WO2015143001A1 - Composition d'astaxanthine thérapeutique et de phospholipide et procédé associé - Google Patents

Composition d'astaxanthine thérapeutique et de phospholipide et procédé associé Download PDF

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Publication number
WO2015143001A1
WO2015143001A1 PCT/US2015/021180 US2015021180W WO2015143001A1 WO 2015143001 A1 WO2015143001 A1 WO 2015143001A1 US 2015021180 W US2015021180 W US 2015021180W WO 2015143001 A1 WO2015143001 A1 WO 2015143001A1
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Prior art keywords
astaxanthin
phospholipid
dietary supplement
composition
sphingolipid
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PCT/US2015/021180
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English (en)
Inventor
John Minatelli
W. Stephen Hill
Rudi Moerck
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U.S. Nutraceuticals, Llc D/B/A Valensa International
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Publication date
Priority claimed from US14/219,484 external-priority patent/US20140205627A1/en
Priority claimed from US14/658,457 external-priority patent/US9763897B2/en
Application filed by U.S. Nutraceuticals, Llc D/B/A Valensa International filed Critical U.S. Nutraceuticals, Llc D/B/A Valensa International
Priority to DE212015000033.8U priority Critical patent/DE212015000033U1/de
Publication of WO2015143001A1 publication Critical patent/WO2015143001A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • 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
    • A61K36/05—Chlorophycota or chlorophyta (green algae), e.g. Chlorella
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4875—Compounds of unknown constitution, e.g. material from plants or animals

Definitions

  • compositions and associated methods that use astaxanthin and phospholipids to treat humans.
  • this krill and/or marine oil can be obtained by the combination of detailed steps as taught in the '808 application, by placing krill and/or marine material in a ketone solvent, separating the liquid and solid contents, recovering a first lipid rich fraction from the liquid contents by evaporation, placing the solid contents and organic solvent in an organic solvent of the type as taught in the specification, separating the liquid and solid contents, recovering a second lipid rich fraction by evaporation of the solvent from the liquid contents and recovering the solid contents.
  • the resultant krill oil extract has also been used in an attempt to decrease lipid profiles in patients with hyperliptdemia.
  • the '808 publication gives details regarding this krill oil as derived using those general steps identified above.
  • a dietary supplement composition includes a therapeutic amount of astaxanthin and at least one of a phospholipid, glycoiipid, and sphingolipid, and formulated into an oral dosage form.
  • the astaxanthin is 0.1 to 15 percent by weight of the at least one phospholipid, glycoiipid, and sphingolipid.
  • the astaxanthin may be derived from a synthetic or natural ester or synthetic diol in an example.
  • the dietary supplement composition is formulated to treat a cardiovascular disease, disorder or impairment in humans.
  • it is formulated to treat a neurological disease, disorder or impairment in humans.
  • it is formulated to treat a cognitive disease, disorder or impairment in humans or treat a dermatological disease, disorder or impairment in humans. It can be formulated to treat an
  • the dietary supplement composition may include a pharmaceutical or food grade diluent.
  • the phospholipid may include at least one of Phosphatidylcholine, Phosphatidylethanoiamine, Phosphatidyiserine, Phosphatidylinositoi, Phosphatide acid, Lyso-Phosphatidylcholine, Lyso-Phosphatidylethanolamine, and Lyso- Phosphatidylserine, in an example.
  • the phospholipid may be derived from at least one of a plant, algae and animal source or synthetic derivative.
  • the composition may include 0.5 to 12 mg of astaxanthin and 50 to 500 mg of the at least one of
  • the dietary supplement composition may be formulated into a single dosage capsule.
  • the dietary supplement composition includes a therapeutic amount of astaxanthin derived from a synthetic ester or dio!, and at least one of a phospholipid, glycolipid, and sphingolipid, and formulated into an oral dosage form.
  • the astaxanthin is 0.1 to 15 percent by weight of the at least one phospholipid, glycolipid, and sphingolipid.
  • the composition is formulated to treat low density lipoprotein (LDL) oxidation in humans.
  • LDL low density lipoprotein
  • [0009JA method to treat low density lipoprotein (LDL) oxidation in humans includes administering a therapeutic amount of a dietary supplement composition comprising 0.5 to 12 mg of astaxanthin derived from a synthetic ester or diol, and at least one of a phospholipid, glycolipid, and sphingolipid, and formulated into an oral dosage form, wherein the astaxanthin is 0.1 to 15 percent by weight of the at least one phospholipid, glycolipid and sphingolipid.
  • a dietary supplement composition comprising 0.5 to 12 mg of astaxanthin derived from a synthetic ester or diol, and at least one of a phospholipid, glycolipid, and sphingolipid, and formulated into an oral dosage form, wherein the astaxanthin is 0.1 to 15 percent by weight of the at least one phospholipid, glycolipid and sphingolipid.
  • composition as related to the kril! oil disclosure in the parent and
  • grandparent 704 and '531 patents includes EPA and DHA functionaiized as marine phospholipids and acyltriglycerides derived from krill.
  • a krill, algae, roe extract, fish oil, and phospholipid compositions in accordance with a non-limiting example, however, may include natural or synthetic or from a synthetic diol esterified astaxanthin.
  • DHA Docosahexaenoid Acid
  • Astaxanthin, Vitamin A, Vitamin E > 1.25 These amounts can vary depending on application and persons.
  • Astaxanthin is also known to reduce C-Reactive Protein (C-RP) blood levels in vivo.
  • C-RP C-Reactive Protein
  • Astaxanthin is so powerful that it has been shown to negate the pro-oxidant activity of Vioxx in vitro, a COX-2 inhibitor belonging to the NSAIDS drug class which is known to cause cellular membrane lipid per-oxidation leading to heart attacks and strokes. For this reason Vioxx was subsequently removed from the US market by the FDA.
  • Astaxanthin is also absorbed in vitro by lens epithelial cells where it suppresses UVB induced lipid per-oxidative mediated cell damage at umol/L concentrations.
  • Reduction of C-Reactive protein (CRP) reduction of LDL oxidation and an increase in the omega-3 index in vivo would presumably all be important positive contributors to cardiovascular health since each are well know biomarkers for cardiovascular health risk.
  • the composition includes 300-500 mg of krili oil or an algae based oil and 2 mg astaxanthin. Up to 8 mg and possibly 12 mg may be used in some examples. It may include 300-500 mg of at least one of a phospholipid, glycolipid, and sphingolipid.
  • Krill oil is typically produced from Antarctic krill (euphausia superba), which is a zooplankton (base of food chain). It is one of the most abundant marine biomass of about 500 million tons according to some estimates. Antarctic krill breeds in the pure uncontaminated deep sea waters. It is a non-exploited marine biomass and the catch per year is less than or equal to about 0.02% according to some estimates.
  • Astaxanthin has an excellent safety record.
  • a conducted study obtained the results as follows:
  • Oral LD 50 600 mg/kg (rats);
  • NOAEL 465 mg/kg (rats); or
  • astaxanthin has three prime sources. 3 mg astaxanthin per 240 g serving of non-farmed raised salmon or a 1% to 12% astaxanthin oleoresin or 1.5-2.5% beadlet derived from microalgae.
  • Literature references pertinent to the above discussion can be found in Lee et a!., Molecules and Cells 16(1): 97-105, 2003; Ohgami et al., Investigative Ophthalmology and Visual Science 44(6): 2694-2701 , 2003; Spver et al., J. of the American College of Nutrition 21 (5): October 2002; and Fry et al., University of Memphis, Human Performance Laboratories, 2001 and 2004, Reports 1 and 2.
  • the krill oil in one example is derived from Euphasia spp., comprising
  • the krill oil includes at least 15% EPA and 9% DHA, of which not less than 45% are in the form of phospholipids, and in one example, greater than 50%.
  • the composition can be delivered advantageously for therapeutic results with 1-4000 mg of krill oil delivered per daily dose.
  • 0.1-50 mg astaxanthin are supplemented to the krill oil per daily dose, and in one example, 0.1-12 mg of astaxanthin.
