EP2675445A1 - Statine et acides gras oméga-3 (epa, dha et dpa) utilisés dans les maladies cardiovasculaires - Google Patents

Statine et acides gras oméga-3 (epa, dha et dpa) utilisés dans les maladies cardiovasculaires

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Publication number
EP2675445A1
EP2675445A1 EP12705591.1A EP12705591A EP2675445A1 EP 2675445 A1 EP2675445 A1 EP 2675445A1 EP 12705591 A EP12705591 A EP 12705591A EP 2675445 A1 EP2675445 A1 EP 2675445A1
Authority
EP
European Patent Office
Prior art keywords
omega
formulation
dha
epa
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12705591.1A
Other languages
German (de)
English (en)
Inventor
George Jackowski
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
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Filing date
Publication date
Application filed by Pivotal Therapeutics Inc filed Critical Pivotal Therapeutics Inc
Publication of EP2675445A1 publication Critical patent/EP2675445A1/fr
Withdrawn legal-status Critical Current

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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
    • A61K31/21—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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to combinations of one or more statins (or
  • HMG-CoA reductase inhibitors a class of drug used to lower cholesterol levels by
  • the invention particularly relates to compositions wherein the omega-3 formulation is designed to mediate omega-3 deficiencies in individuals in need thereof; particularly to
  • compositions containing specific ratios of highly purified long chain fatty acid are provided.
  • compositions which are effective in elevating omega-3 levels to a point at which the risk factors for cardiovascular disease are mitigated, and most particularly to a composition having an EPA:DHA ratio and level of omega-3 purity which enable them to be effective in providing a sustained vasodilatory effect, defined as a vasodilatory effect lasting at least 6 hours.
  • Cardiovascular disease represents the primary cause of mortality for men and women in developed countries globally. These premature deaths come at great cost to both the individuals and their families, as well as representing a huge burden to the health care system of the country.
  • the risk factors for coronary heart disease are well- recognized and include: higher than average serum cholesterol, elevated levels of LDL; a low level of HDL in proportion to the LDL level; higher than average serum triglycerides; higher levels of lipid oxidation products creating plaques and streaks which cause
  • omega-3 fatty acid deficient 70% of Americans are omega-3 fatty acid deficient. Further studies indicate that over 84% of CVD patients are deficient in omega-3 fatty acids, specifically Eicosapentaenoic acid (EPA), Docosahexaenoic acid (DHA) and Docosapentaenoic acid (DP A).
  • EPA Eicosapentaenoic acid
  • DHA Docosahexaenoic acid
  • DP A Docosapentaenoic acid
  • CVD incidence poor diet and sedentary lifestyle are major factors that contribute to increased risk for the development, and progression of CVD. Because of this, clinical management of CVD often includes an attempt to modify a patient's lifestyle to increase exercise, and incorporate a balanced diet, rich in omega-3 fatty acids. Due to non-compliance, and often an inability of a patient to adhere to lifestyle modifications, optimal patient care is not achieved through these efforts alone, and other therapeutic interventions or strategies must be considered.
  • Treatment options may include lipid-regulating medications, such as statins, or fibrates that act to lower low density lipoprotein (LDL) cholesterol (and concomitantly APO-B) and/or triglycerides (TG), metabolic components that are thought to contribute to atherosclerotic plaque buildup, and increase the risk for heart attack or stroke.
  • lipid-regulating medications such as statins, or fibrates that act to lower low density lipoprotein (LDL) cholesterol (and concomitantly APO-B) and/or triglycerides (TG), metabolic components that are thought to contribute to atherosclerotic plaque buildup, and increase the risk for heart attack or stroke.
  • LDL low density lipoprotein
  • APO-B concomitantly APO-B
  • TG triglycerides
  • Statins are cholesterol-lowering drugs, which work by blocking an enzyme the liver needs for cholesterol production. There are at least a half-dozen statins available on the market, from a number of different manufacturers. These statins vary somewhat in their potency and ability to lower LDL cholesterol.
  • the present invention provides a novel composition, which may be incorporated into an orally administered dietary regimen for the reduction of risk factors associated with CVD.
  • the composition of the invention represents a unique combination of one or more statins with an omega 3 fatty acid formulation.
  • Omega-3 fatty acids are natural polyunsaturated fats found in sea foods like fish and which are presently also available as dietary supplements. They contain more than one double bond in the aliphatic chain. They are named according to the number (>1), position and configuration of double bounds.
