WO2011067666A1 - Procédé de production de compositions d'acides gras enrichis - Google Patents

Procédé de production de compositions d'acides gras enrichis Download PDF

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Publication number
WO2011067666A1
WO2011067666A1 PCT/IB2010/003182 IB2010003182W WO2011067666A1 WO 2011067666 A1 WO2011067666 A1 WO 2011067666A1 IB 2010003182 W IB2010003182 W IB 2010003182W WO 2011067666 A1 WO2011067666 A1 WO 2011067666A1
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Prior art keywords
fatty acid
lipase
tank
acid
fatty acids
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PCT/IB2010/003182
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English (en)
Inventor
Inge Bruheim
Svein Rye
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Blt Berg Lipidtech As
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Publication of WO2011067666A1 publication Critical patent/WO2011067666A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23D—EDIBLE OILS OR FATS, e.g. MARGARINES, SHORTENINGS, COOKING OILS
    • A23D9/00—Other edible oils or fats, e.g. shortenings, cooking oils
    • A23D9/02—Other edible oils or fats, e.g. shortenings, cooking oils characterised by the production or working-up
    • 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
    • C11C1/04—Preparation of fatty acids from fats, fatty oils, or waxes; Refining the fatty acids from fats or fatty oils by hydrolysis
    • C11C1/045—Preparation of fatty acids from fats, fatty oils, or waxes; Refining the fatty acids from fats or fatty oils by hydrolysis using enzymes or microorganisms, living or dead

Definitions

  • Fatty acids are one source of lipids that may be derived from natural sources including, but not limited to, fish oils or flax seeds.
  • Methods are disclosed herein that provide enrichment of free fatty acids and/or free fatty acid esters by taking advantage of their relative reaction rates with selective lipase enzymes that synthesize glycerides.
  • Compositions resulting from the disclosed methods comprise enriched fatty acid contents including, but not limited to, palmitoleic acid and/or omega-3 fatty acids.
  • Fatty acids are one source of lipids that may be derived from natural sources including, but not limited to, fish oils or flax seeds.
  • Methods are disclosed herein that provide enrichment of free fatty acids and/or free fatty acid esters by taking advantage of their relative reaction rates with selective lipase enzymes that synthesize glycerides.
  • Compositions resulting from the disclosed methods comprise enriched fatty acid contents including, but not limited to, palmitoleic acid and omega-3 fatty acids.
  • the present invention contemplates a composition comprising a substantially purified palmitoleic fatty acid, wherein the concentration of the fatty acid is at least 10%. In one embodiment, the composition further comprises at least 10% omega-3 fatty acids. In one embodiment, the composition comprises at least 20% palmitoleic acid. In one embodiment, the composition comprises at least 30% palmitoleic acid. In one embodiment, the composition comprises a dietary supplement. In one embodiment, the composition comprises a skin care product. In one embodiment, the skin care product comprises a pharmaceutical formulation selected from the group including but not limited to, a liquid, a paste, an oil, an ointment, a cream, or an emulsion.
  • the present invention contemplates a method, comprising: a) providing; i) a controlled flow rate feed tank comprising a starting mixture, wherein said mixture comprises a plurality of free fatty acid compounds and a first glycerol aliquot; ii) a controlled temperature column comprising an immobilized selective lipase capable of creating a final reaction product; iii) a separation tank capable of removing at least one volatile by-product; and iv) a product tank capable of storing the final reaction product; b) contacting said starting mixture with said lipase under conditions such that an enriched free fatty acid starting mixture is created; c) removing at least one volatile by-product from said enriched free fatty acid starting material under conditions such that a preliminary reaction product is created; and d) contacting said preliminary reaction product with said lipase under conditions such that a final reaction product is created.
  • steps (b) and steps (c) are repeated under conditions such that said preliminary reaction product is used as said starting mixture.
  • the method further comprises providing a second glycerol aliquot.
  • the method further comprises providing a purification tank capable of creating a free fatty acid fraction and a glyceride fraction.
  • the method further comprises step e) purifying said final reaction product in said purification tank under conditions such that a free fatty acid fraction and a glyceride fraction are created, wherein said fractions comprise enriched free fatty acids as compared to said starting material.
  • the purifying comprises distillation.
  • the purifying comprises chromatography.
  • the purifying comprises extraction.
  • the selective lipase comprises a 1, 3 - glycerol selective lipase.
  • the free fatty acid compound comprises a fatty acid alkyl ester. In one embodiment, said free fatty acid compound comprises a fatty acid branched alkyl ester. In one embodiment, said free fatty acid compound comprises an unsaturated fatty acid alkyl ester. In one embodiment, the free fatty acid compound comprises an organic acid. In one embodiment, the free fatty acid compound comprises an aliphatic acid. In one embodiment, the final reaction product comprises a glyceride fraction. In one embodiment, the free fatty acid fraction comprises an omega-3 fatty acid at a 25% greater concentration as compared to said starting material.
  • the glyceride fraction comprises a palmitoleic fatty acid at a 4 - 6 fold greater concentration as compared to said starting material.
  • the starting material is an oil derived from a source selected from the group consisting of a fish, vegetables, animals, algae, fungi, or crustaceans. In one embodiment, the invention does not require the addition of water.
  • the starting mixture comprises trout oil. In one embodiment, the starting mixture comprises a DPA rich source. In one embodiment, the starting mixture comprises a single distilled ethyl ester fraction. In one embodiment, the starting mixture comprises ethyl ester fraction previously enriched.
  • the lipase comprises lipase RM-IM from Rhizomucor miehei. In one embodiment, the lipase comprises used lipase enzyme.
