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PHARMACEUTICAL FORMULATIONS OF FENOFIBRATE HAVING
IMPROVED BIOAVAILABILITY
FIELD OF THE INVENTION
[0001] The present invention relates to pharmaceutical compositions that
include
fenofibrate, a polyethylene glycol, and a polyethylene-polypropylene glycol,
wherein the
composition is made by sublimation of a sublimable carrier from a solid
solution containing
fenofibrate, a polyethylene glycol, a polyethylene-polypropylene glycol, and a
sublimation
carrier like menthol.
BACKGROUND OF THE INVENTION
[0002] Fenofibrate, (2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid,
1-
methylethyl ester) is one of the fibrate class of drug. It is available as
both capsules and
tablets. Fenofibrate is apparently a prodrug. The active moiety is reportedly
the metabolite
fenofibric acid which is reported to be produced in the body by the action of
esterases.
When fenofibrate is administered, apparently no intact fenofibrate is found in
the plasma
(Physician's Desk Reference 58't' ed. 2004 pages 522 - 525 (PDR)).
[0003] Fenofibrate has very poor solubility in water. That is, it is a poorly
water soluble
drug. Despite its poor solubility in water, it is reported to be absorbed to a
therapeutically
acceptable degree when dosed in the "fed state" but less so when dosed in the
"fasted state".
The true "bioavailability" of the metabolite fenofibric acid is uncertain
because much of it is
understood to be metabolized to the glucuronide in both presystemic and first
pass sites.
[0004] The absolute bioavailability of fenofibrate cannot supposedly be
determined
because it is insoluble in media suitable for intravenous injection. Following
oral
administration in healthy volunteers, approximately 60% of a single dose of
radiolabelled
fenofibrate appeared in urine, primarily as fenofibric acid and its
glucuronide conjugate, and
25% was excreted in the feces. (PDR) The absorption of fenofibrate is
understood to be
increased when administered with food. The extent of absorption from orally
administered
tablets is increased by approximately 35% when tablets are taken with food
(PDR, Martindale
33rd ed. Page 889).
[0005] Attempts have been made to improve the formulation of fenofibrate,
especially as
regards the bioavailability of fenofibrate. United States Patents Nos.
4,895,726 and
5,880,148 disclose co-micronizing the fenofibrate with surface active agents.
United States
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Patent Nos. 6,074,670 , 6,277,405 disclose micronized fenofibrate coated onto
hydrosoluble
carriers with optional surface active agents. United States Patent No.
6,814,977 discloses
fenofibrate dissolved in a medium chain glycerol ester of fatty acid. United
States Patent No.
6,719,999 discloses fenofibrate dissolved in glycerin, propylene glycol, or
dimethylisosorbide
and US Patent No. 5,827,536 discloses fenofibrate dissolved in
diethyleneglycol monoethyl
ether.
[0006] Several patents disclose specific formulations of micronized
fenofibrate with
specific polymeric or surface active agent additives and other patents
describe emulsions and
suspensions of fenofibrate. For example, US Patent Application Publication No.
20040087656 discloses fenofibrate of particle size less than 2000 nm claimed
to have an
improved bioavailability. US Patent Application Publication No. 20030224059
discloses
microparticles of active pharmaceutical ingredients, drug delivery vehicles
comprising same,
and methods for making them.
[0007] Micronization of the fenofibrate and combinations of micronized
fenofibrate with
surface active agents have moderately raised the bioavailability of
fenofibrate allowing the
agency-approved amount of drug dosed to be reduced from 100 mg per dose to 67
mg per
dose and then subsequently to 54 mg per dose, whilst maintaining
bioavailability in the fed
state. Nanoparticle formulations of the drug have further allowed the
reduction of the dose to
48 mg per dose with the bioavailability of the "fasted state" being reported
as similar to the
fed state. There is still room for much improvement because it is postulated
that the true
bioavailability of fenofibrate is still relatively low.