  • the three major types of omega-3 fatty acids are alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA).
  • omega-3 polyunsaturated fatty acids have been shown to protect against several types of cardiovascular diseases such as myocardial infarction, arrhythmia, atherosclerosis, and hypertension (Abeywardena and Head, 2001; Kris-Etherton et al., 2003). It is widely accepted that (EPA) (C20:5n-3) and (DHA) (C22:6n-3) are the major biological active polyunsaturated fatty acids contributing to the prevention of a variety of cardiovascular disorders by improving endothelium-dependent vasodilatation and preventing activation of platelets.
  • a combination therapy including a novel omega-3 formulation in combination with one or more statins could be provided for enhancing the patient's lipid profile and mitigating the various risk factors for cardiovascular disease, particularly reduction of overall serum cholesterol levels, reductions in high blood pressure, increase in the HDL. LDL ratio, reduction of triglycerides and homocysteine levels, reduction in apolipoprotein-B levels, and prevention of lipid oxidation and the formation of plaques, a long felt need would be realized.
  • the prior art fails to disclose a pharmaceutical formulation as set forth in the instantly disclosed invention, containing the combination of a statin and an omega-3 composition containing about 90% or greater omega 3 fatty acids by weight having a combination of Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA) in a weight ratio of EPA:DHA of from 5.7 to 6.3, wherein the sum of the EPA, DHA and DPA is about 82% by weight of the total formulation and about 92% of the total omega 3 fatty acid content of the composition.
  • EPA + DHA are about 80% of the total formulation and about 89% of the total omega 3 fatty acid content of the composition.
  • each of these components which independently reduce one or more of the risk factors for cardiovascular disease (CVD), work synergistically to reduce the risk of CVD more effectively than any of these components taken alone.
  • CVD cardiovascular disease
  • omega-3 fatty acid preparations to cause endothelium-dependent relaxations depends on their relative content of EPA and DHA, as well as the purity of the overall formulation and the presence of additional key omega-3 fatty acids, particularly DPA.
  • 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 provides a novel composition, which may be incorporated into an orally administered formulation for the reduction of risk factors associated with CVD, and a novel treatment method.
  • a composition of the formulation of the invention may be used orally to treat and/or prevent risk factors of CVD and stroke, including reduction of high blood pressure and improving overall lipid profiles, e.g. low density lipoprotein (LDL), high density lipoprotein (HDL) and triglycerides. While not wishing to be bound by theory, the inventors believe that the compositions work by acting at different sites and aspects of cardiovascular disease.
  • the compositions of the present invention are preferably presented for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient.
  • the present invention also provides methods of treatment, for example administering to 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.
  • LDL low density lipoprotein
  • HDL high density lipoprotein
  • Delivery of the composition of the invention is also useful for reducing triglycerides and reducing homocysteine.
  • compositions of the invention are formulated such that an effective amount is delivered by multiple tablets (or other suitable formulation) a day.
  • these doses may be taken with meals, mixed into food, or taken on an empty stomach. Generally improvement is observed after two to eight weeks of daily use.
  • compositions of the invention may be delivered daily in a suitable form (e.g., a chew or bar).
  • suitable dosage regimens may be readily developed by one of skill in the art. Such dosage regimens are not a limitation of the invention.
  • compositions of the present invention in addition to their use in treating CVD in humans, may also be useful in treating non-human animals, particularly mammals.
  • these dietary supplements may be useful for companion animals such as dogs and cats, for cattle, horses, and pigs, among other animals.
  • a primary objective of the instant invention is to teach a combined therapy comprising a statin and an omega-3 fatty acid formulation.
  • the combined therapy may be supplied either as single dosage forms or in a combined dosage form.
  • One or more statins HMG-CoA inhibitors
  • hypertriglyceridemia hypercholesterolemia, mixed dyslipidemia, atherosclerotic disease, coronary heart disease (CHD) and cardiovascular disease (CVD), wherein exemplary, albeit non-limiting examples are cerivastatin, atorvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, rosuvastatin, eptastatin, pitavastatin, velostatin, fluindostatin, dalvastatin, pharmaceutically acceptable salts thereof, or a combination thereof, are provided along with mixtures of an omega-3 fatty acid formulation containing a minimum of 90% omega 3 fatty acids by weight including a combination of Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA) in a weight ratio of EPA: DHA of from 5.7 to 6.3, wherein the sum of the EPA, DHA and DPA are about 82% by weight of the total formulation and about 92% of the total omega 3
  • fatty acids of the present invention are understood to include
  • omega-3 formulation and statins may be provided as a single unit dosage form, or as separate and distinct unit dosage forms.
