WO2013138407A1 - Substances permettant d'atténuer la survenue d'événements cardiaques majeurs comprenant de l'epa ou des dérivés de ceux-ci, facultativement, l'acide docosahexanoïque (dha) ou des dérivés de celui-ci et la monacoline k - Google Patents

Substances permettant d'atténuer la survenue d'événements cardiaques majeurs comprenant de l'epa ou des dérivés de ceux-ci, facultativement, l'acide docosahexanoïque (dha) ou des dérivés de celui-ci et la monacoline k Download PDF

Info

Publication number
WO2013138407A1
WO2013138407A1 PCT/US2013/030667 US2013030667W WO2013138407A1 WO 2013138407 A1 WO2013138407 A1 WO 2013138407A1 US 2013030667 W US2013030667 W US 2013030667W WO 2013138407 A1 WO2013138407 A1 WO 2013138407A1
Authority
WO
WIPO (PCT)
Prior art keywords
therapeutic composition
component
monacolin
epa
red yeast
Prior art date
Application number
PCT/US2013/030667
Other languages
English (en)
Inventor
Joar A. OPHEIM
Original Assignee
Nordic Naturals, 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
Priority claimed from US13/420,403 external-priority patent/US20120171311A1/en
Application filed by Nordic Naturals, Inc. filed Critical Nordic Naturals, Inc.
Publication of WO2013138407A1 publication Critical patent/WO2013138407A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
    • 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
    • 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
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/062—Ascomycota
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • compositions relate to compositions and the use of such compositions in therapeutic compositions, nutritional supplements and medicaments, wherein the compositions are combinations of (1) EPA and/or derivatives thereof and, optionally, DHA and/or derivatives thereof derived from fish oils or other sources of EPA and DHA or derivatives thereof, and (2) monacolin K.
  • Statins are members of a group of HMG-CoA reductase inhibitors, used as pharmaceutical agents to lower cholesterol levels in people with or at risk for cardiovascular disease.
  • Statins lower cholesterol by inhibiting the enzyme HMG-CoA reductase, which is the rate-limiting enzyme of the mevalonate pathway of cholesterol synthesis. Inhibition of this enzyme in the liver stimulates low- density lipoprotein (LDL) receptors, resulting in an increased clearance of LDL, so-called "bad cholesterol,” from the bloodstream and a decrease in blood cholesterol levels.
  • LDL low- density lipoprotein
  • Statins are potent cholesterol-lowering agents, and have been reported to lower LDL cholesterol by 30-50% (see Jones et al., "Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study);' Am J Cardiol 1998; 81-(5); 582-7.)
  • Statins are classified as either synthetic or fermentation derived. Lovastatin was isolated from a strain of Aspergillus terreus and it was the first statin approved by the FDA as a drug (August 1987). Lovastatin is a water insoluble, white crystalline solid.
  • lovastatin leads to inadequate dissolution in gastrointestinal fluids and, hence, poor absorption, distribution, and targeted organ delivery.
  • Solubility of lovastatin is enhanced by reaction with 3-cyclodextrin, an oligosaccharide which improves the solubility of lovastatin.
  • the improvement of aqueous solubility in such a case is a valuable goal to improve therapeutic efficacy.
  • Lovastatin can also produce slight to moderate increases in high density lipoproteins (HDL) (10-20%), and slight decreases in triglycerides (5-10%).
  • the usual daily dose of lovastatin is 20-80 mg/day.
  • the statin drugs include lovastatin, pravastatin, fluvastatin, atorvastatin, simvastatin, rosuvastatin, and cerivastatin.
  • Red Yeast Rice Compounds similar to lovastatin have also been found in a natural fermentation product known as Red Yeast Rice. These compounds are also HMG-CoA reductase inhibitors.
  • Alternative Medicine RevieM' (Volume 9, Number 2, 2004) reports that the HMG-CoA reductase inhibitor activity in Red Yeast Rice comes from a naturally occurring family of nine compounds called "monacolins," each of which has HMG-CoA reductase inhibitor activity.
  • Additional active ingredients in Red Yeast Rice include sterols (beta-sitosterol, campesterol, sigmasterol, and sapogenin),
  • monacolin K is said to be the lactone form of the statin drug lovastatin, which is converted to the active acid form in vivo by the liver.
  • Red Yeast Rice is a common foodstuff in Asian countries where the average daily intake is 14-55 grams.
  • the nutritional supplement derived from Red Yeast Rice is known as Red Yeast Rice extract. It is obtained by drying the fermented product of rice on which the yeast Monascus pupureus has been grown and extracting the dried product with a solvent, usually aqueous ethanol or water.
  • the Red Yeast Rice extract thus produced typically contains about 0.2 wt.% monacolin K and about 0.5 wt.% total monacolins.
  • U.S. 6,046,022 is hereby incorporated by reference herein in its entirety.
  • U.S. Patent Application Publication No. 2006/021 1763 published September 21, 2006, by Fawzy et al., discloses a statin drug dissolved in a solvent system comprising natural or synthetic omega-3 fatty acids
  • U.S. Patent Application Publication No. 2006/0034815 published February 16, 2006, by Guzman et al., discloses omega-3 oil solutions of one or more statins.
  • Omega-3 polyunsaturated fatty acids and derivatives thereof can be derived from fish oils and are known to reduce serum triglycerides (see Abe et al., "Soluble cell adhesion molecules in hypertriglyceridemia and potential significance on monocyte adhesion " Arteriosler Thromb Vase Biology 1998, 18:723-731) and adverse coronary events.
  • the principal active ingredients in fish oil are 5,8,1 1,14,17-eicosapentaenoic acid (eicosapentaenoic acid (EPA), (20:5 (n-3)) and 4,7,10,13,16,19-docosahexaenoic acid (docosahexaenoic acid (DHA), 22:6 (n-3)).
  • statin drugs and omega-3 polyunsaturated fatty acids or derivatives thereof have been reported to be cumulative.
