PHARMACEUTICAL COMPOSITIONS COMPRISING EPA AND A CARDIOVASCULAR AGENT AND METHODS OF USING THE SAME

1 . A pharmaceutical composition comprising EPA and a cardiovascular agent, wherein the composition contains not more than 10% DHA by weight, if any.

2 . The composition of claim 1 wherein the cardiovascular agent is an ACAT inhibitor, an ACE inhibitor, an alpha-blocker, an alpha/beta-blocker, an angiotensin II receptor antagonist, an anti-arrythmic agent, an antiplatelet agent, a beta-blocker, a calcium-channel blocker, an HMG-CoA reductase inhibitor, an apoA-1 mimetic, a CETP inhibitor, a bile acid sequestrant, a cholesterol absorption inhibitor, a diuretic, a dyslipidemia agent, an endothelin receptor antagonist, an LDL receptor inducer, an Lp-PLA2 inhibitor, a squalene epoxidase inhibitor, an LCAT activator, a microsomal triglyceride transfer protein inhibitor, an sPLA2 inhibitor, a 5-lipoxygenase inhibitor, a PPAR agonist/activator, a thrombolytic agent, a thyroid receptor beta activator, a platelet aggregation inhibitor, or an aldosterone antagonist.

3 . The composition of claim 1 wherein the cardiovascular agent is selected from the group including of 5-LO inhibitor 6, A-0002, abciximab, ABT-335, ABT-761, acebutolol, acetohexamide, adenosine, AEGR-733, Aldactone, aleglitezar, aliskiren, aliskiren hemifumarate, alliin, amiodarone, amlodipine, amorolfine, amprenavir, anacetrapib, Angpt14 antibody, Anti-oxLDL, APA-01, apixaban, APL180, APP018, aspirin, atenolol, atorvastatin, AVE5530, AZD-2479, BAY-60-5521, benazepril, BMS-200150, bosentan, butenafine, candesartan, captopril, carvedilol, CER-002, chlorothiazide sodium, chlorpropamide, choline fenofibrate, CI-1011, cilostazol, clevidipine butyrate, clonidine, clopidegrel, CMI 977, colesevelam, colestipol, CP-346086, CP-800569, CRD-5, CS-505, CSL111, dalcetrapib, dalteparin, darapladib, defibrotide, diallyl disulfide, diallyl trisulfide, digoxin, diltiazem, dipyridamole, dirlotapide, disopyramide, doxazosin, enalapril, enaliprilat, enoxaparin, epigallocatechin-3-O-gallate, eplerenone, eprosartan, eprotirome, eptifibatide, an estrogen or an analog thereof, ETC-1001, ETC-216, ETC-588-liposome, ETC-642, ethacrynic acid, ezetimibe, fenofibrate, flecamide, fluvastatin, fondoparinux, fosamprenavir, fosinopril, FR194738, furosemide, gemfibrozil, GFT14, GFT505, glimepiride, glipizide, glyburide, GSK-256073, GW501516, hydrochlorothiazide, implitapide, indapamide, indinavir, irbesartan, isradipine, JTT-130, JTT-705, KD-3010, lactacystin, laropiprant, LCAT enzyme, LCP-AtorFen, lidocaine, lisinopril, lonapalene lopinavir, losartan, lovastatin, LY 333013, MAHDL01, MB07811, MBX-8025, metformin, methyldopa, metoprolol succinate, mexiletine, metoprolol, MK-886, moexipril, nadolol, naftifine, nateglinide, NB-598, NCX6560, Nebivolol, nelfinavir, niacin, niaspan, nicardipine, nimodipine, nisoldipine, olmesartan, orlistat, PCSK9 RNAi, PD-348292, perindopril, PF-3185043, pindolol, pioglitazone, PLX204, pravastatin, prazosin, procainamide, propafenone hydrochloride, propranolol hydrochloride, quinapril, quinidine gluconate, R7232, ramipril, recombinant apoA-1, recombinant LCAT, repaglinide, resveratrol (trans-3,4′,5-trihydroxystilbene), reverse D-4F, rilapladib, ritonavir, rosiglitazone, rosiglitazone maleate, rosuvastatin, RVX-208, RWJ 800025, S-allylcysteine, saquinavir, selenocysteine, sildenafil, simvastatin, SLx-4090, Sobetirome (QRX-431), tadalafil, telmisartan, terazosin, terbinafine, thelin, ticlopidine, tirofiban, tocamide, tolazamide, tolbutamide, torcetrapib, torsemide, trandolapril, TRIA-662, triamterene, trimeric ApoA-1, valsartan, vardenafil, VIA-2291, verapamil, verespladib, volibris, WA8242A, WA8242A 2 , WA8242B, ZD2138, zileuton, or a combination thereof.

4 . The composition of claim 1 further comprising an additional cardiovascular agent.

