JP6320715B2 - Alcoholic fatty liver preventive and therapeutic agent - Google Patents

Description

  The present invention relates to an agent for preventing and treating alcoholic fatty liver.

  Fatty liver is a state in which neutral fat (triglyceride) has accumulated excessively in the liver due to heavy drinking and overnutrition (large intake of carbohydrates and fat). Fatty liver not only progresses to hepatitis and cirrhosis, but also increases the risk of developing type 2 diabetes and progresses to various lifestyle-related diseases. Therefore, many lifestyle-related diseases can be prevented if the cause of fatty liver onset is elucidated and a prevention / treatment method for removing the cause is clarified.

There are two types of fatty liver, alcoholic and non-alcoholic. Alcoholic fatty liver is thought to be caused by abnormal lipid metabolism caused by an increase in the NADH / NAD ⁺ ratio in hepatocytes by inhibiting β-oxidation of fatty acids. The cause of nonalcoholic fatty liver is thought to be due to excessive intake and biosynthesis of free fatty acids (NEFA).

  In the past, the present inventors, regarding alcoholic fatty liver, acute alcoholic fatty liver that occurs when a single dose of alcohol is administered to a mouse is the transcriptional regulator SREBP-1c that occurs when alcohol is administered the day before when fish oil is ingested. It was clarified that the activation is suppressed and the expression of genes related to fatty liver onset is reduced (Non-patent Document 1). However, it is unclear whether other food ingredients have substances with similar functions. On the other hand, Non-Patent Document 2 shows that fish oil worsens fatty liver caused by excessive intake of fat in mice. Thus, the effectiveness of fatty liver varies greatly depending on its cause.

  Nubiletin, a kind of flavonoid contained in citrus peels such as mandarin oranges, which is a special product of Shizuoka Prefecture, has accumulated a lot of knowledge that suggests that it suppresses metabolic syndrome.

  Patent Document 1 discloses a health food comprising a whole fruit concentrate of Citrus citrus fruit, a freeze-dried pulverized product of a rind raw fruit, or an alcohol extract of a freeze-dried pulverized product of a rind fruit, It has been disclosed that by taking this health food, the production of lipid peroxide is greatly suppressed, and obesity, arteriosclerosis, and various adult disease factors can be removed.

  Patent Document 2 discloses an anti-obesity food comprising citrus fruit powder from which fruit juice has been removed and green-yellow vegetable powder as essential ingredients. In the examples, freeze-dried products from which eggplant juice has been removed and freeze-dried parsley Disclosed is a result of measuring body weight, triglyceride (TG), cholesterol (TC), and transamylase (GOT, GPT) for rats and humans by giving powder mixed with the product.

Claim 1 of Patent Document 3 discloses a lipolysis promoter comprising a citrus plant as an active ingredient and a skin preparation for external use containing the same, and claim 2 particularly discloses a citrus plant. A skin external preparation composition in which xanthine derivative, β adrenergic stimulant, α ₂ adrenergic inhibitor and bipyridine derivative are blended with a lipolysis accelerator as an active ingredient is disclosed, An effect of suppressing, preventing and improving obesity by accelerating the degradation of triglyceride accumulated in adipose tissue is disclosed.

  Patent Document 4 discloses that Citrus plant extract induces the expression of uncoupling protein and activates uncoupling protein, thereby improving the conversion efficiency from chemical energy coupled to ATP synthesis to thermal energy, It is disclosed that it can be used particularly effectively as an agent for improving lipid and carbohydrate metabolism.

  In Patent Document 5, nobiletin and synephrine act synergistically on adipocytes, so that fat in the cells can be decomposed more efficiently, and the effects of side effects are also felt by diet. However, it is disclosed that obesity can be easily treated and prevented.

  Patent Document 6 discloses a method for managing fat accumulation in adipocytes using a composition comprising a fraction containing at least one polymethoxylated flavone, such as nobiletin, and in certain embodiments, weight A method for preventing rebound weight gain in a subject experiencing a decrease is disclosed.

  Patent Document 7 discloses that a citrus peel extract containing nobiletin suppresses an increase in body weight gain without affecting the amount of food consumed, a mouse in skeletal muscle tissue or skeletal muscle cell. GLUT4 and its homologue, the action of promoting the protein expression of the sugar transporter gene, the action of promoting the enlargement of enlarged peripheral visceral white adipose tissue, and the blood glucose level without affecting the blood triglyceride level It has been disclosed that it can be effectively used as a therapeutic agent for metabolic syndrome.

