U.S. patent application number 14/109338 was filed with the patent office on 2014-04-17 for omega-3 pentaenoic acid compositions and methods of use.
This patent application is currently assigned to MATINAS BIOPHARMA, INC.. The applicant listed for this patent is MATINAS BIOPHARMA, INC.. Invention is credited to GEORGE BOBOTAS, ABDEL AZIZ FAWZY, IHOR TERLECKYJ.
Application Number | 20140107200 14/109338 |
Document ID | / |
Family ID | 49769263 |
Filed Date | 2014-04-17 |
United States Patent
Application |
20140107200 |
Kind Code |
A1 |
FAWZY; ABDEL AZIZ ; et
al. |
April 17, 2014 |
OMEGA-3 PENTAENOIC ACID COMPOSITIONS AND METHODS OF USE
Abstract
Orally administrable composition comprising fatty acids
comprising omega-3-fatty adds, salts or derivatives thereof are
provided. These compositions can be used for the treatment or
prophylaxis of dyslipidemic, cardiovascular, CNS, inflammatory, and
other diseases/conditions or risk factors therefore.
Inventors: |
FAWZY; ABDEL AZIZ; (BOYNTON
BEACH, FL) ; BOBOTAS; GEORGE; (TARPON SPRINGS,
FL) ; TERLECKYJ; IHOR; (BERWYN, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MATINAS BIOPHARMA, INC. |
BEDMINSTER |
NJ |
US |
|
|
Assignee: |
MATINAS BIOPHARMA, INC.
BEDMINSTER
NJ
|
Family ID: |
49769263 |
Appl. No.: |
14/109338 |
Filed: |
December 17, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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PCT/US13/46176 |
Jun 17, 2013 |
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14109338 |
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61780948 |
Mar 13, 2013 |
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61734331 |
Dec 6, 2012 |
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61660757 |
Jun 17, 2012 |
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Current U.S.
Class: |
514/549 ;
514/560 |
Current CPC
Class: |
A61K 9/4825 20130101;
A61K 31/232 20130101; A61P 3/06 20180101; A61K 31/202 20130101;
A61K 31/201 20130101; A61K 9/4858 20130101; A61P 9/00 20180101;
A61K 31/40 20130101; Y10S 514/893 20130101; A61K 31/202 20130101;
A61K 2300/00 20130101; A61K 31/40 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/549 ;
514/560 |
International
Class: |
A61K 31/202 20060101
A61K031/202; A61K 31/232 20060101 A61K031/232 |
Claims
1. A method of treating, preventing, reducing the occurrence of,
and improving symptoms associated with a liver-related disease or
condition in a subject in need thereof, comprising administering to
the subject a 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.
2. The method of claim 1, wherein the liver-related disease or
condition is selected from the group consisting of: fatty liver,
non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver
disease (NAFLD), alcoholic steatohepatitis (ASH), hepatitis, HIV
(human immunodeficiency virus) infection, drug-induced fatty liver
or sequelae, liver failure, liver transplantation, transplanted
liver failure, liver damage associated with renal failure or
disease, abnormally elevated liver enzymes, or type 2 diabetes.
3. The method of claim 1, wherein the ratio of DHA:EPA is less than
1:20.
4. The method of claim 1, wherein the ratio of DHA:DPA is less than
1:1.
5. The method of claim 1, wherein the ratio of EPA to DPA (EPA:DPA)
is between 30:1 and 1:1.
6. The method of claim 1, wherein ratio of DHA:EPA is less than
1:10.
7. The method of claim 1, wherein the composition comprises DHA in
an amount less than 5% of the total amount of fatty acids.
8. The method of claim 1, wherein the composition comprises EPA in
an amount between about 80% and about 90% of the total amount of
fatty acids.
9. The method of claim 1, wherein the composition comprises DPA in
an amount between about 5% and about 15% of the total amount of
fatty acids.
10. The method of claim 1, wherein the composition comprises DPA
free fatty acid or a salt, ester or derivative of DPA.
11. The method of claim 1, wherein composition comprises EPA free
fatty acid or a salt, ester or derivative of EPA.
12. A method of treating, preventing, reducing the occurrence of,
and improving symptoms associated with a liver-related disease or
condition in a subject in need thereof, comprising administering to
the subject a composition comprising eicosapentaenoic acid (EPA) in
an amount between about 750 mg/g to about 950 mg/g, and wherein the
composition comprises no more than 5% DHA of the total amount of
fatty acids, and and wherein the ratio of DHA:DPA is 1:1 or
lower.
13. The method of claim 12, wherein the liver-related disease or
condition is selected from the group consisting of; fatty liver,
non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver
disease (NAFLD), alcoholic steatohepatitis (ASH), hepatitis, HIV
(human immunodeficiency virus) infection, drug-induced fatty liver
or sequelae, liver failure, liver transplantation, transplanted
liver failure, liver damage associated with renal failure or
disease, abnormally elevated liver enzymes, or type 2 diabetes.
14. The method of claim 12, wherein the composition comprises
eicosapentaenoic acid (EPA) in an amount between about 800 mg/g to
about 900 mg/g, and wherein the composition comprises no more than
5% DHA of the total amount of fatty acids, and and wherein the
ratio of DHA:DPA is 1:1 or lower.
15. The method of claim 12, wherein the composition comprises
eicosapentaenoic acid (EPA) in an amount between about 830 mg/g to
about 870 mg/g, and wherein the composition comprises no more than
5% DHA of the total amount of fatty acids, and and wherein the
ratio of DHA:DPA is 1:1 or lower.
16. The method of claim 12, wherein the composition comprises
docosapentaenoic acid (DPA) is an amount between about 60 mg/g to
about 120 mg/g.
17. The method of claim 1, wherein the composition comprises
docosapentaenoic acid (DPA) is an amount between about 70 mg/g to
about 100 mg/g.
18. A method of treating, preventing, reducing the occurrence of,
and improving symptoms associated with a liver-related disease or
condition in a subject in need thereof, comprising administering to
the subject a 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.
19. The method of claim 18, wherein the liver-related disease or
condition is selected from the group consisting of: fatty liver,
non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver
disease (NAFLD), alcoholic steatohepatitis (ASH), hepatitis, HIV
(human immunodeficiency virus) infection, drug-induced fatty liver
or sequelae, liver failure, liver transplantation, transplanted
liver failure, liver damage associated with renal failure or
disease, abnormally elevated liver enzymes, or type 2 diabetes.