  • the astaxanthin is derived from Haematococcus pluvialis algae, Pfaffia, krill, or by synthetic routes, in the known free diol, monoester or diester form, and in one example, at a daily dose of 0.5-8 mg.
  • this amount of astaxanthin, especially as derived from Haematococcus pluvialis is applied to the range of 300-500 mg of krill oil or atgae based oil, the numericai range of about 0.1 to 2.7 percent by weight of the krill oil or algae based oil is obtained.
  • the composition may also include an n ⁇ 3 (omega-3) fatty acid rich oil derived from fish oil, algae oil, flax seed oil, or chia seed oil when the n-3 fatty acid comprises alpha-iinolenic, stearidonic, eicosapentaenoic or docosapentaenoic acid.
  • the composition may include naturally-derived and synthetic antioxidants that are added to retard degradation of fatty acids and astaxanthin.
  • krill oil or algae based oil in synergistic combination with other ingredients. It has also been determined that a fish oil derived, choline based, phospholipid bound ornega-3 fatty acid mixture including phospholipid bound polyunsaturated EPA and DHA is also advantageous for improving blood lipid profiles and reducing LDL either alone or admixed with other ingredients, for example, an LDL per-oxidation blocker.
  • Omega Choline 1520F is Omega Choline 1520F as a phospholipid, omega-3 preparation, which is derived from natural fish oil and sold by Enzymotec Ltd.
  • Omega Choline 1520F is Omega Choline 1520F as a phospholipid, omega-3 preparation, which is derived from natural fish oil and sold by Enzymotec Ltd.
  • Omega Choline 1520F is Omega Choline 1520F as a phospholipid, omega-3 preparation, which is derived from natural fish oil and sold by Enzymotec Ltd.
  • the method improves blood lipid profiles and either alone or in combination with added astaxanthin, such as a peroxidation blocker, and reduces LDL oxidation in a patient by administering a therapeutic amount of a composition including a mixture of fish oil derived, choline based, phospholipid bound omega-3 fatty acid mixture including phospholipid bound
  • the composition is supplemented in combination with astaxanthin in an oral dosage form.
  • the mixture of fish oil derived, choline based, phospholipid bound fatty acid mixture including polyunsaturated EPA and DHA in one example comprises Eicosapentaenoic (EPA) and Docosahexaenoic (DHA) fatty acids in the form of triacylglycerides and phospholipids.
  • the omega choline includes at least 7% EPA and 12% DHA, of which not less than 15% are in the form of phospholipids.
  • an instant formulation can be used for LDL reduction using only a mixture of fish oil derived, choline based, phospholipid bound fatty acid mixture including polyunsaturated EPA and DHA. It is also possible to use a mixture of fish oil derived, choline based, phospholipid bound omega-3 fatty acid mixture (including polyunsaturated EPA and DHA) mixed with astaxanthin, It should also be understood that an enriched version of a mixture of fish oil derived, choline based, phospholipid bound fatty acid mixture including polyunsaturated EPA and DHA can be used wherein the fraction of added fish oil diluents has been decreased and the proportion of fish oil derived phospholipids has been increased. This can be accomplished by using supercritical C02 and/or solvent extractions for selective removal of triacylglycerides from phospholipids.
  • the composition may also include a natural or synthetic
  • composition may also include a gamma-iinoleic acid rich oil comprising Borage (Borago officinalis L) or Safflower (Carthamus tinctonus L), which delivers a metabolic precursor to PGEi synthesis.
  • the composition may also include an n-3 (omega-3) fatty acid rich oil derived from fish oil, algae oii, flax seed oil, chia seed oil or perilla seed oil wherein the n-3 fatty acid source comprises alpha-linolenic, stearidonic, eicosapentaenoic or
  • the composition may include naturally-derived and synthetic antioxidants that are added to retard degradation of fatty acids such as tocopherols, tocotrienols, carnosic acid or carnosol and/or astaxanthin.
  • osteoarthritis and joint pain For example, one clinical trial such as described in commonly assigned U.S. Patent No. 8,481 ,072, the disclosure which is hereby incorporated by reference in its entirety, uses 15 mg of astaxanthin. It has now been determined that lower dosages of astaxanthin may be used instead of these much higher dosages such as 15 mg as in some clinical trials for osteoarthritis or other uses, including cardiovascular treatment, when it is added with at least one of a phospholipid, glycolipid, and sphingolipid or other phospholipids. A pharmaceutical or food grade diluent may be added or other surfactant.
  • Phospholipids may include plant based phospholipids such as from lecithin and lysophospholipids and/or glycophospholipids, including perilla oil such as described in commonly assigned U.S. Patent No. 8,784,904, the disclosure which is hereby incorporated by reference in its entirety. Astaxanthin levels could very from 0.5-2 mg and 0.5-4 mg and in one embodiment is 2-4 mg or 2-6 mg and as broad as 0.5-12 mg and 7-12 mg.
  • herring roe extract As the source of phospholipids that may have some EPA and DHA. Synergistic results are obtained and vast improvements seen.
  • phospholipids from herring roe improved phospholipid and glucose tolerance in healthy, young adults as published by Bjorndal et al., Lipids in Health Disease, 2014, 13:82.
  • the pure roe phospholipid may be formed using extraction techniques. It is a honey-like product that is thinned or diluted with fish oil and/or perilla oil or other seed or plant oil, in an example.
  • the herring roe extract is processed in one example using extraction by ethanol. Triacylglycerides are added and ethanol stripped out to have a robust solution. Seed oil, such as the perilla seed oil as described in the incorporated by reference '904 patent, may be added back to the ethanol extract before stripping to thin and form a high level phospholipid blend.
  • the roe oil extract may be mixed with fish oil and/or seed oil, such as the perilla, or any other marine oil.
  • the herring egg roe extract is mixed with perilla seed oil of at least 1 :1 and preferably as high as 6:1 ALA to LA with the concentrate as having at least 50%, and in another example 60%
  • phospholipids and in another example at least 30%, and in another example 40% triglycerides.
  • An example composition includes a combination of a roe extract from herring or a phospholipid rich roe extract with phospholipid bound EPA and DHA admixed with seed/fish oil and/or seed oil where the seed oil has a ratio of ALA to LA between 1 :1 and 1 :6, and including astaxanthin in one example of about 2-4 mg or 0.5 to 12 mg or other ranges as noted above.
  • the amount of roe egg extract mixed with the seed oil such as periila oil varies and is about 150 to 500 mg, or 300 to 500 mg, or up to 1 ,000 mg daily dose in one example and may include hyaluronic acid.
  • plant based phospholipids may be used, including commercially available lecithins and an egg yolk derivative, including lysophosphofipids and glycophospholipids to act as surfactants. It is possible to use sunflower-based phospholipids and natural plant-based oils and natural surfactant extracts.
  • the astaxanthin is enhanced with fats, surfactants, or phospholipids and can be delivered more efficiently with phospholipids and sunflower based and/or the lipophilic perilia oil as described before.
  • the periila oil is formed as a shelf stable, supercritical, C02 fluid extracted seed oil derived from a cracked biomass of per/7/a frutescens from 60 to 95 percent w/w of PUFAs in a ratio of from 4:1 to 6:1 alpha-linolenic acid (ALA) to linoleic acid (LA).
  • ALA alpha-linolenic acid
  • LA linoleic acid
  • the periila frutescens derived seed oil is made in an example by subjecting the periila frutescens seed to supercritical fluid CO2 extraction to produce a seed oil extract; fractionating the resulting seed oil extract in separate pressure step-down stages for collecting light and heavy fractions of seed oil extract; and separating the heavy fraction from the light fraction to form the final seed oil from the heavy fraction.
  • Selected antioxidants are included in another example and the periila oil includes a mixture of selected lipophilic and hydrophiiic antioxidants.
