WO2007119837A1 - Lipase inhibitor - Google Patents

Abstract

Disclosed is a lipase inhibitor which can be ingested safely by blending it into a pharmaceutical product or food, which contains, as an active ingredient, an extract separated from a food raw material or a compound contained in a plant, and which is useful for the prevention/treatment of a lifestyle-related disease or metabolic syndrome. The lipase inhibitor comprises myricitrin as an active ingredient.

Description

 Specification

 Lipase inhibitor

 Technical field

 [0001] The present invention relates to a novel lipase inhibitor containing myristitrin as an active ingredient, a method for inhibiting lipase comprising administering myristitrin, and myristitrin in the manufacture of a medicine for inhibiting lipase. About the use of. More specifically, the present invention relates to the use of millicitrin in the prevention or treatment of so-called lifestyle-related diseases such as obesity, diabetes, hypertension, hyperlipidemia, arteriosclerosis, and metabolic syndrome. Background art

 [0002] In recent years, the obese population has increased significantly due to the westernization of dietary life, that is, increased fat intake and lifestyle changes such as lack of exercise, which has become a serious problem. Yes. Obesity impairs the body's glucose metabolism, lipid metabolism, blood pressure, etc., resulting in metabolic syndrome, diabetes, hypertension, hyperlipidemia, arteriosclerosis and the like. To improve obesity, dietary therapy with calorie restriction and exercise therapy with energy consumption are common, but continuing these for a long time is mentally stressful, and dietary and Exercise therapy has problems such as a temporary loss of weight and a high possibility of weight rebound.

 [0003] One of the disorders caused by obesity is insulin resistance. Insulin resistance is a term indicating a state in which the sensitivity of target organs such as skeletal muscle, liver, and adipose tissue to insulin secreted by spleen 8 cells is reduced. Insulin resistance is due to a genetic predisposition, but most is due to obesity. The body is compensated for the insulin resistance caused by obesity by vigorous insulin secretion from spleen ι8 cells, and hyperinsulinemia keeps blood glucose close to normal. However, if this persists, the splenic β-cells become exhausted, the insulin secretory ability gradually decreases, and progresses to a diabetic state. Therefore, the improvement of obesity is extremely effective for the reduction of blood insulin concentration and the improvement of insulin resistance, and thus the prevention of diabetes.

[0004] Lipase is a digestive enzyme of fat, and spleen power is also secreted in humans. This river By the hydrolysis, the ester bond of tridalycelide, which is the main component of fat, is hydrolyzed to produce monodalyceride and free fatty acid. These are absorbed from the small intestine and consumed as energy in the body. Excessive fat intake is not used for energy consumption in the body and causes fat to accumulate in tissues, leading to obesity. Thus, lipase is closely related to obesity and hyperlipidemia, and sarcophagus is closely related to insulin resistance, hyperinsulinemia, metabolic syndrome, diabetes, arteriosclerosis, and inhibits lipase activity. It is considered that these substances are effective in preventing and treating these diseases.

 [0005] On the other hand, lipase produced by microorganisms resident in human skin degrades lipids on the skin into glycerin and free fatty acids. Some of these free fatty acids have adverse effects on the skin, and it is known that they can cause skin diseases such as comedones, and free fatty acids can be further decomposed to cause body odor. . Inhibition of lipase activity is also effective in solving such problems.

 [0006] As lipase inhibitors known so far, epigalocatechin gallate, which is a component of green tea (Patent Document 1), water extracts such as bell pepper, pumpkin, shimeji, hijiki, green tea, oolong tea (Patent Document 2), Examples include tamarind seed coat extract containing procyanidins (Patent Document 3), hot water extract of defatted rice bran (Patent Document 4), and polyphenolic substances contained in hops (Patent Document 5). it can. In addition, lipase inhibitors containing various flavonoids other than epigallocatechin gallate have been reported (Patent Documents 6 to 8).

 [0007] However, extracts and ingredients that have been separated from food ingredients in the lipase inhibitors that have been presented so far are actually less effective or under practical ingestion conditions. It was based on the results of experiments. For flavonoids, there are only reports of no saccharides !, flavonoids (Patent Document 6), or glycoside flavonoids (Patent Document 7) that do not contain a myricetin skeleton. It was a force that did not show the effects that could be achieved. Therefore, there has been a demand for a lipase inhibitor containing an active ingredient as an extract isolated from food raw materials or a compound contained in plants, which can be safely ingested by being contained in pharmaceuticals and foods.

[0008] As a plant extract having lipase inhibitory activity, for example, an extract of Myrcia sphaerocarpa (Myrcia sphaerocarpa, Myrcia multiflora) (Patent Document 9), Extracts of Eugenia uniflora (Non-Patent Document 1) are known, but these documents do not describe mycitrin. In addition, since the extraction methods of active ingredients described in these documents have not been efficient, there has been a demand for an efficient method for producing extracts containing active ingredients having lipase inhibitory activity. .

 Patent Document 1: Japanese Patent Laid-Open No. 3-228664

 Patent Document 2: JP-A-3-219872

 Patent Document 3: Japanese Patent Laid-Open No. 9-291039

 Patent Document 4: Japanese Patent Laid-Open No. 2001-97880

 Patent Document 5: Japanese Patent Laid-Open No. 2001-321166

 Patent Document 6: Japanese Patent Laid-Open No. 7-61972

 Patent Document 7: Japanese Patent Laid-Open No. 9-143070

 Patent Document 8: Japanese Unexamined Patent Publication No. 2003-321351

 Patent Document 9: JP 2001-231500 A

 Non-Patent Document 1: J. Ethnopharmacol. 1999 Dec 15; 68 (1-3): 307— 14. Disclosure of Invention

 Problems to be solved by the invention

[0009] An object of the present invention is a lifestyle-related disease comprising, as an active ingredient, an extract isolated from food raw materials or a compound contained in a plant that can be safely ingested by being contained in a pharmaceutical or food. It is to provide a lipase inhibitor useful for the prevention and treatment of metabolic syndrome.