20. The method of claim 18, wherein the composition comprises
eicosapentaenoic acid (EPA) in an amount between about 80% to about
90% of the total amount of fatty acids.
21. The method of 18, wherein the composition comprises
eicosapentaenoic acid (EPA) in an amount between about 82% to about
88% of the total amount of fatty acids.
22. The method of 18, wherein the composition comprises
docosapentaenoic acid (DPA) in amount between about 5% and about
15% of the total amount of fatty acids.
23. The method of 18, wherein the composition comprises
docosapentaenoic acid (DPA) in an amount between about 6% to about
12% of the total amount of fatty acids.
24. The method of claim 18, wherein the composition comprises EPA
free fatty acid or a salt, ester or derivative of EPA.
25. A method of treating, preventing, reducing the occurrence of,
and improving symptoms associated with a liver-related disease or
condition in a subject in need thereof, comprising administering to
the subject a 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.
26. The method of claim 25, wherein the liver-related disease or
condition is selected from the group consisting of: fatty liver,
non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver
disease (NAFLD), alcoholic steatohepatitis (ASH), hepatitis, HIV
(human immunodeficiency virus) infection, drug-induced fatty liver
or sequelae, liver failure, liver transplantation, transplanted
liver failure, liver damage associated with renal failure or
disease, abnormally elevated liver enzymes, or type 2 diabetes.
27. The method of claim 25, wherein the composition comprises
eicosapentaenoic acid (EPA) in a daily dosage amount selected from
the group consisting of: about 1735 mg to about 1855 mg, about 2520
mg to about 2780 mg, and about 3360 mg to about 3710 mg.
28. The method of claim 25, wherein the composition comprises
eicosapentaenoic acid (EPA) in a daily dosage amount selected from
the group consisting of: about 1750 mg to about 1950 mg, about 1800
mg to about 2000 mg about 2650 mg to about 2950 mg, and about 3500
mg to about 3900 mg.
29. The method of claim 25, wherein the composition comprises
eicosapentaenoic acid (EPA) in daily dosage amount selected from
the group consisting of: about 1900 mg to about 2100 mg, about 2700
mg to about 3300 mg, and about 3700 mg to about 4300 mg.
30. The method of claim 25, wherein the composition comprises EPA
free fatty acid or a salt, ester or derivative of EPA.
31. The method of claim 25, wherein the composition comprises DPA
free fatty acid or a salt, ester or derivative of DPA.
32. A method of treating, preventing, reducing the occurrence of,
and improving symptoms associated with a liver-related disease or
condition in a subject in need thereof, comprising administering to
the subject a composition comprising eicosapentaenoic acid (EPA)
and docosapentaenoic add (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.
33. The method of claim 32, wherein the liver-related disease or
condition is selected from the group consisting of; fatty liver,
non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver
disease (NAFLD), alcoholic steatohepatitis (ASH), hepatitis, HIV
(human immunodeficiency virus) infection, drug-induced fatty liver
or sequelae, liver failure, liver transplantation, transplanted
liver failure, liver damage associated with renal failure or
disease, abnormally elevated liver enzymes, or type 2 diabetes.
34. The method of claim 32, wherein the composition comprises a
daily dosage of about 120 mg/day to about 150 mg/day.
35. The method of claim 32, wherein the composition comprises a
daily dosage of DPA of about 150 mg/day to about 200 mg/day.
36. The method of claim 32, wherein the composition comprises a
daily dosage of DPA of about 200 mg/day to about 250 mg/day.
37. The method of claim 32, wherein the composition comprises a
daily dosage of DPA of about 250 mg/day to about 300 mg/day.
38. The method of claim 32, wherein the composition comprises a
daily dosage of DPA of about 300 mg/day to about 400 mg/day.
39. The method of claim 32, wherein the composition comprises a
daily dosage of DPA of about 400 mg/day to about 600 mg/day.
40. The method of claim 32, wherein the composition comprises a
daily dosage of DPA of about 600 mg/day to about 1000 mg/day.
41. The method of claim 32, wherein the composition further
comprises eicosapentaenoic acid (EPA) and, 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.
42. The method of claim 32, wherein the amount of EPA and DPA is
selected from the group consisting of about 60% or more, about 65%
or more, about 70% or more, about 75% or more, about 80% or more,
about 85% or more, and about 90% or more by weight of the total
amount of fatty acids.
43. The method of claim 32, wherein the composition comprises
further omega-6 fatty acids in an amount of no more than 6% of
total amount of fatty acids.
44. The method of claim 32, wherein the composition comprises no
more than about 30% docosahexaenoic acid (DHA) by weight of fatty
acids present in the composition.
45. The method of claim 32, wherein the composition comprises no
more than about 10% docosahexaenoic acid (DHA) by weight of fatty
acids present in the composition.
46. The method of claim 32, wherein the composition comprises no
more than about 5% docosahexaenoic acid (DHA) by weight of fatty
acids present in the composition.
47. The method of claim 32, wherein the composition comprises DPA
in ethyl ester form.
48. The method of claim 32, wherein the composition comprises DPA
in free fatty acid form.
49. The method of claim 32, wherein the composition further
comprises docosahexaenoic acid (DHA), and the ratio of DHA:DPA is
no more than 2:1.
50. The method of claim 32, wherein the composition further
comprises docosahexaenoic acid (DHA), and the ratio of DHA:DPA is
no more than 1:1.
51. The method of claim 32, wherein the composition further
comprises docosahexaenoic acid (DHA), and the ratio of DHA:DPA is
no more than 1:2.
52. The method of claim 32, wherein the composition further
comprises docosahexaenoic acid (DHA), and the ratio of DHA:DPA is
no more than 1:4.
53. The method of claim 32, wherein the composition comprises at
least about 6% docosapentaenoic acid (DPA) by weight of fatty acids
present in the composition.
54. The method of claim 32, wherein the composition comprises at
least about 20% docosapentaenoic acid (DPA) by weight of fatty
acids present in the composition.
55. The method of claim 32, wherein the composition comprises at
least about 50% docosapentaenoic acid (DPA) by weight of fatty
acids present in the composition.
56. A method of treating, preventing, reducing the occurrence of,
and improving symptoms associated with a liver-related disease or
condition in a subject in need thereof, comprising administering to
the subject a composition comprising 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.
57. The method of claim 56, wherein the liver-related disease or
condition is selected from the group consisting of: fatty liver,
non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver
disease (NAFLD), alcoholic steatohepatitis (ASH), hepatitis, HIV
(human immunodeficiency virus) infection, drug-induced fatty liver
or sequelae, liver failure, liver transplantation, transplanted
liver failure, liver damage associated with renal failure or
disease, abnormally elevated liver enzymes, or type 2 diabetes.
