WO2008045465A1 - Acides gras oméga-3 et agent dyslipidémique pour la réduction des niveaux d'apo-b - Google Patents

Acides gras oméga-3 et agent dyslipidémique pour la réduction des niveaux d'apo-b Download PDF

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WO2008045465A1
WO2008045465A1 PCT/US2007/021631 US2007021631W WO2008045465A1 WO 2008045465 A1 WO2008045465 A1 WO 2008045465A1 US 2007021631 W US2007021631 W US 2007021631W WO 2008045465 A1 WO2008045465 A1 WO 2008045465A1
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Prior art keywords
omega
fatty acids
levels
apo
ldl
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PCT/US2007/021631
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English (en)
Inventor
Roelof M. L. Rongen
Robert A. Shalwitz
Douglas Kling
Ralph T. Doyle, Jr.
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Reliant Pharmaceuticals, Inc.
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Priority to MX2009003921A priority Critical patent/MX2009003921A/es
Priority to EP07852630A priority patent/EP2089014A4/fr
Priority to AU2007307007A priority patent/AU2007307007A1/en
Priority to EA200970360A priority patent/EA200970360A1/ru
Priority to CA002672919A priority patent/CA2672919A1/fr
Priority to JP2009532391A priority patent/JP2010505956A/ja
Priority to BRPI0719182-0A2A priority patent/BRPI0719182A2/pt
Publication of WO2008045465A1 publication Critical patent/WO2008045465A1/fr

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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
    • A61K31/33—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
    • A61K31/185—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
    • 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
    • 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
    • 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
    • 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

