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WO2004047835A1 - Utilisation de compositions pharmaceutiques contenant des esters ethyliques d'acides polyinsatures omega-3 afin de prevenir la fibrillation atriale - Google Patents

Utilisation de compositions pharmaceutiques contenant des esters ethyliques d'acides polyinsatures omega-3 afin de prevenir la fibrillation atriale Download PDF

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Publication number
WO2004047835A1
WO2004047835A1 PCT/EP2003/013125 EP0313125W WO2004047835A1 WO 2004047835 A1 WO2004047835 A1 WO 2004047835A1 EP 0313125 W EP0313125 W EP 0313125W WO 2004047835 A1 WO2004047835 A1 WO 2004047835A1
Authority
WO
WIPO (PCT)
Prior art keywords
atrial fibrillation
epa
ethyl esters
drug
dha ethyl
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/EP2003/013125
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English (en)
Inventor
Jadranka Rogan
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.)
VICTORIX ASSETS Ltd
Original Assignee
VICTORIX ASSETS Ltd
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 VICTORIX ASSETS Ltd filed Critical VICTORIX ASSETS Ltd
Priority to AU2003292080A priority Critical patent/AU2003292080A1/en
Priority to EP03767610A priority patent/EP1565177A1/fr
Publication of WO2004047835A1 publication Critical patent/WO2004047835A1/fr
Anticipated expiration legal-status Critical
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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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