 Means for solving the problem

[0010] As a result of diligent research to solve the above-mentioned problems, the present inventors have found that a specific plant or mycitrin from which extract strength is obtained has an excellent lipase inhibitory action, and contains mycitrin The present inventors have found an efficient method for producing the extract to be completed and have completed the present invention.

 [0011] That is, the present invention is as follows.

 (1) A lipase inhibitor characterized by containing mycitrin as an active ingredient.

(2) Myricitrin force Syzygium aqueum (= Eugenia aquea) Zyum 'Panodium guajava, Eugenia malaccensis, Syzygium dombeyi Skeels, Syzyg' Psidium longifolium, Milchiaria 'ciari aria cauliflora Shijigiu-time Samafungensu (Syzygium ¾amarangens Roh, Template Unless they already exist ³ r ©-time '. N'yanbosu (Syzygium jambo s), Korokashia Esukiyurenta (Colocasia esculenta), Shijiumu' Littre Ichiru 'Radi (Psi dium littorale Raddi) and Yuji - §' Interview - The lipase inhibitor according to (1), which is obtained from a plant selected from the group consisting of flora (Eugenia uniflora) or an extract thereof.

(3) The lipase inhibitor according to (1) or (2), comprising a plant containing 0.05% by weight or more of myricitrin or an extract thereof.

 (4) The lipase inhibitor according to (1), wherein myricitrin is synthesized.

 (5) Containing as an active ingredient an extract with a myristitrin content of 0.05% by weight or more obtained by extracting a plant containing mycitrin with water, an organic solvent, or a mixed solvent thereof. A lipase inhibitor characterized by comprising:

 (6) The lipase inhibitor according to (5), wherein the extract is obtained by a purification step by partition using an organic solvent or a purification step by adsorption resin after the extraction step.

 (7) At least one selected from fat absorption inhibitor, blood fat concentration inhibitor, anti-obesity agent, insulin resistance improving agent, blood insulin concentration reducing agent or metabolic syndrome improving or preventing agent, (1) The lipase inhibitor according to any one of to (6).

 (8) A method for producing a myristitrine-containing extract, comprising a step of extracting a plant containing mycitrin with water, an organic solvent, or a mixed solvent thereof.

 (9) The production method according to (8), further comprising a purification step by distribution using an organic solvent or a purification step by adsorption resin after the extraction step.

 (10) A food containing the lipase inhibitor according to any one of (1) to (6).

 (11) The food according to (10), which is a health functional food or a dietary supplement.

(12) The food according to (11), wherein the health functional food is a food for specified health use or a nutritional functional food (13) A cosmetic containing the lipase inhibitor according to any one of (1) to (6).

 (14) A method for inhibiting lipase in a subject, comprising administering to the subject an effective amount of myricitrin.

(15) Syzygium aqueum (= Eugenia aquea), Syzygium guajava, Eugenia malaccensis, Syzygium dombey ), Shijiumu 'Rongifuori © beam (Psidium longifolium), Mirukiaria' Kaurifurora (Myrciaria cauliflora), Shijigiu-time Samafungensu (Syzygium samarangens Roh, Template Unless they already exist ³ r ©-time 'N'yanbosu (Syzygium jambo s), Korokashia. Esukiyurenta (Colocasia esculenta), The method according to (14), which is obtained from a plant selected from the group consisting of Psi dium littorale Raddi and Eugenia uniflora or an extract thereof. .

 (16) The method according to (14), wherein myricitrin is synthesized.

 (17) Any of (14) to (16) for suppressing fat absorption, suppressing blood fat concentration, anti-obesity, improving insulin resistance, decreasing blood insulin concentration or improving or preventing metabolic syndrome The method according to item 1.

 (18) Use of myricitrin in the manufacture of a medicament for inhibiting lipase.

(19) Syzygium aqueum (= Eugenia aquea), Syzygium guajava, Syzygium 'Eugenia malaccensis, Syzygium dombey ), Shijiumu 'Rongifuori © beam (Psidium longifolium), Mirukiaria' Kaurifurora (Myrciaria cauliflora), Shijigiu-time Samafungensu (Syzygium samarangens Roh, Template Unless they already exist ³ r ©-time 'N'yanbosu (Syzygium jambo s), Korokashia. Esukiyurenta (Colocasia esculenta), The use according to (18), which is obtained from a plant selected from the group consisting of Psi dium littorale Raddi and Eugenia uniflora or an extract thereof. .

 (20) The use according to (18) or (19), wherein the medicine comprises a plant containing 0.05% by weight or more of myricitrin or an extract thereof.

 (21) The use according to (18), wherein myricitrin is synthesized.

(22) Plants containing myristitrin with water or an organic solvent or a mixed solvent thereof The use according to (18), wherein the medicament contains an extract obtained by the extracting step and having a myristitrin content of 0.05% by weight or more.

 (23) The use according to (22), wherein the extract is obtained by a purification step by distribution using an organic solvent or a purification step by adsorption resin after the extraction step.

(24) The medicine is at least one selected from fat absorption inhibitor, blood fat concentration inhibitor, anti-obesity agent, insulin resistance improving agent, blood insulin concentration reducing agent or metabolic syndrome improving or preventing agent power, (18) The use according to any one of (23).

(25) The lipase inhibitor according to any one of (1) to (7) above, and the lipase inhibitor comprising the following: fat absorption suppression, blood fat concentration suppression, anti-obesity, insulin resistance improvement, blood insulin A commercial package containing the power that can be used to improve or prevent concentration reduction or metabolic syndrome or documents that should be used.

 (26) The loro as described in (10) above, which is labeled as being used for lipase inhibition.

 (27) The above (26), wherein the lipase inhibition is at least one selected from suppression of fat absorption, suppression of blood fat concentration, anti-obesity, improvement of insulin resistance, reduction of blood insulin concentration or improvement or prevention of metabolic syndrome. Food listed.

