Note: Descriptions are shown in the official language in which they were submitted.
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PHARNIACEUTICAL FORMULATIONS
Related Application Information
This application claims priority to U.S. Application No. 60/829,255, filed
October 12,
2006, the contents of which are lierein incotporated by reference.
This application is a continuation-in-part of U.S. Application No. 11/548,960,
filed on
October 12, 2006, which is a continuation-in-part of U.S. Application No.
11/399,964, filed
on April 7, 2006, which claims priority to U.S. Application No. 60/669,699,
filed on April 8,
2005, the contents of each of which are herein incorporated by reference.
Tllis application is a continuation-in-part of U.S. Application No.
11/548,982, filcd on
October 12, 2006, whicti is a continuation-in-part of U.S. Application No.
11/399,983, filed
on April 7, 2006, which claims priority to U.S. Application No. 60/669,699,
filed on April 8,
2005, the contents of each of which are herein incorporated by reference.
This application is a continuation-in-part of U.S. Application No. 11/549,005,
filed on
October 12, 2006, which is a continuation-in-part of U.S. Application No.
11/400,113, filed
on April 7, 2006, wliich claims priority to U.S. Application I'o. 60/669,699,
ftled on April 8,
2005, the contents of each of which are herein incorporated by reference.
Field of the Invention
The present invention rclates to solid dosage forms comprising salts of 2-[4-
(4-
chlorobenzoyl)phenoxy]-2-methyl-propanoic acid.
Background of the Invention
2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,l-methylethyl ester,
also
known as "fenofibrate", from the family of fibrates, is a lipid-regulating
agent. Fenofibrate is
described in, for example, U.S. Patent Nos. 3,907,792, 4,895,726, 6,074,670
and 6,277,405.
Fenofibrate is commercially available in a variety of different formulations
and is used in the
treatment of adult endogenous hyperlipidemias, hypercholesterolemias and
hypertriglyceridemias. The active metabolite of fcnofibrate is 2-[4-(4-
chlorobenzoyl)phcnoxy]-2-methyl-propanoic acid, which is also known as
fcnofibric acid.
One of the challenges associated with fibrates, such as fenofibrate, is that
these
compounds are hydrophobic and poorly soluble in water. Thus, the
bioavailability of these
compounds (i.e., their absorption in the digestive tract) can be low. Due to
the hydrophobic
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nature and poor solubility of fenofibrate in water, absorption of fenofibrate
in the digestive
tract of a subject is increased affter ingestion of food by the subject (whcn
compared to when
the subject ingests the fenofibrate under fasting conditions). This food
effect is undesirable
when comparing the bioavailability of fenofibrate in fed vei-sus fasting
conditions.
Additionally, subject compliance is an issue with drugs having a food effect
because the
patient must coordinate administration of the drug with the ingestion of food.
Recently,
complex technologies have been used to overcome the food effect issues
associated witll
fenofibrate.
In contrast to fenofibrate, fenofibric acid has higher solubility in the small
intestine
region. However, tliis enhanced solubility could cause problems in connection
with
controlling the delivery of fenofibric acid (such as, the potential for ttie
C,MIX to exceed the
accepted (approved) limits of a reference pharmaceutical composition
containing
fenofibrate). For example, immediate release dosage fonns comprising amoiphous
fenofibric
acid are described, for example, in U.S. Patent Application No. 2005!0148594.
As reported
therein, the formulations comprising amorphous fenofibric acid when
administered to a
subject, exhibit a bioavailability that is twice as high as a fenofibrate-
containing capsule
formulation described in Example 6 of said published application. Thereupon,
in view of
aforementioned described difference in solubility, the active ingredient,
namely, fenofibrate,
simply cannot be replaced with fenofibric acid in such dosage forms.
Moreover, there is a need in the art for solid dosage forms of fenofibric acid
that
exliibit a lack of a significant food effect when administercd to a patient
under fed or fasted
conditions. Such solid dosage forms would improve patient compliance by giving
the patient
the flexibility to take said solid dosage form under either fed or fasted
conditions.
The release rate of a robust drug formulation will be substantially
independent of
properties of the dissolution media. For example, a robust formulation will
have essentially
the same release rates in dissolution media of differing ionic strengths. In
humans, normal
fasting levels for the ionic strength in the GI tract is .10-.14 and higher
values are induced by
the intake of food. It therefore follows that one would expect that the
release rate of a robust
drug formulation will exhibit rninimal variation under fed and fasted
conditions in the Gl
tract. A further feature of a robust drug formulation is that its release rate
will not be effected
during rigorous steps in scaled-up of manufacturing processes.
It is the object of the present invention to provide modified release
fenofibric acid
formulations which are robust. Consequentially the release rate of the
formulations of the
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present invention are substantially independent of thc ion-strength of
dissolution medium.
This objcct is achicved, according to the present invention, by a hydrophilic
gel forming
matrix formulation having a prolonged release of fenofibric acid upon exposure
to the
dissolution media, characterized in that the release rate is substantially
ionic-strength
independent.
Applicants have found several factors contribute in making a modified release
fenofibric acid formulations robust. One factor is the salt selection.