  • a further objective of the instant invention is to teach methods of administering such combinations, and unit dosages of such combinations for the treatment of hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, atherosclerotic disease, and vascular disease in cardiovascular disease patients (CVD), wherein the levels of apolipoprotein-B (APO-B) are lowered.
  • CVD cardiovascular disease patients
  • Figure 1 illustrates the study design for the VASCAZENTM open label study
  • Figure 2 is a plot of improved whole blood EPA + DHA + DPA levels baseline to week 6;
  • Figure 3 illustrates the normal distribution curves for Groups A-C during the Open Label Study
  • Figure 4 illustrates the effect of differing EPA:DHA ratios on the relaxation of coronary artery rings with and without the presence of the endothelium
  • Figure 5 discloses the relaxation effect of an EPA:DHA 6:1 control versus the effect of eNOS and EDHF inhibitors
  • Figure 6 discloses how the presence of Src kinase and PI3-kinase impacts the relaxation effect of an EPA:DHA 6:1 product
  • Figure 7 illustrates the shift in relaxation effect of an EPA:DHA 6: 1 product by membrane permeant analogues
  • Figure 8A illustrates the effect EPA: DHA 6: 1 has on both Akt and eNOS phosphorylation;
  • Figure 8B illustrates Western Blot Data Showing Sustained eNOS
  • Figure 9 demonstrates the relation of purity to the sum of EPA + DHA relative to total Omega-3 ratios on the relaxation of coronary artery rings in the presence or absence of endothelium;
  • Figure 10 illustrates that the relaxation effect of the subject EPA: DHA 6:1 formulation is insensitive to the presence of indomethacin;
  • Figure 1 1 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 12 illustrates the indomethacin sensitivity of the relaxation effect of the EPA:DHA 6: 1 formulation relative to a formulation of like ratio containing certain additives;
  • Figure 13 illustrates the comparative vasorelaxing effect of EPA:DHA 6:1 according to the present invention as compared to EPA:DHA 1 : 1, EPA alone and DHA alone;
  • 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 present invention provides a combination therapy and a method for its use which contains novel combinations of selected mixtures of one or more statins with an omega 3 fatty acid formulation.
  • the methods are useful in the treatment of patients with hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, atherosclerotic disease, cardiovascular disease (CVD) and vascular disease.
  • compositions of these compositions act to reduce serum cholesterol levels and blood pressure, increase HDL levels in proportion to LDL levels, thereby lowering APO-B levels, to protect lipids from oxidation thereby preventing the formation of plaques which block coronary arteries, and to lower both triglyceride levels and homocysteine levels.
  • oral administration of the compositions of this invention acts to reduce the risk of stroke, as well as heart attack, in human adults.
  • One particularly desirable embodiment of the invention is directed toward a composition and a method for its use including an HMG-CoA inhibitor, which is exemplified by, albeit not limited to cerivastatin, atorvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, rosuvastatin, eptastatin, pitavastatin, velostatin, fluindostatm, dalvastatin, or pharmaceutically acceptable salts thereof or a combination thereof; and an omega-3 fatty acid formulation.
  • an HMG-CoA inhibitor which is exemplified by, albeit not limited to cerivastatin, atorvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, rosuvastatin, eptastatin, pitavastatin, velostatin, fluindostatm, dalvastatin, or pharmaceutically acceptable salts thereof or a combination thereof; and an omega-3 fatty acid
  • the present invention provides a long chain fatty acid composition that includes a formulation containing a minimum of about 90% omega 3 fatty acids by weight having a combination of Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA) in a weight ratio of EPA:DHA of from 5.7 to 6.3, wherein the sum of the EPA, DHA and DPA is about 82% by weight of the total formulation and about 92% of the total omega 3 fatty acid content of the composition.
  • EPA + DHA are about 80% of the total formulation and about 89% of the total omega 3 fatty acid content of the composition.
  • the fatty acids of the present invention are understood to include biologically active glyceride forms, e.g. triglycerides, biologically active ester forms, e.g. ethyl ester forms, and biologically active phospholipid forms, their derivatives, conjugates, precursors, and pharmaceutically acceptable salts and mixtures thereof.