Definitions

  • the present invention relates to a method utilizing a single administration or a unit dosage of a combination of a dyslipidemic agent and omega-3 fatty acids for the reduction of apolipoprotein-B levels.
  • This method is especially useful in the treatment of patients with primary hypertriglyceridemia or hypercholesterolemia or mixed dyslipidemia, coronary heart disease (CHD), vascular disease, atherosclerotic disease and related conditions, and for the prevention or reduction of cardiovascular and vascular events.
  • CHD coronary heart disease
  • vascular disease atherosclerotic disease and related conditions
  • cholesterol and triglycerides are part of lipoprotein complexes in the bloodstream, and can be separated via ultracentrifugation into high-density lipoprotein (HDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) fractions.
  • HDL high-density lipoprotein
  • IDL intermediate-density lipoprotein
  • LDL low-density lipoprotein
  • VLDL very-low-density lipoprotein
  • Non-HDL-C non-HDL cholesterol
  • a direct measure of apo-B may provide a better measure of the amount of atherogenic particles per unit of serum.
  • LDL-C remains the lipid value commonly used to assess cardiovascular risk
  • apo-B may better reflect lipid risk.
  • Cardiovascular disease is a broad term that encompasses a variety of diseases and conditions. It refers to any disorder in any of the various parts of the cardiovascular system, which consists of the heart and all of the blood vessels found throughout the body. Diseases of the heart may include coronary artery disease, CHD, cardiomyopathy, valvular heart disease, pericardial disease, congenital heart disease (e.g., coarctation, atrial or
  • RPP/225510.1 2 ventricular septal defects RPP/225510.1 2 ventricular septal defects
  • Diseases of the blood vessels may include arteriosclerosis, atherosclerosis, hypertension, stroke, vascular dementia, aneurysm, peripheral arterial disease, intermittent claudication, vasculitis, venous incompetence, venous thrombosis, varicose veins, and lymphedema.
  • CVD cardiovascular disease
  • Some types of cardiovascular disease are congenital, but many are acquired later in life and are attributable to unhealthy habits, such as a sedentary lifestyle and smoking.
  • CVD cardiovascular
  • MACEs major adverse cardiovascular events
  • MCEs major coronary events
  • Ml myocardial infarction
  • CVD cardiovascular intervention
  • CVD cardiovascular
  • Primary prevention efforts are focused on reducing known risk factors for CVD, or preventing their development, with the aim of delaying or preventing the onset of CVD, MACEs or MCEs. Secondary prevention efforts are focused on reducing recurrent CVD and decreasing mortality, MACEs or MCEs in patients with established CVD.
  • MACEs include cardiac death, other cardiovascular death, MCEs (which include myocardial infarction (Ml) and coronary intervention such as coronary revascularization, angioplasty, percutaneous transluminal coronary angioplasty (PTCA), percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG)), hospitalization for unstable angina, stroke, transient ischemic
  • CHD is defined as symptomatic ischemic heart disease, including Ml, stable or unstable angina, demonstrated myocardial ischemia by noninvasive testing, and history of coronary artery procedures.
  • the ATP III indicates that LDL-C is the primary target of lipid therapy, with other lipids to be controlled including triglycerides (TG), non-HDL-C and HDL-C.
  • Apo-B is listed as an emerging risk factor. While the ATP III was not prepared to replace LDL-C as the primary target of lipid therapy, it noted that limited epidemiological and clinical trial evidence supports apo-B's superiority over LDL-C in risk prediction. [0009] A guiding principle of ATP III is that the intensity of LDL-C lowering therapy is adjusted to the individual's absolute risk for CHD. Risk assessment is broken down into short term ( ⁇ 0-year) and long term (>10-year) risk of CHD, and the LDL-C goals are adjusted accordingly. In addition, ATP III identifies three categories of risk for CHD that modify LDL-C goals: established CHD and CHD risk equivalents, multiple (2+) risk factors, and 0-1 risk factor. Established CHD and CHD risk equivalents include CHD, other clinical atherosclerotic diseases, diabetes mellitus, and multiple risk factors and a 10-year risk for CHD
  • the ATP III also outlines LDL-C goals for patients based on the percentage
  • Agents such as dyslipidemic agents and omega-3 fatty acids, have
  • hyperlipidemias of hypercholesterolemias and of hypertriglyceridemias which are hyperlipidemias of hypercholesterolemias and of hypertriglyceridemias, which are hyperlipidemias of hypercholesterolemias and of hypertriglyceridemias, which are hyperlipidemias of hypercholesterolemias and of hypertriglyceridemias, which are hyperlipidemias of hypercholesterolemias and of hypertriglyceridemias, which
  • cardiac events are generally categorized as "cardiovascular events.”
  • Dyslipidemic agents commonly include HMG CoA reductase inhibitors
  • statins cholesterol absorption inhibitors, niacin and derivatives such as
  • Statins which are 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors, have been used to treat hyperlipidemia and arthrosclerosis, for example.
  • statin monotherapy has been used to treat cholesterol levels, particularly when a patient is not at an acceptable LDL-C level.
  • Statins inhibit the enzyme HMG-CoA reductase, which controls the rate of cholesterol production in the body.
  • statins lower cholesterol by slowing down the production of cholesterol and by increasing the liver's ability to remove the LDL-cholesterol already in the blood. Accordingly, the major effect of the statins is to lower LDL- C levels. Statins have been shown to decrease CHD risk by about one-third. However, statins only appear to have a modest effect on the TG-HDL axis. It is also known that monotherapy with various statins significantly reduces apo-B levels, e.g., by about 25 to about 40% from baseline. See, e.g., Ballantyne et al., Am. Heart J. 151 (5):975.e1-975.e9 (2006).
  • Cholesterol absorption inhibitors such as ezetimibe and MD-0727, are a class of lipid-lowering compounds that selectively inhibit the intestinal absorption of cholesterol.
  • Ezetimibe acts on brush border of the small intestine and decreases biliary and dietary cholesterol from the small intestine uptake into the enterocytes.
  • Results from studies presented at the 2006 World Cardiology Congress show that a combination of ezetimibe and simvastatin has a more positive effect than simvastatin alone on apo-B levels in hypercholesterolemia patients.
  • Orse et al. Effects Of Ezetimibe/simvastatin On Lipoprotein Subclasses
  • CETP Cholesteryl ester transfer protein
  • torcetrapib inhibit the CETP molecule which, among other things, moves cholesterol from the HDL form to the LDL form. Inhibiting this molecule is, therefore, a promising approach to increasing HDL cholesterol levels. It has been reported that torcetrapib also reduced the levels of LDL-C and apo-B, both when given as monotherapy and when administered in combination with a statin. Bhardwaj et al., Indian J. Pharmacol. 37:46 (2005).
  • Niacin (nicotinic acid or 3-pyridinecarboxylic acid) has previously been used to treat hyperlipidemia and atherosclerosis. Niacin is known to reduce total cholesterol, LDL-C and triglycerides and increase HDL-C. Niacin therapy is also known to decrease serum levels of apo-B. However, the magnitude of the individual lipid and lipoprotein response from niacin therapy may be influenced by the severity and type of underlying lipid abnormality. In one study, low-dose niacin plus either atorvastatin (20 mg) or rosuvastatin (10 mg) lowered apo-B levels comparably to an ezetimibe-simvastatin combination or rosuvastatin alone.
  • Fibrates such as fenofibrate, bezafibrate, clofibrate and gemfibrozil, are PPAR-alpha agonists and are used in patients to decrease lipoproteins rich in
  • RPP/225510.1 7 triglycerides to increase HDL and to decrease atherogenic-dense LDL. Fibrates are typically orally administered to such patients.
  • Fenofibrate is an active principle which is very poorly soluble in water and the absorption of fenofibrate in the digestive tract is limited.
  • a treatment of 40 to 300 mg of fenofibrate per day enables a 20 to 25% reduction of cholesterolemia and a 40 to 50% reduction of triglyceridemia to be obtained.
  • Bile acid sequestrants such as cholestyramine, colestipol and colesevelam, are a class of drugs that binds bile acids, prevents their reabsorption from the digestive system, and reduces cholesterol levels.
  • the usual effect of bile acid sequestrants is to lower LDL-cholesterol by about 10 to 20 percent. Small doses of sequestrants can produce useful reductions in LDL- cholesterol.
