U.S. patent application number 13/061865 was filed with the patent office on 2011-09-29 for pharmaceutical composition comprising eicosapentaenoic acid and nicotinic acid and methods of using same.
This patent application is currently assigned to AMARIN CORPORATION PLC.. Invention is credited to Mehar Manku.
Application Number | 20110236476 13/061865 |
Document ID | / |
Family ID | 41350709 |
Filed Date | 2011-09-29 |
United States Patent
Application |
20110236476 |
Kind Code |
A1 |
Manku; Mehar |
September 29, 2011 |
PHARMACEUTICAL COMPOSITION COMPRISING EICOSAPENTAENOIC ACID AND
NICOTINIC ACID AND METHODS OF USING SAME
Abstract
The present invention relates to, inter alia, pharmaceutical
compositions comprising eicosapentaenoic acid and/or derivatives
thereof and nicotinic acid, to methods of manufacturing such
compositions, and to therapeutic methods for treating carious
diseases and disorders.
Inventors: |
Manku; Mehar; (Oxford,
GB) |
Assignee: |
AMARIN CORPORATION PLC.
Dublin
IE
|
Family ID: |
41350709 |
Appl. No.: |
13/061865 |
Filed: |
September 2, 2009 |
PCT Filed: |
September 2, 2009 |
PCT NO: |
PCT/US09/55760 |
371 Date: |
May 23, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61093506 |
Sep 2, 2008 |
|
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Current U.S.
Class: |
424/455 ;
514/356 |
Current CPC
Class: |
A61P 9/06 20180101; A61P
43/00 20180101; A61P 9/04 20180101; A61P 9/00 20180101; A61P 17/00
20180101; A61P 3/06 20180101; A61K 31/202 20130101; A61K 31/232
20130101; A61K 31/455 20130101; A61P 9/12 20180101; A61K 45/06
20130101; A61P 9/10 20180101; A61K 31/202 20130101; A61K 2300/00
20130101; A61K 31/232 20130101; A61K 2300/00 20130101; A61K 31/455
20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/455 ;
514/356 |
International
Class: |
A61K 9/48 20060101
A61K009/48; A61K 31/455 20060101 A61K031/455; A61P 9/00 20060101
A61P009/00; A61P 3/06 20060101 A61P003/06 |
Claims
1. A pharmaceutical composition comprising nicotinic acid in an
amount of not more than about 1200 mg and eicosapentaenoic acid or
a derivative thereof, wherein the composition contains not more
than 10%, by weight, docosahexaenoic acid, if any.
2. The composition of claim 1 wherein the composition contains
substantially no docosahexaenoic acid.
3. The composition of claim 1 wherein the eicosapentaenoic acid or
derivative thereof is present in an amount of about 100 mg to about
5000 mg.
4. The composition of claim 1 wherein the eicosapentaenoic acid or
derivative thereof is present in an amount of about 100 mg to about
1000 mg.
5. The composition of claim 1 wherein the eicosapentaenoic acid or
derivative thereof comprises an eicosapentaenoic acid ethyl
ester.
6. The composition of claim 1 wherein the nicotinic acid is
suspended in the eicosapentaenoic acid or derivative thereof to
form a suspension.
7. The composition of claim 6 wherein the suspension is present in
a capsule.
8. The composition of claim 1 wherein the composition further
comprises a statin.
9. A pharmaceutical composition comprising nicotinic acid in an
amount of not more than about 800 mg and eicosapentaenoic acid
ethyl ester, wherein the composition contains substantially no
amount of docosahexaenoic acid or derivative thereof.
10. A pharmaceutical composition comprising nicotinic acid in an
amount of not more than about 500 mg and about 100 mg to about 1000
mg of eicosapentaenoic acid ethyl ester, wherein the composition
contains no docosahexaenoic acid, the nicotinic acid is suspended
in the eicosapentaenoic acid ethyl ester, and the composition is
present in a capsule.
11. The composition of claim 10 wherein the nicotinic acid is
present in an amount of about 50 mg to about 400 mg and the
eicosapentaenoic acid ethyl ester is present in an amount of about
300 to about 800 mg.
12. A method of treating or preventing a cardiovascular-related
disease or disorder in subject in need thereof, comprising:
administering to the subject a pharmaceutical composition according
to claim 1.
13. A method of treating a cardiovascular-related disease or
disorder in a subject in need thereof, comprising: co-administering
to the subject a first pharmaceutical composition comprising
nicotinic acid in an amount of not more than about 800 mg and a
second pharmaceutical composition comprising eicosapentaenoic acid
or a derivative thereof wherein said second pharmaceutical
composition contains substantially no docosahexaenoic acid or
derivative thereof.
14. The method of claim 13 wherein the co-administering step
comprises administering the first and second pharmaceutical
compositions to the subject within a period of about 24 hours.
15. The method of claim 13 wherein the co-administering step
comprises administering the first and second pharmaceutical
compositions to the subject within a period of about 12 hours.
16. The method of claim 13 wherein the co-administering step
comprises administering the first and second pharmaceutical
compositions to the subject substantially simultaneously.
17. The method of claim 13 wherein the subject does not ingest a
non-steroidal anti-inflammatory agent within about 3 hours prior to
or after said co-administration step.
