U.S. patent application number 13/124628 was filed with the patent office on 2012-04-19 for pharmaceutical compositions comprising epa and a cardiovascular agent and methods of using the same.
This patent application is currently assigned to AMARIN CORPORATION PLC. Invention is credited to Mehar Manku, Jonathan Rowe.
Application Number | 20120093922 13/124628 |
Document ID | / |
Family ID | 43032772 |
Filed Date | 2012-04-19 |
United States Patent
Application |
20120093922 |
Kind Code |
A1 |
Manku; Mehar ; et
al. |
April 19, 2012 |
PHARMACEUTICAL COMPOSITIONS COMPRISING EPA AND A CARDIOVASCULAR
AGENT AND METHODS OF USING THE SAME
Abstract
The present invention relates to, inter alia, pharmaceutical
compositions comprising EPA and one or more cardiovascular agents,
and to therapeutic methods for treating various diseases and
disorders using the same.
Inventors: |
Manku; Mehar; (Oxford,
GB) ; Rowe; Jonathan; (Waterford, CT) |
Assignee: |
AMARIN CORPORATION PLC
Dublin
IE
|
Family ID: |
43032772 |
Appl. No.: |
13/124628 |
Filed: |
April 29, 2010 |
PCT Filed: |
April 29, 2010 |
PCT NO: |
PCT/US2010/032948 |
371 Date: |
December 29, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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61173759 |
Apr 29, 2009 |
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Current U.S.
Class: |
424/451 ;
424/490; 514/158; 514/253.01; 514/274; 514/307; 514/365; 514/423;
514/450; 514/549; 514/560; 514/99 |
Current CPC
Class: |
A61P 3/04 20180101; A61K
31/232 20130101; A61P 31/18 20180101; A61K 9/48 20130101; A61P 7/02
20180101; A61K 31/222 20130101; A61K 31/40 20130101; A61K 31/74
20130101; A61P 9/00 20180101; A61K 31/505 20130101; A61P 25/28
20180101; A61K 47/34 20130101; A61P 7/12 20180101; A61K 47/26
20130101; A61P 3/08 20180101; A61P 9/10 20180101; A61P 9/04
20180101; A61K 45/06 20130101; A61P 3/06 20180101; A61P 9/12
20180101; A61K 31/202 20130101; A61P 3/00 20180101; A61P 1/16
20180101; A61K 47/22 20130101; A61P 3/10 20180101; A61P 9/06
20180101; A61K 31/202 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/451 ;
514/560; 514/423; 514/549; 424/490; 514/450; 514/158; 514/99;
514/253.01; 514/274; 514/307; 514/365 |
International
Class: |
A61K 31/202 20060101
A61K031/202; A61K 31/232 20060101 A61K031/232; A61K 9/50 20060101
A61K009/50; A61K 9/48 20060101 A61K009/48; A61K 31/365 20060101
A61K031/365; A61K 31/635 20060101 A61K031/635; A61K 31/665 20060101
A61K031/665; A61K 31/496 20060101 A61K031/496; A61K 31/513 20060101
A61K031/513; A61K 31/472 20060101 A61K031/472; A61K 31/427 20060101
A61K031/427; A61K 31/4725 20060101 A61K031/4725; A61P 9/10 20060101
A61P009/10; A61P 25/28 20060101 A61P025/28; A61P 9/06 20060101
A61P009/06; A61P 9/00 20060101 A61P009/00; A61P 9/04 20060101
A61P009/04; A61P 9/12 20060101 A61P009/12; A61P 3/06 20060101
A61P003/06; A61P 3/04 20060101 A61P003/04; A61P 3/10 20060101
A61P003/10; A61K 31/40 20060101 A61K031/40 |
Claims
1. A pharmaceutical composition comprising EPA and a cardiovascular
agent, wherein the composition contains not more than 10% DHA by
weight, if any.
2. The composition of claim 1 wherein the cardiovascular agent is
an ACAT inhibitor, an ACE inhibitor, an alpha-blocker, an
alpha/beta-blocker, an angiotensin II receptor antagonist, an
anti-arrythmic agent, an antiplatelet agent, a beta-blocker, a
calcium-channel blocker, an HMG-CoA reductase inhibitor, an apoA-1
mimetic, a CETP inhibitor, a bile acid sequestrant, a cholesterol
absorption inhibitor, a diuretic, a dyslipidemia agent, an
endothelin receptor antagonist, an LDL receptor inducer, an Lp-PLA2
inhibitor, a squalene epoxidase inhibitor, an LCAT activator, a
microsomal triglyceride transfer protein inhibitor, an sPLA2
inhibitor, a 5-lipoxygenase inhibitor, a PPAR agonist/activator, a
thrombolytic agent, a thyroid receptor beta activator, a platelet
aggregation inhibitor, or an aldosterone antagonist.
3. The composition of claim 1 wherein the cardiovascular agent is
selected from the group including of 5-LO inhibitor 6, A-0002,
abciximab, ABT-335, ABT-761, acebutolol, acetohexamide, adenosine,
AEGR-733, Aldactone, aleglitezar, aliskiren, aliskiren
hemifumarate, alliin, amiodarone, amlodipine, amorolfine,
amprenavir, anacetrapib, Angpt14 antibody, Anti-oxLDL, APA-01,
apixaban, APL180, APP018, aspirin, atenolol, atorvastatin, AVE5530,
AZD-2479, BAY-60-5521, benazepril, BMS-200150, bosentan,
butenafine, candesartan, captopril, carvedilol, CER-002,
chlorothiazide sodium, chlorpropamide, choline fenofibrate,
CI-1011, cilostazol, clevidipine butyrate, clonidine, clopidegrel,
CMI 977, colesevelam, colestipol, CP-346086, CP-800569, CRD-5,
CS-505, CSL111, dalcetrapib, dalteparin, darapladib, defibrotide,
diallyl disulfide, diallyl trisulfide, digoxin, diltiazem,
dipyridamole, dirlotapide, disopyramide, doxazosin, enalapril,
enaliprilat, enoxaparin, epigallocatechin-3-O-gallate, eplerenone,
eprosartan, eprotirome, eptifibatide, an estrogen or an analog
thereof, ETC-1001, ETC-216, ETC-588-liposome, ETC-642, ethacrynic
acid, ezetimibe, fenofibrate, flecamide, fluvastatin, fondoparinux,
fosamprenavir, fosinopril, FR194738, furosemide, gemfibrozil,
GFT14, GFT505, glimepiride, glipizide, glyburide, GSK-256073,
GW501516, hydrochlorothiazide, implitapide, indapamide, indinavir,
irbesartan, isradipine, JTT-130, JTT-705, KD-3010, lactacystin,
laropiprant, LCAT enzyme, LCP-AtorFen, lidocaine, lisinopril,
lonapalene lopinavir, losartan, lovastatin, LY 333013, MAHDL01,
MB07811, MBX-8025, metformin, methyldopa, metoprolol succinate,
mexiletine, metoprolol, MK-886, moexipril, nadolol, naftifine,
nateglinide, NB-598, NCX6560, Nebivolol, nelfinavir, niacin,
niaspan, nicardipine, nimodipine, nisoldipine, olmesartan,
orlistat, PCSK9 RNAi, PD-348292, perindopril, PF-3185043, pindolol,
pioglitazone, PLX204, pravastatin, prazosin, procainamide,
propafenone hydrochloride, propranolol hydrochloride, quinapril,
quinidine gluconate, R7232, ramipril, recombinant apoA-1,
recombinant LCAT, repaglinide, resveratrol
(trans-3,4',5-trihydroxystilbene), reverse D-4F, rilapladib,
ritonavir, rosiglitazone, rosiglitazone maleate, rosuvastatin,
RVX-208, RWJ 800025, S-allylcysteine, saquinavir, selenocysteine,
sildenafil, simvastatin, SLx-4090, Sobetirome (QRX-431), tadalafil,
telmisartan, terazosin, terbinafine, thelin, ticlopidine,
tirofiban, tocamide, tolazamide, tolbutamide, torcetrapib,
torsemide, trandolapril, TRIA-662, triamterene, trimeric ApoA-1,
valsartan, vardenafil, VIA-2291, verapamil, verespladib, volibris,
WA8242A, WA8242A.sub.2, WA8242B, ZD2138, zileuton, or a combination
thereof.
4. The composition of claim 1 further comprising an additional
cardiovascular agent.
5. The composition of claim 4 wherein the additional cardiovascular
agent is selected from an ACAT inhibitor, an ACE inhibitor, an
alpha-blocker, an alpha/beta-blocker, an angiotensin II receptor
antagonist, an anti-arrythmic agent, an antiplatelet agent, a
beta-blocker, a calcium-channel blocker, an HMG-CoA reductase
inhibitor, an apoA-1 mimetic, a CETP inhibitor, a bile acid
sequestrant, a cholesterol absorption inhibitor, a diuretic, a
dyslipidemia agent, an endothelin receptor antagonist, an LDL
receptor inducer, an Lp-PLA2 inhibitor, a squalene epoxidase
inhibitor, an LCAT activator, a microsomal triglyceride transfer
protein inhibitor, a PPAR agonist/activator, a thrombolytic agent,
a thyroid receptor beta activator, a platelet aggregation
inhibitor, or an aldosterone antagonist.
6. The composition of claim 1 further comprising a pharmaceutically
acceptable excipient.
7. The composition of claim 6 wherein the excipient is selected
from a carrier, a diluent, an antioxidant, a flavoring agent, a
sweetening agent, a colorant, a suspending agent, or a combination
thereof.
8. The composition of claim 1 wherein the EPA is present in an
amount from about 100 mg to about 1500 mg.
9. The composition of claim 1 wherein the composition contains less
than 0.5% DHA or derivative by weight of total fatty acids.
10. The composition of claim 1 wherein the composition contains
substantially no DHA or derivative thereof.
11. The composition of claim 1 wherein the weight ratio of EPA to
other fatty acids is at least about 96:4.
12. The composition of claim 1 wherein the EPA comprises a
C.sub.1-C.sub.5 alkyl ester.
13. The composition of claim 12 wherein the C.sub.1-C.sub.5 alkyl
ester comprises EPA ethyl ester.
14. The composition of claim 1 wherein the composition contains
less than 1% of tocopherols by weight, if any.
15. The composition of claim 1 wherein the composition is in an
orally deliverable dosage form.
16. The composition of claim 15 wherein the dosage form comprises a
tablet, caplet, capsule, powder, lozenge, sachet, cachet, troche,
pellet, granule, microgranule, encapsulated microgranule, or powder
aerosol.
17. The composition of claim 1 wherein the cardiovascular agent is
suspended in the EPA.
18. The composition of claim 17 wherein the suspension is
substantially uniform.
19. The composition of claim 18 wherein the composition is present
in a capsule.
20. The composition of claim 1 wherein the cardiovascular agent
comprises orlistat or metformin.
21. A method of treating a cardiovascular-related disease
comprising administering to a subject in need thereof EPA and a
cardiovascular agent.
22. The method of claim 21 wherein the cardiovascular-related
disease is selected from the group consisting of acute cardiac
ischemic events, acute myocardial infarction, Alzheimer's disease,
angina, angina pectoris, arrhythmia, arterial fibrulation,
atherosclerosis, atrial fibrillation, cardiac insufficiency,
cardiovascular disease, chronic heart failure, chronic stable
angina, congestive heart failure, coronary artery disease, coronary
heart disease, deep vein thrombosis, diabetes, diabetes mellitus,
diabetic neuropathy, diastolic dysfunction in subjects with
diabetes mellitus, edema, essential hypertension, eventual
pulmonary embolism, fatty liver disease, heart disease, heart
failure, homozygous familial hypercholesterolemia (HoFH),
homozygous familial sitosterolemia, hypercholesterolemia,
hyperlipidemia, hyperlipidemia in HIV positive subjects,
hypertension, hypertriglyceridemia, ischemic complications in
unstable angina and myocardial infarction, low blood pressure,
metabolic syndrome, mixed dyslipidemia, moderate to mild heart
failure, myocardial infarction, obesity management, paroxysmal
atrial fibrillation/flutter (PAF), paroxysmal supraventricular
tachycardias (PSVT), particularly severe or rapid onset edema,
platelet aggregation, primary hypercholesterolemia, primary
hyperlipidemia, pulmonary arterial hypertension, pulmonary
hypertension, recurrent hemodynamically unstable ventricular
tachycardia (VT), recurrent ventricular arrhythmias, recurrent
ventricular fibrillation (VF), ruptured aneurysm, sitisterolemia,
stroke, supraventricular tachycardia, symptomatic atrial
fibrillation/flutter, tachycardia, type-II diabetes, vascular
disease, venous thromboembolism, and ventricular arrhythmias.
23. The method of claim 22 wherein the cardiovascular agent is
selected from the group consisting of an ACAT inhibitor, an ACE
inhibitor, an alpha-blocker, an alpha/beta-blocker, an angiotensin
II receptor antagonist, an anti-arrythmic agent, an antiplatelet
agent, a beta-blocker, a calcium-channel blocker, an HMG-CoA
reductase inhibitor, an apoA-1 mimetic, a CETP inhibitor, a bile
acid sequestrant, a cholesterol absorption inhibitor, a diuretic, a
dyslipidemia agent, an endothelin receptor antagonist, an LDL
receptor inducer, an Lp-PLA2 inhibitor, a squalene epoxidase
inhibitor, an LCAT activator, a microsomal triglyceride transfer
protein inhibitor, a PPAR agonist/activator, a thrombolytic agent,
a thyroid receptor beta activator, a platelet aggregation
inhibitor, or an aldosterone antagonist.
24. The method of claim 23 wherein the cardiovascular agent is
selected from the group consisting of 5-LO inhibitor 6, A-0002,
abciximab, ABT-335, ABT-761, acebutolol, acetohexamide, adenosine,
AEGR-733, Aldactone, aleglitezar, aliskiren, aliskiren
hemifumarate, alliin, amiodarone, amlodipine, amorolfine,
amprenavir, anacetrapib, Angpt14 antibody, Anti-oxLDL, APA-01,
apixaban, APL180, APP018, aspirin, atenolol, atorvastatin, AVE5530,
AZD-2479, BAY-60-5521, benazepril, BMS-200150, bosentan,
butenafine, candesartan, captopril, carvedilol, CER-002,
chlorothiazide sodium, chlorpropamide, choline fenofibrate,
CI-1011, cilostazol, clevidipine butyrate, clonidine, clopidegrel,
CMI 977, colesevelam, colestipol, CP-346086, CP-800569, CRD-5,
CS-505, CSL111, dalcetrapib, dalteparin, darapladib, defibrotide,
diallyl disulfide, diallyl trisulfide, digoxin, diltiazem,
dipyridamole, dirlotapide, disopyramide, doxazosin, enalapril,
enaliprilat, enoxaparin, epigallocatechin-3-O-gallate, eplerenone,
eprosartan, eprotirome, eptifibatide, an estrogen or an analog
thereof, ETC-1001, ETC-216, ETC-588-liposome, ETC-642, ethacrynic
acid, ezetimibe, fenofibrate, flecamide, fluvastatin, fondoparinux,
fosamprenavir, fosinopril, FR194738, furosemide, gemfibrozil,
GFT14, GFT505, glimepiride, glipizide, glyburide, GSK-256073,
GW501516, hydrochlorothiazide, implitapide, indapamide, indinavir,
irbesartan, isradipine, JTT-130, JTT-705, KD-3010, lactacystin,
laropiprant, LCAT enzyme, LCP-AtorFen, lidocaine, lisinopril,
lonapalene lopinavir, losartan, lovastatin, LY 333013, MAHDL01,
MB07811, MBX-8025, metformin, methyldopa, metoprolol succinate,
mexiletine, metoprolol, MK-886, moexipril, nadolol, naftifine,
nateglinide, NB-598, NCX6560, Nebivolol, nelfinavir, niacin,
niaspan, nicardipine, nimodipine, nisoldipine, olmesartan,
orlistat, PCSK9 RNAi, PD-348292, perindopril, PF-3185043, pindolol,
pioglitazone, PLX204, pravastatin, prazosin, procainamide,
propafenone hydrochloride, propranolol hydrochloride, quinapril,
quinidine gluconate, R7232, ramipril, recombinant apoA-1,
recombinant LCAT, repaglinide, resveratrol
(trans-3,4',5-trihydroxystilbene), reverse D-4F, rilapladib,
ritonavir, rosiglitazone, rosiglitazone maleate, rosuvastatin,
RVX-208, RWJ 800025, S-allylcysteine, saquinavir, selenocysteine,
sildenafil, simvastatin, SLx-4090, Sobetirome (QRX-431), tadalafil,
telmisartan, terazosin, terbinafine, thelin, ticlopidine,
tirofiban, tocamide, tolazamide, tolbutamide, torcetrapib,
torsemide, trandolapril, TRIA-662, triamterene, trimeric ApoA-1,
valsartan, vardenafil, VIA-2291, verapamil, verespladib, volibris,
WA8242A, WA8242A.sub.2, WA8242B, ZD2138, zileuton, or a combination
thereof.
25. The method of claim 21 wherein the cardiovascular agent and EPA
are co-administered as separate dosage units.
26. The method of claim 21 wherein the EPA and cardiovascular agent
are coformulated and administered as a single dosage unit.
27. The method of claim 26 wherein the dosage unit is administered
one to a plurality of times per day.
