EP0932395A1 - Procede et compositions mettant en oeuvre des produits de fermentation a base de levure rouge - Google Patents

Procede et compositions mettant en oeuvre des produits de fermentation a base de levure rouge

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Publication number
EP0932395A1
EP0932395A1 EP97945365A EP97945365A EP0932395A1 EP 0932395 A1 EP0932395 A1 EP 0932395A1 EP 97945365 A EP97945365 A EP 97945365A EP 97945365 A EP97945365 A EP 97945365A EP 0932395 A1 EP0932395 A1 EP 0932395A1
Authority
EP
European Patent Office
Prior art keywords
red yeast
monascus
human
yeast fermentation
fermentation product
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP97945365A
Other languages
German (de)
English (en)
Inventor
Mao L. Zhang
Chi X. Pong
Michael N. Chang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Peking University
Pharmanex Inc
Original Assignee
Peking University
Pharmanex Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Peking University, Pharmanex Inc filed Critical Peking University
Publication of EP0932395A1 publication Critical patent/EP0932395A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P1/00—Preparation of compounds or compositions, not provided for in groups C12P3/00 - C12P39/00, by using microorganisms or enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/14—Fungi; Culture media therefor
    • C12N1/145—Fungal isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/645—Fungi ; Processes using fungi

Definitions

  • the invention relates to compositions comprising red yeast fermentation products, that can be used as dietary supplements and/or therapeutic medicaments.
  • the compositions can be used to lower serum cholesterol and triglycerides in mammals.
  • the invention relates to methods of treating cardiovascular disorders and other diseases using the red yeast fermentation products.
  • the invention relates to particular Monascus strains that yield fermentation products with the desired biological activities.
  • red yeast (known in Chinese as Hung-ch'u or Hongqu) have been known and used for hundreds of years in China in rice wine making and as a food preservative.
  • red yeast has been known for hundreds of years as an ancient Chinese medicine or an ingredient in certain ancient Chinese prescriptions; however, red yeast is most well known for its use in food as a preservative and colorant, and its uses in the dye industry.
  • Red yeast is a mixture of several species of Monascus fungi, notably Monascus purpureus .
  • Monascus purpureus The genus of fungus, Monascus was first described in 1884 by van Tieghem (van Tieghem, 1884, Bull Soc Bot France, 31:226). The fungus was initially known to the Western world as a contaminant on cereals, starch and silage.
  • red yeast is described as mild, non-poisonous, and useful for treating indigestion and diarrhea. Red yeast is also described as useful for improving blood circulation, and promoting the health of the spleen and stomach. Furthermore, several "prescriptions" using red yeast for treating aliments, such as indigestion, diarrhea, and heart and abdominal pains, are also provided in this ancient work.
  • red yeast is taught in another publication from the Ming dynasty, T'ien Kung K'ai Wu by Sung Ying-Hsing, which was published in 1637 A.D (see pages 291- 294 in English translation of this ancient writing, "T'ien Kung K'ai Wu - Chinese technology in the seventeenth century", translated by E-tu Zen Sun and Shiou-Chuan Sun, The Pennsylvania State University Press 1966) .
  • Red yeast is described therein as useful for preserving the color and taste of fish or meat.
  • the manufacturing process used red wine mash and cooked non-glutinous rice as starting materials.
  • red yeast which is still the fermentation product of Monascus species, is still used in traditional Chinese medicine, wine making and food coloring in Asia and Asian communities in North America.
  • the red and yellow pigments of Monascus purpureus such as monascorubin and onascin, have been purified, and extensively studied (Fielding et al. , 1961, J Chem Soc, 4579-4589).
  • Lipids and lipoproteins play an essential role in transporting fat-derived metabolites between organs for absorption, metabolism, and distribution (Felig et al., 1975, N Eng J Med, 293:1078-1084).
  • the susceptibility to dietary- induced elevations in blood lipids including cholesterol is extremely common.