  • fluvastatin and cholestyramine produced a significant, dose-dependent reduction in apo-B levels. Bard et al., Am. J. Cardiol., 76(2): 65A-70A (2005).
  • MTP inhibitors such as implitapide, are known to inhibit the secretion of cholesterol and triglycerides.
  • LXRs Liver X receptors
  • LXRs are "cholesterol sensors” that regulate the expression of genes involved in lipid metabolism in response to specific oxysterol ligands (Repa et al., Annu. Rev. Cell Dev. Biol. 16: 459-481 (2000)).
  • LXRs are "cholesterol sensors" that regulate the expression of genes involved in lipid metabolism in response to specific oxysterol ligands (Repa et al., Annu. Rev. Cell Dev. Biol. 16: 459-481 (2000)).
  • RPP/225510.1 8 agonists and antagonists are potential therapeutic agents for dyslipidemia and atherosclerosis.
  • PPAR-gamma agonists such as the thiazolidinediones pioglitazone and rosiglitazone, have been shown to improve surrogate markers of cardiovascular risk and atherosclerosis.
  • thiazolidinediones decrease C-reactive protein and carotid intima-media thickness.
  • Non- thiazolidinediones such as tesaglitazar, naviglitizar and muraglitazar, are dual alpha/gamma PPAR agonists. These compounds are used for lowering glucose, insulin, triglycerides and free fatty acids.
  • rosiglitazone was shown to significantly reduce apo-B levels. Goldberg et al., Diabetes Care 28(7):1547- 1554 (2005).
  • Partial PPAR-gamma agonist/antagonists such as metaglidasen, are used for the treatment of type Il diabetes.
  • Marine oils also commonly referred to as fish oils, are a good source of two omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which have been found to regulate lipid metabolism.
  • Omega-3 fatty acids have been found to have beneficial effects on the risk factors for cardiovascular diseases, especially mild hypertension, hypertriglyceridemia and on the coagulation factor VII phospholipid complex activity.
  • Omega-3 fatty acids lower serum triglycerides, increase serum HDL-cholesterol, lower systolic and diastolic blood pressure and the pulse rate, and lower the activity of the blood coagulation factor Vll-phospholipid complex. Further, omega-3 fatty acids seem to be well tolerated, without giving rise to any severe side effects.
  • omega-3 fatty acid is a concentrate of omega-3, long chain, polyunsaturated fatty acids from fish oil containing DHA and EPA and was sold under the trademark Omacor ® , and is now known as LovazaTM.
  • LovazaTM Such a form of omega-3 fatty acid is described, for example, in U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,594, each incorporated herein by reference.
  • Patients with mixed dyslipidemia or hypercholesteremia often present with blood levels of LDL cholesterol greater than 190 mg/dl, triglyceride levels of 200 mg/dl or higher, and apo-B levels of greater than 0.9 g/l.
  • Hong et a/ investigated the effects of fish oil and simvastatin in patients with coronary heart disease and mixed dyslipidemia.
  • Patients having baseline triglyceride levels of 292.8 mg/dl or 269.5 mg/dl were initially treated with 10-20 mg/day simvastatin for 6-12 weeks. Thereafter the patients were treated with simvastatin and placebo or simvastatin and 3 g/day fish oil
  • RPP/225510.1 10 (MeilekangTM).
  • Combined treatment significantly reduced triglyceride levels, as compared to baseline and placebo.
  • combined treatment numerically increased HDL-C levels, and numerically reduced LDL-C levels, as compared to baseline.
  • the changes in HDL-C levels and LDL-C levels were not statistically significant.
  • Levels of apo-B were raised in the combined treatment group, while the apo-B levels numerically decreased in the placebo group. Hong et al., Chin. Med. Sci. J. 19:145-49 (2004).
  • Contacos et al. investigated the effects of fish oil and pravastatin on patients with mixed hyperlipidemia.
  • Patients having baseline triglyceride levels of 4.6 to 5.5 mmol/l (404 to 483 mg/dl) were initially treated for 6 weeks with 40 mg/day pravastatin, 6 g/day fish oil (HimegaTM, containing 3 g of omega-3 fatty acids, with an EPA/DHA ratio of 2:1 ), or placebo. Thereafter, all patients were treated with pravastatin and fish oil for an additional 12 weeks.
  • Initial treatment with pravastatin significantly reduced LDL-C levels.
  • Combined treatment of pravastatin and fish oil also significantly reduced triglyceride and LDL-C levels.
  • PRAVACHOL ® (pravastatin) is indicated as an adjunct to diet to reduce elevated apo-B levels in patients with primary hypercholesterolemia and mixed dyslipidemia.
  • JuIa et al. studied the effects of diet and simvastatin on various serum lipids in hypercholesterolemic men. After an open placebo period, subjects were allocated to a "habitual diet” or "dietary treatment” group.
  • the dietary treatment consisted of a Mediterranean-type diet in which no more than 10% energy was from saturated and trans-unsaturated fatty acids; cholesterol intake was no more than 250 mg/day; omega-3 fatty acid intake of plant and marine origin was at least 4 g/day, and the ratio of omega-6 fatty acids to omega-3 fatty acids was less than 4; and intake of fruits, vegetables and soluble fiber was increased.
  • Subjects were then also allocated to receive 20 mg/day simvastatin or placebo for 12 weeks in a double-blind, crossover fashion. Subjects in the dietary treatment group and the simvastatin group had significant reductions in apo-B levels. The interaction between the two variables was reported as significant. JuIa et al., JAMA 287(5): 598-605 (2002).
  • U.S. Patent Application Publication No. 2003/0170643 embodiments a method of treating a patient, by administering a therapeutic which lowers plasma concentrations of apo-B and/or an apo-B-containing lipoprotein and/or a component of an atherogenic lipoprotein by stimulating post-ER pre-secretory proteolysis (PERPP).
  • PERPP post-ER pre-secretory proteolysis
  • RPP/225510.1 13 with hypercholesterolemia Patients having baseline triglyceride levels of 1.66 mmol/l (about 146 mg/dl) were treated with 6 g/day Omacor ® for 6 weeks, followed by 40 mg/day lovastatin for an additional 6 weeks, and a combination of both Omacor ® and lovastatin for a final 6 weeks.
  • Lovastatin monotherapy resulted in significant increases in HDL-C levels, and significant decreases in triglyceride and LDL-C levels. After combination treatment, triglyceride and LDL- C levels were further significantly decreased.
  • atorvastatin treatment was supplemented with 2 g/day Omacor ® or placebo.
  • Atorvastatin monotherapy significantly increased HDL-C levels, and triglyceride, LDL-C and apo-B levels significantly decreased, as compared to baseline.
  • Combination treatment further increased HDL-C levels, as compared to atorvastatin alone.
  • Triglyceride, LDL-C and apo-B levels numerically further declined slightly with combination treatment, as compared to atorvastatin monotherapy; however, the decrease was not significant. Nordoy et al., Nutr. Metab. Cardiovasc. Dis. (2001 ) 11 :7-16.
  • Nordoy et al. investigated the effectiveness of combination treatment of 40 mg/day lovastatin and 6 g/day Omacor ® (identified as "K-85") in patients with familial hypercholesterolemia, but who were without cardiovascular disease.
  • the study included three intervention periods, each 6 weeks long, interrupted by washout periods of 6 weeks. The final test was carried out 12 weeks after the last intervention.
  • Apo-B levels numerically reduced slightly with omega-3 fatty acid monotherapy, and were significantly reduced with lovastatin monotherapy.
  • the combination treatment also significantly reduced apo-B levels, as compared to baseline. However, the reduction was not indicated as being significant as compared to lovastatin monotherapy.
  • RPP/225510.1 15 nyperlipidemia Patients having baseline triglyceride levels of 2.76 mmol/l (about 243 mg/dl) or 3.03 mmol/l (about 266 mg/dl) were treated for 5 weeks with 20 mg/day simvastatin or placebo, then all patients were treated for an additional 5 weeks with 20 mg/day simvastatin. Thereafter, patients were additionally treated with 4 g/day Omacor ® or placebo, for a further 5 weeks.
  • the administration of omega-3 fatty acids with simvastatin resulted in moderate reductions in serum total cholesterol and reduction in triglycerol levels, and a small numerical x decrease in apo-B levels. However, the effect attributable to the omega-3 fatty acids was not significant. Nordoy et a/., J. of Internal Medicine, 243:163-170 (1998).
  • Durrington et a/ examined the effectiveness, safety, and tolerability of a combination of Omacor ® omega-3 acids and simvastatin in patients with established coronary heart disease and persisting hypertriglyceridemia.
  • Patients having an average baseline triglyceride levels >2.3 mmol/l average patient serum triglyceride level was 4.6 mmol/l
  • Combination treatment significantly decreased triglyceride levels within 12 weeks, as compared to baseline monotherapy.
  • VLDL cholesterol levels in these patients decreased by 30-40%.
