EP2986148A2 - Compositions comprenant de l'acide docosapentaénoïque et procédés d'utilisation - Google Patents

Compositions comprenant de l'acide docosapentaénoïque et procédés d'utilisation

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Publication number
EP2986148A2
EP2986148A2 EP14779339.2A EP14779339A EP2986148A2 EP 2986148 A2 EP2986148 A2 EP 2986148A2 EP 14779339 A EP14779339 A EP 14779339A EP 2986148 A2 EP2986148 A2 EP 2986148A2
Authority
EP
European Patent Office
Prior art keywords
alternatively
dpa
dha
composition
fatty acids
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP14779339.2A
Other languages
German (de)
English (en)
Inventor
Abdel Aziz FAWZY
George Bobotas
Ihor Terleckyj
Roelof Rongen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Matinas Biopharma Inc
Original Assignee
Matinas Biopharma Inc
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Filing date
Publication date
Application filed by Matinas Biopharma Inc filed Critical Matinas Biopharma Inc
Publication of EP2986148A2 publication Critical patent/EP2986148A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to omega-3 fatty acid compositions, and methods of treating, preventing, reducing the occurrence of, and improving symptoms associated with liver-related conditions.
  • Marine oils also commonly referred to as fish oils, are a good source of the two main omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which have been found to regulate lipid metabolism.
  • Omega-3 fatty acids have been found to have beneficial effects on the risk factors for cardiovascular diseases, especially mild hypertension, hypertriglyceridemia and on the coagulation factor VII phospholipid complex activity.
  • Omega-3 fatty acids lower serum triglycerides (TG), increase serum HDL-cholesterol, lower systolic and diastolic blood pressure and the pulse rate, and lower the activity of the blood coagulation factor Vll-phospholipid complex.
  • omega-3 fatty acids seem to be well tolerated, without giving rise to any severe side effects.
  • omega-3 fatty acids is a concentrate of omega-3, long chain, polyunsaturated fatty acids from fish oil containing DHA ethyl esters, EPA ethyl esters as well as ethyl esters of other omega-3 fatty acids (described in USP35 for LOVAZA®) and is sold under the trademarks OMACOR® and LOVAZA®.
  • omega-3 fatty acid comprises at least 90% omega-3 fatty acids of which at least 80% EPA+DHA (in a ratio of 1 .2:1 ) and is described, for example, in U.S. Pat. Nos... 5,502,077, 5,656,667 and 5,698,594.
  • LOVAZA® (omega-3-acid ethyl esters) is indicated for the treatment of patients with hypertriglyceridemia with TG levels of 500mg/dl_ or higher.
  • EPADEL® omega-3 fatty acid concentrate
  • This product is described as 98% EPA ethyl ester in Lancet (Vol.369; March 31 , 2007; 1090-1098) reporting on a large outcome study with EPADEL®.
  • EPADEL® is known to contain less than 1 % of any fatty acid other than EPA.
  • omega-3 fatty acid concentrate also consists almost entirely of EPA ethyl ester and is known under its developmental stage name AMR101 or its trade name VASCEPA®.
  • AMR101 is described in US patent application 2010/0278879 as comprising at least 95% EPA (typically referred to as 97% or at least 96% in company releases and references) and less than 1 % of any other fatty acid.
  • AMR101 was previously under development for the treatment of Huntingdon's Disease but failed in phase III clinical development. Subsequently, AMR101 was entered in a development program for hypertriglyceridemia and mixed dyslipidemia.
  • EPANOVATM omega-3, long chain, polyunsaturated fatty acids from fish oil containing approximately 75% DHA and EPA as free fatty acids. This product is described as comprising approximately 55% EPA and 20% DHA. EPANOVATM was previously under development for the treatment of Crohn's Disease but failed in phase III clinical development. Subsequently, EPANOVATM was entered in a development program for hypertriglyceridemia and mixed dyslipidemia.
  • omega-3 fatty acid compositions are dose dependent, i.e., the higher the dose, the greater the therapeutic affect and bioavailability.
  • the effect of each specific omega-3 fatty acid composition may be different, and therefore the level of therapeutic effect of one composition at a given dose cannot necessarily be inferred from the level of therapeutic effects of other omega-3 fatty acid compositions at the same or similar dose.
  • Omega-3 fatty acids are known to be "essential fatty acids".
  • EFAs essential fatty acids
  • the main EFAs in the diet are linoleic acid of the omega-6 series and alpha-linolenic acid of the omega-3 series. However, to fulfill most of their biological effects these "parent" EFAs must be metabolised to the other longer chain fatty acids. Each fatty acid probably has a specific role in the body.
  • n-6 series dihomo- gammalinolenic acid (DGLA, 20:3-n6) and arachidonic acid (ARA, 20:4-n6)
  • DGLA dihomo- gammalinolenic acid
  • ARA arachidonic acid
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • U.S. Patent No. 6,479,544 describes an invention in which it is found that ARA is highly desirable rather than undesirable and it may be helpful to administer ARA in association with EPA.
  • This invention provides pharmaceutical formulations containing eicosapentaenoic acid or any appropriate derivative (hereinafter collectively referred to as EPA) and arachidonic acid (ARA), as set out in the granted claims for this patent.
  • EPA eicosapentaenoic acid or any appropriate derivative
  • ARA arachidonic acid
  • ARA may be replaced by one or more of its precursors, DGLA or GLA.
  • the ratio of EPA to ARA is preferably between 1 :1 and 20:1.
  • Patent application PCT/GB 2004/000242 describes the treatment or prevention of psoriasis with a formulation comprising more than 95% EPA and less than 2% DHA.
  • the EPA is replaced with DPA.
  • Patent application PCT/NL 2006/050291 (WO/2007/058538, GB 0301701 .9) describes combinations of idigestible oligosaccharides and long chain polyunsaturated fatty acids such as ARA, EPA, DA, and combinations thereof to improve intestinal barrier integrity, improving barrier function, stimulating gut maturation and/or reducing intestinal barrier permeability.
  • Holub et al. ⁇ Lipids, 201 1 , 46:399-407) discloses a study assessing the effect of oral supplementation with docosapentaenoic acid (DPA) on levels of serum and tissue lipid classes and their fatty acid compositions in rat liver, heart, and kidney.
  • DPA docosapentaenoic acid
  • Non-alcoholic fatty liver disease is thought to be the most common chronic liver disease.
  • NASH non-alcoholic steatohepatitis
  • NAFLD non-alcoholic steatohepatitis
  • NAFLD non-alcoholic steatohepatitis
  • NAFLD and NASH Other co-morbidity factors associated with NAFLD and NASH include obesity, metabolic syndrome and type 2 diabetes. As the incidence rate for all these disease states is currently rising, it is the opinion of those skilled in the art that the incidence and prevalence of NAFLD, NASH, and its consequences will be increasing in the future (AASLD/IASL NAFLD Symposium, 2013, Washington, D.C.).
  • NAFLD may be considered as a precursor to NASH, in the spectrum of disease progression.
  • NAFLD is characterized by high abnormal levels of lipids, primarily in the form of triglycerides, cholesterol and fatty acids, that are elevated and/or stored in the liver (simple steatosis). With prolonged time, the pathophysiology of disease progression can result in the process of fibrosis and necroinflammation, giving rise to the state of NASH.
  • Diagnosis of early NAFLD relies primarily on recognition of elevated liver enzymes, such as ALT, AST and perhaps GGT. In those skilled in the art, elevations of these enzymes may precipitate the need for further tests in the form of imaging, including ultrasound and MRI, or related tests such as but not limited to FIBROTEST®.
  • the current gold standard is histopathological evaluation of the degree of fibrosis determined by examining liver samples obtained thru punch biopsy.
  • Other non-invasive methods for determining fibrosis include determination of liver stiffness by specific ultrasound techniques, and are being evaluated as surrogates and/or replacement for performing liver biopsies.
  • the main objective is to decrease lipid levels in the liver.
  • the first course of therapy is life style modification, mainly by dietary means and a weight loss program.
  • the main objective is to curtail further development of fibrosis.
  • therapeutic agents for the treatment of NASH.
  • the primary agents that could be used include vitamin E and pentoxyfiline.
  • pentoxyfiline the primary agents that could be used.
  • these agents there are limitations to the use of these agents.
  • long term use is associated with an increased risk for cardiovascular events, including myocardial infarct and cardiac death.
  • liver transplantation which is costly, subject to rejection, and predisposes the patient to increased risk of opportunistic microbial infections due to the use of immunosuppressive agents.
  • immunosuppressive agents the availability and suitability of donor livers is highly limited, which would decrease chance of survival for persons in the state of liver failure. Therefore, there is a need in the art for an effective therapy for liver- related conditions.
  • HMG-CoA reductase is a rate controlling exnzyme of the mevalonate pathway.
  • HMG-CoA reductase is the rate limiting step in cholesterol synthesis and is a major drug target for cholesterol reducing drugs like "statins,” or HMG-CoA reductase inhibitors.
  • Proprotein convertase subtilisin/kexin type 9 also known as PCSK9, is an enzyme that in humans is encoded by the PCSK9 gene.
  • PCSK9 is thought to act in cholesterol homeostasis, and drugs that block PCSK9 are thought to be effective in lowering cholesterol, including low-density lipoprotein cholesterol (LDL-D).
  • LDL-D low-density lipoprotein cholesterol
  • the present invention provides omega-3 fatty acid compositions and methods of administering these compositions.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) in an amount of at least 60% of total amount of the fatty acids present in the composition, wherein the ratio of DPA to DHA (DPA:DHA) is between about 10:1 to about 1 :10.
  • DPA docosapentaenoic acid
  • DHA docosahexaenoic acid
  • the present invention provides methods comprising administering the compositions.
  • the present invention provides a method of treating, preventing, reducing the occurrence of, and improving symptoms associated with liver-related conditions.
  • liver-related conditions include, but are not limited to fatty liver, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), hepatitis including but not limited to hepatitis C, HIV (human immunodeficiency virus) infection and any liver syndrome arising from the treatment of HIV, drug-induced fatty liver or sequalae (including but not limited to NAFLD, NASH), liver failure, liver transplantation, transplanted liver failure, liver damage associated with other organ system afflictions including but not limited to renal failure or disease, abnormally elevated liver enzymes (such as ALT, AST and /or GGT) associated with disease (such as diabetes type 2), or drug- induced afflictions.
  • NASH non-alcoholic steatohepati
  • the present invention further provides a method of reducing expression of HMG-CoA reductase and/or reducing levels of HMG-CoA reductase in a subject.
  • the present invention further provides a method of reducing the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) and/or reducing levels of PCSK9 in a subject.
  • PCSK9 proprotein convertase subtilisin/kexin type 9
  • the present invention provides an orally administrable pharmaceutical composition comprising fatty acids.
  • the pharmaceutical composition comprises docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) in an amount of at least 60% of total amount of the fatty acids present in the composition.