Brief Description of Drawings

FIG. 1 is a graph showing the results of a blood fat concentration suppression test in Experimental Example 2 (mean value standard deviation deviation (n = 6), * p <0. 05 (vs control)) ₀

FIG. 2 is a graph showing the results of a blood fat concentration suppression test in Experimental Example 3 (mean standard deviation (n = 6), * ρ <0. 05 (vs control)) ₀

 FIG. 3 is a graph showing the results of a blood fat concentration suppression test in Experimental Example 4 (mean standard deviation (n = 6)).

 FIG. 4 is a graph showing the results of a blood fat concentration suppression test in Experimental Example 5 (mean value standard deviation (n = 6)).

 FIG. 5 is a graph showing the results of a blood fat concentration suppression test in Experimental Example 6 (n = 8, * p <0.05 (vs control)).

FIG. 6 is a graph showing the results of a blood fat concentration suppression test in Experimental Example 7 (n = 8, * p <0. 05 (vs control)).

 BEST MODE FOR CARRYING OUT THE INVENTION

 [0013] Hereinafter, the present invention will be described with a focus on the lipase inhibitor of the present invention. However, these descriptions are different from those of the lipase inhibitor unless they are described differently or clearly contradicted by the present invention. The same applies to the method and use of the present invention.

 [0014] Myricitrin, which is an active ingredient in the present invention, has the following chemical formula:

[0015] [Chemical 1]

 [0016] is a glycoside of myricetin, which is one of flavonols, and has excellent lipase inhibitory activity and suppresses absorption in the body after intake of fat.

 [0017] The myricitrin used in the present invention may be natural or synthesized. The synthesis of myricitrin can be carried out by conventional methods, for example, by alkylating the 3-hydroxyl group of myricetin with aglycone such as rutin and protecting it, and then replacing the sugar with rhamnose. can do.

[0018] In the present invention, for example, Syzygium aqueum (= Eugenia aquea), a common name in Japan: mizurembu, which is used to obtain myristitrine or mycitrin-containing extract, Psidium littorale Raddi (generic name in Japan: Teriha Banjiro), Sijimu 'guava (common name in Psidium guajava, Japan: Banjiro), Eugenia malaccensis (in Japan) Common name: Maleft peach), Syzygium dombeyi Skeels (generic name in Japan: Gurumiyama), Psidium longifolium (generic name in Japan: Kiminovanjiro), Milchiaria 'kauriflora ( Myrciaria cauliflora, common name in Japan: Jaboticapa, Syzyum samarangens (Syzy Gium Samarangens, common name in Japan: Rembu, Syzygium jambos, common name in Japan: F Tomoko), Colocasiaesculenta (generic name in Japan: taro), Eugenia uniflora (generic name in Japan: Tachibana adek), and the like.

 [0019] As a raw material for obtaining myricitrin or myricitrin-containing extract, mature or immature fruit, pericarp, seed, leaf, stem, petiole, branch, root, flower, whole, etc. of the above plant are used. Of these, leaves or stems are preferably used.

 The plants that can be used in the present invention include all dried products obtained by drying the plants themselves, pulverized products, juices obtained by squeezing and extracting the plants themselves, crude extracts, purified products of the extracts, etc. It is.

 The lipase inhibitor of the present invention preferably contains a plant containing 0.05% by weight or more of myristitrin or an extract thereof.

[0020] The method for producing the extract in the present invention is not particularly limited. For example, a plant containing mycitrin as a component (hereinafter also referred to as myristitrin-containing plant) is mixed with water or an organic solvent (alcohol (methanol, ethanol). Etc.) can be obtained by extraction with a mixed solvent thereof. Thereafter, when the obtained extract is further purified by partition using an organic solvent or purified by adsorption resin, a good quality extract can be obtained. The obtained myricitrin-containing extract is used after being appropriately concentrated, purified, sterilized, dried and the like. Examples of the organic solvent used here include ethyl acetate, glycerin, 1,3-butylene glycol, chloroform, dichloromethane, alcohol (methanol, ethanol, etc.), and the like. For purification by partitioning or the like, ethyl acetate or the like, in which a water-insoluble organic solvent is preferred, is more preferred. Alcohols (methanol, ethanol, etc.) are preferred for purification by adsorbent resin. The extraction may be performed at room temperature to under heating, and is usually performed at 1 to 100 ° C, preferably 20 to 90 ° C.

 [0021] Concentration and drying of the extract may be carried out by adding excipients (for example, lactose, sucrose, starch, cyclodextrin, etc.) as appropriate, where the extract may be concentrated and dried as it is. Also good.

[0022] It is more preferable to obtain a myrcitrin-containing extract containing 0.05 to 90% by weight, particularly 1 to 45% by weight of myritol in the above-described production method in a ratio to the dry extract. Since the extract obtained by the above production method has high water solubility, it also has an advantage that it can be easily formulated. In addition, when taken orally, the mycitrin-containing extract obtained in this way is difficult to precipitate, so that it reaches the small intestine and is easily absorbed, so a high effect can be expected.

 [0023] The present invention also provides a fat absorption inhibitor, a blood fat concentration inhibitor, an anti-obesity agent, an insulin resistance improving agent, a blood insulin concentration reducing agent based on the lipase inhibitory action of myricitrin, Provide metabolic syndrome improvement or prevention agent.

 Furthermore, the present invention provides foods and cosmetics containing myricitrin.

 [0024] When myricitrin is naturally derived, that is, derived from a plant or an extract thereof, the lipase inhibitor of the present invention is especially useful for daily continuous intake in the form of food with high safety. preferable. “Food” in the present invention means various forms of food such as solid, semi-solid, and liquid. In addition to general food including so-called health food, it is specified in the health function food system of the Ministry of Health, Labor and Welfare. It is a concept that encompasses functional health foods such as health foods and functional nutritional foods, and so-called functional foods, dietary supplements (nutritional supplements), feeds, food additives, and the like are also included in the foods of the present invention. Is done.

 [0025] There is no particular difficulty in using the lipase inhibitor of the present invention as a food. For example, processed meat products, processed fishery products, bread, as it is, or together with various nutritional components, containing myricitrin or myricitrin. It can be mixed with dairy products, confectionery, jelly, soft drinks, water, and milk to eat and drink.