18. The method of claim 13 wherein the eicosapentaenoic acid or a
derivative thereof is present in the second pharmaceutical
composition in an amount of about 100 mg to about 2000 mg.
19. The method of claim 13 wherein the eicosapentaenoic acid or a
derivative thereof comprises eicosapentaenoic acid ethyl ester.
20. A method of decreasing serum low-density lipoprotein-C and
serum triglyceride levels and increasing serum
high-density-lipoprotein-C levels in a subject in need thereof, the
method comprising administering to the subject a pharmaceutical
composition comprising: (a) nicotinic acid in an amount of not more
than 1000 mg and (b) an oil comprising at least about 95%, by
weight, eicosapentaenoic acid ethyl ester; wherein the
pharmaceutical composition contains no docosahexaenoic acid or
derivative thereof.
21. The method of claim 20 wherein the eicosapentaenoic acid ethyl
ester is present in the composition in an amount of about 100 mg to
about 2000 mg.
22. The method of claim 21 where the composition is administered to
the subject in about 1 to about 4 dosage units per day.
23. A pharmaceutical composition comprising nicotinic acid in an
amount of about 1 mg to about 200 mg dispersed in about 100 mg to
about 1000 mg of an oil comprising at least about 95%, by weight,
eicosapentaenoic acid ethyl ester, wherein the composition contains
no docosahexaenoic acid or derivative thereof and is enclosed in a
capsule shell.
24. A method of reducing risk of cardiac arrest in a subject in
need thereof, the method comprising administering to the subject a
pharmaceutical composition comprising (a) nicotinic acid in an
amount of not more than 1000 mg and (b) an oil comprising at least
about 95%, by weight, eicosapentaenoic acid ethyl ester, wherein
the composition contains no docosahexaenoic acid or derivative
thereof.
25. A kit comprising a first pharmaceutical composition comprising
nicotinic acid in an amount of not more than 1200 mg and a second
pharmaceutical composition comprising eicosapentaenoic acid or a
derivative thereof, wherein the second pharmaceutical composition
contains not more than 10%, by weight, docosahexaenoic acid, if
any.
26. A method of preventing or reducing incidence or severity of
niacin-induced flushing in a subject, comprising (a) providing a
subject that has not yet initiated niacin therapy, (b) pre-treating
the subject with a pharmaceutical composition comprising at least
about 95% by weight EPA or derivative thereof and (c) subsequently
administering niacin to the subject.
27. The method of claim 26 wherein the subject is pre-treated with
the pharmaceutical composition in an amount sufficient to provide
about 1 mg to about 5000 mg of EPA or derivative thereof per day
for a period of about 1 to about 30 days.
28. The method of claim 26 wherein the subject is pre-treated with
the pharmaceutical composition in an amount sufficient to provide
about 1 mg to about 2000 mg of EPA or derivative thereof per day
for a period of about 1 to about 10 days.
29. A method of treating or reducing severity of niacin-induced
flushing in a subject comprising (a) providing a subject on niacin
therapy that experiences flushing and (b) treating the subject with
a pharmaceutical composition comprising at least about 95% by
weight EPA or derivative thereof in an amount sufficient to prevent
reduce severity of said flushing.
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, dislipidemia,
congestive heart failure and stroke.
[0002] At high doses (e.g. >1500 mg) niacin is a potent lipid
lowering drug with the ability to lower very low density and low
density lipoprotein particles and increase high density lipoprotein
cholesterol-C (HDL-C). However, at these doses, niacin causes
vascular-cutaneous flushing mediated by prostaglandin D.sub.2 and
seriously limits patient compliance and thus effectiveness. At
lower doses (e.g. <1500 mg/day) niacin only increases HDL-C
without lowering very low density and low density lipoprotein
particles. Extended- and sustained-release forms of niacin have
been developed and can reduce (but not eliminate) flushing, but can
also cause liver toxicity, gastrointestinal upset, nausea,
diarrhea, sexual dysfunction and fatigue. These side effects
significantly limit the use of niacin therapy.
SUMMARY
[0003] In one embodiment, the present invention provides a
pharmaceutical composition comprising nicotinic acid in an amount
of not more than about 1200 mg, not more than about 1000 mg, not
more than about 750 mg, or not more than about 500 mg and
eicosapentaenoic acid or a derivative thereof. In one embodiment,
the composition contains not more than 10%, by weight,
docosahexaenoic acid, if any. In another embodiment, the
eicosapentaenoic acid or derivative thereof is eicosapentaenoic
acid ethyl ester. In still another embodiment, the composition
contains substantially no amount of docosahexaenoic acid or
derivative thereof, if any.
[0004] In another embodiment, the present invention provides a
method of treating and/or preventing a cardiovascular-related
disease or disorder selected from primary hyperlipidemia,
hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia,
coronary heart disease, vascular disease, stroke, atherosclerosis,
arrhythmia, hypertension, myocardial infarction, and other
cardiovascular events, comprising administering to a subject in
need thereof 1 to a plurality of dosage units comprising a
composition or compositions as disclosed herein.
[0005] In still another embodiment, the invention provides a method
of treating or preventing a cardiovascular-related disease or
disorder in subject in need thereof, comprising administering to
the subject a pharmaceutical composition comprising (a) nicotinic
acid in an amount of not more than about 1200 mg, not more than
about 1000 mg, not more than about 750 mg, or not more than about
500 mg and (b) eicosapentaenoic acid or a derivative thereof;
wherein the composition comprises not more than 10%, by weight,
docosahexaenoic acid or derivative thereof, if any.