58. The method of claim 56, wherein the composition comprises
docosapentaenoic acid (DPA) in an amount between about 50% to 75%
of the total amount of fatty acids.
59. The method of claim 56, wherein the composition comprises
docosapentaenoic acid (DPA) in an amount between about 50% to 65%
of the total amount of fatty acids.
60. The method of claim 56, wherein the composition comprises
docosahexaenoic acid (DHA) in an amount between about 25% to about
35%, of the total amount of fatty acids.
61. The method of claim 56, wherein the composition comprises
docosahexaenoic acid (DHA) in an amount between about 30% to about
35% of the total amount of fatty acids.
62. The method of claim 56, wherein the composition comprises
eicosapentaenoic acid (EPA) in an amount less than about 8% of the
total amount of fatty acids.
63. The method of claim 56, wherein the composition comprises
eicosapentaenoic acid (EPA) in an amount less than about 5% of the
total amount of fatty acids.
Description
RELATED APPLICATIONS
[0001] This application is a continuation-in-part (CIP) application
of PCT International Application No. PCT/US13/46176, filed on Jun.
17, 2013, which claims the benefit of U.S. Provisional Patent
Application No. 61/660,757, filed Jun. 17, 2012, U.S. Provisional
Patent Application No. 61/734,331, filed Dec. 6, 2012, and U.S.
Provisional Patent Application No. 61/780,948, filed Mar. 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 liver-related
conditions.
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).
TABLE-US-00001 Common Name for Omega-3 Codified Fatty Acid
(+abbreviation) Lipid Name Chemical Name Hexadecatrienoic acid
(HTA) 16:3 (n-3) all-cis-7,10,13-hexadecatrienoic acid
.alpha.-Linolenic acid (ALA) 13:3 (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
(DHA) 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 (THA) 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 LOVAZA.RTM.) and is
sold under the trademarks OMACOR.RTM. and LOVAZA.RTM.. 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.
LOVAZA.RTM. (omega-3-acid ethyl esters) is indicated for the
treatment of patients with hypertriglyceridemia with TG levels of
500 mg/dL or higher.
[0006] Another form of omega-3 fatty acid concentrate is sold under
the trademark EPADEL.RTM. .RTM. for the treatment of dyslipidemia.
This product is described as 98% EPA ethyl ester in Lancet (Vol.
369; Mar. 31, 2007; 1090-1098) reporting on a large outcome study
with EPADEL.RTM.. EPADEL.RTM. is known to contain less than 1% of
any fatty acid other than EPA.
[0007] Similar to EPADEL.RTM., 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
VASCEPA.RTM.. 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 III clinical development. Subsequently, AMR101 was entered in
a development program for hypertriglyceridemia and mixed
dyslipidemia.
[0008] Yet another concentrate of omega-3, long chain,
polyunsaturated fatty acids from fish oil containing approximately
75% DHA and EPA as free fatty adds is known under its developmental
stage name EPANOVA.TM.. This product is described as comprising
approximately 55% EPA and 20% DHA. EPANOVA.TM. was previously under
development for the treatment of Crohn's Disease but failed in
phase clinical development. Subsequently, EPANOVA.TM. 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. Pat. 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 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 20041000242 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 polyunsaturated 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] Non-alcoholic fatty liver disease (NAFLD) is thought to be
the most common chronic liver disease. The prevalence of NAFLD, on
a global level, ranges from roughly 15% to 30%, and is associated
with multiple variables. In the United States, estimates of NAFLD
prevalence are in the range of 24%. In Hispanics, this rate is
higher than both European-origin and Afro-American origin
genotypes. Of all the liver transplants in the United States, it
has been estimated that close to 10% are a result of non-alcoholic
steatohepatitis (NASH), which is the most extreme form of NAFLD. In
addition, of all the cardiovascular events resulting in death,
NAFLD co-morbidity is thought to occur in 24% of all cases. Other
co-morbidity factors associated with NAFLD and NASH include
obesity, metabolic syndrome and type 2 diabetes. As the incidence
rate for all these disease states is currently rising, it is the
opinion of those skilled in the art that the incidence and
prevalence of NAFLD, NASH, and its consequences will be increasing
in the future (AASLD/IASL NAFLD Symposium, 2013, Washington,
D.C.).
[0017] There is a high unmet need in the area of liver conditions,
especially fatty liver and more specifically NAFLD and its more
severe form NASH. NAFLD may be considered as a precursor to NASH,
in the spectrum of disease progression. NAFLD is characterized by
high abnormal levels of lipids, primarily in the form of
triglycerides, cholesterol and fatty acids, that are elevated
and/or stored in the liver (simple steatosis). With prolonged time,
the pathophysiology of disease progression can result in the
process of fibrosis and necroinflammation, giving rise to the state
of NASH. As this particular process continues, the level of ensuing
fibrosis increases, as does an inflammatory response, that
decreases normal liver functioning which can ultimately result in
cirrhosis, liver failure and/or death. There is also a high risk of
co-morbidity for liver cancer associated with NAFLD, and especially
NASH.
[0018] Diagnosis of early NAFLD relies primarily on recognition of
elevated liver enzymes, such as ALT, AST and perhaps GGT. In those
skilled in the art, elevations of these enzymes may precipitate the
need for further tests in the form of imaging, including ultrasound
and MRI, or related tests such as but not limited to
FIBROTEST.RTM.. For the diagnosis of NASH, the current gold
standard is histopathological evaluation of the degree of fibrosis
determined by examining liver samples obtained thru punch biopsy.
Other non-invasive methods for determining fibrosis include
determination of liver stiffness by specific ultrasound techniques,
and are being evaluated as surrogates and/or replacement for
performing liver biopsies.
[0019] For NAFLD, the main objective is to decrease lipid levels in
the liver. The first course of therapy is life style modification,
mainly by dietary means and a weight loss program. In the instance
of NASH, the main objective is to curtail further development of
fibrosis. There are currently limited choices of therapeutic agents
for the treatment of NASH. In adults, the primary agents that could
be used include vitamin E and pentoxyfiline. However, there are
limitations to the use of these agents. In the instance of vitamin
E, long term use is associated with an increased risk for
cardiovascular events, including myocardial infarct and cardiac
death.
