BRPI0719183A2 - TREATMENT WITH ANTIARRHYTHICS AND FATTY ACIDS OF OMEGA-3 AND A COMBINATION PRODUCT OF THESE - Google Patents

Description

“TREATMENT WITH ANTIARRHYTICS AND FATTY ACIDS OF OMEGA-3 AND A MATCHING PRODUCT OF THESE”

FIELD OF INVENTION

The present invention relates to a method utilizing a single administration or unit dosage of a combination of one or more antiarrhythmic agents and omega-3 fatty acid mixtures including eicosapentaenoic acid (EPA) and docosaexaenoic acid (DHA). ), preferably LOVAZA ™ omega-3 fatty acids, for the treatment of patients with one or more of the following: hypertriglyceridemia, hypercholesterolemia, coronary heart disease (CHD), cardiac arrest, cardiac arrhythmias, atrial fibrillation, atrial fibrillation paroxysmal, ischemic dementia, coagulation-related disorders, nephropathy, cognitive disorders, inflammatory diseases, metabolic syndrome, vascular disease, atherosclerotic disease and related conditions, dyslipidemia and related conditions,

, kidney disease, high total cholesterol (total-C), high low density lipoprotein cholesterol (LDL-C), high apolipoprotein (Apo B), low high density lipoprotein cholesterol (HDL-C), benign tumors and cholesterol-associated malignant diseases, the treatment and / or prevention and / or reduction of cardiac and / or cardiovascular events and / or vascular events and / or symptoms, and the reduction of cholesterol and triglyceride levels, and / or any another condition that benefits from treatment with such combinations. The present invention also relates to a combination product of single administration of one or more antiarrhythmic agents and mixtures of omega-3 fatty acids including eicosapentaenoic acid (EPA) and docosaexaenoic acid (DHA), preferably omega acids. 3 LOVAZA ™.

BACKGROUND OF THE INVENTION

In humans, cholesterol and triglycerides are part of lipoprotein complexes in the bloodstream, and can be separated by ultracentrifugation into high density lipoprotein (HDL) fractions 1 intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and very low density lipoprotein (VLDL). Cholesterol and triglycerides are synthesized in the liver, incorporated into VLDL, and released into plasma. High total cholesterol (total-C), LDL-C, and apolipoprotein B (a membrane complex for LDL-C) promote human atherosclerosis and decreased levels of HDL-C and its transport complex, apolipoprotein A, that are associated with the atherosclerosis disease process. In addition, cardiovascular morbidity and mortality in humans may vary directly with total-C and LDL-C levels and inversely with HDL-C levels. A state of dyslipidemia, or lipid abnormality, predisposes humans to the occurrence of - Pathophysiological events that may result in acute or chronic electrical disorders of the cardiac system, such as arrhythmias. In addition, once an arrhythmia has occurred, the dyslipidemic state if left untreated will continue to predispose patients to an increased risk for subsequent events.

Antiarrhythmic agents are a pharmaceutical group and are used to treat cardiac arrhythmias such as, for example, atrial fibrillation, atrial agitation, tachycardia, bradycardia, ventricular fibrillation, ventricular arrhythmias, and premature beats.

There are five main classes of antiarrhythmic agents:

Class I antiarrhythmic agents are sodium channel blockers which are believed to act by blocking or modulating Na + channel activity, which is generally divided into three subclasses. Class Ia may include, for example, quinidine (for example, QUINIDEX®), procainamide (for example, PRONESTYL®), and disopyramide (for example, NORPACE®). Class Ib may include, for example,

lidocaine (e.g., XYLOCAINE®), mexiletine (e.g., MEXITIL®), tocanide (e.g., TONOCARD®), and phenytoin. Class Ic may include, for example, encenine (e.g. ENKAID®), flecainide (e.g. TABOCOR®), moricizine and propafenone (e.g. Rhythmol®);

Class II antiarrhythmic agents are beta blockers which are believed to be

act as antisympathetic nervous system agents, ie to inhibit the transmission of nerve signals to the heart, and may include, for example, esmolol (eg BREVIBLOC®), propranolol (eg INDERAL®), acebutolol ( for example, SECTRAL®), sotalol (for example, BETAPACE®), and metoprolol (for example, TOPROL-XL® or LOPRESSOR®);

Class III antiarrhythmic agents are potassium channel blockers and may include, for example, amiodarone (e.g. CORDARONE®), azimilide, bretyl, clofyll, dofetilide, tedisamil, ibutilide, sematilide, dronaderone, RSD-1235, and sotalol (e.g. BETAPACE®);

Class IV antiarrhythmic agents are slow calcium channel blockers and

may include, for example, verapamil (for example CALAN® or ISOPTIN®), mibefradil (for example POSICOR®) and diltiazem (for example CARDIZEM®); and

Class V antiarrhythmic agents work through other or unknown mechanisms and may include, for example, adenosine (eg, ADENOCARD®) and digoxin (eg, LANOXIN®).

Other antiarrhythmic agents include GYKI-16638, CPU-86017, EGIS-7229, KCB-328, L-768673, RWJ-28810, NIP-151, NS-1643, KB-R7943, ATI-2001, AL-275, Cardi- item, KMUP-880708, SLV-316, TY-10835, AZD-1305, CLN-93, PQ-1006, SAR-114646, S-2646, XEN-501, CVT-3619, TRC-30X, AVE-1231, DL-017, PJ-875, Pirmenol, Moracizine, 35 Pilsicainide, Nifekalant, Dexsotalol, Landiolol, Nifedipine, ATI-2042, AVE-0118, Nibentan, Stomaline, YM-758, SSR-149744, Rotigaptide, Tedisamil, and tecadenosone.

It should be noted that some antiarrhythmic agents may work by one or more mechanisms and then be characterized as belonging to more than one class.

Marine oils, also commonly called 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. The 5 omega-3 fatty acids have been found to have beneficial effects on risk factors for cardiovascular disease, and an especially good effect on moderate hypertension, hypertriglyceridemia, and coagulation factor V11 phospholipid complex activity. Omega-3 fatty acids increase serum HDL cholesterol, reduce serum triglycerides, change serum LDL cholesterol particle size pattern, lower systolic and diastolic blood pressure and pulse rate, and reduce blood activity of the blood coagulation factor V11 phospholipid complex. In addition, omega-3 fatty acids are well tolerated without giving rise to any severe side effects.

One form of omega-3 fatty acid is an omega-3, long chain polyunsaturated fatty acid fish oil concentrate that contains DHA and EPA and has been sold 15 under the trademark OMACOR®, and is now known. by the name LOVAZA ™. Such a form of omega-3 fatty acid is described, for example, by U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,594 each of which are incorporated herein by reference in their entirety.

