WO2013032333A1 - Oral dosage units containing astaxanthin, phospholipids and omega-3 fatty acids - Google Patents

Oral dosage units containing astaxanthin, phospholipids and omega-3 fatty acids Download PDF

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Publication number
WO2013032333A1
WO2013032333A1 PCT/NL2012/050599 NL2012050599W WO2013032333A1 WO 2013032333 A1 WO2013032333 A1 WO 2013032333A1 NL 2012050599 W NL2012050599 W NL 2012050599W WO 2013032333 A1 WO2013032333 A1 WO 2013032333A1
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Prior art keywords
astaxanthin
glycerophospholipids
oral dosage
microalgal
fatty acids
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PCT/NL2012/050599
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French (fr)
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Wilhelmus Cornelis Johannes Marie EVERS
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Algae Biotech S.L.
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Publication of WO2013032333A1 publication Critical patent/WO2013032333A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/02—Algae
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L17/00—Food-from-the-sea products; Fish products; Fish meal; Fish-egg substitutes; Preparation or treatment thereof
    • A23L17/60—Edible seaweed
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to oral dosage units containing astaxanthin, phospholipids and co3-fatty acids and to the preparation of such oral dosage units.
  • Astaxanthin is a carotenoid. Like many carotenoids, it is a colorful, lipid-soluble pigment. Astaxanthin is found in microalgae, yeast, salmon, trout, krill, shrimp, crayfish, crustaceans, and the feathers of some birds. It provides the red color of salmon meat and cooked shellfish. While astaxanthin is a natural nutritional component, it can also be used as a food
  • Nutritionally important co ⁇ 3 fatty acids include a-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), all of which are polyunsaturated.
  • co-3 fatty acids include fish oils and some plant oils such as flaxseed oil and algal oil. People with certain circulatory problems, such as varicose veins, may benefit from supplements containing EPA and DHA, which stimulate blood circulation, increase the breakdown of fibrin and, in addition, have been shown to reduce blood pressure, co-3 fatty acids are believed to reduce blood
  • triglyceride levels, and regular intake may reduce the risk of secondary and primary heart attack.
  • Glycerophospholipids are glycerol-based phospholipids. Glycerophospholipids, are vital for the structural integrity of mammalian membranes and lung surfactant. Glycerophospholipids also play a central role in signal transduction, prostaglandin synthesis, lipoprotein secretion and intestinal lipid absorption. Impaired phospholipid supply, either through impaired metabolism or dietary deficiency, has been linked to the pathogenesis of several diseases, such as: non-alcoholic fatty liver disease, cardiovascular disease, diabetes, cystic fibrosis, and dementia.
  • diseases such as: non-alcoholic fatty liver disease, cardiovascular disease, diabetes, cystic fibrosis, and dementia.
  • EP-A 1 820 499 describes a green algal extract comprising astaxanthin at a concentration of 0.5 to 20 wt% expressed in terms of free astaxanthin, and at least one phospholipid, wherein the phospholipid concentration is 0.1 to 15 wt%.
  • Haematococcus pluvialis is mentioned as a preferred green algae source material.
  • the examples describe the use of soybean lecithin as a phospholipid source.
  • WO 2007/062274 describes a human dietary supplement composition comprising the dried biomass of Spirulina platensis in combination with astaxanthin in free and/or ester form.
  • the astaxanthin may be contained in the astaxanthin-bearing dried biomass of Haematococcus.
  • WO 2011/051743 describes a solvent-free process for producing krill oil.
  • These krill oils have a content of: 30-70 wt% phospholipids, 10-70 wt% DHA and EPA and 0.02-0.15 wt% astaxanthin.
  • the international patent application describes a krill oil enriched in phospholipids that has a content of:
  • DHA and EPA from about 10 to 70% w/w, more preferably from about 15 to 60% w/w, and even more preferably from about 20 to 55% w/w;
  • ⁇ neutral lipids from about 30 to 70% w/w, more preferably from about 40% to 65% w/w, and even more preferably from about 45 to 65% w/w;
  • astaxanthin from about 200 to 1.500 mg/kg, more preferably from about 300 to 1.200 mg/kg, and even more preferably from about 400 to 1.000 mg/kg.
  • Example 11 of WO 2011/051743 describes capsules containing 1 ml of the krill oil.
  • US 2011/0195061 describes oral dosage forms of choline-based, phospholipid-bound fatty acid mixture including polyunsaturated EPA and DHA and astaxanthin.
  • the oral dosage forms are used to treat and alleviate symptoms of osteoarthritis and/or rheumatoid arthritis in a patient.
  • WO 2011/01 1607 describes a composition comprising a therapeutically effective amount of a synergistic multi-ingredient composition of mixed carotenoids including at least S, S'- astaxanthin derived from Haematococcus pluvialis, and one or more of lutein and/or trans- zeaxanthin or meso-zeaxanthin admixed with a therapeutically effective amount of krili oil containing phospholipid bound and triglyceride bound EPA and DHA in which said krili oil contains at least 30% total phospholipids.
  • a synergistic multi-ingredient composition of mixed carotenoids including at least S, S'- astaxanthin derived from Haematococcus pluvialis, and one or more of lutein and/or trans- zeaxanthin or meso-zeaxanthin admixed with a therapeutically effective amount of krili oil containing phospholipid bound and trigly
  • This international patent application describes a composition including 50 to 500 mg of krili oil, 0.5 to 8 mg astaxanthin, 2 to 15 mg lutein and 0.2 to 12 mg of trans-zeaxanthin. It further teaches to administer a composition containing 50 to 1000 mg krili oil, 0.5 to 8 mgs astaxanthin, 2 to 15 mg lutein and 0.2 to 12 mg of meso or trans-zeaxanthin per day to prevent or retard degenerative disease of the central nervous system of the eye, or to ameliorate damage resulting from an injury or a disease of the eye.