  • the interaction of genetic predisposition and a high fat, high caloric diet coupled with underactivity can lead to heart disease, hypertension, hypertriglyceridemia, and diabetes in a significant proportion of the United States population.
  • High serum cholesterol is a major risk factor for coronary artery disease.
  • Cholesterol is a major component of atherosclerotic plaque.
  • Other associated lipid abnormalities, including hypertriglyceridemia especially in the presence of lowered HDL cholesterol levels have been recognized as contributory to the risk of cardiovascular disease. There is a reciprocal relationship between elevated triglyceride levels and lowered HDL levels.
  • the level of cholesterol in circulation results from the balance between production of apoB-100 particles and its removal from the circulation.
  • Cholesterol is synthesized from acetyl-CoA via a series of more than 20 enzymatic reactions. This biosynthetic pathway is mainly regulated by the activity of HMG-CoA reductase (hydroxymethylglutaryl coenzyme A reductase) , which catalyzes the reduction of HMG- CoA to mevalonate.
  • HMG-CoA reductase hydroxymethylglutaryl coenzyme A reductase
  • a class of compounds inhibit cholesterol biosynthesis by competing with a natural substrate, HMG-CoA
  • hypocholesterolemic compound structurally related to compactin was independently discovered by Endo in fermentation products of Monascus ruber (the active compound was named monacolin K; Endo, 1979, J Antibiotics, 32:852-854; Endo, 1980, J Antibiotics, 33:334-336; see also German patents DE 3051175, 3051099 and 3006216; British patent GB 2046737 and 2055100) , and by another group from cultures of Aspergillus terreus .
  • the active compound was also named mevinolin, lovastatin or Mevacor ® ; Tobert et al. , 1982, J Clin Invest 69:913-919), and has been available in the United States since 1987 as a prescription drug.
  • lipid regulating agents that have been used to treat hypertriglyceridemia, especially type IV and V hyperlipidemia, include nicotinic acid (e.g., niacin) , and fibric acid derivatives (e.g., gemfibrozil and clofibrate) .
  • nicotinic acid e.g., niacin
  • fibric acid derivatives e.g., gemfibrozil and clofibrate
  • high doses of niacin may causes gastric irritability, hyperuricemia, hyperglycemia, pruritus, and gemfibrozil may lead to malignancy, gallbladder diseases, and abdominal pain.
  • the invention relates to a product of the fermentation of at least one Monascus species that can be used as a dietary supplement or a therapeutic medicament to lower both serum cholesterol and triglyceride levels in humans.
  • the invention is based, in part, on the surprising discovery that red yeast, i.e., the product of the fermentation of certain strains or mixtures of strains of Monascus , are effective at lowering not only the level of serum cholesterol but also the level of serum triglyceride in mammals, particularly humans. Since monacolin K or mevinolin are known not to be significantly effective in lowering serum triglyceride level, the beneficial effect of red yeast products must be related to other components in the fermentate.
  • red yeast can be used as a natural dietary supplement or a medicament to treat or prevent a variety of diseases, including but not limited to cardiovascular diseases, diabetes, fatty liver conditions, stroke, cerebral thrombosis, hypotension, hypertension and obesity, and to modulate the circulating levels of lipids, such as cholesterol and triglyceride.
  • the present invention encompasses methods for treating or preventing these diseases in a human, which comprise administering to the human a therapeutically effective amount of a red yeast fermentation product.
  • the present invention also encompasses methods for improving or maintaining cardiovascular health in a human comprising administering to the human an effective amount of red yeast fermentation product.
  • the present invention further encompasses methods for reducing the serum cholesterol and serum triglyceride levels to normal levels in a human comprising administering to the human a therapeutically effective amount of a red yeast fermentation product.
  • Red yeast can also be used to treat or prevent a variety of ailments or symptoms as related to diseases of the cardiovascular system.
  • red yeast can be manufactured in various dosage forms and formulations. Also disclosed are methods for manufacturing red yeast which are based on the traditional fermentation procedures.