Applicants have
discovered that robust fenofibric acid formulations sliould comprise a soluble
salt. Second,
the percentage of the fenofibric acid salt in the formulation also impacts the
robustness of the
formulation. Finally, the presence or absence of a drug enteric coating may
have some
influence on the robustness of the formulation.
Summary of the Invention
In one aspect, the present invention provides a modified release fonnulation
comprising an active agent in a hydrophilic polymer matrix wherein the active
agent is a salt
of fenofibric acid whercin the rclcase rate of the fonnulation in an in viti-o
dissolution is
substantially independent of the ionic strength of the dissolution media.
Brief Descrigtion of the FiQures
Figure 1 shows the IDR valucs of seven salts of fenofibric acid and fenofibric
acid
verses the difference in drug release at 8 hours in an in vitro dissolution at
high and low ionic
strengths.
Figure 2 shows the in vitro dissolution profile of fenofibric acid tablets
when done in
dissolution media of 0.05M and 0.3M.
Figure 3 shows the in vitro dissolution profile of fenofibric acid choline
salt tablets
when done in dissolution mcdia of 0.05M and 0.3M.
Figure 4 shows the in vitro dissolution profile of fenofibric acid metformin
salt tablets
when done in dissolution media of 0.05M and 0.3M.
Figure 5 shows the in vitro dissolution profile of fenofibric acid procaine
salt tablets
when done in dissolution media of 0.05M and 0.3M.
Figure 6 shows the in vitro dissolution profile of fenofibric acid
diethanolamine salt
tablets when done in dissolution media of 0.05M and 0.3M.
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Figure 7 shows the in vitro dissolution profile of fenofibric acid
ethanolaniine salt
tablets when done in dissolution media of 0.05M and 0.3M.
Figure 8 shows the in vitro dissolution profile of fenofibric acid calcium
salt tablets
when done in dissolution media of 0.05M and 0.3M.
Figure 9 shows the in vitro dissolution profile of fcnofibric acid tris salt
tablets when
done in dissolution media of 0.05M and 0.3M.
Figure 10 shows the in vitro dissolution profiles of fenofibric acid tablets
and
fenofibric acid choline salt tablets at 32.5% drug load when done in
dissolution media of
0.05M and 0.3M.
Figure 1 1 shows the in vitro dissolution profiles of fenofibric acid tablets
and
fenofibric acid clioline salt tablets at 65.5% drug load when done in
dissolution media of
0.05M and 0.3M.
Figure 12 shows the in vitro dissolution profiles of coated and uncoated
fenofibric
acid choline salt tablets when done in dissolution media of 0.05M and 0.3M.
Detailed Description
Another aspect of the present invention provides a modified release
formulation
comprising an active agent in a hydrophilic polymer matrix wherein the active
agent is a salt
of fenofibric acid and wherein the solubility of the active agent is greater
than 16.1 mg/ml in
water.
Anothcr aspect of the prescnt invention provides a modificd relcase
formulation
comprising an active agent in a hydrophilic polymer matrix wherein the active
agent is a salt
of fenofibric acid and wherein the solubility of the active agent is at least
19.0 mg/mi in
water.
In one aspect, the present invention relates to a modified release for-
mulation
comprising an active agent in a hydrophilic polymer matrix wherein the active
agent is a salt
of fenofibric acid and the salt is selected from the group consisting of
choline, ethanolamine,
and diethanolamine, and wherein the solubility of the active agent is greater
than 16.1 mg/ml
in water.
Another aspect of the present invention provides a modified release
formulation
comprising an active agent in a HPMC matrix wherein the active agent is a salt
of fenofibric
acid and wherein the solubility of the active agent is greater than 16.1 mg/ml
in water.
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Another aspect of the present invention provides a modified release
formulation
comprising an active agcnt in a HPMC matrix wherein the active agent is a salt
of fenofibric
acid and wherein the solubility of the active agent is at least 19.0 mg/ml in
water.
Another aspect of the present invention provides a modified release
formulation
comprising an active agent in a hydrophilic polymer matrix wherein the active
agent is a salt
- at
of fenofibric acid and wherein the IDR of the active agent is greater than
7.09mg/min/cm ,
a pH of 6.8.
Another aspect of the present invention provides a modified release
formulation
comprising an active agetlt in a hydrophilic polymer matrix wherein the active
agent is a salt
of fenofibric acid and the salt is selected from the group consisting of
choline, cthanolaminc,
,
and diethanolamine, and wherein the IDR of the active agent is greater than
7.09mg/min/cm
atapHof6.8.
Another aspect of the present invention provides a modified release
formulation
comprising an active agent in a HPMC matrix whercin the active agent is a salt
of fenofibric
~
acid and wherein the IDR of the active agent is greater than 7.09mg/min/cm" at
a pH of 6.8.
Another aspect of the present invention provides a modified release
formulation
comprising an active agent in a hydrophilic polymer matrix wherein the active
agent is a salt
~
of fenofibric acid and wherein the IDR of the active agent is at least 8.05
mg/min/cm- at a pH
of 6.8.
Another aspect of the present invention provides a modified release
formulation
comprising an active agent in a HPMC matrix wherein the active agent is a salt
of fenofibric
acid and wherein the IDR of the active agent is at least 8.05 mg/min/cm ,
` at a pH of 6.8.
