Note: Descriptions are shown in the official language in which they were submitted.
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CONTROLLED RELEASE FORMULATION OF DIVALPROEX SODIUM
'Technical Field
The present invention relates to pharmaceutical formulations. More
particularly, the present invention concerns a formulation comprising valproic
acid, a
pharmaceutically acceptable salt, ester, or amide thereof, or divalproex
sodium, in a
controlled release formulation. These controlled release dosage forms have an
improved pharmacokinetic profile. These dosage forms minimize the variance
between peak and trough plasma levels of valproate, resulting in a reduction
in the
incidence of side effects.
Background
2-Propylpentanoic acid, more commonly known as valproic acid
("VPA") is effective as an antiepilpetic agent. After ingestion, the free acid
dissociates to the valproate ion within the gastrointestinal tract. The
valproate ion is
absorbed and produces the therapeutic effect described above. Physicians Desk
Reference ("PDR"), 52°d Edition, page 426 (2000).
Divalproex sodium is effective in the treatment of epilepsy, migraine, and
bipolar
disorders. It also dissociates to the valproate ion within the
gastrointestinal tract. This
substance is described in more detail in United States Patent No. 4,988,731,
and United
States Patent No. 5,212,326.
The acid moiety of valproic acid has been functionalized in order to produce
prodrugs capable of generating a valproate ion in-vivo. For example, the amide
of valproic
acid, valpromide ("VPO"), has been produced, as well certain salts and esters
of the acid.
Despite the efficacy of these drugs in the treatment of conditions such as
epilepsy, they all suffer from a common disadvantage. These valproate
compounds
have a relatively
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short half life. For example, the half life of valproic acid is reported to be
between six and
seventeen hours in adults and between four and fourteen hours in children.
This leads to
substantial fluctuations in the plasma concentration of the drug, especially
in chronic
administration. To maintain reasonably stable plasma concentrations, it is
necessary to resort
to frequent dosing, and the resulting inconvenience to the patient often
results in lowered
compliance with the prescribed dosing regimen. Moreover, widely fluctuating
plasma
concentrations of the drug may result in administration of less than
therapeutic amounts of
the drug in a conservative dosing regimen, or amounts too large for the
particular patient in
an aggressive dosing regimen. The logical solution to this problem would be to
develop
sustained release dosage forms that decrease the dosing frequency of the
compounds.
However, the pharmacokinetics of valproic acid, and other valproate compounds,
has
complicated such development efforts. The relationship between plasma
concentration and
clinical response is not well documented for valproate. One contributing
factor is the
nonlinear, concentration dependent protein binding of valproate, which affects
the clearance
of the drug. As the dose of valproate increases, serum levels rise faster than
might be
expected since proportionately less of the dose is bound to plasma proteins.
For example,
because the plasma protein binding of valproate is concentration dependant,
the free fraction
increases from approximately 10% at 40pg/ml to 18.5% at 1301xg/ml. .
These nonlinear kinetics significantly increase the difficulty of designing
sustained
release dosage forms. Identical doses of the valproate compound can produce
vastly different
blood levels depending upon the rate at which the valproate compound is
released from the
dosage form.
Further complicating development efforts is the fact that a correlation
between
valproate levels and efficacy is unknown for disease states other than
epilepsy. For example,
therapeutic concentrations required to treat migraine headaches and bipolar
disorders have
not been established.
What impact valproate levels play in a number of side effects is also unknown
at the
present time. GI irritation is very common in patients consuming valproate,
affecting up to
one third of patients. The incidence increases at elevated doses. It is
unknown if this side
effect is caused by local irritation within the GI tract or is mediated via
the stimulation of a
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receptor within the central nervous system (and thus is dependant upon plasma
valproa.te
levels). Other side effects such as asthenia, dizziness, somnolence, alopecia,
and weight gain
are quite common. It is also unknown if these side effects can be correlated
with plasma
levels of valproate. A more detailed discussion of valproate side effects may
be found in PDR
supra, page 421-437.
In spite of the nonlinear kinetics of the compounds, a concerted effort has
been
devoted to the discovery of valproate formulations that will maintain more
constant plasma
levels of the drug following administration. The ultimate goal of these
studies has been the
discovery of a formulation which affords stable plasma levels in a once-a-day
dosing regimen.
These efforts fall generally into one of two categories: (a) finding a form of
the active
ingredient which is more slowly released to the body metabolically, and (b)
finding a
formulation which delivers the drug by either a timed- or controlled-release
mechanism.