  • DPA docosapentaenoic acid
  • DHA docosahexaenoic acid
  • the pharmaceutical composition comprises DPA and DHA in an amount of about 65% or greater, alternatively about 70% or greater, alternatively about 75% or greater, alternatively about 80% or greater, alternatively about 80% or greater, alternatively about 81 % or greater, alternatively about 82% or greater, alternatively about 83% or greater, alternatively about 84% or greater, alternatively about 85% or greater, alternatively about 86% or greater, alternatively about 87% or greater, alternatively about 88% or greater, alternatively about 89% or greater, alternatively about 90% or greater, alternatively about 91 % or greater, alternatively about 92% or greater, alternatively about 93% or greater, alternatively about 94% or greater, alternatively about 95% or greater, alternatively about 96% or greater.alternatively about 97% or greater, alternatively about 98% or greater, or alternatively about 99% or greater of the total amount of fatty acids present in the composition.
  • the pharmaceutical composition comprises DPA and DHA in an amount of between about 70% to about 99%, alternatively about 7
  • the compositions comprise docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) such that the DPA:DHA ratio in the composition is about 10:1 to 1 :10, alternatively about 9:1 to about 1 :9, alternatively about 8:1 to 1 :8, alternatively about 7:1 to about 1 :7, alternatively about 6:1 to about 1 :6, alternatively about 5:1 to about 1 :5, or alternatively about 4:1 to about 1 :4.
  • DPA docosapentaenoic acid
  • DHA docosahexaenoic acid
  • the composition comprises DPA and DHA in a ratio of DPA:DHA of at least 2:1.
  • the composition comprises DPA'.DHA in a ratio of about 2:1 to about 10:1 , alternatively about 2:1 to about 9:1 , alternatively about 2:1 to about 8:1 , alternatively about 2:1 to about 7:1 , alternatively about 2:1 to about 6:1 , alternatively about 2:1 to about 5:1 , alternatively about 2:1 to about 4:1 , alternatively about 3:1 to about 5:1 , or alternatively about 4:1.
  • the composition comprises DPA and DHA in a ratio of DPA:DHA of about 5:1 to about 1 :5, alternatively about 4:1 to about 1 :4, alternatively about 3:1 to about 1 :3, alternatively about 2:1 to about 1 :2, or alternatively about 1 :1.
  • the composition comprises DHA (docosahexaenoic acid) and DPA (docosahexaenoic acid) in a ratio of DHA:DPA of about least 2:1 .
  • the composition comprises DHA:DPA in a ratio of about 2:1 to about 10:1 , alternatively about 2:1 to about 9:1 , alternatively about 2:1 to about 8:1 , alternatively about 2:1 to about 7:1 , alternatively about 2:1 to about 6:1 , alternatively about 2:1 to about 5:1 , alternatively about 2:1 to about 4:1 , alternatively about 3:1 to about 5:1 , or alternatively about 4:1.
  • compositions of the present invention comprise no more than 15:1 of DHA:DPA, alternatively no more than 12:1 of DHA:DPA, alternatively no more than 10:1 of DHA:DPA, alternatively no more than 8:1 of DHA:DPA, alternatively no more than 5:1 of DHA:DPA, alternatively no more than 3:1 of DHA:DPA, alternatively no more than 2:1 of DHA:DPA, alternatively no more than 1 :1 of DHA:DPA, alternatively no more than 1 :2 of DHA:DPA, alternatively no more than 1 :3 of DHA.DPA, alternatively no more than 1 :4 of DHA:DPA, alternatively no more than 1 :5 of DHA:DPA, alternatively no more than 1 :6 of DHA:DPA, alternatively no more than 1 :7 of DHA:DPA, alternatively no more than
  • the ratio of DHA:DPA is less than 2:1 .
  • the docosapentaenoic acid (DPA) may be administered in an orally administrable composition comprising DPA.
  • the compositions comprise DPA in an amount between 1 % and 99% relative to the total amount of fatty acids present in the composition, alternatively between 1 % and 95%, alternatively between 1 % and 90%, alternatively between 1 % and 85%, alternatively between 1 % and 80%, alternatively between 1 % and 75%, alternatively between 1 % and 70%, alternatively between 1 % and 65%, alternatively between 1 % and 60%, alternatively between 1 % and 55%, alternatively between 1 % and 50%, alternatively between 1 % and 45%, alternatively between 1 % and 40%, alternatively between 1 % and 35%, alternatively between 1 % and 30%, alternatively between 1 % and 25%, alternatively between 1 % and 20%, alternatively between 1 % and 15%, alternatively between 1
  • the compositions comprise DPA in an amount of at least about 45% of DPA. In some alternative embodiments, the composition comprises at least 45% or at least 50% or at least 55% or at least 60% or at least 65% or at least 70% or at least 75% or at least 80% or at least 85% or at least 90% or at least 95% of DPA. In some embodiments, the composition comprises at least 20 mg of DPA, alternatively at least 30 mg, alternatively at least 40 mg, alternatively at least 50 mg, alternatively at least 60 mg, alternatively at least 90 mg, alternatively at least 100 mg, alternatively at least 120 mg, alternatively at least 150 mg, alternatively at least 200 mg, alternatively at least 300mg, alternatively at least 400 mg of DPA. In some embodiments, the composition comprises DPA in ester form or in free fatty acid form.
  • the methods of treatment provides a dose of at least 20 mg DPA-N3, alternatively at least 30 mg DPA-N3, alternatively at least 40 mg DPA-N3, alternatively at least 50 mg DPA-N3, alternatively at least 60mg DPA-N3 per day, alternatively at least 70mg DPA-N3 per day, alternatively at least 75mg DPA-N3 per day, alternatively at least 80mg DPA-N3 per day, alternatively at least 90mg DPA-N3 per day, alternatively at least 100mg DPA-N3 per day, alternatively at least 120mg DPA-N3 per day, alternatively at least 150mg DPA-N3 per day, alternatively at least 160mg DPA-N3 per day, alternatively at least 180mg DPA-N3 per day, alternatively at least 200mg DPA-N3 per day, alternatively at least 250mg DPA-N3 per day, alternatively at least 300mg DPA-N3 per day, alternatively at least 350
  • the method of treatment provides a daily dose of at least about at least 20 mg of DPA, alternatively at least 30 mg, alternatively at least 40 mg, alternatively at least 50 mg, alternatively at least 60 mg, alternatively at least 90 mg, alternatively at least 100 mg, alternatively at least 120 mg, alternatively at least 150 mg, alternatively at least 200 mg, alternatively at least 300mg, alternatively at least 400 mg of DPA.
  • the method of treatment provides a daily dose of at least about 1 ,000 mg DPA-N3 per day, alternatively at least about ,500 mg DPA-N3 per day, alternatively at least about 2,000 mg DPA-N3 per day, alternatively at least about 2,500 mg DPA-N3 per day, alternatively at least about 3,000 mg DPA-N3 per day, alternatively at least about 3,500 mg DPA-N3 per day, alternatively at least about 3,750 mg DPA-N3 per day, alternatively at least about 4,000 mg DPA-N3 per day, alternatively at least about 4,250 mg DPA-N3 per day.
  • the method of treatment provides a dose of at least about 1 mg/kg of DPA-N3 per day, alternatively about 2 mg/kg of DPA-N3 per day, alternatively about 3 mg/kg of DPA-N3 per day, alternatively about 4 mg/kg of DPA- N3 per day, alternatively about 6 mg/kg of DPA-N3 per day, alternatively about 8 mg/kg of DPA-N3 per day, alternatively about 10 mg/kg of DPA-N3 per day, alternatively about 20 mg/kg of DPA-N3 per day, alternatively about 30 mg/kg of DPA-N3 per day, and alternatively about 40 mg/kg alternatively about 50 mg/kg of DPA-N3 per day, alternatively about 75 mg/kg of DPA-N3 per day, and alternatively about 100 mg/kg.
  • the method of treatment provides a dose of about 0 mg/kg to 1 mg/kg of DPA-N3 per day, alternatively about 1 mg/kg to 2 mg/kg of DPA- N3 per day, alternatively about 2 mg/kg to 3 mg/kg of DPA-N3 per day, alternatively about 3 mg/kg to 4 mg/kg of DPA-N3 per day, alternatively about 4 mg/kg to 6 mg/kg of DPA-N3 per day, alternatively about 6 mg/kg to 8 mg/kg of DPA-N3 per day, alternatively about 8 mg/kg to 10 mg/kg of DPA-N3 per day, alternatively about 10 mg/kg to 20 mg/kg of DPA-N3 per day, alternatively about 20 mg/kg to 30 mg/kg of DPA-N3 per day, and alternatively about 30 mg/kg to 40 mg/kg alternatively about 40 mg/kg to 50 mg/kg of DPA-N3 per day, alternatively about 50 mg/kg to 75 mg/kg of DPA
  • the docosahexaenoic acid may be administered in an orally administrable composition comprising DHA.
  • the compositions comprise DHA in an amount between 1 % and 99% relative to the total amount of fatty acids present in the composition, alternatively between 1 % and 95%, alternatively between 1 % and 90%, alternatively between 1 % and 85%, alternatively between 1 % and 80%, alternatively between 1 % and 75%, alternatively between 1 % and 70%, alternatively between 1 % and 65%, alternatively between 1 % and 60%, alternatively between 1 % and 55%, alternatively between 1 % and 50%, alternatively between 1 % and 45%, alternatively between 1 % and 40%, alternatively between 1 % and 35%, alternatively between 1 % and 30%, alternatively between 1 % and 25%, alternatively between 1 % and 20%, alternatively between 1 % and 15%, alternatively between 1 % and 10%, alternatively between 1 % and 5%, alternatively between 1 % and 5%, alternatively between 1
  • the compositions comprise DHA in an amount of at least about 45% of DHA. In some alternative embodiments, the composition comprises at least 45% or at least 50% or at least 55% or at least 60% or at least 65% or at least 70% or at least 75% or at least 80% or at least 85% or at least 90% or at least 95% of DHA. In some embodiments, the composition comprises at least 20 mg of DHA, alternatively at least 30 mg, alternatively at least 40 mg, alternatively at least 50 mg, alternatively at least 60 mg, alternatively at least 90 mg, alternatively at least 100 mg, alternatively at least 120 mg, alternatively at least 150 mg, alternatively at least 200 mg, alternatively at least 300mg, alternatively at least 400 mg of DHA. In some embodiments, the composition comprises DHA in ester form or in free fatty acid form.
  • the methods of treatment provides a dose of at least 20 mg DHA-N3, alternatively at least 30 mg DHA-N3, alternatively at least 40 mg DHA-N3, alternatively at least 50 mg DHA-N3, alternatively at least 60mg DHA-N3 per day, alternatively at least 70mg DHA-N3 per day, alternatively at least 75mg DHA-N3 per day, alternatively at least 80mg DHA-N3 per day, alternatively at least 90mg DHA-N3 per day, alternatively at least 100mg DHA-N3 per day, alternatively at least 120mg DHA-N3 per day, alternatively at least 150mg DHA-N3 per day, alternatively at least 160mg DHA-N3 per day, alternatively at least 180mg DHA-N3 per day, alternatively at least 200mg DHA-N3 per day, alternatively at least 250mg DHA-N3 per day, alternatively at least 300mg DHA-N3 per day, alternatively at least 350
  • the method of treatment provides a daily dose of at least about at least 20 mg of DHA, alternatively at least 30 mg, alternatively at least 40 mg, alternatively at least 50 mg, alternatively at least 60 mg, alternatively at least 90 mg, alternatively at least 100 mg, alternatively at least 120 mg, alternatively at least 150 mg, alternatively at least 200 mg, alternatively at least 300mg, alternatively at least 400 mg of DHA.
