Urine acid production inhibitor

Abstract

To provide a urine acid production inhibitor, and a composition, pharmaceutical, food and drink for preventing or improving hyperuricemia and gout.SOLUTION: A urine acid production inhibitor contains at least one of Alpinia speciosa extract, Rumex japonicus extract, Macaranga tanarius extract, Orthosiphon Stamineus Benth extract, compounds derived therefrom, compounds derived from propolis, and compounds derived from Magnolia kobus as an active ingredient.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a uric acid production inhibitor, an agent for preventing or ameliorating hyperuricemia, an agent for treating hyperuricemia, and compositions, pharmaceuticals, foods and beverages, and health foods containing these as active ingredients. [Background technology]

[0002] In humans, nucleic acids and purines are metabolized in the liver and other organs to become uric acid, which is mainly excreted from the kidneys and intestinal tract, and the balance between synthesis and excretion is maintained, but excessive intake of purines, promotion of uric acid synthesis, and reduced excretion of uric acid cause accumulation of uric acid in the body, resulting in hyperuricemia. If this hyperuricemia continues, urate crystals are deposited in or around the joints, causing so-called gout symptoms such as acute arthritis attacks, gouty tophi, joint dysfunction, and joint deformation, and further causing many complications such as kidney disorders such as uric acid stones (uric acid stones) and cardiovascular disorders.

[0003] Xanthine oxidase is an enzyme that catalyzes the conversion of hypoxanthine to xanthine and then to uric acid in nucleic acid metabolism, and allopurinol, an inhibitor of xanthine oxidase, is used as a treatment for gout. However, since allopurinol is known to have side effects such as liver damage, safer, naturally derived uric acid production inhibitors are in demand, and as a naturally derived xanthine oxidase inhibitor, a blood uric acid level lowering agent containing pomegranate extract as an active ingredient is known (Patent Document 1).

[0004] Since uric acid is mainly produced in the liver through the metabolism of purines, if uric acid production in liver cells can be inhibited, it will be useful as an agent for preventing or improving hyperuricemia, an agent for treating hyperuricemia, and compositions, pharmaceuticals, foods, beverages, and health foods containing these as active ingredients. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] JP 2006-016340 A Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide an excellent uric acid production inhibitor, and to provide an agent for preventing or ameliorating hyperuricemia, an agent for treating hyperuricemia, and compositions, pharmaceuticals, foods and beverages, and health foods containing these as active ingredients. [Means for solving the problem]

[0007] The present inventors used hepatocytes to search for natural products that have been consumed and that can solve the above problems. As a result, they found that shell ginger extract and 5,6-dehydrokawain and dihydro-5,6-dehydrokawain isolated from shell ginger, Rumex dock extract and its component nepodin, Macaranga tanarius extract and its components nymphaeol-A, nymphaeol-B, nymphaeol-C, isonymphaeol-B, 3'-geranyl-naringenin, and green propolis components baccharin, drupanin, and artepillin C were isolated from shell ginger extract and its components nepodin, C), yatein and pulviatolide, which are components of pepper, fargesin, kobusin, epimagnolin A, galgravin, veraguensin, and kumiscutin extract, which are components of Magnolia kobus, suppress uric acid production in liver cells, and the present invention was completed.

[0008] That is, The present invention is as follows. [1] A uric acid production inhibitor containing at least one of the following active ingredients: shell ginger extract, Rumex dock extract, Macaranga tanarius extract, Kumiskuchin extract, 5,6-dehydrokawain, dihydro-5,6-dehydrokawain, nepodin, nymphaeol-A, nymphaeol-B, nymphaeol-C, isonymphaeol-B, 3'-geranylnaringenin, baccharin, dorpanin, artepillin C, yatein, pluvialtolide, fargesin, kobusin, epimagnolin A, galgravin, and belaguensin. [2] A preventive and / or therapeutic agent for hyperuricemia, comprising the uric acid production inhibitor described in [1] as an active ingredient. [3] A preventive and / or therapeutic agent for gout, comprising the uric acid production inhibitor described in [1] as an active ingredient. [4] A preventive and / or therapeutic agent for gout complications, comprising the uric acid production inhibitor described in [1] as an active ingredient. [5] A food, drink, or health food for the prevention and / or treatment of hyperuricemia and / or gout, comprising the uric acid production inhibitor described in [1] as an active ingredient. [6] A method for preventing and / or treating hyperuricemia and / or gout, comprising: A method comprising the step of administering a composition described in [1] to [5] to humans or animals suffering from the above-mentioned disease. Effect of the Invention

