Note: Descriptions are shown in the official language in which they were submitted.
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TREATMENT WITH ANTIARRHYTHMICS AND OMEGA-3
FATTY ACIDS AND A COMBINATION PRODUCT THEREOF
FIELD OF THE INVENTION
[0001] 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
LOVAZAT"' 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-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. 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 LOVAZAT"" omega-3
acids.
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BACKGROUND OF THE INVENTION
[0002] In humans, 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.
Cholesterol and triglycerides are synthesized in the liver, incorporated into
VLDL, and released into the plasma. High levels of 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, which are associated with the disease process of
atherosclerosis. Further, 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. In addition, once an arrhythmia has occurred, the dyslipidemic
state if left untreated will continue to predispose individuals to a
heightened
risk for subsequent events.
[0003] 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.
[0004] There are five main classes of antiarrhythmic agents:
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[0005] Class I antiarrhythmic agents are sodium channel blockers that are
believed to act by blocking or modulating Na+ channel activity, which are
generally divided into three subclasses. Class Ia may include, for example,
quinidine (e.g., QUINIDEX ), procainamide (e.g., PRONESTYL ), and
disopyramide (e.g., NORPACE ). Class lb 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
(e.g., Rhythmol );
[0006] Class II 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
LOPRESSOR );
[0007] 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,
RSD-1235, and sotalol (e.g., BETAPACE );
[0008] 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
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[0009] Class V antiarrhythmic agents work by other or unknown mechanisms
and may include, for example, adenosine (e.g., ADENOCARD ) and digoxin
(e.g., LANOXIN ).
[0010] 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, 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 tecadenoson.
[0011 ] It should be noted that some antiarrhythmic agents may work by one
or more mechanism and, therefore, be characterized as belonging to more
than one class.
[0012] 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 VII-phospholipid
complex. Further, omega-3 fatty acids are well tolerated without giving rise
to
any severe side effects.
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[0013] One form of 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
LOVAZAT"'. 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.
[0014] 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.
[0015] 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. 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 remaining statin is
present
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in heterogeneous suspension. Antiarrhythmic agents are not disclosed
among the list of potential active agents, i.e., statins.
[0016] Gillis et al. investigated the effects of dietary fat on the
pharmacodynamics of propafenone in isolated, perfused rabbit hearts. Gillis et
al., Circulation, 85(4):1501-1509 (1992). This study demonstrated that
omega-3 fatty acid content was highest in the fish oil group and that changes
in ventricular conduction time in the fish oil group were intermediate between
the lard and safflower oil groups during propafenone administration.
[0017] Previous studies have shown that the toxic effects of amiodarone may
be depressed using fatty acids. For example, it has been shown that EPA
pretreatment followed by co-treatment with EPA and amiodarone protects
against amiodarone-induced cell injury. Futamura, J. Pharmacol., 69: 335-
341 (1995). Similarly, 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).
[0018] 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. However, 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).
[0019] 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 lidocaine. Kang et al., Proc. Nati. Acad. Sci. Physiol.,
91:
9886-9890 (1994). See also, Dhein et al., Naunyn-Schmiedeberg's Arch
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Pharmacol, 371:202-211 (2005), which discloses class I-like and class IIf-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.
[0020] The prior art does not disclose the combined treatment with one or
more antiarrhythmic agents and omega-3 fatty acids, preferably
LOVAZAT"'omega-3 fatty acids, as disclosed in the present invention. In
addition, 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 LOVAZAT"^ 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
reiated 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.
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SUMMARY OF THE INVENTION
[0021] 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 single
administration of omega-3 fatty acids (e.g., the LOVAZAT"' omega-3 acids)
and one or more antiarrhythmic agents, for example, in a unit dosage to
provide specific therapeutic properties.
[0022] There is also an unmet need in the art for a method of administration
of a single administration or unit dosage product. Moreover, 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., the
LOVAZAT^^ omega-3 acids), wherein the one or more antiarrhythmic agents
are combined with the omega-3 fatty acids to provide specific therapeutic
properties.
