Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/49—Cinchonan derivatives, e.g. quinine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • 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
  • A61P35/00—Antineoplastic agents
• • 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
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics
• • 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 one or more antiarrhythmic agents and mixtures of omega-3 fatty acids that include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), preferably LOVAZATM omega-3 fatty acids, for the treatment of patients with one or more of the following: hypertriglyceridemia, hypercholesterolemia, coronary heart disease (CHD), heart failure, 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, renal disease, elevated total cholesterol (total-C), elevated low density lipoprotein cholesterol (LDL-C), elevated apolipoprotein (Apo B), low high density lipoprotein cholesterol (HDL-C), cholesterol-
• the present invention also relates to a single administration combination product of one or more antiarrhythmic agents and mixtures of omega-3 fatty acids that include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), preferably LOVAZATM omega-3 acids.
• EPA eicosapentaenoic acid
• DHA docosahexaenoic acid
• 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
• total-C total cholesterol
• LDL-C low-density lipoprotein
• apolipoprotein B a membrane complex for LDL-C
• cardiovascular morbidity and mortality in humans can vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C.
• a state of dyslipidemia, or lipid abnormality predisposes humans to the occurrence of pathophysiological events that can result in acute or chronic electrical disturbances of the cardiac system, such as arrhythmias.
• arrhythmia the dyslipidemic state if left untreated will continue to predispose individuals to a heightened risk for subsequent events.
• Antiarrhythmic agents are a group of pharmaceuticals that are used to treat cardiac arrhythmias, such as, e.g., atrial fibrillation, atrial flutter, tachycardia, bradycardia, ventricular fibrillation, ventricular arrhythmias, and premature beats.
• cardiac arrhythmias such as, e.g., atrial fibrillation, atrial flutter, tachycardia, bradycardia, ventricular fibrillation, ventricular arrhythmias, and premature beats.
• Class Ia may include, for example, quinidine (e.g., QUINIDEX®), procainamide (e.g., PRONESTYL®), and disopyramide (e.g., NORPACE®).
• Class Ib may include, for example, lidocaine (e.g., XYLOCAINE®), mexiletine (e.g., MEXITIL®), tocainide (e.g., TONOCARD®), and phenytoin.
• Class Ic may include, for example, encainide (e.g., ENKAID®), flecainide (e.g., TABOCOR®), moricizine and propafenone
• Class Il antiarrhythmic agents are beta blockers that are believed to act as anti-sympathetic nervous system agents, i.e., to inhibit the transmission of nerve signals to the heart, and may include, for example, esmolol (e.g., BREVIBLOC®), propranolol (e.g., INDERAL®), acebutolol (e.g., SECTRAL®), sotalol (e.g., BETAPACE®), and metoprolol (e.g., TOPROL-XL® or
• esmolol e.g., BREVIBLOC®
• propranolol e.g., INDERAL®
• acebutolol e.g., SECTRAL®
• sotalol e.g., BETAPACE®
• metoprolol e.g., TOPROL-XL® or
• Class III antiarrhythmic agents are potassium channel blockers and may include, for example, amiodarone (e.g., CORDARONE® ), azimilide, bretylium, clofilium, dofetilide, tedisamil, ibutilide, sematilide, dronaderone,
• amiodarone e.g., CORDARONE®
• azimilide bretylium, clofilium, dofetilide, tedisamil, ibutilide, sematilide, dronaderone
• RSD-1235 RSD-1235, and sotalol (e.g., BETAPACE®);
• Class IV antiarrhythmic agents are slow calcium channel blockers and may include, for example, verapamil (e.g., CALAN® or ISOPTIN®), mibefradil (e.g., POSICOR®) and diltiazem (e.g., CARDIZEM®); and [0009] Class V antiarrhythmic agents work by other or unknown mechanisms and may include, for example, adenosine (e.g., ADENOCARD®) and digoxin
• LANOXIN® LANOXIN®
• 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, 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, moracizine, pilsicainide, nifekalant, dexsotalol, landiolol, nifedipine, ATI-2042, AVE-0118, nibentan, stobadine, YM-758, SSR-149744, rotigaptide, tedisamil, and tecadenos
• 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, and an especially good effect on mild hypertension, hypertriglyceridemia and on the coagulation factor VII phospholipid complex activity.