  • the present invention contemplates a method, comprising: a) providing; i) a controlled flow rate feed tank comprising a starting mixture, wherein said mixture comprises a plurality of free fatty acid compounds and glycerol; ii) a controlled temperature column comprising an immobilized selective lipase capable of creating a final reaction product; iii) a flash evaporator tank capable of creating a preliminary reaction product; iv) a product tank capable of storing the final reaction product; v) a distillation tank capable of creating a free fatty acid distillate fraction and a glyceride by-product fraction; and b) contacting said starting mixture with said lipase under conditions such that an enriched free fatty acid starting mixture is created; c) flash evaporating said enriched free fatty acid starting material in said flash evaporator tank under conditions such that a preliminary reaction product is created; d) contacting said preliminary reaction product with said lipase under conditions such that a final reaction product is
  • the method further comprises repeating steps (b) and steps (c) under conditions such that said preliminary reaction product is used as said starting mixture.
  • the selective lipase comprises a 1 , 3 - glycerol selective lipase.
  • the free fatty acid compound comprises a fatty acid alkyl ester. In one embodiment, said free fatty acid compound comprises a fatty acid branched alkyl ester. In one embodiment, said free fatty acid compound comprises an unsaturated fatty acid alkyl ester. In one embodiment, the free fatty acid compound comprises an organic acid. In one embodiment, the free fatty acid compound comprises an aliphatic acid. In one embodiment, the final reaction product comprises a glyceride fraction.
  • the free fatty acid fraction comprises an omega-3 fatty acid at a 4-8 fold greater concentration as compared to said starting material.
  • the glyceride fraction comprises a palmitoleic fatty acid at a 3 - 6 fold greater concentration as compared to said starting material.
  • the starting material is an oil derived from a source selected from the group consisting of a fish, vegetables, animals, algae, fungi, or crustaceans.
  • the invention does not require the addition of water.
  • the starting mixture comprises trout oil.
  • the starting mixture comprises a DPA rich source.
  • the starting mixture comprises a single distilled ethyl ester fraction.
  • the starting mixture comprises ethyl ester fraction previously enriched.
  • the lipase comprises lipase RM-IM from Rhizomucor miehei. In one embodiment, the lipase comprises used lipase enzyme.
  • the invention relates to a method, comprising: a) providing; i) a controlled flow rate feed tank comprising a starting mixture, wherein said mixture comprises a plurality of free fatty acid compounds and a first glycerol aliquot; ii) a controlled temperature column comprising an immobilized selective lipase capable of creating a final reaction product; and iii) a separation tank capable of removing at least one volatile byproduct; b) contacting said starting mixture with said lipase under conditions such that an enriched free fatty acid starting mixture is created; c) removing at least one volatile byproduct from said enriched free fatty acid starting material under conditions such that a preliminary reaction product is created; and d) contacting said preliminary reaction product with said lipase under conditions such that a final reaction product is created.
  • steps (b) and steps (c) are repeated under conditions such that said preliminary reaction product is used as said starting mixture.
  • the present invention contemplates a system, comprising: a) a column comprising an immobilized selective lipase, wherein said column is configured to control the temperature of said lipase; b) a feed tank in fluidic communication with said column, wherein said feed tank is configured to control the flow rate of a starting material from said feed tank to said column; c) a separation tank in fluidic communication with said column and said feed tank, wherein said separation tank is configured to operate under a vacuum; d) a product tank in fluidic communication with said column, wherein said product tank is capable of storing a final reaction product.
  • the system further comprises a purification tank capable of receiving said final reaction product.
  • the purification tank comprises a molecular distillation tank. In one embodiment, the purification tank comprises a chromatography tank. In one embodiment, the separation tank comprises an evaporation tank. In one embodiment, the evaporation tank comprises a flash evaporation tank. In one embodiment, the starting mixture comprises fish oil. In one embodiment, the invention does not require the addition of water. In one embodiment, the starting mixture comprises trout oil. In one embodiment, the starting mixture comprises a DPA rich source. In one embodiment, the starting mixture comprises a single distilled ethyl ester fraction. In one embodiment, the starting mixture comprises ethyl ester fraction previously enriched. In one embodiment, the lipase comprises lipase RM-IM from Rhizomucor miehei. In one embodiment, the lipase comprises used lipase enzyme.
  • the present invention contemplates a system, comprising: a) a column comprising an immobilized selective lipase, wherein said column is configured to control the temperature of said lipase; b) a feed tank in fluidic communication with said column, wherein said feed tank is configured to control the flow rate of a starting material from said feed tank to said column; and c) a separation tank in fluidic communication with said column and said feed tank, wherein said separation tank is configured to operate under a vacuum.
  • the present invention contemplates a system, comprising: a) a column comprising an immobilized selective lipase, wherein said column is configured to control the temperature of said lipase; b) a feed tank in fluidic communication with said column, wherein said feed tank is configured to control the flow rate of a starting material from said feed tank to said column; c) a flash evaporation tank in fluidic communication with said column and said feed tank, wherein said flash evaporation tank is configured to operate under a vacuum; d) a product tank in fluidic communication with said column, wherein said product tank is capable of storing a final reaction product; and e) a distillation tank capable of receiving said final reaction product from said product tank, wherein said distillation tank is capable of creating a free fatty acid fraction and a glyceride fraction.
  • the starting mixture comprises a fish oil.
  • the free fatty acid fraction comprises omega-3 fatty acids.
  • the glyceride fraction comprises palmitoleic acid.
  • the invention does not require the addition of water.
  • the starting mixture comprises trout oil.
  • the starting mixture comprises a DPA rich source.