  In Patent Document 8, a composition containing licorice polyphenol and other active ingredients (an antioxidant component, a polyphenol other than licorice polyphenol, such as nobiletin, or a component involved in absorption or metabolism of lipid) is highly safe and easy. And can be used for foods and drinks such as health foods and health functional foods (special health foods, nutritional functional foods), pharmaceuticals, quasi drugs, cosmetics, etc. It has been disclosed that it has an effect of suppressing body fat accumulation, promoting body fat degradation, or promoting energy production, and is useful for the treatment of obesity, metabolic syndrome and the like.

  Patent Document 9 includes compound A: 3 ′, 4 ′, 3,5,6,7,8-heptamethoxyflavone contained in citrus, compound B: 5-hydroxy-3 ′, 4 ′, 6,7, 8-Pentamethoxyflavone, Compound C: 4 ′, 5,6,7,8-Pentamethoxyflavone (Tangeretin), Compound D: 3 ′, 4 ′, 5,6,7,8-Hexamethoxyflavone (Nobiletin) Compound E: 3 ′, 4 ′, 5,6,7-pentamethoxyflavone (sinensetin) and Compound F: 3 ′, 4 ′, 5,7,8-pentamethoxyflavone It has been disclosed that certain compounds have a function of inhibiting fat accumulation in adipocytes.

  Moreover, when nobiletin-containing food (60% lipid energy) is given to mice, β-oxidation of fatty acids is promoted, triglyceride accumulation in the liver is suppressed, and VLDL overproduction from the liver is further suppressed. It has been reported that dyslipidemia and arteriosclerosis are suppressed (Non-patent Document 3).

  As described above, nobiletin for alcoholic fatty liver, etc., although there are many reports on the effects of citrus peel extract containing nobiletin and nobiletin on obesity, diabetes, non-alcoholic fatty liver, etc. The action of polymethoxyflavone has not been reported.

JP-A-57-203014 JP 62-44145 A JP-A-8-81382 JP 2004-149432 A JP 2004-137218 A Special table 2009-506057 gazette WO2010 / 134373 WO2008 / 143182 JP 2008-273935 A

Satoshi Wada, Tomomi Yamazaki, Yukari Kawano, Shinji Miura, Osamu Ezaki, “Fish oil fed prior to ethanol administration prevents acute ethanol-induced fatty liver in mice”, Journal of Hepatology 49 (2008), pp. 441-450. Tomomi Yamazaki, Akiko Nakamori, Eriko Sasaki, Satoshi Wada, Osamu Ezaki, “Fish Oil Prevents Sucrose-Induced Fatty Liver But Exacerbates High-Safflower Oil-Induced Fatty Liver in ddY Mice”, HEPATOLOGY, Vol. 46, No.6, 2007 , pp. 1779-1790. Mulvihill EE et al., “Nobiletin attenuates VLDL overproduction, dyslipidemia, and atherosclerosis in mice with diet-induced insulin resistance”, Diabetes, Vol. 60, pp. 1446-1457 (2011).

  An object of the present invention is to provide a drug effective in preventing and treating alcoholic fatty liver by reducing the concentration of liver triglyceride increased by alcohol.

The gist of the present invention is as follows.
(1) An alcoholic fatty liver preventive / therapeutic agent comprising polymethoxyflavone, citrus pericarp containing polymethoxyflavone or a processed product thereof as an active ingredient.
(2) The preventive / therapeutic agent for alcoholic fatty liver according to (1), wherein the polymethoxyflavone is at least one of nobiletin and tangeretin.
(3) The alcoholic fatty liver preventive / therapeutic agent according to (1), wherein the polymethoxyflavone is nobiletin.
(4) The alcoholic fatty liver preventive / therapeutic agent according to any one of (1) to (3), which is added to food.
(5) The preventive / therapeutic agent for alcoholic fatty liver according to any one of the above (1) to (4), which is a liver triglyceride concentration reducing agent that increases due to alcohol.
(6) An alcoholic beverage comprising the alcoholic fatty liver preventing / treating agent according to any one of (1) to (5).

  By administering the alcoholic fatty liver preventive / therapeutic agent of the present invention to humans or non-human vertebrates, an increase in liver triglyceride concentration induced by alcohol intake is reduced, or liver triglycerides induced by alcohol intake Diseases resulting from the increase in concentration, such as fatty liver, metabolic disorder liver disease, cirrhosis, liver fibrosis, etc. can be prevented and treated.

FIG. 1 is a graph showing the amount of triglycerides in the liver (mg / g liver) when glucose or alcohol was orally administered after oral administration of nobiletin.

