. Furthermore, as shown in Figure 4, a significant improvement in TEWL was also observed with the administration of tomato seed extract and lycoperoside H. This confirmed that tomato seed extract and lycoperoside H suppress inflammation in atopic dermatitis, and are therefore useful as agents for improving atopic dermatitis. Furthermore, as shown in Figure 5, it was shown that the total IgE level in the serum was significantly reduced by administration of tomato seed extract and lycoperoside H. Furthermore, as shown in Figure 6, it was confirmed that the cytokine balance in the skin was improved from the Th2 cytokine dominance seen in allergic dermatitis to a normal balance. This confirmed that tomato seed extract and lycoperoside H are useful as agents for improving the Th1 / Th2 cytokine balance. Furthermore, as shown in Figure 7, microscopic observation of the pathological specimens confirmed epidermal thickening and eosinophil infiltration (black granular cells), which are seen in the skin of patients with atopic dermatitis, in the untreated control group, whereas in the tomato seed extract and lycoperoside H-treated group, these symptoms had recovered to the same extent as in normal mice. It was confirmed that tomato seed extract and lycoperoside H are useful as agents for improving atopic dermatitis. From the above, it was confirmed that tomato seed extract and lycoperoside H are useful as agents for reducing total IgE levels, improving the Th1 / Th2 cytokine balance, and improving atopic dermatitis.

[0046] Formulation examples of the agent of the present invention (tomato seed extract) are given below, but the following formulation examples are not intended to limit the present invention. Formulation example 1: Chewing gum Sugar 52.0wt% Gum base 20.0 Glucose 10.0 Starch syrup 16.0 Fragrance 0.5 Cherry Blossom Extract 0.5 Glucosylceramide 0.5 Tomato Seed Extract 0.5 100.0wt%

[0047] Mixture Example 2: Gummies Reduced starch syrup 38.0wt% Granulated sugar 20.0 Glucose 20.0 Gelatin 4.7 Wednesday 9.68 Kiwi juice 4.0 Kiwi flavor 0.6 Dye 0.02 Cherry Blossom Extract 1.0 Glucosylceramide 1.0 Tomato Seed Extract 1.0 100.0wt%

[0048] Mixture example 3: Candy Sugar 50.0wt% Syrup 33.0 water 14.2 organic acid 2.0 Fragrance 0.2 Cherry Blossom Extract 0.1 Glucosylceramide 0.1 Tomato Seed Extract 0.4 100.0wt%

[0049] Mixture example 4: Yogurt (hard / soft) Milk 41.5wt% Skim milk powder 5.8 Sugar 8.0 Agar 0.15 Gelatin 0.1 Lactic acid bacteria 0.005 Cherry Blossom Extract 0.1 Glucosylceramide 0.1 Tomato Seed Extract 0.4 fragrance trace amount water residue 100.0wt%

[0050] Formulation example 5: Soft drink Fructose glucose liquid sugar 30.0wt% Emulsifier 0.5 Strawberry Seed Extract 0.05 Glucosylceramide 0.05 Tomato Seed Extract 0.05 Fragrance (appropriate amount) Purified water remainder 100.0wt%

[0051] Formulation example 6: Soft capsule Rice germ oil 86.0wt% Cherry Blossom Extract 0.5 Glucosylceramide 0.5 Emulsifier 12.0 Tomato Seed Extract 1.0 100.0wt%

[0052] Formulation Example 7: Tablets Lactose 53.0wt% Crystalline cellulose 30.0 Starch decomposition product 10.0 Cherry Blossom Extract 0.5 Glucosylceramide 0.5 Glycerin fatty acid ester 5.0 Tomato Seed Extract 1.0 100.0wt%

[0053] Formulation Example 8: Granules for oral administration (pharmaceutical) Tomato seed extract 1.0wt% Strawberry Seed Extract 0.5 Glucosylceramide 0.5 Lactose 30.0 Cornstarch 60.0 Microcrystalline cellulose 7.0 Polyvinylpyrrolidone 1.0 100.0wt%