28. A method of treating hypertriglyceridemia in an HIV+ subject,
the method comprising administering to the subject a pharmaceutical
composition comprising an HIV-1 protease inhibitor and ultra-pure
EPA.
29. The method of claim 28 wherein the HIV-1 protease inhibitor
comprises amprenavir, fosamprenavir, indinavir, lopinavir,
nelfinavir, ritonavir, saquinavir, or a combination thereof.
30. A method of treating or preventing obesity in a subject in need
thereof, the method comprising administering to the subject a
pharmaceutical composition comprising EPA and orlistat.
31. The method of claim 30 wherein the EPA and orlistat are
administered in a same dosage unit.
32. The method of claim 30 wherein the EPA and orlistat are
co-administered in separate dosage units.
33. A method of treating Type II diabetes in a subject in need
thereof, the method comprising administering to the subject a
pharmaceutical composition comprising EPA and metformin.
34. The method of claim 33 wherein the EPA and metformin are
administered in a same dosage unit.
35. The method of claim 33 wherein the EPA and metformin are
co-administered in separate dosage units.
Description
BACKGROUND
[0001] Cardiovascular disease is one of the leading causes of death
in the United States and most European countries. It is estimated
that over 70 million people in the United States alone suffer from
a cardiovascular disease or disorder including but not limited to
high blood pressure, coronary heart disease, dyslipidemia,
congestive heart failure and stroke.
SUMMARY
[0002] In one embodiment, the present invention provides a
pharmaceutical composition comprising EPA and optionally one or
more additional cardiovascular agents. In another embodiment, the
EPA comprises eicosapentaenoic acid ethyl ester. In another
embodiment, the composition contains substantially no amount of
docosahexaenoic acid or derivative thereof (e.g. ethyl-DHA), if
any.
[0003] In other embodiments, the present invention provides methods
of treating and/or preventing a cardiovascular-related disease
comprising administering to a subject in need thereof a
pharmaceutical composition or composition(s) comprising EPA and
optionally one or more additional cardiovascular agents.
[0004] In any of the foregoing embodiments, the EPA and additional
cardiovascular agent(s) can be co-formulated as a single dosage
unit or can be formulated as two to a plurality of dosage units for
coordinated, combination or concomitant administration.
[0005] These and other embodiments of the present invention will be
disclosed in further detail herein below.
BRIEF DESCRIPTION OF THE DRAWINGS
[0006] FIG. 1 shows effects of EPA, DHA and Combination Treatment
on membrane lipid peroxidation at cholesterol-to-phospholipid ratio
of 1.0.
[0007] FIG. 2 shows effects of EPA, DHA and Combination Treatment
on membrane lipid peroxidation at cholesterol-to-phospholipid ratio
of 0.5.
[0008] FIG. 3 shows cholesterol-dependent effects of EPA, DHA and
Combination Treatment on membrane lipid peroxidation.
[0009] FIG. 4 EPA, DHA or EPA/DHA with atorvastatin (10:1 Mole
Ratio) on lipid peroxide levels in cholesterol enriched membranes
(1:1 cholesterol-to-phospholipid ratio).
DETAILED DESCRIPTION
[0010] While the present invention is capable of being embodied in
various forms, the description below of several embodiments is made
with the understanding that the present disclosure is to be
considered as an exemplification of the invention, and is not
intended to limit the invention to the specific embodiments
illustrated. Headings are provided for convenience only and are not
to be construed to limit the invention in any manner. Embodiments
illustrated under any heading may be combined with embodiments
illustrated under any other heading.
[0011] The use of numerical values in the various quantitative
values specified in this application, unless expressly indicated
otherwise, are stated as approximations as though the minimum and
maximum values within the stated ranges were both preceded by the
word "about." In this manner, slight variations from a stated value
can be used to achieve substantially the same results as the stated
value. Also, the disclosure of ranges is intended as a continuous
range including every value between the minimum and maximum values
recited as well as any ranges that can be formed by such values.
Also disclosed herein are any and all ratios (and ranges of any
such ratios) that can be formed by dividing a recited numeric value
into any other recited numeric value. Accordingly, the skilled
person will appreciate that many such ratios, ranges, and ranges of
ratios can be unambiguously derived from the numerical values
presented herein and in all instances such ratios, ranges, and
ranges of ratios represent various embodiments of the present
invention.
Eicosapentaenoic Acid
[0012] In one embodiment, compositions of the invention comprise
EPA as an active ingredient. The term "EPA" as used herein refers
to eicosapentaenoic acid (e.g. eicosa-5,8,11,14,17-pentaenoic acid)
and/or a pharmaceutically acceptable ester, derivative, conjugate
or salt thereof, or mixtures of any of the foregoing. The term
"pharmaceutically acceptable" in the present context means that the
substance in question does not produce unacceptable toxicity to the
subject or interaction with other components of the
composition.
[0013] In one embodiment, the EPA comprises all-cis
eicosa-5,8,11,14,17-pentaenoic acid. In another embodiment, the EPA
is in the form of an eicosapentaenoic acid ester (also referred to
herein as E-EPA or ethyl-EPA). In another embodiment, the EPA
comprises a C.sub.1-C.sub.5 alkyl ester of EPA. In another
embodiment, the EPA comprises, eicosapentaenoic acid methyl ester,
eicosapentaenoic acid propyl ester, or eicosapentaenoic acid butyl
ester. In still another embodiment, the EPA comprises all-cis
eicosa-5,8,11,14,17-pentaenoic acid ethyl ester.
[0014] In another embodiment, the EPA comprises lithium EPA, mono,
di- or triglyceride EPA or any other ester or salt of EPA, or the
free acid form of EPA. The EPA may also be in the form of a
2-substituted derivative or other derivative which slows down its
rate of oxidation but does not otherwise change its biological
action to any substantial degree.
[0015] In one embodiment, EPA present in a composition of the
invention comprises ultra-pure EPA. The term "ultra-pure" as used
herein with respect to EPA refers to a composition comprising at
least 96% by weight EPA (as the term "EPA" is defined and
exemplified herein). Ultra-pure EPA can comprise even higher purity
EPA, for example at least 97% by weight EPA or at least 98% by
weight EPA, wherein the EPA is any form of EPA as set forth herein.
Ultra-pure EPA can further be defined (e.g. impurity profile) by
any of the description of EPA provided herein.
[0016] In another embodiment, the EPA comprises an EPA-Fatty Acid
conjugate wherein EPA is conjugated to another molecule of EPA or
to another fatty acid. In one embodiment, the EPA-Fatty Acid
conjugate comprises a diester formed between EPA and EPA or between
EPA a second fatty acid as shown in structures (I) and (II). In one
embodiment, R.sup.1 is a fatty acid acyl group derived from EPA and
R.sup.2 is selected from H, a fatty acid acyl of 12 to 30 carbon
atoms with two or more cis or trans double bonds and fatty alcohol
groups of 12 to 30 carbon atoms, the same or different than
R.sup.1. R.sup.1 and R.sup.2 may both be derived from EPA (EPA-EPA)
or one may be derived from EPA and the second from a different
fatty acid (EPA-Fatty acid), for example gamma-linolenic acid,
dihomo-gamma-linolenic acid, arachidonic acid, adrenic acid,
stearidonic acid, docosapentaenoic acid n-3, etc.). R.sup.3 is
generally either hydrogen, fully hydrocarbon, or containing
heteroatoms, and in one embodiment is a C.sub.1-C.sub.4 alkyl
group.
##STR00001##
[0017] Synthesis of a diester conjugate can be accomplished
according to methods well known in the art, including for example,
using metals, metal-chlorides, or organic acids as catalysts; using
fatty acid chlorides such as EPA-chloride, .gamma.-linolenic acid
chloride (GLA-chloride), dihomo-.gamma.-linolenic acid chloride
(DGLA-chloride), linoleic acid chloride (LA-chloride), arachidonic
acid chloride (AA-chloride), conjugated linoleic acid chloride
(cLA-chloride), ALA-chloride, STA-chloride, ETA-chloride,
DPA-chloride, etc.; and the use of immobilized enzymes as
catalysts.
[0018] In another embodiment, a composition of the present
invention includes a mixture of EPA-Fatty Acid diesters. In a
related embodiment, compositions of the present invention include
less than 20% EPA-DHA conjugate, less than 15% EPA-DHA conjugate,
less than 10% EPA-DHA conjugate, less than 9% EPA-DHA conjugate,
less than 8% EPA-DHA conjugate, less than 7% EPA-DHA conjugate,
less than 6% EPA-DHA conjugate, less than 5% EPA-DHA conjugate,
less than 4% EPA-DHA conjugate, less than 3% EPA-DHA conjugate,
less than 2% EPA-DHA conjugate, less than 1% EPA-DHA conjugate,
less than 0.5% EPA-DHA conjugate, or less than 0.1% EPA-DHA
conjugate, by weight.
[0019] In another embodiment, a composition of the present
invention includes at least 96% EPA-Fatty acid conjugate (e.g.
EPA-EPA), at least 97% EPA-Fatty acid conjugate, at least 98%
EPA-Fatty acid conjugate, or at least 99% EPA-Fatty acid conjugate.
In another embodiment, a composition of the present invention
contains no more than 10%, no more than 9%, no more than 8%, no
more than 7%, no more than 6%, no more than 5%, no more than 4%, no
more than 3%, no more than 2%, no more than 1%, or no more than
0.6%, no more than 0.5%, no more than 0.4%, no more than 0.3%, no
more than 0.2, or no more than 0.1% of any EPA-Fatty Acid conjugate
other than EPA-EPA diester.
[0020] In another embodiment, EPA is present in a composition of
the invention in an amount of about 50 mg to about 5000 mg, about
75 mg to about 2500 mg, or about 100 mg to about 1000 mg, for
example about 75 mg, about 100 mg, about 125 mg, about 150 mg,
about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275
mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about
400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg,
about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625
mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about
750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg,
about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975
mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg,
about 1100 mg, about 1025 mg, about 1050 mg, about 1075 mg, about
1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300
mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg,
about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about
1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625
mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg,
about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about
1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950
mg, about 1975 mg, about 2000 mg, about 2025 mg, about 2050 mg,
about 2075 mg, about 2100 mg, about 2125 mg, about 2150 mg, about
2175 mg, about 2200 mg, about 2225 mg, about 2250 mg, about 2275
mg, about 2300 mg, about 2325 mg, about 2350 mg, about 2375 mg,
about 2400 mg, about 2425 mg, about 2450 mg, about 2475 mg, or
about 2500 mg.
[0021] In one embodiment, a composition of the invention contains
not more than about 10%, not more than about 9%, not more than
about 8%, not more than about 7%, not more than about 6%, not more
than about 5%, not more than about 4%, not more than about 3%, not
more than about 2%, not more than about 1%, or not more than about
0.5%, by weight of total fatty acids, docosahexaenoic acid or
derivative thereof such as ethyl-DHA (E-DHA), if any. In another
embodiment, a composition of the invention contains substantially
no docosahexaenoic acid or derivative thereof such as E-DHA. In
still another embodiment, a composition of the invention contains
no docosahexaenoic acid or E-DHA.
[0022] In another embodiment, EPA represents at least about 60%, at
least about 70%, at least about 80%, at least about 90%, at least
about 95%, at least about 97%, at least about 98%, at least about
99%, or 100%, by weight, of all fatty acids present in a
composition of the invention.
[0023] In another embodiment, a composition of the invention
contains less than 30%, less than 20%, less than 10%, less than 9%,
less than 8%, less than 7%, less than 6%, less than 5%, less than
4%, less than 3%, less than 2%, less than 1%, less than 0.5% or
less than 0.25%, by weight of the total composition or by weight of
the total fatty acid content, of any fatty acid other than EPA, or
derivative thereof. Illustrative examples of a "fatty acid other
than EPA" include linolenic acid (LA) or derivative thereof such as
ethyl-linolenic acid, arachidonic acid (AA) or derivative thereof
such as ethyl-AA, docosahexaenoic acid (DHA) or derivative thereof
such as ethyl-DHA, alpha-linolenic acid (ALA) or derivative thereof
such as ethyl-ALA, stearadonic acid (STA) or derivative thereof
such as ethyl-SA, eicosatrienoic acid (ETA) or derivative thereof
such as ethyl-ETA and/or docosapentaenoic acid (DPA) or derivative
thereof such as ethyl-DPA.
[0024] In another embodiment, a composition of the invention has
one or more of the following features: (a) eicosapentaenoic acid
ethyl ester represents at least 96%, at least 97%, or at least 98%,
by weight, of total fatty acids present in the composition; (b) the
composition contains not more than 4%, not more than 3%, or not
more than 2%, by weight, of total fatty acids other than
eicosapentaenoic acid ethyl ester; (c) the composition contains not
more than 0.6%, 0.5%, or 0.4% of any individual fatty acid other
than eicosapentaenoic acid ethyl ester; (d) the composition has a
refractive index (20.degree. C.) of about 1 to about 2, about 1.2
to about 1.8 or about 1.4 to about 1.5; (e) the composition has a
specific gravity (20.degree. C.) of about 0.8 to about 1.0, about
0.85 to about 0.95 or about 0.9 to about 0.92; (f) the composition
contains not more than 20 ppm, 15 ppm or 10 ppm heavy metals, (g)
the composition contains not more than 5 ppm, 4 ppm, 3 ppm, or 2
ppm arsenic, and/or (h) the composition has a peroxide value not
more than 5, 4, 3, or 2 Meq/kg.
[0025] In another embodiment, a composition useful in accordance
with the invention comprises, consists essentially of or consists
of at least 95% ethyl eicosapentaenoate (EPA-E), about 0.2% to
about 0.5% ethyl octadecatetraenoate (ODTA-E), about 0.05% to about
0.25% ethyl nonaecapentaenoate (NDPA-E), about 0.2% to about 0.45%
ethyl arachidonate (AA-E), about 0.3% to about 0.5% ethyl
eicosatetraenoate (ETA-E), and about 0.05% to about 0.32% ethyl
heneicosapentaenoate (HPA-E), each by weight of total fatty acids
present in the composition. In another embodiment, the composition
is present in a capsule shell. In still another embodiment, the
capsule shell contains no chemically modified gelatin.
[0026] In another embodiment, compositions useful in accordance
with the invention comprise, consist essentially of, or consist of
at least 95%, 96% or 97%, ethyl eicosapentaenoate, about 0.2% to
about 0.5% ethyl octadecatetraenoate, about 0.05% to about 0.25%
ethyl nonaecapentaenoate, about 0.2% to about 0.45% ethyl
arachidonate, about 0.3% to about 0.5% ethyl eicosatetraenoate, and
about 0.05% to about 0.32% ethyl heneicosapentaenoate, each by
weight of all fatty acids present in the composition. Optionally,
the composition contains not more than about 0.06%, about 0.05%, or
about 0.04%, by weight of total fatty acids present, DHA or
derivative there of such as ethyl-DHA. In one embodiment the
composition contains substantially no or no amount of DHA or
derivative thereof such as ethyl-DHA. The composition further
optionally comprises one or more antioxidants (e.g. tocopherol) in
an amount of not more than about 0.5% or not more than 0.05%. In
another embodiment, the composition comprises about 0.05% to about
0.4%, for example about 0.2% by weight tocopherol. In another
embodiment, about 500 mg to about 1 g of the composition is
provided in a capsule shell. In another embodiment, the capsule
shell contains no chemically modified gelatin.
[0027] In another embodiment, compositions useful in accordance
with the invention comprise, consist essentially of, or consist of
at least 96% ethyl eicosapentaenoate, about 0.22% to about 0.4%
ethyl octadecatetraenoate, about 0.075% to about 0.20% ethyl
nonaecapentaenoate, about 0.25% to about 0.40% ethyl arachidonate,
about 0.3% to about 0.4% ethyl eicosatetraenoate and about 0.075%
to about 0.25% ethyl heneicosapentaenoate, each by weight of total
fatty acids present in the composition. Optionally, the composition
contains not more than about 0.06%, about 0.05%, or about 0.04%, by
weight of total fatty acids present, DHA or derivative there of
such as ethyl-DHA. In one embodiment the composition contains
substantially no or no amount of DHA or derivative there of such as
ethyl-DHA. The composition further optionally comprises one or more
antioxidants (e.g. tocopherol) in an amount of not more than about
0.5% or not more than 0.05%. In another embodiment, the composition
comprises about 0.05% to about 0.4%, for example about 0.2% by
weight tocopherol. In another embodiment, the invention provides a
dosage form comprising about 500 mg to about 1 g of the foregoing
composition in a capsule shell. In one embodiment, the dosage form
is a gel- or liquid-containing capsule and is packaged in blister
packages of about 1 to about 20 capsules per sheet.
[0028] In another embodiment, compositions useful in accordance
with the invention comprise, consist essentially of or consist of
at least 96%, 97% or 98%, by weight, ethyl eicosapentaenoate, about
0.25% to about 0.38% by weight ethyl octadecatetraenoate, about
0.10% to about 0.15% by weight ethyl nonaecapentaenoate, about
0.25% to about 0.35% by weight ethyl arachidonate, about 0.31% to
about 0.38% by weight ethyl eicosatetraenoate, and about 0.08% to
about 0.20% ethyl heneicosapentaenoate, each by weight of all fatty
acids present in the composition. Optionally, the composition
contains not more than about 0.06%, about 0.05%, or about 0.04%, by
weight of all fatty acids present, DHA or derivative there of such
as ethyl-DHA. In one embodiment the composition contains
substantially no or no amount of DHA or derivative there of such as
ethyl-DHA. The composition further optionally comprises one or more
antioxidants (e.g. tocopherol) in an amount of not more than about
0.5% or not more than 0.05%. In another embodiment, the composition
comprises about 0.05% to about 0.4%, for example about 0.2% by
weight tocopherol. In another embodiment, the invention provides a
dosage form comprising about 500 mg to about 1 g of the foregoing
composition in a capsule shell. In another embodiment, the capsule
shell contains no chemically modified gelatin.
