Note: Descriptions are shown in the official language in which they were submitted.
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OMEGA-3 PENTAENOIC ACID COMPOSITIONS AND METHODS OF USE
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Patent
Application No.
61/780,948, filed March 13, 2013, the contents of which are incorporated
herein by
reference.
FIELD OF INVENTION
[0002] The present invention relates to omega-3 fatty acid compositions, and
methods of treating, preventing, reducing the occurrence of, and improving
symptoms associated with coronary heart disease (CHD), vascular disease,
atherosclerotic disease or related conditions. The present invention also
provides
methods for the treatment and/or prevention and/or reduction of cardiac events
and/or cardiovascular events and/or vascular events and/or symptoms.
BACKGROUND OF THE INVENTION
[0003] Marine oils, also commonly referred to as fish oils, are a good source
of the
two main omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic
acid (DHA), which have been found to regulate lipid metabolism. Omega-3 fatty
acids have been found to have beneficial effects on the risk factors for
cardiovascular diseases, especially mild hypertension, hypertriglyceridemia
and on
the coagulation factor VII phospholipid complex activity. Omega-3 fatty acids
lower
serum triglycerides (TG), increase serum HDL-cholesterol, lower systolic and
diastolic blood pressure and the pulse rate, and lower the activity of the
blood
coagulation factor VII-phospholipid complex. Further, omega-3 fatty acids seem
to
be well tolerated, without giving rise to any severe side effects.
[0004] The table directly below lists the most common omega-3 fatty acids,
including their 3-letter abbreviation code. In this application, the use of
any of the 3-
letter abbreviations shall refer to the omega-3 fatty acid, unless otherwise
indicated
(e.g. DPA or DPA 22:5 (n-3) or DPA 22:5-n3 or DPA 22:5n3 or DPA-n3, which all
refer to the omega-3 isomer of docosapentaenoic acid).
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Common Name for Omega-3 Fatty Acid (+abbreviation) Codified Lipid Name
Chemical Name
Hexadecatrienoic acid (HTA) 16:3 (n-3) all-cis-7,10,13-
hexadecatrienoic acid
a-Linolenic acid (ALA) 18:3 (n-3) all-cis-9,12,15-
octadecatrienoic acid
Stearidonic acid (SDA) 18:4 (n-3) all-cis-6,9,12,15-
octadecatetraenoic acid
Eicosatrienoic acid (ETE) 20:3 (n-3) all-cis-11,14,17-
eicosatrienoic acid
Eicosatetraenoic acid (ETA) 20:4 (n-3) all-cis-8,11,14,17-
eicosatetraenoic acid
Eicosapentaenoic acid (EPA) 20:5 (n-3) all-cis-5,8,11,14,17-
eicosapentaenoic acid
Heneicosapentaenoic acid (HPA) 21:5 (n-3) all-cis-6,9,12,15,18-
heneicosapentaenoic acid
Docosapentaenoic acid (DPA) or Clupanodonic acid 22:5 (n-3) all-cis-
7,10,13,16,19-docosapentaenoic acid
Docosahexaenoic acid (DNA) 22:6 (n-3) all-cis-4,7,10,13,16,19-
docosahexaenoic acid
Tetracosapentaenoic acid (TPA) 24:5 (n-3) all-cis-9,12,15,18,21-
tetracosapentaenoic acid
Tetracosahexaenoic acid (IRA) or Nisinic acid 24:6 (n-3) all-cis-
6,9,12,15,18,21-tetracosahexaenoic acid
[0005] One form of omega-3 fatty acids is a concentrate of omega-3, long
chain,
polyunsaturated fatty acids from fish oil containing DHA ethyl esters, EPA
ethyl
esters as well as ethyl esters of other omega-3 fatty acids (described in
USP35 for
LOVAZAO) and is sold under the trademarks OMACORO and LOVAZAO. Such a
form of omega-3 fatty acid comprises at least 90% omega-3 fatty acids of which
at
least 80% EPA+DHA (in a ratio of 1.2:1) and is described, for example, in U.S.
Pat.
Nos.. 5,502,077, 5,656,667 and 5,698,594. LOVAZAO (omega-3-acid ethyl esters)
is indicated for the treatment of patients with hypertriglyceridemia with TG
levels of
500mg/dL or higher.
[0006] Another form of omega-3 fatty acid concentrate is sold under the
trademark
EPADEL for the treatment of dyslipidemia. This product is described as 98%
EPA ethyl ester in Lancet (Vol.369; March 31, 2007; 1090-1098) reporting on a
large
outcome study with EPADELO. EPADELO is known to contain less than 1% of any
fatty acid other than EPA.
[0007] Similar to EPADELO, another form of omega-3 fatty acid concentrate also
consists almost entirely of EPA ethyl ester and is known under its
developmental
stage name AMR101 or its trade name VASCEPAO. This product is described in US
patent application 2010/0278879 as comprising at least 95% EPA (typically
referred
to as 97% or at least 96% in company releases and references) and less than 1%
of
any other fatty acid. AMR101 was previously under development for the
treatment of
Huntingdon's Disease but failed in phase Ill clinical development.
Subsequently,
AMR101 was entered in a development program for hypertriglyceridemia and mixed
dyslipidemia.
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[0008] Yet another concentrate of omega-3, long chain, polyunsaturated fatty
acids
from fish oil containing approximately 75% DHA and EPA as free fatty acids is
known under its developmental stage name EPANOVATM. This product is described
as comprising approximately 55% EPA and 20% DHA. EPANOVATM was previously
under development for the treatment of Crohn's Disease but failed in phase Ill
clinical development. Subsequently, EPANOVATM was entered in a development
program for hypertriglyceridemia and mixed dyslipidemia.
[0009] Generally, the bioavailability and therapeutic effect of omega-3 fatty
acid
compositions is dose dependent, i.e., the higher the dose, the greater the
therapeutic
affect and bioavailability. However, the effect of each specific omega-3 fatty
acid
composition may be different, and therefore the level of therapeutic effect of
one
composition at a given dose cannot necessarily be inferred from the level of
therapeutic effects of other omega-3 fatty acid compositions at the same or
similar
dose.
[0010] Omega-3 fatty acids are known to be "essential fatty acids". There are
two
series of essential fatty acids (EFAs) in humans. They are termed "essential"
because they cannot be synthesized de novo in mammals. These fatty acids can
be
interconverted within a series, but the omega-6 (n-6) series cannot be
converted to
the omega-3 series nor can the omega-3 (n-3) series be converted to the omega-
6
series in humans. The main EFAs in the diet are linoleic acid of the omega-6
series
and alpha-linolenic acid of the omega-3 series. However, to fulfill most of
their
biological effects these "parent" EFAs must be metabolised to the other longer
chain
fatty acids. Each fatty acid probably has a specific role in the body. The
scientific
literature suggests that particularly important in the n-6 series are dihomo-
gammalinolenic acid (DGLA, 20:3-n6) and arachidonic acid (ARA, 20:4-n6), while
particularly important in the n-3 series are eicosapentaenoic acid (EPA, 20:5-
n3) and
docosahexaenoic acid (DHA, 22:6-n3).
[0011] U.S. Patent No. 6,479,544 describes an invention in which it is found
that
ARA is highly desirable rather than undesirable and it may be helpful to
administer
ARA in association with EPA. This invention provides pharmaceutical
formulations
containing eicosapentaenoic acid or any appropriate derivative (hereinafter
collectively referred to as EPA) and arachidonic acid (ARA), as set out in the
granted
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claims for this patent. ARA may be replaced by one or more of its precursors,
DGLA
or GLA. In this reference, the ratio of EPA to ARA is preferably between 1:1
and
20:1.
[0012] Patent application PCT/GB 2004/000242 describes the treatment or
prevention of psoriasis with a formulation comprising more than 95% EPA and
less
than 2% DHA. In another embodiment of this invention the EPA is replaced with
DPA.
[0013] Patent application PCT/NL 2006/050291 (WO/2007/058538, GB 0301701.9)
describes combinations of idigestible oligosaccharides and long chain poly-
unsaturated fatty acids such as ARA, EPA, DA, and combinations thereof to
improve
intestinal barrier integrity, improving barrier function, stimulating gut
maturation
and/or reducing intestinal barrier permeability.
[0014] Lindeborg et al. (Prostag Leukotr Ess, 2013, 88:313-319) discloses a
study
evaluating postprandial metabolism of docosapentaenoic acid (DPA) and
eicosapentaenoic acid (EPA) in humans.
[0015] Holub et al. (Lipids, 2011, 46:399-407) discloses a study assessing the
effect of oral supplementation with docosapentaenoic acid (DPA) on levels of
serum
and tissue lipid classes and their fatty acid compositions in rat liver,
heart, and
kidney.
[0016] Cardiovascular disease includes numerous problems, many of which are
related to a process called atherosclerosis. Atherosclerosis is a condition
that
develops when plaque builds up in the walls of the arteries. This buildup
narrows the
arteries, making it harder for blood to flow through. If a blood clot forms,
it can stop
the blood flow. This can cause lead to conditions or event such as myocardial
infarction, stroke, heart failure, arrhythmias, valve dysfunction, and death.
[0017] All references cited herein are incorporated by reference in their
entirety.
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SUMMARY OF THE INVENTION
[0018] The present invention provides omega-3 fatty acid compositions and
methods of administering these compositions.
[0019] The present invention provides a pharmaceutical composition comprising
fatty acids, wherein at least 50% by weight of the fatty acids comprise omega-
3 fatty
acids, salts, esters, or derivatives thereof, wherein the omega-3 fatty acids
comprise
eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA) and wherein the
ratio of docosahexaenoic acid to DHA to EPA (DHA:EPA) is less than 1:10, and
wherein the ratio of DHA to DPA (DHA:DPA) is less than 2:1.
[0020] The present invention provides a pharmaceutical composition comprising
eicosapentaenoic acid (EPA) in an amount between about 70% to about 95% of the
total amount of fatty acids and docosapentaenoic acid (DPA) , wherein the
composition comprises no more than 5% docosahexaenoic acid (DHA) of the total
amount of fatty acids, and wherein the ratio of DHA:DPA is 1:1 or lower.
[0021] The present invention provides a pharmaceutical composition comprising
pharmaceutical composition comprising eicosapentaenoic acid (EPA) in an amount
between about 750 mg/g to about 950 mg/g, and docosapentaenoic acid (DPA),
wherein the composition comprises no more than 5% DHA of the total amount of
fatty acids, and wherein the ratio of DHA:DPA is 1:1 or lower.
[0022] The present invention provides a pharmaceutical composition comprising
eicosapentaenoic acid (EPA) in a daily dosage amount of between about 1000 mg
to
about 5000 mg, and further comprising docosapentaenoic acid (DPA) and
docosahexaenoic acid (DHA), wherein the composition comprises no more than 5%
DHA of the total amount of fatty acids, and wherein the ratio of DHA:DPA is
1:1 or
lower.
[0023] The present invention provides a pharmaceutical composition comprising
eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA), wherein the
amount of EPA and DPA is about 55% or more by weight of the total amount of
fatty
acids, and wherein the ratio of DHA:DPA is no more than 1:1.
[0024] The present invention provides a pharmaceutical composition comprising:
docosapentaenoic acid (DPA) in an amount between about 50% to about 80% of the
total amount of fatty acids, docosahexaenoic acid (DHA) in an amount between
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about 25% to about 40% of the total amount of fatty acids, and optionally
eicosapentaenoic acid (EPA) in an amount less than about 10% of the total
amount
of fatty acids.
[0025] In some embodiments, the compositions of the present invention comprise
additional fatty acids, such as heneicosapentaenoic acid (HPA), arachidonic
acid
(ARA), and omega-6-docosapentaenoic acid (n-6 DPA), tetracosapentaenoic acid
(TPA), and/or gamma-linoleic acid (GLA).
[0026] The present invention provides methods comprising administering the
compositions. The present invention provides a method of treating, preventing,
reducing the occurrence of, and improving symptoms associated with coronary
heart
disease (CHD), vascular disease, atherosclerotic disease or related
conditions,
comprising administering the compositions of the present invention to a
subject in
need thereof. The present invention also provides methods of treatment of
patients
by administering an effective amount of such compositions to a subject or a
subject
in need thereof, such as a subject prone to or afflicted with a
vascular/cardiovascular
disease or condition, a subject at risk of vascular/cardiovascular events, or
a subject
in need of treatment for a vascular/cardiovascular disease or condition.
DETAILED DESCRIPTION OF THE INVENTION
[0027] The present invention provides an orally administrable composition
comprising fatty acids, wherein at least 50% by weight of the fatty acids
comprise
omega-3-fatty acids, salts, esters, or derivatives thereof, wherein the omega-
3 fatty
acids comprise eicosapentaenoic acid (EPA; C20:5-n3), docosapentaenoic acid
(DPA; C22:5-n3), and docosahexaenoic acid (DHA; C22:6-n3), wherein the ratio
of
DHA to EPA (DHA:EPA) is less than 1:20, and wherein the ratio of DHA to DPA
(DHA:DPA) is less than 2:1.
[0028] The present invention provides a pharmaceutical composition comprising
fatty acids, wherein at least 50% by weight of the fatty acids comprise omega-
3 fatty
acids, salts, esters, or derivatives thereof, wherein the omega-3 fatty acids
comprise
eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA) and wherein the
ratio of docosahexaenoic acid to DHA to EPA (DHA:EPA) is less than 1:10, and
wherein the ratio of DHA to DPA (DHA:DPA) is less than 2:1, and methods of
using
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this composition. In some embodiments the composition comprises EPA in an
amount between about 70% and about 95% of the total amount of fatty acids. In
some embodiments, the composition comprises less than about 5% of DHA of the
total amount of fatty acids. In some embodiments, the composition comprises
DPA
in an amount of between about 5% and about 15% of the total amount of fatty
acids.
In some embodiments, the ratio of EPA to DPA (EPA:DPA) is less than about 1:1.
In
some embodiments, the composition further comprises heneicosapentaenoic acid
(H PA) in an amount of at least 1% of the total amount of fatty acids
[0029] The present invention provides a pharmaceutical composition comprising
eicosapentaenoic acid (EPA) in an amount between about 70% to about 95% of the
total amount of fatty acids and docosapentaenoic acid (DPA), wherein the
composition comprises no more than 5% docosahexaenoic acid (DHA) of the total
amount of fatty acids, and wherein the ratio of DHA:DPA is 1:1 or lower, and
methods of using the composition. In some embodiments, the composition
comprises DPA in an amount of between about 5% and about 15% of the total
amount of fatty acids. In some embodiments, the composition further comprises
heneicosapentaenoic acid (HPA) in an amount of at least 1% of the total amount
of
fatty acids. In some embodiments, the ratio of EPA to DPA (EPA:DPA) is less
than
about 1:1. In some embodiments, the ratio of DHA:EPA is less than about 1:10.
[0030] The present invention provides a pharmaceutical composition comprising
pharmaceutical composition comprising eicosapentaenoic acid (EPA) in an amount
between about 750 mg/g to about 950 mg/g, and docosapentaenoic acid (DPA),
wherein the composition comprises no more than 5% DHA of the total amount of
fatty acids, and wherein the ratio of DHA:DPA is 1:1 or lower, and methods of
using
the composition. In some embodiments, the composition comprises about 60 mg/g
to about 120 mg/g of DPA. In some embodiments, the ratio of DHA:EPA is less
than
1:10. In some embodiments, the ratio of EPA:DPA is less than about 1:1. In
some
embodiments, the composition further comprises heneicosapentaenoic acid (H PA)
in
an amount of at least 1% of the total amount of fatty acids.
[0031] The present invention provides a pharmaceutical composition comprising
eicosapentaenoic acid (EPA) in a daily dosage amount of between about 1000 mg
to
about 5000 mg, and further comprising docosapentaenoic acid (DPA) and
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docosahexaenoic acid (DHA), wherein the composition comprises no more than 5%
DHA of the total amount of fatty acids, and wherein the ratio of DHA:DPA is
1:1 or
lower, and methods of using the composition. In some embodiments, the ratio of
DHA:EPA is less than about 1:10. In some embodiments, the ratio of EPA:DPA is
less than about 1:1. In some embodiments, the composition further comprises
heneicosapentaenoic acid (HPA) in an amount of at least 1% of the total amount
of
fatty acids.
[0032] The present invention provides a pharmaceutical composition comprising
eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA), wherein the
amount of EPA and DPA is about 55% or more by weight of the total amount of
fatty
acids, and wherein the ratio of DHA:DPA is no more than 1:1, and methods of
using
the composition. In some embodiments, the composition comprises
docosahexaenoic acid (DHA) in an amount of less than about 30% of the total
amount of fatty acids. In some embodiments, the composition comprises a daily
dosage of DPA of greater than about 120 mg/day. In some embodiments, the
composition comprises omega-6 fatty acids in an amount of no more than 6% of
total
amount of fatty acids. In some embodiments, the composition comprises DPA in
an
amount of at least 6% of the total amount of fatty acids.
[0033] The present invention provides a pharmaceutical composition comprising:
docosapentaenoic acid (DPA) in an amount between about 50% to about 80% of the
total amount of fatty acids, docosahexaenoic acid (DHA) in an amount between
about 25% to about 40% of the total amount of fatty acids, and optionally
eicosapentaenoic acid (EPA) in an amount less than about 10% of the total
amount
of fatty acids, and methods of using the composition. In some embodiments, the
composition comprises docosapentaenoic acid (DPA) in an amount between about
50% to 75%, alternatively about 50% to about 70%, alternatively about 50% to
about
65%, or alternatively about 50% to about 60%, of the total amount of fatty
acids. In
some embodiments, the composition comprises docosahexaenoic acid (DHA) in an
amount between about 25% to about 38%, alternatively about 25% to about 35%,
alternatively about 30% to about 35% of the total amount of fatty acids. In
some
embodiments, the composition comprises eicosapentaenoic acid (EPA) in an
amount
less than about 9%, alternatively less than about 8%, alternatively less than
about
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7%, alternatively less than about 6%, alternatively less than about 5%, of the
total
amount of fatty acids.