When the lipase inhibitor of the present invention is used as a health food, food additive, dietary supplement, etc., for example, using conventional means, tablets, capsules, powders, granules, suspensions, chewables, etc. Can be prepared in the form of an agent, syrup and the like. Furthermore, it is also possible to provide such foods as functional health foods, which include lipase inhibition, fat absorption inhibition, blood fat concentration inhibition, anti-obesity, insulin resistance improvement, blood insulin Also included are foods that are labeled for use in reducing concentrations, improving metabolic syndrome and preventing Z or metabolic syndrome, especially foods for specified health use. The present invention can also be applied to feed applications, and can be ingested or administered to poultry and livestock even when added to normal feed. [0026] Metabolic syndrome refers to a condition in which a series of pathological conditions such as type 2 diabetes, hyperlipidemia, hypertension, visceral fat obesity, and fatty liver based on insulin resistance are combined. Also known as insulin resistance syndrome, visceral fat syndrome, multiple risk factor syndrome. In the present invention, improvement of metabolic syndrome means alleviation or cure of the symptoms in at least one selected disease state group force that is generally known as a disease state of metabolic syndrome such as the above-mentioned disease states. . In the present invention, prevention of metabolic syndrome means preventing or delaying the occurrence of symptoms in at least one pathological condition that is generally selected as a pathological condition of metabolic syndrome such as the above-mentioned pathological conditions. To do.

 [0027] The amount of myricitrin in the food and food composition varies depending on the addition form and the intake form, and can be selected from a wide range. Usually 0.05% to 100% by weight, preferably 0.5% % To 90% by weight may be blended.

 [0028] For example, the blended amount of processed food products, processed fishery products, solid foods such as bread, dairy products, confectionery and jelly, and semi-solid foods is 0.05 to 25% by weight, preferably 0.5%. Weight percent to 10 weight percent is preferred. The amount of liquid food such as soft drinks, water, and milk is 0.05% to 20% by weight, preferably 0.5% to 10% by weight.

 In addition, when myrcitrin is used in health foods, food additives, nutritional supplements, etc., for example, in the case of solid forms such as tablets, powders, granules, powders, the amount of myricitrin in these dosage forms Is preferably 0.05 to 100% by weight, preferably 0.5 to 90% by weight, more preferably 1 to 80% by weight. In the case of a liquid food such as a suspension or syrup, the amount of myricitrin is 0.05 to 90% by weight, preferably 0.5 to 90% by weight, more preferably 5% by weight. % To 50% by weight is preferred.

 [0029] Further, when the food contains a myristitrin-containing plant or an extract thereof, the blending amount of the myricitrin-containing plant or the extract thereof varies depending on the addition form and the intake form, but can be selected from a wide range, for example, In the case of food, it is desirable to add 1 to: L00% by weight, particularly 10% to 90% by weight or more in terms of solvent-extracted dried product.

[0030] For example, in the case where a mycitolin-containing plant or an extract thereof is added to a solid food such as processed meat products, processed fishery products, bread, dairy products, confectionery, jelly, or semi-solid food, solvent extraction 1% to 40% by weight, preferably 1% to 20% by weight, in terms of dry matter. The amount of liquid foods such as soft drinks, water, and milk is 1% by weight to 20% by weight, preferably 2% by weight to 10% by weight, in terms of solvent-extracted dried product.

 In addition, when mycitrin-containing plants or extracts thereof are used in health foods, food additives, dietary supplements, etc., for example, in the case of solid forms such as tablets, powders, granules, powders, etc. The compounding amount in the form is 1% to 100% by weight, preferably 5% to 90% by weight, more preferably 10% to 80% by weight in terms of the solvent-extracted dried product. The amount of liquid foods such as suspensions and syrups is 1% to 100% by weight, preferably 5% to 80% by weight, more preferably 10% to 50% by weight is preferred.

[0031] When using millicitrin as a health food or dietary supplement, the dosage should be 0.1 mg to 5 g, preferably 5 mg to 2 g per adult per day when ingesting purified or synthesized mycitrin. It is preferable to take or take 10 mg to 0.5 g once a day in several divided doses. In this case, the daily intake or the intake per time can be made into one unit package.

 [0032] One day for adults to consume foods such as processed meat products, processed marine products, bread, dairy products, confectionery, jelly, soft drinks, water, milk, etc. with the addition of myricitrin or myricitrin-containing products Mytricitrin intake per capita It is preferable to take it in an amount equivalent to the above-mentioned health food. Even in this case, the daily intake or the daily intake can be packaged in one unit.

 [0033] When the lipase inhibitor of the present invention is used as a pharmaceutical, the form is not particularly limited, and myritol is used as it is or, for example, tablets, granules, fine granules, powders, capsules, It can be formulated into injections, solutions, suspensions, emulsions, creams, suppositories, etc. and administered orally or parenterally (for example, topical, rectal, intravenous administration, etc.). These can be formulated as various preparations by a method known per se using pharmacologically acceptable carriers and additives.

[0034] Examples of the pharmaceutical carrier used include lactose, glucose, D-manntol, starch, crystalline cellulose, calcium carbonate, kaolin, starch, gelatin, and hydroxypropyl. Cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, ethanol, carboxymethylcellulose, carboxymethylcellulose calcium salt, magnesium stearate, talc, acetylcellulose, sucrose, titanium oxide, benzoic acid, paraoxybenzoic acid ester, sodium dehydroacetate, gum arabic, Tragacanth, methylcellulose, egg yolk, surfactant, sucrose, simple syrup, citrate, distilled water, ethanol, glycerin, propylene glycol, macrogol, sodium monohydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate Glucose, sodium chloride salt, funol, thimerosal, parabenzoate, sodium hydrogen sulfite and the like, and these are used as appropriate depending on the dosage form.