PCT / IE99 / 00031 International Application describes a self-emulsifying preconcentrated pharmaceutical composition capable of forming a microemulsion or oil-in-water emulsion in dilution with an aqueous solution. The claimed composition contains: a therapeutically effective amount of a poorly water-soluble therapeutic agent; a pharmaceutically effective amount of a low HLB oil component; and a surfactant system consisting of at least one surfactant having an HLB of about 10 to 20. The therapeutic agent may include cyclosporine, nifedipine or indomethacin and the low HLB oil component may include EPA or DHA. Antiarrhythmic agents are not described as a potential therapeutic agent.

US Patent Application Publication No. 2006/0034815, which is incorporated herein by reference in its entirety, describes a pharmaceutical composition comprising an omega-3 oil and one or more salts of a statin, wherein At least about 80 percent of the statin by weight is present as solid particles in heterogeneous suspension. In another embodiment, the publication provides a pharmaceutical composition comprising an omega-3 oil and one or more salts of a statin, wherein up to 15 percent of the amount of statin by weight is in solution while the amount of of remaining statin is present in the heterogeneous suspension. Antiarrhythmic agents are not described among the list of potential active agents, ie statins.

Gillis and others investigated the effects of dietary fat on propafenone pharmacodynamics in isolated, perfused rabbit hearts. Gillis et al., Circulation, 85 (4): 1501-1509 (1992). This study demonstrated that omega-3 fatty acid content was higher in the fish oil group and that changes in ventricular conduction time in the fish oil group were intermediate between safflower and lard oil groups during propafenone administration.

Previous studies have shown that the toxic effects of amiodarone can be reduced using fatty acids. For example, EPA pretreatment followed by co-treatment with EPA and amiodarone has been shown to protect against amiodarone-induced cell damage. Futamura, J., Pharmacol., 69: 335-341 (1995). Similarly, amiodarone-induced cell damage can also be reduced by pre-treatment with DHA followed by co-treatment with DHA and amiodarone. Futamura, J., Toxicol. Sci. 21: 253-267 (1996).

Kang and others have shown that the administration of anti-arrhythmic drugs of

I, such as mexilitine, may result in over-regulation of cardiac Na + channel expression. However, EPA supplementation, or combination treatment of EPA and mexilitine, has been shown to reduce mexilitin-induced increases in cardiac sodium channel expression. Kang et al., Proc. Natl. Acad. Know. Pharmacol., 94: 2724-2728 (1997).

Finally, the ability of omega-3 fatty acids to prevent lethal cardiac arrhythmias has been shown to be similar to that produced by the class I antiarrhythmic drug idocaine. Kang et al., Proc. Natl. Acad. Know. Physiol., 91: 9886-9890 (1994). See also, Dhein et al., Naunyn-Schmiedeberg's Arch Pharmacol, 371: 202-211 (2005), who describe antiarrhythmic and electrophysiological effects of the class I type and the class III type of omega-3 fatty acids. Administration of one or more antiarrhythmic agents and omega-3 fatty acids is not described.

The prior art does not describe combined treatment with one or more agents

antiarrhythmic agents and omega-3 fatty acids, preferably LOVAZA ™ omega-3 fatty acids, as described in the present invention. In addition, the prior art does not disclose a single administration or unit dosage of a combination of one or more antiarrhythmic agents and omega-3 fatty acids, preferably LOVAZA ™ 30 omega-3 fatty acids, which allow treatment more efficient and new pharmacist for one or more of hypertriglyceridemia, hypercholesterolemia, coronary heart disease (CHD), cardiac arrest, cardiac arrhythmias, atrial fibrillation, paroxysmal atrial fibrillation, ischemic dementia, coagulation-related disorders, nephropathy, cognitive disorders, inflammatory diseases, metabolic syndrome, vascular disease, atherosclerotic disease 35 and related conditions, dyslipidemia and related conditions, kidney disease, high total cholesterol (C-total), high low density lipoprotein cholesterol (LDL-C), high apolipotrotein (Apo B), lipoprotein cholesterol in high-density-lipoprotein (HDL-C), benign and malignant cholesterol-associated tumors, the treatment and / or prevention and / or reduction of cardiac and / or cardiovascular events and / or vascular events and / or symptoms, and reducing cholesterol and triglyceride levels, and / or any other condition that benefits from treatment with such combinations.

SUMMARY OF THE INVENTION

There is an unmet need in the art for a combination product of one or more antiarrhythmic agents and omega-3 fatty acids. In particular, there is an unmet need in the art for a combination product that provides a unique administration of omega-3 fatty acids (eg omega-3L0VAZA ™ acids) 10 and one or more antiarrhythmic agents, for example, in a unit dosage to provide specific therapeutic properties.

There is also an unmet need in the art for a single administration administration method or unit dosage product. In addition, there is an unmet need in the art for a single administration or unit dosage product with one or more antiarrhythmic agents and omega-3 fatty acids (e.g., LOVAZA ™ omega-3 acids), wherein the one or more antiarrhythmic agents are combined with omega-3 fatty acids to provide specific therapeutic properties.

The present invention addresses the unmet needs of the art, as well as others, by providing coadministration or administration of a unit dosage of one or more antiarrhythmic agents and omega-3 fatty acids which may provide a treatment. effective pharmacist of one or more of the following: hypertriglyceridemia, hypercholesterolemia, coronary heart disease (CHD), cardiac arrest, cardiac arrhythmias, atrial fibrillation, paroxysmal atrial fibrillation, ischemic dementia, coagulation-related disorders, nephropathy, cognitive disorders, diseases inflammatory diseases, metabolic syndrome, vascular disease, atherosclerotic disease and related conditions, dyslipidemia and related conditions, kidney disease, high total cholesterol (total-C), high low density lipoprotein cholesterol (LDL-C), high apolipoprotein (Apo B), low high density lipoprotein cholesterol (HDL-C) I benign tumors if cholesterol-associated malignancies, the treatment and / or prevention and / or reduction of cardiac events and / or cardiovascular events and / or vascular events and / or symptoms, and the reduction of cholesterol and triglyceride levels, and / or any other condition that benefits from treatment with such combinations.

Some embodiments of the present invention provide a method for using a combination of one or more antiarrhythmic agents and omega-3 fatty acids in the treatment of one or more of the following: hypertriglyceridemia, hypercholesterolaemia, coronary heart disease (CHD), cardiac arrest, cardiac arrhythmias, atrial fibrillation, paroxysmal atrial fibrillation, ischemic dementia, coagulation-related disorders, nephropathy, cognitive disorders, inflammatory diseases, metabolic syndrome, vascular disease, atherosclerotic disease and related conditions, dyslipidemia and related conditions, kidney disease, high total cholesterol (total-C), high low density lipoprotein cholesterol 5 (LDL-C), high apolipoprotein (Apo B), low high density lipoprotein cholesterol (HDL-C), benign and malignant tumors associated with cholesterol, treatment and / or prevention and / or induction of cardiac and / or cardiovascular events and / or vascular events and / or symptoms, and reduction of cholesterol and triglyceride levels, and / or any other condition that benefits from treatment with such combinations.

