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
  • 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
  • A61K9/4858—Organic 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
• • 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
  • A61P9/10—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

Definitions

• the invention relates to the use of polyunsaturated fatty acids for the primary prevention of major cardiovascular events.
• the invention concerns the use of polyunsaturated fatty acids of the ⁇ -3 series such as eicosapentaenoic acid (EPA, C 20:5 ⁇ -3), docosahexaenoic acid (DHA, C 22:6 ⁇ -3), or their pharmaceutically acceptable derivatives, either alone or mixed together, for the primary prevention of major cardiovascular events.
• polyunsaturated fatty acids of the ⁇ -3 series such as eicosapentaenoic acid (EPA, C 20:5 ⁇ -3), docosahexaenoic acid (DHA, C 22:6 ⁇ -3), or their pharmaceutically acceptable derivatives, either alone or mixed together, for the primary prevention of major cardiovascular events.
• U.S. Pat. No. 5,753,703 describes the use of L-carnitine or its derivatives in association with polyunsaturated fatty acids of the ⁇ -3 series or their esters, in particular EPA and DHA, for the prevention and treatment of cardiovascular disorders, vascular pathologies, diabetic peripheral neuropathies, and atherosclerotic, thromboembolytic and tissue disorders.
• EP-B-0409903 describes a process for preparing high concentration mixtures of EPA and DHA and/or their esters useful for treating hyperlipemia and related pathologies, thrombosis, cardiac infarct, platelet aggregation, as anticoagulants in the prevention of atherosclerosis, for the treatment of cerebral infarct, of lesions and occlusions caused by vasomotor spasms, of diabetes and its complications, of chronic and acute inflammations, of autoimmune symptoms, in the prevention of side effects caused by non-steroid anti-inflammatories at the gastrointestinal level and in tumour prevention.
• CN 1082909 describes compositions based on ethyl esters of EPA and DHA and other polyunsaturated fatty acids of the ⁇ -3 series in association with soya phospholipids, oenothera odorata and ginkgetin, as antithrombotic and antidementia agents for treating for example dementia and infarct of the myocardium.
• U.S. Pat. No. 5,760,081 describes a method for preventing imminent fibrillation of the myocardial ventricle by intravenous infusion of a composition containing EPA, where the subject at risk of imminent fibrillation has already often been the protagonist of an episode of infarct of the myocardium and where the infusion is effected within 3 hours of the infarct episode, possibly using intracardiac injection.
• WO 00/48592 describes the use of a mixture of EPA and DHA ethylesters in quantities greater than 25 wt. % for preventing death, in particular “sudden death” in patients who have already suffered an infarct of the myocardium. This therefore represents the use of said mixture in so-called secondary death prevention, i.e. in subjects who have already suffered infarct.
• the invention relates to the use of polyunsaturated fatty acids of the ⁇ -3 series for the preparation of a drug useful in the primary prevention of a major cardiovascular event in subjects who have not undergone previous infarct episodes, wherein the fatty acids comprise eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA) and/or at least one pharmaceutically acceptable derivative thereof, in quantities greater than or equal to 25 wt % on the total fatty acid weight.
• EPA eicosapentaenoic acid
• DHA docosahexaenoic acid
• polyunsaturated fatty acids of the ⁇ -3 series means those long-chain polyunsaturated fatty acids, generally C 16 -C 24 , containing fish oils, in particular those having a C 20 -C 22 chain, which are predominant in purification processes.
• major cardiovascular event means in particular those events which involve reversible or irreversible cardiovascular damage, such as infarct of the myocardium and of individual coronary branches, death from cardiac causes, sudden death, etc., besides to infarct, broadly speaking, ictus etc., and those conditions prodromal to such major events, such as myocardial fibrillation, atrial and/or ventricular fibrillation, etc.
• Said major cardiovascular events are usually induced by various cardiocirculatory and cardiorespiratory pathologies such as coronary ischemic illness not displayed by previous infarct episodes, and by serious hypoxic/anoxic states caused by a sudden lack of oxygen (for example during anesthesia, surgery, etc.), possibly in the presence of conditions which contemplate an increase in the oxygen requirement (accentuated physical stress, drug abuse, acute hypertensive crises, etc.) and analogous acute and chronic pathologies due to cardiac defects of electrical and/or mechanical type.
• various cardiocirculatory and cardiorespiratory pathologies such as coronary ischemic illness not displayed by previous infarct episodes, and by serious hypoxic/anoxic states caused by a sudden lack of oxygen (for example during anesthesia, surgery, etc.), possibly in the presence of conditions which contemplate an increase in the oxygen requirement (accentuated physical stress, drug abuse, acute hypertensive crises, etc.) and analogous acute and chronic pathologies due to cardiac defects of electrical and/or mechanical type.
• the subjects affected by pathologies of the cardiocirculatory and cardiorespiratory system are representative of subjects definable at various levels as cardiopaths, by being affected, for example, by coronary ischemia detectable by coronarography, scintigraphy of the myocardium, electrocardiogram (ECG) under stress, etc., against which interventions of revascularization (angioplasty) or other possible pharmacological or invasive treatments have been proposed, and of subjects affected by electrical hyperexcitability of the myocardium cells, disorder of the diffusion of electrical excitement or of electrical conduction (arrhythmia, fibrillation, etc.) or by other defects of mechanical type (cardiac insufficiency, decompensation), possibly aggravated by concomitant pathologies such as diabetes.
