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WO2020028263A1 - Compositions d'acide 5,11,14-eicosatriénoïque et leurs procédés de production - Google Patents

Compositions d'acide 5,11,14-eicosatriénoïque et leurs procédés de production Download PDF

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Publication number
WO2020028263A1
WO2020028263A1 PCT/US2019/043944 US2019043944W WO2020028263A1 WO 2020028263 A1 WO2020028263 A1 WO 2020028263A1 US 2019043944 W US2019043944 W US 2019043944W WO 2020028263 A1 WO2020028263 A1 WO 2020028263A1
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Prior art keywords
acid
lipid formulation
lipid
formulation
eicosatrienoic acid
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English (en)
Inventor
Alvin Berger
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Sciadonics Inc
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Sciadonics Inc
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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
    • A61K36/13—Coniferophyta (gymnosperms)
    • 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
    • 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
    • A61K31/201—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 one or two double bonds, e.g. oleic, linoleic acids
    • 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

Definitions

  • compositions containing bioactive fatty acids are provided herein.
  • technology relating to lipid compositions containing bioactive fatty acids and particularly, but not exclusively, to compositions containing 5,l l,l4-eicosatrienoic acid.
  • Bioactive fatty acids have been implicated for the treatment of various diseases and conditions. Bioactive fatty acids from natural sources have formed the basis for many popular and successful dietary supplements including various fish oils.
  • bioactive fatty acids from a variety of sources have been identified including sciadonic acid, pinolenic acid, eicosapentaenoic acid, docosahexaenoic acid, and conjugated linoleic acid, just to name a few.
  • compositions containing bioactive fatty acids are provided herein.
  • technology relating to lipid compositions containing bioactive fatty acids and particularly, but not exclusively, to compositions containing 5,l l,l4-eicosatrienoic acid .
  • the present invention provides lipid formulations comprising from 20% to 90% w/w 5,1 l,l4-eicosatrienoic acid , wherein the lipid formulation is suitable for human use and further comprises one or more of the following properties:
  • the formulation comprises from 0.001% to 4% rosin acids or derivatives thereof (e.g., ethylated rosin acids, 0.01% to 4% rosin acids or derivatives thereof, 0.01% to 2% rosin acids or derivatives thereof, 0.1% to 4% rosin acids or derivatives thereof, or 0.1% to 2% rosin acids or derivatives thereof;
  • a rosin acids or derivatives thereof e.g., ethylated rosin acids, 0.01% to 4% rosin acids or derivatives thereof, 0.01% to 2% rosin acids or derivatives thereof, 0.1% to 4% rosin acids or derivatives thereof, or 0.1% to 2% rosin acids or derivatives thereof;
  • the formulation comprises from 5% to 40% w/w CLA, 10% to 40% w/w CLA, 15% to 35% w/w CLA, 20% to 30% w/w CLA, or 10% to 20% w/w CLA;
  • the formulation comprises from 5% to 40% w/w linoleic acid (18:2 cis-9,l2), 10% to 40% w/w linoleic acid, 15% to 35% w/w linoleic acid, 20% to 30% w/w linoleic acid, or 10% to 20% w/w linoleic acid;
  • the formulation comprises from 0.5% to 5% w/w pinoleic acid, 0.5% to 3% w/w pinoleic acid, or 1.0% to 3% w/w pinoleic acid;
  • the formulation comprises from 0.5% to 5% w/w 11,14 eicosadienoic acid, 0.5% to 3% w/w eicosadienoic acid, or 1.0% to 3.0% w/w eicosadienoic acid;
  • the formulation comprises from 0.1% to 6% w/w 7,1 l,l4-eicosatrienoic acid, 0.5% to 5% w/w 7,l l,l4-eicosatrienoic acid, or 1% to 4% w/w 7,11,14 eicosatrienoic acid
  • conjugated linoleic acid in a ratio of from 1:2 to 2: 1 5,l l,l4-eicosatrienoic acid : conjugated linoleic acid or 1: 1.5 to 1.5: 1 5,l l,l4-eicosatrienoic acid: conjugated linoleic acid;
  • eicosadienoic acid in a ratio of from 8: 1 to 15: 1 5,1 l,l4-eicosatrienoic acid : eicosadienoic acid or 9: 1 to 13: 1 5,l l,l4-eicosatrienoic acid:cis-9,l2 linoleic acid;
  • rosin acids in a ratio of from 10:1 to 30: 1 5,l l,l4-eicosatrienoic acid : rosin acids.
  • the lipid formulation has two or more of properties (a) to (1). In some preferred embodiments, the lipid formulation has three or more of properties (a) to (1). In some preferred embodiments, the lipid formulation has four or more of properties (a) to (1). In some preferred embodiments, the lipid formulation has five or more of properties (a) to (1). In some preferred embodiments, the lipid formulation has six or more of properties (a) to (1). In some preferred embodiments, the lipid formulation has seven or more of properties (a) to (1). In some preferred embodiments, the lipid formulation has eight or more of properties (a) to (1). In some preferred embodiments, the lipid formulation has nine or more of properties (a) to (1).
  • the lipid formulation has ten or more of properties (a) to (1). In some preferred embodiments, the lipid formulation has property (a). In some preferred embodiments, the lipid formulation has property (b). In some preferred embodiments, the lipid formulation has property (c). In some preferred
  • the lipid formulation has properties (a) and (b). In some preferred
  • the lipid formulation has properties (a), (b) and (c). In some preferred embodiments, the lipid formulation has property (d). In some preferred embodiments, the lipid formulation has property (e). In some preferred embodiments, the lipid formulation has property (f). In some preferred embodiments, the lipid formulation has property (g). In some preferred embodiments, the lipid formulation has property (h). In some preferred embodiments, the lipid formulation has properties (a), (b) and (c). In some preferred embodiments, the lipid formulation has property (d). In some preferred embodiments, the lipid formulation has property (e). In some preferred embodiments, the lipid formulation has property (f). In some preferred embodiments, the lipid formulation has property (g). In some preferred embodiments, the lipid formulation has property (h). In some preferred embodiments, the lipid formulation has properties (a), (b) and (c). In some preferred embodiments, the lipid formulation has property (d). In some preferred embodiments, the lipid formulation has property (e). In some preferred embodiments, the lipid formulation has property (f
  • the lipid formulation has property (i). In some preferred embodiments, the lipid formulation has property (j). In some preferred embodiments, the lipid formulation has property (1).
  • the fatty acids in the lipid formulations are esterified to a triglyceride, diglyceride, or phospholipid molecule, or combinations thereof. In some preferred embodiments, the fatty acids are provided as ethyl esters.
  • the formulations further comprise an antioxidant that does not naturally occur with 5,1 l,l4-eicosatrienoic acid.
  • the lipid formulation is encapsulated for oral or topical administration.
  • the present invention provides an oral delivery vehicle, topical formulation, food product, nutritional supplement, dietary supplement or functional food comprising a lipid formulation as described above.
  • the present invention provides methods of treating a subject comprising administering to the subject the lipid formulation, oral delivery vehicle, topical formulation, food product, nutritional supplement, dietary supplement or functional food as described above.
  • the administration is oral, topical, parenteral, enteral, transdermal, intradermal, intraocular, intravitreal, sublingual, or intravaginal.
  • the present invention provides a method of reducing obesity, inducing weight loss, increasing lean body mass, increasing muscularity, increasing muscle mass, improving body composition, alleviating one or more symptoms metabolic syndrome, treating diabetes, decreasing insulin resistance, reducing inflammation, improving concentration, memory, cognitive function, attention and treating, alleviating or improving one or more of the following diseases or conditions: restenosis, arteriosclerosis, coronary heart disease, thrombosis, myocardial infarction, stroke, hypertension, fatty liver, diabetes, hyperglycaemia, hyperinsulinemia, and stenosis, rheumatoid arthritis, systemic vasculitis, systemic lupus erythematosus, systemic sclerosis, dermatomyositis, polymyositis, various autoimmune endocrine disorders (e.g.
  • thyroiditis and adrenalitis various immune mediated neurological disorders (e.g. multiple sclerosis and myastenia gravis), various cardiovascular disorders (e.g. myocarditis, congestive heart failure, arteriosclerosis and stable and unstable angina, and Wegeners granulomatosis), inflammatory bowel diseases and colitis (e.g.,
  • transplantation comprising: administering to a subject in need thereof the lipid formulation, oral delivery vehicle, topical formulation, food product, nutritional supplement, dietary supplement or functional food as described above.
  • the present invention provides a method of treating diabetes, ameliorating the symptoms of diabetes, providing nutritional support to a subject with diabetes, promoting healthy blood sugar levels, supporting efficient insulin production and secretion, and supporting healthy glucose metabolism, comprising: administering to a subject in need thereof the lipid formulation, oral delivery vehicle, food product, nutritional supplement, dietary supplement or functional food as described above.
  • compositions containing bioactive fatty acids and particularly, but not exclusively, to compositions containing 5,l l,l4-eicosatrienoic acid .
  • This technology is described below, wherein the section headings are for organizational purposes only and are not to be construed as limiting the described subject matter in any way.
  • the term“or” is an inclusive“or” operator and is equivalent to the term“and/or” unless the context clearly dictates otherwise.
  • the term“based on” is not exclusive and allows for being based on additional factors not described, unless the context clearly dictates otherwise.
  • the meaning of “a”,“an”, and“the” include plural references. The meaning of“in” includes“in” and“on.”
  • “in vitro” refers to an artificial environment and to processes or reactions that occur within an artificial environment. In vitro environments may include, but are not limited to, test tubes and cell cultures.
  • the term“in vivo” refers to the natural environment (e.g., an animal or a cell) and to processes or reactions that occur within a natural environment.
  • the terms“subject” and“patient” refer to any animal, such as a mammal like a dog, cat, bird, livestock, and preferably a human (e.g., a human with a disease such as obesity, diabetes, or insulin resistance).
  • the term“individual” refers to vertebrates, particularly members of the mammalian species. The term includes but is not limited to domestic animals, sports animals, primates, and humans.
  • an effective amount refers to the amount of a composition sufficient to effect beneficial or desired results.
  • An effective amount can be administered in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or administration route.
  • the term“administration” refers to the act of giving a drug, prodrug, or other agent, or therapeutic treatment to a subject.
  • exemplary routes of administration to the human body can be through the eyes (ophthalmic), mouth (oral), skin (transdermal, topical), nose (nasal), lungs (inhalant), oral mucosa (buccal), ear, by injection (e.g., intravenously, subcutaneously, intratumorally, intraperitoneally, etc.), and the like.
  • the term“co-administration” refers to the administration of at least two agents or therapies to a subject. In some embodiments, the co-administration of two or more agents or therapies is concurrent. In other embodiments, a first agent/therapy is administered prior to a second agent/therapy.