[0009] The uric acid production inhibitor of the present invention has the effect of suppressing uric acid production in various tissues including the liver, and can be used as a composition for preventing and improving hyperuricemia, and can be used as a composition, medicine, food, drink, or health food for preventing, improving, and treating gout. [Brief description of the drawings]

[0010] [Figure 1]This is a graph showing the inhibitory effects of the positive control allopurinol (PC), Shell Ginger extract (ethanol extract (EtOH Ex.), 90% methanol fraction (MeOH fr.), 60% acetonitrile eluted fraction (ACN fr.)), 5,6-dehydrokawain (DK), and dihydro-5,6-dehydrokawain (DDK) on uric acid production in hepatocytes. [Diagram 2] 1 is a graph showing the inhibitory effects of the positive control allopurinol (PC), Rumex dock extract, Macaranga tanarius extract, and Kumiscuching extract on uric acid production in hepatocytes. [Diagram 3] 1 is a graph showing the inhibitory effects of nepodin (Nep), yatein (Yat), pluviatolide (Plu), baccarin (Bac), dorupanin (Dru), and artepillin C (Art) on uric acid production in hepatocytes. [Figure 4] 1 is a graph showing the inhibitory effects of nymphaeol-A (NyA), nymphaeol-B (NyB), nymphaeol-C (NyC), isonymphaeol-B (IsB), 3'-geranylnaringenin (3GN), fargesin (Far), kobsin (Kob), epimagnolin A (EpA), galgravin (Gal), and veraguensin (Ver) on uric acid production in hepatocytes. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The uric acid production inhibitor of the present invention contains at least one of the following active ingredients: shell ginger extract, Rumex dock extract, Macaranga tanarius extract, kumiskuchin extract, 5,6-dehydrokawain, dihydro-5,6-dehydrokawain, nepodin, nymphaeol-A, nymphaeol-B, nymphaeol-C, isonymphaeol-B, 3'-geranylnaringenin, baccharin, dorupanin, artepillin C, yatein, pluviatolide, fargesin, kobsin, epimagnolin A, galgravin, and belaguensin.

[0012] <Embodiment 1: Pharmaceutical composition> According to the present invention, Provided is a pharmaceutical composition for preventing and / or treating hyperuricemia and / or gout, which contains as an active ingredient at least one of shell ginger extract, Rumex dock extract, Macaranga tanarius extract, Kumiskuchin extract, 5,6-dehydrokawain, dihydro-5,6-dehydrokawain, nepodin, nymphaeol-A, nymphaeol-B, nymphaeol-C, isonymphaeol-B, 3'-geranylnaringenin, baccharin, drupanin, artepillin C, yatein, pluviatolide, fargesin, kobsin, epimagnolin A, galgravin, and belaguensin.

[0013] The above-mentioned active ingredients may be used alone or in combination in any ratio. The pharmaceutical composition may contain pharma- ceutical acceptable excipients, lubricants, binders, disintegrants, coating agents, etc. Also, it may contain coloring agents, flavorings, preservatives, etc. Examples of excipients include lactose, glucose, corn starch, sorbitol, crystalline cellulose, etc. Examples of lubricants include talc, magnesium stearate, polyethylene glycol, hardened vegetable oil, etc. Examples of binders include dimethylcellulose, polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic, gelatin, hydroxypropylcellulose, polyvinylpyrrolidone, etc. Examples of disintegrants include starch, sodium alginate, gelatin powder, calcium carbonate, calcium citrate, dextrin, etc. The form of use is not particularly limited, and can be in the form of capsules, powders, granules, tablets, liquids, etc., and can also be used as external preparations in the form of creams, pastes, gels, etc., as well as in the form of sustained release patches.