  • the starting mixture comprises a single distilled ethyl ester fraction.
  • the starting mixture comprises ethyl ester fraction previously enriched.
  • the lipase comprises lipase RM-IM from Rhizomucor miehei.
  • the lipase comprises used lipase enzyme.
  • controlled flow refers to the ability to provide fluidic communication from one location to another at a predictable and stable rate.
  • controlled temperature refers to the ability to provide an environment that is maintained at a predictable and stable temperature (i.e., for example, ⁇ 0.1° C).
  • feed tank refers to any container comprising and inlet and an outlet, wherein an attached pump is capable of maintaining a controlled flow of a liquid contained therein.
  • column refers to any container having an inlet and an outlet comprising a substrate capable of immobilizing enzymes under conditions of controlled temperature and controlled flow of a liquid contained therein.
  • separation tank refers to any container having an inlet and an outlet configured with a vacuum device capable of generating a partial vaporization of a saturated liquid stream.
  • the tank may undergo a reduction in pressure (i.e., for example, by passing the liquid stream through a throttling valve or other throttling device).
  • a separation tank may be a flash evaporation tank where a throttling valve or device is located at the entry into a pressure vessel so that the flash evaporation occurs within the vessel, then the vessel is often referred to as a flash drum. See, Figure 4.
  • the saturated liquid is a single-component liquid (for example, liquid propane or liquid ammonia), a part of the liquid immediately “flashes” into vapor. Both the vapor and the residual liquid are cooled to the saturation temperature of the liquid at the reduced pressure. This is often referred to as “auto-refrigeration” and is the basis of most conventional vapor compression refrigeration systems.
  • the saturated liquid is a multi-component liquid (for example, a mixture of propane, isobutane and normal butane)
  • the flashed vapor is richer in the more volatile components than is the remaining liquid.
  • product tank refers to any container having an inlet and an outlet that is capable of storing a liquid mixture.
  • the product tank may be temperature controlled in order to optimize the stability of the stored mixture.
  • purification tank refers to any container having an inlet and an outlet that is configured such that different components of a liquid mixture may be separated.
  • the separation may be based upon the application of heat wherein purification occurs as a result of differential vapor pressures between components (i.e., for example, a distillation tank).
  • a component having a higher vapor pressure will convert from liquid to gas first, and exit from the distillation tank (i.e., forming a distillate fraction) before a second component having a lower vapor pressure that remains in the distillation tank).
  • a free fatty acid fraction may be separated from a glyceride fraction because free fatty acids have a lower vapor pressure.
  • the purification tank may take advantage of differential affinities of various compounds for a solid surface (i.e., for example, a chromatography tank). Further, the purification tank may take advantage of differential solubility of various compounds in a liquid medium (i.e., for example, an extraction tank).
  • starting material refers to any liquid mixture comprising a plurality of different or the same fatty acids and a molecule comprising an alcohol residue.
  • a starting material may comprise a fish oil and glycerol.
  • enriched refers to any method or composition that increases the proportion of a pre-existing substance or material.
  • a fish oil composition comprising 10% omega-3 fatty acid may be enriched to approximately 60 % by selective lipase cycling and purification.
  • a fish oil composition comprising a palmitoleic acid may be enriched to approximately 50% by selective lipase cycling.
  • preliminary reaction product refers to any mixture transferred from a separation tank to a feed tank that has passed through a column of immobilized selective lipase enzymes at least once.
  • final reaction product refers to any mixture transferred from a column of immobilized selective lipase enzymes to a product tank that has passed through a separation tank at least once.
  • used lipase enzyme refers to any lipase enzymes which have been previously employed in an enzymatic process at least once.
  • in fluidic communication refers to the ability to transfer a liquid or gaseous material from one component to another without any changes in physical properties of the liquid or gaseous material.
  • vacuum refers to any reduced pressure environment whether produced naturally or artificially.
  • a pump may be attached to a separation tank to create a low pressure area thereby facilitating the removal of highly volatile compound (i.e., for example, low molecular weight alcohols).
  • omega-3 fatty acid refers to polyunsaturated fatty acids that have the final double bond in the hydrocarbon chain between the third and fourth carbon atoms from the methyl end of the molecule.
  • Non-limiting examples of omega-3 fatty acids include, all-cis-9,12,15-octadecatrienoic acid (ALA), all-cis-5,8,l l,14,17-eicosapentaenoic acid (EPA), all-cis-4,7,10,13,16,19-docosahexanoic acid (DHA), all-cis 7,10,13,16,19- docosapentaenoic acid (DP A) and all-cis-6,9,12,15-octadecatetraenoic acid (SDA).
  • ALA all-cis-9,12,15-octadecatrienoic acid
  • EPA all-cis-5,8,l l,14,17-eicosapentaenoic acid
  • fish oil refers to any oil obtained from a marine source (e.g. tuna oil, seal oil, squid oil and algae oil).
  • lipase refers to any enzyme capable of hydrolyzing fatty acid esters.
  • a “selective lipase” may be used to breakdown fats or oils that results in the esterification of available alcohol residues.
  • the reaction may result in the esterification of a glycerol with a free fatty acid.
  • a 1 ,3 glycerol lipase reaction may result in the esterification of the 1 and 3 hydroxyl positions of a glycerol molecule, thereby creating a did-glyceride molecule.
  • Sugar et al. "Process for producing partial glyceride" United States Patent 6,337,414 (herein incorporated by reference) [1].
  • fatty acid alkyl ester refers to a derivative of a fatty acid.
  • the fatty acid has a chain length from 1 to 24 carbons and double bonds ranging from 0 to 6.