[0023] 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),
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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.
[0024) 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 that would benefit from treatment with
such
combinations.
[0025] Other embodiments of the present invention are directed to a
combination product, for example, a unit dosage, comprising one or more
antiarrhythmic agents and omega-3 fatty acids. In one aspect of the
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embodiment, 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 the reduction of cholesterol and
triglyceride levels, and/or any other conditions that would benefit from
treatment with such combinations.
[0026] 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
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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 agents and omega-3
fatty acids, preferably, the specific product LOVAZAT^" omega-3 acids.
[0027] Other features and advantages of the present invention will become
apparent to those skilled in the art upon examination of the following or upon
learning by practice of the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0028] The present invention is directed to the utilization of one or more
antiarrhythmic agents and omega-3 fatty acids, preferably LOVAZAT"'omega-
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, and/or any other conditions that would benefit from treatment with
such
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combinations, and a combination product or unit dosage comprising one or
more antiarrhythmic agents and one or more omega-3 fatty acids.
[0029] 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), 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 patient. In a preferred
embodiment, the administration comprises omega-3 fatty acids, preferably in
the form of the LOVAZAT"^ omega-3 acids, and one or more antiarrhythmic
agents, wherein the LOVAZAT"" omega-3 acids are administered
simultaneous to administration of the one or more antiarrhythmic agents.
[0030] In other preferred embodiments, the administration comprises omega-3
fatty acids, preferably in the form of the LOVAZAT""omega-3 acids, and one or
more antiarrhythmic agents, wherein the LOVAZAT "omega-3 acids are
administered apart from the administration of the one or more antiarrhythmic
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agents. For example, 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., LOVAZAT'" capsules). One skilled in the art with the
benefit
of the present disclosure will understand that the precise dosage and
schedule for the administration of the LOVAZAT " omega-3 acids and the one
or more antiarrhythmic agents will vary depending on numerous factors, such
as, for example, the route of administration and the seriousness of the
conditions.
[0031] The present invention may incorporate now known or future known
antiarrhythmic agents in an amount generally recognized as safe. For
example, antiarrhythmic agents may include: class Ia antiarrhythmic agents
(for example, quinidine (e.g., QUINIDEX ), procainamide (e.g.,
PRONESTYL ), and disopyramide (e.g., NORPACE ); class lb
antiarrhythmic agents (for example, lidocaine (e.g., XYLOCAINE ), mexiletine
(e.g., MEXITIL ), 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., RHYTHMOL )); class
II antiarrhythmic agents (for example, esmolol (e.g., BREVIBLOC ),
propranolol (e.g., INDERAL ), acebutolol (e.g., SECTRAL ), sotalol (e.g.,
BETAPACE ), and metoprolol (TOPROL-XL or LOPRESSOR ); class III
antiarrhythmic agents (for example, amiodarone (e.g., CORDARONE ),
azimilide, bretylium, clofilium, dofetilide, tedisamil, ibutilide, sematilide,
dronaderone, RSD-1235, and sotalol (e.g., BETAPACE )); class IV
antiarrhythmic agents (for example, verapamil (e.g., CALAN or ISOPTIN ),
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mibefradil (e.g., POSICOR ) and diltiazem (e.g., CARDIZEM )); and class V
antiarrhythmic agents (for example, adenosine (e.g., ADENOCARD ) and
digoxin (e.g., LANOXIN )). 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-1 14646, 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 tecadenoson. In a preferred embodiment, 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-0118, nibentan, stobadine, YM-758, SSR-149744,
rotigaptide, tedisamil, and/or tecadenoson.
[0032] The combination products of this invention involving one or more
antiarrhythmic agents are distinct. In some embodiments, more than one
form of the one or more antiarrhythmic agents is combined with amounts of
omega-3 fatty acids.
[0033] As used herein, the term "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. Examples of omega-3 fatty acid oils include but
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are not limited to omega-3 polyunsaturated, long-chain fatty acids such as a
eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and a-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. The
omega-3 fatty acids or their esters, derivatives, conjugates, precursors,
salts
and mixtures thereof can be used either in their pure form or as a component
of an oil such as fish oil, preferably 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 A.S., 1326 Lysaker, Norway).