  • the inventors have designed oral dosage units that provide a nutritionally well balanced combination of astaxanthin, glycerophospholipids and ⁇ 3 -fatty acids that are prepared by mixing a microalgal astaxanthin isolate with one or more microalgal oil isolates. More particularly the present invention relates to a method of preparing an oral dosage unit containing 200-1200 mg of a micronutrient composition, said micronutrient composition comprising:
  • co3-fatty acids selected from eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and combinations thereof;
  • said method comprising mixing together:
  • microalgal astaxanthin isolate having an astaxanthin content of at least 1 wt.%; and • 80-99.5 parts by weight of one or more microalgal oil isolates, said one or more microalagal isolates containing at least 10 wt.% of co3-fatty acids selected from EPA, DHA and combinations thereof and/or at least 1 wt.% of glycerophospholipids.
  • the oral dosage unit of the present invention when consumed on a daily basis over a prolonged period of time offers the advantage that it prevents and reduces the risk of appearance of hypercholesterolemia, hyperlipidemia, cardiovascular and immune conditions.
  • microalgal isolates as a source of the astaxanthin, the ⁇ 3 -fatty acids and the glycerophospholipids enables the preparation of a micronutrient composition that is nutritionally very well balanced and that does not contain nutritionally undesirable components. Furthermore, the oral dosage units of the present invention offer the advantage that they have a bland taste.
  • One aspect of the invention relates to a method or preparing an oral dosage unit containing 200-1200 mg of a micronutrient composition, said micronutrient composition comprising: ⁇ 0.1-5 mg of astaxanthin;
  • co3-fatty acids selected from eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and combinations thereof;
  • said method comprising mixing together:
  • microalgal astaxanthin isolate having an astaxanthin content of at least 1 wt.%
  • microalagal isolates containing at least 10 wt.% of co3-fatty acids selected from EPA, DHA and combinations thereof and/or at least 1 wt.% of glycerophospholipids.
  • oral dosage unit encompasses any dosage unit that can suitably be used for administering the present micronutrient composition to humans.
  • astaxanthin unless indicated otherwise, this term includes free astaxanthin as well as bound astaxanthin, notably astaxanthin mono-esters and astaxanthin di-esters.
  • fatty acid unless indicated otherwise, said term includes free fatty acids as well as fatty acid residues.
  • a fatty acid concentration unless otherwise indicated, said concentration is calculated by weight of the total amount of fatty acids, including free fatty acids and fatty acids contained in fatty acid esters such as glyceride and phosphate esters.
  • microalgal isolate refers to a component that has been isolated from microalgal biomass, e.g. by extraction and/or drying of microalgal biomass.
  • the microalgal isolates of the present invention e.g. microalgal astaxanthin isolate or microalgal oil isolate
  • extract or "microalgal extract” as used herein, unless indicated otherwise, refers to a component that has been isolated from microalgal biomass by means of solvent extraction.
  • micronutrient composition employed in accordance with the present invention suitably contains at least 10 wt.%, more preferably at least 15 wt.%, even more preferably at least 20 wt.%, and most preferably at least 25 wt.% of glyceride fatty acids esters selected from the group consisting of triglycerides, diglycerides, monoglycerides, glycerophopholipids containing one or two fatty acid residues and combinations thereof.
  • microalgal isolates employed in accordance with the invention may have a liquid, solid, semi-solid or paste-like consistency.
  • the aforementioned microalgal isolates may have been isolated from microalgae biomass by means of e.g. solvent extraction and/or drying.
  • the microalgal isolates are microalgal extracts that have been isolated from microalgal biomass by means of solvent extraction.
  • the microalgal astaxanthin isolate employed in accordance with the present invention typically comprises 0.1-25 wt.%, preferably 1-15 wt.% of astaxanthin, said astaxanthin comprising:
  • the astaxanthin comprises:
  • composition is typical of an astaxanthin isolate obtained from
  • microalgal oil isolate employed in accordance with the invention typically contains:
  • At least 20 wt.%, more preferably at least 25 wt.%> and most preferably at least .. wt.%) of the fatty acid residues of the glycerophospholipids contained in the microalgal oil isolate are ⁇ 3 -fatty acid residues selected from EPA, DHA and combinations thereof.
  • EPA and DHA are typically contained in the microalgal oil isolate in a weight ratio that lies within the range of 1 : 30 to 1 : 1,000, more preferably within the range of 1 : 40 to 1 :900 and most preferably within the range of 1 : 50 to 1 :500.
  • the microalgal astaxanthin isolate is isolated from Haematococcus, Schizochytrium or Nannochloropsis most preferably from Haematococcus pluvialis.
  • the microalgal oil isolate is isolated from Schizochytrium, most preferably from Schizochytrium sp.
  • Both the microalgal astaxanthin isolate and the microalgal oil isolate are preferably obtained by an isolation process that does not employ apolar organic solvents. Such a process is described, for instance, in WO 2010/039030.
  • microalgal isolates of the present invention typically contain at least trace amounts of DNA, RNA, DNA-fragments and/or RNA fragments of the microalgae species from which the isolate was obtained.
  • the oral dosage unit may contain other components, such as capsule material and/or coatings.
  • examples of oral dosage units include capsules and tablets.
  • the oral dosage unit is a capsule, more preferably a soft gelled capsule.
  • capsule refers to a small case enclosing a dose of medication or supplement.
  • the oral dosage unit is a capsule that is filled with the micronutrient composition.
  • said micronutrient composition is an oil that is liquid at 15°C.
  • the micronutrient composition typically constitutes at least 40 wt.%, more preferably at least 60 wt.% and most preferably at least 80 wt.% of the oral dosage unit.