  • the appropriate dosage for co-administration can be readily determined by one skilled in the art. In some embodiments, when agents or therapies are co-administered, the respective agents or therapies are administered at lower dosages than appropriate for their administration alone. Thus, co-administration is especially desirable in embodiments where the co administration of the agents or therapies lowers the requisite dosage of a potentially harmful (e.g., toxic) agent.
  • the term“pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for therapeutic use.
  • compositions that do not substantially produce adverse reactions, e.g., toxic, allergic, or immunological reactions, when administered to a subject.
  • treating includes reducing or alleviating at least one adverse effect or symptom of a disease or disorder through introducing in any way a therapeutic composition of the present technology into or onto the body of a subject.
  • Treatment refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder.
  • Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in whom the disorder is to be prevented.
  • sample is used in its broadest sense. In one sense, it is meant to include a specimen or culture obtained from any source, as well as biological and environmental samples. Biological samples may be obtained from animals (including humans) and encompass fluids, solids, tissues, and gases. Biological samples include blood products, such as plasma, serum and the like. Environmental samples include environmental material such as surface matter, soil, water, crystals and industrial samples. Such examples are not however to be construed as limiting the sample types applicable to the present technology.
  • Sciadonic acid is known to have many beneficial effects when administered to humans and animals.
  • the utilization of sciadonic acid in dietary supplements and topical agents has been limited to difficulties in identifying natural sources of sciadonic acid that contain sciadonic acid in commercially useful amounts.
  • Both Tall Oil Fatty Acids (TOFA) and Tall Oil Distillate (TOD) contain free fatty acids, including different amounts of sciadonic acid. Contamination of tall oil products with rosin acids is a problem when it is desired to manufacture a fatty acid supplement for human use. It has been found that while TOFA has very low levels of rosin acids, it contains only low amounts of sciadonic acid.
  • TOD Up concentration of sciadonic acid from TOFA would be cost-prohibitive.
  • TOD has higher levels of sciadonic acid (e.g., for 4% to 12% w/w), but it also has much higher levels of rosin acids (e.g., 40% - 50% w/w) which render the TOD unsuitable for use in human supplements.
  • the present invention solves the problem of providing sciadonic acid in amounts useful for formulation of human and animal dietary supplements and topical agents by providing methods for up-concentrating sciadonic acid from TOD while removing rosin acids to levels that do not interfere with use of the compositions.
  • bioactive lipid formulations comprising one or more bioactive fatty acids, and in particularly preferred embodiments sciadonic acid in combination with other bioactive fatty acids.
  • the fatty acids may be provided in the formulation as free fatty acids, as methyl or ethyl esters, or in the form of diglycerides, triglycerides, or phospholipids to which the fatty acid is attached.
  • the fatty acids are provided as esters, with ethyl esters being the most preferred.
  • the bioactive lipid formulations are preferably characterized by comprising a particular ratio of the bioactive fatty acids to one another.
  • the lipid compositions according to the present technology are either fatty acids analogous to naturally occurring fatty acids, especially sciadonic acid and its analogs, alone in combination with other bioactive fatty acids, or naturally occurring lipids comprising the fatty acids.
  • Incorporation of the fatty acids in naturally occurring lipids e.g., monoglycerides, diglycerides, triglycerides, and/or phospholipids
  • naturally occurring lipids e.g., monoglycerides, diglycerides, triglycerides, and/or phospholipids
  • incorporating fatty acids in naturally occurring lipids may also increase the bioavailability or stability.
  • the present invention provides a lipid
  • composition comprising lipids characterized in comprising an effective amount of 5,11,14- eicosatrienoic acid , preferably an ethyl ester of 5,1 l,l4-eicosatrienoic acid , wherein the lipid composition is suitable for human consumption and is combined with one or more additional compounds that is characteristic of tall oil, for example, a fatty acid or ester thereof.
  • the lipid composition comprises conjugated linoleic acids or esters thereof.
  • the lipid composition comprises a rosin acid or ester thereof, albeit in a low amount as it is an object of the invention to remove rosin acids from the lipid compositions.
  • compositions are described as containing ranges of particular fatty acids such as 5,l l,l4-eicosatrienoic acid and other components such as rosin acids on a weight/weight (w/w) basis.
  • fatty acids such as 5,l l,l4-eicosatrienoic acid
  • other components such as rosin acids on a weight/weight (w/w) basis.
  • w/w weight/weight
  • composition comprising from 20% to 90% w/w 5,11,14- eicosatrienoic acid and from 20% to 40% conjugated linoleic acid
  • the composition can contain up to (and not exceed) 100% w/w combined 5,11,14- eicosatrienoic acid and conjugated linoleic acid.
  • the lipid compositions of the present invention comprise from about 20% to 90% w/w 5,1 l,l4-eicosatrienoic acid as determined by gas chromatography where the weight percentage of the 5,1 l,l4-eicosatrienoic acid is expressed as g/lOOg fatty acids. In some preferred embodiments, the lipid compositions of the present invention comprise from about 20% to 80% w/w 5,1 l,l4-eicosatrienoic acid as determined by gas chromatography where the weight percentage of the 5,1 l,l4-eicosatrienoic acid is expressed as g/lOOg fatty acids.
  • the lipid compositions of the present invention comprise from about 20% to 70% w/w 5,1 l,l4-eicosatrienoic acid as determined by gas chromatography where the weight percentage of the 5,l l,l4-eicosatrienoic acid is expressed as g/lOOg fatty acids. In some preferred embodiments, the lipid compositions of the present invention comprise from about 20% to 60% w/w 5,11,14- eicosatrienoic acid as determined by gas chromatography where the weight percentage of the 5,l l,l4-eicosatrienoic acid is expressed as g/lOOg fatty acids.
  • the lipid compositions of the present invention comprise from about 20% to 50% w/w 5,1 l,l4-eicosatrienoic acid as determined by gas chromatography where the weight percentage of the 5,1 l,l4-eicosatrienoic acid is expressed as g/lOOg fatty acids. In some preferred embodiments, the lipid compositions of the present invention comprise from about 20% to 40% w/w 5,l l,l4-eicosatrienoic acid as determined by gas chromatography where the weight percentage of the 5,1 l,l4-eicosatrienoic acid is expressed as g/lOOg fatty acids.
  • the lipid compositions of the present invention comprise from about 20% to 30% w/w 5,1 l,l4-eicosatrienoic acid as determined by gas chromatography where the weight percentage of the 5,1 l,l4-eicosatrienoic acid is expressed as g/lOOg fatty acids.
  • the lipid compositions of the present invention are prepared using tall oil as the starting material.
  • Rosin acids include, but are not limited to, compounds such as abietic acid, monounsaturated abietic acids, dehydroabietic acid, secodehydroabietic acids, neoabietic acid, isopimaric acid, 8,15 isopimaric acid, sandaracopimaric acid, dimethozystilbene, and palustric acid.
  • the lipid compositions of the present invention that comprise 5,1 l,l4-eicosatrienoic acid as described above further comprise from about 0.001% to 4% rosin acids or derivatives thereof (e.g., ethylated rosin acids) as determined by gas chromatography where the weight percentage of the rosin acids is weight of the rosin acids or derivative thereof per the total weight of the lipid composition.
  • rosin acids or derivatives thereof e.g., ethylated rosin acids
  • the lipid compositions of the present invention that comprise 5,1 l,l4-eicosatrienoic acid as described above further comprise from about 0.01% to 4% rosin acids or derivatives thereof (e.g., ethylated rosin acids) as determined by gas chromatography where the weight percentage of the rosin acids is weight of the rosin acids or derivative thereof per the total weight of the lipid composition.
  • rosin acids or derivatives thereof e.g., ethylated rosin acids
  • the lipid compositions of the present invention that comprise 5,11,14- eicosatrienoic acid as described above further comprise from about 0.01% to 2% rosin acids or derivatives thereof (e.g., ethylated rosin acids) as determined by gas chromatography where the weight percentage of the rosin acids is weight of the rosin acids or derivative thereof per the total weight of the lipid composition.
  • rosin acids or derivatives thereof e.g., ethylated rosin acids
  • the lipid compositions of the present invention that comprise 5,1 l,l4-eicosatrienoic acid as described above further comprise from about 0.1% to 4% rosin acids or derivatives thereof (e.g., ethylated rosin acids) as determined by gas chromatography where the weight percentage of the rosin acids is weight of the rosin acids or derivative thereof per the total weight of the lipid composition.
  • rosin acids or derivatives thereof e.g., ethylated rosin acids
  • the lipid compositions of the present invention that comprise 5,l l,l4-eicosatrienoic acid as described above further comprise from about 0.1% to 2% rosin acids or derivatives thereof (e.g., ethylated rosin acids) as determined by gas chromatography where the weight percentage of the rosin acids is weight of the rosin acids or derivative thereof per the total weight of the lipid composition.
  • rosin acids or derivatives thereof e.g., ethylated rosin acids
  • the rosin acids or derivatives thereof are substantially free of (e.g., contain less than 10 pmm) of the following rosin acids or derivatives thereof: 8,15 pimaric acid, pimaric acid, 8,15 isopimaric acid, or neoabietic acid (i.e., less than 10 ppm 8,15 pimaric acid, less than 10 ppm pimaric acid, etc.).
  • the lipid compositions described above further comprise conjugated linoleic acid (CLA).
  • CLA includes various isomers of linoleic acid that contain a conjugated double bond system, for example 9c, 1 lt-octadecadienoic acid, l0t,l2c- octadecadienoic acid, etc.
  • the lipid compositions of the present invention comprise from about 5% to 40% w/w CLA as determined by gas chromatography where the weight percentage of the CLA is expressed as g/lOOg fatty acids.
  • the lipid compositions of the present invention comprise from about 10% to 40% w/w CLA as determined by gas chromatography where the weight percentage of the CLA is expressed as g/lOOg fatty acids. In some preferred embodiments, the lipid compositions of the present invention comprise from about 15% to 35% w/w CLA as determined by gas chromatography where the weight percentage of the CLA is expressed as g/lOOg fatty acids. In some preferred embodiments, the lipid compositions of the present invention comprise from about 20% to 30% w/w CLA as determined by gas chromatography where the weight percentage of the CLA is expressed as g/lOOg fatty acids. In some preferred embodiments, the lipid compositions of the present invention comprise from about 10% to 20% w/w CLA as determined by gas chromatography where the weight percentage of the CLA is expressed as g/lOOg fatty acids.
  • the lipid compositions described above further comprise linoleic acid (not conjugated; 18:2 cis-9,l2).
  • the lipid compositions of the present invention comprise from about 5% to 40% w/w linoleic acid as determined by gas chromatography where the weight percentage of the linoleic acid is expressed as g/lOOg fatty acids.
  • the lipid compositions of the present invention comprise from about 10% to 40% w/w linoleic acid as determined by gas chromatography where the weight percentage of the linoleic acid is expressed as g/lOOg fatty acids.
  • the lipid compositions of the present invention comprise from about 15% to 35% w/w linoleic acid as determined by gas chromatography where the weight percentage of the linoleic acid is expressed as g/lOOg fatty acids. In some preferred embodiments, the lipid compositions of the present invention comprise from about 20% to 30% w/w linoleic acid as determined by gas chromatography where the weight percentage of the linoleic acid is expressed as g/lOOg fatty acids.