Another aspect of the present invention provides a modified release
formulation
comprising an active agent in a hydrophilic polymer matrix wherein the active
agent is a salt
of fenofibric acid wherein the release rate of the formulation in an in vitro
dissolution is
substantially independent of the ionic strength of the dissolution media.
Another aspect of the present iiivention providcs a modified release
formulation
comprising an active agent in a HPMC matrix wherein the active agent is a salt
of fenofibric
acid wherein thc release rate of the formulation in an in vitro dissolution is
substantially
independent of the ionic strength of the dissolution media.
Another aspect of the present invention provides a modified release
formulation
comprising an active agent in a hydrophilic polymer matrix wherein the active
agent is a salt
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of fenofibric acid and wherein in an in viti-o dissolution the differcnce in
percentage dissolved
at timc points 0.5, 1, 2, 4, 6, and 8 houis is not greater than 25% when
dissolved in
dissolution media of 0.05M and 0.3M.
Another aspect of the present invention provides a modified release
formulation
comprising an active agent in a hydrophilic polymer matrix wherein the active
agent is a salt
of fenofibric acid and the salt is selected from the group consisting of
clloline, ethanolarnine,
and diethanolamine, and wherein in an in vitro dissolution the difference in
percentage
dissolved at time points 0.5, 1, 2, 4, 6, and 8 hours is not greater than 25 %
when dissolved in
dissolution media of 0.05M and 0.3M.
Another aspect of the present invention provides a modified release
formulation
comprising an active agent in a HPMC matrix wherein the active agent is a salt
of fenofibric
acid and wherein in an in viti-o dissolution the difference in percentage
dissolved at time
points 0.5, 1, 2, 4, 6, and 8 hours is not greater than 25% when dissolved in
dissolution media
of 0.05M and 0.3M.
Another aspect of the present invention provides a modified release
formulation
comprising an active agent in a hydrophilic polymer matrix wherein the active
agent is a salt
of fenofibric acid and wherein in an in viti-o dissolution the difference in
percentage dissolved
at time points 0.5, 1, 2, 4, 6, and 8 hours is not greater than 21.4% when
dissolvcd in
dissolution media of 0.05M and 0.3M.
Another aspect of the present invention provides a modified release
formulation
comprising an active agent in a HPMC matrix wherein the active agent is a salt
of fenofibric
acid and wherein in an in vitro dissolution the difference in percentage
dissolved at time
points 0.5, 1, 2, 4, 6, and 8 hours is not greater than 21.4% when dissolved
in dissolution
media of 0.05M and 0.3M.
Another aspect of the present invention provides a modified release
formulation
comprising an active agent in a hydrophilic polymer matrix wherein the active
agent is a salt
of fenofibric acid wherein the percentage of active agent in the formulation
is between 33%
and 75%.
Another aspect of the present invention provides a modified release
formulation
comprising an active agent in a HPMC matrix wherein the active agent is a salt
of fenofibric
acid wherein the percentage of active agent in the formulation is between 33%
and 75%.
Another aspect of the present invention provides a modified retease
formulation
comprising an active agent in a hydrophilic polymer matrix wherein the active
agent is a salt
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of fenofibric acid wherein the percentage of active agent in the formulation
is between 50%
and 75%.
Another aspect of the present invention provides a modified release
formulation
comprising an active agent in a hydrophilic polymer matrix wherein the active
agent is a salt
of fenofibric acid and the salt is selected from the group consisting of
choline, ethanolamine,
and diethanolamine, wherein the percentage of active agent in the formulation
is between
50% and 75%.
Another aspect of the present invention provides a modified release
formulation
comprising an active agent in a HPMC matrix wherein the active agent is a salt
of fenofibric
acid wherein the percentage of active agent in the formulation is between 50%
and 75%.
Another aspect of the present invention provides a modified release
formulation
comprising an active agent in a hydrophilic polymer matrix wherein the active
agent is a
soluble salt of fenofibric acid wherein the percentage of active agent in the
formulation is
between 33% and 75%.
Another aspect of the present invention provides a modified release
formulation
comprising an active agent in a hydrophilic polymer matrix whercin the active
agent is a
soluble salt of fenofibric acid wherein the percentage of active agent in the
formulation is
between 50% and 75%.
Anotller aspect of the present invention provides a modified release
formulation
comprising an active agent in a hydrophilic polymer matrix wherein the active
agent is a salt
of fenofibric acid wherein the percentage of active agent in the formulation
is between 33%
and 75% and wherein the rclease rate of the formulation is substantially
independent of the
ionic strength of the dissolution media.
Another aspect of the present invention provides a modified release for-
mulation
comprising an active agent in a hydrophilic polymer matrix wherein the active
agent is a salt
of fenofibric acid wherein the percentage of active agent in the formulation
is between 50%
and 75% and wherein the release rate of the formulation is substantially
independent of the
ionic strength of the dissolution media.
Another aspect of the present invention provides a hydrophilic polymer matrix
wherein the active agent is a salt of fenofibric acid wherein the difference
in disintegration
times of the active agent when disintegrated in media of .3M or .05M ionic
strength is less
than 475 minutes.