  • statin simvastatin were given 2 grams twice daily of EPA+DHA, there was a further sustained significant decrease of 20-30% in
  • Omega-3 polyunsaturated fatty acids and derivatives thereof are also well known to those skilled in the art to reduce inflammation, decrease arrhythmias, decrease risk of sudden cardiac death and cardiac arrest.
  • a therapeutic composition comprising (1) a mixture comprising (A) EPA, pharmaceutically acceptable derivatives of EPA or mixtures thereof, and, optionally, (B) DHA, pharmaceutically acceptable derivatives of DHA or mixtures thereof, wherein the weight ratio of A:B is about 7.5: 1 or more, and (2) monacolin K, a source of monacolin or mixtures thereof.
  • the source of monacolin K can be Red Yeast Rice extract.
  • the weight ratio of A:B may be 7.5: 1, 13:1, 16: 1, 18: 1 or 50: 1.
  • component (1) is essentially all or all EPA and/or derivatives of EPA.
  • the term “about” means that the value or amount to which it refers can vary by ⁇ 5%.
  • the term “essentially all” means that the component to which it refers is at least 98% of that component.
  • the present invention also provides therapeutic compositions wherein the derivatives of EPA and derivatives of DHA are selected from the group consisting of esters, alkyl esters, glycerides and phospholipids.
  • the derivatives of EPA and derivatives of DHA can be triglycerides.
  • the source of monacolin K is Red Yeast Rice extract.
  • the Red Yeast Rice extract can comprise about 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.6, 0.8, 1.2, 2.0 or 2.4 wt.% or more monacolin K.
  • the Red Yeast Rice extract can comprise about 0.8 to about 25 wt.% monacolin K.
  • a therapeutic composition wherein the weight ratio of component (1) to Red Yeast Rice extract is in the range between about 1 : 1 to about 10: 1 In some embodiments, the weight ratio of component (1) to Red Yeast Rice extract is about 4: 1 to 10:1. In some embodiments the weight ratio of component (1) to Red Yeast Rice extract is about 4: 1. In some embodiments
  • the weight ratio of component (1) to Red Yeast Rice extract is about 9: 1.
  • the present invention also provides therapeutic compositions further comprising a dispersing agent, wherein the dispersing agent can comprise lysine and bamboo.
  • the present invention also includes soft gelatin capsules into which component (1), component (2) and dispersing agent are loaded, and wherein a daily dose of the therapeutic composition is delivered by an integral number of capsules.
  • the present invention also provides a daily dose of the therapeutic composition wherein the daily dose of therapeutic composition can comprise about 2200 mg of component (1) and a sufficient amount of component (2) to provide at least about 6.0 mg of monacolin K, or the daily dose can comprise about 2700 mg of component (1) and a sufficient amount of component (2) to provide about 6.4 mg of monacolin K. Also provided in accordance with the present invention are therapeutic compositions wherein a daily dose of the therapeutic composition comprises about 2400 mg of (A) and 320 mg (B) and a sufficient amount of component (2) to provide about 6.4 mg of monacolin K, or the daily dose can comprise about 3240 mg of (A) and about 180 (B) and sufficient Red Yeast Rice extract to provide about 9.6 mg of monacolin .
  • the therapeutic composition of the present invention can also include an antioxidant.
  • the antioxidant can be chosen from the group consisting of rosemary, vitamin E, astaxanthine, carnitine, ascorbyl palmitate, and tocophero.
  • the present invention relates to a therapeutic composition or medicament comprising (1) a mixture comprising (A) EPA, pharmaceutically acceptable derivatives of EPA or mixtures thereof, and, optionally, (B) DHA, pharmaceutically acceptable derivatives of DHA or mixtures thereof, wherein the weight ratio of A:B is about 7.5: 1 or more (referred to herein as "component (1)"), and (2) monacolin K, a source of monacolin K or mixtures thereof (referred to herein as "component (2)").
  • Component (2) can be dispersed in component (1) so that component (1) and component (2) are administered simultaneously, or component (1) and component (2) can be administered separately. Simultaneous administration is preferred.
  • the weight ratio of A:B may be 7.5: 1 , about 13 : 1 , about 16: 1 , about 18: 1 or about 50: 1.
  • component (1) is essentially all or all EPA and/or derivatives of EPA. These weight ratios are to be understood to include any weight ratio or range of weight ratios between 7.5: 1 and the case where component (1) is all EPA and/or derivatives of EPA, wherein the number for A is increased in increments of 0.01.
  • the therapeutic composition includes compositions in which component (1) comprises about 60% or more of omega-3 oils, or about 70% or more omega-3 oils in which the omega-3 oils contain component (1).
  • the therapeutic composition includes compositions which contain Red Yeast Rice extract wherein the Red Yeast Rice extract comprises about 0.1 wt.% or more monacolin K.
  • the therapeutic composition includes compositions in which the Red Yeast Rice extract comprises about .
  • the Red Yeast Rice extract can comprise about 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.6, 0.8, 1.2, 2.0 or 2.4 wt.% or more monacolin K.
  • the therapeutic composition includes compositions in which the Red Yeast Rice extract comprises about 0.8 to about 25 wt.% monacolin K.
  • the therapeutic composition has a weight ratio of component (1) to Red Yeast Rice extract in the range between about 1 : 1 to about 10: 1 In some embodiments, the weight ratio of component (1) to Red Yeast Rice extract is about 4: 1 to 10: 1. In some embodiments the weight ratio of component (1) to Red Yeast Rice extract is about 4: 1. In some embodiments, the weight ratio of component (1) to Red Yeast Rice extract is about 9: 1. In some embodiments, the therapeutic composition has a weight ratio of component (1) to Red Yeast Rice extract of about 0.98: 1 , about 1.05: 1 , about 1.98: 1, about 3.4: 1 , about 3.8: 1 or about 8.55: 1. These weight ratios are to be understood to include any weight ratio or range of weight ratios between about 1 : 1 and about 10: 1 in increments of 0.01.