  The polymethoxyflavone used in the present invention means a flavone substituted with 2 or more, preferably 4 to 7 methoxy groups. Examples of the polymethoxyflavone include 5,6,7,4′-tetramethoxyflavone, 5,6,7,8,4′-pentamethoxyflavone (tangeretin), 5,6,7,3 ′, 4′- Pentamethoxyflavone (sinensetin), 5,6,7,8,3 ′, 4′-hexamethoxyflavone (nobiletin), 3,5,6,7,3 ′, 4′-hexamethoxyflavone, 3,5,5 6,7,8,3 ′, 4′-heptamethoxyflavone, preferably 5,6,7,8,4′-pentamethoxyflavone (tangeretin), 5,6,7,8,3 ′, 4′- Hexamethoxyflavone (nobiletin) is mentioned.

  Since polymethoxyflavone is contained in a large amount in the pericarp of the citrus citrus genus, the pericarp powder obtained by finely pulverizing the pericarp may be used as it is, but the content of polymethoxyflavone is increased. It is preferable to use it as a processed product such as an extract or a purified product thereof.

  Citrus citrus plants include, for example, C. unshiu, C. tachibana, C. deliciosa, C. kinokuni, C. erythrosa, Dancy tangerine ( C. tangerina), Sunki, Citrus depressa, C. tardiva, P. retuculata, C. hanayu, and C. calamondin.

  Polymethoxyflavone has two or more methoxy groups, and as a specific example, the above-mentioned polymethoxyflavone has no hydroxyl group. Therefore, since polymethoxyflavone is highly lipophilic, the content of polymethoxyflavone can be increased by extracting and further purifying as necessary using this property. Since polymethoxyflavone is generally hardly soluble in water and ether, it is preferable to extract and elute using other organic solvents.

  Examples of the extraction solvent include alcohols such as methanol, ethanol, propanol and butanol; esters such as acetate such as ethyl acetate; ketones such as acetone and the like.

  For details on the extraction method, see Polymethoxylated Flavonoids from the Peels of Citrus depressa (Yoshihiro Mimaki et al., Natural Medicines 54 (6), 351 (2000)).

  By eluting the fractionated lipophilic polyalkoxyflavone with a lipophilic solvent, an eluate containing a high lipophilic polyalkoxyflavone (tangeretin, nobiletin, etc.) at a high concentration can be obtained. Furthermore, a powder formulation can be obtained by spray-drying or freeze-drying this concentrated solution.

  Further purification can be performed by appropriately combining silica gel column chromatography, high performance liquid chromatography and the like.

  The preventive / therapeutic agent for alcoholic fatty liver of the present invention is formulated by combining polymethoxyflavone, citrus pericarp containing polymethoxyflavone or a processed product thereof with a known food carrier or pharmaceutical carrier be able to. The dosage form is not particularly limited and is appropriately selected as necessary. In general, tablets, capsules, granules, fine granules, powders, solutions, syrups, suspensions, emulsions, elixirs, etc. Used as an oral agent. Moreover, the alcoholic fatty liver preventive / therapeutic agent of the present invention can be added to foods, chewing gums, beverages and the like to make so-called foods for specified health use.

  The alcoholic fatty liver preventive / therapeutic agent of the present invention can reduce the liver triglyceride concentration increased by alcohol when taken before or during drinking, and can prevent or suppress alcoholic fatty liver. .

  The dose of the prophylactic / therapeutic agent for alcoholic fatty liver of the present invention varies depending on the patient's age, body weight, degree of disease, and administration route, but for oral administration, it is usually 5 to 300 mg per day as polymethoxyflavone. The administration frequency is usually 1 to 3 times a day for oral administration.

  Oral preparations are produced according to a conventional method using excipients such as starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, and inorganic salts.

  In this type of preparation, a binder, a disintegrant, a surfactant, a lubricant, a fluidity promoter, a corrigent, a colorant, a fragrance and the like can be appropriately used in addition to the above-mentioned excipients.

  Specific examples of the binder include crystalline cellulose, crystalline cellulose / carmellose sodium, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carmellose sodium , Ethylcellulose, carboxymethylethylcellulose, hydroxyethylcellulose, wheat starch, rice starch, corn starch, potato starch, dextrin, pregelatinized starch, partially pregelatinized starch, hydroxypropyl starch, pullulan, polyvinylpyrrolidone, aminoalkyl methacrylate copolymer E, aminoalkyl METAKU Rate copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer, polyvinyl acetal diethylamino acetate, polyvinyl alcohol, gum arabic, gum arabic powder, agar, gelatin, white shellac, tragacanth, purified sucrose, macrogol.

  Specific examples of disintegrants include crystalline cellulose, methylcellulose, low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, wheat starch, rice starch, corn starch, potato starch, and partially pregelatinized. Starch, hydroxypropyl starch, sodium carboxymethyl starch, tragacanth can be mentioned.

  Specific examples of surfactants include soybean lecithin, sucrose fatty acid ester, polyoxyl stearate, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, sorbitan sesquioleate, sorbitan trioleate, sorbitan monostearate Sorbitan monopalmitate, sorbitan monolaurate, polysorbate, glyceryl monostearate, sodium lauryl sulfate, lauromacrogol.