5 . The composition of claim 4 wherein the additional cardiovascular agent is selected from an ACAT inhibitor, an ACE inhibitor, an alpha-blocker, an alpha/beta-blocker, an angiotensin II receptor antagonist, an anti-arrythmic agent, an antiplatelet agent, a beta-blocker, a calcium-channel blocker, an HMG-CoA reductase inhibitor, an apoA-1 mimetic, a CETP inhibitor, a bile acid sequestrant, a cholesterol absorption inhibitor, a diuretic, a dyslipidemia agent, an endothelin receptor antagonist, an LDL receptor inducer, an Lp-PLA2 inhibitor, a squalene epoxidase inhibitor, an LCAT activator, a microsomal triglyceride transfer protein inhibitor, a PPAR agonist/activator, a thrombolytic agent, a thyroid receptor beta activator, a platelet aggregation inhibitor, or an aldosterone antagonist.

6 . The composition of claim 1 further comprising a pharmaceutically acceptable excipient.

7 . The composition of claim 6 wherein the excipient is selected from a carrier, a diluent, an antioxidant, a flavoring agent, a sweetening agent, a colorant, a suspending agent, or a combination thereof.

8 . The composition of claim 1 wherein the EPA is present in an amount from about 100 mg to about 1500 mg.

9 . The composition of claim 1 wherein the composition contains less than 0.5% DHA or derivative by weight of total fatty acids.

10 . The composition of claim 1 wherein the composition contains substantially no DHA or derivative thereof.

11 . The composition of claim 1 wherein the weight ratio of EPA to other fatty acids is at least about 96:4.

12 . The composition of claim 1 wherein the EPA comprises a C 1 -C 5 alkyl ester.

13 . The composition of claim 12 wherein the C 1 -C 5 alkyl ester comprises EPA ethyl ester.

14 . The composition of claim 1 wherein the composition contains less than 1% of tocopherols by weight, if any.

15 . The composition of claim 1 wherein the composition is in an orally deliverable dosage form.

16 . The composition of claim 15 wherein the dosage form comprises a tablet, caplet, capsule, powder, lozenge, sachet, cachet, troche, pellet, granule, microgranule, encapsulated microgranule, or powder aerosol.

17 . The composition of claim 1 wherein the cardiovascular agent is suspended in the EPA.

18 . The composition of claim 17 wherein the suspension is substantially uniform.

19 . The composition of claim 18 wherein the composition is present in a capsule.

20 . The composition of claim 1 wherein the cardiovascular agent comprises orlistat or metformin.

21 . A method of treating a cardiovascular-related disease comprising administering to a subject in need thereof EPA and a cardiovascular agent.

22 . The method of claim 21 wherein the cardiovascular-related disease is selected from the group consisting of acute cardiac ischemic events, acute myocardial infarction, Alzheimer's disease, angina, angina pectoris, arrhythmia, arterial fibrulation, atherosclerosis, atrial fibrillation, cardiac insufficiency, cardiovascular disease, chronic heart failure, chronic stable angina, congestive heart failure, coronary artery disease, coronary heart disease, deep vein thrombosis, diabetes, diabetes mellitus, diabetic neuropathy, diastolic dysfunction in subjects with diabetes mellitus, edema, essential hypertension, eventual pulmonary embolism, fatty liver disease, heart disease, heart failure, homozygous familial hypercholesterolemia (HoFH), homozygous familial sitosterolemia, hypercholesterolemia, hyperlipidemia, hyperlipidemia in HIV positive subjects, hypertension, hypertriglyceridemia, ischemic complications in unstable angina and myocardial infarction, low blood pressure, metabolic syndrome, mixed dyslipidemia, moderate to mild heart failure, myocardial infarction, obesity management, paroxysmal atrial fibrillation/flutter (PAF), paroxysmal supraventricular tachycardias (PSVT), particularly severe or rapid onset edema, platelet aggregation, primary hypercholesterolemia, primary hyperlipidemia, pulmonary arterial hypertension, pulmonary hypertension, recurrent hemodynamically unstable ventricular tachycardia (VT), recurrent ventricular arrhythmias, recurrent ventricular fibrillation (VF), ruptured aneurysm, sitisterolemia, stroke, supraventricular tachycardia, symptomatic atrial fibrillation/flutter, tachycardia, type-II diabetes, vascular disease, venous thromboembolism, and ventricular arrhythmias.

23 . The method of claim 22 wherein the cardiovascular agent is selected from the group consisting of an ACAT inhibitor, an ACE inhibitor, an alpha-blocker, an alpha/beta-blocker, an angiotensin II receptor antagonist, an anti-arrythmic agent, an antiplatelet agent, a beta-blocker, a calcium-channel blocker, an HMG-CoA reductase inhibitor, an apoA-1 mimetic, a CETP inhibitor, a bile acid sequestrant, a cholesterol absorption inhibitor, a diuretic, a dyslipidemia agent, an endothelin receptor antagonist, an LDL receptor inducer, an Lp-PLA2 inhibitor, a squalene epoxidase inhibitor, an LCAT activator, a microsomal triglyceride transfer protein inhibitor, a PPAR agonist/activator, a thrombolytic agent, a thyroid receptor beta activator, a platelet aggregation inhibitor, or an aldosterone antagonist.

