U.S. patent application number 17/022180 was filed with the patent office on 2021-07-29 for compositions comprising 15-ohepa and methods of using the same.
The applicant listed for this patent is Afimmune Limited. Invention is credited to John Climax, Kevin Duffy, Jonathan Rowe.
Application Number | 20210228524 17/022180 |
Document ID | / |
Family ID | 1000005510404 |
Filed Date | 2021-07-29 |
United States Patent
Application |
20210228524 |
Kind Code |
A1 |
Rowe; Jonathan ; et
al. |
July 29, 2021 |
COMPOSITIONS COMPRISING 15-OHEPA AND METHODS OF USING THE SAME
Abstract
The present invention relates to the compositions, formulations
and methods of treating fatty liver disorders, such as
non-alcoholic fatty liver disease (NAFLD) and non-alcoholic
steatohepatitis (NASH) and their sequelae by administration of
15-OHEPA.
Inventors: |
Rowe; Jonathan; (Waterford,
CT) ; Duffy; Kevin; (Dublin, IE) ; Climax;
John; (Dublin, IE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Afimmune Limited |
Dublin |
|
IE |
|
|
Family ID: |
1000005510404 |
Appl. No.: |
17/022180 |
Filed: |
September 16, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16527841 |
Jul 31, 2019 |
10813903 |
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17022180 |
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14695865 |
Apr 24, 2015 |
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16527841 |
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PCT/EP2014/051455 |
Jan 24, 2014 |
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14695865 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/557 20130101;
A61K 9/48 20130101; A61P 1/16 20180101; A61K 31/202 20130101; A61K
9/0053 20130101 |
International
Class: |
A61K 31/202 20060101
A61K031/202; A61K 31/557 20060101 A61K031/557; A61P 1/16 20060101
A61P001/16; A61K 9/00 20060101 A61K009/00; A61K 9/48 20060101
A61K009/48 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 30, 2013 |
GB |
1301626.6 |
Claims
1. A method for treating or preventing liver disease in a subject
comprising, administering to the subject 15-HEPE in an amount
effective to treat or prevent liver disease in the subject.
2. The method of claim 1 wherein the 15-HEPE is present in a
pharmaceutical composition.
3. The method of claim 1, wherein the liver disease is
non-alcoholic steatohepatitis.
4. The method of claim 2, wherein the 15-HEPE is present in the
pharmaceutical composition in an amount from about 1 mg to about
1000 mg.
5. The method of claim 2, wherein the 15-HEPE represents at least
about 1% to about 95% of all fatty acids present in the
pharmaceutical composition.
6. The method of claim 2, wherein the 15-HEPE represents at least
about 60%, by weight, of all fatty acids present in the
pharmaceutical composition.
7. The method of claim 2, wherein the 15-HEPE represents at least
about 70%, by weight, of all fatty acids present in the
pharmaceutical composition.
8. The method of claim 2, wherein the 15-HEPE represents at least
about 90%, by weight, of all fatty acids present in the
pharmaceutical composition.
9. The method of claim 2, wherein the 15-HEPE represents
substantially all fatty acids present in the pharmaceutical
composition.
10. The method of claim 2, wherein the 15-HEPE represents all fatty
acids present in the pharmaceutical composition.
11. The method of claim 2 wherein the composition is free of any
other omega-3 fatty acids.
12. The method of claim 2, wherein the administering step includes
administering the pharmaceutical composition to the subject about 1
to about 4 times per day.
13. The method of claim 2, wherein the pharmaceutical composition
is present in one or more dosage units.
14. The method of claim 13, wherein the one or more dosage units
comprise orally deliverable capsules.
15. The method of claim 1, wherein the subject has a predisposition
to and/or a diagnosis of the liver disease.
16. The method of claim 1, wherein the liver disease is
non-alcoholic fatty liver disease (NAFLD).
17. The method of claim 2, wherein the pharmaceutical composition
comprises about 0.1% to about 99%, by weight, 15-HEPE.
18. The method of claim 2, wherein the pharmaceutical composition
comprises at least about 50%, by weight, 15-HEPE.
Description
PRIORITY CLAIM
[0001] The present application is a continuation of U.S. patent
application Ser. No. 16/527,841, filed on Jul. 31, 2019 (now U.S.