[0034] In some embodiments, the compositions of the present invention comprise
at least 50% omega-3 fatty acids, alternatively at least 55%, alternatively at
least
60%, alternatively at least 65%, alternatively at least 70%, alternatively at
least 75%,
alternatively at least 80%, alternatively at least 85%, alternatively at least
95%, most
preferably at least 90% omega-3 fatty acids of the total amount of fatty
acids. In
some embodiments, the composition comprises at least about 92% to about 99%,
alteratively about 93% to about 98%, alternatively about 94% to about 98%,
omega-
3 fatty acids of the total amount of fatty acids.
[0035] In other embodiments, EPA and DPA are jointly present in the
compositions
of the present invention at between about 55% and about 100% of total fatty
acids,
alternatively between about 60% and about 100%, alternatively between about
65%
and about 100%, alternatively between about 70% and about 100%, alternatively
between about 75% and about 100%, alternatively between about 80% and about
100%, alternatively between about 85% and about 95%, alternatively about 85%
to
about 100%, alternatively between about 85% and about 97%, alternatively
between
about 88% and about 95%, alternatively between about 88% and about 97%,
alternatively about 88% to about 100%, alternatively between about 90% and
about
95%, alternatively between about 90% and about 97%, alternatively about 90% to
about 100%, alternatively about 95% to about 100%, alternatively about 97% to
about 100% of the total amount of fatty acids.
[0036] On a EPA+DPA daily dose basis, the compositions of the present
invention
may be provided in a dose of between 100 mg and 10,100 mg/day, alternatively
between 200 mg and 8,100 mg/day, alternatively between 300 mg and 6,100
mg/day, alternatively between 400 mg and 5,100 mg/day, alternatively between
500
mg and 4,100 mg/day. In some embodiments, on a EPA+HPA+DPA daily dose
basis, the compositions and methods of the present invention may be provided
in a
dose of between 100 mg and 10,100 mg/day, alternatively between 200 mg and
8,100 mg/day, alternatively between 300 mg and 6,100 mg/day, alternatively
between 400 mg and 5,100 mg/day, alternatively between 500 mg and 4,100
mg/day. In some embodiments, on an omega-3-pentaenoic acid daily dose basis,
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the methods and compositions of the present invention may be provided in a
dose
of between 100 mg and 10,100 mg/day, alternatively between 200 mg and 8,100
mg/day, alternatively between 300 mg and 6,100 mg/day, alternatively between
400
mg and 5,100 mg/day, alternatively between 500 mg and 4,100 mg/day.
[0037] The fatty acids, such as EPA and DPA, may be present in free fatty acid
form, or as a salt, ester, or derivative. The fatty acids are preferably
composed as a
triglyceride, an ester (such as an ethyl ester) or free fatty acid. Other
forms of the
fatty acids which may be useful include salts, esters of any type, amides,
mono-, di-
or triglycerides, phospholipids or any other form which can lead to
metabolization of
the fatty acids (such as EPA and/or DPA), or the incorporation of the fatty
acids
(such as EPA and/or DPA) into body fluids, tissues or organs.
[0038] Omega-3 fatty acids may be grouped by the number of double bonds
contained in the fatty acid chain. For instance, hexadecatrienoic acid (HTA),
alpha-
linolenic acid (ALA) and eicosatrienoic acid (ETE) are omega-3-trienoic acids;
stearidonic acid (SDA) and eicosatetraenoic acid (ETA) are omega-3-tetraenoic
acids; EPA, heneicosapentaenoic acid (HPA), DPA and tetracosapentaenoic acid
(TPA) are omega-3-pentaenoic acids; and DHA and tetracosahexaenoic acid (THA)
are omega-3-hexaenoic acids. In some preferred embodiments, the term omega-3-
pentaenoic acids will refer to a mixture of at least two omega-3 pentaenoic
acids in a
ratio of at least 1:25, more preferably in a ratio of at least 1:50, more
preferably in a
ratio of at least 1:75, more preferably in a ratio of at least 1:100, more
preferably in a
ratio of at least 1:125, more preferably in a ratio of at least 1:150, more
preferably in
a ratio of at least 1:200. In some embodiments, the ratio refers to the ratio
of the
least prevalent omega-3 pentaenoic acid in the mixture to the most prevalent
omega-
3 pentaenoic acid in the mixture.
[0039] In some embodiments, the compositions of the present invention comprise
EPA, HPA, DPA and TPA, alternatively EPA and DPA, and alternatively the
compositions of the present invention comprise EPA, HPA and DPA.
[0040] In some embodiments, the omega-3-pentaenoic acids in the compositions
of
the present invention comprise no more than 99.5% of a single omega-3-
pentaenoic
acid, alternatively no more than 99%;
alternatively no more than 98.5%;
alternatively no more than 98%; alternatively no more than 97.5%;
alternatively no
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more than 96%; alternatively no more than 95%; alternatively no more than 94%;
alternatively no more than 93%; alternatively no more than 92%; alternatively
no
more than 91%; alternatively no more than 90%; alternatively no more than 88%;
alternatively no more than 85%; alternatively no more than 80%; alternatively
no
more than 75%; alternatively no more than 70%; alternatively no more than 65%;
alternatively no more than 60%; alternatively no more than 55%; alternatively
no
more than 50%; alternatively no more than 45%; alternatively no more than 40%;
alternatively no more than 30%.
[0041] In some embodiments, the compositions of the present invention wherein
at
least 10%, alternatively at least 20%, alternatively at least 25%,
alternatively at least
35%, alternatively at least 50%, alternatively at least 60%, alternatively at
least 65%,
alternatively at least 70%, alternatively at least 75%, by weight of the fatty
acids
comprise omega-3-pentaenoic acids, salts, esters, or derivatives thereof.
[0042] In some embodiments, compositions and methods comprise significant
amounts of omega-3-pentaenoic acids or their glycerol or ethyl esters may be
used
in the methods of the present invention. In some embodiments, the compositions
and methods comprise at least 100 mg omega-3-pentaenoic acids per day,
alternatively at least 200mg omega-3-pentaenoic acids per day, alternatively
at least
300mg omega-3-pentaenoic acids per day, alternatively at least 500mg omega-3-
pentaenoic acids per day, alternatively at least 700mg omega-3-pentaenoic
acids
per day, alternatively at least 900mg omega-3-pentaenoic acids per day,
alternatively at least 1000mg omega-3-pentaenoic acids per day, alternatively
at
least 1500mg omega-3-pentaenoic acids per day, alternatively at least 1900mg
omega-3-pentaenoic acids per day, alternatively at least 2000mg omega-3-
pentaenoic acids per day, alternatively at least 2500mg omega-3-pentaenoic
acids
per day, alternatively at least 2900mg omega-3-pentaenoic acids per day,
alternatively at least 3000mg omega-3-pentaenoic acids per day, alternatively
at
least 3500mg omega-3-pentaenoic acids per day, alternatively at least 3900mg
omega-3-pentaenoic acids per day, alternatively at least 4000mg omega-3-
pentaenoic acids per day, alternatively at least 4100mg omega-3-pentaenoic
acids
per day, alternatively at least 4500mg omega-3-pentaenoic acids per day,
alternatively at least 5000mg omega-3-pentaenoic acids per day, alternatively
at
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least 5500mg omega-3-pentaenoic acids per day, alternatively at least 6000mg
omega-3-pentaenoic acids per day, alternatively at least 6100mg omega-3-
pentaenoic acids per day or their glycerol or ethyl esters.
[0043] In some embodiments, the compositions provide a DHA as compared to the
amount of omega-3-pentaenoic acids (N3-5enoicFA) such that the DHA:N3-
5enoicFA ratio is no more than 15:1 of DHA:N3-5enoicFA, alternatively no more
than
12:1 of DHA:N3-5enoicFA, alternatively no more than 10:1 of DHA:N3-5enoicFA,
alternatively no more than 8:1 of DHA:N3-5enoicFA, alternatively no more than
5:1
of DHA:N3-5enoicFA, alternatively no more than 3:1 of DHA:N3-5enoicFA,
alternatively no more than 2:1 of DHA:N3-5enoicFA, alternatively no more than
1:1
of DHA:N3-5enoicFA, alternatively no more than 1:2 of DHA:N3-5enoicFA,
alternatively no more than 1:3 of DHA:N3-5enoicFA, alternatively no more than
1:5
of DHA:N3-5enoicFA, alternatively no more than 1:8 of DHA:N3-5enoicFA,
alternatively no more than 1:10 of DHA:N3-5enoicFA, alternatively no more than
1:15 of DHA:N3-5enoicFA, alternatively a relative amount of no more than 1:20
of
DHA:N3-5enoicFA.
[0044] In some embodiments, the compositions of the present invention comprise
at least 0.01% HPA of total fatty acids in the composition, alternatively at
least 0.05%
HPA, alternatively at least 0.10% HPA, alternatively at least 0.15% HPA,
alternatively at least 0.2% HPA, alternatively at least 0.3% HPA,
alternatively at least
0.4% HPA, alternatively at least 0.5% HPA, alternatively at least 0.75% HPA,
alternatively at least 1% HPA, alternatively at least 1.5% HPA, alternatively
at least
2% HPA, alternatively at least 2.5% HPA, alternatively at least 3% HPA,
alternatively
at least 3.5% HPA, alternatively at least 4% HPA, alternatively at least 4.5%
HPA,
alternatively at least 5% HPA, alternatively at least 6% HPA, alternatively at
least 7%
HPA, alternatively the compositions of the present invention comprise at least
9%
HPA of total fatty acids in the composition.ln some embodiments, the
compositions
of the present invention comprise no more than 20% HPA of total fatty acids in
the
composition, alternatively no more than 15% HPA, alternatively no more than
12%
HPA, alternatively no more than 10% HPA, alternatively no more than 8% HPA,
alternatively no more than 7% HPA, alternatively no more than 6% HPA,
alternatively
no more than 5% HPA, alternatively no more than 4% HPA, alternatively no more
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than 3% HPA, alternatively no more than 2% HPA, alternatively no more than
1.5%
HPA, alternatively the compositions of the present invention comprise at least
1%
HPA of total fatty acids in the composition. In some embodiments, the
compositions
of the present invention comprise 1% to 20% HPA of the total fatty acids in
the
composition. In some embodiments, the compositions of the present invention
comprise about 1% to about 6% HPA, alternatively about 2% to about 5% HPA,
alternatively about 3% to about 4% HPA, relative to the total amount of fatty
acids in
the composition. In some embodiments, the compositions of the present
invention
comprise about 10 mg/g to about 50 mg/g HPA, alternatively about 15 mg/g to
about
45 mg/g, alternatively about 20 mg/g to about 40 mg/g, alternatively about 25
mg/g
to about 35 mg/g, alternatively about 30 mg/g HPA.
[0045] In some embodiments, the present invention provides compositions and
methods which comprise significant amounts of omega-3 heneicosapentaenoic acid
(HPA) or its glycerol or ethyl esters. In some embodiments, the methods of
treatment may provide to a subject in need thereof a dose of at least 10 mg
HPA per
day, alternatively at least 15 mg HPA per day, alternatively at least 20 mg
HPA per
day, alternatively at least 25 mg HPA per day, alternatively at least 30mg HPA
per
day, alternatively at least 40mg HPA per day, alternatively at least 50mg HPA
per
day, alternatively at least 60mg HPA per day, alternatively at least 70mg HPA
per
day, alternatively at least 80mg HPA per day, alternatively at least 90mg HPA
per
day, alternatively at least 100mg HPA per day, alternatively at least 120mg
HPA per
day, alternatively at least 150mg HPA per day, alternatively at least 160mg
HPA per
day, alternatively at least 180mg HPA per day, alternatively at least 200mg
HPA per
day, alternatively at least 250mg HPA per day, alternatively at least 300mg
HPA per
day, alternatively at least 350mg HPA per day, alternatively at least 400mg
HPA per
day, alternatively at least 500mg HPA per day, alternatively at least 600mg
HPA per
day, alternatively at least 800mg HPA or its glycerol or ethyl esters per day.
[0046] In some embodiments, the compositions of the present invention comprise
no more than 10% omega-3 fatty acids that are not omega-3-pentaenoic acids,
alternatively no more than 9%, alternatively no more than 8%, alternatively no
more
than 7%, alternatively no more than 6%, alternatively no more than 5%,
alternatively
no more than 4.5%, alternatively no more than 4%, alternatively no more than
3.5%,
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alternatively no more than 3%, alternatively no more than 2.5%, alternatively
no
more than 2%, alternatively no more than 1.5%, alternatively no more than
1.25%,
alternatively no more than 1%, alternatively no more than 0.75%, alternatively
no
more than 0.5%, alternatively no more than 0.4%, alternatively no more than
0.3%,
alternatively no more than 0.2%, alternatively the compositions of the present
invention comprise no more than 0.1% omega-3 fatty acids that are not omega-3-
pentaenoic acids.
[0047] In the embodiments of the present invention, the compositions comprise
EPA and DPA in an EPA:DPA ratio between 99:1 and 1:99 EPA:DPA, alternatively
between 90:1 and 1:90, alternatively between 60:1 and 1:60, alternatively
between
60:1 and 1:20, alternatively between 60:1 and 1:4, alternatively between 40:1
and
1:20, alternatively between 30:1 and 1:20, alternatively between 30:1 and
1:10,
alternatively between 30:1 and 1:5, alternatively between 40:1 and 1:4,
alternatively
between 30:1 and 1:4, alternatively between 30:1 and 1:2, alternatively
between 30:1
and 1:1, alternatively between 30:1 and 2:1, alternatively between 30:1 and
5:1,
alternatively between 20:1 and 1:20, alternatively between 20:1 and 1:10,
alternatively between 20:1 and 1:5, alternatively between 20:1 and 1:2,
alternatively
between 20:1 and 1:1, alternatively between 20:1 and 2:1, alternatively
between 20:1
and 5:1, alternatively between 20:1 and 10:1, alternatively between 20:1 and
10:1,
alternatively between 30:1 and 10:1, alternatively between 60:1 and 10:1,
alternatively comprise EPA and DPA in an EPA:DPA ratio between 40:1 and 10:1.
In some embodiments, the ratio of EPA:DPA is greater than 1:1, preferably
greater
than 2:1, and more preferably greater than 5:1. In some embodiments, the ratio
of
EPA:DPA is 1:1 to 25:1, preferably 5:1 to 20:1, more preferably 8:1 to 15:1,
even
more preferably 9:1 to 13:1, even more most preferably about 10:1 to 11:1, and
most
preferably about 10:1.
[0048] In some embodiments of the present invention, the compositions comprise
EPA in an amount between 55% and 95% relative to the total amount of fatty
acids
present in the composition, alternatively between 60% and 95%, alternatively
between 65% and 95%, alternatively between 70% and 95%, alternatively between
75% and 95%, alternatively between 90% and 95%, alternatively between 80%
and 95%, alternatively between 90% and 95%, alternatively between 55% and
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90%, alternatively between 60% and 90%, alternatively between 65% and 90%,
alternatively between 70% and 90%, alternatively between 75% and 90%,
alternatively between 80% and 90%, alternatively between 85% and 90%,
alternatively between 55% and 92%, alternatively between 60% and 92%,
alternatively between 65% and 92%, alternatively between 70% and 92%,
alternatively between 75% and 92%, alternatively between 80% and 92%,
alternatively between 85% and 92%, alternatively between 55% and 93%,
alternatively between 60% and 93%, alternatively between 65% and 93%,
alternatively between 70% and 93%, alternatively between 75% and 93%,
alternatively between 80% and 93%, alternatively between 85% and
93 /0,alternatively more than 85%, alternatively more than 85%,
alternatively
between 85% and 95% EPA relative to the total amount of fatty acids present in
the
composition. In some embodiments, the compositions comprise about 70% to about
95%, 80% to about 90%, alternatively about 81% to about 88%, alternatively
about
82% to about 88%, alternatively about 83% to about 87%, alternatively about
84% to
about 86%, alternatively about 85% EPA relative to the total amount of fatty
acids
present in the composition. In some embodiments, the compositions comprise
about
750 mg/g to about 950 mg/g, alternatively about 800 mg/g to about 900 mg/g,
alternatively about 830 mg/g to about 870 mg/g, alternatively about 840 mg/g
to
about 870 mg/g, alternatively 845 mg/g to about 865 mg/g, alternatively 846
mg/g to
about 860 mg/g, alternatively 847 mg/g to about 859 mg/g, alternatively about
848
mg/g to about 858 mg/g, alternatively about 849 mg/g to about 857 mg/g,
alternatively about 850 mg/g to about 856 mg/g, alternatively about 851 mg/g
to
about 855 mg/g, alternatively about 852 mg/g to about 854 mg/g, alternatively
about
853 mg/g EPA.