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Another aspect of the present invention provides a hydrophilic polymer matrix
whercin the active agent is a salt of fenofibric acid and the salt is sclectcd
from the group
consisting of choline, ethanolamine, and diethanolamine, wherein the
difference in
disintegration times of the active agent when disintegrated in media of .3M or
.05M ionic
strength is less than 475 niinutes.
Another aspect of the present invention provides a hydrophilic polymer matrix
wherein the active agent is a salt of fenofibric acid wherein the difference
in disintegration
times of the active agent when disintegrated in media of .3M or .05M ionic
strength is less
than 100 minutes.
Another aspect of the present invention provides a HPMC matrix wherein the
active
agent is a salt of fenofibric acid wherein the difference in disintegration
times of the active
agent when disintegrated in media of.3M or.05M ionic strength is less than 475
minutes.
Another aspect of the present invention provides a HPMC matrix whereiii the
active
agent is a salt of fenofibric acid wherein the difference in disintegration
times of the active
agent when disintegrated in media of .3M or .05M ionic strength is less than
100 minutcs.
Definitions
As used in this specification and the appended claims, the singular forms "a,"
"atl"
and "the" include plural references unless the context clearly dictates
otherwise. Thus, for
example, reference to "an active agent" includes a single active agent as well
two or more
different active agents in combination, reference to "an excipicnt" includes
mixtures of two or
more excipients as well as a single excipient, and the like.
In describing and claiming the present invention, the following terminology
will be
used in accordance with the definitions set out below.
As used herein, the term "about" is used synonymously with the term
"approximately." Illustratively, the use of the term "about" indicates that
values slightly
outside the cited values, namely, plus or minus 10`%. Such dosages are thus
encompassed by
the scope of the claims reciting the terms "about" and "approximately."
As used herein, the terms "active agent," "pharmacologically active agent,"
and
"drug" are used interchangeably herein to refer to salts of 2-[4-(4-
chlorobenzoyl)phenoxy]-2-
methyl-propanoic acid (fenofibric acid). The terms also encompass buffered 2-
[4-(4-
chlorobenzoyl)phenoxy]-2-methyl-propanoic acid. Salts of fenofibric acid
include, but are
not limited to choline, ethanolamine, diethanolamine, dicyclohexylamine,
tromethamine,
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lysine, piperazine, calcium, cyclohexylarnine, procaine, metoformin,
potassium, lysine,
mcgluminc, dicthylaminc, sodium and ctliylcncdiaminc. Exaniplcs of countcr-
ions that can be
used to provide buffered fenofibric acid, include, but are not limited to,
calcium hydroxide,
choline hydroxide, diethylethanolamine, diethanolamine, ethylenediaminc,
guanidine,
magnesium hydroxide, meglumine, ethanolamine, piperazine, peperidine, sodium
hydroxide,
triethylainine, tromethamine, benzathine , benzene-ethanamine, adenine,
aluminum
hydroxide, ammonium hydroxide, cytosine, diethylamine, glucosamine, guanine,
nicotinamide, potassium hydroxide, zinc hydroxide, hydrabamine, tributylamine,
deanol,
epolamine, lithium hydroxide, procaine, pyridoxine, triethanolamine,
ornithine, glycine,
lysine, arginine, valine, serine, proline, aspartic acid, alanine, isoleucine,
leucine, methionine
or threnine. The solid state form of the active agent used in preparing the
solid dosage forms
of the present invention is not critical. For example, active agent used in
preparing the solid
dosage form can be amorphous or crystalline. The final dosage form contains at
least a
detectable amount of crystalline active agent. The crystalline nature of the
active agent can
be detected using powder X-ray diffraction analysis, by differential scanning
calorimetry or
any othcr techniques known in the art.
As used herein, the term "cloud point" refers to a phenomenon observed in HPMC
gels with increase in their temperature resulting in a precipitation of the
polymer molecules, a
property which can be measured by light transmission. The temperature at which
light
transmission reaches 50% is called cloud point.
As used herein, the term "delayed release" refer to a typc of modificd relcase
whcrcin
a drug dosage form exhibits a time delay between oral administration of the
drug dosage form
and the release of the drug from said dosage form. Pulsed release systems
(also known as
pulsatile drug release") and the use of enteric coatings, which are well known
to those skilled
in the art, are examples of delayed release mechanisms.
As used herein, the term "dissolution media" means aqueous solutions in which
release of the drug from the tablet formulations is determined. These
solutions could be
potassium phosphate (monobasic) solutions with two concentrations (0.05M and
0.3M). 0.05
M and 0.3 M KH2PO4 represent high and low ionic strengths, respectively. pH of
these
solutions are adjusted to 6Ø
As used herein, the phrase "dissolution at a single pH", "a single pH" or a
"single pH
system", as used interchangeably herein, refers to the method described in
Table 1 below:
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Table 1
Parameter Condition
Apparatus USP Apparatus 2 (USP 29 NF 24)
Agitation 100 RPM 4%
Medium 1) 0.05 M potassium phosphate buffer 900
mL, pH 6.0 f 0.05 maintained at 37 ~
0.5 C
2) 0.3 M potassium phosphate buffer 900
mL, pH 6.0 0.05 maintained at 37 t
0.5 C
Sampling Time Points 30 minutes to 12 hours
UV Spectrophotometry Analysis At 298 nm
By an "effective amount" or a "therapeutically effective amount" of an active
agent is
meant a nontoxic but sufficient amount of the active agent to provide the
desired effcct. The
amount of active agent that is "effective" will vary from subject to subject,
depending on the
age and general condition of the individual, the particular active agent or
ageiits, and the like.