Pat. No. 10,813,903), which is a continuation of U.S. patent
application Ser. No. 14/695,865, filed on Apr. 24, 2015, which is a
continuation of International Application PCT/EP2014/051455, filed
on Jan. 24, 2014, which claims priority to GB Application No. GB
1301626.6, filed on Jan. 30, 2013, the entireties of each of the
foregoing which are incorporated herein by reference.
TECHNICAL FIELD
[0002] The invention pertains to the compositions, formulations and
methods of treating fatty liver disorders (FLD), such as
non-alcoholic fatty liver disease (NAFLD) and non-alcoholic
steatohepatitis (NASH) and their sequelae by administration of a
pharmaceutical composition comprising 15-hydroxy eicosapentaenoic
acid (known as 15-OHEPA or 15-HEPE) in a subject in need thereof.
In particular, the invention relates to a pharmaceutical
composition with improved efficacy over one comprising EPA as the
significant active component, rather than 15-OHEPA, for the
treatment of subjects suffering from FLD and/or complications of
FLD, to reduce fatty deposits in the liver to treat or prevent FLD
and its associated complications.
SUMMARY
[0003] Fatty liver disorders, also known as fatty liver or fatty
liver disease (FLD), relates to a condition where large vacuoles of
triglyceride fat accumulate in liver cells via the process of
steatosis, or abnormal retention of lipids within a cell. Despite
having multiple causes, fatty liver is considered a single disease
that occurs frequently in subjects with excessive alcohol intake
and/or those who are obese (with or without effects of insulin
resistance). The condition is also associated with other diseases
that influence fat metabolism. FLD may be categorized into two
separate conditions: alcoholic FLD and non-alcoholic FLD. Both
conditions show micro-vesicular and macro-vesicular fatty changes
at different stages of the disease. Accumulation of fat may also be
accompanied by a progressive inflammation of the liver (hepatitis),
called steatohepatitis. Fatty liver is also known in the art as
alcoholic steatosis and non-alcoholic fatty liver disease (NAFLD),
and the more severe forms as alcoholic steatohepatitis (part of
alcoholic liver disease) and non-alcoholic steatohepatitis (NASH).
Nonalcoholic fatty liver disease-associated cirrhosis is the most
severe form of the disease and is characterized by liver
inflammation that leads to scarring of the liver tissue, ultimately
resulting in liver failure.
[0004] Obesity, metabolic syndrome, type 2 diabetes, and
atherosclerosis are increasing at an alarming rate in the Western
world. In recent years, fatty liver has emerged as an independent
risk factor for these diseases. Fatty liver is the accumulation of
triglycerides and other fats within hepatocytes. Fatty liver
disease can range from fatty liver alone (also known as
"steatosis"), to fatty liver associated with inflammation or
steatohepatitis. Non-alcoholic fatty liver disease (NAFLD) and
non-alcoholic steatohepatitis (NASH) are the most common causes of
chronic liver disease in the adult population and represents a
crucial risk factor for progression to liver failure, cirrhosis and
hepatocellular carcinoma. While steatosis affects approximately 30%
of the population, 80% of obese patients have NAFLD and 50% of
patients undergoing bariatric surgery have steatohepatitis. NAFLD
also represents the most common cause of liver disease in children.
It is estimated that NAFLD affects up to 20 percent of adults and
nearly 5 percent of children. Some experts estimate that about two
thirds of obese adults and half of obese children may have fatty
liver. In the past ten years, as the rates of obesity in have
doubled in adults and tripled in children and teenagers, NAFLD and
NASH are becoming more common. NASH can cause scarring and
hardening of the liver, leading to cirrhosis, a very serious
disease that may require a liver transplant, and eventually to
hepatocellular carcinoma.
[0005] There is no single established medical treatment for fatty
liver. Presently, treatment of NAFLD is limited to 1) treatment of
associated metabolic disorders such as diabetes and hyperlipidemia;
2) the management of insulin resistance focusing on weight loss,
exercise and/or a pharmacological approach; and 3) the use of
antioxidants as hepatic protection agents. Despite the use of many
different therapeutic modalities, no clear treatment is currently
available to address NAFLD. Because it is clinically important to
resolve NAFLD and its sequelae, new approaches aimed at preventing
and reversing fat accumulation in the liver are necessary.
