Note: Descriptions are shown in the official language in which they were submitted.
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SUSTAINED RELEASE FORMULATIONS OF BEMPEDOIC ACID
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority to U.S. Provisional
Application No.
62/710,417, filed on February 16, 2018 and U.S. Provisional Application No.
62/774,083, filed
on November 30, 2018, each of which is hereby incorporated by reference in its
entirety.
BACKGROUND OF THE INVENTION
[0002] Bempedoic acid (ETC-1002) behaves as a prodrug in vivo where it is
converted to an
active species (ETC-1002¨CoA) by endogenous liver acyl-Coenzyme (CoA)
synthetase (ACS)
activity. A specific ACS isozyme, very long-chain acyl-CoA synthetase
(ACSVL1), is required
to form the active species. Once activated, ETC-1002-CoA directly inhibits ATP-
citrate lyase
(ACL) and through that action mediates effects on lipid metabolism. With
traditional
formulations, a fraction of bempedoic acid within a dosage form becomes
activated, with the
remaining unactivated fraction of the administered dose being eliminated. In
part, this is because
many Biopharmaceutics Classification System ("B CS") Class II active
pharmaceutical
ingredients ("APIs") -- such as bempedoic acid -- have low solubility and high
permeability.
What is needed, then, is a means for increasing the exposure of the active
drug in liver without
increasing the dose of bempedoic acid administered to patients.
SUMMARY OF THE INVENTION
[0003] The inventors have found that sustained-release of bempedoic acid
affords an increased
activation efficiency to the active species and improved exposure of the
activated drug in liver.
[0004] Aspects of the disclosure comprise a pharmaceutical formulation
comprising the
components: (i) 50-70% bempedoic acid, (ii) a filler, (iii) a diluent or
solubilizer, and (iv) a
binder, wherein the formulation is formulated for the sustained release of
bempedoic acid. In
some aspects, the filler is selected from the group consisting of, e.g.,
microcrystalline cellulose,
sodium carboxymethylcellulose, and a combination of microcrystalline cellulose
and sodium
carboxmethylcellulose. In some aspects, the diluent or solubilizer is selected
from a group
consisting of, e.g., sodium lauryl sulfate and sodium starch glycolate. In
some aspects, the binder
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is, e.g., hydroxylpropyl methylcellulose (HMPC). In some aspects, the
formulation is formulated
as a solid. In some aspects, the formulation is formulated for oral
administration.
[0005] In some aspects, any of the formulation described above comprise
bempedoic acid
dispersed within a polymeric matrix. In some aspects, any of the formulations
described above
are formulations which exhibit a drug release profile corresponding to a
pattern wherein, e.g.,
after 2 hours, no more than 30% of the total mass of the bempedoic acid is
released into a
subject. In some aspects, any of the formulations described above are
formulations which
exhibit a drug release profile corresponding to a pattern wherein, e.g., after
4 hours, no more
than 75% of the total mass of bempedoic acid is released. In some aspects, any
of the
formulations described above are formulations which exhibit a drug release
profile
corresponding to a pattern wherein, e.g., after 8 hours, no more than 90% of
the total mass of
bempedoic acid is released. In some aspects, any of the formulations described
above are
formulations providing a therapeutically effective concentration of bempedoic
acid over a period
of, e.g., 24 hours when administered to a human subject.
[0006] In some aspects, in any of the formulations described above, the filler
component is, e.g.,
microcrystalline cellulose, or sodium carboxymethylcellulose, or a combination
of sodium
carboxymethylcellulose and microcrystalline cellulose. In some aspects, the
amount of filler
component in the formulation is 5-50% w/w. In some aspects, the binder
component is about
0.1-1.5% w/w. In some aspects, the formulations described above comprise,
e.g., 50-70% w/w
bempedoic acid, 30%-45% w/w filler component, 1-5% w/w diluent or solubilizer
component,
and 0.1-1.5% w/w binder component. In some aspects, the formulations described
above
comprise, e.g., 55-65% w/w bempedoic acid, 30-45% w/w filler component, 1-5%
w/w diluent
or solubilizer component, and 0.1-1.5% w/w binder component. In some aspects,
the
formulations described above comprise, e.g., 40, 50, 60, 70, 80, 90, 100, 110,
120, 130, 140, 150,
160, 170, 180, 190, 200, 210, or 220 mg of bempedoic acid.
[0007] In some aspects, the formulations described above dissolve at a zero
order release rate for
at least, e.g., 8, 9, 10, 11, or 12 hours. In some aspects, the formulations
described above
comprise bempedoic acid and a polymer matrix, and have a hardness of, e.g., 2-
30 kg. In some
aspects, the formulations described above are either shaped as a sphere or
else have a ratio of
thickness to diameter that is effective to permit erosion when dissolution is
tested.
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[0008] In some aspects, any of the formulations described above provide a
therapeutically
effective concentration of bempedoic acid over a period of 24 hours when
administered to a
human subject. In some aspects, the formulation provides a maximum blood
plasma
concentration (Cmax) of bempedoic acid of no more than, e.g., 50 g/mL, 60
g/mL, 70 g/mL,
or 80 g/mL when administered to a human subject. In some aspects, the
formulation provides a
maximum blood plasma concentration (Cmax) of bempedoic acid in a range from,
e.g., 45 g/mL
to 60 g/mL, for e.g., 20, 21, 22, 23, or 24 hours after administration to a
human subject.
[0009] In some aspects, any of the formulations described above are formulated
as, e.g., gelatin
capsules or tablets. In some aspects, the gelatin capsule comprises, e.g., a
powder excipient.
[0010] In some aspects, the disclosure encompasses methods of administering a
bempedoic acid
formulation to a human subject in need thereof, wherein the formulation
comprises bempedoic
acid and a polymer matrix, and wherein, the administration results in a
maximum blood plasma
concentration (Cmax) of bempedoic acid of no more than about, e.g., 60 [tg/mL,
and wherein the
blood plasma concentration is in a range from about 45-57 g/mL for 24 hours
after
administration. In a related aspect, the formulation is one of the
formulations described above.
[0011] In some aspects, the disclosure encompasses methods of treating
cardiovascular disease
or reducing the risk of cardiovascular disease in a subject, the method
comprising administering
an effective amount of a pharmaceutical formulation to a human subject in need
thereof, wherein
the formulation comprises the components of bempedoic acid and a polymer, and
wherein the
dissolution of the formulation exhibits a drug release profile corresponding
to a pattern, e.g.,
after 2 hours, no more than 30% of the bempedoic acid is released; after 4
hours, no more than
75% of the bempedoic acid is released; after 8 hours, no more than 90% of the
bempedoic acid is
released. In some aspects, the method provides a therapeutically effective
concentration of
bempedoic acid over a period of 24 hours to treat cardiovascular disease or
reduce the risk of
cardiovascular disease when administered to the subject. In another related
aspect, the
administered formulation does not release more than 95% of the bempedoic acid
after 8 hours. In
a related aspect, the administered formulation is one of the formulations
described above.
[0012] In certain aspects of the methods described above, the polymer is
hydroxypropyl
methylcellulose (HPMC). In certain other aspects, the bempedoic acid in the
administered
formulation is, e.g., about 30-80% by weight and the polymer is hydroxypropyl
methylcellulose
(HPMC) and is, e.g., about 15-35% by weight.
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[0013] In certain aspects of any of the methods described above, the method
lowers total
cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C) when
administered to a human
subject having, e.g., hypercholesterolemia, mixed dyslipidemia, type II
diabetes mellitus,
obesity, chronic liver disease or kidney disease. In certain other aspects of
any of the methods
described above, the method decreases the level of very low density
lipoprotein (VLDL) in the
subject below that of a control subject receiving placebo. In certain other
aspects of any of the
methods described above, the method decreases the size of VLDL particles in
the subject below
that of a control subject receiving placebo. In certain other aspects of any
of the methods
described above, the method decreases the ratio of apolipoprotein B (ApoB) to
apolipoprotein A-
1 (ApoAl) in the subject below that of a control subject receiving placebo. In
certain other
aspects of any of the methods described above, the method decreases the level
of low-density
lipoprotein cholesterol (LDL-C) in the subject. In certain other aspects of
any of the methods
described above, the method decreases LDL-C levels by at least 5%, 10%, 15%,
or 20% relative
to an otherwise untreated subject or a placebo-treated subject. In certain
other aspects of any of
the methods described above, the method decreases LDL-C levels by 5-40%
relative to an
otherwise untreated subject or a placebo-treated subject. In certain other
aspects of any of the
methods described above, the method decreases LDL-C levels in a subject at
least as effectively
as an equal dose of an immediate release bempedoic acid formulation. In
certain other aspects of
any of the methods described above, the method decreases LDL-C levels in a
subject at least as
effectively as a higher dose of an immediate release bempedoic acid
formulation, wherein the
higher dose is 180 mg/day.
[0014] Further, the sustained-release compositions described herein provide an
efficient means
for systemically delivering bempedoic acid. As a result, a lower dose and/or
less frequent
administration (relative to known bempedoic acid formulations) is required to
produce the same
effect. In this manner, unwanted side effects can be reduced, minimized or
eliminated.
[0015] In one aspect the disclosure provides for a pharmaceutical composition
comprising a
solid dosage form, the solid dosage form comprising bempedoic acid and a
polymer matrix. In
one aspect the disclosure provides for a solid dosage form that is a capsule
or a tablet.
[0016] In one aspect, the disclosure provides for a sustained-release
pharmaceutical dosage form
comprising a solid oral dosage form, wherein the solid oral dosage form
comprises: bempedoic
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acid and a polymeric matrix. In one aspect, the bempedoic acid is dispersed
within a polymeric
matrix.
[0017] In one aspect, the disclosure provides for a zero-order sustained-
release composition
comprising bempedoic acid and a polymer matrix. In one aspect, the zero-order
sustained-
release composition comprises bempedoic acid dispersed within a polymeric
matrix.
[0018] In one aspect, the disclosure provides for a pharmaceutical composition
comprising a
solid dosage form, where the solid dosage form has physical properties such
that it exhibits a
certain dissolution profile when dissolution tested using a United States
Pharmacopeia (USP)
apparatus.
[0019] In one aspect, the disclosure provides for methods of treating or
reducing the risk of
cardiovascular disease in a subject by administering the compositions
disclosed herein, which
may be sustained release formulations in some embodiments or immediate release
formulations
in other embodiments. In one aspect, the disclosure provides for methods of
treating a metabolic
syndrome in a subject by administering the compositions disclosed herein. In
one aspect, the
disclosure provides for methods of treating non-alcoholic fatty liver disease
(NAFLD) in a
subject by administering the compositions disclosed herein. In one aspect, the
disclosure
provides for methods of treating non-alcoholic steatohepatitis (NASH) in a
subject by
administering the compositions disclosed herein.
[0020] In some aspects, the disclosure encompasses a method of inhibiting ATP-
citrate lyase
(ACL) enzyme in a subject, wherein the method comprises administering to the
subject the
pharmaceutical dosage form of any of the above formulations.
[0021] In some aspects, the disclosure encompasses a method of treating
metabolic syndrome in
a subject, wherein the method comprises administering an effective amount of a
pharmaceutical
dosage form of any of the above formulations.
[0022] In some aspects, the disclosure encompasses a method of treating
metabolic syndrome in
a subject, wherein the subject is obese, has hypercholesterolemia, has mixed
dyslipidemia, has
type 2 diabetes, or any combination thereof, and wherein the method comprises
administering an
effective amount of a pharmaceutical dosage form of any of the above
formulations.
[0023] In some aspects, the disclosure encompasses a method of treating
metabolic syndrome in
a subject, wherein the subject has hypercholesterolemia, and wherein the
method comprises
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administering an effective amount of a pharmaceutical dosage form of any of
the above
formulations.
[0024] In some aspects, the disclosure encompasses a method of treating
metabolic syndrome in
a subject, wherein the metabolic syndrome is non-alcoholic fatty liver disease
(NAFLD), and
wherein the method comprises administering an effective amount of a
pharmaceutical dosage
form of any of the above formulations.
[0025] In some aspects, the disclosure encompasses a method of treating
metabolic syndrome in
a subject, wherein the metabolic syndrome is non-alcoholic steatohepatitis
(NASH), and wherein
the method comprises administering an effective amount of a pharmaceutical
dosage form of any
of the above formulations.
[0026] Further, the sustained-release compositions described herein provide an
efficient means
for systemically delivering bempedoic acid. As a result, a lower dose and/or
less frequent
administration (relative to known bempedoic acid formulations) is required to
produce the same
effect. In this manner, unwanted side effects can be reduced, minimized or
eliminated.
[0027] In one aspect the disclosure provides for a pharmaceutical composition
comprising a
solid dosage form, the solid dosage form comprising bempedoic acid and a
polymer matrix. In
one aspect the disclosure provides for a solid dosage form that is a capsule
or a tablet.
[0028] In one aspect, the disclosure provides for a sustained-release
pharmaceutical dosage form
comprising a solid oral dosage form, wherein the solid oral dosage form
comprises: bempedoic
acid and a polymeric matrix. In one aspect, the bempedoic acid is dispersed
within a polymeric
matrix.
[0029] In one aspect, the disclosure provides for a zero-order sustained-
release composition
comprising bempedoic acid and a polymer matrix. In one aspect, the zero-order
sustained-
release composition comprises bempedoic acid dispersed within a polymeric
matrix.
[0030] In one aspect, the disclosure provides for a pharmaceutical composition
comprising a
solid dosage form, where the solid dosage form has physical properties such
that it exhibits a
certain dissolution profile when dissolution tested using a United States
Pharmacopeia (USP)
apparatus.
[0031] In one aspect, the disclosure provides for methods of treating or
reducing the risk of
cardiovascular disease in a subject by administering the compositions
disclosed herein, which
may be sustained release formulations in some embodiments or immediate release
formulations
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in other embodiments. In one aspect, the disclosure provides for methods of
treating a metabolic
syndrome in a subject by administering the compositions disclosed herein. In
one aspect, the
disclosure provides for methods of treating non-alcoholic fatty liver disease
(NAFLD) in a
subject by administering the compositions disclosed herein. In one aspect, the
disclosure
provides for methods of treating non-alcoholic steatohepatitis (NASH) in a
subject by
administering the compositions disclosed herein.
[0032] In another aspect, the disclosure provides for methods of administering
or methods of
delivering bempedoic acid by administering the compositions disclosed above
and described in
more detail below.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0033] These and other features, aspects, and advantages of the present
invention will become
better understood with regards to the following description, and accompanying
drawings, where:
[0034] Figure 1A is a graph showing the plasma serum concentrations of
bempedoic acid (ETC-
1002) in the liver of Male Han Wistar rats after: 1. a single bolus
administration of bempedoic
acid (circles) and 2. multiple split bolus administrations of bempedoic acid
(squares).
[0035] Figure 1B is a graph displaying the concentrations of liver Acetyl-CoA
in Male Han
Wistar rats after: 1. a single bolus administration of bempedoic acid
(circles) and 2. multiple split
bolus administrations of bempedoic acid (squares).
[0036] Figure 1C is a graph displaying the concentrations of the active
species, ETC-1002-CoA
in livers of Male Han Wistar rats after: (1) a single bolus administration of
bempedoic acid
(circles) and (2) multiple split administrations of bempedoic acid (squares).
[0037] Figure 2A is a graph showing the concentration versus times of
bempedoic acid released
from multiple bempedoic acid formulations upon testing in a USP dissolution
assay.
[0038] Figure 2B is a graph showing the concentration versus time of bempedoic
acid released
from bempedoic acid formulations CU07-101 and CU07-118 upon testing in a USP
dissolution
assay.
[0039] Figure 3 is a graph showing the mean plasma concentration of bempedoic
acid in human
subjects after administration of immediate release tablet comprising 180 mg of
bempedoic acid
active ingredient.
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[0040] Figure 4 is a graph showing the mean plasma concentration of bempedoic
acid in obese
but otherwise healthy subjects after administration of a single dose of
sustained release tablets
comprising 50 mg, 100 mg, and 200 mg of bempedoic acid.
[0041] Figure 5 is a graph showing the percent change in LDL-C levels from
baseline after 14
days of dosing of sustained release tablet comprising 100 mg of bempedoic
acid.
[0042] Figure 6 summarizes the study design of Immediate Release (IR) Study 1.
[0043] Figure 7 summarizes the study design of Immediate Release (IR) Study 2.
[0044] Figure 8 summarizes the study design of Immediate Release (IR) Study 3.
[0045] Figure 9 summarizes the study design of the Sustained Release (SR)
Study.
DETAILED DESCRIPTION OF THE INVENTION
Advantages and utility
[0046] In one aspect, the present disclosure provides for compositions and
methods for
sustained-release formulations of bempedoic acid.
[0047] Included are sustained-release compositions comprising bempedoic acid
and a polymer
matrix. The present disclosure covers a variety of components to form a
sustained-release
formulation comprising bempedoic acid and a polymer material. For example, the
present
disclosure includes formulations for parenteral use such as tablets or caplets
that are filled or
unfilled. In the case of unfilled caplets, the polymer may be of sufficient
porosity so as to allow
fluid to enter one or more caplet chambers and drive the release by osmotic
pressure. One
example of such this technology is the sustained-release caplet pump developed
by Alza Corp as
described in e.g., U.S. Pat Nos. 3,760,984, 3,845,770, 4,008,719, 4,036,227,
4,093,708,
4,111,202, 4,449,983, 4,455,143, 4,576,604, 4,673,405, 4,732,915, and
4,777,049.
[0048] Sustained release technologies of the present disclosure include
delayed-release and
extended release formulations. These systems modify the temporal delivery of
drug delivery by
allowing the active ingredient to be released either by intermittent dosing
(an example of
delayed-release) or by controlled or maintained dosing (an example of extended
release) to a
therapeutic level of the active drug for a prolonged period. Delayed-release
tablets or caplets
can be configured for repeat-action and are enteric-coated so that timed
release is achieved by
the slow diffusion of the active thru the barrier coating. Such extended
release formulations may
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be a tablet filled with a material, usually a polymer that is a degraded in
vivo in a controlled
manner.
[0049] These compositions improve the bioavailability of the activated form of
bempedoic acid
and effectively extend the half-life of the administered drug. Such
compositions are useful for
treating or reducing the risk of cardiovascular disease and other related co-
morbidities.