  • the derivative can be an alkyl group with 1 to 12 carbons. Any alkyl group found suitable is contemplated such as branched, unsaturated and substituted alkyl chains.
  • fatty acid refers to any organic compound comprising carbon, hydrogen and oxygen that is capable of forming an ester bond with an alcohol residue.
  • Fatty acids are generally classified as either saturated or unsaturated fatty acids.
  • a fatty acid may become esterified with a glycerol molecule to form a fat molecule (i.e., for example, a glyceride).
  • a fatty acid may form a phosphodiester bond with phosphatidic acid moiety to from a phospholipid molecule (i.e., for example, phosphatidylcholine).
  • Fatty acids may be derived from any organism including, but not limited to, animals, fish, crustaceans, vegetables, bacteria, or fungi.
  • aliphatic fatty acid refers to any saturated fatty acid generally defined as C n H 2n+ iCOOH (i.e., for example, lauric acid) containing a single carboxyl group. Saturated aliphatic fatty acids may occur naturally, usually in the form of esters in fats, waxes, and essential oils.
  • organic acid fatty acid refers to any saturated or unsaturated organic acid (i.e., for example, palmitic acid) that has a single carboxyl group and usually an even number of carbon atoms and that occur naturally in the form of glycerides in fats and fatty oils.
  • omega-6 fatty acid refers to polyunsaturated fatty acids that have the final double bond in the hydrocarbon chain between the sixth and seventh carbon atoms from the methyl end of the molecule.
  • Non-limiting examples of omega-6 fatty acids include, all-cis-6,9,12-octadecatrienoic acid (GLA), all-cis 5,8,11,14 eicosatetrenoic acid (ARA) and all- cis-9,12-octadecadienoic acid (LA).
  • alcohol refers to any compound which comprises an OH group.
  • Non-limiting examples of alcohols include glycerol, propylene glycol, glucose, ethanol, methanol, or hexanol.
  • free fatty acid refers to a fatty acid that is not attached to a core molecule such as glycerol (i.e., a glyceride) or a phosphatidic acid (i.e., a phospholipid).
  • glycerol i.e., a glyceride
  • phosphatidic acid i.e., a phospholipid
  • alcohol residue refers to any reactive -OH group on a molecule.
  • molecules may include, but are not limited to, glycerol, propylene glycol, carbohydrates, or any aliphatic alcohol (i.e., for example, methanol, ethanol, propanol, etc.)
  • At risk for refers to a medical condition or set of medical conditions exhibited by a patient which may predispose the patient to a particular disease or affliction.
  • these conditions may result from influences that include, but are not limited to, behavioral, emotional, chemical, biochemical, or environmental influences.
  • the data obtained from these cell culture assays and additional animal studies can be used in formulating a range of dosage for human use.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 5 0 with little or no toxicity.
  • the dosage varies within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
  • symptom refers to any subjective or objective evidence of disease or physical disturbance observed by the patient.
  • subjective evidence is usually based upon patient self-reporting and may include, but is not limited to, pain, headache, visual disturbances, nausea and/or vomiting.
  • objective evidence is usually a result of medical testing including, but not limited to, body temperature, complete blood count, lipid panels, thyroid panels, blood pressure, heart rate, electrocardiogram, tissue and/or body imaging scans.
  • disease refers to any impairment of the normal state of the living animal or plant body or one of its parts that interrupts or modifies the performance of the vital functions. Typically manifested by distinguishing signs and symptoms, it is usually a response to: i) environmental factors (as malnutrition, industrial hazards, or climate); ii) specific infective agents (as worms, bacteria, or viruses); iii) inherent defects of the organism (as genetic anomalies); and/or iv) combinations of these factors
  • Attachment refers to any interaction between a medium (or carrier) and a drug. Attachment may be reversible or irreversible. Such attachment includes, but is not limited to, covalent bonding, ionic bonding, Van der Waals forces or friction, and the like.
  • administering refers to any method of providing a composition to a patient such that the composition has its intended effect on the patient.
  • one method of administering is by an indirect mechanism using a medical device such as, but not limited to a catheter, applicator gun, syringe etc.
  • a second exemplary method of administering is by a direct mechanism such as, local tissue administration (i.e., for example, extravascular placement), oral ingestion, transdermal patch, topical, inhalation, suppository etc.
  • patient is a human or animal and need not be hospitalized.
  • out-patients persons in nursing homes are "patients.”
  • a patient may comprise any age of a human or non-human animal and therefore includes both adult and juveniles (i.e., children). It is not intended that the term "patient” connote a need for medical treatment, therefore, a patient may voluntarily or involuntarily be part of experimentation whether clinical or in support of basic science studies.
  • affinity refers to any attractive force between substances or particles that causes them to enter into and remain in chemical combination.
  • an inhibitor compound that has a high affinity for a receptor will provide greater efficacy in preventing the receptor from interacting with its natural ligands, than an inhibitor with a low affinity.
  • derived from refers to the source of a compound or sequence.
  • a compound or sequence may be derived from an organism or particular species.
  • a compound or sequence may be derived from a larger complex or sequence.
  • pharmaceutically or “pharmacologically acceptable”, as used herein, refer to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human.
  • purified may refer to a peptide composition that has been subjected to treatment (i.e., for example, fractionation) to remove various other components, and which composition substantially retains its expressed biological activity.
  • substantially purified this designation will refer to a composition in which the protein or peptide forms the major component of the composition, such as constituting about 50%, about 60%, about 70%, about 80%, about 90%, about 95% or more of the composition (i.e., for example, weight/weight and/or weight/volume).