[0006] We have surprisingly found that 15-HEPE, a metabolite of
EPA, is more potent than EPA in the treatment of FLD.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] FIGS. 1A, 1B, 2A, and 2B present data from an in vivo
efficacy study of 15-OHEPA and EPA in STAM model of non-alcoholic
steatohepatitis, as discussed in the Examples herein.
[0008] FIG. 1A shows that there was no significant change in body
weight in any of the experimental groups. FIG. 1B shows that only
the 15-OHEPA treatment group (500 mg/kg) and the positive control
(telmisartan) had a significant reduction in liver weight as
compared to the vehicle control.
[0009] FIGS. 2A and 2B show that NAS significantly decreased only
in the 15-OHEPA (500 mg/kg) and the positive control (telmisartan)
groups as compared to the vehicle control.
[0010] Other features and advantages of the invention will be
apparent from the following detailed description.
DETAILED DESCRIPTION
[0011] The present invention relates to compositions and methods
for treating fatty liver disorders, including non-alcoholic fatty
liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), by
administration of a composition comprising 15-HEPE in a subject in
need thereof.
[0012] As used herein, "15-OHEPA" is
15-Hydroxy-eicosa-5,8,11,13,17-pentaenoic acid. 15-OHEPA can be
synthesized from eicosapentaenoic acid, EPA according to methods
known in the art. As used herein, the term "15-OHEPA" refers to
15-OHEPA in its free acid form (e.g,
15-hydroxy-eicosa-5,8,11,13,17-pentaenoic acid) and/or a
pharmaceutically acceptable ester, conjugate or salt thereof, or
mixtures of any of the foregoing. A derivative of 15-OHEPA may be
used instead, though this does not include any derivative compound
missing the hydroxy group of 15-OHEPA. In some embodiments, the
15-OHEPA is used in the free acid form. Alternatively,
pharmaceutically acceptable esters or salts of 15-OHEPA are used in
the invention. In some embodiments, the 15-OHEPA is in the form of
a C.sub.1-4 alkyl ester such as methyl ester or ethyl ester
form.
[0013] As used herein, "EPA" is eicosa-5,8,11,14,17-pentaenoic
acid, also known as 20:5n-3, an omega-3 fatty acid. EPA is readily
obtainable through commercial sources.
[0014] Accordingly, in one aspect of the present invention, a
method of treating a fatty liver disorder in a subject is provided,
comprising administering to the subject a therapeutically effective
amount of a composition comprising 15-OHEPA.
[0015] The present invention provides 15-OHEPA, or a composition
comprising 15-OHEPA, for use in the treatment of a fatty liver
disorder.
[0016] The present invention provides a use of 15-OHEPA, or a
composition comprising 15-OHEPA, in the manufacture of a medicament
for treating a fatty liver disorder.
[0017] In another aspect, the present invention provides a
pharmaceutical composition comprising a therapeutically effective
amount of 15-OHEPA. The 15-OHEPA may be the sole significant active
ingredient in that composition and in the methods and uses as
stated herein. The 15-OHEPA may be the sole active ingredient.
Alternatively, the 15-OHEPA may be combined for co-formulation or
co-administration with other agents for treating FLD. If an
additional active agent is to be used, the 15-OHEPA can be
co-formulated as a single dosage unit or can be formulated as two
to a plurality of dosage units for coordinated, combination or
concomitant administration.
[0018] The invention also provides formulations of 15-OHEPA and
formulations comprising 15-OHEPA and methods of using these
formulations for treating fatty liver disorders, including
non-alcoholic fatty liver disease (NAFLD) and non-alcoholic
steatohepatitis (NASH).
[0019] 15-OHEPA is a chiral molecule and may be used in the (S)- or
(R)-enantiomeric form, or as a racemic mixture. Used herein,
"15-OHEPA" includes all such forms, with no limitation as to
stereospecifcity. In another embodiment, the 15-OHEPA comprises the
(S) form: 15(S)-Hydroxy-(5Z,8Z,11Z,13E,17Z)-eicosapentaenoic acid.
In some embodiments, the 15-OHEPA may be used in the form of the
ethyl ester. In other embodiments the 15-OHEPA may be used as the
free acid.
[0020] The present invention further provides an pharmaceutical
composition for oral delivery, comprising 15-OHEPA. That
composition may comprise a pharmaceutically acceptable excipient.