United States Patent No. 4,369,172 to Schor, et al. describes, for example, a
prolonged
release therapeutic composition based on mixtures of hydroxypropyl
methylcellulose, ethyl
cellulose and/or sodium carboxymethyl cellulose. The patentees provide a long
list of
therapeutic agents which they suggest can be incorporated into the formulation
including
sodium valproate.
United States Patent No. 4,913,906 to Friedman, et al. discloses a controlled
release
dosage form of valproic acid, its amide, or one of its salts or esters in
combination with a
natural or synthetic polymer, pressed into a tablet under high pressure.
United States Patent No. 5,009,897 to Brinker, et al. discloses granules,
suitable for
pressing into tablets, the granules comprising a core of divalproex sodium and
a coating of a
mixture of a polymer and microcrystalline cellulose.
United States Patent No. 5,019,398 to Daste discloses a sustained-release
tablet of
divalproex sodium in a matrix of hydroxypropyl methylcellulose and hydrated
silica.
United States Patent No. 5,055,306 to Barry, et aL discloses an effervescent
or water-
dispersible granular sustained release formulation suitable for use with a
variety of therapeutic
agents. The granules comprise a core comprising the active ingredient and at
least one
excipient, and a water insoluble, water-swellable coating comprising a
copolymer of ethyl
acrylate and methyl methacrylate and a water soluble hydroxylated cellulose
derivative. The
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patentees suggest a list of therapeutic agents which may be used in the
formulation of the
invention, including sodium valproate.
United States Patent No. 5,169,642 to Brinkler, et al. discloses a sustained
release
dosage form comprising granules of divalproex sodium or amides or esters of
valproic acid
coated with a sustained release composition comprising ethyl cellulose or a
methacrylic
methyl ester, a plasticizer, a detackifying agent, and a slow-release
polymeric viscosity agent.
United States Patent No. 5,185,159 to Aubert, et al. discloses a formulation
of valproic
acid and sodium valproate which is prepared without the use of either a binder
or a
granulating solvent. The formulation optionally contains precipitated silica
as an anti-
sticking or detackifying agent.
United States Patent No. 5,589,191 to Exiglia, et al. discloses a slow release
sodium
valproate tablet formulation in which the tablets are coated with ethyl
cellulose containing
silicic acid anhydride.
Published PCT application WO 94/27587 to Ayer, et al. discloses a method for
control of epilepsy by delivering a therapeutic composition of~divalproex
sodium in
combination with a poly (alkylene oxide):
Bialer, et al., "liletabolism ofAntiepileptic Drugs," pp. 143-151, R. H. Levy,
Ed.,
Raven Press, New York, 1984; Int.~. Pharmaceutics, 20: 53-63 (1984); and
Biopharmaceutics and Drug Disposition, 6: 401-411 (1985); and Israel T. Med.
Sci., 20: 46-49
(1995) report the pharmacokinetic evaluation of several sustained release
formulations of
valproic acid.
Despite all of these efforts, there remains the need for a sustained release
formulation
of divaproex sodium, and other valproate compounds, that will permit once-a-
day dosing.
Further, there remains the need for a formulation which will effectively
maintain plasma
concentrations of the drug at more constant levels over a 24 hour dosing
period (i.e. minimize
the variation between peak and trough plasma levels). Further, sustained
release formulations
are needed that will decrease the incidence of side effects associated with
valproate therapy.
More specifically, there remains the need to reduce the incidence of nausea,
vomiting,
asthenia, somnolence, alopecia, weight gain, etc. in patients undergoing
valproate therapy.
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Brief Description of the Drawings
In the drawings, which form a part of this specification:
FIGURE 1 is a graphical representation of the release of drug from several
tests
controlled release tablet formulations under in uitro conditions.
FIGURE 2 is a graphical representation of in rritro release of drug from two
preferred
controlled release tablet formulations of the invention.
FIGURE 3 is a graphical representation of plasma valproate levels of two qd
(once-a-
day) and one bid (twice-a-day) dosage form.
FIGURE 4 is a graphical representation of plasma valproate levels of a qd
(once-a-
day) and bid (twice-a-day) dosage form.
Suanmar3r of the Invention
In accordance with the present invention, a new oral controlled release
formulation
suitable for the once-a-day administration of valproate compounds, such as
divalproex
sodium, has been discovered. This formulation exhibits significant advantages
over the
sustained release valproate formulations of the prior art. This formulation
minimizes the
variation between peak and trough plasma levels of valproate over a 24 hour
dosing period.