Cardiovascular Agents
[0029] In one embodiment, a composition (or co-administration
regimen) of the invention comprises one or more additional
cardiovascular agents. The one or more additional cardiovascular
agents can be co-formulated with EPA or can be co-administered with
EPA. The interchangeable terms "cardiovascular agent" or
"cardiovascular drug" herein refer to a drug or agent that is
capable of treating, preventing, or reducing the risk of developing
a cardiovascular disease or disorder, or a risk factor or symptom
thereof, in a subject. Cardiovascular agents herein can include,
without limitation, cholesterol and triglyceride modulating agents,
agents that treat coronary artery disease, agents that treat
hypertension or pulmonary arterial hypertension, agents that treat
arterial fibrillation or arrhythmia, agents that treat stroke,
agents that treat myocardial ischemia and/or agents that treat
thrombosis.
[0030] Non-limiting examples of classes from which cardiovascular
agents suitable for use in accordance with the present invention
can be selected include: Acyl-coenzyme A: cholesterol
acyltransferase (ACAT) inhibitors including selective inhibitors of
ACAT-1, ACAT-2 as well as dual inhibitors of ACAT-1 and ACAT-2,
alpha-adrenergic blocking drugs (alpha-blockers), alpha/beta
blockers, angiotensin-converting enzyme (ACE) inhibitors,
aldosterone antagonists, angiotensin II receptor antagonists,
anti-arrhythmics, anticoagulants, antiplatelet agents,
apolipoprotein A-1 (apoA-1) mimetics, beta-blockers, bile acid
sequestrants, calcium-channel blockers, ApoB cholesteryl ester
transfer protein (CETP) inhibitors, cholesterol absorption
inhibitors, diuretics, dyslipidemia agents, endothelin receptor
antagonists, fibrates, 3-hydroxy-3-methyl-glutaryl-coenzyme A
(HMG-CoA) reductase inhibitors, LCAT activators, LDL receptor
inducers, lipase inhibitors, lipoprotein-associated phospholipase
A2 (Lp-PLA2) inhibitors, microsomal triglyceride transfer protein
(MTP) inhibitors, platelet aggregation inhibitors, PPAR agonists
and activators including PPAR.gamma. agonists, PPAR.alpha. agonists
and PPAR dual .alpha./.gamma. agonists, PCSK9 antisense or RNAi,
squalene epoxidase inhibitors, squalene synthetase inhibitors,
thrombolytics, and thyroid receptor beta activators.
ACAT Inhibitors.
[0031] Acyl-CoA cholesteryl acyl transferase ("ACAT") is an
acyltransferase enzyme. In bile acid biosynthesis, ACAT catalyzes
the intracellular formation of cholesterol esters from cholesterol.
ACAT promotes accumulation of cholesterol esters in vascular
tissues. Agents that inhibit ACAT, therefore, are useful in
preventing or treating atherosclerosis. Non-limiting examples of
suitable ACAT inhibitors include CI-1011 (Avasimibe, Pfizer),
CS-505 (Pactimibe sulfate, Sankyo Pharma), or combinations
thereof.
[0032] One or more ACAT inhibitors, if desired, are typically
present in a composition of the invention (or co-administered with
EPA according to other embodiments of the invention) in an amount
of about 1 mg to about 1000 mg, for example about 1 mg, about 5 mg,
about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg,
about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg,
about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225
mg, about 250 mg, about 266 mg, about 275 mg, about 300 mg, about
324 mg, about 325 mg, about 330 mg, about 350 mg, about 375 mg,
about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500
mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about
625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg,
about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850
mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about
975 mg, about 1000 mg.
ACE Inhibitors.
[0033] Angiotensin I converting enzyme ("ACE") converts
angiontensin I to angiotensin II and inhibits bradykinin. Because
increased angiotensin II and decreased bradykinin levels both
promote a variety of cardiovascular diseases and disorders, agents
that inhibit ACE are useful in preventing or treating
cardiovascular-related diseases such as hypertension, heart
failure, diabetic neuropathy, and type 2 diabetes. Non-limiting
examples of suitable ACE inhibitors include captopril, enalapril,
enaliprilat, trandolapril, moexipril, ramipril, quinapril,
perindopril, lisinopril, benazepril, fosinopril, or combinations
thereof.
[0034] One or more ACE inhibitors, if desired, are typically
present in a composition of the invention (or co-administered with
EPA according to other embodiments of the invention) in an amount
of about 0.5 mg to about 50 mg, for example about 0.5 mg, about
0.75 mg, about 1 mg, about 1.25 mg, about 2 mg, about 2.5 mg, about
3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 7.5 mg,
about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg,
about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg,
about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg,
about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg,
about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg,
about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg,
about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg,
about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg,
about 48 mg, about 49 mg, or about 50 mg.
Aldosterone Antagonists.
[0035] Aldosterone is a steroidal hormone that contributes to
hypertension by inhibiting kidney function. Agents that compete
with aldosterone for mineralo-corticoid receptors are therefore
useful in preventing or treating hypertension. Non-limiting
examples of suitable aldosterone agents include eplerenone and
aldactone, or combinations thereof.
[0036] Aldosterone antagonists, if desired, are typically present
in a composition of the invention (or co-administered with EPA
according to other embodiments of the invention) in an amount of
about 5 mg to about 100 mg, for example about 5 mg, about 10 mg,
about 12 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg,
about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg,
about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg,
about 85 mg, about 90 mg, about 95, or about 100 mg.
Alpha Blockers.
[0037] Alpha blockers, also called adrenergic alpha-antagonists,
compete with adrenaline binding at .alpha.-adrenoreceptors.
Adrenaline binding at such receptors leads to vasoconstriction and
therefore hypertension. Agents that compete with adrenaline or
block .alpha.-adrenoreceptors are therefore useful in preventing or
treating hypertension. Non-limiting examples of suitable alpha
blockers include doxazosin, methyldopa, clonidine, prazosin,
terazosin, or combinations thereof.
[0038] Alpha blockers, if desired, are typically present in a
composition of the invention (or co-administered with EPA according
to other embodiments of the invention) in an amount of about 0.02
mg to about 0.5 mg, for example about 0.02 mg, about 0.03 mg, about
0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08
mg, about 0.09 mg, about 0.1 mg, about 0.2 mg, about 2.5 mg, about
0.3 mg, about 3.5 mg, about 0.4 mg, about 4.5 mg, or about 0.5 mg;
in an amount of about 0.5 mg to about 15 mg, for example about 0.5
mg, about 0.75 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg,
about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about
10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about
15 mg; or in an amount of about 100 mg to about 500 mg, for example
about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200
mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about
325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg,
about 450 mg, about 475 mg, or about 500 mg.
Alpha/Beta Blockers.
[0039] One or more alpha/beta blockers, if desired, are typically
present in a composition of the invention (or co-administered with
EPA according to other embodiments of the invention) in an amount
of about 1 mg to about 25 mg, for example about 1 mg, about 2 mg,
about 3 mg, about 3.125 mg, about 4 mg, about 5 mg, about 6 mg,
about 6.25 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg,
about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg,
about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg,
about 21 mg, about 22 mg, about 23 mg, about 24, or about 25 mg. A
non-limiting example of an alpha/beta blocker is carvedilol.
Angiotensin II Receptor Antagonists.
[0040] Angiotensin II receptor antagonists, alternately called
angiotensin receptor blockers, ARBs, AT.sub.1-receptor antagonists,
or sartans, are useful in treating hypertension, congestive heart
failure, and various other diseases and disorders. Non-limiting
examples of angiotensin II receptor antagonists include
candesartan, irbesartan, olmesartan, losartan, valsartan,
telmisartan, eprosartan, or combinations thereof.
[0041] One or more angiotensin II receptor antagonists, if desired,
are typically present in a composition of the invention (or
co-administered with EPA according to other embodiments of the
invention) in an amount of about 1 mg to about 100 mg, for example
about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6
mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 12 mg,
about 15 mg, about 16 mg, about 20 mg, about 24 mg, about 25 mg,
about 28 mg, about 30 mg, about 32 mg, about 35 mg, about 40 mg,
about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg,
about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg,
about 95 mg, about 100 mg; in an amount of about 40 mg to about 320
mg, for example, about 40 mg, about 60 mg, about 80 mg, about 100
mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about
200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg,
about 300 mg, about 320 mg; in an amount of about 200 mg to about
800 mg, for example about 200 mg, about 250 mg, about 300 mg, about
350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg,
about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about
800 mg.
Anti-Arrhythmic Agents.
[0042] Anti-arrhythmic drugs act to correct an irregular heartbeat
and/or slow a heart that is beating too rapidly. Non-limiting
examples of suitable anti-arrhythmic agents include adenosine,
amiodarone, digoxin, disopyramide, flecamide, lidocaine,
mexiletine, procainamide, quinidine gluconate, propafenone
hydrochloride, tocamide, or combinations thereof.
[0043] One or more anti-arrhythmics, if desired, are typically
present in a composition of the invention (or co-administered with
EPA according to other embodiments of the invention) in an amount
of about 0.1 mg to about 1500 mg, about 1 mg to about 1200 mg, or
about 5 mg to about 1000 mg, for example about 0.1 mg, about 0.5
mg, about 0.75 mg, about 1 mg, about 5 mg, about 6 mg, about 10 mg,
about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg,
about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg,
about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250
mg, about 266 mg, about 275 mg, about 300 mg, about 324 mg, about
325 mg, about 330 mg, about 350 mg, about 375 mg, about 400 mg,
about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525
mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about
650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg,
about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875
mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about
1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100
mg, about 1025 mg, about 1050 mg, about 1075 mg, or about 1200 mg,
about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about
1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425
mg, about 1450 mg, about 1475 mg, or about 1500 mg.
[0044] In an another embodiment, one or more anti-arrhythmics can
be present in an amount of about 1 mg per mL to about 500 mg per
mL, for example about 1 mg per mL, about 2 mg per mL, about 3 mg
per mL, about 4 mg per mL, about 5 mg per mL, about 6 mg per mL,
about 10 mg per mL, about 25 mg per mL, about 50 mg per mL, about
75 mg per mL, about 80 mg per mL, about 100 mg per mL, about 125 mg
per mL, about 150 mg per mL, about 175 mg per mL, about 200 mg per
mL, about 225 mg per mL, about 250 mg per mL, about 275 mg per mL,
about 300 mg per mL, about 325 mg per mL, about 350 mg per mL,
about 375 mg per mL, about 400 mg per mL, about 425 mg per mL,
about 450 mg per mL, about 475 mg per mL, or about 500 mg per
mL.
[0045] In another embodiment, an anti-arrhythmics is present in an
amount of about 0.01% to about 5%, for example about 0.01%, about
0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about
0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about
0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%,
about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about
1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%,
about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about
2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%,
about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about
3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%,
about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about
4.7%, about 4.8%, about 4.9%, or about 5% by weight of the total
composition.
Antiplatelet Agents.
[0046] Antiplatelet agents inhibit platelet aggregation and
therefore combat thrombus development. Non-limiting examples of
antiplatelet agents include adeparin, aspirin, clopidogrel,
danaparoid, deltaparin, denaparoid, ticlopidine, cilostazol,
abciximab, eptifibatide, tirofiban, defibrotide, enoxaparin,
dipyridamole, tinzaparin, or combinations thereof.
[0047] One or more antiplatelet agents, if desired, are typically
present in a composition of the invention (or co-administered with
EPA according to other embodiments of the invention) in an amount
of about 10 mg to about 100 mg, for example about 10 mg, about 12.5
mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35
mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60
mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85
mg, about 90 mg, about 95 mg, or about 100 mg; in an amount of
about 50 mg to about 300 mg, for example about 50 mg, about 75 mg,
about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200
mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg.
[0048] In another embodiment, one or more antiplatelet agents are
present in an amount of about 25 .mu.g per mL to about 50 .mu.g per
mL, for example about 25 .mu.g per mL, about 30 .mu.g per mL, about
35 .mu.g per mL, about 40 .mu.g per mL, about 45 .mu.g per mL, or
about 50 .mu.g per mL; or in an amount of about 1 mg per mL to
about 2 mg per mL, for example about 1 mg per mL, about 1.25 mg per
mL, about 1.50 mg per mL, about 1.75, or about 2 mg per mL.
apoA-1 Mimetics.
[0049] Apolipoprotein A-1 ("apoA-1") is the primary protein
component of serum HDL cholesterol. Non-limiting examples of apoA-1
mimetics include ETC-216, ETC-588-liposome, ETC-642, trimeric
apoA-1, CSL-111, APP018, reverse D-4F, or combinations thereof.
[0050] One or more apoA-1 mimetics, if desired, are typically
present in a composition of the invention (or co-administered with
EPA according to other embodiments of the invention) in an amount
of about 0.1 mg to about 1500 mg, about 1 mg to about 1200 mg, or
about 5 mg to about 1000 mg, for example about 0.1 mg, about 0.5
mg, about 0.75 mg, about 1 mg, about 5 mg, about 6 mg, about 10 mg,
about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg,
about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg,
about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250
mg, about 266 mg, about 275 mg, about 300 mg, about 324 mg, about
325 mg, about 330 mg, about 350 mg, about 375 mg, about 400 mg,
about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525
mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about
650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg,
about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875
mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about
1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100
mg, about 1025 mg, about 1050 mg, about 1075 mg, or about 1200 mg,
about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about
1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425
mg, about 1450 mg, about 1475 mg, or about 1500 mg. Beta
blockers.
[0051] Beta blockers block responses to the beta nerve receptor
which tends to slow heart rate and lower blood pressure.
Non-limiting examples of suitable beta blockers include acebutolol,
atenolol, metoprolol, nadolol, nebivolol, pindolol, propranolol, or
combinations thereof.
[0052] One or more beta blockers, if desired, are typically present
in a composition of the invention (or co-administered with EPA
according to other embodiments of the invention) in an amount of
about 1 mg to about 1000 mg, about 1 mg to about 750 mg, or about 1
mg to about 500 mg, for example about 1 mg, about 2 mg, about 2.5
mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 20 mg,
about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg,
about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg,
about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225
mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about
350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg,
about 475 mg, or about 500 mg.
Bile Acid Sequestrants.
[0053] Bile acid sequestrants interrupt the enterohepatic
circulation of bile acids by binding bile acid components in the
gastrointestinal tract, rendering them unabsorbable thereafter.
Bile acid sequestrants are thus useful in preventing or treating
hyperlipidemia, among other diseases and disorders. Non-limiting
examples of bile acid sequestrants include colesevelam Hcl,
colestipol, locholest and cholestyramine or combinations
thereof.
[0054] One or more bile acid sequestrants, if desired, are
typically present in a composition of the invention (or
co-administered with EPA according to other embodiments of the
invention) in an amount of about 4 mg to about 32 mg, for example
about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 24 mg,
about 32 mg; or in an amount of about 300 mg to about 4000 mg, for
example about 300 mg, about 325 mg, about 350 mg, about 400 mg,
about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 625
mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about
900 mg, about 1000 mg, about 1250 mg, about 1500 mg, about 1750 mg,
about 2000 mg, about 2250 mg, about 2500 mg, about 2750 mg, about
3000 mg, about 3250 mg, about 3500 mg, about 3750, or about 4000
mg.
Calcium Channel Blockers.
[0055] Calcium channel blockers are useful in preventing or
treating hypertension by their vasodilating action. Non-limiting
examples of calcium channel blockers include nicardipine,
diltiazem, clevidipine butyrate, isradipine, nimodipine,
nisoldipine, verapamil, and amlodipine besylate, or combinations
thereof. Non-limiting examples of combination calcium channel
blockers include amlodipine, olmesartan, valsartan, or combinations
thereof.
[0056] One or more calcium channel blockers, if desired, are
typically present in a composition of the invention (or
co-administered with EPA according to other embodiments of the
invention) in an amount of about 1 mg to about 10 mg, for example
about 1 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about
5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10
mg; in an amount of about 5 mg to about 34 mg, for example about 5
mg, about 6 mg, about 7 mg, about 8 mg, about 8.5 mg, about 9 mg,
about 10 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5
mg, about 25 mg, about 25.5 mg, about 27.5 mg, about 30 mg, about
32.5, or about 34 mg; in an amount of about 10 mg to about 60 mg,
for example about 10 mg, about 15 mg, about 20 mg, about 25 mg,
about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg,
about 55 mg, or about 60 mg; in an amount of about 20 mg to about
120 mg, for example about 20 mg, about 30 mg, about 40 mg, about 50
mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100
mg, about 110, or about 120 mg; in an amount of about 60 mg to
about 420 mg, for example about 60 mg, about 70 mg, about 80 mg,
about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 140
mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about
240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg,
about 340 mg, about 360 mg, about 380 mg, about 400, or about 420
mg.