  • Lipophilic antioxidants can be used either alone or in combination with at least one of: a) phenolic antioxidants including at least one of sage, oregano, and rosemary; b) tocopherol; c) tocotrienol(s); d) carotenoids including at least one of astaxanthin, lutein, and zeaxanthin; e) ascorbylacetate; f) ascorbylpalmitate; g) Butylated hydroxytoluene (BHT); h)
  • BHT Butylated hydroxytoluene
  • a hydrophiiic antioxidant or sequesterant may include hydrophiiic phenolic antioxidants including at least one of grape seed extract, tea extracts, ascorbic acid, citric acid, tartaric acid, and malic acid.
  • a peroxide value of this periila seed oil is under 10.0 meq/Km.
  • this periila seed oil is from 85 to 95 percent w/w of PUFAs and the PUFAs are at least greater than 56 percent alpha-linolenic acid (ALA).
  • the periila seed oil is shelf stable at room temperature up to 32 months, in another example, this perilla seed oil is derived from a premilied or flake-rolled cracked biomass of perilla frutescens.
  • the mixture of selected antioxidants may include astaxanthin, phenolic antioxidants and natural tocopherols.
  • the perilla seed oil may also include at least one of dispersed nano- and micro-particles of rice or sugar cane based poltcosanol,
  • the composition is encapsulated into a single dosage capsule and referred to as a deep ocean caviar capsule
  • the encapsulated composition includes herring caviar phospholipid extract (herring roe) perilla ⁇ perilla frutescens) seed extract, olive oil, Zanthin® astaxanthin (Haematococcus pluvialis algae extract), gelatin, spice extract, non-GMO natural tocopherols, cholecalciferoi, riboflavin, and methylcobalamin.
  • the composition includes fish as herring roe and tilapia gelatin. It may include low molecular weight hyaluronic acid as an additive for joint care. An example is set forth in the following chart.
  • Vitamin B 2 (Riboflavin) 1.7 mg; 100% DV
  • the processing components may contain a mix of marine omega-3 phospholipids derived from herring caviar and perilia seed oil. It may contain an 02BTM botanical peroxidation blocker, including spice extract, non-GMO tocopherols and ascorbyl palmitate. It can be packaged as a bulk product in sealed drums 45 and 190 kg net with inert headspace, complying with European and American standards for food products. It preferably stores at below room temperature. The product is protected against light and heat. If drums are opened for sampling, the headspace can be flushed with inert gas during sampling and prior to storing.
  • 02BTM botanical peroxidation blocker including spice extract, non-GMO tocopherols and ascorbyl palmitate. It can be packaged as a bulk product in sealed drums 45 and 190 kg net with inert headspace, complying with European and American standards for food products. It preferably stores at below room temperature. The product is protected against light and heat. If drums are opened for sampling, the headspace can be flushed with in
  • Heavy metals (sum of Pb, mg/kg 10 AM1015 Hg, Cd & in-organic As) 2 )
  • the astaxanthin is at least about 0.1 to about 15 percent by weight of the at least one phospholipid, glycolipid, and sphingolipid.
  • the astaxanthin in an example is derived from a natural or synthetic ester or synthetic dioi.
  • a pharmaceutical or food grade diluent may be added. It can be used to treat various disorders, including cardiobasciuar, neurological, cognitive, dermatological diseases, disorders or impairments, and joint pain problems.
  • a dietary supplement composition is formed and can be formulated in a therapeutic amount to treat and alleviate symptoms of joint pain in a person having joint pain.
  • the triglycerides have two types of molecules as a glycerol and three fatty acids, while the phospholipids contain glycerol and fatty acids, but have one glycerol molecule and two fatty acid molecules. In place of that third fatty acid, a polar group is instead attached to the glycerol molecule so that the phospholipids are partly hydrophilic as compared to hydrophobic triglycerides. Lysophosphoitpids may be used as a derivative of a phospholipid in which one or both acyl derivatives have been removed by hydrolysis. Lecithin and its derivatives may be used as an emulsifier and surfactant as a wetting agent to reduce surface tension of liquids. Other phospholipids may be used. Different phospholipids include
  • phosphatidylinositoi phosphatidic acid
  • lyso-phosphatidylcholine lyso- phosphatidyiethanolamine
  • lyso-Phosphatidylserine Some may be derived from egg yo!k and extracted chemically using hexane, ethanoi, acetone, petroleum ether or benzene, and also extracted mechanically, including from different sources such as soybeans, eggs, milk, marine sources, and sunflower.
  • phospholipids may include those products mentioned before, including phosphatidic acid.
  • compositions such as lecithin may be hydrolyzed
  • lysophospholipids that can be added to the roe extract as explained above.
  • One phospholipase is phospholipase A2 where the fatty acid is removed at the C2 position of glycerol. Fractionation may be used.
  • glycolipids are primarily derivatives of ceramides where a fatty acid is bonded or connected to the amino alcohol sphingosine. It should be understood that the phospholipid sphingomyelin is also derived from a ceramide. Glycolipids, however, contain no phosphates in comparison to the phospholipids. The fat is connected to a sugar molecule in a glycolipid and are fats bonded to sugars. Because it is built from a sphingosine, fat and sugar, some refer to it as a glycosphingolipid.
  • a sphingolipid is a lipid that contains a backbone of sphingoid basis and set of aiphatic amino alcohols that include the sphingosine.
  • the phospholipid and other components may be derived from at least one of a plant, algae and animal source, or a synthetic derivative thereof.
  • the phospholipid and other components may be derived from at least one of soybean, sunflower, grapeseed, egg yolk, krill, fish body, fish roe, squid, and aigae.
  • the phospholipid and other components may be formed as compound rich mono- or di-glcerides or fatty acids where the fatty acid contains between 2 and 20 carbon atoms.
  • the composition is formed by dispersing the astaxanthin and phospholipid and optionally a diluent under high shear conditions.
  • the diluent may be a pharmaceutical or food grade diluent as known to those skilled in the art.
  • the astaxanthin is about 2 to about 10 percent by weight of the phospholipid and glycolipid and derived from a natural or synthetic ester or synthetic dioi. In yet another example, 50 to 500 mg of phospholipid, glycolipid, and sphingolipid may be used.
  • the dietary supplement composition may be formulated into a single dosage capsule.
  • the astaxanthin may be derived from Haematococcus piuvialis algae, Pfaffia, krili, or by synthetic routes, in the free or synthetic dioi, monoester or diester form, both natural and synthetic, at a daily dose of 0.5-8 mg or 0.5-12 mg, in one example, and in another example, 1-2 mg, 2-4 mg, 1-6 mg, and other ranges, and up to 12 mg, including 7-12 mg.
  • the astaxanthin can vary between 2 to 4 mg or 0.5 to 12 mg and other ranges as disclosed above. It should be understood that the astaxanthin and the at least one of phospholipid, glycolipid, and sphingolipid or other components as described above may be used for many different purposes and results, it may be used to aid in treating or improving blood lipid profiles and reducing LDL per-oxidation in humans. It may be used to counter or treat depression and other neurologica! disorders. It may be used for respiratory illnesses and skin ailments or diseases.
  • the composition may also include an n-3 (omega-3) fatty acid rich oil derived from fish oil, algae oil, flax seed oil, chia seed oil, or perilla seed oil.
  • n-3 fatty acid comprises alpha-linolenic, stearidonic, eicosapentaenoic or
  • docosapentaenoic acid in one example composition as noted before, it has been found that an algae based oil may be used instead of kril! oil. Hydrofyzed or unhydro!yzed collagen and eiastin derived from eggshell membranes can also be advantageously added.
  • the composition may also include anti-inflammatory and/or natural joint health promoting compounds comprising at least one of preparations of green lipped mussel (Perna canaliculus), Boswellia serrata, turmeric (Curcuma longa), stinging nettle (Urtica dioica), Andrographis, Cat's claw (Uncaria tomentosa), bromelain,
  • composition may include naturally-derived and synthetic antioxidants that are added to retard degradation of fatty acids and astaxanthin.
  • a pure diol of the S, S'astaxanthin including a synthetic diol with the surfactant and/or phospholipid. It is possible to use that pure diol in combination with the EPA rich algae based oil or other fish, roe extract, or plant based oil and/or phospholipid and/or surfactant as described above, and which is admixed with either astaxanthin derived from Haematococcus pluvialis or the free diol form in substantially pure S,S' enantiomer form. It is possible to add synthetically derived mixed enantiomers of the diol.
