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WO1994028891A1 - Procede permettant le traitement d'une coronaropathie au moyen d'acide docosahexaenoique - Google Patents

Procede permettant le traitement d'une coronaropathie au moyen d'acide docosahexaenoique Download PDF

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Publication number
WO1994028891A1
WO1994028891A1 PCT/US1994/006316 US9406316W WO9428891A1 WO 1994028891 A1 WO1994028891 A1 WO 1994028891A1 US 9406316 W US9406316 W US 9406316W WO 9428891 A1 WO9428891 A1 WO 9428891A1
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Prior art keywords
oil
dha
single cell
administered
cell oil
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PCT/US1994/006316
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English (en)
Inventor
David John Kyle
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Martek Biosciences Corp
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Martek Biosciences Corp
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Priority to AU70534/94A priority Critical patent/AU7053494A/en
Publication of WO1994028891A1 publication Critical patent/WO1994028891A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • 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

Definitions

  • This invention relates to a method of treating coronary vascular disease in a human by administering a serum cholesterol reducing effective amount of docosahexaenoic acid (DHA) to said human.
  • DHA docosahexaenoic acid
  • the DHA is administered in the form of a single cell oil containing DHA in the form of a triglyceride.
  • Hypercholesterolemia is defined by the presence of excess cholesterol in the blood. High levels of blood cholesterol can be a major risk factor in the premature development of atherosclerosis. It follows that hypercholesterolemia is a major risk factor for the development of coronary vascular disease. Accordingly, reduction of blood cholesterol levels in humans can be useful in preventing both atherosclerosis and coronary vascular disease.
  • Fish oils comprise a complex mixture of bioactive fatty acids, including two omega-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) .
  • the relative amounts of each of these two omega-3 PUFAs can vary, depending upon the species of fish.
  • the present invention relates to a method of treating hypercholesterolemia in a human by administering a serum cholesterol reducing effective amount of DHA to said human.
  • the DHA is in the form of a DHA-containing single cell edible oil.
  • single cell edible oil refers to a lipid product of a unicellular organism. More specifically, it refers to a lipid product in triglyceride form.
  • FIG. 1 is a graphic illustration of C. cohnii biomass accumulation over time with the addition of various nutrients.
  • coronary vascular disease is treated by administering to a human patient in need of such treatment a serum cholesterol reducing effective amount of DHA so as to reduce the amount of cholesterol in the patient's blood.
  • the DHA is in the form of a triglyceride and is obtained as a single cell oil by the cultivation of a DHA-producing microorganism under oil-producing conditions.
  • microorganisms capable of producing a single cell oil containing DHA are cultivated in a fermentor in a nutrient solution capable of supporting the growth of such organisms.
  • the single cell oil is enriched in DHA, meaning it will contain at least about 20% by weight DHA.
  • Microorganisms capable of producing a single- cell edible oil containing DHA can be used in the present invention.
  • Microorganisms which can be used can be identified by the presence of DHA in the fatty acid profile of the biomass.
  • species of photosynthetic algae such as Chattonella, Skeletonema, Thalassiosira, Isochrysis , Hymenomonas , Euglena and Cryptomonas can be used.
  • Preferred microorganisms are heterotrophic species of algae which include, but are not limited to the Dinophyceae (e.g., Crypthecodinium) , or fungi such as Chytridiomycetes (e.g., Thraustochi trium and Schi tzochytr ⁇ um) or Oomycetes (e.g., Mortierella, Saptrolegnia and Mucor) .
  • preferred microorganisms produce oils containing DHA and essentially no EPA (i.e., less than about 5% EPA) .
  • Producing oils with essentially no EPA to be administered to patients to treat coronary vascular disease is desirable because (1) as EPA is known to be a blood thinning agent, the administration of a microbial oil containing EPA is undesirable to patients whose blood is already thin or where an increased prothrombin time may be contraindicated (e.g., elderly patients, hypertensive patients, pregnant women, etc.) ; and (2) there are some indications that EPA may actually increase blood cholesterol levels in humans. See, e.g. , Bonaa, K. et al . , "Habitual Fish Consumption Plasma Phospholipid Fatty Acids, and Serum Lipids : the Tronso Study," Am J. Nutr. , 55(6) , pp.