[0057] In another embodiment, one or more calcium channel blockers
is present in an amount of about 0.05 mg per mL to about 2.5 mg per
mL, for example about 0.05 mg per mL, about 0.1 mg per mL, about
0.2 mg per mL, about 0.3 mg per mL, about 0.4 mg per mL, about 0.5
mg per mL, about 0.6 mg per mL, about 0.7 mg per mL, about 0.8 mg
per mL, about 0.9 mg per mL, about 1.0 mg per mL, about 1.25 mg per
mL, about 1.5 mg per mL, about 1.75 mg per mL, about 2.0 mg per mL,
about 2.25 mg per mL, or about 2.5 mg per mL.
CETP Inhibitors.
[0058] Cholesteryl ester transfer protein ("CETP") plays an
important role in transferring cholesteryl esters and
triglycerides. Inhibition of CETP, also called plasma lipid
transfer protein, is therefore useful in preventing or treating
atherosclerosis and other cardiovascular diseases and disorders.
Non-limiting examples of CETP inhibitors include torcetrapib,
anacetrapib, JTT-705, BAY-60-5521, PF-3185043, and CP-800569, or
combinations thereof.
[0059] One or more CETP inhibitors, if desired, are present in a
composition of the invention (or co-administered with EPA according
to other embodiments of the invention) in an amount sufficient to
provide the subject with a dose of about 25 mg per kg body weight
("mg per kg") to about 100 mg per kg, for example about 25 mg per
kg, about 30 mg per kg, about 35 mg per kg, about 40 mg per kg,
about 45 mg per kg, about 50 mg per kg, about 55 mg per kg, about
60 mg per kg, about 65 mg per kg, about 70 mg per kg, about 75 mg
per kg, about 80 mg per kg, about 85 mg per kg, about 90 mg per kg,
about 95 mg per kg, or about 100 mg per kg.
[0060] In another embodiment, one or more CETP inhibitors, if
desired, are present in a composition of the invention (or
co-administered with EPA according to other embodiments of the
invention) in an amount of about 100 mg to about 10 g, about 500 mg
to about 9 g, or about 750 mg to about 5 g.
Cholesterol Absorption Inhibitors.
[0061] Cholesterol absorption inhibitors reduce the cholesterol
content of chylomicrons and chylomicron remnants by preventing the
uptake of micellar cholesterol from the small intestine. As a
result, less cholesterol is delivered to the liver and thereby
reduces LDL. Non-limiting examples of cholesterol absorption
inhibitors include ezetimibe and simvastatin, or combinations
thereof.
[0062] One or more cholesterol absorption inhibitors, if desired,
are typically present in a composition of the invention (or
co-administered with EPA according to other embodiments of the
invention) in an amount of about 1 mg to about 10 mg, for example
about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6
mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg; or in an
amount of about 10 to about 80 mg, for example about 10 mg, about
15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40
mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65
mg, about 70 mg, about 75 mg, or about 80 mg.
Diuretics.
[0063] Diuretics increase urination rates forcing diuresis. Some
diuretics also provide antihypertensive effects. Non-limiting
examples of diuretics include hydrochlorothiazide, torsemide,
ethacrynic acid, furosemide, triamterene, indapamide,
chlorothiazide sodium, aliskiren, or combinations thereof.
[0064] One or more diuretics, if desired, are typically present in
a composition of the invention (or co-administered with EPA
according to other embodiments of the invention) in an amount of:
(a) about 0.25 mg to about 2.5 mg, for example about 0.25 mg, about
0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg,
about 1.75 mg, about 2 mg, about 2.25 mg, or about 2.5 mg; (b) in
an amount of about 5 mg to about 25 mg, for example about 5 mg,
about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20
mg, about 22.5 mg, or about 25 mg; (c) in an amount of about 2 mg
to about 100 mg, for example about 2 mg, about 3 mg, about 4 mg,
about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg,
about 17.5 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg,
about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg,
about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg,
about 90 mg, about 95 mg, or about 100 mg; (d) about 10 mg to about
50 mg, for example about 10 mg, about 12.5 mg, about 15 mg, about
17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 30 mg,
about 35 mg, about 40 mg, about 45 mg, or about 50 mg; in an amount
of about 5 mg to about 60 mg, for example about 5 mg, about 10 mg,
about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg,
about 40 mg, about 45 mg, about 50 mg, about 55 mg, (e) or about 60
mg; in an amount of about 25 mg to about 100 mg, for example about
25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50
mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about
100 mg; in an amount of about 75 mg to about 300 mg, for example
about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175
mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or
about 300 mg; (f) about 0.1 g to about 0.5 g, for example about 0.1
g, about 0.2 g, about 0.3 g, about 0.4 g, or about 0.5 g; or (g) in
an amount of about 1 mg per mL to about 10 mg per mL, for example
about 1 mg per mL, about 2 mg per mL, about 3 mg per mL, about 4 mg
per mL, about 5 mg per mL, about 6 mg per mL, about 7 mg per mL,
about 8 mg per mL, about 9 mg per mL, or about 10 mg per mL.
Dyslipidemia Agents.
[0065] Dyslipidemia is a class of diseases that includes
hyperlipidemia. Fredrickson's Type I dyslipidemia (sometimes
referred to as Buerger-Gruetz syndrome, primary
hyperlipoproteinaemia, or familial hyperchylomicronemia) is
characterized by elevated cholesterol levels, subjects with
Fredrickson's Type IIa dyslipidemia (also known as familial
hypercholesterolemia) exhibit elevated LDL levels. Those with
Fredrickson's Type IIb dyslipidemia (familial combined
hyperlipoproteinemia (FCH) or secondary combined
hyperlipoproteinemia) show increased LDL and VLDL levels.
Fredrickson's Type III dyslipidemia (sometimes called beta disease
or dysbetalipoproteinemia) features elevated intermediate density
lipoproteins ("IDL"), while Fredrickson's Type IV dyslipidemics
(sometimes called "pure hypertriglyceridemics") have elevated VLDL
levels. Subjects with Fredrickson's Type V dyslipidemia have
increased VLDL and chylomicron levels.
[0066] Non-limiting examples of dyslipidemia agents include Angpt14
antibody, APA-01 (Phosphagenics), CRD-5 (ImaSight), NCX6560
(NicOx), PCSK9 RNAi (Alnylam), recombinant apoA-1 (SemBio Sys
Genetics), anti-oxLDL (Genentech), APL180 (Novartis), APP018 (D4F)
(Novartis), CER-002 (Cerenis Therapeutics), CP-800,569 (Pfizer),
GSK-256073 (GlaxoSmithKline), MB07811 (Metabasis), PF-3185043
(Pfizer), R7232 (Roche), rilapladib (GlaxoSmithKline), RVX-208
(Resverlogix), Sobetirome (QRX-431 (QuatRx)), anacetrapib (Merk),
CSL111 (CSL Limited), darapladib (GlaxoSmithKline), eprotirome
(Karo Bio), GFT505 (Genfit), MAHDLO1 (Marzal Plant Pharma),
MBX-8025 (Metabolex), PLX204 (Wyeth/Plexxikon), aleglitezar
(Roche), dalcetrapib (Roche), SLx4090 (Surface Logix), verespladib
(Anthera Pharmaceuticals), AEGR-733 (Aegerion), ABT-335 (Abbott
Laboratories), AVE5530 (Sanofi-Aventis), LCP-AtorFen (LifeCycle
Pharma), TRIA-662 (Cortria), fenofibrate, choline fenofibrate,
ezetimibe, colsevelam, laropiprant, or combinations of any of the
foregoing.
[0067] One or more dyslipidemia agents, if desired, are typically
present in a composition of the invention (or co-administered with
EPA according to other embodiments of the invention) in an amount
of about 1 mg to about 1000 mg, for example about 1 mg, about 2 mg,
about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8
mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg,
about 30 mg, about 35 mg, about 40 mg, about 43 mg, about 45 mg,
about 48 mg, about 50 mg, about 54 mg, about 55 mg, about 60 mg,
about 65 mg, about 67 mg, about 70 mg, about 75 mg, about 80 mg,
about 85 mg, about 87 mg, about 90 mg, about 95 mg, about 100 mg,
about 105 mg, about 107 mg, about 110 mg, about 115 mg, about 120
mg, about 125 mg, about 130 mg, about 134 mg, about 135 mg, about
140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg,
about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185
mg, about 190 mg, about 195 mg, about 200 mg, about 250 mg, about
275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg,
about 400 mg, about 425 mg, about 450 mg, about 500 mg, about 550
mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about
675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg,
about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900
mg, about 925 mg, about 950 mg, about 975 mg, or about 1000 mg.
Endothelin Receptor Antagonists.
[0068] Binding of endothelin-1 at endothelin-A (ETA) or
endothelin-B (ETB) receptors causes pulmonary vasoconstriction.
Endothelin receptor antagonists compete with endothelin-1 binding,
thereby attenuating pulmonary vasoconstriction. Endothelin receptor
antagonists, therefore, are useful in treating pulmonary
hypertension. Non-limiting examples of endothelin receptor
antagonists include ambrisentan, bosentan, volibris, thelin, or
combinations thereof.
[0069] One or more endothelin receptor antagonists, if desired, are
typically present in a composition of the invention (or
co-administered with EPA according to other embodiments of the
invention) in an amount of about 1 mg to about 10 mg, for example
about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6
mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg; in an
amount of about 50 mg to about 250 mg, for example about 50 mg,
about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175
mg, about 200 mg, about 225 mg, or about 250 mg.
HMG-CoA Reductase Inhibitors.
[0070] HMG-CoA reductase (also known as HMGR) converts HMG-CoA
(3-hydroxy-3-methyl-glutaryl-co enzyme A) to mevalonic acid
(3,5-dihydroxy-3-methyl-pentanoic acid) along the metabolic pathway
that produces cholesterol. HMG-CoA reductase inhibitors, also
called statins, inhibit HMG-CoA reductase and thereby reduce
cholesterol production. As a result, HMG-CoA reductase inhibitors
are useful in treating a variety of cardiovascular diseases and
disorders including, for example, hypercholesterolemia,
hyperlipidemia, mixed dyslipidemia, hypertriglyceridemia,
atherosclerosis, Non-limiting examples of HMG-CoA reductase
inhibitors include lovastatin, lovastatin+niacin, mevastatin,
pitavastatin, pravastatin, rosuvastatin, fluvastatin, atorvastatin,
atorvastatin+amlodipine besylate, simvastatin, simvistatin+niacin,
ezetimibe, and pravastatin, among others.
[0071] One or more HMG-CoA reductase inhibitors, if desired, are
typically present in a composition of the invention (or
co-administered with EPA according to other embodiments of the
invention) in an amount of about 1 mg to about 1000 mg, for example
about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6
mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg; about 15
mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40
mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65
mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100
mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about
225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg,
about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450
mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about
575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg,
about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800
mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about
925 mg, about 950 mg, about 975 mg, or about 1000 mg.
LCAT Activators.
[0072] Lecithin-cholesterol acyltransferase ("LCAT") converts
cholesterol into cholesteryl ester. In subjects with deficient
levels of LCAT, unesterified cholesterol accumulates in body
tissues. This can lead to elevated serum levels of HDL and
eventually atherosclerosis. LCAT activators are therefore useful in
reducing serum HDL levels and treating or preventing
atherosclerosis. Non-limiting examples of LCAT activators include
LCAT enzyme, recombinant LCAT, genetic therapy agents that include
a nucleic acid sequence coding for expression of LCAT, estrogens,
estrogen analogs, and combinations thereof for example as disclosed
in U.S. Pat. No. 6,635,614 incorporated by reference herein in its
entirety.
[0073] One or more LCAT activators, if desired, are typically
present in a composition of the invention (or co-administered with
EPA according to other embodiments of the invention) in an amount
sufficient to raise the serum LCAT level of the subject to a
desired level. Subjects with abnormally low LCAT serum levels may
be administered an amount of a composition of the invention
comprising EPA and LCAT enzyme, estrogen, estrogen analogs, or
combinations thereof sufficient to raise the subject's serum LCAT
level to normal levels, typically about 5 .mu.g per mL or greater.
In another embodiment, subjects with about normal LCAT serum levels
may be treated with a composition of the invention comprising EPA
and LCAT enzyme, estrogen, estrogen analogs, or combinations
thereof in an amount sufficient to raise the LCAT serum level to
about 6 .mu.g per mL or more, about 7 .mu.g per mL or more, about 8
.mu.g per mL or more, about 9 .mu.g per mL or more, or about 10
.mu.g per mL or more.
LDL Receptor Inducers.
[0074] LDL receptors are cell surface proteins. Along with adaptin,
LDL receptors bind free LDL cholesterol to form clathrin-coated
vesicles, reducing serum LDL levels. Thus, agents that induce LDL
receptors further reduce serum LDL levels and are useful in
preventing or treating atherosclerosis. A non-limiting example of
LDL receptor is lactacystin.
[0075] One or more LDL receptor inducers, if desired, are typically
present in a composition of the invention (or co-administered with
EPA according to other embodiments of the invention) in an amount
of about 1 mg to about 1000 mg, for example about 1 mg, about 2 mg,
about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8
mg, about 9 mg, or about 10 mg about 15 mg, about 20 mg, about 25
mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50
mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75
mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150
mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about
275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg,
about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500
mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about
625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg,
about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850
mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about
975 mg, or about 1000 mg.
Lp-PLA2 Inhibitors.
[0076] Compositions of the invention may comprise one or more
lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitors.
Lp-PLA2 hydrolyzes oxidized phospholipids in LDL cholesterols. High
levels of Lp-PLA2 seem to trigger a cascade of inflammatory events
in atherosclerosis and an increased risk of stroke. Lp-PLA2
inhibitors, therefore, are useful in slowing or preventing
development of atherosclerosis. Non-limiting examples of Lp-PLA2
inhibitors include rilapladib, darapladib, and combinations
thereof.
[0077] One or more Lp-PLA2 inhibitors, if desired, are typically
present in a composition of the invention (or co-administered with
EPA according to other embodiments of the invention) in an amount
of about 1 mg to about 1000 mg, for example about 1 mg, about 2 mg,
about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8
mg, about 9 mg, or about 10 mg; about 15 mg, about 20 mg, about 25
mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50
mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75
mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150
mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about
275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg,
about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500
mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about
625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg,
about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850
mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about
975 mg, or about 1000 mg.
5-Lipoxygenase Inhibitors.
[0078] 5-lipoxygenase inhibitors are useful in accordance with
various embodiments of the invention. Non-limiting examples of
5-lipixygenase inhibitors include VIA-2291, MK-886, CMI 977,
ABT-761, ZD2138, lonapalene, zileuton, 5-LO inhibitor 6, L-739,010,
CGS 22745, SC 45662, and combinations thereof.
[0079] Additional 5-lipoxygenase inhibitors suitable for use in
accordance with embodiments of the instant invention are disclosed
in the following U.S. patents and patent applications, each of
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[0080] One or more 5-lipoxygenase inhibitors, if desired, are
typically present in a composition of the invention (or
co-administered with EPA according to other embodiments of the
invention) in an amount of about 0.01 mg to about 2500 mg, about
0.1 mg to about 1500 mg, about 1 mg to about 1200 mg, or about 5 mg
to about 1000 mg, for example about 0.1 mg, about 0.5, about 0.75
mg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg,
about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg,
about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175
mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about
300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg,
about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525
mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about
650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg,
about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875
mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about
1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100
mg, about 1025 mg, about 1050 mg, about 1075 mg, or about 1200 mg,
about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about
1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425
mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg,
about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about
1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750
mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg,
about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about
1975 mg, about 2000 mg, about 2025 mg, about 2050 mg, about 2075
mg, about 2100 mg, about 2125 mg, about 2150 mg, about 2175 mg,
about 2200 mg, about 2225 mg, about 2250 mg, about 2275 mg, about
2300 mg, about 2325 mg, about 2350 mg, about 2375 mg, about 2400
mg, about 2425 mg, about 2450 mg, about 2475 mg or about 2500
mg.
Microsomal Triglyceride Transfer Protein Inhibitors.
[0081] Microsomal triglyceride transfer protein ("MTTP" or "MTP")
is a heterodimeric protein involved in lipoprotein assembly. MTP
inhibitors are thus useful in slowing or preventing the production
of lipoproteins and therefore cardiovascular diseases and
disorders. Non-limiting examples of MTP inhibitors include
SLx-4090, AEGR-733, implitapide, BMS-200150, CP-346086, JTT-130,
dirlotapide, and combinations thereof.
[0082] Additional MTP inhibitors suitable for use in accordance
with embodiments of the instant invention are disclosed in the
following U.S. patents and patent applications, each of which is
hereby incorporated by reference herein in its entirety: U.S.
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[0083] In one embodiment, one or more MTP inhibitors, if desired,
are typically present in a composition of the invention (or
co-administered with EPA according to other embodiments of the
invention) in an amount sufficient to provide the subject with a
dose of about 1 .mu.g per kg of body weight (.mu.g per kg) to about
100 .mu.g per kg, for example about 25 .mu.g per kg, about 30 .mu.g
per kg, about 35 .mu.g per kg, about 40 .mu.g per kg, about 45
.mu.g per kg, about 50 .mu.g per kg, about 55 .mu.g per kg, about
60 .mu.g per kg, about 65 .mu.g per kg, about 70 .mu.g per kg,
about 75 .mu.g per kg, about 80 .mu.g per kg, about 85 .mu.g per
kg, about 90 .mu.g per kg, about 95 .mu.g per kg, or about 100
.mu.g per kg. In another embodiment, one or more MTP inhibitors, if
desired, are present in a composition of the invention (or
co-administered with EPA according to other embodiments of the
invention) in an amount of about 30 .mu.g to about 20 mg, about 50
.mu.g to about 15 mg, or about 70 .mu.g to about 10 mg.