  • the invention relates to compositions comprising the product of the fermentation of at least one Monascus species. These compositions are useful for reducing the levels of both serum cholesterol and serum triglycerides in mammals, and in particular humans. In addition, the compositions are useful for modulating the levels of both serum cholesterol and triglycerides to maintain healthy levels despite intrinsic (aging) or extrinsic (stress) factors that affect serum cholesterol and triglyceride levels.
  • compositions and methods of the present invention are based, in part, on the discovery that the fermentate of Monascus species display hypocholesterolemic properties, and also unexpectedly, the ability to lower serum triglyceride levels. Since monacolin K is known not to be significantly effective in lowering serum triglyceride level, the beneficial effect of red yeast products must be related to other components of the fermentate. The ability of red yeast products to lower serum triglyceride level provides the art with a unique, natural alternative to the use of prescription hypocholesterolemic compounds.
  • red yeast fungi or “Monascus” as used herein refer to the pre-fermented organism, while the terms “red yeast”, “red yeast product”, “red yeast extract” and the like refer to a product that results form the fermentation of at least one Monascus . Further, these latter terms include traditional and improved red yeast products as described below. More specifically, “red yeast product” as used herein refers to the product of fermentation, e.g., the fermentate, of one or a mixture of Monascus fungus.
  • red yeast product is the fermentation product of at least one of the following Monascus fungi: Monascus albidus, Monascus anka , Monascus araneous , Monascus aurantiacus , Monascus bakeri Dangerd, Monascus fuliginosus, Monascus kaoliang, Monascus major, Monascus paxii , Monascus pilosus, Monascus pubigerus , Monascus purpureus , Monascus ruber , Monascus rubiginosus , Monascus rubropunctatus , and Monascus serorubescens.
  • Monascus fungi Monascus albidus, Monascus anka , Monascus araneous , Monascus aurantiacus , Monascus baker
  • red yeast is the fermentation product of a mixture of Monascus fungi, comprising chiefly Monascus purpureus Went , and in lesser proportions other Monascus species, e.g., preferably Monascus ruber van Tieghem , Monascus Fuliginosus Sato , Monascus Pilosus Sato and Monascus albidus Sato .
  • Monascus fungi comprising chiefly Monascus purpureus Went , and in lesser proportions other Monascus species, e.g., preferably Monascus ruber van Tieghem , Monascus Fuliginosus Sato , Monascus Pilosus Sato and Monascus albidus Sato .
  • red yeast is the fermentation product of at least one of the following strains of Monascus fungi: Monascus purpureus Went ATCC 30141, AS 3.562, AS 3.991, AS 3.4446 [ATCC 16365], AS 3.4642 [NRRL 2897], AS 3.4643 [NRRL 96], AS 3.4644, AS 3.4645, AS 3.4651, Monascus ruber van Tieghem AS 3.549, IFFI 05007, IFFI 05008, IFFI 05010, IFFI 05011, and Monascus anka IFFI 05038 (reference numbers provided in China Catalogue of Cultures, 1992, China Committee for Culture Collection of Microorganism, China Machine Press, Beijing 1992); and Monascus purpureus Went mutant strain M4027, 4028 and M4184.
  • traditional red yeast refers to a red yeast product which is the result of fermentation using a mixture of Monascus fungi that has been used traditionally to manufacture red yeast.
  • an "improved red yeast” is produced by fermentation using one or more natural or mutant strains of Monascus species, which yield a fermentate with an improved biological or nutritional properties, e.g., higher hypocholesterolemic and hypotriglyceridemic activities than traditional red yeast.
  • the red yeast products of the present invention are red-purple powders that have a slightly bitter but mild and pleasant taste.
  • the red yeast products have a pleasant odor. The color and/or odor may vary with the fermentation process, the strains used and the processing steps.
  • red yeast can be prepared by traditional fermentation procedures or by modification of the traditional procedures.
  • red yeast can be prepared by the fermentation of washed and cooked non-glutinous rice using red wine mash, natural juice of Polygonum grass, and alum water.