  • the micronutrient composition preferably is contained in the oral dosage unit in an amount 200-1000 mg, more preferably 250-900 mg and most preferably 300-800 mg.
  • the ⁇ 3 -fatty acids may be contained in the micronutrient composition in the form of free fatty acids or in the form of esters, e.g. glycerol esters.
  • esters e.g. glycerol esters.
  • at least 60 wt.%, more preferably at least 80 wt.% of the co3-fatty acids is comprised in glycerol esters selected from triglycerides, diglycerides, monoglycerides and glycerophospholipids.
  • a substantial part, e.g. at least 1 wt.% of the co3- fatty acids (DHA and/or EPA) in the micronutrient composition is contained in
  • glycerophospholipids More preferably, at least 5 wt.%, even more preferably at least 10 wt.% and most preferably at least 20 wt.% of the co3-fatty acids in the micronutrient composition is contained in glycerophospholipids
  • both the ⁇ 3 -fatty acids and the glycerophospholipids originate from microalgae.
  • microalgae from which the co3- fatty acids may be sourced include Schizochytrium, Chysophyceae, Xantophyceae,
  • Eustigmatophyceae Baccilariophyceae, Dinophyceae, Rodophyceae, Phaeophyceae, Chlorophyceae, Prasinophyceae, Cryptophyceae, Botrycoccus, Isochrysis, Tetraselmis, Neochloris, Scenedesmus, Chlorobotrys, Eustigmatos, Pseudostaurastrum, Vischeria, Monodopsis, Ellipsoidion, Pseudocharaciopsis and combinations thereof.
  • the ⁇ 3 -fatty acids and the glycerophospholipids originate from microalgae belonging to a genus or class selected from Schizochytrium, Eustigmatophyceae,
  • the ⁇ 3 -fatty acids and the glycerophospholipids contained in the micronutrient composition preferably originate from the same microalgae species.
  • a significant fraction of the co3-fatty acid residues are comprised in the glycerophospholipids.
  • at least 20 wt.%, more preferably at least 25 wt.% and most preferably at least 30 wt.% of the fatty acid residues of the glycerophospholipids are co3- fatty acid residues selected from EPA, DHA and combinations thereof.
  • the astaxanthin contained in the micronutrient composition preferably also is of marine origin. More preferably, the astaxanthin originates from algae, even more preferably from microalgae. According to a particularly preferred embodiment, the astaxanthin originates from Haematococcus, Nannochloropsis and/or Schizochytrium. Most preferably, the astaxanthin originates from Haematococcus pluvialis.
  • the present invention encompasses an embodiment in which the astaxanthin, the ⁇ 3 -fatty acids and the glycerophospholipids contained in the micronutrient composition originate from a single microalgae species.
  • said microalgae species belongs to Schizochytrium (e.g Schizochytrium limanicum or Schizochytrium aggregatum).
  • the astaxanthin, the phospholipids as well as the co3-fatty acids originate from microalgae.
  • the micronutrient composition is composed of:
  • microalgal astaxanthin isolate • 0.1-10 wt.%, preferably 0.2-8 wt.% of microalgal astaxanthin isolate from
  • Haematococcus preferably from Haematococcus pluvialis;
  • the latter two microalgal isolates are solvent extracts and together represent at least 60 wt.%), more preferably at least 80 wt.%> and most preferably at least 90 wt.%> of the micronutrient composition.
  • Another advantageous embodiment of the invention relates to an oral dosage unit containing 200-1200 mg of a powder composition, said powder composition comprising:
  • microalgal astaxanthin isolate • 0.1-20 wt.%), preferably 0.2-10 wt.%> of a microalgal astaxanthin isolate from
  • Haematococcus preferably from Haematococcus pluvialis;
  • Shyzochytrium sp preferably from Shyzochytrium sp.
  • both microalgal isolates consist of dried biomass and together represent at least 60 wt.%), more preferably at least 80 wt.%> and most preferably at least 90 wt.%> of the micronutrient composition.
  • the amount of glycerophospholipid contained in the micronutrient composition preferably lies in the range of 2-250 mg, more preferably of 10-230 mg, even more preferably of 20-210 mg and most preferably of 40-200 mg.
  • the ⁇ 3 -fatty acids are preferably contained in the micronutrient composition in an amount of 70-400 mg, more preferably of 100-380 mg and most preferably of 150-350 mg.
  • the amount of EPA contained in the micronutrient composition preferably is within the range of 0.3-100 mg, more preferably of 0.5-80 mg and most preferably of 1-50 mg.
  • the amount of DHA contained in the micronutrient composition preferably is within the range of 30-400 mg, more preferably of 50-380 mg and most preferably of 70-350 mg.
  • the amount of astaxantin in the micronutrient composition preferably lies in the range of 0.1- 2 mg, more preferably of 0.2-1.5 mg and most preferably of 0.3-1.4 mg.
  • the micronutrient composition may suitably contain other component such as excipients and other active ingredients.
  • glycerophospholipids and glycerol esters of EPA and/or DHA other than glycerophospholipids together represent at least 30 wt.%, more preferably at least 40 wt.% and most preferably 50 wt.% of the micronutrient composition.
  • the oral dosage units according to the present invention offer the advantage that prolonged oral administration prevents and reduces the risk of appearance of hypercholesterolemia, hyperlipidemia, cardiovascular and immune conditions. Accordingly, the present invention also pertains to oral dosage units for use in therapeutic or prophylactic treatment, said treatment comprising daily administration of 1-3 oral dosage units as defined herein before.
  • a particularly preferred embodiment relates to oral dosage units for use in therapeutic or prophylactic treatment of hypercholesterolemia, hyperlipidemia, cardiovascular and immune conditions.
  • Another aspect of the invention relates to an oral dosage unit obtained by the preparation method as defined herein before.