[0084] In another embodiment, one or more MTP inhibitors, if
desired, are present in a composition of the invention (or
co-administered with EPA according to other embodiments of the
invention) in an amount of about 0.01 mg to about 2500 mg, about
0.1 mg to about 1500 mg, about 1 mg to about 1200 mg, or about 5 mg
to about 1000 mg, for example about 0.1 mg, about 0.5, about 0.75
mg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg,
about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg,
about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175
mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about
300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg,
about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525
mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about
650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg,
about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875
mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about
1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100
mg, about 1025 mg, about 1050 mg, about 1075 mg, or about 1200 mg,
about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about
1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425
mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg,
about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about
1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750
mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg,
about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about
1975 mg, about 2000 mg, about 2025 mg, about 2050 mg, about 2075
mg, about 2100 mg, about 2125 mg, about 2150 mg, about 2175 mg,
about 2200 mg, about 2225 mg, about 2250 mg, about 2275 mg, about
2300 mg, about 2325 mg, about 2350 mg, about 2375 mg, about 2400
mg, about 2425 mg, about 2450 mg, about 2475 mg or about 2500
mg.
PPAR Agonists and Activators.
[0085] Peroxisome proliferator-activated receptors ("PPARs") are
nuclear receptor proteins regulating the expression of genes by
acting as transcription factors in combination with the retinoid X
receptor ("RXR"). Agents that inhibit or activate PPARs are
therefore useful in modifying the expression of certain genes
including, for example, genes associated with metabolic disorders
such as hypercholesterolemia. Non-limiting examples of PPAR
agonists and activators include fenofibrate, bezafibrate,
ciprofibrate, clofibrate, gemfibrozil, CER-002, rosiglitazone,
GW501516, RWJ 800025, KD-3010, and combinations thereof.
[0086] One or more PPAR agonists and/or activators, if desired, are
typically present in a composition of the invention (or
co-administered with EPA according to other embodiments of the
invention) in an amount of about 0.5 mg to about 4 mg, for example
about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5
mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about
2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, or
about 4 mg; or in an amount of about 20 mg to about 120 mg, for
example about 20 mg, about 30 mg, about 40 mg, about 50 mg, about
60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about
110 mg, or about 120 mg.
sPLA2 Inhibitors.
[0087] sPLA2 inhibitors are suitable for use in accordance with
various embodiments of the present invention. Non-limiting examples
of sPLA2 inhibitors include LY 333013, varespladib, WA8242A,
WA8242A.sub.2, WA8242B, A-0001, A-0002 and combinations
thereof.
[0088] Additional sPLA2 inhibitors suitable for use in accordance
with embodiments of the instant invention are disclosed in the
following U.S. patents and patent applications, each of which is
hereby incorporated by reference herein in its entirety: U.S. Pat.
No. 6,974,831, U.S. Pat. No. 6,916,840, U.S. Pat. No. 6,992,100,
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[0089] One or more sPLA2 inhibitors, if desired, are typically
present in a composition of the invention (or co-administered with
EPA according to other embodiments of the invention) in an amount
of about 0.01 mg to about 2500 mg, about 0.1 mg to about 1500 mg,
about 1 mg to about 1200 mg, or about 5 mg to about 1000 mg, for
example about 0.1 mg, about 0.5, about 0.75 mg, about 1 mg, about 5
mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50
mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100
mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about
225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg,
about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450
mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about
575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg,
about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800
mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about
925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg,
about 1050 mg, about 1075 mg, about 1100 mg, about 1025 mg, about
1050 mg, about 1075 mg, or about 1200 mg, about 1225 mg, about 1250
mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg,
about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about
1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575
mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg,
about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about
1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900
mg, about 1925 mg, about 1950 mg, about 1975 mg, about 2000 mg,
about 2025 mg, about 2050 mg, about 2075 mg, about 2100 mg, about
2125 mg, about 2150 mg, about 2175 mg, about 2200 mg, about 2225
mg, about 2250 mg, about 2275 mg, about 2300 mg, about 2325 mg,
about 2350 mg, about 2375 mg, about 2400 mg, about 2425 mg, about
2450 mg, about 2475 mg or about 2500 mg.
Squalene Epoxidase Inhibitors.
[0090] Squalene epoxidase, also called squalene monooxygenase,
catalyzes the oxidation of squalene in the cholesterol biosynthesis
pathway. Thus, agents that inhibit squalene epoxidase are useful in
preventing or slowing the cholesterol production. Non-limiting
examples of squalene epoxidase inhibitors include terbinafine,
naftifine, amorolfine, butenafine, FR194738, NB-598, resveratrol
(trans-3,4',5-trihydroxystilbene), epigallocatechin-3-O-gallate,
S-allylcysteine, selenocysteine, alliin, diallyl trisulfide,
diallyl disulfide, and combinations thereof.
[0091] One or more squalene epoxidase inhibitors, if desired, are
typically present in a composition of the invention (or
co-administered with EPA according to other embodiments of the
invention) in an amount of about 100 mg to 250 mg, for example
about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200
mg, about 225 mg, or about 250 mg; or in an amount of about 0.5% to
about 5%, by weight of the composition, for example about 0.5%,
about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, about
2%, about 2.25%, about 2.5%, about 2.75%, about 3%, about 3.25%,
about 3.5%, about 3.75%, about 4%, about 4.25%, about 4.5%, about
4.75%, or about 5%, by weight.
Thrombolytic Agents.
[0092] Thrombolytic agents dissolve blood clots. Thrombolytic
agents are therefore useful in treating cardiovascular diseases and
disorders including, for example, deep vein thrombosis, pulmonary
embolism, ischemic complications, unstable angina, myocardial
infarction, and venous thromboembolism, among others. Non-limiting
examples of thrombolytic agents include fondoparinux, dalteparin,
enoxaparin, apixaban, PD-348292, and combinations thereof.
[0093] One or more thrombolytic agents, if desired, are typically
present in a composition of the invention (or co-administered with
EPA according to other embodiments of the invention) in an amount
sufficient to provide a dosage of about 0.5 mg per kg of body
weight ("mg per kg") to about 40 mg per kg, for example about 0.5
mg per kg, about 1 mg per kg, about 2 mg per kg, about 3 mg per kg,
about 4 mg per kg, about 5 mg per kg, about 6 mg per kg, about 7 mg
per kg, about 8 mg per kg, about 9 mg per kg, about 10 mg per kg,
about 11 mg per kg, about 12 mg per kg, about 13 mg per kg, about
14 mg per kg, about 15 mg per kg, about 16 mg per kg, about 17 mg
per kg, about 18 mg per kg, about 19 mg per kg, about 20 mg per kg,
about 21 mg per kg, about 22 mg per kg, about 23 mg per kg, about
24 mg per kg, about 25 mg per kg, about 26 mg per kg, about 27 mg
per kg, about 28 mg per kg, about 29 mg per kg, about 30 mg per kg,
about 31 mg per kg, about 32 mg per kg, about 33 mg per kg, about
34 mg per kg, about 35 mg per kg, about 36 mg per kg, about 37 mg
per kg, about 38 mg per kg, about 39 mg per kg, or about 40 mg per
kg, or in a total amount of about 30 mg to about 3.5 g.
[0094] In another embodiment, one or more thrombolytic agents are
present in a composition of the invention (or co-administered with
EPA according to other embodiments of the invention) in an amount
of about 0.5 mg to about 2.5 mg, for example 0.5 mg, about 0.75 mg,
about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg,
about 2.25 mg, or about 2.5 mg; or in an amount sufficient to
provide about 60 international units per kg of body weight ("IU per
kg") to about 240 IU per kg, for example 60 IU per kg, about 70 IU
per kg, about 80 IU per kg, about 90 IU per kg, about 100 IU per
kg, about 110 IU per kg, about 120 IU per kg, about 130 IU per kg,
about 140 IU per kg, about 150 IU per kg, about 160 IU per kg,
about 170 IU per kg, about 180 IU per kg, about 190 IU per kg,
about 200 IU per kg, about 210 IU per kg, about 220 IU per kg,
about 230 IU per kg, or about 240 IU per kg.
Other Cardiovascular Agents.
[0095] Other cardiovascular agents are also useful in preventing,
inhibiting, or treating cardiovascular diseases or disorders.
Non-limiting examples of other cardiovascular agents include
gemfibrozil, niaspan, orlistat, GFT14, AZD-2479, ETC-1001, and
combinations thereof.
[0096] One or more of these other cardiovascular agents, if
desired, can be present in a composition of the invention (or may
be co-administered with EPA according to other embodiments of the
invention) in an amount corresponding to the recommended or
suggested dosage for the particular cardiovascular agent(s). In a
related embodiment, the cardiovascular agent(s) may be present in a
composition of the invention (or may be co-administered with EPA
according to other embodiments of the invention) in an amount less
than the recommended or suggested dosage for the particular
cardiovascular agent(s). For example, a composition of the
invention may comprise EPA and one or more of these other
cardiovascular agents in an amount of about 5 mg to about 1500 mg
for example about 10 mg, about 20 mg, about 30 mg, about 40 mg,
about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg,
about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200
mg, about 225 mg, about 250 mg, about 266 mg, about 275 mg, about
300 mg, about 324 mg, about 325 mg, about 330 mg, about 350 mg,
about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475
mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about
600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg,
about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825
mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about
950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg,
about 1075 mg, about 1100 mg, about 1025 mg, about 1050 mg, about
1075 mg, or about 1200 mg, about 1225 mg, about 1250 mg, about 1275
mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg,
about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, or
about 1500 mg.
[0097] Headings used to describe cardiovascular agents herein are
not to be construed as limiting in any manner. Many cardiocascular
agents can have multiple modes of action and can be described under
one or more headings.
Salts and Other Derivatives
[0098] Salts, hydrates, solvate, esters, amides, enantiomers,
isomers, tautomers, polymorphs, prodrugs, and derivatives of any of
the foregoing drugs may be used in accordance with the invention
and may be prepared using standard procedures known to those
skilled in the art of synthetic organic chemistry. See, e.g.,
March, Advanced Organic Chemistry: Reactions, Mechanisms and
Structure, 4th Ed. (New York: Wiley-Interscience, 1992); Leonard et
al., Advanced Practical Organic Chemistry (1992); Howarth et al.,
Core Organic Chemistry (1998); and Weisermel et al., Industrial
Organic Chemistry (2002).
[0099] "Pharmaceutically acceptable salts," or "salts," include the
salt of a drug prepared from formic, acetic, propionic, succinic,
glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,
glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,
anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic,
phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic,
benzenesulfonic, pantothenic, toluenesulfonic,
2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic,
algenic, beta-hydroxybutyric, galactaric and galacturonic
acids.
[0100] In one embodiment, acid addition salts are prepared from the
free base forms using conventional methodology involving reaction
of the free base with a suitable acid. Suitable acids for preparing
acid addition salts include both organic acids, e.g., acetic acid,
propionic acid, glycolic 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, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic
acid, salicylic acid, and the like, as well as inorganic acids,
e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, and the like.
[0101] In another embodiment, base addition salts are prepared from
the free acid forms using conventional methodology involving
reaction of the free acid with a suitable base.
[0102] In other embodiments, an acid addition salt is reconverted
to the free base by treatment with a suitable base. In a further
embodiment, the acid addition salts are halide salts, which are
prepared using hydrochloric or hydrobromic acids. In still other
embodiments, the basic salts are alkali metal salts, e.g., sodium
salt. In other embodiments, a base addition salt is reconverted to
the free acid by treatment with a suitable acid.
[0103] In one embodiment, EPA and one or more cardiovascular
agent(s) are present in a composition of the invention, or are
co-administered in a weight ratio of EPA:cardiovascular agent of
about 1:1000 to about 1000:1, about 1:500 to about 500:1, about
1:100 to about 100:1, about 1:50 to about 50:1, about 1:25 to about
25:1, about 1:10 to about 10:1, about 1:5 to about 5:1, about 1:4
to about 4:1 about 1:3 to about 3:1, about 1:2 to about 2:1 or
about 1:1.
Antiretroviral Therapy
[0104] In one embodiment, the present invention provides a method
of treating a cardiovascular-related disease as defined herein, for
example dyslipidemia or hyperlipidemia, in an HIV positive subject.
In another embodiment, the method comprises co-administration, or
concomitant administration, of a composition or compositions as
disclosed herein with one or more HIV-1 protease inhibitors.
Non-limiting examples of HIV-1 protease inhibitors include
amprenavir, fosamprenavir, indinavir, lopinavir, nelfinavir,
ritonavir and saquinavir.
[0105] One or more HIV-1 protease inhibitors, if desired, are
typically present in a composition of the invention (or
co-administered with EPA according to other embodiments of the
invention) in an amount of about 100 mg to about 2500 mg, for
example about 125 mg, about 150 mg, about 175 mg, about 200 mg,
about 225 mg, about 250 mg, about 300 mg, about 350 mg, about 400
mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about
625 mg, about 650 mg, about 700 mg, about 800 mg, about 900 mg,
about 1000 mg, about 1100 mg, about 1200 mg, about 1250 mg, about
1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700
mg, about 1800 mg, about 1825 mg, about 1900 mg, about 2000 mg,
about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, or
about 2500 mg; in an amount of about 200 mg to about 1000 mg, for
example about 200 mg, about 300 mg, about 400 mg, about 500 mg,
about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about
1000 mg; in an amount of about 50 mg to about 400 mg, for example
about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250
mg, about 300 mg, about 350 mg, or about 400 mg; in an amount of
about 200 mg to about 1066 mg, for example about 200 mg, about 250
mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about
500 mg, about 533 mg, about 550 mg, about 600 mg, about 650 mg,
about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900
mg, about 950 mg, about 1000 mg, or about 1066 mg; in an amount of
about 50 mg to about 1200 mg, for example about 50 mg, about 100
mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about
350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg,
about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800
mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about
1050 mg, about 1100 mg, about 1150 mg, or about 1200 mg; or in an
amount of about 15 mg per kg body weight to about 40 mg per kg body
weight, for example about 15 mg per kg, about 20 mg per kg, about
25 mg per kg, about 30 mg per kg, about 35 mg per kg, about mg per
kg, or about 40 mg per kg.
Dosage Forms
[0106] In one embodiment, compositions of the invention are orally
deliverable. The terms "orally deliverable" or "oral
administration" herein include any form of delivery of a
therapeutic agent or a composition thereof to a subject wherein the
agent or composition is placed in the mouth of the subject, whether
or not the agent or composition is swallowed. Thus "oral
administration" includes buccal and sublingual as well as
esophageal administration.
[0107] In some embodiments, compositions of the invention are in
the form of solid dosage forms. Non-limiting examples of suitable
solid dosage forms include tablets (e.g. suspension tablets, bite
suspension tablets, rapid dispersion tablets, chewable tablets,
melt tablets, effervescent tablets, bilayer tablets, etc), caplets,
capsules (e.g. a soft or a hard gelatin capsule filled with solid
and/or liquids), powder (e.g. a packaged powder, a dispensable
powder or an effervescent powder), lozenges, sachets, cachets,
troches, pellets, granules, microgranules, encapsulated
microgranules, powder aerosol formulations, or any other solid
dosage form reasonably adapted for oral administration.
[0108] EPA and/or any other desired cardiovascular agent(s) can be
co-formulated in the same dosage unit, or can be individually
formulated in separate dosage units. The terms "dose unit" and
"dosage unit" herein refer to a portion of a pharmaceutical
composition that contains an amount of a therapeutic agent suitable
for a single administration to provide a therapeutic effect. Such
dosage units may be administered one to a plurality (i.e. 1 to
about 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 2) of times per day, or as
many times as needed to elicit a therapeutic response.
[0109] In one embodiment, a composition of the invention comprises
one or more cardiovascular agents dispersed or suspended in EPA,
wherein the dispersion or suspension is present in a capsule (for
example gelatin or HPMC capsule), sachet, or other dosage form or
carrier as described herein. In another embodiment, the dispersion
or suspension is substantially uniform. In still another
embodiment, where co-administration of two or more dosage units is
desired, the EPA is present in a first dosage unit, for example a
suspension in a capsule, and the cardiovascular agent is present in
second dosage unit, for example a tablet. Optionally, any desired
additional cardiovascular agent can be present in a third
composition.
[0110] In another embodiment, composition(s) of the invention can
be in the form of liquid dosage forms or dose units to be imbibed
directly or they can be mixed with food or beverage prior to
ingestion. Non-limiting examples of suitable liquid dosage forms
include solutions, suspension, elixirs, syrups, liquid aerosol
formulations, etc.
[0111] In one embodiment, compositions of the invention, upon
storage in a closed container maintained at room temperature,
refrigerated (e.g. about 5 to about 5-10.degree. C.) temperature,
or frozen for a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
or 12 months, exhibit at least about 90%, at least about 95%, at
least about 97.5%, or at least about 99% of the active
ingredient(s) originally present therein.
