WO2009134147A1 - Compositions lipidiques renfermant des dérivés d’epa et de dha et leur utilisation - Google Patents

Compositions lipidiques renfermant des dérivés d’epa et de dha et leur utilisation Download PDF

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Publication number
WO2009134147A1
WO2009134147A1 PCT/NO2009/000170 NO2009000170W WO2009134147A1 WO 2009134147 A1 WO2009134147 A1 WO 2009134147A1 NO 2009000170 W NO2009000170 W NO 2009000170W WO 2009134147 A1 WO2009134147 A1 WO 2009134147A1
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lipid composition
pro
composition according
formula
chosen
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PCT/NO2009/000170
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English (en)
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Anne Kristin Holmeide
Jenny Rosman
Ragnar Hovland
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Pronova Biopharma Norge As
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C305/00—Esters of sulfuric acids
    • C07C305/02—Esters of sulfuric acids having oxygen atoms of sulfate groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C305/14—Esters of sulfuric acids having oxygen atoms of sulfate groups bound to acyclic carbon atoms of a carbon skeleton being acyclic and unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/96—Esters of carbonic or haloformic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/113—Esters of phosphoric acids with unsaturated acyclic alcohols

Definitions

  • the present invention relates to a lipid composition
  • a lipid composition comprising at least pro-drugs of omega-3 polyunsaturated alcohols, which pro-drugs of omega-3 polyunsaturated alcohols comprise at least one pro-drug of (all-Z) 5,8,11,14,17- eicosapentaen-1-ol and at least one pro-drug of (all-Z)-4,7,10,13,16,19-docosahexaen- l-ol and their use as pharmaceuticals for reducing elevated triglyceride levels in humans and animals, including non-human mammals.
  • the present invention also relates to methods for the preparation of these pro-drugs of polyunsaturated alcohols from marine oils.
  • the invention further relates to novel pro-drugs of omega-3 polyunsaturated alcohols and salts of said pro-drugs.
  • Salts of the pro-drugs can be, for example, salts of phosphonates or sulphonates.
  • Highly purified polyunsaturated fatty acids in the form of ethyl esters have been shown to efficiently reduce elevated levels of triglycerides in humans.
  • omega-3 fatty acids is a concentrate of omega-3, long chain, polyunsaturated fatty acids from fish oil containing DHA and EPA as ethyl esters, described, for example, in U.S. Patent Nos. 5,502,077; 5,656,667; and 5,698,594, each incorporated herein by reference, and is sold under the trademark Omacor® or Lovaza®.
  • a fatty acid composition containing a high concentration, of at least 80% by weight, of omega-3 fatty acids as ethyl esters, where EPA ethyl ester and DHA ethyl ester are present in relative amounts of 1:2 to 2:1, and constitute about at least 75% of the total fatty acids in the composition has shown surprisingly advantageous effects on several risk factors for cardiovascular diseases, especially exhibiting beneficial effects on hypertriglyceridemia, mild hypertension, and on the coagulation factor VII phospholipid complex activity.
  • Such compounds including Omacor® and Lovaza®, lower serum LDL-cholesterol, increase serum HDL-cholesterol, lower serum triglycerides, lower systolic and diastolic blood pressure and the pulse rate, and lower the activity of the blood coagulation factor VII- phospholipid complex.
  • EPA and DHA have been shown to operate synergistically. Additionally, at least one advantage of a fatty acid composition described herein is that they are very well tolerated, not giving rise to any severe side effects.
  • the aim of the present invention is to provide a new lipid composition comprising pro-drugs of omega-3 polyunsaturated alcohols having therapeutic activity.
  • the present invention includes a number of aspects. Some of these aspects are:
  • a novel lipid composition comprising pro-drugs of omega-3 polyunsaturated alcohols.
  • a novel lipid composition comprising a combination of a pro-drug of (all-Z)- 5,8, 11 , 14, 17-eicbsa ⁇ entaen- 1 -ol and a pro-drug of (all-Z)-4,7, 10,13,16,19- docosahexaen- 1 -ol.
  • a lipid composition for use as a medicament, a pharmaceutical and/or a supplement 3.
  • lipid composition for the manufacture of a medicament, a pharmaceutical and/or a food or nutritional supplement, for the treatment and/or prevention of hypertriglyceridemia, dyslipidemia, hypertension, hypercholesteremia, post-myocardial infarction (MI), heart failure, cardiac arrhythmias or atrial fibrillation, IgA nephropathy, vascular diseases and/or atherosclerotic diseases.
  • hypertriglyceridemia dyslipidemia
  • hypertension hypercholesteremia
  • post-myocardial infarction (MI) post-myocardial infarction
  • MI post-myocardial infarction
  • heart failure cardiac arrhythmias or atrial fibrillation
  • IgA nephropathy IgA nephropathy
  • vascular diseases vascular diseases and/or atherosclerotic diseases.