[0034] 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.
[0035] Another preferred composition includes omega-3 fatty acids present in
a concentration of at least 40% by weight, preferably at least 50% by weight,
more preferably at least 60% by weight, still more preferably at least 70% by
weight, most preferably at least 80% by weight, or even at least 90% by
weight. Preferably, 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
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weight. Preferably 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. Preferably 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.
[0037] 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.
[0038] The most preferred form of omega-3 fatty acids is the LOVAZA TM
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
Docosahexaenoic acid C22:6 347 mg/g 403 m/
EPA and DHA 800 m/ 880 m/
Total n-3 fatty acids 90 % w/w
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[0039] The combination product of one or more antiarrhythmic agents and
omega-3 fatty acids, preferably the LOVAZAT"' 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 orally administered.
[0040] 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.
[0041] 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.
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.
[0042] 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
known generally herein as "excipients"). Non-active ingredients, for example,
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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. Thus, 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.
[0043] In most embodiments, 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. The use of 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.
[0044] 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. Preferably, in the unit dosage
form,
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.
[0045] In one embodiment of the present invention, one or more
antiarrhythmic agents, depending on the selection of such antiarrhythmic
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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.
[0046] In some variations of the present invention, the combination of one or
more antiarrhythmic agents and omega-3 fatty acids (e.g., LOVAZAT"' omega-
3 acids) is formulated into a single administration or unit dosage.
[0047] 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.
[0048] In some preferred embodiments, 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. 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.
[0049] 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 a-,
,(3-, y-, 6-, ,'1-, ,'2- and ri-tocopherols, their dl, d and I forms and their
structural
analogues, such as tocotrienols; the corresponding derivatives, e.g., esters,
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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.
[0050] Another group of 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, d-
valerolactone, Q-butyrolactone, isomers thereof and mixtures thereof.
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[0051] 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 Cl-12 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.
[0052] Another group of solubilizers includes phospholipids. Preferred
phospholipids include phosphatidylcholine, phosphatidylethanolamine,
phosphatidyiserine, phosphatidylinositol, lecithins, lysolecithins,
lysophosphatidylcholine, polyethylene glycolated
phospholipids/lysophospholipids, lecithins/lysolecithins and mixtures thereof.
[0053] 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.
[0054] 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 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
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monoglycerides with fatty acids having about 6-12 carbons, medium chain
diglycerides with fatty acids having about 6-12 carbons and mixtures thereof.
[0055] 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 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.
[0056] Another group of solubilizers are ethylene glycol esters. 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. Alternatively, the ethylene glycol ester may be a polyethylene glycol
fatty acid monoesters, polyethylene glycol fatty acid diesters 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
LABRAFIL and LABRASOL names.
[0057] Polyoxyethylene-sorbitan-fatty acid esters (also called polysorbates),
e.g. of from 4 to 25 alkylene moieties, for example mono- and tri-lauryl,
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paimityl, stearyl and oleyl esters of the type known and commercially
available
under the trade name TWEEN are also suitable as surfactants.
[0058] 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. a
polyalkylene glycol, e.g. poly(C2_3)alkylene glycol. A typical example is a
polyethylene glycol. Alternatively the hydrophilic component may preferably
comprise an N-alkylpyrolidone, e.g. N-(Cl-14alkyl)pyrolidone, e.g. N-
methylpyrolidone, tri(Cl-4alkyl)citrate, e.g. triethylcitrate,
dimethylisosorbide,
(C5-C13)alkanoic acid, e.g. caprylic acid or propylene carbonate.
[0059] The hydrophilic solvent may comprise a main or sole component, e.g.
an alcohol, e.g. Cl-4-alcohol, e.g. ethanol, or alternatively 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 C2H5-[O-(CH2)2]2-OH), GLYCOFUROL (also known as
tetrahydrofurfuryl alcohol polyethylene glycol ether), or lower alkanols such
as
ethanol.