  • biologically active glyceride forms e.g. triglycerides
  • biologically active ester forms e.g. ethyl ester forms
  • biologically active phospholipid forms their derivatives, conjugates, precursors, and pharmaceutically acceptable salts and mixtures thereof.
  • the pharmaceutical formulation of the instant invention is contemplated as being administered in amounts providing a daily dosage of 1 to 4 gm of said formulation.
  • the pharmaceutical formulation at such dosage level being effective for the treatment or prophylaxis of risk factors of cardiovascular disease and the protection against sudden death in patients with CVD.
  • compositions of the instant invention may be provided wherein a unit form is a gel or liquid capsule.
  • An exemplary unit dosage form includes from about 645 to about 715 mg/gm EPA, for example about 680 mg/gm EPA and from about 105 to 115 mg/gm, for example about 1 10 mg/gm DHA.
  • the unit dosage can include from about 22 to about 28 mg/gm DPA for example about 25 mg/gm DPA.
  • Unit doses may additionally include a stabilizer, e.g. tocopherol in amounts up to about 0.5 %, for example about 0.15% to about 0.25% or about 0.2% by weight.
  • the effective unit dosage is generally 3 gm to 4 gm of the pharmaceutical formulation which are provided daily to CVD patients in one or more unit doses, for example about 3 - 4 one gram capsules per day.
  • one or more optional ingredients can be included in the formulations. Such ingredients may be separately added or may be components of the source from which the omega 3 fatty acids in the formulation are derived.
  • the formulation may further contain about 30 mg/gm of arachidonic acid (AA). In some embodiments, the formulation may further contain up to about 5%, for example about 3% or about 30 mg/gm of arachidonic acid (AA). It has been discovered that aspirin-acetylated COX-2 is also able to convert Omega-6 AA through lipoxygenases (LOX) to lipoxins (LXs), which are potent anti-inflammatory mediators (Nature Chemical Biology, Vol. 6, June 2010, pp 401-402). [0049] Some embodiments of the formulation contains >2%, for example >3%, of
  • 18 carbon Omega-3 fatty acids either individually or in total.
  • exemplary 18 carbon atom omega-3 fatty acids include alpha-linolenic acid (ALA) and Stearidonic acid (SDA), either alone or in combination.
  • ALA alpha-linolenic acid
  • SDA Stearidonic acid
  • the composition is formulated with a specific amount of DHA consisting of about 400 mg per daily dose.
  • 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),
  • 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
  • Other fatty acids may be present in higher quantities.
  • 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.
  • the daily dose of formulated composition provides a strong antiinflammatory and mood enhancing effect with a specific amount of DHA for the protection against sudden death in patients with CVD.
  • TG high density phospholipids
  • LDL low density lipoprotein
  • a highly potent omega-3 formulation in accordance with the present invention is marketed by Pivotal Therapeutics, Inc., under the trade name
  • VASCAZENTM to alleviate the cardiovascular risks associated with omega-3 deficiency.
  • VASCAZENTM has been formulated for the dietary management of omega-3 deficiency in patients with CVD, providing EPA and DHA to levels not attainable through normal dietary modifications.
  • the VASCAZENTM product exemplifies the present invention in being composed of about 90% or more omega-3 fatty acids at a ratio of eicosapentaenoic acid (EPA) to docosahexaenoic acid (DHA) within the range of 5.7: 1 - 6.3 : 1, respectively.
  • the formulation contains about 680mg/g of EPA, about 1 l Omg/g of DHA, and about 25 mg/g of DPA per capsule.
  • Each capsule has a total weight of about 1000 mg. It is generally contemplated that a daily regimen of VASCAZENTM includes 4 tablets per day given either in one dose or in separate doses throughout the day. With respect to a 1000 mg fill, the formulation contains at least about 90% or more omega-3 fatty acids, wherein about 80% is the sum of EPA+DHA, and about 82% the sum of EPA + DPA + DHA. Embodiments can also contain about 30mg/g of
  • arachidonic acid an omega-6 fatty acid, and/or >3% of 18 carbon Omega-3 fatty acids.
  • the present invention provides a novel composition, which may be incorporated into an orally administered formulation for the reduction of risk factors associated with CVD, and a novel treatment method.