• polyunsaturated fatty acids of the w-3 series according to the invention is particularly indicated if the occurrence of a major event is predicted, such as an infarct, in particular of the myocardium, death from a cardiological cause, or sudden death, and where such an occurrence takes place in cardiopathic subjects affected, for example, by coronary ischemia, arrhythmia, atrial and/or ventricular fibrillation, electrical hyperexcitability of the myocardium cells, disorder of the diffusion of electrical excitement or of electrical conduction of the myocardium, or cardiac disorders of mechanical type, for example cardiac insufficiency or cardiac decompensation, possibly affected by diabetic pathology concomitant with the cardiopathy.
• a major event such as an infarct, in particular of the myocardium, death from a cardiological cause, or sudden death, and where such an occurrence takes place in cardiopathic subjects affected, for example, by coronary ischemia, arrhythmia, atrial and/or ventricular fibrillation, electrical hyperex
• the content of EPA and/or DHA and/or of the at least one derivative thereof is between 50% and 100%, in particular between 75% and 95%, and more preferably about 85% by weight on the total fatty acid weight.
• the preferred EPA and/or DHA derivatives are selected from the corresponding C 1 -C 3 alkyl esters and/or from their salts with pharmaceutically acceptable bases such as sodium hydroxide, lysine, arginine or aminoalcohols such as choline.
• pharmaceutically acceptable bases such as sodium hydroxide, lysine, arginine or aminoalcohols such as choline.
• the ethylesters of EPA and DHA, in particular mixed together in any concentration and percentage, are the most preferred.
• the drug is administered preferably orally, in particular in the form of soft gelatin capsules.
• the unit dose generally comprises 100-1000 mg of polyunsaturated fatty acids of the ⁇ -3 series, preferably 500-1000 mg or 300-500 mg, the total dose being usually around 0.1-3.0 g per day or per alternate day, according to the case concerned, and preferably 0.3-2.0 g per day and in particular 1.0 g per day.
• the effective dose of the drug suitable for the use of the invention is 1.0-60.0 mg/kg of body weight/day.
• formulation for oral administration are also suitable for the purposes of the invention; for example hard capsules or tablets, in which the polyunsaturated fatty acids are adsorbed on solid supports. It is also possible to use emulsions, granulates in dispersing excipients, syrups, droplets, etc., and other forms of administration able to ensure systemic absorption of the drug, such as sterile solutions or emulsions and the like, suitable for parenteral use and the like, as evaluated by the expert of the art, on the basis of the severity of the pathology.
• compositions illustrated in the European Pharmacopea 2000 containing quantities greater than or equal to 80 wt % of mixtures of EPA and DHA ethylesters and a total of ⁇ -3 polyunsaturated fatty acid ethylesters greater than or equal to 90 wt % are also suitable for the purposes of the present invention.
• compositions and the drugs suitable for the use of the invention can be prepared by methods known to the expert of the art, such as those described in U.S. Pat. No. 5,130,061, WO 89/11521, IT 1235879, JP 02/25447, which are incorporated into the present description with regard to the method of preparation.
• the drug suitable for use according to the present invention can also comprise other active principles and/or drugs, in association, possessing activity complementary to or synergic with that of the drug suitable for use according to the invention, and also at least one pharmaceutically acceptable vehicle and/or one diluent and/or one surfactant and/or one thickener and/or one binder and/or one lubricant and/or one aromatizer and/or one colorant and/or one stabilizer and the like, which can easily be selected by the expert of the art.
• stabilizers antioxidants such as vitamin E (tocopherol), ascorbyl palmitate, ascorbic acid, hydroxytoluene and the like, which can be easily selected by the expert of the art, are particularly preferred.
• the invention relates to a method for the primary prevention of a major cardiovascular event in subjects who have not undergone previous infarct episodes, comprising the administration of an effective dose of a drug comprising polyunsaturated fatty acids of the ⁇ -3 series as hereinbefore described.
• the method of the invention is indicated whenever the occurrence of a major cardiac event is predicted such as an infarct, in particular of the myocardium, death from a cardiological cause or sudden death.
• compositions illustrated in the following table were prepared by the methods described in U.S. Pat. No. 5,130,061 (compositions A, C, D, F), IT 1235879 (composition B), JP 02/25447 (composition E) and WO 89/11521 (compositions G-I).
• compositions illustrated in the following table were prepared by methods known in the art.
• compositions of the invention were evaluated on the basis of tests carried out on small laboratory animals (mouse, guinea pig, rat); this experimental model was chosen because of the ability to make rapid and highly reproducible verifications and to use a sufficiently large number of animals, such as to enable a statistically accurate evaluation of the results to be made without exposing the patient to risk, with evident ethical implications.
• the experimental sudden death model was obtained by cardiac arrest induced by intravenous (i.v.) administration of a cardiotoxic agent (ouabain).
• ouabain a cardiotoxic agent
• various doses of ouabain were administered to non-anesthetized guinea pigs of both sexes of weight 300-380 g, in order to determine the minimum lethal dose for 100% of the animals within 15 minutes from i.v. injection (240 mg/kg, intravenously administered over 3 minutes).
• composition A 3 groups of 15 male mice, initial weight 25-32 g, were treated orally for 15 days with physiological solution (control group) and with 50 or 100 mg/kg of a composition containing 85% of EPA and DHA ethylesters (Ex. 1, composition A).
• T t 1 (sec) t 2 (sec) t 3 (sec) S C 123 ⁇ 12 174 ⁇ 7 214 ⁇ 32 00/15 (15/15) (15/15) (15/15) 50 mg/kg 168 ⁇ 8 235 ⁇ 16 350 ⁇ 26 09/15 (08/15) (06/15) (06/15) 100 mg/kg 195 ⁇ 15 284 ⁇ 18 378 ⁇ 35 12/15 (05/15) (03/15) (03/15)
• composition C 4 groups of 10 male mice, initial weight 26-32 g, were treated orally for 5 days with physiological solution (control group) and with 10, 30 and 60 mg/kg of a composition containing 80% of EPA and DHA ethylesters (Ex. 1, composition C).