[0006] In another embodiment, the present invention provides a
method of treating or preventing a cardiovascular-related disease
or disorder in a subject in need thereof, comprising:
co-administering to the subject a first pharmaceutical composition
comprising nicotinic acid in an amount of not more than about 1200
mg, not more than about 1000 mg, not more than about 750 mg, or not
more than about 500 mg and a second pharmaceutical composition
comprising eicosapentaenoic acid or a derivative thereof wherein
said second pharmaceutical composition contains not more than 10%,
by weight, docosahexaenoic acid or derivative thereof, if any,
substantially no docosahexaenoic acid or derivative thereof, or no
docosahexaenoic acid or derivative thereof.
[0007] In another embodiment, the invention provides a method of
one or more of: (a) decreasing serum low-density lipoprotein
cholesterol ("LDL-C"), (b) decreasing serum triglyceride levels,
(c) increasing serum high-density-lipoprotein cholesterol ("HDL-C")
levels, (d) reducing apolipoprotein B ("Apo B") levels compared to
baseline, and/or (e) decreasing serum non-high density lipoprotein
cholesterol ("non-HDL-C"; i.e. the difference between total
cholesterol and HDL-C) levels in a subject in need thereof, the
method comprising administering to the subject a pharmaceutical
composition or compositions comprising (a) nicotinic acid in an
amount of not more than about 1500 mg, not more than about 1200 mg,
not more than about 1000 mg, not more than about 750 mg, or not
more than about 500 mg and (b) eicosapentaenoic acid or a
derivative thereof, wherein the composition contains not more than
10%, by weight, docosahexaenoic acid or derivative thereof, if any,
substantially no docosahexaenoic acid or derivative thereof, or no
docosahexaenoic acid or derivative thereof.
[0008] In another embodiment, the present invention provides a
method of delaying or reducing the risk of cardiac arrest in a
subject in need thereof, the method comprising administering to a
subject in need thereof a pharmaceutical composition comprising (a)
nicotinic acid in an amount of not more than about 1500 mg, not
more than about 1200 mg, not more than about 1000 mg, not more than
about 750 mg, or not more than about 500 mg and (b)
eicosapentaenoic acid or a derivative thereof, wherein the
composition contains not more than 10%, by weight, docosahexaenoic
acid or derivative thereof, if any, substantially no
docosahexaenoic acid or derivative thereof, or no docosahexaenoic
acid or derivative thereof.
[0009] In still another embodiment, the present invention provides
a kit comprising a first pharmaceutical composition comprising
nicotinic acid in an amount of not more than about 1500 mg, not
more than about 1200 mg, not more than about 1000 mg, not more than
about 750 mg, or not more than about 500 mg, and a second
pharmaceutical composition comprising eicosapentaenoic acid or a
derivative thereof, wherein the second pharmaceutical composition
contains not more than 10%, by weight, docosahexaenoic acid, if
any.
[0010] In another embodiment, the invention provides a method of
reducing niacin-induced flushing in a subject comprising providing
a subject that is to begin niacin therapy, pre-treating the subject
with EPA and administering niacin to the subject following said
pre-treatment.
[0011] These and other embodiments of the present invention will be
disclosed in further detail herein below.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1 shows that administration of -97% pure EPA to
subjects results in increased RBC EPA and decreased RBC arachidonic
acid levels.
DETAILED DESCRIPTION
[0013] 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.
[0014] 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. As used herein, the terms "about" and "approximately" when
referring to a numerical value shall have their plain and ordinary
meanings to one skilled in the pertinent art at issue. 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.
[0015] Without being held to a particular theory, it is believed
that eicosapentaenoic acid is a competitive inhibitor of
arachidonate metabolism in the cyclo-oxygenase pathway and that
reduction of PGD.sub.2 levels by EPA attenuates niacin flushing. In
addition to attenuating niacin-induced flushing, it is also
believed, without being bound by theory, that EPA can provide
beneficial cardiovascular effects such as reduced platelet
aggregation, vasodilation and plaque stabilization, which are
independent of an in crease in HDL-C as seen at low doses of
niacin. As such, in one embodiment of the invention, a combination
of low dose niacin with EPA (or pre-treatment with EPA followed by
low dose niacin) is provided. In another embodiment, such therapy
provides effective cardiovascular benefits with reduced side
effects compared to conventional niacin dosing.
Eicosapentaenoic Acid
[0016] In one embodiment, compositions of the invention comprise
eicosapentaenoic acid or a pharmaceutically acceptable ester,
derivative, conjugate or salt thereof, or mixtures of any of the
foregoing, collectively referred to herein as "EPA." 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.
[0017] In one embodiment, the EPA comprises an eicosapentaenoic
acid ester. In another embodiment, the EPA comprises a
C.sub.1-C.sub.5 alkyl ester of eicosapentaenoic acid, in another
embodiment, the EPA comprises eicosapentaenoic acid ethyl ester,
eicosapentaenoic acid methyl ester, eicosapentaenoic acid propyl
ester, or eicosapentaenoic acid butyl ester.
[0018] In another embodiment, the EPA is in the form of ethyl-EPA,
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.