  • the method of treatment provides a daily dose of at least about 1 ,000 mg DHA-N3 per day, alternatively at least about 1 ,500 mg DHA-N3 per day, alternatively at least about 2,000 mg DHA-N3 per day, alternatively at least about 2,500 mg DHA-N3 per day, alternatively at least about 3,000 mg DHA-N3 per day, alternatively at least about 3,500 mg DHA-N3 per day, alternatively at least about 3,750 mg DHA-N3 per day, alternatively at least about 4,000 mg DHA-N3 per day, alternatively at least about 4,250 mg DHA-N3 per day.
  • the method of treatment provides a dose of at least about 1 mg/kg of DHA-N3 per day, alternatively about 2 mg/kg of DHA-N3 per day, alternatively about 3 mg/kg of DHA-N3 per day, alternatively about 4 mg/kg of DHA- N3 per day, alternatively about 6 mg/kg of DHA-N3 per day, alternatively about 8 mg/kg of DHA-N3 per day, alternatively about 10 mg/kg of DHA-N3 per day, alternatively about 20 mg/kg of DHA-N3 per day, alternatively about 30 mg/kg of DHA-N3 per day, and alternatively about 40 mg/kg alternatively about 50 mg/kg of DHA-N3 per day, alternatively about 75 mg/kg of DHA-N3 per day, and alternatively about 100 mg/kg.
  • the method of treatment provides a dose of about 0 mg/kg to 1 mg/kg of DHA-N3 per day, alternatively about 1 mg/kg to2 mg/kg of DHA- N3 per day, alternatively about 2 mg/kg to 3 mg/kg of DHA-N3 per day, alternatively about 3 mg/kg to 4 mg/kg of DHA-N3 per day, alternatively about 4 mg/kg to 6 mg/kg of DHA-N3 per day, alternatively about 6 mg/kg to 8 mg/kg of DHA-N3 per day, alternatively about 8 mg/kg to 10 mg/kg of DHA-N3 per day, alternatively about 10 mg/kg to 20 mg/kg of DHA-N3 per day, alternatively about 20 mg/kg to 30 mg/kg of DHA-N3 per day, and alternatively about 30 mg/kg to 40 mg/kg alternatively about 40 mg/kg to 50 mg/kg of DHA-N3 per day, alternatively about 50 mg/kg to 75 mg/kg of DHA
  • the present invention also provides an administrable composition comprising fatty acids, wherein at least 50% by weight of the fatty acids comprise omega-3-fatty acids, salts, esters, or derivatives thereof, wherein the omega-3 fatty acids comprise eicosapentaenoic acid (EPA; C20:5-n3), docosapentaenoic acid (DPA; C22:5-n3), and docosahexaenoic acid (DHA; C22:6-n3), wherein the ratio of DHA to EPA (DHA:EPA) is less than 1 :20, and wherein the ratio of DHA to DPA (DHADPA) is less than 2:1.
  • omega-3 fatty acids comprise eicosapentaenoic acid (EPA; C20:5-n3), docosapentaenoic acid (DPA; C22:5-n3), and docosahexaenoic acid (DHA; C22:6-n3), wherein the ratio of D
  • compositions of the present invention comprise at least 50% omega-3 fatty acids, alternatively at least 55%, alternatively at least 60%, alternatively at least 65%, alternatively at least 70%, alternatively at least 75%, alternatively at least 80%, alternatively at least 85%, alternatively at least 95%, most preferably at least 90% omega-3 fatty acids of the total amount of fatty acids.
  • EPA and DPA are jointly present in the compositions of the present invention at between 55% and 100% of total fatty acids, alternatively between 60% and 100%, alternatively between 65% and 100%, alternatively between 70% and 100%, alternatively between 75% and 100%, alternatively between 80% and 100%, alternatively between 85% and 95%, alternatively between 85% and 97%, alternatively between 88% and 95%, alternatively between 88% and 97%, alternatively between 90% and 95%, alternatively between 90% and 97% of the total amount of fatty acids.
  • EPA and DHA are jointly present in the compositions of the present invention at between 55% and 100% of total fatty acids, alternatively between 60% and 100%, alternatively between 65% and 100%, alternatively between 70% and 100%, alternatively between 75% and 100%, alternatively between 80% and 100%, alternatively between 85% and 95%, alternatively between 85% and 97%, alternatively between 88% and 95%, alternatively between 88% and 97%, alternatively between 90% and 95%, alternatively between 90% and 97% of the total amount of fatty acids.
  • the fatty acids such as EPA, DHA, and DPA
  • the fatty acids may be present in free fatty acid form, or as a salt, ester, or derivative.
  • the fatty acids are preferably composed as a triglyceride, an ester (such as an ethyl ester) or free fatty acid.
  • Other forms of the fatty acids which may be useful include salts, esters of any type, amides, mono-, di- or triglycerides, phospholipids or any other form which can lead to metabolization of the fatty acids (such as EPA, DHA, and/or DPA), or the incorporation of the fatty acids (such as EPA and/or DPA) into body fluids, tissues or organs.
  • the compositions of the present invention comprise at least 0.01 % HPA of total fatty acids in the composition, alternatively at least 0.05% HPA, alternatively at least 0.10% HPA, alternatively at least 0.15% HPA, alternatively at least 0.2% HPA, alternatively at least 0.3% HPA, alternatively at least 0.4% HPA, alternatively at least 0.5% HPA, alternatively at least 0.75% HPA, alternatively at least 1 % HPA, alternatively at least 1 .5% HPA, alternatively at least 2% HPA, alternatively at least 2.5% HPA, alternatively at least 3% HPA, alternatively at least 3.5% HPA, alternatively at least 4% HPA, alternatively at least 4.5% HPA, alternatively at least 5% HPA, alternatively at least 6% HPA, alternatively at least 7% HPA, alternatively the compositions of the present invention comprise at least 9% HPA of total fatty acids in the composition.
  • the compositions of the present invention comprise no more than 20% HPA of total fatty acids in the composition, alternatively no more than 15% HPA, alternatively no more than 12% HPA, alternatively no more than 10% HPA, alternatively no more than 8% HPA, alternatively no more than 7% HPA, alternatively no more than 6% HPA, alternatively no more than 5% HPA, alternatively no more than 4% HPA, alternatively no more than 3% HPA, alternatively no more than 2% HPA, alternatively no more than 1 .5% HPA, alternatively the compositions of the present invention comprise at least 1 % HPA of total fatty acids in the composition. In some embodiments, the compositions of the present invention comprise 1 % to 20% of the total fatty acids in the composition.
  • the compositions comprise EPA and DPA in an EPA:DPA ratio between 99:1 and 1 :99 EPA:DPA, alternatively between 90:1 and 1 :90, alternatively between 60:1 and 1 :60, alternatively between 60:1 and 1 :20, alternatively between 60:1 and 1 :4, alternatively between 40:1 and 1 :20, alternatively between 30:1 and 1 :20, alternatively between 30:1 and 1 :10, alternatively between 30:1 and 1 :5, alternatively between 40:1 and 1 :4, alternatively between 30:1 and 1 :4, alternatively between 30:1 and 1 :2, alternatively between 30:1 and 1 :1 , alternatively between 30:1 and 2:1 , alternatively between 30:1 and 5:1 , alternatively between 20:1 and 1 :20, alternatively between 20:1 and 1 :10, alternatively between 20:1 and 1 :5, alternatively between 20:1 and 1 :2, alternatively
  • the ratio of EPA:DPA is greater than 1 :1 , preferably greater than 2:1 , and more preferably greater than 5:1. In some embodiments, the ratio of EPA:DPA is 1 :1 to 25:1 , preferably 5:1 to 20:1 , more preferably 8:1 to 15:1 , even more preferably 9:1 to 13:1 , even more most preferably about 10:1 to 1 1 :1 , and most preferably about 10:1 .
  • the compositions comprise EPA and DHA in an EPA:DHA ratio between 99:1 and 1 :99 EPA:DHA, alternatively between 90:1 and 1 :90, alternatively between 60:1 and 1 :60, alternatively between 60:1 and 1 :20, alternatively between 60:1 and 1 :4, alternatively between 40:1 and 1 :20, alternatively between 30:1 and 1 :20, alternatively between 30:1 and 1 :10, alternatively between 30:1 and 1 :5, alternatively between 40:1 and 1 :4, alternatively between 30:1 and 1 :4, alternatively between 30:1 and 1 :2, alternatively between 30:1 and 1 :1 , alternatively between 30:1 and 2:1 , alternatively between 30:1 and 5:1 , alternatively between 20:1 and 1 :20, alternatively between 20:1 and 1 :10, alternatively between 20:1 and 1 :5, alternatively between 20:1 and 1 :2, alternatively
  • the ratio of EPA:DHA is greater than 1 :1 , preferably greater than 2:1 , and more preferably greater than 5:1. In some embodiments, the ratio of EPA:DHA is 1 :1 to 25:1 , preferably 5:1 to 20:1 , more preferably 8:1 to 15:1 , even more preferably 9:1 to 13:1 , even more most preferably about 10:1 to 1 1 :1 , and most preferably about 10:1.
  • a relatively small amount of DHA relative to the total amount of fatty acids present in the composition is present.
  • the compositions of the present invention comprise no more than 20% DHA, alternatively no more than 15% DHA, alternatively no more than 12% DHA, alternatively no more than 10% DHA, alternatively no more than 8% DHA, alternatively no more than 7% DHA, alternatively no more than 6% DHA, alternatively no more than 5% DHA, alternatively no more than 4% DHA, alternatively no more than 3% DHA, alternatively no more than 2% DHA, alternatively no more than 1 % DHA relative to the total amount of fatty acids present in the composition.
  • the ratio of DPA:HPA is about 250:1 to 1 :1 , alternatively 200:1 to 2:1 , alternatively 150:1 to 3:1 , alternatively 100:1 to 4:1 , alternatively 50:1 to 5:1 , alternatively 25:1 to 6:1 , and alternatively 10:1 to 7:1.
  • the ratio of DPA:HPA is about 8:1 .
  • the ratio of DPA:HPA is about 3:0.
  • the ratio of DHA:HPA is about 250:1 to 1 :1 , alternatively 200:1 to 2:1 , alternatively 150:1 to 3:1 , alternatively 100:1 to 4:1 , alternatively 50:1 to 5:1 , alternatively 25:1 to 6:1 , and alternatively 10:1 to 7:1 .
  • the ratio of DHA:HPA is about 8:1.
  • the ratio of DHA:HPA is about 3:0.