Definitions

  • the present invention relates to the use of ethyl esters of polyunsaturated acids of the ⁇ -3 series obtained from fish oil, and in particular ethyl esters of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in high concentrations, alone or mixed, for the preparation of medicaments for the prevention of atrial fibrillation.
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • Atrial fibrillation the most common alteration of the heart rhythm, is responsible for significant morbidity and mortality among the population as a whole. Its prevalence increases progressively with age, reaching percentages of over 9% in men aged between 65 and 80 years old. Atrial fibrillation (AF) is a particularly important risk factor for stroke, which is largely responsible for the fact that mortality associated with this alteration in the heart rhythm has doubled.
  • the etiological factors responsible for sustained atrial fibrillation include histological alterations of the atrium such as dilation and fibrosis, which are among the normal age-associated cardiac modifications.
  • post-operative atrial fibrillation has an incidence of between 20 and 70% after open-heart surgery such as artery bypasses and valve operations, which involve a significant increase in morbidity and hospital costs.
  • Various antiarrhythmic drugs have been studied and used to treat atrial fibrillation, especially to prevent recurrences in patients with a history of paroxystic atrial fibrillation or persistent post-cardioversion atrial fibrillation, and to prevent post-operative atrial fibrillation.
  • the ideal drug namely one which is wholly manageable and therefore suitable in all circumstances, and able to prevent arrhythmia entirely, is not yet available.
  • the recommendation to select the treatment carefully on the basis of each patient's specific characteristics and history is commonly followed for safety reasons.
  • the risk associated with the use of class I antiarrhythmic drugs due to their potential proarrhythmic effect, which makes their use inadvisable in the prevention of post-operative arrhythmia, as well as the organ toxicity induced by class III drugs such as amiodarone and the contraindications of beta-blockers are well known.
  • Polyunsaturated fatty acids of the ⁇ -3 series, especially EPA and DHA, purified and concentrated as ethyl esters, are known for their potential usefulness in the treatment of some cardiovascular diseases and modulation of the corresponding risk factors.
  • EP 0.409.903-B1 patent IT 1.235.978 and others describe their efficacy in the treatment of hyperlipaemia, hypercholesterolaemia and hypertension.
  • Atrial fibrillation was induced in the dog by pacing with a suitable battery-operated pacemaker designed to provide rapid atrial pulses at a frequency starting from 500 bpm, for at least 20 beats, until atrial fibrillation took place.
  • a complete atrioventricular block was previously effected by means of suitable ablation.
  • compositions of ethyl esters of ⁇ -3 polyunsaturated acids to which the invention relates mainly represented by EPA and/or DHA ethyl esters at a high concentration, are easily obtainable according to methods well known to those skilled in the art, such as those described in WO 89/11521, US 5130061, IT 1.235.879, US 4.377.526, US 4.554.107 and others, which are incorporated herein as regards the production methods.
  • the EPA and/or DHA ethyl ester content generally exceeds 25%; in particular it ranges between approx. 50% and approx. 100%, and preferably between 80% and 90% (approx. 85%).
  • the percentage of EPA ethyl ester is preferably 40 to 60%, and the percentage of DHA ethyl ester is preferably in the 25-50% range; in any event the ratio between the EPA and DHA ethyl esters should be between 0.9 and 1.5.
  • said oily compositions comprising high concentrations of EPA and/or DHA ethyl esters are used to make a drug useful in reducing the risk of mortality in patients suffering from heart failure.
  • the drug is preferably administered orally, in particular using a pharmaceutical formulation of soft gelatin capsules.
  • the preparation process of said capsules, which are particularly suitable to carry oily active ingredients, is well known to those skilled in the art.
  • the unit dose of the capsules is usually 0.5-1 g, and preferably 1 g, while the daily dose is between 0.5 and 2 g, depending on the severity of the disorder and the doctor's opinion, and preferably around 1 g/day.
  • oral formulations may also be suitable, such as hard capsules, tablets and granulates in which the oily composition can be adsorbed on a solid medium, or drops, syrups, etc., as known in pharmaceutical technology.
  • compositions include parenteral formulations such as sterile emulsions and the like.
  • the medicament in accordance with this invention may also include other active ingredients with synergic or complementary activity, diluents, thickeners, surfactants, dyes, flavouring agents, stabilisers and antioxidants, in accordance with the usual practice.
  • Vitamin E (tocopherol) and p-oxybenzoates are particularly preferred as antioxidants.
  • Typical pharmacological results of the therapeutic activity claimed are reported in Examples 1 and 2, and some compositions of soft gelatin capsule formulations are reported in Examples 3-6.
  • Example 1 Example 1
  • the electrodes required to record the atrial electrogram were inserted through the femoral vein and the pacing wires required to measure the atrial effective refractory period (AERP) were sutured to the two atria; a complete atrioventricular block was then effected by means of radiofrequency ablation to prevent ventricular involvement.
  • Unipolar epicardial leads were then sutured to the right ventricle and atrium and connected to a pacemaker regulated at 80 bpm and a pulse generator programmed to pace the atrium at 780 bpm, respectively.
  • Rapid atrial pacing shortened the AERP by approx. 30 milliseconds in the controls; this shortening was reduced by approx. 60% in the animals treated with EPA and DHA ethyl esters.
  • Atrial fibrillation was induced in 8 out of 12 animals in the control group (67%) and 3 out of 12 animals in the treated group (25%).
  • the dogs underwent thoracotomy under anaesthesia; after pericardiotomy the heart was cradled in the pericardium and three pairs of partly coated stainless steel wire electrodes were sutured to the atria, and one to the right ventricle.
  • a complete atrioventricular block was effected by means of radiofrequency ablation to prevent ventricular interference, and the ventricular rate was maintained with pacing at 80-100 bpm.
  • An attempt was made to induce atrial fibrillation with rapid atrial pacing for at least 20 beats at a frequency of 500-800 bpm until fibrillation was obtained; the fibrillation was only taken into consideration for the analysis if it lasted for at least 5 minutes.
  • Atrial fibrillation was induced in 9 dogs out of 12 (75%) in the control group, and 3 dogs out of 12 (25%) in the treated group.
  • Example 3 Composition of soft gelatin capsules containing 1 g of a mixture of
  • Example 4 Composition of soft gelatin capsules containing 1 g of a mixture of
  • Ethyl esters of polyunsaturated fatty acids 500 mg with an EPA ethyl ester and DHA ethyl ester content, ratio 0.9-1.5, of 425 mg d- 1 - ⁇ tocopherol 0.15 mg gelatin succinate 139 mg glycerol 40 mg sodium ethyl p-oxybenzoate 0.66 mg sodium propyl p-hydroxybenzoate 0.32 mg
  • Example 6 Ethyl esters of polyunsaturated fatty acids 500 mg with an EPA ethyl ester and DHA ethyl ester content, ratio 0.9-1.5, of 425 mg d- 1 - ⁇ tocopherol 0.15 mg gelatin succinate 139 mg glycerol 40 mg sodium ethyl p-oxybenzoate 0.66 mg sodium propyl p-hydroxybenzoate 0.32 mg