Other embodiments of the present invention are directed to a combination product

nation, for example, a unit dosage comprising one or more antiarrhythmic agents and omega-3 fatty acids. In one aspect of the embodiment, the combination product is used to treat one or more of the following: hypertriglyceridemia, hypercholesterolemia, coronary heart disease (CHD), cardiac arrest, cardiac arrhythmias, atrial fibrillation, paroxysmal atrial fibrillation, ischemic dementia, coagulation-related disorders, nephropathy, cognitive disorders, inflammatory diseases, metabolic syndrome, vascular disease, atherosclerotic disease and related conditions, dyslipidemia and related conditions, kidney disease, high total cholesterol (total-C), high low density lipoprotein cholesterol (LDL-C), high apolipoprotein cholesterol (Apo B), low high density lipoprotein cholesterol (HDL-C), cholesterol-associated benign and malignant tumors, treatment and / or prevention and / or reduction of cardiac and / or cardiovascular events and / or vascular events and / or symptoms, and the reduction of cholesterol and triglyceride levels, and / or any other condition that benefits from treatment with such combinations.

However other embodiments of the present invention are methods for treating

one or more of the following: hypertriglyceridemia, hypercholesterolaemia, coronary heart disease (CHD), cardiac arrest, cardiac arrhythmias, atrial fibrillation, paroxysmal atrial fibrillation, ischemic dementia, coagulation-related disorders, nephropathy, cognitive disorders, diseases inflammatory diseases, metabolic syndrome, vascular disease, atherosclerotic disease and related conditions, dyslipidemia and related conditions, kidney disease, high total cholesterol (total-C), high low density lipoprotein cholesterol (LDL-C), high apolipoprotein ( Apo B), low-density lipoprotein (HDL-C) cholesterol, benign and malignant cholesterol-associated tumors, treatment and / or prevention and / or reduction of cardiac and / or cardiovascular events and / or vascular events and / or symptoms, and reduced cholesterol and triglyceride levels, and / or any other condition that benefits from treatment with such combinations, comprising a combined administration of one or more antiarrhythmic agents and omega-3 fatty acids, preferably the LOVAZA ™ omega-3 acid specific product.

Other features and advantages of the present invention will become apparent to those skilled in the art in examining the following or learning by practicing the invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is directed to the use of one or more antiarrhythmic agents and omega-3 fatty acids, preferably LOVAZA ™ omega-3 fatty acids, for the treatment of one or more of the following: hypertriglyceridemia, hypercholesterolaemia, coronary heart disease (CHD). ), cardiac arrest, cardiac arrhythmias, atrial fibrillation, paroxysmal atrial fibrillation, ischemic dementia, coagulation-related disorders, nephropathy,

a, cognitive disorders, inflammatory diseases, metabolic syndrome, vascular disease, atherosclerotic disease and related conditions, dyslipidemia and related conditions, renal disease, high total cholesterol (C-total), high low density lipoprotein cholesterol (LDL-C), high apolipoprotein (Apo B), low high density lipoprotein cholesterol (HDL-C), cholesterol-associated benign and malignant tumors, treatment and / or prevention and / or reduction of cardiac events and / or cardiovascular events and / or vascular events and / or symptoms, and the reduction of cholesterol and triglyceride levels, and / or any other condition that benefits from treatment with such combinations, and a combination product or unit dosage which comprise one or more antiarrhythmic agents and one or more omega-3 fatty acids.

In some embodiments, this invention provides a novel combination product for the treatment of one or more of the following: hypertriglyceridemia, hypercholesterolemia, coronary heart disease (CHD), cardiac arrest, cardiac arrhythmias, atrial fibrillation, paroxysmal atrial fibrillation, ischemic dementia , coagulation-related disorders, nephropathy, cognitive disorders, inflammatory diseases, metabolic syndrome, vascular disease, atherosclerotic disease and related conditions, dyslipidemia and related conditions, kidney disease, high total cholesterol (C-total), lipoprotein cholesterol high-density lipoprotein (LDL-C), high apolipoprotein (Apo B), low-density lipoprotein (HDL-C) cholesterol, benign and malignant cholesterol-associated tumors, treatment 30 and / or prevention and / or reduction of cardiac and / or cardiovascular events and / or ev vascular diseases and / or symptoms, and the reduction of cholesterol and triglyceride levels, and / or any other condition that benefits from treatment with such combinations, comprising administering the combination product to a patient. In a preferred embodiment, the administration comprises omega-3 fatty acids, preferably in the form of LOVAZA ™ omega-3 acids, and one or more antiarrhythmic agents, wherein LOVAZA ™ omega-3 acids are administered concurrently with administration. one or more antiarrhythmic agents. δ In other preferred embodiments, administration comprises omega-3 fatty acids, preferably in the form of LOVAZA ™ omega-3 acids, and one or more antiarrhythmic agents, wherein the LOVAZA ™ omega-3 acids are administered separately. administration of one or more antiarrhythmic agents. For example, one or more antiarrhythmic agents may be administered once weekly (e.g., by a patch) with daily influx of omega-3 fatty acids (e.g., LOVAZA ™ capsules). One skilled in the art for the benefit of the present disclosure will understand that the precise dosage and program for administration of LOVAZA ™ omega-3 acids and one or more antiarrhythmic agents will vary depending upon numerous factors, such as, for example, the routine administration and the seriousness of the conditions.

The present invention may incorporate known or future known antiarrhythmic agents in an amount generally recognized as safe. For example, antiarrhythmic agents may include: class Ia antiarrhythmic agents (e.g., quinidine (e.g., QUINIDEX®), procainamide (e.g., PRONESTYL®), and disopyramide (e.g., NORPACE®); class Ib antiarrhythmic agents (eg lidocaine (eg, XYLOCAINE®), mexiletine (eg MEXITIL®), tocainide (eg, TONOCARD®), and phenytoin); class Ic antiarrhythmic agents (eg, encainide (eg ENKAID®), flecainide (eg TABOCOR®), moricizine and propafenone (eg RHYTHMOL®)); class II antiarrhythmic agents (eg esmolol (eg BREVIBLOC® ), propranolol (eg INDERAL®), acebutolol (eg SECTRAL®), sotalol (eg BETAPACE®), and metoprolol (TOPROL-XL® or LOPRESSOR®); class III antiarrhythmic agents (eg , amiodarone (e.g. CORDARONE®), the zimilide, bretyl, clophilium, dofetilide, tedisamil, ibutilide, sematilide, dronaderone, RSD-1235, and sotalol (e.g., BETAPACE®)); class IV antiarrhythmic agents (eg verapamil (eg CALAN® or ISOPTIN®), mibefradil (eg POSICOR®) and diltiazem (eg CARDIZEM®)); and class V antiarrhythmic agents (e.g. adenosine (e.g. ADENOCARD®) and