  • Some embodiments of the present invention provide for a method of utilizing a combination of a dyslipidemic agent and omega-3 fatty acids for the reduction of apo-B levels, which is suitable for the treatment of one or more of the following: hypercholesterolemia, hypertriglyceridemia, mixed dyslipidemia, coronary heart disease, vascular disease, atherosclerotic disease and related conditions, and/or for the prevention or reduction of cardiovascular and vascular events.
  • Some embodiments according to the present invention include a method of blood lipid therapy in a subject comprising administering to the subject an effective amount of a dyslipidemic agent and an omega-3 fatty acid, wherein an apo-B level in the subject is reduced as compared to treatment with the dyslipidemic agent alone.
  • the present invention includes methods of reducing an apo-B level in a subject group, comprising providing a subject group, and reducing the apo-B level of the subject group by administering to the subject group a combination of a dyslipidemic agent and omega-3 fatty acids in an amount effective to reduce the apo-B level of the subject group as compared to treatment with a dyslipidemic agent alone.
  • the subject group has at least one of the following conditions: hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, vascular disease, and/or atherosclerotic disease and related conditions.
  • the dyslipidemic agent and the omega-3 fatty acid are administered as a single pharmaceutical composition as a combination product, for example, a unit dosage, comprising the dyslipidemic agent and the omega-3 fatty acids.
  • the pharmaceutical composition(s) comprise LovazaTM omega-3 fatty acids, as described in U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,594.
  • the pharmaceutical composition(s) comprise omega-3 fatty acids present in a concentration of at least 40% by weight as compared to the total fatty acid content of the composition(s).
  • omega-3 fatty acids comprise at least 50% by weight of EPA and DHA as compared to the total fatty acid content of the composition, and the EPA and DHA are in a weight ratio of EPA:DHA of from 99:1 to 1:99, preferably from 1 :2 to 2:1.
  • the dyslipidemic agent is a statin including, but not limited to, pitavastatin, simvastatin, rosuvastatin, pravastatin, atorvastatin, lovastatin and fluvastatin.
  • the statin used in combination with omega-3 fatty acids is simvastatin.
  • the combination product is used in the treatment of subjects with primary hypertriglyceridemia or hypercholesterolemia or mixed dyslipidemia.
  • the triglyceride levels in the serum of the subject (or the subject group) prior to the first administration of a combination of a dyslipidemic agent and omega-3 fatty acids, i.e., at baseline, is about 200 to about 499 mg/dl.
  • the invention also includes the use of an effective amount of a dyslipidemic agent and omega-3 fatty acids for the manufacture of a medicament useful for any of the treatment methods indicated herein.
  • the present invention is directed to the utilization of dyslipidemic agents and omega-3 fatty acids for reduction of apo-B levels beyond that which is obtained with treatment of the dyslipidemic agent alone.
  • the methods of the present invention are especially useful for the treatment of primary
  • a subject has baseline apo-B levels of greater than 0.9 g/l, and the use of the invention reduces the apo-B levels to less than 0.9 g/l.
  • a subject has non-HDL-C levels of at least 130 mg/dl, more preferably at least 160 mg/dl, and the use of the invention reduces the apo-B levels, preferably by at least 2% as compared to baseline and/or further than treatment with a dyslipidemic agent alone.
  • a subject has elevated LDL-C levels (e.g., at least 100 mg/dl, at least 100 mg/dl and less than 130 mg/dl, at least 130 mg/dl, or at least 160 mg/dl) and/or elevated triglyceride levels (e.g., at least 150 mg/dl, at least 200 mg/dl, 200-499 mg/dl, or at least 500 mg/dl) and, if both, can be qualified as a subject with mixed dyslipidemia.
  • LDL-C levels e.g., at least 100 mg/dl, at least 100 mg/dl and less than 130 mg/dl, at least 130 mg/dl, or at least 160 mg/dl
  • elevated triglyceride levels e.g., at least 150 mg/dl, at least 200 mg/dl, 200-499 mg/dl, or at least 500 mg/dl
  • the invention provides a novel combination.
  • the combination comprises omega-3 fatty acids and a dyslipidemic agent, wherein the omega-3 fatty acids are administered simultaneous to administration of the dyslipidemic agent, e.g., as a single fixed dosage pharmaceutical composition or as separate compositions administered at the same time.
  • the administration comprises omega-3 fatty acids and a dyslipidemic agent, wherein the omega-3 fatty acids are administered apart from the administration of the dyslipidemic agent, but in a
  • the dyslipidemic agent may be administered once daily and the omega-3 fatty acids may be administered twice daily.
  • the precise dosage and schedule for the administration of the omega-3 fatty acids and the dyslipidemic agent will vary depending on numerous factors, such as, for example, the route of administration, the seriousness of the condition, other comorbidities, and the use of other medications.
  • the claimed method of administration is a first- line therapy, meaning that it is the first type of therapy given for the condition or disease.
  • the claimed method of administration is a second-line therapy, meaning that the treatment is given when initial treatment (first-line therapy, e.g., dyslipidemic agent or omega-3 fatty acid treatment alone) does not work adequately with respect to treatment goals, or ceases to be adequate, e.g. due to physiological changes in the patient or changes in CHD risk factors.
  • first-line therapy e.g., dyslipidemic agent or omega-3 fatty acid treatment alone
  • the invention is suitable for primary prevention. In other embodiments, the invention is suitable for secondary prevention. [00059] In preferred embodiments, the selected subject group was receiving dyslipidemic agent therapy prior to the combination therapy of the dyslipidemic agent and the omega-3 fatty acids. Other active agents (other than omega-3 fatty acids) may also have been employed prior to the combination therapy of the dyslipidemic agent and the omega-3 fatty acids.
  • the present invention includes a method of blood lipid therapy in a subject group comprising administering to the subject group an effective amount of a dyslipidemic agent and omega-3 fatty acids, and wherein after administration to the subject group the triglyceride level and an apo-B level of the subject group are reduced as compared to a control group treated with the dyslipidemic agent alone, and an HDL-C level of the subject group is increased as compared to a control group treated with the dyslipidemic agent alone and/or as compared to baseline.
  • the subject group preferably has a baseline triglyceride level of 200 to 499 mg/dl.
  • the present invention includes a method of blood lipid therapy in a subject group comprising administering to the subject group an effective amount of a dyslipidemic agent and omega-3 fatty acids, and wherein after administration to the subject group the triglyceride level and an apo-B level of the subject group are reduced as compared to a control group treated with the dyslipidemic agent alone, without increasing LDL-C more than 1% as compared to baseline.
  • the subject group preferably has a triglyceride level of 200 to 499 mg/dl.
  • the present invention includes a method of blood lipid therapy in a subject group, comprising administering to the subject group an effective amount of a dyslipidemic agent and omega-3 fatty acids, wherein after administration to the subject group a non-HDL-C level, a total cholesterol level, a triglyceride level, and an apo-B level of the subject group is reduced as compared to a control group treated with the dyslipidemic agent
  • the present invention includes a method of blood lipid therapy in a subject group comprising administering to the subject group an effective amount of a dyslipidemic agent and omega-3 fatty acids, and wherein after administration to the subject group a non-HDL-C level of the subject group is reduced as compared to a control group treated with the dyslipidemic agent alone.
  • the subject group preferably has a baseline triglyceride level of 200 to 499 mg/dl.
  • the invention includes a method of reducing a triglyceride level and an apo-B level in a subject group without increasing an LDL-C level in the subject group, comprising providing a subject group, and reducing the triglyceride level and the apo-B level of the subject group by administering to the subject group a combination of a dyslipidemic agent and omega-3 fatty acids in an amount effective to reduce the triglyceride level and the apo-B level of the subject group as compared to treatment with an HMG-CoA reductase inhibitor alone without increasing the LDL-C level.