Thus, it is not always possible to specify an exact "effective amount."
However, an
appropriate "effective amount" in any individual case may be determined by one
of ordinary
skill in the art using routine experimentation.
As used hcrcin, the term "extended relcase" or "sustained release" refers to a
drug
formulation that provides for gradual release of a drug over an extended
period of time.
As used herein, a "fasted" patient, "fasting conditions" or "fasting" refers
to a patient
who has not eaten any food, i.e., who has fasted for at least 10 hours before
the
administration of the oral formulation of the present invention comprising at
least one active
agent and who does not cat any food and continues to fast for at least 4 hours
after the
administration of the formulation. The fonnulation is preferably administered
with 240 ml of
water during the fasting period, and water can be allowed ad libituin up to I
hour before and
1 hour after ingestion.
As uscd herein, a "fed patient", "fed conditions" or "fed" refers to a patient
who has
fasted for at least 10 hours overnight and then has consumed an cntire test
nlcal beginning 30
minutes before the first ingestion of the test formulations. The formulation
of the present
invention is administered with 240 ml of water within 5 minutes after
completion of the meal.
No food is then allowed for at least 4 hours post-dose. Water can be allowed
ad libituna up to
1 hour before and 1 hour after ingestion. A high fat test meal provides
approximately 1000
calories to the patient of which approxirnately 50% of the caloric content is
derived from fat
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content of the meal. A representative high fat high calorie test meal
comprises 2 eggs fi-ied in
butter, 2 strips of bacon, 2 slices of toast with butter, 4 ounces of llash
brown potatoes and 9
ounces of whole milk to provide 150 protein calories, 250 carbohydrate
calories and 500 to
600 fat calories. High fat meals can be used in clinical effect of food
studies of fenofibric
acid. A patient who receives such a high fat test meal is referred to herein
as being under
"high fat fed conditions". A low fat test meal provides approximately 500
calories to the
patient of which approximately 30% of the caloric content is derived from fat
content of the
meal. A patient who receives such a low fat test meal is referred to herein as
being under
"low fat fed conditions".
As used herein, the terms "forrnulation", "form" or "dosage form" as used
interchangeably herein, denotes any form of a pharmaceutical coniposition that
contains an
amount of active agent sufficient to achieve the desired therapeutic effect.
The frequency of
administration that will provide the most effective results in an efficient
manner without
overdosing will vary with the characteristics of the pai-ticular active agent,
including both its
pharmacological characteristics and its physical characteristics.
As used herein, the term "hydrophilic polymer" include, but are not limited
to,
hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, hydroxycthyl
cellulose,
polyethylene oxide, polyethylene glycols ("PEG"), xanthum gum, alginates,
polyvinyl
pyrrolidone, starches, cross-linked homopolymers and copolymers of acrylic
acid and other
pharmaceutically acceptable substances with swelling and/or gel-forming
properties and
combinations thereof.
As used herein, the term "ionic strength" of a solution means concentration of
ions in
a solution or a function of the concentration of ions in a solution. It can be
calculated based
on the molality of the concentration of ions and the charges of ions.
As used herein, the term "IDR" is abbreviation of intrinsic dissolution rate.
The
intrinsic dissolution rate is the rate of dissolution of pharmaceutically
acceptable ingredients
when conditions such as surface area, agitation or stirring speed, pH and
ionic strength of the
dissolution medium are held constant.
As used herein, the term "inert substrate" refers to (a) water insoluble
substrates or
seeds comprising different oxides, celluloses, organic polymers and other
materials, alone or
in mixtures; or (b) water soluble substrates or seeds comprising different
inorganic salts,
sugars, non-pareils and other materials, alone or in mixtures.
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As used herein, the term "membrane" refers to a film or laycr that is pct-
mcable to
aqueous solutions or bodily fluids and may also be pcrmcablc to the active
agent.
As used herein, the term "modified" refers to a drug containing formulation in
which
release of the drug is not immediate (See, for example, Guiclance for Industry
SUPAC-,t1R:
Il-lodified Release Solid Ora/ Dosage Forms, Scale-Up and Postapproval
C17anges:
Cheniistrv, AlanufactUring, and Conti=ols; In Vltl'o DISSOlunon, Testing and
In Vivo
BIoeq1fZVQlence Documentation, U.S. Department of Health and Human services,
Food and
Drug Administration, Center for Drug Evaluation and Research ("CDER"),
Scptember 1997
CMC 8, page 34, herein incorporated by reference.). In a modified formulation,
administration of said formulation does not result in immediate release of the
drug or active
agent into an absorption pool. The term is used interchangeably with
"nonimmediate release"
as defined in Remington: The Science and Pr-actice af Pharniacv, Nineteenth
Ed. (Easton,
Pa.: Mack Publishing Company, 1995). As used herein, the term "modified
release" includes
extended release, sustained release, delayed release, and controlled release
formulations.