  • the diol of the S, S'astaxanthin is possible because in cases of kriil oil and algae and phospholipids and Hp derived and other types, there are principally diesters and monoesters respectively with very little diol, which is insoluble. Some research indicates that it may be many times more btoavai!able than either the monoester or diester form. It is possible to synthesize asymmetrically the S.S' pure diol. Despite the pure diol's poor solubility in some examples, there may be an active transport mechanism related to its bioavailability, or conversely, that only in the diol form is the monoester or diester forms transferred from the intestines to the blood.
  • the phospholipid or glycoiipid based product presenting EPA and/or DHA along with the added astaxanthin in its various forms and especially the S,S' enantiomeric form in principally monoester form from Haematococcus pluvialis or pure diol form from asymmetric synthesis could be viable.
  • astaxanthin (3,3'-dihydroxy-p-P-carotene-4,4'-dione) is a xanthophyll carotenoid found in many marine species including crustaceans, salmonid fish and algae. Astaxanthin cannot be synthesized by mammals, but when consumed in the diet has shown effectiveness as an antioxidant, anti-inflammatory agent and with benefit to eye health, heart health, and the immune system.
  • Astaxanthin has a hydroxyl group on each ⁇ -ionone moiety, therefore it can be found in its free (diol) form as well as mono- or di-esterified.
  • astaxanthin is commonly found as a mixture: primarily mono-esters of C12-C18 fatty acids and lesser amounts of di-ester and free diol.
  • Synthetic astaxanthin is commonly provided in only the free diol form.
  • the astaxanthin molecule has two E/Z chirai centers and three optical R/S isomers.
  • Haematococcus pluvialis algae produces natural astaxanthin solely in the (3S,3'S) isomer. This is explained in the article from Renstrom B., G. Borch,
  • yeast Phaffia rhodozyma synthesizes only the 3R,3'R configuration. This is explained in the article from Andrewes A. and M. Starr entitled, “(3R,37?)-Astaxanthin from the Yeast Phaffia Rhodozyma," Phytochemistry,
  • Wild salmon predominately contain the (3S,3'S) form with a (3S,3'S), (3R,3'S), and (3R,3'R) isomer ratio of 22:1 :5. This is explained in the article from Turujman, S, W. Warner, R. Wei and R. Albert entitled, "Rapid Liquid Chromatographic Method to Distinguish Wild Salmon From Aquacultured Salmon Fed Synthetic Astaxanthin," J. AOAC Int., 80(3): 622-632, 1997, the disclosure which is hereby incorporated by reference in its entirety.
  • astaxanthin produced by traditional synthesis will contain a racemic mixture in a (3S,3'S), (3R,3'S; meso), (3R3'R) ratio of 1 :2:1. This ratio is also seen in many species of shrimp, which are able to racemize (3S,3'S) to the meso form. This is explained in the article from Schiedt, K., S. Bischof and E. Glinz entitled, "Metabolism of Carotenoids and in vivo Racemization of (3S,3'S)-Astaxanthin in the Crustacean Penaeus," Methods in Enzymology, 214:148-168, 1993, the disclosure which is hereby incorporated by reference in its entirety.
  • Astaxanthin for use in human food supplements is currently derived from the cultivated freshwater algae Haematococcus pluvialis. This algae produces 3S,3'S astaxanthin ester in a fatty acid matrix which can be isolated with solvent or carbon dioxide extraction. This oily extract can be used directly in edible formulations or further processed into solid powder or beadlet preparations. Many clinical studies have been conducted with H. pluvialis derived astaxanthin to demonstrate beneficial health effects and safety. Food additive approvals for astaxanthin-rich algae extracts have been approved for many suppliers in the US and EU.
  • Haematococcus algae cultivation for use in dietary supplements cannot always match demand for use of astaxanthin in dietary supplements.
  • Use of synthetic astaxanthin diol can also benefit applications which need a concentrated, standardized astaxanthin source.
  • Conventional racemic synthetic astaxanthin sources are used as a colorant in Salmonid aquaculture as a feed ingredient. This racemic mixture may have limited use since only one-quarter of the compound is the 3S,3'S isomer commonly found in natural Salmon and has been studied in humans for efficacy and safety.
  • Astaxanthin may also be synthesized with in a stereospecific manner, so that the output is exclusively the generally accepted 3S,3'S isomer in a free dioi form.
  • the free dio! crystals can be suspended in a vegetable oil or solid beadlet for use in edible preparations or pill, capsule, tablet form.
  • the 3S,3'S product has the advantage of greater consistency than algal preparations and also with lower odor. Therefore algal- derived astaxanthin can be replaced with synthetic 3S,3'S astaxanthin dio! in existing formulations with the same or increased effectiveness.
  • hyaluronic acid alone and/or in combination with astaxanthin is beneficial and synergistic.
  • low molecular weight hyaluronic acid in its different forms can be given to patients in an amount from 1-500 mg per day and preferably about 10-70 mg per day, and in another example, 20-60 mg, 25-50 mg, 35 mg, and 45 mg.
  • Astaxanthin of about 2-4 mg may be added in an example, but could range from 0.5 to 4 mg a day, and 7-12 mg range in another example, or 0.5 to 12 mg.
  • the hyaluronic acid may be given in the form of a proinflammatory low molecular weight sodium hyaluronate fragments that are about 0.5-300 kDa corresponding to the pro-inflammatory low molecular weight fragments.
  • astaxanthin and phospholipids such as from kri!l oil, algae oil, roe, fish oil product, or plant based oils helps in delivering the hyaluronic acid, still the low molecular weight hyaiuronic acid and in the form of the fragments preferably is still small enough to enter through the gut and be used in an oral administration.
  • astaxanthin with the low molecular weight hyaiuronic acid.
  • Different amounts can be used, and in one example, 2-4 mg per day, and in another example, 0.5-12 mg per day can be used with low molecular weight hyaluronic acid such as the amount of 1-500 mg and preferably about 10-70 mg and with 0.5-12 mg or 4-12 mg of astaxanthin.
  • About 40-120 mg of low molecular weight hyaluronic acid may be used in an example.
  • a dosage of astaxanthin may be about 6-8 mg and the low molecular weight hyaluronic acid could be in the range of about 60-80 mg.
  • hyaluronic acid fragments such as the pro-inflammatory low molecular weight sodium hyaluronate fragments are potent as innate immune system ceil receptors signaling molecules associated with the inflammatory cascade and the oral hyaluronic acid in the form of low molecular weight fragments can reach joints as compared to the higher molecular weight hyaluronic acid that is injected since it is not orally administered.
  • the composition may include with the astaxanthin and phospholipid a pro-inflammatory microbial fermented sodium hyaluronate fragments having a molecular weight of 0,3 to 300 kiiodaltons (kDa), and in an example, from 0.5 to 230 kDa, and from 0.5 to 100 kDa, all in an oral dosage form for alleviating symptoms of non-disease state joint pain, but may also be used to treat and alleviate symptoms of osteoarthritis and/or rheumatoid arthritis when combined with the astaxanthin and phospholipid as described above.
  • kDa kiiodaltons
  • hyaluronic acid or sodium hyaluronate can be derived from microbial fermentation or animal tissue.
  • Daily dosages can vary, but can be about 1-500 mg of hyaiuronan, and in an example, between 10 and 70 mg/dose and at 20 to 60, 25 to 50, and 35 and 45 mg per dose.
  • This hyaiuronan or hyaluronic acid and its fragments are micro- or nano-dispersed within the composition.
  • the hyaluronic acid is derived from a
  • biofermentation process or also from microbial fermentation or animal tissue.
  • the pure low molecular weight hyaluronic acid oligomers are fragments and derived principally and practically from microbial fermentation, but can also be derived from hydrolyzed animal tissue.
  • This microbial fermentation process is known to produce extraordinarily pure low molecular sodium hyaluronate free from amino acid conjugation.