[0019] In another embodiment, the EPA comprises an EPA-Fatty Acid
conjugate, in one embodiment, the EPA-Fatty Acid conjugates are
diesters formed between EPA, a second fatty acid or EPA, and a
linker as shown in structures (I)-(II), wherein R.sup.1 and R.sup.2
are acyl fatty acid groups derived from EPA or another fatty acid.
R.sup.1 and R.sup.2 may both be derived from EPA (EPA-EPA) or may
be derived from EPA and a different fatty acid (EPA-Fatty Acid).
R.sup.3 is generally either hydrogen, fully hydrocarbon, or
containing heteroatoms, and is preferably a C.sub.1-C.sub.4 alkyl
group.
##STR00001##
[0020] The linker may be any suitable diol including, for example,
an alkyl diol such as 1,3-propanediol, an alkenyl diol, an alkynyl
diol, an aryl diol such as 1,4-dihydroxybenzene (hydroquinone),
etc., or a geminal diol, for example a C.sub.1-C.sub.4 alkyl
geminal diol, an alkyl geminal diol, etc. The second fatty acid may
be any suitable fatty acid including for example EPA, LA, AA, ALA,
STA, ETA, or DPA. Synthesis of the diester conjugate is
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.
[0021] 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 of all fatty acids present.
[0022] In another embodiment, a composition of the present
invention includes at least 96% EPA-EPA conjugate, at least 97%
EPA-EPA conjugate, at least 98% EPA-EPA conjugate, or at least 99%
EPA-EPA conjugate by weight of all fatty acids present. In another
embodiment, a composition of the present invention contains not
more than 10%, not more than 9%, not more than 8%, not more than
7%, not more than 6%, not more than 5%, not more than 4%, not more
than 3%, not more than 2%, not more than 1%, not more than 0.6%,
not more than 0.5%, not more than 0.4%, not more than 0.3%, not
more than 0.2, or not more than 0.1% of any EPA-Fatty Acid
conjugate other than EPA-EPA diester by weight of all fatty acids
present.
[0023] 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.
[0024] 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, docosahexaenoic acid or derivative thereof, by
weight of the total composition or of all fatty acids present. In
another embodiment, a composition of the invention contains
substantially no docosahexaenoic acid or derivative thereof. In
still another embodiment, a composition of the invention contains
no docosahexaenoic acid or derivative thereof.
[0025] In another embodiment, EPA comprises at least 60%, at least
70%, at least 80%, at least 90%, at least 95%, at least 97%, at
least 98%, at least 99%, or 100%, by weight of all fatty acids
present in a composition.
[0026] In another embodiment, a composition of the invention
contains 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%, 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. Illustrative examples of a "fatty
acid other than EPA" include linolenic acid (LA), arachidonic acid
(AA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA),
stearadonic acid (STA), eicosatrienoic acid (ETA) and/or
docosapentaenoic acid (DPA).
[0027] 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 all fatty acids present in the composition; 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; 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; 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; contains not more
than 20 ppm, 15 ppm or 10 ppm heavy metals, contains not more than
5 ppm, 4 ppm, 3 ppm, or 2 ppm arsenic, and/or has a peroxide value
not more than 5, 4, 3, or 2 meq/kg.
Nicotinic Acid
[0028] In one embodiment, a composition of the invention comprises
nicotinic acid (also referred to herein as "niacin", "3-Pyridine
carboxamide" and/or "vitamin B3"). In another embodiment, the
nicotinic acid is in crystalline form. In one embodiment, the EPA
and nicotinic acid are not covalently linked.
[0029] In one embodiment, the nicotinic acid is present in a
composition of the invention in an amount of about 5 mg to about
1200 mg, about 10 mg to about 800 mg, about 15 mg to about 750 mg,
about 20 mg to about 500 mg, about 25 mg to about 400 mg, or about
50 mg to about 200 mg, for example in an amount of about 25 mg,
about 50 mg, 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 1125 mg, about 1150 mg, about 1175 mg, or about 1200
mg.
[0030] In various embodiments, the nicotinic acid can be in
immediate-release, extended-release or sustained-release form. The
term "immediate-release" in the present context refers to nicotinic
acid formulations from which nicotinic acid, upon ingestion by a
human subject, is absorbed at a rate of about 400 to about 600
mg/hr, for example about 500 mg/hr. Typically, immediate-release
nicotinic acid is not coated with any release-modifying barrier or
layer. The immediate-release nicotinic acid can be in crystalline
form. Niacor.RTM. (Upsher-Smith Laboratories) is an illustrative
immediate-release nicotinic acid formulation. The term
"extended-release nicotinic acid" herein refers to nicotinic acid
formulations from which nicotinic acid, upon ingestion by a human
subject, is absorbed at a rate of about 80 to about 200 mg/hr, for
example about 100 mg/hr. Niaspan.RTM. (Kos Pharmaceuticals) is an
illustrative extended-release nicotinic acid formulation. The term
"sustained-release" in the present context refers to nicotinic acid
formulations from which the nicotinic acid, when ingested by a
human subject, is absorbed at a rate of about 25 mg/hr to about 75
mg/hr, for example about 50 mg/hr.
[0031] In one embodiment, nicotinic acid and EPA are present in a
composition of the invention, or are co-administered in a weight
ratio 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.