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

Abstract

L'invention concerne l'utilisation d'esters éthyliques d'acides polyinsaturés des séries O-3 obtenus à partir d'huile de poisson, en particulier des esters éthyliques d'acide eicosapentaenoique (EPA) et d'acide docosahexaenoique (DHA) en concentrations élevées, seuls ou mélangés, afin de préparer des médicaments permettant de prévenir la fibrillation atriale.
PCT/EP2003/013125 2002-11-26 2003-11-21 Utilisation de compositions pharmaceutiques contenant des esters ethyliques d'acides polyinsatures omega-3 afin de prevenir la fibrillation atriale Ceased WO2004047835A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2003292080A AU2003292080A1 (en) 2002-11-26 2003-11-21 Use of pharmaceutical compositions containing ethyl esters of omega-3 polyunsaturated acids to prevent atrial fibrillation
EP03767610A EP1565177A1 (fr) 2002-11-26 2003-11-21 Utilisation de compositions pharmaceutiques contenant des esters ethyliques d'acides polyinsatures omega-3 afin de prevenir la fibrillation atriale

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT002511A ITMI20022511A1 (it) 2002-11-26 2002-11-26 Uso di composizioni farmaceutiche contenenti esteri etilici di acidi poliinsaturi omega-3 nella orevenzione della fibrillazione atriale.
ITMI2002A002511 2002-11-26

Publications (1)

Publication Number Publication Date
WO2004047835A1 true WO2004047835A1 (fr) 2004-06-10

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Family Applications (1)

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PCT/EP2003/013125 Ceased WO2004047835A1 (fr) 2002-11-26 2003-11-21 Utilisation de compositions pharmaceutiques contenant des esters ethyliques d'acides polyinsatures omega-3 afin de prevenir la fibrillation atriale

Country Status (4)