  • the lipid compositions of the present invention comprise from about 10% to 20% w/w linoleic acid as determined by gas chromatography where the weight percentage of the linoleic acid is expressed as g/lOOg fatty acids.
  • the lipid compositions described above further comprise pinoleic acid.
  • the lipid compositions of the present invention comprise from about 0.5% to 5% w/w pinoleic acid as determined by gas chromatography where the weight percentage of the pinoleic acid is expressed as g/lOOg fatty acids.
  • the lipid compositions of the present invention comprise from about 0.5% to 3% w/w pinoleic acid as determined by gas chromatography where the weight percentage of the pinoleic acid is expressed as g/lOOg fatty acids.
  • the lipid compositions of the present invention comprise from about 1.0% to 3% w/w pinoleic acid as determined by gas chromatography where the weight percentage of the pinoleic acid is expressed as g/lOOg fatty acids.
  • the lipid compositions described above further comprise eicosadienoic acid.
  • the lipid compositions of the present invention comprise from about 0.5% to 5% w/w eicosadienoic acid as determined by gas chromatography where the weight percentage of the eicosadienoic acid is expressed as g/lOOg fatty acids.
  • the lipid compositions of the present invention comprise from about 0.5% to 3% w/w eicosadienoic acid as determined by gas chromatography where the weight percentage of the eicosadienoic acid is expressed as g/lOOg fatty acids.
  • the lipid compositions of the present invention comprise from about 1.0% to 3.0% w/w eicosadienoic acid as determined by gas chromatography where the weight percentage of the eicosadienoic acid is expressed as g/lOOg fatty acids.
  • the lipid compositions of the present invention may be described by ratios of subcomponents such as fatty acids. Unless otherwise noted, the ratios are calculated based on the weight percentage of the fatty acids (or other components such as rosin acids) in the lipid composition as determined by gas chromatography.
  • the lipid compositions of the present invention comprise 5,11,14- eicosatrienoic acid and conjugated linoleic acid in a ratio of from 1 :2 to 2: 1 5,11,14- eicosatrienoic acid : conjugated linoleic acid.
  • the ratio of eicosatrienoic acidxonjugated linoleic acid is about 1: 1.5 to 1.5: 1.
  • the lipid compositions of the present invention further comprise cis-9,l2 linoleic acid in a ratio of from 1 :2 to 2: 1 5,1 l,l4-eicosatrienoic acid :9,l2 linoleic acid.
  • the ratio of eicosatrienoic acid:cis-9,l2 linoleic acid is about 1 : 1.5 to 1.5 : 1.
  • the lipid compositions of the present invention further comprise eicosadienoic acid in a ratio of from 8: 1 to 15: 1 5,11,14- eicosatrienoic acid : eicosadienoic acid. In some preferred embodiments, the ratio of eicosatrienoic acid:cis-9,l2 linoleic acid is about 9: 1 to 13: 1. In some preferred
  • the lipid compositions of the present invention further comprise oleic acid in a ratio of from 3: 1 to 8: 1 5,l l,l4-eicosatrienoic acid : oleic acid.
  • oleic acid in a ratio of from 3: 1 to 8: 1 5,l l,l4-eicosatrienoic acid : oleic acid.
  • the ratio of eicosatrienoic acid: oleic acid is about 4: 1 to 7: 1.
  • the lipid compositions of the present invention further comprise rosin acids in a ratio of from 10: 1 to 30: 1 5,l l,l4-eicosatrienoic acid : rosin acids.
  • the ratio of eicosatrienoic acid: rosin acids is about 10: 1 to 30: 1.
  • the fatty acids in the lipid composition are esterified to a triglyceride, diglyceride, monoglyceride or phospholipid molecule.
  • the fatty acids in the lipid composition are provided as ethyl or methyl esters. In some particularly preferred embodiments, the fatty acids in the lipid composition are provided as ethyl esters.
  • the lipid composition described herein are prepared from tall oil, and in particularly preferred embodiments a tall oil distillate (Kraton AB). Both tall oil and tall oil distillate contain a larger percentage of rosin acids that must be removed to provide a 5,1 l,l4-eicosatrienoic acid lipid composition that is suitable for human use, for example as an oral or topical preparation. The rosin acids must be removed while preserving or even up concentrating the amount of 5,1 l,l4-eicosatrienoic acid in the lipid composition.
  • the present invention addresses this problem by mildly ethylating tall or tall oil distillate following by chromatography on an appropriate medium.
  • the chromatography step may be in fixed columns or by simulated moving bed chromatography. Suitable chromatography procedures are described in, for example, U.S. Pat. No. 9,790,162, the entire contents of which are incorporated herein by reference.
  • suitable feed mixtures for fractionating by the process of the present invention may be obtained from natural sources such as tall oil and including tall oil distillate.
  • the tall oil distillate is prepared by saponification of a tall oil head heads fraction, solvent extraction of an organic extract phase, and acidulation of the organic extract phase to provide a tall oil distillate. See, e.g., U.S Pat. No. 3,804,819, the entire contents of which are incorporated herein by reference.
  • the tall oil distillate is subjected to mild ethylation, resulting in a feed stream comprising fatty acid ethyl esters and rosin ethyl esters.
  • the feed mixtures typically contain the desired fatty acids or ethyl esters thereof (e.g., ethyl esters of 5,1 l,l4-eicosatrienoic acid ) and at least one more polar component and at least one less polar component.
  • the less polar components have a stronger adherence to the adsorbent used in the process of the present invention than does the 5,1 l,l4-eicosatrienoic acid product.
  • such less polar components typically move with the solid adsorbent phase in preference to the liquid eluent phase.
  • the more polar components have a weaker adherence to the adsorbent used in the process of the present invention than does the 5,l l,l4-eicosatrienoic acid product.
  • such more polar components typically move with the liquid eluent phase in preference to the solid adsorbent phase.
  • more polar components will be separated into a raffinate stream, and less polar components will be separated into an extract stream.
  • Examples of the more and less polar components include (1) other compounds occurring in natural oils (e.g., tall oil or tall oil distillate), (2) byproducts formed during storage, refining and previous concentration steps and (3) contaminants from solvents or reagents which are utilized during previous concentration or purification steps.
  • Examples of (1) include rosin acids, other unwanted 5,l l,l4-eicosatrienoic acids; saturated fatty acids; sterols; vitamins; and environmental pollutants, such as polychlorobiphenyl (PCB), polyaromatic hydrocarbon (PAH) pesticides, chlorinated pesticides, dioxines and heavy metals. Rosin acids, PCB, PAH, dioxines and chlorinated pesticides are all non-polar components.
  • Examples of (2) include isomers and oxidation or decomposition products from tall oil fatty acids, for instance, auto-oxidation polymeric products of fatty acids or their derivatives.
  • Examples of (3) include urea which may be added to remove saturated or mono- unsaturated fatty acids from the feed mixture.
  • simulated moving bed (SMB) chromatography is utilized, although stationary columns may also be utilized.
  • SMB simulated moving bed
  • the process of the invention requires a plurality of zones in the chromatography apparatus. Typically, two or more zones are used. The number of zones is not particularly limited, but in general there are 2 to 5 zones.
  • each zone of the apparatus used in the process of the present invention has different polarities.
  • a) the aqueous organic solvent eluent present in each zone has a different water: organic solvent ratio; and/or (b) the rate at which liquid collected via the extract and raffinate streams in each zone is recycled back into the same zone is adjusted such that the 5,1 l,l4-eicosatrienoic acid product can be separated from different components of the feed mixture in each zone.
  • the present invention typically provides a chromatographic separation process for recovering a 5,l l,l4-eicosatrienoic acid product, from a feed mixture, which process comprises introducing the feed mixture to a simulated or actual moving bed chromatography apparatus having a plurality of linked chromatography columns containing, as eluent, an aqueous organic solvent, wherein the apparatus has a first zone and a second zone, each zone having an extract stream and a raffinate stream from which liquid can be collected from the plurality of linked chromatography columns, and wherein (a) a raffinate stream containing the 5,11,14- eicosatrienoic acid product together with more polar components is collected from a column in the first zone and introduced to a nonadjacent column in the second zone, and/or (b) an extract stream containing the 5,1 l,l4-eicosatrienoic acid product together with less polar components is collected from a column
  • the apparatus used in the process of the present invention contains two zones
  • the eluent in the first zone contains more organic solvent than the eluent in the second zone
  • the second zone is downstream of the first zone with respect to the flow of eluent in the system.
  • the eluent in the system typically moves from the first zone to the second zone.
  • the solid adsorbent phase typically moves from the second zone to the first zone.
  • the two zones do not overlap, i.e. there are no chromatographic columns which are in both zones.
  • the apparatus has a first zone, a second zone and a third zone.
  • the water: organic solvent ratios of the aqueous organic solvent eluent present in the first, second and third zones are typically different. As will be evident to one skilled in the art, this has the consequence that impurities having different polarities can be removed in each zone.
  • the eluent in the first zone contains more organic solvent than the eluent in the second zone and the third zone and the first zone is upstream of the second and third zones with respect to the flow of eluent in the system.
  • the eluent in the second zone contains more organic solvent than the eluent in the third zone and the second zone is upstream of the third zone with respect to the flow of eluent in the system.
  • the 5,1 l,l4-eicosatrienoic acid product is separated from components of the feed mixture which are less polar than the 5,1 l,l4-eicosatrienoic acid product.
  • the 5,l l,l4-eicosatrienoic acid product is separated from components of the feed mixture which are less polar than the 5,11,14- eicosatrienoic acid product but more polar than the components separated in the first zone.
  • the 5,1 l,l4-eicosatrienoic acid product is separated from components of the feed mixture which are more polar than the 5,1 l,l4-eicosatrienoic acid product.
  • the 5,1 l,l4-eicosatrienoic acid product in the first zone, is separated from components of the feed mixture which are less polar than the 5,11,14- eicosatrienoic acid product, in the second zone, the 5,l l,l4-eicosatrienoic acid product is separated from components of the feed mixture which are more polar than the 5,11,14- eicosatrienoic acid product, and in the third zone, the 5,1 l,l4-eicosatrienoic acid product is separated from components of the feed mixture which are more polar than the 5,11,14- eicosatrienoic acid product and also more polar than the components separated in the second zone.
  • Any known simulated or actual moving bed chromatography apparatus may be utilized for the purposes of the method of the present invention, as long as the apparatus is configured with the multiple, in particular two, zones which characterize the process of the present invention.
  • the number of columns used in the apparatus is not particularly limited. A skilled person would easily be able to determine an appropriate number of columns to use.
  • the number of columns is typically 8 or more, preferably 15 or more. In a more preferred embodiment 15 or 16 columns are used. In another more preferred embodiment, 19 or 20 columns are used. In other more preferred embodiments, 30 or more columns are used.