The 15-OHEPA may be in any form as discussed herein. The 15-OHEPA
may be present from about 50 mg to about 3000 mg.
[0021] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention pertains.
Although methods and materials similar or equivalent to those
described herein can be used in the practice of the present
invention, suitable methods and materials are described below. All
publications, patent applications, patents, and other references
mentioned herein are expressly incorporated by reference in their
entirety. In cases of conflict, the present specification,
including definitions, will control. In addition, the materials,
methods, and examples described herein are illustrative only and
are not intended to be limiting.
Pharmaceutical Compositions
[0022] While the present invention is capable of being embodied in
various forms, the description below of several embodiments is made
with the understanding that the present disclosure is to be
considered as an exemplification of the invention, and is not
intended to limit the invention to the specific embodiments
illustrated. Headings are provided for convenience only and are not
to be construed to limit the invention in any manner. Embodiments
illustrated under any heading may be combined with embodiments
illustrated under any other heading.
[0023] The use of numerical values in the various quantitative
values specified in this application, unless expressly indicated
otherwise, are stated as approximations as though the minimum and
maximum values within the stated ranges were both preceded by the
word "about." In this manner, slight variations from a stated value
can be used to achieve substantially the same results as the stated
value. Also, the disclosure of ranges is intended as a continuous
range including every value between the minimum and maximum values
recited as well as any ranges that can be formed by such values.
Also disclosed herein are any and all ratios (and ranges of any
such ratios) that can be formed by dividing a recited numeric value
into any other recited numeric value. Accordingly, the skilled
person will appreciate that many such ratios, ranges, and ranges of
ratios can be unambiguously derived from the numerical values
presented herein and in all instances such ratios, ranges, and
ranges of ratios represent various embodiments of the present
invention.
15-Hydroxy Eicosapentaenoic Acid
[0024] In one embodiment, compositions of the invention comprise
15-OHEPA as an active ingredient. 15-OHEPA is the abbreviation for
15-Hydroxy eicosapentaenoic acid, a metabolite of eicosapentaenoic
acid (EPA) that can be synthesized via ways known in the art, such
as exposure of eicospentaenoic acid to the enzyme 15-lipoxygenase.
As used herein, the term "15-OHEPA" refers to 15-OHEPA in its free
acid form (e.g., 15-Hydroxy eicosapentaenoic acid) and/or a
pharmaceutically acceptable ester, conjugate or salt thereof, or
mixtures of any of the foregoing. A derivative of 15-OHEPA may be
used instead, though this does not include any derivative compound
missing the hydroxy group of 15-OHEPA. The term "pharmaceutically
acceptable" in the present context means that the substance in
question does not produce unacceptable toxicity to the subject or
interaction with other components of the composition.
[0025] In one embodiment, the 15-OHEPA is in the form of an ester
(also referred to herein as E-15-OHEPA or ethyl-15-OHEPA). In
another embodiment, the 15-OHEPA comprises a C.sub.1-C.sub.5 alkyl
ester of 15-OHEPA. In another embodiment, the 15-OHEPA comprises
15-OHEPA methyl ester, 15-OHEPA propyl ester, or 15-OHEPA butyl
ester. In still another embodiment, the 15-OHEPA comprises the
optically active 15(S)-Hydroxy-(5Z,8Z,11Z,13E,17Z)-eicosapentaenoic
acid. This isomer may be used in any of the forms discussed
above.
[0026] In another embodiment, the 15-OHEPA comprises lithium
15-OHEPA, mono, di- or triglyceride 15-OHEPA or any other ester or
salt of 15-OHEPA, or the free acid form of 15-OHEPA.
[0027] In various embodiments, the invention provides
pharmaceutical compositions, for example orally deliverable
compositions, comprising 15-OHEPA. In one embodiment, the
compositions comprise a therapeutically effective amount of
15-OHEPA. In one embodiment, the pharmaceutical composition
comprises about 0.1% to about 99%, about 1% to about 95%, about 5%
to about 90% by weight of 15-OHEPA.
[0028] In one embodiment, the pharmaceutical composition comprises
about at least about 70%, at least about 80% or at least about 90%,
by weight, of 15-OHEPA. In one embodiment, the pharmaceutical
composition comprises at least about 50%, at least about 60%, at
least about 70%, at least about 80% or at least about 90%, by
weight of 15-OHEPA.