[0032] In another embodiment, an additional cardiovascular agent is
co-formulated with EPA and/or nicotinic acid, or is co-administered
with EPA and/or nicotinic acid. The additional cardiovascular agent
can illustratively include a 3-hydroxy-3-methyl glutaryl coenzyme A
(HMG-CoA) reductase inhibitor (also referred to as a "statin"), a
fibrate, or a bile salt sequesterant or binding resin.
[0033] In one embodiment, a composition of the invention comprises
EPA and a statin. Non-limiting examples of suitable statins that
can be used in accordance with various embodiments of the invention
include prevastatin, lovastatin, simvastatin, atorvastatin,
fluvastatin, pitavastatin and rosuvastatin and salts thereof. In a
related embodiment, the composition contains not more than 10% DHA
or derivative thereof, if any. In another related embodiment, the
composition contains no DHA or derivative thereof such as
ethyl-DHA.
[0034] A statin, if present in a composition or compositions of the
invention, can be present in an amount of about 1 to about 300 mg,
about 5 mg to about 200 mg, about 10 mg to about 180 mg, about 20
mg to about 150 mg, about 30 mg about 100 mg, or about 40 mg to
about 60 mg.
[0035] Pravastatin (Pravachol.RTM.; manufactured by Bristol-Myers
Squibb, Princeton, N.J.) is hydrophilic and is best absorbed
without food. Prevastatin can be present in a composition of the
invention (or co-administered therewith) in an amount of about 1 to
about 80 mg, about 5 mg to 60 mg, or about 10 mg to about 40
mg.
[0036] Lovastatin (Mevacor.RTM.; by Merck, Whitehouse Station,
N.J.) can be present in a composition of the invention (or
co-administered therewith) in an amount of about 1 mg to about 100
mg, about 5 mg to about 80 mg, or about 10 mg to about 40 mg.
[0037] Simvastatin (Zocor.RTM. by Merck, Whitehouse Station, N.J.)
can be present in a composition of the invention (or
co-administered therewith) in an amount of about 1 mg to about 80
mg per day, about 2 mg to 60 about mg, or about 5 mg to about 40
mg.
[0038] Atorvastatin (Lipitor.RTM. by Pfizer, New York, N.Y.) can be
present in a composition of the invention (or co-administered
therewith) in an amount of about 1 mg to about 100 mg, about 5 mg
to about 80 mg, or about 10 mg to about 40 mg.
[0039] Fluvastatin, (Lescol.RTM. by Novartis, New York, N.Y.) can
be present in a composition of the invention (or co-administered
therewith) in an amount of about 5 mg to about 160 mg, about 10 mg
to about 120 mg, or about 20 mg to about 80 mg.
[0040] Rosuvastatin (Crestor.RTM. by Astra Zeneca, Wilmington,
Del.) The dosage of rosuvastatin, in the combined administration of
concentrated omega-3 fatty acids is from 1 to 80 mg, preferably 2
to 60 mg, and more preferably from 5 to 40 mg per dosage of
concentrated omega-3 fatty acids.
[0041] In another embodiment, a pharmaceutical composition
consisting of, or consisting essentially of, EPA, nicotinic acid
(and optionally a statin and/or a fibrate) and one or more
pharmaceutically acceptable excipients is provided. In another
embodiment, a pharmaceutical composition containing active
ingredients consisting of, or consisting essentially of, EPA and
nicotinic acid niacin is provided. In another embodiment, a
pharmaceutical composition containing active ingredients consisting
of, or consisting essentially of, EPA, nicotinic acid and a statin
is provided.
Dosage Forms
[0042] 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.
[0043] 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.
[0044] EPA, nicotinic acid, a statin and/or any other desired
active ingredient 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.
[0045] In one embodiment, a composition of the invention comprises
nicotinic acid and/or a statin 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 nicotinic acid is present in
second dosage unit, for example a tablet. Optionally, any desired
statin can be present in a third composition.
[0046] 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.
Storage Stability
[0047] 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.
Excipients
[0048] 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.
[0049] 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.
[0050] 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.
[0051] 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.
[0052] 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.
[0053] 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.
[0054] 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.
[0055] Suitable anti-adherents include talc, cornstarch,
DL-leucine, sodium lauryl sulfate and metallic stearates. Talc is a
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.
[0056] 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.
[0057] 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.
[0058] 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.
[0059] 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
[0060] 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
[0061] In one embodiment, compositions of the invention are useful
for treatment and/or prevention of a cardiovascular-related disease
or disorder. The term "cardiovascular-related disease or disorder"
herein refers to any disease or disorder of the heart or blood
vessels (i.e. arteries and veins) or any symptom thereof.
Non-limiting examples of a cardiovascular-related disease or
disorder include hypertriglyceridemia, hypercholesterolemia, mixed
dyslipidemia, coronary heart disease, vascular disease, stroke,
atherosclerosis, arrhythmia, hypertension, myocardial infarction,
and other cardiovascular events.
[0062] 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.
[0063] In one 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 about 150 mg/dl or greater than about 175
mg/dl, for example about 200 mg/dl to about 600 mg/dl or about 200
mg/dl to about 500 mg/dl.