  • C. cohnii is especially preferred because it contains a natural oil with a fatty acid profile in which DHA is abundant and the only long chain (i.e, . at least 20 carbon atoms) polyunsaturated fatty acid present in significant quantities (greater than about 1% of the total amount of PUFAs) .
  • DHA-containing oil produced by C.
  • cohnii is essentially free of EPA and other PUFAs, which provides an advantage for using the microbial oil rather than fish oil to treat hypercholesteremia.
  • Samples of one strain of C. cohnii which produces abundant levels of DHA have been deposited with the American Type Culture Collection at Rockville, Maryland, in accordance with the provisions of the Budapest Treaty, and assigned accession number 40750.
  • the term "microorganism”, or any specific type of. microorganism includes wild strains, mutants or recombinant types. Any microorganism which produces enhanced levels of oil containing DHA is considered to be- within the scope of this invention.
  • wild-type and recombinant microorganisms designed to produce single cell oil containing DHA are an aspect of this invention.
  • Such recombinant organisms would include those designed to produce greater quantities of DHA in the single cell oil, greater quantities of total oil, or both, as compared to the quantities produced by the same wild type microorganism, when provided with the same substrates.
  • the DHA-producing microorganisms can be cultivated in a simple medium containing a carbon source, such as glucose, and a nitrogen source, such as yeast extract.
  • a carbon source such as glucose
  • a nitrogen source such as yeast extract.
  • Use of these components in a suitable nutrient solution such as seawater provides economically significant growth rates and cell densities. For example, during the course of a 3-5 day fermentation, microorganism cell densities of at least 10 grams of biomass per liter of solution, and typically from 20 to about 40 grams per liter, can be attained.
  • cultivation can occur in any suitable fermentor, preferably the organism is grown either in a stirred tank fermentor (STF) or in an air lift fermentor (ALF) , both types known to those of skill in the art.
  • STF stirred tank fermentor
  • ALF air lift fermentor
  • agitation is provided using either Rushton-type high efficiency turbines or pitched-blade or marine impellers. Agitation and sparging renew the supply of oxygen to the microorganisms.
  • the rate of agitation normally is increased as the biomass increases, due to the increased demand for oxygen. It is desirable to keep the tip speed at not greater than about 500 cm/sec, preferably not greater than about 300 cm/sec. Selection of strains of microorganisms which are capable of withstanding greater tip speeds without undergoing shear is within the purview of those of skill in the art . The use of such strains is expressly included in this invention.
  • seawater is an acceptable medium for the nutrient solution.
  • the seawater can be either natural, filtered or an artificial mix, each of which can be diluted to reduced salinities, such as 1/2 to 1/4 normal strength, with tap water or concentrated to 2 times normal strength.
  • C. cohnii can be grown, for example, in Instant Ocean ® (10) brand artificial seawater, or a mixture of NaCl (4.5-20 g/L) , MgS0 4 *7H 2 0 (1.23 g/L), and CaCl 2 *2H-0 (90 mg/L) in water.
  • micronutrients known to those of skill in the art can be added and may be required at such low salinities. If the organism selected is heterotrophic, such as C. cohnii , then a carbon source is added.
  • the fermentor containing the medium is sterilized and cooled prior to adding the nutrients and a seeding population of microorganism.
  • the nutrients and microorganism can be added simultaneously or sequentially.
  • An effective seed concentration can be determined by those of skill in the art.
  • a STF When a STF is used, the addition of a population of from about 0.05 to 1.0 grams of dry weight equivalent per liter at the beginning of the fermentation is preferred. This is about 1-5 x 10 6 cells per ml. Thus, for a 30 liter fermentor, 1-3 liters of seeding media, containing viable cells at a density of 10-20g dry weight per liter would be added.
  • Oxygen levels preferably are maintained at a D.O. of at least about 10% of air saturation level.
  • Biosynthesis of DHA requires oxygen and, accordingly, higher yields of DHA require D.O. levels at from about 10% to 50% of air saturation levels.