  • a composition of the formulation of the invention may be used orally to treat and/or prevent risk factors of CVD and stroke, including reduction of high blood pressure and improving overall lipid profiles, e.g. low density lipoprotein (LDL), high density lipoprotein (HDL) and triglycerides. While not wishing to be bound by theory, the inventors believe that the compositions work by acting at different sites and aspects of cardiovascular disease.
  • the compositions of the present invention are preferably presented for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient.
  • omega-3 deficient due to lack of consumption of this essential nutrient in the typical "western diet", which includes an overabundance of proinflammatory omega-6 fatty acid intake, by comparison.
  • this dietary trend can be particularly dangerous. Coupled with other cardiometabolic risk factors, omega-3 deficiency further exacerbates the chronic progression of this disease.
  • a growing body of evidence has demonstrated the cardiovascular health risks associated with chronic omega-3 deficiency.
  • a dietary deficiency of EPA acid and DHA in particular allows for downward pro-inflammatory pressures created by the metabolism of arachidonic acid (AA) that is typically very high in the diets of most Americans.
  • AA arachidonic acid
  • omega-3 fatty acid deficiency contributes to a pro-inflammatory state, the consequences of which include negative effects on cardiovascular health, including increased risk for development of dyslipidemia (high cholesterol, high triglycerides), atherosclerotic plaque buildup, hypertension, and cardiac arrhythmia.
  • Subject# 035-MH was 55 year old male a Caucasian subject enrolled in the open label study of VASCAZEN, as described, and presented to the clinic with a medical history of cardiovascular disease. The patient was being treated by his cardiologist for hypertension and dyslipidemia for three years with the following medications: Crestor 200mg (dyslipidemia, statin), Acebutolol 200mg (hypertension, ACE),
  • the patient was familiar with, and had tried over the counter omega-3 fish oil products, but without gaining any measurable clinical benefit, likely due to the low Omega-3 content of the products that were available to him.
  • the subject was treated with VASCAZENTM at a dose of 4 capsules per day, providing 2720 mg EPA, 440 mg DHA, and 100 mg DPA per day.
  • the subject followed up with his own family practitioner, to obtain blood work (lipid panel for cholesterol and triglycerides), with the following results.
  • His clinical improvement for dyslipidemia included a 58% reduction of triglycerides from 6.76 mmol/L to 2.84 mmol/L, a 26% reduction of LDL cholesterol from 3.15 mmol/L to 2.32 mmol/L with concomitant lowering of APO-B levels, an 8% reduction in total cholesterol from 5.19 mmol/L to 4.76 mmol/L, a 12% increase in HDL cholesterol from 1.03 mmol/L to 1.15 mmol/L, and a 17% reduction in the total cholesterol (TC)/HDL cholesterol ratio from 5.04 mmol/L to 4.14 mmol/L. No adverse events were reported with this individual.
  • VASCAZENTM whole blood omega-3 fatty acid levels were examined in 143 patients, and the inventive formulation was administered to patients for two or six-week follow-ups, providing about 2800 mg/day EPA and about 480 mg/day DHA.
  • the primary outcome measure was the change in the sum of blood EPA+DHA+DPA. levels (the Omega-ScoreTM ), expressed as a percentage of total blood fatty acid levels over a two or six-week duration.
  • the formulation in accordance with the present invention was generally well tolerated, with only minor adverse events reported in a small proportion of study
  • Subjects were eligible for the study if they met all inclusion and exclusion criteria set out in the clinical study protocol. All eligible subjects provided informed consent prior study enrollment, and entered Group A ( Figure 1.). Sixty three subjects were provided 4 capsules per day of VASCAZENTM (Group B), an oral dose of 2720mg EPA and 440mg DHA per day. After two weeks of treatment, whole blood omega-3 blood level was assessed, and 31 subjects entered into Group C, for continued treatment. Group C subjects provided whole blood samples at weeks 4 and week 6, for follow-up Omega-ScoreTM assessment. [0063] The primary outcome measure was the change in Omega-Score values expressed as a percentage of total blood fatty acid levels over a 2-week period for Group B, and 6-week period for Group C. The baseline Omega-ScoreTM value for Group A was calculated as the mean percentage at week 0, prior to VASCAZENTM intervention, and Groups B and C Omega-ScoreTM means were evaluated at the specified time points accordingly.
  • Fatty acids were extracted from 200 of whole blood sample using a mixture of methanol and chloroform. Fatty acids were then methylated with 10% (w/v) BC1 3 in methanol by incubation at 90 °C for 25 min to form fatty acid methyl esters (FAMEs). After cooling the FAMEs were extracted with water/hexane mixture and 1 uL of n-hexane extract was injected for GC-MS analysis.