[0049] On a EPA daily dose basis, the compositions of the present invention
are
preferably provided in a dose of between 100 mg and 10,000 mg/day,
alternatively
between 200 mg and 8,000 mg/day, alternatively between 300 mg and 6,000
mg/day, alternatively between 400 mg and 5,000 mg/day, alternatively between
500
mg and 4,000 mg/day. In some embodiments, the compositions and methods of the
present invention are provided in a dose of between about 1000 mg/day to about
5000 mg/day, alternatively about 1200 mg/day to about 3000 mg/day,
alternatively
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about 1500 mg/day to about 2500 mg/day, alternatively 1600 mg/day to about
1950
mg/day, alternatively about 1735 mg/day to about 1855 mg/day, alternatively
about
1740 mg/day to about 1840 mg/day, alternatively about 1745 mg/day to about
1820
mg/day, alternatively about 1750 mg/day to about 1800 mg/day, alternatively
about
1755 mg/day to about 1790 mg/day, alternatively about 1760 mg/day to about
1780
mg/day, alternatively about 1770 mg/day of EPA. In some embodiments, the
compostiions of the present invention are provided in a dose of between about
2300
mg/day to about 3000 mg/day, alternatively about 2400 mg/day to about 2800
mg/day, alternatively about 2520 mg/day to about 2780 mg/day, alternatively
about
2600 mg/day to about 2700 mg/day, alternatively about 2610 mg/day to about
2680
mg/day, alternatively about 2620 mg/day to about 2670 mg/day, alternatively
about
2630 mg/day to about 2665 mg/day, alternatively about 2640 mg/day to about
2660
mg/day, alternatively about 2650 mg/day of EPA. In some embodiments, the
compostions of the present invention are provided in a dose of between about
3200
mg/day to about 3900 mg/day, alternatively 3300 mg/day to about 3800 mg/day,
alternatively 3360 mg/day to about 3710 mg/day, alternatively about 3400
mg/day to
about 3700 mg/day, alternatively about 3450 mg/day to about 3650 mg/day,
alternatively about 3500 mg/day to about 3600 mg/day, alternatively about 3530
mg/day to about 3580 mg/day, alternatively about 3540 mg/day to about 3560
mg/day, alternatively about 3550 mg/day of EPA.
[0050] In some embodiments, the compositions of the present invention are
provided in a dose of between about about 1650 mg/day to about 2050 mg/day,
alternatively about 1700 mg/day to about 2000 mg/day, alternatively about 1750
mg/day to about 1950 mg/day, alternatively about 1775 mg/day to about 1925
mg/day, alternatively about 1800 mg/day to about 1900 mg/day, alternatively
about
1800 mg/day to about 2000 mg/day, alternatively about 1820 mg/day to about
1880
mg/day, alternatively about 1830 mg/day to about 1870 mg/day, alternatively
about
1840 mg/day to about 1860 mg/day, alternatively about 1850 mg/day of EPA. In
some embodiments, the compostions of the present invention are provided in a
dose
of between about about 2500 mg/day to about 3100 mg/day, alternatively about
2600 mg/day to about 2000 mg/day, alternatively about 2650 mg/day to about
2950
mg/day, alternatively about 2700 mg/day to about 2900 mg/day, alternatively
about
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2725 mg/day to about 2875 mg/day, alternatively about 2750 mg/day to about
2850
mg/day, alternatively about 2780 mg/day to about 2820 mg/day, alternatively
about
2790 mg/day to about 2810 mg/day, alternatively about 2800 mg/day of EPA. In
some embodiments, the compostions of the present invention are provided in a
dose
of between about 3300 mg/day to about 4000 mg/day, alternatively about 3400
mg/day to about 3900 mg/day, alternatively about 3500 mg/day to about 3900
mg/day, alternatively about 3550 mg/day to about 3850 mg/day, alternatively
about
3600 mg/day to about 3800 mg/day, alternatively about 3650 mg/day to about
3750
mg/day, alternatively about 3680 mg/day to about 3725 mg/day, alternatively
about
3690 mg/day to about 3710 mg/day, alternatively about 3700 mg/day of EPA.
[0051] In some embodiments, the compositions of the present invention are
provided in a dose of between about 1500 mg/day to about 2500 mg/day,
alternatively about 1750 mg/day to about 2300 mg/day, alternatively about 1800
mg/day to about 2200 mg/day, alternatively about 1900 mg/day to about 2100
mg/day, alternatively about 1950 mg/day to about 2050 mg/day, alternatively
about
1975 mg/day to about 2025 mg/day, alternatively about 2000 mg/day of EPA. In
some embodiments, the compositions of the present invention are provided in a
dose of between about 2500 mg/day to about 3500 mg/day, alternatively about
2700
mg/day to about 3300 mg/day alternatively about 2750 mg/day to about 3300
mg/day, alternatively about 2800 mg/day to about 3200 mg/day, alternatively
about
2900 mg/day to about 3100 mg/day, alternatively about 2950 mg/day to about
3050
mg/day, alternatively about 2975 mg/day to about 3025 mg/day, alternatively
about
3000 mg/day of EPA. In some embodiments, the compositions of the present
invention are provided in a dose of between about 3500 mg/day to about 4500
mg/day, alternatively about 3700 mg/day to about 4300 mg/day, alternatively
about
3750 mg/day to about 4300 mg/day, alternatively about 3800 mg/day to about
4200
mg/day, alternatively about 3900 mg/day to about 4100 mg/day, alternatively
about
3950 mg/day to about 4050 mg/day, alternatively about 3975 mg/day to about
4025
mg/day, alternatively about 4000 mg/day of EPA.
[0052] In other embodiments of the present invention, the compositions
comprise
DPA in an amount between 1'3/o and 99% relative to the total amount of fatty
acids
present in the composition, alternatively between 1% and 95%, alternatively
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alternativelybetween 1% and 90%, alternatively between 1% and 85%,
alternatively
between 1 /0 and 80%, alternatively between 1% and 75%, alternatively between
1% and 70%, alternatively between 1% and 65%, alternatively between 1% and
60%, alternatively between 1% and 55%, alternatively between 1% and 50%,
alternatively between 1% and 45%, alternatively between 1% and 40%,
alternatively between 1% and 35%, alternatively between 1% and 30%,
alternatively between 1% and 25%, alternatively between 1% and 20%,
alternatively between 1% and 15%, alternatively between 1% and 10%,
alternatively between 1% and 5%, alternatively between 2% and 99%,
alternatively
between 2% and 95%, alternatively between 2% and 90%, alternatively between
2% and 85%, alternatively between 2% and 80%, alternatively between 2% and
75%, alternatively between 2% and 70%, alternatively between 2% and 65%,
alternatively between 2% and 60%, alternatively between 2% and 55%,
alternatively between 2% and 50%, alternatively between 2% and 45%,
alternatively between 2% and 40%, alternatively between 2% and 35%,
alternatively between 2% and 30%, alternatively between 2% and 25%,
alternatively between 2% and 20%, alternatively between 2% and 15%,
alternatively between 2% and 10%, alternatively between 2% and 5%,
alternatively
between 3% and 99%, alternatively between 3% and 95%, alternatively between 3%
and 90%, alternatively between 3% and 85%, alternatively between 3% and 80%,
alternatively between 3% and 75%, alternatively between 3% and 70%,
alternatively between 3% and 65%, alternatively between 3% and 60%,
alternatively between 3% and 55%, alternatively between 3% and 50%,
alternatively between 3% and 45%, alternatively between 3% and 40%,
alternatively between 3% and 35%, alternatively between 3% and 30%,
alternatively between 3% and 25%, alternatively between 3% and 20%,
alternatively between 3% and 15%, alternatively between 3% and 10%,
alternatively between 3% and 5%, alternatively between 4% and 99%,
alternatively
between 4% and 95%, alternatively between 4% and 90%, alternatively between
4% and 85%, alternatively between 4% and 80%, alternatively between 4% and
75%, alternatively between 4% and 70%, alternatively between 4% and 65%,
alternatively between 4% and 60%, alternatively between 4% and 55%,
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alternatively between 4% and 50%, alternatively between 4% and 45%,
alternatively between 4% and 40%, alternatively between 4% and 35%,
alternatively between 4% and 30%, alternatively between 4% and 25%,
alternatively between 4% and 20%, alternatively between 4% and 15%,
alternatively between 4% and 10%, alternatively between 4% and 5%,
alternatively
between 5% and 99%, alternatively between 5% and 95%, alternatively between 5%
and 90%, alternatively between 5% and 85%, alternatively between 5% and 80%,
alternatively between 5% and 75%, alternatively between 5% and 70%,
alternatively between 5% and 65%, alternatively between 5% and 60%,
alternatively between 5% and 55%, alternatively between 5% and 50%,
alternatively between 5% and 45%, alternatively between 5% and 40%,
alternatively between 5% and 35%, alternatively between 5% and 30%,
alternatively between 5% and 25%, alternatively between 5% and 20%,
alternatively between 5% and 15%, alternatively between 5% and 12%,
alternatively between 5% and 10%, alternatively between 6% and 99%,
alternatively
between 6% and 95%, alternatively between 6% and 90%, alternatively between
6% and 85%, alternatively between 6% and 80%, alternatively between 6% and
75%, alternatively between 6% and 70%, alternatively between 6% and 65%,
alternatively between 6% and 60%, alternatively between 6% and 55%,
alternatively between 6% and 50%, alternatively between 6% and 45%,
alternatively between 6% and 40%, alternatively between 6% and 35%,
alternatively between 6% and 30%, alternatively between 6% and 25%,
alternatively between 6% and 20%, alternatively between 6% and 15%,
alternatively between 6% and 12%, alternatively between 6% and 11%,
alternatively between 6% and 10%, alternatively between 7% and 99%,
alternatively
between 7% and 95%, alternatively between 7% and 90%, alternatively between
7% and 85%, alternatively between 7% and 80%, alternatively between 7% and
75%, alternatively between 7% and 70%, alternatively between 7% and 65%,
alternatively between 7% and 60%, alternatively between 7% and 55%,
alternatively between 7% and 50%, alternatively between 7% and 45%,
alternatively between 7% and 40%, alternatively between 7% and 35%,
alternatively between 7% and 30%, alternatively between 7% and 25%,
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alternatively between 7% and 20%, alternatively between 7% and 15%,
alternatively between 7% and 12%, alternatively between 7% and
11%,
alternatively between 7% and 10%, alternatively between 8% and 99%,
alternatively
between 8% and 95%, alternatively between 8% and 90%, alternatively between
8% and 85%, alternatively between 8% and 80%, alternatively between 8% and
75%, alternatively between 8% and 70%, alternatively between 8% and 65%,
alternatively between 8% and 60%, alternatively between 8% and 55%,
alternatively between 8% and 50%, alternatively between 8% and 45%,
alternatively between 8% and 40%, alternatively between 8% and 35%,
alternatively between 8% and 30%, alternatively between 8% and 25%,
alternatively between 8% and 20%, alternatively between 8% and 15%,
alternatively between 8% and 12%, alternatively between 9% and 95%,
alternatively between 9% and 90%, alternatively between 9% and 85%,
alternatively between 9% and 80%, alternatively between 9% and 75%,
alternatively between 9% and 70%, alternatively between 9% and 65%,
alternatively between 9% and 60%, alternatively between 9% and 55%,
alternatively between 9% and 50%, alternatively between 9% and 45%,
alternatively between 9% and 40%, alternatively between 9% and 35%,
alternatively between 9% and 30%, alternatively between 9% and 25%,
alternatively between 9% and 20%, alternatively between 9% and 15%,
alternatively between 9% and 12%, relative to the total amount of fatty acids
present
in the composition. In
some embodiments, the compositions comprise
docosapentaenoic acid (DPA) in an amount between about 5% to about 15%,
alternatively about 6% to about 12%, alternatively about 7% to about 11%,
alternatively about 8% to about 10% relative to the total amount of fatty
acids present
in the composition. In some alternative embodiments, the composition comprises
at
least about 4% or at least about 5% or at least about 6% or at least about 7%
or at
least about 8% or at least about 9% or at least about 10% or at least about
15% or at
least about 20% or at least about 25% or at least about 30% or at least about
35% or
at least about 40% or at least about 45% or at least about 50% or at least
about 55%
or at least about 60% or at least about 65% or at least about 70% or at least
about
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75% or at least about 80% or at least about 85% or at least about 90% or at
least
about 95% of docosapentaenoic acid (DPA).
[0053] In some embodiments, the compositions comprise docosapentaenoic acid
(DPA) in an amount of about 60 mg/g to about 120 mg/g, alternatively about 70
mg/g
to about 100 mg/g, 75 mg/g to about 90 mg/g, alternatively about 77 mg/g to
about
85 mg/g, alternatively about 78 mg/g to about 84 mg/g, alternatively about 79
mg/g
to about 83 mg/g, alternatively about 80 mg/g to about 82 mg/g, alternatively
about
81 mg/g to about 82 mg/g. In some embodiments, the compositions comprise
docosapentaenoic acid (DPA) in an daily dosage amount of at least about 20
mg/day, alternatively at least about 25 mg/day, alternatively at least about
30
mg/day, alternatively at least about 40 mg/day, alternatively at least about
50
mg/day, alternatively at least about 60 mg/day alternatively, at least about
70 mg/day
alternatively at least about 75 mg/day, alternatively at least about 80
mg/day,
alternatively at least about 90 mg/day, alternatively at least about 100
mg/day,
alternatively at least about 120 mg/day, alternatively at least about 150
mg/day,
alternatively at least about 160 mg/day, alternatively at least about 180
mg/day,
alternatively at least about 200 mg/day, alternatively at least about 250
mg/day,
alternatively at least about 300 mg/day, alternatively at least about 350
mg/day, or
alternatively at least about 400 mg/day, alternatively at least about 500
mg/day,
alternatively at least about 600 mg/day, alternatively at least about 800
mg/day, or
alternatively at least about 1000 mg/day, alternatively at least about 1200
mg/day,
alternatively at least about 1500 mg/day, or alternatively at least about 2000
mg/day,
or alternatively at least about 3000 mg/day, or alternatively at least about
3500
mg/day, or alternatively at least about 4000 mg/day, or alternatively at least
about
4250 mg/day. In some embodiments, the composition comprises DPA in a daily
dosage of about 120 mg/day to about 150 mg/day, alternatively about 150 mg/day
to
about 200 mg/day, alternatively about 200 mg/day to about 250 mg/day,
alternatively
about 250 mg/day to about 300 mg/day, alternatively about 300 mg/day to about
400
mg/day, alternatively about 400 mg/day to about 600 mg/day, alternatively
about 600
mg/day to about 1000 mg/day. In some embodiments, the method of treatment
provides a dose of at least about 1 mg/kg of docosapentaenoic acid (DPA) per
day,
alternatively about 2 mg/kg of DPA per day, alternatively about 3 mg/kg of DPA
per
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day, alternatively about 4 mg/kg of DPA per day, alternatively about 6 mg/kg
of DPA
per day, alternatively about 8 mg/kg of DPA per day, alternatively about 10
mg/kg of
DPA per day, alternatively about 20 mg/kg of DPA per day, alternatively about
30
mg/kg of DPA per day, and alternatively about 40 mg/kg of DPA per day,
alternatively about 50 mg/kg of DPA per day, alternatively about 75 mg/kg of
DPA
per day, and alternatively about 100 mg/kg of DPA per day.
[0054] In some embodiments, a relatively small amount of docosahexaenoic acid
(DHA) as compared to EPA is present. In some embodiments, the compositions of
the present invention comprise no more than 1:1 of DHA:EPA, alternatively no
more
than 1:2, alternatively no more than 1:3, alternatively no more than 1:3,
alternatively
no more than 1:4, alternatively no more than 1:5 of DHA:EPA, alternatively no
more
than 1:6 of DHA:EPA, alternatively no more than 1:7 of DHA:EPA, alternatively
no
more than 1:8 of DHA:EPA, alternatively no more than 1:9 of DHA:EPA,
alternatively
no more than 1:10 of DHA:EPA, alternatively no more than 1:12 of DHA:EPA,
alternatively no more than 1:15 of DHA:EPA, alternatively no more than 1:20 of
DHA:EPA, alternatively no more than 1:25 of DHA:EPA, alternatively no more
than
1:30 of DHA:EPA, alternatively no more than 1:40 of DHA:EPA, alternatively no
more than 1:50 of DHA:EPA, alternatively no more than 1:75 of DHA:EPA,
alternatively no more than 1:90 of DHA:EPA, alternatively no more than 1:99 of
DHA:EPA. Alternatively, DHA may be present in the compositions of this
invention
at a relative amount of ratio less than 1% than the amount of EPA.
Alternatively,
docosahexaenoic acid (DHA) may be present in the compositions of this
invention at
a DHA:EPA ratio of less than 1:99.
[0055] In some embodiments, a relatively small amount of docosahexaenoic acid
(DHA) relative to the total amount of fatty acids present in the composition
is present.
In some embodiments, the compositions of the present invention comprise no
more
than 30% DHA, alternatively no more than 20% DHA, alternatively no more than
15% DHA, alternatively no more than 12% DHA, alternatively no more than 10%
DHA, alternatively no more than 9% DHA, alternatively no more than 8% DHA,
alternatively no more than 7% DHA, alternatively no more than 6% DHA,
alternatively no more than 5% DHA, alternatively no more than 4% DHA,
alternatively no more than 3% DHA, alternatively no more than 2% DHA,
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alternatively no more than 1`)/0 DHA relative to the total amount of fatty
acids present
in the composition. In some embodiments, the compositions and methods comprise
less than 1500mg of DHA, alternatively less than 1200mg of DHA, alternatively
less
than 1000mg of DHA, alternatively less than 800mg of DHA, alternatively less
than
700mg of DHA, alternatively less than 600mg of DHA, alternatively less than
500mg
of DHA, alternatively less than 400mg of DHA, alternatively less than 350mg of
DHA,
alternatively less than 300mg of DHA, alternatively less than 250mg of DHA,
alternatively less than 200mg of DHA alternatively less than 150mg of DHA,
alternatively less than 120mg of DHA, alternatively less than 100 mg of DHA,
alternatively less than 80 mg of DHA, alternatively less than 60 mg of DHA,
alternatively less than 40 mg of DHA, alternatively less than 30 mg of DHA,
alternatively less than 25 mg of DHA, alternatively less than 20 mg of DHA or
its
glycerol or ethyl esters as a totally daily dose.