SUMMARY OF THE INVENTION
[0008] In one aspect, the present invention relates to a pharmaceutical
composition
comprising non-mechanically micronized microparticles of fenofibrate,
especially
sublimation micronized microparticles of fenofibrate using menthol as a
sublimable carrier;
polyethylene glycol, especially polyethylene glycol 6000; and a polyethylene-
polypropylene
glycol, especially poloxamer 407. The pharmaceutical composition can further
include a
pharmaceutical disintegrant selected from the group consisting of
crospovidone, a
carboxymethyl celulose, especially crosslinked carboxymethylcellulose sodium
(croscarmellose sodium), the bicarbonate or carbonate salts; especially alkali
metal
bicarbonates or carbonates like sodium bicarbonate; the organic carboxylic
acids, especially
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citric acid, tanic acid, ascorbic acid, benzoic acid, citric acid, fumaric
acid, lactic acid, malic
acid, sorbic acid, and tartaric acid;and combinations of any of the foregoing.
[0009] In another aspect, the present invention relates to a solid oral dosage
form
including a pharmaceutical composition that includes about 15% to about 25% by
weight of
non-mechanically micronized microparticles of fenofibrate, especially
sublimation
micronized fenofibrate; about 7% to about 13% by weight poloxamer 407; about
7% to about
13% polyethylene glycol 6000; about 15% by weight microcrystalline cellulose;
about 18%
crospovidone by weight; about 12% sodium bicarbonate by weight; and about 12%
by weight
of either citric acid or tartaric acid.
[00010] In yet a further aspect, the present invention relates to a solid oral
dosage form
including a pharmaceutical composition that includes about 15% to about 25% by
weight of
non-mechanically micronized microparticles of fenofibrate, especially
sublimation
micronized fenofibrate; about 7% to about 13% by weight poloxamer 407; about
7% to about
13% polyethylene glycol 6000; about 15% by weight microcrystalline cellulose;
about 18%
crospovidone by weight; about 12% sodium bicarbonate by weight; and about 12%
by weight
of either citric acid or tartaric acid; wherein the dosage form has a time-
dependent in vitro
fenofibrate release profile such that at least about 51 % by weight,
especially about 51 % to
about 81% of the fenofibrate is released in about 10 minutes, at least about
73%, especially
about 73% to about 93%, by weight of the fenofibrate is released in about 15
minutes, and at
least about 85% by weight, especially about 85% by weight to essentially all
of the
fenofibrate is released in about 30 minutes.
[00011] In another aspect, the present invention relates to a solid oral
dosage form,
especially a compressed tablet, comprising a pharmaceutical composition that
includes about
145 mg of sublimation micronized fenofibrate wherein in human in vivo
pharmacokinetic
studies in which the dosage form is administered in the fasted state, the area
under the 48-
hour AUC curve (AUC48) is about 121367 h*ng/g to about 287539 h*ng/g; the area
under the
AUC curve extrapolated to infinite time (AUC,,,,) is about 134750 h*ng/g to
about 345390
h*ng/g; and the maximum plasma concentration (Cma,,) is about 6357 ng/g to
about 14627
ng/g. Typically, such solid oral dosage form will exhibit an average AUC48 of
about 175335
h*ng/g, an average AUC,,,, of about 213652 h*ng/g, and an average Cmax of
about 10570 ng/g.
[00012] In still yet another aspect, the present invention relates to a solid
oral dosage form,
especially a compressed tablet, that includes a pharmaceutical composition
having about 145
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mg of sublimation micronized fenofibrate wherein, in human in vivo
pharmacokinetic studies
in which the dosage form is administered in the fed state, the area under the
48-hour AUC
curve (AUC48) is about 91601 h*ng/g to about 217512 h*ng/g; the area under the
AUC curve
extrapolated to infinite time (AUC,) is about 97182 h*ng/g to about 308070
h*ng/g, and
further wherein the average AUC48 is about 150511 h*ng/g and the average AUCoo
is about
185149 h*ng/g. The dosage form can include a disintegrant.
[00013] In yet a further aspect, the present invention relates to a
pharmaceutical
composition having a plurality of pharmaceutical carrier particles, especially
particles of
microcrystalline cellulose, having deposited thereon a combination of
fenofibrate; especially
about 15% to about 25% by weight fenofibrate; a polyethylene glycol,
especially
polyethylene glycol 6000 at about 7% to about 13% by weight; and a
polyethylene-
polypropylene glycol, especially poloxamer 407 at about 7% to about 13% by
weight;
wherein the combination is deposited by sublimation of a sublimable carrier,
especially
menthol, from a solid solution that comprises fenofibrate, the polyethylene
glycol, the
polyethylene-polypropylene glycol, and the sublimable carrier. The composition
can also
include a phan-naceutical disintegrant selected from the group consisting of
crospovidone, a
crosslinked carboxymethylcellulose salt (especially crosslinked
carboxymethylcellulose
sodium), the bicarbonate or carbonate salts; especially alkali metal
bicarbonates or carbonates
like sodium bicarbonate; the organic carboxylic acids, especially citric acid,
tanic acid,
ascorbic acid, benzoic acid, citric acid, fumaric acid, lactic acid, malic
acid, sorbic acid, and
tartaric acid;and combinations of any of the foregoing.