This formulation follows a zero-order release pattern thus producing
essentially flat plasma
levels of valproate, once steady-state levels have been achieved. This results
in a significantly
lower incidence of side effects for patients consuming such a formulation.
The qd formulation produces the following pharmacokinetic profile. Peak
concentrations of valproate, Cm~.r, are statistically significantly (p<0.05)
below those produced
by valproate dosage forms suitable for twice a day administration (over a 24
hour period).
Trough levels of valproate, Cmin, are not statistically significantly
different from those
obtained with a twice-a-day dosage form (over a 24 hour period). The extent of
absorption,
as defined by area under the curve (AUC), is equivalent to those produced by
the twice a day
valproate dosage forms (over a 24 hour period). Such a combination of
properties has
unexpected benefits. It allows therapeutic levels of valproate to be
maintained over a 24 hour
dosing period. Further, it has been discovered that a significantly lower
incidence of side
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effects has been achieved by this reduction in peak plasma concentration.
Gastrointestinal
side effects, alopecia, and certain CNS side effects have been reduced.
The controlled release once-a-day formulation ("qd") is a hydrophilic matrix
dosage
form. It comprises a valproate compound that is in admixture with a sufficient
quantity of at
least one pharmaceutically acceptable polymer. A sufficient duantity of the
polymer is
utilized, so that said formulation exhibits the following in-vitro dissolution
profile, when
measured in a type 2 dissolution apparatus (paddle) at 100rpm, at a
temperature of 37 +
0.5°C, in 500m1 of O.1N HCl for 45 minutes, followed by 900m1 of 0.05M
phosphate buffer
containing 75 ml~I sodium laurel sulfate (pH 5.5), for the remainder of the
testing period:
i. no more than about 30 % of total valproate is released after 3 hours of
measurement in said apparatus;
ii. from about 40 to about 70% of total valproate is released after 9 hours
of measurement in said apparatus;
iii. from about 55 to 95% of total valproate is released after 12 hour of
measurement in said apparatus; and
iv. not less than 85% of total valproate is released after 18 hours of
measurement in said apparatus.
Upon ingestion, a formulation meeting this profile produces the Cmax,
Cm~°, and AUC
described above. Further, this formula produces steady state plasma valproate
levels having a
degree of fluctuation that is lower than that produced by a corresponding
twice-a-day
valproate dosage form. The qd formulation also provides for total absorption
of the valproate
compound that is at least 80% of that achieved by a daily dose of the
corresponding twice-a-
day formulation. Such a pharmacokinetic profile leads to a reduction in side
effects
associated with valproate therapy.
A more specific embodiment of this invention is directed to a once-a-day
divalproex
sodium dosage form. This formulation will meet the dissolution profile listed
immediately
above. It has a degree of fluctuation that is less than that achieved by a
divalproex sodium
delayed release tablet. This qd dosage form also produces total valproate
absorption that is at
least 80% of that achieved by the divalproex sodium delayed release tablets.
Peak steady
state plasma valproate levels obtained with the qd dosage form are 10-20 %
lower than that
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produced by the divalproex sodium delayed release tablets. Trough levels,
which are
important in maintaining control of epileptic seizures, are not statistically
significantly
different from those obtained with the divalproex sodium delayed release
tablets. This qd
dosage form has a reduced incidence of side effects when compared to the
divalproex delayed
release tablets.
Detailed Description
I. De$mitions and Backpronnd Information
As noted above, the invention relates to new and improved dosage forms of
valproic
acid and other valproate compounds which disassociate in-uiao to produce a
valproate ion.
Several valproate compounds are currently available commercially in the United
States or
have been described in the literature.
One such compound is valproic acid. Valproic acid may be represented by the
following structure:
H3C CHI-CHZ
O
C /
H C
H ~
C Ch+
CH ~
3 H
~
Valproic acid is available commercially from Abbott Laboratories of Abbott
Park,
Illinois. Methods for its synthesis are described in Oberreit, Ber. 29, 1998
(1896) and Keil, Z.
Physiol. Chem. 282, 137 (1947). It's activity as an antiepileptic compound is
described in the
Physician Desk Reference, 52"d Edition, page 421 (1998). Upon oral ingestion
within the
gastrointestinal tract, the acid moiety disassociates to form a carboxylate
moiety ( i.e. a
valproate ion).
The sodium salt of valproic acid is also known in the art as an anti-epileptic
agent. It
is also known as sodium valproate and is described in detail in The Merck
Index, 12~h
Edition, page 1691 (1996). Further descriptions may be found in the Physician
Desk
Reference, 52"d Edition, page 417 (1998).