  • the rice is fermented in open air for 7 days on bamboo trays under very clean conditions.
  • the rice changes its color from white to black, black to brown, brown to red and then red to yellow, which is then harvested as red yeast.
  • non-glutinous rice can be fermented in a hole in the ground lined by bamboo mats, which is securely covered. Fermentation is allowed to take place underground for one year or more, up to four years.
  • improved red yeast of the invention can be prepared as follows: culture media containing kidney-bean juice 2%, sugar 4%, yeast 0.5% are added to rice (40 - 80 ml per lOOg) and sterilized by heat, while the pH is maintained at pH3 to 8. Red yeast fungi
  • Monascus purpureus Went strain M4184 is added and cultured at 15-35 °C for 9 days.
  • the fermentation broth is drained and discarded, while the solid residue is sterilized by heat (for example, by high pressure steam) , dried and crushed into powder.
  • This powder can be used directly in the various compositions and formulations provided by the present invention.
  • the dried crushed red yeast powder can be further processed, e.g., extracted with organic solvents, such as but not limited to, ethanol (75%) to remove starch and/or agar. After evaporation to dryness, the extract can be used in the various compositions and formulations as provided by the present invention.
  • organic solvents such as but not limited to, ethanol (75%) to remove starch and/or agar.
  • the extract can be used in the various compositions and formulations as provided by the present invention.
  • the isolation or purification of particular components of the product is not desired or contemplated by the present invention.
  • red yeast can be used as a natural dietary supplement or a pharmaceutical medicament to maintain health or to treat or prevent a variety of diseases, including but not limited to cardiovascular diseases, diabetes, stroke, hypertension and obesity, and to modulate the circulating levels of lipids and lipoproteins, such as cholesterol and triglycerides. Red yeast can also be used to treat or prevent a variety of symptoms related to these above-mentioned diseases and associated with poor cardiovascular health due to aging and other intrinsic and extrinsic factors.
  • cardiovascular diseases may include but are not limited to myocardial infarction, coronary heart disease, atherosclerosis, arteriosclerosis.
  • the present invention includes the treatment or prevention of cerebrovascular disease such as stroke, memory loss due to stroke, and cerebral thrombosis.
  • the present invention also encompasses a composition comprising a therapeutically effective amount of a red yeast product, for example 2-4 grams per day, useful in humans for the treatment or prevention of hyperlipidemic disease, cardiovascular disease, cerebrovascular disease, hypertension, hypotension, diabetes, fatty liver conditions, or obesity, or a combination thereof.
  • the present invention further encompasses a composition comprising a therapeutically effective amount of a red yeast product, useful for the modulation of serum lipid and lipoprotein levels in a human in need of therapy to maintain the lipid and lipoprotein levels within a healthy normal range.
  • the composition is adapted for use in the treatment or prevention of hypertriglyceridemia.
  • such a composition is used for reducing serum cholesterol and serum triglyceride levels in humans.
  • the present invention further encompasses a composition comprising a therapeutically effective amount of improved red yeast product, useful for the treatment of any one of the following symptoms: shortness of breath, asthenic breathing, lethargy, dizziness, chronic headache, chest pain and tightness, heartache, loss of appetite, limb swelling, tightness and distention, and excess expectoration.
  • terapéuticaally effective amount means an amount sufficient to provide a therapeutic benefit in the treatment or prevention of the disease, or in the level of serum lipids and lipoproteins.
  • the present invention provides methods for treating a human afflicted by a variety of disease, disorder, and symptoms.
  • the methods of the invention can also be used for prevention in a human susceptible to such diseases, disorders or symptoms.
  • the invention encompasses methods of treatment of hyperlipidemic disease, cardiovascular disease, cerebrovascular disease, hypertension (hereditary and non- hereditary) , hypotension, angina, stroke, diabetes, fatty liver conditions, or obesity, or a combination thereof in a human, comprising administering to the human a therapeutically effective amount of a red yeast product, or compositions containing said product.