[0029] In another embodiment, 15-OHEPA is present in a composition
of the invention in an amount of about 1 mg to about 10,000 mg, 25
mg to about 7500 mg, about 25 mg to about 5000 mg, about 50 mg to
about 5000 mg, about 50 mg to about 3000 mg, about 75 mg to about
2500 mg, or about 100 mg to about 1000 mg, for example about 25 mg,
about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg,
about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275
mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about
400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg,
about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625
mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about
750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg,
about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975
mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg,
about 1100 mg, about 1025 mg, about 1050 mg, about 1075 mg, about
1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300
mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg,
about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about
1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625
mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg,
about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about
1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950
mg, about 1975 mg, about 2000 mg, about 2025 mg, about 2050 mg,
about 2075 mg, about 2100 mg, about 2125 mg, about 2150 mg, about
2175 mg, about 2200 mg, about 2225 mg, about 2250 mg, about 2275
mg, about 2300 mg, about 2325 mg, about 2350 mg, about 2375 mg,
about 2400 mg, about 2425 mg, about 2450 mg, about 2475 mg, or
about 2500 mg.
[0030] In one embodiment, 15-OHEPA present in a composition of the
invention comprises at least 90% by weight 15-OHEPA (as the term
"15-OHEPA" is defined and exemplified herein). 15-OHEPA
compositions can comprise even higher purity 15-OHEPA, for example
at least 95% by weight 15-OHEPA or at least 97% by weight 15-OHEPA,
wherein the 15-OHEPA is any form of 15-OHEPA as set forth herein.
The purity of 15-OHEPA can further be defined (e.g. impurity
profile) by any of the descriptions of 15-OHEPA provided
herein.
[0031] Above are discussed the amounts of the 15-OHEPA in the
pharmaceutical composition and their purity. The nature of the
essential fatty acids and their synthesis is such that the 15-OHEPA
composition may include moieties from other essential fatty acids
in the essential fatty acid metabolic cascade.
[0032] In one embodiment, a composition of the invention contains
not more than about 10%, not more than about 9%, not more than
about 8%, not more than about 7%, not more than about 6%, not more
than about 5%, not more than about 4%, not more than about 3%, not
more than about 2%, not more than about 1%, or not more than about
0.5%, by weight of other omega-3 fatty acids including alpha
linolenic acid, stearidonic acid, docosahexaenoic acid (DHA) or
derivatives thereof. In other embodiments there is substantially
no, or no such other omega-3 fatty acids present.
[0033] In another embodiment, 15-OHEPA represents at least about
60%, at least about 70%, at least about 80%, at least about 90%, at
least about 95%, at least about 97%, at least about 98%, at least
about 99%, or 100%, by weight, of all fatty acids present in a
composition of the invention.
[0034] There may be present some residual eicosapentaenoic acid
from the synthesis of the 15-OHEPA. There may be not more than
about 10%, not more than about 9%, not more than about 8%, not more
than about 7%, not more than about 6%, not more than about 5%, not
more than about 4%, not more than about 3%, not more than about 2%,
not more than about 1%, or not more than about 0.5%, by weight EPA.
Alternatively, there is substantially no, or no, EPA in a form
which has not been modified to the hydroxyl-form.
Additional Active Agents
[0035] In one embodiment, the pharmaceutical composition further
comprises one or more additional active agent(s). In one
embodiment, the pharmaceutical composition comprises an amount of
the additional active agent that is less than the generally
recognized therapeutically effective amount for that agent. In one
embodiment, the pharmaceutical composition comprises an amount of
the additional active agent that is equal to or greater than the
generally recognized therapeutically effective amount for that
agent.
[0036] EPA itself has beneficial properties in treating FLD and it
is possible to combine the 15-OHEPA with EPA in an alternative
embodiment.
[0037] In one embodiment, 15-OHEPA and one or more active agent(s)
are present in a composition of the invention, or are
co-administered in a weight ratio of 15-OHEPA: additional agent of
about 1:1000 to about 1000:1, about 1:500 to about 500:1, about
1:100 to about 100:1, about 1:50 to about 50:1, about 1:25 to about
25:1, about 1:10 to about 10:1, about 1:5 to about 5:1, about 1:4
to about 4:1 about 1:3 to about 3:1, about 1:2 to about 2:1 or
about 1:1.