  • lipid composition comprising at least a pro-drug of (all-Z)- 5,8, 11 , 14, 17-eicosapentaen- 1 -ol and a pro-drug of (all-2)-4,7, 10,13,16,19- docosahexaen-1-ol for treatment of hyperlipidemic conditions, such as for treatment of hypertriglyceridemia (HTG).
  • HMG hypertriglyceridemia
  • the present invention relates to a lipid composition comprising pro-drugs of at least omega-3 polyunsaturated alcohols, wherein the omega-3 polyunsaturated alcohols comprise at least (all-Z)-5,8, 11 , 14, 17-eicosa ⁇ entaen- 1 -ol and (all-Z)-4,7, 10,13,16,19- docosahexaen- 1 -ol.
  • a lipid or pharmaceutical composition comprises pro-drugs of alcohols of the omega-3 fatty acid ethyl ester compositions described in the U.S. patents 5,502,077; 5,656,667; and 5,698,594, such as for instance a lipid composition comprising pro-drugs of:
  • the invention relates to a lipid .com ⁇ osition, . wherein_a pro-drug of_(alkZ) j5 . ,8,!l,14,17-eicosapentaen-l-ol is a compound of formula (III):
  • R 1 is chosen from:
  • R 2 is chosen from: - a C 1 -C 22 alkyl
  • the invention relates to a lipid composition, wherein a pro-drug of (all-Z)-4,7,10,13,16,19-docosahexaen-l-ol is a compound of formula (IV):
  • R 1 is chosen from:
  • R 2 is chosen from:
  • the invention relates to a lipid composition, wherein a pro-drug of (all-Z) 5,8,11,14,17-eicosapentaen-l-ol j s chosen from (all-Z)-5,8,l l,14,17-eicosapentaen-l-yl phosphonate, (all-Z)-5,8,l 1,14,17- eicosapentaen-1-yl di-methylphosphonate, (all-ZJ-5,8,11,14,17-eicosapentaen-l-yl sulphonate, and (all-Z)-5,8,ll,14,17-eicosapentaen-l-yl t-butyl carbonate.
  • the invention relates to a lipid composition, wherein a pro-drug of (all-Z)-4,7,10,13,16,19-docosahexaen-l-ol is chosen from (all-Z)-4,7,10,13,16,19-docosahexaen-l-yl phosphonate, (all-Z)- 4,7, 10, 13 , 16, 19-docosahexaen-l -yl di-methylphosphonate, (all-Z)-4,7, 10,13,16,19- docosahexaen-1-yl sulphonate, and (all-Z)-4,7,10,13,16,19-docosahexaen-l-yl t-butyl carbonate.
  • a pro-drug of (all-Z)-4,7,10,13,16,19-docosahexaen-l-ol is chosen from (all-Z)-4,7,10,13,
  • the present invention relates to a use of a lipid composition for the manufacture of a medicament, a pharmaceutical and/or a food or nutritional supplement, for the prevention and/or treatment of hyperlipidemic conditions.
  • the present invention relates to a use of a lipid composition for the manufacture of a medicament, a pharmaceutical and/or a food or nutritional supplement, for the treatment and/or prevention of hypertriglyceridemia (HTG), dyslipidemia, hypertension, hypercholesteremia, post-myocardial infarction (MI), heart failure, cardiac arrhythmias or atrial fibrillation, vascular diseases and/or atherosclerotic diseases.
  • HMG hypertriglyceridemia
  • MI post-myocardial infarction
  • MI post-myocardial infarction
  • heart failure cardiac arrhythmias or atrial fibrillation
  • vascular diseases and/or atherosclerotic diseases vascular diseases and/or atherosclerotic diseases.
  • the present invention relates to a method of treatment and/or prevention of hypertriglyceridemia (HTG), dyslipidemia, hypertension, hypercholesteremia, post-myocardial infarction (MI), heart failure, cardiac arrhythmias or atrial fibrillation, high risk patients with homeostasis, IgA nephropathy, vascular diseases and/or atherosclerotic diseases, wherein a therapeutically effective amount of the lipid composition is administered to a human or an animal.
  • HMG hypertriglyceridemia
  • MI post-myocardial infarction
  • the present invention relates to a method for reducing abnormal triglyceride levels in a patient, wherein a therapeutically effective amount of the lipid composition is administered to a human or an animal.
  • the present invention relates to a process for manufacture of a lipid composition as described herein.
  • An eighth aspect of the invention relates to a compound of formula (III):
  • OH , OMe f 1 O , ⁇ and VV R2 , and R 2 is chosen from:
  • R 1 is chosen from:
  • R 2 is chosen from:
  • the invention relates to phosphonates of omega-3 polyunsaturated compounds, or salts thereof, chosen from:
  • the invention relates to sulphonates a-3 polyunsaturated compounds, or salts thereof, chosen from:
  • the invention relates to carbonates of omega-3 polyunsaturated compounds chosen from:
  • the present invention meets these needs with a lipid composition
  • a lipid composition comprising pro-drugs of omega-3 polyunsaturated alcohols, which pro-drugs of omega-3 polyunsaturated alcohols comprise at least one pro-drug of (all-Z)- 5,8, 11 , 14, 17-eicosa ⁇ entaen- 1 -ol, and at least one pro-drug of (all-Z)-4,7, 10,13,16,19- docosahexaen- 1 -ol.