  • the therapeutic composition further comprises a dispersing agent.
  • the dispersing agent comprises 3% lysine and 2% bamboo.
  • the therapeutic composition further comprises a soft gelatin capsule into which the therapeutic composition and dispersing agent are loaded.
  • the therapeutic composition comprises a daily dose of the therapeutic composition which is delivered by an integral number of capsules.
  • the daily dose of the therapeutic composition can comprise about 2200 mg of component (1) and a sufficient amount of component (2) to provide at least about 6.0 mg of monacolin , or the daily dose can comprise about 2700 mg of component (1) and a sufficient amount of component (2) to provide about 6.4 mg of monacolin K.
  • a daily dose of the therapeutic composition comprises about 2400 mg of (A) and 320 mg (B) and a sufficient amount of component (2) to provide about 6.4 mg of monacolin
  • the daily dose can comprise about 3240 mg of (A) and about 180 (B) and sufficient Red Yeast Rice extract to provide about 9.6 mg of monacolin .
  • the therapeutic composition further comprises an antioxidant.
  • the antioxidant is chosen from the group consisting of rosemary, vitamin E, astaxanthine, carnitine, ascorbyl palmitate, and tocopherols.
  • the present invention further relates to a method of reducing serum cholesterol, triglycerides or both in a subject comprising administering a daily dosage of a therapeutic composition of this invention.
  • the daily dosage comprises those recited above.
  • the invention also relates to compositions comprising component (1) and component (2), and the use of such compositions to treat a subject. If Red Yeast Rice extract is the source of monacolin K, the Red Yeast Rice extract preferably comprises at least one and preferably more than one monacolin compound.
  • the monacolin compound comprises monacolin K.
  • the monacolin compounds comprise monacolin K and at least one other monacolin compound.
  • the monacolin compounds comprise all of the monacolin compounds in Red Yeast Rice.
  • the Red Yeast Rice extract contains about 0.2 wt.% monacolin K and about 0.5 wt.% of total monacolins.
  • compositions of the present invention provide several advantages over the use of lovastatin to reduce cholesterol and triglyceride level in a subject.
  • the Red Yeast Rice extract is water soluble, whereas lovastatin is not.
  • the water insolubility of lovastatin leads to inadequate dissolution in
  • lovastatin gastrointestinal fluids and, hence, poor absorption, distribution, and targeted organ delivery. While the water solubility of lovastatin can be enhanced, it is believed that the water soluble Red Yeast Rice extract will enter the subjects system easier than lovastatin.
  • Red Yeast Rice extract can produce better lipid reducing results at lower dosages (based on the amount of monacolin in the Red Yeast Rice extract) than lovastatin. This reduces the risk of undesirable and possibly harmful side effects in the subject.
  • the Red Yeast Rice extract is prepared by fermenting white rice, preferably non-glutinous white rice, with Monascus purpureus strain of yeast by culturing said Monascus purpureus strain in a culture medium comprising rice at a temperature of about 15°C to about 35°C for a period of about 2 to about 20 days to provide a crude fermentation product containing Red Yeast Rice; drying said crude fermentation product to obtain Red Yeast Rice, extracting said Red Yeast Rice with a solvent to provide an extract; and drying said extract to remove the solvent and produce Red Yeast Rice extract.
  • the solvent is preferably either aqueous ethanol or water.
  • Other culture media may also be added to the rice. For example, sugar; an additional carbon source chosen from the group consisting of glycerine, malt, and potato juice; and thick beet juice or mixtures thereof may be used. In addition, a defoamer may be added.
  • the Red Yeast Rice extract used in the therapeutic compositions of this invention contains relatively high levels of monacolin K. If it is desired that these high-monacolin K Red Yeast Rice extracts be used, they can be prepared as described above with the fermentation step being continued to increase the monacolin K level to the desired amount.
  • the Red Yeast Rice extract used in the compositions of the present invention contains about 0.1 wt.% or more monacolin K. In some embodiments, the Red Yeast Rice extract used in the compositions of the present invention contains about 0.1 wt.% or more monacolin K. In some embodiments, the Red Yeast Rice extract used in the compositions of the present invention contains about 0.1 wt.% or more monacolin K. In some
  • the Red Yeast Rice extract contains about In some embodiments, the Red Yeast Rice extract can comprise about 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.6, 0.8, 1.2, 2.0 or 2.4 wt.% or more monacolin K. In some embodiments, the Red Yeast Rice extract can comprise about 0.8 to about 25 wt.% monacolin K. These weight
  • percentages are to be understood to include any weight percent or range of weight percents between 0.1 wt% and 25 wt% in increments of 0.01 wt%.
  • Red Yeast Rice extracts are readily available in commerce in the United States and may be purchased already prepared. If it is desired to employ Red Yeast Rice extracts containing higher amounts of monacolin K than is available commercially, they may be prepared as described above.
  • omega-3 polyunsaturated fatty acids are omega-3 polyunsaturated fatty acids.
  • omega-3 polyunsaturated fatty acid(s) refers to the fact that EPA and DHA have a carbon-carbon bond in the n-3 position (i.e., the third bond from the methyl end of the molecule).