[0056] In some embodiments, the composition comprises about 5 mg/g to about 20
mg/g, alternatively about 8 mg/g to about 18 mg/g, alternatively about 9 mg/g
to
about 15 mg/g, alternatively about 10 mg/g to about 14 mg/g, alternatively
about 11
mg/g to about 13 mg/g, alternatively about 12 mg/g to about 13 mg/g of
docosahexaenoic acid (DHA).
[0057] In some embodiments, the ratio of EPA:HPA is about 1500:1 to 25:1,
alternatively 1000:1 to 50:1, alternatively 800:1 to 60:1, alternatively 500:1
to 60:1,
alternatively 250:1 to 75:1, and alternatively 100:1 to 80:1. In some
preferred
embodiments, the ratio of EPA:HPA is about 85:1. In some preferred
embodiments,
the ratio of EPA:HPA is about 30:1. In some embodiments, the ratio of DPA:HPA
is
about 250:1 to 1:1, alternatively 200:1 to 2:1, alternatively 150:1 to 3:1,
alternatively
100:1 to 4:1, alternatively 50:1 to 5:1, alternatively 25:1 to 6:1, and
alternatively 10:1
to 7:1. In some preferred embodiments, the ratio of DPA:HPA is about 8:1. In
some
embodiments, the ratio of DPA:HPA is about 3:0.
[0058] In other embodiments, a relatively small amount of DHA as compared to
DPA is present. In these embodiments, the compositions of the present
invention
comprise no more than 15:1 of DHA:DPA, alternatively no more than 12:1 of
DHA:DPA, alternatively no more than 10:1 of DHA:DPA, alternatively no more
than
8:1 of DHA:DPA, alternatively no more than 5:1 of DHA:DPA, alternatively no
more
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than 4:1 of DHA:DPA, alternatively no more than 3:1 of DHA:DPA, alternatively
no
more than 2:1 of DHA:DPA, alternatively no more than 1:1 of DHA:DPA,
alternatively
no more than 1:2 of DHA:DPA, alternatively no more than 1:3 of DHA:DPA,
alternatively no more than 1:4 of DHA:DPA, alternatively no more than 1:5 of
DHA:DPA, alternatively no more than 1:6 of DHA:DPA, alternatively no more than
1:7 of DHA:DPA, alternatively no more than 1:8 of DHA:DPA, alternatively no
more
than 1:10 of DHA:DPA, alternatively no more than 1:12 of DHA:DPA,
alternatively no
more than 1:15 of DHA:DPA, alternatively no more than 1:20 of DHA:DPA,
alternatively no more than 1:25 of DHA:DPA, alternatively no more than 1:50 of
DHA:DPA, alternatively no more than 1:75 of DHA:DPA, alternatively no more
than
1:90 of DHA:DPA, alternatively no more than 1:95 of DHA:DPA, alternatively no
more than 1:100 of DHA:DPA. In some embodiments, the ratio of DHA:DPA is
preferably less than 2:1.
[0059] In other embodiments, a relatively small amount of DHA as compared to
HPA is present. In these embodiments, the compositions of the present
invention
comprise no more than 15:1 of DHA:HPA, alternatively no more than 12:1 of
DHA:HPA, alternatively no more than 10:1 of DHA:HPA, alternatively no more
than
8:1 of DHA:HPA, alternatively no more than 5:1 of DHA:HPA, alternatively no
more
than 3:1 of DHA:HPA, alternatively no more than 2:1 of DHA:HPA, alternatively
no
more than 1:1 of DHA:HPA, alternatively no more than 1:2 of DHA:HPA,
alternatively
no more than 1:3 of DHA:HPA, alternatively no more than 1:5 of DHA:HPA,
alternatively no more than 1:8 of DHA:HPA, alternatively no more than 1:10 of
DHA:HPA, alternatively no more than 1:15 of DHA:HPA, alternatively no more
than
1:20 of DHA:HPA, alternatively no more than 1:25 of DHA:HPA, alternatively no
more than 1:50 of DHA:HPA, alternatively no more than 1:75 of DHA:HPA,
alternatively no more than 1:90 of DHA:HPA, alternatively no more than 1:95 of
DHA:HPA, alternatively no more than 1:100 of DHA:HPA.
[0060] In yet other embodiments, the compositions of the present invention
comprise no more than 10% omega-6 fatty acids relative to the total amount of
fatty
acids, alternatively no more than 9%, alternatively no more than 8%,
alternatively no
more than 7%, alternatively no more than 6%,alternatively no more than 5%,
alternatively no more than 4.5%, alternatively no more than 4%, alternatively
no
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more than 3.5%, alternatively no more than 3%, alternatively no more than
2.5%,
alternatively no more than 2%, alternatively no more than 1.7%, alternatively
no
more than 1.5%, alternatively no more than 1.2%, alternatively no more than
1%,
alternatively no more than 0.5% omega-6 fatty acids versus the total amount of
fatty
acids comprised by the compositions of the present invention.
[0061] Omega-6 fatty acids include, but are not limited to: linoleic acid (LA;
018:2-
n6); gamma-linoleic acid (GLA; 018:3-n6); eicosadienoic acid (020:2-n6);
dihomo-
gamma-linoleic acid (DGLA; C20:3-n6); arachiconic acid (ARA; C20:4-n6); and
omega-6 docosapentaenoic acid (DPA; C22:5-n6).
[0062] In further embodiments, the compositions of the present invention
comprise
no more than 10% omega-6 fatty acids relative to the total amount of omega-3
fatty
acids plus omega-6 fatty acids, alternatively no more than 9%, alternatively
no more
than 8%, alternatively no more than 7%, alternatively no more than 6%,
alternatively
no more than 5%, alternatively no more than 4.5%, alternatively no more than
4%,
alternatively no more than 3.5%, alternatively no more than 3%, alternatively
no
more than 2.5%, alternatively no more than 2%, alternatively no more than
1.7%,
alternatively no more than 1.5%, alternatively no more than 1.2%,
alternatively no
more than 1%, alternatively no more than 0.5% omega-6 fatty acids versus the
total
amount of omega-3 fatty acids plus omega-6 fatty acids comprised by the
compositions of the present invention.
[0063] In yet other embodiments, the compositions of the present invention
comprise no more than 8% arachidonic acid (ARA; C20:4-n6) relative to the
total
amount of omega-3 fatty acids plus omega-6 fatty acids, alternatively no more
than
7%, alternatively no more than 6%, alternatively no more than 5%,
alternatively no
more than 4.5%, alternatively no more than 4%, alternatively no more than
3.5%,
alternatively no more than 3%, alternatively no more than 2.5%, alternatively
no
more than 2%, alternatively no more than 1.7%, alternatively no more than
1.5%,
alternatively no more than 1.2%, alternatively no more than 1 /0,
alternatively no
more than 0.5% arachidonic acid (ARA; C20:4-n6) versus the total amount of
omega-3 fatty acids plus omega-6 fatty acids comprised by the compositions of
the
present invention.
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[0064] In some embodiments, a relatively small amount of omega-3 fatty acids
in
aggregate other than EPA, ETA, HPA and DPA (alternatively indicated as non-
EPA,
non-ETA, non-HPA and non-DPA omega-3 fatty acids in aggregate) relative to the
total amount of fatty acids present in the composition is present. In some
embodiments, the compositions of the present invention comprise no more than
20%
non-EPA, non-ETA, non-HPA and non-DPA omega-3 fatty acids, alternatively no
more than 15% non-EPA, non-ETA, non-HPA and non-DPA omega-3 fatty acids,
alternatively no more than 12% non-EPA, non-ETA, non-HPA and non-DPA omega-
3 fatty acids, alternatively no more than 10% non-EPA, non-ETA, non-HPA and
non-
DPA omega-3 fatty acids, alternatively no more than 8% non-EPA, non-ETA, non-
HPA and non-DPA omega-3 fatty acids, alternatively no more than 7% non-EPA,
non-ETA, non-HPA and non-DPA omega-3 fatty acids, alternatively no more than
6% non-EPA, non-ETA, non-HPA and non-DPA omega-3 fatty acids, alternatively no
more than 5% non-EPA, non-ETA, non-HPA and non-DPA omega-3 fatty acids,
alternatively no more than 4% non-EPA, non-ETA, non-HPA and non-DPA omega-3
fatty acids, alternatively no more than 3% non-EPA, non-ETA, non-HPA and non-
DPA omega-3 fatty acids, alternatively no more than 2% non-EPA, non-ETA, non-
HPA and non-DPA omega-3 fatty acids, alternatively no more than 1% non-EPA,
non-ETA, non-HPA and non-DPA omega-3 fatty acids in aggregate relative to the
total amount of fatty acids present in the composition.
[0065] In some embodiments, a relatively small amount of the sum of ALA, SDA
and DHA relative to the total amount of fatty acids present in the composition
is
present, while at the same time large amounts of the sum of EPA, DPA-n3, HPA
and
ETA are present. In some embodiments, the compositions of the present
invention
comprise no more than 20% of the sum of ALA, SDA and DHA, alternatively no
more
than 15% of the sum of ALA, SDA and DHA, alternatively no more than 12% of the
sum of ALA, SDA and DHA, alternatively no more than 10% of the sum of ALA, SDA
and DHA, alternatively no more than 8% of the sum of ALA, SDA and DHA,
alternatively no more than 7% of the sum of ALA, SDA and DHA, alternatively no
more than 6% of the sum of ALA, SDA and DHA, alternatively no more than 5% of
the sum of ALA, SDA and DHA, alternatively no more than 4% of the sum of ALA,
SDA and DHA, alternatively no more than 3% of the sum of ALA, SDA and DHA,
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alternatively no more than 2% of the sum of ALA, SDA and DHA, alternatively no
more than 1% of the sum of ALA, SDA and DHA relative to the total amount of
fatty
acids present in the composition, while at the same time contain more than 40%
the
sum of EPA, DPAn-3, HPA and ETA, alternatively more than 50% the sum of EPA,
DPAn-3, HPA and ETAõ alternatively more than 60% the sum of EPA, DPAn-3,
HPA and ETA, alternatively more than 70% the sum of EPA, DPAn-3, HPA and ETA,
alternatively more than 75% the sum of EPA, DPAn-3, HPA and ETA, alternatively
more than 80% the sum of EPA, DPAn-3, HPA and ETA, alternatively more than
85% the sum of EPA, DPAn-3, HPA and ETA, alternatively more than 90% the sum
of EPA, DPAn-3, HPA and ETA, alternatively more than 95% the sum of EPA,
DPAn-3, HPA and ETA, alternatively between 80% and 98% the sum of EPA, DPAn-
3, HPA and ETA, alternatively between 80% and 96% the sum of EPA, DPAn-3,
HPA and ETA, alternatively between 85% and 98% the sum of EPA, DPAn-3, HPA
and ETA, alternatively between 85% and 96% the sum of EPA, DPAn-3, HPA and
ETA, alternatively between 90% and 98% the sum of EPA, DPAn-3, HPA and ETA,
alternatively between 90% and 97% the sum of EPA, DPAn-3, HPA and ETA,
alternatively between 90% and 96% the sum of EPA, DPAn-3, HPA and ETA,
alternatively between 90% and 95% the sum of EPA, DPAn-3, HPA and ETA,
relative to the total amount of fatty acids present in the composition is
present.
[0066] In further embodiments, the compositions of the present invention
comprise
no more than 8% arachidonic acid (ARA; C20:4-n6) relative to the total amount
of
fatty acids, alternatively no more than 7%, alternatively no more than 6%,
alternatively no more than 5%, alternatively no more than 4.5%, alternatively
no
more than 4%, alternatively no more than 3.5%, alternatively no more than 3%,
alternatively no more than 2.5%, alternatively no more than 2%, alternatively
no
more than 1.7%, alternatively no more than 1.5%, alternatively no more than
1.2%,
alternatively no more than 1%, alternatively no more than 0.5% arachidonic
acid
(ARA; C20:4-n6) relative the total amount of fatty acids comprised by the
compositions of the present invention.
[0067] In other embodiments, the compositions of the present invention
comprise
no more than 2.5% arachidonic acid (ARA; C20:4-n6), no more than 0.4% omega-6-
docosapentaenoic acid (DPA; C22:5-n6) and no more than 0.2% gamma-linoleic
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acid (GLA; C18:3-n6) relative the total amount of fatty acids comprised by the
compositions of the present invention.
[0068] Further embodiments provide fatty acid compositions comprising no more
than 2.5% arachidonic acid (ARA; C20:4-n6), no more than 0.3% omega-6
docosapentaenoic acid (DPA; C22:5-n6) and no more than 0.1% gamma-linoleic
acid (GLA; C18:3-n6) relative the total amount of fatty acids comprised by the
compositions of the present invention.
[0069] In some embodiments, the composition of the present invention further
comprises TPA at concentration of at least 0.05%. In some embodiments, the TPA
concentration is about 0.01% to about 5%, alternatively about 0.05% to about
2%,
alternatively about 0.1% to about 1%, alternatively about 0.2% to about 0.8%,
alternatively about 0.4% to about 0.6%, alternatively about 0.5%.
[0070] The compositions of the present invention may also be taken as a
general
nutritional supplement.
[0071] In yet other embodiments, the active ingredient of the formulations of
the
present invention consists essentially wholly of the EPA and DPA or precursors
thereof (ethyl ester, triglyceride, or any other pharmaceutically acceptable
salt or
derivative thereof). In that case, no large amounts (preferably less than 15%,
alternatively less than 12%, alternatively less than 10%, alternatively less
than 9%,
alternatively less than 8%, alternatively less than 7%, alternatively less
than 6%,
alternatively less than 5%, alternatively less than 4%, alternatively less
than 3%,
alternatively less than 2%, alternatively less than 1%, alternatively less
than 0.5%,
alternatively less than 0.25%) of any other fatty acids are present.
[0072] In further embodiments, the active ingredient of the formulations of
the
present invention consists essentially wholly of omega-3-pentaenoic acids or
precursors thereof (ethyl ester, triglyceride, or any other pharmaceutically
acceptable
salt or derivative thereof). In that case, no large amounts (preferably less
than 15%,
alternatively less than 12%, alternatively less than 10%, alternatively less
than 9%,
alternatively less than 4%, alternatively less than 4%, alternatively less
than 4%,
alternatively less than 4%, alternatively less than 4%, alternatively less
than 3%,
alternatively less than 2%, alternatively less than 1%, alternatively less
than 0.5%,
alternatively less than 0.25%) of any other fatty acids are present.
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[0073] The fatty acid percentage is determined on a weight/weight, mol/mol, or
chromatography area percent basis relative to all fatty acids present in the
composition as determined by methods such as disclosed in the European
Pharmacopeia monograph for omega-3 fatty acid concentrates, European
Pharmacopeia monograph for omega-3-acid ethyl esters 90%, or European
Pharmacopeia monograph method 2.4.29, USP monograph for fish oil dietary
supplements, USP 35 omega-3-acid ethyl esters (LOVAZAO) monograph, or any
essentially equivalent methods (whether by gas chromatography, HPLC, FPLC or
any other chromatographic method).
[0074] In some embodiments, the fatty acid percentage is determined not as a
percentage of all fatty acids present in the composition but as a specific
type of fatty
acid ethyl esters as percentage of all fatty acid ethyl esters present in the
composition, thus excluding from the fatty acid percentage determination such
fatty
acids present as, for instance: free fatty acids; mono-, di-, and tri-
glycerides; or fatty
acids present in phospholipids (such as phosphatidylserine or
phosphatidylcholine)
or polysorbates (such as Tween 80, Tween 20, or polysorbate 40).
[0075] In other embodiments, the fatty acid percentage is determined not as a
percentage of all fatty acids present in the composition but as a specific
type of free
fatty acid as percentage of all free fatty acids present in the composition,
thus
excluding from the fatty acid percentage determination such fatty acids
present as,
for instance: fatty acid ethyl esters; mono-, di-, and tri-glycerides; or
fatty acids
present in phospholipids (such as phosphatidylserine or phosphatidylcholine)
or
polysorbates (such as Tween 80, Tween 20, or polysorbate 40).
[0076] In yet other embodiments, the fatty acid percentage is determined not
as a
percentage of all fatty acids present in the composition but as a specific
type of
glycerol fatty acid ester as percentage of all glycerol fatty acid esters
present in the
composition, thus excluding from the fatty acid percentage determination such
fatty
acids present as, for instance: fatty acid ethyl esters; free fatty acids; or
fatty acids
present in phospholipids (such as phosphatidylserine or phosphatidylcholine)
or
polysorbates (such as Tween 80, Tween 20, or polysorbate 40).
[0077] In further embodiments, the fatty acid percentage is determined not as
a
percentage of all fatty acids present in the composition but as di- or tri-
fatty acid
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esters with glycerol as percentage of all glycerol di- and tri-fatty acid
esters present
in the composition, thus excluding from the fatty acid percentage
determination such
fatty acids present as, for instance: glycerol-mono-fatty acid esters; fatty
acid ethyl
esters; free fatty acids; or fatty acids present in phospholipids (such as
phosphatidylserine or phosphatidylcholine) or polysorbates (such as Tween 80,
Tween 20, or polysorbate 40).
[0078] In yet other embodiments, the fatty acid percentage is determined not
as a
percentage of all fatty acids present in the composition but as a tri-fatty
acid esters
with glycerol as percentage of all glycerol tri-fatty acid esters present in
the
composition, thus excluding from the fatty acid percentage determination such
fatty
acids present as, for instance: mono- and di-fatty acid esters of glycerol;
fatty acid
ethyl esters; free fatty acids; or fatty acids present in phospholipids (such
as
phosphatidylserine or phosphatidylcholine) or polysorbates (such as Tween 80,
Tween 20, or polysorbate 40).