  • the oral dosage is for use in therapeutic or prophylactic treatment, preferably the treatment of hypercholesterolemia, hyperlipidemia, cardiovascular conditions or immune conditions.
  • the oral dosage may also suitably be used in therapeutic or prophylactic treatment of cognitive decline, e.g. in cognitive decline associated with ageing, Alzheimer's disease, Parkinson's disease etc.
  • said treatments comprises daily administration of 1-3 of said oral dosage units.
  • a microalgal oil extract was produced as described herein below.
  • a microalgal astaxanthin extract was produced using the same procedure as described in Example 1.
  • the characteristics of the microalgae strain used were as follows:
  • CCAP 34/6 from the Culture Collection of Algae and Protozoa (CCAP)
  • Isolator Droop (1951); Origin: Freshwater; rain pool; Ostpicken Island, Tvarmimme, Finland,
  • the astaxanthin extract obtained had an astaxanthin content of about 5 wt.%.
  • Unit dosages in the form of 500 mg soft gel capsules were prepared by filling these capsules with a blend of 96 parts by weight of the microalgal oil extract of Example 1 and 4 parts by weight of the microalgal astaxanthin extract of Example 2.
  • the composition of the micronutrient composition contained in the capsules is shown in
  • Dry microalgal biomass that is rich in omega-3 fatty acids and phospholipids was produced using the procedure described in steps 1) and 2) of Example 1.
  • the dry biomass so obtained was milled to produce a powder having a volume weight mean particle size of approximately 2-10 ⁇ .
  • Dry microalgal biomass that is rich in astaxanthin was produced by repeating steps 1) and 2) of the procedure described in Example 2. Again, the dry biomass so obtained was milled to produce a powder having a volume weight mean particle size of approximately .2-10. ⁇ .
  • Unit dosages in the form of 700 mg hard gel capsules were prepared by filling these capsules with a powder blend of 96.0% by weight of the omega-3 and phospholipid rich microalgal dry biomass and 4.0% by weight of the astaxanthin rich microalgal dry biomass.

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Abstract

The invention relates to a method of preparing an oral dosage unit containing 200-1200 mg of a micronutrient composition, said micronutrient composition comprising: · 0.1-5 mg of astaxanthin; • 50-500 mg of ω3-fatty acids selected from eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and combinations thereof; • 1-300 mg of glycerophospholipids; and • 0-600 mg of other components; said method comprising mixing together: • 0.5-20 parts by weight of microalgal astaxanthin isolate having an astaxanthin content of at least 1 wt.%; and • 80-99.5 parts by weight of one or more microalgal oil isolates, said one or more microalagal isolates containing at least 10 wt.% of co3-fatty acids selected from EPA, DHA and combinations thereof and/or at least 1 wt.% of glycerophospholipids. The invention also related to an oral dosage unit that is obtained by the aforementioned method. This oral dosage unit, when consumed on a daily basis over a prolonged period of time, offers the advantage that it prevents and reduces the risk of appearance of hypercholesterolemia, hyperlipidemia, cardiovascular conditions, immune conditions and cognitive decline.

Description

ORAL DOSAGE UNITS CONTAINING ASTAXANTHIN, PHOSPHOLIPIDS AND
OMEGA-3 FATTY ACIDS
TECHNICAL FIELD OF THE INVENTION
The present invention relates to oral dosage units containing astaxanthin, phospholipids and co3-fatty acids and to the preparation of such oral dosage units.
BACKGROUND OF THE INVENTION
Astaxanthin is a carotenoid. Like many carotenoids, it is a colorful, lipid-soluble pigment. Astaxanthin is found in microalgae, yeast, salmon, trout, krill, shrimp, crayfish, crustaceans, and the feathers of some birds. It provides the red color of salmon meat and cooked shellfish. While astaxanthin is a natural nutritional component, it can also be used as a food
supplement. The U.S. Food and Drug Administration (FDA) has approved astaxanthin as a food coloring for specific uses in animal and fish foods. The European Commission considers it food dye and it is given the E number E 161 j . Research shows that due to astaxanthin's potent antioxidant activity, it may be beneficial in cardiovascular, immune, inflammatory and neurodegenerative diseases. co-3 fatty acids are essential unsaturated fatty acids with a double bond (C=C) starting after the third carbon atom from the end of the carbon chain. Nutritionally important co~3 fatty acids include a-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), all of which are polyunsaturated. Common sources of co-3 fatty acids include fish oils and some plant oils such as flaxseed oil and algal oil. People with certain circulatory problems, such as varicose veins, may benefit from supplements containing EPA and DHA, which stimulate blood circulation, increase the breakdown of fibrin and, in addition, have been shown to reduce blood pressure, co-3 fatty acids are believed to reduce blood
triglyceride levels, and regular intake may reduce the risk of secondary and primary heart attack.
Glycerophospholipids are glycerol-based phospholipids. Glycerophospholipids, are vital for the structural integrity of mammalian membranes and lung surfactant. Glycerophospholipids also play a central role in signal transduction, prostaglandin synthesis, lipoprotein secretion and intestinal lipid absorption. Impaired phospholipid supply, either through impaired metabolism or dietary deficiency, has been linked to the pathogenesis of several diseases, such as: non-alcoholic fatty liver disease, cardiovascular disease, diabetes, cystic fibrosis, and dementia.
EP-A 1 820 499 describes a green algal extract comprising astaxanthin at a concentration of 0.5 to 20 wt% expressed in terms of free astaxanthin, and at least one phospholipid, wherein the phospholipid concentration is 0.1 to 15 wt%. Haematococcus pluvialis is mentioned as a preferred green algae source material. The examples describe the use of soybean lecithin as a phospholipid source.
