Definitions

• the present invention relates to a use of a bioflavonoid for increasing the plasma high density lipoprotein(HDL) level in a mammal.
• the present inventors have endeavored to develop a non- toxic plasma HDL level increasing agent from natural materials, and, as a result, have discovered that bioflavonoids isolated from edible plants are effective to increase the plasma HDL level.
• bioflavonoids such as those listed in Table I
• Hesperidin is the major bioflavonoid component found in orange, lemon and tangerine
• naringin represents the major bioflavonoid component in grapefruit
• naringin and hesperidin are present in citron in nearly equal amounts.
• bioflavonoids have never been reported to have plasma HDL level increasing activity.
• a bioflavonoid of formula(I) or a plant extract containing same for increasing the plasma HDL level in a mammal: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently hydrogen; a hydroxy group; a C,_ 9 alkoxy group optionally substituted with one or more substituents selected from the group consisting of a hydroxy, C,_ 5 alkoxy, aryloxy, and phenyl group substituted with 1 to 3 substituents selected from the group consisting of a hydroxy, alkoxy, aryloxy, halogen, nitro and amido group; a C 5 - 9 cycloalkyloxy group substituted with 1 to 3 substituents selected from the group consisting of a hydroxy, alkoxy, aryloxy, halogen, nitro and amido group; a C 5 _ 9 cyclo
• bioflavonoids of the present invention preferred are those of formula(I) wherein: R 1 is H; R 2 is OH, a rutinosyl or rhaminosyl group; R 3 is H; R 4 is OH; R 5 is H,
• R 6 is H;
• R 7 is H or OH;
• R 8 is OH or
• bioflavonoids of formula(I) of the present invention are shown in Table II.
• the bioflavonoids of the present invention may be extracted from various plants including vegetables such as lettus and onion, fruits such as citrus fruit, and grains such as buckwheat, or synthesized in accordance with the conventional process described by Zemplen, Bognar in Ber . , 1043(1943) and Seka, Prosche, Monatsh. , 69, 284(1936).
• rutin and quercetin may be extracted from buckwheat by using a suitable solvent such as water or aqueous alcohol under a high temperature and pressure.
• buckwheat seeds may be allowed to stand overnight in an aqueous solution of Ca(OH) 2 or NaOH, and then crude rutin precipitates may be collected after neutralization.
• dry powders of buckwheat seeds, leaves, stems and flowers may also be used.
• the content of rutin in leaves and stems of buckwheat is about 0.6% and that in buckwheat flower is about 3%.
• the citrus which can be used in the present invention may be tangerine, orange, lemon, grapefruit and citron. It is preferable to use the peel of citrus fruits unconta inated by chemical pesticides.
• the citrus peel extract may be prepared by any of the conventional methods using water or other suitable solvents such as aqueous alcohol, Ca(OH) 2 and NaOH.
• neohesperidin dihydrochalcone (C 28 H 36 0 15 ) of formula(II), which can be easily derived from naringin and has a 1,000 to 1,500 fold higher sweetness than sucrose, may also be used for increasing the plasma HDL level:
• Bioflavonoids of formula(I) and (II) start to exert a plasma HDL level increasing effect at a dose of only 0.1 g/kg/day, the effect increasing with the dose thereof.
• the bioflavonoid and plant extract containing same show little toxicity or mitogenicity in tests using mice. More specifically, naringin, naringenin, hesperidin, hesperetin, diosmin, neohesperidin dihydrochalcone, quercetin or rutin exhibits no toxicity when it is orally administered to a mouse at a dose of 1,000 mg/kg. Further, the bioflavonoid or the citrus peel extract exerts no adverse effects on the liver function.
• the present invention also provides a pharmaceutical composition for increasing the plasma HDL level, which comprise the bioflavonoid or the plant extract containing same as an active ingredient and pharmaceutically acceptable excipients, carriers or diluents.
• a pharmaceutical formulation may be prepared in accordance with any of the conventional procedures .
• the active ingredient is preferably admixed or diluted with a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet or other container.
• the carrier serves as a diluent, it may be a solid, semi-solid or liquid material acting as a vehicle, excipient or medium for the active ingredient.
• the formulations may be in the form of a tablet, pill, powder, sachet, elixir, suspension, emulsion, solution, syrup, aerosol, soft and hard gelatin capsule, sterile injectable solution, sterile packaged powder and the like.
• suitable_carriers, excipients, and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, alginates, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, p ⁇ lyvinylpyrrolidone, water, methylhydroxybenzoates, propylhydroxybenzoates , talc, magnesium stearate and mineral oil.
• the formulations may additionally include fillers, anti-agglutinating agents, lubricating agents, wetting agents, flavoring agents, emulsifiers, preservatives and the like.
• the compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after their administration to a mammal by employing any of the procedures well known in the art.
• the pharmaceutical composition of the present invention can be administered via various routes including oral, transdermal, subcutaneous, intravenous and intramuscular introduction.
• a typical daily dose of the bioflavonoid may range from about 0.1 to 500 mg/kg body weight, preferably 0.5 to 100 mg/kg body weight, and can be administered in a single dose or in divided doses.