Dosage Forms
[0038] A composition for use in accordance with the disclosure can
be formulated as one or more dosage units. The terms "dose unit"
and "dosage unit" herein refer to a portion of a pharmaceutical
composition that contains an amount of a therapeutic agent suitable
for a single administration to provide a therapeutic effect. Such
dosage units may be administered one to a plurality (i.e. 1 to
about 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 2) of times per day, or as
many times as needed to elicit a therapeutic response.
[0039] In some embodiments, compositions of the invention are in
the form of orally deliverable dosage forms or units. Non-limiting
examples of suitable dosage forms include tablets (e.g. suspension
tablets, bite suspension tablets, rapid dispersion tablets,
chewable tablets, etc), caplets, capsules (e.g. a soft or a hard
gelatin capsule or HPMC capsule), lozenges, sachets, cachets,
troches, pellets, suspension, elixirs, syrups or any other solid
dosage form reasonably adapted for oral administration. The terms
"oral delivery" and "oral administration" herein include any form
of delivery wherein the agent or composition is placed in the mouth
of the subject under treatment, whether swallowed or not. This
therefore includes buccal and sublingual administration, as well as
esophagael administration.
[0040] Alternatively, compositions of the invention can also be
formulated for rectal, topical, or parenteral (e.g. subcutaneous,
intramuscular, intravenous and intradermal or infusion)
delivery.
[0041] In discussing the amount of 15-OHEPA in a composition of the
invention, this may be split over several dosage forms. There is a
limit as to the size for oral administration. If a subject is to be
administered 1 to 4 g 15-OHEPA a day, this may be by up to 4
capsules, each providing 1 g 15-OHEPA.
[0042] Compositions of the invention can be in the form of liquid
dosage forms or dose units to be imbibed directly or they can be
mixed with food or beverage prior to ingestion. Non-limiting
examples of suitable liquid dosage forms include solutions,
suspensions, elixirs, syrups, liquid aerosol formulations, and the
like.
[0043] In another embodiment, compositions of the invention
comprise one or more pharmaceutically acceptable excipients. The
term "pharmaceutically acceptable excipient" herein means any
substance, not itself a therapeutic agent, used as a carrier or
vehicle for delivery of a therapeutic agent to a subject or added
to a pharmaceutical composition to improve its handling or storage
properties or to permit or facilitate formation of a unit dose of
the composition, and that does not produce unacceptable toxicity or
interaction with other components in the composition. By way of
example only, a pharmaceutical composition according to the present
disclosure may comprise one or more of: antioxidants, surfactants,
preservatives, flavouring agents, co-solvents, viscosity aids,
suspension aids, and lipophilic phases.
[0044] In one embodiment, the pharmaceutical composition comprises
one or more antioxidants such as ascorbic acid, palmitic acid,
ascorbyl palmitate, a-tocopherol, idebenone, ubiquinone, ferulic
acid, coenzyme Q10, lycopene, green tea, catechins,
epigallocatechin 3-gallate (EGCG), green tea polyphenols (GTP),
silymarin, coffeeberry, resveratrol, grape seed, pomegranate
extracts, genisten, pycnogenol, niacinamide, and the like. In one
embodiment, the pharmaceutical composition comprises about 0.01 wt.