  • the lipid compositions according to the invention comprise pro-drugs of alcohols of the omega-3 fatty acids, as described in U.S. Patent Nos. 5, 502,077; 5,656,667; and 5,698,594.
  • lipid composition comprising at least the combination of pro-drugs of omega-3 polyunsaturated alcohols of formula (I):
  • (II) is suitable and may be useful for achieving the desired pharmaceutical activity.
  • alkyl refers to a saturated straight or branched chain group of 1 to 22 carbon atoms, such as a straight or branched chain group of 1-10 or 1-6 carbon atoms.
  • alkenyl refers to an unsaturated straight or branched chain of 2 to 22 carbon atoms having from 1 to 6 carbon-carbon double bonds in either the Z or E configuration, such as a straight or branched chain group of 2-10 or 2-6 carbon atoms.
  • An exemplary alkenyl is a C 12 -C 22 polyunsaturated alkenyl with 2 to 6 methylene interrupted double bonds in Z configuration.
  • An alkyl or alkenyl group may be optionally substituted with one or more substituents selected from alkoxy, aryl, aryloxy, carboxy, carboxyalkyl, cycloalkyl, halogen, hydroxy, phosphonate, sulphonate, sulphonylalkyl, sulphoxyalkyl and_thio.alkyl._
  • alkoxy refers to an alkyl group attached to an oxygen.
  • aryl refers to a mono-, bi-, or other multi- carbocyclic, aromatic ring system.
  • the aryl group can optionally be fused to one or more rings selected from aryls and cycloalkyls.
  • aryloxy refers to an aryl group attached to an oxygen.
  • carboxy refers to the radical -COOH.
  • carboxy also includes salts such as -COONa, etc.
  • carboxyalkyl refers to a carboxy group attached to an alkyl group, e.g., -alkyl-COOH or salts such as -alkyl-COONa, etc.
  • cycloalkyl refers to a monovalent saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of 3-12 carbons derived from a cycloalkane by the removal of a single hydrogen atom, e.g., cyclohexanes, cyclohexenes, cyclopentanes, and cyclopentenes. Cycloalkyl groups can be fused to other cycloalkyl or aryl groups.
  • halogen refers to refer to F, Cl, Br, or I.
  • hydroxy refers to the radical -OH.
  • phosphonate refers to the radical - P(O)OR 3 OR b, where R a and R b are each independently selected from hydrogen, alkyl, alkenyl, aryl, and cycloalkyl.
  • R a and R b are each independently selected from hydrogen, alkyl, alkenyl, aryl, and cycloalkyl.
  • phosphonate also includes salts, such as those described herein.
  • sulphonate refers to the radical -SO 3 H. Sulfonate also includes salts, such as those described herein.
  • sulphonylalkyl refers to an alkyl group attached to a -SO 2 R 0 group, where R 0 is selected from alkyl, alkenyl, aryl, and cycloalkyl.
  • sulphoxylalkyl refers to an alkyl group attached to a -SOR d group, where Ra is selected from alkyl, alkenyl, aryl, and cycloalkyl.
  • thioalkyl refers to an -alkyl-S-R e group, where R e is selected from alkyl, alkenyl, aryl, and cycloalkyl.
  • pro-drugs of polyunsaturated omega-3 alcohols according to the invention,-are pro-drugs o£formulae_(III), (I ⁇ )_and (Y):
  • the lipid composition comprises at least a pro-drug of an omega-3 polyunsaturated alcohol of formula (VI):
  • the lipid composition comprises at least-a-pro-drug of-an omega-3-polyunsaturated-alcohol of formula (VIII):
  • the lipid composition comprises at least a pro-drug of an omega-3 polyunsaturated alcohol of formula (X):
  • the lipid composition comprises at least a pro-drug of an omega-3 polyunsaturated alcohol of formula (XII):
  • Another lipid composition according to the invention includes prodrugs of omega-3 polyunsaturated alcohols, in a concentration of least 30% by weight as compared to the total lipid content of the composition, such as at least 50% by weight, such as at least 60%, such as at least 70% by weight, such as at least 80% by weight, and such as at least 90% by weight.
  • the pro-drugs of omega-3 polyunsaturated alcohols in the lipid composition comprise at least about 20% by weight of at least one pro-drug of (all-Z)- 5,8,11,14,17-eicosapentaen-l-ol, and at least one pro-drug of (all-Z)-4,7,10,13,16,19- docosahexaen-1-ol, such as at least 60% by weight, such as at least about 70% by weight, and such as at least about 80% by weight.
  • the pro-drugs of omega-3 polyunsaturated alcohols comprise about 84% by weight of at least one pro-drug of (all-Z)-5,8,l 1,14,17-eicosapentaen-l-ol and at least one pro-drug of (all-Z)-4,7, 10, 13 , 16, 19-docosahexaen- 1 -ol.