[0054] Formulation example 9: Tablet confectionery Sugar 75.4wt% Glucose 19.0 Sucrose fatty acid ester 0.2 Strawberry Seed Extract 0.5 Glucosylceramide 0.5 Tomato Seed Extract 0.5 Purified water 3.9 100.0wt%

[0055] Example 10: Cat food Corn 33.0wt% Wheat flour 35.0 Meat meal 15.0 Beef tallow 8.9 Salt 1.0 Bonito extract 4.0 Strawberry Seed Extract 0.5 Glucosylceramide 0.5 Tomato Seed Extract 1.0 Taurine 0.1 Vitamins 0.5 Minerals 0.5 100.0wt%

[0056] Example 11: Dog food Corn 30.0wt% Meat (chicken) 15.0 Defatted soybeans 10.0 Wheat flour 24.0 Bran 5.0 Cherry Blossom Extract 0.5 Glucosylceramide 0.5 Tomato Seed Extract 5.0 Animal fats and oils 8.9 Oligosaccharides 0.1 Vitamin 0.5 Minerals 0.5 100.0wt%

[0057] Formulation example 12: Cosmetic cream Squalane 20.0wt% Beeswax 5.0 Refined Jojoba Oil 5.0 Glycerin 5.0 Glycerin Monostearate 2.0 Polyoxyethylene (20) Sorbitan- Monostearate 2.0 Tomato Seed Extract 2.0 Preservatives (appropriate amount) Fragrance (appropriate amount) Purified water remainder 100.0wt%

[0058] Formulation example 13: Lotion Ethanol 5.0wt% Glycerin 2.0 1,3-Butylene glycol 2.0 Polyethylene oleyl ether 0.5 Sodium citrate 0.1 Citric acid 0.1 Tomato Seed Extract 0.1 Purified water remainder 100.0wt%

[0059] Formulation example 14: Body gel Macadamia nut oil 2.0wt% Octyldodecyl myristate 10.0 Methylphenylpolysiloxane 5.0 Behenyl Alcohol 3.0 Stearic Acid 3.0 Batyl alcohol 1.0 Glyceryl Monostearate 1.0 Polyoxyethylene sorbitol tetraoleate 2.0 Hydrogenated soy phospholipids 1.0 Ceramide 0.1 Retinol Palmitate 0.1 Preservatives (appropriate amount) Centella asiatica extract 1.0 Tomato Seed Extract 1.0 1,3-Butylene glycol 5.0 Purified water remainder 100.0wt%

[0060] Formulation example 15: Emulsion Squalane 4.0wt% Vaseline 2.5 Cetanol 2.0 Glycerin 2.0 Lipophilic glyceryl monostearate 1.0 Stearic acid 1.0 L-Arginine 1.0 Tomato Seed Extract 0.5 Potassium hydroxide 0.1 fragrance trace amount Purified water remainder 100.0wt%

[0061] Formulation example 16: Bath additive (liquid) Propylene glycol 50.0wt% Ethanol 20.0 Sodium sulfate 5.0 Tomato Seed Extract 0.5 Lanolin 0.5 Avocado oil 0.5 Dye 1.5 Fragrance 22.0 100.0wt% [Industrial Applicability]

[0062] As described above, the present invention can provide a novel Th1 / Th2 cytokine balance regulator and an atopic dermatitis ameliorator using the same.

Claims

1. An agent for improving Th1 / Th2 cytokine balance, comprising tomato seeds and / or an extract thereof as an active ingredient.

2. A Th1 / Th2 cytokine balance improver with lycoperoside H as the active ingredient.

3. A total IgE reducing agent containing tomato seeds and / or their extracts as active ingredients.

4. A total IgE reducer with lycoperoside H as the active ingredient.

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