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WO2012112527A1 - Préparations à base d'oméga-3 comprenant epa, dha et dpa pour le traitement des facteurs de risque dans la maladie cardiovasculaire - Google Patents

Préparations à base d'oméga-3 comprenant epa, dha et dpa pour le traitement des facteurs de risque dans la maladie cardiovasculaire Download PDF

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Publication number
WO2012112527A1
WO2012112527A1 PCT/US2012/025021 US2012025021W WO2012112527A1 WO 2012112527 A1 WO2012112527 A1 WO 2012112527A1 US 2012025021 W US2012025021 W US 2012025021W WO 2012112527 A1 WO2012112527 A1 WO 2012112527A1
Authority
WO
WIPO (PCT)
Prior art keywords
omega
formulation
epa
dha
accordance
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.)
Ceased
Application number
PCT/US2012/025021
Other languages
English (en)
Inventor
George JACROWSKI
Rachelle MACSWEENEY
Nisar Shaikh
Jason Yantha
Valerie SCHINI-KERTH
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.)
Pivotal Therapeutics Inc
Original Assignee
Pivotal Therapeutics Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Pivotal Therapeutics Inc filed Critical Pivotal Therapeutics Inc
Priority to CA2827579A priority Critical patent/CA2827579A1/fr
Priority to JP2013554542A priority patent/JP2014505731A/ja
Priority to EP12707420.1A priority patent/EP2675446A1/fr
Priority to US13/584,466 priority patent/US20120302639A1/en
Priority to PCT/US2012/051086 priority patent/WO2013122621A1/fr
Priority to EP12753874.2A priority patent/EP2814477A1/fr
Publication of WO2012112527A1 publication Critical patent/WO2012112527A1/fr
Anticipated expiration legal-status Critical
Priority to US14/692,503 priority patent/US20150224075A1/en
Ceased 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
    • A61K31/185—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
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61P9/08—Vasodilators for multiple indications

Definitions

  • EPA:DHA ratio of about 6: 1 induced significantly greater relaxations than an EPA:DHA 1 :1 preparation despite their similar content of omega-3 fatty acids.
  • EPA is likely to be a more potent endothelium-dependent vasorelaxant agonist than DHA.
  • the fact that the two major omega-3 fatty acids do not have similar biological activity to cause endothelium-dependent relaxation is important since the leading commercial omega-3 preparations (Lovaza ® ) has a ratio of EPA:DHA 1.2: 1.
  • the optimization of the ratio of EPA:DHA in omega-3 preparations may provide new products with an enhanced vascular protective potential.
  • the present invention also provides methods of treatment, for example administering a patient having an omega-3 fatty acid deficiency, that may be evidencing one or more risk factors for CVD, a therapeutically effective amount of a formulation in accordance with the invention to achieve a therapeutic level of omega-3; whereby mitigation of said one or more risk factors for CVD is achieved.
  • the invention is also a method for providing a sustained vasodilatory effect in a patient by administering a therapeutically effective amount of a formulation in accordance with the invention, whereby an indomethacin-independent sustained vasodilatory effect is achieved.
  • composition of the invention By providing a method of treatment for mediating omega-3 deficiencies, use of the instant invention to improve the health of the heart and to reduce risk factors associated with cardiovascular disease by delivering to an individual the composition of the invention is realized.
  • Delivery of the composition of the invention e.g., by oral administration, has been shown to be useful for preventing oxidation of low density lipoprotein (LDL), increasing high density lipoprotein (HDL), and for reducing total cholesterol.
  • Delivery of the composition of the invention is also useful for reducing triglycerides and reducing homocysteine.
  • the compositions of the invention are formulated such that an effective amount is delivered by multiple tablets (or other suitable formulation) a day.
  • Figure 8B illustrates Western Blot Data Showing Sustained eNOS
  • Figure 11 A and Figure 1 IB illustrate the indomethacin sensitivity of the relaxation effect of the subject EPA:DHA 6:1 formulation relative to several over the counter Omega-3 products;
  • Figure 14 illustrates the mechanism by which EPA:DHA 6:1 stimulates the endothelial formation of NO via the redox-sensitive activation of the Phosphoinositide 3- Kinase (PI3-Kinase)/ Protein Kinase (Akt) pathway.
  • PI3-Kinase Phosphoinositide 3- Kinase
  • Akt Protein Kinase
  • the composition can contain additional fatty acids in lesser amounts, usually less than about 1% of each that is present. Exemplary embodiments contain about 0.3- 0.7%, or about 5% of any of the additional fatty acids,
  • additional fatty acids can include, for example, omega -6 fatty acids such as Dihomo-gamma-linolenic acid (DGLA; 20:3n6), Docosapentaenoic acid (Osbond acid; 22:5n6); omega-9 fatty acids such as Oleic acid (18:ln9) and others such as 7,10,13,15-hexadecatetraenoic acid and (16:4nl), 9,12,15,17-octadecatetraenoic acid (18:4nl).
  • omega -6 fatty acids such as Dihomo-gamma-linolenic acid (DGLA; 20:3n6), Docosapentaenoic acid (Osbond acid; 22:5n6)
  • omega-9 fatty acids such as Oleic acid (18
  • Eicosatetraenoic acid (ETA; 20:4n3) may be present in amounts up to about 2%, for example about 1.5%
  • Heneicosapentaenoic acid (HPA; 21 :5n3) may be present in amounts up to about 3%, for example at about 2.3%.
  • HPA Heneicosapentaenoic acid
  • These additional fatty acids may be added separately or may be present in formulations obtained from particular sources using particular methods.
  • Other additional components and fatty acids may also be present in small amounts, for example 0-0.25% of the formulation.
  • composition is formulated with a DHA content to provide about 400 mg per daily dose.
  • TG high density phospholipids
  • omega-3 deficiency in patients with CVD are well documented, with numerous studies linking EPA and DHA deficiency. Many studies and current therapeutic approaches have categorized omega-3 as a
  • eNOS phosphorylation at Serl 16, Thr497, Ser635, and Serl 179
  • Residue numbers are for the bovine sequence, equivalent to Serl 14, Thr495, Ser633, and Serl 177 in the human sequence
  • positive and negative protein modulators such as caveolin (Cav-1) and heat shock protein 90 (Garcia-Cardena et al., 1998; Ju et al., 1997; Pritchard et al., 2001).
  • ⁇ -nitro-L-arginine L-NA, 300 ⁇
  • NOS NO synthase
  • TRAM 34 100 nM
  • apamin 100 nM
  • IKCa and SKCa Ca 2+ -activated potassium channels
  • Pig coronary artery endothelial cells were harvested, cleaned with phosphate buffered saline solution (PBS) without calcium to remove any residual blood.
  • Endothelial cells were isolated by collagenase (type I, Worthington, 1 mg/ml, 14 min at 37°C) and cultured in medium MCDB131 (Invitrogen) supplemented with 15% v/v fetal calf serum, 2 mM glutamine, 100 U/mL penicillin, 100 U/mL streptomycin and 250 mg/ml fungizone (Sigma, St Louis, MO) at 37°C in 5% C0 2 . All experiments were performed with confluent endothelial cells used at first passage. Endothelial cells were exposed to MCDB131 with 0.1% v/v fetal calf serum 5 h before treatment with different substances.
  • PBS phosphate buffered saline solution
  • TETESEPTTM has a more than fivefold higher vitamin E content than that of the