• Omega-3 fatty acids increase serum HDL- cholesterol, lower serum triglycerides, alter the particle size pattern of serum LDL-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 are 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 by the name LOVAZATM. 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 is incorporated herein by reference in their entireties.
• International Application PCT/IE99/00031 discloses a self emulsifying preconcentrate pharmaceutical composition capable of forming an oil in water microemulsion or emulsion upon 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 from 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 ⁇ disclosed as a potential therapeutic agents.
• U.S. Patent Application Publication No. 2006/0034815 which is incorporated herein by reference in its entirety, discloses 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.
• 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 remaining statin is present in heterogeneous suspension.
• Antiarrhythmic agents are not disclosed among the list of potential active agents, i.e., statins.
• amiodarone-induced cell injury may also be reduced by pretreatment with DHA followed by co-treatment with DHA and amiodarone. Futamura, J. Toxicol. Sci., 21 : 253-267 (1996).
• Kang et al. have shown that administration of class I antiarrhythmic drugs, such as mexilitine, may result in up-regulation of cardiac Na + channel expression.
• EPA supplementation, or combination treatment of EPA and mexilitine has been shown to reduce mexilitine-induced increases in cardiac sodium channel expression. Kang et al., Proc. Natl. Acad. Sci. Pharmacol., 94: 2724-2728 (1997).
• omega-3 fatty acids to prevent lethal cardiac arrhythmias has been shown to be similar to that produced by the class I antiarrhythmic drug lidocaine.
• Kang et al. Proc. Natl. Acad. Sci. Physiol., 91 : 9886-9890 (1994).
• Dhein et al. Naunyn-Schmiedeberg's Arch Pharmacol, 371 :202-211 (2005), which discloses class l-like and class Ill-like antiarrhythmic and electrophysiological effects of omega-3 fatty acids.
• Administration of one or more antiarrhythmic agents and omega-3 fatty acids is not disclosed.
• the prior art does not disclose the combined treatment with one or more antiarrhythmic agents and omega-3 fatty acids, preferably LOVAZATMomega-3 fatty acids, as disclosed in the present invention.
• the prior art does not disclose a single administration or a unit dosage of a combination of one or more antiarrhythmic agents and omega-3 fatty acids, preferably LOVAZATM omega-3 fatty acids, that allows for a novel and more efficient pharmaceutical treatment for one or more of hypertriglyceridemia, hypercholesterolemia, coronary heart disease (CHD), heart failure, 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, renal disease, elevated total cholesterol (total-C), elevated low density lipoprotein cholesterol (LDL-C), elevated apolipoprotein (Apo B), low high
• omega-3 fatty acids e.g., the LOVAZATM omega-3 acids
• antiarrhythmic agents for example, in a unit dosage to provide specific therapeutic properties.
• the present invention meets the unmet needs of the art, as well as others, by providing a co-administration or an administration of a unit dosage of one or more antiarrhythmic agents and omega-3 fatty acids that can provide an effective pharmaceutical treatment of one or more of the following: hypertriglyceridemia, hypercholesterolemia, coronary heart disease (CHD), heart failure, 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, renal disease, elevated total cholesterol (total-C), elevated low density lipoprotein cholesterol (LDL-C), elevated apolipoprotein (Apo B), low high density lipoprotein cholesterol (HDL-C) 1 cholesterol-associated benign and malignant tumors, the treatment and/or prevention and/or reduction of cardiac events and/or cardiovascular events and/or vascular events and/or symptoms, and
• Some embodiments of the present invention provide for a method of utilizing a combination of one or more antiarrhythmic agents and omega-3 fatty acids in the treatment of one or more of the following: hypertriglyceridemia, hypercholesterolemia, coronary heart disease (CHD), heart failure, 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, renal disease, elevated total cholesterol (total-C), elevated low density lipoprotein cholesterol (LDL-C), elevated apolipoprotein (Apo B), low high density lipoprotein cholesterol (HDL-C), cholesterol-associated benign and malignant tumors, 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 conditions
• a combination product for example, a unit dosage, comprising one or more antiarrhythmic agents and omega-3 fatty acids.