[00014] In still yet a further aspect, the present invention relates to a
solid oral dosage
form that includes a pharmaceutical composition having about 145 mg of
fenofibrate that has
been deposited on a plurality of particles of microcrystalline cellulose by
sublimation of a
sublimable carrier from a solid solution comprising fenofibrate and the
sublimable carrier;
wherein in human in vivo pharmacokinetic studies in which the dosage form is
administered
in the fasted state, the area under the 48-hour AUC curve (AUC48) is about
121367 h*ng/g to
about 287539 h*ng/g; the area under the AUC curve extrapolated to infinite
time (AUC.) is
about 134750 h*ng/g to about 345390 h*ng/g; and the maximum plasma
concentration (Cmax)
is about 6357 ng/g to about 14627 ng/g. This solid oral dosage, in certain of
its detailed
aspects, exhibits an average AUC48 of about 175335 h*ng/g, an average AUC" of
about
213652 h*ng/g, and an average Cmax of about 10570 ng/g.
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DETAILED DESCRIPTION OF THE INVENTION
[00015] In one embodiment, the present invention provides a pharmaceutical
composition
that includes non-mechanically micronized microparticles of fenofibrate, a
polyethylene
glycol, and a polyethylene-polypropylene glycol.
[00016] Non-mechanically micronized microparticles have mean dimensions of
about 0.1
m to about 10 m and are produced by non-mechanical comminution techniques.
Non-
mechanical comminution techniques are techniques other than milling (ball,
impingement,
high energy), spray drying, and high-pressure homogenization. For purposes of
the present
application, the technique of lyophilization is considered a mechanical
micronization
technique and, hence, microparticles produced by lyophilization are excluded
from non-
mechanically micronizaed microparticles. Particle size measurement is well-
known to the
skilled artisan and can be accomplished by, for example, the well-known
technique of laser
light-scattering.
[00017] The non-mechanically micronized microparticles of fenofibrate of the
present
invention can be obtained by, for example, the technique of sublimation
micronization.
Microparticles so obtained are referred to as "sublimation micronized"
microparticles and the
material of which such microparticle are comprised is referred to as
"sublimation
micronized". The technique of sublimation micronization is described in
published United
States Patent Application US 2003/0224059 (Lerner et al.), herein incorporated
in its entirety
by reference.
[00018] The microparticles of fenofibrate of the present invention are
obtained via
sublimation micronization by removing a sublimable carrier from a solid
solution of
fenofibrate in the sublimable carrier. The fenofibrate can be present with the
sublimable
carrier in the solid solution as discrete molecules, or it can be present in
aggregates of a few
hundred, a few thousand, or more molecules. The drug need only be dispersed on
a
sufficiently small scale so that sufficiently small, discrete microparticles
are ultimately
obtained. Preferably, the fenofibrate in the solid solution is dissolved in
the sublimable
carrier.
[00019] Sublimable carriers have a measurable vapor pressure below their
melting point.
Preferred sublimable carriers have a vapor pressure of at least about 10
Pascal, more
preferably at least about 50 Pascal at about 10 C or more below their normal
melting points.
Preferably, the sublimable carrier has a melting point between about -10 C
and about 200 C,
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more preferably between about 20 C and about 60 C, most preferably between
about 40 C
and about 50 C. Preferably, the sublimable carrier is a substance that is
classified by the
United States Food and Drug Administration as generally recognized as safe
(i.e., GRAS).
Examples of suitable sublimable carriers include menthol, thymol, camphor, t-
butanol,
trichloro-t-butanol, imidazole, coumarin, acetic acid (glacial),
dimethylsulfone, urea, vanillin,
camphene, salicylamide, and 2-aminopyridine. Menthol is a particularly
preferred
sublimable carrier.