  • the safety population was defined as a patient group that had a minimum of 2 weeks and maximum of 6 weeks VASCAZENTM, at a dose of 4 capsules per day.
  • Primary analyses of treatment efficacy were performed on the subset of enrolled study subjects for whom blood measurements were taken at baseline and after 2 weeks of study treatment.
  • the change in blood Omega- ScoreTM levels over the 2-week period was computed for each study subject.
  • the distribution of changes in blood Omega-ScoreTM levels over 2 weeks were tested for normality using the Pearson- D'Agostino test. A paired t-test was conducted in order to test the change in blood Omega-ScoreTM levels over the 2-week period.
  • VASCAZENTM intervention for 2 weeks had a significant (PO.0001) improvement in their scores (Figure 2, Table 2), with mean values improving from 3.6% to 5.5% ( Figure 3, Table 3), a 52.8% score increase. Over two weeks of intervention, study participants considered “at risk” were reduced from 80.6% to 46.8% (Table 3). Over the course of 6 weeks VASCAZENTM intervention, Group C subjects had significant mean score improvements (P ⁇ 0.0001 )( Figure 2, Table 2), with mean values improving from 3.4% to 7.5% between baseline and week 6 ( Figure 3, Table 3), and representing a 120.6% increase in whole blood levels of EPA+DHA+DPA
  • Omega-ScoreTM (%) % of Patients At Risk ( ⁇ 6.1% Omega-
  • VASCAZENTM significantly (PO.0001) increased mean scores from 3.4% to 7.9%, representing a 132.4% improvement, bringing the mean score of the total population to well within the >6.1% low risk quartile. Indeed, only 15% of study participants remained below this benchmark level after 4 weeks, a level that is sustained in the study group through 6 weeks of VASCAZENTM intervention.
  • VASCAZENTM was generally well tolerated with a low incidence, of minor adverse events that are typical for omega-3 polyunsaturated fatty acid ethyl esters. This study has highlighted the prevalence of chronic omega-3 deficiency in the majority of people (84%), both men and women.
  • omega-3 deficiency The consequences of 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
  • the present invention as exemplified by VASCAZENTM intervention provides essential balanced levels of EPA and DHA that are difficult for many CVD patients to incorporate into their daily diet through food alone.
  • the average American consumes 15 times less omega-3 fatty acids from fish than what is required to attain and maintain clinically beneficial levels of EPA and DHA.
  • this essential nutrient to provide the daily dose that the present invention can provide, one would have to eat fish every single day, for more than one meal per day. This is unrealistic for most people.
  • formulations according to the invention have been shown to provide a sustainable eNOS vasodilatory effect, defined as a vasodilatory effect persisting for 6 hours or more, which has heretofore not been achievable with either prescription or OTC grade omega-3 supplements.
  • ROS Reactive oxygen species Reactive Oxygen Species
  • sGC Soluble guanylyl cyclase
  • the endothelium consists of a single endothelial cell layer lining the luminal surface of all blood vessels. Endothelial cells play an important function in the regulation of vascular homeostasis. They regulate the contact of blood with the underlying
  • thrombogenic arterial wall respond to numerous physiological stimuli such as circulating hormones and shear stress by releasing several short-lived potent endothelium- derived vasoactive factors such as nitric oxide (NO) and endothelium- derived
  • EDHF hyperpolarizing factor
  • NO is produced by endothelial nitric oxide synthase (eNOS) from L- arginine, NO plays critical roles in normal vascular biology and pathophysiology. NO induces relaxation of the vascular smooth muscle by activating soluble guanylyl cyclase resulting in the formation of cyclic guanosine 3'-5'monophosphate (cGMP). In addition to the regulation of vascular tone and inhibition of platelet aggregation, NO also inhibits many key steps involved in atherogenesis including vascular smooth muscle cell proliferation, monocyte adhesion (Dimmeler et al., 1997; Hermann et al., 1997; Tsao et al., 1996) and cell death.
  • eNOS endothelial nitric oxide synthase
  • eNOS can be activated by receptor-dependent and -independent agonists as a consequence of an increase in the intracellular concentration of free Ca ([Ca 2+ ]i) and the association of a Ca 2+ / Calmodulin (CaM) complex with eNOS leading to its activation (Fleming et al., 2001). Indeed both the agonist-induced NO formation and subsequent vasorelaxation are abolished by the removal of Ca from the extracellular space as well as by CaM antagonists.