  • Agitation tip speeds of 150-200 cm/sec in combination with an aeration rate of 1 WM (volume of air/volume of fermentor per minute) provides D.O. levels of from about 20% to about 30% at biomass densities of about 25 g dry weight/liter of culture. Higher cell densities may require higher D.O. levels, which can be attained by increased aeration rates by 0 2 sparging, or by increasing the back pressure in the fermentor.
  • Acceptable carbon sources are known to those of skill in the art.
  • carbon can be provided to microorganisms in the form of mono- or di- saccharides, such as glucose and sucrose.
  • Other heterotrophs can use other reduced carbon sources, a matter easily determined by those of skill in the art, and autotrophs utilize carbon dioxide.
  • Microorganisms will also grow on other reduced, more complex, carbon sources.
  • a fermentation is initiated with about 10-50 g/liter glucose. More glucose is added during the fermentation as required. Alternatively, from about 50 to 150 g, preferably 50 to lOOg glucose/liter initially can be added, thereby minimizing the frequency of future additions.
  • the amount of carbon source provided to other organisms can readily be determined by those of skill in the art .
  • a nitrogen source such as yeast extract (YE) or peptone
  • yeast extract or peptone
  • yeast extract or peptone is acceptable.
  • yeast extract and peptone are organic nitrogen sources which also contain micronutrients.
  • Other organic nitrogen sources easily can be determined by those of skill in the art. However, such compounds are generally more expensive than yeast extract.
  • Variants capable of growing on urea, ammonia or nitrates also can be used.
  • the fermentation is initiated with about 6-12 g YE/liter. More YE can be added as required.
  • a typical fermentation run requires from about 8 to 15 g YE/liter over the course of the run. Accordingly, that amount of YE can be added initially with a reduced need for further additions. The precise amount can be determined by those of skill in the art. Generally, the ratio of glucose to YE is from about 2:1 to about 25:1.
  • the cultivation can be carried out at any life- sustaining temperature.
  • Some algae and fungi have an effective temperature range of from about 10-40°C.
  • C. cohnii will grow at temperatures ranging from about 15°C to 34°C.
  • the temperature is maintained at about 20- 30°C.
  • Strains which grow at higher temperatures are preferred, because they will have a faster doubling time, thereby reducing the fermentation time.
  • Appropriate temperature ranges for other microorganisms are readily determined by those of skill in the art.
  • the cultivation can be carried out over a broad pH range, typically from about pH 5.0 to 9.0.
  • a pH range of from about 6.0 to about 7.0 is used for the growth phase.
  • a base such as KOH or NaOH
  • KOH or NaOH is used to adjust the media pH prior to inoculation.
  • the culture medium pH may increase or decrease.
  • acid or base pH controls can be used to correct alkalinity during the growth phase.
  • Production of the single cell oil is induced in the microorganisms by the imposition of a stationary phase (e.g., by nitrogen depletion, phosphate depletion or a pH rise) .
  • Nitrogen deficiencies are caused by providing the nitrogen source, such as YE, in a limiting amount such that the medium runs out of YE while available glucose remains. It is the carbon source to nitrogen source ratio which promotes the efficient production of the single cell oil .
  • a preferred ratio of carbon source to nitrogen source at inoculation is about 10-15 parts glucose to 1 part nitrogen source. Similar ratios for other carbon and nitrogen sources can be calculated by those of skill in the art.
  • the culture After induction of oil production, the culture is grown for about 24 additional hours. During this period of oleosynthesis, the single cell oil containing DHA is being synthesized and visible oil droplets become apparent within the cells.
  • Those of skill in the art can readily calculate the time of fermentation required to achieve the expected amount of cell biomass based upon the added amount of nitrogen source. When that time has passed, the culture is grown for an additional 24 hours and harvested. In general, the microorganisms are cultivated for a time sufficient to produce single cell oil, usually from about 60 to about 90 hours, although this time is subject to variation.
  • the resultant biomass comprises extractable oil .
  • Strain selection can increase this percentage and such selection is within the capabilities of one with ordinary skill in the art.
  • the oil comprises greater than about 70% triglycerides.