[00020] The microparticles of the present invention are formed by removal of
sublimable
carrier from a solid solution, made as described above, at a temperature below
the melting
point of the solid solution. The solid solution must be kept at a temperature
below its melting
point to preserve the solid solution during the process of removing the
sublimable carrier.
The sublimable carrier can be removed from the solid solution by, for example,
treating the
solid solution, deposited on a pharmaceutical carrier particle where
applicable as discussed
infra, in a stream of air, preferably heated air, in, for example, a fluidized
bed drier.
[00021] The pharmaceutical compositions of the present invention further
include
polyalkylene glycols. Preferably the pharmaceutical compositions of the
present invention
include at least one polyethylene glycol (PEG) and at least one polyethylene-
polypropylene
glycol.
[00022] Polyethylene glycols useful in the practice of the present invention
have the
general formula -(-CH2-CH2-O-)x- and can be characterized by the arithmetic
mean
value of X(<X,>) or the molecular weight corresponding thereto as described
in, for
example, Polyethylene Glycols, 23 National Formulary, 3052 (United States
Pharmacopeial
Convention, 2005). Polyethylene glycol 6000 is a preferred polyethylene glycol
for use in
the practice of the present invention.
[00023] Polyethylene-polypropylene glycols useful in the practice of the
present invention
have the general structure -(O-CH2CH2-)a O-(-CH(CH3)CH2-)b-(-O-CHZCH2-),,-
OH and are commonly referred to as "poloxamers". Preferred poloxamers for use
in the
practice of the present invention are described in the monograph of like name
in the U.S.
National Formulary. Poloxamers, 23 National Formulary, 3051 (United States
Pharmacopeial Convention, 2005). The polyethylene - polypropylene glycol
commonly
designated "poloxamer 407" is a particularly preferred polyethylene -
polypropylene glycol
for use in the practice of the present invention.
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[00024] The pharmaceutical compositions of the present invention can be and in
preferred
embodiments are deposited on a plurality of pharmaceutical carrier particles.
Pharmaceutical
carrier particles useful as support, substrate, or carrier for the
pharmaceutical formulation of
the present invention are made of comestible substances and are well known in
the art.
Examples of useful pharmaceutical carrier particles include particles, that
can be non-pariel
pellets, typically between about 0.1 mm. and about 2 mm. in diameter, and made
of, for
example, starch, particles of microcrystalline cellulose, lactose particles
or, particularly, sugar
particles. Suitable sugar particles (pellets, e.g. non-pariel 103, Nu-core, Nu-
pariel) are
commercially available in sizes from 35 to 40 mesh to 18 to 14 mesh. Preferred
pharmaceutical carrier particles are made of non-hydrosoluble material, for
example
microcrystalline cellulose. Carrier particles comprised of microcrystalline
cellulose (e.g.
Avicel ) are particularly preferred pharmaceutical carrier particles. The
skilled artisan
knows other pellets or spheres useful as pharmaceutical carrier particles.
[00025] Pharmaceutical compositions according to the present invention can be
made by
combining fenofibrate, polyethylene glycol, polyethylene - polypropylene
glycol, and a
sublimable carrier. The above components can be combined neat or, in
embodiments in
which the composition is deposited on a plurality of pharmaceutical carrier
particles, together
with a suitable solvent. Suitable solvents dissolve fenofibrate, polyethylene
glycol,
polyethylene - polypropylene glycol, and the sublimable carrier, but do not
dissolve
pharmaceutical carrier particles and further are chemically inert to any of
the components,
and can be readily removed at a convenient temperature, especially a
temperature < 100 C,
optionally with the aid of an applied vacuum. Ethanol is an example of a
suitable solvent.
[00026] The combination of components are combined and warmed to form a
homogeneous mixture, preferably a solution, and cooled to obtain a solid
solution. The
fenofibrate can be present with the sublimable carrier in the solid solution
as discrete
molecules, or it can be present in aggregates of a few hundred, a few
thousand, or more
molecules. The drug need only be dispersed on a sufficiently small scale so
that sufficiently
small, discrete microparticles are ultimately obtained.
[00027] Preferably, the drug in the solid solution is dissolved in the
sublimable carrier. In
embodiments in which the sublimation micronized microparticles are deposited
on a plurality
of pharmaceutical carrier particles, the warm solution of components in
sublimable carrier is
combined with pharmaceutical carrier particles, for example by mixing, and the
combination
allowed to cool to form the solid solution on the pharmaceutical carrier
particles.