digoxin (e.g. LANOXIN®)). Other potential antiarrhythmic agents may include GYKI-16638, CPU-66017, EGIS-7229, KCB-326, L-767267, RWJ-28810, NIP-151, NS-1643, KB-R7943, ATI-2001, AL -275, Cardiostem, KMUP-880708, SLV-316, TY-10835, AZD-1305, CLN-93, PQ-1006, SAR-114646, S-2646, XEN-501, CVT-3619, TRC-30X, AVE -1231, DL-017, PJ-875, pyrmenol, moracizine, pilsicainide, nifecalant, dexsotalol, landiolol, nifedipine, ATI-2042, AVE-0118, nibentan, stobadine, YM-758, SSR-149744, roti-35 gaptida, tedisamil, and tecadenoson. In a preferred embodiment, the one or more antiarrhythmic agents include class Ic antiarrhythmic agents, preferably flecainide and / or propafenone, and / or class III antiarrhythmic agents, preferably amiodarone, azilimilide, dronaderone, RSD-1235, sotalol, ibutilide. , dofetilide, and / or other antiarrhythmic agents such as ATI-2042, AVE-01 18, nibentan, stobadine, YM-758, SSR-149744, rotigaptide, tedisamil, and / or tecadenosone.

The combination products of this invention involving one or more antiarrhythmic agents are distinct. In some embodiments, more than one form of one or more antiarrhythmic agents is combined with amounts of omega-3 fatty acids.

As used herein, the term "omega-3 fatty acids" includes natural or synthetic omega-3 fatty acids, or pharmaceutically acceptable esters, derivatives, conjugates (see, for example, Zaloga et al., Patent Application Publication). No. 2004/0254357, and Horrobin et al., US Patent No. 6,245,811, each hereby incorporated by reference), precursors or salts thereof and mixtures thereof. Examples of omega-3 fatty acid oils include, but are not limited to, omega-3 long-chain polyunsaturated fatty acids such as eicosapentaenoic acid (EPA), docosaexaenoic acid (DHA), and σ-linolenic acid. ; glycerol omega-3 fatty acid esters such as mono-, di- and triglycerides; and omega-3 fatty acid esters and a primary, secondary or tertiary alcohol such as fatty acid methyl esters and fatty acid ethyl esters. Preferred omega-3 fatty acid oils are long chain fatty acids such as EPA or DHA, triglycerides thereof, ethyl esters thereof and mixtures thereof. Omega-3 fatty acids or their esters, derivatives, conjugates, precursors, salts and mixtures thereof may be used either in their pure form or as a component of an oil such as fish oil, preferably highly purified fish oil concentrates. . Commercial examples of omega-3 fatty acids suitable for use in the invention include Incromega F2250, F2628, E2251, F2573, TG2162, TG2779, TG2928, TG3525 and E5015 (Croda International PLC, Yorkshire, England), and EPAX6000FA, EPAX5000TG, EPAX4510TG , EPAX2050TG, K85TG, K85EE, K80EE, and EPAX7010EE (EPAX AS, 1326 Lysaker, Norway).

Preferred forms of omega-3 fatty acids are recited in U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,694, which are hereby incorporated by reference in their entirety.

Another preferred composition includes omega-3 fatty acids present in a

concentration of at least 40 wt%, preferably at least 50 wt%, more preferably at least 60 wt%, even more preferably at least 70 wt%, preferably at least 80 wt%, or even at least 90 wt% by weight Preferably, the omega-3 fatty acids comprise at least 50 wt% EPA and DHA, more preferably at least 60 wt%, even more preferably at least 70 wt%, preferably at least 80 wt%. as about 84% by weight. Preferably the omega-3 fatty acids comprise from about 5 to about 100 wt%, more preferably from about 25 to about 75 wt%, even more preferably from about 40 to about 55 wt%, and preferably about 46 wt% EPA. Preferably omega-3 fatty acids comprise about 5 to about 100% by weight, more preferably about 25 to about 75% by weight, even more preferably about 30 to about 60% by weight, and preferably about 38 wt% DHA. All of the above percentages are by weight compared to the total fatty acid content in the composition, unless otherwise indicated. The weight percent may be based on free ester or acid forms, although it is preferably based on the ethyl ester form of omega-3 fatty acids even if other forms are used according to 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, preferably 2: 1 to 1: 2. Omega-3 fatty acids may comprise pure EPA or pure DHA.

Omega-3 fatty acid oil 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, Iecithin and a mixture thereof.

The most preferred form of omega-3 fatty acids is LOVAZA ™ omega-3 acid (K85EE, Pronova Biocare A.S., Lysaker, Norway) and preferably comprises the following characteristics (per dosage form):

Test Minimum Value Maximum Value Eicosapentaenoic Acid C20: 5 430 mg / g 495 mg / g Docosaexaenoic Acid C22: 6 347 mg / g 403 mg / g EPA and DHA 800 mg / g 880 mg / g Total n-3 Fatty Acids 90% (weight / weight) The combination product of one or more antiarrhythmic agents and fatty acids of

Omega-3, preferably LOVAZA ™ omega-3 acids, may be administered by any means known in the art. Such modes include oral, rectal, nasal, topical (including buccal and sublingual) or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. These compositions are preferably administered orally. The dosage of active ingredients in the compositions of this invention may be varied.

gives; however, the amount of active ingredients must be such that a suitable dosage form is obtained. The dosage selected depends on the desired therapeutic effect, routine administration, and duration of treatment. Compositions of some embodiments of the invention basically comprise an effective dose, a pharmaceutically effective amount, or a therapeutically effective amount of one or more antiarrhythmic agents. The combination product of one or more antiarrhythmic agents and omega-3 fatty acids may be administered in a capsule, a tablet, a powder that can be dispersed in a beverage, a liquid, a soft gel capsule or otherwise. convenient dosage such as oral liquid in a capsule as known in the art. In some embodiments, the capsule is comprised of hard gelatin. The combination product may also be contained in a liquid suitable for injection or infusion.

The active ingredients of the present invention, one or more antiarrhythmic agents and omega-3 fatty acids, may also be administered with a combination of one or more non-active pharmaceutical ingredients (also commonly referred to herein as "excipients"). Non-active ingredients, for example, serve to solubilize, suspend, thicken, dilute, emulsify, stabilize, preserve, protect, color, flavor, and shape the active ingredients into an applicable and effective preparation that is safe, convenient, and otherwise. acceptable mode for use. Thus, non-active ingredients may include colloidal silicon dioxide, crospovidone, lactose monohydrate, lecithin, microcrystalline cellulose, polyvinyl alcohol, povidone, sodium lauryl sulfate, sodium stearyl fumarate, talc, dioxide. of titanium and xanthan gum.