[0112] In another embodiment, the invention provides a
pharmaceutical composition comprising EPA and a cardiovascular
agent (fill) encapsulated in a capsule shell, wherein the fill has
a baseline peroxide value not greater than about 10 Meq/kg, about 9
Meq/kg, about 8 Meq/kg, about 7 Meq/kg, about 6 Meq/kg, about 5
Meq/kg, about 4 Meq/kg, about 3 Meq/kg or about 2 Meq/kg, wherein
upon storage of the composition at 23.degree. C. and 50% RH for a
period about 1, about 2, about 3, about 4, about 5, about 6, about
7, about 8, about 9, about 10, about 11, about 12, about 13, about
14, about 15, about 16, about 17, about 18, about 19, about 20,
about 21, about 22, about 23 or about 24 months, the ultra-pure EPA
has a second peroxide value not greater than about 25 Meq/kg, about
24 Meq/kg, about 23 Meq/kg, about 22 Meq/kg, about 21 Meq/kg, about
20 Meq/kg, about 19 Meq/kg, about 18 Meq/kg, about 17 Meq/kg, about
16 Meq/kg, about 15 Meq/kg, about 14 Meq/kg, about 13 Meq/kg, about
12 Meq/kg, about 11 Meq/kg, about 10 Meq/kg, about 9 Meq/kg, about
8 Meq/kg, about 7 Meq/kg, about 6 Meq/kg, about 5 Meq/kg, about 4
Meq/kg, about 3 Meq/kg or about 2 Meq/kg.
[0113] Upon storage, some pharmaceutical compositions degrade over
time. Degradation products can alter a composition's efficacy, for
example by delivering less active ingredient to a subject than
recommended. Degradation products for new drugs above certain
thresholds should be reported to the Food & Drug Administration
(FDA) in accordance with current Guidance Documents. Degradation
products above a certain threshold amount should be identified. A
degradation product is "identified" when its structural
characterization has been achieved. Degradation products above a
certain amount should be qualified. A degradation product is
"qualified" when its biological safety is acquired and
evaluated.
[0114] In one embodiment, compositions of the invention with a
maximum daily dose of less than or equal to 1 gram, upon storage
under light, heat, humidity, acid/base hydrolytic, and/or oxidative
conditions, contain less than about 0.1% of any degradation product
not reported to the Food and Drug Administration (FDA). In another
embodiment, compositions of the invention with a maximum daily dose
of greater than 1 gram, upon storage under light, heat, humidity,
acid/base hydrolytic, and/or oxidative conditions, contain less
than about 0.05% of any degradation product not reported to the
FDA.
[0115] In one embodiment, compositions of the invention with a
maximum daily dose of less than 1 mg, upon storage under light,
heat, humidity, acid/base hydrolytic, and/or oxidative conditions,
contain less than about 1% of any unidentified degradation product.
In another embodiment, compositions of the invention with a maximum
daily dose of less than 1 mg, upon storage under light, heat,
humidity, acid/base hydrolytic, and/or oxidative conditions,
contain less than about 5 .mu.g of any unidentified degradation
product.
[0116] In one embodiment, compositions of the invention with a
maximum daily dose of 1 mg to 10 mg, upon storage under light,
heat, humidity, acid/base hydrolytic, and/or oxidative conditions,
contain less than about 0.5% of any unidentified degradation
product.
[0117] In another embodiment, compositions of the invention with a
maximum daily dose of 1 mg to 10 mg, upon storage under light,
heat, humidity, acid/base hydrolytic, and/or oxidative conditions,
contain less than about 20 .mu.g of any unidentified degradation
product.
[0118] In one embodiment, compositions of the invention with a
maximum daily dose of 10 mg to 2 g, upon storage under light, heat,
humidity, acid/base hydrolytic, and/or oxidative conditions,
contain less than about 0.2% of any unidentified degradation
product. In another embodiment, compositions of the invention with
a maximum daily dose of 10 mg to 2 g, upon storage under light,
heat, humidity, acid/base hydrolytic, and/or oxidative conditions,
contain less than about 2 mg of any unidentified degradation
product.
[0119] In one embodiment, compositions of the invention with a
maximum daily dose of greater than 2 g, upon storage under light,
heat, humidity, acid/base hydrolytic, and/or oxidative conditions,
contain less than about 0.1% of any unidentified degradation
product.
[0120] In one embodiment, compositions of the invention with a
maximum daily dose of less than 10 mg, upon storage under light,
heat, humidity, acid/base hydrolytic, and/or oxidative conditions,
contain less than about 1% of any unqualified degradation product.
In another embodiment, compositions of the invention with a maximum
daily dose of less than 10 mg, upon storage under light, heat,
humidity, acid/base hydrolytic, and/or oxidative conditions,
contain less than about 50 .mu.g of any unqualified degradation
product.
[0121] In one embodiment, compositions of the invention with a
maximum daily dose of 10 mg to 100 mg, upon storage under light,
heat, humidity, acid/base hydrolytic, and/or oxidative conditions,
contain less than about 0.5% of any unqualified degradation
product. In another embodiment, compositions of the invention with
a maximum daily dose of 10 mg to 100 mg, upon storage under light,
heat, humidity, acid/base hydrolytic, and/or oxidative conditions,
contain less than about 200 .mu.g of any unqualified degradation
product.
[0122] In one embodiment, compositions of the invention with a
maximum daily dose of 100 mg to 2 g, upon storage under light,
heat, humidity, acid/base hydrolytic, and/or oxidative conditions,
contain less than about 0.2% of any unqualified degradation
product. In another embodiment, compositions of the invention with
a maximum daily dose of 100 mg to 2 g, upon storage under light,
heat, humidity, acid/base hydrolytic, and/or oxidative conditions,
contain less than about 3 mg of any unqualified degradation
product.
[0123] In one embodiment, compositions of the invention with a
maximum daily dose of greater than 2 g, upon storage under light,
heat, humidity, acid/base hydrolytic, and/or oxidative conditions,
contain less than about 0.15% of any unqualified degradation
product.
[0124] In some embodiments, compositions of the invention comprise
a stabilizing agent that suppresses, prevents, hinders, or
otherwise attenuates the decomposition of the active ingredient(s)
during storage. For example, oxidative decomposition of EPA in
compositions of the invention may be prevented or attenuated by the
presence of antioxidants. Non-limiting examples of suitable
antioxidants include tocopherol, lecithin, citric acid and/or
ascorbic acid. One or more antioxidants, if desired, are typically
present in a composition in an amount of about 0.01% to about 0.1%,
by weight, or about 0.025% to about 0.05%, by weight.
Excipients
[0125] Compositions of the invention optionally comprise one or
more pharmaceutically acceptable excipients. The term
"pharmaceutically acceptable excipient" herein means any substance,
not itself a therapeutic agent, used as a carrier or vehicle for
delivery of a therapeutic agent to a subject or added to a
pharmaceutical composition to improve its handling or storage
properties or to permit or facilitate formation of a unit dose of
the composition, and that does not produce unacceptable toxicity or
interaction with other components in the composition.
[0126] Compositions of the invention optionally comprise one or
more pharmaceutically acceptable diluents as excipients. Suitable
diluents illustratively include, either individually or in
combination, lactose, including anhydrous lactose and lactose
monohydrate; starches, including directly compressible starch and
hydrolyzed starches (e.g., Celutab.TM. and Emdex.TM.); mannitol;
sorbitol; xylitol; dextrose (e.g., Cerelose.TM. 2000) and dextrose
monohydrate; dibasic calcium phosphate dihydrate; sucrose-based
diluents; confectioner's sugar; monobasic calcium sulfate
monohydrate; calcium sulfate dihydrate; granular calcium lactate
trihydrate; dextrates; inositol; hydrolyzed cereal solids; amylose;
celluloses including microcrystalline cellulose, food grade sources
of .alpha.- and amorphous cellulose (e.g., Rexcel.TM.) and powdered
cellulose; calcium carbonate; glycine; bentonite;
polyvinylpyrrolidone; and the like. Such diluents, if present,
constitute in total about 5% to about 99%, about 10% to about 85%,
or about 20% to about 80%, of the total weight of the
composition.
[0127] Compositions of the invention optionally comprise one or
more pharmaceutically acceptable disintegrants as excipients.
Suitable disintegrants include, either individually or in
combination, starches, including sodium starch glycolate (e.g.,
Explotab.TM. of PenWest) and pregelatinized corn starches (e.g.,
National.TM. 1551, National.TM. 1550, and Colocorn.TM. 1500), clays
(e.g., Veegum.TM. HV), celluloses such as purified cellulose,
microcrystalline cellulose, methylcellulose, carboxymethylcellulose
and sodium carboxymethylcellulose, croscarmellose sodium (e.g.,
Ac-Di-Sol.TM. of FMC), alginates, crospovidone, and gums such as
agar, guar, xanthan, locust bean, karaya, pectin and tragacanth
gums. Such disintegrants, if present, typically comprise in total
about 0.2% to about 30%, about 0.2% to about 10%, or about 0.2% to
about 5%, of the total weight of the composition.
[0128] Compositions of the invention optionally comprise one or
more antioxidants. Illustrative antioxidants include sodium
ascorbate and vitamin E (tocopherol). One or more antioxidants, if
present, are typically present in a composition of the invention in
an amount of about 0.001% to about 5%, about 0.005% to about 2.5%,
or about 0.01% to about 1%, by weight.
[0129] Compositions of the invention optionally comprise one or
more pharmaceutically acceptable binding agents or adhesives as
excipients. Such binding agents and adhesives can impart sufficient
cohesion to a powder being tableted to allow for normal processing
operations such as sizing, lubrication, compression and packaging,
but still allow the tablet to disintegrate and the composition to
be absorbed upon ingestion. Suitable binding agents and adhesives
include, either individually or in combination, acacia; tragacanth;
sucrose; gelatin; glucose; starches such as, but not limited to,
pregelatinized starches (e.g., National.TM. 1511 and National.TM.
1500); celluloses such as, but not limited to, methylcellulose and
carmellose sodium (e.g., Tylose.TM.); alginic acid and salts of
alginic acid; magnesium aluminum silicate; PEG; guar gum;
polysaccharide acids; bentonites; povidone, for example povidone
K-15, K-30 and K-29/32; polymethacrylates; HPMC;
hydroxypropylcellulose (e.g., Klucel.TM.); and ethylcellulose
(e.g., Ethocel.TM.). Such binding agents and/or adhesives, if
present, constitute in total about 0.5% to about 25%, about 0.75%
to about 15%, or about 1% to about 10%, of the total weight of the
composition.
[0130] Compositions of the invention optionally comprise one or
more pharmaceutically acceptable wetting agents as excipients.
Non-limiting examples of surfactants that can be used as wetting
agents in compositions of the invention include quaternary ammonium
compounds, for example benzalkonium chloride, benzethonium chloride
and cetylpyridinium chloride, dioctyl sodium sulfosuccinate,
polyoxyethylene alkylphenyl ethers, for example nonoxynol 9,
nonoxynol 10, and octoxynol 9, poloxamers (polyoxyethylene and
polyoxypropylene block copolymers), polyoxyethylene fatty acid
glycerides and oils, for example polyoxyethylene (8)
caprylic/capric mono- and diglycerides (e.g., Labrasol.TM. of
Gattefosse), polyoxyethylene (35) castor oil and polyoxyethylene
(40) hydrogenated castor oil; polyoxyethylene alkyl ethers, for
example polyoxyethylene (20) cetostearyl ether, polyoxyethylene
fatty acid esters, for example polyoxyethylene (40) stearate,
polyoxyethylene sorbitan esters, for example polysorbate 20 and
polysorbate 80 (e.g., Tween.TM. 80 of ICI), propylene glycol fatty
acid esters, for example propylene glycol laurate (e.g.,
Lauroglycol.TM. of Gattefosse), sodium lauryl sulfate, fatty acids
and salts thereof, for example oleic acid, sodium oleate and
triethanolamine oleate, glyceryl fatty acid esters, for example
glyceryl monostearate, sorbitan esters, for example sorbitan
monolaurate, sorbitan monooleate, sorbitan monopalmitate and
sorbitan monostearate, tyloxapol, and mixtures thereof. Such
wetting agents, if present, constitute in total about 0.25% to
about 15%, about 0.4% to about 10%, or about 0.5% to about 5%, of
the total weight of the composition.
[0131] Compositions of the invention optionally comprise one or
more pharmaceutically acceptable lubricants (including
anti-adherents and/or glidants) as excipients. Suitable lubricants
include, either individually or in combination, glyceryl behapate
(e.g., Compritol.TM. 888); stearic acid and salts thereof,
including magnesium (magnesium stearate), calcium and sodium
stearates; hydrogenated vegetable oils (e.g., Sterotex.TM.);
colloidal silica; talc; waxes; boric acid; sodium benzoate; sodium
acetate; sodium fumarate; sodium chloride; DL-leucine; PEG (e.g.,
Carbowax.TM. 4000 and Carbowax.TM. 6000); sodium oleate; sodium
lauryl sulfate; and magnesium lauryl sulfate. Such lubricants, if
present, constitute in total about 0.1% to about 10%, about 0.2% to
about 8%, or about 0.25% to about 5%, of the total weight of the
composition.
[0132] Suitable anti-adherents include talc, cornstarch,
DL-leucine, sodium lauryl sulfate and metallic stearates. Talc is
an anti-adherent or glidant used, for example, to reduce
formulation sticking to equipment surfaces and also to reduce
static in the blend. Talc, if present, constitutes about 0.1% to
about 10%, about 0.25% to about 5%, or about 0.5% to about 2%, of
the total weight of the composition. Glidants can be used to
promote powder flow of a solid formulation. Suitable glidants
include colloidal silicon dioxide, starch, talc, tribasic calcium
phosphate, powdered cellulose and magnesium trisilicate.
[0133] Compositions of the present invention optionally comprise
one or more flavoring agents, sweetening agents, and/or colorants.
Flavoring agents useful in the present invention include, without
limitation, acacia syrup, alitame, anise, apple, aspartame, banana,
Bavarian cream, berry, black currant, butter, butter pecan,
butterscotch, calcium citrate, camphor, caramel, cherry, cherry
cream, chocolate, cinnamon, citrus, citrus punch, citrus cream,
cocoa, coffee, cola, cool cherry, cool citrus, cyclamate, cylamate,
dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger,
glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit,
honey, isomalt, lemon, lime, lemon cream, MagnaSweet.RTM., maltol,
mannitol, maple, menthol, mint, mint cream, mixed berry, nut,
orange, peanut butter, pear, peppermint, peppermint cream,
Prosweet.RTM. Powder, raspberry, root beer, rum, saccharin,
safrole, sorbitol, spearmint, spearmint cream, strawberry,
strawberry cream, stevia, sucralose, sucrose, Swiss cream,
tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut,
watermelon, wild cherry, wintergreen, xylitol, and combinations
thereof, for example, anise-menthol, cherry-anise, cinnamon-orange,
cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime,
lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint,
etc.
[0134] Sweetening agents that can be used in the present invention
include, for example, acesulfame potassium (acesulfame K), alitame,
aspartame, cyclamate, cylamate, dextrose, isomalt, MagnaSweet.RTM.,
maltitol, mannitol, neohesperidine DC, neotame, Prosweet.RTM.
Powder, saccharin, sorbitol, stevia, sucralose, sucrose, tagatose,
thaumatin, xylitol, and the like.
[0135] Flavoring agents, sweetening agents, and/or colorants can be
present in compositions of the invention in any suitable amount,
for example about 0.01% to about 10%, about 0.1% to about 8%, or
about 1% to about 5%, by weight.
[0136] Compositions of the invention optionally comprise a
suspending agent. Non-limiting illustrative examples of suitable
suspending agents include silicon dioxide, bentonite, hydrated
aluminum silicate (e.g. kaolin) and mixtures thereof. One or more
suspending agents are optionally present in compositions of the
invention in a total amount of about 0.01% to about 3.0%, about
0.1% to about 2.0%, or about 0.25% to about 1.0%, by weight
[0137] The foregoing excipients can have multiple roles as is known
in the art. For example, starch can serve as a filler as well as a
disintegrant. The classification of excipients above is not to be
construed as limiting in any manner. Excipients categorized in any
manner may also operate under various different categories of
excipients as will be readily appreciated by one of ordinary skill
in the art.
Therapeutic Methods
[0138] In various embodiments, compositions of the invention are
useful for treatment and/or prevention of a cardiovascular-related
disease. The term "cardiovascular-related disease" herein refers to
any disease or disorder of the heart or blood vessels (i.e.
arteries and veins) or any symptom thereof, or any disease or
condition that causes or contributes to a cardiovascular disease."