[0035] When the lipase inhibitor of the present invention is used as a pharmaceutical or a pharmaceutical composition, myricitrine is usually 0.05 to 100% by weight in the preparation. / ₀ , preferably 5 to 90% by weight. In addition, when a myritolin-containing plant or an extract thereof is included in the preparation, the myristitrin-containing plant or the extract thereof is 1 to: LOO wt%, preferably 10 Up to 90% by weight can be blended.

 [0036] The administration target of the lipase inhibitor of the present invention includes mammals such as mice, rats, hamsters, rabbits, cats, nu, ushi, hidge, monkeys and humans.

 [0037] When the lipase inhibitor of the present invention is used as a medicament, the dose of myricitrin varies depending on the patient's pathology, age, administration method, etc., but is usually 0.01 to 20 gZ days per day for human adults. The dose is preferably about 0.05 to 10 gZ days, more preferably about 0.1 to 3 gZ days, and this is divided into 1 to 5 doses as needed.

[0038] When the lipase inhibitor of the present invention is used as a cosmetic product, oils, waxes, fatty acids, and the like that are usually used in cosmetics depending on the purpose within a range that does not impair the effects of the agent. Combine ingredients such as surfactants, alcohols, esters, hydrocarbons, vitamins, amino acids, enzymes, nucleic acids, etc. that are listed in the Cosmetic Raw Material Standards, Japanese Pharmacopoeia, Food Additives, etc. Also good. As cosmetics, it can be used in the form of basic cosmetics such as creams, lotions, emulsions, knocks, makeup cosmetics such as foundations, bathing agents, stone jars and the like. These products can be manufactured using a general manufacturing method for cosmetics, except that a predetermined amount of the agent is contained. [0039] In the case of cosmetics, millicitrin is 0.05 to 100 weight. / ₀ , preferably 5 to 90% by weight or more. In addition, when formulating a myristitrin-containing plant or an extract thereof, the myristitrin-containing plant or an extract thereof is added in an amount of 1 to LOO% by weight, preferably 10 to 90% by weight in terms of a solvent-extracted dried product. sell.

 [0040] Furthermore, foods, pharmaceuticals and cosmetics containing the lipase inhibitor of the present invention are known to be used in foods, pharmaceuticals and cosmetics as long as they do not adversely affect the lipase inhibitory activity of myricitrin as a whole. Components such as xanthine derivatives, | 8 adrenergic agonists, << 2 adrenergic inhibitors, biviridine derivatives, and myrtaceae plant extracts may be used alone or in combination.

 [0041] The xanthine derivative that can be used in the present invention is not particularly limited. For example, xanthine, aminophylline, theophylline, choline theophylline, caffeine, theobromine, 1,7-dimethylxanthine, oxtrifin, diprofylline, proxyphylline. And so on. These can be used alone or in combination of two or more. As these xanthine derivatives, those synthesized or those substantially isolated from plants such as tea can be used.

[0042] The β-adrenergic agonist that can be used in the present invention is not particularly limited. Chlorprenalin, Hexoprenalin, Trimethoquinol, Proterol hydrochloride, Prenalterol, Forskolin, Disodium (R, R) — 5— [[[[2— (3—Black mouthfeel) 1 2 Hydrochetyl ] Amino] propyl] fur] phenoxyacetic acid, [2 hydroxy 5— [2— [[2 —hydroxy 1 3— [4— (1-methyl 4 trifluoromethyl) 1H-imidazol 1-2-yl] ] Phenoxy] propyl] amino] ethoxy] benzamide monomethanesulfonate, ELIS mouthpiece DL—1— (7-methinoreida One 4-Iruokishi) and 3-isopropylamino-pig Hmm 2- ol and pharmaceutically acceptable salts of these pharmacologically like. Examples of pharmacologically acceptable salts include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, and organic amine addition salts. In the present invention, isoproterenol, dobutamine, salbutamol and their pharmacologically acceptable salt strength are selected as one type or It is preferable to use two or more types of salts. In this case, hydrochloride and sulfate are preferred.

 [0043] The a 2 adrenergic inhibitor that can be used in the present invention is not particularly limited. Toxins, laurosine, piperoxane and pharmacologically acceptable salts thereof may be mentioned. These can be used alone or in combination of two or more. As the pharmacologically acceptable salt, mesylate, tartrate and hydrochloride are preferred.

 [0044] The biviridine derivatives used in the present invention are not particularly limited, but include amrinone, milrinone, 5ciano [3,4, monobiviridine] -6 (1H) -one, 5-streptylamylone [3,4, 1 biviridine] -6 (1H) -one and pharmacologically acceptable salts thereof.

 [0045] The present invention provides a method of inhibiting lipase in a subject, comprising administering to the subject an effective amount of myricitrin, and the use of millicitrin in the manufacture of a medicament for inhibiting lipase. Furthermore, a lipase inhibitor and the lipase inhibitor should be used or capable of being used for fat absorption suppression, blood fat concentration suppression, anti-obesity, insulin resistance improvement, blood insulin concentration reduction and metabolic syndrome improvement or prevention And provide a commercial package that includes documentation that states

 [0046] Hereinafter, the present invention will be illustrated more specifically with reference to Examples and Experimental Examples, but the present invention is not limited thereto.

 Example

 [0047] Test example 1: Lipase activity case. Harm test, test

 Porcine spleen lipase (Sigma) 1250 μ1, colipase (Sigma) 50 μ1, 0.5 カ ル シ ウ ム calcium chloride 101, 1M sodium chloride ZlM Ν Tris (hydroxymethyl) methyl 2 aminoethanesulfonic acid (TES ) (ρΗ7.0) 500 μ1 and distilled water 690 μ1 were mixed to prepare an enzyme solution.

