WO2012112902A1 - Procédé de préparation d'acides gras polyinsaturés libres - Google Patents

Procédé de préparation d'acides gras polyinsaturés libres Download PDF

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Publication number
WO2012112902A1
WO2012112902A1 PCT/US2012/025666 US2012025666W WO2012112902A1 WO 2012112902 A1 WO2012112902 A1 WO 2012112902A1 US 2012025666 W US2012025666 W US 2012025666W WO 2012112902 A1 WO2012112902 A1 WO 2012112902A1
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WO
WIPO (PCT)
Prior art keywords
dha
acid
oil
fatty acid
fatty acids
Prior art date
Application number
PCT/US2012/025666
Other languages
English (en)
Inventor
Xuejun Tang
Original Assignee
Martek Biosciences Corporation
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 Martek Biosciences Corporation filed Critical Martek Biosciences Corporation
Publication of WO2012112902A1 publication Critical patent/WO2012112902A1/fr

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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
    • A61K31/185—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
    • A61K31/202—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 having three or more double bonds, e.g. linolenic
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11C—FATTY ACIDS FROM FATS, OILS OR WAXES; CANDLES; FATS, OILS OR FATTY ACIDS BY CHEMICAL MODIFICATION OF FATS, OILS, OR FATTY ACIDS OBTAINED THEREFROM
    • C11C1/00—Preparation of fatty acids from fats, fatty oils, or waxes; Refining the fatty acids
    • C11C1/007—Preparation of fatty acids from fats, fatty oils, or waxes; Refining the fatty acids using organic solvents
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11C—FATTY ACIDS FROM FATS, OILS OR WAXES; CANDLES; FATS, OILS OR FATTY ACIDS BY CHEMICAL MODIFICATION OF FATS, OILS, OR FATTY ACIDS OBTAINED THEREFROM
    • C11C1/00—Preparation of fatty acids from fats, fatty oils, or waxes; Refining the fatty acids
    • C11C1/02—Preparation of fatty acids from fats, fatty oils, or waxes; Refining the fatty acids from fats or fatty oils
    • C11C1/025—Preparation of fatty acids from fats, fatty oils, or waxes; Refining the fatty acids from fats or fatty oils by saponification and release of fatty acids
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11C—FATTY ACIDS FROM FATS, OILS OR WAXES; CANDLES; FATS, OILS OR FATTY ACIDS BY CHEMICAL MODIFICATION OF FATS, OILS, OR FATTY ACIDS OBTAINED THEREFROM
    • C11C3/00—Fats, oils, or fatty acids by chemical modification of fats, oils, or fatty acids obtained therefrom
    • C11C3/003—Fats, oils, or fatty acids by chemical modification of fats, oils, or fatty acids obtained therefrom by esterification of fatty acids with alcohols