  • the pro-drugs of omega- 3 polyunsaturated alcohols in the lipid composition comprise at least about 20% to 30% by weight of at least one pro-drug of (all-Z)-5,8,l 1,14,17-eicosapentaen-l-ol, and at least one pro-drug of (all-Z)-4,7, 10, 13 , 16, 19-docosahexaen- 1 -ol.
  • This may, for instance, be the case when the raw material, or crude oil, is a cod-liver oil or a sardine oil.
  • the pro-drugs of omega-3 polyunsaturated alcohols comprise about 5% to about 95% by weight of at least one pro-drug of (all-Z)-5,8,l 1,14,17-eicosapentaen-l-ol of the total lipid content in the composition, such as about 40% to about 55% by weight of at least one pro-drug of (all-Z)-5,8,l 1,14,17-eicosapentaen-l-ol.
  • the pro-drugs of omega-3 polyunsaturated alcohols can comprise about 5% to about 95% by weight of at least one pro-drug of (all-Z)-4,7,l 0,13, 16,19-docosahexaen- l-ol of the total lipid content in the composition, such as the pro-drugs of omega-3 polyunsaturated alcohols comprise about 30% to about 60% by weight of at least one pro-drug of (all-Z)-4,7,10,13,16,19- docosahexaen- 1 -ol.
  • the pro-drugs of omega- 3 polyunsaturated alcohols comprise about 43% to 50 % of at least one pro-drug of (all-Z)-5,8,l 1,14,17-eicosapentaen-l-ol and 35% to 40% of at least one pro-drug of (all-Z)-4,7,l 0,13, 16,19-docosahexaen- l-ol,-by-weight of the total lipid content in the - composition.
  • the pro-drugs of omega- 3 polyunsaturated alcohols may comprise at least one pro-drug of (all-Z)-5,8,l 1,14,17- eicosapentaen-l-ol and at least one pro-drug of (all-Z)-4,7,10,13,16,19-docosahexaen- l-ol in a weight ratio of (all-Z)-5,8,l 1,14,17-eicosapentaen-l-ol pro-drug: (all-Z)- 4,7,10,13, 16,19-docosahexaen- l-ol pro-drug from 99:1 to 1:99, such as in a weight ratio of (all-2)-5,8,l 1,14,17-eicosapentaen-l-ol pro-drug: (all-Z)-4,7,l 0,13, 16,19- docosahexaen-1-ol
  • At least 6 % by weight of the pro-drugs of omega-3 polyunsaturated alcohols is comprised of at least one pro-drug of (all-Z)-5,8,l 1,14,17-eicosapentaen- 1- ol and at least one pro-drug of (all-Z)-4,7,10,13,16,19-docosahexaen-l-ol, in a weight ratio of (all-Z)-5,8,l 1,14,17-eicosapentaen-l-ol pro-drug:(all-Z)-4,7,10,13,16,19- docosahexaen-1-ol pro-drug from 3:1 to 1 :3.
  • At least 70% by weight of the pro-drugs of omega-3 polyunsaturated alcohols is comprised of at least one pro-drug of (all-Z)-5,8,l 1,14,17-eicosapentaen-l-ol and at least one pro-drug of (all-Z)-4,7,l 0,13, 16, 19-docosahexaen-l-ol, in a weight ratio of (all-Z)-5,8,l 1,14,17- eicosapentaen-l-ol pro-drug: (all-Z)-4,7,l 0,13, 16, 19-docosahexaen-l-ol pro-drug from 1:2 to 2:1.
  • At least 70% by weight of the pro-drugs of omega-3 polyunsaturated alcohols is comprised of at least one pro-drug of (all-Z)- 5,8,11,14,17-eicosapentaen-l-ol and at least one prodrug of (all-Z)-4,7,l 0,13, 16, 19-docosahexaen-l-ol, in a weight ratio of (all-2) 5,8,11,14,17-eicosapentaen-l-ol pro-drug:(all-2)-4,7,10,13,16,19-docosahexaen-l-ol pro-drug from about 0.0 to 1.5.
  • the lipid composition is a pharmaceutical composition, a nutritional composition, or a dietary composition.
  • these compositions may further comprise an effective amount of an acceptable antioxidant, e.g., tocopherol or mixtures of tocopherols, in an amount of up to 6 mg per gram, such as 0.2 to 4 mg per gram, and such as 0.5 to 2 mg per gram.
  • an acceptable antioxidant e.g., tocopherol or mixtures of tocopherols
  • all compositions-according to the invention maybe formulated for oral- administration.
  • the lipid composition is shaped in a form of a capsule, which could also be a microcapsule generating a powder or a sachet.
  • the composition may also be present as a solid dosage form.
  • the capsule may be flavoured.
  • This embodiment also includes a capsule, wherein both the capsule and the encapsulated composition according to the invention is flavoured. By flavouring the capsule, it becomes more attractive to the user.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired, and the disorder being treated or prevented.