  • the resulting low molecular weight hyaluronic acid is obtained from a mutant strain of streptococcus bacteria with the fermentation process, followed by isolation and denaturation of the organism and its proteins with ethanol and heat, followed by filtration and chemical modification of its molecular weight with acid aqueous chemical hydrolysis as a chemical reaction.
  • the final product is isolated by ethanol precipitation of the sodium salt and drying to produce proinflammatory low molecular weight microbial fermented sodium hyaluronate fragments. It is a chemical reaction degradation product of a mutant strain streptococcus bacteria! fermentation using in one example the bacterial strain streptococcus zooepidemicus and the production strain is a non-hemolytic mutant of a parent strain, NCTC7023.
  • the production strain is produced by nitroso-guanidine mutagenesis with a unique ribosomai genome sequence, not naturally found in nature.
  • the major manufacturing steps have three stages of: 1) fermentation; 2) purification; and 3) refining.
  • Other sources of the low molecular weight hyaluronic acid may include chicken sternal cartilage extract and may include elastin, elastin precursors, and collagen. It may be contained in a matrix form with chondroitin sulfate and naturally occurring hydrolyzed collagen Type-il nutraceutical ingredients. It may include the Type-I collagen derived from bovine collagen or chicken sternal cartilage collagen Type-li or natural eggshell membrane that includes hyaluronic acid that is processed to form low molecular weight hyaluronic acid. It may be derived from rooster combs.
  • the composition may include collagen, boron, and hyaluronic acid. Astaxanthin may be used alone such as 0.5 to 4 mg, or 0.5 to 12 mg of astaxanthin plus 30-45 mg of low molecular weight hyaluronic acid, but smaller amounts can be used.
  • a cartilage blend as a mixture of cartilage and salt may be used.
  • the cartilage blend includes cartilage and potassium chloride to provide undenatured Type-ll collagen. It may also include glucosamine hydrochloride and
  • MSM methylsulfonymethane
  • omega-3 fatty acids such as EPA and DHA. It is known that fish and krili do not produce omega-3 fatty acids but accumulate those fatty acids from the algae they consume. Omega-3 bioavailability varies and is made available at the site of physiological activity depending on what form it is contained. For example, fish oil contains omega-3 fatty acids in a triglyceride form that are insoluble in water and require emulsification by bile salts via the formation of micelles and subsequent digestion by enzymes and subsequent absorption. Those omega-3 fatty acids that are bound to polar lipids, such as phospholipids and
  • glycolipids are not dependent on bile for digestion and go through a simpler digestion process before absorption.
  • these omega-3 fatty acids such as from an algae based oil, have greater bioavailability for cell growth and functioning as compared to the omega-3 triglycerides of fish oil.
  • algae There are many varieties of algae that contain EPA conjugated with phospholipid and glycolipid polar lipids or contain EPA and DHA conjugated with phospholipids and glycolipids.
  • algae or “microaigae” may be used interchangeably to each other with microaigae referring to photosynthetic organisms that are native to aquatic or marine habitats and are too small to be seen easily as individual organisms with the naked eye.
  • photoautotropic refers to growth with light as the primary source of energy and carbon dioxide as the primary source of carbon.
  • biomass may refer to a living or recently dead biological cellular material derived from plants or animals.
  • polar may refer to the compound that has portions of negative and/or positive charges forming negative and/or positive poles.
  • oil may refer to a combination of fractionabie lipid fractions of a biomass. As known to those skilled in the art, this may include the entire range of various hydrocarbon soluble in non-polar solvents and insoluble, or relatively insoluble in water as known to those skilled in the art.
  • the microaigae may also include any naturally occurring species or any genetically engineered microaigae to have improved lipid production.
  • This algae based oil provides an aigae sourced EPA or an EPA/DHA based oil in which oils are present in phospholipid and glycerotipid forms, as glycolipids.
  • Different algae based oils derived from different microaigae may be used.
  • One preferred example algae based oil has the EPA titre higher than the DHA as compared to a class of omega-3's from fish oils that are triacylglycerides. These algae based oils are rich in EPA and in the phospholipid and glycolipid forms.
  • An example marine based aigae oil is produced by Parry Nutraceuticals as a division of EID Parry (India) Ltd. as an omega-3 (EPA) oil.
  • the following first table shows the specification of an algae based oil as manufactured by Parry Nutraceuticals identified above, followed by a second table for a fatty acid profile chart of that algae based oil.
  • a third table is a comparative chart of the fatty acid profiles for non-algae based oils. These charts show that the algae based oil has a high EPA content of phospholipids and glycolipids.
  • the algae based oils may be processed to enrich selected constituents using supercritical CO2 and/or solvent extractions as noted above and other techniques.
  • nannochloropsis oculata as a source of EPA.
  • Another algae that may be used is thalassiosira weissflogii such as described in U.S. Patent No. 8,030,037 assigned to the above-mentioned Parry Nutraceuticals, a Division of EID Parry (India) Ltd., the disclosure which is hereby incorporated by reference in its entirety.
  • Other types of algae as disclosed include chaetoceros sp. or prymnesiophyta or green algae such as chlorophyta and other microalgae that are diamons tiatoms.
  • the chlorophyta could be tetraselmis sp. and include prymnesiophyta such as the class prymnesiophyceae and such as the order isochrysales and more specifically, isochrysis sp. or pavtova sp.
  • algae/fungi phosphoiipid/glycolipid sources include: grateloupia turuturu; porphyridium cruentum; monodus subterraneus; phaeodactylum tncornutum; isochrysis galbana; navicula sp.; pythium irregule; nannochloropsis sp.; and nitzschia sp.
  • ⁇ Q07Z ⁇ Porphyridium cruentum is a red algae in the family porphyridtophyceae and also termed rhodophyta and is used as a source for fatty acids, lipids, cell-wall
  • polysaccharides and pigments The polysaccharides of this species are sulphated.
  • Some porphyridium cruentum biomass contains carbohydrates of up to 57%.
  • Phaeodactylum tricornutum is a diatom and unlike most diatoms, it can grow in the absence of silicon and the biogenesis of silicified frustules is facultative.
  • Isochrysis galbana is a microalgae and used in the bivalve aquaculture industry.
  • Navicula sp. is a boat-shaped algae and is a diatom. Pythium irregule is a soiiborne pathogen found on plant hosts.
  • Nannochloropsis sp. occurs in a marine environment, but also occurs in fresh and brackish water.
  • the species are small, nonmotiie spheres that do not express any distinct morphological feature.
  • These algae have chlorophyll A and lack chlorophyll B and C. They can build high concentrations of pigment such as astaxanthin, zeaxanthin and canthaxinthin. They are about 2-3 micrometers in diameter. They may accumulate high levels of polyunsaturated fatty acids.
  • Nitzschia sp. is a pinnate marine diatom and usually found in colder waters and associated with both Arctic and Antarctic polar sea ice where it is a dominant diatom. It produces a neurotoxin known as domoic acid which is responsible for amnesic shell fish poisoning. It may grow exponentially at temperatures between -4 and -6 degrees C. It may be processed to form and extrapolate the fatty acids.
  • microalgae As a source of polyunsaturated fatty acids, microalgae competes with other micro-organisms such as fungi and bacteria. There may be some bacterial strains that could be an EPA source, but microalgae has been found to be a more adequate and readily available source. Microalgae is a good source of oil and EPA when derived from phaeodactyium, isochrysis and monodus. The microalgae phaeodactylum thcornutum produces a high proportion of EPA. Other different strains and species of microalgae, fungi and possibly bacteria that can be used to source EPA include the following:
  • Different microalgae may be used to form the algae based oil comprising glycolipids and phospholipids and at least EPA and/or EPA DHA. Examples include: Chlorophyta, Cyanophyta (Cyanobacteria), and Heteromonyphyta.
  • the microalgae may be from one of the following classes: Bacillariophyceae, Eustigmatophyceae, and Chrysophyceae.