  • the invention encompasses methods of preventing hyperlipidemic disease, cardiovascular disease, cerebrovascular disease, hypertension, hypotension, angina, stroke, diabetes, fatty liver conditions such as fatty liver deposits, obesity or a combination thereof, which comprises administering an effective amount of a red yeast product of the present invention.
  • the method of the invention is used to treat or prevent hypertriglyceridemia and associated diseases, such as hyperuricemia, pancreatitis and diabetes, in a human.
  • cardiovascular diseases may include myocardial infarction, coronary heart disease, atherosclerosis, arteriosclerosis; and cerebrovascular diseases or conditions, including stroke, cerebral thrombosis or memory loss due to stroke.
  • the present invention also provides methods for modulating serum lipid and lipoprotein levels in a human in need of lowering the lipid and lipoprotein levels to a healthy normal range, which comprise administering to the human a therapeutically effective amount of a red yeast product, or compositions containing said product.
  • the method of the invention is used to reduce serum cholesterol and serum triglyceride levels in a human.
  • the methods of the invention are particularly useful for the treatment of geriatric patients and post-menopausal women.
  • the present invention further provides methods for treating a human afflicted by shortness of breath, asthenic breathing, lethargy, dizziness, chronic headache, loss of appetite, limb swelling, tightness and distention, abdominal distention, and excess expectoration or a combination thereof, which comprises administering to the human a therapeutically effective amount of a red yeast product, or compositions containing said product.
  • the preventive or therapeutic dose of traditional red yeast or improved red yeast in the treatment or prevention of diseases and in the management of serum lipid and lipoprotein levels will vary with the condition to be treated and the severity of the condition to be treated.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose range of red yeast, for the conditions described herein is from about O.lg to about 5g administered in single or divided doses orally.
  • a preferred oral daily dose range should be from about 0.3g to about 4g, while most preferably an oral daily dose should be about 1.2 to about 2.5g.
  • two capsules each containing 0.6g of red yeast may be taken orally twice a day to obtain the preferred dose.
  • a course of treatment should be at least 4 weeks. It may be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art. Further, it is noted that the nutritionist, dietician, clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response.
  • the present invention encompasses new uses of traditional red yeast, and novel red yeast products and novel methods of using those products.
  • the present invention encompasses compositions and methods of using traditional and novel or improved red yeast products as dietary supplements.
  • the red yeast products provide the individual with a means for maintaining normal or healthy levels of serum cholesterol and triglycerides despite intrinsic deterioration, e.g. , from aging and extrinsic factors such as stress, lack of exercise and poor nutrition.
  • the dietary supplements also provide a means for preventing, or reducing the likelihood of experiencing, the diseases discussed above.
  • the dietary supplements can be used to prevent weight gain or obesity.
  • the dietary supplements containing red yeast products are particularly useful for the elderly and post-menopausal women.
  • the dietary supplements should be taken daily for at least four weeks and can be used permanently on a daily basis.
  • a daily dose is from about O.lg to about 5.0g; preferably about 1 to about 4g; and most preferably about 1.2 to about 2.4 grams per day.
  • compositions of the present invention comprise a red yeast product, or an extract thereof, as active ingredient, and may also contain a pharmaceutically acceptable carrier or excipient, and optionally, other ingredients.
  • compositions comprising red yeast can be added directly to foods so that a therapeutically effective amount of red yeast is ingested during normal meals. Any methods known to those skilled in the art may be used to add or incorporate red yeast to natural or processed foods.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of a red yeast product, as a powder or granules, or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • compositions of the present invention may additionally include binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose) ; binders or fillers (e.g., lactose, pentosan, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate) ; or wetting agents (e.g., sodium lauryl sulphate).
  • binding agents e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • binders or fillers e.g., lactose, pentosan, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g., magnesium stearate, talc or silica
  • disintegrants e.g., potato starch
  • Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils) ; and preservatives (e.g. , methyl or propyl-p-hydroxybenzoates or sorbic acid) .