  • the lipid composition may be formulated to provide a daily dosage of, e.g., 0.1 g to 10 g; 0.5 g to 3 g; or 0.5 g to 1.5 g of the pro-drugs of omega-3 polyunsaturated alcohols described herein.
  • a daily dosage is meant the dosage per 24 hours.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired, and the disorder indicated. Typically, a physician will determine the actual dosage which will be most suitable for an individual subject.
  • the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.
  • a "pharmaceutically active amount” relates to an amount that will lead to the desired pharmacological and/or therapeutic effects, i.e., an amount of at least one pro-drug of omega-3 polyunsaturated alcohols which is effective to achieve its intended purpose. While individual patient needs may vary, determination of optimal ranges for effective amounts of the pro-drugs of omega-3 polyunsaturated alcohols are within the skill of the art. Generally, the dosage regimen for treating a condition with the compounds and/or compositions of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet, and medical condition of the patient.
  • a medicament is meant a lipid composition according to the invention, in any form suitable to be used for a medical or non-medical purpose, e.g., in-the form of a medicinal product,. a pharmaceutical preparation or.product,...a-dietary - product, a food stuff or a food supplement, or a so called "lifestyle" supplement.
  • Treatment includes any therapeutic application that can benefit a human or a non-human mammal. Both human and veterinary treatments are within the scope of the present invention. Treatment may be for an existing condition or it maybe prophylactic. An adult, a juvenile, an infant, a fetus, or a part of any of the aforesaid (e.g., an organ, tissue, cell, or nucleic acid molecule) may be treated.
  • the lipid composition may be used on its own but will generally be administered in the form of a pharmaceutical composition in which the pro-drugs of omega-3 polyunsaturated alcohols (the active ingredient) are in association with a pharmaceutically acceptable carrier, an excipient, a diluent, or a combination thereof.
  • a pharmaceutically acceptable carrier an excipient, a diluent, or a combination thereof.
  • acceptable carriers, excipients and diluents for therapeutic use are well- known in the pharmaceutical art, and can be selected with regard to the intended route of administration and standard pharmaceutical practice.
  • Examples encompass binders, lubricants, suspending agents, coating agents, solubilising agents, preserving agents, wetting agents, emulsifiers, sweeteners, colourants, flavouring agents, odourants, buffers, suspending agents, stabilising agents, and/or salts.
  • a pharmaceutical composition according to the invention is formulated for oral administration to a human or an animal.
  • the pharmaceutical composition may also be formulated for administration through any other route where the active ingredients may be efficiently absorbed and utilized, e.g. intravenously, subcutaneously, intramuscularly, intranasally, rectally, vaginally, or topically.
  • the lipid composition comprises at least pro-drugs of (all-Z)-5,8,l 1,14,17-eicosapentaen-l-ol chosen from a compound of formula (III):
  • R 2 is chosen from:
  • Ci-C 22 alkenyl with 1 to 6 double bonds in Z or E configuration wherein the alkyl and alkenyl groups are optionally substituted, or a salt thereof.
  • the lipid composition comprises at least pro-drugs of (all-Z)-4,7,10,13,16,19-docosahexaen-l-ol chosen from a compound of formula (IV);
  • the present invention also relates to a lipid or pharmaceutical composition according to the invention for use as a medicament, a pharmaceutical, or for use in therapy.
  • the invention relates to the use of a lipid composition, or a pharmaceutical composition, for the production of a medicament, a pharmaceutical and/or a food or nutritional supplement for:
  • hypertriglyceridemia HSG
  • dyslipidemia hyperlipidemia
  • hypertension hypertension
  • hypercholesteremia hypercholesteremia
  • MI post-myocardial infarction
  • heart failure heart failure
  • cardiac arrhythmias cardiac arrhythmias
  • atrial fibrillation the prevention and/or treatment of post-myocardial infarction
  • the lipid composition, or pharmaceutical composition, according to the invention is used for treatment of hyperlipidemic conditions.
  • the present invention includes methods of blood lipid therapy in a subject comprising administering to the subject a pharmaceutically effective amount of a lipid composition according to the , invention, wherein the subject has a baseline triglyceride level of 200 to 499 mg/dl, and wherein after administration to the subject the triglyceride level, such as a LDL cholesterol level, of the subject are reduced.
  • the triglyceride level of a subject is generally considered to be normal if less than 150 mg/dL, borderline to high if within about 150-199 mg/dL, high if within about 200-499 mg/dL and very high if 500 mg/dL or higher.
  • the present invention may be used to reduce the triglyceride level of a "very high” down to a "high” or "high to borderline”.
  • the lipid composition comprising pro-drugs of omega-3 polyunsaturated alcohols as described herein are useful for the treatment and prophylaxis of multiple risk factors known for cardiovascular diseases, such as hypertension, hypertriglyceridemia and high coagulation factor VII phospholipid complex activity.
  • the pro-drugs of omega-3 polyunsaturated alcohols acting as an lipid lowering or decreasing drug, maybe used for the treatment of elevated blood lipids in humans.