[0020] For instances of liver failure, the only viable alternative
is liver transplantation, which is costly, subject to rejection,
and predisposes the patient to increased risk of opportunistic
microbial infections due to the use of immunosuppressive agents. In
addition, the availability and suitability of donor livers is
highly limited, which would decrease chance of survival for persons
in the state of liver failure. Therefore, there is a need in the
art for an effective therapy for liver-related conditions.
[0021] All references cited herein are incorporated by reference in
their entirety.
SUMMARY OF THE INVENTION
[0022] The present invention provides omega-3 fatty acid
compositions and methods of administering these compositions.
[0023] 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.
[0024] 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.
[0025] 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.
[0026] 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.
[0027] The present invention provides a pharmaceutical composition
comprising eicosapentaenoic add (EPA) and docosapentaenoic add
(DPA), wherein the amount of EPA and DPA is about 55% or more by
weight of the total amount of fatty adds, and wherein the ratio of
DHA:DPA is no more than 1:1.
[0028] 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.
[0029] 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).
[0030] 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 liver-related conditions.
Examples of liver-related conditions include, but are not limited
to fatty liver, non-alcoholic steatohepatitis (NASH), non-alcoholic
fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH),
hepatitis including but not limited to hepatitis C, HIV (human
immunodeficiency virus) infection and any liver syndrome arising
from the treatment of HIV, drug-induced fatty liver or sequalae
(including but not limited to NAFLD, NASH), liver failure, liver
transplantation, transplanted liver failure, liver damage
associated with other organ system afflictions including but not
limited to renal failure or disease, abnormally elevated liver
enzymes (such as ALT, AST and for GGT) associated with disease
(such as diabetes type 2), or drug-induced afflictions.
DETAILED DESCRIPTION OF THE INVENTION
[0031] 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 adds 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.
[0032] 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 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 (HPA) in an
amount of at least 1% of the total amount of fatty acids
[0033] 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.
[0034] 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 adds, 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 (HPA) in an
amount of at least 1% of the total amount of fatty adds.
[0035] 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,
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.
[0036] 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.
[0037] 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 7%, alternatively less than about 6%,
alternatively less than about 5%, of the total amount of fatty
acids.
[0038] 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%, alternatively about 93% to about 98%, alternatively about 94%
to about 98%, omega-3 fatty acids of the total amount of fatty
acids.
[0039] 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.
[0040] 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+FHPA+FDPA 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,
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.
[0041] 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.
[0042] 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.
[0043] 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.
[0044] 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 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%.
[0045] 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.
[0046] 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 200 mg omega-3-pentaenoic acids per day,
alternatively at least 300 mg omega-3-pentaenoic acids per day,
alternatively at least 500 mg omega-3-pentaenoic acids per day,
alternatively at least 700 mg omega-3-pentaenoic acids per day,
alternatively at least 900 mg omega-3-pentaenoic acids per day,
alternatively at least 1000 mg omega-3-pentaenoic acids per day,
alternatively at least 1500 mg omega-3-pentaenoic acids per day,
alternatively at least 1900 mg omega-3-pentaenoic acids per day,
alternatively at least 2000 mg omega-3-pentaenoic acids per day,
alternatively at least 2500 mg omega-3-pentaenoic acids per day,
alternatively at least 2900 mg omega-3-pentaenoic acids per day,
alternatively at least 3000 mg omega-3-pentaenoic acids per day,
alternatively at least 3500 mg omega-3-pentaenoic acids per day,
alternatively at least 3900 mg omega-3-pentaenoic acids per day,
alternatively at least 4000 mg omega-3-pentaenoic acids per day,
alternatively at least 4100 mg omega-3-pentaenoic acids per day,
alternatively at least 4500 mg omega-3-pentaenoic adds per day,
alternatively at least 5000 mg omega-3-pentaenoic adds per day,
alternatively at least 5500 mg omega-3-pentaenoic adds per day,
alternatively at least 6000 mg omega-3-pentaenoic adds per day,
alternatively at least 6100 mg omega-3-pentaenoic adds per day or
their glycerol or ethyl esters.
[0047] 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.
[0048] 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. In 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 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.
[0049] 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 30 mg HPA per day, alternatively at least 40
mg HPA per day, alternatively at least 50 mg HPA per day,
alternatively at least 60 mg HPA per day, alternatively at least 70
mg HPA per day, alternatively at least 80 mg HPA per day,
alternatively at least 90 mg HPA per day, alternatively at least
100 mg HPA per day, alternatively at least 120 mg HPA per day,
alternatively at least 150 mg HPA per day, alternatively at least
160 mg HPA per day, alternatively at least 180 mg HPA per day,
alternatively at least 200 mg HPA per day, alternatively at least
250 mg HPA per day, alternatively at least 300 mg HPA per day,
alternatively at least 350 mg HPA per day, alternatively at least
400 mg HPA per day, alternatively at least 500 mg HPA per day,
alternatively at least 600 mg HPA per day, alternatively at least
800 mg HPA or its glycerol or ethyl esters per day.
[0050] 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%, 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.
[0051] 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.
[0052] 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 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%, 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.
[0053] 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 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
compositions 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.
[0054] In some embodiments, the compositions of the present
invention are provided in a dose of between 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 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 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.
[0055] 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.
[0056] In other embodiments of the present invention, the
compositions comprise DPA in an amount between 1% and 99% relative
to the total amount of fatty acids present in the composition,
alternatively between 1% and 95%, alternatively alternatively
between 1% and 90%, alternatively between 1% and 85%, alternatively
between 1% 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%, 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%, 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 add (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 75% or at least about 80% or at least
about 85% or at least about 90% or at least about 95% of
docosapentaenoic add (DPA).
[0057] In some embodiments, the compositions comprise
docosapentaenoic add (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 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.
[0058] 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.
[0059] 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, alternatively no more than
1% DHA relative to the total amount of fatty acids present in the
composition. In some embodiments, the compositions and methods
comprise less than 1500 mg of DHA, alternatively less than 1200 mg
of DHA, alternatively less than 1000 mg of DHA, alternatively less
than 800 mg of DHA, alternatively less than 700 mg of DHA,
alternatively less than 600 mg of DHA, alternatively less than 500
mg of DHA, alternatively less than 400 mg of DHA, alternatively
less than 350 mg of DHA, alternatively less than 300 mg of DHA,
alternatively less than 250 mg of DHA, alternatively less than 200
mg of DHA alternatively less than 150 mg of DHA, alternatively less
than 120 mg 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.
[0060] 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).
[0061] 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.
[0062] 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
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.
[0063] 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.
[0064] 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 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.