• the combination product is used in the treatment of one or more of the following: hypertriglyceridemia, hypercholesterolemia, coronary heart disease (CHD), heart failure, 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, renal disease, elevated total cholesterol (total-C), elevated low density lipoprotein cholesterol (LDL-C), elevated apolipoprotein (Apo B), low high density lipoprotein cholesterol (HDL-C), cholesterol-associated benign and malignant tumors, the treatment and/or prevention and/or reduction of cardiac events and/or cardiovascular events and/or vascular events and/or symptoms, and
• Yet other embodiments of the present invention are methods for the treatment of one or more of the following: hypertriglyceridemia, hypercholesterolemia, coronary heart disease (CHD), heart failure, 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, renal disease, elevated total cholesterol (total-C), elevated low density lipoprotein cholesterol (LDL-C), elevated apolipoprotein (Apo B), low high density lipoprotein cholesterol (HDL-C), cholesterol-associated benign and malignant tumors, 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 conditions that would benefit from treatment with such combinations, comprising a combined administration of one or more antiarrhythmic
• the present invention is directed to the utilization of one or more antiarrhythmic agents and omega-3 fatty acids, preferably LOVAZATMomega- 3 fatty acids, for the treatment of one or more of the following: hypertriglyceridemia, hypercholesterolemia, coronary heart disease (CHD), heart failure, 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, renal disease, elevated total cholesterol (total-C), elevated low density lipoprotein cholesterol (LDL-C), elevated apolipoprotein (Apo B), low high density lipoprotein cholesterol (HDL-C), cholesterol-associated benign and malignant tumors, 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
• this invention provides a novel combination product for the treatment of one or more of the following: hypertriglyceridemia, hypercholesterolemia, coronary heart disease (CHD), heart failure, 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, renal disease, elevated total cholesterol (total-C), elevated low density lipoprotein cholesterol (LDL-C), elevated apolipoprotein (Apo B), low high density lipoprotein cholesterol (HDL-C), cholesterol-associated benign and malignant tumors, 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 conditions that would benefit from treatment with such combinations, comprising the administration of the combination product to a
• the administration comprises omega-3 fatty acids, preferably in the form of the LOVAZATM omega-3 acids, and one or more antiarrhythmic agents, wherein the LOVAZATM omega-3 acids are administered simultaneous to administration of the one or more antiarrhythmic agents.
• the administration comprises omega-3 fatty acids, preferably in the form of the LOVAZATMomega-3 acids, and one or more antiarrhythmic agents, wherein the LOVAZATM omega-3 acids are administered apart from the administration of the one or more antiarrhythmic agents.
• the one or more antiarrhythmic agents may be administered once weekly (e.g., through a patch) with daily intake of omega-3 fatty acids (e.g., LOVAZATM capsules).
• antiarrhythmic agents may include: class Ia antiarrhythmic agents
• class Ib antiarrhythmic agents for example, lidocaine (e.g., XYLOCAINE®), mexiletine (e.g., MEXIT ⁇ L®), tocainide (e.g., TONOCARD®), and phenytoin); class Ic antiarrhythmic agents (for example, encainide (e.g., ENKAID®), flecainide (e.g., TABOCOR®), moricizine and propafenone (e.g., RHYTH MO L®)); class Il antiarrhythmic agents (for example, esmolol (e.g., BREVIBLOC®), propranolol (e.g., INDERAL®), acebutolol (e.g., SECTRAL®),
• esmolol e.g., BREVIBLOC®
• propranolol e.g., INDERAL®
• acebutolol e.g
• Other potential antiarrhythmic agents may include GYKI-16638, CPU-86017, EGIS-7229, KCB-328, L-768673, 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, pirmenol, moracizine, pilsicainide, nifekalant, dexsotalol, landiolol, nifedipine, ATI-2042, AVE-01 18, nibentan, stobadine, YM-758, SSR-149744, rotigaptide, tedisamil, and tecade
• the one or more antiarrhythmic agents include class Ic, preferably propafenone and/or flecainide, 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 tecadenoson.