Non-limiting examples of cardiovascular-related diseases and
disorders include acute cardiac ischemic events, acute myocardial
infarction, angina, angina pectoris, arrhythmia, atrial
fibrulation, atherosclerosis, arterial fibrillation, cardiac
insufficiency, cardiovascular disease, chronic heart failure,
chronic stable angina, congestive heart failure, coronary artery
disease, coronary heart disease, deep vein thrombosis, diabetes,
diabetes mellitus, diabetic neuropathy, diastolic dysfunction in
subjects with diabetes mellitus, edema, essential hypertension,
eventual pulmonary embolism, fatty liver disease, heart disease,
heart failure, homozygous familial hypercholesterolemia (HoFH),
homozygous familial sitosterolemia, hypercholesterolemia,
hyperlipidemia, hyperlipidemia in HIV positive subjects,
hypertension, hypertriglyceridemia, ischemic complications in
unstable angina and myocardial infarction, low blood pressure,
metabolic syndrome, mixed dyslipidemia, moderate to mild heart
failure, myocardial infarction, obesity management, paroxysmal
atrial/arterial fibrillation/fibrulation/flutter, paroxysmal
supraventricular tachycardias (PSVT), particularly severe or rapid
onset edema, platelet aggregation, primary hypercholesterolemia,
primary hyperlipidemia, pulmonary arterial hypertension, pulmonary
hypertension, recurrent hemodynamically unstable ventricular
tachycardia (VT), recurrent ventricular arrhythmias, recurrent
ventricular fibrillation (VF), ruptured aneurysm, sitisterolemia,
stroke, supraventricular tachycardia, symptomatic atrial
fibrillation/flutter, tachycardia, type-II diabetes, vascular
disease, venous thromboembolism, ventricular arrhythmias, and other
cardiovascular events.
[0139] The term "treatment" in relation a given disease or
disorder, includes, but is not limited to, inhibiting the disease
or disorder, for example, arresting the development of the disease
or disorder; relieving the disease or disorder, for example,
causing regression of the disease or disorder; or relieving a
condition caused by or resulting from the disease or disorder, for
example, relieving, preventing or treating symptoms of the disease
or disorder. The term "prevention" in relation to a given disease
or disorder means: preventing the onset of disease development if
none had occurred, preventing the disease or disorder from
occurring in a subject that may be predisposed to the disorder or
disease but has not yet been diagnosed as having the disorder or
disease, and/or preventing further disease/disorder development if
already present.
[0140] In some embodiments, compositions of the present invention
can be co-administered or administered concomitantly with one or
more additional cardiovascular agents. The terms "co-administered,"
"concomitant administration," and "administered concomitantly" are
used interchangeably herein and each refer to, for example,
administration of two or more agents (e.g., EPA or a derivative
thereof and a cardiovascular agent) at the same time, in the same
dosage unit, one immediately after the other, within five minutes
of each other, within ten minutes of each other, within fifteen
minutes of each other, within thirty minutes of each other, within
one hour of each other, within two hours of each other, within four
hours of each other, within six hours of each other, within twelve
hours of each other, within one day of each other, within one week
of each other, within two weeks of each other, within one month of
each other, within two months of each other, within six months of
each other, within one year of each other, etc.
[0141] In one embodiment, the present invention provides a method
of treating a cardiovascular-related disease comprising
administering to a subject in need thereof a composition or
compositions comprising EPA and one or more additional
cardiovascular agents (either as a single dosage unit or as
multiple dosage units), wherein one or more lipid parameters are
improved by comparison with lipid parameters achieved by the
additive effects of the individual treatments.
[0142] In a related embodiment, upon treatment in accordance with
the present invention, for example over a period of about 1 to
about 200 weeks, about 1 to about 100 weeks, about 1 to about 80
weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about
1 to about 20 weeks, about 1 to about 15 weeks, about 1 to about 12
weeks, about 1 to about 10 weeks, about 1 to about 5 weeks, about 1
to about 2 weeks or about 1 week, the subject or subject group
exhibits one or more of the following outcomes: [0143] (a) reduced
triglyceride levels compared to baseline or a placebo arm; [0144]
(b) reduced Apo B levels compared to baseline or a placebo arm;
[0145] (c) increased HDL-C levels compared to baseline or a placebo
arm; [0146] (d) no increase in LDL-C levels compared to baseline or
a placebo arm; [0147] (e) a reduction in LDL-C levels compared to
baseline or a placebo arm; [0148] (f) a reduction in non-HDL-C
levels compared to baseline or a placebo arm; [0149] (g) a
reduction in vLDL levels compared to baseline or a placebo arm;
[0150] (h) an increase in apo A-I levels compared to baseline or a
placebo arm; [0151] (i) an increase in apo A-I/apo B ratio compared
to baseline or a placebo arm; [0152] (j) a reduction in lipoprotein
A levels compared to baseline or a placebo arm; [0153] (k) an
increase in LDL particle number compared to baseline or a placebo
arm; [0154] (l) a reduction in LDL size compared to baseline or a
placebo arm; [0155] (m) a reduction in remnant-like particle
cholesterol compared to baseline or a placebo arm; [0156] (n) a
reduction in oxidized LDL compared to baseline or a placebo arm;
[0157] (o) no change or a reduction in fasting plasma glucose (FPG)
compared to baseline or a placebo arm; [0158] (p) a reduction in
hemoglobin A.sub.1c (HbA.sub.1c) compared to baseline or a placebo
arm; [0159] (q) a reduction in homeostasis model insulin resistance
compared to baseline or a placebo arm; [0160] (r) a reduction in
lipoprotein associated phospholipase A2 compared to baseline or a
placebo arm; [0161] (s) a reduction in intracellular adhesion
molecule-1 compared to baseline or a placebo arm; [0162] (t) a
reduction in interleukin-6 compared to baseline or a placebo arm;
[0163] (u) a reduction in plasminogen activator inhibitor-1
compared to baseline or a placebo arm; [0164] (v) a reduction in
high sensitivity C-reactive protein (hsCRP) compared to baseline or
a placebo arm; [0165] (w) an increase in serum phospholipid EPA
compared to baseline or a placebo arm; [0166] (x) an increase in
red blood cell membrane EPA compared to baseline or a placebo arm;
and/or [0167] (y) a reduction or increase in one or more of serum
phospholipid and/or red blood cell content of docosahexaenoic acid
(DHA), docosapentaenoic acid (DPA), arachidonic acid (AA), palmitic
acid (PA), staeridonic acid (SA) or oleic acid (OA) compared to
baseline or a placebo arm.
[0168] In one embodiment, methods of the present invention comprise
measuring baseline levels of one or more markers set forth in
(a)-(y) above prior to dosing the subject or subject group. In
another embodiment, the methods comprise administering a
composition as disclosed herein to the subject after baseline
levels of one or more markers set forth in (a)-(y) are determined,
and subsequently taking an additional measurement of said one or
more markers.
[0169] In another embodiment, upon treatment with a composition of
the present invention, for example over a period of about 1 to
about 200 weeks, about 1 to about 100 weeks, about 1 to about 80
weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about
1 to about 20 weeks, about 1 to about 15 weeks, about 1 to about 12
weeks, about 1 to about 10 weeks, about 1 to about 5 weeks, about 1
to about 2 weeks or about 1 week, the subject or subject group
exhibits any 2 or more of, any 3 or more of, any 4 or more of, any
5 or more of, any 6 or more of, any 7 or more of, any 8 or more of,
any 9 or more of, any 10 or more of, any 11 or more of, any 12 or
more of, any 13 or more of, any 14 or more of, any 15 or more of,
any 16 or more of, any 17 or more of, any 18 or more of, any 19 or
more of, any 20 or more of, any 21 or more of, any 22 or more of,
any 23 or more, any 24 or more, or all 25 of outcomes (a)-(y)
described immediately above.
[0170] In another embodiment, upon treatment with a composition of
the present invention, for example over a period of about 1 to
about 200 weeks, about 1 to about 100 weeks, about 1 to about 80
weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about
1 to about 20 weeks, about 1 to about 15 weeks, about 1 to about 10
weeks, about 1 to about 5 weeks, about 1 to about 2 weeks or about
1 week, the subject or subject group exhibits one or more of the
following outcomes: [0171] (a) a reduction in triglyceride level of
at least about 5%, at least about 10%, at least about 15%, at least
about 20%, at least about 25%, at least about 30%, at least about
35%, at least about 40%, at least about 45%, at least about 50%, at
least about 55% or at least about 75% (actual % change or median %
change) as compared to baseline or a placebo arm; [0172] (b) a less
than 30% increase, less than 20% increase, less than 10% increase,
less than 5% increase or no increase in non-HDL-C levels or a
reduction in non-HDL-C levels of at least about 1%, at least about
3%, at least about 5%, at least about 10%, at least about 15%, at
least about 20%, at least about 25%, at least about 30%, at least
about 35%, at least about 40%, at least about 45%, at least about
50%, at least about 55% or at least about 75% (actual % change or
median % change) as compared to baseline or a placebo arm; [0173]
(c) substantially no change, no change or an increase in HDL-C
levels of at least about 5%, at least about 10%, at least about
15%, at least about 20%, at least about 25%, at least about 30%, at
least about 35%, at least about 40%, at least about 45%, at least
about 50%, at least about 55% or at least about 75% (actual %
change or median % change) as compared to baseline or a placebo
arm; [0174] (d) a less than 60% increase, less than 50% increase,
less than 40% increase, less than 30% increase, less than 20%
increase, less than 15% increase or no increase in LDL-C levels or
a reduction in LDL-C levels of at least about 5%, at least about
10%, at least about 15%, at least about 20%, at least about 25%, at
least about 30%, at least about 35%, at least about 40%, at least
about 45%, at least about 50%, at least about 55%, at least about
55% or at least about 75% (actual % change or median % change) as
compared to baseline or a placebo arm; [0175] (e) a decrease in Apo
B levels of at least about 5%, at least about 10%, at least about
15%, at least about 20%, at least about 25%, at least about 30%, at
least about 35%, at least about 40%, at least about 45%, at least
about 50%, at least about 55% or at least about 75% (actual %
change or median % change) as compared to baseline or a placebo
arm; [0176] (f) a reduction in vLDL levels of at least about 5%, at
least about 10%, at least about 15%, at least about 20%, at least
about 25%, at least about 30%, at least about 35%, at least about
40%, at least about 45%, at least about 50%, or at least about 100%
(actual % change or median % change) compared to baseline or a
placebo arm; [0177] (g) an increase in apo A-I levels of at least
about 5%, at least about 10%, at least about 15%, at least about
20%, at least about 25%, at least about 30%, at least about 35%, at
least about 40%, at least about 45%, at least about 50%, or at
least about 100% (actual % change or median % change) compared to
baseline or a placebo arm; [0178] (h) an increase in apo A-I/apo B
ratio of at least about 5%, at least about 10%, at least about 15%,
at least about 20%, at least about 25%, at least about 30%, at
least about 35%, at least about 40%, at least about 45%, at least
about 50%, or at least about 100% (actual % change or median %
change) compared to baseline or a placebo arm; [0179] (i) a
reduction in lipoprotein (a) levels of at least about 5%, at least
about 10%, at least about 15%, at least about 20%, at least about
25%, at least about 30%, at least about 35%, at least about 40%, at
least about 45%, at least about 50%, or at least about 100% (actual
% change or median % change) compared to baseline or a placebo arm;
[0180] (j) a reduction in mean LDL particle number of at least
about 5%, at least about 10%, at least about 15%, at least about
20%, at least about 25%, at least about 30%, at least about 35%, at
least about 40%, at least about 45%, at least about 50%, or at
least about 100% (actual % change or median % change) compared to
baseline or a placebo arm; [0181] (k) an increase in mean LDL
particle size of at least about 5%, at least about 10%, at least
about 15%, at least about 20%, at least about 25%, at least about
30%, at least about 35%, at least about 40%, at least about 45%, at
least about 50%, or at least about 100% (actual % change or median
% change) compared to baseline or a placebo arm; [0182] (l) a
reduction in remnant-like particle cholesterol of at least about
5%, at least about 10%, at least about 15%, at least about 20%, at
least about 25%, at least about 30%, at least about 35%, at least
about 40%, at least about 45%, at least about 50%, or at least
about 100% (actual % change or median % change) compared to
baseline or a placebo arm; [0183] (m) a reduction in oxidized LDL
of at least about 5%, at least about 10%, at least about 15%, at
least about 20%, at least about 25%, at least about 30%, at least
about 35%, at least about 40%, at least about 45%, at least about
50%, or at least about 100% (actual % change or median % change)
compared to baseline or a placebo arm; [0184] (n) substantially no
change, no change or a reduction in fasting plasma glucose (FPG) of
at least about 5%, at least about 10%, at least about 15%, at least
about 20%, at least about 25%, at least about 30%, at least about
35%, at least about 40%, at least about 45%, at least about 50%, or
at least about 100% (actual % change or median % change) compared
to baseline or a placebo arm; [0185] (o) substantially no change,
no change or a reduction in hemoglobin A.sub.1c, (HbA.sub.1c) of at
least about 5%, at least about 10%, at least about 15%, at least
about 20%, at least about 25%, at least about 30%, at least about
35%, at least about 40%, at least about 45%, or at least about 50%
(actual % change or median % change) compared to baseline or a
placebo arm; [0186] (p) a reduction in homeostasis model index
insulin resistance of at least about 5%, at least about 10%, at
least about 15%, at least about 20%, at least about 25%, at least
about 30%, at least about 35%, at least about 40%, at least about
45%, at least about 50%, or at least about 100% (actual % change or
median % change) compared to baseline or a placebo arm; [0187] (q)
a reduction in lipoprotein associated phospholipase A2 of at least
about 5%, at least about 10%, at least about 15%, at least about
20%, at least about 25%, at least about 30%, at least about 35%, at
least about 40%, at least about 45%, at least about 50%, or at
least about 100% (actual % change or median % change) compared to
baseline or a placebo arm; [0188] (r) a reduction in intracellular
adhesion molecule-1 of at least about 5%, at least about 10%, at
least about 15%, at least about 20%, at least about 25%, at least
about 30%, at least about 35%, at least about 40%, at least about
45%, at least about 50%, or at least about 100% (actual % change or
median % change) compared to baseline or a placebo arm; [0189] (s)
a reduction in interleukin-6 of at least about 5%, at least about
10%, at least about 15%, at least about 20%, at least about 25%, at
least about 30%, at least about 35%, at least about 40%, at least
about 45%, at least about 50%, or at least about 100% (actual %
change or median % change) compared to baseline or a placebo arm;
[0190] (t) a reduction in plasminogen activator inhibitor-1 of at
least about 5%, at least about 10%, at least about 15%, at least
about 20%, at least about 25%, at least about 30%, at least about
35%, at least about 40%, at least about 45%, at least about 50%, or
at least about 100% (actual % change or median % change) compared
to baseline or a placebo arm; [0191] (u) a reduction in high
sensitivity C-reactive protein (hsCRP) of at least about 5%, at
least about 10%, at least about 15%, at least about 20%, at least
about 25%, at least about 30%, at least about 35%, at least about
40%, at least about 45%, at least about 50%, or at least about 100%
(actual % change or median % change) compared to baseline or a
placebo arm; [0192] (v) an increase in serum plasma and/or RBC EPA
of at least about 5%, at least about 10%, at least about 15%, at
least about 20%, at least about 25%, at least about 30%, at least
about 35%, at least about 40%, at least about 45%, at least about
50%, at least about 100%, at least about 200% or at least about
400% (actual % change or median % change) compared to baseline or a
placebo arm; [0193] (w) an increase in serum phospholipid and/or
red blood cell membrane EPA of at least about 5%, at least about
10%, at least about 15%, at least about 20%, at least about 25%, at
least about 30%, at least about 35%, at least about 40%, at least
about 45%, or at least about 50%, at least about 100%, at least
about 200%, or at least about 400% (actual % change or median %
change) compared to baseline or a placebo arm; [0194] (x) a
reduction or increase in one or more of serum phospholipid and/or
red blood cell DHA, DPA, AA, PA and/or OA of at least about 5%, at
least about 10%, at least about 15%, at least about 20%, at least
about 25%, at least about 30%, at least about 35%, at least about
40%, at least about 45%, at least about 50%, at least about 55% or
at least about 75% (actual % change or median % change) compared to
baseline or a placebo arm; and/or [0195] (y) a reduction in total
cholesterol of at least about 5%, at least about 10%, at least
about 15%, at least about 20%, at least about 25%, at least about
30%, at least about 35%, at least about 40%, at least about 45%, at
least about 50%, at least about 55% or at least about 75% (actual %
change or median % change) compared to baseline or a placebo
arm.
[0196] In one embodiment, methods of the present invention comprise
measuring baseline levels of one or more markers set forth in
(a)-(y) prior to dosing the subject or subject group. In another
embodiment, the methods comprise administering a composition as
disclosed herein to the subject after baseline levels of one or
more markers set forth in (a)-(y) are determined, and subsequently
taking a second measurement of the one or more markers as measured
at baseline for comparison thereto.
[0197] In another embodiment, upon treatment with a composition of
the present invention, for example over a period of about 1 to
about 200 weeks, about 1 to about 100 weeks, about 1 to about 80
weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about
1 to about 20 weeks, about 1 to about 15 weeks, about 1 to about 12
weeks, about 1 to about 10 weeks, about 1 to about 5 weeks, about 1
to about 2 weeks or about 1 week, the subject or subject group
exhibits any 2 or more of, any 3 or more of, any 4 or more of, any
5 or more of, any 6 or more of, any 7 or more of, any 8 or more of,
any 9 or more of, any 10 or more of, any 11 or more of, any 12 or
more of, any 13 or more of, any 14 or more of, any 15 or more of,
any 16 or more of, any 17 or more of, any 18 or more of, any 19 or
more of, any 20 or more of, any 21 or more of, any 22 or more of,
any 23 or more of, any 24 or more of, or all 25 of outcomes (a)-(y)
described immediately above.