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Alternatively, pharmaceutical carrier particles are combined with a solution
of sublimable
carrier, fenofibrate, polyethylene glycol, and polyethylene - polypropylene
glycol in a
suitable solvent (e.g. ethanol). The solvent is removed, optionally with the
aid of applied
heat and vacuum, to obtain pharmaceutical carrier particles having deposited
thereon a solid
solution of the fenofibrate, polyethylene glycol, and polyethylene -
polypropylene glycol in
the sublimable carrier (e.g. menthol).
[00028] After formation of the solid solution, whether deposited on
pharmaceutical carrier
particles or not, the pharmaceutical formulations of the present invention are
subsequently
formed by removal of sublimable carrier from the solid solution, made as
described above, at
a temperature below the melting point of the solid solution. The solid
solution must be kept
at a temperature below its melting point to preserve the solid solution during
the process of
removing the sublimable carrier. The sublimable carrier can be removed from
the solid
solution by, for example, treating the solid solution, deposited on a
pharmaceutical carrier
particle where applicable, in a stream of air, preferably heated air, in, for
example, a fluidized
bed drier.
[00029] In preferred embodiments, removal of the sublimable carrier reasults
in formation
of non-mechanically micronized microparticles of fenofibrate, which
microparticles can
further contain at least a portion of the polyethylene glycol and polyethylene-
polypropylene
glycol. Furthermore, at least a portion of the fenofibrate can be in solution
or intimately
asociated with either or both of the polyethylene glycol and polyethylene-
polypropylene
glycol that are not necessarily with the non-mechanically micronized
microparticles.
[00030] Applicants' invention is not limited by a particular theory of
operation. But
applicants believe that, after removal of the sublimable carrier, at least a
portion of the
fenofibrate is dissolved in or intimately associated with the polyalkylene
glycols. The
expression "intimately associated" excludes a simple physical mixture such as
can be
achieved by, for exainple, dry blending, dry granulation, or wet granulation
in the presence of
a liquid that does not at least partially dissolve the components.
[00031] The pharmaceutical compositions of the present invention, particularly
when
deposited on a plurality of pharmaceutical carrier particles, are well suited
for manufacture of
liquid and especially solid oral dosage forms such as compressed tablets and
filled capsules.
In another embodiment, the present invention provides oral dosage forms,
especially solid
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oral dosage forms, preferably compressed tablets, that include the
pharmaceutical
compositions of the present invention.
[00032] Compressed tablets are formulated from pharmaceutical compositions
containing
the microparticles of the pharmacologically active substance or drug, or using
pharmaceutical
carrier particles bearing such microparticles, and pharmacologically inert
(pharmaceutically
acceptable) additives or excipients.
[00033] For making a tablet, it will typically be desirable to include one or
more benign
pharmaceutical excipients in the pharmaceutical composition. The
pharmaceutical
composition of the present invention may contain one or more diluents added to
make the
tablet larger and, hence, easier for the patient and caregiver to handle.
Common diluents are
microcrystalline cellulose (e.g. Avicel ), microfine cellulose, lactose,
starch, pregelitinized
starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin,
dextrose, dibasic calcium
phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate,
magnesium
oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragi?), potassium
chloride,
powdered cellulose, sodium chloride, sorbitol and talc.
[00034] Binders also may be included in tablet formulations to help hold the
tablet
together after compression. Some typical binders are acacia, alginic acid,
carbomer (e.g.
carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin,
guar gum,
hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose
(e.g. Klucel ),
hydroxypropyl methyl cellulose (e.g. Methocel ), liquid glucose, magnesium
aluminum
silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g.
Kollidon ,
Plasdone ), pregelatinized starch, sodium alginate and starch.
[00035] The tablet may further include a disintegrant to accelerate
disintegration of the
tablet in the patient's stomach. Disintegrants include alginic acid,
carboxymethyl cellulose
calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, crosslinked
carboxymethylcellulose sodium or calcium (croscarmellose sodium (e.g. Ac-Di-
Sol ,
Primellose or croscarmelose calcium), crospovidone (e.g. Kollidon ,
Polyplasdone ), guar
gum, magnesium aluminum silicate, methyl cellulose, microcrystalline
cellulose, polacrilin
potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium
starch
glycolate (e.g. Explotab ) and starch.