  • compositions of the present invention comprise no more than 10% omega-6 fatty acids relative to the total amount of fatty acids, alternatively no more than 9%, alternatively no more than 8%, alternatively no more than 7%, alternatively no more than 6%, alternatively no more than 5%, alternatively no more than 4.5%, alternatively no more than 4%, alternatively no more than 3.5%, alternatively no more than 3%, alternatively no more than 2.5%, alternatively no more than 2%, alternatively no more than 1 .7%, alternatively no more than 1 .5%, alternatively no more than 1.2%, alternatively no more than 1 %, alternatively no more than 0.5% omega-6 fatty acids versus the total amount of fatty acids comprised by the compositions of the present invention.
  • Omega-6 fatty acids include, but are not limited to: linoleic acid (LA; C18:2- n6); gamma-linoleic acid (GLA; C18:3-n6); eicosadienoic acid (C20:2-n6); dihomo- gamma-linoleic acid (DGLA; C20:3-n6); arachiconic acid (ARA; C20:4-n6); and omega-6 docosapentaenoic acid (DPA; C22:5-n6).
  • LA linoleic acid
  • GLA gamma-linoleic acid
  • C20:2-n6 eicosadienoic acid
  • DGLA dihomo- gamma-linoleic acid
  • ARA arachiconic acid
  • DPA omega-6 docosapentaenoic acid
  • compositions of the present invention comprise no more than 10% omega-6 fatty acids relative to the total amount of omega-3 fatty acids plus omega-6 fatty acids, alternatively no more than 9%, alternatively no more than 8%, alternatively no more than 7%, alternatively no more than 6%, alternatively no more than 5%, alternatively no more than 4.5%, alternatively no more than 4%, alternatively no more than 3.5%, alternatively no more than 3%, alternatively no more than 2.5%, alternatively no more than 2%, alternatively no more than 1.7%, alternatively no more than 1 .5%, alternatively no more than 1 .2%, alternatively no more than 1 %, alternatively no more than 0.5% omega-6 fatty acids versus the total amount of omega-3 fatty acids plus omega-6 fatty acids comprised by the compositions of the present invention.
  • compositions of the present invention comprise no more than 8% arachidonic acid (ARA; C20:4-n6) relative to the total amount of omega-3 fatty acids plus omega-6 fatty acids, alternatively no more than 7%, alternatively no more than 6%, alternatively no more than 5%, alternatively no more than 4.5%, alternatively no more than 4%, alternatively no more than 3.5%, alternatively no more than 3%, alternatively no more than 2.5%, alternatively no more than 2%, alternatively no more than 1.7%, alternatively no more than 1.5%, alternatively no more than 1 .2%, alternatively no more than 1 %, alternatively no more than 0.5% arachidonic acid (ARA; C20:4-n6) versus the total amount of omega-3 fatty acids plus omega-6 fatty acids comprised by the compositions of the present invention.
  • ARA arachidonic acid
  • a relatively small amount of omega-3 fatty acids in aggregate other than EPA, ETA, HPA and DPA (alternatively indicated as non-EPA, non-ETA, non-HPA and non-DPA omega-3 fatty acids in aggregate) relative to the total amount of fatty acids present in the composition is present.
  • compositions of the present invention comprise no more than 20% non-EPA, non-ETA, non-HPA and non-DPA omega-3 fatty acids, alternatively no more than 15% non-EPA, non-ETA, non-HPA and non-DPA omega-3 fatty acids, alternatively no more than 12% non-EPA, non-ETA, non-HPA and non-DPA omega- 3 fatty acids, alternatively no more than 10% non-EPA, non-ETA, non-HPA and non- DPA omega-3 fatty acids, alternatively no more than 8% non-EPA, non-ETA, non- HPA and non-DPA omega-3 fatty acids, alternatively no more than 7% non-EPA, non-ETA, non-HPA and non-DPA omega-3 fatty acids, alternatively no more than 6% non-EPA, non-ETA, non-HPA and non-DPA omega-3 fatty acids, alternatively no more than 5% non-EPA, non-ETA, non-HPA and non-DPA omega-3 fatty acids, alternatively no more than 5% non-EPA,
  • a relatively small amount of the sum of ALA, SDA and DHA relative to the total amount of fatty acids present in the composition is present, while at the same time large amounts of the sum of EPA, DPA-n3, HPA and ETA are present.
  • compositions of the present invention comprise no more than 20% of the sum of ALA, SDA and DHA, alternatively no more than 15% of the sum of ALA, SDA and DHA, alternatively no more than 12% of the sum of ALA, SDA and DHA, alternatively no more than 10% of the sum of ALA, SDA and DHA, alternatively no more than 8% of the sum of ALA, SDA and DHA, alternatively no more than 7% of the sum of ALA, SDA and DHA, alternatively no more than 6% of the sum of ALA, SDA and DHA, alternatively no more than 5% of the sum of ALA, SDA and DHA, alternatively no more than 4% of the sum of ALA, SDA and DHA, alternatively no more than 3% of the sum of ALA, SDA and DHA, alternatively no more than 2% of the sum of ALA, SDA and DHA, alternatively no more than 1 % of the sum of ALA, SDA and DHA relative to the total amount of
  • compositions of the present invention comprise no more than 8% arachidonic acid (ARA; C20:4-n6) relative to the total amount of fatty acids, alternatively no more than 7%, alternatively no more than 6%, alternatively no more than 5%, alternatively no more than 4.5%, alternatively no more than 4%, alternatively no more than 3.5%, alternatively no more than 3%, alternatively no more than 2.5%, alternatively no more than 2%, alternatively no more than 1.7%, alternatively no more than 1.5%, alternatively no more than 1.2%, alternatively no more than 1 %, alternatively no more than 0.5% arachidonic acid (ARA; C20:4-n6) relative the total amount of fatty acids comprised by the compositions of the present invention.
  • ARA arachidonic acid
  • the composition of the present invention further comprises TPA at concentration of at least 0.05%.
  • the TPA concentration is about 0.01 % to about 5%, alternatively about 0.05% to about 2%, alternatively about 0.1 % to about 1 %, alternatively about 0.2% to about 0.8%, alternatively about 0.4% to about 0.6%, alternatively about 0.5%.
  • compositions of the present invention comprise no more than 2.5% arachidonic acid (ARA; C20:4-n6), no more than 0.4% omega-6- docosapentaenoic acid (DPA; C22:5-n6) and no more than 0.2% gamma-linoleic acid (GLA; C18:3-n6) relative the total amount of fatty acids comprised by the compositions of the present invention.
  • ARA arachidonic acid
  • DPA omega-6- docosapentaenoic acid
  • GLA gamma-linoleic acid
  • fatty acid compositions comprising no more than 2.5% arachidonic acid (ARA; C20:4-n6), no more than 0.3% omega-6 docosapentaenoic acid (DPA; C22:5-n6) and no more than 0.1 % gamma-linoleic acid (GLA; C18:3-n6) relative the total amount of fatty acids comprised by the compositions of the present invention.
  • ARA arachidonic acid
  • DPA docosapentaenoic acid
  • GLA gamma-linoleic acid
  • the active ingredient of the formulations of the present invention consists essentially wholly of the DPA and DHA or precursors thereof (ethyl ester, triglyceride, or any other pharmaceutically acceptable salt or derivative thereof).
  • no large amounts preferably less than 15%, alternatively less than 12%, alternatively less than 10%, alternatively less than 9%, alternatively less than 8%, alternatively less than 7%, alternatively less than 6%, alternatively less than 5%, alternatively less than 4%, alternatively less than 3%, alternatively less than 2%, alternatively less than 1 %, alternatively less than 0.5%, alternatively less than 0.25%
  • any other fatty acids are present.
  • the fatty acid percentage is determined on a weight/weight, mol/mol, or chromatography area percent basis relative to all fatty acids present in the composition as determined by methods such as disclosed in the European Pharmacopeia monograph for omega-3 fatty acid concentrates, European Pharmacopeia monograph for omega-3-acid ethyl esters 90%, or European Pharmacopeia monograph method 2.4.29, USP monograph for fish oil dietary supplements, USP 35 omega-3-acid ethyl esters (LOVAZA®) monograph, or any essentially equivalent methods (whether by gas chromatography, HPLC, FPLC or any other chromatographic method).
  • the fatty acid percentage is determined not as a percentage of all fatty acids present in the composition but as a specific type of fatty acid ethyl esters as percentage of all fatty acid ethyl esters present in the composition, thus excluding from the fatty acid percentage determination such fatty acids present as, for instance: free fatty acids; mono-, di-, and tri-glycerides; or fatty acids present in phospholipids (such as phosphatidylserine or phosphatidylcholine) or polysorbates (such as Tween 80, Tween 20, or polysorbate 40).
  • phospholipids such as phosphatidylserine or phosphatidylcholine
  • polysorbates such as Tween 80, Tween 20, or polysorbate 40.
  • the fatty acid percentage is determined not as a percentage of all fatty acids present in the composition but as a specific type of free fatty acid as percentage of all free fatty acids present in the composition, thus excluding from the fatty acid percentage determination such fatty acids present as, for instance: fatty acid ethyl esters; mono-, di-, and tri-glycerides; or fatty acids present in phospholipids (such as phosphatidylserine or phosphatidylcholine) or polysorbates (such as Tween 80, Tween 20, or polysorbate 40).
  • fatty acids present for instance: fatty acid ethyl esters; mono-, di-, and tri-glycerides; or fatty acids present in phospholipids (such as phosphatidylserine or phosphatidylcholine) or polysorbates (such as Tween 80, Tween 20, or polysorbate 40).
  • the fatty acid percentage is determined not as a percentage of all fatty acids present in the composition but as a specific type of glycerol fatty acid ester as percentage of all glycerol fatty acid esters present in the composition, thus excluding from the fatty acid percentage determination such fatty acids present as, for instance: fatty acid ethyl esters; free fatty acids; or fatty acids present in phospholipids (such as phosphatidylserine or phosphatidylcholine) or polysorbates (such as Tween 80, Tween 20, or polysorbate 40).
  • fatty acids present for instance: fatty acid ethyl esters; free fatty acids; or fatty acids present in phospholipids (such as phosphatidylserine or phosphatidylcholine) or polysorbates (such as Tween 80, Tween 20, or polysorbate 40).
  • the fatty acid percentage is determined not as a percentage of all fatty acids present in the composition but as di- or tri-fatty acid esters with glycerol as percentage of all glycerol di- and tri-fatty acid esters present in the composition, thus excluding from the fatty acid percentage determination such fatty acids present as, for instance: glycerol-mono-fatty acid esters; fatty acid ethyl esters; free fatty acids; or fatty acids present in phospholipids (such as phosphatidylserine or phosphatidylcholine) or polysorbates (such as Tween 80, Tween 20, or polysorbate 40).
  • phospholipids such as phosphatidylserine or phosphatidylcholine
  • polysorbates such as Tween 80, Tween 20, or polysorbate 40.
  • the fatty acid percentage is determined not as a percentage of all fatty acids present in the composition but as a tri-fatty acid esters with glycerol as percentage of all glycerol tri-fatty acid esters present in the composition, thus excluding from the fatty acid percentage determination such fatty acids present as, for instance: mono- and di-fatty acid esters of glycerol; fatty acid ethyl esters; free fatty acids; or fatty acids present in phospholipids (such as phosphatidylserine or phosphatidylcholine) or polysorbates (such as Tween 80, Tween 20, or polysorbate 40).