  • the invention provides for the use of pro-drugs of omega-3 polyunsaturated alcohols for the manufacture of a medicament for lowering triglycerides in the blood of mammals and/or at the same time may increase HDL cholesterol levels in the serum of a human patients.
  • a pharmaceutical composition for the treatment of elevated triglyceride levels comprises at least pro-drugs of omega-3 polyunsaturated alcohols in a concentration of at least 80% by weight as compared to the-totaLlipidxontent-of-the composition, and wherein at least-7Q%-of.the-prordrugs.of omega-3 polyunsaturated alcohols is comprised of a combination of at least one prodrug of (all-2)-5,8, 11,14,17-eicosapentaen- 1 -ol and at least one pro-drug of (all-Z)- 4,7,10,13,16,19-docosahexaen-l-ol in a weight ratio of (all-Z)-5,8,l 1,14,17- eicosapentaen-1-ol pro-drug:(all-Z)-4,7,10,13,16,19-docosahexaen-l-ol pro-drug from
  • a pharmaceutical composition according to the invention may also provide an increased effect on inflammatory diseases, including chronic inflammatory diseases characterized by leukocyte accumulation and leukocyte-mediated tissue injury, neural development and visual functions, hi an exemplary embodiment, the present invention also provides for the use of a lipid composition according to the invention for the manufacture of a medicament or pharmaceutical for the treatment and/or the prevention of atherosclerosis, psoriasis, multiple sclerosis and/or rheumatoid arthritis.
  • a lipid composition according to the invention may also be used for the prevention and/or treatment of amyliodosis-related diseases.
  • Amyliodosis-related conditions or diseases associated with deposition of amyloid includes Alzheimer's disease or dementia, Parkinson's disease, amyotropic lateral sclerosis, the spongiform encephalopathies, such as Creutzfeld-jacob disease, cystic fibrosis, primary or secondary renal amyloidoses, IgA nephropathy, and amyloid depostion in arteries, myocardium and neutral tissue.
  • These diseases can be sporadic, inherited or even related to infections such as TBC (tuberculosis) or HIV (human immunodeficiency virus), and are often manifested only late in life even if inherited forms may appear much earlier.
  • TBC tumor necrosis
  • HIV human immunodeficiency virus
  • a lipid composition according to the invention may also be used for the treatment due to reduction of amyloid aggregates, prevention of misfolding of proteins that may lead to formation of so called fibrils or plaque, treatment due to decreasing the production of precursor protein such as A ⁇ -protein (amyloid beta protein), and prevention and/or treatment due to inhibiting or slowing down the formation of protein fibrils, aggregates, or plaque.
  • Prevention of fibril accumulation, or formation, by administering the lipid composition- is also-included-herein-
  • the novel lipid compositions are used for the treatment of TBC or HIV.
  • a lipid composition according to the invention may be administered to patients with symptoms of atherosclerosis of arteries supplying the brain, for instance a stroke or transient ischaemic attack, in order to reduce the risk of a further, possibly fatal, attack.
  • the present invention relates to the use of an lipid composition comprising pro-drugs of omega-3 polyunsaturated alcohols according to the invention for the manufacture of a medicament or pharmaceutical for the treatment and/or the prevention of at least one of: atherosclerosis or IgA nephropathy, prophylaxis of multiple risk factors for cardiovascular diseases, heart failure, atrial fibrillation and/or a post-myocardial infarct, stroke, treatment of TBC or HIV, and treatment of HTG HIV patients.
  • nonalcoholic fatty liver disease is a common condition associated with metabolic syndrome. More specifically, fatty liver is primarily associated with hyperinsulinemia and insulin-resistance.
  • a lipid composition comprising pro-drugs of omega-3 polyunsaturated alcohols may act as an insulin-sensitizing agent and reduce liver steatosis.
  • fatty liver disease occurs in two major forms - alcoholic and nonalcoholic. Both forms are marked by accumulation of fat in the liver with variable amounts of liver injury, inflammation, and fibrosis.
  • fatty liver disease ranges from simple steatosis (considered benign and non-progressive), to steatohepatitis (fatty liver with liver cell injury and inflammation), to progressive hepatic fibrosis and cirrhosis. All these conditions are included in the prevention and/or treatment with at least pro-drugs of omega-3 polyunsaturated alcohols according to the invention.
  • the invention also relates to methods for the prevention and/or treatment of all conditions and diseases mentioned above, comprising administering to a patient, such as a mammal in need thereof, a pharmaceutically active amount of a lipid composition according to the invention.
  • An exemplary embodiment relates to a method for reducing abnormal triglyceride levels in a patient, such as patients having triglyceride levels of about 200 to about 499 mg/dl before treatment, wherein a therapeutically effective amount of the lipid composition according to the invention is administered to a human or an animal.
  • the present invention encompasses a method for -manufacturing lipid compositions according to-the-invention.
  • lipid composition is prepared from a vegetable, a microbial and/or an animal source, such as from a marine oil, further such as from a fish oil or a krill oil.