[0079] The EPA, HPA, DPA, or omega-3-pentaenoic acids may be derived from
any appropriate source including plant seed oils, microbial oils from algae or
fungal
or marine oils from fish or other marine animals. Certain species are a
particular
good source of oils containing DPA, for example seal oil. They may be used in
the
form of the natural oil, if that oil meets the required purity requirements of
the present
invention, or may be purified to give products containing the fatty acid
composition of
the present invention.
[0080] The compositions of the present invention may be produced through a
range
of the methods. Such methods may include: distillation, including short path
distillation; urea precipitation; enzymatic conversion concentration;
conventional
chromatography; HPLC/FPLC; supercritical carbondioxide extraction;
supercritical
carbondioxide chromatography; simulated moving bed chromatography;
supercritical
carbondioxide simulated moving bed chromatography; or chemical conversion
methods such as iodolactonization. Such methods are generally known to those
skilled in the art of purifying and isolating omega-3 fatty acids,
[0081] Typically, the omega-3 fatty acid concentration/purification process is
initiated by esterifying the fatty acids comprised by the marine oil raw
material (such
as crude fish oil) with ethanol (to form fatty acid ethyl esters) in order to
separate
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omega-3 fatty acids from other fatty acids covalently bound together in the
natural
triglyceride molecules of the source oil. Subsequently, the material may be
distilled
once or several times to achieve omega-3-acid ethyl ester concentrations above
60%-70%. Alternatively, enzymatic concentration, urea precipitation or
supercritical
extraction may be used alone or in conjunction with distillation to reach
omega-3
levels above 70%-90%. In order to prepare a highly pure concentrate of a
single
omega-3 fatty acid, methods such as chromatography, supercritical
chromatography,
simulated moving bed chromatography, supercritical simulated moving bed
chromatography, or chemical conversion methods such as iodolactolization are
typically most practical to reach levels above 50%, alternatively above 60%,
alternatively above 70%, alternatively above 80%, alternatively above 90%,
alternatively above 95%, of a single omega-3 fatty acid such as ETA, EPA, HPA,
DPA, TPA, or DHA.
[0082] Those skilled in the art will be able to design processes suited to
prepare a
certain omega-3 fatty acid composition as desired, based on the methods
described
above. Such processes are flexible enough to affect the relative proportions
between the long chain C18, C20, 021 and 022 fatty acids which occur naturally
in
available fish oil raw materials and other marine oils. It provides not only
for the
concentration of the individual omega-3 fatty acids, but the ratio between
them will
remain within a pattern of variation caused by variations in nature. However,
suitable methods compensate for sometimes extreme variations which may occur
naturally. Thus, for those skilled in the art, it will be possible to make a
product with a
constant and predetermined composition.
[0083] EPA is relatively abundant in fish oils or other marine oils and can be
relatively easy obtained through the application of concentration and
purification
technologies from such fish or marine oils. DPA and HPA are present at much
lower
concentrations. In order to prepare the compositions of the present invention,
DPA
or HPA may be concentrated and purified from fish or other marine oils
according to
the methods referred to above, either alone or DPA combined with EPA and/or
HPA.
Alternatively, the DPA or HPA may be chemically prepared from a high purity
EPA
concentrate by elongation of the EPA fatty-acid chain with two or one hydrogen-
saturated carbons (02-elongation or C1-elongation) on the carboxyl side of the
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molecule (for instance with a method similar to or alternate methods with
equivalent
results such as described by Kuklev DV and Smith WL in Chem Phys Lipids, 2006;
144(2): 172-177). In another alternative approach, a high purity EPA
concentrate
may be partially converted to DPA (or HPA) using a method for 02-elongation
(or
C1-elongation) of EPA similar to those described above, thus directly yielding
compositions of the present invention or intermediates therefore.
[0084] Once the oils containing one or more of the desired fatty acids have
been
obtained, and purified as necessary, these oils may be blended to give the
desirable
relative amounts of EPA, DPA, HPA, DHA, TPA, other omega-3 fatty acids and
omega-6 fatty acids to obtain the compositions of the present invention
described in
detail above.
[0085] Fish oils may also contain by-products and contaminants such as
pesticides,
chlorinated or brominated hydrocarbons, heavy metals, cholesterol and
vitamins.
During the production of the concentrate, the concentrations of these
components
are significantly reduced compared to untreated fish oils. Such reduction is
inherent
due to the nature of purification methods and their ability to concentrate of
several or
specific omega-3 fatty acids, thus removing other compounds.
[0086] Triglycerides comprising more than 60% of the omega-3 fatty acids in
the
composition may be produced from ethyl esters and glycerol by well known,
published, or alternative chemical synthetic or enzymatic procedures. The free
acids
may be produced from ethyl esters by well known hydrolization or
saponification
procedures. Methods for converting ethyl esters to triglycerides, free fatty
acids,
and other molecular forms comprising fatty acids, are generally known to those
skilled in the art chemically or enzymatically converting omega-3 fatty acids
from one
form to another.
[0087] In some embodiments, the compositions of the present invention have
improved pharmacological features as demonstrated by improved bioavailability
in a
mammal of EPA, HPA, DPA, DHA, EPA+DHA, EPA+DPA or EPA+HPA+DPA
combined, total omega-3-pentaenoic acids, or of total omega-3 fatty acids. Key
parameters for determining bioavailability are maximum concentration of a
therapeutic compound or a metabolite thereof (Cmax); the time from
administration
to maximum concentration (Tmax); and the area under the concentration curve
over
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time (AUC). Such parameters may be determined under single dose or multiple
dose administration regimens. Methods to determine comparative bioavailability
in
mammals are generally known to those skilled in the art.
[0088] Meal conditions during administration to a subject of omega-3 fatty
acid
compositions or omega-3 fatty acid formulations can be of special significance
for
absorption and bioavailability of omega-3 fatty acids. The meal conditions
typically
considered are: fasting (no food at all prior for 8-12 hours prior to
administration and
2-3 hours post administration of the treatment); a low fat meat (a meal
typically
containing less than 25 gram of fat [350-600 Kcal] consumed just before or
after the
administration of the treatment; typically within a 15-30 minute range); or a
high fat
meat (a meal containing 40 gram to 75 gram of fat [700-1000 Kcal] consumed
just
before or after the administration of the treatment; typically within a 15-30
minute
range).
[0089] In some embodiments of the present invention, compositions of the
present
invention are more rapidly absorbed as measured by the time to reach the
maximum
concentration (Tmax) in blood, serum or plasma of EPA, DPA, DHA , EPA+DPA,
EPA+DHA, total omega-3-pentaenoic acids, or total omega-3 fatty acids. In
preferred embodiments of the present invention, Tmax under high fat meal
administration conditions is less than 8 hours, alternatively less than 6
hours,
alternatively approximately 5 hours, alternatively 4 hours or less. In other
preferred
embodiments of the present invention, Tmax under low fat meal administration
conditions is less than 8 hours, alternatively less than 6 hours,
alternatively
approximately 5 hours, alternatively 4 hours or less. In
yet other preferred
embodiments of the present invention, Tmax under fasting administration
conditions
is less than 8 hours, alternatively less than 6 hours, alternatively
approximately 5
hours, alternatively 4 hours or less.
[0090] In yet other embodiments of the present invention, Tmax for EPA, DPA,
DHA, EPA+DPA, EPA+DHA, or total omega-3 fatty acids are equal or less than
than
Tmax for AMR101 for EPA, DPA, DHA , EPA+DPA, EPA+DHA, total omega-3-
pentaenoic acids, or total omega-3 fatty acids under high fat meat, low fat
meal, and
fasting administration conditions. Finally, in other embodiments of the
present
invention, Tmax for EPA, DPA, DHA, EPA+DPA, EPA+DHA, or total omega-3 fatty
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acids are less than Tmax for AMR101 for EPA+DHA and to EPA, DPA, DHA ,
EPA+DPA, EPA+DHA, or total omega-3 fatty acids under either low fat meal,
fasting,
or both administration conditions.
[0091] In some embodiments, the improved bioavailability features described
above
are apparent upon single dose administration, while in other embodiments the
improved bioavailability features described above are apparent after multiple
dose
administration of formulations according to the present invention as compared
to
referenced comparator products above or substantial equivalent forms thereof.
[0092] In another embodiment, the compositions of the present invention are
more
potent and effective than other omega-3 compositions known in the prior art
(such as
LOVAZAO, EPANOVATM or VASCEPAO).
[0093] The formulation may be a single daily dose preparation to give in one
dose
the above intakes, or may be in convenient divided doses, for example, a daily
dose
formed of two to four soft gelatin or other dosage forms, each containing 300-
1500
mg of EPA, EPA+DPA, EPA+DPA+HPA, or omega-3-pentaenoic acids in any form
embodied in the present invention.
[0094] Flavourants or emulsifiers may be included, for instance, to make the
preparation palatable. Other conventional additives, diluents and excipients
may be
present. The preparation for ingestion may be in the form of a capsule, a dry
powder, a tablet, a solution, an oil, an emulsion or any other appropriate
form. The
capsules may be hard or soft gelatin capsules, agar capsules, or any other
appropriate capsule.
[0095] Use of the formulations of the invention in the manufacture of a
medicament
for the treatment or prevention of any disease or disorder, including those
mentioned
above, is included in the present invention.
[0096] The omega-3 fatty acid composition optionally includes chemical
antioxidants, such as alpha tocopherol, which are administered in pure form or
suspended in a vegetable oil, such as soybean oil or corn oil.
[0097] The blended fatty acid compositions may then be incorporated into any
appropriate dosage form for oral, enteral, parenteral, rectal, vaginal, dermal
or other
route of administration. Soft or hard gelatin capsules, flavoured oil blends,
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emulsifiers or other liquid forms, and microencapsulate powders or other dry
form
vehicles are all appropriate ways of administering the products.
[0098] The formulated final drug product containing the omega-3 fatty acid
composition may be administered to a mammal or patient in need thereof in a
capsule, a tablet, a powder that can be dispersed in a beverage, or another
solid oral
dosage form, a liquid, a soft gel capsule or other convenient dosage form such
as
oral liquid in a capsule, as known in the art. In some embodiments, the
capsule
comprises a hard gelatin. The combination product may also be contained in a
liquid
suitable for injection or infusion.
[0099] Example pharmaceutical grade finished dosage forms: (a) Soft or hard
gelatin capsules each containing 500 mg or 1000 mg of a mix 20 parts of EPA as
a
free fatty acid to 1 parts of DPA as a free fatty acid; (b) As in (a) but
where the EPA
and DPA free fatty acids are replaced with the fatty acids in any other
appropriate
bioassimilable form such as the ethyl esters; (c) As in (a)-(b) but where the
material
is in the form of a microencapsulated powder which can be used as a powder or
compressed into tablets. Such powders may be prepared by a variety of
technologies known to those skilled in the art; (d) As in (a)-(b) but where
the
formulation is a liquid or emulsion, appropriately flavoured for palatable
oral
administration; (e) As in (a)-(b) but where the material is formulated into a
pharmaceutically acceptable vehicle appropriate for topical application such
as a
cream or ointment.
[0100] The omega-3 compositions of the present invention may also be
administered with a combination of one or more non-active pharmaceutical
ingredients (also known generally herein as "excipients"). Non-active
ingredients, for
example, serve to solubilize, suspend, thicken, dilute, emulsify, stabilize,
preserve,
protect, color, flavor, and fashion the active ingredients into an applicable
and
efficacious preparation that is safe, convenient, and otherwise acceptable for
use.
Thus, the non-active ingredients may include colloidal silicon dioxide,
crospovidone,
lactose monohydrate, lecithin, microcrystalline cellulose, polyvinyl alcohol,
povidone,
sodium lauryl sulfate, sodium stearyl fumarate, talc, titanium dioxide and
xanthum
gum.
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[0101] The term "pharmaceutically acceptable vehicle," as used herein,
includes
any of the following: a solution where the first API and optional other
ingredients are
wholly dissolved in a solubilizer (e.g., a pharmaceutically acceptable solvent
or
mixture of solvents), wherein the solution remains in clear liquid form at
about room
temperature; a suspension; an oil; or a semi-solid, wherein the first API and
optionally other ingredients are dissolved wholly or partially in a
solubilizer (an
emulsion, cream, etc.).
[0102] A "pharmaceutical grade finished dosage form" as used herein may be
construed as a unit dose form suitable for administration to, for example,
human or
animal subjects, and having content uniformity acceptable to regulatory
authorities.
For example, under the USP requirements for content uniformity, a
pharmaceutical
grade finished dosage form should have an amount of API within the range of
85%
to 115% of the desired dosage and an RSD less than or equal to 6.0%. In
addition, a
pharmaceutical grade finished dosage form must be stable (i.e., have a "shelf
life")
for a pharmaceutically acceptable duration of time, preferably at least six
months,
alternatively at least one year,or at least two years, when stored at room
temperature
(about 23 degree Celcius to 27 degree Celcius , preferably about 25 degree
Celcius)
and 60% relative humidity. Typically, stability is determined by physical
appearance
and/or chemical modification of the ingredients, in accordance with standards
well-
known in the pharmaceutical arts, including those documented in ICH
guidelines.
[0103] The omega-3 fatty acid dosage form optionally includes chemical
antioxidants, such as alpha tocopherol, oils, such as soybean oil and
partially
hydrogenated vegetable oil, and lubricants such as fractionated coconut oil,
lecithin
and a mixture of the same.
[0104] The compositions of the present invention may be used for the treatment
of
patients by administering an effective amount of such compositions to a
subject in
need thereof, such as a subject prone to or afflicted with a disease or
condition or in
need of treatment for a disease or condition. The present invention provides
methods of treating, preventing, and reducing the symptoms, pathology or
events
associated with a disease or condition comprising administration of any of the
compositions of the present invention. The present invention provides methods
of
treating, preventing, reducing the occurrence of, and reducing symptoms
associated
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with coronary heart disease (CHD), vascular disease, atherosclerotic disease,
or
related conditions. The present invention also provides methods of treating,
preventing, reducing the occurrence of, and reducing the symptoms, pathology
or
events associated with vascular-related diseases or conditions. Examples of
vascular diseases and conditions include, but are not limited to:
atherosclerosis,
atherosclerosis associated with hypercholesterolemia, hypertriglyceridemia or
mixed
dyslipidemia, coronary heart disease (CHD), vascular disease, peripheral
artery
disease (PAD), heart failure, cardiac arrhythmias, blood coagulatory
conditions
associated with cardiac arrhythmias, hypertension, coagulation related
disorders
(including but not limited to post-surgical deep vein thrombosis or other high
risk
thrombosis conditions), nephropathy and other kidney diseases, renal
impairment,
retinopathy, cognitive impairment, dementia (including but not limited to
ischemic
dementia and vascular dementia), and metabolic syndrome. The compositions of
the present invention may be used for the treatment of patients by
administering an
effective amount of such compositions to a subject or a subject in need
thereof, such
as a subject prone to or afflicted with a vascular/cardiovascular disease or
condition,
a subject at risk of vascular/cardiovascular events, or a subject in need of
treatment
for a vascular/cardiovascular disease or condition.
[0105] Determination of such cardiovascular diseases/conditions and prevention
of
events/symptoms in mammals and methods to determine treatment and
preventative/therapeutic effects therefore are generally know to those skilled
in the
art.
[0106] Administration to or treatment of subject with the compositions of the
present
inventions results in significant clinical improvements, including but not
limited to the
following. In some embodiments, the present invention provides for the
prevention
of death (including all cause mortality, cardiovascular mortality, and cardiac
death);
the treatment and/or prevention of cardiac events, cardiovascular events
and/or
vascular events and/or symptoms. In some embodiments, the present invention
also
provides for the reduction of number or frequency of such events, as well as a
reduction or amelioration of symptoms associated with such events. Vascular,
cardiovascular and/or cardiac events may include, but are not limited to:
death due
to cardiovascular event (including cardiovascular death and cardiac death),
sudden
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cardiac death, myocardial infarction (fatal or non-fatal), ischemic cardiac
attack,
ischemic attack, angina, stroke, transient ischemic cerebral attack,
thrombosis, deep
vein thrombosis, pulmonary embolism, coronary revascularization, coronary
revascularization with stent placement, carotid artery revascularization,
carotid artery
revascularization with stent placement, peripheral artery revascularization,
peripheral
artery revascularization with stent placement, major coronary event, coronary
artery
bypass grafting, other blood vessel grafting, treatment of aneurism, plaque
rupture,
and hospitalization due to cardiovascular event (including angina, acute
angina and
unstable angina). Cardiovascular and/or cardiac events may also include other
events deemed to fall in such category by those skilled in the art. Study
endpoints
may comprise individual events or a composite of several of the events
described
directly above (for the latter the term Major Adverse Cardiovascular Event or
MACE
is often used).
[0107] In some embodiments, the present invention provides methods of
retarding
the atherosclerotic disease process or improves the vascular healing process
in
response to presence of atherogenic disease. Such retardation or healing may
be
demonstrated by reduced stenosis and/or restenosis at specific vascular sites
over
time, reduced or lesser increase in intima-media thickness (IMT) of the
arterial wall
over time, larger lumen size and/or larger vascular diameter at vascular sites
with
stenosis or clot built-up over time. Such retardation or healing may be
determined
by intravascular ultrasound (IVUS), radiographic, echocardiographic,
radiologic, non-
invasive ultrasound, tomography, magnetic resonance interference (MRI), or
other
acceptable methods. In other embodiments, such retardation or improved healing
may be demonstrated by the vascular wall composition, such as a reduced foam
cell
presence or fibrillated tissue in the vessel wall. In yet other embodiments,
such
improved vascular healing is demonstrated by improved inflammatory markers in
the
vascular wall or specific types of staining of vascular tissue.
[0108] In some embodiments, the compositions of the present invention may
differentially alter the ratio between blood platelets and fragments thereof
(also
known as platelet microparticles). Such fragments may be evaluated as a whole
or
examined and described as fragment sub-categories.