  • the phrase "compared to treatment with dyslipidemic agent alone” can refer to treatment of the same subject or subject group, or treatment of a comparable subject or subject group (i.e., subject(s) within the same class with respect to a particular blood protein or lipid, such as a cholesterol or triglyceride level) in a different treatment group.
  • a comparable subject or subject group i.e., subject(s) within the same class with respect to a particular blood protein or lipid, such as a cholesterol or triglyceride level
  • the dyslipidemic agent alone statistically significantly reduces or increases certain levels (such as reducing apo-B levels), and the combination therapy of the dyslipidemic agent and the omega-3 fatty acids further statistically significantly reduces or increases the levels.
  • the methods and compositions of the invention may also be used to reduce any of the following lipid levels in a treated subject or subject group, as compared to treatment with the dyslipidemic agent alone: non-HDL-C levels, triglyceride levels, VLDL-C levels, total C levels, RLP-C levels, Lp-PLA2 levels and/or Apo-C3 levels.
  • the methods and compositions of the invention may also be used to increase HDL-C levels, as compared to treatment with the dyslipidemic agent alone.
  • the methods and compositions of the invention are utilized without increasing LDL-C levels, as compared to baseline.
  • non-HDL-C levels may be reduced at least about 5%, preferably at least about 7%, from baseline and/or at least about 5%, preferably at least about 7%, further than treatment with the dyslipidemic agent alone.
  • the triglyceride levels may be reduced by at least about 20%, preferably at least about 25%, as compared to baseline and/or at least
  • RPP/225510.1 24 about 10%, preferably at least about 15%, more preferably at least about 20%, further than treatment with the dyslipidemic agent alone.
  • the VLDL-C levels may be reduced by at least about 15%, preferably at least about 20%, more preferably at least about 25%, as compared to baseline and/or at least about 10%, preferably at least about 15%, more preferably at least about 20%, further than treatment with the dyslipidemic agent alone.
  • the total C levels may be reduced by at least about 3%, preferably at least about 5%, as compared to baseline and/or at least about 2%, preferably at least about 3%, further than treatment with the dyslipidemic agent alone.
  • the RLP-C levels may be reduced by at least about 15%, preferably at least about 20%, more preferably at least about 25%, as compared to baseline and/or at least about 10%, preferably at least about 15%, more preferably at least about 20%, further than treatment with the dyslipidemic agent alone.
  • the Lp-PLA2 levels may be reduced by at least about 5%, preferably at least about 7%, more preferably at least about 10%, as compared to baseline and/or at least about 3%, preferably at least about 5%, more preferably at least about 7%, further than treatment with the dyslipidemic agent alone.
  • the apo-B levels may be reduced by at least about 3%, preferably at least about 4%, as compared to baseline and/or at least about 1%,
  • RPP/225510.1 25 preferably at least about 2%, further than treatment with the dyslipidemic agent alone.
  • the Apo-C3 levels may be reduced by at least about 5%, preferably at least about 7%, as compared to baseline and/or at least about 8%, preferably at least about 10%, further than treatment with the dyslipidemic agent alone.
  • the HDL-C levels may be increased by at least about 2%, preferably at least about 3%, as compared to baseline and/or at least about 3%, preferably at least about 5%, further than treatment with the dyslipidemic agent alone.
  • the present invention also decreases the ratio of total cholesterol to HDL-C, preferably by at least about 5%, more preferably at least about 10%, as compared to baseline and/or at least about 5%, preferably at least about 10%, further than treatment with the dyslipidemic agent alone.
  • dyslipidemic agents include HMG CoA reductase inhibitors including statins, cholesterol absorption inhibitors such as but not limited to ezetimibe, niacin and derivatives such as nicotinamide, CETP inhibitors such as but not limited to torcetrapib, fibrates such as but not limited to fenofibrate, bezafibrate, clofibrate and gemfibrozil, bile acid sequestrants such as but not limited to cholestyramine, cholestipol and colesevelam, MTP inhibitors such as but not limited to those disclosed in WO 00/38725 and Science, 282, 23 October 1998, pp. 751-754,
  • LXR agonists and/or antagonists such as but not limited to PPAR-alpha, PPAR-gamma, PPAR-delta, PPAR-alpha/gamma, PPAR-gamma/delta, PPAR-alpha/delta, and PPAR-alpha/gamma/delta agonists, antagonists and partial agonists and/or antagonists) such as but not limited to the thiazolidinediones, the non- thiazolidinediones and metaglidasen.
  • statins There are currently six statins that are widely available: atorvastatin, rosuvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin.
  • a seventh statin, pitavastatin, is in clinical trials.
  • An eighth statin, cerivastatin has been removed from the U.S. market at the time of this writing.
  • cerivastatin may be used in conjunction with some embodiments of the present invention if cerivastatin is ultimately determined to be safe and effective.
  • the effect of the dyslipidemic agent is dose dependent, i.e., the higher the dose, the greater the therapeutic affect.
  • omega-3 fatty acids includes natural or synthetic omega-3 fatty acids, or pharmaceutically acceptable esters, derivatives, conjugates (see, e.g., Zaloga et al., U.S. Patent Application Publication No. 2004/0254357, and Horrobin et al., U.S. Patent No. 6,245,811 , each hereby
  • omega-3 fatty acid oils include but are not limited to omega-3 polyunsaturated, long-chain fatty acids such as a eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and ⁇ -linolenic acid; esters of omega-3 fatty acids with glycerol such as mono-, di- and triglycerides; and esters of the omega-3 fatty acids and a primary, secondary or tertiary alcohol such as fatty acid methyl esters and fatty acid ethyl esters.
  • omega-3 polyunsaturated, long-chain fatty acids such as a eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and ⁇ -linolenic acid
  • esters of omega-3 fatty acids with glycerol such as mono-, di- and triglycerides
  • omega-3 fatty acid oils are long- chain fatty acids such as EPA or DHA, triglycerides thereof, ethyl esters thereof and mixtures thereof.
  • the omega-3 fatty acids or their esters, derivatives, conjugates, precursors, salts and mixtures thereof can be used either in their pure form or as a component of an oil such as fish oil, preferably purified fish oil concentrates.
  • omega-3 fatty acids suitable for use in the invention include lncromega F2250, F2628, E2251 , F2573, TG2162, TG2779, TG2928, TG3525 and E5015 (Croda International PLC, Oxford, England), and EPAX6000FA, EPAX5000TG, EPAX4510TG, EPAX2050TG, K85TG, K85EE, K80EE and EPAX7010EE (Pronova Biocare a.s., 1327 Lysaker, Norway).
  • compositions include omega-3 fatty acids as recited in U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,694, which are hereby incorporated herein by reference in their entireties.
  • Another preferred composition includes omega-3 fatty acids present in a concentration of at least 40% by weight, preferably at least 50% by weight, more preferably at least 60% by weight, still more preferably at least 70% by
  • the omega-3 fatty acids comprise at least 50% by weight of EPA and DHA, more preferably at least 60% by weight, still more preferably at least 70% by weight, most preferably at least 80%, such as about 84% by weight.
  • the omega-3 fatty acids comprise about 5 to about 100% by weight, more preferably about 25 to about 75% by weight, still more preferably about 40 to about 55% by weight, and most preferably about 46% by weight of EPA.
  • the omega-3 fatty acids comprise about 5 to about 100% by weight, more preferably about 25 to about 75% by weight, still more preferably about 30 to about 60% by weight, and most preferably about 38% by weight of DHA. All percentages above are by weight as compared to the total fatty acid content in the composition, unless otherwise indicated. The percentage by weight may be based on the free acid or ester forms, although it is preferably based on the ethyl ester form of the omega-3 fatty acids even if other forms are utilized in accordance with the present invention.
  • the EPA:DHA ratio may be from 99:1 to 1 :99, preferably 4:1 to 1 :4, more preferably 3:1 to 1 :3, most preferably 2:1 to 1 :2.
  • the omega-3 fatty acids may comprise pure EPA or pure DHA.
  • the omega-3 fatty acid composition optionally includes chemical antioxidants, such as alpha tocopherol, oils, such as soybean oil and partially hydrogenated vegetable oil, and lubricants such as fractionated coconut oil, lecithin and a mixture of the same.