  • the oil can have, in general, the following fatty acid composition. 15-20% myristic acid (C 14:0 )
  • the crude oil is characterized by a yellow-orange color and is liquid at room temperature. Desirably, the oil contains at least about 20% DHA by weight, preferably at least about 40% DHA by weight, and most preferably about 50% DHA by weight.
  • the organisms are harvested by conventional means, known to those of skill in the art, such as centrifugation, flocculation or filtration, and can be processed immediately or dried for future processing. In either event, the oil can be extracted readily with an effective amount of solvent. Suitable solvents can be determined by those of skill in the art. However, preferred solvents include pure hexane and supercritical fluids, such as supercritical C0 2 .
  • Certain lipophilic antioxidants can be added prior to extraction. These compounds help protect the oil from oxidation during the extraction and refining processes.
  • a suitable ratio of hexane to dry biomass is about 4 liters of hexane per kilogram of dry biomass.
  • the hexane preferably is mixed with the biomass in a stirred reaction vessel at a temperature of about 20-50°C for about 2 hours. After mixing, the biomass is filtered and separated from the hexane containing the oil .
  • a wet biomass paste (30-35% solids) can be extracted directly with more polar solvents, such as ethanol, isopropanol or hexane/isopropanol mixtures. The solvent then is removed from the oil by distillation techniques known to those of skill in the art.
  • Conventional oilseed processing equipment is suitable to perform the filtering, separation and distillation. Additional processing steps, known to those of skill in the art, can be performed if required or desirable for a particular application. These steps also will be similar to those involved in conventional vegetable oil processing and allow the separation of DHA-enriched polar lipid fractions.
  • compositions containing DHA can be formulated in a conventional manner for administration by any suitable route.
  • suitable routes of administration include, but are not limited to, oral, nasal, topical, and parenteral (including subcutaneous, intramuscular, intravenous and intradermal) , with oral or parenteral being preferred. It will be appreciated that the preferred route can vary with the condition and age of the recipient .
  • DHA oil While not essential, it is preferable for the DHA oil to be administered as part of a pharmaceutical formulation.
  • the formulations of the present invention comprise DHA together with one or more pharmaceutically acceptable carriers and optionally with other therapeutic ingredients.
  • the carrier(s) are "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the formulations include those suitable for oral, nasal, topical, or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the formulations conveniently can be presented in unit dosage form, e.g., emulsions, tablets and sustained release capsules, and can be prepared by any suitable pharmaceutical methods.
  • Such methods include, but are not limited to, the step of bringing DHA oil into association with the pharmaceutically-acceptable carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association DHA with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the present invention suitable for oral administration can be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of DHA; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, etc.
  • the oils also can be administered by adding the purified and sterilized oil to a prepared enteral formula which then is placed in the feeding tube of a patient who is unable to swallow.
  • formulations of the present invention are administered via gel capsules or oil-in- water liquid emulsions.
  • Example 4 below describes one way to produce suitable gel capsules for administration of the formulations of the present invention.
  • a tablet can be made by compression or molding the DHA oil with one or more pharmaceutically-acceptable, dry, inert accessory ingredients such as carboxymethylcellulose.
  • Compressed tablets can be prepared by compressing in a suitable machine DHA, mixed with a powder or granules, binder, lubricant, inert diluent, preservative and/or surface-active or dispersing agent in accordance with conventional tableting procedures.
  • the tablets optionally can be coated or scored and can be formulated so as to provide slow or controlled release of the active ingredient therein.
  • compositions suitable for oral administration include lozenges comprising DHA in a flavored basis, such as sucrose and acacia or tragacanth; and pastilles comprising DHA in an inert basis such as gelatin and glycerin, or sucrose and acacia.
  • Suitable formulations for oral administration of DHA containing oils also include dietary supplements and/or food products made with DHA containing oils.
  • DHA containing oils can be incorporated into food products such as cookies or biscuits, and these food products can be given to patients in need of coronary vascular disease treatment.
  • DHA containing oils can be used to supplement, or can be used instead of, typical cooking oils during the preparation of food products and/or dietary supplements.
  • Formulations suitable for topical administration to the skin can be presented as ointments, creams, gels and pastes comprising DHA and a pharmaceutically acceptable carrier.