[0064] In a related 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 subjects exhibit one or more of: (a) reduced
triglyceride levels compared to baseline, (b) reduced Apo B levels
compared to baseline, (c) increased HDL-C levels compared to
baseline, (d) no increase in LDL-C levels compared to baseline, (e)
a reduction in LDL-C levels compared to baseline, (f) a reduction
in non-HDL-C levels compared to baseline, and/or (g) no flushing or
reduced flushing compared to: (i) treatment with more than 1 g per
day of nicotinic acid, (ii) treatment with more than 3 g per day of
nicotinic acid, or (iii) treatment with a combination of about 1 to
about 3 g per day of nicotinic acid plus about 4 g of Omacor.RTM..
Each Omacor.RTM. capsule contains 900 mg of the ethyl ester of
omega-3 fatty acids--approximately 465 mg EPA and 375 mg DHA--and 4
mg .alpha.-tocopherol.
[0065] Relevant serum total cholesterol, HDL-C, non-HDL-C, and
LDL-C levels can be measured in accordance with any of the well
known analytical methods available in the art, for example using a
Synchron 4CX.RTM. 4CE to perform a blood panel analysis. In one
embodiment, subjects fast for up to 12 hours prior to blood sample
collection.
[0066] In another embodiment, upon treatment with a composition of
the present invention, the subject or subjects exhibit one or more
of (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%, or at least about 50% as compared to
baseline; (b) a reduction in non-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%, or at least about 50% as compared to
baseline; (c) 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%, or at least about 50% as compared to
baseline; (d) 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%, or at least about 50% as compared to
baseline; (e) a reduction 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%, or at least about 50% as compared to
baseline; and/or (f) no flushing or reduced flushing compared to:
treatment with 1 g or more per day of nicotinic acid or 3 g or more
per day of nicotinic acid, or a combination of about 1 to about 3 g
per day of nicotinic acid plus Omacor.RTM., for example about 4 g
per day of Omacor.RTM..
[0067] In another 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 one or more
compositions 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 nicotinic
acid extended-release monotherapy is considered inadequate
(Frederickson type IV hyperlipidemia).
[0068] 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 one or more
compositions as disclosed herein.
[0069] 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 a subject in need thereof one or more compositions
as disclosed herein.
[0070] 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 one or more
compositions as disclosed herein.
[0071] 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 one or more compositions as disclosed
herein.
[0072] In another embodiment optionally associated with any of the
methods disclosed herein, administration of any composition or
compositions disclosed herein to a subject results in an absence of
flushing or reduced flushing by comparison with administration of
conventional high dose (e.g. >1.5 g, for example about 2 g to
about 3 g maintenance dose) immediate-release, extended-release or
sustained-release nicotinic acid therapy or combination therapy.
The term "flushing" herein includes facial flushing or flushing
associated with any other area of the skin, for example redness,
itching, burning and/or tingling sensations that typically occur on
the face, neck, chest, and back.
[0073] In another embodiment, administration of a composition of
the invention to a subject or plurality of subjects results in no
flushing, tolerable flushing or decreased flushing by comparison
with: (a) 3 g or more per day of nicotinic acid therapy, (b) 2 g or
more per day of nicotinic acid therapy, (c) 1 g or more per day of
nicotinic acid therapy, (d) at least 2 g, 3 g or 4 g of Omacor.RTM.
per day plus greater than 1 g per day of nicotinic acid therapy, or
(e) at least 2 g, 3 g or 4 g Omacor.RTM. per day plus 2 g or more
per day of nicotinic acid therapy or 3 g or more per day of
nicotinic acid therapy.
[0074] In another embodiment optionally associated with any of the
methods disclosed herein, administration of any of the compositions
of the invention to a subject or plurality of subjects results in
substantially no or no liver toxicity or reduced liver toxicity
compared to administration of extended-release or sustained-release
nicotinic acid dosage units to a subject or plurality of subjects
in an amount of more than 1.5 g per day or greater, for example 2 g
per day or greater, or 3 g per day or greater.
[0075] In still another embodiment, administration of any of the
compositions disclosed herein to a subject results in no flushing
or decreased flushing, and no increase in LDL or reduced increase
in LDL by comparison with daily co-administration of four 1 g
Omacor.RTM. capsules plus 3 g of immediate-release nicotinic
acid.
[0076] In still another embodiment, administration of any of the
compositions disclosed herein to a subject results in increased
subject compliance and or decreased subject withdrawal from
treatment by comparison with daily administration of four 1 g
Omacor.RTM. capsules plus 3 g of immediate-release nicotinic acid.
In another embodiment, subject compliance (% of subjects
substantially complying with the prescribed dosage regimen) is
greater than 70%, greater than 80%, greater than 90%, greater than
93%, greater than 95%, or greater than 98%, for example over a
period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19 or 20 days, and/or subject withdrawal or non-compliance
due to flushing (% of subjects substantially not complying with the
prescribed dosage regimen due to flushing effects) is less than 8%,
less than 7%, less than 5% or less than 3%, for example over a
period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19 or 20 days.
[0077] One embodiment of the invention comprises treating or
preventing a cardiovascular-related disease or disorder as defined
herein by administering to a subject in need thereof about 50 mg to
about 1500 mg per day of immediate-release nicotinic acid, about 50
mg to about 5 g per day of EPA, for example ethyl ester EPA
containing no DHA, and/or about 10 mg to about 300 mg per day of a
statin.