  • chemical antioxidants such as alpha tocopherol, oils, such as soybean oil and partially hydrogenated vegetable oil
  • lubricants such as fractionated coconut oil, lecithin and a mixture of the same.
  • omega-3 fatty acids The most preferred form of omega-3 fatty acids is the LovazaTM omega-3 acid (K85EE, Pronova Biocare A.S., Lysaker, Norway) and preferably comprises the following characteristics (per dosage form):
  • the combination product of a dyslipidemic agent and concentrated omega-3 fatty acids may be administered in a capsule, a tablet, a powder that can be dispersed in a beverage, or another solid oral dosage form, a liquid, a soft gel capsule, a coated soft gel capsule (see U.S. Application Serial No. 11/716,020, hereby incorporated by reference) or other convenient dosage form such as oral liquid in a capsule, as known in the art.
  • the capsule comprises a hard gelatin.
  • the combination product may also be contained in a liquid suitable for injection or infusion.
  • the active ingredients of the present invention may also be administered with a combination of one or more non-active pharmaceutical ingredients (also known generally herein as "excipients").
  • Non-active ingredients serve to solubilize, suspend, thicken, dilute, emulsify, stabilize, preserve, protect, color, flavor, and fashion the
  • Excipients include surfactants, such as propylene glycol monocaprylate, mixtures of glycerol and polyethylene glycol esters of long fatty acids, polyethoxylated castor oils, glycerol esters, oleoyl macrogol glycerides, propylene glycol monolaurate, propylene glycol dicaprylate/dicaprate, polyethylene-polypropylene glycol copolymer, and polyoxyethylene sorbitan monooleate, cosolvents such ethanol, glycerol, polyethylene glycol, and propylene glycol, and oils such as coconut, olive or safflower oils.
  • surfactants, cosolvents, oils or combinations thereof is generally known in the pharmaceutical arts, and as would be understood to one skilled in the art, any suitable surfactant may be used in conjunction with the present invention and embodiments thereof.
  • the concentrated omega-3 fatty acids can be administered in a daily amount of from about 0.1 g to about 10 g, more preferably about 1 g to about 8 g, and most preferably from about 2 g to about 6 g. In one embodiment, the omega-3 fatty acids are administered in an amount up to 4 g/day.
  • the dyslipidemic agent may be administered in an amount more than, equal to or less than the conventional full-strength dose as a single-administered product. For example, the dyslipidemic agent may be administered in an amount of from 10-100%, preferably about 25-100%, most preferably about 50-80%, of the conventional full-strength dose as a single-administered product. In one embodiment of the present invention, the dyslipidemic agent is a HMG-CoA
  • RPP/225510.1 31 reductase inhibitor, or statin which can generally be present in an amount from about 0.5 mg to 80 mg, more preferably from about 1 mg to about 40 mg, and most preferably from about 5 mg to about 20 mg, per gram of omega-3 fatty acid.
  • the daily dose may range from about 2 mg to about 320 mg, preferably about 4 mg to about 160 mg.
  • the combination of dyslipidemic agent and the omega-3 fatty acids is formulated into a single administration or unit dosage.
  • the dyslipidemic agent is a statin selected from the following group: pitavastatin, atorvastatin, rosuvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin.
  • Pravastatin which is known in the market as Pravachol ® manufactured by Bristol-Myers Squibb, Princeton, NJ, is hydrophilic. Pravastatin is best absorbed without food, i.e., an empty stomach.
  • the dosage of pravastatin, in the combined administration of concentrated omega-3 fatty acids is preferably from 2.5 to 80 mg, preferably 5 to 60, and more preferably from 10 to 40 mg per dosage of concentrated omega-3 fatty acids.
  • the combination product using pravastatin is taken at or around bedtime, e.g., 10 pm.
  • Lovastatin which is marketed under the name Mevacor ® by Merck, Whitehouse Station, NJ, is hydrophobic. Unlike pravastatin, lovastatin should be taken with meals and accordingly, in some embodiments, the combination product of concentrated omega-3 fatty acids and lovastatin should be taken with food.
  • the dosage of lovastatin, in the combined administration of concentrated omega-3 fatty acids is preferably from 2.5 to 100 mg, preferably 5 to 80 mg, and
  • RPP/225510.1 32 more preferably from 10 to 40 mg per dosage of concentrated omega-3 fatty acids.
  • the dosage of simvastatin, in the combined administration of concentrated omega-3 fatty acids is preferably from
  • Atorvastatin which is marketed under the name Lipitor ® by Pfizer, New
  • the dosage of atorvastatin, in the combined administration of concentrated omega-3 fatty acids is preferably from 2.5 to 100 mg, preferably 5 to 80 mg, and more preferably from 10 to 40 mg per dosage of concentrated omega-3 fatty acids.
  • Fluvastatin which is marketed under the name Lescol ® by Novartis,
  • the dosage of fluvastatin, in the combined administration of concentrated omega-3 fatty acids is from 5 to 160 mg, preferably 10 to 120 mg, and more preferably from 20 to 80 mg per dosage of concentrated omega-3 fatty acids.
  • Rosuvastatin is marketed under the name Crestor ® by Astra Zeneca,
  • the dosage of rosuvastatin, in the combined administration of concentrated omega-3 fatty acids is from 1 to 80 mg, preferably 2 to 60 mg, and more preferably from 5 to 40 mg per dosage of concentrated omega-3 fatty acids.
  • the daily dosages of dyslipidemic agent and concentrated omega-3 fatty acids can be administered together in from 1 to 10 dosages, with the preferred number of dosages from 1 to 4 times a day, most preferred 1 to 2 times a day.
  • the administration is preferably oral administration, although other forms of administration that provides a unit dosage of dyslipidemic agent and concentrated omega-3 fatty acids may be used.
  • the formulations of the present invention allow for improved effectiveness of each active ingredient, with one or both administered as a conventional full-strength dose, as compared to the formulations in the prior art.
  • the formulations of the present invention may allow for reduced dosages of dyslipidemic agent and/or omega-3 fatty acids, as compared to the formulations in the prior art, while still maintaining or even improving upon the effectiveness of each active ingredient.
  • the present combination of a dyslipidemic agent and concentrated omega-3 fatty acids may allow for a greater effect than any expected combined or additive effect of the two drugs alone.
  • the combined or additive effect of the two drugs may depend on the initial level of triglycerides in the blood of a subject.
  • the triglyceride level of a subject is generally as normal if less than 150 mg/dL, borderline to high if within about 150-199 mg/dL, high if within about 200-499 mg/dL and very high if 500 mg/dL or higher.
  • the present invention may be used to reduce the triglyceride level of a "very high" down to a "high” or "borderline to high” in less than 48 weeks, preferably within 24 weeks, more preferably within 12 weeks, and most preferably within 8 weeks.
  • the present invention may also be used to reduce the triglyceride level of a "high” down to a "borderline to high" or "normal” in less than 48 weeks, preferably within 24 weeks, more preferably within 12 weeks, and most preferably within 8 weeks.
  • Tables 4A, 4B and 5 show the apo-B reduction and other lipid parameter changes with LovazaTM or placebo treatment for specific LDL-C and Non-HDL-C patient subgroups.
  • LovazaTM reduces apo-B while at lower baseline levels, apo-B changes by LovazaTM versus placebo are insignificant.
  • Table 4B shows that the Apo-B reducing effect is even more profound at higher LDL-C baseline levels, and seems to be accompanied by a reduction in LDL-C levels.
  • Table 6 shows the apo-B reduction and other lipid parameter changes with LovazaTM or placebo treatment for above 200 mg/dL triglyceride baseline levels versus below this level. At higher triglyceride baseline levels ( ⁇ 00 mg/dL), LovazaTM reduces apo-B while at lower baseline triglyceride levels, Apo- B changes by LovazaTM versus placebo are insignificant.
  • Triglycerides (mg/dL) * 186.2 -25.2 189.1 4.6 0.0183
  • Non-HDL-C (mg/dL) 137.7 -9.3 141.7 -1.9 ⁇ 0.0001
  • Triglycerides (mg/dL) 272.3 -30.2 274.7 -6.3 ⁇ 0.0001
  • VLDL-C (mg/dL) 53.0 -27.8 53.7 -7.2 ⁇ 0.0001
  • Tables 7 and 8 show the apo-B reduction and other lipid parameter changes with LovazaTM or placebo treatment for specific LDL-C/Triglyceride and Non-HDL-C/Triglyceride patient subgroups.
  • LovazaTM reduces apo-B while at lower baseline levels, apo-B changes by LovazaTM versus placebo are insignificant.