WO 2007/062274 describes a human dietary supplement composition comprising the dried biomass of Spirulina platensis in combination with astaxanthin in free and/or ester form. The astaxanthin may be contained in the astaxanthin-bearing dried biomass of Haematococcus.
WO 2011/051743 describes a solvent-free process for producing krill oil. These krill oils have a content of: 30-70 wt% phospholipids, 10-70 wt% DHA and EPA and 0.02-0.15 wt% astaxanthin. The international patent application describes a krill oil enriched in phospholipids that has a content of:
• total phospholipids from about 30 to 70% w/w, more preferably from about 35 to 60% w/w, and even more preferably from about 35 to 55% w/w;
• DHA and EPA from about 10 to 70% w/w, more preferably from about 15 to 60% w/w, and even more preferably from about 20 to 55% w/w;
· neutral lipids from about 30 to 70% w/w, more preferably from about 40% to 65% w/w, and even more preferably from about 45 to 65% w/w; and
• astaxanthin from about 200 to 1.500 mg/kg, more preferably from about 300 to 1.200 mg/kg, and even more preferably from about 400 to 1.000 mg/kg.
Example 11 of WO 2011/051743 describes capsules containing 1 ml of the krill oil.
US 2011/0195061 describes oral dosage forms of choline-based, phospholipid-bound fatty acid mixture including polyunsaturated EPA and DHA and astaxanthin. The oral dosage forms are used to treat and alleviate symptoms of osteoarthritis and/or rheumatoid arthritis in a patient.
WO 2011/01 1607 describes a composition comprising a therapeutically effective amount of a synergistic multi-ingredient composition of mixed carotenoids including at least S, S'- astaxanthin derived from Haematococcus pluvialis, and one or more of lutein and/or trans- zeaxanthin or meso-zeaxanthin admixed with a therapeutically effective amount of krili oil containing phospholipid bound and triglyceride bound EPA and DHA in which said krili oil contains at least 30% total phospholipids. This international patent application describes a composition including 50 to 500 mg of krili oil, 0.5 to 8 mg astaxanthin, 2 to 15 mg lutein and 0.2 to 12 mg of trans-zeaxanthin. It further teaches to administer a composition containing 50 to 1000 mg krili oil, 0.5 to 8 mgs astaxanthin, 2 to 15 mg lutein and 0.2 to 12 mg of meso or trans-zeaxanthin per day to prevent or retard degenerative disease of the central nervous system of the eye, or to ameliorate damage resulting from an injury or a disease of the eye.
SUMMARY OF THE INVENTION
The inventors have designed oral dosage units that provide a nutritionally well balanced combination of astaxanthin, glycerophospholipids and ω3 -fatty acids that are prepared by mixing a microalgal astaxanthin isolate with one or more microalgal oil isolates. More particularly the present invention relates to a method of preparing an oral dosage unit containing 200-1200 mg of a micronutrient composition, said micronutrient composition comprising:
· 0.1-5 mg of astaxanthin;
• 50-500 mg of co3-fatty acids selected from eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and combinations thereof;
• 1-300 mg of glycerophospholipids; and
• 0-600 mg of other components;
said method comprising mixing together:
• 0.5-20 parts by weight of microalgal astaxanthin isolate having an astaxanthin content of at least 1 wt.%; and • 80-99.5 parts by weight of one or more microalgal oil isolates, said one or more microalagal isolates containing at least 10 wt.% of co3-fatty acids selected from EPA, DHA and combinations thereof and/or at least 1 wt.% of glycerophospholipids. The oral dosage unit of the present invention when consumed on a daily basis over a prolonged period of time offers the advantage that it prevents and reduces the risk of appearance of hypercholesterolemia, hyperlipidemia, cardiovascular and immune conditions.
The use of microalgal isolates as a source of the astaxanthin, the ω3 -fatty acids and the glycerophospholipids enables the preparation of a micronutrient composition that is nutritionally very well balanced and that does not contain nutritionally undesirable components. Furthermore, the oral dosage units of the present invention offer the advantage that they have a bland taste.
DETAILED DESCRIPTION OF THE INVENTION
One aspect of the invention relates to a method or preparing an oral dosage unit containing 200-1200 mg of a micronutrient composition, said micronutrient composition comprising: · 0.1-5 mg of astaxanthin;
• 50-500 mg of co3-fatty acids selected from eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and combinations thereof;
• 1-300 mg of glycerophospholipids; and
• 0-600 mg of other components;
said method comprising mixing together:
• 0.5-20 parts by weight of microalgal astaxanthin isolate having an astaxanthin content of at least 1 wt.%; and
• 80-99.5 parts by weight of one or more microalgal oil isolates, said one or more
microalagal isolates containing at least 10 wt.% of co3-fatty acids selected from EPA, DHA and combinations thereof and/or at least 1 wt.% of glycerophospholipids.
The term "oral dosage unit" as used herein encompasses any dosage unit that can suitably be used for administering the present micronutrient composition to humans. Whenever reference is made herein to "astaxanthin", unless indicated otherwise, this term includes free astaxanthin as well as bound astaxanthin, notably astaxanthin mono-esters and astaxanthin di-esters. Whenever reference is made herein to "fatty acid", unless indicated otherwise, said term includes free fatty acids as well as fatty acid residues.
Whenever reference is made herein to a fatty acid concentration, unless otherwise indicated, said concentration is calculated by weight of the total amount of fatty acids, including free fatty acids and fatty acids contained in fatty acid esters such as glyceride and phosphate esters.
The term "isolate" or "microalgal isolate" as used herein, unless indicated otherwise, refers to a component that has been isolated from microalgal biomass, e.g. by extraction and/or drying of microalgal biomass. The microalgal isolates of the present invention (e.g. microalgal astaxanthin isolate or microalgal oil isolate) can take the form of e.g. a liquid, a paste or a powder. Besides the aforementioned micronutrients these isolates may contain substantial levels of other biomass components. The term "extract" or "microalgal extract" as used herein, unless indicated otherwise, refers to a component that has been isolated from microalgal biomass by means of solvent extraction.