  • phospholipids such as phosphatidylserine or phosphatidylcholine
  • polysorbates such as Tween 80, Tween 20, or polysorbate 40.
  • the EPA, HPA, DPA, DHA, or omega-3-pentaenoic acids may be derived from any appropriate source including plant seed oils, microbial oils from algae or fungal or marine oils from fish or other marine animals. Certain species are a particular good source of oils containing DPA, for example seal oil. They may be used in the form of the natural oil, if that oil meets the required purity requirements of the present invention, or may be purified to give products containing the fatty acid composition of the present invention.
  • compositions of the present invention may be produced through a range of the methods.
  • Such methods may include: distillation, including short path distillation; urea precipitation; enzymatic conversion concentration; conventional chromatography; HPLC/FPLC; supercritical carbondioxide extraction; supercritical carbondioxide chromatography; simulated moving bed chromatography; supercritical carbondioxide simulated moving bed chromatography; or chemical conversion methods such as iodolactonization.
  • distillation including short path distillation; urea precipitation; enzymatic conversion concentration; conventional chromatography; HPLC/FPLC; supercritical carbondioxide extraction; supercritical carbondioxide chromatography; simulated moving bed chromatography; supercritical carbondioxide simulated moving bed chromatography; or chemical conversion methods such as iodolactonization.
  • Such methods are generally known to those skilled in the art of purifying and isolating omega-3 fatty acids.
  • the omega-3 fatty acid concentration/purification process is initiated by esterifying the fatty acids comprised by the marine oil raw material (such as crude fish oil) with ethanol (to form fatty acid ethyl esters) in order to separate omega-3 fatty acids from other fatty acids covalently bound together in the natural triglyceride molecules of the source oil. Subsequently, the material may be distilled once or several times to achieve omega-3-acid ethyl ester concentrations above 60%-70%. Alternatively, enzymatic concentration, urea precipitation or supercritical extraction may be used alone or in conjunction with distillation to reach omega-3 levels above 70%-90%.
  • chromatography In order to prepare a highly pure concentrate of a single omega-3 fatty acid, methods such as chromatography, supercritical chromatography, simulated moving bed chromatography, supercritical simulated moving bed chromatography, or chemical conversion methods such as iodolactolization are typically most practical to reach levels above 50%, alternatively above 60%, alternatively above 70%, alternatively above 80%, alternatively above 90%, alternatively above 95%, of a single omega-3 fatty acid such as ETA, EPA, HPA, DPA, TPA, or DHA.
  • a single omega-3 fatty acid such as ETA, EPA, HPA, DPA, TPA, or DHA.
  • EPA is relatively abundant in fish oils or other marine oils and can be relatively easy obtained through the application of concentration and purification technologies from such fish or marine oils.
  • DPA and HPA are present at much lower concentrations.
  • DPA or HPA may be concentrated and purified from fish or other marine oils according to the methods referred to above, either alone or DPA combined with EPA and/or HPA.
  • the DPA or HPA may be chemically prepared from a high purity EPA concentrate by elongation of the EPA fatty-acid chain with two or one hydrogen- saturated carbons (C2-elongation or C1 -elongation) on the carboxyl side of the molecule (for instance with a method similar to or alternate methods with equivalent results such as described by Kuklev DV and Smith WL in Chem Phys Lipids, 2006; 144(2): 172-177).
  • a high purity EPA concentrate may be partially converted to DPA (or HPA) using a method for C2-elongation (or C1 -elongation) of EPA similar to those described above, thus directly yielding compositions of the present invention or intermediates therefore.
  • oils containing one or more of the desired fatty acids may be blended to give the desirable relative amounts of EPA, DPA, HPA, DHA, TPA, other omega-3 fatty acids and omega-6 fatty acids to obtain the compositions of the present invention described in detail above.
  • Fish oils may also contain by-products and contaminants such as pesticides, chlorinated or brominated hydrocarbons, heavy metals, cholesterol and vitamins. During the production of the concentrate, the concentrations of these components are significantly reduced compared to untreated fish oils. Such reduction is inherent due to the nature of purification methods and their ability to concentrate of several or specific omega-3 fatty acids, thus removing other compounds.
  • triglycerides comprising more than 60% of the omega-3 fatty acids in the composition, alternatively more than 70%, alternatively more than 80%, alternatively more than 90% of the omega-3 fatty acids in the composition, may be produced from ethyl esters and glycerol by well known, published, or alternative chemical synthetic or enzymatic procedures.
  • Di-glycerides (either 1 ,2 di-glycerides, 1 ,3 diglycerides, mixtures thereof) comprising more than 60% of the omega-3 fatty acids in the composition, alternatively more than 70%, alternatively more than 80%, alternatively more than 90% of the omega-3 fatty acids in the composition, may be produced from ethyl esters and glycerol by well known, published, or alternative chemical synthetic or enzymatic procedures.
  • ono- glycerides comprising more than 60% of the omega-3 fatty acids in the composition, alternatively more than 70%, alternatively more than 80%, alternatively more than 90% of the omega-3 fatty acids in the composition, may be produced from ethyl esters and glycerol by well known, published, or alternative chemical synthetic or enzymatic procedures.
  • the free acids may be produced from ethyl esters by well known hydrolization or saponification procedures. Methods for converting ethyl esters to triglycerides, free fatty acids, and other molecular forms comprising fatty acids, are generally known to those skilled in the art chemically or enzymatically converting omega-3 fatty acids from one form to another.
  • compositions of the present invention may be used for the treatment of patients by administering an effective amount of such compositions to a subject in need thereof, such as a subject prone to or afflicted with a disease or condition or in need of treatment for a disease or condition.
  • the compositions of the present invention may be used for the treatment of patients by administering an effective amount of such compositions to a subject in need thereof, such as a subject prone to or afflicted with a disease or condition or in need of treatment for a disease or condition.
  • the present invention provides methods of treating, preventing, and reducing the symptoms, pathology or events associated with a disease or condition comprising administration of any of the compositions of the present invention.
  • liver-related disorders or conditions include, but are not limited to the following: fatty liver, non-alcoholic steaohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), hepatitis including but not limited to hepatitis C, HIV (human immunodeficiency virus) infection and any liver syndrome arising from the treatment of HIV, drug-induced fatty liver or sequalae (including but not limited to NAFLD, NASH), liver failure, liver transplantation, transplanted liver failure, and liver damage.
  • NASH non-alcoholic steaohepatitis
  • ASH alcoholic steatohepatitis
  • the liver damage may include damage associated with afflictions of other organ systems, such as renal failure or disease and diabetes, and damage caused or induced by drugs.
  • the methods may be also be useful in the treatment of conditions associated with abnormally elevated liver enzymes (such as ALT, AST and /or GGT).
  • compositions of the present invention may be attributed in part to its activity in modulating lipid metabolism, including that of the liver, from a state of production and accumulation to a state of decreased production and removal vis-a-vis oxidation.
  • the compositions may elicit anti-inflammatory effects through a variety of mechanisms that can decrease levels of proinflammatory or pro— fibrotic mediators, such as TNF-alpha or TGF-beta, and increase levels of anti-inflammatory mediators, including IL-10 and arginase.
  • the compositions may also be effective in decreasing the levels of lipids, specifically stored triglycerides, and to decrease pro-inflammatory mediators associated with fibrotic mechanisms.
  • the present invention further provides a method of reducing expression of HMG-CoA reductase and/or reducing levels of HMG-CoA reductase in a subject.
  • the present invention further provides a method of reducing the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) and/or reducing levels of PCSK9 in a subject.
  • Expression or levels may be determined by typical molecular biology methodologies or biochemical assays, such as mRNA levels to determine gene expression, ELISA assays to determine protein levels, or other techniques know to those with skill in the art.
  • the present invention provides methods of treating, preventing, and reducing symptoms associated with a disease or condition comprising administration of a composition of the present invention.
  • diseases or conditions include, but are not limited to: hypertriglyceridemia (for example, by those skilled in the art typically established by assessing fasting triglyceride (TG) levels); hypertriglyceridemia with TG>500mg/dL (VHTG); hypertriglyceridemia with TG 200- 499mg/dl_; hypertriglyceridemia with TG 200-499mg/dL while on statin treatment (HTG); hypercholesterolemia; mixed dyslipidemia; coronary heart disease (CHD); vascular disease; atherosclerotic disease and related conditions; heart failure; cardiac arrhythmias; blood coagulatory conditions associated with cardiac arrhytmias; hypertension; coagulation related disorders, including post-surgical deep vein thrombosis or other high risk thrombosis conditions; nephropathy;
  • the present invention also provides for the treatment and/or prevention of cardiac events and/or cardiovascular events and/or vascular events and/or symptoms.
  • the present invention also provides for the reduction of number of such events, as well as a reduction or amelioration of symptoms associated with such events.
  • the compositions of the present invention may be useful for any subjects, including those with and without comorbidities.
  • the subjects to be treated with or administered the compositions of the present invention are selected based on the presence of certain comorbidities.
  • treatment with the compositions of the present invention results in clinical improvement of such comorbidities.
  • administration with the compositions of the present invention may reduce the time necessary to achieve clinical improvement and/or attain treatment goals.
  • compositions can result in clinical improvements in clinical markers, such as levels of liver enzymes and biomarkers.
  • Clinical improvement relating to liver conditions, such as NAFLD and/or NASH, can be assessed utilizing a multitude of methodologies known to those practiced in the art.
  • Liver biopsy histopathology scoring for fibrosis and ultrasound measurements of liver stiffness can be used for clinical assessment, measurement in the baseline changes in liver enzymes and any additional biomarkers such as but not limited to the FIBROTEST® and/or the nonalcoholic fatty liver disease (NAFLD) activity score, which is based on a standardized grading system for steatosis (on a scale of 0 to 3), lobular inflammation (on a scale of 0 to 3), and hepatocellular ballooning (on a scale of 0 to 2), with higher scores indicating increasing severity of disease.
  • any additional biomarkers such as but not limited to the FIBROTEST® and/or the nonalcoholic fatty liver disease (NAFLD) activity score, which is based on a standardized grading system for steatosis (on a scale of 0 to 3), lobular inflammation (on a scale of 0 to 3), and hepatocellular ballooning (on a scale of 0 to 2), with higher scores
  • compositions of the present invention described for use in NASH can be administered by a multitude of routes, including oral, intravenous, topical, rectal and direct injection to the site of action.
  • compositions of the present invention may be co-administered with one or more other therapeutic agents.
  • clinical benefits resulting from the administration or treatment of subjects with the compositions of the present invention may be improved with concomitant use or in combination with other therapeutic agents.
  • the co-administration may result in a synergistic, more potent and efficacious course of treatment.
  • Examples of such concomitant or fixed combination treatments may include coadministration with one or more of the following: PPAR gamma agents (such as pioglitazone), mixed PPAR agents such as those affecting the alpha/delta receptors, bile-acid derivatives, vitamin E, pentoxyfiline, hepatitis virus anti-viral agents, immunosuppressants associated with organ transplant, anti-platelet agents, antihypertensive drugs, diuretics, anti-inflammatory agents, anti-fibrotic agents, anti- cell death agents, anti-cell necrotic agents, and biological agents such as but not limited to monoclonal antibodies, or soluble receptors.