Abstract

L'invention concerne des procédés d'utilisation d'une administration combinée ou d'une unité posologique d'une combinaison d'un agent dyslipidémique et d'acides gras oméga-3 pour la réduction des niveaux d'apolipoprotéine B. Les procédés sont particulièrement utiles pour le traitement de patients présentant une hypertriglycéridémie ou une hypercholestérolémie ou une dyslipidémie mixte, une coronaropathie (CHD), une maladie vasculaire, une maladie athérosclérotique ou des troubles associés, et pour la prévention ou la réduction des événements cardiovasculaires, cardiaques et vasculaires.
PCT/US2007/021631 2006-10-10 2007-10-10 Acides gras oméga-3 et agent dyslipidémique pour la réduction des niveaux d'apo-b WO2008045465A1 (fr)

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MX2009003921A MX2009003921A (es) 2006-10-10 2007-10-10 Acidos grasos omega-3 y agente dislipidemico para la reduccion de los niveles de apo-b.
EP07852630A EP2089014A4 (fr) 2006-10-10 2007-10-10 Acides gras oméga-3 et agent dyslipidémique pour la réduction des niveaux d'apo-b
AU2007307007A AU2007307007A1 (en) 2006-10-10 2007-10-10 Omega-3 fatty acids and dyslipidemic agent for reduction of apo-B levels
EA200970360A EA200970360A1 (ru) 2006-10-10 2007-10-10 Омега-3 жирные кислоты и средство для лечения дислипидемии для снижения уровней аро-в
CA002672919A CA2672919A1 (fr) 2006-10-10 2007-10-10 Acides gras omega-3 et agent dyslipidemique pour la reduction des niveaux d'apo-b
JP2009532391A JP2010505956A (ja) 2006-10-10 2007-10-10 Ａｐｏ−ｂレベル低下のためのオメガ−３脂肪酸および脂質異常症剤
BRPI0719182-0A2A BRPI0719182A2 (pt) 2006-10-10 2007-10-10 Ácidos graxos omega 3 e agente dislipidêmico para redução de níveis de apo-b