[0198] Parameters (a)-(y) can be measured in accordance with any
clinically acceptable methodology. For example, triglycerides,
total cholesterol, HDL-C and fasting blood sugar can be sample from
serum and analyzed using standard photometry techniques. VLDL-TG,
LDL-C and VLDL-C can be calculated or determined using serum
lipoprotein fractionation by preparative ultracentrifugation and
subsequent quantitative analysis by refractometry or by analytic
ultracentrifugal methodology. Apo A1, Apo B and hsCRP can be
determined from serum using standard nephelometry techniques.
Lipoprotein (a) can be determined from serum using standard
turbidimetric immunoassay techniques. LDL particle number and
particle size can be determined using nuclear magnetic resonance
(NMR) spectrometry. Remnants lipoproteins and LDL-phospholipase A2
can be determined from EDTA plasma or serum and serum,
respectively, using enzymatic immunoseparation techniques. Oxidized
LDL, intercellular adhesion molecule-1 and interleukin-2 levels can
be determined from serum using standard enzyme immunoassay
techniques. These techniques are described in detail in standard
textbooks, for example Tietz Fundamentals of Clinical Chemistry,
6.sup.th Ed. (Burtis, Ashwood and Borter Eds.), WB Saunders
Company.
[0199] In a related embodiment, the reductions or increases of
parameters (a)-(y) above are statistically significant.
[0200] In another embodiment, the present invention provides a
method of blood lipid therapy comprising administering to a subject
in need thereof 1 to a plurality of dosage units comprising a
composition or compositions as disclosed herein. In another
embodiment, the subject being treated has a baseline triglyceride
level, prior to treatment with a composition of the present
invention, greater than or equal to about 150 mg/dl, greater than
or equal to about 175 mg/dl, greater than or equal to about 250
mg/dl, or greater than or equal to about 500 mg/dl, for example
about 200 mg/dl to about 2000 mg/dl, about 300 to about 1800 mg/dl,
or about 500 mg/dl to about 1500 mg/dl.
[0201] In one embodiment, methods of the present invention comprise
measuring baseline levels of one or more markers set forth in
(a)-(y) prior to dosing the subject or subject group. In another
embodiment, the methods comprise administering a composition as
disclosed herein to the subject after baseline levels of one or
more markers set forth in (a)-(y) are determined, and subsequently
taking a second measurement of the one or more markers as measured
at baseline for comparison thereto.
[0202] In one embodiment, the present invention provides a method
of treating or preventing primary hypercholesteremia and/or mixed
dyslipidemia (Fredrickson Types IIa and IIb) in a subject in need
thereof, comprising administering to the subject a composition or
compositions comprising EPA and one or more additional
cardiovascular agents (either as a single dosage unit or as
multiple dosage units) as disclosed herein. In a related
embodiment, the present invention provides a method of reducing
triglyceride levels in a subject or subjects when treatment with a
statin or niacin extended-release monotherapy is considered
inadequate (Frederickson type IV hyperlipidemia). Statin or niacin
extended-release monotherapy is considered inadequate when, for
example, the subject's non-HDL-C level is not lowered or is not
lowered to the degree desired, the subject's LDL-C level is not
improved or is not improved to the degree desired, the subject's
HDL-C level is not improved or is not improved to the degree
desired, and/or the subject's triglyceride level is not improved or
is not improved to the degree desired.
[0203] In another embodiment, the present invention provides a
method of treating or preventing nonfatal myocardial infarction,
comprising administering to the subject a composition or
compositions comprising EPA and one or more additional
cardiovascular agents (either as a single dosage unit or as
multiple dosage units) as disclosed herein.
[0204] In another embodiment, the present invention provides a
method of treating or preventing risk of recurrent nonfatal
myocardial infarction in a subject with a history of myocardial
infarction, comprising administering to the subject a composition
or compositions comprising EPA and one or more additional
cardiovascular agents (either as a single dosage unit or as
multiple dosage units) as disclosed herein.
[0205] In another embodiment, the present invention provides a
method of slowing progression of or promoting regression of
atherosclerotic disease in a subject in need thereof, comprising
administering to the subject a composition or compositions
comprising EPA and one or more additional cardiovascular agents
(either as a single dosage unit or as multiple dosage units) as
disclosed herein.
[0206] In another embodiment, the present invention provides a
method of treating obesity in a subject in need thereof, comprising
administering to a subject in need thereof a composition or
compositions comprising EPA and one or more additional
cardiovascular agents (either as a single dosage unit or as
multiple dosage units) as disclosed herein.
[0207] In another embodiment, the present invention provides a
method of treating or preventing very high serum triglyceride
levels (e.g. Types IV and V hyperlipidemia) in a subject in need
thereof, comprising administering to the subject a composition or
compositions comprising EPA and one or more additional
cardiovascular agents (either as a single dosage unit or as
multiple dosage units) as disclosed herein.
[0208] In another embodiment, the present invention provides a
method of treating subjects having very high serum triglyceride
levels (e.g. greater than 1000 mg/dl or greater than 2000 mg/dl)
and that are at risk of developing pancreatitis, comprising
administering to the subject a composition or compositions
comprising EPA and one or more additional cardiovascular agents
(either as a single dosage unit or as multiple dosage units) as
disclosed herein.
[0209] In another embodiment, the present invention provides a
method of preventing recurrence of stroke, comprising administering
to a subject with a history of stroke a composition or compositions
comprising EPA and one or more additional cardiovascular agents
(either as a single dosage unit or as multiple dosage units) as
disclosed herein.
[0210] In another embodiment, the present invention provides a
method of preventing onset and/or recurrence of cardiovascular
events in a subject who has escaped the unstable period after
cardiovascular angioplasty, comprising administering to the subject
a composition or compositions comprising EPA and one or more
additional cardiovascular agents (either as a single dosage unit or
as multiple dosage units) as disclosed herein.
[0211] In another embodiment, the present invention provides a
method of reducing Apo-B and non-HDL cholesterol levels in a
subject group with a baseline LDL-cholesterol level of at least 100
mg/dl, a baseline non-HDL-cholesterol level of at least 130 mg/dl
and a baseline triglyceride level of at least 200 mg/dl, and
reducing the Apo-B and the non-HDL-cholesterol level of the subject
group by administering a composition or compositions comprising EPA
and one or more additional cardiovascular agents (either as a
single dosage unit or as multiple dosage units) as disclosed herein
to members of the subject group.
[0212] In another embodiment, the invention provides a method of
reducing Apo-B levels in a subject group, comprising measuring
LDL-cholesterol, non-HDL-cholesterol, and triglyceride levels in
subjects, providing a subject group with a baseline LDL-cholesterol
level of at least 100 mg/dL, a baseline non-HDL-cholesterol level
of at least 130 mg/dL, and a baseline triglyceride level of at
least 200 mg/dL, and reducing the Apo-B levels of the subject group
by administering to members of the subject group a composition or
compositions comprising EPA and one or more additional
cardiovascular agents (either as a single dosage unit or as
multiple dosage units) as disclosed herein in an amount effective
to reduce the Apo-B levels of the subject group in a statistically
significant amount as compared to a control treatment, wherein an
increase or statistically significant increase of LDL-cholesterol
level is avoided.
[0213] In another embodiment, the invention provides a method of
reducing Apo-B levels in a subject group, comprising providing a
subject group with a baseline LDL-cholesterol level of at least 100
mg/dL, a baseline non-HDL-cholesterol level of at least 130 mg/dL,
and a baseline triglyceride level of at least 200 mg/dL, reducing
the Apo-B levels of the subject group by administering to members
of the subject group a composition or compositions comprising EPA
and one or more additional cardiovascular agents (either as a
single dosage unit or as multiple dosage units) as disclosed herein
in an amount effective to reduce the Apo-B levels of the subject
group in a statistically significant amount as compared to a
control treatment, and determining the reduction in the Apo-B
levels of the subject group.
[0214] In one embodiment, a composition of the invention is
administered to a subject in an amount sufficient to provide a
daily EPA dose of about 1 mg to about 10,000 mg, 25 about 5000 mg,
about 50 to about 3000 mg, about 75 mg to about 2500 mg, or about
100 mg to about 1000 mg, for example about 75 mg, about 100 mg,
about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225
mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about
350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg,
about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575
mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about
700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg,
about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925
mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about
1050 mg, about 1075 mg, about 1100 mg, about 1025 mg, about 1050
mg, about 1075 mg, about 1200 mg, about 1225 mg, about 1250 mg,
about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about
1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475
mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg,
about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about
1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about 1800
mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg,
about 1925 mg, about 1950 mg, about 1975 mg, about 2000 mg, about
2025 mg, about 2050 mg, about 2075 mg, about 2100 mg, about 2125
mg, about 2150 mg, about 2175 mg, about 2200 mg, about 2225 mg,
about 2250 mg, about 2275 mg, about 2300 mg, about 2325 mg, about
2350 mg, about 2375 mg, about 2400 mg, about 2425 mg, about 2450
mg, about 2475 mg, or about 2500 mg.
[0215] In the various embodiments of the invention described
herein, the EPA and optional one or more additional cardiovascular
agents can be administered as a co-formulated single dosage unit,
or as individual dosage units. Where the EPA and optional one or
more additional cardiovascular agents are co-administered as
separate dosage units, each dosage unit can be administered to a
subject at substantially the same or substantially different
times.
[0216] In one embodiment, where two or more individual dosage units
are to be administered daily, each dosage unit can be administered
to the subject within a period of about 24 hours, 18 hours, 12
hours, 10 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, or 0.5
hours.
[0217] In another embodiment, the EPA and one or more optional
cardiovascular agents can be administered sequentially. For
example, EPA can be administered to a subject as a sole agent
during an EPA loading period. The loading period can be, for
example, 1 day, 2 days, 4 days, 6 days, 2 weeks, 3 weeks, 4 weeks,
5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks or 10 weeks. After any
such loading period, one or more additional cardiovascular agents
can be initiated together with current EPA administration or in
place of EPA treatment.
[0218] In another embodiment, EPA is administered to a subject in
the morning, for example from about 4 am to about 10 am, about 5 am
to about 9 am, or about 6 am to about 8 am, and the optional one or
more cardiovascular agents are administered to the subject in the
afternoon or evening, for example from about 1 pm to about 11 pm,
about 2 pm to about 10 pm, or about 3 pm to about 9 pm, or vice
versa.
[0219] In another embodiment, the invention provides the use of EPA
and one or more cardiovascular agents in the manufacture of a
medicament for treatment or prevention of a cardiovascular-related
disease such as hypertriglyceridemia, hypercholesterolemia, mixed
dyslipidemia, coronary heart disease, vascular disease, stroke,
atherosclerosis, arrhythmia, hypertension, myocardial infarction,
and other cardiovascular events. In one embodiment, the composition
contains not more than 10% DHA, if any. In another embodiment, the
composition contains substantially no or no DHA.
[0220] In another embodiment, the invention provides a
pharmaceutical composition comprising EPA and one or more
cardiovascular agents for the treatment and/or prevention of a
cardiovascular-related disease, wherein the composition contains
not more than 10% DHA, if any. In a related embodiment, the
composition contains substantially no DHA or no DHA.
[0221] In one embodiment, a subject being treated with a
composition or regimen set forth herein is a diabetic or
pre-diabetic subject.
[0222] In one embodiment, any of the methods disclosed herein are
used in treatment or prevention of a subject or subjects that
consume a traditional Western diet. In one embodiment, the methods
of the invention include a step of identifying a subject as a
Western diet consumer or prudent diet consumer and then treating
the subject if the subject is deemed to consume a Western diet. The
term "Western diet" herein refers generally to a typical diet
consisting of, by percentage of total calories, about 45% to about
50% carbohydrate, about 35 to about 40% fat, and about 10% to about
15% protein. A Western diet may further be characterized by
relatively high intakes of red and processed meats, sweets, refined
grains, and desserts, for example where half or more or 70% or more
calories come from these sources.
[0223] It is to be understood that a wide range of changes and
modifications to the embodiments described above will be apparent
to those skilled in the art and are contemplated. It is, therefore,
intended that the foregoing detailed description be regarded as
illustrative rather than limiting, and that it be understood that
it is the following claims, including all equivalents, that are
intended to define the spirit and scope of the invention.
[0224] It should be understood that various changes and
modifications to the presently preferred embodiments described
herein will be apparent to those skilled in the art. Such changes
and modifications can be made without departing from the spirit and
scope of the present subject matter and without diminishing its
intended advantages. It is therefore intended that such changes and
modifications be covered by the appended claims.
EXAMPLES
[0225] The following non-limiting examples are for illustrative
purposes only and are not to be construed as limiting the invention
in any manner.
Example 1
[0226] An experiment was conducted to test EPA, DHA, EPA+DHA with
and without with atorvastatin in model membranes enriched with
PUFAs and cholesterol at levels that reproduce disease or high
CV-risk conditions (i.e. hypercholesterimia). As is shown below,
EPA exhibits a potent antioxidant benefit in cholesterol-enriched
membranes that was superior to that observed with DHA. Moreover,
the combination of EPA and atorvastating provided even further
antioxidant benefit by comparison to EPA alone.
[0227] EPA and DHA were tested individually at a fixed
concentration of 10.0 .mu.M or in combination at 5.65 .mu.M and
4.35 .mu.M (EPA and DHA, respectively), which is a mole ratio of
1.3:1. Separate and combined effects of these agents on lipid
peroxide (LOOH) formation were examined at
cholesterol-to-phospholipid (C/P) mole ratios of 0.5:1, 1.0:1 and
1.5:1. Levels of lipid hydroperoxides were also measured for EPA,
DPH and EPA/DPH in cholesterol-enriched membrane prepared in the
absence and presence of atorvastatin.
[0228] 1,2-Dilinoleoyl-3-sn-phosphatidylcholine (DLPC) was obtained
from Avanti Polar Lipids (Alabaster, Ala.) and stored in chloroform
(25 mg/ml) at -80.degree. C. until use. Cholesterol obtained and
stored in chloroform (10 mg/ml) at -20.degree. C. CHOD-iodide color
reagent (stock) was prepared according to a procedure modified from
El-Saadani et al. (El-Saadani M, Esterbauer H, El-Sayed M, Goher M,
Nassar A Y, Jurgens G. A spectrophotometric assay for lipid
peroxides in serum lipoproteins using commercially available
reagent. J Lipid Res 1989; 30:627-30) consisted of 0.2 M
K.sub.2HPO.sub.4, 0.12 M KI, 0.15 mM NaN.sub.3, 10 .mu.M ammonium
molybdate, and 0.1 g/L benzalkonium chloride. Prior to experimental
use, the CHOD reagent was activated by adding 24 .mu.M
ethylenediaminetetraacetic acid (EDTA), 20 .mu.M butylated
hydroxytoluene (BHT), and 0.2% Triton X-100. Atorvastatin was
prepared in ethanol just prior to experimental use and added
together with component lipids containing fixed amounts of EPA, DPH
or EPA/DPH at equimolar levels. The compounds and lipids were added
in combination during membrane sample preparation to ensure full
incorporation into the lipid bilayers.
[0229] Membrane samples consisting of DLPC.+-.cholesterol, with
cholesterol-to-phospholipid (C/P) mole ratios ranging from 0.5 to
1.5, were prepared as follows. Component lipids (in chloroform)
were transferred to 13.times.100 mm test tubes and shell-dried
under a steady stream of nitrogen gas while vortex mixing. The
lipid was co-dried with EPA, DPH or EPA/DPH prepared in the absence
or presence of the atorvastatin at equimolar levels.
[0230] Residual solvent was removed by drying for a minimum of 3 h
under vacuum. After desiccation, each membrane sample was
resuspended in diffraction buffer (0.5 mM HEPES, 154 mM NaCl, pH
7.3) to yield a final phospholipid concentration of 1.0 mg/ml.
Multilamellar vesicles (MLV) were formed by vortex mixing for 3
minutes at ambient temperature. Bangham A D, Standish M M, Watkins
J C. Diffusion of univalent ions across the lamellae of swollen
phospholipids. J Mol Biol 1965; 13:238-52. Immediately after
initial MLV preparation, aliquots of each membrane sample will be
taken for baseline (0 h) peroxidation analyses.
[0231] All lipid membrane samples were subjected to time-dependent
autoxidation by incubating at 37.degree. C. in an uncovered,
shaking water bath. Small aliquots of each sample were removed at
24 h intervals and combined with 1.0 ml of active CHOD-iodide color
reagent. To ensure spectrophotometric readings within the optimum
absorbance range, sample volumes taken for measurement of lipid
peroxide formation were adjusted for length of peroxidation and
range between 100 and 10 .mu.l. Test samples were immediately
covered with foil and incubated at room temperature for >4 h in
the absence of light. Absorbances were measured against a CHOD
blank at 365 nm using a Beckman DU-640 spectrophotometer.
[0232] The CHOD colorimetric assay is based on the oxidation of
iodide (I.sup.-) by lipid hydroperoxides (LOOH) and proceeds
according to the following reaction scheme:
LOOH+2H.sup.+3I.sup.-LOH+H.sub.2O+I.sub.3.sup.-
[0233] The quantity of triiodide anion (I.sub.3.sup.-) liberated in
this reaction is directly proportional to the amount of lipid
hydroperoxides present in the membrane sample. The molar
absorptivity value (.epsilon.) of I.sub.3.sup.- is
2.46.times.10.sup.4 M.sup.-1 cm.sup.-1 at 365 nm.
[0234] Results are shown in FIGS. 1-4.
* * * * *