In most embodiments, the excipients mainly include surfactants such as propylene glycol monocaprylate, glycerol mixtures and long fatty acid polyethylene esters, polyethoxylated castor oils, glycerol esters, oleoyl macrogol glycerides, monolaurate glycol propylene glycol, propylene glycol dicaprylate / dicaprate, polyethylene polypropylene glycol copolymer, and polyoxyethylene sorbitan monooleate, co-solvents such as ethanol, glycerol, polyethylene glycol, and propylene glycol, and oils such as coconut oils , olive oil or saffron. The use of surfactants, co-solvents, oils or combinations thereof is generally known in the pharmaceutical arts, and as would be understood by one skilled in the art, any suitable surfactant may be used in conjunction with the present invention and embodiments thereof.

Omega-3 fatty acids may be administered in a daily amount of from about 0.1 g to about 10 g, more preferably about 0.5 g to about 8 g, and preferably from about 0.75 g to about 10 g. 4 g. Preferably, the omega-3 fatty acids are present in an amount from about 0.1 g to about 2 g, preferably about 0.5 g to about 1.5 g, in unit dosage form, more preferably about 1 g.

In one embodiment of the present invention, one or more antiarrhythmic agents, depending upon the selection of such antiarrhythmic agents, may generally be present in an amount from about 0.5 mg to about 1000 mg, preferably about 1 mg to about 750 mg, more preferably about 2.5 mg to about 500 mg.

In some variations of the present invention, the combination of one or more antiarrhythmic agents and omega-3 fatty acids (e.g., LOVAZA ™ omega-3 acids) is formulated in a single administration or unit dosage.

Daily dosages of one or more antiarrhythmic agents and omega-3 fatty acids may be administered together in from 1 to 10 dosages, with the preferred number of dosages from 1 to 4 times per day. Administration is preferably oral administration, although other administration forms which provide a unit dosage of one or more antiarrhythmic agents and omega-3 fatty acids may be used.

In some preferred embodiments, a soft gelatin capsule is used. The manufacture of soft gelatin capsules is generally known to those of ordinary skill in the art. For example, see Ebert (1978), "Soft Elastic Gelatin Capsules: The Unity Dosage Form," Pharmaceutical Technology 1 (5), herein incorporated by reference. In some embodiments, one or more antiarrhythmic agents and / or omega-3 fatty acids are contained in the soft gelatin capsule. In certain embodiments, the active ingredients in the soft gelatin capsule are combined with a solubilizer. Solubilizers include surfactants, hydrophilic or hydrophobic solvents, oils or combinations thereof.

One type of solubilizer that can be used is a vitamin E substance. This group of solubilizers includes a substance that belongs to the group of α-, β-, γ-, δ-, ζ1-, ζ2- and η-tocopherols, their d1, I forms and their structural analogs, such as tocotrienols; the corresponding derivatives, for example esters, produced with organic acids; and mixtures of these. Preferred vitamin E substance solubilizers include tocopherols, tocotrienols and tocopherol derivatives with organic acids such as acetic acid, propionic acid, bile acid, lactic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid. , maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, polyethylene glycol sucate and salicylic acid. Particularly preferred vitamin E solubilizers include alpha-tocopherol, alpha-tocopheryl acetate, alpha-tocopheryl acid succinate, alpha-tocopheryl polyethylene glycol 1000 succinate and mixtures thereof.

Another group of solubilizers are the monohydric alcohol esters of organic acids. For example, the monohydric alcohol may be ethanol, isopropanol, t-butanol, a fatty alcohol, phenol, cresol, benzyl alcohol or a cycloalkyl alcohol. The organic acid may be, for example, acetic acid, propionic acid, butyric acid, a 6-22 carbon atom fatty acid, bile acid, lactic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid. , maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid and salicylic acid. Preferred solubilizers in this group include trialkyl citrates, lower alcohol fatty acid esters and lactones. Preferred trialkyl citrates include triethyl citrate, acetyltriethyl citrate, tributyl citrate, acetyltributyl citrate and mixtures thereof with triethyl citrate being particularly preferred. Particularly preferred lower alcohol fatty acid esters include ethyl oleate, ethyl iinoleate, ethyl caprylate, ethyl caprate, isopropyl myristate, isopropyl palmitate and mixtures thereof. Iactones may also serve as a solubilizer. Examples include e-caprolactone, d-valerolactone, β-butyrolactone, isomers thereof and mixtures thereof.

The solubilizer may be a nitrogen containing solvent. Preferred nitrogen-containing solvents include dimethylformamide, dimethylacetamide, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam and mixtures thereof wherein C 10 alkyl is a branched or straight chain alkyl. Particularly preferred nitrogen-containing solvents include N-methyl 2-pyrrolidone, N-ethyl 2-pyrrolidone or a mixture thereof. Alternatively, the nitrogen-containing solvent may be in the form of a polymer such as polyvinylpyrrolidone.

Another group of solubilizers includes phospholipids. Preferred phospholipids include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, lecithins, lysolecithins, glycolated polyethylene lysophospholipids, lecithins / lysolecithins and mixtures thereof.

Another group of preferred solubilizers are glycerol acetates and acetylated glycerol fatty acid esters. Preferred glycerol acetates include acetin, diacetin, triacetin and mixtures thereof, with triacetin being particularly preferred. Preferred acetylated glycerol fatty acid esters include acetylated monoglycerides, acetylated diglycerides and mixtures thereof.

In addition, the solubilizer may be a glycerol fatty acid ester. The fatty acid component is about 6-22 carbon atoms. The glycerol fatty acid ester 25 may be a monoglyceride, diglyceride, triglyceride or mixtures thereof. Preferred glycerol fatty acid esters include monoglycerides, diglycerides, medium chain fatty acid triglycerides having about 6-12 carbons and mixtures thereof. Particularly preferred glycerol fatty acid esters include medium chain fatty acid monoglycerides having about 6-12 carbons, mid chain fatty acid diglycerides having about 6-12 carbons and mixtures thereof.

The solubilizer may be a propylene glycol ester. Preferred propylene glycol esters include propylene carbonate, propylene glycol monoacetate, propylene glycol diacetate, propylene glycol fatty acid esters, acetylated propylene glycol fatty acid esters and mixtures thereof. Alternatively, the propylene glycol fatty acid ester may be a propylene glycol fatty acid monoester, propylene glycol fatty acid diester or mixtures thereof. Fatty acid has about 6-22 carbon atoms. It is particularly preferred that the propylene glycol ester is propylene glycol monocaprylate (CAPRYOL®). Other preferred propylene glycol esters include propylene glycol dicaprylate, propylene glycol dicaprate, propylene glycol dicaprylate / dicaprate and mixtures thereof.

Another group of solubilizers is ethylene glycol esters. Ethylene glycol esters 5 include monoethylene glycol monoacetates, diethylene glycol esters, polyethylene glycol esters and mixtures thereof. Additional examples include ethylene glycol monoacetates, ethylene glycol diacetates, ethylene glycol fatty acid monoesters, ethylene glycol fatty acid diesters, and mixtures thereof. Alternatively, the ethylene glycol ester may be a polyethylene glycol fatty acid monoester, polyethylene glycol fatty acid diester or mixtures thereof. Again, the fatty acid component will contain about 6-22 carbon atoms. Particularly preferred ethylene glycol esters are those marketed under the names LABRAFI L® and LABRASOL®.