  • Each zone typically consists of an approximately equal share of the total number of columns.
  • each zone typically consists of approximately half of the total number of chromatographic columns in the system.
  • the first zone typically comprises 4 or more, preferably 8 or more, more preferably about 8 columns.
  • the second zone typically comprises 4 or more, preferably 7 or more, more preferably 7 or 8 columns.
  • the columns in each zone typically have identical dimensions but may, for certain applications, have different dimensions.
  • the flow rates to the column are limited by maximum pressures across the series of columns and will depend on the column dimensions and particle size of the solid phases. One skilled in the art will easily be able to establish the required flow rate for each column dimension to ensure efficient desorption. Larger diameter columns will in general need higher flows to maintain linear flow through the columns.
  • a raffinate stream containing the 5,l l,l4-eicosatrienoic acid product together with more polar components is collected from a column in the first zone and introduced to a nonadjacent column in the second zone, and the rate at which liquid collected via the extract stream from the first zone is recycled back into the first zone is faster than the rate at which liquid collected via the extract stream from the second zone is recycled back into the second zone.
  • the rate at which liquid collected via the extract stream from the first zone is recycled back into the first zone is slower than the rate at which liquid collected via the extract stream from the second zone is recycled back into the second zone.
  • the rate at which liquid collected via the raffinate stream from the second zone is recycled back into the second zone is faster than the rate at which liquid collected via the raffinate stream from the first zone is recycled back into the first zone.
  • an extract stream containing the 5,1 l,l4-eicosatrienoic acid product together with less polar components is collected from a column in the second zone and introduced to a nonadjacent column in the first zone, and the rate at which liquid collected via the raffinate stream from the second zone is recycled back into the second zone is faster than the rate at which liquid collected via the raffinate stream from the first zone is recycled back into the first zone.
  • the rate at which liquid collected via the raffinate stream from the second zone is recycled back into the second zone is slower than the rate at which liquid collected via the raffinate stream from the first zone is recycled back into the first zone.
  • Each chromatographic column may contain the same or a different adsorbent.
  • each column contains the same adsorbent.
  • Examples of such commonly used materials are polymeric beads, preferably polystyrene reticulated with DVB (divinylbenzene); and silica gel, preferably reverse phase bonded silica gel with C8 or Cl 8 alkanes, especially Cl 8. Cl 8 bonded reverse phase silica gel is preferred.
  • the adsorbent used in the process of the present invention is preferably non polar.
  • the shape of the adsorbent stationary phase material may be, for example, spherical or non-spherical beads, preferably substantially spherical beads.
  • Such beads typically have a diameter of 5 to 500 microns, preferably 10 to 500 microns, more preferably 15 to 500 microns, more preferably 40 to 500 microns, more preferably 100 to 500 microns, more preferably 250 to 500 microns, even more preferably 250 to 400 microns, most preferably 250 to 350 microns.
  • beads with a diameter of 5 to 35 microns may be used, typically 10 to 30 microns, preferably 15 to 25 microns.
  • Some preferred particle sizes are somewhat larger than particle sizes of beads used in the past in simulated and actual moving bed processes.
  • adsorbent beads of large particle size may be used in the process of the present invention (with their associated advantages) without any loss in resolution.
  • the adsorbent typically has a pore size of from 10 to 50 nm, preferably 15 to 45 nm, more preferably 20 to 40 nm, most preferably 25 to 35 nm.
  • the eluent used in the process of the present invention is preferably an alcohol such as ethanol or other aqueous organic solvent.
  • Ether solvents are well known to the person skilled in the art.
  • Ethers are typically short chain ethers.
  • Ethers typically are of formula R-O- R', wherein R and R are the same or different and represent a straight or branched Ci-C6 alkyl group.
  • the Ci-C6 alkyl group is preferably unsubstituted.
  • Preferred ethers include diethylether, diisopropylether, and methyl t-butyl ether (MTBE).
  • Ester solvents are well known to the person skilled in the art.
  • Esters are typically short chain esters.
  • Preferred esters include methylacetate and ethylacetate.
  • Preferred ketones include acetone, methylethylketone and methyl isobutyl ketone (MIBK).
  • Nitrile solvents are well known to the person skilled in the art.
  • Nitriles are typically short chain nitriles.
  • Nitriles typically are of formula R-CN, wherein R represents a straight or branched Ci-C6 alkyl group.
  • the Ci-C6 alkyl group is preferably unsubstituted.
  • Preferred nitriles include acetonitrile.
  • the aqueous solvent is preferably an alcohol solvent.
  • the aqueous alcohol typically comprises water and one or more short chain alcohols.
  • the short chain alcohol typically has from 1 to 6 carbon atoms. Examples of alcohols include methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, s-butanol and t-butanol.
  • the eluent is not in a supercritical state.
  • the eluent is a liquid.
  • the eluting power of the eluent in each of the zones is typically different.
  • the eluting power of the eluent in the first zone is greater than that of the eluent in the second and subsequent zones.
  • this is achieved by varying the relative amounts of water and solvent in each zone. Depending on the choice of organic solvent, they may be more powerful desorbers than water. Alternatively, they may be less powerful desorbers than water.
  • the water: organic solvent ratio of the eluents in each zone may be the same or different.
  • the water: organic solvent ratio of the eluent in the first zone is lower than the water: organic solvent ratio of the eluent in the second zone.
  • the water: organic solvent ratio of the eluent in the first zone is higher than the water: organic solvent ratio of the eluent in the second zone.
  • the water: organic solvent ratio of the eluent in the first zone is the same as the water: organic solvent ratio of the eluent in the second zone. It will be appreciated that the ratios of water and organic solvent in each zone referred to above are average ratios within the totality of the zone.
  • the water: organic solvent ratio of the eluent in each zone is controlled by introducing water and/or organic solvent into one or more columns in the zones.
  • water is typically introduced more slowly into the first zone than the second zone.
  • essentially pure organic solvent and essentially pure water may be introduced at different points in each zone. The relative flow rates of these two streams will determine the overall solvent profile across the zone.
  • different organic solvent/water mixtures may be introduced at different points in each zone. That will involve introducing two or more different organic solvent/water mixtures into the zone, each organic solvent/water mixture having a different organic solvent water ratio. The relative flow rates and relative concentrations of the organic solvent/water mixtures in this embodiment will determine the overall solvent profile across the zone.
  • the same organic solvent/water mixture is introduced to each zone.
  • the process of the present invention is conducted at from 15 to 55°C, preferably at from 20 to 40°C, more preferably at about 30°C.
  • the process is typically carried out at room temperature, but may be conducted at elevated temperatures.
  • the process of the present invention involves introducing a feed stream into one zone (for example the first zone), collecting a first intermediate stream enriched with the 5,l l,l4-eicosatrienoic acid product and introducing the first intermediate stream into another zone (for example the second zone).
  • the process involves either (a) collecting a first intermediate stream from the first zone and introducing it into the second zone, or (b) collecting a first intermediate stream from the second zone and introducing it into the first zone.
  • the 5,1 l,l4-eicosatrienoic acid product can be separated from both more and less polar components in a single process.
  • the apparatus has two zones, and the process of the present invention comprises:
  • the lipid compositions provided herein are suitable for human consumption on a daily basis for an extended period of time, e.g., 1 month, 2 months, 6 months, 1 year or 2 years, when provided in daily dosage of from 200 mg to 5 or 10 grams.
  • the lipid compositions further comprise a food safe antioxidant.
  • the lipid compositions are provided in an oral delivery vehicle, topical composition, pharmaceutical composition, food product, nutritional supplement, dietary supplement or functional food.
  • pharmaceutical compositions comprising a therapeutically effective amount of a lipid composition according to the present technology and a pharmaceutically acceptable carrier, diluent, or excipient (including combinations thereof).
  • a composition according to the technology comprises or consists of a therapeutically effective amount of the lipid composition. In some embodiments, it includes a
  • pharmaceutically acceptable carrier diluent, or excipient (including combinations thereof).
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art and are described, for example, in Remington’s Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).
  • the choice of pharmaceutical carrier, excipient, or diluent is selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the pharmaceutical comprise as, or in addition to, the carrier, excipient, or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and/or solubilizing agent(s).
  • This pharmaceutical composition will desirably be provided in a sterile form. It may be provided in unit dosage form and will generally be provided in a sealed container. A plurality of unit dosage forms may be provided.
  • compositions within the scope of the present technology may include one or more of the following: preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, odorants, and/or salts.
  • Compounds of the present technology may themselves be provided in the form of a pharmaceutically acceptable salt.
  • embodiments may comprise buffers, coating agents, antioxidants, suspending agents, adjuvants, excipients, and/or diluents. Examples of preservatives include sodium benzoate, sorbic acid, and esters of p-hydroxybenzoic acid.
  • compositions of the present technology may also contain other therapeutically active agents in addition to compounds of the present technology. Where two or more therapeutic agents are used they may be administered separately (e.g., at different times and/or via different routes) and therefore do not always need to be present in a single composition. Thus, combination therapy is within the scope of the present technology.
  • a pharmaceutical composition within the scope of the present technology may be adapted for administration by any appropriate route.
  • it may be administered by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes.
  • Such a composition may be prepared by any method known in the art of pharmacy, for example, by admixing one or more active ingredients with a suitable carrier.
  • different drug delivery systems are used to administer pharmaceutical compositions of the present technology, depending upon the desired route of administration.
  • Drug delivery systems are described, for example, by Langer ⁇ Science 249: 1527-1533 (1991)) and by Illum and Davis ⁇ Current Opinions in Biotechnology 2: 254- 259 (1991)).
  • agents of the present technology may be administered alone but will generally be administered as a pharmaceutical composition-e.g., the agent is in admixture with a suitable pharmaceutical excipient, diluent, or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • a suitable pharmaceutical excipient e.g., orally or topically
  • the agent is administered (e.g., orally or topically) in the form of tablets, capsules, ovules, elixirs, solutions, or suspensions, which may contain flavoring or coloring agents, for immediate, delayed, modified, sustained, pulsed, and/or controlled-release applications.
  • tablets contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and/orglycine;
  • disintegrants such as starch (preferably com, potato, or tapioca starch), sodium starch gly collate, croscarmellose sodium, and/or certain complex silicates; and/or granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC),
  • hydroxypropylcellulose HPC
  • sucrose sucrose
  • gelatin hydroxypropylcellulose
  • lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate, and talc may be included.
  • solid compositions of a similar type are also employed as fillers in gelatin capsules.
  • excipients in this regard include lactose, starch, a cellulose, milk sugar, or high molecular weight polyethylene glycols.
  • the agent is combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol, and glycerin, and combinations thereof.
  • the routes for administration include, but are not limited to, one or more of: oral (e.g. as a tablet, capsule, or as an ingestable solution), topical, mucosal (e.g. as a nasal spray or aerosol for inhalation), nasal, parenteral (e.g. by an injectable form), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, rectal, buccal, via the penis, vaginal, epidural, sublingual.