[0050] Advantages of the disclosed sustained-release bempedoic acid
compositions approach are
numerous. These bempedoic acid compositions not only maximize conversion to
the active
moiety and optimize pharmacokinetic properties, e.g., increased amount of the
activated form of
the drug in the liver, etc., the compositions can be used to reduce the dose
per day. The
sustained-release bempedoic acid compositions disclosed herein provide a
therapeutically-
effective amount of bempedoic acid over a longer period of time (as compared
to immediate-
release formulations) and in concentrations inside the therapeutic window for
a longer period of
time.
Definitions
[0051] Terms used in the claims and specification are defined as set forth
below unless
otherwise specified. The practice of the present invention includes the use of
conventional
techniques of pharmaceutical chemistry that are within the skill of the art.
[0052] The term "cardiovascular diseases" refers to diseases of the heart and
circulatory system.
These diseases are often associated with dyslipoproteinemias and/or
dyslipidemias.
Cardiovascular diseases which the compositions of the present invention are
useful for
preventing or treating include but are not limited to arteriosclerosis;
atherosclerosis; stroke;
ischemia; endothelium dysfunctions, particularly those dysfunctions affecting
blood vessel
elasticity; peripheral vascular disease; coronary heart disease; myocardial
infarction; cerebral
infarction and restenosis.
[0053] In general, the term "sustained release" refers to a dosage form
designed to release a drug
at a predetermined (but not necessarily constant) rate in order to maintain a
desired range of drug
concentration over a specific period of time, e.g., 8 hours, 12 hours, 16
hours, 20 hours, 24
hours, etc., with minimum side effects. This can be achieved through a variety
of formulations,
as exemplified by the bempedoic acid sustained release formulations described
herein.
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[0054] The term "dyslipidemias" refers to disorders that lead to or are
manifested by aberrant
levels of circulating lipids. To the extent that levels of lipids in the blood
are too high, the
compositions of the invention are administered to a patient to restore normal
levels. Normal
levels of lipids are reported in medical treatises known to those of skill in
the art. For example,
recommended blood levels of LDL, HDL, free triglycerides and other parameters
relating to lipid
metabolism can be found at the web sites of the American Heart Association and
that of the
National Cholesterol Education Program of the National Heart, Lung and Blood
Institute.
Currently, the recommended level of HDL cholesterol in the blood is above 35
mg/dL; the
recommended level of LDL cholesterol in the blood is below 130 mg/dL; the
recommended
LDL: HDL cholesterol ratio in the blood is below 5:1, ideally 3.5:1; and the
recommended level
of free triglycerides in the blood is less than 200 mg/dL.
[0055] The term "metabolic syndrome" refers to a cluster of conditions ¨
increased blood
pressure, high blood sugar, excess body fat around the waist, and abnormal
cholesterol or
triglyceride levels ¨ that occur together, increasing your risk of heart
disease, stroke and
diabetes. These conditions are the co-occurrence of several known
cardiovascular risk factors,
including insulin resistance, obesity, atherogenic dyslipidemia and
hypertension.
[0056] The term "nonalcoholic fatty liver disease (NAFLD)" refers to a
condition in which
excess fat is stored in your liver. This buildup of fat is not caused by heavy
alcohol use.
Nonalcoholic fatty liver disease (NAFLD) is characterized or diagnosed by the
presence of fat in
the liver (hepatic steatosis) either on imaging or on liver histology after
the exclusion of
secondary causes of fat accumulation in the liver (e.g., significant alcohol
consumption, certain
medications, and other medical conditions). NAFLD is further categorized
histologically into
nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH).
[0057] The term "simple fatty liver or nonalcoholic fatty liver (NAFL)" refers
to a form of
NAFLD in which you have fat in your liver but little or no inflammation or
liver cell damage.
NAFL is characterized with hepatic steatosis with no evidence of
hepatocellular injury in the
form of hepatocyte ballooning.
[0058] The term "nonalcoholic steatohepatitis (NASH)" refers to a form of
NAFLD in which
you have hepatitis¨inflammation of the liver¨and liver cell damage, in
addition to fat in your
liver. Inflammation and liver cell damage can cause fibrosis, or scarring, of
the liver. NASH is
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characterized with the presence of hepatic steatosis and inflammation with
hepatocyte injury
(ballooning) with or without fibrosis.
[0059] The term "subject" refers to any mammal including humans, and so
includes mammals
such as those animals of veterinary and research interest that are including,
but not limited to:
simians, cattle, horses, dogs, cats, and rodents. The term "subject" is
interchangeable with the
term "patient."
[0060] The term "mammal" as used herein includes both humans and non-human
mammals, e.g.,
non-human primates, canines, felines, murines, bovines, equines, and porcines.
[0061] The term "administering" or "administration" of a drug and/or therapy
to a subject (and
grammatical equivalents of this phrase) refers to both direct or indirect
administration, which
may be administration to a subject by a medical professional, self-
administration, and/or indirect
administration, which may be the act of prescribing or inducing one to
prescribe a drug and/or
therapy to a subject.
[0062] The term "treating" or "treatment of" a disorder or disease refers to
taking steps to
alleviate the symptoms of the disorder or disease, or otherwise obtain some
beneficial or desired
results for a subject, including clinical results. Any beneficial or desired
clinical results may
include, but are not limited to, alleviation or amelioration of one or more
symptoms of cancer or
conditional survival and reduction of tumor load or tumor volume; diminishment
of the extent of
the disease; delay or slowing of the tumor progression or disease progression;
amelioration,
palliation, or stabilization of the tumor and/or the disease state; or other
beneficial results.
[0063] The term "ameliorating" refers to any therapeutically beneficial result
in the treatment of
a disease state, e.g., a disease state of the cardiovascular system, including
prophylaxis, lessening
in the severity or progression or remission thereof.
[0064] The term "in situ" or "in vitro" refers to processes that occur in a
living cell growing
separate from a living organism, e.g., growing in tissue culture.
[0065] The term "in vivo" refers to processes that occur in a living organism.
[0066] The term "sufficient amount" means an amount sufficient to produce a
desired effect.
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[0067] The term "bempedoic acid" or "ETC-1002" refers to 8-hydroxy-2,2,14,14
tetramethylpentadecanedioic acid:
H OH
OH
[0068] The term "activated bempedoic acid" or "activated ETC-1002" refers to
(9R)-1-
[(2R,3 S,4R,5R)-5-(6-Amino-9H-purin-9-y1)-4-hydroxy-3-(phosphonooxy)tetrahydro-
2-furany1]-
3,5,9,26-tetrahydroxy-8,8,20,20,32,32-hexamethy1-10,14,19-trioxo-2,4,6-trioxa-
18-thia-11,15-
diaza-3,5-di phosphatritriacontan-33-oic acid 3,5-dioxide:
H2N N
)7N
\\-N OH
;,OH
0, -"OH
0
,....-
0 0 OH 0 I
W
0,11,0H
HO SNN 0 1:21
OH 0 0
[0069] The term "zero order release rate" refers to a substantially constant
release rate, such that
a drug dissolves in the fluid of the environment of use at a substantially
constant rate. A zero
order release rate can vary by as much as about 25% and preferably by no more
than about 10%
from its average release rate.
[0070] The term "a therapeutically effective concentration" or "a
therapeutically effective
amount" means an amount of the drug that is effective to ameliorate a symptom
of a disease, e.g.
an amount that treats at least one symptom of cardiovascular disease or means
an amount of the
drug that reduces, in a statistically significant way, the risk of
cardiovascular disease in the
subject.
[0071] The term "phosphate buffer" means any buffer solution containing
disodium hydrogen
phosphate and sodium chloride. Some such buffer solutions contain potassium
cations in
addition to or in place of sodium cations. Regardless, the skilled artisan is
well aware of the
compatible inorganic compounds and organic compounds that might be added to
these solutions
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(commercially available or otherwise standardly prepared in the laboratory) as
small
modifications/ additions can be made (such as the addition of relatively small
amounts of Ca',
Fe', and/or ethylenediaminetetraacetic acid (ETDA) for example) as necessary
as long as the
capacity of the solution to maintain a reasonably constant pH is not altered.
The skilled artisan
can refer to, for example, Conover, W. I Chem. Educ., 1998, 75 (2), 153, which
is herein
incorporated by reference in its entirety.
[0072] The term "Cmax" refers to the overall maximum observed plasma
concentration of an
analyte, such as a drug or a prodrug.
[0073] The pharmacokinetic parameters described herein include: area under the
plasma
concentration-time curve (AUC04 and AUC0-., both with units of
amount*time/volume);
AUCT,ss; maximum plasma concentration (Cmax); time of maximum plasma
concentration
(Tmax); and terminal elimination half-life (T1/2). The time of maximum
concentration (Tmax) is
determined as the time corresponding to Cmax. Area under the plasma
concentration-time curve
up to the time corresponding to the last measurable concentration (AUCo-t) is
calculated by
numerical integration using the linear trapezoidal rule as follows:
fl Eq. 1
A LIC:0_t = .5 = (Ci ""f) =(r ¨tI)
1=1
where CI is the plasma drug concentrations at the corresponding sampling time
point ti
and n is the number of time points up to and including the last quantifiable
concentration.
The terminal half-life (T1/2) is calculated using the following equation:
0.693 Eq.
T111
where 2\., is the terminal elimination rate constant.
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The area under the plasma concentration-time curve from time zero to infinity
is
calculated according to the following equation:
riast Eq. 3
A tiCo.õ, = A UCo_t ______________
A.7
where Clast is the last measurable concentration.
[0074] The term "Tmax" refers to the time at which the plasma concentration of
an analyte, such
as a drug or a prodrug, attains the maximum plasma concentration.
[0075] The term "AUCT,ss" refers to the area under the concentration-time
curve during a
dosing interval at steady state wherein the units are defined to be
amount*time/volume.
[0076] The term "therapeutic window" is the range of doses of a drug/ API that
elicits a
therapeutic response without causing any significant adverse effect in
patients. Generally, the
therapeutic window is a ratio of the minimum effective concentration (MEC) to
the minimum
toxic concentration (MTC).
[0077] The term "polycellulose' means a polymer made from cellulose, having a
weight average
molecular weight from 500 Da to 5,000,000 Da, optionally cross-linked, and
including
derivatives of cellulose. Such derivatives include "functionalized" cellulose
polymers that result
from the reaction or cross-linking of cellulose polymers with one or more
organic functional
groups. The functional group(s) is/are pendent and although they may change
the chemo-
physical properties of the cellulose polymer, they do not fundamentally change
(1) the core
structure of the saccharide repeating chemical motif, or (2) where (i.e.,
carbon numbers on the
respective saccharides that the 0-glycosidic linkage is attached thru) and how
(alpha/beta) the
saccharides are covalently attached. The skilled artisan is well aware of such
functional groups
and methods of preparing these derivatives. The skilled artisan can refer to
Handbook of
Polymers for Pharmaceutical Technologies: Biodegradable Polymers, Vol. 3,
Vijay Kumar
Thakur & Manju Kumari Thakur, Wiley, 2015, which is herein incorporated by
reference in its
entirety.
[0078] The term "weight average molecular weight" refers to Mw or a molecular
weight that
takes into account the molecular weight of a chain in determining
contributions to the molecular
weight average. Mw is determined by analytical methods that are sensitive to
the molecular size
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of the polymer chains rather than just the count of chains. Analytical
techniques such dynamic
light scattering provide Mw. Mw is calculated by:
ENiMi2
mw =
N M
where Mi is the molecular weight of a chain and Ni is the number of chains of
that molecular
weight.
[0079] It must be noted that, as used in the specification and the appended
claims, the singular
forms "a," "an" and "the" include plural referents unless the context clearly
dictates otherwise.
Pharmaceutical compositions
[0080] Herein disclosed are sustained-release pharmaceutical dosage forms
comprising a solid
oral dosage form. In some embodiments, the solid oral dosage form comprises
bempedoic acid
and a polymer matrix. In some embodiments, the solid oral dosage form
comprises bempedoic
acid dispersed within a polymeric material.
[0081] In some aspects, the disclosure provides for a sustained-release
pharmaceutical dosage
form comprising a solid oral dosage form comprising bempedoic acid and a
polymer matrix,
wherein the polymer is hydroxypropyl methylcellulose (HPMC). In some aspects,
the solid oral
dosage form comprises bempedoic acid dispersed within HPMC. In some aspects,
the bempedoic
acid is not dispersed within the polymer. In some aspects, the bempedoic acid
is not dispersed
within HPMC.
[0082] In one aspect, the disclosure provides for a sustained-release
pharmaceutical dosage form
comprising a solid oral dosage form, wherein the solid oral dosage form
comprises: bempedoic
acid and a polymeric matrix, and wherein the solid oral dosage form provides a
therapeutically
effective concentration of bempedoic acid over a period of 12 hours, over a
period of 14 hours,
over a period of 16 hours, over a period of 18 hours, over a period of 20
hours, over a period of
22 hours, over a period of 24 hours, over a period of 36 hours, or over a
period of 48 hours when
administered to a subject.
[0083] In one aspect, the disclosure provides for a solid oral dosage form
that is a gelatin
capsule. In one aspect, the solid oral dosage form is a hard-shelled capsule
containing
spheronized powder particles. In one aspect, the solid oral dosage form that
is a soft-shelled
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capsule. In one aspect, the solid oral dosage form is gelatin capsule further
comprising a powder
excipient. In one aspect, the solid oral dosage form is gelatin capsule
further comprising an
excipient in a suspension. In one aspect, the solid oral dosage form is
gelatin capsule further
comprising one or more plasticizers such as glycerin or sorbitol. In one
aspect, the solid oral
dosage form is gelatin capsule further comprising one or more of: coloring
agents, preservatives,
disintegrants, lubricants and surface treatment agents.
[0084] In one aspect, the disclosure provides for a solid oral dosage form
that is a tablet. In one
aspect, the disclosure provides for a solid oral dosage form that is a
lozenge.
[0085] In one aspect, the disclosure provides for a solid oral dosage form
that is a gelatin
capsule. In one aspect, the disclosure provides for a solid oral dosage form
that is a capsule
containing a solid composition comprising bempedoic acid and one or more
excipients.
Bempedoic Acid ¨ Structure and Synthesis
[0086] The structure of bempedoic acid (also known as ETC-1002 or 8-hydroxy-
2,2,14,14-
tetramethylpentadecaned¨ioic acid) is:
OH
OH
[0087] ETC-1002 and the processes for the synthesis of ETC-1002 are disclosed
in issued U.S.
Patent No. 7,335,799. The details of this process can be found in published
U.S. Patent
Publication No. US2005/0043278A1, in paragraphs [0247] - [0343] of the
specification, which is
herein incorporated by reference in its entirety.
[0088] As used herein the term "bempedoic acid" also encompasses
pharmaceutically acceptable
salts of the compound. Such pharmaceutically acceptable salts include, but are
not limited to,
hydrochloric, hydrobromic, hydroiodic, sulfuric, citric, tartaric,
methanesulfonic, fumaric, malic,
maleic and mandelic acids, mucate, N-oxide, sulfate, acetate, phosphate
dibasic, phosphate
monobasic, acetate trihydrate, bi(heptafluorobutyrate ), bi(methylcarbamate ),
bi(pentafluoropropionate ), bi(pyridine-3-carboxylate ), bi(trifluoroacetate
), bitartrate,
chlorhydrate, and sulfate pentahydrate, benzenesulfonate, benzoate,
bicarbonate, bitartrate,
bromide, calcium edetate, camsylate, carbonate, chloride, citrate,
dihydrochloride, edetate,
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edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate,
glycollylarsanilate,
hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate,
iodide,
isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate,
methylbromide,
methyinitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate),
pantothenate,
phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate,
succinate, sulfate,
tannate, tartrate, teoclate, triethiodide, benzathine, chloroprocaine,
choline, diethanolamine,
ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium,
potassium,
sodium propionate, and zinc salts and the like.
Polymer matrix
Hydrophilic & hydrophobic components
[0089] According to the present disclosure, a major component of the matrix
for the sustained-
release formulations can be a hydrophilic polymer. Hydrophilic polymers are
well suited for oral
controlled drug delivery because they can reproduce a desirable drug profile
and are cost
effective. However, bempedoic acid is hydrophobic and the process of
absorption in the body
relies to some extent on the lipophilic nature of a dosage form. Consequently,
a desired release
profile can be obtained by including both hydrophilic and hydrophobic
components and/or
excipients in the dosage form, the exact nature of which is worked out on a
case by case basis.
[0090] The matrix of sustained-release pharmaceutical compositions includes a
polymer as a
major component. Both synthetic and natural polymers, and/or their
derivatives, and/or
combinations thereof, can be used in compositions within the scope of the
present disclosure.
[0091] Polysaccharides can be used as a polymer in the oral sustained-release
formulations of
the present disclosure. Such formulations can include cellulose (polymer)
derivatives such as
hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),
hydroxyethylcellulose
(HEC), ethylcellulose, and methylcellulose (MC). Each cellulose derivative
possesses different
grades and has different properties in terms of molecular weight, viscosity,
solubility, hydration,
etc. Accordingly, distinct polymers and their respective distinct derivatives
can be used to
formulate dissolution-controlled and diffusion-controlled release systems of
the present
disclosure. Polymers following diffusion-control are generally water
insoluble, though some are
not. Commonly used polymers for diffusion-controlled systems (reservoir and
monolithic
systems) include cellulose (e.g., ethylcellulose), collagen, nylon,
poly(alkylcyanoacrylate),
polyethylene, poly(ethylene- co -vinylacetate), poly(hydroxyethyl
methacrylate),
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poly(hydroxypropylethyl methacrylate), poly(methyl methacrylate),
polyurethane, and silicon
rubber.
[0092] Besides dissolution release kinetics, polymer glass transition
temperature (Tg) is a very
important polymer property. Tg affects properties such as flowability,
compactibility, flexibility,
permeability, etc.
[0093] Plasticizers can optionally be included into polymer blends of the
present disclosure.
Examples of plasticizers are glycerin, glyceryl triacetate (triacetin),
poly(ethylene glycol) (PEG),
and propylene glycol. Plasticizers are also commonly used in film coating to
help polymer(s)
achieve desired film quality. Since plasticizers reduce the stiffness of
polymer molecules, they
are useful for increasing the diffusion rate of bempedoic acid through the
dosage form.
Synthetic/ natural polymers & derivatives
[0094] So called "natural polymers" are polymeric substances that are found in
nature and can
be extracted. These are often water-soluble materials. Examples of naturally
occurring polymers
include polysaccharides such as cellulose, polynucleotides such as RNA or DNA,
and
polyamides such as proteins.