  • purified to homogeneity is used to include compositions that have been purified to 'apparent homogeneity” such that there is single protein species (i.e., for example, based upon SDS-PAGE or HPLC analysis).
  • a purified composition is not intended to mean that some trace impurities may remain.
  • substantially purified refers to molecules, either nucleic or amino acid sequences, that are removed from their natural environment, isolated or separated, and are at least 60% free, preferably 75% free, and more preferably 90% free from other components with which they are naturally associated.
  • An "isolated polynucleotide” is therefore a substantially purified polynucleotide.
  • dietary supplement or “nutraceutical” refers to any composition derived from a foodstuff that is believed to provide health or medical benefits in addition to its basic nutritional value.
  • a supplement or nutraceutical may comprise one or more fatty acids derived from biological sources including, but not limited to, fish oils, vegetable oils, fungal oils, algal oils, or animal fat oils.
  • Figure 1 presents one embodiment of a system comprising a continuous enzyme packed bed reactor.
  • Figure 2 presents two embodiments of omega-3 fatty acids.
  • Panel A Eicosapntaenoic acid (EPA).
  • Panel B Docosahexaenoic acid (DHA).
  • Figure 4 presents one embodiment of a separation tank.
  • Fatty acids are one source of lipids that may be derived from natural sources including, but not limited to, fish oils or flax seeds.
  • Methods are disclosed herein that provide enrichment of free fatty acids and/or free fatty acid esters by taking advantage of their relative reaction rates with selective lipase enzymes that synthesize glycerides.
  • Compositions resulting from the disclosed methods comprise enriched fatty acid contents including, but not limited to, palmitoleic acid and omega-3 fatty acids.
  • Fish oil comprises oils derived from the tissues of an oily fish.
  • Fish oil contains significant levels of fatty acids.
  • Representative fish oil may be obtained from fish species including, but not limited to salmon, cod, tuna, anchovies, or sardines. Several methods have been reported to concentrate fish oil fatty acids from their natural state into compositions useful for industrial application.
  • Fish oil is recommended for a healthy diet because it contains the omega-3 fatty acids (i.e., for example, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)) and are believed precursors to eicosanoids that may reduce inflammation throughout the body.
  • omega-3 fatty acids i.e., for example, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • palmitoleic acid a 16:1 (n-7) fatty acid
  • a 16:1 (n-7) fatty acid are commonly found in the fats and oils from most biological organisms, including, but not limited to, plants, animals, fish, and algae.
  • the concentration of naturally occurring palmitoleic acid is generally low, except for a few and rare vegetable sources.
  • the berry pulp from seabuckthorn contains approximately 30% palmitoleic acid (16:1), 30% palmitic acid (16:0), 20% oleic acid, ⁇ 10% cis-vaccenic acid, ⁇ 10%) linoleic acid, and ⁇ 10% linolenic acid.
  • Another example is macadamia nuts having approximately 20-25%) palmitoleic acid.
  • Fish oil may also contain aliphatic fatty acids or organic acid fatty acids, including, but not limited to, decanoic acid (10:0), undecanoic acid (1 1 :0), 10-undecanoic acid (11 :1), lauric acid (12:0), cis-5-dodecanoic acid (12:1), tridecanoic acid (13:0), myristic acid (14:0), myristoleic acid (cis-9-tetradecenoic acid, 14:1), pentadecanoic acid (15:0), palmitic acid (16:0), palmitoleic acid (cis-9-hexadecenoic acid, 16:1), heptadecanoic acid (17:1), stearic acid (18:0), elaidic acid (trans-9-octadecenoic acid, 18: 1), oleic acid (cis-9-octadecanoic acid, 18: 1), nonadecanoic acid (19:0), eicos
  • Palmitoleic acid has been concentrated from fish oil using selective enzymatic hydrolysis followed by crystallization. Cain et al, "Palmitoleic acid and its use in foods" United States Patent No. US 6,461 ,662 (herein incorporated by reference) [5]. For example, palmitoleic acid levels from fish oils typically range from between approximately 4% to 8%.
  • Palmitoleic acid or (Z)-9-hexadecenoic acid
  • is an omega-7 monounsaturated fatty acid with the formula CH 3 (CH 2 ) 5 CH CH(CH 2 ) 7 COOH that is a common constituent of the glycerides of human adipose tissue. See, Figure 3. It is present in all tissues, but generally found in higher concentrations in the liver. It is biosynthesized from palmitic acid by the action of the enzyme delta-9 desaturase.
  • Palmitoleic acid can be abbreviated by 16:1 ⁇ 9.
  • Dietary sources of palmitoleic acid include, but are not limited to, a variety of fish oils, animal oils, vegetable oils, and marine oils. As discussed above, macadamia oil ⁇ Macadamia integrifolia) and sea buckthorn oil (Hippophae rhamnoides) are botanical sources with high palmitoleic acid concentrations (i.e., for example, approximately between 17-40 %. Alternatively, most fish oils comprise palmitoleic acid levels between approximately 5-8%.
  • palmitoleic acid may behave like a saturated fatty acid and not a monounsaturated fatty acid, at least on its effect on LDL cholesterol levels.
  • Palmitoleic acid may act as a signaling molecule to prevent weight gain. This hypothesis is consistent with previous observations that palmitoleic acid is utilized by the enzymes that control fat oxidation at extraordinarily high rates. Power, et al, "The influence of diet on the activity of carnitine palmitoyltransferase 1 toward a range of acyl CoA esters" Lipids 32:31- 37 (1997) [7]. Consequently, it may be speculated that oil types manufactured to contain high palmitoleic acid content might be useful in combating obesity.