  • eNOS is also regulated in endothelial cells at a post- translational level primarily through protein/protein interactions and multisite
  • 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).
  • Akt PI3-kinase-dependent mechanisms
  • Akt one of the major regulatory targets of PI3-kinase, has been shown to directly phosphorylate eNOS at Serl 179 and activate the enzyme in response to vascular endothelial growth factor (VEGF), sphingosine-1 -phosphate, and estrogens (Dimmeler et al., 1997; Fulton et al., 1999).
  • VEGF vascular endothelial growth factor
  • sphingosine-1 -phosphate sphingosine-1 -phosphate
  • estrogens Dimmeler et al., 1997; Fulton et al., 1999.
  • eNOS-Serl 179 can also be phosphorylated by AMP-activated protein kinase (Busse et al., 2002), protein kinase A (PKA), and protein kinase G (PKG). Exactly which protein kinase(s) phosphorylates eNOS-Serl 179 in intact cells appears to be dependent on the type of endothelial cells and stimuli.
  • AMP-activated protein kinase Busse et al., 2002
  • PKA protein kinase A
  • PKG protein kinase G
  • shear stress phosphorylates eNOS Serl 179 by a PI3-kinase- and PKA-dependent manner without involving Akt whereas EGF phosphorylates eNOS Serl 179 by a PI3-kinase- and Akt-dependent manner (Boo et al., 2002).
  • EGF phosphorylates eNOS Serl 179 by a PI3-kinase- and Akt-dependent manner
  • the ischemia-reperfusion injury activates the PKA pathway leading to the phosphorylation of eNOS at Serl 179 and Ser635 (Li et al., 2010).
  • eNOS expression can be modulated by several factors including shear stress (Butt et al., 2000), hypoxia, low- density lipoproteins (LDL) (Chen et al., 2008; Chen et al., 1999) and oxidized fatty acids (Corson et al., 1996).
  • Endothelium-dependent vasorelaxation has also been observed in some blood vessels following inhibition of NO and PGI2 synthesis and has been attributed to endothelium-derived hyperpolarizing factor (EDHF).
  • EDHF relaxes blood vessels through hyperpolarization of the vascular smooth muscle. This effect will close voltage-operated Ca 2+ channels resulting in reduction of the intracellular free Ca 2+ level and subsequent relaxation of the vascular smooth muscle. Potassium (K + ) channels underlie the
  • endothelial dysfunction which is characterized by impaired NO
  • the initial experiment was designed to determine the ability of omega-3 fatty acids (EPA, DHA and different ratios of EPA:DHA) to cause endothelium-dependent relaxations in rings of porcine coronary arteries, thereby enabling the characterization of the role of NO and EDHF in endothelium-dependent relaxation and identification of the signal transduction pathway involved.
  • omega-3 fatty acids EPA, DHA and different ratios of EPA:DHA
  • Rings with or without endothelium were suspended in organ baths containing rebs bicarbonate solution (composition in mM: NaCl 1 18.0, KC1 4.7, CaCl 2 2.5, MgS0 4 1.2, NaHC0 3 23.0; KH 2 P0 4 1.2 and glucose 11.0, pH 7.4, 37°C) oxygenated with a mixture of 95% 0 2 and 5% C0 2 .
  • rebs bicarbonate solution composition in mM: NaCl 1 18.0, KC1 4.7, CaCl 2 2.5, MgS0 4 1.2, NaHC0 3 23.0; KH 2 P0 4 1.2 and glucose 11.0, pH 7.4, 37°C
  • ⁇ -nitro-L-arginine L-NA, 300 ⁇
  • NOS NO synthase
  • TRAM 34 100 nM
  • apamin 100 nM
  • IKCa and SKCa Ca -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
  • endothelial cells were rinsed twice with PBS and lysed with extraction buffer (composition in mM: Tris / HC1 20, pH 7.5 (QBiogene), NaCl 150, Na 3 V0 4 1, Na 4 P 2 0 7 10, NaF 20, okadaic acid 0.01 (Sigma), protease inhibitors (Complete Roche) and 1% Triton X-100). 25 ⁇ g of total proteins were separated on SDS- polyacrylamide (Sigma 8%) at 100 V for 2 h. Separated proteins were transferred onto a polyvinylidene fluoride membrane (Amersham) by electrophoresis at 100 V for 2 h.