  Specific examples of lubricants include wheat starch, rice starch, corn starch, stearic acid, calcium stearate, magnesium stearate, hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, dry aluminum hydroxide gel, talc, Examples thereof include magnesium aluminate metasilicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, sucrose fatty acid ester, waxes, hydrogenated vegetable oil, and polyethylene glycol.

  Specific examples of the fluidity promoter include hydrous silicon dioxide, light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, and magnesium silicate.

  Moreover, the alcoholic fatty liver preventive / therapeutic agent of the present invention may contain a flavoring agent and a coloring agent when administered as a solution, syrup, suspension, emulsion, or elixir.

  In addition, when the alcoholic fatty liver preventive / therapeutic agent of the present invention is blended in an alcoholic beverage, the alcoholic fatty liver preventive / therapeutic agent of the present invention is taken simultaneously with drinking, so the liver triglyceride concentration is unlikely to increase, It can be set as the alcoholic beverage which is hard to become alcoholic fatty liver.

  In the present invention, the alcoholic beverage means alcoholic beverages, so-called liquors, such as sake, synthetic sake, shochu, mirin, beer, fruit liquors (fruit and sweet fruit liquor), whiskeys (whiskey and Brandy), spirits, liqueurs and miscellaneous sake.

  The alcoholic beverage of the present invention refers to an alcoholic beverage containing “polymethoxyflavone, or citrus peel or processed product thereof containing polymethoxyflavone” according to the present invention. It may or may not contain fruit juice, but it can be used just like normal “citrus sake”, “polymethoxyflavone, or citrus pericarp that contains polymethoxyflavone, or its peel Fruit liquor that does not contain "processed products" is not included.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated further more concretely, the scope of the present invention is not limited to these Examples.

[Example 1] Effect of pre-administration of nobiletin on the development of alcoholic fatty liver (test method)
A single dose of alcohol in rats, mice, and other laboratory animals causes fatty liver, and this animal model has physiological characteristics similar to those who drink alcohol (Satoshi Wada, Tomomi Yamazaki, Yukari Kawano, Shinji Miura, Osamu Ezaki, “Fish oil fed prior to ethanol administration prevents acute ethanol-induced fatty liver in mice”, Journal of Hepatology 49 (2008), pp. 441-450; Carson EJ, Pruett SB, “Development and characterization of a binge drinking model in mice for evaluation of the immunological effects of ethanol ”, Alcohol Clin Exp Res, Vol. 20, pp. 132-138 (1996)). Therefore, a drug that suppresses the increase in the amount of triglyceride in the liver by a single administration of alcohol is generally considered to suppress the onset of alcoholic fatty liver. Therefore, the test was performed according to the following method.

  Nobiletin (0 to 1,000 μg / mouse) was orally administered to mice, fasted for 2 hours, and then alcohol or glucose was orally administered. Alcohol was administered at 3 mg / g body weight of ethanol. A 40% ethanol aqueous solution was used as the solution, and the solution was administered at a rate of 0.15 ml / 20 g body weight. The glucose administration group administered glucose with the same calories as the alcohol administration group. A 40% aqueous glucose solution was used as the solution, and the solution was administered at a rate of 0.27 ml / 20 g body weight. From the time of ethanol and glucose administration to dissection, the animals were fasted and water was bred freely. Four hours after alcohol administration, the mice were sacrificed under ether anesthesia, and then the liver was removed and the amount of triglyceride in the liver was measured.

(result)
As shown in FIG. 1, the amount of triglyceride in the liver decreased as the dose of nobiletin increased. Therefore, it was suggested that ingestion of nobiletin before drinking significantly suppressed the accumulation of triglycerides in the liver by drinking.

Claims (7)

  A preventive agent for alcoholic fatty liver, which comprises polymethoxyflavone, or pericarp of citrus citrus or a processed product thereof containing polymethoxyflavone, and is taken before drinking. The alcoholic fatty liver preventive agent according to claim 1, which is taken once before drinking. The preventive agent for alcoholic fatty liver according to claim 1, which is taken once within 2 hours before drinking. The alcoholic fatty liver preventive agent according to any one of claims 1 to 3, wherein the polymethoxyflavone is at least one of nobiletin and tangeretin. The alcoholic fatty liver preventive agent according to any one of claims 1 to 3 , wherein the polymethoxyflavone is nobiletin. The alcoholic fatty liver preventive agent according to any one of claims 1 to 5 , which is added to food. The preventive agent for alcoholic fatty liver according to any one of claims 1 to 6 , which is an agent for reducing the concentration of liver triglyceride that is increased by alcohol.