[0078] In another embodiment, a composition of the invention is
administered to a subject in an amount sufficient to provide a
daily maintenance dose of nicotinic acid of about 5 mg to about
1500 mg, about 10 mg to about 1000 mg, about 20 mg to about 800 mg,
about 50 mg to about 500 mg, or about 75 mg to about 450 mg, for
example in a daily amount of about 25 mg, about 50 mg, 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 1125 mg,
about 1150 mg, about 1175 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, or
about 1475 mg.
[0079] 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.
[0080] In another embodiment, the statin is administered to the
subject in a daily amount of about 1 to about 300 mg, about 5 mg to
about 200 mg, about 10 mg to about 180 mg, about 20 mg to about 150
mg, about 30 mg about 100 mg, or about 40 mg to about 60 mg.
[0081] Nicotinic acid, EPA and/or a statin can be administered as a
co-formulation or as individual dosage units. Where the nicotinic
acid, EPA and/or a statin are co-administered as separate dosage
units, each dosage unit can be administered to a subject over a
time period of 24 hours, 18 hours, 12 hours, 10 hours, 8 hours, 6
hours, 4 hours, 2 hours, 1 hour, 0.5 hours, or substantially
simultaneously.
[0082] In another embodiment, nicotinic acid, EPA and/or a statin
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,
nicotinic acid and/or statin treatment can be initiated together
with EPA or in place of EPA treatment.
[0083] In another embodiment, EPA is administered to a subject in
the morning, for example from about 4 am to about 10 am, and low
dosee nicotinic acid (i.e. less than 1500 mg is administered to the
same subject in the afternoon or evening, for example from about 12
pm to about 11 pm.
[0084] 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:
[0085] (a) reduced triglyceride levels compared to baseline;
[0086] (b) reduced Apo B levels compared to baseline;
[0087] (c) increased HDL-C levels compared to baseline;
[0088] (d) no increase in LDL-C levels compared to baseline;
[0089] (e) a reduction in LDL-C levels compared to baseline;
[0090] (f) a reduction in non-HDL-C levels compared to
baseline;
[0091] (g) a reduction in vLDL levels compared to baseline;
[0092] (h) an increase in apo A-I levels compared to baseline;
[0093] (i) an increase in apo A-I/apo B ratio compared to
baseline;
[0094] (j) a reduction in lipoprotein a levels compared to
baseline;
[0095] (k) a reduction in LDL particle number compared to
baseline;
[0096] (l) a reduction in LDL size compared to baseline;
[0097] (m) a reduction in remnant-like particle cholesterol
compared to baseline;
[0098] (n) a reduction in oxidized LDL compared to baseline;
[0099] (o) a reduction in fasting plasma glucose (FPG) compared to
baseline;
[0100] (p) a reduction in hemoglobin A.sub.1c (HbA.sub.1c) compared
to baseline;
[0101] (q) a reduction in homeostasis model insulin resistance
compared to baseline;
[0102] (r) a reduction in lipoprotein associated phospholipase A2
compared to baseline;
[0103] (s) a reduction in intracellular adhesion molecule-1
compared to baseline;
[0104] (t) a reduction in interleukin-2 compared to baseline;
[0105] (u) a reduction in plasminogen activator inhibitor-1
compared to baseline;
[0106] (v) a reduction in high sensitivity C-reactive protein
(hsCRP) compared to baseline;
[0107] (w) an increase in serum phospholipid EPA compared to
baseline;
[0108] (x) an increase in red blood cell membrane EPA compared to
baseline; and/or
[0109] (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.
[0110] 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.
[0111] 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.
[0112] In another embodiment, upon treatment with a composition of
the present invention, the subject or subject group exhibits one or
more of the following outcomes:
[0113] (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;
[0114] (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;
[0115] (c) 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;
[0116] (d) a less than 30% increase, less than 20% increase, less
than 10% increase, less than 5% 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;
[0117] (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;
[0118] (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;
[0119] (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;
[0120] (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;
[0121] (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;
[0122] (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;
[0123] (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;
[0124] (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;
[0125] (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;
[0126] (n) 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;
[0127] (o) 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;
[0128] (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;
[0129] (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;
[0130] (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;
[0131] (s) a reduction in interleukin-2 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;
[0132] (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;
[0133] (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;
[0134] (v) an increase in serum phospholipid 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;
[0135] (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%, r
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;
[0136] (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; and/or
[0137] (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.
[0138] 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.
[0139] 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 26 or more of outcomes
(a)-(y) described immediately above.
[0140] 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.
[0141] In one embodiment, subjects fast for up to 12 hours prior to
blood sample collection, for example about 10 hours.
[0142] In another embodiment, the invention provides the use of
nicotinic acid, EPA and optionally a statin or fibrate in the
manufacture of a medicament for treatment or prevention of a
cardiovascular-related disease or disorder 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 no DHA.
[0143] In another embodiment, the invention provides a
pharmaceutical composition comprising nicotinic acid and EPA for
the treatment and/or prevention of a cardiovascular-related disease
or disorder, wherein the composition contains not more than 10%
DHA, if any. In a related embodiment, the composition contains no
DHA.