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2083622A1 (fr) * 2006-10-18 2009-08-05 Reliant Pharmaceuticals, Inc. Procédés d'utilisation d'acides gras oméga-3 pour réduire les taux de lp-pla2
WO2010147994A1 (fr) 2009-06-15 2010-12-23 Amarin Pharma, Inc. Compositions et procédés pour abaisser les triglycérides sans élever les taux de ldl-c chez un sujet soumis à une thérapie concomitante aux statines
US8431560B1 (en) 2009-02-10 2013-04-30 Amarin Pharmaceuticals Ireland Limited Methods of treating hypertriglyceridemia
US8563608B2 (en) 2009-04-29 2013-10-22 Amarin Pharmaceuticals Ireland Limited Methods for lowering triglycerides without raising LDL-C levels in a subject on concomitant statin therapy
US8617593B2 (en) 2009-04-29 2013-12-31 Amarin Pharmaceuticals Ireland Limited Stable pharmaceutical composition and methods of using same
US8784886B2 (en) 2006-03-09 2014-07-22 GlaxoSmithKline, LLC Coating capsules with active pharmaceutical ingredients
US9283201B2 (en) 2013-03-14 2016-03-15 Amarin Pharmaceuticals Ireland Limited Compositions and methods for treating or preventing obesity in a subject in need thereof
US9452151B2 (en) 2013-02-06 2016-09-27 Amarin Pharmaceuticals Ireland Limited Methods of reducing apolipoprotein C-III
US9585859B2 (en) 2013-10-10 2017-03-07 Amarin Pharmaceuticals Ireland Limited Compositions and methods for lowering triglycerides without raising LDL-C levels in a subject on concomitant statin therapy
US9603826B2 (en) 2012-06-29 2017-03-28 Amarin Pharmaceuticals Ireland Limited Methods of reducing the risk of a cardiovascular event in a subject on statin therapy
US9624492B2 (en) 2013-02-13 2017-04-18 Amarin Pharmaceuticals Ireland Limited Compositions comprising eicosapentaenoic acid and mipomersen and methods of use thereof
US9662307B2 (en) 2013-02-19 2017-05-30 The Regents Of The University Of Colorado Compositions comprising eicosapentaenoic acid and a hydroxyl compound and methods of use thereof
US9814733B2 (en) 2012-12-31 2017-11-14 A,arin Pharmaceuticals Ireland Limited Compositions comprising EPA and obeticholic acid and methods of use thereof
US9827219B2 (en) 2012-01-06 2017-11-28 Amarin Pharmaceuticals Ireland Limited Compositions and methods for lowering levels of high-sensitivity C-reactive protein (HS-CRP) in a subject
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US10314803B2 (en) 2008-09-02 2019-06-11 Amarin Pharmaceuticals Ireland Limited Pharmaceutical composition comprising eicosapentaenoic acid and nicotinic acid and methods of using same
US10406130B2 (en) 2016-03-15 2019-09-10 Amarin Pharmaceuticals Ireland Limited Methods of reducing or preventing oxidation of small dense LDL or membrane polyunsaturated fatty acids
US10493058B2 (en) 2009-09-23 2019-12-03 Amarin Pharmaceuticals Ireland Limited Pharmaceutical composition comprising omega-3 fatty acid and hydroxy-derivative of a statin and methods of using same
US10537544B2 (en) 2011-11-07 2020-01-21 Amarin Pharmaceuticals Ireland Limited Methods of treating hypertriglyceridemia
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US11058661B2 (en) 2018-03-02 2021-07-13 Amarin Pharmaceuticals Ireland Limited Compositions and methods for lowering triglycerides in a subject on concomitant statin therapy and having hsCRP levels of at least about 2 mg/L
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US11179362B2 (en) 2012-11-06 2021-11-23 Amarin Pharmaceuticals Ireland Limited Compositions and methods for lowering triglycerides without raising LDL-C levels in a subject on concomitant statin therapy
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US11547710B2 (en) 2013-03-15 2023-01-10 Amarin Pharmaceuticals Ireland Limited Pharmaceutical composition comprising eicosapentaenoic acid and derivatives thereof and a statin
US11712428B2 (en) 2010-11-29 2023-08-01 Amarin Pharmaceuticals Ireland Limited Low eructation composition and methods for treating and/or preventing cardiovascular disease in a subject with fish allergy/hypersensitivity
US11712429B2 (en) 2010-11-29 2023-08-01 Amarin Pharmaceuticals Ireland Limited Low eructation composition and methods for treating and/or preventing cardiovascular disease in a subject with fish allergy/hypersensitivity

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102824636A (zh) * 2012-08-15 2012-12-19 四川大学 一种含他汀类药物和多不饱和脂肪酸的药物组合物及其用途
JP6227535B2 (ja) * 2012-08-30 2017-11-08 株式会社三和化学研究所 脂質異常症の予防又は治療薬
CN106232121A (zh) * 2014-02-05 2016-12-14 田边三菱制药株式会社 用于治疗或预防心血管疾病的胆固醇酯转移蛋白(cetp)抑制剂和含所述抑制剂的药物组合物

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060211762A1 (en) * 2004-12-06 2006-09-21 Rongen Roelof M Omega-3 fatty acids and dyslipidemic agent for lipid therapy

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030170643A1 (en) * 1999-10-26 2003-09-11 Edward Fisher Regulation of apoB treatment and drug screening for cardiovascular and metabolic disorders or syndromes
MX2008000915A (es) * 2005-07-18 2008-04-04 Reliant Pharmaceuticals Inc Tratamiento con inhibidores de absorcion de colesterol basados en azetidinona y acidos grasos omega-3 y un producto de combinacion de los mismos.

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060211762A1 (en) * 2004-12-06 2006-09-21 Rongen Roelof M Omega-3 fatty acids and dyslipidemic agent for lipid therapy

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CONTACOS ET AL.: "Effect of pravastatin and omega-3 fatty acids on plasma lipids and lipoprotein in patients with combined hyperlipidemia", ARTERIOSCLER. THROMB. VASC. BIOL., vol. 13, 1996, pages 1755 - 1762, XP009016030 *
See also references of EP2089014A4 *

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US8784886B2 (en) 2006-03-09 2014-07-22 GlaxoSmithKline, LLC Coating capsules with active pharmaceutical ingredients
EP2083622A4 (fr) * 2006-10-18 2009-12-09 Reliant Pharmaceuticals Inc Procédés d'utilisation d'acides gras oméga-3 pour réduire les taux de lp-pla2
EP2083622A1 (fr) * 2006-10-18 2009-08-05 Reliant Pharmaceuticals, Inc. Procédés d'utilisation d'acides gras oméga-3 pour réduire les taux de lp-pla2
US10314803B2 (en) 2008-09-02 2019-06-11 Amarin Pharmaceuticals Ireland Limited Pharmaceutical composition comprising eicosapentaenoic acid and nicotinic acid and methods of using same
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WO2010147994A1 (fr) 2009-06-15 2010-12-23 Amarin Pharma, Inc. Compositions et procédés pour abaisser les triglycérides sans élever les taux de ldl-c chez un sujet soumis à une thérapie concomitante aux statines
US11439618B2 (en) 2009-06-15 2022-09-13 Amarin Pharmaceuticals Ireland Limited Compositions and methods for lowering triglycerides
EP3318255B1 (fr) 2009-06-15 2021-03-10 Amarin Pharmaceuticals Ireland Limited Compositions et procédés pour le traitement de l'accident vasculaire cérébral chez un sujet suivant une thérapie concomitante aux statines
EP3318255A1 (fr) * 2009-06-15 2018-05-09 Amarin Pharmaceuticals Ireland Limited Compositions et procédés pour abaisser les triglycérides sans élever les taux de ldl-c chez un sujet suivant une thérapie concomitante aux statines
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US11464757B2 (en) 2009-06-15 2022-10-11 Amarin Pharmaceuticals Ireland Limited Compositions and methods for lowering triglycerides
EP2443246A4 (fr) * 2009-06-15 2012-11-28 Amarin Pharma Inc Compositions et procédés pour abaisser les triglycérides sans élever les taux de ldl-c chez un sujet soumis à une thérapie concomitante aux statines
AU2017268633B2 (en) * 2009-06-15 2019-11-14 Amarin Pharmacuticals Ireland Limited Compositions and methods for lowering triglycerides without raising ldl-c levels
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EP3698781A1 (fr) * 2009-06-15 2020-08-26 Amarin Pharmaceuticals Ireland Limited Compositions comprenant de l'acide eicosapentaenoique pour traiter une infarction du myocarde chez un sujet suivant une thérapie concomitante aux statines
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EP2089014A4 (fr) 2009-12-09
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