Triolein 16 μ 1, lOOmg / ml L—a—phosphatidinorecholine 18. 3 1, 0.1M sodium chloride ZO. 1M TES (pH7.0) 1216 1 and taurocholate 0.915mg A substrate solution was prepared. Enzyme solution 25 / zl and test sample 12.51 in Table 1 dissolved in pure water were mixed and allowed to stand at room temperature for 5 minutes, then substrate solution 12.51 was added and reacted at room temperature for 60 minutes. . After the reaction, the reaction solution of 41 was taken, and the amount of fatty acid decomposed and released by lipase was measured with NEFA C test kit (Wako Pure Chemical Industries, Ltd.). As a control, water was used in place of the test sample in the same manner, and the ratio (%) relative to the control in the presence of the test sample was calculated to evaluate the inhibitory action. As a result, mycitrin was found to have an inhibitory effect, and the concentration at which control activity was inhibited by 50% was 0.215 mM. The results including those of other flavonoids are shown in Table 1 below. Myristin and Myricetin were purchased from ChromaDex from Genistin, Chemfuerol, Quercetin, (-)-Epicatechin, Rutin, (Shi) Naringenin, and (1) Epigalocatechin Galate, respectively.

[table 1]

(1) Samples lg were obtained from Mizlenbu, Teriha bunjirou, Banjiro, Tachibana adek, Gurumiyama, Jabochikapa, Rembu's leaves. Take a sample in a container equipped with a stirrer, add 40 ml of water, stir at a temperature of 30 ° C for 2 hours, then filter the contents at room temperature under reduced pressure using a Buchner funnel and filter paper (5A) to extract the solid content. The liquid was separated into 40 ml. 40 ml of ethyl acetate was added to the obtained extract and the extraction was repeated 3 times to obtain 120 ml of ethyl acetate extract. Add 40ml of water, stir for 5 minutes at 30 ° C, centrifuge (lOOOg, 10 minutes) And separated into an ethyl acetate layer and an aqueous layer. After 120 ml of the obtained ethyl acetate layer was transferred to a vacuum dryer, the extraction solvent was distilled off at 40 ° C. for 30 minutes under a reduced pressure of 50 mmHg to obtain 0.05 g of a myristitrine-containing extract. The millicitrin content of each extract was evaluated by the following method.

[0050] Analysis and evaluation of myristitrine-containing extracts

 For each mycitrin-containing extract produced, the extract was analyzed by the following method to analyze the myristitrin content.

 5 mg of each extract was dispersed in 50 ml of methanol. This dispersion was used as an analysis sample. This analysis sample was subjected to high performance liquid chromatography under the following conditions to analyze myristitrin. As a standard sample, commercially available myricitrin purchased from ChromaDex was used.

 When the analysis was carried out by the following method, the elution peak of myricitrin was detected around 50 minutes. Quantification was performed using the area ratio of the detected peaks.

 As shown in Table 2, all mycitrin contents of each extract were high.

 <Conditions for high performance liquid chromatography>

 Stationary phase: Shiseido Capcell Pak C18—

 Column diameter: 4.6 mm, column length: 250 mm

 Developing solvent: 0.1% trifluoroacetic acid aqueous solution power 0.1% trifluoroacetic acid—40% linear nitrile aqueous solution for 80 minutes

 Developing solvent flow: lmlZ min

 Detector: UV (350nm)

[0051] [Table 2] Plant name Myristitrin content (%)

 ^ Remb— 1 2

 Teriha Banjiro 1 0

 / Kunjiro 24

 Tachibana Adek 42

 Gurumiyama 1 4

 Japoticava 30

 Rembu 20

 [0052] (2) The leaf strength of Mizurembu, Teriha Banjiro, Banjiro, Gurumiyama, Jaboticapa, Rembu was also obtained for each sample lg. Take a sample in a container equipped with a stirrer, add 40 ml of water, stir at a temperature of 60 ° C for 2 hours, then filter the contents at room temperature under reduced pressure using a Buchner funnel and filter paper (5A) to obtain a solid and an extract. Separated into 40 ml. Thereafter, the extract was passed through an adsorption resin (Diaion HP-20 manufactured by Mitsubishi Chemical Corporation) lg at a rate of lOmlZ, and the components were adsorbed. The adsorbed resin was sequentially washed with 4 ml of water and 20% ethanol, and then eluted with 4 ml of 40% ethanol. 4 ml of this 40% ethanol-eluted fraction was transferred to a vacuum dryer, and then the extraction solvent was distilled off at 40 ° C for 1 hour under a reduced pressure of 50 mmHg to obtain 0.05 g of a myristitrin-containing extract.

 For each mycitrin-containing extract produced, the extract was analyzed by the same method as in (1) to analyze the myristitrin content. As shown in Table 3, all mycitrin contents of the extracts were high.

 [0053] [Table 3]

 Plant name Myristitrin content (%)

 Mizlen: J 1 1

 Teriha Banjiro 15

 / Kunjiro 16

 Gurumiyama 1 1

 Japoticava 15

 Remb 21

 [0054] Test Example 2: Mizurenb, Terihabanjiro Blood Fat Concentration Test, Test (Soybean Oil Test, Test)

Mizlenbu or terihabanjiro leaves 10ml per lg of 70% ethanol solution at room temperature Extraction was performed at, and dried up was used for the test. Male ICR mice (9 weeks old) were orally administered 20% soybean oil by lOmlZkg, and immediately, 0.5% sodium carboxymethylcellulose (Control) or the prepared extract suspended in Control at a dose of 500 mg / kg Orally. In addition, the prepared extract contained 1.0% by weight in the case of the mycitrin extract mizurembu extract and 1.5% by weight in the case of the terihabanjirou extract. Blood samples were collected from the fundus vein before administration, 2, 3, and 4 hours after administration, and plasma tridalycide levels were measured with a Fuji Dry Chemslide (Fuji Film). The difference between the triglyceride value before administration of each individual and the tridalylide value at each time after administration was determined to determine the plasma triglyceride change / area under the time curve. The results are shown in Figure 1. As can be seen from the figure, the increase in plasma tridalylide level was suppressed in the group administered with the extract.