• class Ic preferably propafenone and/or flecainide
• 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
• combination products of this invention involving one or more antiarrhythmic agents are distinct.
• more than one form of the one or more antiarrhythmic agents is combined with amounts of omega-3 fatty acids.
• 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 incorporated by reference), precursors or salts thereof and mixtures thereof.
• 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.
• 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 can 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 lncromega 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 A.S., 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 herein by reference in their entireties.
• 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 weight, most preferably at least 80% by weight, or even at least 90% by weight.
• 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. [0036]
• 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 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, 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 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 one or more antiarrhythmic agents and omega-3 fatty 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 orally administered.
• the dosage of active ingredients in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredients be such that a suitable dosage form is obtained. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the 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 other convenient dosage form such as oral liquid in a capsule, as known in the art.
• 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 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 active ingredients into an applicable and efficacious preparation that is safe, convenient, and otherwise acceptable for use.
• the non-active ingredients may include colloidal silicon dioxide, crospovidone, lactose monohydrate, lecithin, microcrystalline cellulose, polyvinyl alcohol, povidone, sodium lauryl sulfate, sodium stearyl fumarate, talc, titanium dioxide and xanthum gum.
• excipients primarily 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 omega-3 fatty acids can 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 most preferably from about 0.75 g to about 4 g.
• 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, more preferably about 1 g.
• one or more antiarrhythmic agents can 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.
• the combination of one or more antiarrhythmic agents and omega-3 fatty acids is formulated into a single administration or unit dosage.
• the daily dosages of one or more antiarrhythmic agents and 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.
• the administration is preferably oral administration, although other forms of administration that provide a unit dosage of one or more antiarrhythmic agents and omega-3 fatty acids may be used.
• a soft gelatin capsule is used.
• the manufacture of soft gelatin capsules is generally known by those of ordinary skill in the art. See, for example, Ebert (1978), “Soft Elastic Gelatin Capsules: A Unique Dosage Form," Pharmaceutical Technology 1 (5), hereby incorporated by reference.
• one or more antiarrhythmic agents and/or omega-3 fatty acids are contained in the soft gelatin capsule.
• 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 may be used is a vitamin E substance.
• This group of solubilizers includes a substance belonging to the group of ⁇ -, /?-, Y-, S-, fl-, ⁇ 2- and ⁇ -tocopherols, their dl, d and I forms and their structural analogues, such as tocotrienols; the corresponding derivatives, e.g., esters, produced with organic acids; and mixtures thereof.
• 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 succinate and salicylic acid.
• Particularly preferred vitamin E substance solubilizers include alpha-tocopherol, alpha- tocopheryl acetate, alpha-tocopheryl acid succinate, alpha-tocopheryl polyethylene glycol 1000 succinate and mixtures thereof.
• solubilizers are monohydric alcohol esters of organic acids.
• the monohydric alcohol can be, for example, ethanol, isopropanol, t- butanol, a fatty alcohol, phenol, cresol, benzyl alcohol or a cycloalkyl alcohol.
• the organic acid can be, for example, acetic acid, propionic acid, butyric acid, a fatty acid of 6-22 carbon atoms, 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 linoleate, ethyl caprylate, ethyl caprate, isopropyl myristate, isopropyl palmitate and mixtures thereof.
• Lactones may also serve as a solubilizer. Examples include e-caprolactone, ⁇ - valerolactone, /?-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 alkyl is a C 1 - 12 branched or straight chain alkyl.
• Particularly preferred nitrogen-containing solvents include N-methyl 2-pyrrolidone, N-ethyl 2-pyrrolidone or a mixture thereof.
• the nitrogen-containing solvent may be in the form of a polymer such as polyvinylpyrrolidone.
• solubilizers includes phospholipids.
• Preferred phospholipids include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, lecithins, lysolecithins, lysophosphatidylcholine, polyethylene glycolated phospholipids/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.
• the solubilizer may be a glycerol fatty acid ester.
• the fatty acid component is about 6-22 carbon atoms.
• the glycerol fatty acid ester can be a monoglyceride, diglyceride, triglyceride or mixtures thereof.