[0095] Synthetic polymers are derived from petroleum oil, and made by
scientists and engineers.
Examples of synthetic polymers include (poly)vinyl, acrylates, nylon,
polyethylene, polyester,
and Teflon.
[0096] In some aspects, the present disclosure provides for a polymer matrix
wherein the
polymer is a synthetic polymer and is selected from the group consisting of:
poly(vinyl alcohol)s
(PVA), poly(acrylic acid)s, poly(ethylene oxide) (PE0s), poloxamers,
pluronics, and
polymethacrylates.
[0097] In some aspects, the present disclosure provides for a polymer matrix
wherein the
polymer is a combination of two synthetic polymers and the two polymers are
selected from the
group consisting of: Carbopol, Eudragit, Avicel PH-101, HPMC 606, Avicel CL-
611 and
Aqualon.
[0098] In some aspects, the present disclosure provides for a polymer matrix
wherein the
polymer is selected from the group consisting of: hydroxypropylmethylcellulose
(HPMC), HPC
(hydroxypropyl cellulose), hydroxyethylcellulose (HEC), EC(ethyl cellulose),
MC (methyl
cellulose), Alginate Na, Carboxymethylcellulose Na, Carbopol, Eudragit, Avicel
PH-101, HPMC
606, Avicel CL-611, microcrystalline cellulose, and Aqualon. In some aspects,
the present
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disclosure provides for a polymer matrix wherein the polymer is a combination
of two polymers
and the two polymers are selected from the group consisting of:
hydroxypropylmethylcellulose
(HPMC), HPC (hydroxypropyl cellulose), hydroxyethylcellulose (HEC), EC(ethyl
cellulose),
MC (methyl cellulose), Alginate Na, Carboxymethylcellulose Na, Carbopol,
Eudragit, Avicel
PH-101, HPMC 606, Avicel CL-611, microcrystalline cellulose, and Aqualon. In
some aspects,
the present disclosure provides for a polymer matrix wherein the polymer is a
combination of
three polymers and the three polymers are selected from the group consisting
of:
hydroxypropylmethylcellulose (HPMC), HPC (hydroxypropyl cellulose),
hydroxyethylcellulose
(HEC), EC(ethyl cellulose), MC (methyl cellulose), Alginate Na,
Carboxymethylcellulose Na,
Carbopol, Eudragit, Avicel PH-101, HPMC 606, Avicel CL-611, microcrystalline
cellulose, and
Aqualon.
[0099] In some aspects, the present disclosure provides for a polymer matrix
wherein the
polymer is a combination of four or more synthetic polymers selected from any
of the polymers
named herein.
[00100] In any of the aspects described herein, the present disclosure
provides for a polymer
matrix wherein the polymer is a synthetic polymer and the matrix includes a
plasticizer. In some
aspects, the plasticizer may be one or more of the plasticizers named herein.
Plasticizers are well
known in the art and, as a result, the skilled artisan may consult a reference
text disclosed herein
and choose any one of the plasticizers listed within. Examples of plasticizers
include, but are not
limited to: glycerin, glyceryl triacetate (triacetin), poly(ethylene glycol)
(PEG), propylene
glycol, and combinations thereof.
[00101] In some aspects, the present disclosure provides for a polymer matrix
wherein the
polymer is selected from the group consisting of: polycellulose,
microcrystalline cellulose,
polyvinyl acetate, polyvinylpyrrolidone, polyacrylate, a pH-insensitive
ammonium polymer, and
mixtures thereof.
[00102] In
some aspects, the present disclosure provides for a polymer matrix wherein the
polymer is selected from the group consisting of: (poly)cellulose (e.g.,
ethylcellulose), collagen,
nylon, poly(alkylcyanoacrylate), polyethylene, poly (ethylene-co-
vinylacetate),
poly(hydroxyethyl methacrylate), poly(hydroxypropylethyl methacrylate),
poly(methyl
methacrylate), polyurethane, and silicon rubber.
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[00103] In some aspects, the present disclosure provides for a polymer matrix
wherein the
polymer is microcrystalline cellulose. In some aspects, the present disclosure
provides for a
polymer matrix wherein the polymer is a mixture of microcrystalline cellulose
and polycellulose.
In some aspects, the present disclosure provides for a polymer matrix wherein
the polymer is a
mixture of microcrystalline cellulose and hydroxypropylmethyl cellulose
(HPMC). In some
aspects, the present disclosure provides for a polymer matrix wherein the
polymer is
hydroxypropylmethyl cellulose (HPMC). In some aspects, the present disclosure
provides for a
polymer matrix wherein the polymer is a polycellulose.
Porosity & permeability
[00104] API tableting and solid granulating has an effect on dosage form
density, porosity,
and hardness, disintegration and particle size. Increases in solid density and
hardness will result
in a decrease in permeability and solvent penetrability.
[00105] In some aspects, the present disclosure provides for a polymer matrix
that is not
porous but rather is amorphous. In some aspects, the present disclosure
provides for a polymer
matrix that has a relatively low porosity. Porosity can be calculated by:
= [Ca D$ ceõ.)ti
where e is porosity of the matrix, T is tortuosity, Co is the total amount of
drug present per unit
volume in the matrix, Ca is the solubility of the drug in the release medium,
at time, t, M is the
amount of drug release per unit area, and Ds is the diffusion coefficient of
drug in the release
medium.
[00106] In some aspects, the present disclosure provides for a polymer matrix
with a mean
particle size from 10-200 [tm. In some aspects, the present disclosure
provides for a polymer
matrix with a mean particle size from 20-180 [tm. In some aspects, the present
disclosure
provides for a polymer matrix with a mean particle size from 20-150 [tm. In
some aspects, the
present disclosure provides for a polymer matrix with a mean particle size
from 40-100 [tm.
[00107] In some aspects, the present disclosure provides for a polymer matrix
with a mean
pore size from 10-200 nm, from 20-180 nm, from 20-150 nm, or from 40-100 nm.
Synthesis examples
[00108] In some aspects, the present disclosure provides for a polymer matrix
wherein the
polymer is a derivative of a synthetic or natural polymer. The skilled artisan
can synthesize the
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monomer compound with organic synthetic techniques so long as the reacting
organic functional
group of the monomer does not also simultaneously (thermally) polymerize.
Another way for the
skilled artisan to prepare a derivative of a synthetic polymer is to
polymerize (in a controlled
polymerization reaction) the desired polymer, i.e., starting material, or in
the case of a natural
polymer, obtain a desired commercial natural polymer starting material from
companies such as
Sigma Aldrich, TCI Chemicals, Strem, etc. and then perform one or more organic
synthesis
reactions to the polymer to functionalize it with the desired pendant groups.
The reaction can be
initiated with organic functional groups of the polymer that are potentially
reactive, i.e. ones that
either nucleophilic or electrophilic in nature. The skilled artisan is careful
not to react the
functional groups that covalently attach each of the monomeric units of the
polymer since
reacting these groups would degrade the polymer and decrease the average
molecular weight of
the polymer chains. However, in the case of natural polymers it is often that
such chain scission
does occur and the skilled artisan will try to mitigate such harsh reaction
conditions.
[00109] One example of the first approach employs an acrylate polymer. An
acrylate
monomer can be functionalized through the carboxylate via esterification or
amidation reactions
with a desired nucleophilic functional group becoming the pendant group. For
example, acrylic
acid can be functionalized with a polyethylene glycol of 3000 Da through
Steglich esterification
reaction conditions. The resulting ethylene glycol acrylate ester can be
polymerized under
thermal conditions with AIBN "azoisobutylnitrile" (optionally with another
monomeric
compound like methyl methacrylate to produce a copolymer) in a controlled
manner to make a
polymer with the desired Tg and other physical properties.
[00110] Another example of synthesizing a polymer derivative applies to
natural polymer and
includes preparing the derivative by functionalizing the natural polymer with
organic functional
groups. For example, the natural polymer cellulose can be reacted through
hydroxyl functional
groups with propylene oxide and methyl chloride with sodium hydroxide reagent.
The product
formed is a cellulose polymer (polycellulose) having (methyl and isopropyl)
ether functional
groups at a certain percentage of the former hydroxyl functional groups. In
some aspects, the
percentage of ether functional groups is from 0.1-50%, preferably from 0.1-
45%, preferably
from 0.1-30%, preferably from 0.1-15%, preferably from 0.1-10%, preferably
from 0.1-9%,
preferably from 0.1-8%, preferably from 0.1-7%, preferably from 0.1-6%,
preferably from 0.1-
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5%, preferably from 0.1-4%, preferably from 0.1-3%, preferably from 0.1-2%,
preferably from
0.1-1%, or more preferably from 0.1-0.5%.
[00111] Such derivatization reactions and preparations are well within the
purview of the
skilled artisan. Textbooks such as Biodegradable Polymers in Pharmacy and
Medicine.
Classification, Chemical Structure, Principles of Biodegradation and Use, Jan
Gajdziok Roman
Gonec David Vetch, Verlag, 2016; Cellulose and Cellulose Derivatives:
Synthesis,
Modification and Applications, Ibrahim H. Mondal,.Nova Science Publishers
Incorp., 2015 and
Biomedical Polymers: Synthesis and Processing, Vinod B. Damodaran, Divya
Bhatnagar, N.
Sanjeeva Murthy, Springer, 2016 which are herein incorporated by reference in
their entirety, are
available for the skilled artisan for reference.
Excipients
Components for a solid dosage form
[00112] The dissolution rate of a pure drug can be altered when mixed with
various excipients
during the manufacturing process of solid dosage forms.
[00113] The skilled artisan can commercially buy certain compounds and
materials to use for
excipients or rather can derivatize known compounds and starting material.
Such methods of
synthesis (and of using these excipients in formulating solid dosage forms)
are well known in the
art and found in the primary texts reference herein as well as in Handbook of
Pharmaceutical
Excipients, 4th ed. Rowe RC, Sheskey PJ, Weller PJ, ed. London, UK: AphA and
the
Pharmaceutical Press, 2003, which is herein incorporated by reference in its
entirety.
[00114] In some aspects, the present disclosure provides for a solid dosage
form comprising
bempedoic acid and a polymer matrix, wherein the solid dosage form further
comprises a
surfactant. In some aspects, the present disclosure provides for a solid
dosage form comprising
bempedoic acid and a polymer matrix, wherein the solid dosage form further
comprises an
anionic surfactant. In some aspects, the present disclosure provides for a
solid dosage form
comprising bempedoic acid and a polymer matrix, wherein the solid dosage form
further
comprises an anionic surfactant, wherein the anionic surfactant is sodium
lauryl sulfate.
[00115] In some aspects, the present disclosure provides for a solid dosage
form comprising
bempedoic acid and a polymer matrix, wherein the solid dosage form further
comprises
microcrystalline cellulose and sodium lauryl sulfate.
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[00116] Other suitable compounds to use as excipients for the solid oral
dosage forms
disclosed herein are also found in the primary textbooks referenced herein
such as Remington,
The Science and Practice of Pharmacy. Easton, Pa: Mack Pub. Co. 21' Ed.
Classes of excipients
[00117] Excipients can be added to satisfy certain pharmaceutical functions
such as diluents
(fillers), dyes, binders, granulating agents, disintegrants, and lubricants.
[00118] In some aspects, the present disclosure provides for a solid dosage
form comprising
bempedoic acid and a polymer matrix, wherein the solid dosage form further
comprises a binder,
a filler, a diluent, a dye, a granulating agent, a disintegrant, a lubricant,
or any combination
thereof.
[00119] In some aspects, the present disclosure provides for a solid dosage
form comprising
bempedoic acid, a polymer matrix, and a binder, a filler, a diluent, a dye, a
granulating agent, a
disintegrant, a lubricant, or any combination thereof. In some aspects, the
present disclosure
provides for a solid dosage form comprising bempedoic acid, a polymer matrix,
and a binder and
a lubricant. In some aspects, the present disclosure provides for a solid
dosage form comprising
bempedoic acid, a polymer matrix, and a binder and a lubricant, wherein the
lubricant is a
surfactant. In some aspects, the present disclosure provides for a solid
dosage form comprising
bempedoic acid, a polymer matrix, and a binder and a lubricant, wherein the
lubricant is a
sodium lauryl sulfate.
Solid dosage forms
[00120] Pharmaceutical dosage forms can include a variety of solid forms,
e.g., the
pharmaceutical may be a pill, e.g., a tablet, a tablet like buccal dosage form
being a tablet or
lozenge, e.g. a sub-lingual or orally-disintegrating gum, pill or lozenge, a
thin film, etc.
[00121] Generically, sustained-release solid oral dosage forms may be
categorized into three
basic categories: matrix-based tablets/ pills, multi-particulate solids, and
osmotic solid dosage
forms. The present disclosure provides for a sustained-release pharmaceutical
dosage form
comprising a solid oral dosage form, wherein the solid oral dosage form
comprises bempedoic
acid and a polymer. In some aspects the polymer is in the form of a polymer
matrix. In other
aspects, the polymer is a neat, dry powder. The presently disclosed solid oral
dosage form can
be formulated into a dosage form of any one of the categories mentioned above.
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[00122] In one aspect, the present disclosure provides for a solid oral dosage
form comprising
bempedoic acid and a polymer matrix.
[00123] In one aspect, the present disclosure provides for a solid oral dosage
form, wherein
the solid dosage form is a tablet.
[00124] In one aspect, the present disclosure provides for a solid oral dosage
form, wherein
the solid dosage form is a gelatin capsule. In one aspect, the present
disclosure provides for a
solid oral dosage form, wherein the solid dosage form is a gelatin capsule
further comprising a
powder excipient.
[00125] In one aspect, the present disclosure provides for a solid oral dosage
form, wherein
the dosage form is not diffusion-controlled but rather dissolution controlled.
Formulation properties
[00126] In some aspects, the present disclosure provides for a solid dosage
form comprising
bempedoic acid, wherein the dosage form provides for a sustained-release of
bempedoic acid
over a period of at least 2-8 hours following oral administration, or produces
a certain release
profile for bempedoic acid, e.g., a Cmax plateau sustained for at least an
hour for bempedoic
acid (or its metabolite, activated bempedoic acid) following oral
administration of bempedoic
acid.
Weight ranges & composition amounts
[00127] In one aspect, the disclosure provides for a solid oral dosage form
wherein the
bempedoic acid is from 30-50% by weight, from 35-55% by weight, from 40-60% by
weight,
from 45-65% by weight, 50-70% by weight, 55-75% by weight, or 60-80% by
weight.
[00128] In some aspects, the present disclosure provides for the
administration of a sustained
release formulation of bempedoic acid wherein the dosage is 40 mg/day, 50
mg/day, 60 mg/day,
70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130
mg/day, 140
mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, 200
mg/day, 210
mg/day, 220 mg/day, 230 mg/day, 240 mg/day, or 250 mg/day.
[00129] In some aspects, the present disclosure provides for the
administration of a sustained
release formulation of bempedoic acid wherein the dosage is 45-55 mg/day, 55-
65 mg/day, 65-
75 mg/day, 75-85 mg/day, 85-95 mg/day, 95-105 mg/day, 105-115 mg/day, 115-125
mg/day,
125-135 mg/day, 135-145 mg/day, 145-155 mg/day, 155-165 mg/day, 165-175
mg/day, 175-185
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mg/day, 185-195 mg/day, 195-205 mg/day, 205-215 mg/day, 215-225 mg/day, 225-
235 mg/day,
235-245 mg/day, or 245-255 mg/day.
[00130] In one aspect, the disclosure provides for a solid oral dosage form
wherein HMPC is
from 0-10% by weight, from 0-5% by weight, from 0-4% by weight, from 0-3% by
weight, from
0-2% by weight, or from 0-1% by weight.
[00131] In one aspect, the disclosure provides for a solid oral dosage form
comprising:
bempedoic acid from 40-60% by weight and HPMC is from 0-3% by weight, or the
bempedoic
acid is from 60-80% by weight and HPMC from 0-5% by weight.
[00132] In one aspect, the disclosure provides for a solid oral dosage form
wherein the
pharmaceutical dosage form comprises:
60.0% w/w bempedoic acid;
37.3% w/w microcrystalline cellulose;
0.7 w/w hydroxypropyl methylcellulose; and
2% w/w sodium lauryl sulfate.
[00133] In one aspect, the disclosure provides for a solid oral dosage form
wherein the
pharmaceutical dosage form comprises:
60.0% w/w bempedoic acid;
9.3% w/w microcrystalline cellulose;
28.0% w/w microcrystalline cellulose / sodium carboxymethylcellulose;
0.7% w/w hydroxypropyl methylcellulose
2.0% w/w sodium lauryl sulfate.
[00134] In one aspect, the disclosure provides for a solid oral dosage form
wherein the
pharmaceutical dosage form comprises:
60.0% w/w bempedoic acid;
33.7% w/w microcrystalline cellulose;
3.7% w/w sodium carboxymethylcellulose;
0.7% w/w hydroxypropyl methylcellulose; and
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2.0% w/w sodium lauryl sulfate.
[00135] In some aspects, the present disclosure provides for a pharmaceutical
composition
wherein the composition comprises at least 40% and no more than 80% bempedoic
acid w/w, at
least 45% and no more than 80% bempedoic acid, at least 50% and no more than
80%
bempedoic acid w/w, at least 55% and no more than 80% bempedoic acid w/w, at
least 60% and
no more than 80% bempedoic acid w/w, at least 65% and no more than 80%
bempedoic acid
w/w, at least 70% and no more than 80% bempedoic acid w/w, at least 75% and no
more than
80% bempedoic acid w/w.
[00136] In some aspects, the present disclosure provides for a pharmaceutical
composition
wherein the composition comprises at least 5% and no more than 50% of the
polymer w/w, at
least 10% and no more than 50% of the polymer w/w, at least 15% and no more
than 50% of the
polymer w/w, at least 20% and no more than 50% of the polymer w/w, at least
25% and no more
than 50% of the polymer w/w, at least 30% and no more than 50% of the polymer
w/w, at least
35% and no more than 50% of the polymer w/w, at least 40% and no more than 50%
of the
polymer w/w, at least 45 and no more than 50 of the polymer w/w.
[00137] In some aspects, the present disclosure provides for a pharmaceutical
composition
wherein the polymer component is hydroxypropyl methylcellulose (HPMC) and is
at least 0.1%
and no more than 10% of the HPMC w/w, at least 0.5% and no more than 10% of
the HPMC
w/w, at least 1% and no more than 10% of HPMC w/w, at least 5% and no more
than 10% of the
HPMC w/w.