The term "micronutrient composition" employed in accordance with the present invention suitably contains at least 10 wt.%, more preferably at least 15 wt.%, even more preferably at least 20 wt.%, and most preferably at least 25 wt.% of glyceride fatty acids esters selected from the group consisting of triglycerides, diglycerides, monoglycerides, glycerophopholipids containing one or two fatty acid residues and combinations thereof.
The microalgal isolates employed in accordance with the invention may have a liquid, solid, semi-solid or paste-like consistency. The aforementioned microalgal isolates may have been isolated from microalgae biomass by means of e.g. solvent extraction and/or drying.
Preferably, the microalgal isolates are microalgal extracts that have been isolated from microalgal biomass by means of solvent extraction. The microalgal astaxanthin isolate employed in accordance with the present invention typically comprises 0.1-25 wt.%, preferably 1-15 wt.% of astaxanthin, said astaxanthin comprising:
• 60-95 wt.%), preferably 75-93 wt.%> of astaxanthin mono-ester;
· 3-30 wt.%), preferably 5-15 wt.%) of astaxanthin di-ester;
• 0.2-20 wt.%, preferably 0.4-10 wt.% of free astaxanthin;
and wherein, following enzymatic de-esterification, the astaxanthin comprises:
• 50-95 wt.%), preferably 65-90 wt.%> of E-astaxanthin;
• 3-30 wt.%), preferably 5-20 wt.%> of 9Z-astaxanthin;
· 3-30 wt.%), preferably 4-15 wt.%> of 13Z-astaxahntin.
The aforementioned composition is typical of an astaxanthin isolate obtained from
Haematococcus pluvialis.
The microalgal oil isolate employed in accordance with the invention typically contains:
• 0.1-1 wt.%, preferably 0.2-0.8 wt.% of EPA;
• 10-30 wt.%, preferably 15-30 wt.% of DHA;
• 1-40 wt.%), preferably 10-30 wt.%> of glycerophospholipids;
• 10-40 wt.%), preferably 10-30 wt.%> of glycerol fatty acid esters other than
glycerophospholipids; and
• 0-50 wt.%), preferably 0-20 wt.%> and most preferably 0-5 wt.%> of other components.
Preferably, at least 20 wt.%, more preferably at least 25 wt.%> and most preferably at least .. wt.%) of the fatty acid residues of the glycerophospholipids contained in the microalgal oil isolate are ω3 -fatty acid residues selected from EPA, DHA and combinations thereof.
EPA and DHA are typically contained in the microalgal oil isolate in a weight ratio that lies within the range of 1 : 30 to 1 : 1,000, more preferably within the range of 1 : 40 to 1 :900 and most preferably within the range of 1 : 50 to 1 :500.
According to a particularly preferred embodiment, the microalgal astaxanthin isolate is isolated from Haematococcus, Schizochytrium or Nannochloropsis most preferably from Haematococcus pluvialis. According to another particularly preferred embodiment the microalgal oil isolate is isolated from Schizochytrium, most preferably from Schizochytrium sp.
Both the microalgal astaxanthin isolate and the microalgal oil isolate are preferably obtained by an isolation process that does not employ apolar organic solvents. Such a process is described, for instance, in WO 2010/039030.
The microalgal isolates of the present invention typically contain at least trace amounts of DNA, RNA, DNA-fragments and/or RNA fragments of the microalgae species from which the isolate was obtained.
Besides the micronutrient composition, the oral dosage unit may contain other components, such as capsule material and/or coatings. Examples of oral dosage units include capsules and tablets. Preferably, the oral dosage unit is a capsule, more preferably a soft gelled capsule. Here the term "capsule" refers to a small case enclosing a dose of medication or supplement.
According to another preferred embodiment, the oral dosage unit is a capsule that is filled with the micronutrient composition. Most preferably, said micronutrient composition is an oil that is liquid at 15°C.
The micronutrient composition typically constitutes at least 40 wt.%, more preferably at least 60 wt.% and most preferably at least 80 wt.% of the oral dosage unit.
The micronutrient composition preferably is contained in the oral dosage unit in an amount 200-1000 mg, more preferably 250-900 mg and most preferably 300-800 mg.
The ω3 -fatty acids may be contained in the micronutrient composition in the form of free fatty acids or in the form of esters, e.g. glycerol esters. Preferably, at least 60 wt.%, more preferably at least 80 wt.% of the co3-fatty acids is comprised in glycerol esters selected from triglycerides, diglycerides, monoglycerides and glycerophospholipids. According to another preferred embodiment a substantial part, e.g. at least 1 wt.% of the co3- fatty acids (DHA and/or EPA) in the micronutrient composition is contained in
glycerophospholipids. More preferably, at least 5 wt.%, even more preferably at least 10 wt.% and most preferably at least 20 wt.% of the co3-fatty acids in the micronutrient composition is contained in glycerophospholipids
In accordance with a particularly preferred embodiment, both the ω3 -fatty acids and the glycerophospholipids originate from microalgae. Examples of microalgae from which the co3- fatty acids may be sourced include Schizochytrium, Chysophyceae, Xantophyceae,
Eustigmatophyceae, Baccilariophyceae, Dinophyceae, Rodophyceae, Phaeophyceae, Chlorophyceae, Prasinophyceae, Cryptophyceae, Botrycoccus, Isochrysis, Tetraselmis, Neochloris, Scenedesmus, Chlorobotrys, Eustigmatos, Pseudostaurastrum, Vischeria, Monodopsis, Ellipsoidion, Pseudocharaciopsis and combinations thereof. Even more preferably, the ω3 -fatty acids and the glycerophospholipids originate from microalgae belonging to a genus or class selected from Schizochytrium, Eustigmatophyceae,
Chlorophyceae and combinations thereof, Schizochytrium and Nannochloropsis being most preferred.