• P referred glycerol fatty acid esters include monoglycerides, diglycerides, medium chain triglycerides with fatty acids having about 6-12 carbons and mixtures thereof.
• Particularly preferred glycerol fatty acid esters include medium chain monoglycerides with fatty acids having about 6-12 carbons, medium chain diglycerides with fatty acids 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.
• the propylene glycol fatty acid ester may be a propylene glycol fatty acid monoester, propylene glycol fatty acid diester or mixture thereof.
• the 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.
• Ethylene glycol esters 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.
• the ethylene glycol ester may be a polyethylene glycol fatty acid monoesters, polyethylene glycol fatty acid diesters or mixtures thereof.
• the fatty acid component will contain about 6-22 carbon atoms.
• Particularly preferred ethylene glycol esters are those marketed under the LABRAFI L ® and LABRASOL ® names.
• Polyoxyethylene-sorbitan-fatty acid esters also called polysorbates
• Polysorbates e.g. of from 4 to 25 alkylene moieties, for example mono- and tri-lauryl, palmityl, stearyl and oleyl esters of the type known and commercially available under the trade name TWEEN ® are also suitable as surfactants.
• Hydrophilic solvents which may be used include an alcohol, e.g. a water miscible alcohol, e.g. absolute ethanol, or glycerol.
• Other alcohols include glycols, e.g. any glycol obtainable from an oxide such as ethylene oxide, e.g. 1 ,2-propylene glycol.
• Other examples are polyols, e.g.
• the hydrophilic component may preferably comprise an N-alkylpyrolidone, e.g. N-(Ci-i 4 alkyl)pyrolidone, e.g. N- methylpyrolidone, tri(Ci- 4 alkyl)citrate, e.g. triethylcitrate, dimethylisosorbide, (C 5 -Ci 3 )alkanoic acid, e.g. caprylic acid or propylene carbonate.
• the hydrophilic solvent may comprise a main or sole component, e.g.
• an alcohol e.g. e.g. ethanol
• a co-component e.g. which may be selected from partial lower ethers or lower alkanols.
• Preferred partial ethers are, for example, TRANSCUTOL ® (which has the formula C 2 H 5 -[O-(CH 2 ) 2 ] 2 -OH), GLYCOFUROL ® (also known as tetrahydrofurfuryl alcohol polyethylene glycol ether), or lower alkanols such as ethanol.
• a pharmaceutical composition in unit dosage form comprises an essentially homogeneous solution comprising one or more antiarrhythmic agents essentially dissolved in 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 the one or more antiarrhythmic agents is undissolved in the solvent system.
• the one or more antiarrhythmic agents are substantially dissolved in the omega-3 fatty acid oil to provide a substantially homogeneous composition.
• this aspect of the present invention does not include high amounts of solubilizers to dissolve the one or more antiarrhythmic agents.
• the one or more antiarrhythmic agents are contained in the pharmaceutical composition without the use of large amounts of solubilizers (other than the omega-3 fatty acids), and is substantially dissolved (i.e., less than 10%, preferably less than 5% remains undissolved in the solvent system).
• the one or more antiarrhythmic agents are completely dissolved.
• solubilizers other than the omega-3 fatty acids are present in amounts of 50% or less w/w based on the total weight of the solvent system in the dosage form, preferably 40% or less, more preferably 30% or less, even more preferably 20% or less, still more preferably 10% or less and most preferably 5% or less.
• the solvent system contains no solubilizers other than the omega-3 fatty acids.
• solvent system includes the omega-3 fatty acids, generally in the form of an oil.
• the weight ratio of omega-3 fatty acids to other 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 most preferably at least 10 to 1.
• omega-3 fatty acids are present in amounts of at least 30% w/w based on the total weight of the solvent system in the dosage form, more preferably at least 40%, even more preferably at least 50%, and most preferably at least 60%. In certain embodiments, the amount can be at least 70%, at least 80% or at least 90%.
• Dosage forms including the essentially homogenous solution should be stable at room temperature (about 23 0 C to 27 0 C, preferably about 25 0 C) and 60% relative humidity for a period of at least one month, preferably at least six months, more preferably at least one year, and most preferably at least two years.