[00138] In some aspects, the present disclosure provides for a pharmaceutical
composition
wherein the polymer is microcrystalline cellulose and is at least 1% and no
more than 60% of the
microcrystalline cellulose w/w, at least 5% and no more than 60% of the
microcrystalline
cellulose w/w, at least 10% and no more than 60% of microcrystalline cellulose
w/w, at least
15% and no more than 60% of the microcrystalline cellulose w/w, at least 20%
and no more than
60% of the microcrystalline cellulose w/w, at least 25% and no more than 60%
of the
microcrystalline cellulose w/w, at least 30% and no more than 60% of the
microcrystalline
cellulose w/w, at least 35% and no more than 60% of the microcrystalline
cellulose w/w, at least
40% and no more than 60% of the microcrystalline cellulose w/w, at least 45%
and no more than
60% of microcrystalline cellulose w/w, at least 50% and no more than 60% of
the
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microcrystalline cellulose w/w, at least 55% and no more than 60% of the
microcrystalline
cellulose w/w.
[00139] In some aspects, the present disclosure provides for a pharmaceutical
composition
wherein the polymer is sodium carboxymethylcellulose and is at least 1% and no
more than 50%
of the sodium carboxymethylcellulose w/w, at least 5% and no more than 50% of
the sodium
carboxymethylcellulose w/w, at least 10% and no more than 50% of sodium
carboxymethylcellulose w/w, at least 15% and no more than 50% of the sodium
carboxymethylcellulose w/w, at least 20% and no more than 50% of the sodium
carboxymethylcellulose w/w, at least 25% and no more than 50% of the sodium
carboxymethylcellulose w/w, at least 30% and no more than 50% of the sodium
carboxymethylcellulose w/w, at least 35% and no more than 50% of the sodium
carboxymethylcellulose w/w, at least 40% and no more than 50% of the sodium.
[00140] In some aspects, the present disclosure provides for a pharmaceutical
composition
comprising sodium lauryl sulfate and is at least 0.1% and no more than 10% of
the sodium lauryl
sulfate w/w, at least 0.5% and no more than 10% of the sodium lauryl sulfate
w/w, at least 1%
and no more than 10% of sodium lauryl sulfate w/w, at least 5% and no more
than 10% of the
sodium lauryl sulfate w/w.
[00141] In some aspects, the present disclosure provides for a pharmaceutical
composition
comprising sodium starch glycolate and is at least 0.1% and no more than 10%
of the sodium
starch glycolate w/w, at least 0.5% and no more than 10% of the sodium starch
glycolate w/w, at
least 1% and no more than 10% of sodium starch glycolate w/w, at least 5% and
no more than
10% of the sodium starch glycolate w/w.
[00142] In some aspects, the present disclosure provides for a pharmaceutical
composition
comprising a ratio of bempedoic acid to polymer of about 4 to 1.
[00143] In some aspects, the present disclosure provides for a pharmaceutical
composition
comprising a ratio of bempedoic acid to polymer of about 3 to 2.
[00144] In some aspects, the present disclosure provides for a pharmaceutical
composition
comprising a ratio of bempedoic acid to polymer of about 2 to 1.
[00145] In some aspects, the present disclosure provides for a solid dosage
form, wherein the
mean particle size is from 1-200um. In some aspects, the present disclosure
provides for a solid
dosage form, wherein the mean particle size is from 1-150um. In some aspects,
the present
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disclosure provides for a solid dosage form, wherein the mean particle size is
from 1-125[tm. In
some aspects, the present disclosure provides for a solid dosage form, wherein
the mean particle
size is from 10-100[tm. In some aspects, the present disclosure provides for a
solid dosage form,
wherein the mean particle size is from 20-100[tm. In some aspects, the present
disclosure
provides for a solid dosage form, wherein the mean particle size is from 40-
100[tm. In some
aspects, the present disclosure provides for a solid dosage form, wherein the
mean particle size is
from 50-100[tm. In some aspects, the present disclosure provides for a solid
dosage form,
wherein the mean particle size is from 80-100[tm.
Threshold & saturation
[00146] Toxicity-related side effects often result post administration when
either the rate of
rise and/or actual bempedoic acid serum plasma concentrations exceed the
threshold maximum
tolerable concentration (MTC). At the same time, in order to obtain a
therapeutic effect,
concentrations need to be sustained above a minimum effective concentration
(MEC).
[00147] In some aspects, the present disclosure provides for a solid dosage
form wherein,
when dosed as recommended, the resulting maximum serum concentration is
measured over the
dose interval.
[00148] In some aspects, the present disclosure provides for a solid dosage
form wherein,
when dosed as recommended, the resulting minimum serum concentration (MEC) is
measured
over the dose interval (i.e., the period between repeated dosings).
[00149] In some aspects, the present disclosure provides for a solid dosage
form, wherein
bempedoic acid concentration is maintained between MEC and MTC for: at least 8
hours and no
more than 48 hours; at least 12 hours and no more than 48 hours; or at least
24 hours and no
more than 36 hours after administration.
[00150] In some aspects, the present disclosure provides for a solid dosage
form, wherein the
solid oral dosage form provides a therapeutically effective concentration of
bempedoic acid over
a period of 24 hours when administered to a subject. In some aspects, the
present disclosure
provides for a solid dosage form, wherein the solid oral dosage form provides
a therapeutically
effective concentration of bempedoic acid over a period of 36 hours when
administered to a
subject. In some aspects, the present disclosure provides for a solid dosage
form, wherein the
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solid oral dosage form provides a therapeutically effective concentration of
bempedoic acid over
a period of 48 hours when administered to a subject.
Unit dose
[00151] A unit dose form is a term that is generally understood by the skilled
artisan. A unit
dose form is a pharmaceutical drug product that is marketed for a specific
use. The drug product
includes the active ingredient(s) and any inactive components, most often in
the form of
polymers and pharmaceutically acceptable carriers or excipients.
[00152] In some aspects, the sustained-release composition is formulated in
one (1) unit dose
form that is effective for at least twelve (12) hours, eighteen (18), twenty
four (24), thirty (30),
thirty six (36), or forty eight (48) hours.
[00153] In some aspects, the sustained-release composition is formulated in at
least two (2)
separately distinct unit dose forms with distinct release profiles.
Pharmacodynamics
[00154] Orally administered API formulations must be absorbed before they
become
bioavailable, circulating systemically. For most drugs/APIs, pre-systemic
clearance occurs at
sites of the GI tract and significantly affects drug/API absorption.
Degradation of orally
administered drugs occurs, to some extent, with hydrolysis in the stomach and
upper GI or by
digestion from enzymes in the gut. Moreover, drugs are metabolized by
microorganisms in the
gut and by enzymes in the liver (i.e., the first pass effect). These
degradation processes can affect
variable or poor drug absorption. It is generally observed that the greater
the efficiency of the
absorption of the drug/ API, the greater the bioavailability of the API.
Measures of
bioavailability include values for Cmax, Tmax, and AUC, amongst others. Blood
plasma
concentrations of bempedoic acid in a subject may be determined by clinical
assays, well known
to the skilled artisan, to determine pharmacokinetic parameter values and to
ascertain the
correlation between tolerability and clinical effect and blood plasma
concentrations of
bempedoic acid.
[00155] In some aspects, the present disclosure provides for a solid dosage
form, wherein the
solid dosage form provides for bempedoic acid a Cmax of at least 8 tg/L.
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[00156] In some aspects, the present disclosure provides for a solid dosage
form, wherein the
solid dosage form provides for bempedoic acid an AUC of at least 0.6 ng*hr/mL
per mg of
bempedoic acid.
[00157] In some aspects, the present disclosure provides for a solid dosage
form, wherein the
solid dosage form provides for bempedoic acid a T1/2 of at least 24 hours.
[00158] In some aspects, the present disclosure provides for a solid d osage
form, wherein the
solid dosage form provides for activated bempedoic acid a Cmax of at least 10
ug/L.
[00159] In some aspects, the present disclosure provides for a solid dosage
form, wherein the
solid dosage form provides for activated bempedoic acid a Cmax of 60 ug/mL, 57
ug/mL, 55
ug/mL, 53 ug/mL, 50 ug/mL, 47 ug/mL, 45 ug/mL, or 40 ug/mL.
[00160] In some aspects, the present disclosure provides for a solid dosage
form, wherein the
solid dosage form provides for activated bempedoic acid an AUC of at least 0.8
ng*hr/mL per
mg of bempedoic acid.
[00161] In some aspects, the present disclosure provides for a solid dosage
form, wherein the
solid dosage form provides for activated bempedoic acid at least 28 hours.
[00162] In some aspects, the present disclosure provides for a solid dosage
form, wherein the
solid dosage form provides an AUC of 1.1 ng*hr/mL per mg of bempedoic acid
following oral
administration of a single 180 mg bempedoic acid capsule.
[00163] In some aspects, the present disclosure provides for a solid dosage
form, wherein the
solid dosage form provides an AUC of at least 50 ug*hr/L per mg of activated
bempedoic acid
following oral administration of a single 180 mg bempedoic acid capsule.
Zero order release
[00164] The ideal release of an API from a given dosage form maintains
therapeutic blood
and tissue levels of the drug for an extended period of time, usually greater
than 8 hours. Such a
maintained concentration is typically accomplished by obtaining a zero-order
release rate of the
API from the dosage form. Zero-order release is an API release from the dosage
form that is
independent of the amount of drug in the delivery system (i.e., a constant
release rate).
[00165] In one aspect, the disclosure provides for a solid oral pharmaceutical
dosage form that
has a zero order release rate for at least 12 hours when dissolution tested
using United States
Pharmacopoeia Apparatus 2 (paddles 50 rpm) in 50 mM phosphate buffer at 20 C,
the solid oral
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pharmaceutical dosage form comprising: bempedoic acid and a polymer matrix,
wherein the
pharmaceutical dosage form has a hardness of 2-30 kg and is either shaped as a
sphere or else
has a ratio of thickness to diameter effective to permit erosion and
penetration control sufficient
for controlled surface erosion thereof when dissolution tested.
[00166] In one aspect, the disclosure provides for a solid oral pharmaceutical
dosage form that
has a zero order release rate for at least 6 hours, for at least 8 hours, for
at least 10 hours, for at
least 12 hours, for at least 14 hours, for at least 16 hours, for at least 18
hours, for at least 20
hours, for at least 22 hours, for at least 24 hours, or for at least 36 hours.
In some aspects, each
solid oral pharmaceutical dosage form corresponding to the 6-36 hour period of
time for zero-
order release when dissolution tested using United States Pharmacopoeia
Apparatus 2 (paddles
50 rpm) in 50 mM phosphate buffer at 20 C maintains a zero-order rate of
release over that
period of time.
Dissolution & pH
[00167] Solid dosage forms may release the API according to erosion
(dissolution) and/or
diffusion mechanisms depending on the nature of the polymer matrix and API
chemo-physical
properties.
[00168] Erosion (dissolution) of many API formulations, and of known bempedoic
acid
formulations in particular, are prone to dose "dumping." That is, once the
dosage form has been
solvated beyond a certain threshold, a significant amount of the API leaks out
of the
compositions in an uncontrolled matter. The effect of the pH of the local
media on the release of
the API is largest on those systems that are under erosion control. At
relatively high and low pH
media, API formulations are susceptible to hydrolysis or degradation such that
the dosage form
becomes sufficiently solvated so that erosion, and dumping is more likely to
occur.
[00169] The sustained-release bempedoic acid solid oral dosage forms herein
disclosed are
also characterized (at least in part) by their physical characteristics, i.e.,
the physical properties
of the dosage form that provide a certain dissolution profile of bempedoic
acid.
[00170] Herein disclosed are sustained-release pharmaceutical dosage forms
comprising a
solid oral dosage form, wherein the solid oral dosage form comprises bempedoic
acid and a
polymer matrix and wherein the solid oral dosage form does not dump bempedoic
acid for 24
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after administration. In one aspect, the disclosure provides for a solid oral
dosage form that does
not dump more than 10% bempedoic acid in media of pH 8 after 30 minutes.
[00171] Solid dosage form erosion and uptake of the dissolution medium uptake
may be
determined, amongst other ways, gravimetrically in the same conditions as used
for the
dissolution testing. Basic calculations are as shown below.
Dissolution Medium Uptake (%) - 100 (Wet Weight - Remaining Dry Weight)
Remaining Dry Weight
Remaining Mass (%): 100 (Remaining Dry Weight)
Original Dry Weight
[00172] The rotating disk system of USP Wood Apparatus or USP Dissolution
Apparatus 2
(United States Pharmacopeia 34/National Formulary 29, 2011, General Chapter
<711>
Dissolution, herein incorporated by reference in its entirety, see also
Chapter 35, pages 679-687
in Remington, J. P. (1995). Remington, The Science and Practice of Pharmacy.
Easton, Pa: Mack
Pub. Co. 21st Ed., also herein incorporated by reference in its entirety) is
used by skilled artisans
to determine the dissolution profile or dissolution rate for sustained-release
dosage forms.
Briefly, the apparatus has three parts: the steel punch, a die, and a base
plate. The die base is
attached to the base plate and the fixed screws on the base plate are inserted
onto the die. The
punch is inserted into the die cavity thereby compressing the material inside.
The pellet and die
assembly are then inserted with the pellet side up, into the bottom of the
dissolution vessel (1
liter). It is important that the vessel be flat bottomed. The paddles of the
USP Apparatus 2 stirs
the material and care is taken that no air bubbles are formed on the pellet
surface and that no
change in the temperature (37 C) occurs.
[00173] The dissolution apparatus can be USP Type I, II, IV, and VII, that is,
rotating basket,
rotating paddle, flow-through cell, and reciprocating holder. In the
dissolution medium the
skilled artisan may select certain parameters based on API stability,
sensitivity of assay, sink
condition in which the final drug concentration is at least three times lower
than a saturated
concentration is needed, etc. It is worth noting that current USP dissolution
tests exert minimal
mechanical force on the solid dosage form.
[00174] In one aspect, the disclosure provides for a sustained-release
pharmaceutical dosage
form comprising a solid oral dosage form, wherein the solid oral dosage form
comprises:
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Bempedoic acid dispersed within a polymeric matrix, wherein the solid oral
dosage form
when dissolution tested using United States Pharmacopoeia Apparatus 2 (paddles
50 rpm) in 50
mM phosphate buffer at 20 C exhibits a drug release profile substantially
corresponding to the
following pattern:
after 2 hours, no more than 30% of the total mass of bempedoic acid is
released;
after 4 hours, no more than 75% of the total mass of bempedoic acid is
released; and
after 8 hours, no more than 90% of the total mass of bempedoic acid is
released.
[00175] In some aspects, the present disclosure provides for a solid dosage
form, wherein the
solid oral dosage form comprises:
Bempedoic acid dispersed within a polymeric matrix, wherein the solid oral
dosage form
when dissolution tested using United States Pharmacopoeia Apparatus 2 (paddles
50 rpm) in 50
mM phosphate buffer at 20 C exhibits a drug release profile substantially
corresponding to the
following pattern: after 1 hour, no more than 8% of the total mass of
bempedoic acid is released,
or no more than 10% of the total mass of bempedoic acid is released, or no
more than 6% of the
total mass of bempedoic acid is released, or no more than 4% of the total mass
of bempedoic
acid is released, or no more than 3% of the total mass of bempedoic acid is
released.
[00176] In some aspects, the present disclosure provides for a solid dosage
form, wherein the
solid oral dosage form comprises:
Bempedoic acid dispersed within a polymeric matrix, wherein the solid oral
dosage
form when dissolution tested using United States Pharmacopoeia Apparatus 2
(paddles 50 rpm)
in 50 mM phosphate buffer at 20 C exhibits a drug release profile
substantially corresponding to
the following pattern: after 2 hours, no more than 30% of the total mass of
bempedoic acid is
released, or no more than 25% of the total mass of bempedoic acid is released,
or no more than
20% of the total mass of bempedoic acid is released, or no more than 15% of
the total mass of
bempedoic acid is released, or no more than 13% of the total mass of bempedoic
acid is released.
[00177] In some aspects, the present disclosure provides for a solid dosage
form, wherein the
solid oral dosage form comprises:
Bempedoic acid dispersed within a polymeric matrix, wherein the solid oral
dosage
form when dissolution tested using United States Pharmacopoeia Apparatus 2
(paddles 50 rpm)
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in 50 mM phosphate buffer at 20 C exhibits a drug release profile
substantially corresponding to
the following pattern: after 3 hours, no more than 50% of the total mass of
bempedoic acid is
released, or no more than 45% of the total mass of bempedoic acid is released,
or no more than
40% of the total mass of bempedoic acid is released, or no more than 35% of
the total mass of
bempedoic acid is released, or no more than 33% of the total mass of bempedoic
acid is released.
[00178] In some aspects, the present disclosure provides for a solid dosage
form, wherein the
solid oral dosage form comprises:
Bempedoic acid dispersed within a polymeric matrix, wherein the solid oral
dosage
form when dissolution tested using United States Pharmacopoeia Apparatus 2
(paddles 50 rpm)
in 50 mM phosphate buffer at 20 C exhibits a drug release profile
substantially corresponding to
the following pattern: after 4 hours, no more than 75% of the total mass of
bempedoic acid is
released, or no more than 65% of the total mass of bempedoic acid is released,
or no more than
60% of the total mass of bempedoic acid is released, or no more than 55% of
the total mass of
bempedoic acid is released, or no more than 53% of the total mass of bempedoic
acid is released.
[00179] In some aspects, the present disclosure provides for a solid dosage
form, wherein the
solid oral dosage form comprises:
Bempedoic acid dispersed within a polymeric matrix, wherein the solid oral
dosage
form when dissolution tested using United States Pharmacopoeia Apparatus 2
(paddles 50 rpm)
in 50 mM phosphate buffer at 20 C exhibits a drug release profile
substantially corresponding to
the following pattern: after 8 hours, no more than 90% of the total mass of
bempedoic acid is
released, or no more than 85% of the total mass of bempedoic acid is released,
or no more than
80% of the total mass of bempedoic acid is released, or no more than 78% of
the total mass of
bempedoic acid is released, or no more than 75% of the total mass of bempedoic
acid is released.