  • suspending agents e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats
  • emulsifying agents e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters
  • the preparations can also be made to resemble foods, containing buffer salts, flavoring, coloring and sweetening agents as appropriate.
  • Any dosage form may be employed for providing the patient with an effective dosage of the red yeast product.
  • Dosage forms include tablets, capsules, dispersions, suspensions, solutions, capsules, and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers as described above are employed.
  • the compounds of the present invention may also be administered by controlled release means. However, the most preferred oral solid preparations are capsules.
  • a tablet may be prepared by compression or molding, optionally, with one more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine red yeast in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent.
  • red yeast in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent.
  • the composition is a capsule containing 0.3g of red yeast in powder form.
  • Red yeast of the present invention were shown to dramatically decrease serum total cholesterol (TC) of endogenous hyperlipidemic rabbits; remarkably decrease serum TC and total triglyceride (TG) of exogenous hyperlipidemic rabbits; inhibit formation of arteriosclerosis plaque and lipid deposition in liver in hyperlipidemic rabbits; and decrease serum TC and TG of hyperlipidemic quails.
  • TC total cholesterol
  • TG total triglyceride
  • a LD 50 value cannot be determined.
  • the highest tolerance dose of red yeast in mice is over 16g/kg, which is 533 times over the dose used in clinical treatment.
  • rats were continuously force-fed red yeast for four months; no rats died or showed toxic symptoms due to this drug.
  • Hematological indices, main viscera indices, blood biological indices, routine uroscopy and pathological examination did not show any differences between experimental groups and control groups.
  • the following sections contain the methodologies and results of two human clinical trials that were carried out in China.
  • the trials were aimed to determine the efficacy of a red yeast product in modulating circulating serum lipid and lipoprotein levels in humans, in resolving symptoms according to traditional Chinese medicine, and in establishing the safety of a red yeast product.
  • the patients also had the following symptoms: limb weakness, asthenic breathing, pain and oppressed feeling in chest, loss of appetite, distention and swelling on gastric region, whitish or purple dots on the tongue, the thick-white or thick-slimy fur on the tongue, taut-slippery or hesitant-weak pulse.
  • the treated group took two Xuezhikang capsules orally, twice a day for 8 weeks.
  • the control group took three Jiaogulan tablets twice a day for 8 weeks. All the patients maintained the same lifestyle and habits as before.
  • the following tests were performed at four weeks, and at eight weeks after the trial began: weight, blood pressure, cardiac rhythm, electrocardiogram and routine physical examination. The following parameters were monitored by laboratory tests: blood urea nitrogen (BLTN) , creatinine, serum glutamic pyruvic transa inase (SGPT, ALT) , serum glucose, and creatinine kinase (CK) .
  • BLTN blood urea nitrogen
  • SGPT serum glutamic pyruvic transa inase
  • ALT serum glutamic pyruvic transa inase
  • CK creatinine kinase
  • (+) indicates increase
  • (-) indicates decrease *:p,0.01, **:p ⁇ 0.001 vs. baseline +:p ⁇ 0.05; ++:p ⁇ 0.01; +++:p ⁇ 0.001 vs. control
  • Those symptoms were: condition of tongue (whitish or purple dots on the tongue; thick-slimy fur) ; pulse (slippery-taut or hesitant-weak) , oppressed feeling in chest; loss of appetite; abdominal distention and swelling.
  • the efficacy scores for curing or reducing total serum cholesterol and total triglyceride level in the treated group were greater than that in the control group.
  • the score for normalizing or increasing HDL-C, level and the score for reducing Atherosclerosic Index in the treated group were also much better than the control (P ⁇ 0.001).
  • Table 2 indicates that both Xuezhikang-treated and control groups showed marked desirable changes in the levels of TC, TG, (TC - HDL-C) /HDL-C, HDL-C serum levels markedly.
  • the effectiveness of Xuezhikang was found to be superior to that of Jiaogulan.