% to about 2 wt. % of an antioxidant, for example about 0.01 wt. %,
about 0.02 wt. %, about 0.03 wt. %, about 0.04 wt. %, about 0.05
wt. %, about 0.06 wt. %, about 0.07 wt. %, about 0.08 wt. %, about
0.09 wt. %, about 0.1 wt. %, about 0.11 wt. %, about 0.12 wt. %,
about 0.13 wt. %, about 0.14 wt. %, about 0.15 wt. %, about 0.16
wt. %, about 0.17 wt. %, about 0.18 wt. %, about 0.19 wt. %, about
0.2 wt. %, about 0.21 wt. %, about 0.22 wt. %, about 0.23 wt. %,
about 0.24 wt. %, about 0.25 wt. %, about 0.26 wt. %, about 0.27
wt. %, about 0.28 wt. %, about 0.29 wt. %, about 0.3 wt. %, about
0.31 wt. %, about 0.32 wt. %, about 0.33 wt. %, about 0.34 wt. %,
about 0.35 wt. %, about 0.36 wt. %, about 0.37 wt. %, about 0.38
wt. %, about 0.39 wt. %, about 0.4 wt. %, about 0.41 wt. %, about
0.42 wt. %, about 0.43 wt. %, about 0.44 wt. %, about 0.45 wt. %,
about 0.46 wt. %, about 0.47 wt. %, about 0.48 wt. %, about 0.49
wt. %, about 0.5 wt. %, about 0.51 wt. %, about 0.52 wt. %, about
0.53 wt. %, about 0.54 wt. %, about 0.55 wt. %, about 0.56 wt. %,
about 0.57 wt. %, about 0.58 wt. %, about 0.59 wt. %, about 0.6 wt.
%, about 0.61 wt. %, about 0.62 wt. %, about 0.63 wt. %, about 0.64
wt. %, about 0.65 wt. %, about 0.66 wt. %, about 0.67 wt. %, about
0.68 wt. %, about 0.69 wt. %, about 0.7 wt. %, about 0.71 wt. %,
about 0.72 wt. %, about 0.73 wt. %, about 0.74 wt. %, about 0.75
wt. %, about 0.76 wt. %, about 0.77 wt. %, about 0.78 wt. %, about
0.79 wt. %, about 0.8 wt. %, about 0.81 wt. %, about 0.82 wt. %,
about 0.83 wt. %, about 0.84 wt. %, about 0.85 wt. %, about 0.86
wt. %, about 0.87 wt. %, about 0.88 wt. %, about 0.89 wt. %, about
0.9 wt. %, about 0.91 wt. %, about 0.92 wt. %, about 0.93 wt. %,
about 0.94 wt. %, about 0.95 wt. %, about 0.96 wt. %, about 0.97
wt. %, about 0.98 wt. %, about 0.99 wt. %, about 1 wt. %, about 1.1
wt. %, about 1.2 wt. %, about 1.3 wt. %, about 1.4 wt. %, about 1.5
wt. %, about 1.6 wt. %, about 1.7 wt. %, about 1.8 wt. %, about 1.9
wt. %, or about 2 wt. % of the one or more antioxidant.
[0045] Therapeutic Methods
[0046] The compositions and formulations disclosed herein may be
used in the treatment of fatty liver disease. In one embodiment the
fatty liver disease is non-alcoholic fatty liver disease. In
another embodiment the fatty liver disease is non-alcoholic
steatohepatitis. In one embodiment, the method comprises
administering a pharmaceutical composition as disclosed herein to a
subject once per day, twice per day, three times per day, or more
than three times per day.
[0047] As used herein, "treating" or "treatment" of a disease,
disorder, or condition includes at least partially: (1) preventing
the disease, disorder, or condition, i.e. causing the clinical
symptoms of the disease, disorder, or condition not to develop in a
mammal that is exposed to or predisposed to the disease, disorder,
or condition but does not yet experience or display symptoms of the
disease, disorder, or condition; (2) inhibiting the disease,
disorder, or condition, i.e., arresting or reducing the development
of the disease, disorder, or condition or its clinical symptoms; or
(3) relieving the disease, disorder, or condition, i.e., causing
regression of the disease, disorder, or condition or its clinical
symptoms. The term "prevention" in relation to a given disease or
disorder means: preventing the onset of disease development if none
had occurred, preventing the disease or disorder from occurring in
a subject that may be predisposed to the disorder or disease but
has not yet been diagnosed as having the disorder or disease,
and/or preventing further disease/disorder development if already
present.