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• Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (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)
• Urology & Nephrology (AREA)
• Hospice & Palliative Care (AREA)
• Vascular Medicine (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Fats And Perfumes (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Preparation Of Compounds By Using Micro-Organisms (AREA)

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Cited By (40)

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• 2001
  • 2001-11-12 IT IT2001MI002384A patent/ITMI20012384A1/it unknown
• 2002
  • 2002-10-15 EP EP02023126A patent/EP1310249B1/en not_active Revoked
  • 2002-10-15 PT PT02023126T patent/PT1310249E/pt unknown
  • 2002-10-15 DK DK02023126T patent/DK1310249T3/da active
  • 2002-10-15 DE DE60212786T patent/DE60212786T2/de not_active Expired - Lifetime
  • 2002-10-15 AT AT02023126T patent/ATE331510T1/de active
  • 2002-10-15 ES ES02023126T patent/ES2262741T3/es not_active Expired - Lifetime
  • 2002-10-25 JP JP2002310878A patent/JP4731789B2/ja not_active Expired - Fee Related
  • 2002-10-28 US US10/281,208 patent/US20030100610A1/en not_active Abandoned
• 2004
  • 2004-02-17 US US10/778,182 patent/US7553870B2/en not_active Expired - Lifetime
• 2006
  • 2006-07-31 CY CY20061101067T patent/CY1105119T1/el unknown
• 2007
  • 2007-11-19 US US11/984,485 patent/US7619002B2/en not_active Expired - Fee Related
• 2009
  • 2009-09-29 US US12/568,997 patent/US8648061B2/en not_active Expired - Fee Related

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