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une préparation permettant de traiter une carence en acides gras oméga-3, contenant environ 90 % ou plus d'acides gras oméga-3 en poids constitués d'une combinaison d'acide eicosapentaénoïque (EPA), d'acide docosapentaénoïque (DPA) et d'acide docosahexaénoïque (DHA) selon un rapport pondéral EPA/DHA allant de 5,7 à 6,3, la somme de EPA, de DHA et de DPA constituant environ 82 % en poids de la préparation totale et environ 92 % de la teneur totale en acides gras oméga-3 de la composition. EPA + DHA représentent environ 80 % de la préparation totale et environ 89 % de la teneur totale en acides gras oméga-3 de la composition. La préparation peut en outre contenir des quantités spécifiques d'acide arachidonique (AA) et d'acides gras oméga-3 ayant 18 atomes de carbone, notamment un ou plusieurs acides parmi l'acide stéaridonique (SDA) et l'acide alpha-linolénique (ALA).
PCT/US2012/025021 2011-02-16 2012-02-14 Préparations à base d'oméga-3 comprenant epa, dha et dpa pour le traitement des facteurs de risque dans la maladie cardiovasculaire Ceased WO2012112527A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
CA2827579A CA2827579A1 (fr) 2011-02-16 2012-02-14 Preparations a base d'omega-3 comprenant epa, dha et dpa pour le traitement des facteurs de risque dans la maladie cardiovasculaire
JP2013554542A JP2014505731A (ja) 2011-02-16 2012-02-14 心血管疾患のリスク因子を治療するための、ＥＰＡ、ＤＨＡおよびＤＰＡを含むω３製剤
EP12707420.1A EP2675446A1 (fr) 2011-02-16 2012-02-14 Préparations à base d'oméga-3 comprenant epa, dha et dpa pour le traitement des facteurs de risque dans la maladie cardiovasculaire
US13/584,466 US20120302639A1 (en) 2011-02-16 2012-08-13 Omega 3 formulations for treatment of risk factors for cardiovascular disease and protection against sudden death
PCT/US2012/051086 WO2013122621A1 (fr) 2012-02-14 2012-08-16 Formulations d'oméga-3 pour le traitement de facteurs de risque pour des maladies cardiovasculaires et la protection contre la mort subite
EP12753874.2A EP2814477A1 (fr) 2012-02-14 2012-08-16 Formulations d'oméga-3 pour le traitement de facteurs de risque pour des maladies cardiovasculaires et la protection contre la mort subite
US14/692,503 US20150224075A1 (en) 2011-02-16 2015-04-21 Omega 3 formulations for treatment of risk factors for cardiovascular disease and protection against sudden death