  • the microalgae may be from one of the following genera:
  • Nannochloropsis Chlorella, Dunaliella, Scenedesmus, Selenastrum, Oscillatoria, Phormidium, Spiruiina, Amphora, and Ochromonas.
  • microalgae species include: Achnanthes orientalis, Agmeneltum spp., Amphiprora hyaline, Amphora coffeiformis, Amphora coffeiformis var. linea, Amphora coffeiformis var. punctata, Amphora coffeiformis var. taylori, Amphora coffeiformis var. tenuis, Amphora americanissima, Amphora americanissima var.
  • Chaetoceros sp. Chlamydomas perigranulata, Chlorella anitrata, Chlorella antarctica, Chlorella aureoviridis, Chlorella Candida, Chlorella capsulate, Chlorella desiccate, Chlorella ellipsoidea, Chlorella emersonii, Chlorella fusca, Chlorella fusca var. vacuolata, Chlorella glucotropha, Chlorella infusionum, Chlorella infusionum var. actophila, Chlorella infusionum var.
  • Chlorella kessleri Chlorella lobophora
  • Chlorella luteoviridis Chlorella luteoviridis var. aureoviridis
  • Chlorella luteoviridis var. lutescens Chlorella miniata, Chlorella minutissima, Chlorella mutabitis, Chlorella nocturna, Chlorella ovalis, Chlorella parva, Chlorella photophila, Chlorella pringsheimii, Chlorella protothecoides, Chlorella protothecoides var. acidicola, Chlorella regularis, Chlorella regularis var. minima, Chlorella regularis var.
  • Nannochloris sp. Nannochloropsis salina, Nannochloropsis sp., Navicula acceptata, Navicuia biskanterae, Navicuia pseudotenelloides, Navicula peilicu!osa, Navicula saprophila, Navicula sp., Nephrochloris sp., Nephroselmis sp., Nitschia communis, Nitzschia alexandrina, Nitzschia closterium, Nitzschia communis, Nitzschia dissipata, Nitzschia frustulum, Nitzschia hantzschiana, Nitzschia inconspicua, Nitzschia intermedia, Nitzschia microcephala, Nitzschia pusilla, Nitzschia pusilla elliptica, Nitzschia pusilla monoensis, Nitzschia quadrangular, Nitzschia sp., Ochromona
  • Rhodococcus opacus Sarcinoid chrysophyte, Scenedesmus armatus, Schizochytrium, Spirogyra, Spirulina platensis, Stichococcus sp., Synechococcus sp., Synechocystisf, Tagetes erecta, Tagetes patula, Tetraedron, Tetraselmis sp., Tetraselmis suecica, Thalassiosira weissfiogii, and Viridiella fridericiana.
  • the microalgae are autotrophic.
  • yeast that can be used include: Cryptococcus curvatus, Cryptococcus terricolus, Lipomyces starkeyi, Lipomyces lipofer, Endomycopsis vernalis, Rhodotorula glutinis, Rhodotorula gracilis, Candida 107, Saccharomyces paradoxus, Saccharomyces mikatae, Saccharomyces bayanus, Saccharomyces cerevisiae, any Cryptococcus, C. neoformans, C.
  • fungi include Mortierella, Mortierrla vinacea, Mortierella alpine, Pythium debaryanum, Mucor circinelloides, Aspergillus ochraceus, Aspergillus terreus,
  • Rhizopus and Pythium.
  • bacteria may be used that includes lipids, proteins, and carbohydrates, whether naturally occurring or by genetic engineering.
  • bacteria include: Escherichia coli, Acinetobacter sp. any actinomycete, Mycobacterium tuberculosis, any streptomycete, Acinetobacter calcoaceticus, P.
  • aeruginosa Pseudomonas sp., R. erythropolis, N. erthopolis, Mycobacterium sp., B., U, zeae, U. maydis, B. lichenformis, S. marcescens, P. fluorescens, B. subtilis, B. brevis, ⁇ . polmyma, C. lepus, N. erthropolis, T. thiooxidans, D. polymorphs, P. aeruginosa and Rhodococcus opacus.
  • Possible algae sourced, EPA DHA based oils that are derived from an algae and contain glycol and phospholipid bound EPA and/or EPA/DHA and may include a significant amount of free fatty acids, triglycerides and phospholipids and glycoiipids in the range of 35-40% or more of total lipids are disclosed in the treatise "Chemicals from Microalgae” as edited by Zvi Cohen, CRC Press, 1999.
  • the algae oil was provided at 1.5 grams of EPA and no DHA as compared to krill oil that was provided at 1.02 grams EPA and 0.54 grams DHA.
  • the participants consumed both oils in random order and separated by seven days and the blood samples were collected before breakfast and at several time points up to 10 hours after taking the oils.
  • the researchers determined that the algae based oil had a greater concentration of EPA and plasma than krill oil with the EPA concentration higher with the algae based oil at 5, 6, 8 and 10 hours (P ⁇ 0.05) intended to be higher at 4 hours (P 0.094).
  • the maximum concentration (CMAX) of EPA was higher with algae oil than with krill oil (P 0.010).
  • This difference may relate to the different chemical composition and possibly the presence of the glycoiipids where the presence of DHA in krill oil limits the incorporation of EPA into plasma lipids.
  • the n-3 polyunsaturated fatty acids within glycoiipids as found in the algae oil, but not in a krill oil may be an effective system for delivering EPA to humans.
  • the incorporated by reference ⁇ 37 patent describes the benefit of using an algae based oil, and more particularly, a marine based algae oil and discloses different manufacturing and production techniques. icroaigae can be cultured
  • the concentrated microaigae products as disclosed in the ⁇ 37 patent may contain EPA and DHA and lipid products containing EPA and DHA purified from microaigae.
  • the concentrated microaigae composition may be prepared by cultivating microaigae photoautotrophically outdoors in open ponds under filtered sunlight in a continuous or batch mode and at a dilution rate of less than 35% per day.
  • the microaigae may be harvested in the exponential phase when the cell number is increasing at a rate of at least 20% of maximal rate.
  • the microaigae is concentrated.
  • at least 40% by weight of lipids in the microaigae are in the form of glycodiacyigiycerides, phosphodiacylglycerides, or a combination thereof and at least 5% by weight of the fatty acids are DHA, EPA, or a combination thereof.
  • the microaigae are Tetraselmis sp. cultivated at above 20°C or in another example at above 30°C.
  • the EPA yield in the microaigae has been found to be at least 10 mg/liter culture.
  • the microaigae can be Isochrvsis sp. or Pavlova sp. in another example, or are Thalassiosira sp. or Chaetecoros sp.
  • the microaigae may be different diatoms and are cultivated photoautotrophically outdoors in open ponds for at least 14 days under filtered sunlight and at least 20% by weight of the fatty acids are EPA.
  • the use of this algae based oil overcomes the technical problems associated with the dwindling supplies of fish oil and/or Antarctic kriil, which are now more difficult to harvest and obtain and use economically because these products are in high demand.
  • a major difference between fish oils and algae based oils is their structure.
  • Fish oils are storage lipids and are in the form of triacylglycerides.
  • the algae based oils as lipids are a mixture of storage lipids and membrane lipids.
  • the EPA and DHA present in algae based oils is mainly in the form of glycolipids and a small percentage is in the form of phospholipids. Glycolipids are primarily part of chloroplast membranes and phospholipids are part of cell membranes.
  • the ⁇ 37 patent describes various methods for culturing microalgae
  • shade cloth or netting can be used for this purpose. It was determined that for most strains, the optimal solar intensity for growth, for maintaining a pure culture, and for omega-3 fatty acid accumulation was about 40,000 to 50,000 lux, approximately half of the 110,000 lux of full sunlight. Shade cloth or netting is suitable for filtering the sunlight to the desired intensity.
  • microalgae photoautotrophically outdoors and produce EPA and DHA by using small dilutions and a slow dilution rate of less than 40% per day, preferably less than 35% per day, more preferably from about 15% to about 30% per day.
  • the dilution rate is 15-40% per day or 15-35% per day, and in yet other examples, the dilution rate is 10-30%, 10-35%, or 10-40% per day.