  • oral e.g. as a tablet, capsule, or as an ingestable solution
  • mucosal e.g. as a nasal spray or aerosol for inhalation
  • nasal parenteral (e.g. by an injectable form)
  • gastrointestinal intraspinal
  • composition comprises more than one active component, then those components may be administered by different routes.
  • agents of the present technology are administered parenterally, then examples of such administration include one or more of: intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrastemally, intracranially, intramuscularly, or subcutaneously administering the agent; and/or by using infusion techniques.
  • compositions adapted for oral administration are provided as capsules or tablets; as powders or granules; as solutions, syrups or suspensions (in aqueous or non-aqueous liquids); as edible foams or whips; or as emulsions.
  • Tablets or hard gelatine capsules may comprise lactose, maize starch or derivatives thereof, stearic acid or salts thereof.
  • Soft gelatine capsules may comprise vegetable oils, waxes, fats, semi-solid, or liquid polyols etc.
  • Solutions and syrups may comprise water, polyols and sugars.
  • oils e.g., vegetable oils
  • An active agent intended for oral administration may be coated with or admixed with a material that delays disintegration and/or absorption of the active agent in the gastrointestinal tract (e.g., glyceryl monostearate or glyceryl distearate may be used).
  • a material that delays disintegration and/or absorption of the active agent in the gastrointestinal tract e.g., glyceryl monostearate or glyceryl distearate may be used.
  • a material that delays disintegration and/or absorption of the active agent in the gastrointestinal tract e.g., glyceryl monostearate or glyceryl distearate may be used.
  • glyceryl monostearate or glyceryl distearate may be used.
  • compositions adapted for transdermal administration may be provided as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis, e.g., as described in Pharmaceutical Research , 3: 318 (1986)).
  • the agent of the present technology can be administered in the form of a suppository or pessary, or it may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder.
  • the agent of the present technology may also be dermally or transdermally administered, for example, by the use of a skin patch. They may also be administered by the pulmonary or rectal routes. They may also be administered by the ocular route.
  • the compounds can be formulated as micronised suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a
  • benzylalkonium chloride may be formulated in an ointment such as petrolatum.
  • the agent of the present technology can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • it can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • compositions adapted for rectal administration may be provided as suppositories or enemas.
  • compositions adapted for nasal administration may use solid carriers, e.g., powders (e.g., having a particle size in the range of 20 to 500 microns). Powders can be administered in the manner in which snuff is taken, e.g., by rapid inhalation through the nose from a container of powder held close to the nose.
  • Compositions adopted for nasal administration may alternatively use liquid carriers, e.g., nasal sprays or nasal drops. These may comprise aqueous or oil solutions of the active ingredient.
  • Compositions for administration by inhalation may be supplied in specially adapted devices, e.g., in pressurized aerosols, nebulizers, or insufflators. These devices can be constructed so as to provide predetermined dosages of the active ingredient
  • compositions adapted for vaginal administration may be provided as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • agents of the present technology include one or more of: intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrastemally, intracranially, intramuscularly or subcutaneously administering the agent; and/or by using infusion techniques.
  • parenteral administration the agent is best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • the preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
  • Transdermal refers to the delivery of a compound by passage through the skin and into the blood stream.
  • Transmucosal refers to delivery of a compound by passage of the compound through the mucosal tissue and into the blood stream.
  • Transurethral or “intraurethral” refers to delivery of a drug into the urethra, such that the drug contacts and passes through the wall of the urethra and enters into the blood stream.
  • Porture enhancement or“permeation enhancement” refers to an increase in the permeability of the skin or mucosal tissue to a selected pharmacologically active compound such that the rate at which the compound permeates through the skin or mucosal tissue is increased.
  • Penetration enhancers may include, for example, dimethylsulfoxide (DMSO);
  • DMF dimethyl formamide
  • DMA N,N-dimethylacetamide
  • CIOMSO decylmethylsulfoxide
  • PEGML poly ethyleneglycol monolaurate
  • lecithin 1- substituted azacycloheptanones, particularly l-N-dodecylcyclaza-cycloheptanones (e.g., as available under the trademark AzoneTM from Nelson Research & Development Co., Irvine, Calif.), alcohols, and the like.
  • Carriers or“vehicles” refers to carrier materials suitable for compound administration and include any such material known in the art such as, for example, any liquid, gel, solvent, liquid diluent, solubilizer, or the like, which is non-toxic and which does not interact with any components of the composition in a deleterious manner.
  • Examples of pharmaceutically acceptable carriers include, for example, water, salt solutions, alcohol, silicone, waxes, petroleum jelly, vegetable oils, polyethylene glycols, propylene glycol, sugars, gelatin, lactose, amylose, magnesium stearate, talc, surfactants, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty add esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, and the like.
  • a physician will determine the actual dosage which will be most suitable for an individual subject.
  • the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of that compound; the age, body weight, general health, sex, diet, mode and time of administration; rate of excretion; drug combination; the severity of the particular condition; and the individual undergoing therapy.
  • the agent and/or the pharmaceutical composition of the present technology may be administered in accordance with a regimen of from 1 to 10 times per day, such as once or twice per day.
  • the daily dosage level of the agent may be in single or divided doses.
  • the agent may be administered at a dose of from 0.01 to 30 mg/kg body weight, such as from 0.1 to 10 mg/kg or from 0.1 to 1 mg/kg body weight.
  • the dosages mentioned herein are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited.
  • “Therapeutically effective amount” refers to the amount of the therapeutic agent that is effective to achieve its intended purpose. While individual patient needs may vary, determination of optimal ranges for effective amounts of the compounds related to the technology is within the skill of the art. Generally, the dosage regimen for treating a condition with the compounds and/or compositions of this technology is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient; the severity of the dysfunction; the route of administration;
  • the dosage regimen actually employed may vary widely and therefore may deviate from the exemplary dosage regimens set forth herein.
  • the lipid formulations may be used in combination with one or more other pharmaceutically active agents.
  • Other agents are sometimes referred to auxiliary agents.
  • the fatty acids may be in the form of, and/or may be administered as, a
  • a pharmaceutically acceptable salt may be readily prepared by using a desired acid or base, as appropriate.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • Suitable acid addition salts are formed from acids that form non-toxic salts such as hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p- toluenesulphonate, and pamoate salts.
  • non-toxic salts such as hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-
  • Suitable base salts are formed from bases that form non-toxic salts and examples are sodium, potassium, aluminum, calcium, magnesium, zinc, and diethanolamine salts.
  • the lipid formulations of this invention are contained in acceptable excipients and/or carriers for oral consumption as a dietary supplement.
  • the actual form of the carrier, and thus, the composition itself, is not critical.
  • the carrier may be a liquid, gel, gelcap, capsule, powder, solid tablet (coated or non-coated), tea, or the like.
  • the lipid composition may be in the form of dry powders, granules, pills, tablets, capsules, lozenges, dry products for reconstitution with water or other suitable carrier, aqueous or oily solutions or suspensions, gels, pastes, emulsions or syrups.
  • the composition is preferably in the form of a tablet or capsule and most preferably in the form of a soft gelatin capsule.
  • Suitable excipient and/or carriers include maltodextrin, calcium carbonate, dicalcium phosphate, tricalcium phosphate, microcrystalline cellulose, dextrose, rice flour, magnesium stearate, stearic acid, croscarmellose sodium, sodium starch glycolate, crospovidone, sucrose, vegetable gums, lactose, methylcellulose, povidone, carboxymethylcellulose, com starch, and the like (including mixtures thereof).
  • Preferred carriers include calcium carbonate, magnesium stearate, maltodextrin, and mixtures thereof.
  • the various ingredients and the excipient and/or carrier are mixed and formed into the desired form using conventional techniques.
  • the tablet or capsule of the present invention may be coated with an enteric coating that dissolves at a pH of about 6.0 to 7.0.
  • a suitable enteric coating that dissolves in the small intestine but not in the stomach is cellulose acetate phthalate. Further details on techniques for formulation for and administration may be found in the latest edition of Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA).
  • the composition contains no traces of organic solvents which is an important property regarding the safety of consuming such compounds.
  • the supplement is provided as a powder or liquid suitable for adding by the consumer to a food or beverage.
  • the dietary supplement can be administered to an individual in the form of a powder, for instance to be used by mixing into a beverage, or by stirring into a semi-solid food such as a pudding, topping, sauce, puree, cooked cereal, or salad dressing, for instance, or by otherwise adding to a food.
  • the lipid formulations of the present invention may also be formulated with a number of other compounds. These compounds and substances add to the palatability or sensory perception of the particles (e.g., flavorings and colorings) or improve the nutritional value of the particles (e.g., minerals, vitamins, phytonutrients, antioxidants, etc.).
  • the dietary supplement may comprise one or more inert ingredients, especially if it is desirable to limit the number of calories added to the diet by the dietary supplement.
  • the dietary supplement of the present invention may also contain optional ingredients including, for example, herbs, vitamins, minerals, enhancers, colorants, sweeteners, flavorants, inert ingredients, and the like.
  • the dietary supplement of the present invention may contain one or more of the following: ascorbates (ascorbic acid, mineral ascorbate salts, rose hips, acerola, and the like), dehydroepiandrosterone (DHEA), Fo-Ti or Ho Shu Wu (herb common to traditional Asian treatments), Cat's Claw ( ancient herbal ingredient), green tea (polyphenols), inositol, kelp, dulse, bioflavinoids, maltodextrin, nettles, niacin, niacinamide, rosemary, selenium, silica (silicon dioxide, silica gel, horsetail, shavegrass, and the like), spirulina, zinc, and the like.
  • Such optional ingredients may be either naturally occurring or concentrated forms.
  • the dietary supplements further comprise vitamins and minerals including, but not limited to, calcium phosphate or acetate, tribasic; potassium phosphate, dibasic; magnesium sulfate or oxide; salt (sodium chloride); potassium chloride or acetate; ascorbic acid; ferric orthophosphate; niacinamide; zinc sulfate or oxide; calcium pantothenate; copper gluconate; riboflavin; beta-carotene; pyridoxine hydrochloride; thiamin mononitrate; folic acid; biotin; chromium chloride or picolonate; potassium iodide; sodium selenate; sodium molybdate; phylloquinone; vitamin D3; cyanocobalamin; sodium selenite; copper sulfate; vitamin A; vitamin C; inositol; potassium iodide.