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[0109] In some embodiments, the compositions of the present invention may
differentially alter the surface charge of blood platelets and fragments
thereof, either
in resting state (non-activated platelets) or activated stage.
[0110] In some embodiments, the compositions of the present invention may
affect
the coagulatory cascade and differentially alter coagulation or bleeding times
or
platelet aggregation times and density.
[0111] The compositions of the present invention may be useful for any
subjects
and they may be especially useful in certain patient populations, including
but not
limited to the following: subjects having receiving treatment for or in need
of
treatment for hypertriglyceridemia, hypercholesterolemia, Frederickson
dyslipidemia,
and other comorbidities. The present invention provides for methods of
treatment of
subjects with no previous cardiovascular events, or subjects with one or more
previous cardiovascular events. In some embodiments, the subjects to be
treated
with or administered the compositions of the present invention, are selected
based
on their dyslipidemic profile. Subjects may be selected for
treatment/administration
from the following categories: hypertriglyceridemia (such as TG?.750mg/dL,
TG?.500mg/dL, TG?200mg/dL, TG?..150mg/dL, TG500-2000mg/dL, TG500-
1500mg/dL, TG750-2000mg/dL, TG750-1500mg/dL, TG200-499mg/dL, TG300-
499mg/dL, TG350-499mg/dL, TG300-750mg/dL, TG300-700mg/dL, TG200-
499mg/dL, or TG150-199mg/dL); hypercholesterolemia (such as LDL-C<70mg/dL,
LDL-C?.70mg/dL, LDL-C?.100mg/dL, LDL-C?130/dL, LDL-C.?160mg/dL, LDL-
C?190mg/dL, LDL-C 70-100mg/dL, LDL-C 100-130mg/dL, LDL-C 130-160mg/dL,
LDL-C 160-190mg/dL, LDL-C 130-190mg/dL, LDL-C 100-160mg/dL, LDL-C 70-
130mg/dL, LDL-C 70-160mg/dL, LDL-C 100-190mg/dL, LDL-C 70-190mg/dL, NON-
HDL-C<100mg/dL, NON-HDL-C?_100mg/dL, NON-HDL-C?130mg/dL, NON-HDL-
C?_160/dL, NON-HDL-C?.190mg/dL, NON-HDL-C 100-130mg/dL, NON-HDL-C 130-
160mg/dL, NON-HDL-C 160-190mg/dL, NON-HDL-C 130-190mg/dL, NON-HDL-C
100-160mg/dL, or NON-HDL-C 100-190mg/dL); or Frederickson dyslipidemia type
(either, Type I, Type Ila, Type Ilb, Type III, Type IV, or Type V). In some
embodiments, the subjects to be treated with or administered the compositions
of the
present invention, are selected based on the presence of certain
comorbidities.
Such comorbidities may include, but are not limited to the following: renal
disease,
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nephropathy, IgA nephropathy, renal impairment, renal failure (also kidney
failure or
renal insufficiency), renal insufficiency requiring dialysis, renal
insufficiency without
dialysis treatment, chronic analgesic nephritis, polycystic kidney disease,
proteinuria,
hypertension, thrombotic microangiopathy, renal failure (acute renal failure,
chronic
renal failure), uremic pericarditis, uremia, renal artery stenosis, renal
ischemia,
hypertensive nephropathy, renovascular hypertension, renal osteodystrophy,
nephroptosis, renal cortical necrosis, glomerulitis, metabolic syndrome,
diabetes, or
pre-diabetes. In some embodiments, the methods of administering the
compositions
of the present invention are useful in subjects having cardiopathy, coronary
ischemia, cardiac decompensation, or diabetic pathology with cardiopathy, and
subjects with previous myocardial infarction, stroke, recent myocardial
infarction
(post-MI), Acute Coronary Syndrome (ACS), ACS without ST-segment elevation
(NSTEMI), ACS with ST-segment elevation (STEMI), or any other major
cardiovascular event. In some embodiments, the compositions of the present
invention may reduce the reoccurrence of such cardiovascular events.
[0112] In some embodiments, treatment with the compositions of the present
invention results in clinical improvement of such comorbidities. In
some
embodiments, administration with the compositions of the present invention may
reduce the time necessary to achieve clinical improvement and/or attain
treatment
goals. In some embodiments, the administration of compositions can result in
clinical improvements in clinical markers, including, but not limited to:
glomerular
filtration rate, serum creatinine, serum urea, serum phosphate levels, serum
potassium levels, systolic or diastolic blood pressure, progression to
dialysis,
progression to renal failure, progression to need for renal transplant,
fasting serum
glucose levels, postprandial serum glucose levels, serum fructosamine levels,
therapeutic insulin utilization, progression to diabetes, hypo-glucose events,
hyper-
glucose events, or hemoglobin Al C.
[0113] The compositions of the present invention may be co-administered with
one
or more other therapeutic agents. In some embodiments, clinical benefits
resulting
from the administration or treatment of subjects with the compositions of the
present
invention may be improved with concomitant use or in combination with other
therapeutic agents. Examples of such concomitant or fixed combination
treatments
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may include coadministration with one or more of the following: an HMG-CoA
reductase inhibitor ("statin"), an anti-platelet agent (such as aspirin or
clopidogrel),
an anti-coagulant (such as warfarin) an antihypertensive (such as a diuretic,
beta-
blocker, calcium channel blocker, ACE-inhibitor, angiotensin II receptor (ARB)
antagonist), or other treatments for cardiovascular diseases.
[0114] The present invention also provides pharmaceutical compositions, for
example, a unit dosage, comprising one or more HMG-CoA reductase inhibitors
("statins") and an omega-3 fatty acid composition of the present invention. In
some
embodiments, the present invention provides a fixed dose combination product
comprising both a statin and the composition of the present invention. The
present
invention may incorporate currently known or future known statins in an amount
generally recognized as safe and effective. There are currently seven statins
that
are widely available: atorvastatin, rosuvastatin, fluvastatin, lovastatin,
pravastatin,
pitavastatin, and simvastatin. An eighth statin, cerivastatin, has been
removed from
the U.S. market at the time of this writing. However, it is conceivable to one
skilled in
the art that cerivastatin may be used in conjunction with some embodiments of
the
present invention if cerivastatin is ultimately determined to be safe and
effective in
certain treatment regimens. Such statins are typically used at their common
daily
doses, which include, but are not limited to lovastatin 10mg, 20mg, 40mg;
pravastatin 10mg, 20mg, 40mg, 80mg; simvastatin 5mg, 10mg, 20mg, 40mg, 80mg;
fluvastatin 20mg, 40mg, 80mg; atorvastatin 10mg, 20mg, 40mg, 80mg;
rosuvastatin
5mg, 10mg, 20mg, 40mg; and pitavastatin 1mg, 2mg, 4mg, 8mg. Generally, the
effect of statins is dose dependent, i.e., the higher the dose, the greater
the
therapeutic affect. However, the effect of each statin is different, and
therefore the
level of therapeutic effect of one statin cannot be necessarily be directly
correlated to
the level of therapeutic effects of other statins. For example,
bioavailability varies
widely among the statins. Specifically, it has been shown that simvastatin is
less
than 5% bioavailable, while fluvastatin is approximately 24% bioavailable.
Statins
are absorbed at rates ranging from about 30% with lovastatin to 98% with
fluvastatin.
First-pass metabolism occurs in all statins except pravastatin. Pravastatin is
also the
least protein-bound of the statins (about 50%), compared with the others,
which are
more than 90% protein-bound. Accordingly, the statins possess distinct
properties
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from one another. The combination products of this invention involving each
statin
or a plurality of statins are also distinct. The method of treatment may
combine the
administration of one or more statins at its common dose or an alternative
dose with
the composition of the present invention
EXAMPLES
[0115] Example 1
[0116] A composition according to the present invention is prepared by mixing
and
homogenizing in a ratio of 98:2 the intermediates MEGAPEX E9ODOOEE (90% EPA
ethyl ester,) and MAXOMEGA DPA95 FFA (?.95 /0 DPA synthetic fatty acid
produced
from EPA ethyl ester concentrate) converted to ethyl ester, respectively.
These
intermediates were prepared and commercially offered for sale by Chemport
Korea
(MEGAPEX) and Equateq Ltd from Scotland, UK (MAXOMEGA). The relative
amounts of fatty acids present in the starting intermediates and in the
resulting novel
composition are listed in Table 1 below. The resulting novel composition
comprises
89.10% EPA, 1.95% DPA, 0.19% HPA, 91.24% omega-3-pentaenoic acids, less
than 0.01% DHA, 91.24% omega-3-pentaenoic acids, 93.09% total omega-3 fatty
acids, 3.15% ARA and 3. 57% omega-6 fatty acids (all Area%).
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Table 1. Fatty acid Composition (Area %) of intermediates and novel
composition according to Example 1
98.0% 2.0%
Fatty Acid Megapex E9ODOOEE
Maxomega DPA95FFA => EE Novel Composition
c18:0 0.05 o 0.05
c18:1n9 0.06 o 0.06
c18:1n7 0.02 o 0.02
c18:2n6 0.01 0 0.01
c18:3n6 0.02 o 0.02
c18:3n3 0.03 0 0.03
c18:4n3 0.42 0 0.41
c18:4n1 0.07 0 0.07
c20:0 o o 0.00
c20:1n11 o o 0.00
c20:1n9 o o 0.00
c20:1n7 0 0 0.00
c20:2n6 0.25 o 0.25
c20:3n9 o o 0.00
c20:3n6 0.15 o 0.15
c21:0 o o 0.00
c20:4n6 3.21 0 3.15
c20:3n3 o o 0.00
c20:4n3 1.44 0 1.41
c20:5n3 90.92 0 89.10
c22:0 0.3 o 0.29
c22:1n11 0.07 0 0.07
c22:1n9 0.18 0 0.18
c22:1n7 0.19 0 0.19
c21:5n3 0.19 0 0.19
c22:5n6 o o 0.00
c22:5n3 0 97.27 1.95
c22:6n3 o o 0.00
c24:0 0 0.33 0.01
OTHER 2.42 2.4 2.42
100 100 100
[0117] Example 2
[0118] A composition according to the present prevention is prepared by mixing
and
homogenizing in a ratio of 96:4 the intermediates MEGAPEX E9OD00EE (90% EPA
ethyl ester,) and MAXOMEGA DPA95 FFA (?_95`)/0 DPA synthetic fatty acid
produced
from EPA ethyl ester concentrate), converted to ethyl ester, respectively.
These
intermediates were prepared and commercially offered for sale by Chemport
Korea
(MEGAPEX) and Equateq Ltd from Scotland, UK (MAXOMEGA). The relative
amounts of fatty acids present in the starting intermediates and in the
resulting novel
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composition is listed in Table 2 below. The resulting novel composition
comprises
87.28% EPA, 3.89% DPA, 0.18% HPA, 91.35% omega-3-pentaenoic acids, less
than 0.01% DHA, 93.17% total omega-3 fatty acids and 3.49% omega-6 fatty acids
(all Area%).
Table 2. Fatty acid Composition (Area %) of intermediates and novel
composition according to Example 2
96.0% 4.0%
Fatty Acid Megapex E9ODOOEE
Maxomega DPA95FFA => EE Novel Composition
c18:0 0.05 o 0.05
c18:1n9 0.06 0 0.06
c18:1n7 0.02 o 0.02
c18:2n6 0.01 o 0.01
c18:3n6 0.02 0 0.02
c18:3n3 0.03 0 0.03
c18:4n3 0.42 0 0.40
c18:4n1 0.07 0 0.07
c20:0 0 0 0.00
c20:1n11 0 0 0.00
c20:1n9 0 0 0.00
c20:1n7 o o 0.00
c20:2n6 0.25 0 0.24
c20:3n9 o o 0.00
c20:3n6 0.15 0 0.14
c21:0 o o 0.00
c20:4n6 3.21 o 3.08
c20:3n3 0 0 0.00
c20:4n3 1.44 o 1.38
c20:5n3 90.92 0 87.28
c22:0 0.3 0 0.29
c22:1n11 0.07 0 0.07
c22:1n9 0.18 o 0.17
c22:1n7 0.19 0 0.18
c21:5n3 0.19 o 0.18
c22:5n6 o o 0.00
c22:5n3 0 97.27 3.89
c22:6n3 0 0 0.00
c24:0 o 0.33 0.01
OTHER 2.42 2.4 2.42
100 100 100
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[0119] Example 3
[0120] A composition according to the present invention is prepared by mixing
and
homogenizing in a ratio of 94:6 the intermediates MEGAPEX E90DOOEE (90% EPA
ethyl ester,) and MAXOMEGA DPA95 FFA (?95% DPA synthetic fatty acid produced
from EPA ethyl ester concentrate) converted to ethyl ester, respectively.
These
intermediates were prepared and commercially offered for sale by Chemport
Korea
(MEGAPEX) and Equateq Ltd from Scotland, UK (MAXOMEGA). The relative
amounts of fatty acids present in the starting intermediates and in the
resulting novel
composition are listed in table 3 below. The resulting novel composition
comprises
85.46% EPA, 5.84% DPA, 0.18% HPA, 91.48% omega-3-pentaenoic acids, less
than 0.01 /0 DHA, 93.26% total omega-3 fatty acids, 3.02% ARA, and 3.42% omega-
6 fatty acids (all Area%).
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Table 3. Fatty acid Composition (Area %) of intermediates and novel
composition according to Example 3
94.0% 6.0%
Fatty Acid Megapex E9ODOOEE
Maxomega DPA95FFA => EE Novel Composition
c18:0 0.05 0 0.05
c18:1n9 0.06 0 0.06
c18:1n7 0.02 0 0.02
c18:2n6 0.01 0 0.01
c18:3n6 0.02 0 0.02
c18:3n3 0.03 0 0.03
c18:4n3 0.42 0 0.39
c18:4n1 0.07 0 0.07
c20:0 0 0 0.00
c20:1n11 0 0 0.00
c20:1n9 0 0 0.00
c20:1n7 0 0 0.00
c20:2n6 0.25 0 0.24
c20:3n9 0 0 0.00
c20:3n6 0.15 0 0.14
c21:0 0 0 0.00
c20:4n6 3.21 0 3.02
c20:3n3 0 0 0.00
c20:4n3 1.44 0 1.35
c20:5n3 90.92 0 85.46
c22:0 0.3 0 0.28
c22:1n11 0.07 0 0.07
c22:1n9 0.18 0 0.17
c22:1n7 0.19 0 0.18
c21:5n3 0.19 0 0.18
c22:5n6 0 0 0.00
c22:5n3 0 97.27 5.84
c22:6n3 0 0 0.00
c24:0 0 0.33 0.02
OTHER 2.42 2.4 2.42
100 100 100
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[0121] Example 4
[0122] A composition according to the present invention is prepared by mixing
and
homogenizing in a ratio of 75:25 the intermediates MEGAPEX E9OD00EE (90% EPA
ethyl ester,) and MAXOMEGA DPA95 FFA (?.95% DPA synthetic fatty acid produced
from EPA ethyl ester concentrate, converted to ethyl ester, respectively.
These
intermediates were prepared and commercially offered for sale by Chemport
Korea
(MEGAPEX) and Equateq Ltd from Scotland, UK (MAXOMEGA). The relative
amounts of fatty acids present in the starting intermediates and in the
resulting novel
composition is listed in table 4 below. The resulting novel composition
comprises
68.10% EPA, 24.32% DPA, 0.19% HPA, 92.65% omega-3-pentaenoic acids, less
than 0.01% DHA, 94.07% total omega-3 fatty acids, 2.41% ARA and 2.73% omega-6
fatty acids (all Area%).
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Table 4. Fatty acid Composition (Area %) of intermediates and novel
composition according to Example 4
75.0% 25.0%
Fatty Acid Megapex E9OD00EE Maxomega DPA95FFA
=> EE Novel Composition
c18:0 0.05 0 0.04
c18:1n9 0.06 0 0.05
c18:1n7 0.02 0 0.02
c18:2n6 0.01 0 0.01
c18:3n6 0.02 0 0.02
c18:3n3 0.03 0 0.02
c18:4n3 0.42 o 0.32
c18:4n1 0.07 o 0.05
c20:0 0 o 0.00
c20:1n11 o 0 0.00
c20:1n9 o o 0.00
c20:1n7 o 0 0.00
c20:2n6 0.25 0 0.19
c20:3n9 o o 0.00
c20:3n6 0.15 0 0.11
c21:0 o o 0.00
c20:4n6 3.21 0 2.41
c20:3n3 0 0 0.00
c20:4n3 1.44 0 1.08
c20:5n3 90.92 0 68.19
c22:0 0.3 0 0.23
c22:1n11 0.07 o 0.05
c22:1n9 0.18 o 0.14
c22:1n7 0.19 o 0.14
c21:5n3 0.19 0 0.14
c22:5n6 0 0 0.00
c22:5n3 0 97.27 24.32
c22:6n3 o o 0.00
c24:0 0 0.33 0.08
OTHER 2.42 2.4 2.42
100 100 100
[0123] Example 5
[0124] A composition according to the present invention isprepared by mixing
and
homogenizing in a ratio of 60:40 the intermediates KD-PharmaKD-PUR 900EE and
MAXOMEGA DPA95 FFA converted to ethyl ester, respectively. These
intermediates were prepared and commercially offered for sale by KD-Pharma
Germany (KD-Pharma) and Equateq Ltd from Scotland, UK (MAXOMEGA). The
relative amounts of fatty acids present in the starting intermediates and in
the
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resulting novel composition is listed in table 5 below. The resulting novel
composition comprises 55.74% EPA, 39.26% DPA, 2.39% HPA, 97.44% omega-3-
pentaenoic acids, and 98.06% total omega-3 fatty acids (all Area%).