[0060] The combination product of one or more antiarrhythmic agents and
omega-3 fatty acids is aided by the solubility of the one or more
antiarrhythmic
agents in the 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 solvent system comprising natural or synthetic
omega-3 fatty acids or pharmaceutically acceptable esters, derivatives,
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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. 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 the omega-3 fatty acids), and is substantially
dissolved
(i.e., less than 10%, preferably less than 5% remains undissolved in the
solvent system).
[0061] In a preferred embodiment, the one or more antiarrhythmic agents are
completely dissolved. In preferred embodiments, if present at all,
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. In some
embodiments, the solvent system contains no solubilizers other than the
omega-3 fatty acids. As used herein, "solvent system" includes the omega-3
fatty acids, generally in the form of an oil. In other preferred embodiments,
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.
[0062] In preferred embodiments, 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
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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%.
[0063] Dosage forms including the essentially homogenous solution should
be stable at room temperature (about 23 C to 27 C, preferably about 25 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. By "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%.
[0064] In addition, 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.
[0065] 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.
[0066] Other embodiments of the present invention are directed to
suspensions of one or more antiarrhythmic agents in omega-3 fatty acids. In
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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
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. 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 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.
[0067] 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 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.
[0068] Another embodiment of the present invention is directed to a soft
gelatin capsule coated with one or more antiarrhythmic agents. In such an
embodiment, 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.
Preferred
coating materials will include antioxidants, solubilizers, chelating agents
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and/or absorption enhancers. Surfactants may act as both solubilizers and
absorption enhancers.
[0069] 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.
[0070] 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 (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 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.
[0071] 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,
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polyvinylpyrrolidone/vinyl acetate copolymer, ethyl cellulose aqueous
dispersions and the like. The protective coating layer may include
antioxidants, chelating agents, colors or dyes.
[0072] 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.
[0073] Enteric polymers include cellulose acetate phthalate, Cellulose acetate
trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate
phthalate, carboxymethylethyfcellulose, 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. EUDRAGIT L 30D-55,
EUDRAGIT L100-55, EUDRAGIT S100, EUDRAGIT preparation 4110D
(Rohm Pharma); AQUATERIC, AQUACOAT CPD 30 (FMC); KOLLICOAT
MAE 30D and 30DP (BASF); EASTACRYL 30D (Eastman Chemical).
[0074] A sustained release film coat may include a water insoluble material
such as a wax or a wax-like substance, fatty alcohols, shellac, zein,
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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. 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 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. Examples of suitable 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
methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate
copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate
copolymers.
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[0075] 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.
[0076] In one embodiment of the invention, 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. In other embodiments,
there is an immediate release of the first portion, followed by a delayed or
sustained release of the second portion. In further embodiments, there is a
delayed release of the first portion, followed by a bolus of the second
portion.
[0077] While coating technology is used extensively in the pharmaceutical
industry, e.g. for the application of functional or non-functional coats to
single
dosage forms and for the deposition of APIs onto sugar beads, there are
several challenges which can be encountered during coating of soft gelatin
capsules. These challenges are often attributed to the properties of gelatin
and the dosage form. Soft gelatin capsules generally contain a medicament
dissolved or dispersed in oils or hydrophilic liquids (fill liquid). 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 tablets or hard gelatin capsules.
Atmospheric moisture may permeate into the capsule shell or into the fill
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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.
Volatile components in soft gelatin capsules may escape into the atmosphere.
[0078] As noted above, 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. In the case of soft gelatin capsules, 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.
[0079] In addition, 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.
[0080] 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
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capsule and controlling the temperature during the coating process to produce
a physically and chemically stable coated soft gelatin capsule.
[0081] In other embodiments, 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).
[0082] 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.
[0083] 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 full-strength dose. In other embodiments, 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.
[0084] 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. Thus, 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
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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).
[0085] All references cited herein are hereby incorporated by reference in
their entirety.
33