[0065] Omega-6 fatty acids include, but are not limited to:
linoleic acid (LA; C18:2-n6); gamma-linoleic acid (GLA; C18:3-n6);
eicosadienoic acid (C20:2-n6); dihomo-gamma-linoleic acid (DGLA;
C20:3-n6); arachiconic acid (ARA; C20:4-n6); and omega-6
docosapentaenoic acid (DPA; C22:5-n6).
[0066] 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.
[0067] 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%, 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.
[0068] 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.
[0069] 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, 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 ETA, 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.
[0070] In further embodiments, the compositions of the present
invention comprise no more than 8% arachidonic add (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 adds comprised by the
compositions of the present invention.
[0071] In other embodiments, the compositions of the present
invention comprise no more than 2.5% arachidonic add (ARA;
C20:4-n6), no more than 0.4% omega-6-docosapentaenoic add (DPA;
C22:5-n6) and no more than 0.2% gamma-linoleic add (GLA; C18:3-n6)
relative the total amount of fatty adds comprised by the
compositions of the present invention.
[0072] Further embodiments provide fatty add compositions
comprising no more than 2.5% arachidonic acid (ARA; C20:4-n6), no
more than 0.3.degree./a omega-6 docosapentaenoic acid (DPA;
C22:5-n6) and no more than 0.1% gamma-linoleic add (GLA; C18:3-n6)
relative the total amount of fatty acids comprised by the
compositions of the present invention.
[0073] 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%.
[0074] The compositions of the present invention may also be taken
as a general nutritional supplement.
[0075] 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.
[0076] 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.
[0077] 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 (LOVAZA.RTM.) monograph, or any essentially equivalent
methods (whether by gas chromatography, HPLC, FPLC or any other
chromatographic method).
[0078] 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).
[0079] 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).
[0080] 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).
[0081] 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 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).
[0082] 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).
[0083] 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.
[0084] 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.
[0085] 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 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.
[0086] 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, C21 and C22 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.
[0087] 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 (C2-elongation or C1-elongation) on the
carboxyl side of the molecule (for instance with a method similar
to or alternate methods with equivalent results such as described
by Kuklev D V and Smith W L 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 C2-elongation (or C1-elongation) of EPA similar to those
described above, thus directly yielding compositions of the present
invention or intermediates therefore.
[0088] 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.
[0089] 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.
[0090] 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 OF 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.
[0091] 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 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.
[0092] 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).
[0093] 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.
[0094] 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
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.
[0095] 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.
[0096] 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 LOVAZA.RTM.,
EPANOVA.TM. or VASCEPA.RTM..
[0097] 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.
[0098] 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.
[0099] 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.
[0100] 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.
[0101] 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, emulsifiers or other
liquid forms, and microencapsulate powders or other dry form
vehicles are all appropriate ways of administering the
products.
[0102] 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.
[0103] 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.
[0104] 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.
[0105] 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.).
[0106] 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.
[0107] 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.
[0108] 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, and reducing the symptoms, pathology or
events associated with liver-related disorders or conditions.
Examples of liver-related disorders or conditions include, but are
not limited to the following: fatty liver, non-alcoholic
steaohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD),
alcoholic steatohepatitis (ASH), hepatitis including but not
limited to hepatitis C, HIV (human immunodeficiency virus)
infection and any liver syndrome arising from the treatment of HIV,
drug-induced fatty liver or sequalae (including but not limited to
NAFLD, NASH), liver failure, liver transplantation, transplanted
liver failure, and liver damage. The liver damage may include
damage associated with afflictions of other organ systems, such as
renal failure or disease and diabetes, and damage caused or induced
by drugs. The methods may be also be useful in the treatment of
conditions associated with abnormally elevated liver enzymes (such
as ALT, AST and for GGT).
[0109] The effectiveness of the compositions of the present
invention may be attributed in part to its activity in modulating
lipid metabolism, including that of the liver, from a state of
production and accumulation to a state of decreased production and
removal vis-a-vis oxidation. Also, the compositions may elicit
anti-inflammatory effects through a variety of mechanisms that can
decrease levels of pro-inflammatory mediators, such as TNF-alpha,
and increase levels of anti-inflammatory mediators, including IL-10
and arginase. The compositions may also be effective in decreasing
the levels of lipids, specifically stored triglycerides, and to
decrease pro-inflammatory mediators associated with fibrotic
mechanisms.
[0110] The compositions of the present invention may be useful for
any subjects, including those with and without comorbidities. 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:
hypertriglyceridemia, dyslipidemia, hypercholesteremia, renal
disease, nephropathy, IgA nephropathy, renal impairment, renal
failure (also kidney failure or renal insufficiency) 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, or any other
major cardiovascular event.
[0111] 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, such as levels of liver
enzymes and biomarkers. Clinical improvement relating to liver
conditions, such as NAFLD and/or NASH, can be assessed utilizing a
multitude of methodologies known to those practiced in the art.
Liver biopsy histopathology scoring for fibrosis and ultrasound
measurements of liver stiffness can be used for clinical
assessment, measurement in the baseline changes in liver enzymes
and any additional biomarkers such as but not limited to the
FIBROTEST.RTM. and/or the nonalcoholic fatty liver disease (NAFLD)
activity score, which is based on a standardized grading system for
steatosis (on a scale of 0 to 3), lobular inflammation (on a scale
of 0 to 3), and hepatocellular ballooning (on a scale of 0 to 2),
with higher scores indicating increasing severity of disease.
[0112] The compositions of the present invention described for use
in NASH can be administered by a multitude of routes, including
oral, intravenous, topical, rectal and direct injection to the site
of action.
[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. The co-administration may result in
a synergistic, more potent and efficacious course of treatment. In
addition, it may be possible to use lower doses of these agents to
elicit the synergistic effect, which may reduce the number and
severity of adverse effects that are associated when they are used
alone. Examples of such concomitant or fixed combination treatments
may include coadministration with one or more of the following:
PPAR gamma agents (such as pioglitazone), mixed PPAR agents such as
those affecting the alpha/delta receptors, vitamin E,
pentoxyfiline, hepatitis virus anti-viral agents,
immunosuppressants associated with organ transplant, anti-platelet
agents, anti-hypertensive drugs, diuretics, anti-inflammatory
agents, anti-fibrotic agents, anti-cell death agents, anti-cell
necrotic agents, and biological agents such as but not limited to
monoclonal antibodies, or soluble receptors.