As used herein, the phrase "pllatmaceutically acceptable," such as in the
recitation of
a "pharmaceutically acceptable excipicnt," or a"pharmaccutically acceptable
additive," is
meant a material that is non-toxic or otherwise physiologically acceptable.
As used herein, the term "soluble salt" means all feno acid salts of which the
solubility in water at 25 C is greater than 16.1 mg/ml.
As used herein, the term "subject" refers to an animal, preferably a mammal,
including a human or non-human. The tcrnis patient and subject may be used
intcrchangcably
herein.
As used herein the term "substantially independent" of ionic strength means
release of
the drug, fenofibric acid salts, from the tablet formulations in the
dissolution media is less
affected by the change in iotiic strength of the dissolution media, that is,
the difference in %
drug released when dissolutions are conducted in mcdia of low (0.05M) and
higli (0.3M)
ionic strengths at each time point within 8 hours is less 25%.
As used herein, the terms "treating" and "treatment" refer to reduction in
severity
and/or frequency of symptoms, elimination of symptoms and/or underlying cause,
prevention
of the occurrence of symptoms and/or their underlying cause, and improvement
or
remediation of damage. Thus, for example, "treating" a patient involves
prevention of a
particular disorder or adverse physiological event in a susceptible individual
as well as
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treatment of a clinicatly symptomatic individual by inhibiting or causing
regression of a
disorder or discasc.
1. Salt Selection
Dissolution Rates and Disintegration Times
Applicants have determined that the selcction of the salt in a fenobric acid
salt
formulation affects the robustness of the formulation. Applicants studied the
release rates of
fenofibric acid formulations comprising seven different salts of fenofibric
acid and fenofibric
acid alone. The ingredients for each of the studied formulations are shown in
Table 2. The
method used to make the tablets is described in Example 1, which follows Table
2.
The solubility of each salt was dctcrmincd according to Examplc 2. Likcwisc,
the IDR
values for each salt of fenofibric acid were determined according to Example
3. The salts of
fenofibric acid and their respective solubility and IDR are shown in Table 4.
Applicants determined the dissolution rates of each of the fenofibric acid
salt
formulations in dissolution media at a high and low ionic strength using the
single pH method
as defined above. Table 4 sllows the % dissolved after 8 hours at 0.05M and
0.3M and the
difference for each formulation at these ionic strengths. Applicants have
depicted their
findings in Figure 1. The graph in Figure 1 plots the IDR for cach fenofibric
acid salt
formulation verses the difference in dissolution values at 8 hours. As can be
seen in Figure 1
and in Table 4 the fenofibric acid salts with greater salt solubility and
higher IDR values are
less sensitive to the ionic strength of the dissolution media (that is the
difference in the
dissolution values at 8 hours and throughout the profile is less when compared
at high and
low ionic strcngths).
Figures 2-9 show the dissolution profiles for the fenofibric acid salt and
fenofibric
acid formulations at 0.05M and.3M ionic strength dissolution media (Table 5
shows
dissolution data for formulations tested in media of low ionic strength and
Table 6 shows the
dissolution data for formulations tested in media of high ionic strength). As
can be seen from
these figures the formulations with the more solublc fcnofibric acid salts are
more robust and
thus the release rates are less sensitive to the ionic strength of the
dissolution media.
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Table 2
Ingredient Forinulations (%)
Intra2ranular A B C D E F G H
Feno acid 65.5
Choline salt 65.5
Diethanolamine salt 65.5
Ethanolamine salt 65.5
Metformin salt 65.5
Procaine salt 65.5
Tris salt 65.5
Calcium salt 65.5
HPMC K15M 27 27 27 27 27 27 27 27
PVP K30 3 3 3 3 3 3 3 3
Water gs gs gs gs gs gs gs gs
Extragranular
Silicon dioxide 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5
HPC exf 3 3 3 3 3 3 3 3
SSF 1 1 1 1 1- 1 I 1
Tablet weight: 275 mg
Example 1
Tablet Preparation:
The intra granular ingredients were added into a granulator (or mixer) and dry
mixed
followed by gradual addition of a suitable amount of water to the granulator
and granulating
until optimal granulation was achieved. The granulation was then wet massed if
necessary
for an additional period of time and then dried in an oven or a fluid bed
dryer. The dried
granules were using the fitzmill or manually screened using a mesh. The
Silicon Dioxide and
HPC Exf were screened through a 40-mesh screen. The milled granules, and
screened silicon
dioxide and HPC were charged into a V-blender and blended for 5 minutes at -
26 rpm. The
SSF was screened through a 40-mesh screen. The screened SSF was added into the
blender
and blended for additional 5 minutes. The granules were weighed and compressed
using the
rounder tooling into a table with target weight of 275 mg/tablet. Target
tablet hardness was
-20 SCU.
Example 2
Solubility Determination:Solubility values of fenofibric acid salts in water
were
determined at 25 C. The salts were weighed into glass vials and water was
added. The
suspensions were rotated from end to end for about 2 days in a 25 C water
bath. The pH of
the suspensions was measured. The residual solid was then removed via
filtration through a
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0.45 m PTFE membrane filter. The resulting saturated solution was diluted
appropriately
into the HPLC mobile phase, and analyzed by the HPLC assay dcscribed below
(Tablc 3).