[00036] In addition to or in place of alginic acid, other organic carboxylic
acids can be
included in the formulation. The organic acids include tannic acid, citric
acid, fumaric acid
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tartaric acid, lactic acid, malic acid, ascorbic acid, benzoic acid, sorbic
acid, and the like.
Tannic acid and citric acid are particularly preferred organic carboxylic
acids for use in this
and other embodiments of the present invention.
[00037] The pharmaceutical compositions of the present invention can, and in
preferred
embodiments do contain a bicarbonate or carbonate, especially an alkali metal
bicarbonate or
carbonate. Examples of preferred alkali metal carbonates and bicarbonates
include sodium
bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate.
Alkailne earth
metal carbonates like calcim carbonate and magnesium carbonate can also be
used.
[00038] A pharmaceutical composition for making compressed tablets may further
include
glidants, lubricants, flavorings, colorants and other commonly used
excipients.
[00039] Pharmaceutical carrier particles bearing microparticles of a drug made
in
accordance with the present invention have excellent bulk flow properties and
can be used
directly, alone or in combination with carrier particles that do not carry a
drug, to make
capsule dosage forms. If necessary, diluents such as lactose, mannitol,
calcium carbonate,
and magnesium carbonate, to mention just a few, can be formulated with the
microparticle-
bearing pharmaceutical carrier particles when making capsules
[00040] Liquid oral phannaceutical compositions of the present invention
comprise
microparticles or microparticle-bearing pharmaceutical carrier particles and a
liquid carrier
such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol
or glycerin, most
preferably water.
[00041] Liquid oral phannaceutical compositions may contain emulsifying agents
to
disperse uniformly throughout the composition the active ingredient, drug
delivery vehicle, or
excipient having low solubility in the liquid carrier. Emulsifying agents that
may be useful in
liquid compositions of the present invention include, for example, gelatin,
egg yolk, casein,
cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer,
cetostearyl
alcohol and cetyl alcohol.
[00042] Liquid oral phannaceutical compositions of the present invention may
also
contain a viscosity enhancing agent to improve the mouth-feel of the product
and/or coat the
lining of the gastrointestinal tract. Such agents include acacia, alginic acid
bentonite,
carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol,
methyl cellulose,
ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl
cellulose,
hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone,
propylene
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carbonate, propylene glycol alginate, sodium alginate, sodium starch
glycolate, starch
tragacanth and xanthan gum.
[00043] The liquid oral pharmaceutical composition also may contain sweetening
agents,
such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose,
mannitol and
invert sugar; preservatives and chelating agents such as alcohol, sodium
benzoate, butylated
hydroxy toluene, butylated hydroxyanisole and ethylenediamine tetraacetic
acid; and buffers
such as guconic acid, lactic acid, citric acid or acetic acid, sodium
gluconate, sodium lactate,
sodium citrate or sodium acetate.
[00044] Solid oral dosage forms formulated and compounded with the sublimation
micronized microparticles of fenofibrate together with a polyethylene glycol
and a
polyethylene-polypropylene glycol, prepared as hereinabove described, provide
for improved
bioavailability of fenofibrate as demonstrated by both in vitro dissolution
(release) and
human in vivo pharmacokinetic (plasma concentration) testing. The results of
both in vivo
and in vitro testing disclosed herein were obtained with tablets containing
about 145 mg
fenofibrate and having a nominal weight of 792 mg each.
[00045] Time-dependent in vitro release (dissolution) profiles disclosed
herein were
obtained at 37 C using a USP Type-II dissolution tester operating at 50 rpm
and filled with
1000 mL of 0.5 wt-% sodium lauryl sulfate in water. The concentration of
fenofibrate in the
test liquid was determined by HPLC.
[00046] Pharmacokinetic data disclosed herein were obtained in human in vivo
experiments by determining the blood plasma concentration of the metabolite,
fenofibric
acid, as a function of time to afford a well-know Boltzmann-shaped cumulative
plasma
concentration (AUC) curve. Individual points are reported with reference to
selected actual
or extrapolated time points on the AUC curve.
[00047] Thus, the area under the 48-hour AUC curve, AUC48, refers to the
cumulative
blood concentration up to the 48 hour time point (the last point measured).