  • vitamins and minerals including, but not limited to, calcium phosphate or acetate, tribasic; potassium
  • the lipid formulations comprise at least one food flavoring such as acetaldehyde (ethanal), acetoin (acetyl methylcarbinol), anethole (parapropenyl anisole), benzaldehyde (benzoic aldehyde), N-butyric acid (butanoic acid), d- or l-carvone (carvol), cinnamaldehyde (cinnamic aldehyde), citral (2,6-dimethyloctadien-2,6-al-8, gera- nial, neral), decanal (N-decylaldehyde, capraldehyde, capric aldehyde, caprinaldehyde, aldehyde C-IO), ethyl acetate, ethyl butyrate, 3 -methyl-3 -phenyl glycidic acid ethyl ester (ethyl-methyl-
  • compositions comprise at least one synthetic or natural food coloring (e.g., annatto extract, astaxanthin, beet powder, ultramarine blue,
  • canthaxanthin caramel, carotenal, beta carotene, carmine, toasted cottonseed flour, ferrous gluconate, ferrous lactate, grape color extract, grape skin extract, iron oxide, fruit juice, vegetable juice, dried algae meal, tagetes meal, carrot oil, com endosperm oil, paprika, paprika oleoresin, riboflavin, saffron and turmeric).
  • compositions comprise at least one phytonutrient (e.g., soy isoflavonoids, oligomeric proanthcyanidins, indol-3-carbinol, sulforaphone, fibrous ligands, plant phytosterols, ferulic acid, anthocyanocides, triterpenes, conjugated fatty acids such as conjugated linoleic acid and conjugated linolenic acid, polyacetylene, quinones, terpenes, cathechins, gallates, and quercitin).
  • phytonutrient e.g., soy isoflavonoids, oligomeric proanthcyanidins, indol-3-carbinol, sulforaphone, fibrous ligands, plant phytosterols, ferulic acid, anthocyanocides, triterpenes, conjugated fatty acids such as conjugated linoleic acid and conjugated linolenic acid, poly
  • Sources of plant phytonutrients include, but are not limited to, soy lecithin, soy isoflavones, brown rice germ, royal jelly, bee propolis, acerola berry juice powder, Japanese green tea, grape seed extract, grape skin extract, carrot juice, bilberry, flaxseed meal, bee pollen, ginkgo biloba, red clover, burdock root, dandelion, parsley, rose hips, milk thistle, ginger, Siberian ginseng, rosemary, curcumin, garlic, lycopene, grapefruit seed extract, spinach, and broccoli.
  • the compositions comprise at least one vitamin (e.g., vitamin A, thiamin (Bl), riboflavin (B2), pyridoxine (B6), cyanocobalamin (B 12), biotin, ascorbic acid (vitamin C), retinoic acid (vitamin D), vitamin E, folic acid and other folates, vitamin K, niacin, and pantothenic acid).
  • the particles comprise at least one mineral (e.g., sodium, potassium, magnesium, calcium, phosphorus, chlorine, iron, zinc, manganese, fluorine, copper, molybdenum, chromium, selenium, and iodine).
  • a dosage of a plurality of particles includes vitamins or minerals in the range of the recommended daily allowance (RDA) as specified by the United States Department of Agriculture.
  • the particles comprise an amino acid supplement formula in which at least one amino acid is included (e.g., 1 -carnitine or tryptophan).
  • the present invention likewise provides methods of using the lipid formulations. These methods and uses are described in detail below but may be summarized as follows.
  • the present invention provides methods of treating a subject comprising administering to the subject the bioactive lipid formulation or oral delivery vehicle, food product, nutritional supplement, dietary supplement or functional food comprising the lipid formulation to a subject in need thereof.
  • the administration is oral, topical, parenteral, enteral, transdermal, intradermal, intraocular, intravitreal, sublingual, or intravaginal and may preferably comprise an effective amount of the composition.
  • the present invention provides methods of reducing obesity, inducing weight loss, increasing lean body mass, increasing muscularity, increasing muscle mass, improving body composition, alleviating one or more symptoms metabolic syndrome, treating diabetes, decreasing insulin resistance, reducing inflammation, improving concentration, memory, cognitive function, attention and treating, alleviating or improving one or more of the following diseases or conditions: restenosis, arteriosclerosis, coronary heart disease, thrombosis, myocardial infarction, stroke, hypertension, fatty liver, diabetes, hyperglycaemia, hyperinsulinemia, and stenosis, rheumatoid arthritis, systemic vasculitis, systemic lupus erythematosus, systemic sclerosis, dermatomyositis, polymyositis, various autoimmune endocrine disorders (e.g.
  • thyroiditis and adrenalitis various immune mediated neurological disorders (e.g. multiple sclerosis and myastenia gravis), various cardiovascular disorders (e.g. myocarditis, congestive heart failure, arteriosclerosis and stable and unstable angina, and Wegeners granulomatosis), inflammatory bowel diseases and colitis (e.g.,
  • the bioactive lipid composition structured phospholipid composition or structured acylglyceride composition or oral delivery vehicle, food product, nutritional supplement, dietary supplement or function food as described above.
  • the administration or oral, topical, parenteral, enteral, transdermal, intradermal, intraocular, intravitreal, sublingual, or intravaginal and may preferably comprise an effective amount of the composition.
  • the treatment is preferably performed under conditions such that the disease or condition is alleviated or improved as compared to an untreated state.
  • the present technology relates to the use of a composition according to embodiments of the technology for the manufacture of a medicament for the treatment and/or prevention of a condition selected from diabetes, inflammatory disorders, metabolic syndrome, obesity, hypertension, fatty liver, diabetes, hyperglycaemia, hyperinsulinemia, and stenosis.
  • the present technology provides use of a compound according to the technology for the manufacture of a medicament for lowering concentration of cholesterol and triglycerides in the blood of mammals and/or inhibiting the oxidative modification of low density lipoprotein.
  • the present technology provides a method for producing weigh loss or a reduction of the fat mass in a human or non-human animal in need thereof, comprising administering thereto an effective amount of a compound of the technology or a pharmaceutically acceptable salt thereof.
  • the present technology provides a method for the modification of the fat distribution and content of animals in order to improve the quality of the meat, or product such as milk and eggs, comprising administering thereto an effective amount of a compound of the technology or a pharmaceutically acceptable salt thereof.
  • the animal is an agricultural animal, such as gallinaceous birds, bovine, ovine, caprine or porcine mammals.
  • the animal may be a fish or shellfish, such as salmon, cod, Tilapia, clams, oysters, lobster or crabs.
  • the present technology provides use of a compound according to the technology or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the inhibition and/or prevention of the growth of tumors.
  • the present technology provides use of a compound according to the technology in the manufacture of a medicament for the inhibition and/or prevention of the invasion of a primary tumor into the connective tissue.
  • the present technology provides use of a compound according to the technology for the manufacture of a medicament for the inhibition and/or prevention of the metastatic properties of a tumor, e.g., to inhibit the formation of secondary tumors.
  • the use of the present compounds may increase the overall survival of mammals with tumors.
  • the present technology provides a method for the treatment and/or inhibition of primary and secondary metastatic neoplasms, comprising administering a compound of the technology or a pharmaceutically acceptable salt thereof.
  • the present technology provides use of a compound of the technology or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention and/or treatment of proliferative skin disorders such as psoriasis, atopic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, lamellar ichthyosis, epidermolytic hyperkeratosis, pre malignant sun induced keratosis, and seborrhea.
  • proliferative skin disorders such as psoriasis, atopic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, lamellar ichthyosis, epidermolytic hyperkeratosis, pre malignant sun induced keratosis, and seborrhea.
  • the present technology provides use of a compound of the technology or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the inhibition of proliferation and/or induction of differentiation of keratinocytes.
  • the present technology provides use of a compound of the technology or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention and/or treatment of inflammatory disorders.
  • the present technology provides use of a compound of the technology or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention and/or treatment of inflammatory disorders, wherein the inflammatory disorder is selected from the group comprising immune mediated disorders such as rheumatoid arthritis, systemic vasculitis, systemic lupus erythematosus, systemic sclerosis, dermatomyositis, polymyositis, various autoimmune endocrine disorders (e.g.
  • thyroiditis and adrenalitis various immune mediated neurological disorders (e.g. multiple sclerosis and myastenia gravis), various cardiovascular disorders (e.g. myocarditis, congestive heart failure, arteriosclerosis and stable and unstable angina, and Wegeners granulomatosis), inflammatory bowel diseases and colitis (e.g., Crohn’s colitis), nephritis, various inflammatory skin disorders (e.g. psoriasis, atopic dermatitis and food allergy) and acute and chronic allograft rejection after organ transplantation.
  • various immune mediated neurological disorders e.g. multiple sclerosis and myastenia gravis
  • cardiovascular disorders e.g. myocarditis, congestive heart failure, arteriosclerosis and stable and unstable angina, and Wegeners granulomatosis
  • inflammatory bowel diseases and colitis e.g., Crohn’s colitis
  • nephritis various inflammatory skin disorders (e.g.
  • the present technology provides a method for enhancing the endogenous production of interleukin- 10 (IL-10) in mammalian cells or tissues, comprising administering a compound of the technology or a pharmaceutically acceptable salt thereof.
  • the mammal has developed or is susceptible to develop an autoimmune and/or inflammatory disorder.
  • the present technology provides a method for suppression of the endogenous production of interleukin-2 (IL-2) in mammalian cells or tissues, comprising administering a compound of the technology or a pharmaceutically acceptable salt thereof.
  • IL-2 interleukin-2
  • the mammal has developed or is susceptible to develop an autoimmune and/or inflammatory disorder.
  • the present technology provides use of a compound of the technology or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the inhibition of proliferation of stimulated peripheral mononuclear cells (PBMC).
  • PBMC peripheral mononuclear cells
  • the methods comprise co-administration of a delta-6 desaturase inhibitor, particularly where the lipid formulations comprise 5,11,14- eicosatrienoic acid and 11,14 eicosadienoic acid (20:2 n-6).
  • the present invention is not limited to any particular delta-6 desaturase inhibitor.
  • the delta-6 desaturase inhibitor is 2,2-diphenyl-5-(4-[[(l E)-pyridin-3-yl-methylidene]amino]piperazin- l-yl)pentanenitrile (SC-26196.
  • Obesity is a chronic disease that is highly prevalent in modem society and is associated not only with a social stigma, but also with decreased life span and numerous medical problems, including adverse psychological development, reproductive disorders such as polycystic ovarian disease, dermatological disorders such as infections, varicose veins, Acanthosis nigricans, and eczema, exercise intolerance, diabetes mellitus, insulin resistance, hypertension, hypercholesterolemia, cholelithiasis, osteoarthritis, orthopedic injury, thromboembolic disease, cancer, and coronary heart disease.
  • the present technology provides a treatment regimen that is useful in returning the body weight of obese subjects toward a normal body weight. In some embodiments, the technology provides a therapy for obesity that results in maintenance of the lowered body weight for an extended period of time. Further, in some embodiments the present technology reduces or inhibits the weight gain normally induced by fat rich diets.
  • the present technology prevents obesity and, once treatment has begun, to arrests progression or prevents the onset of diseases that are the consequence of, or secondary to, the obesity, such as hypertension and fatty liver.
  • the obesity herein may be due to any cause, whether genetic or environmental.
  • disorders that may result in obesity or be the cause of obesity include overeating and bulimia, polycystic ovarian disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich’s syndrome, Type II diabetes, GH-deficiency, normal variant short stature, Turner’s syndrome, and other pathological conditions showing reduced metabolic activity.