The ω3 -fatty acids and the glycerophospholipids contained in the micronutrient composition preferably originate from the same microalgae species. According to a particularly preferred embodiment, a significant fraction of the co3-fatty acid residues are comprised in the glycerophospholipids. Advantageously, at least 20 wt.%, more preferably at least 25 wt.% and most preferably at least 30 wt.% of the fatty acid residues of the glycerophospholipids are co3- fatty acid residues selected from EPA, DHA and combinations thereof.
The astaxanthin contained in the micronutrient composition preferably also is of marine origin. More preferably, the astaxanthin originates from algae, even more preferably from microalgae. According to a particularly preferred embodiment, the astaxanthin originates from Haematococcus, Nannochloropsis and/or Schizochytrium. Most preferably, the astaxanthin originates from Haematococcus pluvialis.
The present invention encompasses an embodiment in which the astaxanthin, the ω3 -fatty acids and the glycerophospholipids contained in the micronutrient composition originate from a single microalgae species. Preferably said microalgae species belongs to Schizochytrium (e.g Schizochytrium limanicum or Schizochytrium aggregatum).
In accordance with a particularly advantageous embodiment of the present invention the astaxanthin, the phospholipids as well as the co3-fatty acids originate from microalgae.
Typically, at least 90 wt.%, preferably at least 95 wt.% and most preferably 100 wt.% of the micronutrient composition originates from microalgae. According to an advantageous embodiment of the invention the micronutrient composition is composed of:
• 0.1-10 wt.%, preferably 0.2-8 wt.% of microalgal astaxanthin isolate from
Haematococcus, preferably from Haematococcus pluvialis; and
• 30-99.8 wt.%, preferably 40-99.8 wt.% of microalgal oil isolate from Schizochytrium, preferably from Shyzochytrium sp.
Preferably the latter two microalgal isolates are solvent extracts and together represent at least 60 wt.%), more preferably at least 80 wt.%> and most preferably at least 90 wt.%> of the micronutrient composition. Another advantageous embodiment of the invention relates to an oral dosage unit containing 200-1200 mg of a powder composition, said powder composition comprising:
• 0.1-20 wt.%), preferably 0.2-10 wt.%> of a microalgal astaxanthin isolate from
Haematococcus, preferably from Haematococcus pluvialis; and
• 50-99.9 wt.%, preferably 80-99.8 wt.% of microalgal isolate from Schizochytrium,
preferably from Shyzochytrium sp.
Preferably, both microalgal isolates consist of dried biomass and together represent at least 60 wt.%), more preferably at least 80 wt.%> and most preferably at least 90 wt.%> of the micronutrient composition. The amount of glycerophospholipid contained in the micronutrient composition preferably lies in the range of 2-250 mg, more preferably of 10-230 mg, even more preferably of 20-210 mg and most preferably of 40-200 mg. The ω3 -fatty acids are preferably contained in the micronutrient composition in an amount of 70-400 mg, more preferably of 100-380 mg and most preferably of 150-350 mg.
The amount of EPA contained in the micronutrient composition preferably is within the range of 0.3-100 mg, more preferably of 0.5-80 mg and most preferably of 1-50 mg.
The amount of DHA contained in the micronutrient composition preferably is within the range of 30-400 mg, more preferably of 50-380 mg and most preferably of 70-350 mg. The amount of astaxantin in the micronutrient composition preferably lies in the range of 0.1- 2 mg, more preferably of 0.2-1.5 mg and most preferably of 0.3-1.4 mg.
Besides astaxanthin, EPA, DHA and glycerophospholipids, the micronutrient composition may suitably contain other component such as excipients and other active ingredients.
Preferably, glycerophospholipids and glycerol esters of EPA and/or DHA other than glycerophospholipids together represent at least 30 wt.%, more preferably at least 40 wt.% and most preferably 50 wt.% of the micronutrient composition.
As explained herein before, the oral dosage units according to the present invention offer the advantage that prolonged oral administration prevents and reduces the risk of appearance of hypercholesterolemia, hyperlipidemia, cardiovascular and immune conditions. Accordingly, the present invention also pertains to oral dosage units for use in therapeutic or prophylactic treatment, said treatment comprising daily administration of 1-3 oral dosage units as defined herein before. A particularly preferred embodiment relates to oral dosage units for use in therapeutic or prophylactic treatment of hypercholesterolemia, hyperlipidemia, cardiovascular and immune conditions.
Another aspect of the invention relates to an oral dosage unit obtained by the preparation method as defined herein before.
In accordance with a preferred embodiment of the present invention the oral dosage is for use in therapeutic or prophylactic treatment, preferably the treatment of hypercholesterolemia, hyperlipidemia, cardiovascular conditions or immune conditions. The oral dosage may also suitably be used in therapeutic or prophylactic treatment of cognitive decline, e.g. in cognitive decline associated with ageing, Alzheimer's disease, Parkinson's disease etc. Typically, said treatments comprises daily administration of 1-3 of said oral dosage units.
The invention is further illustrated by the following non-limiting examples.
EXAMPLES
Example 1
A microalgal oil extract was produced as described herein below.
1) Schizochytrium sp. microalgae were harvested at their exponential growing phase and the cell suspension was centrifuged to eliminate excess of water with a centrifuge of the type Alfa Laval CLARA 80.
2) Next, the cell slurry was spray dried. The moisture content of the resulting cell powder was in the range of 2-6% moisture on dry weight.