• stable applicants mean that the solubilized one or more antiarrhythmic agents should not precipitate out of solution and not become chemically modified to any appreciable degree, for example, in amounts of less than 10%, preferably less than 5%.
• dosage forms including the essentially homogenous solution should preserve the one or more antiarrhythmic agents from degradation.
• Some embodiments include unit dosage forms 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 maintained after one month storage at room temperature and 60% relative humidity.
• the combination product may be manufactured by any method known by those of ordinary skill in the art, by combining the one or more antiarrhythmic agents with the omega-3 fatty acid(s), and optionally with hydrophilic solvent(s), surfactant(s), other solubilizing agents, and/or other excipients.
• compositions comprising suspensions of one or more antiarrhythmic agents in omega-3 fatty acids where a portion of the one or more antiarrhythmic agents is solubilized in the omega-3 fatty acids or in another component of the composition.
• the present invention provides a pharmaceutical composition comprising omega-3 fatty acids and one or more antiarrhythmic agents, wherein about 1- 15% of the one or more antiarrhythmic agents by weight are in solution while the remaining amount of the one or more antiarrhythmic agents are present in suspension.
• 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 90%, even more preferably about 95%, and most preferably about 99%, of the one or more antiarrhythmic agents by weight are present as solid particles in suspension.
• Another embodiment of the present invention is directed to a soft gelatin capsule coated with one or more antiarrhythmic agents.
• at least one coating applied to the outside of the soft gelatin capsule comprises the one or more antiarrhythmic agents and a coating material, such as a film forming material and/or binder, and optionally other conventional additives such as lubricants, fillers and antiadherents.
• a coating material such as a film forming material and/or binder
• other conventional additives such as lubricants, fillers and antiadherents.
• Preferred coating materials will include antioxidants, solubilizers, chelating agents and/or absorption enhancers.
• Surfactants may act as both solubilizers and absorption enhancers.
• the coating(s) may be applied by any conventional technique such as pan coating, fluid bed coating or spray coating.
• the coating(s) may be applied as a suspension, spray, dust or powder.
• the coating(s) may be formulated for immediate release, delayed/enteric release or sustained release of the second pharmaceutical active in accordance with methods well known in the art. Conventional coating techniques are described, e.g., in Remington's Pharmaceutical Sciences, 18th Ed. (1990), hereby incorporated by reference.
• An immediate release coating is commonly used to improve product elegance as well as for a moisture barrier, and taste and odor masking. Rapid breakdown of the film in gastric media is important, leading to effective disintegration and dissolution.
• EUDRAGIT RD100 Rostm
• EUDRAGIT RD100 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 readily dispensable into an easily sprayable suspension that dries to leave a smooth film. Such films rapidly disintegrate in aqueous media at a rate that is independent of pH and film thickness.
• a protective coating layer (i.e., seal coat) may be applied, if desired, by conventional coating techniques such as pan coating or fluid bed coating using solutions of polymers in water or suitable organic solvents or by 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 cellulose aqueous dispersions and the like.
• the protective coating layer may include antioxidants, chelating agents, colors or dyes.
• the enteric coating layer may be applied onto the cores with or without seal coating by conventional coating techniques, such as pan coating or fluid bed coating using solutions of polymers in water or suitable organic solvents or by using aqueous polymer dispersions. All commercially available pH-sensitive polymers are included.
• the pharmaceutical active is not released in the acidic stomach environment of approximately below pH 4.5, but not limited to this value. The pharmaceutical active should become available when the pH-sensitive layer dissolves at the greater pH; after a certain delayed time; or after the unit passes through the stomach.
• the preferred delay time 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, co-polymerized methacrylic acid/methacrylic acid methyl esters such as, for instance, materials known under the trade name EUDRAGIT L12.5, L100, or EUDRAGIT S12.5, S100 or similar compounds used to obtain enteric coatings.
• Aqueous colloidal polymer dispersions or re-dispersions can be also applied, e.g.