  • EPA and DHA can be found in nature, and these natural omega-3
  • polyunsaturated fatty acids frequently have all of their carbon-carbon double bonds in the c/s-configuration.
  • EPA is 5,8,1 1 , 14, 17-eicosapentaenoic acid (eicosapentaenoic acid or "EPA,” (20:5 (n-3)) and DHA is 4,7,10,13, 16, 19-docosahexaenoic acid (docosahexaenoic acid or "DHA,” 22:6 (n-3)).
  • Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are found in nature in fish oils, and have been used in a variety of dietary/therapeutic compositions.
  • EPA derivative(s) and DHA derivative(s) refer to EPA and DHA that have been reacted with another compound or otherwise modified so that the EPA and DHA no longer contains a free carboxylic acid.
  • examples of EPA and DHA derivatives include salts, esters (such as alkyl esters including, but not limited to, methyl and ethyl esters) and glycerides.
  • the EPA and DHA can also be one or more of the fatty acid moieties in a phospholipid molecule. Since the derivatives are intended to be administered to a subject, they should be pharmaceutically acceptable.
  • pharmaceutically acceptable means that the material to which it refers is not harmful to the subject.
  • glycolide means a glycerol molecule (i.e., OHCH 2 CHOHCH 2 OH) in which one, two or all three of the hydroxyls have been esterified with a carboxylic acid, e.g., an omega-3 polyunsaturated fatty acid.
  • triglyceride refers to glycerides in which all three hydroxyls on the glycerol have been esterified with (the same or different) carboxylic acids.
  • 'Triglyceride refers to glycerides in which only two of the hydroxyls on the glycerol have been esterified with (the same or different) carboxylic acids.
  • “Monoglyceride” refers to glycerides in which only one hydroxyl on the glycerol has been esterified with a carboxylic acid.
  • Omega-3 fatty acids are found in nature in the triglyceride form (a glycerol with three fatty acids attached).
  • the natural triglyceride form as found in raw fish oil cannot be readily separated as it occurs into purified EPA/DHA mixtures by ordinary means such as distillation or crystallization, because the fatty acids are non-uniformly distributed among the triglyceride molecules. There are very few, if any, single triglyceride molecules which are composed of either three EPAs or three DHAs.
  • a DHA typically, there is a DHA, an EPA, and another fatty acid in a triglyceride molecule. So in order to purify fatty acids to increase the proportion of EPA, DHA, or the total fraction of omega-3 's, it is necessary to hydrolyze the triglycerides to remove at least some fatty acids from the glycerol.
  • the triglycerides may be converted by any method known to one skilled in the art without limitation.
  • the triglycerides may be converted by lipase- catalyzed esterification or lipase catalyzed acidolysis with ethyl or lauryl alcohol, which can selectively leave the highest amount of EPA and DHA bonded to glycerols and remove other components, leaving EPA and/or DHA as mono- or di-glycerides.
  • the mono- and di-glycerides can then be separated into fractions with different EPA/DHA ratios, by methods familiar to those skilled in the art such as multiple stage vacuum distillation and/or fractional crystallization in urea.
  • the purified EPA and DHA esters after concentration, can be reattached to glycerol molecules using enzymatic reacylation to recreate glycerides which are otherwise identical to the original natural triglycerides, except that they are more concentrated in EPA and DHA combined, and they may also have a different ratio of EPA:DHA than the original fish oil.
  • at least 60% of the omega-3 fatty acids, and preferably 70% or more are converted to the triglyceride form in the reacylation process. The process may be successively repeated with addition of additional catalyst and/or enzyme and additional EPA and DHA until the desired specification proportions are met. About 60% of triglycerides can be made in the first pass of reacylation, with most of the remainder of the product being mono- and di-glycerides.
  • Polyunsaturated fatty acid triglycerides can be prepared using the following method.
  • Raw fish oil in the natural triglyceride molecular form preferably from anchovies and sardines which contain about 18% EPA and 12% DHA is heated to 60°C to decrease viscosity.
  • Sodium oxide is added to bind with free fatty acids in the oil.
  • the mixture is moved to a separator where sodium oxide bound to free fatty acids (soap) floats to the top and is removed.
  • the oil is then moved to a second separator where warm water is preferably added to help remove traces of sodium oxide, as sodium oxide partitions to water, yet does not interact with the fish oil.
  • Citric acid may then be added to support splitting the oil from the
  • Oil is moved to a separate stripping tank, and heated to 200°C.
  • Ethyl esters can be added to support the removal of impurities, which bind to ethyl esters.
  • Impurities such as dioxins, heavy metals, polychlorinated biphenyls (PCBs), fire retardants, furans and others evaporate and are drawn to the middle of the tank where a refrigerating element cools them down and drain them.
  • the added esters are also removed with the impurities.
  • the oil is moved to an esterification tank. Ethanol and sodium metal are added. Sodium metal is a catalyst for breaking off fatty acid strands from the glycerol backbone of the triglyceride fatty acid molecule, the free fatty acids then combined with ethanol to form ethyl esters. Water can be added to bind to sodium metal, where the combination of water and sodium metal can be removed.
  • the oil is then moved to a distiller where it is heated to about 120°C under vacuum. Mono esters and shorter carbon chain molecules move to the middle where they are cooled and drained, leaving longer carbon chains remaining as a concentrate.
  • the process typically increases the key fatty acids by 100% during the first distillation; typically between 30-50% during the second distillation.