Polyoxyethylene sorbitan fatty acid esters (also called polysorbates), for example, from 4 to 25 alkylene moieties, for example mono- and tri-lauryl, palmityl, stearyl and oleyl esters of the known and commercial types available under the tradename TWEEN® are also suitable as surfactants.

Hydrophilic solvents that may be used include an alcohol, for example, a water miscible alcohol, for example absolute ethanol, or glycerol. Other alcohols include glycols, for example, any glycol obtainable from an oxide such as ethylene oxide, for example 1,2-propylene glycol. Other examples are polyols, for example a polyalkylene glycol, for example poly (C2.3) alkylene glycol. A typical example is a polyethylene glycol. Alternatively the hydrophilic component may comprise an N-alkylpyrrolidone, preferably, for example, N- (C 1-4 alkyl) pyrrolidone, for example, N-methylpyrrolidone, tri (C 1-4 alkyl) citrate, for example triethylcitrate, dimethylisorbide, (C5 -C13) alkanoic acid, for example caprylic acid or propylene carbonate.

The hydrophilic solvent may comprise a major or exclusive component, for example an alcohol, for example, C1-4-alcohol, for example, ethanol, or alternatively a co-component, for example, which may be selected from partial or lower ethers. lower channels. Preferred partial ethers are, for example, TRANSCUTOL® (which has the formula C2H5- [0- (CH2) 2] 2-0H), GLYCOFUROL® (also known as tetrahydrofurfuryl alcohol polyethylene glycol ether), or lower alkanols such as ethanol.

The product of combining one or more antiarrhythmic agents and omega-3 fatty acids is aided by the solubility of one or more antiarrhythmic agents in omega-3 fatty acid oil. In some embodiments of the present invention, a pharmaceutical composition in unit dosage form comprises an essentially homogeneous solution comprising one or more antiarrhythmic agents essentially dissolved in the solvent system comprising natural or synthetic omega-3 fatty acids or pharmaceutically acceptable esters. derivatives, conjugates, precursors or salts thereof, or mixtures thereof, wherein less than about 10% of one or more antiarrhythmic agents are undissolved in the solvent system. The one or more antiarrhythmic agents are substantially dissolved in omega-3 fatty acid oil to provide a substantially homogeneous composition. Preferably, this aspect of the present invention does not include high amounts of solubilizers to dissolve the one or more antiarrhythmic agents. Preferably, the one or more antiarrhythmic agents are contained in the pharmaceutical composition without the use of large amounts of solubilizers (other than omega-3 fatty acids), and is substantially dissolved (i.e. less than 10%, preferably minus 10%). 5% remain undissolved in the solvent system).

In a preferred embodiment, the one or more antiarrhythmic agents are completely dissolved. In preferred, if not all, embodiments, solubilizers other than omega-3 fatty acids are present in amounts of 50% or less by weight / weight based on the total weight of the solvent system in the dosage form, preferably 15%. 40% or less, more preferably 30% or less, still more preferably 20% or less, still more preferably 10% or less and preferably 5% or less. In some embodiments, the solvent system contains no solubilizers except omega-3 fatty acids. As used herein, "solvent system" includes omega-3 fatty acids, usually in the form of an oil. In other preferred embodiments, the weight ratio of omega-3 fatty acids to another solubilizer (s) is at least 0.5 to 1, more preferably at least 1 to 1, even more preferably at least 5 to 1, and more preferably at least 10 to 1.

In preferred embodiments, omega-3 fatty acids are present in amounts of at least 30 wt% based on the total weight of the solvent system in dosage form, more preferably at least 40%, even more preferably. - at least 50%, and preferably at least 60%. In certain embodiments, the amount may be at least 70%, at least 80% or at least 90%.

Dosage forms including the essentially homogeneous solution should be stable at room temperature (about 23 ° C to 27 ° C, preferably about 25 ° C) and 30 60% relative humidity over a period of at least one month, preferably at least six months, more preferably at least one year, and preferably at least two years. By "stable" we mean that the one or more solubilized antiarrhythmic agents should not precipitate from the solution and should not become chemically modified to any appreciable degree, for example in amounts of less than 35%, preferably less than 5%.

In addition, dosage forms including the essentially homogeneous solution should preserve one or more antiarrhythmic degrading agents. Some modalities include unit dosage forms of one or more omega-3 fatty acid and antiarrhythmic agents in which at least 90% of the initial amount of one or more antiarrhythmic agents in the dosage form within one time. initial measurement (to) should be kept after one month of storage at room temperature and 60% relative humidity.

The combination product may be manufactured by any method known to those of ordinary skill in the art by combining one or more more antiarrhythmic agents such as omega-3 fatty acids, and optionally with hydrophilic solvent (s). surfactant (s), other solubilizing agents, and / or other excipients.

Other embodiments of the present invention are directed to suspensions of one or more

more antiarrhythmic agents in omega-3 fatty acids. In some embodiments, the suspensions comprise inert solid crystalline particles, inert solid amorphous particles, or mixtures thereof of one or more antiarrhythmic agents in omega-3 fatty acids. Other embodiments include pharmaceutical compositions comprising suspensions of one or more omega-3 fatty acid antiarrhythmic agents wherein a portion of the one or more antiarrhythmic agents is solubilized in omega-3 fatty acids or another component of the composition. For example, in some embodiments, the present invention provides a pharmaceutical composition comprising omega-3 fatty acids and one or more antiarrhythmic agents, wherein about 1-15% of one or more antiarrhythmic agents by weight. are in solution while the remaining amount of one or more antiarrhythmic agents is present in the suspension.

In other embodiments, the present invention provides a pharmaceutical composition comprising omega-3 fatty acids and one or more antiarrhythmic agents, wherein at least about 80%, preferably about 85%, more preferably about 25 90%. even more preferably about 95%, and preferably about 99%, of one or more antiarrhythmic agents by weight is present as solid suspended particles.

Another embodiment of the present invention is directed to a soft gelatin capsule covered with one or more antiarrhythmic agents. In such an embodiment, at least one coating applied outside the soft gelatin capsule comprises one or more antiarrhythmic agents and a coating material, such as a film-forming and / or binder material, and optionally other conventional additives. such as lubricants, fillers and nonstick. Preferred coating materials will include antioxidants, solubilizers, chelating agents, and / or absorption enhancers. Surfactants can act as solubilizers and absorption enhancers.

The coating (s) may be applied by any conventional technique such as pan coating, fluidized bed coating or spray coating. The coating (s) may be applied as a suspension, spray, dust or dust. The coating may be formulated for immediate release, delayed release / enteral release or extended release the second active pharmacist according to methods well known in the art. Conventional coating techniques are described, for example, in Remington's Pharmaceutical Sciences, 18th Ed. (1990), hereby incorporated by reference.