24 . The method of claim 23 wherein the cardiovascular agent is selected from the group consisting of 5-LO inhibitor 6, A-0002, abciximab, ABT-335, ABT-761, acebutolol, acetohexamide, adenosine, AEGR-733, Aldactone, aleglitezar, aliskiren, aliskiren hemifumarate, alliin, amiodarone, amlodipine, amorolfine, amprenavir, anacetrapib, Angpt14 antibody, Anti-oxLDL, APA-01, apixaban, APL180, APP018, aspirin, atenolol, atorvastatin, AVE5530, AZD-2479, BAY-60-5521, benazepril, BMS-200150, bosentan, butenafine, candesartan, captopril, carvedilol, CER-002, chlorothiazide sodium, chlorpropamide, choline fenofibrate, CI-1011, cilostazol, clevidipine butyrate, clonidine, clopidegrel, CMI 977, colesevelam, colestipol, CP-346086, CP-800569, CRD-5, CS-505, CSL111, dalcetrapib, dalteparin, darapladib, defibrotide, diallyl disulfide, diallyl trisulfide, digoxin, diltiazem, dipyridamole, dirlotapide, disopyramide, doxazosin, enalapril, enaliprilat, enoxaparin, epigallocatechin-3-O-gallate, eplerenone, eprosartan, eprotirome, eptifibatide, an estrogen or an analog thereof, ETC-1001, ETC-216, ETC-588-liposome, ETC-642, ethacrynic acid, ezetimibe, fenofibrate, flecamide, fluvastatin, fondoparinux, fosamprenavir, fosinopril, FR194738, furosemide, gemfibrozil, GFT14, GFT505, glimepiride, glipizide, glyburide, GSK-256073, GW501516, hydrochlorothiazide, implitapide, indapamide, indinavir, irbesartan, isradipine, JTT-130, JTT-705, KD-3010, lactacystin, laropiprant, LCAT enzyme, LCP-AtorFen, lidocaine, lisinopril, lonapalene lopinavir, losartan, lovastatin, LY 333013, MAHDL01, MB07811, MBX-8025, metformin, methyldopa, metoprolol succinate, mexiletine, metoprolol, MK-886, moexipril, nadolol, naftifine, nateglinide, NB-598, NCX6560, Nebivolol, nelfinavir, niacin, niaspan, nicardipine, nimodipine, nisoldipine, olmesartan, orlistat, PCSK9 RNAi, PD-348292, perindopril, PF-3185043, pindolol, pioglitazone, PLX204, pravastatin, prazosin, procainamide, propafenone hydrochloride, propranolol hydrochloride, quinapril, quinidine gluconate, R7232, ramipril, recombinant apoA-1, recombinant LCAT, repaglinide, resveratrol (trans-3,4′,5-trihydroxystilbene), reverse D-4F, rilapladib, ritonavir, rosiglitazone, rosiglitazone maleate, rosuvastatin, RVX-208, RWJ 800025, S-allylcysteine, saquinavir, selenocysteine, sildenafil, simvastatin, SLx-4090, Sobetirome (QRX-431), tadalafil, telmisartan, terazosin, terbinafine, thelin, ticlopidine, tirofiban, tocamide, tolazamide, tolbutamide, torcetrapib, torsemide, trandolapril, TRIA-662, triamterene, trimeric ApoA-1, valsartan, vardenafil, VIA-2291, verapamil, verespladib, volibris, WA8242A, WA8242A 2 , WA8242B, ZD2138, zileuton, or a combination thereof.

25 . The method of claim 21 wherein the cardiovascular agent and EPA are co-administered as separate dosage units.

26 . The method of claim 21 wherein the EPA and cardiovascular agent are coformulated and administered as a single dosage unit.

27 . The method of claim 26 wherein the dosage unit is administered one to a plurality of times per day.

28 . A method of treating hypertriglyceridemia in an HIV+ subject, the method comprising administering to the subject a pharmaceutical composition comprising an HIV-1 protease inhibitor and ultra-pure EPA.

29 . The method of claim 28 wherein the HIV-1 protease inhibitor comprises amprenavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or a combination thereof.

30 . A method of treating or preventing obesity in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising EPA and orlistat.

31 . The method of claim 30 wherein the EPA and orlistat are administered in a same dosage unit.

32 . The method of claim 30 wherein the EPA and orlistat are co-administered in separate dosage units.

33 . A method of treating Type II diabetes in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising EPA and metformin.

34 . The method of claim 33 wherein the EPA and metformin are administered in a same dosage unit.

35 . The method of claim 33 wherein the EPA and metformin are co-administered in separate dosage units.