[0048] An "effective amount," as used herein, refers to the amount
of an active composition that is required to confer a therapeutic
effect on the subject. A "therapeutically effective amount," as
used herein, refers to a sufficient amount of an agent or a
compound being administered which will relieve to some extent one
or more of the symptoms of the disease, disorder, or condition
being treated. In some embodiments, the result is a reduction
and/or alleviation of the signs, symptoms, or causes of a disease,
or any other desired alteration of a biological system. For
example, in some embodiments, an "effective amount" for therapeutic
uses is the amount of the composition including a compound as
disclosed herein required to provide a clinically significant
decrease in disease symptoms without undue adverse side effects. In
some embodiments, an appropriate "effective amount" in any
individual case is determined using techniques, such as a dose
escalation study. The term "therapeutically effective amount"
includes, for example, a prophylactically effective amount. In
other embodiments, an "effective amount" of a compound disclosed
herein, such as a compound of Formula (A) or Formula (I), is an
amount effective to achieve a desired pharmacologic effect or
therapeutic improvement without undue adverse side effects. In
other embodiments, it is understood that "an effect amount" or "a
therapeutically effective amount" varies from subject to subject,
due to variation in metabolism, age, weight, general condition of
the subject, the condition being treated, the severity of the
condition being treated, and the judgment of the prescribing
physician. The term "pharmaceutically acceptable" in the present
context means that the substance in question does not produce
unacceptable toxicity to the subject or interaction with other
components of the composition.
[0049] Without further description, it is believed that one of
ordinary skill in the art may, using the preceding description and
the following illustrative examples, make and utilize the agents of
the present disclosure and practice the claimed methods. The
following working examples are provided to facilitate the practice
of the present disclosure, and are not to be construed as limiting
in any way the remainder of the disclosure.
EXAMPLES
[0050] The purpose of this study was to examine the effects of
15-OHEPA and EPA in the STAM model of Non-alcoholic
Steatohepatitis.
Protocol
[0051] Pathogen-free 15-day-pregnant C57BL/6 mice were obtained
from Charles River Laboratories in Japan Inc. (Kanagawa, Japan).
NASH was established in male mice by a single subcutaneous
injection of streptozotocin (STZ) (Sigma, USA) after birth and
feeding with a high fat diet (HFD; CLEA) Japan, Japan) ad libitum
after 4 weeks of age (day 28.+-.2). Mice were randomized into 5
groups of 8 mice at 5 weeks of age (day 35.+-.2) the day before the
start of treatment.
[0052] During the treatment period, individual body weight was
measured daily as well as clinical signs of behavior and
survival.
Groups
[0053] Group 1 (Vehicle): Eight NASH mice were orally administered
vehicle [olive oil] in a volume of 10 mL/kg once daily from 5 to 9
weeks of age.
[0054] Group 2 (15-OHEPA 50 mg/kg): Eight NASH mice were orally
administered vehicle supplemented with 15-OHEPA at a dose of 50
mg/kg once daily from 5 to 9 weeks of age.
[0055] Group 3 (15-OHEPA 500 mg/kg): Eight NASH mice were orally
administered vehicle supplemented with 15-OHEPA at a dose of 500
mg/kg once daily from 5 to 9 weeks of age.
[0056] Group 4 (EPA 500 mg/kg): Eight NASH mice were orally
administered vehicle supplemented with EPA at a dose 500 mg/kg once
daily from 5 to 9 weeks of age.
[0057] Group 5 (positive control): Eight NASH mice were orally
administered pure water supplemented with Telmisartan at a dose of
10 mg/kg once daily from 5 to 9 weeks of age.
[0058] At 9 weeks of age, all mice were sacrificed and the
following data was recorded; [0059] Individual liver weight [0060]
Liver to body weight ratio
[0061] Histopathological analyses of liver sections were performed
using HE staining (to estimate NAFLD Activity score). For HE
staining, sections were cut from paraffin blocks of liver tissue
prefixed in Bouin's solution and stained with Lillie-Mayer's
Hematoxylin (Muto Pure Chemicals, Japan) and eosin solution (Wako
Pure Chemical Industries). NAFLD Activity score (NAS) was
calculated according to the criteria of Kleiner (Kleiner D E. et
al., Hepatology, 2005; 41:1313).
[0062] Statistical tests were performed using Bonferroni Multiple
Comparison Test. P values <0.05 were considered statistically
significant.
Results
[0063] FIG. 1A shows that there was no significant change in body
weight in any of the experimental groups.
[0064] FIG. 1B shows that only the 15-OHEPA treatment group (500
mg/kg) and the positive control (telmisartan) had a significant
reduction in liver weight as compared to the vehicle control.
[0065] FIGS. 2A and 2B show that NAS significantly decreased only
in the 15-OHEPA (500 mg/kg) and the positive control (telmisartan)
groups as compared to the vehicle control.
* * * * *