  • Palmitoleic acid is a natural component of skin fat and when applied directly to the surface it has a moisturizing effect on the skin.
  • the fatty acid supports cell regeneration and can help heal burns and wounds, and reduce dermatitis and eczema.
  • Most of the research on the effects of palmitoleic acid on skin health has involved seabuckthom oil and macadamia nut oil. These oils contain respectively about 20% and about 30% palmitoleic acid.
  • omega-3 fatty acids have been reported to confer many beneficial effects, but are not readily extracted from vegetable, animal, or algal sources. Fish do not actually produce omega-3 fatty acids, but instead accumulate them from either consuming microalgae that produce these fatty acids, as is the case with fish like herring and sardines, or, as is the case with fatty predatory fish, by eating prey fish that have accumulated omega-3 fatty acids from microalgae.
  • Omega-3 fatty acids i.e., for example, EPA and DHA
  • cold water oily fish such as salmon, herring, mackerel, anchovies and sardines. See, Figure 2.
  • Other types of omega-3 fatty acids are also contemplated for enrichment by embodiments of the present invention. See, Table 1.
  • omega-3 fatty acids include botanical sources.
  • flax seeds (Linum usitatissimum) produce linseed oil that is known to have a very high omega-3 fatty acid content.
  • flax seed may comprise approximately six times more omega-3 fatty acids than most fish oils. Bartram, Thomas, 1998, In: Bartram's Encyclopedia of Herbal Medicine, p. 271 [8].
  • Flaxseed oil comprises approximately 55% ALA (alpha- linolenic acid). 15 grams of flaxseed oil provides ⁇ 8 grams of ALA, which is converted in the body to EPA and then DHA at an efficiency of 5-10% and 2-5%, respectively.
  • Omega-3 fatty acids have been shown in numerous studies to have beneficial effects on a range of conditions such as cardiovascular heart disease, inflammation, metabolic syndrome, improvements in cognitive function in the young and elderly as well as on joint performance.
  • WO2007052162 [9], Breslowet al., Am. J. Clin. Nutr., 83: 1477S-1482S (2006) [10]; and Calder et al, Am. J. Clin. Nutr., 83:1505S-1519S (2006) [11].
  • Symptoms of some cardiovascular diseases comprising circulatory problems (i.e., for example, varicose veins) have been reduced by supplements containing EPA and DHA. It is believed that omega-3 fatty acids stimulate blood circulation, increase the breakdown of fibrin, a compound involved in clot and scar formation, and additionally have been shown to reduce blood pressure.
  • Morris et al "Does fish oil lower blood pressure? A meta-analysis of controlled trials” Circulation 88 (2): 523-533 (1993) [12]; and Mori et al "Docosahexaenoic acid but not eicosapentaenoic acid lowers ambulatory blood pressure and heart rate in humans" Hypertension 34(2): 253-260 (1993) [13].
  • omega-3 fatty acids may reduce blood triglyceride levels. Harris et al, "Omega-3 fatty acids and serum lipoproteins: human studies" Am J Clin Nutr 65 (5 Sup.): 1645S-1654S (1997) [14]; Sanders et al, "Influence of omega-6 versus omega-3 polyunsaturated fatty acids in diets low in saturated fatty acids on plasma lipoproteins and hemostatic factors” Arteriosclerosis, Thrombosis, and Vascular Biology 17:3449-3460 (1997) [15]; Roche et al.,. "Postprandial triacylglycerolaemia: the effect of low-fat dietary treatment with and without fish oil supplementation” Eur J Clin Nutr.
  • Omega-3 fatty acids may reduce prostate tumor growth, slow histopathological progression, and increase survival.
  • Omega-3 fatty acids may reduce prostate tumor growth, slow histopathological progression, and increase survival.
  • Omega-3 fatty acids have been suggested to have beneficial effects for memory- associated diseases including, but not limited to, dementia or Alzheimer's disease.
  • a group of mice were genetically modified to develop accumulation of amyloid and tau proteins in the brain similar to that seen in people with poor memory.
  • the mice were divided into four groups with one group receiving a typical American diet (with high ratio of omega-6 to omega-3 fatty acids being 10: 1).
  • the other three groups were given food with a balanced 1 : 1 omega-6 to omega-3 ratio and two additional groups supplemented with DHA plus long chain omega-6 fatty acids. After three months of feeding, all the DHA supplemented groups were observed to have a lower accumulation of beta amyloid and tau protein.
  • Omega-3 fatty acids have been shown to exert neuroprotective action in experimental models of Parkinson's disease. Mice were give a high omega-3 diet from two to twelve months of age and then treated them with a neurotoxin to induce Parkinson's-like symptoms. The omega-3 group did not develop the neurotoxin-induced decrease of dopamine seen in the control group. Bousquet et al., "Beneficial effects of dietary omega-3 polyunsaturated fatty acid on toxin-induced neuronal degeneration in an animal model of Parkinson's disease" Fed Am Soc Exper Bio J 22: ⁇ 2 ⁇ - ⁇ 225 (2008) [34]. There is preliminary evidence that omega-3 fatty acids supplementation might be helpful in cases of depression and anxiety.
  • the fatty acids in fish oils may be processed and isolated by a number of methods.
  • the direct molecular distillation of fish oil fatty acids is commonly used to increase the concentration of cis-5,8,l l,14,17-eicosapentaenoic acid (EPA) and cis- 4,7,10,13,16,19-docosahexaenoic (DHA).
  • Disadvantages of direct molecular distillation of fish oils include, but are not limited to, a maximum concentration of 70%, and the production of a large amount of by-products.
  • the molecular distillation by-products are depleted of omega-3 fatty acids and usually are enriched in fatty acids such as palmitoleic acids.