  • the process can be repeated, although preferably the process is ideally only repeated once, as when oils undergo heat it can produce oxidation and degradation of the fatty acids in general. Oil waste is also increasing with repeated distillation, making the process less economical.
  • Oils having higher EPA content can be produced by repeating the molecular distillation step to separate EPA from other fatty acids, including separation from DHA.
  • the oil is then moved to a reesterification tank where the ethyl ester molecules are reconverted to the triglyceride form, which is the natural form of that fatty acid molecule. 98% of fats ingested by humans are in this natural triglyceride form.
  • the esterification process takes place under low vacuum at about 80°C.
  • Glycerol is added to form the backbone of the glyceride molecules. Nitrogen can be added from the bottom of the tank to cause oil movement.
  • Lipase enzymes are added as catalysts to facilitate the fatty acids binding to glycerol.
  • the vacuum in the distillation tank removes the ethanol which was previously bound to the fatty acids.
  • the enzymes used are lipases produced from bacteria or yeast. Perhaps the most effective enzymes are Candidan Antarctica lipase, and Chromobacterium Viscosum Lipase; other enzymes that can be used effectively are Psuedomonas, Mucor miehei, and Candida Cylindracea as well as other enzymes may also be used.
  • the reesterification process typically takes 24 hours, at which point the triglycerides typically reaches 60-65%, the remaining glycerides being diglycerides and monoglycerides. Around 3% of the fish oil will remain as ethyl esters, which can be removed together with the ethanol. Adding additional enzymes and/or continuing the enzymatic process can produce triglyceride molecule concentration of up to 99%. The 60 - 65 % level is probably optimum from an economic point of view.
  • the oil in triglyceride form is then moved to a cooling tank at 0°C, where saturated fats, in particular stearic acid are crystallized.
  • the pulp is then pumped to a filter press, where the crystals are removed, essentially removing the vast majority of saturated fats from the oil. Depending on the amount of saturated fats in the oil, approximately 5-10% of the oil is lost during this process.
  • the oil is then removed to a bleaching tank at 60°C, where bleaching earth or bentonite earth is added to the oil. Any water in the oil evaporates due to the temperature. Any remaining impurities (trace minerals, etc) in the oil attach to the bentonite earth.
  • the oil is then run through a bentonite earth filter to remove the bentonite earth together with the impurities.
  • Antioxidants in particular rosemary and mixed tocopherols can be added to the final oil to dramatically reduce the oxidation process.
  • Sources of the omega-3 polyunsaturated fatty acids or derivatives thereof include natural sources including, but not limited to, fish oil (e.g., cod liver oil), flax seed oil, marine oils, sea oils, krill oil, algae and the like. Fish oil is a preferred source.
  • omega-3 polyunsaturated fatty acids or derivatives thereof which is rich in omega-3 oils, preferably containing at least 70% omega-3 oils.
  • the oil can also be rich in EPA and may contain some DHA.
  • omega oils are EPA+DHA, and more preferably 85% or more are EPA+DHA, with the majority (if not all) being EPA.
  • the Red Yeast Rice extract is water soluble and is not soluble in component (1).
  • a dispersing agent is used to keep the Red Yeast Rice extract in suspension.
  • the dispersing agent is about 70% silica bamboo with lysine made from sunflower oil.
  • a suitable method for making a therapeutic composition of the present invention is to vigorously mix Red Yeast Rice extract with fish oil (containing a suitable amount of component (1)) , bamboo (2%), and lysine (3%). The resulting mixture may then be diluted to the desired component (1 ) to Red Yeast Rice extract ratio.
  • the component (1)/Red Yeast Rice extract is then encapsulated in soft gelatin capsules for dispensing.
  • a dosage of the therapeutic composition of the present invention further includes antioxidants such as rosemary, vitamin E, astaxanthine, carnitine, ascorbyl palmitate, tocopherols or other antioxidants known in the art for stabilizing fish oil and/or omega-3 polyunsaturated fatty acids or derivatives thereof.
  • Red Yeast Rice extract contains monacolin K, the lactone form of the statin drug Mevacor® (lovastatin).
  • Red Yeast Rice extract has been tested in clinical trials at daily dosages of 1.2g and 2.4g.
  • the monacolin K content of the Red Yeast Rice extract used in the clinical trials was 0.20% of the Red Yeast Rice extract.
  • the monacolin K dose was therefore 2.4 to 4.8 mg/day.
  • the total cholesterol, LDL cholesterol, and triglycerides dropped by 23%, 31%, and 34% respectively.
  • the reduction was 17%, 23%, and 16% respectively (see Monograph by Thorne Research Inc., Alternative Medicine Review, 2004, 9: 1).
  • Lovastatin has been shown to have a cholesterol lowering effect in doses ranging from 5 to 80 mg/day (see Bates et al., "Effectiveness of low dosage lovastatin in lowering serum cholesterol. Experience with 56 patients.” Archives of Internal Medicine 1990, 150: 1947-1950). A study was performed to show the effectiveness of low-dose lovastatin in lowering serum cholesterol (see Heber et al., "Cholesterol lowering effects of proprietary Chinese red yeast rice dietary supplement," Ann J Clin Vutr 1999, 69:231- 236). Fifty-six patients were given 20 mg/day of lovastatin for 24 weeks. Total cholesterol fell by 26% and triglycerides fell by 12%.
  • Mevacor® lovastatin in its package insert reported extensive clinical trials at dosages of 10, 20, and 40 mg/day. Total cholesterol was reduced in the range from 16-24%, LDL was reduced by 21-32%, and triglycerides were reduced by 10 to 6% (higher reduction observed at lower dosage).