  • Table - 3 Effects of Xuezhikang capsule on patients with different abnormal levels serum lipid and lipoprotein.
  • Treated Group 88 Baseline 1.2210.19 1.210.19 1.0510.25
  • apoA-I apolipoprotein A-I
  • apoB apolipoprotein B
  • red yeast is a safe, effective agent for modulating serum lipid and lipoprotein levels.
  • Red yeast can also be used as a therapeutic agent for coronary artery disease and cerebrovascular disease caused by hyperlipidemia and/or athyrosis because red yeast not only significantly reduced plasma TC, TG and
  • Atherosclerosis Index but also markedly raised plasma apolipoprotein A-I level.
  • Chest tightness and pain 0 none (-) no Chest tightness and pain light (+) having Chest tightness and pain occasionally moderate (++) having medium Chest tightness and pain very often severe (+++) having severe Chest tightness and pain at rest
  • Symptom severity light: score ⁇ 12 moderate score 12 - 20 Severe score > 20 Patients diagnosed by traditional Chinese medicine according to the above symptoms, and patients with primary hyperlipidemia were enrolled.
  • a myocardial infarction, cerebrovascular disease, severe wound or major surgery during last half year
  • b nephritic syndrome, hypothyroidism, acute and/or chronic hepatobiliary disorder, diabetes, gout
  • c familial hypercholesterolemia (monogenic- hypercholesterolemia)
  • d secondary hyperlipidemia caused by other medication, for instance: phenothiazine, beta-adrenergic blocking agents, corticosteroid, oral contraceptive
  • e patients who used other lipid modulators during the last four weeks and patients using heparin or were on thyroidization
  • f pregnant and breast-feeding women
  • g patients with disorder of the other organs
  • h hylaxis syndrome, and psychosis.
  • the total number of patients enrolled was 116. There were 84 patients in the treated group and 32 patients in the control group. No difference of distribution in age, sex and course of disease were found between the two groups.
  • a randomized single-blind trial was conducted with two groups.
  • the treated group (84 cases) took two Xuezhikang capsules (i.e., a red yeast product of the present invention) twice a day.
  • the control group (32 cases) took three Jiaogulan tablets (ShanXi factory of Chinese material medica, lot number: 940730) twice a day.
  • the course of treatment was eight weeks.
  • the measurements of serum lipid and lipoprotein levels and other scoring were performed prior to the therapy, and at four weeks and at eight weeks after therapy.
  • the safety tests were conducted before and after therapy. Venous blood samples were taken from patients before breakfast, who were not allowed to consume alcohol or food with a high fat content in the last meal.
  • BUN blood and urea nitrogen
  • SGPT serum glutamic pyruvic transaminase
  • ALT serum glutamic pyruvic transaminase
  • CK creatinine kinase
  • TC total serum cholesterol
  • TG total serum triglyceride
  • hepatospleno-palpation were recorded.
  • Table 5 shows a comparison of the overall efficacy score of the two groups.
  • Table 6 shows a comparison of efficacies as defined by the standards of traditional Chinese medicine.
  • the percentage of patients who reported elimination of the symptoms as diagnosed by traditional Chinese medicine in the treated group was much higher than that in the control group (p ⁇ 0.05 ), especially in the aspect of pain and oppressed feeling in chest, loosing appetite, distention and swelling on gastric region as well as purplish dots on the tongue.
  • the scores for curing or reducing total serum cholesterol level in the treated group were greater than that in the control group.
  • Table 10 shows the changes in Atherosclerosic Index which is the ratio of (TC-HDL-C) /HDL-C.
  • Table 11 shows the effect of Xuezhikang on regulating serum lipid and lipoprotein levels (X+/-S) .
  • Table 11 indicates that Xuezhikang improved TC, TG, (TC - HDL-C) /HDL-C, HDL-C serum levels markedly, but control group only improved TG significantly.
  • the ability to regulate TC, LDL-C of Xuezhikang therapy was found to be superior to the control.