  • Another technique to successfully culture microalgae photoautotrophically outdoors and produce EPA and EPA DHA is to harvest the microalgae in exponential phase rather than stationary phase.
  • Harvesting in exponential phase reduces the risk of contamination in outdoor photoautotrophic cultures and has surprisingly been found to give a good yield of EPA and DHA.
  • To drive fat accumulation in microbial cultures the cultures are harvested in stationary phase because cells in the stationary phase tend to accumulate storage lipids.
  • the ⁇ 37 patent teaches that EPA and DHA accumulate in large amounts as membrane lipids in cultures harvested in the exponential phase.
  • the membrane lipids containing EPA and DHA are predominantly phosphodiacylglycerides and glycodiacylglycerides, rather than the triaclygiycerides found in storage lipids.
  • cultures are harvested often when ceil number is increasing at a rate at least 20% of the maximal rate, i.e., the maximal rate achieved at any stage during the outdoor photoautotrophic growth of the harvested culture.
  • the cultures are harvested in exponential phase when cell number is increasing at a rate of at least 30%, at least 40%, or at least 50% of maximai rate. It is also possible to use recombinant DNA techniques.
  • Example 1 The strain Thalassiosira sp. is a diatom and this strain used was isolated from Bay of Bengal, and it dominates during summer months. This example strain was isolated from seawater collected near Chemai, India, and the culture was maintained in open tubs. The particular strain was identified as Thalassiosira weissflogii, which is capable of growth at high temperatures (35-38°C). The fatty acid profile was good even when the alga was grown at high temperature with 25-30% EPA (as a percentage of fatty acids).
  • Culturing The lab cultures were maintained in tubs in an artificial seawater medium, under fluorescent lights (3000-4000 lux) and the temperature was maintained at 25°C. Initial expansion of the culture was done under laboratory condition in tubs. The dilution rate was 15% to 30% of the total culture volume per day. Once the volume was 40-50 liters, it was transferred to an outdoor pond. The outdoor ponds were covered with netting to control the light (40,000 to 50,000 lux). The dilution continued until the culture reached 100,000 liters volume. The culture was held in 500 square meter ponds at this time with a culture depth of 20 cm. The culture was stirred with a paddle wheel and CO2 was mixed to keep the culture pH neutral.
  • the whole pond was harvested by filtration.
  • the filtered biomass was washed with saltwater (15 parts per thousand concentration) and then spray dried.
  • the mode of culturing was batch mode.
  • the EPA productivity was 2-3 mg/lit day.
  • the ponds can also be run continuously for several weeks by harvesting part of the culture, recycling the filtrate into the ponds and replenishing required nutrients.
  • Example 2 The strain Tetraselmis sp. is in the division Chlorophyta and the class Prosinophyceae or Micromanadophyceae. This strain was obtained from the Central Marine Fisheries Research Institute, India. It was isolated from the local marine habitats in India. The culture was maintained in flasks in artificial seawater medium, and expanded as described for Thalassiosira. With culture outdoors in open ponds as described for Thalassiosira, the strain gave a good lipid yield (200-300 mg/liter) and an EPA content of 6-7% of fatty acids.
  • Example 3 The strain Chaetoceros sp. is another diatom strain obtained from the Centra! Marine Fisheries Research Institute, India, and isolated from local marine habitats in India. Chaetoceros sp. was maintained in flasks and cultivated in outdoor ponds photoautotrophicaily as described in Example 1. It gave similar EPA productivity and EPA content as Thalassiosira as described in Example 1.
  • Example 4 The strain Isochrysis sp. is in the Prymnesiophyta, class Prymnesiophyceae, order Isochrysidates. It was obtained from the Central Marine Fisheries Research Institute, India, and isolated from local marine habitats in India. It was maintained and grown as described in Example 1. It was expanded from
  • Example 5 Harvesting and Drying: The harvesting may be done by floccuiation.
  • the commonly used flocculants include Alum with polymer and FeCI3 with or without polymer and chitosan.
  • the concentration of flocculent will depend on the cell number in the culture before harvest. The range may vary from 100 ppm to 500 ppm.
  • harvesting is done by filtration using appropriate meshes. Removal of adhered chemicals (other than salt) is accomplished by washing the cells in low salinity water.
  • the harvested slurry is then taken for spray drying.
  • the slurry is
  • the concentration of encapsulating agent may vary from 0.1 to 1.0% on a dry weight basis. Modified starch is a suitable encapsulating agent.
  • the spray dryer is usually an atomizer or nozzle type. The inlet temperature ranges from 160 to 190°C and the outlet temperature ranges from 60 to 90°C. The spray dried powder is used immediately for extraction, if storage is required, the powder is packed in aluminum laminated pouches and sealed after displacing the air by nitrogen. The packed powder is stored at ambient temperature until further use.
  • Example 6 Extraction of EPA/DHA is carried out using a wet slurry or dry powder and solvents, which include hexane, ethanol, methanol, acetone, ethyl acetate, isopropanol and cycfohexane and water, either alone or in combination of two solvents.
  • the solvent to biomass ratio depends on the starting material. If it is a slurry, the ratio is 1 :2 to 1 :10. With a spray dried powder, on the other hand, the ratio Is 1 :4 to 1 :30.
  • the extraction is carried out in an extraction vessel under inert atmosphere, with
  • solvent temperature ranges from 25 to 60°C and with time varying from one hour to 10 hours. Solvent addition is made one time or in parts based on the lipid level in the cells.
  • the mixture is passed through a centrifuge or filtration system to remove the cell debris.
  • the lipid in the filtrate is concentrated by removing the solvent by distillation, which is carried out under vacuum.
  • the resulting product is a crude lipid extract, which contains approximately 10% omega-3 fatty acid (EPA DHA).
  • the extract can be used as it is or purified further to enrich the omega-3 fatty acids. Further purification may involve removal of unsaponifiables such as pigments, sterols and their esters.
  • the composition may have other uses besides improving blood lipid profiles and reducing low density lipoprotein (LDL) per-oxidation in humans or used with joint care treatment to reduce joint pain.
  • Possible uses of the composition include use as a treatment for depression that may counter neurological disorders associated with depression. This could include treatment for a deficiency of neurotransmitters at postsynaptic receptor sites.
  • the composition may be used to treat manic episodes in bipolar treatments and treat panic disorder and reduce the frequency and severity of panic attacks and the severity of agoraphobia.
  • the composition may be used to treat Obsessive Compulsive Disorder (OCD) and malfunctioning neurotransmitters and serotonin receptors.
  • OCD Obsessive Compulsive Disorder
  • the composition may also be used in the treatment of Alzheimer's Disease (AD) and reduce the presence of aluminosiiicates at the core of senile plaque and diseased neurons.
  • the composition may be used to treat aging disorders for cellular differentiation, proliferation and regeneration. It may also be used to treat age- related changes in mitochondrial function and age-related hearing loss.
  • composition may also possibly maintain metabolic activity and available energy by maintaining levels of phospholipids in normal cells and maintain membrane integrity and regulate enzyme activities and membrane transport processes through changes in membrane fluidity.
  • the composition may be beneficial for biological functions of essential fatty acids, including neural tissues such as the brain and retina and treat dementia- related diseases to increase mental function, memory, concentration and judgment and overcome the effects of Alzheimer's Disease.
  • the composition may also be used to restore and preserve liver function and protect the liver against damage from
  • alcoholism pharmaceuticals, pollutant substances, viruses and other toxic influences that may damage cell membranes. It may possibly have antioxidant activity.
  • Additives may be used with the composition and pharmaceutical or nutraceutical formulations may be made by methods known in the art.
  • the composition may be formulated using one or more pharmaceutically or nutraceutically acceptable carriers.
  • the composition may be formulated for oral administration.
  • the pharmaceutical or nutraceutical compositions as
  • compositions may take the form of, for example, tablets or capsules prepared by conventional techniques with pharmaceutically or nutraceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylceilufose); filters (e.g., lactose, microcrystal!ine cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); distntegrants (e.g., potato starch or sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate).