  • PPAR gamma agents such as pioglitazone
  • mixed PPAR agents such as those affecting the alpha/delta receptors
  • bile-acid derivatives such as those affecting the alpha/delta receptors
  • vitamin E such as bile-acid derivatives
  • pentoxyfiline such as those affecting the alpha
  • Cardiovascular and/or cardiac events that may benefit from treatment with the compositions of the present invention may include, but are not limited to: myocardial infarction, ischemic cardiac attack, ischemic attack, acute angina, hospitalization due to acute angina, stroke, transient ischemic cerebral attack, cardiac revascularization, cardiac revascularization with stent placement, carotid artery revascularization, carotid artery revascularization with stent placement, peripheral artery revascularization, peripheral artery revascularization with stent placement, plaque rupture, death due to cardiovascular event, and hospitalization due to cardiovascular event. Cardiovascular and/or cardiac events may also include other events deemed to fall in such catergory by those skilled in the art.
  • the improved profile of the compositions of the present invention may be demonstrated upon treatment of a subject by differentially altering the ration between blood platelets and fragments thereof (also known as platelet microparticles). Such fragments may be evaluated as a whole or examined and described as fragment sub-categories.
  • the improved profile of the compositions of the present invention may be demonstrated upon treatment of a subject by differentially altering the surface charge of blood platelets and fragments thereof, either in resting state (non-activated platelets) or activated stage.
  • treatment with compositions of the present invention improves the vascular healing process in response to atherogenic disease.
  • Such healing may be demonstrated by reduced stenosis and/or restenosis over time, reduced or lesser increase in intima-media thickness (IMT) of the arterial wall, larger lumen size and/or larger vascular diameter at vascular sites with stenosis or clot built-up, as determined by either by intravascular ultrasound (IVUS), radiographic, radiologic, non-invasive ultrasound, tomography, magnetic resonance interference (MRI), or other acceptable methods.
  • IVUS intravascular ultrasound
  • MRI magnetic resonance interference
  • the vascular wall composition such as a reduced foam cell presence or fibrillated tissue in the vessel wall.
  • such improved vascular healing is demonstrated by improved inflammatory markers in the vascular wall.
  • such improved healing may be demonstrated by the retardation, halting or reversing of the fibrosis process in the liver or other organs or tissues.
  • the improved profile resulting from treatment with the compositions of the present invention may also be demonstrated by a differentiated impact on blood/serum/plasma lipid and lipoprotein levels in a mammal; these include, but are not limited to: Triglycerides (TG), total-cholesterol, non-HDL-cholesterol, LDL- cholesterol, VLDL-cholesterol, apolipoprotein B, apolipoprotein A, apolipoprotein C- III, HDL-cholesterol, and Lp-PLA2.
  • TG Triglycerides
  • compositions of the present invention may also be used to provide a beneficial impact on the one or more of the following: apolipoprotein A-l (apo A-l), apolipoprotein B (apo B), apo A-l/apo B ratio, lipoprotein(a) (Lp[a]), lipoprotein-associated phospholipase A2 (Lp-PLA2), low density lipoprotein (LDL) particle number and size, oxidized LDL, C-reactive protein (CRP), high sensitivity C-reactive protein (HSCRP), intracellular adhesion molecule- 1 (ICAM-1 ), E-selectin, P-selectin, vascular cell adhesion molecule 1 (VCAM-1 ) or cluster of differentiation 106 (CD106), interleleukin -1 ⁇ ( ⁇ _-1 ⁇ ), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-12 (IL-12), interle
  • compositions of the present invention may also be taken as a general nutritional supplement.
  • compositions of the present invention are preferably provided in a dose of between 100 mg and 10,100 mg/day, alternatively between 200 mg and 8,100 mg/day, alternatively between 300 mg and 6,100 mg/day, alternatively between 400 mg and 5,100 mg/day, alternatively between 500 mg and 4,100 mg/day.
  • compositions of the present invention are preferably provided in a dose of between 100 mg and 10,100 mg/day, alternatively between 200 mg and 8,100 mg/day, alternatively between 300 mg and 6,100 mg/day, alternatively between 400 mg and 5,100 mg/day, alternatively between 500 mg and 4,100 mg/day.
  • compositions of the present invention are preferably provided in a dose of between 100 mg and 10,100 mg/day, alternatively between 200 mg and 8,100 mg/day, alternatively between 300 mg and 6,100 mg/day, alternatively between 400 mg and 5,100 mg/day, alternatively between 500 mg and 4,100 mg/day.
  • the formulation may be a single daily dose preparation to give in one dose the above intakes, or may be in convenient divided doses, for example, a daily dose formed of two to four soft gelatin or other dosage forms, each containing 300-1500 mg of EPA+DPA or EPA+DPA+HPA or DPA+DHA in any form embodied in the present invention.
  • Flavourants or emulsifiers may be included, for instance, to make the preparation palatable. Other conventional additives, diluents and excipients may be present.
  • the preparation for ingestion may be in the form of a capsule, a dry powder, a tablet, a solution, an oil, an emulsion or any other appropriate form.
  • the capsules may be hard or soft gelatin capsules, agar capsules, or any other appropriate capsule.
  • the omega-3 fatty acid composition optionally includes chemical antioxidants, such as alpha tocopherol, which are administered in pure form or suspended in a vegetable oil, such as soybean oil or corn oil.
  • the blended fatty acid compositions may then be incorporated into any appropriate dosage form for oral, enteral, parenteral, rectal, vaginal, dermal or other route of administration.
  • Soft or hard gelatin capsules, flavoured oil blends, emulsifiers or other liquid forms, and microencapsulate powders or other dry form vehicles are all appropriate ways of administering the products.
  • the formulated final drug product containing the omega-3 fatty acid composition may be administered to a mammal or patient in need thereof in a capsule, a tablet, a powder that can be dispersed in a beverage, or another solid oral dosage form, a liquid, a soft gel capsule or other convenient dosage form such as oral liquid in a capsule, as known in the art.
  • the capsule comprises a hard gelatin.
  • the combination product may also be contained in a liquid suitable for injection or infusion.
  • Example pharmaceutical grade finished dosage forms (a) Soft or hard gelatin capsules each containing 500 mg or 1000 mg of a mix 20 parts of DHA as a free fatty acid to 1 parts of DPA as a free fatty acid; (b) As in (a) but where the DHA and DPA free fatty acids are replaced with the fatty acids in any other appropriate bioassimilable form such as the ethyl esters; (c) As in (a)-(b) but where the material is in the form of a microencapsulated powder which can be used as a powder or compressed into tablets.
  • Such powders may be prepared by a variety of technologies known to those skilled in the art; (d) As in (a)-(b) but where the formulation is a liquid or emulsion, appropriately flavoured for palatable oral administration; (e) As in (a)-(b) but where the material is formulated into a pharmaceutically acceptable vehicle appropriate for topical application such as a cream or ointment.
  • the omega-3 compositions of the present invention may also be administered with a combination of one or more non-active pharmaceutical ingredients (also known generally herein as "excipients").
  • Non-active ingredients serve to solubilize, suspend, thicken, dilute, emulsify, stabilize, preserve, protect, color, flavor, and fashion the active ingredients into an applicable and efficacious preparation that is safe, convenient, and otherwise acceptable for use.
  • the non-active ingredients may include colloidal silicon dioxide, crospovidone, lactose monohydrate, lecithin, microcrystalline cellulose, polyvinyl alcohol, povidone, sodium lauryl sulfate, sodium stearyl fumarate, talc, titanium dioxide and xanthum gum.
  • pharmaceutically acceptable vehicle includes any of the following: a solution where the first API and optional other ingredients are wholly dissolved in a solubilizer (e.g., a pharmaceutically acceptable solvent or mixture of solvents), wherein the solution remains in clear liquid form at about room temperature; a suspension; an oil; or a semi-solid, wherein the first API and optionally other ingredients are dissolved wholly or partially in a solubilizer (an emulsion, cream, etc.).
  • a solubilizer e.g., a pharmaceutically acceptable solvent or mixture of solvents
  • a "pharmaceutical grade finished dosage form” as used herein may be construed as a unit dose form suitable for administration to, for example, human or animal subjects, and having content uniformity acceptable to regulatory authorities.
  • a pharmaceutical grade finished dosage form should have an amount of API within the range of 85% to 1 15% of the desired dosage and an RSD less than or equal to 6.0%.
  • a pharmaceutical grade finished dosage form must be stable (i.e., have a "shelf life") for a pharmaceutically acceptable duration of time, preferably at least six months, alternatively at least one year.or at least two years, when stored at room temperature (about 23 degree Celcius to 27 degree Celcius , preferably about 25 degree Celcius) and 60% relative humidity.
  • stability is determined by physical appearance and/or chemical modification of the ingredients, in accordance with standards well- known in the pharmaceutical arts, including those documented in ICH guidelines.
  • the omega-3 fatty acid dosage form optionally includes chemical antioxidants, such as alpha tocopherol, oils, such as soybean oil and partially hydrogenated vegetable oil, and lubricants such as fractionated coconut oil, lecithin and a mixture of the same.
  • chemical antioxidants such as alpha tocopherol, oils, such as soybean oil and partially hydrogenated vegetable oil
  • lubricants such as fractionated coconut oil, lecithin and a mixture of the same.
  • a composition according to the present prevention is prepared by mixing and homogenizing in a ratio of 98:2 the intermediates MEGAPEX E90D00EE (90% EPA ethyl ester,) and MAXOMEGA DPA95 FFA (>95% DPA synthetic fatty acid produced from EPA ethyl ester concentrate) converted to ethyl ester, respectively.
  • MEGAPEX E90D00EE 90% EPA ethyl ester,
  • MAXOMEGA DPA95 FFA >95% DPA synthetic fatty acid produced from EPA ethyl ester concentrate
  • the resulting novel composition comprises 89.10% EPA, 1.95% DPA, 0.19% HPA, 91.24% omega-3-pentaenoic acids, less than 0.01 % DHA, 91.24% omega-3-pentaenoic acids, 93.09% total omega-3 fatty acids, 3.15% ARA and 3. 57% omega-6 fatty acids (all Area%).
  • a composition according to the present prevention is prepared by mixing and homogenizing in a ratio of 96:4 the intermediates MEGAPEX E90D00EE (90% EPA ethyl ester,) and MAXOMEGA DPA95 FFA (>95% DPA synthetic fatty acid produced from EPA ethyl ester concentrate), converted to ethyl ester, respectively.
  • MEGAPEX E90D00EE 90% EPA ethyl ester,
  • MAXOMEGA DPA95 FFA >95% DPA synthetic fatty acid produced from EPA ethyl ester concentrate
  • MAXOMEGA DPA95 FFA
  • the resulting novel composition comprises 87.28% EPA, 3.89% DPA, 0.18% HPA, 91.35% omega-3-pentaenoic acids, less than 0.01 % DHA, 93.17% total omega-3 fatty acids and 3.49% omega-6 fatty acids (all Area%).