[0014] <Embodiment 2: Food and drink composition> The shell ginger extract, Rumex dock extract, Macaranga tanarius extract, Kumiskuchin extract, 5,6-dehydrokawain, dihydro-5,6-dehydrokawain, nepodin, nymphaeol-A, nymphaeol-B, nymphaeol-C, isonymphaeol-B, 3'-geranylnaringenin, baccharin, drupanin, artepillin C, yatein, pluvialtolide, fargesin, kobusin, epimagnolin A, galgravin, and beraguensin of the present invention can be used as supplements for the prevention and improvement of hyperuricemia and gout, or can be mixed with food and drink, or used as a food and drink composition. When used as a supplement, it can be used in the form of tablets or granules and may be mixed with other useful ingredients. When used as a food or drink composition, it can be provided as a health food or drink, a food or drink for specified health uses, a food or drink with functional claims, a food or drink with nutrient functions, a health supplement food or drink, etc. These foods or drinks can be provided as functional foods that are useful for preventing or improving lifestyle-related diseases, and the foods or drinks for specified health uses, foods with functional claims, and other supplements, health foods or drinks, etc., can be labeled with functions such as lowering uric acid levels, suppressing an increase in uric acid levels, etc.

[0015] The edible composition may be in various forms such as solid, liquid, powder, granule, paste, etc., and specific examples thereof include beverages such as soft drinks, lactic acid drinks, beverages, coffee, green tea, black tea, oolong tea, etc.; confectioneries such as candy, chocolate, biscuits, sweet breads, cakes, mochi confectioneries, rice crackers, etc.; vegetable and fruit products such as fruit drinks, vegetable drinks, jams, pastes, etc.; sake, shochu, wine, Chinese liquor, whiskey, vodka, brandy, gin, rum, sake, beer, soft alcoholic drinks, fruit liquor, etc. Examples of the food and drink products include alcoholic beverages such as liqueurs, dairy products such as yogurt, ice cream, butter, cheese, condensed milk, and powdered milk, oils and fats such as dressings, mayonnaise, tempura oil, and salad oil, seasonings such as soy sauce, sauces, vinegar, mirin, and dressing-type seasonings, dried foods and drinks such as powdered juice, powdered soup, instant coffee, instant noodles, instant curry, instant miso soup, cooked foods, cooked drinks, and cooked soups, and processed grain products such as processed flour products and processed starches. For example, the food and drink products may be used as solids such as candy, cookies, chewing gum, and biscuits, or as liquids such as soft drinks, milk, yogurt, and syrup. When used as food and drink products, additives that are usually used in food and drink products, such as citric acid, lactic acid, and casein, may be blended.

[0016] The pharmaceutical compositions and cosmetics may be administered orally or parenterally, such as by intravenous injection, intramuscular injection, subcutaneous administration, rectal administration, or transdermal administration, and may take the form of creams, lotions, ointments, skin lotions, milky lotions, etc. The content of active ingredients in pharmaceutical compositions, supplements, or edible compositions such as foods and beverages containing Shell Ginger extract, Rumex dock extract, Macaranga tanarius extract, Kumiscuching extract, 5,6-dehydrokawain, dihydro-5,6-dehydrokawain, nepodin, nymphaeol-A, nymphaeol-B, nymphaeol-C, isonymphaeol-B, 3'-geranylnaringenin, baccharin, dorpanin, artepillin C, yatein, pluviatolide, fargesin, kobsin, epimagnolin A, galgravin, or belaguensin varies depending on the dosage form, but may be contained in an amount of 0.001 to 50% by weight, preferably 0.01 to 20% by weight, of the total composition. The amount of the active ingredient to be ingested can be appropriately increased or decreased in consideration of the age, sex, weight, type of symptoms, severity of symptoms, etc. of the person taking the active ingredient, but it is preferable to set the daily intake amount to 0.01 to 500 mg / kg according to each administration form. In any form of pharmaceutical composition, food and drink composition, or biocompatible material, the active ingredient may be administered or ingested once a day or in several divided doses.