 [0055] ms Grumichiyama ¾ ^ 屮,) rfn. Width n) city U, experiment (m)

 Extraction was carried out at room temperature with 10 ml of 70% ethanol solution per lg of Gurumiyama leaves, and the dried up ones were used for the test. Male ICR mice (6 weeks old) were orally administered 20% soybean oil at 10 mlZkg, and 0.5% sodium carboxymethylcellulose (Control) or the prepared extract was suspended in Control at a dose of 500 mgZkg. Orally administered. The prepared extract contained 1.2% by weight of myristitrin. Blood samples were collected from the fundus vein before administration and 2, 3, and 4 hours after administration, and plasma tridalylide values were measured with Fuji Dry Chem Slide (manufactured by Fuji Film). The difference between the tridaylicide value before administration of each individual and the tridalyride value at each time after administration was taken, and the area under the plasma triglyceride change-time curve was determined. The result is shown in figure 2. As is clear from the figure, the increase in the plasma tridalycelide level was suppressed in the group to which the extract was applied.

[0056] Test Example 4: Japotikaba or Rembu Serum Fat Concentration Test, Experiment (soybean oil loaded mi

Jaboticapa or Lembu leaves were extracted with 10 ml of 70% ethanol solution per lg at room temperature and dried up and used for the test. Male ICR mice (8 weeks old) were orally administered 20% soybean oil in lOmlZkg and immediately suspended in 0.5% carboxymethylcellulose sodium (Control) or the prepared extract in Control solvent at a dose of 500mgZkg. Orally. In addition, mycitrin is extracted from jaboticapa in the prepared extract. In the case of the product, 0.9% by weight, and in the case of Rembu extract, 1.2% by weight were contained. Before administration and 1, 2, 3 and 4 hours after administration, blood was collected from the fundus vein, and plasma tridalylide value was measured with Fuji Dry Chemslide (Fuji Film). The area under the plasma triglyceride change time curve was determined by taking the difference between the tridalyceride value before administration and the tridalylide value at each time after administration. The results are shown in Figure 3. As is apparent from the figure, the increase in plasma triglyceride level was suppressed in the group administered with the extract.

[0057] Test {Row 5: Japachikaba 柚 ίΒ · ίΐΠ 冲 · ΐΠ 冲 ΐΠ 冲 ΐΠ 冲 jjj¾¾ l! II 、 试 (大 ^: ¾ load test)

 Extraction was carried out at room temperature with 10 ml of 70% ethanol solution per lg of jaboticapa, and the dried up product was used for the test. Male ICR mice (7 weeks old) were orally administered 20% soybean oil at 10 mlZkg, and immediately, 0.5% sodium carboxymethylcellulose (Control) or a suspension of the prepared extract in Control solvent was administered at a dose of 500 mgZkg. Was administered orally. The prepared extract contained 0.3% by weight of myristitrin. Blood samples were collected from the fundus vein before administration, 2, 3, and 4 hours after administration, and plasma tridalycelide levels were measured with Fuji Dry Chemslide (Fuji Film). The difference between the tridalylide value before administration and the tridalyride value at each time after administration for each individual was determined, and the area under the plasma triglyceride change / time curve was determined. The results are shown in Fig. 4. As can be seen from the figure, the increase in plasma tridalylide level was suppressed in the group administered with the extract.

 [0058] me Tachibana Adek>,> rfn. Effect) Town U, Trial (Olive ¾ Trial, Trial)

 Extraction was performed at room temperature with 10 ml of 70% ethanol solution per lg of Tachibana adek, and the dried up was used for the test. To male C57BL6J mice (12 weeks old), 20% olive oil was orally administered at 10 mlOlZkg, and 0.5% sodium carboxymethylcellulose (Control) or the prepared extract was suspended in Control solvent. Orally administered. Blood samples were collected from the fundus vein before administration, 2, 4, and 6 hours after administration, and plasma triglyceride values were measured with Fuji Dry Chemslide (Fuji Film). The results are shown in FIG. As is clear from the figure, the increase in plasma tridalylide level was suppressed in the group to which the extract was administered.

 [0059] Test example 7: Blood fat level of myricitrin Control test, test (olive oil loading test)

Myricitrin purchased from Wako was used for the test. Male C57BL6J mice (1 20% olive oil was orally administered at 2 weeks of age, immediately followed by oral administration of 0.5% sodium carboxymethylcellulose (Control) or a prepared extract suspended in Control solvent at a dose of lgZkg. did. Blood samples were collected from the fundus vein before administration, 2, 4, and 6 hours after administration, and plasma triglyceride values were measured with Fuji Dry Chem Slide (manufactured by Fuji Film). The result is shown in FIG. As is clear from the figure, the increase in plasma triglyceride levels was suppressed in the group administered myricitrin.

[0060] Example 2: Example of tablet manufacturing

 Tachibana adek leaf extract (prepared as in Example 1) 1. Okg

 Lactose 8.5 kg

 Eggshell calcium 0.25 kg

 Sucrose fatty acid ester 0.25 kg

 A

 O doo B I 10. Okg

 After mixing each of the above components, the tablet can be tableted with a single tableting machine to obtain a tablet with a diameter of 10 mm and a weight of 400 mg.

 [0061] ¾ Example 3: e ^ row of granules

 Tachibana adek leaf extract (prepared as in Example 1) 1.5 kg

 Lactose 6.5 kg

 Starch 1. 9kg

 Magnesium stearate 0.1 kg

 Total 10. Okg

 After mixing each of the above components, a pressure bias is obtained with a roller compactor. This pressure-biased product is pulverized with an oscillator, and after sizing, it is passed through a sieve to obtain granules having a particle size of 20 to L00 mesh.

[0062] Example 4: Granules notification example

 Myricitrin 1. Okg

 Lactose 7. Okg

 Starch 1. 9kg

Magnesium stearate 0.1 kg Total 10. Okg

 After mixing the above components, extrusion granulation is performed by a conventional method, and then passed through a sieve to obtain a particle size of 20

~ 100 mesh granules can be obtained.

Example 5: Production example of capsule

 Capsules can be prepared by filling 250 mg of powder of Tachibana adek leaf extract prepared in the same manner as in Example 1 into hard capsules.