Table 5. Fatty acid Composition (Area %) of intermediates and novel
composition according to Example 5
60.0% 40.0%
Fatty Acid KD-Pur 900EE Maxomega DPA95FFA => EE
Novel Composition
c18:0 0 0 0.00
c18:1n9 o o 0.00
c18:1n7 0 o 0.00
c18:2n6 o o 0.00
c18:3n6 0 o 0.00
c18:3n3 0 o 0.00
c18:4n3 0 0 0.00
c18:4n1 o o 0.00
c20:0 0 0 0.00
c20:1n11 o 0 0.00
c20:1n9 o o 0.00
c20:1n7 0 0 0.00
c20:2n6 0 0 0.00
c20:3n9 o o 0.00
c20:3n6 o o 0.00
c21:0 0 o 0.00
c20:4n 6 0 0 0.00
c20:3n3 0 0 0.00
c20:4n3 1.04 o 0.62
c20:5n3 92.99 0 55.79
c22:0 0 0 0.00
c22:1n11 o o 0.00
c22:1n9 o o 0.00
c22:1n7 o 0 0.00
c21:5n3 3.98 o 2.39
c22:5n6 0 0 0.00
c22:5n3 0.58 97.27 39.26
c22:6n3 0 o 0.00
c24:0 0 0.33 0.13
OTHER 1.41 2.4 1.81
100.00 100 100.00
[0125] Example 6
[0126] A composition according to the present invention is prepared by mixing
and
homogenizing in a ratio of 96:4 the intermediates KD-PUR 900EE KD-Pharma and
MAXOMEGA DPA95 FFA converted to ethyl ester, respectively. These
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intermediates were prepared and commercially offered for sale by KD-Pharma
Germany (KD-Pharma) and Equateq Ltd from Scotland, UK (MAXOMEGA). The
relative amounts of fatty acids present in the starting intermediates and in
the
resulting novel composition is listed in table 6 below. The resulting novel
composition comprises 89.27% EPA, 4.45% DPA, 3.82% HPA, 97.54% omega-3-
pentaenoic acids, and 98.54% total omega-3 fatty acids (all Area%).
Table 6. Fatty acid Composition (Area %) of intermediates and novel
composition according to Example 6
96.0% 4.0%
Fatty Acid KD-Pur 900EE Maxomega DPA95FFA =>
EE Novel Composition
c18:0 0 0 0.00
c18:1n9 0 0 0.00
c18:1n7 0 0 0.00
c18:2n6 0 0 0.00
c18:3n 6 0 0 0.00
c18:3n3 0 0 0.00
c18:4n3 0 0 0.00
c18:4n1 o o 0.00
c20:0 0 0 0.00
c20:1n11 0 0 0.00
c20:1n9 0 o 0.00
c20:1n7 0 o 0.00
c20:2n6 0 0 0.00
c20:3n9 0 0 0.00
c20:3n6 o o 0.00
c21:0 0 0 0.00
c20:4n 6 0 0 0.00
c20:3n3 0 0 0.00
c20:4n3 1.04 0 1.00
c20:5n3 92.99 0 89.27
c22:0 0 0 0.00
c22:1n11 0 0 0.00
c22:1n9 0 0 0.00
c22:1n7 0 0 0.00
c21:5n3 3.98 0 3.82
c22:5n6 0 0 0.00
c22:5n3 0.58 97.27 4.45
c22:6n3 0 0 0.00
c24:0 0 0.33 0.01
OTHER 1.41 2.4 1.45
100.00 100 100.00
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[0127] Example 7
[0128] A composition according to the present invention is prepared by mixing
and
homogenizing in a ratio of 91.8:8.2 the intermediates KD-PUR 910EE KD-Pharma
and DPA95 FFA converted to ethyl ester, respectively. The relative amounts of
fatty
acids present in the starting intermediates and in the resulting novel
composition is
listed in table 7 below.
Table 7. Fatty acid Composition (Area %) of intermediates and novel
composition according to Example 7
91.8% 8.2%
Fatty Add KD-Pur EPA910EE DPA - 95% Est Novel
compositio N6 N3 ,
c18:0 0 0 0.00
c18:1n9 0 0 0.00
c18:1n7 0 0 0.00
c18:2n6 0 0 0.00 0.00
c18:3n6 0 0 0.00 0.00
c18:3n3 0 0 0.00 0.00
c18:4n3 0 0 0.00 0.00
c18:4n1 0 0 0.00
c20:0 0 0 0.00
c20:1n11 0.1 0 0.09
c20:1n9 0 0 0.00
c20:1n7 0 0 0.00
c20:2n6 0 0 0.00 0.00
c20:2n9 0 0.2 0.02
c20:3n9 0 0 0.00
c20:3n6 0 0 0.00 0.00
c21:0 0 0 0.00
c20:4n6 0.3 0 0.28 0.28
c20:3n3 0 0 0.00 0.00
c20:4n3 1.2 0.3 1.13 1.13
c20:5n3 92.5 0 85.34 85.34
c22:0 0.2 0 0.18
c22:1n11 0 0 0.00
c22:1n9 0 0 0.00
c22:1n7 0 0 0.00
c22:4n3 0 1.9 0.16 0.16
c21:5n3 3.3 0.1 3.08 3.08
c22:5n6 0 0 0.00 0.00
c22:5n3 0.2 97 8.16 8.16
c22:6n3 1.5 0 1.25 1.25
c24:0 0 0 0.00
OTHER 0.7 0.5 0.68
100.00 100 100.36 0.28 99.11
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[0129] Example 8
[0130] The ethyl ester composition of Example 4 may be converted into a free
fatty
acid composition with essentially the same fatty acid composition according to
"Conversion Method EE to FFA" below. This method is indiscriminate with
respect to
the type, degree of saturation or length of fatty acid if performed for an
adequate
amount of time under the described conditions.
Conversion Method EE to FFA
1. Fatty Acid Ethyl Ester (FAEE GMP, approx. 3mmol/g) oil is brought into a
closed heated/cooled reaction chamber under nitrogen atmosphere
(preferably with pressure control), and heated to 50-60 degree Celcius
under stirring.
2. 2M NaOH solution in water is added under firm stirring to ensure phase
mixing (est. 2-3 x FAEE w/w) and stir until no ethyl ester is presence (est.
2-4 hrs). Test ethyl ester presence at lab scale/in process with TLC
(hexanes/Et0Ac 9:1) and with EP GC method to confirm reaction
completion under GMP.
3. Under cooling (keep mixture below 70 degree Celcius), add 6M HCI in
water (est. <1 hr) until slightly acid (-pH3-4). It may be necessary to
control pressure to prevent excessive foaming. Then halt stirring, give
time to let phases separate, and remove water phase from bottom (keep
oil protected from oxygen, apply nitrogen atmosphere blanket).
4. Add demineralized water (est. 2-3 x FAEE w/w) and wash out NaCI and
ethanol from oil under firm stirring (est. -1hr). Halt stirring, give time to
let
phases separate, and remove water phase from bottom (keep oil protected
from oxygen, apply nitrogen atmosphere blanket).
5. Repeat Step 4 several times (-2x) to remove ethanol and Na CI.
6. Remove water and remaining ethanol [determine in-process controls],
confirm under GMP with USP residual solvent method (target: ethanol <
100ppm) by stirring oil while applying vacuum 10-50 mbar (with solvent
trap) and heat oil (70-80 degree celcius) until water/ethanol target is met
(est. 2-4 hrs).
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7. Add anti-oxidants (i.e. alpha-D-tocopherol, USP, target 4 mg/g) and/or
other excipients.
8. All reagents and excipients USP grade.
[0131] Example 9
[0132] The ethyl ester composition of Example 3 is converted into a free fatty
acid
composition with essentially the same fatty acid composition according to
"Conversion Method EE to FFA" above. This method is indiscriminate with
respect
to the type, degree of saturation or length of fatty acid if performed for an
adequate
amount of time under the described conditions.
[0133] Example 10
[0134] The ethyl ester composition of Example 6 is converted into a free fatty
acid
composition with essentially the same fatty acid composition according to
"Conversion Method EE to FFA" above. This method is indiscriminate with
respect
to the type, degree of saturation or length of fatty acid if performed for an
adequate
amount of time under the described conditions.
[0135] Example 11
[0136] The composition of Example 4 is formulated into a soft gelatin capsule.
Prior
to encapsulation, an anti-oxidant preparation (composed of 4000 mg alpha-D-
tocopherol in one liter of corn oil; corn oil is a triglyceride low in omega-
3) is added to
the composition of Example 4, by mixing and homogenizing 100mL of this anti-
oxidant preparation into 100 liters of the oil composition of Example 4
followed by
thorough homogenization. The resulting pre-encapsulation formulated oil
contains
approximately 4mg/gram alpha-D-tocopherol. Subsequently, the formulated oil is
encapsulated into soft gelatin capsules with printed logo according to general
methods typically used by Accucaps in Canada for fish oils or by any other
documented and operational encapsulation method. The fill mass of the oil is
approximately 1.08 gram/capsule, providing a dose of approximately 1000mg
omega-3-pentaenoic-acids ethyl esters per capsule. Finally, the capsules are
bottled
in HDPE bottles with induction seal and child resistant cap.
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[0137] Example 12
[0138] The composition of Example 9 is formulated into a soft gelatin capsule.
Prior
to encapsulation, an anti-oxidant preparation (composed of 4000 mg alpha-D-
tocopherol in one liter of corn oil; corn oil is a triglyceride low in omega-
3) is added to
the composition of Example 4, by mixing and homogenizing 100mL of this anti-
oxidant preparation into 100 liters of the oil composition of Example 4
followed by
thorough homogenization. The resulting pre-encapsulation formulated oil
contains
approximately 4mg/gram alpha-D-tocopherol. Subsequently, the formulated oil is
encapsulated into soft gelatin capsules with printed logo according to general
methods typically used by Banner in High Point, NC, for fish oils or by any
other
documented and operational encapsulation method. The fill mass of the oil is
approximately 1.09 gram/capsule, providing a dose of approximately 1000mg
omega-3-pentaenoic-acids per capsule. Finally, the capsules are bottled in
HDPE
bottles with induction seal and child resistant cap.
[0139] Example 13
[0140] The composition of Example 5 is formulated into a soft gelatin capsule.
Prior
to encapsulation, an anti-oxidant preparation (composed of 4000 mg alpha-D-
tocopherol in one liter of corn oil; corn oil is a triglyceride low in omega-
3) is added to
the composition of Example 4, by mixing and homogenizing 100mL of this anti-
oxidant preparation into 100 liters of the oil composition of Example 4
followed by
thorough homogenization. The resulting pre-encapsulation formulated oil
contains
approximately 4mg/gram alpha-D-tocopherol. Subsequently, the formulated oil is
encapsulated into soft gelatin capsules with printed logo according to general
methods typically used by Catelent in St.Petersburg, FL, for fish oils or by
any other
documented and operational encapsulation method. The fill mass of the oil is
approximately 1.05 gram/capsule, providing a dose of approximately 1000mg
omega-3-pentaenoic-acids ethyl esters per capsule. Finally, the capsules are
bottled
in HDPE bottles with induction seal and child resistant cap.
[0141] Example 14
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[0142] The composition of Example 10 is formulated into a soft gelatin
capsule.
Prior to encapsulation, an anti-oxidant preparation (composed of 4000 mg alpha-
D-
tocopherol in one liter of corn oil; corn oil is a triglyceride low in omega-
3) is added to
the composition of Example 4, by mixing and homogenizing 100mL of this anti-
oxidant preparation into 100 liters of the oil composition of Example 4
followed by
thorough homogenization. The resulting pre-encapsulation formulated oil
contains
approximately 4mg/gram alpha-D-tocopherol. Subsequently, the formulated oil is
encapsulated into soft gelatin capsules with printed logo according to general
methods typically used by Banner in High Point, NC, for fish oils or by any
other
documented and operational encapsulation method. The fill mass of the oil is
1.06
gram/capsule, providing a dose of approximately 1000mg omega-3-pentaenoic-
acids
per capsule. Finally, the capsules are bottled in HDPE bottles with induction
seal
and child resistant cap.
[0143] Example 15
[0144] A patient is diagnosed with vascular disease. Thereupon, the patient
may
be initiated on daily treatment with one of the encapsulated compositions
according
to Examples 10, 11, 12 or 13. Four capsules per day are administered to this
patient
(4g/d).
[0145] Example 16
[0146] A patient is treated as per Example 15. The treatment results in
significant
reduction of the occurrence of MACE.
[0147] Example 17
[0148] The following are examples of preferred embodiments of the present
invention.
COMPOSITION la
Composition Minimum Maximum
Target (mg/g)
(mg/g) (mg/g)
Omega-3 pentaenoic acid 880 980 930
Eicosapentaenoic acid (EPA) 800 950 850
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Heneicosapentaenoic acid (HPA) 5 60 30
Docosapentaenoic acid (DPA) 60 100 80
Docosahexaenoic acid (DHA) 25 <10
COMPOSITION lb
Composition Minimum Maximum
Target (mg/g)
(mg/g) (mg/g)
Omega-3 pentaenoic acid 870 990 920
Eicosapentaenoic acid (EPA) 750 950 830
Heneicosapentaenoic acid (HPA) 5 70 40
Docosapentaenoic acid (DPA) 50 130 90
Docosahexaenoic acid (DHA) 40 20
In COMPOSITIONS la and 1 b, the EPA:HPA ratio is between 13 and 190, the
EPA:DPA ratio is between 8 and 15, the HPA:DPA ration between 0.05 and 1, the
DPA:DHA ratio more than 2.4, preferably more than 4, more preferably more than
6,
most preferably more than 10, and the EPA:DHA ratio more than 32, preferably
more
than 38, more preferably more than 80, most preferably more than 95. The EPA,
HPA, DPA and DHA may be composed as a glyceride (such as triglyceride), an
ester
(such as ethyl ester), or a free fatty acid.
[0149] Example 18
[0150] The following is an example of a preferred embodiment of the present
invention.
COMPOSITION 2
Composition Minimum Maximum
Target (mg/g)
(mg/g) (mg/g)
Omega-3 pentaenoic acid 900 980 940
Eicosapentaenoic acid (EPA) 15 60 30
Heneicosapentaenoic acid (HPA) 5 60 30
Docosapentaenoic acid (DPA) 800 950 880
Docosahexaenoic acid (DHA) 25 <10
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In COMPOSITION 2, the EPA:HPA ratio is between 0.25 and 12, the DPA:EPA ratio
is between 13 and 63, the DPA:HPA ration between 13 and 190, the DPA:DHA ratio
more than 32, preferably more than 38, more preferably more than 80, most
preferably more than 95, and the EPA:DHA ratio more than 00.6, preferably more
than 1.5, more preferably more than 2.4, most preferably more than 6. The EPA,
HPA, DPA and DHA may be composed as a glyceride (such as triglyceride), an
ester
(such as ethyl ester), or a free fatty acid.
[0151] Example 19
[0152] The following is an example of an embodiment of the present invention.
COMPOSITION 3
Composition Minimum Maximum
Target (mg/g)
(mg/g) (mg/g)
Docosapentaenoic acid (DPA n-3) 800 990 920
The DPA may be composed as a glyceride (such as triglyceride), an ester (such
as
ethyl ester), or a free fatty acid.
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[0153] Example 20
[0154] The following is an example of an embodiment of the present invention.
COMPOSITION 4
Composition Minimum Maximum
Target (mg/g)
(mg/g) (mg/g)
Omega-3 pentaenoic acid 930 1000 966
Eicosapentaenoic acid (EPA) 840 870 853
Heneicosapentaenoic acid (HPA) 20 40 30
Docosapentaenoic acid (DPA) 60 100 81
Docosahexaenoic acid (DHA) 5 20 12
[0155] Example 21
[0156] A mixture of DPA and EPA was prepared by combining 1g DPA Ethyl Ester
(SE-133-11I) with 10g EPA Ethyl Ester, 914 mg/g (KD Pharma FM13001) in 150m1
of
95% ethanol/water containing 35ml of 2M sodium hydroxide. This reaction
mixture
was stirred overnight at ambient temperature. TIc analysis showed complete
conversion of the ethyl esters to the corresponding acids. The reaction
mixture was
cooled in an ice bath, acidified with 6N hydrochloric acid and concentrated on
a
rotavap under reduced pressure. Water and ethyl acetate were added, the phases
separated and the aqueous residue extracted with ethyl acetate. The ethyl
acetate
extracts were combined, dried over sodium sulfate and concentrated to dryness
on a
rotavap under reduced pressure. Yield: 9.83 g . The ethyl ester mixture was
then
converted to the free fatty acids as described in Example 8.
[0157] A representative sample of this ethyl ester composition was analysed
using
split inject by capillary gas chromatography by a 30 meter x 0.25 mm Restek
Stabil
wax column using temperature programming.
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[0158] DESCRIPTION OF EMBODIMENTS OF THE PRESENT INVENTION
1. A fatty acid composition comprising at least 50% omega-3-fatty acids, salts
or
derivatives thereof, while comprising eicosapentaenoic acid (EPA; C20:5-n3)
and
docosapentaenoic acid (DPA; C22:5-n3) and wherein the EPA:DHA ratio is
higher than 20:1.
2. A fatty acid composition comprising at least 60% omega-3-fatty acids, salts
or
derivatives thereof, while comprising eicosapentaenoic acid (EPA; C20:5-n3)
and
docosapentaenoic acid (DPA; C22:5-n3) and wherein the EPA:DHA ratio is
higher than 20:1.
3. A fatty acid composition comprising at least 70% omega-3-fatty acids, salts
or
derivatives thereof, while comprising eicosapentaenoic acid (EPA; C20:5-n3)
and
docosapentaenoic acid (DPA; C22:5-n3) and wherein the EPA:DHA ratio is
higher than 20:1.