Country Link
EP (1) EP1565177A1 (fr)
AU (1) AU2003292080A1 (fr)
IT (1) ITMI20022511A1 (fr)
WO (1) WO2004047835A1 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2902659A1 (fr) * 2006-06-23 2007-12-28 Pierre Fabre Medicament Sa Ester de dha et son utilisation dans le traitement et la prevention des maladies cardiovasculaires
WO2008066745A1 (fr) * 2006-11-22 2008-06-05 Reliant Pharmaceuticals, Inc. Prophylaxie et traitement de la fibrillation auriculaire avec des acides gras oméga-3
RU2362553C1 (ru) * 2007-12-10 2009-07-27 Федеральное государственное учреждение "Федеральный центр сердца, крови и эндокринологии имени В.А. Алмазова Федерального агентства по высокотехнологичной медицинской помощи" Способ профилактики фибрилляции предсердий после операции коронарного шунтирования у пациентов с ишемической болезнью сердца
WO2011041710A3 (fr) * 2009-10-01 2011-05-26 Martek Biosciences Corporation Bouchons en gel d'acide docosahexaénoïque
WO2012020094A1 (fr) 2010-08-11 2012-02-16 Pierre Fabre Medicament Docosahexanoate de panthényle et son utilisation pour traiter et prévenir les maladies cardiovasculaires
US8324276B2 (en) 2005-01-24 2012-12-04 Pronova Biopharma Norge As Fatty acid composition for treatment of alzheimer's disease and cognitive dysfunction
US10028928B2 (en) 2009-03-09 2018-07-24 Pronova Biopharma Norge As Compositions comprising a fatty acid oil mixture and a free fatty acid, and methods and uses thereof
US20210100764A1 (en) * 2009-04-29 2021-04-08 Amarin Pharmaceuticals Ireland Limited Methods of treating mixed dyslipidemia
US20210212975A1 (en) * 2009-04-29 2021-07-15 Amarin Pharmaceuticals Ireland Limited Stable pharmaceutical composition and methods of using same
US11986452B2 (en) 2021-04-21 2024-05-21 Amarin Pharmaceuticals Ireland Limited Methods of reducing the risk of heart failure
US12171738B2 (en) 2009-06-15 2024-12-24 Amarin Pharmaceuticals Ireland Limited Compositions and methods for lowering triglycerides
US12246003B2 (en) 2018-09-24 2025-03-11 Amarin Pharmaceuticals Ireland Limited Methods of reducing the risk of cardiovascular events in a subject
US12427134B2 (en) 2019-11-12 2025-09-30 Amarin Pharmaceuticals Ireland Limited Methods of reducing the risk of cardiovascular events in a subject with atrial fibrillation and/or atrial flutter

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000048592A1 (fr) * 1999-02-17 2000-08-24 Pharmacia & Upjohn S.P.A. Acides gras essentiels destines a la prevention d'accidents cardio-vasculaires
EP1157692A1 (fr) * 2000-05-22 2001-11-28 Quatex N.V. Composition pharmaceutique d'acides gras, contenant au moins 80% en poids de EPA et DHA
WO2002058793A1 (fr) * 2001-01-25 2002-08-01 Pharmacia Italia S.P.A. Utilisation d'acides gras n-3 essentiels dans le traitement de l'insuffisance cardiaque et de l'arret cardiaque
WO2003068216A1 (fr) * 2002-02-12 2003-08-21 Victorix Assets Ltd. Utilisation d'esters ethyliques d'acides polyinsatures omega 3 chez des patients atteints d'une insuffisance cardiaque

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000048592A1 (fr) * 1999-02-17 2000-08-24 Pharmacia & Upjohn S.P.A. Acides gras essentiels destines a la prevention d'accidents cardio-vasculaires
EP1157692A1 (fr) * 2000-05-22 2001-11-28 Quatex N.V. Composition pharmaceutique d'acides gras, contenant au moins 80% en poids de EPA et DHA
WO2002058793A1 (fr) * 2001-01-25 2002-08-01 Pharmacia Italia S.P.A. Utilisation d'acides gras n-3 essentiels dans le traitement de l'insuffisance cardiaque et de l'arret cardiaque
WO2003068216A1 (fr) * 2002-02-12 2003-08-21 Victorix Assets Ltd. Utilisation d'esters ethyliques d'acides polyinsatures omega 3 chez des patients atteints d'une insuffisance cardiaque