Example 6: Production example of drink

 Aspartame 2. Og

 Cenoic acid 12. Og

 Vitamin C 10. Og

 Tachibana adek leaf extract (prepared as in Example 1) 300. Og

 Vitamin E 30. 0g

 Cyclodextrin 5.0 g

 Blend the above ingredients, add water to make 10 liters, and mix well to prepare a beverage. 100ml can be used as a single serving.

[0065] The foregoing is a detailed description of some of the specific embodiments of the invention. Those skilled in the art will recognize that the particular embodiments shown can be varied without departing from the teachings and advantages of the invention. Corrections and changes can be made. Accordingly, all such modifications and changes are intended to be included within the spirit and scope of the present invention as claimed.

 This application is based on Japanese Patent Application No. 2006-112790 filed in Japan, the contents of which are incorporated in full in this application.

 Industrial applicability

[0066] The lipase inhibitor of the present invention has effects such as suppression of fat absorption, suppression of blood fat concentration, anti-obesity, improvement of insulin resistance, reduction of blood insulin concentration, improvement or prevention of metabolic syndrome, It is useful as an absorption inhibitor, blood fat concentration inhibitor, anti-obesity agent, insulin resistance improving agent, blood insulin concentration lowering agent, or metabolic syndrome improving or preventing agent.

Furthermore, the lipase inhibitor of the present invention suppresses absorption in the body after fat intake, Suppresses subsequent increase in triglycerides, can help improve the health status of people who tend to eat fat, and makes it difficult for people who are concerned about body fat and triglycerides Such effects can also be provided. Therefore, it is effective for prevention or treatment of diseases such as obesity, diabetes, hypertension, hyperlipidemia, arteriosclerosis, and other lifestyle-related diseases and metabolic syndrome.

Claims

The scope of the claims  [1] A lipase inhibitor characterized by containing mycitrin as an active ingredient. [2] Myricitrin force Syzygium aqueum (= Eugenia aquea), Syzyg guajava, Syzygium accurasis (Eugenia malaccensis), Sigigyum 'Donbei' Schizygium dombeyi Skeels), Sijimu 'Psidium longifolium, Myrciaria cauliflora, Syzygium Samarangens, Nychigium jamboent', oc The lipase inhibitor according to claim 1, which is obtained from a plant selected from the group consisting of Psidium 1 ittorale Raddi and Eugenia uniflora or an extract thereof. [3] The plant comprising 0.05% by weight or more of myricitrin or an extract thereof, The lipase inhibitor according to 1 or 2. [4] The lipase inhibitor according to claim 1, wherein myricitrin is synthesized. [5] As an active ingredient, an extract having a myristitrin content of 0.05% by weight or more obtained by a step of extracting a plant containing mycitrin with water, an organic solvent, or a mixed solvent thereof. A lipase inhibitor characterized by 6. The lipase inhibitor according to claim 5, wherein the extract is obtained by a purification step by partitioning using an organic solvent or a purification step by adsorption resin after the extraction step.  [7] The fat absorption inhibitor, blood fat concentration inhibitor, anti-obesity agent, insulin resistance improving agent, blood insulin concentration lowering agent or metabolic syndrome improving or preventing agent power is at least one selected from the above, The lipase inhibitor according to any one of 1 to 6.  [8] A method for producing an extract containing myricitrin, comprising a step of extracting a plant containing myricitrin with water, an organic solvent, or a mixed solvent thereof.  [9] The production method according to claim 8, further comprising a purification step by distribution using an organic solvent or a purification step by adsorption resin after the extraction step. [10] A food containing the lipase inhibitor according to any one of claims 1 to 6. [11] The food according to claim 10, which is a health functional food or a dietary supplement. [12] The food according to claim 11, wherein the functional health food is food for specified health use or functional food for nutrition  P PPo  [13] A cosmetic comprising the lipase inhibitor according to any one of claims 1 to 6. [14] A method of inhibiting lipase in a subject, comprising administering to the subject an effective amount of myricitrin.  [15] Myricitrin force Syzygium aqueum (= Eugenia aquea), Syzyg guajava, Sugezy malaccensis, Syzygium 'Syzygium dombeyi Skeels), Sijimu 'Psidium longifolium, Myrciaria cauliflora, Syzygium Samarangens, Nychigium jamboent', oc 15. The method according to claim 14, wherein the method is obtained from a plant selected from the group consisting of Psidium 1 ittorale Raddi and Eugenia uniflora or an extract thereof. [16] The method according to claim 14, wherein myricitrin is synthesized. [17] Claims 14 to 16 of claim 14 for reducing fat absorption, suppressing blood fat concentration, anti-obesity, improving insulin resistance, lowering blood insulin concentration or improving or preventing metabolic syndrome! The method according to item. [18] Use of myricitrin in the manufacture of a medicament for inhibiting lipase. [19] Mysycitrin force Syzygium aqueum (= Eugenia aquea), Syzyg 'guanoku (Psidium guajava), Shujia' Eugenia malaccensis, Sigigyum 'Donbei' Schizygium dombeyi Skeels), Sijimu 'Psidium longifolium, Myrciaria cauliflora, Syzygium Samarangens, Nychigium jamboent', oc The use according to claim 18, which is obtained from a plant selected from the group consisting of Psidium 1 ittorale Raddi and Eugenia uniflora or an extract thereof. [20] The medicine comprises a plant containing 0.05% by weight or more of myristitrin or an extract thereof. 20. Use according to claim 18 or 19. [21] The use according to claim 18, wherein myricitrin is synthesized. [22] The medicinal product contains an extract having a myristitrin content of 0.05% by weight or more obtained by extracting a plant containing mycitrin with water, an organic solvent, or a mixed solvent thereof. 19. Use according to claim 18. [23] The use according to claim 22, wherein the extract is obtained by a purification step by distribution using an organic solvent or a purification step by adsorption resin after the extraction step. [24] The medicine is at least one selected from fat absorption inhibitors, blood fat concentration inhibitors, anti-obesity agents, insulin resistance improving agents, blood insulin concentration reducing agents, or metabolic syndrome improving or preventing agents. 24. Use according to any one of claims 18 to 23.