[0017] The pharmaceutical composition, supplement, or food and drink composition such as food and drink containing shell ginger extract, Rumex dock extract, Macaranga tanarius extract, Kumiskuchin extract, 5,6-dehydrokawain, dihydro-5,6-dehydrokawain, nepodin, nymphaeol-A, nymphaeol-B, nymphaeol-C, isonymphaeol-B, 3'-geranylnaringenin, baccharin, dorupanin, artepillin C, yatein, pluvialtolide, fargesin, kobusin, epimagnolin A, galgravin, and beraguensin of the present invention is intended for mammals including humans. Examples of mammals other than humans include primates such as monkeys, rodents such as rats and mice, sheep, pigs, cows, cats, and dogs.

[0018] <Embodiment 3: Method for preventing or treating lifestyle-related diseases> According to the present invention, A method for preventing or treating hyperuricemia or gout, the method comprising: A method is provided which includes the step of administering to a human or animal suffering from hyperuricemia or gout a pharmaceutical composition or food or drink containing shell ginger extract, Rumex extract, Macaranga tanarius extract, Kumiskuchin extract, 5,6-dehydrokawain, dihydro-5,6-dehydrokawain, nepodin, nymphaeol-A, nymphaeol-B, nymphaeol-C, isonymphaeol-B, 3'-geranylnaringenin, baccharin, drupanin, artepillin C, yatein, pluvialtolide, fargesin, kobsin, epimagnolin A, galgravin, or beraguensin.

[0019] When the above pharmaceutical composition or food or drink is administered to a patient, the dosage varies depending on various conditions such as the severity of the patient's symptoms, age, body weight, PSA value, urinary flow rate, and health condition. In general, the above-mentioned dosage and method may be administered once or more times a day, and the number and amount of administration may be appropriately increased or decreased depending on the above-mentioned various conditions. The daily dose, administration period and administration frequency of the pharmaceutical composition or pharmaceutical preparation for preventing or treating lifestyle-related diseases or food and drink may be the same as those of the above-mentioned therapeutic drug. The administration of the pharmaceutical composition or pharmaceutical preparation for preventing or treating lifestyle-related diseases may be terminated at the discretion of a doctor or at the patient's own discretion.

[0020] <Active ingredient> The active ingredients of the present invention are shell ginger extract, Rumex dock extract, Macaranga tanarius extract, Kumiskuchin extract, 5,6-dehydrokawain, dihydro-5,6-dehydrokawain, nepodin, nymphaeol-A, nymphaeol-B, nymphaeol-C, isonymphaeol-B, 3'-geranylnaringenin, baccharin, drupanin, artepillin C, yatein, pluvialtolide, fargesin, kobusin, epimagnolin A, galgravin, and belaguensin. The method of producing these is not particularly limited, but the shell ginger of the ginger family used for producing the shell ginger extract is Shima shell ginger (scientific name: Alpinia zerumbet) or Tairin shell ginger (scientific name: Alpinia uraiensis). Rumex japonicus (Polygonaceae) can be used to produce Rumex extract, as well as Rumex longiflorus, Rumex arvensis, and Rumex serrata. Macaranga tanarius (Euphorbiaceae) can be used to produce Macaranga extract. Orthosiphon aristatus (Lamiaceae) can be used to produce Kumis-kuching extract.

[0021] For the production of these extracts, any part such as fruit, flower, bud, leaf, seed, bark, root, etc. can be used, and residues after various processing can also be used. In addition, these extraction materials may be processed, such as dried, or may be stored at low temperature. As a solvent for extracting these extraction materials, water, hot water, or an organic solvent can be used. Examples of organic solvents include, but are not limited to, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, and propylene glycol, as well as lower esters such as ethyl acetate and methyl acetate, acetonitrile, acetone, and hexane. The extracts can be used as they are as each extract, but the active ingredients can be further concentrated using known separation methods such as filtration, centrifugation, concentration, distribution, and fractionation.