[00180] In some aspects, the sustained-release composition does not release
more than 3 mg
of bempedoic acid during a given 5 minute period of time up to 8 hours after
administration,
during a given 15 minute period of time up to 8 hours after administration,
during a given 30
minute period of time up to 8 hours after administration, or during a given 1
hour period of time
up to 8 hours after administration.
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Preparation of the formulation
[00181] Numerous references exist that inform the skilled artisan how to make
the sustained-
release pharmaceutical compositions (and solid oral dosage forms) disclosed
herein, for example,
see the Handbook of Pharmaceutical Excipients, American Pharmaceutical
Association ( current
edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and
Schwartz, editors)
current edition, published by Marcel Dekker, Inc., as well as Remington's
Pharmaceutical
Sciences (Arthur Osol, editor), (current edition), all of which are hereby
incorporated by
reference in their entirety. Briefly, in preparing sustained-release
formulations in an oral dosage
form, many commercially-available excipients and pharmaceutical media are
employed. For
example, suitable excipient carriers and additives added include water,
glycols, oils, alcohols,
flavoring agents, preservatives, coloring agents, starches, sugars, diluents,
granulating agents,
lubricants, binders, disintegrating agents and the like, many of which are
disclosed in the above
section entitled "Excipients". Specific excipients may include, for example,
sucrose, mannitol,
polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose,
sodium lauryl
sulphate, chremophor, tweens, spans, pluronics, microcrystalline cellulose,
calcium phosphate,
talc, fumed silica, hydroxypropyl methyl cellulose, wax, and fatty acids, etc.
[00182] As mentioned above, the solid oral dosage forms fall into: matrix-
based tablets/ pills,
multi-particulate solids, and osmotic solid categories. Many distinct or
separate processes can be
used for all of or either one of the three approaches, however there are some
preferred or usual
processes for each.
[00183] The formulation processes for making matrix-based tablets or pills is
based on both
diffusion and dissolution (i.e., matrix erosion) controlled systems. The drug
release from
hydrophilic matrix systems involves both diffusion and dissolution since the
size of the matrix
decreases as more drug/API is released, the amount of drug/API released is
then also decreased,
that is, resulting in a non-zero-order release. Typical lipophilic matrix
systems are often
observed to be only under diffusion control. Herein disclosed solid dosage
forms may comprise
either a hydrophilic matrix or a lipophilic matrix.
[00184] The skilled artisan can use a variety of granulation processes to
formulate the matrix-
based solid dosage forms disclosed herein. These include dry blend (direct
compression), roller
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compaction, wet granulation, fluid bed granulation, foam granulation and melt
extrusion
granulation, all of which are useful for making matrix tablets.
[00185] Toward this end, the processes to make solid dosage form include a
generic processes
such as manufacturing by the wet granulation technique. For example, bempedoic
acid and
polymer(s) are blended using a solvent, such as methanol, as the granulation
fluid. The
remaining excipients are dissolved in a portion of granulation fluid and this
mixture is wet
blended slowly added to the bempedoic acid with continual mixing in the
blender. Granulating
fluid is added until a wet blend is produced, which wet mass blend is then
forced through a
predetermined screen onto oven trays. The blend is dried for 18 to 24 hours at
24 C. to 40 C. in
a forced-air oven. The dried granules are then sieved. Then a lubricant such
as magnesium
stearate is granulated into the mixture and then put into milling jars.
Milling involves mixing on
ajar mill for about 10-30 minutes. Following that, the composition is then co-
pressed and
perhaps coated with a further excipient.
[00186] Considerations for which process to use include drug loading,
flowability, and
compactibility. For example, both wet granulation and fluid bed granulation
may not be optimal
for moisture-sensitive drugs while melt extrusion granulation may not be
suitable for thermally
unstable drugs.
[00187] On the other hand, multi-particulate solid dosage forms comprise both
the drug/ API
and layered beads or microspheres. Fluid-bed granulation, extrusion and
spheronization, hot-
melt extrusion granulation, spray congealing, or roller compaction are a few
common methods
used for micronizing and coating particles of such dosage forms. Bead
formation can be
performed by non-covalent alginate layer crosslinking with calcium cations to
form alginate
beads.
[00188] Finally, solid dose form osmotic tablets, such as the solid dosage
forms developed by
Alza Corporation, typically contain four components: a drug/API compartment,
the swelling
compartment containing an osmotically active salt, a membrane(s), and
microscopic hole(s) for
release. The drug/API and swelling compartments are made by the granulation
processes
described for matrix-based systems above. The osmotic tablet works by forming
a "pull¨push"
osmotic pump of sorts with the drug/API and swelling compartments. Both
compartments are
compressed into a bilayer tablet and a membrane(s) containing holes (made with
created by laser
drilling) is coated (see the processes above for spray drying and the
Remington reference) over
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the tablet. The membrane allows free diffusion of water but not drug. When the
tablet is exposed
to water or any fluid in the body, water will flow into the tablet because of
the osmotic pressure
difference. For processes on making osmotic tablets, see, e.g., U.S. Patent
Nos. 8,629,179 and
8,163,798, and Remington's Pharmaceutical Sciences (Arthur Osol, editor;
current edition).
[00189] The most significant advantage for osmotic systems is that the dosage
form to some
extent is pH-independent and provides a steady release rate for an extended
time period even as
the dosage form moves thru the inhomogeneous microenvironments (with respect
to pH, salinity,
ion concentration, etc.) of various sections of the GI tract. Santus and
Baker, "Osmotic drug
delivery: a review of the patent literature," Journal of Controlled Release 35
(1995) pp. 1-21,
incorporated in its entirety by reference herein, is a nice review of such
systems. Moreover, U.S.
patents issued to ALZA Corporation, describe how to make and use osmotic
dosage forms, each
of which are incorporated in their entirety herein: U.S. Pat. Nos. 3,845,770;
3,916,899;
3,995,631; 4,008,719; 4,111,202; 4,160,020; 4,327,725; 4,519,801; 4,578,075;
4,681,583;
5,019,397; and 5,156,850.
[00190] Some exemplary swelling polymers for osmotic systems include, but are
not limited
to L poly(alkylene oxide) of 1 million to 15 million number-average molecular
weight, as
represented by poly(ethylene oxide), and poly(alkali carboxymethylcellulose)
of 500,000 to
3,500,000 number-average molecular weight (alkali: sodium, potassium or
lithium), acidic
carboxypolymer, acrylic acid cross-linked with polyalkenyl ethers or divinyl
glycol, cross-linked
homopolymers and copolymers of acrylic acid including divinyl glycol and/or
C10-C30 alkyl
acrylate crosslinked with allyl pentaerythritol as the copolymer, a polymer of
acrylic cross-
linked with a polyallyl sucrose number-average molecular weight- 250,000 to
4,000,000; acrylic
acid polymers, polyacrylamides; cross-linked water swellable indenemaleic
anhydride polymers;
polyacrylic acid number-average molecular weight-80,000 to 200,000; acrylate
polymer
polysaccharides composed of condensed glucose units e.g., diester cross-linked
polygluran; and
the like. Some hydrogel forming polymers include those described in U.S. Pat.
No. 3,865,108,
U.S. Pat. No. 4,002,173, U.S. Pat. No. 4,207,893, and in Handbook of Common
Polymers, Scott
and Roff, Chemical Rubber Co., Cleveland, OH. Suitable osmotic agent solutes
include, but are
not limited to: sodium chloride, potassium chloride, lithium chloride,
magnesium sulfate,
magnesium chloride, potassium sulfate, sodium sulfate, lithium sulfate,
potassium acid
phosphate, mannitol, urea, inositol, magnesium succinate, tartaric acid,
raffinose, sucrose,
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glucose, lactose, sorbitol, inorganic salts, organic salts and carbohydrates.
Suitable solvents
suitable for manufacturing the dosage form components comprise aqueous or
inert organic
solvents that do not adversely harm the materials used in the system. The
solvents include, but
are not limited to: aqueous buffer solvents, e.g., phosphate buffer, alcohols,
ketones, esters,
ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatics,
aromatics, heterocyclic
solvents and mixtures thereof. Typical solvents include acetone, diacetone
alcohol, methanol,
ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate,
isopropyl acetate, n-butyl
acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n-heptane,
ethylene glycol
monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride,
ethylene dichloride,
propylene dichloride, carbon tetrachloride nitroethane, nitropropane
tetrachloroethane, ethyl
ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha,
1,4-dioxane,
tetrahydrofuran, diglyme, water, aqueous solvents containing inorganic salts
such as sodium
chloride, calcium chloride, and the like, and mixtures thereof such as acetone
and water, acetone
and methanol, acetone and ethyl alcohol, methylene dichloride and methanol,
and ethylene
dichloride and methanol.
[00191] Finally, techniques for drilling the holes in the outer membrane,
including mechanical
and laser drilling, are disclosed in U.S. Pat. Nos. 3,916,899 and in U.S. Pat.
No. 4,088,864, both
of which are incorporated in their entirety herein.
[00192] Accordingly, the disclosure provides for a sustained-release
pharmaceutical dosage
form comprising a solid oral osmotic dosage form comprising bempedoic acid and
a polymer
matrix. In some aspects, the disclosure provides for a sustained-release
pharmaceutical dosage
form comprising a solid oral osmotic dosage form comprising bempedoic acid and
a polymer
matrix, wherein the polymer is selected from a group consisting of
hydroxypropyl
methylcellulose (HPMC), microcrystalline cellulose, and sodium
carboxymethylcellulose.
Methods of use
[00193] Herein disclosed are methods of treating cardiovascular disease or
reducing the risk
of cardiovascular disease in a subject by administering a sustained-release
composition
comprising bempedoic acid and a polymer matrix.
[00194] Pharmaceutical compositions useful according to the present invention
are given to a
subject, administration is preferably in a "therapeutically effective amount"/
"therapeutically
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effective concentration" (meaning the same) or a "prophylactically effective
amount" (as the
case can be, although prophylaxis can be considered therapy), this being
sufficient to show
benefit to the individual. The actual amount administered, and rate- and time-
course of
administration, will depend on the nature and severity of the disease being
treated. The course
and prescription of treatment, e.g., decisions on dosage, etc., is within the
responsibility of
general practitioners and other medical doctors, and typically takes account
of the disorder to be
treated, the condition of the individual patient, the site of delivery, the
method of administration
and other factors known to practitioners. Exemplary therapeutically effective
amounts are 50,
100, 200, 300, 400 or 500 mg per day, more preferably 50, 100 or 200 mg per
day, even more
preferably 90 or 180 mg per day. Exemplary prophylactically effective amounts
are 50, 100,
200, 300, 400 or 500 mg per day, more preferably 50, 100 or 200 mg per day,
even more
preferably 90 or 180 mg per day.
[00195] In one aspect, the disclosure provides for a method of treating
cardiovascular disease
or reducing the risk of cardiovascular disease in a subject, the method
comprising:
administering an effective amount of a solid oral dosage form to a subject in
need
thereof, wherein the solid oral dosage form comprises bempedoic acid and a
polymer, and
wherein the solid oral dosage form when dissolution tested using United States
Pharmacopoeia
Apparatus 2 (paddles 50 rpm) in 50 mM phosphate buffer exhibits a drug release
profile
substantially corresponding to the following pattern:
after 2 hours, no more than 30% of the bempedoic acid is released;
after 4 hours, no more than 75% of the bempedoic acid is released;
after 8 hours, no more than 90% of the bempedoic acid is released; and
wherein the solid oral dosage form provides a therapeutically effective
concentration of
bempedoic acid over a period of 24 hours to treat cardiovascular disease or
reduce the risk of
cardiovascular disease when administered to the subject.
[00196] In one aspect, the disclosure provides for a method wherein the solid
oral dosage
form does not release more than 95% of the bempedoic acid after 8 hours when
dissolved in 50
mM phosphate buffer having a pH of 8.5 at 20 C.
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[00197] In one aspect, the disclosure provides for a method of inhibiting ATP-
citrate lyase
(ACL) enzyme in a subject, the method comprising administering to the subject
the
pharmaceutical dosage form of any one disclosed herein.
[00198] In one aspect, the disclosure provides for a method wherein the solid
oral dosage
form comprises from 5 mg to 500 mg bempedoic acid. In one aspect, the
disclosure provides for
a method wherein the solid oral dosage form comprises from 5 mg to 100 mg
bempedoic acid. In
one aspect, the disclosure provides for a method wherein the solid oral dosage
form comprises
from 5 mg to 50 mg bempedoic acid. In one aspect, the disclosure provides for
a method wherein
the solid oral dosage form comprises from 180 mg to 240 mg bempedoic acid. In
one aspect, the
disclosure provides for a method wherein the solid oral dosage form comprises
from 200 mg to
240 mg bempedoic acid.
[00199] In one aspect, the disclosure provides for a method wherein the
polymer is
microcrystalline cellulose. In one aspect, the disclosure provides for a
method wherein the
polymer is a mixture of microcrystalline cellulose and polycellulose. In one
aspect, the
disclosure provides for a method wherein the polymer is a mixture of
microcrystalline cellulose
and hydroxypropylmethyl cellulose (HPMC). In one aspect, the disclosure
provides for a method
wherein the polymer is hydroxypropylmethyl cellulose (HPMC). In one aspect,
the disclosure
provides for a method wherein the polymer is a polycellulose.
Cardiovascular disease & bempedoic acid delivery
Clinical endpoints
[00200] In one aspect, the disclosure provides for methods for decreasing the
level of a blood
lipid, lipoprotein or cholesterol in a subject. In some aspects, lowering is
determined by
comparing levels of an analyte measured from a sample obtained from the
subject before and
after administration of the drug. In some aspects, lowering is based on
results of clinical trial
results comparing matched populations, one receiving drug, and one receiving a
placebo. In one
aspect, the disclosure provides for methods of lowering low-density
lipoprotein cholesterol
(LDL-C) in a subject.
[00201] In one aspect, the disclosure provides for methods for lowering total
cholesterol (TC)
in a subject. In one aspect, the disclosure provides for methods wherein the
method lowers total
cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C) in a subject.
In one aspect,
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the disclosure provides for methods for lowering total cholesterol (TC) when
administered to a
human subject having hypercholesterolemia, mixed dyslipidemia, type II
diabetes mellitus,
obesity, chronic liver disease or kidney disease. In one aspect, the
disclosure provides for
methods for lowering total cholesterol (TC) and low density lipoprotein-
cholesterol (LDL-C)
when administered to a human subject having hypercholesterolemia, mixed
dyslipidemia, type II
diabetes mellitus, obesity, chronic liver disease or kidney disease.
[00202] In one aspect, the disclosure provides for methods for decreasing the
level of very
low density lipoprotein (VLDL) in a subject.
[00203] In one aspect, the disclosure provides for methods for decreasing the
size of VLDL
particles in a subject.
[00204] In one aspect, the disclosure provides for methods for decreasing the
level of
apolipoprotein B (ApoB) in a subject. In one aspect, the disclosure provides
for methods for
decreasing the level of apolipoprotein A-1 (ApoAl) in a subject.
[00205] In one aspect, the disclosure provides for methods for decreasing the
ratio of
apolipoprotein B (ApoB) to apolipoprotein A-1 (ApoAl) in a subject below. In
one aspect, the
disclosure provides for methods for not changing the ratio of apolipoprotein B
(ApoB) to
apolipoprotein A-1 (ApoAl) in a subject.
[00206] In one aspect, the disclosure provides for methods wherein the subject
has
hypercholesterolemia. In one aspect, the disclosure provides for methods
wherein the subject
has mixed dyslipidemia, type II diabetes mellitus, obesity, chronic liver
disease, kidney disease,
or any combination thereof.
[00207] In one aspect, the disclosure provides for methods wherein the subject
is a mammal.
In one aspect, the disclosure provides for methods wherein the subject is
human.
Therapeutic window
[00208] The therapeutic window can also be generally expressed as a ratio
between minimum
effective concentrations (MEC, also known as minimum inhibitory concentration
(MIC)) to the
minimum toxic concentration (MTC) (of the drug/API). An important goal of drug
delivery is to
keep the plasma levels of drug between MEC and MTC to provide the most
beneficial and most
risk-free therapeutic effects. If the drug concentration crosses MTC, then
toxic effects will be
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observed;on the other hand, if drug concentration is unable to surpass MEC,
then the treatment
suffers therapeutic failure.
[00209] The therapeutic index (TI) describes a relationship between the doses
of a drug that
causes lethal or toxic effects with the dose that causes therapeutic effects.
It can be calculated by:
Therapeutic index (TI) = LD50/ED5o
where LD50 is the minimum amount of drug that causes adverse effects in 50% of
the population.
LD5o could also be replaced with Toxic dose (TD5o). ED5o is the quantity of a
drug that can
produce desired therapeutic effects in 50% of the population.
[00210] In some aspects, the present disclosure provides for methods wherein
the
concentration of bempedoic acid is between the MEC and the MTC for a duration
of time from
20 minutes to 8 hours after administration. In some aspects, the present
disclosure provides for
methods wherein the concentration of bempedoic acid is between the MEC and the
MTC for a
duration of time from: 20 minutes to 9 hours, 20 minutes to 10 hours, 20
minutes to 12 hours, 20
minutes to 14 hours, 20 minutes to 16 hours, 20 minutes to 18 hours, 20
minutes to 20 hours, 20
minutes to 24 hours, 20 minutes to 36 hours, or 20 minutes to 48 hours after
administration.
[00211] In some aspects, the present disclosure provides for methods wherein
the
pharmaceutical dosage form provides an AUC for bempedoic acid in the rat of
7.5 mg/kg or 30
mg/kg bempedoic acid capsule. In some aspects, the present disclosure provides
for methods
wherein the pharmaceutical dosage form provides an AUC for activated bempedoic
acid in the
rat of 661 ng*hr/mL per mg of bempedoic acid following oral administration of
a single 7.5
mg/kg or 30 mg/kg bempedoic acid capsule.
[00212] In some aspects, the present disclosure provides for methods wherein
the
pharmaceutical dosage form, when administered at a unit dose of 180 mg of
bempedoic acid to a
1 kg male Sprague-Dawley rat results in a maximum blood plasma concentration
(Cmax) of
bempedoic acid in the rat of no more than 60 pg/mL pg/mL and is in a range
from 45 pg/mL -
59 pg/mL for 24 hours after administration.
[00213] In some aspects, the present disclosure provides for methods wherein
the
pharmaceutical dosage form provides a Tmax in the rat of greater than 8 hours
following oral
administration of a single 50, 100, 200, or 180 mg bempedoic acid tablet.