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1565177A1 *

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8324276B2 (en) 2005-01-24 2012-12-04 Pronova Biopharma Norge As Fatty acid composition for treatment of alzheimer's disease and cognitive dysfunction
US8609726B2 (en) 2005-01-24 2013-12-17 Pronova Biopharma Norge As Fatty acid composition for treatment of Alzheimer's disease and cognitive dysfunction
US8227479B2 (en) 2006-06-23 2012-07-24 Pierre Fabre Medicament DHA esters and use thereof in treatment and prevention of cardiovascular disease
JP2009544576A (ja) * 2006-06-23 2009-12-17 ピエール、ファーブル、メディカマン Ｄｈａエステルならびに心血管疾患の治療および予防におけるその使用
US8034377B2 (en) 2006-06-23 2011-10-11 Pierre Fabre Medicament DHA esters and use thereof in treatment and prevention of cardiovascular disease
RU2451672C2 (ru) * 2006-06-23 2012-05-27 Пьер Фабр Медикамент Эфиры докозагексаеновой кислоты и их применение для лечения и предупреждения сердечно-сосудистого заболевания
FR2902659A1 (fr) * 2006-06-23 2007-12-28 Pierre Fabre Medicament Sa Ester de dha et son utilisation dans le traitement et la prevention des maladies cardiovasculaires
WO2007147899A3 (fr) * 2006-06-23 2008-03-13 Pf Medicament Esters de dha et leur utilisation dans le traitement et la prévention d'une maladie cardiovasculaire
WO2008066745A1 (fr) * 2006-11-22 2008-06-05 Reliant Pharmaceuticals, Inc. Prophylaxie et traitement de la fibrillation auriculaire avec des acides gras oméga-3
RU2362553C1 (ru) * 2007-12-10 2009-07-27 Федеральное государственное учреждение "Федеральный центр сердца, крови и эндокринологии имени В.А. Алмазова Федерального агентства по высокотехнологичной медицинской помощи" Способ профилактики фибрилляции предсердий после операции коронарного шунтирования у пациентов с ишемической болезнью сердца
US11612579B2 (en) 2009-03-09 2023-03-28 Pronova Biopharma Norge As Compositions comprising a fatty acid oil mixture and a surfactant, and methods and uses thereof
US11395811B2 (en) 2009-03-09 2022-07-26 Pronova Biopharma Norge As Compositions comprising a fatty acid oil mixture comprising EPA and DHA in free acid form and a surfactant, and methods and uses thereof
US10028928B2 (en) 2009-03-09 2018-07-24 Pronova Biopharma Norge As Compositions comprising a fatty acid oil mixture and a free fatty acid, and methods and uses thereof
US10596142B2 (en) 2009-03-09 2020-03-24 Pronova Biopharm Norge AS Compositions comprising a fatty acid oil mixture and a free fatty acid, and methods and uses thereof
US20210113509A1 (en) * 2009-04-29 2021-04-22 Amarin Pharmaceuticals Ireland Limited Methods of treating mixed dyslipidemia
US20210100764A1 (en) * 2009-04-29 2021-04-08 Amarin Pharmaceuticals Ireland Limited Methods of treating mixed dyslipidemia
US20210212975A1 (en) * 2009-04-29 2021-07-15 Amarin Pharmaceuticals Ireland Limited Stable pharmaceutical composition and methods of using same
US12171738B2 (en) 2009-06-15 2024-12-24 Amarin Pharmaceuticals Ireland Limited Compositions and methods for lowering triglycerides
WO2011041710A3 (fr) * 2009-10-01 2011-05-26 Martek Biosciences Corporation Bouchons en gel d'acide docosahexaénoïque
WO2012020094A1 (fr) 2010-08-11 2012-02-16 Pierre Fabre Medicament Docosahexanoate de panthényle et son utilisation pour traiter et prévenir les maladies cardiovasculaires
US12246003B2 (en) 2018-09-24 2025-03-11 Amarin Pharmaceuticals Ireland Limited Methods of reducing the risk of cardiovascular events in a subject
US12427134B2 (en) 2019-11-12 2025-09-30 Amarin Pharmaceuticals Ireland Limited Methods of reducing the risk of cardiovascular events in a subject with atrial fibrillation and/or atrial flutter
US11986452B2 (en) 2021-04-21 2024-05-21 Amarin Pharmaceuticals Ireland Limited Methods of reducing the risk of heart failure

Also Published As

Publication number Publication date
ITMI20022511A1 (it) 2004-05-27
AU2003292080A1 (en) 2004-06-18
EP1565177A1 (fr) 2005-08-24

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