  • a preferred topical delivery system is a transdermal patch containing the oil to be administered.
  • the carrier is a liquid, such as those used in a conventional nasal spray or nasal drops.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which optionally can contain pharmaceutically-acceptable anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient and aqueous and non-aqueous sterile suspensions which can include suspending agents and thickening agents.
  • the formulations can be presented in unit-dose or multi- dose containers, for example, sealed ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • sterile liquid carrier for example water for injections
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described.
  • formulations of this invention can include other suitable agents having regard to the type of formulation in question.
  • suitable formulations of DHA-containing oils for oral administration can include flavoring agents.
  • compositions of the present invention are formulated into doses which will provide a serum cholesterol reducing effective amount of DHA.
  • a useful daily dose is within a range from about 0.50 to about 100 mg per kg of body weight of recipient per day (mg/kg/day) , preferably from about 5 to about 50 mg/kg/day.
  • the acceptable daily dose of DHA may be conveniently administered by giving the DHA oil in 1 to 3 doses per day.
  • the precise dose administered will depend on the age and condition of the recipient. Once a patient's blood cholesterol level has been brought within the normal range, as defined by the American Medical Association for the patient's sex and age, through the administration of the DHA-containing single cell oil, the patient desirably continues to take the medication at a dose rate to maintain his cholesterol within a desirable range.
  • the agitation tip speed was increased to 175 cm/sec and at 55 hours to 225 cm/sec. At 76 hours, the tip speed was decreased to 150 cm/sec and the culture was permitted to grow for an additional time sufficient to convert the final charge of glucose into cellular oil. The culture then was harvested. The harvested cells were dried to about a 4% moisture content. Hexane was added to the dried biomass and stirred in a glass kettle for 2 hours at 25°C. A rotary evaporator was used to remove the hexane, producing about 700 g of crude DHA-containing oil.
  • Example 2 Into a 15,000 liter fermenter (10,000 L net volume) was loaded 60 kg of yeast extract, 45 kg of NaCl, 12.3 kg of MgS0 4 »7H 2 0, and 0.9 kg of CaCl 2 »H 2 0 in 7,000 L of water. This solution was sterilized before adding 3,000 L of a separately sterilized glucose solution (650 kg glucose per 3,000 L) . The initial pH was set to 6.3, the temperature to 28°C, aeration to 0.5-1.0 wm, vessel back pressure to 0.2 bar, and agitation to 120 cm/sec (tip speed) before inoculating the vessel with 300 L of an inoculum culture of C.
  • the fermentor was cooled to 17°C and the fermentation broth was processed through a centrifuge producing 608 kg of a slurry containing 25% solids.
  • the slurry was spray dried producing about 150 kg dry algal powder which contained about 30-40 kg of oil with a DHA content of 40-45%.
  • the dry algal powder (5% moisture content) was extracted with hexane using standard vegetable oil extraction equipment and methods and desolventized crude oil was degummed by the addition of water at 50°C.
  • the degummed oil was collected by centrifugation and refined by mixing with caustic and phosphoric acid at 55°C for one hr.
  • the refined and degummed oil was then collected by centrifugation and gently bleached at 90°C by the additional of citric acid and bleaching clay. Filtration of the bleaching clay produced the refined/bleached oil (RB-oil) with a peroxide value of less than 5 mEq/kg.
  • the RB oil then was deodorized by high vacuum short path distillation and the resulting deodorized RB-oil (RBD-oil) was then ready for encapsulation, tableting, or bulk shipping.
  • the resulting oil had a peroxide value less than 1 mEq/kg, a free fatty acid content of less than 0.5%, a DHA content of 45-47%, and an iodine number of about 200.
  • Example 3 Into a 1.7 L STF was loaded 2.5 g NaCl, 5 g
  • a sterile solution containing 10 ⁇ g thyamine-Hcl, 0.1 g NaHC0 3 , and lO ⁇ g vitamin b 12 was added, followed by 150 ml of sterile 30% glucose and 50 ml of sterile 10% yeast extract.