An immediate release coating is generally used to improve product elegance as well as a moisture barrier, and taste and odor masking. Rapid decomposition of the film in the gastric environment is important, leading to effective disintegration and dissolution. EUDRAGIT RD100 (Rohm) is an example of such a coating. It is a combination of a water insoluble cationic methacrylate copolymer with a water soluble cellulose ether. In powder form, it is easily dispensable in an easily sprayable suspension that dries to leave a smooth film. Such films disintegrate rapidly in aqueous media at a rate that is independent of pH and film thickness.

A protective coating layer (i.e. seal coating) may be applied.

each, if desired, by conventional coating techniques such as pan coating or fluid bed coating using water polymer solutions or suitable organic solvents or using aqueous polymer dispersions. Suitable materials for the protective layer include cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone / vinyl acetate copolymer, ethyl and cellulose aqueous dispersions. - homes. The protective coating layer may include antioxidants, chelating agents, dyes or dyes.

The enteric coating layer may be applied to the uncoated or uncoated cores by conventional coating techniques such as pan coating or fluidized bed coating using water polymer solutions or suitable organic solvents or using polymer dispersions. watery. All commercially available pH sensitive polymers are included. The pharmaceutical active is not released into the acidic stomach environment of about below pH 4.5, 30 but is not limited to this value. The pharmaceutical asset would become available when the pH-sensitive layer dissolved at the higher pH; after some delayed time; or after the unit passes through the stomach. The preferred retardation is in the range of one to six hours.

Enteric polymers include cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, methacrylic acid / methacrylic acid methyl esters such as, for example, known materials under the tradename EUDRAGIT L12.5, LI00, or EUDRAGIT SI2.5, SI00 or similar compounds used to obtain enteric coatings. Aqueous colloidal polymer dispersions or redispersions may also be applied, for example EUDRAGIT L 30D-55, EUDRAGIT L100-55, EUDRAGIT S100, EUDRAGIT Preparation 411OD (Rohm Pharma); AQUATERIC, AQUACOAT CPD 30 (FMC); KOLLICOAT MAE 30D and 30DP (BASF); EASTACRYL 30D (Eastman Chemical).

An extended release film coating may include a water-insoluble material such as a wax or a wax-like substance, fatty alcohols, gum, zein, hydrogenated vegetable oils, water-insoluble celluloses, methacrylic acid polymers. and / or acrylic, and any other dispersible or slowly digestible solids known in the art. The solvent for the hydrophobic coating material may be organic or aqueous. Preferably, the hydrophobic polymer is selected from (i) a water-insoluble cellulosic polymer, such as an alkylcellulose, preferably ethylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof. In other preferred embodiments of the present invention, the hydrophobic material comprising the controlled release coating is an acrylic polymer. Any pharmaceutically acceptable acrylic polymer may be used for the purpose of the present invention. The acrylic polymers may be cationic, anionic or nonionic polymers and may be acrylates, methacrylates, formed of methacrylic acid or esters of methacrylic acid. Examples of suitable acrylic polymers include, but are not limited to, acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate, methyl methacrylate, copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, methyl methacrylate copolymers, methyl methacrylate copolymers, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, methacrylic acid copolymers, methacrylate methacrylate copolymers , poly (acrylic) acid, poly (methacrylic) acid, methacrylic acid alkylamine copolymer, poly (methyl) methacrylate, poly (methacrylic) anhydride, methyl methacrylate, polymethacrylate, methyl methacrylate copolymer , poly (methyl) methacrylate, poly (methyl) methacrylate copolymer, polyacrylamide, α-methacrylate copolymer minoalkyl, poly (methacrylic acid) anhydride, and glycidyl methacrylate copolymers.

A barrier coating may be enclosed between an outer coating and the soft gelatin shell. The barrier coating may be comprised of an enteric / prolonged release coating (as above), or a (non-functional) barrier layer, which serves as a protective coating to prevent bark leaching from the external pharmaceutical active component or vice versa.

In one embodiment of the invention, one or more omega-3 fatty acid antiarrhythmic agents are divided into first and second portions, one portion disposed in a coating, and the second portion disposed in the soft gelatin capsule. The dosage form is provided with a latency time between administration of the first portion and administration of the second portion, for example an enteric coating provided as a barrier layer. In other embodiments, there is an immediate release of the first portion, followed by a delayed or continuous release of the second portion. In additional embodiments, there is a delayed release of the first portion, followed by a bolus of the second portion.

While coating technology is extensively used in the pharmaceutical industry, for example for the application of functional or non-functional coatings for single dosage forms and for the deposition of APIs on sugar beads, there are several challenges that may be encountered. be found during the coating of soft gelatin capsules. These challenges are often attributed to the gelatin properties and dosage form. Soft gelatin capsules usually contain a drug dissolved or dispersed in hydrophilic oils or liquids (liquid filler). The inherent flexibility of the soft gelatin capsule is due to the presence of plasticizers and residual moisture in the capsule shell. Thus, the soft gelatin capsule is a more dynamic system than conventional hard gelatin tablets or capsules. Atmospheric moisture can penetrate the shell of the capsule or the liquid charge. The drug or liquid filler can migrate in the capsule shell while the wastewater plasticizer or gelatin can potentially migrate in the liquid filler. Volatile components in soft gelatin capsules may escape into the atmosphere.

As noted above, polymeric coatings are generally applied as aqueous based solutions, organic based solutions or dispersions, in which the polymer-containing droplets are atomized with air and sprayed onto the substrate. Heat may be added to the coating equipment to facilitate solvent evaporation and film formation. In the case of soft gelatin capsules, spray rate and bed temperature processing parameters should be controlled. Because gelatin is water soluble, spraying an aqueous based polymeric material at a high rate could lead to gelatin solubilization and capsule agglomeration. A high bed temperature may result in evaporation of residual water from the 30 capsule shell, causing the capsule to become brittle. Thus, the present invention comprises a method of coating the soft gelatin capsules in which these consequences are avoided.

In addition, the deposition of a low dose of one or more antiarrhythmic agents on the surface of high precision soft gelatin capsules could be affected by several factors. Accuracy of deposition needs to be demonstrated by assessing coating uniformity including the mass variance of the coated capsules and the variance of the content of one or more coated antiarrhythmic agents. The present invention provides a method for coating a soft gelatin capsule comprising mixtures of omega-3 fatty acids with a coating comprising a coating material and one or more antiarrhythmic agents, the method comprising controlling the deposition rate. coating the soft gelatin capsule and controlling the temperature during the coating process to produce a stable physically and chemically coated soft gelatin capsule.

In other embodiments, the coating of the present invention may also be applied over a hard gelatin capsule or a tablet. The hard gelatin capsule may contain instead of liquid, powder, beads or microcompressed (e.g., U.S. Patent No. 5,681,588, incorporated herein by reference).