[0022] The method for producing 5,6-dehydrokawain, dihydro-5,6-dehydrokawain, nepodin, nymphaeol-A, nymphaeol-B, nymphaeol-C, isonymphaeol-B, 3'-geranylnaringenin, baccharin, dorupanin, artepillin C, yatein, pluvialtolide, fargesin, kobusin, epimagnolin A, galgravin, and beraguensin is not particularly limited. For example, 5,6-dehydrokawain, dihydro-5,6 3'-Dehydrokawain can be obtained from the above-mentioned shell ginger extract, nepodin from the above-mentioned Rumex dock extract, nympheol-A, nympheol-B, nympheol-C, isonympheol-B and 3'-geranylnaringenin from the above-mentioned Macaranga tanarius extract and propolis extract derived from Macaranga tanarius, baccharin, drupanin and artepillin C from Brazilian green propolis and an extract of Baccharis dracunculifolia of the Asteraceae family, yatein and pluvialtolide from an extract of Piper cubeba, and fargesin, kobusin, epimagnolin A, galgravin and belaguensin from Magnolia kobus of the Magnoliaceae family and the herbal medicine xinyi, all of which can be obtained by known separation methods.

[0023] Although the embodiments of the present invention have been described above, these are merely examples of the present invention, and various configurations other than those described above can also be adopted. EXAMPLES

[0024] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0025] [Example 1] Effect on uric acid production in hepatocytes 1 The effect on uric acid production was examined using mouse-derived AML12 hepatocytes (obtained from ATCC). AML12 hepatocytes were suspended in DMEM / F-12 medium containing 10% fetal horse serum, ITS liquid medium supplement (Sigma-Aldrich), and dexamethasone, seeded in a 96-well plate at 25,000 cells / well, and cultured for 3 days. The medium was replaced with DMEM / F-12 medium containing 1% fetal horse serum, ITS liquid medium supplement (Sigma-Aldrich), and dexamethasone (40 ng / mL), and cultured overnight. After that, the test sample was added to a predetermined concentration, and the cells were cultured for 4 hours in Krebs buffer containing 100 μM each of guanosine and inosine, which are uric acid precursors. The uric acid concentration in the culture supernatant was measured using Uric Acid C-Test Wako (Fujifilm Wako Pure Chemical Corporation), which quantifies the amount of uric acid produced by uricase colorimetry. Allopurinol was used as a positive control, which is known to suppress uric acid production. The results are expressed as relative values ​​(%), with the value of the control group, which contains a uric acid precursor and does not contain the test sample, set at 100 (Figures 1 to 4).

[0026] It was confirmed that the uric acid concentration in the culture supernatant was significantly increased in the control group (CN) to which the uric acid precursors guanosine and inosine were added, compared to the negative control group (BL) that did not contain any uric acid precursors. In the positive control group (PC) to which 0.1 μM allopurinol was added, the uric acid concentration was reduced to 40% or less compared to the control (CN) (Figure 1). When the ethanol extract of shell ginger (EtOH Ex.) was added, the uric acid concentration in the culture supernatant was reduced in a concentration-dependent manner (Figure 1). Similarly, in the groups to which the 90% methanol fraction (90% MeOH fr.) and the 60% acetonitrile elution fraction (60% ACN fr.), which were further fractionated from the ethanol extract of shell ginger, were added, the uric acid concentration in the culture supernatant was also reduced in a concentration-dependent manner (Figure 1). Furthermore, in the groups to which 5,6-dehydrokawain (DK) and dihydro-5,6-dehydrokawain (DDK) were added, the uric acid concentration in the culture supernatant was also reduced in a concentration-dependent manner (Figure 1). These results were consistent with those of shell ginger extract, 5,6-dehydrokawain, and dihydro-5,6-dehydrokawain. These results indicate that urin inhibited uric acid production in liver cells, indicating that it may be useful in the prevention, improvement, and treatment of hyperuricemia and gout.