  • the pH was adjusted to 6.0, the sparging to 1.0 wm, and agitation to 300 rpm before inoculation with 100 ml of a 5-day old shake flask culture of Thraustochytrium areum grown in the same medium.
  • the culture was harvested after 9 days to yield about 4 g dry weight of biomass.
  • the DHA content of the lipid in the biomass was 10-15%.
  • Example 4 The DHA-rich oil was prepared for oral use by either encapsulating or tableting. Clear sealed gelatin capsules of 1 g/capsule were prepared by conventional manufacturing methods. Banded gel caps containing DHA-rich microbial oil (45% DHA) were prepared by allotting 250 ⁇ L of oil in the gel cap bottoms using a positive displacement manifold pipetter.
  • the tops were then placed over the gel caps and they were banded with dyed gelatin using a capsule banding machine.
  • the gel cap bottoms were filled with carboxymethylcellulose (CMC) and 100 mg (120 ⁇ L) of oil were pipetted directly onto this binder where it was adsorbed preventing any leakage.
  • the tops were then placed over the gel caps and they were banded with dyed gelatin using a capsule banding machine.
  • the CMC was mixed with the oil (three parts CMC to one part oil) in a separate container and pressed into tablets using a tablet press.
  • Example 5 Treatment of hypercholesterolemia using DHA-rich oil from C. cohnii is initiated by providing 1000 mg gel caps (containing about 450 mg DHA per capsule) at a dose of 3-9 capsules per day, three times per day with meals. Treatment continues until serum cholesterol drops to normal levels for age and sex as determined by the American Heart Association. Once reaching normal cholesterol levels, a dose regimen of a single 1000 mg gel cap per day can be used in order to maintain the normal cholesterol levels.

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Abstract

L'invention concerne un procédé permettant de traiter une coronaropathie chez un homme. Ledit procédé comprend l'administration, audit homme, d'une quantité efficace d'une huile contenant du DHA, produite par un organisme unicellulaire, réduisant le taux de cholestérol sérique.
PCT/US1994/006316 1993-06-04 1994-06-02 Procede permettant le traitement d'une coronaropathie au moyen d'acide docosahexaenoique Ceased WO1994028891A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU70534/94A AU7053494A (en) 1993-06-04 1994-06-02 Method of treating coronary vascular disease using docosahexaenoic acid

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US7093093A 1993-06-04 1993-06-04
US08/070,930 1993-06-04

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US8188146B2 (en) 1999-01-27 2012-05-29 Amarin Corporation Plc. Highly purified ethyl EPA and other EPA derivatives
US8202907B2 (en) 2004-09-17 2012-06-19 Suntory Holdings Limited Composition with preventive or improvement effect on symptoms or diseases associated with stress-induced behavior disorders
US8293728B2 (en) 2009-02-10 2012-10-23 Amarin Pharmaceuticals Ireland Limited Methods of treating hypertriglyceridemia
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2098065A (en) * 1981-04-14 1982-11-17 Nippon Suisan Kaisha Ltd Antithrombotic compositions containing docosahexaenoic acid
US5012761A (en) * 1988-11-17 1991-05-07 Oh Suk Y Chicken egg having relatively high percentage of long chain fatty acids and method of reducing heart related disease in humans using such eggs
US5130242A (en) * 1988-09-07 1992-07-14 Phycotech, Inc. Process for the heterotrophic production of microbial products with high concentrations of omega-3 highly unsaturated fatty acids

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2098065A (en) * 1981-04-14 1982-11-17 Nippon Suisan Kaisha Ltd Antithrombotic compositions containing docosahexaenoic acid
US5130242A (en) * 1988-09-07 1992-07-14 Phycotech, Inc. Process for the heterotrophic production of microbial products with high concentrations of omega-3 highly unsaturated fatty acids
US5012761A (en) * 1988-11-17 1991-05-07 Oh Suk Y Chicken egg having relatively high percentage of long chain fatty acids and method of reducing heart related disease in humans using such eggs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
EXCERPTA MEDICA AMSTERDAM, issued 1993, IKEDA et al., "Differential Effect of Detary Docosahesaenoic and Eicosapentaenoic Acids on Lipid Metabolism in Rats", pages 223-26. *

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