  • the present technology provides a treatment regimen that is useful in lowering the blood pressure. Further, in some embodiments the present technology provides a treatment regimen that is useful in lowering the concentration of triacylglycerols in the liver. It is anticipated that such a regimen provides an inhibiting effect on the development of a fatty liver condition and is suited as a method for the treatment of the manifested disease.
  • the compounds of the present technology activate the oxidation, and also reduce the concentration, of triglycerides in the liver.
  • metabolic syndrome is used to describe a multimetabolic syndrome that is inter alia characterized by hyperinsulinemia, insulin resistance, obesity, glucose intolerance, Type 2 diabetes mellitus, dyslipidemia, or hypertension.
  • the compounds of the present technology provide a positive effect on all the conditions mentioned above, e.g., by regulating both glucose and lipid homeostasis, and thus it is anticipated that the compounds of the present technology are suitable agents for the regulation of the above defined metabolic disease (sometimes called syndrome X). Diabetes
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM noninsulin-dependent diabetes mellitus
  • Type I diabetes severe diabetes mellitus, usually of abrupt onset prior to maturity, characterized by low plasma insulin levels, polydipsia, polyuria, increased appetite, weight loss and episodic ketoacidosis; also referred to as IDDM.
  • Type II diabetes an often mild form of diabetes mellitus, often of gradual onset, usually in adults, characterized by normal to high absolute plasma insulin levels which are relatively low in relation to plasma glucose levels; also referred to as NIDDM.
  • Type I and II diabetes are in accordance with an etiologic classification considered as primary diabetes respectively.
  • Secondary diabetes comprises pancreatic, extrapancreatic and/or endocrine or drug- induced diabetes. Further, some types of diabetes are classified as exceptional forms. These include lipoatrophic, myatonic diabetes, and a type of diabetes caused by disturbance of insulin receptors.
  • the present technology provides a treatment regimen that is useful in lowering the blood glucose and to treat a diabetic condition.
  • the present technology provides a treatment regimen that is useful in lowering the concentration of insulin in the blood, and to increase the effect of the remaining insulin.
  • the compositions of the present invention are useful for ameliorating the symptoms of diabetes, providing nutritional support to a subject with diabetes, promoting healthy blood sugar levels, supporting efficient insulin production and secretion, and/or supporting healthy glucose metabolism.
  • pathological conditions have been found to be associated with smooth muscle cell proliferation. Such conditions include restenosis, arteriosclerosis, coronary heart disease, thrombosis, myocardial infarction, stroke, smooth muscle neoplasms such as leiomyoma, and leiomyosarcoma of the bowel and uterus and uterine fibroid or fibroma.
  • interventional intravascular procedures Over half a million interventional intravascular procedures are performed each year. While such invasive procedures continue to improve over time, as many as 30% to 50% of the procedures performed each year fail as a result of restenosis, e.g., the formation of secondary stenosis. The reduction of restenosis is, therefore, often cited as the most critical factor in increasing the success realized in the treatment of cardiovascular disease through the use of interventional intravascular procedures, such as angioplasty, atherectomy, and procedures utilizing stents, and laser technology.
  • a small incision is made to an artery in the patient’s leg or arm and a long hollow tube, called a guide catheter, is inserted into the artery.
  • a thick guide wire and deflated balloon catheter are then inserted into the guide catheter and are carefully advanced through the patient’s blood vessels using X-ray visualization.
  • the deflated balloon is advanced until it reaches the site of the luminal narrowing, at which point the physician inflates the balloon one or more times to a pressure of about 4-6 atm for about 60 seconds.
  • the balloon When inflated, the balloon cracks and fractures the plaque and stretches the muscle fiber in the artery wall beyond its ability to recoil completely. Although no plaque is removed in this procedure, the fracturing of the plaque and the stretching of the arterial wall increase the vessel lumen, thereby allowing for increased blood flow.
  • the restenosis that accompanies such procedures is characterized by platelet aggregation and adhesion, smooth muscle cell proliferation, narrowing of the vessel lumen, restricted vasodilatation, and an increase in blood pressure.
  • Smooth muscle cells in the intimal layer of the artery have been reported to enter the growth cycle within about 2-3 days of these procedures and to proliferate for several days thereafter (intimal hyperplasia).
  • Compounds that reportedly suppress smooth muscle proliferation in vitro may have undesirable pharmacological side effects when used in vivo.
  • Heparin is an example of one such compound, which reportedly inhibits smooth muscle cell proliferation in vitro but when used in vivo has the potential adverse side effect of inhibiting coagulation.
  • chemotherapeutic agents for cancer treatment requires considering a variety of factors including cytotoxicity, tumor cell proliferation, invasion, and metastasis.
  • Conventional anticancer agents have typically been identified on the basis of their cytotoxicity alone.
  • Tumor progression is thought to occur when variant cells having selective growth properties arise within a tumor cell population, and one of the final stages of tumor progression is the appearance of the metastatic phenotype.
  • the tumor cells During metastasis, the tumor cells invade the blood vessels, survive against circulating host immune defenses, and then extravasate, implant, and grow at sites distant from the primary tumor. This ability of tumor cells to invade neighboring tissues and to colonize other organs is among the leading causes of cancer related deaths.
  • metastasis encompasses a number of phenotypic traits that together result in the clinical problem that most often leads to death from cancer.
  • the cells lose their adherence and restrained position within an organized tissue, move into adjacent sites, develop the capacity both to invade and to egress from blood vessels, and become capable of proliferating in unnatural locations or environments.
  • These changes in growth patterns are accompanied by an accumulation of biochemical alterations that have the capacity to promote the metastatic process. So far, little is known about the intrinsic mechanism involved in the metastatic cascade. It is likely that in some cases the augmented metastatic potential of certain tumor cells may be due to an increased expression of oncogenes, which normally are responsible for control of various cellular functions, including differentiation, proliferation, cell motility, and communication.
  • Cancer is a disease of inappropriate tissue accumulation. This derangement is most evident clinically when tumor tissue bulk compromises the function of vital organs. Contrary to what is generally thought, human malignant disorders are usually not diseases of rapid cell proliferation. In fact, the cells of most common cancers proliferate more slowly than many cells in normal tissues. It is a relatively slow accumulation of tumor tissue within vital organs that proves fatal to most patients who die of cancer.
  • Chemotherapeutic agents share one characteristic: they are usually more effective in killing or damaging malignant cells than normal cells. However, the fact that they do harm normal cells indicates their potential for toxicity. Nearly all chemotherapeutic agents currently in use interfere with DNA synthesis, with the provision of precursors for DNA and RNA synthesis, or with mitosis. Such drugs are most effective against cycling cells. The mechanism of cell death after treatment with any single agent or combination of agents is complex and is likely to include more than one process. Because most clinically detectable tumors are composed mostly of non-cycling cells, it is not surprising that chemotherapy is not always effective in eradicating cancer.
  • the strategy of cancer treatment is to shift tumor cells from a non-cycling
  • Cancer treatment requires inhibition of a variety of factors including tumor cell proliferation, metastatic dissemination of cancer cells to other parts of the body, invasion, tumor-induced neovascularization, and enhancement of host immunological responses and cytotoxity.
  • the present technology provides a method for the prevention and/or treatment of primary and metastatic neoplasms that involves using a fatty acid analogue, or a lipid comprising a fatty acid analogue, of the present technology to treat a patient suffering from a cancer.
  • carcinoma in situ The two essential features of cancer are invasion and metastasis. At one extreme, microinvasion of the basement membrane characterizes the transition from neoplasia to cancer, and at the other extreme, metastases generally lead to death. Invasion into the underlying connective tissue by primary tumor proceeds in stages and is facilitated by various mediators produced by the tumor cells. Tumor cells that have not invaded the basement membrane and remain confined within the epithelium are termed carcinoma in situ.
  • Metastases may form when circulating tumor cells with adherent lymphocytes and platelets are trapped in capillaries and the tumor cell membrane interacts with the capillary endothelium.
  • the capillary endothelial junctions retract, and tumor cell ligands bind to receptors on the endothelial and basement membranes.
  • Tumor cells then release collagenase IV, which destroys collagen IV, a major component of the underlying basement membrane. Invasion of the subcapillary connective tissue is aided by binding to the glycoproteins laminin and fibronectin, by the release of proteases that destroy the matrix, and by the secretion of motility and chemotactic factors. Tumor cells then may proliferate and synthesise platelet aggregatory factors such as thromboxanes and procoagulants, thereby leading to the deposition of a fibrin cocoon around the cells. Such a cocoon may protect the micrometastasis from attack by the host’s immune system.
  • Cancers that can be prevented and/or treated by the compositions and methods of the present technology include, but are not limited to, human sarcomas and carcinomas, e.g. carcinomas, e.g., colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, thyroid cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary
  • adenocarcinomas cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms’s tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemias, e.g., acute lymphocytic leukemia and acute myelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic, monocy
  • Proliferative skin diseases are widespread throughout the world and afflict millions of humans and their domesticated animals. Proliferative skin diseases are characterized by keratinocyte cell proliferation, or division, and may also be associated with incomplete epidermal differentiation. Psoriasis is the most serious of the proliferative skin diseases with which this technology is concerned. Psoriasis is a genetically determined disease of the skin characterized by two biological hallmarks. First, there is a profound epidermal hyperproliferation related to accelerated and incomplete differentiation. Second, there is a marked inflammation of both epidermis and dermis with an increased recruitment of T lymphocytes, and in some cases, formation of neutrophil microabcesses. Many pathologic features of psoriasis can be attributed to alterations in the growth and maturation of epidermal keratinocytes, with increased proliferation of epidermal cells, occurring within 0.2 mm of the skin’s surface.
  • psoriasis vulgaris A common form of psoriasis, psoriasis vulgaris, is characterized by well-demarcated erythematous plaques covered by thick, silvery scales.
  • a characteristic finding is the isomorphic response (Koebner phenomenon), in which new psoriatic lesions arise at sites of cutaneous trauma. Lesions are often localized to the extensor surfaces of the extremities, and the nails and scalp are also commonly involved.
  • corticosteroids is the most convenient outpatient therapy.
  • the retinoids are also an effective treatment for psoriasis.
  • Etretinate is especially useful in the exfoliative and pustular varieties of psoriasis.
  • several major potential complications must be monitored in patients placed on retinoids.
  • the retinoids are potent teratogens and should not be given to women of childbearing age who are not using adequate contraception.
  • Etretinate like other retinoids, can produce elevations in cholesterol and triglyceride levels; therefore dietary regulation may be necessary.
  • etretinate can induce hepatotoxicity, liver function tests should be performed before and at regular intervals during use of the drug.
  • Cytokines are a class of secreted soluble proteins normally present in very low concentration in a variety of cells. Lymphoid, inflammatory hemopoietic, and other cells such as connective tissue cells (e.g. fibroblasts, osteoblasts) secrete a variety of cytokines which regulate the immune, inflammatory, repair, and acute phase responses by controlling cell proliferation, differentiation, and effector functions. The effects of cytokines are mediated through binding to high affinity receptors on specific cell types.