[0144] In one embodiment, the invention provides a method of
treating a cardiovascular-related disease or disorder in a subject
in need thereof comprising providing the subject with EPA
pre-treatment followed by one or more doses of nicotinic acid. In
one embodiment, the dose of nicotinic acid is sufficient to provide
the subject with not more than 3000 mg, not more than 2000 mg, not
more than 1000 mg, not more than 750 mg, not more than 500 mg, or
not more than 250 mg of nicotinic acid. The term "pre-treatment" in
the present context means providing the subject with one or more
doses of EPA about 0.1 to about 96 hours, about 1 to about 48
hours, about 2 to about 24 hours, about 3 to about 15 hours, or
about 4 to about 12 hours prior to providing the subject with an
initial dose of nicotinic acid as set forth herein, for example a
dose of not more than 3000 mg, not more than 2000 mg, not more than
1000 mg, not more than 750 mg, not more than 500 mg, or not more
than 250 mg of nicotinic acid. In a related embodiment, the subject
is pre-treated with EPA in an amount of about 1 mg to about 5000 mg
per day, 1 mg to about 4000 mg per day, 1 mg to about 3000 mg per
day, 1 mg to about 2000 mg per day, or 1 mg to about 1000 mg per
day for a period of about 1 to about 30 days, 1 to about 20 days, 1
to about 15 days, 1 to about 10 days, 1 to about 8 days, 1 to about
6 days, 1 to about 4 days or 1 to about 2 days.
[0145] In another embodiment, the invention provides a method of
preventing or reducing niacin-induced flushing in a subject
comprising (a) providing a subject that is to begin niacin therapy,
(b) pre-treating the subject with EPA and (c) administering niacin
to the subject after said pre-treatment. In one embodiment, the
niacin is administered at a dose of not more than 3000 mg, not more
than 2000 mg, not more than 1000 mg, not more than 750 mg, not more
than 500 mg, or not more than 250 mg per day. In another
embodiment, the subject is pre-treated with EPA in an amount of
about 1 mg to about 5000 mg per day, 1 mg to about 4000 mg per day,
1 mg to about 3000 mg per day, 1 mg to about 2000 mg per day, or 1
mg to about 1000 mg per day for a period of about 1 to about 30
days, 1 to about 20 days, 1 to about 15 days, 1 to about 10 days, 1
to about 8 days, 1 to about 6 days, 1 to about 4 days or 1 to about
2 days.
[0146] In another embodiment, the invention provides a method of
reducing or attenuating niacin-induced flushing in a subject on
niacin therapy, comprising (a) identifying a subject on niacin
therapy and that is experiencing flushing and (b) administering EPA
to the subject. In one embodiment, the niacin is administered at a
dose of not more than 3000 mg, not more than 2000 mg, not more than
1000 mg, not more than 750 mg, not more than 500 mg, or not more
than 250 mg per day. In another embodiment, the EPA is administered
to the subject in an amount of about 1 mg to about 5000 mg per day,
1 mg to about 4000 mg per day, 1 mg to about 3000 mg per day, 1 mg
to about 2000 mg per day, or 1 mg to about 1000 mg per day.
[0147] In other embodiments, 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.
EXAMPLES
[0148] The following example is for illustrative purposes and is
not to be construed as limiting the invention in any manner.
[0149] An analysis was performed to assess the impact of red blood
cell (RBC) EPA incorporation on arachidonic acid formation. In
various studies, patients were randomized, on a double-blind basis,
to receive either placebo (liquid paraffin) or 0.5 1, 2 or 4 g of
97% pure ethyl-EPA/day for 12 weeks. All the doses were
administered in eight identical appearing capsules. RBCs were
analyzed for EPA and AA following in general the methodology of
Manku et al. M. S. Manku, D. F. Horrobin, Y. S. Huang and N. Morse,
Fatty acids in plasma and red cell membranes in normal humans.
Lipids 18 (1983), pp. 906-908).
[0150] Venous blood was collected into a tube pretreated with EDTA
and centrifuged at 1500 gav for 15 min. The plasma layer and the
buffy coat were separated off and the red cells washed with an
equal volume of 0.9% saline. Samples were stored at -80.degree. C.
prior to analysis. On thawing, the RBCs were suspended in
NaCL/H2SO4aq. (17 mmol/l NaCl, 1 mmol/l Sulfuric acid, 1.8 ml),
then shaken with methanol (3 ml). Chloroform (6 ml) and C17:O
internal standard were added and the sample was stirred vigorously
using a vortex mixer. After centrifugation at 2000 gav for 10 min,
the lower layer containing the total lipid extract was carefully
removed and filtered through anhydrous sodium sulphate before
evaporation to dryness. The lipids were transesterified using
Sulfuric acid/methanol. The methyl esters were purified by loading
onto an isohexane-washed silica column prior to elution with
isohexane:diethyl ether (95:5). The resulting methyl esters of the
fatty acids were separated and measured using a Hewlett-Packard
HP5890 Series II Plus Gas chromatograph (cp-wax 52CB 25m capillary
column, Chrompack UK). The carrier gas was hydrogen (1 ml/min). The
oven temperature was programmed to rise from 1701 to 2201.degree.
C. at 41.degree. C./min. The detector temperature was 300.degree.
C. and injector temperature 230.degree. C. Retention times and peak
areas were automatically computed by Hewlett-Packard HP 3365 Chem.
Station.
[0151] As shown in FIG. 1, increasing RBC EPA incorporation results
in decreasing arachidonic acid formation. The figure below is a
average for all data collected from several clinical studies.
* * * * *