Definitions

  • the free fatty acid product comprises DHA.
  • Some embodiments provided herein also provide an efficient process to achieve polyunsaturated fatty acid esters, free fatty acids, and triglycerides in high purity without lengthy distillation cycles.
  • animal sources include aquatic animals (e.g., fish, marine mammals; crustaceans such as krill and other euphausids; rotifers, etc.) and lipids extracted from animal tissues (e.g., brain, liver, eyes, etc.) and animal products such as eggs or milk.
  • plant sources include macroalgae, flaxseeds, rapeseeds, corn, evening primrose, soy and borage.
  • microorganisms include microalgae, protists, bacteria and fungi (including yeast).
  • the composition of DHA is a microbial oil or is derived from microbial oil.
  • exemplary microbes, from which microbial oil may be obtained include, among others, the microbial groups Stramenopiles, Thraustochytrids, and Labrinthulids.
  • the Thraustochytrids include the genera Schizochytrium (species include aggregatum, limnaceum, mangrovei, minutum, octosporum), Thraustochytrium (species include arudimentale, aureum, benthicola, globosum, kinnei, motivum, multirudimentale, pachydermum, proliferum, roseum, striatum), Ulkenia (species include amoeboidea, kerguelensis, minuta, profunda, radiate, sailens, sarkariana, schizochytrops, visurgensis, yorkensis), Aplanochytrium (species include haliotidis, kerguelensis, profunda, stocchinoi), Japonochytrium (species include marinum), Althornia (species include crouchii), and Elina (species include marisalba, sinorifica).
  • the microbial oil source is oleaginous microorganisms, such as certain marine algae.
  • oleaginous microorganisms are defined as microorganisms capable of accumulating greater than 20% of the dry weight of their cells in the form of lipids.
  • the DHA is derived from a phototrophic or heterotrophic single cell organism or multicellular organism, e.g., an algae.
  • the DHA may be derived from a diatom, e.g., a marine dinoflagellates (algae), such as Crypthecodinium sp., Thraustochytrium sp., Schizochytrium sp., or combinations thereof.
  • a diatom e.g., a marine dinoflagellates (algae)
  • algae marine dinoflagellates
  • Exemplary samples of C. cohnii have been deposited with the American Type Culture Collection at Rockville, MD, and assigned the accession numbers 40750, 30021, 30334-30348, 3054130543, 30555-30557, 30571, 30572, 30772-30775, 30812, 40750, 50050-50060, and 50297-50300.
  • the ester is a carboxylic acid protective ester group, esters with aralkyl (e.g., benzyl, phenethyl), esters with lower alkenyl (e.g., allyl, 2-butenyl), esters with lower-alkoxy-lower-alkyl (e.g., methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl), esters with lower-alkanoyloxy-lower- alkyl (e.g., acetoxymethyl, pivaloyloxymethyl, 1-pivaloyloxyethyl), esters with lower- alkoxycarbonyl-lower-alkyl (e.g., methoxycarbonylmethyl, isopropoxycarbonylmethyl), esters with carboxy-lower alkyl (e.g., carboxymethyl), esters with lower- alkoxycarbonyloxy-lower-alkyl (e.g., l-
  • Microbial oils useful in the present invention can be recovered from microbial sources by any suitable means known to those in the art.
  • the oils can be recovered by extraction with solvents such as chloroform, hexane, methylene chloride, methanol and the like, or by supercritical fluid extraction.
  • the oils can be extracted using extraction techniques, such as are described in U.S. Pat. No. 6,750,048 and International Pub. No. WO 2001/053512, both filed Jan. 19, 2001, and entitled "Solventless extraction process," both of which are incorporated herein by reference in their entirety. Processes for the preparation of various forms of DHA are also described in, among others, US Patent Publication No.
  • the undiluted DHA oil can be enriched by cold fractionation (resulting in oil containing about 60% w/w of DHA triglyceride), which DHA fraction optionally can be transesterified, and subjected to further downstream processing to produce the active DHA of the invention.
  • downstream processing of the oil comprises distillation and/or silica refinement.
  • the following steps can be used.: fermentation of a DHA producing microorganism; harvesting the biomass; spray drying the biomass; extracting oil from the biomass; refining the oil; bleaching the oil; chill filtering the oil; deodorizing the oil; and adding an antioxidant to the oil.
  • the microorganism culture can be progressively transferred from smaller scale Kirters to a production size femienter.
  • the culture can be harvested by centrifugation then pasteurized and spray dried, in certain embodiments, the dried biomass can be flushed with nitrogen and packaged before being stored frozen at -20 °C.
  • the weight % of the DHA in the composition of DHA is at least 50 wt% of total wt of fatty acid content, at least 60 wt% of total wt of fatty acid content; at least 70 wt% of total wt of fatty acid content; at least 80 wt% of total wt of fatty acid content; at least 85 wt% of total wt of fatty acid content; at least 90 wt% of total wt of fatty acid content; at least 95 wt% of total wt of fatty acid content; at least 96 wt% of total wt of fatty acid content; at least 97 wt% of total wt of fatty acid content; at least 98 wt% of total wt of fatty acid content; or at least 99 wt% of total wt of fatty acid content.
  • an oil is characterized by one or more the following fatty acids (or esters thereof), expressed as wt% of the total fatty acid content.
  • the embodiments provided herein may further comprise about 2% or less (w/w) of capric acid (CI 0:0).
  • the embodiments provided herein may further comprise about 6% or less (w/w) of lauric acid (C12:0).
  • the embodiments provided herein may further comprise about 20% or less, or about 10 to about 20% (w/w) of myristic acid (C14:0).
  • the embodiments provided herein may further comprise about 15% or less, or about 5 to about 15% (w/w) of palmitic acid (C16:0).
  • DHASCO® is an oil derived from Crypthecodinium cohnii containing high amounts of docosahexaenoic acid (DHA), and more specifically contains the following approximate exemplary amounts of these fatty acids, as a percentage of the total fatty acids: myristic acid (14:0) 10-20%; palmitic acid (16:0) 10-20%; palmitoleic acid (16:1) 0-2%; stearic acid (18:0) 0-2%; oleic acid (18:1) 10-30%; linoleic acid (18:2) 0-5%; arachidic acid (20:0) 0-1%; behenic acid (22:0) 0-1%; docosapentaenoic acid (22:5) 0-1%; docosahexanoic acid (22:6) (DHA) 40-45%; nervonic acid (24:1) 0-2%; and others 0-3%.
  • DHA docosahexaenoic acid
  • the ratio of wt% of DHA to wt% of DPAn6 is about 2.5 to about 2.7.
  • An oil with the preceding characteristics may comprise Life's DHATM (also formerly referenced as DHATM-S and DHASCO®-S), Martek Biosciences, Columbia, MD), an oil derived from the Thraustochytrid, Schizochytrium sp., that contains a high amount of DHA and also contains docosapentaenoic acid (n-6) (DPAn-6).
  • the oil comprises, measured in percentage of free fatty acid, about 35-45% DHA (22:6 n-3); about 0-2% lauric acid (12:0); about 5-10% myristic acid (14:0); about 5-20% palmitic acid (16:0); about 0-5% palmitoleic acid (16:1); about 0-5% stearic acid (18:0); about 0-5% vaccenic acid or oleic acid (18:1 n-7 and n-9, respectively); about 0-2% linoleic acid (18:2, n-6); about 0-5% stearidonic acid (18:4 n- 3); about 0-10% arachidonic acid (20:4 n-3, n-5, or n-6); about 0-2% adrenic acid (22:4 n- 6); about 0-5% DPA n-3 (22:5); about 10-25% DP A n-6 (22:5); and 0-2% 24:0.
  • the filtrate is evaporated in vacuo at 25 °C to 1/6 of the original volume.
  • the concentrated aqueous mixture is diluted with water (1.5 ml/g oil) and acidified with 10 N sulfuric acid (ca 0.25 ml/g oil).
  • the resulting mixture is stirred at room temperature for 2 hours and extracted with hexanes (0.75 ml/g oil, twice).
  • the combined hexanes extracts are washed with saturated sodium chloride (0.25 ml/g oil, twice) and then filtered.
  • the filtrate is evaporated in vacuo at 40 °C and chased with hexanes (0.5 ml/g oil).
  • the oil-like liquid is pumped under high vacuum overnight at room temperature to give a crude DHA free fatty acid with a FAME area percentage of 92-99% in a DHA-based yield of 50-81%.