  • the molecular distillation by-product i.e., for example, a glyceride fraction
  • the molecular distillation by-product may comprise between approximately 10% - 20% palmitoleic acid (i.e., for example, a 2-4 fold enrichment from crude fish oil).
  • palmitoleic acid levels are higher as compared to natural fish oil, but lower than in oils from seabuckthorn and macadamia nuts.
  • current extraction and purification techniques have (until now) been unable to reconstitute these fatty acids in a commercially available form at these high concentrations.
  • fatty acid ethyl esters could be reacted with a higher alcohol such as hexanol to create fatty acid ethyl esters.
  • Reaction rates between fatty acid ethyl esters and glycerol catalyzed by a selective lipase have been reported to be slow, but may be increased by adding hot steam to the reaction mixture.
  • the reported yield of a fatty acid alkyl ester - glycerol reaction was about 50% and it is therefore not particularly economical beneficial.
  • This invention is not limited to any particular fatty acid alkyl ester.
  • any fatty acid alkyl ester that reacts at a different rate with glycerol as compared to other fatty acids are contemplated using the process disclosed herein.
  • acyl residues may be conjugated, hydroxylated, epoxidated, or diydroxyepoxidated acyl residues.
  • the present invention contemplates a method comprising providing a fatty acid starting material (i.e., for example obtained from fish oil), a selective lipase (i.e., for example, isolated from Rhizomucor miehei (RM-IM)) immobilized on a solid support material, wherein the lipase creates a glyceride fraction and a free fatty acid fraction comprising different fatty acid compositions.
  • the method further comprises terminating the lipase reaction before reaching equilibrium.
  • the lipase enzyme may include, but is not limited to, Thermomyces lanuginosus lipase, Rhizomucor miehei lipase, Candida antarctica lipase, Pseudomonas fluorescence lipase, or Mucor javanicus lipase.
  • the fatty acids include, but are not limited to, ethyl esters, free fatty acids, alkyl esters, or any other fatty acid derivative.
  • the alcohol residues include, but are not limited to, glycerol, propylene glycol, carbohydrates, or any aliphatic alcohol (i.e., for example, methanol, ethanol, propanol, etc.)
  • the selective lipase preferentially esterifies saturated and mono-unsaturated fatty acids with an alcohol residue (i.e., for example, a glycerol molecule) at a higher rate than polyunsaturated fatty acids (i.e., for example, omega-3 fatty acids). It is further believed that by action of a selective lipase the concentration of the saturated fatty acids and mono- unsaturated fatty acids are depleted in the starting material at a faster rate than the concentration of unsaturated fatty acids. In one embodiment, the free fatty acid fraction is enriched in omega-3 fatty acids as compared to the starting material.
  • the present invention contemplates a system comprising: i) a selective lipase packed bed reactor capable of catalyzing differential enzymatic reaction rates between free fatty acids and glycerol and/or free fatty acids alkyl esters and glycerol; and ii) a flash tank evaporator operating under reduced pressure capable of removing volatile byproducts (i.e., for example, ethanol).
  • the selective reaction is terminated prior to reaching equilibrium and the enriched free fatty acid fraction or the enriched free fatty acids alkyl ester fraction is isolated from the glyceride by-product fraction using short path distillation.
  • the system comprises a continuous loop interconnecting elements including, but not limited to, a feed tank (1), a reaction column (2), a separation tank (3), and a product tank (4). See, Figure 1.
  • the continuous loop comprises a plurality of pipes capable of transporting fluids between some of the interconnecting elements.
  • the reaction column comprises a plurality of immobilized lipase enzymes configured such that the starting materials can be pumped through the column in a desired number of cycles depending on which conversion is selected.
  • a feed tank (1) may be filled with ethyl esters comprising 20% EPA and 50% DHA and glycerol to create a starting material.
  • the starting material is then pumped through a column (2) packed with immobilized selective lipase enzymes (i.e., for example, RM-IM, Novozymes, Bagsvaerd, Denmark) wherein a reaction product mixture is generated.
  • the reaction product mixture may then be transported to a separation tank (3) operated under vacuum in order to remove volatile reaction by-products (i.e., for example, ethanol), thereby creating a preliminary enriched reaction mixture.
  • the preliminary enriched reaction mixture may then be transferred back to the feed tank for a second passage through column (2).
  • the feed tank-column-flash tank cycle may be repeated for any number of passages until a final reaction mixture is created.
  • a valve (4) may be opened such that the final reaction mixture flows into the product tank (5).
  • the removal of the volatile by-products increases the reaction rate thereby improving the efficiency of the lipase reaction.
  • hot steam can be added to the separation tank to further improve efficient removal of the volatile reaction by-products. It should be noted that the present embodiment does not perform the lipase reaction under vacuum and the column (2) is not contacted with hot steam. Although it is not necessary to understand the mechanism of an invention, it is believed that this reaction system may be performed without mechanical stirring.
  • cycle was repeated a number of times.
  • the column and the container were kept at a temperature of 40 °C.
  • the fatty acid profile of the ester fraction was recorded using GC-FID at different time intervals.
  • the percentage of EPA was reduced from 22.6% to 12.9% during the course of the method.
  • the percentage of DP A was reduced from 9.4% to 3.5% during the course of the method.
  • the percentage of DHA was enriched from 48.3% to 70.0% during the course of the method.
  • the lipid composition was monitored using GPC (Gel Permeation Chromatography).
  • the percentage of MG was enriched from 0.0% to 13.6% during the course of the method.