  • Red Yeast Rice extract at a dosage of 2.4 mg/day of monacolin K produced better lipid reducing results than Mevacor at 10 - 40 mg/day. It is, therefore, unlikely that the lipid lowering effects with Red Yeast Rice result from the monacolin K content alone of Red Yeast Rice, but are probably attributable in whole or in part to the other monacolins, sterols (beta-sitosterol, campesterol, sigmasterol, and sapogenin), isoflavones, and monounsaturated fatty acids Red Yeast Rice extract (see Durington et al., "An omega-3 polyunsaturated fatty acid concentration administered for one year decreased triglycerides in simvastin treated patients with CM," Heart
  • Red Yeast Rice extract can be purchased as a nutritional supplement in the United States. Preferred sources include DRACO Natural Products (539 Parrott St., San Jose, CA 951 12) Red Yeast Rice Extract 10:1 , and the Thorne Research product, Choleast. Purchased Red Yeast Rice preferably should contain about 0.2 wt.% or more of monacolin K and about 0.5 wt.% or more of total monacolins.
  • compositions of this invention can contain other ingredients besides the ingredients recited above. These include, but are not limited to, flavor agents, fillers, surfactants (e.g., polysorbate 80 and sodium lauryl sulfate), color agents including, e.g., dyes and pigments, sweeteners, antioxidants and additional ingredients.
  • surfactants e.g., polysorbate 80 and sodium lauryl sulfate
  • color agents including, e.g., dyes and pigments, sweeteners, antioxidants and additional ingredients.
  • Useful flavor agents include natural and synthetic flavoring sources including, but not limited to, volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins and extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof.
  • Useful flavor agents include, e.g., citric oils, e.g., lemon, orange, grape, lime and grapefruit, fruit essences including, e.g., apple, pear, peach, banana, grape, berry, strawberry, raspberry, blueberry, blackberry, cherry, plum, pineapple, apricot, and other fruit flavors.
  • flavor agents include, e.g., aldehydes and esters (e.g., benzaldehyde (cherry, almond)), citral, i.e., alpha-citral (lemon, lime), neral, i.e., beta- citral (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehyde C-12 (citrus fruits), tolyl aldehyde (cherry, almond), 2,6- dimethyloctanal (green fruit), 2-dodedenal (citrus, mandarin) and mixtures thereof, chocolate, cocoa, almond, cashew, macadamia nut, coconut, mint, chili pepper, pepper, cinnamon, vanilla, tooty fruity, mango and green tea. Mixtures of two or more flavor agents may also be employed. When a flavor agent is used, the amount employed will depend upon the particular flavor agent used. However, cit
  • Useful color agents include, e.g., food, drug and cosmetic (FD&C) colors including, e.g., dyes, lakes, and certain natural and derived colorants.
  • Useful lakes include dyes absorbed on aluminum hydroxide and other suitable carriers. Mixtures of color agents may also be employed. When a color agent is employed, the amount used will depend upon the particular color agent used. However, in general, the color agent can constitute from about 0.5% to about 5% by weight of the composition.
  • Natural and/or artificial sweetening agents can also be added to the composition.
  • sweeteners include sugars such as sucrose, glucose, invert sugar, fructose, and mixtures thereof, saccharin and its various salts (e.g., sodium and calcium salt of saccharin), cyclamic acid and its various salts, dipeptide sweeteners (e.g., aspartame), dihydrochalcone, and sugar alcohols including, e.g., sorbitol, sorbitol syrup, mannitol and xylitol, and combinations thereof.
  • Natural sweeteners that can be employed include, but are not limited to, luo han, stevia or mixtures thereof.
  • Luo han sweetener is derived from luo han guo fruit (siraitia grosvenorii) that is mainly found in China. It is about 300 times sweeter by weight than sucrose. Luo han is commercially available from, e.g., Barrington Nutritionals (Harrison, New York). Stevia is derived from a South American herb, Stevia rebaudiana. It can be up to about 300 times sweeter than sucrose. Because luo han and stevia have such a sweet taste, only a small amount need be used in the composition. When a sweetening agent is employed the amount used will depend upon the particular sweetening agent used.
  • the sweetening agent can constitute from about 0.0005% to about 30%o, by weight of the composition.
  • a sweetener having a very sweet taste such as luo han or stevia
  • small amounts such as about 0.0005% to about 0.1 %> (for example about 0.005%> to about 0.015% or about 0.002%> to about 0.003%) by weight can be used.
  • compositions of the present invention can contain additional ingredients.
  • additional ingredients include, but are not limited to, vitamins, minerals and/or herbs.
  • vitamin refers to trace organic substances that are required in the diet.
  • the term vitamin(s) include, without limitation, thiamin, riboflavin, nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B12, lipoic acid, ascorbic acid, vitamin A, vitamin D, vitamin E and vitamin K.
  • coenzymes are also included within the term vitamin. Coenzymes are specific chemical forms of vitamins.
  • Coenzymes include thiamine pyrophosphates (TPP), flavin mononucleotide (FMM), flavin adenine dinucleotive (FAD), Nicotinamide adenine dinucleotide (AND), Nicotinamide adenine dinucleotide phosphate (NADP), Coenzyme A (Co A), Coenzyme Q10 (CoQI O), pyridoxal phosphate, biocytin, tetrahydrofolic acid, coenzyme B12, lipoyllysine, W -cis- retinal, and 1,25-dihydroxycholecalciferol.
  • the term vitamin(s) also includes choline, carnitine, and alpha, beta, and gamma carotenes.
  • the term “mineral” refers to inorganic substances, metals, and the like required in the human diet.
  • the term “mineral” as used herein includes, without limitation, calcium, iron, zinc, selenium, copper, iodine, magnesium, phosphorus, chromium and the like, and mixtures thereof. Compounds containing these elements are also included in the term “mineral.”