3) The algae cell powder was combined with 100% pure ethanol (2: 1). The mixture was stirred for 4 hours at room temperature in erlenmeyer flasks with glass stoppers. The extract was filtered by suction and the filtrate collected. Solvent was removed from the filtrate in a rotational evaporator (65°C, 200 mbar) and oil was obtained.
The concentration of omega-3 fatty acids EPA and DHA as well as the concentration of phospholipids was determined. The results are shown in Table 1.
Table 1
Figure imgf000013_0001
Example 2
A microalgal astaxanthin extract was produced using the same procedure as described in Example 1. The characteristics of the microalgae strain used were as follows:
Haematococcus pluvialis.
Flotow (1844), Division: Chlorophyta, Class: Clorophyceae, Order: Volvocales.
CCAP 34/6 from the Culture Collection of Algae and Protozoa (CCAP)
Isolator: Droop (1951); Origin: Freshwater; rain pool; Ostpicken Island, Tvarmimme, Finland,
Culture: Medium EG:JM; A; cryo
The astaxanthin extract obtained had an astaxanthin content of about 5 wt.%. Example 3
Unit dosages in the form of 500 mg soft gel capsules were prepared by filling these capsules with a blend of 96 parts by weight of the microalgal oil extract of Example 1 and 4 parts by weight of the microalgal astaxanthin extract of Example 2. The composition of the micronutrient composition contained in the capsules is shown in
Table 2. Table 2
Figure imgf000013_0002
Example 4
Dry microalgal biomass that is rich in omega-3 fatty acids and phospholipids was produced using the procedure described in steps 1) and 2) of Example 1. The dry biomass so obtained was milled to produce a powder having a volume weight mean particle size of approximately 2-10 μιη.
Dry microalgal biomass that is rich in astaxanthin was produced by repeating steps 1) and 2) of the procedure described in Example 2. Again, the dry biomass so obtained was milled to produce a powder having a volume weight mean particle size of approximately .2-10. μιη.
Unit dosages in the form of 700 mg hard gel capsules were prepared by filling these capsules with a powder blend of 96.0% by weight of the omega-3 and phospholipid rich microalgal dry biomass and 4.0% by weight of the astaxanthin rich microalgal dry biomass.
The composition of the microalgal dry biomass components and of the micronutrient composition obtained by blending these components is shown in Table 3. Table 3
Figure imgf000014_0001

Claims

A method of preparing an oral dosage unit containing 200-1200 mg of a micronutrient composition, said micronutrient composition comprising:
• 0.1-5 mg of astaxanthin;
• 50-500 mg of co3-fatty acids selected from eicosapentaenoic acid (EPA),
docosahexaenoic acid (DHA) and combinations thereof;
• 1-300 mg of glycerophospholipids;
• 0-600 mg of other components;
said method comprising mixing together:
• 0.5-20 parts by weight of microalgal astaxanthin isolate having an astaxanthin content of at least 1 wt.%; and
• 80-99.5 parts by weight of one or more microalgal oil isolates, said one or more
microalagal isolates containing at least 10 wt.% of co3-fatty acids selected from EPA, DHA and combinations thereof and/or at least 1 wt.% of glycerophospholipids.
Method according to claim 1, wherein the microalgal astaxanthin isolate contains 0.1-25 wt.%), preferably 1-15 wt.%> of astaxanthin, said astaxanthin comprising:
• 60-95 wt.% of astaxanthin mono-ester;
• 3-30 wt.%) of astaxanthin di-ester;
• 0.2-20 wt.%) of free astaxanthin;
and wherein, following enzymatic de-esterification, the astaxanthin comprises:
• 50-95 wt.% of E-astaxanthin;
• 3 -30 wt. % of 9Z-astaxanthin;
• 3-30 wt.%) of 13Z-astaxahntin.
Method according to claim 1 or 2, wherein the microalgal oil isolate contains:
• 0.1-1 wt.% of EPA;
• 10-30 wt.% of DHA;
• 1-40 wt.% of glycerophospholipids;
• 10-40 wt.%) of glycerol fatty acid esters other than glycerophospholipids and
• 0-50 wt.%) of other components. 4. Method according to any one of the preceding claims, wherein the microalgal astaxanthin isolate is isolated from Haematococcus..
5. Method according to any one of the preceding claims, wherein the microalgal oil isolate is isolated from Schizochytrium or Nannochloropsis.
6. Method according to any one of the preceding claims, wherein the co3-fatty acids and the glycerophospholipids originate from the same microalgae species.
7. Method according to any one of the preceding claims, wherein at least 20 wt.% of the fatty acid residues of the glycerophospholipids are ω3 -fatty acid residues selected from EPA, DHA and combinations thereof.
8. Method according to any one of the preceding claims, wherein the micronutrient
composition contains 0.1-2, mg, preferably 0.2-1.5 mg of astaxanthin.
9. Method according to any one of the preceding claims, wherein the micronutrient
composition contains 70-400 mg, preferably 100-380 mg of the ω3 -fatty acids.
10. Method according to any one of the preceding claims, wherein the micronutrient
composition contains 0.3-100 mg, preferably 0.5-80 mg of EPA.
11. Method according to any one of the preceding claims, wherein the micronutrient
composition contains 50-380 mg, preferably 70-350 mg of DHA.
12. Method according to any one of the preceding claims, wherein the micronutrient
composition contains 2-250 mg, preferably 10-230 mg of glycerophospholipids.
13. Method according to any one of the preceding claims, wherein the oral dosage unit is a capsule, preferably a soft-gelled capsule.
14. An oral dosage unit obtained by a method according to any one of the preceding claims. 15. Oral dosage unit according to claim 14 for use in therapeutic or prophylactic treatment, preferably the treatment of hypercholesterolemia, hyperlipidemia, cardiovascular conditions, immune conditions or cognitive decline, said treatment comprising daily administration of 1-3 of said oral dosage units.
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