EXAMPLES
Example 1
[0114] A composition according to the present invention is prepared
by mixing and homogenizing in a ratio of 98:2 the intermediates
MEGAPEX E90D00EE (90% EPA ethyl ester,) and MAXOMEGA DPA95 FFA
(.gtoreq.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 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 %).
TABLE-US-00002 TABLE 1 Fatty acid Composition (Area %) of
intermediates and novel composition according to Example 1 98.0%
2.0% Megapex Maxomega Novel Fatty Add E90D00EE DPA95FFA => EE
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 0.41 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 0.25 c20:3n9
0 0 0.00 c20:3n6 0.15 0 0.15 c21:0 0 0 0.00 c20:4n6 3.21 0 3.15
c20:3n3 0 0 0.00 c20:4n3 1.44 0 1.41 c20:5n3 90.92 0 89.10 c22:0
0.3 0 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 0 0 0.00 c22:5n3 0 97.27 1.95
c22:6n3 0 0 0.00 c24:0 0 0.33 0.01 OTHER 2.42 2.4 2.42 100 100
100
Example 2
[0115] A composition according to the present prevention is
prepared by mixing and homogenizing in a ratio of 96:4 the
intermediates MEGAPEX E90D00EE (90% EPA ethyl ester,) and MAXOMEGA
DPA95 FFA (.gtoreq.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 Equated 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 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-US-00003 TABLE 2 Fatty acid Composition (Area %) of
intermediates and novel composition according to Example 2 96.0%
4.0% Megapex Maxomega Novel Fatty Acid E90D00EE DPA95FFA => EE
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 0.40 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 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 3.08
c20:3n3 0 0 0.00 c20:4n3 1.44 0 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 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 3.89
c22:6n3 0 0 0.00 c24:0 0 0.33 0.01 OTHER 2.42 2.4 2.42 100 100
100
Example 3
[0116] A composition according to the present invention is prepared
by mixing and homogenizing in a ratio of 94:6 the intermediates
MEGAPEX E90D00EE (90% EPA ethyl ester,) and MAXOMEGA DPA95 FFA
(.gtoreq.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% DHA, 93.26% total omega-3 fatty acids, 3.02% ARA,
and 3.42% omega-6 fatty acids (all Area %).
TABLE-US-00004 TABLE 3 Fatty acid Composition (Area %) of
intermediates and novel composition according to Example 3 94.0%
6.0% Megapex Maxomega Novel Fatty Acid E90D00EE DPA95FF4 => EE
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
Example 4
[0117] A composition according to the present invention is prepared
by mixing and homogenizing in a ratio of 75:25 the intermediates
MEGAPEX E90D00EE (90% EPA ethyl ester,) and MAXOMEGA DPA95 FFA
(.gtoreq.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 %).
TABLE-US-00005 TABLE 4 Fatty acid Composition (Area %) of
intermediates and novel composition according to Example 4 75.0%
25.0% Megapex Maxomega Novel Fatty Acid E90D00EE DPA95FFA => EE
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 0 0.32 c18:4n1 0.07 0 0.05 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 0.19 c20:3n9
0 0 0.00 c20:3n6 0.15 0 0.11 c21:0 0 0 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 0 0.05 c22:1n9 0.18 0 0.14 c22:1n7 0.19 0
0.14 c21:5n3 0.19 0 0.14 c22:5n6 0 0 0.00 c22:5n3 0 97.27 24.32
c22:6n3 0 0 0.00 c24:0 0 0.33 0.08 OTHER 2.42 2.4 2.42 100 100
100
Example 5
[0118] A composition according to the present invention is prepared
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
Equated 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 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-US-00006 TABLE 5 Fatty acid Composition (Area %) of
intermediates and novel composition according to Example 5 40.0%
60.0% Maxomega Novel Fatty Acid KD-Pur 900EE DPA95FFA => EE
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 c18:3n6 0 0 0.00 c18:3n3 0 0 0.00 c18:4n3 0 0 0.00
c18:4n1 0 0 0.00 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 0 0.00 c20:3n9 0 0 0.00 c20:3n6 0 0 0.00
c21:0 0 0 0.00 c20:4n6 0 0 0.00 c20:3n3 0 0 0.00 c20:4n3 1.04 0
0.02 c20:5n3 92.99 0 55.79 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 2.39 c22:5n6 0 0 0.00
c22:5n3 0.58 97.27 39.26 c22:6n3 0 0 0.00 c24:0 0 0.33 0.13 OTHER
1.41 2.4 1.81 100.00 100 100.00
Example 6
[0119] 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 intermediates were prepared and
commercially offered for sale by KD-Pharma Germany (KD-Pharma) and
Equated Ltd from Scotland, UK (MAXOMEGA). The relative amounts of
fatty adds 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 adds, and 98.54% total omega-3 fatty
adds (all Area %).
TABLE-US-00007 TABLE 6 Fatty acid Composition (Area %) of
intermediates and novel composition according to Example 6 4.0%
96.0% Maxomega Novel Fatty Acid KD-Pur 900EE DPA95FFA => EE
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 c18:3n6 0 0 0.00 c18:3n3 0 0 0.00 c18:4n3 0 0 0.00
c18:4n1 0 0 0.00 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 0 0.00 c20:3n9 0 0 0.00 c20:3n6 0 0 0.00
c21:0 0 0 0.00 c20:4n6 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
Example 7
[0120] 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-US-00008 TABLE 7 Fatty acid Composition (Area %) of
intermediates and novel composition according to Example 7 91.8%
8.2% Novel Fatty Acid KD-Pur EPA910EE DPA-95% Est 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
Example 8
[0121] 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.
[0122] Conversion Method EE to FFA [0123] 1. Fatty Acid Ethyl Ester
(FAEE GMP, approx. 3 mmol/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. [0124] 2. 2M NaOH solution in water is
added under firm stirring to ensure phase mixing (est.
2-3.times.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/EtOAc 9:1) and with EP GC method to confirm reaction
completion under GMP. [0125] 3. Under cooling (keep mixture below
70 degree Celcius), add 6M HCl in water (est. <1 hr) until
slightly acid (.about.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). [0126] 4. Add demineralized water (est. 2-2.times.FAEE
w/w) and wash out NaCl and ethanol from oil under firm stirring
(est. .about.1 hr). Halt stirring, give time to let phases
separate, and remove water phase from bottom (keep oil protected
from oxygen, apply nitrogen atmosphere blanket). [0127] 5. Repeat
Step 4 several times (.about.2.times.) to remove ethanol and NaCl.