4. A fatty acid composition comprising at least 75% omega-3-fatty acids, salts
or
derivatives thereof, while comprising eicosapentaenoic acid (EPA; C20:5-n3)
and
docosapentaenoic acid (DPA; C22:5-n3) and wherein the EPA:DHA ratio is
higher than 20:1.
5. A fatty acid composition comprising at least 80% omega-3-fatty acids, salts
or
derivatives thereof, while comprising eicosapentaenoic acid (EPA; C20:5-n3)
and
docosapentaenoic acid (DPA; C22:5-n3) and wherein the EPA:DHA ratio is
higher than 20:1.
6. A fatty acid composition comprising at least 85% omega-3-fatty acids, salts
or
derivatives thereof, while comprising eicosapentaenoic acid (EPA; C20:5-n3)
and
docosapentaenoic acid (DPA; C22:5-n3) and wherein the EPA:DHA ratio is
higher than 20:1.
7. A fatty acid composition comprising at least 90% omega-3-fatty acids, salts
or
derivatives thereof, while comprising eicosapentaenoic acid (EPA; C20:5-n3)
and
docosapentaenoic acid (DPA; C22:5-n3) and wherein the EPA:DHA ratio is
higher than 20:1.
8. A fatty acid composition comprising at least 95% omega-34atty acids, salts
or
derivatives thereof, while comprising eicosapentaenoic acid (EPA; C20:5-n3)
and
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docosapentaenoic acid (DPA; C22:5-n3) and wherein the EPA:DHA ratio is
higher than 20:1.
9. A composition according to one of the preferred embodiments 1 through 8,
comprising at least 2% docosapentaenoic acid (DPA; C22:5-n3).
10.A composition according to one of the preferred embodiments 1 through 8,
comprising at least 4% docosapentaenoic acid (DPA; C22:5-n3).
11.A composition according to one of the preferred embodiments 1 through 8,
comprising at least 5% docosapentaenoic acid (DPA; C22:5-n3).
12.A composition according to one of the preferred embodiments 1 through 8,
comprising at least 6% docosapentaenoic acid (DPA; C22:5-n3).
13.A composition according to one of the preferred embodiments 1 through 8,
comprising at least 7% docosapentaenoic acid (DPA; C22:5-n3).
14.A composition according to one of the preferred embodiments 1 through 8,
comprising at least 8% docosapentaenoic acid (DPA; C22:5-n3).
15.A composition according to one of the preferred embodiments 1 through 8,
comprising at least 10% docosapentaenoic acid (DPA; C22:5-n3).
16.A composition according to one of the preferred embodiments 1 through 8,
comprising at least 12% docosapentaenoic acid (DPA; C22:5-n3).
17.A composition according to one of the preferred embodiments 1 through 8,
comprising at least 15% docosapentaenoic acid (DPA; C22:5-n3).
18.A composition according to one of the preferred embodiments 1 through 17,
comprising no more than 95% EPA.
19.A composition according to one of the preferred embodiments 1 through 17,
comprising no more than 10% omega-6 fatty acids.
20.A composition according to one of the preferred embodiments 1 through 17,
comprising no more than 7% omega-6 fatty acids.
21.A composition according to one of the preferred embodiments 1 through 17,
comprising no more than 5% omega-6 fatty acids.
22.A composition according to one of the preferred embodiments 1 through 17,
comprising no more than 3% omega-6 fatty acids.
23.A composition according to one of the preferred embodiments 1 through 22,
comprising no more than 5% arachidonic acid (C22:4-n6).
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24.A composition according to one of the preferred embodiments 1 through 22,
comprising no more than 4% arachidonic acid (C22:4-n6).
25.A composition according to one of the preferred embodiments 1 through 22,
comprising no more than 3% arachidonic acid (C22:4-n6).
26.A composition according to one of the preferred embodiments 1 through 22,
comprising no more than 2% arachidonic acid (C22:4-n6).
27.A composition according to one of the preferred embodiments 1 through 22,
comprising no more than 1% arachidonic acid (C22:4-n6).
28.A composition according to one of the preferred embodiments 1 through 27,
also
comprising heneicosapentaenoic acid (C21:5-n3).
29.A composition according to one of the preferred embodiments 1 through 27,
comprising at least 0.01 /o heneicosapentaenoic acid (C21:5-n3).
30.A composition according to one of the preferred embodiments 1 through 27,
comprising at least 0.1% heneicosapentaenoic acid (C21:5-n3).
31.A composition according to one of the preferred embodiments 1 through 27,
comprising at least 0.3% heneicosapentaenoic acid (C21:5-n3).
32.A composition according to one of the preferred embodiments 1 through 27,
comprising at least 0.5% heneicosapentaenoic acid (C21:5-n3).
33.A composition according to one of the preferred embodiments 1 through 27,
comprising at least 1% heneicosapentaenoic acid (C21:5-n3).
34.A composition according to one of the preferred embodiments 1 through 27,
comprising at least 2% heneicosapentaenoic acid (C21:5-n3).
35.A composition according to one of the preferred embodiments 1 through 27,
comprising at least 3% heneicosapentaenoic acid (C21:5-n3).
36.A composition according to one of the preferred embodiments 1 through 27,
comprising at least 4% heneicosapentaenoic acid (C21:5-n3).
37.A composition according to one of the preferred embodiments 1 through 27,
comprising at least 5% heneicosapentaenoic acid (C21:5-n3).
38.A composition according to one of the preferred embodiments 1 through 37,
comprising no more than 5% omega-3 fatty acids that are not omega-3-
pentaenoic acids.
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39.A composition according to one of the preferred embodiments 1 through 37,
comprising no more than 4% omega-3 fatty acids that are not omega-3-
pentaenoic acids.
40.A composition according to one of the preferred embodiments 1 through 37,
comprising no more than 3% omega-3 fatty acids that are not omega-3-
pentaenoic acids.
41.A composition according to one of the preferred embodiments 1 through 37,
comprising no more than 2% omega-3 fatty acids that are not omega-3-
pentaenoic acids.
42.A composition according to one of the preferred embodiments 1 through 37,
comprising no more than 1.5% omega-3 fatty acids that are not omega-3-
pentaenoic acids.
43.A composition according to one of the preferred embodiments 1 through 37,
comprising no more than 1.25% omega-3 fatty acids that are not omega-3-
pentaenoic acids.
44.A composition according to one of the preferred embodiments 1 through 37,
comprising no more than 1% omega-3 fatty acids that are not omega-3-
pentaenoic acids.
45.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 99:1 and 1:99.
46.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 60:1 and 1:60.
47.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 50:1 and 1:10.
48.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 40:1 and 1:3.
49.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 40:1 and 1:2.
50.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 40:1 and 1:1.
51.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 30:1 and 1:1.
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52.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 20:1 and 1:1.
53.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 10:1 and 1:1.
54.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 5:1 and 1:1.
55.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 10:1 and 2:1.
56.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 20:1 and 2:1.
57.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 30:1 and 2:1.
58.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 40:1 and 2:1.
59.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 50:1 and 2:1.
60.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 10:1 and 3:1.
61.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 20:1 and 3:1.
62.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 30:1 and 3:1.
63.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 40:1 and 3:1.
64.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 50:1 and 3:1.
65.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 60:1 and 3:1.
66.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 10:1 and 5:1.
67.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 20:1 and 5:1.
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68.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 30:1 and 5:1.
69.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 40:1 and 5:1.
70.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 50:1 and 5:1.
71.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 60:1 and 5:1.
72.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 20:1 and 10:1.
73.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 30:1 and 10:1.
74.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 40:1 and 10:1.
75.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 50:1 and 10:1.
76.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 60:1 and 10:1.
77.A composition according to one of the preferred embodiments 1 through 44,
wherein the EPA:DPA ratio is between 100:1 and 10:1.
78.A composition according to one of the preferred embodiments 1 through 44,
comprising between 55% and 95% EPA.
79.A composition according to one of the preferred embodiments 1 through 44,
comprising between 60% and 95% EPA.
80.A composition according to one of the preferred embodiments 1 through 44,
comprising between 65% and 95% EPA.
81.A composition according to one of the preferred embodiments 1 through 44,
comprising between 70% and 95% EPA.
82.A composition according to one of the preferred embodiments 1 through 44,
comprising between 75% and 95% EPA.
83.A composition according to one of the preferred embodiments 1 through 44,
comprising between 80% and 95% EPA.
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84.A composition according to one of the preferred embodiments 1 through 44,
comprising between 85% and 95% EPA.
85.A composition according to one of the preferred embodiments 1 through 44,
comprising between 90% and 95% EPA.
86.A composition according to one of the preferred embodiments 1 through 44,
comprising between 1% and 3% DPA.
87.A composition according to one of the preferred embodiments 1 through 44,
comprising between 1% and 5% DPA.
88.A composition according to one of the preferred embodiments 1 through 44,
comprising between 2% and 10% DPA.
89.A composition according to one of the preferred embodiments 1 through 44,
comprising between 3% and 20% DPA.
90.A composition according to one of the preferred embodiments 1 through 44,
comprising between 3% and 30% DPA.
91.A composition according to one of the preferred embodiments 1 through 44,
comprising between 3% and 50% DPA.
92.A composition according to one of the preferred embodiments 1 through 44,
comprising between 3% and 75% DPA.
93.A composition according to one of the preferred embodiments 1 through 44,
comprising between 3% and 90% DPA.
94.A fatty acid composition according to one of the preferred embodiments 1
through 93, in which the fatty acids are present as ethyl esters.
95.A fatty acid composition according to one of the preferred embodiments 1
through 93, in which the fatty acids are present as free fatty acids.
96.A fatty acid composition according to one of the preferred embodiments 1
through 93, in which the fatty acids are present as esters in di-glyceride
form.
97.A fatty acid composition according to one of the preferred embodiments 1
through 93, in which the fatty acids are present as esters in triglyceride
form.
98.A fatty acid composition according to one of the preferred embodiments 94
through 97, also comprising a suitable anti-oxidant in a concentration
sufficient to
protect the fatty acids of the composition from oxidation.
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99.A pharmaceutically suitable formulation comprising one of the compositions
according to preferred embodiments 94 through 98, in which the amount of
eicosapentaenoic acid plus docosapentaenoic acid is present in an amount
between 100 and 10,000 mg.
100. A pharmaceutically suitable formulation or dosage form comprising one of
the
compositions according to preferred embodiments 94 through 98, in which the
amount of eicosapentaenoic acid plus docosapentaenoic acid is present in an
amount between 250 and 1,250 mg.
101. A pharmaceutically suitable formulation or dosage form comprising one of
the
compositions according to preferred embodiments 94 through 98, in which the
amount of eicosapentaenoic acid plus docosapentaenoic acid is present in an
amount between 500 and 1,100 mg.
102. A pharmaceutically suitable formulation or dosage form comprising one of
the
compositions according to preferred embodiments 94 through 98, in which the
amount of eicosapentaenoic acid plus docosapentaenoic acid is present in an
amount between 100 and 10,000 mg.
103. A method of administration or treatment to a subject of a formulation or
dosage form according to one of the preferred embodiments 94 through 102 at a
daily dose between 100 and 10,000 mg.
104. A method of administration or treatment to a subject of a formulation or
dosage form according to one of the preferred embodiments 94 through 102 at a
daily dose between 500 and 5,000 mg.
105. A method of administration or treatment to a subject of a formulation or
dosage form according to one of the preferred embodiments 94 through 102 at a
daily dose between 1,500 and 4,100 mg.
106. A method of treatment according to preferred e embodiments 103 through
105, in which the subject is a patient diagnosed with very high triglycerides
(equal
or more than 500 mg/dL).
107. A method of treatment according to preferred embodiments 103 through 105,
in which the subject is a patient diagnosed with high triglycerides (equal to
or
more than 200 mg/dL but less than 500 mg/dL).
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108. A method of treatment according to preferred embodiments 103 through 105,
in which the subject is a patient already undergoing treatment with a statin
and
then diagnosed with high triglycerides (equal to or more than 200 mg/dL but
less
than 500 mg/dL).
109. A method of treatment according to preferred embodiments 103 through 105,
in which the subject is a patient diagnosed with mixed dyslipidemia with TG
200-
499 mg/dL and LDL-cholesterol equal to or more than 190 mg/dL.
110. A method of treatment according to preferred embodiments 103 through 105,
in which the subject is a patient diagnosed with mixed dyslipidemia with TG
300-
700 mg/dL and LDL-cholesterol equal to or more than 190 mg/dL.
111. A method of treatment according to preferred embodiments 103 through 105,
in which the subject is a patient diagnosed with mixed dyslipidemia with TG
200-
499 mg/dL and non-HDL-cholesterol equal to or more than 200 mg/dL.
112. A method of treatment according to preferred embodiments 103 through 105,
in which the subject is a patient diagnosed with mixed dyslipidemia with TG
300-
700 mg/dL and non-HDL-cholesterol equal to or more than 200 mg/dL.
113. A method of treatment according to preferred embodiments 103 through 105,
in which the subject is a patient diagnosed with mixed dyslipidemia with TG
200-
499 mg/dL and LDL-cholesterol equal to or more than 160 mg/dL.
114. A method of treatment according to preferred embodiments 103 through 105,
in which the subject is a patient diagnosed with mixed dyslipidemia with TG
300-
700 mg/dL and LDL-cholesterol equal to or more than 160 mg/dL.
115. A method of treatment according to preferred embodiments 103 through 105,
in which the subject is a patient diagnosed with mixed dyslipidemia with TG
200-
499 mg/dL and non-HDL-cholesterol equal to or more than 160 mg/dL.
116. A method of treatment according to preferred embodiments 103 through 105,
in which the subject is a patient diagnosed with mixed dyslipidemia with TG
300-
700 mg/dL and non-HDL-cholesterol equal to or more than 160 mg/dL.
117. A method of treatment according to preferred embodiments 103 through 105,
in which the subject is a patient diagnosed with mixed dyslipidemia with TG
200-
499 mg/dL and LDL-cholesterol equal to or more than 130 mg/dL.
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118. A method of treatment according to preferred embodiments 103 through 105,
in which the subject is a patient diagnosed with mixed dyslipidemia with TG
300-
700 mg/dL and LDL-cholesterol equal to or more than 130 mg/dL.
119. A method of treatment according to preferred embodiments 103 through 105,
in which the subject is a patient diagnosed with mixed dyslipidemia with TG
200-
499 mg/dL and non-HDL-cholesterol equal to or more than 130 mg/dL.
120. A method of treatment according to preferred embodiments 103 through 105,
in which the subject is a patient diagnosed with mixed dyslipidemia with TG
300-
700 mg/dL and non-HDL-cholesterol equal to or more than 130 mg/dL.
121. A method of treatment according to preferred embodiments 103 through 105,
in which the subject is a patient diagnosed/assessed to be at substantially
elevated risk for cardiovascular events.
122. A method of treatment according to preferred embodiments 103 through 105,
in which the subject is a patient diagnosed with diabetes.
123. A method of treatment according to preferred embodiments 103 through 105,
in which the subject is a patient diagnosed with pre-diabetes or metabolic
syndrome.
124. A method of treatment according to one of the preferred embodiments 103
through 123, in which the treatment results in significant reduction of blood,
serum or plasma triglyceride levels.
125. A method of treatment according to one of the preferred embodiments 103
through 123, in which the treatment results in significant reduction of blood,
serum or plasma triglyceride levels while not significantly increasing blood,
serum or plasma LDL-cholesterol levels.
126. A method of treatment according to one of the preferred embodiments 103
through 123, in which the treatment results in significant reduction of blood,
serum or plasma total-cholesterol levels.
127. A method of treatment according to one of the preferred embodiments 103
through 123, in which the treatment results in significant reduction of blood,
serum or plasma non-HDL-cholesterol levels.
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128. A method of treatment according to one of the preferred embodiments 103
through 123, in which the treatment results in significant reduction of blood,
serum or plasma LDL-cholesterol levels.
129. A method of treatment according to one of the preferred embodiments 103
through 123, in which the treatment results in significant reduction of blood,
serum or plasma VLDL-cholesterol levels.
130. A method of treatment according to one of the preferred embodiments 103
through 123, in which the treatment results in significant reduction of blood,
serum or plasma VLDL-cholesterol levels while not significantly increasing
blood, serum or plasma LDL-cholesterol levels.
131. A method of treatment according to one of the preferred embodiments 103
through 123, in which the treatment results in significant reduction of blood,
serum or plasma apo-B levels.
132. A method of treatment according to one of the preferred embodiments 103
through 123, in which the treatment results in significant reduction of blood,
serum or plasma apo-C-III levels.
133. A method of treatment according to one of the preferred embodiments 103
through 123, in which the treatment results in significant reduction of blood,
serum or plasma LP-PLA2 levels.
134. A method of treatment according to one of the preferred embodiments 103
through 123, in which the treatment results in significant reduction of blood,
serum or plasma hs-CRP levels.
135. A method of treatment according to one of the preferred embodiments 103
through 123, in which the treatment results in significant increase of blood,
serum or plasma HDL-cholesterol levels.
136. A method of treatment according to one of the preferred embodiments 103
through 123, in which the treatment results in significant increase of blood,
serum or plasma apo-A levels.
137. A method of treatment according to one of the preferred embodiments 103
through 123, in which the treatment results in significant reduction of the
risk of
suffering certain cardiovascular events.
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138. The composition of claim 1, wherein the ratio of EPA to DPA (EPA:DPA) is
between 15:1 to 8:1.
139. An orally administrable composition comprising fatty acids, wherein at
least
50% by weight of the fatty acids comprise omega-3-pentaenoic acids, salts,
esters,
or derivatives thereof, wherein the composition comprises eicosapentaenoic
acid
(EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA), and
wherein the ratio of DHA to EPA (DHA:EPA) is less than 1:20, and wherein the
ratio
of DHA to DPA (DHA:DPA) is less than 2:1.