[0027] [Example 2] Effect on uric acid production in hepatocytes 2 As in Example 1, the inhibitory effect on uric acid production in another test sample was examined. It can be confirmed that the uric acid concentration in the culture supernatant is significantly increased in the control group (CN) to which uric acid precursors guanosine and inosine were added, compared with the negative control group (BL) that does not contain uric acid precursors. In the positive control group (PC) to which 0.1 μM allopurinol was added, the uric acid concentration was reduced to 50% or less compared with the control (CN) (Figure 2). When Rumex extract, Macaranga tanarius extract, or Kumiscutin extract was added, the uric acid concentration in the culture supernatant was reduced (Figure 2). These results indicate that Rumex extract, Macaranga tanarius extract, and Kumiscutin extract inhibited uric acid production in hepatocytes, and are useful for preventing, improving, and treating hyperuricemia and gout.

[0028] [Example 3] Effect on uric acid production in hepatocytes 3 As in Example 1, the inhibitory effect on uric acid production in another test sample was examined. Compared with the negative control group (BL) that did not contain a uric acid precursor, the control group (CN) to which uric acid precursors guanosine and inosine were added showed a large increase in uric acid concentration in the culture supernatant (Figure 3). When nepodin (Nep), yatein (Yat), pluvialtolide (Plu), baccarin (Bac), drupanin (Dru), or artepillin C (Art) were added, the uric acid concentration in the culture supernatant decreased in a concentration-dependent manner (Figure 3). These results indicate that nepodin, yatein, pluvialtolide, baccarin, drupanin, and artepillin C inhibited uric acid production in hepatocytes, and are useful for preventing, improving, and treating hyperuricemia and gout.

[0029] [Example 4] Effect on uric acid production in hepatocytes 4 As in Example 1, the inhibitory effect on uric acid production in another test sample was examined. Compared with the negative control group (BL) that did not contain a uric acid precursor, the control group (CN) to which uric acid precursors guanosine and inosine were added showed a large increase in the uric acid concentration in the culture supernatant (Figure 4). When nymphaeol-A (NyA), nymphaeol-B (NyB), nymphaeol-C (NyC), isonymphaeol-B (IsB), 3'-geranylnaringenin (3GN), fargesin (Far), kobsin (Kob), epimagnolin A (EpA), galgravin (Gal), or veraguensin (Ver) were added, the uric acid concentration in the culture supernatant decreased in a concentration-dependent manner (Figure 4). These results indicate that nymphaeol-A, nymphaeol-B, nymphaeol-C, isonymphaeol-B, 3'-geranylnaringenin, fargesin, kobsin, epimagnolin A, garglavin, or beraguensin inhibited uric acid production in hepatocytes, indicating that they may be useful in the prevention, amelioration, or treatment of hyperuricemia and gout.

[0030] The present invention has been described above based on the embodiments. However, these embodiments are merely illustrative, and it will be understood by those skilled in the art that various modifications are possible and that such modifications are also included within the scope of the present invention. [Industrial Applicability]

[0031] The uric acid production inhibitor of the present invention containing at least one of shell ginger extract, Rumex dock extract, Macaranga tanarius extract, kumiskuchin extract, 5,6-dehydrokawain, dihydro-5,6-dehydrokawain, nepodin, nymphaeol-A, nymphaeol-B, nymphaeol-C, isonymphaeol-B, 3'-geranylnaringenin, baccharin, dorpanin, artepillin C, yatein, pluviatolide, fargesin, kobsin, epimagnolin A, galgravin, or belaguensin as an active ingredient can be used as an agent for preventing or improving hyperuricemia or an agent for treating hyperuricemia, and can be used as a medicine, food, drink, and health food for the prevention, improvement, and treatment of gout.

Claims

1. A uric acid production inhibitor containing at least one active ingredient selected from the group consisting of Macaranga tanarius extract, nymphaeol-A, nymphaeol-B, nymphaeol-C, isonymphaeol-B, and 3'-geranylnaringenin.

2. 2. A preventive and / or therapeutic agent for hyperuricemia, comprising the uric acid production inhibitor according to claim 1 as an active ingredient.

3. 2. A preventive and / or therapeutic agent for gout, comprising the uric acid production inhibitor according to claim 1 as an active ingredient.

4. 10. A food, drink, or health food for preventing and / or treating hyperuricemia and / or gout, comprising the uric acid production inhibitor according to claim 1 as an active ingredient.

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