AUC"' refers to
the area under the AUC curve extrapolated to infinite time. Cmax refers to the
maximum
absolute plasma concentratioii measured in the 48 hour test (i.e. the maximum
point on the
48-hour AUC curve). Average AUC (<AUC>) is the arithmetic average plasma
concentration of fenofibric acid measured over the course of the plasma
concentration
measurement period (about 48 hours).
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[00048] The present invention, in certain of its embodiments, is illustrated
by the
following non-limiting examples. In the following examples, fed state means
that the subject
has not taken food within the ten hours preceding dosing. Fed state means that
the subject
has taken food about one-half hour prior to dosing.
EXPERIMENTAL
[00049] A. Fenofibrate granulate
[00050] Menthol (1.333Kg) was melted in a glass reactor at 50 C, with
stirring.
Fenofibrate (133.3 gm), poloxamer 407 (Lutrol F127, 76 gm), and polyethylene
glyco16000
(76 gm) were charged to the reactor. The menthol melt was stirred at 50 C
until all the
components had dissolved. Microcrystalline cellulose (Avicel PH 101, 106.7 gm)
was added
to the melt, which was stirred until a uniform suspension was obtained.
[00051] The menthol melt was divided into three equal portions and poured into
three
trays (stainless steel, 0.133 m2 each) that were cooled to -40 C for quick
solidification of the
menthol suspension. The solid material on the trays was removed and coarsely
milled
through a 2.5 mm screen using an Erweka mill. The obtained powder was again
divided into
three portions and returned to the trays. Menthol was removed from the
material on the trays
by sublimation in a high vacuum tray drier at 0.2 mbar and 36 C for about 53
hours. The
resulting powder was removed from the trays and milled through a 1.6 mm screen
using an
Erweka mill so as to not effect substantial comminution of the already-formed
particles. The
granulate so obtained was weighed (346.4 gm) for a yield of 88%.
[00052] B. Fenofibrate Tablets (145 mg) -
[00053] The Fenofibrate granulate from step A was milled through a 0.8 mm
screen using
an Erweka mill. The milled granulate (336 gm) was added to a polyethylene bag
(50 x 70
cm). Crospovidone (108 gm), sodium bicarbonate (72 gm) and citric acid
anhydrous (72 gm)
were added and the blend mixed for 5 minutes. Magnesium stearate (12 gm) was
added to
the bag and the blend mixed for a further 1/2 minute. The total amount of
blend so obtained
was 600 grams.
[00054] The blend was compressed into tablets on a Manesty F3 single punch
tabletting
machine using oval shaped (8.8 mm x 17.6 mm ) normal concave punches. Tablet
design
weight was 785 mg 39.3 mg at a hardness of 5 - 7 Kp. The tablets obtained
had an
average weight of 792 mg and a hardness of 6 Kp. Several batches were made and
labeled
MAZ149B, MAZ149B1 and MAZ149B2, respectively.
12
CA 02634094 2008-06-18
WO 2007/075171 PCT/US2005/047346
[00055] C In vitro release
[00056] The release (dissolution) of fenofibrate from the tablets was tested
using a USP
type II dissolution tester filled with 1000 ml 0.5% sodium lauryl sulfate
(SLS) (w/v) in water
at 37 C and 50 revolutions per minute (rpm). The amount of fenofibrate in each
sample was
determined by HPLC as above. The results are given in tables C 1-C3 for three
batches.