• a sustained release film coat may include a water insoluble material such as a wax or a wax-like substance, fatty alcohols, shellac, zein, hydrogenated vegetable oils, water insoluble celluloses, polymers of acrylic and/or methacrylic acid, and any other slowly digestible or dispersible solids known in the art.
• the solvent for the hydrophobic coating material may be organic or aqueous.
• 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.
• the hydrophobic material comprising the controlled release coating is an acrylic polymer. Any acrylic polymer which is pharmaceutically acceptable can be used for the purposes of the present invention.
• the acrylic polymers may be cationic, anionic or non- ionic polymers and may be acrylates, methacrylates, formed of methacrylic acid or methacrylic acid esters.
• acrylic polymers include but are not limited to acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl 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, methyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid, methacrylic acid alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, methyl methacrylate copolymer, poly(methyl methacrylate), poly(methyl methacryl
• a barrier coat may be included between an outer coat and the soft gelatin shell.
• the barrier coat may be comprised of an enteric/delayed release coat (as above), or a barrier (non-functional) layer, which serves as a protective coat to prevent leaching from the shell to the outer pharmaceutical active component, or vice versa.
• one or more antiarrhythmic agents with omega-3 fatty acids are split into first and second portions, with one portion disposed on a coating, and the second portion disposed in the soft gelatin capsule.
• the dosage form is provided with a lag time between the administration of the first portion and the administration of the second portion, e.g., by an enteric coating provided as a barrier layer.
• coating technology is used extensively in the pharmaceutical industry, e.g.
• Soft gelatin capsules generally contain a medicament dissolved or dispersed in oils or hydrophilic liquids (fill liquid).
• fill liquid oils or hydrophilic liquids
• the inherent flexibility of the soft gelatin capsule is due to the presence of plasticizers and residual moisture in the capsule shell.
• the soft gelatin capsule is a more dynamic system than conventional tablets or hard gelatin capsules. Atmospheric moisture may permeate into the capsule shell or into the fill liquid. The drug or fill liquid may migrate into the capsule shell, while the plasticizer or residual water gelatin can potentially migrate into the fill liquid.
• polymeric coatings are generally applied as aqueous- based solutions, organic-based solutions or dispersions, in which polymer- containing droplets are atomized with air and sprayed onto the substrate. Heat may be added to the coating equipment to facilitate evaporation of the solvent and film formation.
• the processing parameters of spray rate and bed temperature must be controlled. Because gelatin is soluble in water, spraying an aqueous-based polymeric material at a high rate could lead to solubilization of the gelatin and capsule agglomeration. A high bed temperature may result in the evaporation of residual water from the capsule shell, causing the capsule to become brittle. Therefore, the present invention comprises a method of coating soft gelatin capsules in which these consequences are avoided.
• the deposition of a low dose of one or more antiarrhythmic agents onto the surface of the soft gelatin capsules with high degree of accuracy could be affected by several factors.
• the accuracy of deposition needs to be demonstrated by evaluating coating uniformity which includes the mass variance of the coated capsules and the variance of the content of the coated one or more antiarrhythmic agents.
• the present invention provides for a method of 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 rate of coating deposition on the soft gelatin capsule and controlling the temperature during the coating process to produce a physically and chemically stable coated soft gelatin capsule.
• the coating of the present invention may also be applied onto a hard gelatin capsule or a tablet.
• the hard gelatin capsule may contain, instead of liquid, powder, beads or microtablets (e.g., similar system to U.S. Patent No. 5,681 ,588, incorporated herein by reference).
• Yet 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 maintained after one month storage at room temperature and 60% relative humidity.
• 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.
• the formulations of the present invention may allow for reduced dosages of one or more antiarrhythmic agents 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 one or more antiarrhythmic agents and omega-3 fatty acids may allow for a greater effect than any expected combined or additive effect of the two drugs alone.
• the combined treatment of the two active ingredients, separately or through the novel combination product of the present invention may cause an unexpected increase in effect of the active ingredients that allows increased effectiveness with standard dosages or maintained effectiveness with reduced dosages of the two active ingredients. It is well accepted in practice that an 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 may also be reduced as a result of the lower dosage amount and the reduction in excipients (e.g., surfactants).

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