  • binding agents e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylceilufose
  • filters e.g., lactose, microcrystal!ine cellulose or calcium phosphate
  • lubricants e.g., magnesium
  • suspensions or they may be presented as a dry product for use with water or another suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional techniques with pharmaceutically or nutraceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agents e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
  • preservatives e.g., methyl or propyl p-
  • composition when used as a nutraceutical, it can be in the form of foods, beverages, energy bars, sports drinks, supplements or other forms as known in the art. This composition is also useful in cosmetic preparations, e.g., moisturizing creams, sun-block products and other topical cosmetic products as known in the art.
  • the composition may possibly be used in the treatment or prevention of a variety of disease states including: liver disease; chronic hepatitis; steatosis; liver fibrosis; alcoholism; malnutrition; chronic parenteral nutrition; phospholipid deficiency; lipid peroxidation; disarrhythmia of cell regeneration; destabilization of cell membranes; coronary artery disease caused by hypercholesterolemia; high blood pressure;
  • cancer e.g., skin cancer
  • hypertension aging
  • benign prostatic hyperplasia kidney disease
  • edema skin diseases
  • peripheral vascular system diseases e.g. leg ulcers
  • neurodegenerative and psychiatric diseases e.g. Parkinson's, Alzheimer's, autism, attention deficit disorder, learning disorders, mood disorders, bipolar depression, multiple sclerosis, muscular dystrophy.
  • the composition may also be useful for targeting tumors and may be used in conjunction with radioisotopes for diagnosing central nervous system tumors.
  • the composition may also be used to reduce local fat deposits and reducing visible celiulite.
  • the composition may also be used in aesthetics such as breast enlargement by acting on the lobular tissue of the breast and by increasing hydration of the breast.
  • the composition may be used to treat and/or prevent cardiovascular diseases, arthritis, skin cancer, diabetes, premenstrual syndrome and transdermal transport enhancement. It may be used to decrease cholesterol in vivo and inhibit platelet adhesion and plaque formation and reduce vascular endothelial inflammation in a patient and offer hypertension prophylaxis.
  • the composition may prevent oxidation of low-density lipoprotein and have an inhibitory effect on the secretion of VLDL possibly due to increased intracellular degradation of APO B-100. It may offer a post-myocardial infarction prophylaxis possibly because of its ability to decrease CHI apolipoprotein B, to decrease C3 non-apoliproprotein B lipoproteins and to increase antithrombin 3 levels.
  • cardiovascular disease it may be suitable for prophylactic usage against cardiovascular disease in humans where it relates to coronary disease, hyperlipidemia, hypertension, ischemic disease such as relating to angina, myocardial infarction, cerebral ischemia, and shock without clinical or laboratory evidence of ischemia or arrhythmia.
  • ischemic disease such as relating to angina, myocardial infarction, cerebral ischemia, and shock without clinical or laboratory evidence of ischemia or arrhythmia.
  • the composition may be suitable to offer symptomatic relief for arthritis, Still's Disease, polyarticular or pauciarticular juvenile rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, and may provide clinical improvement in decreasing the number of tender joints and analgesics consumed daily by decreasing the production of interleukin and interleukin-1 in human patients.
  • the composition may also be used as a skin cancer prophylactic. It may have some retinal and anti-carcinogenic effects.
  • the composition may be used to reduce the pain and mood changes associated with premenstrual syndrome in women.
  • the composition may be used to treat or prevent a cardiometabolic disorder/metabolic syndrome.
  • the cardiometabolic disorder could be atherosclerosis, arteriosclerosis, coronary heart ⁇ carotid artery) disease (CHD or CAD), acute coronary syndrome (or ACS), valvular heart disease, aortic and mitral valve disorders,
  • arrhythmia/atrial fibrillation arrhythmia/atrial fibrillation, cardiomyopathy and heart failure, angina pectoris, acute myocardial infarction (or AMI), hypertension, orthostatic hypotension, shock, embolism (pulmonary and venous), endocarditis, diseases of arteries, the aorta and its branches, disorders of the peripheral vascular system (peripheral arterial disease or PAD), Kawasaki disease, congenital heart disease (cardiovascular defects) and stroke
  • hypothalamic hematoma hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma,
  • the composition may also be used to treat, prevent or improve cognition and/or a cognitive disease, disorder or impairment (memory, concentration, learning (deficit)), or of treating or preventing neurodegenerative disorders.
  • the cognitive disease, disorder or impairment could be Attention Deficit Disorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD), autism/autism spectrum disorder (ASD),
  • the composition may be used to inhibit, prevent or treat inflammation or an inflammatory disease.
  • the inflammation or inflammatory disease may be due to organ transplant rejection; reoxygenation injury resulting from organ transplantation (see Grupp et al., J. Mol. Cell. Cardiol. 31: 297-303 (1999)) including, but not limited to, transplantation of the following organs: heart, lung, liver and kidney; chronic
  • inflammatory diseases of the joints including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory bowel diseases (IBD) such as ileitis, ulcerative colitis (UC), Barrett's syndrome, and Crohn's disease (CD); inflammatory lung diseases such as asthma, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD); inflammatory diseases of the eye including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic inflammatory diseases of the gum, including gingivitis and periodontitis; inflammatory diseases of the kidney including uremic complications, glomerulonephritis and nephrosis; inflammatory diseases of the skin including sclerodermatitis, psoriasis and eczema; inflammatory diseases of the central nervous system, including chronic demyelinating diseases of the nervous system, multiple sclerosis, AIDS-related
  • the inflammatory disease may also be a systemic inflammation of the body, exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory cytokines.
  • shock can be induced, e.g., by a chemotherapeutic agent that is administered as a treatment for cancer.
  • Other disorders include depression, obesity, allergic diseases, acute cardiovascular events, muscle wasting diseases, and cancer cachexia.
  • inflammation that results from surgery and trauma may possibly be treated.

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Abstract

La présente invention concerne un complément alimentaire qui comprend une quantité thérapeutique d'astaxanthine dérivée d'un diol ou d'un ester synthétique ou naturel, et au moins un lipide parmi un phospholipide, un glycolipide et un sphingolipide, et formulée sous une forme galénique orale, l'astaxanthine représentant 0,1 à 15 % en poids du ou des phospholipide, glycolipide et sphingolipide. La composition comprend 0,5 à 12 mg d'astaxanthine et peut être utilisée pour traiter l'oxydation des lipoprotéines de basse densité (LDL) chez l'homme et d'autres maladies, troubles et déficiences.
PCT/US2015/021180 2014-03-19 2015-03-18 Composition d'astaxanthine thérapeutique et de phospholipide et procédé associé WO2015143001A1 (fr)

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US14/219,484 2014-03-19
US14/219,484 US20140205627A1 (en) 2010-04-30 2014-03-19 Composition and method to improve blood lipid profiles and reduce low density lipoprotein (ldl) per-oxidation in humans using algae based oils and astaxanthin
US14/658,457 2015-03-16
US14/658,457 US9763897B2 (en) 2010-04-30 2015-03-16 Therapeutic astaxanthin and phospholipid composition and associated method

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WO2019038764A1 (fr) * 2017-08-23 2019-02-28 Gavish-Galilee Bio Applications Ltd. Compositions et méthodes de traitement d'une maladie cardiovasculaire athéroscléreuse
JP7053231B2 (ja) 2017-11-27 2022-04-12 国立大学法人富山大学 藻類、栄養剤、栄養成分補給用組成物及び栄養成分の製造方法
JP2022533900A (ja) * 2019-04-01 2022-07-27 テル ハショメール メディカル リサーチ インフラストラクチャ アンド サービシーズ リミテッド 神経変性疾患、タンパク質ミスフォールディングに関連する障害及び認知機能低下の予防及び／又は治療のためのドナリエラ藻類製剤
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WO2020055913A1 (fr) * 2018-09-10 2020-03-19 Cardax, Inc. Procédés de réduction de la protéine c réactive et/ou de traitement d'une maladie cardiovasculaire

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