[0128] 6. Remove water and remaining ethanol [determine in-process
controls], confirm under GMP with USP residual solvent method
(target: ethanol <100 ppm) by stirring oil while applying vacuum
10-50 mbar (with solvent trap) and heat oil (70-80 degree celcius)
until water/ethanol target is net (est. 2-4 hrs). [0129] 7. Add
anti-oxidants i.e. alpha-D-tocopherol, USP, target 4 mg/g) and/or
other excipients. [0130] 8. All reagents and excipients LISP
grade.
Example 9
[0131] 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.
Example 10
[0132] 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.
Example 11
[0133] 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 100 mL 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 4
mg/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 1000 mg
omega-3-pentaenoic-acids ethyl esters per capsule. Finally, the
capsules are bottled in HDPE bottles with induction seal and child
resistant cap,
Example 12
[0134] 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 100 mL 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 4
mg/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, N.C.,
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 1000 mg
omega-3-pentaenoic-acids per capsule. Finally, the capsules are
bottled in HDPE bottles with induction seal and child resistant
cap.
Example 13
[0135] 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 100 mL 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 4
mg/gram alpha-D-tocopherol. Subsequently, the formulated oil is
encapsulated into soft gelatin capsules with printed logo according
to general methods typically used by Catalent in St. Petersburg,
Fla., 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 1000 mg
omega-3-pentaenoic-acids ethyl esters per capsule. Finally, the
capsules are bottled in HOPE bottles with induction seal and child
resistant cap.
Example 14
[0136] 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 100 mL 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 4
mg/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, N.C.,
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 1000 mg
omega-3-pentaenoic-acids per capsule. Finally, the capsules are
bottled in HOPE bottles with induction seal and child resistant
cap.
Example 15
[0137] A patient is diagnosed with NAFLD 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 (4 g/d).
Example 16
[0138] A patient is treated as per Example 15. The treatment
results in significant clinical improvement, including reduction in
liver enzyme levels.
Example 17
[0139] The following are examples of preferred embodiments of the
present invention.
TABLE-US-00009 COMPOSITION 1a Minimum Maximum Target Composition
(mg/g) (mg/g) (mg/g) Omega-3 pentaenoic acid 880 980 930
Eicosapentaenoic acid (EPA) 800 950 850 Heneicosapentaenoic acid
(HPA) 5 60 30 Docosapentaenoic acid (DPA) 60 100 80 Docosahexaenoic
acid (DHA) 25 <10
TABLE-US-00010 COMPOSITION 1b Minimum Maximum Target Composition
(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
[0140] In COMPOSITIONS 1a and 1b, 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.
Example 18
[0141] The following is an example of a preferred embodiment of the
present invention.
TABLE-US-00011 COMPOSITION 2 Minimum Maximum Target Composition
(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
[0142] 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.
Example 19
[0143] The following is an example of an embodiment of the present
invention.
TABLE-US-00012 COMPOSITION 3 Minimum Maximum Target Composition
(mg/g) (mg/g) (mg/g) Docosapentaenoic acid (DPA n-3) 800 990
920
[0144] The DPA may be composed as a glyceride (such as
triglyceride), an ester (such as ethyl ester), or a free fatty
acid.
Example 20
[0145] The following is an example of an embodiment of the present
invention.
TABLE-US-00013 COMPOSITION 4 Minimum Maximum Target Composition
(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
Example 21
[0146] A mixture of DPA and EPA was prepared by combining 1 g DPA
Ethyl Ester (SE-133-III) with 10 g EPA Ethyl Ester, 914 mg/g (KO
Pharma FM13001) in 150 ml of 95% ethanol/water containing 35 ml of
2M sodium hydroxide. This reaction mixture was stirred overnight at
ambient temperature. Tlc 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.
[0147] A representative sample of this ethyl ester composition was
analysed using split inject by capillary gas chromatography by a 30
meter.times.0.25 mm Restek Stabil wax column using temperature
programming.
DESCRIPTION OF EMBODIMENTS OF THE PRESENT INVENTION
[0148] 1. A fatty acid composition comprising at least 50%
omega-3-fatty adds, salts or derivatives thereof, while comprising
eicosapentaenoic add (EPA; C20:5-n3) and docosapentaenoic add (DPA;
C225-n3) and wherein the EPA:DHA ratio is higher than 20:1. [0149]
2. A fatty add composition comprising at least 60% omega-3-fatty
adds, salts or derivatives thereof, while comprising
eicosapentaenoic add (EPA; C20:5-n3) and docosapentaenoic add (DPA;
C22:5-n3) and wherein the EPA:DHA ratio is higher than 20:1, [0150]
3. A fatty add 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.
[0151] 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,
[0152] 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.
[0153] 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 add
(DPA; C22:5-n3) and wherein the EPA:DHA ratio is higher than 20:1.
[0154] 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.
[0155] 8. A fatty acid composition comprising at least 95%
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.
[0156] 9. A composition according to one of the preferred
embodiments 1 through 8, comprising at least 2% docosapentaenoic
acid (DPA; C22:5-n3). [0157] 10. A composition according to one of
the preferred embodiments 1 through 8, comprising at least 4%
docosapentaenoic acid (DPA; C22:5-n3). [0158] 11. A composition
according to one of the preferred embodiments 1 through 8,
comprising at least 5% docosapentaenoic acid (DPA; C22:5-n3).
[0159] 12. A composition according to one of the preferred
embodiments 1 through 8, comprising at least 6% docosapentaenoic
acid (DPA; C22:5-n3). [0160] 13. A composition according to one of
the preferred embodiments 1 through 8, comprising at least 7%
docosapentaenoic acid (DPA; C22:5-n3). [0161] 14. A composition
according to one of the preferred embodiments 1 through 8,
comprising at least 8% docosapentaenoic acid (DPA; C22:5-n3).
[0162] 15. A composition according to one of the preferred
embodiments 1 through 8, comprising at least 10% docosapentaenoic
acid (DPA; C22:5-n3). [0163] 16. A composition according to one of
the preferred embodiments 1 through 8, comprising at least 12%
docosapentaenoic acid (DPA; C22:5-n3). [0164] 17. A composition
according to one of the preferred embodiments 1 through 8,
comprising at least 15% docosapentaenoic acid (DPA; C22:5-n3).