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Wood Science & Technology (AREA)
  • Organic Chemistry (AREA)
  • Microbiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Fats And Perfumes (AREA)

Abstract

L'invention concerne des procédés de préparation de compositions d'acides gras libres et d'esters alkyliques d'acides gras polyinsaturés (PUFA). Elle concerne également des compositions comprenant un PUFA choisi parmi un acide gras libre ou un ester, le PUFA étant préparé conformément à un procédé de l'invention.
PCT/US2012/025666 2011-02-18 2012-02-17 Procédé de préparation d'acides gras polyinsaturés libres WO2012112902A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161444696P 2011-02-18 2011-02-18
US61/444,696 2011-02-18

Publications (1)

Publication Number Publication Date
WO2012112902A1 true WO2012112902A1 (fr) 2012-08-23

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9050309B2 (en) 2012-01-06 2015-06-09 Omthera Pharmaceuticals, Inc. DPA-enriched compositions of omega-3 polyunsaturated fatty acids in free acid form
US9492545B2 (en) 2012-05-07 2016-11-15 Omthera Pharmaceuticals Inc. Compositions of statins and omega-3 fatty acids
CN107709528A (zh) * 2015-05-13 2018-02-16 艾帕克斯挪威联合股份有限公司 来自天然油的非常长链多不饱和脂肪酸

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2915537A (en) * 1955-10-01 1959-12-01 Meade Edwin Marshall Separation of olefinic fatty acids
US4601856A (en) * 1984-06-12 1986-07-22 Nippon Oil And Fats Company, Limited Method of purifying oleic acid
US4792418A (en) * 1985-08-14 1988-12-20 Century Laboratories, Inc. Method of extraction and purification of polyunsaturated fatty acids from natural sources
US6846942B2 (en) * 2003-05-20 2005-01-25 David Rubin Method for preparing pure EPA and pure DHA

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2915537A (en) * 1955-10-01 1959-12-01 Meade Edwin Marshall Separation of olefinic fatty acids
US4601856A (en) * 1984-06-12 1986-07-22 Nippon Oil And Fats Company, Limited Method of purifying oleic acid
US4792418A (en) * 1985-08-14 1988-12-20 Century Laboratories, Inc. Method of extraction and purification of polyunsaturated fatty acids from natural sources
US6846942B2 (en) * 2003-05-20 2005-01-25 David Rubin Method for preparing pure EPA and pure DHA

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9050309B2 (en) 2012-01-06 2015-06-09 Omthera Pharmaceuticals, Inc. DPA-enriched compositions of omega-3 polyunsaturated fatty acids in free acid form
US9050308B2 (en) 2012-01-06 2015-06-09 Omthera Pharmaceuticals, Inc. DPA-enriched compositions of omega-3 polyunsaturated fatty acids in free acid form
US10117844B2 (en) 2012-01-06 2018-11-06 Omthera Pharmaceuticals, Inc. DPA-enriched compositions of omega-3 polyunsaturated fatty acids in free acid form
US9492545B2 (en) 2012-05-07 2016-11-15 Omthera Pharmaceuticals Inc. Compositions of statins and omega-3 fatty acids
CN107709528A (zh) * 2015-05-13 2018-02-16 艾帕克斯挪威联合股份有限公司 来自天然油的非常长链多不饱和脂肪酸
EP3294850A1 (fr) 2015-05-13 2018-03-21 Epax Norway AS Acides gras polyinsaturés à chaîne très longue
JP2018514644A (ja) * 2015-05-13 2018-06-07 エーパックス ノルウェー アクスイェ セルスカプ 天然油由来の超長鎖多価不飽和脂肪酸
US10501704B2 (en) * 2015-05-13 2019-12-10 Epax Norway As Very long chain polyunsaturated fatty acids from natural oils
AU2016262315B2 (en) * 2015-05-13 2020-09-03 Epax Norway As Very long chain polyunsaturated fatty acids from natural oils
EP3294850B1 (fr) 2015-05-13 2020-09-30 Epax Norway AS Acides gras polyinsaturés à chaîne très longue

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