Still other embodiments of the present invention include a unit dosage of one or more antiarrhythmic agents and omega-3 fatty acids in which at least 90% of the initial amount of one or more antiarrhythmic agents in the dosage form at an initial measurement time ( to) should be kept after storage for one month at room temperature and 60% relative humidity.

In some embodiments, the formulations of the present invention allow for improved effectiveness of each active ingredient with one or both administered as a conventional maximum dose. In other embodiments, the formulations of the present invention may permit reduced dosages of one or more antiarrhythmic agents and / or omega-3 fatty acids as compared to prior art formulations while still maintaining or even improving the effectiveness of each active ingredient.

The present combination of one or more antiarrhythmic agents and omega-3 fatty acids may allow a greater effect than any expected combined or additive effect of the two drugs alone. Thus, the combined treatment of the two active ingredients, either separately or by the novel combination product of the present invention, may cause an unexpected increase in effect of the active ingredients allowing increased effectiveness at standard dosages or sustained effectiveness at reduced dosages of the two active ingredients. It is well accepted in practice that improved bioavailability or effectiveness of a drug or other active ingredient allows for an appropriate reduction in the daily dosage amount. Any undesirable side effects can also be reduced as a result of the lower dosage amount and the reduction in excipients (eg surfactants).

All references cited herein are hereby incorporated by reference in their entirety.

Claims (19)

1. Pharmaceutical composition, characterized in that it comprises: а. a unit dosage form comprising omega-3 fatty acids and optionally a solubilizer, and b. one or more outer coatings in unit dosage form, wherein at least one outer coat comprises one or more antiarrhythmic agents, and c. optionally one or more barrier coatings between the unit dosage form and one or more outer coatings, and d. optionally a seal coating in unit dosage form. Pharmaceutical composition according to claim 1, characterized in that the one or more outer coatings are formulated for immediate release, delayed release / enteral release or prolonged release of one or more antiarrhythmic agents. Pharmaceutical composition according to Claim 1, characterized in that one or more barrier coatings are formulated for enteral / delayed release of omega-3 fatty acids, or as a non-functional protective layer. Pharmaceutical composition according to Claim 1, characterized in that the unit dosage form is a soft gelatin capsule, a hard gelatin capsule, or a tablet. Pharmaceutical composition according to Claim 1, characterized in that the one or more antiarrhythmic agents are selected from quinidine, procaine, disopyramide, lidocaine, mexiletine, tocainide, phenytoin, encainide, flecainide, morcizine, propafenone, esmolol, propranolol, acebutolol, sotalol, metoprolol, amiodarone, azimilide, bretylium, clophilium, dofetilide, tedisamil, ibutilide, sematilide, dronaderone, RSD-1235, sotaolol, verapamil, dibiazemine, mibefradene GYKI-16638, CPU-86017, EGIS-7229, KCB-328, L-768673, RWJ-28810, NIP-151, NS-1643, KB-R7943, ATI-2001, Cardiostem, KMUP-880708, SLV-316, TY-10835, AZD-1305, CLN-93, PQ-1006, SAR-114646, S-2646, XEN-501, CVT-3619, TRC-30X, AVE-1231, DL-017, PJ- 875, pirmenol, monadizine, pilsicainide, nifekalant, dexsotalol, landiolol, nifedipine, ATI-2042, AVE-0118, niben- tan, stobadine, YM-758, SSR-149744, rotigaptide, tedisamil, and tecadenosone. Pharmaceutical composition according to claim 5, characterized in that the one or more antiarrhythmic agents are selected from propafenone, flecainide, amiodarone, azimilide, dronaderone, RSD-1235, sotalol, ibutilide, dofetilide, ATI-2042, AVE-0118, nibentan, stobadine, YM-758, SSR-149744, rotigaptide, tedisamil, and tecadenosone. Pharmaceutical composition according to claim 1, characterized in that it comprises from about 0.5 mg to about 1000 mg of one or more antiarrhythmic agents. Pharmaceutical composition according to claim 1, characterized in that the omega-3 fatty acids contain at least about 70% EPA and DHA. Pharmaceutical composition according to claim 1, characterized in that it comprises from about 0.1 g to about 10 g of omega-3 fatty acids. Pharmaceutical composition according to claim 1, characterized in that the at least one outer coating comprising one or more antiarrhythmic agents is sprayed onto the unit dosage form while controlling the rate of coating deposition and controlling the temperature during the coating process to produce a physically and chemically stable coated unit dosage form. Pharmaceutical composition in unit dosage form, characterized in that it comprises a heterogeneous suspension or essentially homogeneous solution of one or more antiarrhythmic agents in a solvent system comprising omega-3 fatty acids. Pharmaceutical composition according to Claim 11, characterized in that the omega-3 fatty acids contain at least about 70% EPA and DHA. Pharmaceutical composition according to Claim 12, characterized in that the pharmaceutical composition comprises a heterogeneous suspension of essentially inert particles containing one or more antiarrhythmic agents. Pharmaceutical composition according to Claim 13, characterized in that at least about 80% of one or more antiarrhythmic agents are present as solid particles in the suspension. Pharmaceutical composition according to Claim 11, characterized in that the pharmaceutical composition comprises an essentially homogeneous solution. Pharmaceutical composition according to claim 15, characterized in that less than about 10% of one or more antiarrhythmic agents are undissolved in the solvent system. Pharmaceutical composition according to claim 16, characterized in that the solvent system additionally comprises at least one solubilizer in an amount of 50% or less by weight based on the total weight of the solvent system. Pharmaceutical composition according to Claim 15, characterized in that no more than 10% of the one or more dissolved antiarrhythmic agents precipitate out of the essentially homogeneous solution when the pharmaceutical composition is stored at room temperature and 60 ° C. % relative humidity over a period of at least one month. 19. Method, characterized in that it is to treat a patient having one or more conditions selected from the group consisting of hypertriglyceridemia, hypercholesterolemia, coronary heart disease (CHD), cardiac arrest, cardiac arrhythmias, atrial fibrillation, paroxysmal atrial fibrillation, ischemic dementia, coagulation-related disorders, nephropathy, cognitive disorders, inflammatory diseases, metabolic syndrome, vascular disease, atherosclerotic disease and related conditions, dyslipidemia and related conditions, kidney disease, high total cholesterol (total-C), high density lipoprotein cholesterol (LDL-C), high apolipoprotein cholesterol (Apo B), low density lipoprotein cholesterol (HDL-C) cholesterol, benign and malignant tumors associated with cholesterol, treatment and / or prevention and / or reduction of cardiac events and / or cardiovascu- lar events and / or vascular events and / or symptoms, and the reduction of cholesterol and triglyceride levels, and / or any other condition that benefits from treatment with such combinations, while comprising administering to the patient an effective amount of one or more plus antiarrhythmic agents and omega-3 fatty acids.