[00214] In some aspects, the present disclosure provides a method of
administering
bempedoic acid, the method, comprising: administering to a subject an
effective amount of a
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pharmaceutical dosage form comprising a solid oral dosage form to a subject in
need thereof,
wherein the solid oral dosage form comprises bempedoic acid and a polymer, and
wherein, when
assayed in a standard pharmacokinetic assay, e.g., rat, said administration
results in a maximum
blood plasma concentration (Cmax) of no more than 60 [tg/mL and, wherein said
is in a range
from 45 [tg/mL-60 [tg/mL for 24 hours after administration.
[00215] In some aspects, the present disclosure provides for methods wherein
bempedoic acid
is delivered at a rate such that it is independent on the amount of bempedoic
acid in the dosage
form. In such aspects, the method provides for zero-order release of bempedoic
acid. In some
aspects, the present disclosure provides for methods wherein bempedoic acid is
delivered at a
near constant rate (meaning deviation from average delivery rate of not more
than +/- 10% over
the effective delivery lifetime of the dosage form) for at least 2 hours, at
least 4 hours, at least 6
hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14
hours, at least 16 hours, at
least 18 hours, at least 20 hours, at least 22 hours, at least 24 hours, but
no longer than 36 hours
(i.e., covering periods from 2-36 hr).
[00216] In some aspects, the described methods can be practiced by
administering a
pharmaceutical dosage form of bempedoic acid described in this application.
Combination therapy and dosage forms
[00217] In some aspects, the present disclosure provides for methods and
compositions
wherein the sustained-release pharmaceutical compositions further comprise
therapeutically-
effective amounts of Ezetimibe. In such aspects, the formulations need not
provide for sustained-
release of Ezetimibe, but do provide sustained-release of bempedoic acid in
accordance with this
disclosure.
[00218] In some aspects, the present disclosure provides for methods and
compositions
wherein the sustained-release pharmaceutical compositions further comprise
therapeutically-
effective amounts of a statin. In such aspects, the formulations need not
provide a sustained-
release of a statin, but do provide sustained-release of bempedoic acid in
accordance with this
disclosure.
[00219] In some aspects, the present disclosure provides for methods wherein
the sustained-
release pharmaceutical composition is administered in combination with other
lipid-lowering
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treatments, either simultaneously or sequentially dependent upon the clinical
situation of the
cardiovascular condition that is being treated.
[00220] In some aspects, the present disclosure provides for methods and
compositions
wherein the sustained-release pharmaceutical compositions further comprise
therapeutically-
effective amounts of an antibody that lowers proprotein convertase subtilisin-
kexin type 9
(PCSK9 inhibitor). In some aspects, the present disclosure provides for
methods and
compositions wherein the sustained-release pharmaceutical compositions further
comprise
therapeutically-effective amounts of a bile acid sequestrant.
[00221] In some aspects, the present disclosure provides for methods and
compositions
wherein the sustained-release pharmaceutical compositions further comprise
therapeutically-
effective amounts of a biguanide (e.g., metformin), or adenosine monophosphate
activated
protein kinase (AMPK) activators, or alpha-glucosidase inhibitors, or amylin
analogs, or
dipeptidyl peptidase 4 inhibitors, or incretin mimetics, or meglinitides, or
sulfonylureas, or non-
sulfonylureas, or sodium-glucose transporter-2 (SGLT2) inhibitors, or
thiozolidinediones, or
glucagon like peptide -1 (GLP-1) and/or combinations thereof.
[00222] In some aspects, the present disclosure provides for methods and
compositions
wherein the sustained-release pharmaceutical compositions further comprise
therapeutically-
effective amounts of a farnesoid-X-receptor (FXR) and/or bile acid receptor
agonists, or
peroxi some proliferator activated receptor (PPAR)-alpha agonist, or PPAR-
gamma agonists, or
PPAR-delta agonists, or PPAR-alpha/gamma agonist, PPAR-alpha/delta agonists,
or pan PPAR
agonists, or cysteine depleting agents, or phosphodiesterase-4 (PDE-4)
inhibitors, or apoptosis
signal-regulating kinase 1( ASK-1) inhibitors, or chemokine receptor
inhibitors, including
CCR2/CCR5 inhibitors, or combinations thereof
[00223] In some aspects, the present disclosure provides for methods and
compositions
wherein the sustained-release pharmaceutical compositions further comprise
therapeutically-
effective amounts of a compound that lowers levels of (inhibitor of) alanine
aminotransferase,
alkaline phosphatase, total bilirubin, or triglycerides or Cytokeratin-18.
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Administration schedule
[00224] In some aspects, the present disclosure provides for methods wherein
the sustained-
release pharmaceutical composition is administered twice daily, once every
day, or once every
two days.
Metabolic syndrome treatment with bempedoic acid
Metabolic syndromes / disorders
[00225] Metabolic syndromes and/or metabolic disorders are associated with
conditions such
as increased adiposity, insulin resistance, dyslipidemia, hepatic steatosis,
inflammation and
atherosclerosis. These abnormalities are linked to some degree to the process
of atherogenesis.
Although bempedoic acid may improve metabolic dysregulation pathways related
to some of
these abnormalities, it unclear whether the therapeutic efficacy is limited by
pharmacodynamic
parameters.
[00226] Herein the inventors disclose that targeting the enzymes ACL and AMPK
with a
sustained release formulation of bempedoic acid increases the efficiency of
formation, residence
lifetime, and therapeutic efficacy of activated bempedoic acid, which in turn
provides
significantly more therapeutic value in treating metabolic syndrome diseases
and disorders such
as NAFLD, NASH, hepatic steatosis, inflammation, fibrosis, or any combination
thereof.
[00227] In one aspect, the disclosure provides methods of treating a metabolic
syndrome
and/or a metabolic disorder in a subject, the method comprising administering
to the subject an
effective amount of any one of the sustained release formulations/dosage forms
disclosed herein.
In one aspect, the disclosure provides for methods of treating hepatic
steatosis in a subject, the
method comprising administering to the subject an effective amount of any one
of the sustained
release formulations/dosage forms disclosed herein. In one aspect, the
disclosure provides for
methods of treating inflammation or fibrosis in a subject, the method
comprising administering
to the subject an effective amount of any one of the sustained release
formulations/ dosage forms
disclosed herein.
[00228] In one aspect, the disclosure provides for methods of treating a
metabolic syndrome,
metabolic disorder, hepatic steatosis, inflammation, fibrosis or any
combination thereof in a
subject diagnosed or measured by liver biopsy pathology or imaging
methodologies disclosed
herein.
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Nonalcoholic fatty liver disease (NAFLD)
[00229] If the rate of lipid delivery to the liver and de novo lipogenesis
within the liver are not
matched by the rates of fatty acid 13-oxidation and VLDL secretion, then
hepatocytes will
increase lipid droplet formation and NAFLD will ensue. NAFLD is the hepatic
manifestation of
the metabolic syndrome due to its tight association with obesity,
dyslipidemia, and type 2
diabetes (see, e.g., Asrih, M., and F. R. Jornayvaz. 2015. Molecular and
Cellular Endocrinology.
418: 55-65). NAFLD encompasses a spectrum of disorders from simple steatosis
to
steatohepatitis.
[00230] NAFLD is largely asymptomatic in the early stages. The standard for
diagnosing
NAFLD is a liver biopsy. Non-invasive NAFLD diagnosis includes methods using
imaging
modalities, plasma markers, and scoring algorithms. Imaging is done with
ultrasound, computed
tomography (CT), magnetic resonance imaging (MM), transient elastography, or
FibroScang.
Plasma markers used to assess liver function include alanine and aspartate
transaminases (ALT
and AST, respectively), albumen, platelet count, glucose, insulin, TG, and
cholesterol (see, e.g.,
Machado, M. V., and H. Cortez-Pinto. 2013. Journal of Hepatology. 58: 1007-
1019; Pacana, T.,
and A. J. Sanyal. 2015. F1000Prime Rep. 7: 28). There are also many scoring
algorithms using
these plasma measurements in addition to age, gender, body mass index, insulin
resistance and
glycemia, hypertension, and the results from imaging tools.
[00231] Herein disclosed are sustained release formulation comprising
bempedoic acid
effective in the treatment of NAFLD, NASH and/or NAFL.
[00232] In one aspect, the disclosure provides for methods of treating NAFLD
in a subject,
the method comprising administering to the subject an effective amount of any
one of the
sustained release formulations/ dosage forms disclosed herein.
Nonalcoholic steatohepatitis (NASH)
[00233] NAFLD progresses to a very serious disease termed nonalcoholic
steatohepatitis
(NASH). This disease is hallmarked by increased inflammation and fibrosis.
NASH
histologically presents as simple steatosis with hepatocyte ballooning,
monocyte infiltration, and
collagen deposition (see, e.g., Yeh, M. M., and E. M. Brunt. 2014.
Gastroenterology. 147: 754-
764). The increase in fibrosis and inflammation seen with NASH greatly
increases the risk of
liver cancer.
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[00234] In one aspect, the disclosure provides for methods of treating NASH in
a subject, the
method comprising administering to the subject an effective amount of any one
of the sustained
release formulations/ dosage forms disclosed herein.
[00235] In one aspect, the disclosure provides for methods of treating NAFLD,
NAFL and/or
NASH wherein the subject is obese, has hypercholesterolemia, has mixed
dyslipidemia, has type
2 diabetes, or any combination thereof.
EXAMPLES
[00236] Below are examples of specific embodiments for carrying out the
present invention.
The examples are offered for illustrative purposes only, and are not intended
to limit the scope of
the present invention in any way. Efforts have been made to ensure accuracy
with respect to
numbers used (e.g., amounts, temperatures, etc.), but some experimental error
and deviation
should, of course, be allowed for.
[00237] The practice of the present invention will employ, unless otherwise
conventional
methods of pharmaceutical chemistry and pharmacology, within the skill of the
art. Such
techniques are explained fully in the literature. See, e.g., Remington's
Pharmaceutical Sciences,
18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990).
Example 1 ¨ Experimental conditions and protocol for pharmacokinetics (PK)
studies in
animals
Animals & administration
[00238] Male Han Wistar [Crl:WI(Han)] rats were purchased from Charles River
and were
acclimated to study conditions for four days prior to initial dose
administration. Certified
Rodent Diet #2016C (Envigo RMS, Inc.) was provided ad libitum. Water was
provided fresh
daily, ad libitum. Animals were assigned to 1 of 3 groups where group 1
received ETC-1002 (30
mg/kg) as a single bolus oral dose, group 2 received ETC-1002 (30 mg/kg) over
4 separate dosed
at 7.5 mg/kg) approximately 4 hours apart, and group three received no dose
(Table 1). Animals
were identified via individual cage cards and implantable microchip
identification devices in the
right, dorsal lumbar region.
Dosage, Collection, & Analysis
[00239] Individual doses were calculated based on body weights recorded on the
day prior to
dose administration and the oral dose was administered via oral gavage. Blood
samples were
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collected at pre-dose and at approximately 2, 4, 6, 8, 10, 12, 14, 20, and 24
hours post dose
according to Table 2 schedule via a jugular vein by syringe and needle
(approximately 0.3 mL)
or by cardiac puncture under appropriate anesthesia. Blood was transferred
into tubes containing
no anticoagulant (serum separator tubes).
[00240] Blood was allowed to clot at ambient temperature prior to
centrifugation to obtain
serum. Centrifugation began within 1 hour of collection. Serum was placed into
the appropriate
tubes and maintained on dry ice prior to storage at approximately -70 C.
Liver samples were
collected from three animals/group/time point at approximately 2, 6, 10, 14,
20, and 24 hours
post-dose (Table 2). The liver was harvested as quickly as possible using pre-
cooled clamps.
Afterwards, the tissue and clamp was immediately flash frozen by emersion in
liquid nitrogen.
Following freezing, the tissues were packaged in foil and maintained on dry
ice prior to storage
at approximately -70 C.
[00241] Serum was then analyzed for levels of ETC-1002 using a validated LC-
MS/MS
methods, and ETC-1002-CoA (activated bempedoic acid) and acetyl-CoA levels
were
determined in liver samples following extraction of homogenates in Me0H-formic
acid. An
acetyl-CoA standard concentration curve was generated in control liver
homogenates, and
unknown sample concentrations were calculated using a linear curve fit model.
ETC1002-CoA
levels are expressed as changes in peak area (acetyl-CoA i.tg equivalents).
Study Design
Table 1.
Target Target
Number Dose Target Dose Dose
of Male Test Dose Level Concentration Volume
Group Animals Article Route (mg/kg) (mg/mL) (mL/kg)
ETC-
1 18 Oral 30 3 10
1002
ETC-
2 18 Oral' 7.5 3 2.5
1002
3 3 NA NA NA NA NA
NA: Not applicable, designated for control collections.
: Animals were dosed four times over 12 hours (approximately 4 hours apart)
for a
total of 30 mg/kg (3 mg/mL and 10 mL/kg).
Table 2.
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Animals/ Time Points (Hours Post-dose)
Group Jugulara Cardiac Puncture
1-3 Pre-dose 2
4-6 4b 6
7-9 8' 10
10-12 12d 14
13-15 20
16-18 24
a: All collections were based on the first daily dose for Group 2.
b: For Group 2, samples were collected prior to the second dose.
For Group 2, samples were collected prior to the third dose.
d: For Group 2, samples were collected prior to the fourth dose.
Formulation
[00242] ETC-1002 formulations were prepared in the appropriate volume of 0.5%
CMC (pH
7-8) and were stirred throughout the course of dosing. Specific information
regarding dose
preparation is in Table 3.
Table 3.
Total Target Dose
Test Article Vehicle Concentration Calculated
Dose
Weight Volume (mg/mL) Concentration
Groups (mg) (mL) (mg/mL)
1 and 2 390.025 130 3 3.00
Example 2: Single bolus PK study in animals ¨ exemplary immediate release
bempedoic
acid formulation
[00243] Existing orally-administered formulations are rapidly absorbed in the
small intestine
(see, e.g., Bilen et al., Curr Atheroscler Rep., 2016; 18(10): 61). The
purpose of this Example is
to establish a baseline pharmacodynamic profile for an exemplary immediate
release bempedoic
acid formulation. The experimental procedures employed are described in the
"Example 1 ¨
Experimental conditions and protocol for pharmacokinetics (PK) studies in
animals", above.
Results
[00244] The single bolus PK measurements were: Tmax = 2 hours, Cmax = 97.1
g/mL, and
AUCo-2411r = 1244.0m=hr/mL. Bempedoic acid serum levels provided a peak
maximum
concentration near 100,000 ng/mL (100m/m1) within 1 hour after administration.
Further,
single bolus administration provided liver ETC-1002-CoA concentrations below
250 ng/gm over
a 20 hour period.
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Example 3: Multiple split administration PK study in animals to simulate the
sustained
release of bempedoic acid formulation
[00245] Multiple split administrations were employed to simulate the sustained-
release of
bempedoic acid in vivo. The effect of bempedoic acid absorption on PK
properties is tested here
in light of biological metabolism. The purpose of this study is to determine
the
pharmacodynamic profile for a representative sustained-release bempedoic acid
formulation.
The following procedures are described in the "Example 1 ¨ Experimental
conditions and
protocol for pharmacokinetics (PK) studies in animals," described above.
Results
[00246] Multiple split PK measurements were: Tmax = 10 hours, Cmax = 55.5
pg/mL, and an
AUC0-2411r = 661 1.tg.hr/mL. Multiple split administration provided bempedoic
acid serum levels
at a maximum concentration around 60,000 ng/mL over 10 hours post-
administration. Further,
multiple split bolus administration demonstrated an approximately 28% increase
in AUCo-24,ss
and an approximately 24% increase AUCo-24hr in liver ETC-1002-CoA.
Example 4: Sustained-release vs. immediate release bempedoic acid formulation
PK study
comparison in rats
[00247] The purpose of this example is to provide support for the proof of
concept of
bempedoic acid (ETC-1002) sustained-release formulations possessing increased
PK activities
by showing that a reduced absorption rate provides an improved pharmacokinetic
profile in liver
and plasma. An improved PK profile is defined as having either a higher ETC-
1002-CoA
AUCo-2411r in liver with equal or reduced serum ETC-1002 Cmax or AUCo-24m, or
an equal amount
of ETC-1002-CoA AUC0-2411r in liver with reduced serum ETC-1002 Cmax or AUC0-
2411r for any
given dosage level.
Results
[00248] Significant differences in serum pharmacokinetics were observed
between single
bolus and multiple split bempedoic acid administrations. Surprisingly,
simulating sustained-
release with multiple split bolus administration provided a slow climb in
bempedoic acid serum
concentration irrespective of rapid absorption. This in contrast to the single
bolus
administration, which provided a characteristic short Tmax in bempedoic acid
serum levels almost
immediately followed by a precipitous fall over the following 22 hours (Figure
1A).
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[00249] Hepatic acetyl-CoA was suppressed in both groups for the entire 24
hour duration of
the study (Figure 1B). However, multiple split administration, i.e., simulated
sustained-release,
showed a more significant decrease in liver acetyl-CoA activity despite
achieving a lower
maximum serum exposure (47%, Figure 1B).
[00250] Moreover, simulated sustained-release achieved greater hepatic ETC-
1002-CoA
exposure in comparison to the single bolus. Interestingly, the ratio of liver
ETC-1002-CoA
exposure to serum ETC-1002 exposure was greater for the simulated sustained-
release by more
than 2-fold (Figure 1C). These findings support the conclusion that prodrug
conversion
efficiency was increased by the altered rate of bempedoic acid absorption in
the gut.
Example 5: Sustained release formulations of bempedoic acid and their
respective
dissolution data
Formulations
[00251] Several formulations comprising bempedoic acid and a hydrophilic
cellulosic
polymer matrix, hydroxypropyl methylcellulose (HPMC), were prepared and tested
in USP
dissolution assays. Formulations were constructed as solid microparticle
spheres. Each
formulation was sieved.
[00252] The individual batches were distinctly formulated to include the
compounds
described in Tables 4-13 below.
Table 4.
CU07-089
Ingredient Chemical Name mg/dose s% w/w % w/w g/batch
ETC-1002 Bempedoic Acid 200.0 60.0% 36.5% 217.0
Avicel PH-101 Microcrystalline 124.3 37.3% 22.7% 134.9
Cellulose
HPMC 606 Hydroxypropyl 2.4 0.7% 0.4% 2.6
Methylcellulose
Sodium Lauryl Sulfate Sodium Lauryl Sulfate 6.5 2.0%
1.2% 7.1
Treated Water Water 39.1% 232.5
Total 333.3 100% 100% 594.1
Table 5.