  • herb refers to organic substances defined as any of various often aromatic plants used especially in medicine or as seasoning.
  • the term “herb” as used herein includes, but is not limited to, black currant, ginsing, ginko bilboa, cinnamon, and the like, and mixtures thereof.
  • antioxidants include antioxidants, glucosamine and mixtures thereof.
  • compositions of this invention are suitable for therapeutic and/or nutritional purposes in treating a subject in need of such treatment.
  • subject includes, but is not limited to, a non-human animal, such as a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, or guinea pig; and a human.
  • the amount of the composition of the invention that is effective will vary depending upon the condition being treated, and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed will also depend on the relative amounts of the components of the compositions of the invention, route of administration, and the seriousness of the condition being treated and should be decided according to the judgment of the practitioner and each subject's circumstances.
  • suitable effective dosage amounts for the compositions of the invention typically are at least about 2 grams per day, typically administered in the form of capsules containing at least about 1 gram of the composition per capsule.
  • compositions of the present invention comprise component (1) and component (2) wherein components (1) and (2) are present in amounts effective to help reduce LDL cholesterol and/or triglycerides in a subject.
  • present in amounts effective to help reduce LDL cholesterol and/or triglycerides in a subject means that components (1) and (2) are used in an amount, individually and in combination, effective for a therapeutic, preventive or nutritional activity in a subject that promotes or supports reduction of LDL cholesterol and/or triglycerides in the subject.
  • promote or support reduction of LDL cholesterol and/or triglycerides in a subject is meant the compositions help lower (or at least help maintain) LDL
  • cholesterol and/or triglyceride levels in the subject are administered to the subject.
  • amount individually and in combination effective is meant that each individual component is present in an amount sufficient to perform its function as well as the overall composition being in an amount sufficient to perform its overall function.
  • composition of the invention is administered to the subject is not critical.
  • the composition is administered as a liquid, as a dispersion or in a capsule.
  • the composition is administered in the form of individual doses.
  • dose includes both the case where component (1) and component (2) are administered together (such as in the form of a capsule containing both components), and the case where component (1) and component (2) are administered separately (but, typically, at essentially the same time). It is preferred that components (1) and (2) be administered together, such as in the form of a single capsule.
  • the composition of the invention is administered in the form of a daily dose.
  • this may not be required, and the period between administration of the doses may be longer than one day.
  • the term "administer" includes both the case where a third party administers the dose to the subject and the case where the subject self- administers the dose.
  • a daily dose of the therapeutic compositions of the present invention comprises four 1000 mg doses of Formula I, II, III, IV, V, or VI in the tables above.
  • the daily dose comprises four capsules, each containing 1000 mg of Formula I, II, III, IV, V, or VI.
  • a daily dose is taken, the dose comprising 3200 mg of fish oil containing component (1) and sufficient Red Yeast Rice extract to provide 6.4 mg of monacolin K
  • Such a dose could include 2400 mg EPA (triglyceride form), 320 mg DHA (triglyceride form) and 6.4 mg monacolin K.
  • the weight ratio of fish oil to Red Yeast Rice extract is 4: 1.
  • a daily dose is taken, the dose comprising 3600 mg of fish oil containing component (1) and sufficient Red Yeast Rice extract to provide 9.6 mg of monacolin K
  • a dose could include 3240 mg EPA (triglyceride form), 180 mg DHA (triglyceride form) and 9.6 mg monacolin K.
  • the weight ratio of fish oil to Red Yeast Rice extract is 9: 1.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Animal Behavior & Ethology (AREA)
  • Mycology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Polymers & Plastics (AREA)
  • Food Science & Technology (AREA)
  • Nutrition Science (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Biotechnology (AREA)
  • Botany (AREA)
  • Medical Informatics (AREA)
  • Microbiology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Emergency Medicine (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Médicaments et compositions thérapeutiques comprenant (1) un mélange constitué (A) d'EPA, de dérivés acceptables sur le plan pharmaceutique d'acide Docosahexaénoïque (DHA) ou de mélanges de ceux-ci, dans lesquels le rapport en poids de A:B est d'environ 7,5:1 ou plus, et (2) de la monacoline K, d'une source de monacoline K ou de mélanges de ceux-ci. Une source de composant (1) est de l'huile de poisson. Une source de monacoline K est un extrait de Levure de Riz Rouge. Les compositions sont utiles pour réduire les niveaux de cholestérol et/ou de triglycérides chez un sujet.
PCT/US2013/030667 2012-03-14 2013-03-13 Substances permettant d'atténuer la survenue d'événements cardiaques majeurs comprenant de l'epa ou des dérivés de ceux-ci, facultativement, l'acide docosahexanoïque (dha) ou des dérivés de celui-ci et la monacoline k WO2013138407A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US13/420,403 US20120171311A1 (en) 2007-06-01 2012-03-14 Substances for reducing occurrence of major cardiac events comprising epa or derivatives thereof, optionally, dha or derivatives thereof and monacolin k
US13/420,403 2012-03-14