• the amount of the active ingredient actually administered ought to be determined in light of various relevant factors including the condition to be treated, the chosen route of administration, the age, sex and body weight of the individual patient, and the severity of the patient's symptom; and, therefore, the above dose should not be intended to limit the scope of the invention in any way.
• the bioflavonoid or the plant extract containing same in the form of an additive or a dietary supplement can be incorporated in foods or beverages for the purpose of increasing the plasma HDL level.
• the foods or beverages may include meats; juices such as a vegetable juice(e.g., carrot juice and tomato juice) and a fruit juice(e.g., orange juice, grape juice, pineapple juice, apple juice and banana juice); chocolates; snacks; confectionery; pizza; foo.ds made from cereal flour such as breads, cakes, crackers, cookies, biscuits, noodles and the likes; gums; dairy products such as milk, cheese, yogurt and ice creams; soups; broths; pastes, ketchups and sauces; teas; alcoholic beverages; carbonated beverages such as Coca-Cola® and Pepsi-Cola®; vitamin complexes; and various health foods.
• juices such as a vegetable juice(e.g., carrot juice and tomato juice) and a fruit juice(e.g., orange juice, grape juice,
• the content of the bioflavonoid in a food or beverage may range from 0.01 to 50% by weight, preferably 0.05 to 10% by weight.
• the beverage according to the present invention may comprise 200 to 10,000 mg of the bioflavonoid per 1000 ml of the beverage.
• the content thereof in a food or beverage may range from 0.5 to 30% by weight.
• a bioflavonoid or a plant extract containing same can be used as an effective, non-toxic pharmaceutical agent for increasing the plasma HDL level.
• the following Examples are intended to further illustrate the present invention without limiting its scope. Further, percentages given below for solid in solid mixture, liquid in liquid, and solid in liquid are on a wt/wt, vol/vol and wt/vol basis, respectively, and all the reactions were carried out at room temperature, unless specifically indicated otherwise.
• mice were alive at day 10 and rutin showed no toxicity at a dose of 1,000 mg/kg.
• mice 40 three-week-old Sprague-Dawley rats (Tainan laboratory animal center, Korea) each weighing about 90 to 110 g were evenly divided into four dietary groups by a randomized block design.
• the rats of the four groups were fed with four different high-cholesterol diets, i.e., AIN-76 laboratory animal diet(ICN Biochemicals, Cleveland, OH, U.S.A.) containing 1% cholesterol (Control group), 1% cholesterol plus 0.1% hesperetin(Hesperetin group), 1% cholesterol plus 0.1% naringin(Naringin group) and 1% cholesterol plus 16.7% citrus peel extract(Citrus peel extract group), respectively.
• the compositions of diets fed to the four groups are shown in Table III.
• the rats were allowed to feed freely on the specified diet together with water for eight weeks, the ingestion amount was recorded daily and the rats were weighed every 7 days, and then the record was analyzed. All rats showed a normal growth rate and there was observed no significant difference among the three groups in terms of the feed ingestion amount and the weight gain.
• Test diet 5799M-B comprises 21% vitamin free casein, 15% sucrose, 3% cellulose, 2% vitamin mixture, 5% mineral mixture, 0.15% D,L-methionine, 0.5% sodium cholate, 32.15% dextrin, 20% lard, 0.2% choline chloride and 1% cholesterol.
• 8 or 9 rats were allotted to each group and diosmin, neohesperidin dihydrochalcone and rutin were purchased from Sigma Chemical Company(St. Louis, Mo., U.S.A.). The rats were bred for 6 weeks while being allowed free access to the diets and water.
• bioflavonoids of the present invention increase the plasma HDL remarkably in an animal and, thereby, suppressing the onset of cardio- circulary diserses.
• naringin and hesperidin increased the plasma HDL level by 18% and 19%, respectively, in comparison to that before the administration.
• Hard gelatin capsules were prepared using the following ingredients:
• Rutin was added to a wheat flour in an amount ranging from 0.01 to 50 wt% and breads, cakes, cookies, crackers and noodles were prepared by using the mixture to obtain health- improving foods .
• Diosmin was added to ground beef in an amount ranging from 0.01 to 50 wt% to obtain a health-improving ground beef.
• Rutin or Quercetin was added to milk in an amount ranging from 0.01 to 50 wt% to obtain a health-improving milk.
• rutin or quercetin was added to the coagulated milk protein
• rutin or quercetin was added to the coagulated milk protein after the fermentation.
• Example 8 Health foods containing Bioflavonoids
• a health food was prepared by mixing the following ingredients and tableting the mixture. Quantity ( t/wt %) Naringin, hesperidin or a plant extract containing it 5 Ginseng powder or extract 20
• Buckwheat seeds, leaves, stems and flowers were dried at a room temperature and then powdered.
• a medicine or health food containing the rutin powder or extract thus obtained may be prepared in accordance with a conventional method.
• the mixture was added to a conventional fodder in an amount of 5 wt% and the resulting fodder was fed to rats for

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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines Containing Plant Substances (AREA)
• Coloring Foods And Improving Nutritive Qualities (AREA)
• Bakery Products And Manufacturing Methods Therefor (AREA)
• Seasonings (AREA)
• Saccharide Compounds (AREA)
• Pyrane Compounds (AREA)

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• 1998
  • 1998-10-20 JP JP2000576848A patent/JP2003501343A/ja active Pending
  • 1998-10-20 CA CA002346325A patent/CA2346325A1/en not_active Abandoned
  • 1998-10-20 EP EP98951779A patent/EP1123096A1/de not_active Withdrawn

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