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161457271P 2011-02-16 2011-02-16
US61/457,271 2011-02-16

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/584,466 Continuation-In-Part US20120302639A1 (en) 2011-02-16 2012-08-13 Omega 3 formulations for treatment of risk factors for cardiovascular disease and protection against sudden death

Publications (1)

Publication Number Publication Date
WO2012112527A1 true WO2012112527A1 (fr) 2012-08-23

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Country Status (4)

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EP (1) EP2675446A1 (fr)
JP (1) JP2014505731A (fr)
CA (1) CA2827579A1 (fr)
WO (1) WO2012112527A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014063190A1 (fr) * 2012-10-23 2014-05-01 Deakin University Procédé pour la réduction de triglycérides
CN104321055A (zh) * 2012-01-06 2015-01-28 翁特拉制药公司 游离酸形式的ω-3多不饱和脂肪酸的富含dpa组合物
US9492545B2 (en) 2012-05-07 2016-11-15 Omthera Pharmaceuticals Inc. Compositions of statins and omega-3 fatty acids

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US20070141138A1 (en) * 2005-12-20 2007-06-21 Cenestra Llc Omega 3 fatty acid formulations
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WO2010103402A1 (fr) * 2009-03-09 2010-09-16 Pronova Biopharma Norge As Compositions comprenant un mélange oléagineux à base d'acides gras comportant de l'epa et du dha sous forme d'acide libre et un tensioactif, et procédés et utilisations associés
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JP2008522970A (ja) * 2004-12-06 2008-07-03 レリアント ファーマスーティカルズ インコーポレイテッド 脂質療法用のオメガ−３脂肪酸類及び異常脂質血症薬剤
CN101098690A (zh) * 2004-12-06 2008-01-02 瑞莱恩特医药品有限公司 用于血脂治疗的ω-3脂肪酸和脂血异常剂
CN101495106A (zh) * 2005-07-18 2009-07-29 瑞莱恩特医药品有限公司 用基于氮杂环丁酮的胆固醇吸收抑制剂和ω-3脂肪酸进行的治疗及其组合产品
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US5562913A (en) 1993-03-19 1996-10-08 Scotia Holdings Plc Formulation for use in smokers
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FR2862873A1 (fr) * 2003-12-01 2005-06-03 Pf Medicament Utilisation des acides gras polyinsatures omega 3 dans l'apnee du sommeil
US20070141138A1 (en) * 2005-12-20 2007-06-21 Cenestra Llc Omega 3 fatty acid formulations
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EP1800675A1 (fr) * 2005-12-23 2007-06-27 Nutricia N.V. Composition comprenant des acides gras polyinsaturés, des protéines et du manganèse et/ou du molybdène, pour améliorer la composition des mebranes cellulaires
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104321055A (zh) * 2012-01-06 2015-01-28 翁特拉制药公司 游离酸形式的ω-3多不饱和脂肪酸的富含dpa组合物
US9050309B2 (en) 2012-01-06 2015-06-09 Omthera Pharmaceuticals, Inc. DPA-enriched compositions of omega-3 polyunsaturated fatty acids in free acid form
US9050308B2 (en) 2012-01-06 2015-06-09 Omthera Pharmaceuticals, Inc. DPA-enriched compositions of omega-3 polyunsaturated fatty acids in free acid form
EP2800563A4 (fr) * 2012-01-06 2015-06-17 Omthera Pharmaceuticals Inc Compositions enrichies en dpa d'acides gras oméga-3 polyinsaturés sous forme d'acide libre
CN107050457A (zh) * 2012-01-06 2017-08-18 翁特拉制药公司 游离酸形式的ω‑3多不饱和脂肪酸的富含dpa组合物
EP3348262A1 (fr) * 2012-01-06 2018-07-18 Omthera Pharmaceuticals Inc. Procédés pour la préparation des compositions enrichies en dpa d'acides gras oméga-3 polyinsaturés sous forme d'acide libre
US10117844B2 (en) 2012-01-06 2018-11-06 Omthera Pharmaceuticals, Inc. DPA-enriched compositions of omega-3 polyunsaturated fatty acids in free acid form
US9492545B2 (en) 2012-05-07 2016-11-15 Omthera Pharmaceuticals Inc. Compositions of statins and omega-3 fatty acids
WO2014063190A1 (fr) * 2012-10-23 2014-05-01 Deakin University Procédé pour la réduction de triglycérides

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Publication number Publication date
EP2675446A1 (fr) 2013-12-25
CA2827579A1 (fr) 2012-08-23
JP2014505731A (ja) 2014-03-06

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