Table C1. Results of in vitro release of fenofibrate (% label claim) MAZ149B
Time(min) Vessell Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Vessel 7
80.2 69.2 75.2 76.2 78.0 75.5 71.8
92.7 86.9 90.5 90.5 90.8 88.6 87.5
30 99.3 94.8 96.6 97.7 96.9 93.0 95.6
Time(min) Vessel 8 Vessel 9 Vesse110 Vesse111 Vessel 12 Avg %RSD
10 80.1 75.2 73.9 80.5 80.3 76.3 4.75
15 89.6 88.9 88.3 89.1 89.2 89.4 1.76
30 95.2 95.4 94.6 95.4 94.4 95.7 1.74
Table C2. Results of in vitro release of fenofibrate (% label claim) MAZ 149B
1
Time(min) Vessel I Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Avg %RSD
10 58.6 55.8 51.4 55.2 51.5 61.5 55.7 7.11
15 79.5 77.3 73.6 77.5 74.4 79.2 76.9 3.16
30 90.7 88.9 86.5 88.5 89.1 89.5 88.9 1.56
Table C3. Results of in vitro release of fenofibrate (% label claim) MAZ 149B2
Time(min) Vessell Vessel 2 Vessel 3 Vessel 4 Vessel 5 Vessel 6 Avg %RSD
10 69.0 66.3 68.9 71.0 72.4 63.8 68.6 4.54
15 80.2 79.6 81.1 81.1 81.0 77.6 80.1 1.72
30 86.9 87.8 88.0 87.1 87.1 86.9 87.3 0.56
[00057] D. In vivo pharmacokinetic trial
[00058] Pharmacokinetic Test of MAZ149B and TriCor 145 mg
[00059] A four way crossover bioequivalence pharmacokinetic trial was carried
out in 12
healthy volunteers using MAZ 149B (145 mg, described supra) and TriCor (145
mg) as
two of the test arms. The other two arms were other test fonnulations prepared
accordiong to
the present invention. A one week washout was taken between each arm of the
test. Blood
samples were taken at 0, 1, 2, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 8, 9, 10,
12, 16, 24 and 48 hours
(19 samples per trial) and analyzed for fenofibric acid by a validated method.
The 4 arm
trials were carried out in both the fasted and fed states.
[00060] Results
13
CA 02634094 2008-06-18
WO 2007/075171 PCT/US2005/047346
[00061] Fasted-state data was obtained for volunteers 1- 11 for the test MAZ
149B (N=11)
and for volunteers 2- 11 for the reference TriCor (N-10). The results are
collected in table
D1. The average values showed the bioavailability of the test to be 97.4% of
the reference
based on AUC48 (175334 vs. 180010 h*ng/g) and 97.7% of the reference based on
AUC,,
(213653 vs. 218628 h*ng/g). The corresponding geometric mean values showed
97.5%
based on AUC48 (169481 vs. 173880 h*ng/g) and 97.5% based on AUC., (205217 vs.
210558
h*ng/g). The geometric mean of the ratio of the individual ratios of test to
reference AUC,,,
was 1.006. The average values for C,,,ax showed the test to be 99% of the
reference (10570
vs. 10624 ng/g) and the geometric mean to be 100.7% (10340 vs. 10270 ng/g).
The
geometric mean of the ratios of the test to reference of the individual
volunteers was 1.021.
The variability of the bioavailability was very similar 28.95% vs. 27.16% for
%CV (variation
in the variable) of the AUC48 values. The average terminal half life (terminal
half-life for
elimination) was 20.0 hours for the test product and 19.9 hours for the
reference while the
average Tmax was 2.5 hours for the test and 2.1 hours for the reference. One
can conclude that
the two formulations are bioequivalent in the fasted state.
[00062] Fed-state data was obtained for volunteers 1-5, 7-10 and 12 (N=10) for
both the
test MAZ149B and the TriCor reference product. The results are collected in
table D2.
The average values showed the bioavailability of the test to be107.1 % of the
reference based
on AUC48 (150511 vs. 140627 h*ng/g) and 112.0% of the reference based on AUC~
(185149
vs. 165310 h*ng/g). The corresponding geometric mean values showed 106.8%
based on
AUC48 (145402 vs. 136134 h*ng/g) and 111.2% based on AUC,,,) (174021 vs.
156459
h*ng/g). The geometric mean of the ratio of the individual ratios of test to
reference AUC,,,
was 1.112. The average values for Cmax showed the test to be 79.0 % of the
reference (7557
vs.9567 ng/g) and the geometric mean to be 77.5% ( 7147 vs. 9217 ng/g). The
geometric
mean of the ratios of the test to reference of the individual volunteers was
0.775. The
variability of the bioavailability was very similar 27.16% vs. 26.41 % for %CV
(variation in
the value) of the AUC48 values. The average terminal half life was 17.4 hours
for the test
product and 16.1 hours for the reference while the average Tmax was 8.0 hours
for the test
and 3.6 hours for the reference. The improved bioavailability coupled to a
lower C,,ax and the
later Tmax indicate an improved product in the fed state.
14
CA 02634094 2008-06-18
WO 2007/075171 PCT/US2005/047346
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