[0165] 18. A composition according to one of the preferred
embodiments 1 through 17, comprising no more than 95% EPA. [0166]
19. A composition according to one of the preferred embodiments 1
through 17, comprising no more than 10% omega-6 fatty acids. [0167]
20. A composition according to one of the preferred embodiments 1
through 17, comprising no more than 7% omega-6 fatty acids. [0168]
21. A composition according to one of the preferred embodiments 1
through 17, comprising no more than 5% omega-6 fatty acids. [0169]
22. A composition according to one of the preferred embodiments 1
through 17, comprising no more than 3% omega-6 fatty acids. [0170]
23. A composition according to one of the preferred embodiments 1
through 22, comprising no more than 5% arachidonic acid (C22:4-n6).
[0171] 24. A composition according to one of the preferred
embodiments 1 through 22, comprising no more than 4% arachidonic
acid (C22:4-n6). [0172] 25. A composition according to one of the
preferred embodiments 1 through 22, comprising no more than 3%
arachidonic acid (C22:4-n6). [0173] 26. A composition according to
one of the preferred embodiments 1 through 22, comprising no more
than 2% arachidonic acid (C22:4-n6). [0174] 27. A composition
according to one of the preferred embodiments 1 through 22,
comprising no more than 1% arachidonic acid (C22:4-n6). [0175] 28.
A composition according to one of the preferred embodiments 1
through 27, also comprising heneicosapentaenoic acid (C21:5-n3).
[0176] 29. A composition according to one of the preferred
embodiments 1 through 27, comprising at least 0.01%
heneicosapentaenoic acid (C21:5-n3). [0177] 30. A composition
according to one of the preferred embodiments 1 through 27,
comprising at least 0.1% heneicosapentaenoic acid (C21:5-n3).
[0178] 31. A composition according to one of the preferred
embodiments 1 through 27, comprising at least 0.3%
heneicosapentaenoic acid (C21:5-n3). [0179] 32. A composition
according to one of the preferred embodiments 1 through 27,
comprising at least 0.5% heneicosapentaenoic acid (C21:5-n3).
[0180] 33. A composition according to one of the preferred
embodiments 1 through 27, comprising at least 1%
heneicosapentaenoic acid (C21:5-n3). [0181] 34. A composition
according to one of the preferred embodiments 1 through 27,
comprising at least 2% heneicosapentaenoic acid (C21:5-n3). [0182]
35. A composition according to one of the preferred embodiments 1
through 27, comprising at least 3% heneicosapentaenoic acid
(C21:5-n3), [0183] 36. A composition according to one of the
preferred embodiments 1 through 27, comprising at least 4%
heneicosapentaenoic acid (C21:5-n3). [0184] 37. A composition
according to one of the preferred embodiments 1 through 27,
comprising at least 5% heneicosapentaenoic acid (C21:5-n3). [0185]
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. [0186] 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.
[0187] 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. [0188] 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. [0189] 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.
[0190] 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. [0191] 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. [0192] 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. [0193] 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. [0194] 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. [0195] 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. [0196] 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. [0197] 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. [0198] 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. [0199] 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. [0200] 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. [0201] 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. [0202] 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. [0203] 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. [0204] 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. [0205] 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. [0206] 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. [0207] 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. [0208] 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. [0209] 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. [0210] 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. [0211] 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. [0212] 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. [0213] 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. [0214] 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. [0215] 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. [0216] 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. [0217] 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. [0218] 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. [0219] 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. [0220] 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.
[0221] 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. [0222] 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. [0223] 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. [0224] 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. [0225] 78. A composition according
to one of the preferred embodiments 1 through 44, comprising
between 55% and 95% EPA. [0226] 79. A composition according to one
of the preferred embodiments 1 through 44, comprising between 60%
and 95% EPA. [0227] 80. A composition according to one of the
preferred embodiments 1 through 44, comprising between 65% and 95%
EPA. [0228] 81. A composition according to one of the preferred
embodiments 1 through 44, comprising between 70% and 95% EPA.
[0229] 82. A composition according to one of the preferred
embodiments 1 through 44, comprising between 75% and 95% EPA.
[0230] 83. A composition according to one of the preferred
embodiments 1 through 44, comprising between 80% and 95% EPA.
[0231] 84. A composition according to one of the preferred
embodiments 1 through 44, comprising between 85% and 95% EPA.
[0232] 85. A composition according to one of the preferred
embodiments 1 through 44, comprising between 90% and 95% EPA.
[0233] 86. A composition according to one of the preferred
embodiments 1 through 44, comprising between 1% and 3% DPA. [0234]
87. A composition according to one of the preferred embodiments 1
through 44, comprising between 1% and 5% DPA. [0235] 88. A
composition according to one of the preferred embodiments 1 through
44, comprising between 2% and 10% DPA. [0236] 89. A composition
according to one of the preferred embodiments 1 through 44,
comprising between 3% and 20% DPA. [0237] 90. A composition
according to one of the preferred embodiments 1 through 44,
comprising between 3% and 30% DPA. [0238] 91. A composition
according to one of the preferred embodiments 1 through 44,
comprising between 3% and 50% DPA. [0239] 92. A composition
according to one of the preferred embodiments 1 through 44,
comprising between 3% and 75% DPA. [0240] 93. A composition
according to one of the preferred embodiments 1 through 44,
comprising between 3% and 90% DPA. [0241] 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. [0242]
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. [0243] 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. [0244] 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. [0245] 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. [0246]
99. A pharmaceutically suitable formulation comprising one of the
compositions according to preferred embodiments 94 through 98, in
which the amount of eicosapentaenoic add plus docosapentaenoic add
is present in an amount between 100 and 10,000 mg, [0247] 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 add plus
docosapentaenoic add is present in an amount between 250 and 1,250
mg.
[0248] 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
add plus docosapentaenoic acid is present in an amount between 500
and 1,100 mg. [0249] 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. [0250] 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. [0251] 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. [0252] 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. [0253] 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). [0254] 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). [0255]
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). [0256]
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. [0257] 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. [0258] 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. [0259] 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. [0260] 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. [0261] 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. [0262] 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. [0263] 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, [0264] 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. [0265] 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. [0266] 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. [0267] 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. [0268] 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. [0269] 122.
A method of treatment according to preferred embodiments 103
through 105, in which the subject is a patient diagnosed with
diabetes. [0270] 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. [0271] 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. [0272]
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. [0273] 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. [0274] 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. [0275] 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. [0276] 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. [0277]
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. [0278] 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. [0279] 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. [0280] 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. [0281] 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. [0282] 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. [0283] 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, [0284] 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. [0285] 138. The composition of claim
1, wherein the ratio of EPA to DPA (EPA:DPA) is between 15:1 to
8:1. [0286] 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.
* * * * *