  • a composition according to the present prevention is prepared by mixing and homogenizing in a ratio of 94:6 the intermediates MEGAPEX E90D00EE (90% EPA ethyl ester,) and MAXOMEGA DPA95 FFA (>95% DPA synthetic fatty acid produced from EPA ethyl ester concentrate) converted to ethyl ester, respectively.
  • MEGAPEX E90D00EE 90% EPA ethyl ester,
  • MAXOMEGA DPA95 FFA >95% DPA synthetic fatty acid produced from EPA ethyl ester concentrate
  • the resulting novel composition comprises 85.46% EPA, 5.84% DPA, 0.18% HPA, 91 .48% omega-3-pentaenoic acids, less than 0.01 % DHA, 93.26% total omega-3 fatty acids, 3.02% ARA, and 3.42% omega- 6 fatty acids (all Area%).
  • Example 4 A composition according to the present prevention is prepared by mixing and homogenizing in a ratio of 75:25 the intermediates MEGAPEX E90D00EE (90% EPA ethyl ester,) and MAXOMEGA DPA95 FFA (>95% DPA synthetic fatty acid produced from EPA ethyl ester concentrate, converted to ethyl ester, respectively. These intermediates were prepared and commercially offered for sale by Chemport Korea (MEGAPEX) and Equateq Ltd from Scotland, UK (MAXOMEGA). The relative amounts of fatty acids present in the starting intermediates and in the resulting novel composition is listed in table 4 below.
  • the resulting novel composition comprises 68.10% EPA, 24.32% DPA, 0.19% HPA, 92.65% omega-3-pentaenoic acids, less than 0.01 % DHA, 94.07% total omega-3 fatty acids, 2.41 % ARA and 2.73% omega-6 fatty acids (all Area%).
  • a composition according to the present prevention isprepared by mixing and homogenizing in a ratio of 60:40 the intermediates KD-PharmaKD-PUR 900EE and MAXOMEGA DPA95 FFA converted to ethyl ester, respectively. These intermediates were prepared and commercially offered for sale by KD-Pharma Germany (KD-Pharma) and Equateq Ltd from Scotland, UK (MAXOMEGA). The relative amounts of fatty acids present in the starting intermediates and in the resulting novel composition is listed in table 5 below. The resulting novel composition comprises 55.74% EPA, 39.26% DPA, 2.39% HPA, 97.44% omega-3- pentaenoic acids, and 98.06% total omega-3 fatty acids (all Area%).
  • a composition according to the present prevention is prepared by mixing and homogenizing in a ratio of 96:4 the intermediates KD-PUR 900EE KD-Pharma and MAXOMEGA DPA95 FFA converted to ethyl ester, respectively. These intermediates were prepared and commercially offered for sale by KD-Pharma
  • the relative amounts of fatty acids present in the starting intermediates and in the resulting novel composition is listed in table 6 below.
  • the resulting novel composition comprises 89.27% EPA, 4.45% DPA, 3.82% HPA, 97.54% omega-3- pentaenoic acids, and 98.54% total omega-3 fatty acids (all Area%).
  • the ethyl ester composition of Example 4 may be converted into a free fatty acid composition with essentially the same fatty acid composition according to "Conversion Method EE to FFA" below. This method is indiscriminate with respect to the type, degree of saturation or length of fatty acid if performed for an adequate amount of time under the described conditions.
  • Fatty Acid Ethyl Ester (FAEE GMP, approx. 3mmol/g) oil is brought into a closed heated/cooled reaction chamber under nitrogen atmosphere (preferably with pressure control), and heated to 50-60 degree Celcius under stirring.
  • Step 4 Repeat Step 4 several times ( ⁇ 2x) to remove ethanol and NaCI.
  • Example 3 The ethyl ester composition of Example 3 is converted into a free fatty acid composition with essentially the same fatty acid composition according to "Conversion Method EE to FFA" above. This method is indiscriminate with respect to the type, degree of saturation or length of fatty acid if performed for an adequate amount of time under the described conditions.
  • Example 6 The ethyl ester composition of Example 6 is converted into a free fatty acid composition with essentially the same fatty acid composition according to "Conversion Method EE to FFA" above. This method is indiscriminate with respect to the type, degree of saturation or length of fatty acid if performed for an adequate amount of time under the described conditions.
  • Example 4 The composition of Example 4 is formulated into a soft gelatin capsule. Prior to encapsulation, an anti-oxidant preparation (composed of 4000 mg alpha-D- tocopherol in one liter of corn oil; corn oil is a triglyceride low in omega-3) is added to the composition of Example 4, by mixing and homogenizing 100ml_ of this antioxidant preparation into 100 liters of the oil composition of Example 4 followed by thorough homogenization. The resulting pre-encapsulation formulated oil contains approximately 4mg/gram alpha-D-tocopherol.
  • an anti-oxidant preparation composed of 4000 mg alpha-D- tocopherol in one liter of corn oil; corn oil is a triglyceride low in omega-3
  • the resulting pre-encapsulation formulated oil contains approximately 4mg/gram alpha-D-tocopherol.
  • the formulated oil is encapsulated into soft gelatin capsules with printed logo according to general methods typically used by Accucaps in Canada for fish oils or by any other documented and operational encapsulation method.
  • the fill mass of the oil is approximately 1 .08 gram/capsule, providing a dose of approximately 1000mg omega-3-pentaenoic-acids ethyl esters per capsule.
  • the capsules are bottled in HDPE bottles with induction seal and child resistant cap.
  • Example 1 [0128] The composition of Example 8 is formulated into a soft gelatin capsule. Prior to encapsulation, an anti-oxidant preparation (composed of 4000 mg alpha-D- tocopherol in one liter of corn oil; corn oil is a triglyceride low in omega-3) is added to the composition of Example 4, by mixing and homogenizing 100ml_ of this antioxidant preparation into 100 liters of the oil composition of Example 4 followed by thorough homogenization. The resulting pre-encapsulation formulated oil contains approximately 4mg/gram alpha-D-tocopherol.
  • an anti-oxidant preparation composed of 4000 mg alpha-D- tocopherol in one liter of corn oil; corn oil is a triglyceride low in omega-3
  • the resulting pre-encapsulation formulated oil contains approximately 4mg/gram alpha-D-tocopherol.
  • the formulated oil is encapsulated into soft gelatin capsules with printed logo according to general methods typically used by Banner in High Point, NC, for fish oils or by any other documented and operational encapsulation method.
  • the fill mass of the oil is approximately 1.09 gram/capsule, providing a dose of approximately 1000mg omega-3-pentaenoic-acids per capsule.
  • the capsules are bottled in HDPE bottles with induction seal and child resistant cap.
  • Example 5 The composition of Example 5 is formulated into a soft gelatin capsule. Prior to encapsulation, an anti-oxidant preparation (composed of 4000 mg alpha-D- tocopherol in one liter of corn oil; corn oil is a triglyceride low in omega-3) is added to the composition of Example 4, by mixing and homogenizing 100ml_ of this antioxidant preparation into 100 liters of the oil composition of Example 4 followed by thorough homogenization. The resulting pre-encapsulation formulated oil contains approximately 4mg/gram alpha-D-tocopherol.
  • an anti-oxidant preparation composed of 4000 mg alpha-D- tocopherol in one liter of corn oil; corn oil is a triglyceride low in omega-3
  • the resulting pre-encapsulation formulated oil contains approximately 4mg/gram alpha-D-tocopherol.
  • the formulated oil is encapsulated into soft gelatin capsules with printed logo according to general methods typically used by Catalent in St.Petersburg, FL, for fish oils or by any other documented and operational encapsulation method.
  • the fill mass of the oil is approximately 1.05 gram/capsule, providing a dose of approximately 1000mg omega-3-pentaenoic-acids ethyl esters per capsule.
  • the capsules are bottled in HDPE bottles with induction seal and child resistant cap.
  • Example 9 The composition of Example 9 is formulated into a soft gelatin capsule. Prior to encapsulation, an anti-oxidant preparation (composed of 4000 mg alpha-D- tocopherol in one liter of corn oil; corn oil is a triglyceride low in omega-3) is added to the composition of Example 4, by mixing and homogenizing 100ml_ of this antioxidant preparation into 100 liters of the oil composition of Example 4 followed by thorough homogenization. The resulting pre-encapsulation formulated oil contains approximately 4mg/gram alpha-D-tocopherol.
  • an anti-oxidant preparation composed of 4000 mg alpha-D- tocopherol in one liter of corn oil; corn oil is a triglyceride low in omega-3
  • the resulting pre-encapsulation formulated oil contains approximately 4mg/gram alpha-D-tocopherol.
  • the formulated oil is encapsulated into soft gelatin capsules with printed logo according to general methods typically used by Banner in High Point, NC, for fish oils or by any other documented and operational encapsulation method.
  • the fill mass of the oil is 1 .06 gram/capsule, providing a dose of approximately l OOOmg omega-3-pentaenoic-acids per capsule.
  • the capsules are bottled in HDPE bottles with induction seal and child resistant cap.
  • the EPA: HPA ratio is between 13 and 190
  • the EPA:DPA ratio is between 8 and 15, the HPA:DPA ration between 0.05 and 1
  • the EPA, HPA, DPA and DHA may be composed as a glyceride (such as triglyceride), an ester (such as ethyl ester), or a free fatty acid.
  • Example 15 [0136] The following is an example formulation.
  • the EPA:HPA ratio is between 0.25 and 12
  • the DPA:EPA ratio is between 13 and 63
  • the DPA:HPA ration between 13 and 190
  • the EPA:DHA ratio more than 00.6, preferably more than 1.5, more preferably more than 2.4, most preferably more than 6.
  • the EPA, HPA, DPA and DHA may be composed as a glyceride (such as triglyceride), an ester (such as ethyl ester), or a free fatty acid.
  • the DPA may be composed as a glyceride (such as triglyceride), an ester (such as ethyl ester), or a free fatty acid.
  • Docosapentaenoic acid (DPA n-3) 650 950 800
  • a patient is diagnosed with NAFLD. Thereupon, the patient may be initiated on daily treatment with one of the encapsulated compositions according to Examples 10, 1 1 , 12 or 13, or Compostions 1 , 2, 3, 4, 5, or 6.
  • the treatment results in significant clinical improvement, including reduction in liver enzyme levels.
  • the study tests the effects of preparations comprising about 90% DPA and DHA on Zucker rats.
  • the rats are placed in 5 active treatment groups: (1 ) a high DPA/low DHA preparation (ratio of DPA:DHA of about 4:1 ), at 200 mg/kg, (2) a low DPA/high DHA preparation (ratio of DPA:DHA of about 1 :4) at 200 mg/kg. (3) a DPA/DHA preparation at 50 mg/kg, (4) a DPA/DHA preparation at 200 mg/kg, and (5) a DPA/DHA preparation at 600 mg/kg.
  • the effect with these treatment groups is compared to inactive control (water) and active controls bile acid and pioglotazone.
  • the treatment duration is 8 to 12 weeks, with final bleed and full necropsy upon sacrificing the animals at study termination. Liver, and select other tissues are frozen. Part of the liver is prepared for histology. Effect on gene expression by mRNA probe is used to test the effects of the treatments on the regulation of fatty liver disease associated genes. The study shows a beneficial effect.