The powder x-ray diffraction pattern of the collected residual solid was
recorded at the end of
experiment.
HPLC Analysis:
Table 3
HPLC Assay for Fenofibric Acid.
Parameters Conditions
Column Waters Symmetry Shield RP18, 5 um, 250x4.6 mm
Autosampler Temperature Ambient
Column Temperature - 35 C
Flow Rate - 1 ml/min
Detection Wavelength 286 nm
Injection Volume 25 ul
Mobile phase A 25 mM K2 HPO 4 in water, pH adjusted to 2.5 with
H3 PO4
Mobile phase B Acetonitrile
Isocratic clution A/B = 40/60
Retention time minutes
Examele 3
Intrinsic Dissolution Rate (IDR): The IDR of salts of fenfibric acid were
determined in 50 mM sodium citrate buffer at
pH 4.0 or pH 6.8 (u = 0.155 M with NaCI).
Pellets of the salts were prepared by compressing ca. 100 mg of the compound
in a
stainless steel die under 1300 pounds force with a dwell time of one minute.
The die
containing the tablet was submerged in 400 mL of the dissolution medium at 37
C. The
solution was stirred by a paddle at -60 rpm. At each time point, 3 mL of
sample was
withdrawn and filtered. After discarding the first half of the filtrate, the
remainder was
collected and assayed by HPLC method above. The total volume of the
dissolution medium
was kept at a constant by replenishing the lost volume at each data point with
fresh buffer at
37 C.
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Tablc 4
Salt Solubility m/ml IDR* % in 0.05M 8h % in 0.3M@8h Difference@8h
Choline >300 14.50 80.0 58.6 21.4
Diethanolamine > 250 12.80 69.2 55.5 13.7
Ethanolamine 19.0 8.05 66.3 50.1 16.2
Metformin 16.1 7.09 55.2 98.8 43.6
Procaine 7.2 1.06 37.0 101.6 64.6
Tris 5.45 0.67 32.0 107.5 75.5
Calcium 0.36 0.10 19,6 95.3 75.7
Free acid 0.265 0.30 21.6 103.5 81.9
*units for IDR mg/min/cm ,
`; IDR measured at a pH of 6.8
Table 5
Time Dissolution of Formulations in 0.05M Phosphate Buffer, pH 6.0 65.5%
Loadin )
(h) A B C D E F G H
Free acid Choline Diethanolamine Ethanolamine Metformin Procaine Tris Calciurr
0.5 1.6 12.2 9.5 8.0 8.3 4.9 5.2 1.1
1 2.4 19.3 15.1 13.3 12 7.3 7.8 2.2
2 5 31.8 24.3 22.5 19.8 12.4 12.0 4.7
4 10.5 51.8 40.5 38.1 32.8 21.4 19,4 9.4
6 55.6 52.4 44.3 29.5 25.6 14.3
8 21.6 80 69.2 66.3 55.2 37.0 32.0 19.6
81.4 78.9 65 43.9 37.4 24.0
12 32.1 98.7 74.3 50.5
5 Table 6
Time Dissotution of Formulations in 0.3M Phosphate Buffer, pH 6.0 (65.5%
Loading)
(h) A B C D E F G H
Free acid Choline Diethanolamine Ethanolamine Metformin Procaine Tris Calcium
0.5 82.9 10.6 10.4 7.8 97 100.2 106.5 -1.7
. .... . . ......_ . . ._. . .... _..._ ..__ ... ...
1 95.6 15.3 15.6 12.3 97.9 101.4 107.0 5.3
.... __ .... .... ......... ................. ........... ............. ....
.........__........_..... .............. ......... . .. .. . ..
............... ....... ... ................ .. . . . .... ................ .
. . .. ..... ... . .....
~._ ....... ..........101....._...........23.8.........
.....__...23.6._..._...... _.........19.9.......... 98.2 101.4 107.0 30.8
_ .. ... ....... ...... ..... ....._.._.. . ._ ...
4 102.9 37.9 36.0 32.0 98.5 101.4 107.2 78.3
_.....: ... .. _ _ .. :_._ _, . ... ,_.: ... .... .._ _. ___._ _ . _
6 46.3 41.8 98.6 101.4 107.3 89.9
................. ............................ .................. ......... .
... ............. .... . ............................ .................. . ..
8 103.5 58.6 55.5 50.1 98.7 101.6 107.5 95.3
10 63.8 57.3 98.8 101.8 107.7 98.4
_.__ .. _ ....... _ _ .:__..... __ .. .. __ .. _ ... . _. _,.. ....... _ _
__.. ___ _ _ _.
12 103.8 73.7 98.9 101.7
Applicants also measured the disintegration times of fenofibric acid salt
formulations and
determined that the more soluble the salt the less disintegration time would
be impacted by
10 the ionic strength of the media. The method for measuring disintegration
time is presented in
Example 4. The disintegration times for the choline fenofibric acid salt, the
dicthanolaminc
fcnofibric acid salt and fenofibric acid are presented in Table 7.