  • One advantage of preparing pro-drugs of omega-3 polyunsaturated alcohols according to the invention is that it is possible to start with a mixed fatty acid composition, comprising omega-3 fatty acids or esters, known in the art, and then to carry out a reduction step, by reduction of the acids or esters, to their respective alcohols.
  • the lipid composition according to the invention is prepared directly from a pre-concentrated mixed-fatty acid composition comprising at least 70% of weight of omega-3 fatty acid esters, comprising esters of at least (all-Z)-5,8,l 1,14,17-eicosa ⁇ entaen-l-oic acid and (all-Z)-4,7,10,13,16,19- docosahexaen-1-oic acid, wherein the esters of (all-2)-5,8,l 1,14,17-eicosapentaen-l- oic acid and (all-Z)-4,7,10,13,16,19-docosahexaen-l-oic acid are reduced to polyunsaturated alcohols by using a reagent that transfers a hydride to the carbonyl compound.
  • the reagent is chosen from lithium aluminium hydrides, such as LiAlH 4 , LiAlH 2 (OCH 2 CH 2 OCH 3 ), or LiAlH[OC(CH 3 ) 3 ] 3 , and boron hydrides such as LiBH 4 , or Ca(BH ⁇ ) 2 .
  • lithium aluminium hydrides such as LiAlH 4 , LiAlH 2 (OCH 2 CH 2 OCH 3 ), or LiAlH[OC(CH 3 ) 3 ] 3
  • boron hydrides such as LiBH 4 , or Ca(BH ⁇ ) 2 .
  • the alcohol is then converted into a pro-drug by reaction with a suitable reagent, such as, for example, di-t-butyl ⁇ iV-diisopropylphosphoramidite followed by trifluoroacetic acid, dimethyl N,iV-diisopropylphosphoramidite, SO 3 •pyridine, and di-t-butyl carbonate.
  • a suitable reagent such as, for example, di-t-butyl ⁇ iV-diisopropylphosphoramidite followed by trifluoroacetic acid, dimethyl N,iV-diisopropylphosphoramidite, SO 3 •pyridine, and di-t-butyl carbonate.
  • Category A Lipid compounds [pro-drugs derived from EPA-, DHA-, and ALA-alcohols]
  • Phosphonate salts are described by using (all-Z)-4,7,10,13,16,19- docosahexaen-1-yl phosphonate as a non limiting example.
  • a and B are each independently an anion or hydrogen, provided that A and B are not both hydrogen; n is 1 or 2; y is 1 or 2, where when y is 1, Z + is selected from Li + , Na + , K + , NH 4 + ,
  • Z 7 2+ is selected from Mg .2+ , ⁇ Ca radical2+ , Ethylenediamine,
  • Z 2+ is selected from Mg 2+ , Ca 2+ ,
  • Lipid compositions 1 and 2 comprising pro-drags of the alcohols in the form of phosphonates
  • Lipid compositions comprising pro-drugs of the alcohols in the form of sulphonates
  • Lipid compositions comprising pro-drugs of the alcohols in the form of carbonates
  • Different concentrates of polyunsaturated esters can be reduced to their corresponding alcohols by using a reagent that transfers a hydride to the carbonyl compound.
  • Non-limiting examples of such reducing agents are: lithium aluminium hydrides, such as LiAlH 4 , LiAlH 2 (OCH 2 CH 2 OCH 3 ), LiAlH[OC(CH 3 ) 3 ] 3 and boron hydrides, such as LiBH 4 and Ca(BH 4 ) 2 .
  • lipid mixture containing 90% omega-3 polyunsaturated fatty acids as ethyl esters was used as starting material.
  • the mixture contained approximately 85% w/w of ethyl (all-Z)-5,8,ll,14,17-eicosapentaenoate and ethyl (all-Z)-4,7,10,13,16,19-docosahexaenoate in a ratio of 1.2 w/w .
  • tMs " Mxrure is " called " K85 EEr
  • a lipid mixture containing approximately 55% omega-3 polyunsaturated fatty acids as ethyl esters was used as staring material.
  • the mixture contained approximately 50% w/w of ethyl (all-Z)-5,8,l 1,14,17- eicosapentaenoate and ethyl (all-Z)-4,7,10,13,16,19-docosahexaenoate.
  • this mixture is called K50 EE
  • omega-3 polyunsaturated fatty acid ester mixtures can be used as staring material.
  • K50 EE (10Og) in dry THF (450 mL) was added dropwise to a stirred suspension OfLiAlH 4 (11.56 g, 0.304 mol) in dry THF (500 mL) held at 0 0 C.
  • the mixture was stirred at O 0 C under inert atmosphere for 2.5 h, then added 10% NH 4 Cl (200 mL) and filtered through a short pad of celite. The pad was washed with water (250 mL) and heptane (250 mL) and the layers were separated.
  • the aqueous phase was extracted-with-heptane (500 mL) and the combined organic layer was -washed with brine (200 mL) and dried (Na 2 SO 4 ). This afforded 78 g of a mixture of (all-Z) 5,8,11,14,17-eicosapentaen-l-ol and (all-Z)-4,7,10,13,16,19-docosahexaen-l-ol (and other unidentified compounds) as a yellow oil.