CU07-101
Ingredient Chemical Name mg/dose s% w/w % w/w Wbatch
ETC-1002 Bempedoic Acid 200.0 60.0% 40.0% 217.0
Avicel PH-101 Microcrystalline 31.1 9.3% 6.2% 33.7
Cellulose
Avicel CL-611 Microcrystalline 93.3 28.0% 18.7% 101.2
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Cellulose/Carboxymeth
ylcellulose Sodium
HPMC 606 Hydroxypropyl 2.4 0.7% 0.5% 2.6
Methylcellulose
Sodium Lauryl Sulfate Sodium Lauryl Sulfate 6.5 2.0%
1.3% 7.1
Treated Water Water 33.3% 180.5
Total 333.3 100% 100% 542.1
Table 6.
CU07-103
Ingredient Chemical Name mg/dose s% w/w % w/w g/batch
ETC-1002 Bempedoic Acid 200.0 60.0% 40.0% 217.0
Microcrystalline
Avicel CL-611 Cellulose/Carboxymethyl 124.3 37.3% 24.9% 134.9
cellulose Sodium
Hydroxypropyl
HPMC 606 2.4 0.7% 0.5% 2.6
Methylcellulose
Sodium Lauryl Sulfate Sodium Lauryl Sulfate 6.5 2.0%
1.3% 7.1
Treated Water Water - - 33.3% 180.5
Total 333.3 100% 100% 542.1
Table 7.
CU07-105
Ingredient Chemical Name mg/dose s% w/w % w/w g/batch
ETC-1002 Bempedoic Acid 250.0 75.0% 53.5% 271.2
Microcrystalline
Avicel PH-101 74.4 22.3% 15.9% 80.7
Cellulose
Hydroxypropyl
HPMC 606 2.4 0.7% 0.5% 2.6
Methylcellulose
Sodium Lauryl Sulfate Sodium Lauryl Sulfate 6.5 2.0%
1.4% 7.1
Tr - eated Water Water - 28.7% 145.5
Total 333.3 100% 100% 507.1
Table 8.
CU07-107
Ingredient Chemical Name mg/dose s% w/w % w/w g/batch
ETC-1002 Bempedoic Acid 200.0 60.0% 33.2% 217.0
Microcrystalline
Avicel PH-101 111.0 33.3% 18.4% 120.4
Cellulose
Hydroxypropyl
HPMC 606 2.4 0.7% 0.4% 2.6
Methylcellulose
Sodium Lauryl Sulfate Sodium Lauryl Sulfate 6.5 2.0%
1.1% 7.1
Explotab Sodium Starch Glycolate 13.4 4.0% 2.2% 14.5
Tr - eated Water Water - 44.7% 292.5
Total 333.3 100% 100% 654.1
Table 9.
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CU07-109
Ingredient Chemical Name mg/dose s% w/w % w/w g/batch
ETC-1002 Bempedoic Acid 200.0 60.0% 40.0% 217.0
Microcrystalline
Avicel CL-611 Cellulose/Carboxymethy 126.7 38.0% 25.4% 137.5
lcellulose Sodium
Sodium Lauryl Sulfate Sodium Lauryl Sulfate 6.5 2.0%
1.3% 7.1
Tr - eated Water Water - 33.3% 180.5
Total 333.3 100% 100% 542.1
Table 10.
CU07-111
Ingredient Chemical Name mg/dose s% w/w % w/w g/batch
ETC-1002 Bempedoic Acid 200.0 60.0% 40.0% 217.0
Microcrystalline
Avicel PH-101 110.2 33.1% 22.1% 119.6
Cellulose
Aqualon Sodium 16.5 5.0% 3.3% 17.9
Carboxymethylcellulose
Sodium Lauryl Sulfate Sodium Lauryl Sulfate 6.5 2.0%
1.3% 7.1
Treated Water Water - 33.3% 180.5
Total 333.3 100% 100% 542.1
Table 11.
CU07-117
Ingredient Chemical Name mg/dose s% w/w % w/w g/batch
ETC-1002 Bempedoic Acid 200.0 60.0% 42.4% 217.0
Microcrystalline
Avicel PH-101 103.9 31.2% 22.0% 112.7
Cellulose
Aqualon Sodium 22.9 6.9% 4.8% 24.8
Carboxymethylcellulose
Sodium Lauryl Sulfate Sodium Lauryl Sulfate 6.5 2.0%
1.4% 7.1
Treated Water Water - 29.4% 150.5
Total 333.3 100% 100% 512.1
Table 12.
CU07-115
Ingredient Chemical Name mg/dose s% w/w % w/w g/batch
ETC-1002 Bempedoic Acid 200.0 60.0% 43.2% 217.0
Microcrystalline
Avicel PH-101 97.6 29.3% 21.1% 105.9
Cellulose
Aqualon Sodium 29.1 8.7% 6.3% 31.6
Carboxymethylcellulose
Sodium Lauryl Sulfate Sodium Lauryl Sulfate 6.5 2.0%
1.4% 7.1
Treated Water Water - 28.0% 140.5
Total 333.3 100% 100% 502.1
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Table 13.
CU07-118
Ingredient Chemical Name mg/dose s% w/w % w/w g/batch
ETC-1002 Bempedoic Acid 200.0 60.0% 40.0% 217.0
Avicel PH-101 Microclystalline Cellulose 112.2 33.7% 22.4%
121.7
Aqualon Sodium 12.2 3.7% 2.4% 13.2
Carboxymethylcellulose
HPMC 606 Hydroxypropyl 2.4 0.7% 0.5% 2.6
Methylcellulose
Sodium Lauryl Sulfate Sodium Lauryl Sulfate 6.5 2.0%
1.3% 7.1
Treated Water Water 33.3% 180.5
Total 333.3 100.0% 100.0% 542.1
Dissolution Assay
[00253] A USP dissolution experiment evaluates the rate and extent that a
compound forms a
solution under carefully controlled conditions. The dissolution test helps
evaluate the
performance of a drug product. For detailed description of apparatus set-ups
and experimental
procedures, please see United States Pharmacopeial Convention, USP35 NF30,
2012: U S.
Pharmacopoeia National Formulary, The United States pharmacopeia, 2011,
Chapter 711,
5642-5648.
[00254] Physical properties of the dosage form such as: unit dose wettability,
permeability,
swelling, disintegration and de-aggregation affect the dissolution of
pharmaceutical dosage
forms.
[00255] The results of the dissolution assay are described below in Table 14
and presented in
Figures 2A and Figure 2B respectively.
Table 14 ¨ Dissolution Assay Results
Time (minutes)
Batch # 0 15 60 120 180 240 360 480 600 720
CU07-089 0 26 38 46 53 62 70 76 80
CU07-101 0 44 62 72 79 89 94 97 99
CU07-103 0 50 68 78 85 94 98 100 102
CU07-105 0 31 46 56 64 75 83 88 93
CU07-107 0 38 54 64 72 82 88 93 96
CU07-109 0 56 74 84 90 95 98 100 101
CU07-111 0 54 71 80 86 92 95 97 99
CU07-117 0 69 86 93 96 98 99 99 100
CU07-115 0 77 93 97 98 99 99 99 99
CU07-118 0 44 62 72 79 88 93 96 99
IR Tablet 0 84 94 98 99 99 99 99 99 99
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- Numerical values are expressed as the percentage released into solution from
the starting total amount of
Bempedoic acid in the formulation. *Batches CU07-105 and CU07-107 have
relatively low yields in the
desired 16/30 sieve cut range. Batches CU07-117 and CU07-115 exhibited
sticking behavior during the
manufacturing process and also have relatively low overall yields. The 720 min
time point is the infinity
time-point.
Example 6: Compositions of drug products for immediate release (IR) and
sustained
release (SR) formulations of bempedoic acid
[00256] This example describes the compositions of products and formulations
of both
immediate release and sustained release of bempedoic acid.
[00257] Table 15 describes the composition of immediately release (IR)
formulation of
bempedoic acid.
COMPOSITION OF IMMEDIATE RELEASE FORMULATION OF BEMPEDOIC ACID
Table 15 ¨ Composition of Bempedoic Acid 180 mg Tablets
Component Function Amount (mg/tablet)
Core Tablet:
Bempedoic Acid Active 180.0
Microcrystalline Cellulose Filler 64.0
Lactose Filler 30.0
Sodium Star Glycolate Disintegrant 23.0
Hydroxy Propyl Cellulose Binder 16.0
Magensium Stearate Lubricant 9.0
Colloidal Sillicon Dioxide Glidant 5.0
Purified Watera Solvent N/A
Core Tablet Weight 327.0 mg
Film Coating Suspension:
Purified Watera Solvent N/A
OPADRY White (85F18422) Colorant 10.0
Total Tablet Weight 337.0mg
Abbreviations: IND=Investingational new drug; LDL-C=low-density lipoprotein-
cholesterol.
a Removed during processing.
[00258] Table 16 describes the drug product of IR formulation of bempedoic
acid and placebo
tablets.
Table 16 ¨ Investigational Medicinal Products (IMP) of Immediate Release
Formulation of
Bempedoic Acid and Placebo Tablets
Product Name: Investigational Medicinal Product
Bempedoic acid Placebo to Match Bempedoic
Acid
Dosage Form: Film-coated CR tablets Film-coated tablets
Unit Dose: 180 mg Not applicable
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Container/Closure: 9 count blister card with child resistant 9 count
blister card with child resistant
closures closures
Route of Administmtion: Oml, daily at approximately
the same Oml, daily at approximately the same
time, with or without food time, with or without food
Physical Description: Oval, white to off-while
film-coated Oval, white to off-while film-coated
tablet debossed with "ABC" on one face tablet debossed with "ABC"
on one face
and debossed with "000" on the opposite and debossed with "000" on
the opposite
face face
Manufacturer Patheon Patheon
(Fill/Finish): 2100 Syntex Court 2100 Syntex Court
Mississauga, Ontario Mississauga, Ontario
L5N 7K9 L5N 7K9
Canada Canada
[00259] Table 17 describes the composition of the SR formulation of bempedoic
acid.
COMPOSITION OF SUSTAINED RELEASE FORMULATION OF BEMPEDOIC ACID
Table 17¨ Composition for Sustained Release Formulation of Bempedoic Acid
Capsule
Component Chemical Name Function s% wiwa mg/Capsulea
50 mg 100
200 mg
mg
ETC-1002 Bempedoic Acid Active 60.0% 50.0 100.0
200.0
Pharmaceutical
Ingredient
Avicel PH-101 Microcrystalline Filler 33.7% 28.1 56.1
112.2
Cellulose
Aqualon Sodium Filler 3.7% 3.1 6.1 12.2
Carboxymethylcellulose
Sodium Lauryl Sodium Lauryl Sulfate Diluent/solubilizer 2.0%
-- 1.6 -- 3.3 -- 6.5
Sulfate
HPMC 606 Hydroxypropyl Binder 0.7% 0.6 1.2 2.4
Methylcellulose
Purified Water') --- Solvent
Total Fill Weight 100.0% 83.4
166.7 333.3
Capsule Shell:
Two-piece, white, opaque, capsule shelld Capsule shell 1
N/A 1
(Size #3)
(Size #0)
a Values have been rounded to the nearest decimal shown. The total sums are
determined from exact
values and may not be representative of the rounded individual values shown.
b Water and HPMC 606 will be added as a premixed solution.
Water is processing aid and is not included in the final formulation.
Therefore, "Total" does not
include water.
d The capsule shell is comprised of titanium dioxide (E171) (2.9079%) as an
opacifer and gelatin
(quantity sufficient for 100%).
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DESCRIPTION OF THE CAPSULES SPHERES FOR
SUSTAINED RELEASE FORMULATION OF BENIPEDOIC ACID
[00260] The sustained release (SR) bempedoic acid capsules are white opaque
hard gelatin
capsules filled with spheres made of bempedoic acid and excipients. Two
capsule sizes and
doses are available for the NASH study:
= "Size 3" for 50 mg bempedoic acid SR capsule
= "Size 0" for 200 mg bempedoic acid SR capsule
Example 7 ¨ Administration of representative sustained release bempedoic acid
formulation to humans
[00261] The primary objective is to assess the LDL-C lowering efficacy of a
representative
bempedoic acid sustained-release solid oral dosage form (tablet) versus
placebo administered
daily for 6 weeks in patients with elevated LDL-C.
[00262] Secondary objectives are to assess:
1. The effect of a bempedoic acid sustained-release formulation versus
placebo on
non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC),
apolipoprotein B (ApoB), high-sensitivity C-reactive protein (hs-CRP), TG, and
HDL-C.
2. The effect of bempedoic acid (180 mg) sustained-release solid oral
dosage form
(tablet) on percent of patients achieving LDL-C level <70 mg/dL.
3. The effect of bempedoic acid (180 mg) sustained-release solid oral
dosage form
(tablet) versus placebo on percent of patients achieving LDL-C reduction >50%
4. The safety and tolerability of bempedoic acid (180 mg) sustained-release
solid oral
dosage form (tablet) versus placebo.
[00263] The primary endpoint being used to evaluate the objectives of this
study is the percent
change from baseline to Week 6 in LDL-C levels. Secondary endpoints also
include percent
changes from baseline to Week 6 in non-HDL-C, TC, ApoB, hs-CRP, TG, and HDL-C
levels,
percent change from baseline to Week 6 in Percent of patients with LDL-C <70
mg/dL at Week
6, and percent of patients with LDL-C reduction of >50% from baseline to Week
6.
Administration of the Drug ¨ Treatment of Patients
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[00264] During the Treatment Period, patients are randomized to receive IMP of
either
sustained-release bempedoic acid solid dosage forms or placebo once daily.
Each daily
allotment of IMP was comprised of one bempedoic acid tablet in a blister
package. The placebo
blister pack contains the corresponding matching placebo of the bempedoic acid
solid dosage
forms. Patients are instructed to ingest IMP orally once daily with or without
food. On clinic
visit days, patientsare instructed to delay ingestion of IMP until all study
procedures were
completed.
Example 8: Single-dose study of immediate release formulation of bempedoic
acid in
healthy subjects (IR Study 1)
[00265] This example describes a single-dose study that evaluated the
safety, tolerability and
pharmacokinetics of bempedoic acid in healthy subjects. Figure 6 summarizes
the design of this
study.
[00266] A key objective of this study was to evaluate and characterize the
pharmacokinetic
(PK) profile of bempedoic acid and its metabolite after administration of
single, escalating, oral
doses to healthy subjects.
[00267] This was a single-center, randomized, double-blind, placebo-
controlled, escalating,
single-dose, cross-over study. The cross-over design involved 2 cohorts of 9
subjects each. Each
cohort escalated cautiously through 3 single-dose groups. Each dose group
comprised 6 subjects
randomized and received bempedoic acid and 3 subjects randomized and received
placebo. The
randomization scheme ensured that subjects received a total of 2 separate
doses of active drug
and a single administration of placebo. Dose groups were separated by a
washout period no less
than 10 days between administration of study medication. Dose escalation was
contingent upon
acceptable safety, tolerance and pharmacokinetic data and followed clearly
defined stopping
rules including an exposure limit. The bempedoic acid AUC0-24 exposure limit
of 2001.tg=hr/mL
in this study was higher than the estimated therapeutic exposure of 36 to 72
j.tg.hr/mL, provided
an opportunity to fully explore the high end of the dose range in the most
controlled phase of
drug development.
Results
[00268] Table 18 shows measured and dose-corrected pharmacokinetic (PK)
parameters after
single dose of immediate release (IR) formulation of bempedoic acid in healthy
subjects.
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Table 18 ¨ Measured and Dose-Corrected PK Parameters after A Single Dose of
Immediate Release Formulation of Bempedoic Acid from IR Study 1.
Single Dose Immediate Release in Healthy Subject
Dose (ing) immediate
tIrma AUC int (h.i.tg/mL) Cm ( )1E2-,/mL
)=1
50 46 2.95
100 3-3.5 hours 128 7.38
200 334 16.3
a Parameters were dose-corrected to a 50, 100, or 200 mg dose, respectively.
Example 9: Multiple ascending dose study of immediate release formulation of
bempedoic
acid in subjects with mild dyslipidemia (IR Study 2)
[00269] This example describes a multiple ascending dose study of bempedoic
acid in
subjects with mild dyslipidemia. Figure 7 summarizes the design of this study.
[00270] Key objectives of this study evaluated and characterized the
pharmacokinetic (PK)
profile and pharmacodynamic (PD) endpoints, such as low-density lipoprotein-
cholesterol (LDL-
C) level, of bempedoic acid and its metabolite after administration of
multiple ascending doses
of bempedoic acid to subjects with mild dyslipidemia.
[00271] This was a single-center, randomized, double-blind (sponsor-open),
placebo-
controlled, ascending, multiple-dose study with 4 ascending cohorts followed
by an optional 5th
cohort. The first 4 cohorts included 8 male and female subjects each (6
active/2 placebo) with
mildly elevated LDL-C level treated for 14 days duration in the Clinical Unit.
Dose escalation in
the first 4 cohorts were contingent upon acceptable safety, tolerance, and PK
data and will
follow clearly defined stopping rules including a predefined exposure limit
for AUCo-24 of 200
1.tg=h/mL for the sum of bempedoic acid and its metabolite ESP15228. Provided
that the safety
profile from the first 4 cohorts was acceptable, an optional 5th cohort of 24
free living male and
female subjects (18 active/6 placebo) with mildly elevated LDL-C and
triglycerides levels
treated for 28 days was completed.
[00272] Bempedoic acid capsules (20 mg) or placebo capsules were used for this
study.
Multiple oral doses of 20, 60, 100, and 120 mg were administered to subjects
in the fasting state
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in Cohorts 1 to 4 and did not exceed the predefined exposure limit for AUCo-24
of 200 pg.h/mL
for the sum of bempedoic acid and its metabolite ESP15228.
Results
[00273] Table 19 shows measured and dose-corrected pharmacokinetic (PK)
parameters after
single dose of immediate release (IR) formulation of bempedoic acid in healthy
subjects.