  • extraction buffer composition in mM: Tris / HC1 20, pH 7.5 (QBiogene), NaCl 150, Na 3 V0 4 1, Na 4 P 2 0 7 10, NaF 20, okadaic acid 0.01 (Sigma), protease inhibitors (Complete Roche) and 1% Triton X-100.
  • membranes were blocked with blocking buffer containing 3% bovine serum albumin in TBS-T (Tris-buffered saline solution, Biorad, containing 0.1% Tween 20, Sigma) for 1 h.
  • TBS-T Tris-buffered saline solution, Biorad, containing 0.1% Tween 20, Sigma
  • membranes were incubated in TBS-T containing the respective primary antibodies (p-eNOS Ser 1 177, p-eNOS Thr 495 and p-Akt Ser 473 (dilution
  • Bonferoni post-hoc test A P value of ⁇ 0.05 is considered statistically significant.
  • the omega-3 fatty acid preparation EPA:DHA 1 :1 induced concentration- dependent relaxations of coronary artery rings with endothelium whereas only small relaxations were obtained in those without endothelium contracted with U46619 ( Figure 4).
  • the relaxations to EPA:DHA 1 : 1 was observed at volumes greater than 0.01 % v/v and they reached about 75% at 0.4 % v/v ( Figure 4).
  • the omega-3 fatty acid preparation EPA:DHA 6: 1 also induced endothelium-dependent relaxations which were more potent than those induced by EPA:DHA 1 : 1 ( Figure 4).
  • omega-3 fatty acid preparation EPA:DHA 6: 1 induces endothelium-dependent relaxations involving both NO and EDHF.
  • Omega-3 in % signifies total omega-3 in % of total fatty acids as EE (ethyl esters)
  • Indomethacin is an inhibitor of COX-1 and thus will prevent the formation of vasorelaxing prostanoids.
  • the magnitude of the endothelium-dependent relaxation is dependent on the purity of the formulation ( Figure 9) and on the EPA:DHA ratio ( Figure 4).
  • the EPA:DHA 6: 1 formulation caused similar endothelium-dependent relaxation as the OTC Omega-3 product TETESEPTTM with an omega-3 purity (as defined above) of 22.2 % as compared to that of the EPA:DHA 6: 1 formulation of 75.1 % and was much more effective than the other OTC Omega-3s tested (ABTEI LACHSOLTM 1300, DOPPELHE Z ® , SCHAEBENSTM and OPTISANATM ( Figure 1 1 A).
  • TETESEPTTM has a more than fivefold higher vitamin E content than that of the
  • Vitamin E has been shown to cause endothelium-dependent relaxation which is inhibited by indomethacin (Wu et al., J Nutr. 135: 1847-1853, 2005). Both omega-3 purity and additives, contribute to the endothelium-dependent relaxation observed with Omega-3 products. This is further illustrated by comparing the relaxation induced by the EPA: DHA 6:1 formulation to that of the MET AGENIC STM EPA-DHA 6: 1 formulation.
  • omega-3 fatty acid preparations are potent endothelium-dependent vasodilators and that this effect is dependent on the ratio and the omega-3 purity of EPA and DHA within the capsule. They further suggest that omega-3 fatty acids activate eNOS via a redox-sensitive PI3 -kinase/ Akt pathway leading to changes in the phosphorylation level of eNOS as illustrated in Figure 14.
  • All patents and publications mentioned in this specification are indicative of the levels of those skilled in the art to which the invention pertains. All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

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Abstract

La présente invention concerne une composition et un procédé de traitement utilisant une association de statines (ou inhibiteurs de la HMG-CoA réductase), une classe de médicaments utilisés pour baisser la cholestérolémie par inhibition de l'enzyme HMG-CoA réductase, avec des mélanges d'une préparation d'acides gras oméga-3 contenant environ 90 % ou plus d'acides gras oméga-3 en poids comprenant 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 d'EPA, de DHA et de DPA représentant 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). L'invention concerne en outre des procédés d'administration desdites associations, et concerne des formes unitaires desdites associations pour la réduction des taux d'apolipoprotéine B.
EP12705591.1A 2011-02-16 2012-02-14 Statine et acides gras oméga-3 (epa, dha et dpa) utilisés dans les maladies cardiovasculaires Withdrawn EP2675445A1 (fr)

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