  • Variations of method II described above might include trans- esterification of, for instance, a crude fish oil to a mixture of esters. This ester mixture can be distilled prior to the reduction procedure. After reduction, the alcohol mixture can be purified according to methods well-known in the art.
  • Step 1 (all-ZV5,8,ll,14,17-eicosapentaen-l-yl di-t-butyl-phosphonate
  • Step 2 (all-Z)-5,8,l 1,14,17-eicosapentaen-l-yl phosphonate
  • mice Female heterozygous APOE*3Leiden mice were used, and housed during the experiment in macrolon cages (three or four mice per cage), in clean- conventional animal rooms (relative humidity 50-60%, temperature ⁇ 21°C, light cycle 7 am to 7 pm). Individual animals were marked by ear punch-holes. Mice were supplied-with-food and-acidifi ⁇ d -tap water ad libitum.
  • mice received a semi-synthetic modified Western-type diet (WTD) as described by Nishina et al (J Lipid Res 1990; 31 : 859), containing cholesterol (0.25 % w/w, final concentration) and 15% cocoa butter.
  • WTD semi-synthetic modified Western-type diet
  • test compounds were administered orally as admix to the Western- type diet.
  • the lyophilized diet chunks were stored in vacuum bags in the dark in an alarm-secured -20°C room.
  • the diets on the cages of the mice were changed twice a week.

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Abstract

La présente invention concerne une composition lipidique renfermant au moins des précurseurs d’alcools oméga-3 polyinsaturés, lesquels précurseurs d’alcools oméga-3 polyinsaturés comprennent au moins un précurseur du (tout Z)-5,8,11,14,17-éicosapentaén-1-ol et au moins un précurseur du (tout Z)-4,7,10,13,16,19-docosahexaén-1-ol et leur utilisation en tant que produit pharmaceutique, en particulier pour le traitement de taux élevés de triglycérides. L’invention a également pour objet des procédés de préparation de ces précurseurs à partir d’huiles marines.
PCT/NO2009/000170 2008-05-02 2009-04-30 Compositions lipidiques renfermant des dérivés d’epa et de dha et leur utilisation WO2009134147A1 (fr)

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US8609157B2 (en) 2009-10-30 2013-12-17 Tharos Ltd. Solvent-free process for obtaining phospholipids and neutral enriched krill oils
KR20160002732A (ko) * 2013-02-28 2016-01-08 프로노바 바이오파마 너지 에이에스 2-((5z,8z,11z,14z,17z)-이코사-5,8,11,14,17-펜타에닐옥시)부탄산의 제조방법
CN105341184A (zh) * 2015-10-14 2016-02-24 中国农业科学院油料作物研究所 一种具有预防心脑血管疾病和糖尿病风险因子作用的功能性油脂组合物
CN111504957A (zh) * 2019-01-31 2020-08-07 吉林大学 一种维多利亚蓝b及其衍生物在制备异构化蛋白的探针或抑制剂中的应用

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Publication number Priority date Publication date Assignee Title
US8609157B2 (en) 2009-10-30 2013-12-17 Tharos Ltd. Solvent-free process for obtaining phospholipids and neutral enriched krill oils
US8772516B2 (en) 2009-10-30 2014-07-08 Tharos. Ltd. Solvent-free process for obtaining phospholipids and neutral enriched krill oils
US8865236B2 (en) 2009-10-30 2014-10-21 Tharos Ltd. Solvent-Free Process for Obtaining Phospholipids and Neutral Enriched Krill Oils
US9011942B2 (en) 2009-10-30 2015-04-21 Tharos, Ltd. Solvent-free process for obtaining phospholipids and neutral enriched krill oils
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KR20160002732A (ko) * 2013-02-28 2016-01-08 프로노바 바이오파마 너지 에이에스 2-((5z,8z,11z,14z,17z)-이코사-5,8,11,14,17-펜타에닐옥시)부탄산의 제조방법
EP2961727B1 (fr) * 2013-02-28 2016-12-28 Pronova BioPharma Norge AS Procédés de préparation de dérivés d'acide gras
KR102179351B1 (ko) 2013-02-28 2020-11-18 바스프 에이에스 2-((5z,8z,11z,14z,17z)-이코사-5,8,11,14,17-펜타에닐옥시)부탄산의 제조방법
CN105341184A (zh) * 2015-10-14 2016-02-24 中国农业科学院油料作物研究所 一种具有预防心脑血管疾病和糖尿病风险因子作用的功能性油脂组合物
CN111504957A (zh) * 2019-01-31 2020-08-07 吉林大学 一种维多利亚蓝b及其衍生物在制备异构化蛋白的探针或抑制剂中的应用
CN111504957B (zh) * 2019-01-31 2021-12-03 吉林大学 一种维多利亚蓝b及其衍生物在制备异构化蛋白的探针或抑制剂中的应用

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