Table 19 ¨ LS Mean Percent Change from Baseline in LDL-C After Single Dose of
Immediate Release Formulation of Bempedoic Acid from IR Study 2
IR Study 1 Treatment
.=== .===
= = Comparison
Time Point Treatment LS Mean Difference p-
value
Group (SE) from PBO
Day 15 Placebo 10.6 (4.5)
20 mg 3.5 (5.0) -7.1
0.2974
60 mg -11.2 (5.1) -21.8
0.0035
100 mg -16.5 (5.1) -27.1
0.0003
120 mg -15.0 (5.0) -25.6
0.0004
Example 10: Multiple ascending dose study of immeidate release formulation of
bempedoic
acid in healthy subjects (IR Study 3)
[00274] This example describes a multiple ascending dose study of bempedoic
acid at doses
above 120 mg/day in health subjects. Figure 8 summarizes the design of this
study.
[00275] Key objectives of this study evaluated and characterized the
pharmacokinetic (PK)
profile and pharmacodynamic (PD) endpoints, such as low density lipoprotein-
cholesterol (LDL-
C) level, of bempedoic acid and its metabolite after administration of
multiple ascending doses
of bempedoic acid to healthy subjects.
[00276] This was a single-center, randomized, double-blind (sponsor-open),
placebo-
controlled, ascending, multiple-dose study with approximately 4 ascending
cohorts, each with 8
healthy male or female subjects (6 active/2 placebo) treated for 14 days
duration in the Clinical
Unit. Dose escalation in the next cohort was contingent upon acceptable
safety, tolerance, and
PK data and followed clearly defined stopping rules including a predefined
exposure limit for
mean AUCo-24 of 400 pg=h/mL for the sum of bempedoic acid and its metabolite
ESP15228.
[00277] Bempedoic acid 20 mg capsules or placebo capsules were used for this
study.
Multiple oral doses of 140, 180, 220 and 260 mg/day were administered to
subjects in the fasting
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state and did not exceed the predefined exposure limit for mean AUC0-24 of 400
pg.h/mL for the
sum of bempedoic acid and its metabolite ESP15228.
Results
[00278] Table 20 shows the mean steady-state PK parameters of immediate
release
formulation of bempedoic acid.
Table 20 ¨ Mean Steady-State PK Parameters of Immediate Release Formulation of
Bempedoic Acid From IR Study 3'
:
EUM:MataItitterEN:UMME:V.4100S.i:MM:im
Cmax (pg/mL) 21.6
AUCT,ss 307
(hr*pg/mL)b
Peak to Trough 13.1
Fluctuation (pg/mL)
a Predicated from 180 mg dose data assuming linear kinetics. b Median.
[00279] Table 21 shows the Least Square Mean percent change from baseline in
LDL-C after
single dose of immediate release formulation of bempedoic acid from IR Study
3.
Table 21 ¨ LS Mean Percent Change from Baseline in LDL-C After a Single Dose
of
Immediate Release Formulation From IR Study 3
IR Study 3 Treatment
Comparison
Time Point Treatment LS Mean Difference p-
value
Group (SE) from PBO
Day 15 Placebo 4.4 (5.4)
140 mg -21.3 (5.4) -25.7
0.0012
180 mg -27.1 (5.4) -31.5
0.0001
220 mg -36.1 (5.4) -40.5
<0.0001
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Example 11: Single- and repeat-dose study of sustained release formulation of
bempedoic
acid in overweight/obese otherwise healthy subjects (SR Study)
[00280] This example describes a single- and repeat-dose study of sustained
release
formulation of bempedoic acid carried out on overweight/obese but otherwise
healthy subjects.
Figure 9 summarizes the design of this study.
[00281] The formulations of the bempedoic acid sustained release tablets used
in this study
can be found in Tables 13 and 17.
[00282] The key objectives of this study were to evaluate the
pharmacokinetics, safety,
tolerability, and pharmacodynamics endpoints, such as LDL-C, of bempedoic acid
sustained
release therapy in overweight/obese but otherwise healthy subjects.
[00283] Period 1 assessed single-dose PK, safety, and tolerability. Period 1
was randomized,
but was not blinded or placebo-controlled. Screening occured up to 21 Days
prior to
randomization. Subjects admitted to the Clinical Research Unit (CRU) on the
evening of day -1
until the morning of Day 2. On the morning of Day 1, subjects were randomized
to receive a
single dose of bempedoic acid sustained-release formulation of 50 mg (n = 6),
100 mg (n = 6), or
200 mg (n = 6). The sustained-release formulation of bempedoic acid was
outlined in Tables 13
and 17. These treatments were administered in parallel (not sequentially).
Serial testing of PK
occured on Day 1. On the morning of Day 2, additional blood samples were
collected, a meal
was provided, and if appropriate, subjects were released from the CRU.
Subjects returned to the
CRU for outpatient morning clinic visits to collect additional blood samples
on Days 3, 5, 7, 9,
and 11. Preliminary PK, safety, and tolerability data from Period 1 were
assessed prior to
initiation of Period 2.
[00284] Period 2 assessed repeat-dose PK, safety, and tolerability during the
14-day treatment
phase. De novo lipogenesis was assessed on Day -7 and Day 1, and PD biomarkers
were
assessed on Day 13. Period 2 was randomized, placebo-controlled, and double-
blind. Screening
occurred up to 28 days prior to randomization. Subjects were admitted to the
CRU on 3 separate
occasions. The first occasion was in the afternoon of Day -8 followed on Day -
7 with testing of
de novo lipogenesis and discharge from the CRU. The second occasion the
subjects were
admitted to the CRU was on the afternoon of Day -1, followed on Day 1 by the
first dose of
bempedoic acid SR, testing of de novo lipogenesis, and discharge from the CRU.
Eligible
subjects were randomized on Day 1 and received bempedoic acid sustained-
release formulation
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of 50 mg (n = 10), 100 mg (n = 10), or 200 mg (n = 10), or placebo (n = 10)
for 14 days. The
sustained-release formulation of bempedoic acid is outlined in Tables 13 and
17. These
treatments were administered in parallel (not sequentially). The third
occasion that the subjects
were admitted to the CRU was on the evening of Day 13 to the morning of Day 15
for serial PK
sampling. On Days 3 to 13, subjects were reported to the CRU in the morning
for dosing and, if
required, PK sample collection. Subjects returned to the clinic for PK
sampling and safety
monitoring the morning of Days 17 and 22. De novo lipogenesis was assessed
during Period 2 at
baseline (Day -7) and with a single dose of study drug (Day 1). The stable
isotope tracer (2H20)
was primed for 2 days prior to each de novo lipogenesis assessment, with 3
small doses of 2H20
taken throughout each day. Beginning in the morning of the de novo lipogenesis
assessment for
hours, hepatic fatty acid synthesis was stimulated with oral fructose feeding
every 30 minutes
and hourly blood samples were collected to assess incorporation of label into
circulating very
low density lipoprotein (VLDL) triglycerides.
[00285] During both periods 1 and 2, subjects received study drug after
fasting for a minimum
of 10 hours with up to 8 ounces of water. On days that serial PK blood samples
were collected
(Period 1 = Day 1; Period 2 = Day 14) dosing was followed by 4 hours of
additional fasting and
a standardized meal at 4 and 10 hours post dose. Concentrations of bempedoic
acid and
metabolite ESP15228 were measured from serial blood samples to assess PK
parameters.
Results
[00286] Table 22 shows the measured PK parameters of patients following
administrations of
a single dose of a sustained release tablet of bempedoic acid.
Table 22 ¨ Measured PK Parameters after A Single Dose of Sustained Release
Formulation
of SR Study
Single Dose Sustained Release in Obese and:
Dose (mg) sustained Healthy Subjects
releasek AUCia(h=Rg/mL) Cm\ (pg/mL)
50 37.8 1.8
100 4.5 to 5 hours 126 5.54
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200 242 8.68
a The sustained release formulation of bempedoic acid is described in Tables
13 and 17.
[00287] Table 23 shows the mean steady-state PK parameters of bempedoic acid
sustained
release tablets.
Table 23 ¨ Mean Steady-State PK Parameters of Sustained Release Formulation of
Bempedoic Acid Tablet (SR Study)
rwmParamottrimmommVAloosimom
Cmax (ng/mL) 15.9
AUCT,ss 283
(hr*ng/mL)a
Peak to Trough 6.7
Fluctuation (ng/mL)
a Median
[00288] Table 24 describes the data of percent change from baseline in LDL-C
levels in
patients treated with sustained release formulation of bempedoic acid during
period 2 of this
study.
64
Attorney Ref: 32040-42638/US
Table 24 - Percent Change from Baseline in LDL-C in Patients Treated with
Sustained Release Formulation of Bempedoic
Acid During Period 2 of SR Study
0
Treatment Visit N Mean SD Min Median Max N Mean SD
Min Median Max t..)
o
,-,
Bempedoic Baseline 10 108.1 24.7 69 109.0 151
,-,
Acid 50mg/day Day 14 10 96.8 26.52 64 93.0 141 10 -
10.6 12.27 -26 -7.9 11 o
-.1
(N=10)
Bempedoic Baseline 10 112.7 24.83 63 117.5 151
Acid Day 14 10 82.1 21.57 50 84.5 123
10 -27.0 10.43 -44 -27.5 -12
100mg/day Day 15 1 124.0 124 124.0 124
1 -17.9 -18 -17.9 -18
(N=10) End of Study 1 137.0 137 137.0 137
1 -9.3 -9 -9.3 -9 P
Bempedoic Baseline 10 113.0 36.33 65 105.5 190
'
rõ
2
Acid Day 14 9 81.2 30.38 36 71.0 132
9 -27.1 16.25 -45 -30.5 10 .
, .3
,
,
200mg/day
(N=10)
Total (N=30) Baseline 30 111.3 28.20 63 113.0 190
Day 14 29 86.9 26.32 36 86.0 141 29 -
21.3 14.91 -45 -24.1 11
Day 15 1 124.7 124 124.0 124
1 -17.9 -18 -17.9 -18 1-d
n
1-i
End of Study 1 137.0 137 137.0 137
1 -9.3 -9 -9.3 -9
cp
t..)
o
,-,
Placebo (N=10) Baseline 10 105.1 27.67 114.5 114.5
132 ,.tD
O-
,-,
Day 14 10 112.1 28.56 118.0 118.0
151 10 8.8 16.48 -10 4.3 41 cio
u,
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[00289] Table 25 shows the Least Square (LS) Mean percent change from baseline
in LDL-C
of patients following administrations of sustained release formulation tablet
of bempedoic acid at
day 14 during period 2.
Table 25 ¨ LS Mean Percent Change from Baseline in LDL-C After a Single Dose
of
Sustained Release Formulation of Bempedoic Acid from SR Study'
SR Study Treatment
Comparison
= ===
,==
Time Point Treatment LS Mean Difference p-
value
Group (SE) from PBO
Day 14 Placebo 3.8
50 mg -8.1 -11.9 0.41
100 mg -24.7 -28.5 0.09
200 mg -26.3 -26.3 0.11
a Statistics are estimated based on an Analysis of Covariance (ANCOVA) model
with fixed terms for
treatment and baseline of LDL-C level. ANCOVA analysis (LS Mean and p value)
was performed post
hoc without repeat measures. Baseline is defined as the last value collected
prior to the first dose of study
drug.
[00290] In addition to the results in Table 31, Figure 5 further demonstrates
the change in
LDL-C between patients who received placebo versus patients who received 100
mg of sustained
release formulation of bempedoic acid tablet, wherein a change of -24.7% in
LDL-C level was
estimated from baseline in patients who received the sustained release tablet
of bempedoic acid.
Example 12: Comparison of PK parameters and PD endpoints from IR studies 1, 2,
and 3
with those from the SR study
[00291] This example compares various PK parameters and PD endpoints from IR
Study 1
(Example 8), IR Study 2 (Example 9), and IR Study 3 (Example 10) with those
from the SR
Study (Example 11).
[00292] Table 26 shows the comparison between dose-corrected PK parameters of
IR Study 1
and those obtained from the SR study at dosages of 50 mg, 100 mg, and 200 mg
respectively.
Table 26¨ PK Comparison between IR Study 1 and the SR Study
IR Study 1 in Healthy Subjects
Dose (mg) immediate
.==
.==
release
.== .==
.========
= ::'=
AUCmc(h-pg/mL)" Cma, ( p.g/mL ).1
=
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50 46 2.95
100 3-3.5 hours 128 7.38
200 334 16.3
SR Study in Obese and Healthy Subjectg,
..
= .==
Dose (mg) sustained
..
.= ....................................................
... releaseb tillaN AUCinf (11* 11 almL) iiiii C max
( [t g/mL )
:
..
.====== õ.
.== .==
. ...
.==
.==.==
. õ. ... .....
:
:..:.
:
. ..... . . õ.
: :
õ==
= . õ. .== .== ..
.
:
. õ.
50 4.5 to 5 hours 37.8 1.8
100 126 5.54
200 242 8.68
a Parameters were dose-corrected to a 50, 100, or 200 mg dose, respectively. b
The sustained
release formulation of bempedoic acid is described in Tables 13 and 17.
[00293] Table 27 shows the comparison of the mean steady-state PK parameters
of IR study 3
and those obtained from the SR study.
Table 27 ¨ Comparison of Mean Steady-State PK Parameters of IR Study 3 and the
SR
Study
Parameter Sustained Immediate Percent Difference
Release" Releasec
Cmax (pg/mL) 15.9 21.6 -26
AUCT,ss 283 307 -8
(hr*pg/mL)a
Peak to Trough 6.7 13.1 -49
Fluctuation (pg/mL)
a Median
b Sustained release formulation of bempedoic acid is described in Tables 13
and 17.
'Predicted from 180 mg dose data assuming linear kinetics
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[00294] As evident from Table 26 and Table 27, the SR formulation provided
delayed
delivery of bempedoic acid as compared to the IR formulation since less amount
of bempedoic
acid was detected in patients who received the SR formulation at similar times
and dosages as
compared to those who received IR formulation.
[00295] Table 28 shows the comparison of least-square mean percent change in
LDL-C levels
in patients from IR Study 1, IR Study 2 and the SR Study.
Table 28 - Comparison of Mean Percent Change in LDL-C Levels in Patients from
IR
Study 2, IR Study 3 and the SR Study.
R Study 1 Treatment. .
:= := := := :::= Comparison
.::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::
::
=::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::
: :::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::
Time Point Treatment LS Mean Difference p-
value
Group (SE) from PBO
Day 15 Placebo 10.6 (4.5)
20 mg 3.5 (5.0) -7.1
0.2974
60 mg -11.2(5.1) -21.8
0.0035
100 mg -16.5 (5.1) -27.1
0.0003
200 mg -15.0 (5.0) -25.6
0.0004
IR Study / ::::
:: .=.: .=.:
:: :::::
::
::: Treatment ..
= :: ..
.
..
.==
.== .==
=
. :
: :: = = :: Comparison
=
Time Point Treatment LS Mean Difference p-
value
Group (SE) from PBO
Day 15 Placebo 4.4 (5.4)
140 mg -21.3 (5.4) -25.7
0.0012
180 mg -27.1 (5.4) -31.5
0.0001
220 mg -36.1 (5.4) -40.5
<0.0001
SR Study' : Treatment
Comparison
:=:=:=:::::::::::::::::::::::::::::::::::
Time Point Treatment LS Mean Difference p-
value
Group (SE) from PBO
Day 14 Placebo 3.8
50 mg -8.1 -11.9 0.41
100 mg -24.7 -28.5 0.09
200 mg -26.3 -26.3 0.11
a Statistics are estimated based on an Analysis of Covariance (ANCOVA) model
with fixed terms for
treatment and baseline of LDL-C level. ANCOVA analysis (LS Mean and p value)
was performed
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post hoc without repeat measures. Baseline is defined as the last value
collected prior to the first
dose of study drug.
[00296] As Table 28 demonstrates, treatment with the SR formulation of
bempedoic acid in
obese/overweight but otherwise healthy patients provided consistent and dose-
related LDL-C
lowering from baseline of up to 27%. Furthermore, treatment with the SR
formulation of
bempedoic acid provided LDL-C lowering across dosages that was consistent with
treatments of
IR formulation from similar studies, namely IR Studies 1, 2, and 3.
Example 13: Preparation of Bempedoic Acid Sustained Release Formulation
[00297] The following describes the process for making a sustained release
formulation of
bempedoic acid. The process comprises four general steps: granulation,
extrusion,
spheronization and drying. During the granulation step, the raw materials
bempedoic acid,
microcrystalline cellulose, sodium carboxymethylcellulose, and sodium lauryl
are dispensed.
Separately, HPMC 606 or hydroxypropyl methylcellulose is added to treated
water and mixed
until the solution is uniform. Next, a GMX High Shear Granulator is set up
with a four-liter bowl
equipped with an impeller and a chopper. The remaining raw materials are added
to the bowl
and the resulting composition is mixed with only the impeller at 560 RPM.
After two minutes,
the composition inside the GMX bowl is mixed with the addition of the chopper,
at a speed of
1800 rpm, while maintaining the impeller at 560 RPM. Simultaneously, the HMPC
606 solution
is added to the GMX bowl via a pump at a rate of 30 g/min and the resulting
composition is
mixed for an additional minute following the complete addition of the HPMC 606
solution. The
granulator is then stopped momentarily to ensure that all of the composition
inside the GMX
bowl is scraped to the center of the bowl. One minute of additional mixing
follows. The
granulation process is then stopped and the granulated composition is
collected.
[00298] Next, a DG-L1 Extruder is set up with a 0.8 mm plate and 5 shims for
the extrusion
step. The granulated composition comprising ETC-1002 is then extruded at a
speed of 60 RPM
with recordation of the exact speed, time and amperage during this process.
Next, a QJ-230
Spheronizer with a 2 mm plate is set up for the spheronization step. The ETC-
1002 Extrudate
from the extrusion step is then spheronized at 1350 RPM. The resulting spheres
are collected
from the Spheronizer onto a drying tray, which is then placed in an oven
preheated to 40 C.
The wet spheres comprising ETC-1002 are then dried until their moisture
content, as measured
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in terms of loss on drying (LOD), is <2%. The trays containing ETC-1002
spheres are removed
from the oven, and the individual ETC-1002 spheres are placed into a poly bag.
[00299] While the invention has been particularly shown and described with
reference to a
preferred embodiment and various alternate embodiments, it will be understood
by persons
skilled in the relevant art that various changes in form and details can be
made therein without
departing from the spirit and scope of the invention.
[00300] All references, issued patents and patent applications cited within
the body of the
instant specification are hereby incorporated by reference in their entirety,
for all purposes.