  • the percentage of DG was enriched from 0.0% to 39.0% during the course of the method. In one embodiment, the percentage of TG was enriched from 0.0% to 4.5% during the course of the method. In one embodiment, the percentage of FAEE + glycerol was reduced from 100.0% to 42.7% during the course of the method. In one embodiment the two fractions could be separated using molecular distillation according to the method described in US Patent 4554107 [48] and US Patent Application 20060177486 [49]. In on embodiment the invention relates to enrichment of fish oil derived fatty acid ethyl esters with used enzymes. In one embodiment the enzymes had been used for 100 hours for other purposes.
  • the fatty acid and lipid profile for used enzymes show no significant reduction in enzymatic activity.
  • the invention relates to the enrichment of a single distilled ethyl ester fraction.
  • molecular distillation of fish oil derived ethyl esters results in a residue fraction and a distillate fraction having an EPA and DHA content of at least 20% and 5%, respectively.
  • a single distilled fraction can be used as a starting material.
  • the present system does not require the addition of water.
  • the starting mixture comprises trout oil.
  • the starting mixture comprises a DPA rich source.
  • the starting mixture comprises a single distilled ethyl ester fraction.
  • the starting mixture comprises ethyl ester fraction previously enriched.
  • the lipase comprises lipase RM-IM from Rhizomucor miehei.
  • the lipase comprises used lipase enzyme.
  • the present invention contemplates a composition comprising palmitoleic acid and omega-3 fatty acids, wherein the concentration of both the palmitoleic acid and omega-3 fatty acids are enriched as compared to a naturally occurring source.
  • the composition comprises at least 10% palmitoleic acid and 10% EPA/DHA.
  • the composition comprises 20% palmitoleic acid and at least 10 % EPA/DHA.
  • the composition comprises more than 30% palmitoleic acid and more than 10% EPA/DHA.
  • the composition comprises a dietary supplement.
  • the present invention contemplates a method comprising treating a subject suffering from metabolic dysfunction with the composition.
  • the present invention further provides pharmaceutical compositions (e.g., comprising the enriched fatty acid compositions described above).
  • the pharmaceutical compositions of the present invention may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • compositions and formulations for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets or tablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids or binders may be desirable.
  • the pharmaceutical formulations of the present invention may be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • compositions of the present invention may be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, liquid syrups, soft gels, suppositories, and enemas.
  • the compositions of the present invention may also be formulated as suspensions in aqueous, non-aqueous or mixed media.
  • Aqueous suspensions may further contain substances that increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran.
  • the suspension may also contain stabilizers.
  • the pharmaceutical compositions may be formulated and used as foams.
  • Pharmaceutical foams include formulations such as, but not limited to, emulsions, microemulsions, creams, jellies and liposomes. While basically similar in nature these formulations vary in the components and the consistency of the final product.
  • compositions of the present invention may additionally contain other adjunct components conventionally found in pharmaceutical compositions.
  • the compositions may contain additional, compatible, pharmaceutically-active materials such as, for example, antipruritics, astringents, local anesthetics or anti-inflammatory agents, or may contain additional materials useful in physically formulating various dosage forms of the compositions of the present invention, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers.
  • additional materials useful in physically formulating various dosage forms of the compositions of the present invention such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers.
  • such materials when added, should not unduly interfere with the biological activities of the components of the compositions of the present invention.
  • the formulations can be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously interact with the nucleic acid(s) of the formulation.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously interact with the nucleic acid(s) of the formulation.
  • dosage is from 0.01 ⁇ g to 100 g per kg of body weight, and may be given once or more daily, weekly, monthly or yearly.
  • the treating physician can estimate repetition rates for dosing based on measured residence times and concentrations of the drug in bodily fluids or tissues.
  • a stainless steel column having the dimensions (25 mm/250 mm) was packed with 23 g lipase RM-IM ⁇ Rhizomucor miehei) from Novozymes (Bagsvaerd, Denmark) A.
  • a stainless steel container B 299 g FAEE 20-50 was mixed with glycerol.
  • the container was connected to a vacuum pump.
  • the mixture was pumped through the column at a pressure of 3 bars, before being transferred to an evacuated chamber and finally back to the container (for details see Figure 1). This cycle was repeated a number of times.
  • the column and the container were kept at a temperature of 40 °C.
  • Lipoprotein Profile and Aortic Cholesterol Accumulation are Similar to Those of Other Unsaturated Fatty Acids in the FIB Golden Syrian Hamster, J. Nutr. 139, 215- 221.

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Abstract

Cette invention concerne le domaine des lipides et/ou de la technologie des lipides. Les acides gras sont une source de lipides qui peuvent être issus de sources naturelles comprenant, entre autres, les huiles de poisson ou les graines de lin. La présente invention concerne des procédés qui permettent l'enrichissement d'acides gras libres et/ou d'esters d'acide gras libres en tirant profit de leurs vitesses de réaction relatives avec des enzymes lipases sélectives qui synthétisent des glycérides. Les compositions obtenues grâce aux procédés de l'invention présentent des teneurs enrichies en acide gras libres comprenant, entre autres, l'acide palmitoléique et les acides gras oméga-3.
PCT/IB2010/003182 2009-12-03 2010-11-29 Procédé de production de compositions d'acides gras enrichis WO2011067666A1 (fr)

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US9200236B2 (en) 2011-11-17 2015-12-01 Heliae Development, Llc Omega 7 rich compositions and methods of isolating omega 7 fatty acids
WO2019023668A1 (fr) * 2017-07-27 2019-01-31 Shaaban Basil Adil Composition de cannabinoïdes présentant un profil d'acides gras de l'excipient optimisé

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