  • Table 12 shows the efficacy of Xuezhikang therapy on different baseline of serum lipid and lipoprotein
  • Table - 12 Efficacy comparison of Xuezhikang therapy on different baseline of serum lipid and lipoprotein.

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Abstract

On décrit des procédés et compositions mettant en oeuvre des produits de fermentation à base de levure rouge, que l'on peut utiliser en tant que compléments diététiques naturels et/ou médicaments destinés au traitement ou à la prévention de l'hyperlipidémie et des états et symptômes associés, tels que les maladies cardio-vasculaires et cérébro-vasculaires, le diabète, l'hypertension, l'obésité, la respiration asthénique, les maux de tête chroniques, les douleurs thoraciques et l'oppression, l'oedème et le gonflement des membres, la perte d'appétit et les expectorations importantes. Ces procédés et compositions sont efficaces pour abaisser les taux à la fois du cholestérol et des triglycérides sériques, et on peut les utiliser pour maintenir une bonne santé cardio-vasculaire. L'invention concerne également des souches de champignon Monascus, lesquelles donnent des produits de fermentation possédant les activités biologiques voulues.
EP97945365A 1996-09-30 1997-09-29 Procede et compositions mettant en oeuvre des produits de fermentation a base de levure rouge Withdrawn EP0932395A1 (fr)

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US72054896A 1996-09-30 1996-09-30
US720548 1996-09-30
PCT/US1997/017574 WO1998014177A1 (fr) 1996-09-30 1997-09-29 Procede et compositions mettant en oeuvre des produits de fermentation a base de levure rouge

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CA (1) CA2267340A1 (fr)
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US6436406B1 (en) 2000-06-15 2002-08-20 A. Glenn Braswell Compositions and methods for reducing or controlling blood cholesterol, lipoproteins, triglycerides and atherosclerosis
KR100426880B1 (ko) * 2002-02-04 2004-04-13 학교법인 영광학원 모나스쿠스 피로수스를 이용한 적색 메주색소의 제조방법
KR20020093147A (ko) * 2002-05-30 2002-12-13 지니스생명공학 주식회사 성인병 예방 및 치료 보조제
JPWO2004112809A1 (ja) * 2003-06-24 2006-07-20 大塚製薬株式会社 血清尿酸低減組成物
US20100119600A1 (en) * 2007-06-01 2010-05-13 Joar Opheim Substances for reducing occurrence of major cardiac events comprising red yeast rice extract and omega-3 polyunsaturated fatty acid or derivative thereof
TW201038205A (en) * 2009-04-29 2010-11-01 Sunway Biotech Co Ltd The compositions of Monascus fermented products with a function that reduces body fatness formation and the method for manufacturing the same
JP2010273569A (ja) * 2009-05-26 2010-12-09 Wasaburo Sato メタボリックシンドローム改善作用を有する飲料及びサプリメント
JP5912361B2 (ja) * 2011-09-16 2016-04-27 晨暉生物科技股▲分▼有限公司 血液脂質を引き下げ、ｈｄｌコレステロールを引き上げることができる混合物とその製造方法
ES2666459T3 (es) 2011-12-26 2018-05-04 Beijing Peking University Wbl Biotech Co., Ltd Derivado de esterol, procedimiento de preparación y finalidad del mismo
CN113171316B (zh) * 2021-04-23 2022-06-14 科丝美诗(中国)化妆品有限公司 一种修复、缓解皮肤刺激化妆品及制备方法

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JP3168298B2 (ja) * 1993-02-05 2001-05-21 有限会社フジ・バイオ研究所 紅麹を使用した酒精飲料の製造法

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AU4658797A (en) 1998-04-24
HUP9904650A2 (hu) 2000-05-28
BR9712168A (pt) 2000-01-18
KR20000048765A (ko) 2000-07-25
WO1998014177A1 (fr) 1998-04-09
IL129216A0 (en) 2000-02-17
CA2267340A1 (fr) 1998-04-09

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