Publications (1)

Publication Number Publication Date
WO2013138407A1 true WO2013138407A1 (fr) 2013-09-19

Family

ID=49161743

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2013/030667 WO2013138407A1 (fr) 2012-03-14 2013-03-13 Substances permettant d'atténuer la survenue d'événements cardiaques majeurs comprenant de l'epa ou des dérivés de ceux-ci, facultativement, l'acide docosahexanoïque (dha) ou des dérivés de celui-ci et la monacoline k

Country Status (1)

Country Link
WO (1) WO2013138407A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023073226A1 (fr) * 2021-10-29 2023-05-04 Meda Pharma S.p.A Compositions comprenant de la levure rouge de riz

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080299187A1 (en) * 2007-06-01 2008-12-04 Joar Opheim Substances for Reducing Occurence of Major Cardiac Events in Humans
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

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080299187A1 (en) * 2007-06-01 2008-12-04 Joar Opheim Substances for Reducing Occurence of Major Cardiac Events in Humans
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

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023073226A1 (fr) * 2021-10-29 2023-05-04 Meda Pharma S.p.A Compositions comprenant de la levure rouge de riz

Similar Documents

Publication Publication Date Title
US11406602B2 (en) Substances for reducing occurrence of major cardiac events comprising red yeast rice extract and omega-3 polyunsaturated fatty acid or derivative thereof
US10744146B2 (en) Composition having effects of preventing or ameliorating conditions or diseases caused by brain hypofunction
KR102271711B1 (ko) 에이코사펜타엔산 (ｅｐａ) 제형
US20120171285A1 (en) Substances for reducing occurrence of major cardiac events comprising omega-3 polyunsaturated fatty acid or derivatives thereof and high-monacolin k content red yeast rice extract
EP0457950B1 (fr) Utilisation de l'acide stéaridonique pour le traitement des maladies inflammatoires
US20120219619A1 (en) Substances for reducing occurrence of major cardiac events in humans
US20110223246A1 (en) Docosahexaenoic acid bound in phospholipids and method of recovering same from a natural source
JP2007008863A (ja) 器質的脳障害に起因する高次脳機能の低下に対する改善作用を有する組成物
US20110217275A1 (en) Compositions comprising probiotic bacteria of the strain bacillus coagulans and omega-3 polyunsaturated fatty acids or derivatives thereof
JP2006083136A (ja) ストレスに起因する脳機能の低下およびそれに伴う症状あるいは疾患の予防又は改善作用を有する組成物
US20120195987A1 (en) Substances for reducing occurrence of major cardiac events comprising epa or derivatives thereof, optionally, dha or derivatives thereof and monacolin k
US20110218151A1 (en) Substances for promoting healthy joint function comprising omega-3 polyunsaturated fatty acids or drivatives thereof, undenatured type ii collagen and, optionally, glucosamine sulfate
NZ780733A (en) Cannabinoids compositions with polyunsaturated fatty acid monoglycerides, methods and uses thereof
US20110217370A1 (en) Substances for promoting healthy joint function comprising glucosamine sulfate, omega-3 polyunsaturated fatty acids or derivatives thereof, and undenatured type ii collagen
US20140256813A1 (en) Methods for the treatment of brain injury using omega-3 fatty acids
WO2013138407A1 (fr) Substances permettant d'atténuer la survenue d'événements cardiaques majeurs comprenant de l'epa ou des dérivés de ceux-ci, facultativement, l'acide docosahexanoïque (dha) ou des dérivés de celui-ci et la monacoline k
WO2013138411A1 (fr) Substances permettant d'atténuer la survenue d'événements cardiaques majeurs comprenant des acides gras polyinsaturés oméga -3 ou des dérivés correspondants et un extrait de riz à levure rouge à haute teneur en monacoline k
JP4721642B2 (ja) 肝障害を伴う肝臓疾患の予防又は改善剤
JP5496163B2 (ja) 脳機能の低下に起因する症状あるいは疾患の予防又は改善作用を有する組成物
CA2676583C (fr) Composition renfermant de la levure de riz rouge et un acide gras omega-3 polyinsature
WO2024043787A1 (fr) Composition d'acide cétoléique

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13760474

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13760474

Country of ref document: EP

Kind code of ref document: A1