  • IL-10 An important cytokine is IL-10, a 35-40 kDa peptide produced by helper T-cells, B- cells, monocytes, macrophages, and other cell types.
  • helper T-cells a 35-40 kDa peptide produced by helper T-cells, B- cells, monocytes, macrophages, and other cell types.
  • IL-10 has demonstrated immunosuppressive properties as evidenced by its ability to suppress cytokine production including IL-l and TNFa.
  • IL-10 also inhibits activation of other inflammatory cytokines, and therefore has potent anti-inflammatory activity.
  • Such diseases or conditions include loosening of prosthetic joint implants, inflammation, diabetes, cancer, graft versus host diseases, viral, fungal and bacterial infections, lipopolysaccharide endotoxin shock, diseases of depressed bone marrow function, thrombocytopenia, osteoporosis,
  • spondyloarthropathies Paget’s disease, inflammatory bowel disease, arthritis, osteoarthritis, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and connective tissue diseases.
  • purified IL-10 has been shown in vitro to suppress certain types of viral infections.
  • U.S. Pat. No. 5,665,345 discloses a method for inhibiting replication of the human immunodeficiency virus, retro-viruses, and Kaposi sarcoma in human cells by administering IL-10.
  • IL-10 has also been suggested for use in the treatment of certain cancers.
  • No. 5,570,190 discloses administering exogenous IL-10 to treat mammals suffering from acute myelogenous leukemia and acute lymphocytic leukemia.
  • IL-10 is the to be
  • IL-10 was shown to inhibit bone marrow metastasis in severe combined immunodeficient mice.
  • IL-10 is a protein
  • proteins often leach out of solution and bind to the plastic or glass used in intravenous administration sets.
  • proteins are often incompatible and precipitate when mixed with physiological solutions such as dextrose or saline.
  • oral and topical routes are unavailable for IL-10 administration. The oral route is unavailable because protein is degraded in the gastrointestinal tract. None of the above approaches suggests enhancing endogenous IL-10 production in mammals for prophylaxis and treatment of diseases or conditions.
  • IL-10 is a powerful deactivator of macrophages and T cells, and inadequate production has been implicated in various autoimmune and inflammatory disorders.
  • embodiments of the compound or composition of the present technology are useful in the treatment of the following disorders: cancer, inflammation or inflammatory disease, dermatological disorders, fever, cardiovascular effects, hemorrhage, coagulation and acute phase response, cachexia, anorexia, acute infection, HIV infection, shock states, graft-versus-host reactions, autoimmune disease, reperfusion injury, meningitis, migraine and aspirin-dependent anti-thrombosis; tumor growth, invasion and spread, angiogenesis, metastases, malignant, ascites and malignant pleural effusion; cerebral ischemia, ischaemic heart disease, osteoarthritis, rheumatoid arthritis, osteoporosis, asthma, multiple sclerosis, neurodegeneration, Alzheimer’s disease, atherosclerosis, stroke, vasculitis, Crohn’s disease and ulcerative colitis; periodontitis, gingivitis; psoriasis, atopic dermatitis, chronic ulcers, epidermolysis bullosa
  • embodiments of the compound or composition of the present technology are useful in the treatment of the following disorders: cytokine and cell proliferation/differentiation activity; immunosuppressant or immunostimulant activity (e.g., for treating immune deficiency, including infection with human immune deficiency virus; regulation of lymphocyte growth; treating cancer and many autoimmune diseases, and to prevent transplant rejection or induce tumor immunity); regulation of hematopoiesis, e.g. treatment of myeloid or lymphoid diseases; promoting growth of bone, cartilage, tendon, ligament and nerve tissue, e.g.
  • immunosuppressant or immunostimulant activity e.g., for treating immune deficiency, including infection with human immune deficiency virus
  • regulation of lymphocyte growth e.g. treatment of myeloid or lymphoid diseases
  • promoting growth of bone, cartilage, tendon, ligament and nerve tissue e.g.
  • follicle-stimulating hormone for healing wounds, treatment of bums, ulcers and periodontal disease and neurodegeneration; inhibition or activation of follicle-stimulating hormone (modulation of fertility); chemotactic/chemokinetic activity (e.g. for mobilizing specific cell types to sites of injury or infection); hemostatic and thrombolytic activity (e.g. for treating hemophilia and stroke); anti-inflammatory activity (for treating e.g. septic shock or Crohn’s disease); as antimicrobials; modulators of e.g. metabolism or behavior; as analgesics; treating specific deficiency disorders; in treatment of e.g. psoriasis, in human or veterinary medicine.
  • chemotactic/chemokinetic activity e.g. for mobilizing specific cell types to sites of injury or infection
  • hemostatic and thrombolytic activity e.g. for treating hemophilia and stroke
  • anti-inflammatory activity for treating e.g. septic shock or Crohn’
  • compositions of the present technology are useful in the treatment of the following disorders: macrophage inhibitory and/or T cell inhibitory activity and thus, anti-inflammatory activity; anti-immune activity, e.g., inhibitory effects against a cellular and/or humoral immune response, including a response not associated with inflammation; inhibit the ability of macrophages and T cells to adhere to extracellular matrix components and fibronectin, as well as up-regulated fas receptor expression in T cells; inhibit unwanted immune reaction and inflammation including arthritis, including rheumatoid arthritis, inflammation associated with hypersensitivity, allergic reactions, asthma, systemic lupus erythematosus, collagen diseases and other autoimmune diseases, inflammation associated with atherosclerosis, arteriosclerosis, atherosclerotic heart disease, reperfusion injury, cardiac arrest, myocardial infarction, vascular inflammatory disorders, respiratory distress syndrome or other cardiopulmonary diseases, inflammation associated with peptic ulcer, ulcerative colitis and other diseases of the gastrointestinal tract, he
  • conjunctivitis conjunctivitis, chorioretinitis, uveoretinitis, optic neuritis, intraocular inflammation, e.g., retinitis or cystoid macular oedema, sympathetic ophthalmia, scleritis, retinitis pigmentosa, immune and inflammatory components of degenerative fondus disease, inflammatory components of ocular trauma, ocular inflammation caused by infection, proliferative vitreo- retinopathies, acute ischaemic optic neuropathy, excessive scarring, e.g.
  • Parkinson’s disease complication and/or side effects from treatment of Parkinson’s disease, AIDS-related dementia complex HIV-related encephalopathy, Devic’s disease, Sydenham chorea, Alzheimer’s disease and other degenerative diseases, conditions or disorders of the CNS, inflammatory components of stokes, post-polio syndrome, immune and inflammatory components of psychiatric disorders, myelitis, encephalitis, subacute sclerosing pan- encephalitis, encephalomyelitis, acute neuropathy, subacute neuropathy, chronic neuropathy, Guillaim-Barre syndrome, Sydenham chora, myasthenia gravis, pseudo-tumor cerebri, Down’s Syndrome, Huntington’s disease,
  • monocyte or leukocyte proliferative diseases e.g. leukaemia
  • monocytes or lymphocytes for the prevention and/or treatment of graft rejection in cases of transplantation of natural or artificial cells, tissue and organs such as cornea, bone marrow, organs, lenses, pacemakers, natural or artificial skin tissue.
  • Embodiments of the technology include any therapeutic application that can benefit a human or non-human animal, for example a mammal. As such, both human and veterinary treatments are within the scope of the present technology.
  • Treatment may be in respect of an existing condition or it may be prophylactic. It may be of an adult, a juvenile, an infant, a fetus, or directed to an.an organ, tissue, or cell.
  • an active agent for use in treatment is administered via any appropriate route and at any appropriate dosage. Dosages can vary between wide limits, depending upon the nature of the treatment, the age and condition of the individual to be treated, etc., and a physician will ultimately determine appropriate dosages to be used.
  • a daily dosage of a compound of the present technology of from 1 pg to 1 mg/kg body weight may be suitable.
  • the dosage may be repeated as often as appropriate. If side effects develop, the amount and/or frequency of the dosage can be reduced, in accordance with good clinical practice.
  • Tall oil distillate is obtained from a commercial supplier.
  • the tall oil distillate is ethylated (see US 2015/0203789, incorporated herein by reference for ethylation procedures, with the exception that the TOD contains free fatty acids as opposed to triglycerides) and then is fractionated by SMB chromatography as described in the description above.
  • the product is analyzed by gas chromatography to determine the content.
  • Tables 1,3, and 4 provide exemplary results.
  • Table 2 provides an analysis of rosin acids in the starting TOD material.

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Abstract

L'invention concerne une technologie relative à des compositions lipidiques contenant des acides gras bioactifs et, en particulier, mais pas exclusivement, des compositions contenant de l'acide 5,11,14-eicosatriénoïque.
PCT/US2019/043944 2018-07-30 2019-07-29 Compositions d'acide 5,11,14-eicosatriénoïque et leurs procédés de production Ceased WO2020028263A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT202200005462A1 (it) * 2022-03-21 2023-09-21 Green Innovation Gmbh Veterinary topical composition for the antimicrobic treatment of dairy animal udders / composizione topica veterinaria per il trattamento antimicrobico delle mammelle degli animali da latte

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US20060172023A1 (en) * 2005-01-31 2006-08-03 Loders Croklaan B.V. Use of pinolenic acid
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WO2017048774A1 (fr) * 2015-09-18 2017-03-23 Sciadonics, Inc. Formulations de lipides contenant des acides gras bioactifs
WO2017091647A1 (fr) * 2015-11-25 2017-06-01 Sciadonics, Inc. Formulations lipidiques contenant des acides gras bioactifs
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US5456912A (en) * 1993-12-28 1995-10-10 The Regents Of The University Of California Non-methylene interrupted fatty acids as immunomodulators
US20060172023A1 (en) * 2005-01-31 2006-08-03 Loders Croklaan B.V. Use of pinolenic acid
US20160022622A1 (en) * 2013-03-11 2016-01-28 Jan Remmereit Lipid compositions containing bioactive fatty acids
WO2017048774A1 (fr) * 2015-09-18 2017-03-23 Sciadonics, Inc. Formulations de lipides contenant des acides gras bioactifs
WO2017091647A1 (fr) * 2015-11-25 2017-06-01 Sciadonics, Inc. Formulations lipidiques contenant des acides gras bioactifs
US20180021281A1 (en) * 2016-07-20 2018-01-25 Sciadonics, Inc. Lipid formulations containing bioactive fatty acids and other bioactive agents

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT202200005462A1 (it) * 2022-03-21 2023-09-21 Green Innovation Gmbh Veterinary topical composition for the antimicrobic treatment of dairy animal udders / composizione topica veterinaria per il trattamento antimicrobico delle mammelle degli animali da latte
EP4248945A1 (fr) * 2022-03-21 2023-09-27 Green Innovation GmbH Composition topique vétérinaire pour le traitement antimicrobique des pis d'animaux laitiers

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