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Example 4
Disintegration
Disintegration times were detennined by dropping tablets into a hcatcd (37 C)
aqucous
media (900 ml 0.05M KH2PO4 pH 6.0 and 900 ml 0.3M KH2PO4 pH 6.0). The tablets
were
then bobbed up and down at a fixcd rate until they were fully disintegrated,
the time for
disintegration was recorded in minutes.
Table 7
Disintegration Disintegratioll Tin7e (IT1inUtes)
Medium pH 6.0
Choline (B) Diethanolamine (C) Fenofibric acid (A)
.3 M phosphate 47 5 39 3.6 11 1
buffer
.05 M phosphate 66 1 71t12 486 17
buffer
Difference 19 32 475
(minutcs)
11. Salt of Fenofibric Acid Concentration
Applicants have discovered that the percentage of the fenofibric acid salt in
the
formulation also impacts the robustness of the fonnulation. Applicants
compared
formulations with different pcrccntagcs of fcnofibric acid salt or fenofibric
acid and found
that when the percentage of the fenofibric acid salt or fenofibric acid is
between 33 and 75
the formulation is most robust. Applicants compared the robustness of
formulations I and K
(presented in Table 8) to formulations A and B (presented in Table 2) by
evaluating the
impact of the ionic strength of the dissolution media on the dissolution rate
of the
formulation. Figures 10 and 11 dcpict the dissolution curvcs for thc
formulations of diffcrcnt
concentration active ingredient. Figure 10 shows the release rate of
formulations I and K
with 32.5% drug load and Figure 11 shows the release profile of formulations A
and B at
65.5% drug load in dissolution media of high and low ionic strengths.
Applicants discovered
that the dissolution profiles of fenofibric acid salt formulations are less
affected by the ionic
strength at a higher drug load.
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Tablc 8
Inaredient Formulations (%0)
Intragranular I J K L
Feno acid 49.5 32.75
Feno Choline salt 32.75
HPMC K15M 27 27 27 27
PVP K30 3 3 3 3
Lactose monohydrate 32.75 16 32.75 65.5
Water gs cls cLs qs
Extragranular
Silicon dioxide 0.5 0.5 0.5 0.5
HPC exf 3 3 3 3
SSF 1 1 1 1
Tablet weight: 275 mg
III. Enteric Coatin~
Applicants have determined that the presence or absence of an enteric coating
may
have some influence on the robustness of the formulation. Applicants compared
the
dissolutions profiles of fenofibric acid choline salt made with and without a
coating. The
composition of the formulations tested, with and without the coating, is shown
in Table 9.
These tablets were manufactured according to the manufacturing process of
Example 6.
Figure 12 shows the dissolution profiles of the coated and uncoated tablets
when dissolved in
the .05 M and .3 M dissolution media. As shown in Figure 12, the coated
tablets' dissolution
is less impacted by the ionic strength of the dissolution media.
Table 9
Fenofibric acid
choline salt (with or
without coatin )
Intra-granule
Fenofibric Acid Choline Salt 65
HPMC K15M 15
Avicci PHIOI 15.75
PVP K30 3.0
Extra- ranules
Silicon Dioxide 0.75
Magnesium Stearate 0.5
Coatin o tional
Eudragit L30 D55 10.61
Talc 5.31
Trieth l Citrate 1.59
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Example 5
Manufacturing process for coated and uncoated tablets:
Granulations were prepared by dry blending the powders, followed by the
gradual
addition of water until optimal granulation was achieved. The granulation was
then wet
massed if necessary for an additional period of time and then dried in an oven
or a fluid bed
dryer. The dried granulation was milled using the fitzrnill or manually
screened using a mesh
and then blended with the extra-granular excipients such as magnesium
stearate. The final
blend was weighed out and punched into tablets using a compression machine.
Tablets were
optionally coated using a pan coater.
One skilled in the art would readily appreciate that the present invention is
well
adapted to carry out the objects and obtain the ends and advantages mentioned,
as well as
those inherent therein. The compositions, formulations, methods, procedures,
treatments,
molecules, specific compounds described herein are presently representative of
preferred
embodiments, are exemplary, and are not intended as limitations on the scope
of the
invention. It will be readily apparent to one skilled in the art that varying
substitutions and
modifications may be made to the invention disclosed herein without departing
from thc
scope and spirit of the invention.
All patents and publications mentioned in the specification are indicative of
the levels
?0 of those skilled in the art to which the invention pertains. All patents
and publications are
herein incorporated by refercnce to the same extcnt as if each individual
publication was
specifically and individually indicated to be incorporated by reference.
The invention illustratively described herein suitably may be practiced in the
absence
of any element or elements, limitation or limitations which is not
specifically disclosed
herein. Thus, for example, in each instance herein any of the terms
"comprising," "consisting
essentially of' and "consisting of' may be replaced with cither of the other
two terms. The
terms and expressions which have been employed are used as terms of
description and not of
limitation, and there is no intention that in the use of such terms and
expressions of excluding
any equivalents of the features shown and described or portions thereof, but
it is recognized
that various modifications are possible within the scope of the invention
claimed. Thus, it
should be understood that although the present invention has been specifically
disclosed by
preferred embodiments and optional features, modification and variation of the
concepts
hcrein disclosed may bc resorted to by those skillcd in the art, and that such
modifications
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and variations are considered to be within the scope of this invention as
defined by the
appended claims.