  • a fatty acid composition comprising at least 50% omega-3-fatty acids, salts or derivatives thereof, while comprising eicosapentaenoic acid (EPA; C20:5-n3) and docosapentaenoic acid (DPA; C22:5-n3) and wherein the EPA:DHA ratio is higher than 20:1 .
  • EPA eicosapentaenoic acid
  • DPA docosapentaenoic acid
  • a fatty acid composition comprising at least 60% omega-3-fatty acids, salts or derivatives thereof, while comprising eicosapentaenoic acid (EPA; C20:5-n3) and docosapentaenoic acid (DPA; C22:5-n3) and wherein the EPA:DHA ratio is higher than 20:1.
  • EPA eicosapentaenoic acid
  • DPA docosapentaenoic acid
  • a fatty acid composition comprising at least 70% omega-3-fatty acids, salts or derivatives thereof, while comprising eicosapentaenoic acid (EPA; C20:5-n3) and docosapentaenoic acid (DPA; C22:5-n3) and wherein the EPA:DHA ratio is higher than 20:1 .
  • EPA eicosapentaenoic acid
  • DPA docosapentaenoic acid
  • a fatty acid composition comprising at least 75% omega-3-fatty acids, salts or derivatives thereof, while comprising eicosapentaenoic acid (EPA; C20:5-n3) and docosapentaenoic acid (DPA; C22:5-n3) and wherein the EPA:DHA ratio is higher than 20:1 .
  • EPA eicosapentaenoic acid
  • DPA docosapentaenoic acid
  • a fatty acid composition comprising at least 80% omega-3-fatty acids, salts or derivatives thereof, while comprising eicosapentaenoic acid (EPA; C20:5-n3) and docosapentaenoic acid (DPA; C22:5-n3) and wherein the EPA:DHA ratio is higher than 20:1 .
  • EPA eicosapentaenoic acid
  • DPA docosapentaenoic acid
  • a fatty acid composition comprising at least 85% omega-3-fatty acids, salts or derivatives thereof, while comprising eicosapentaenoic acid (EPA; C20:5-n3) and docosapentaenoic acid (DPA; C22:5-n3) and wherein the EPA:DHA ratio is higher than 20:1.
  • EPA eicosapentaenoic acid
  • DPA docosapentaenoic acid
  • a fatty acid composition comprising at least 90% omega-3-fatty acids, salts or derivatives thereof, while comprising eicosapentaenoic acid (EPA; C20:5-n3) and docosapentaenoic acid (DPA; C22:5-n3) and wherein the EPA:DHA ratio is higher than 20:1.
  • EPA eicosapentaenoic acid
  • DPA docosapentaenoic acid
  • a fatty acid composition comprising at least 95% omega-3-fatty acids, salts or derivatives thereof, while comprising eicosapentaenoic acid (EPA; C20:5-n3) and docosapentaenoic acid (DPA; C22:5-n3) and wherein the EPA:DHA ratio is higher than 20:1.
  • EPA eicosapentaenoic acid
  • DPA docosapentaenoic acid
  • composition according to one of the preferred embodiments 1 through 8 comprising at least 2% docosapentaenoic acid (DPA; C22:5-n3).
  • DPA docosapentaenoic acid
  • composition according to one of the preferred embodiments 1 through 8 comprising at least 4% docosapentaenoic acid (DPA; C22:5-n3).
  • DPA docosapentaenoic acid
  • composition according to one of the preferred embodiments 1 through 8 comprising at least 5% docosapentaenoic acid (DPA; C22:5-n3).
  • DPA docosapentaenoic acid
  • composition according to one of the preferred embodiments 1 through 8 comprising at least 6% docosapentaenoic acid (DPA; C22:5-n3).
  • DPA docosapentaenoic acid
  • composition according to one of the preferred embodiments 1 through 8 comprising at least 7% docosapentaenoic acid (DPA; C22:5-n3).
  • DPA docosapentaenoic acid
  • composition according to one of the preferred embodiments 1 through 8 comprising at least 8% docosapentaenoic acid (DPA; C22:5-n3).
  • DPA docosapentaenoic acid
  • a composition according to one of the preferred embodiments 1 through 8 comprising at least 10% docosapentaenoic acid (DPA; C22:5-n3).
  • DPA docosapentaenoic acid
  • composition according to one of the preferred embodiments 1 through 8 comprising at least 12% docosapentaenoic acid (DPA; C22:5-n3).
  • DPA docosapentaenoic acid
  • composition according to one of the preferred embodiments 1 through 8 comprising at least 15% docosapentaenoic acid (DPA; C22:5-n3).
  • DPA docosapentaenoic acid
  • composition according to one of the preferred embodiments 1 through 22, comprising no more than 5% arachidonic acid (C22:4-n6).
  • composition according to one of the preferred embodiments 1 through 22, comprising no more than 4% arachidonic acid (C22:4-n6).
  • composition according to one of the preferred embodiments 1 through 22, comprising no more than 3% arachidonic acid (C22:4-n6).
  • composition according to one of the preferred embodiments 1 through 22, comprising no more than 2% arachidonic acid (C22:4-n6).
  • composition according to one of the preferred embodiments 1 through 22, comprising no more than 1 % arachidonic acid (C22:4-n6).
  • composition according to one of the preferred embodiments 1 through 27, comprising at least 0.01 % heneicosapentaenoic acid (C21 :5-n3).
  • composition according to one of the preferred embodiments 1 through 27, comprising at least 0.3% heneicosapentaenoic acid (C21 :5-n3).
  • composition according to one of the preferred embodiments 1 through 27, comprising at least 0.5% heneicosapentaenoic acid (C21 :5-n3).
  • composition according to one of the preferred embodiments 1 through 27, comprising at least 3% heneicosapentaenoic acid (C21 :5-n3).
  • composition according to one of the preferred embodiments 1 through 27, comprising at least 4% heneicosapentaenoic acid (C21 :5-n3).
  • composition according to one of the preferred embodiments 1 through 27, comprising at least 5% heneicosapentaenoic acid (C21 :5-n3).
  • a composition according to one of the preferred embodiments 1 through 37 comprising no more than 5% omega-3 fatty acids that are not omega-3- pentaenoic acids.
  • a composition according to one of the preferred embodiments 1 through 37 comprising no more than 4% omega-3 fatty acids that are not omega-3- pentaenoic acids.
  • a composition according to one of the preferred embodiments 1 through 37 comprising no more than 3% omega-3 fatty acids that are not omega-3- pentaenoic acids.
  • a composition according to one of the preferred embodiments 1 through 37 comprising no more than 2% omega-3 fatty acids that are not omega-3- pentaenoic acids.
  • a composition according to one of the preferred embodiments 1 through 37 comprising no more than 1 .5% omega-3 fatty acids that are not omega-3- pentaenoic acids.
  • a composition according to one of the preferred embodiments 1 through 37 comprising no more than 1 .25% omega-3 fatty acids that are not omega-3- pentaenoic acids.
  • a composition according to one of the preferred embodiments 1 through 37 comprising no more than 1 % omega-3 fatty acids that are not omega-3- pentaenoic acids.
  • composition according to one of the preferred embodiments 1 through 44, wherein the EPA:DPA ratio is between 60:1 and 1 :60.
  • composition according to one of the preferred embodiments through 44 comprising between 55% and 95% EPA.
  • a composition according to one of the preferred embodiments 1 through 44 comprising between 60% and 95% EPA.
  • composition according to one of the preferred embodiments 1 through 44 comprising between 65% and 95% EPA.
  • composition according to one of the preferred embodiments 1 through 44 comprising between 75% and 95% EPA.
  • composition according to one of the preferred embodiments 1 through 44 comprising between 90% and 95% EPA.
  • composition according to one of the preferred embodiments 1 through 44 comprising between 1% and 5% DPA.
  • composition according to one of the preferred embodiments 1 through 44 comprising between 2% and 10% DPA.
  • composition according to one of the preferred embodiments 1 through 44 comprising between 3% and 20% DPA.
  • composition according to one of the preferred embodiments 1 through 44 comprising between 3% and 30% DPA.
  • composition according to one of the preferred embodiments 1 through 44 comprising between 3% and 50% DPA.
  • composition according to one of the preferred embodiments 1 through 44 comprising between 3% and 75% DPA.
  • composition according to one of the preferred embodiments 1 through 44 comprising between 3% and 90% DPA.
  • a pharmaceutically suitable formulation comprising one of the compositions according to preferred embodiments 94 through 98, in which the amount of eicosapentaenoic acid plus docosapentaenoic acid is present in an amount between 100 and 10,000 mg.
  • a pharmaceutically suitable formulation or dosage form comprising one of the compositions according to preferred embodiments 94 through 98, in which the amount of eicosapentaenoic acid plus docosapentaenoic acid is present in an amount between 250 and 1 ,250 mg.
  • a pharmaceutically suitable formulation or dosage form comprising one of the compositions according to preferred embodiments 94 through 98, in which the amount of eicosapentaenoic acid plus docosapentaenoic acid is present in an amount between 500 and 1 ,100 mg.
  • a pharmaceutically suitable formulation or dosage form comprising one of the compositions according to preferred embodiments 94 through 98, in which the amount of eicosapentaenoic acid plus docosapentaenoic acid is present in an amount between 100 and 10,000 mg.
  • a method of treatment according to preferred embodiments 103 through 105 in which the subject is a patient already undergoing treatment with a statin and then diagnosed with high triglycerides (equal to or more than 200 mg/dL but less than 500 mg/dL).
  • a method of treatment according to preferred embodiments 103 through 105 in which the subject is a patient diagnosed with mixed dyslipidemia with TG 300- 700 mg/dL and LDL-cholesterol equal to or more than 160 mg/dL.
  • a method of treatment according to preferred embodiments 103 through 105 in which the subject is a patient diagnosed with mixed dyslipidemia with TG 200- 499 mg/dL and non-HDL-cholesterol equal to or more than 160 mg/dL.

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Abstract

La présente invention concerne une composition pouvant être administrée par voie orale et comprenant des acides gras comprenant de l'acide docosapentaénoïque (DPA) et de l'acide docosahexaénoïque (DHA). Ces compositions peuvent être utilisées pour le traitement ou la prophylaxie d'une variété de pathologies, notamment des pathologies hépatiques.
EP14779339.2A 2013-03-13 2014-03-12 Compositions comprenant de l'acide docosapentaénoïque et procédés d'utilisation Withdrawn EP2986148A2 (fr)

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EP2968246A1 (fr) 2016-01-20
WO2014143275A1 (fr) 2014-09-18
WO2014158256A1 (fr) 2014-10-02
CA2905795A1 (fr) 2014-10-09
WO2014143272A1 (fr) 2014-09-18
WO2014165190A3 (fr) 2015-01-29
JP2016518315A (ja) 2016-06-23
JP2016512544A (ja) 2016-04-28
WO2014165190A2 (fr) 2014-10-09
CA2905671A1 (fr) 2014-09-18
EP2968246A4 (fr) 2016-08-03

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