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Divalproex sodium is effective as an antiepileptic agent and is also used for,
migraine
;and bipolar disorders. Methods for its preparation may be found in United
States Patent
No.'s 4,988, 731 and 5,212,326. Like valproic acid, it also disassociates
within the
;gastrointestinal tract to form a valproate ion.
In addition to these specific compounds, one of ordinary skill in the art
would readily
recognize that the carboxylic moiety of the valproate compound may be
functionalized in a
variety of ways. This includes forming compounds which readily metabolize in-
vivo to
produce valproate, such as valproate amide (valproimide), as well as other
pharmaceutically
acceptable amides and esters of the acid (i.e. prodrugs). This also includes
forming a variety
of pharmaceutically acceptable salts.
Suitable pharmaceutically acceptable basic addition salts include, but are not
limited
to canons based on alkali metals or alkaline earth metals such as lithium,
sodium, potassium,
calcium, magnesium and aluminum salts and the like and nontoxic quaternary
ammonia and
amine canons including ammonium, tetramethylammonium, tetraethylammonium,
methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine,
ethylamine and
the like. Other representative organic amines useful for the formation of base
addition salts
include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine
and the like.
Other possible compounds include pharmaceutically acceptable amides and
esters.
"Pharmaceutically acceptable ester" refers to those esters which retain, upon
hydrolysis of the
ester bond, the biological effectiveness and properties of the carboxylic acid
and are not
biologically or otherwise undesirable. For a description of pharmaceutically
acceptable
esters as prodrugs, see Bundgaard, E., ed., ( 1985) Design of Prodrugs,
Elsevier Science
Publishers, Amsterdam. These esters are typically formed from the
corresponding carboxylic
acid and an alcohol. Generally, ester formation can be accomplished via
conventional
synthetic techniques. (See, e.g., March Advanced Organic Chemistry, 3rd Ed.,
John Wiley &
Sons, New York p. 1157 (1985) and references cited therein, and Mark et al.
Encyclopedia of
Chemical Technology, John Wiley & Sons, New York (1980). The alcohol component
of the
ester will generally comprise (i) a CZ ~-C,2 aliphatic alcohol that can or can
not contain one
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or more double bonds and can or can not contain branched carbons or (ii) a C~ -
C12 aromatic
or heteroaromatic alcohols. This invention also contemplates the use of those
compositions
which are both esters as described herein and at the same time are the
pharmaceutically
acceptable salts thereof.
"Pharmaceutically acceptable amide" refers to those amides which retain, upon
hydrolysis of the amide bond, the biological effectiveness and properties of
the carboxylic
acid and are not biologically or otherwise undesirable. For a description of
pharmaceutically
acceptable amides as prodrugs, see Bundgaard, H., Ed., (1985) Design of
Prodrugs, Elsevier
Science Publishers, Amsterdam. These amides are typically formed from the
corresponding
carboxylic acid and an amine. Generally, amide formation can be accomplished
via
conventional synthetic techniques. (See, e.g., March Advanced Organic
Chemistry, 3'd Ed.,
John Wiley & Sons, New York, p. 1152 (1985) and Mark et al. Encyclopedia of
Chemical
Technology, John Wiley & Sons, New York (1980). This invention also
contemplates the
use of those compositions which are amides, as described herein, and at the
same time are the
pharmaceutically acceptable salts thereof.
As used in this application:
a) any reference to "valproate" or "valproate compounds" should be construed
as
including a compound which disassociates within the gastrointestinal tract, or
within
in-vitro dissolution media, to produce a valproate ion including, but not
limited to,
valproic acid, the sodium salt of valproate, divalproex sodium, any of the
various salts
of valproic acid described above, and any of the prodrugs of valproic acid
described
above. Divalproex sodium is the most preferred valproate compound of the
present
invention.
b) "Cmax " means maximum plasma concentration of the valproate ion, produced
by the
ingestion of the composition of the invention or the twice-a-day comparator
(BID).
c) "Cm;n " means minimum plasma concentration of the valproate ion, produced
by the
ingestion of the composition of the invention or the BID comparator.
d) "Ca,,g " means the average concentration of valproate ion within the 24-
hour interval
produced by the ingestion of tithe composition of the invention or the BID
comparator.
C~~.g is calculated as AUC over a 24 hour interval divided by 24.s
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e) "Tm:"' " means time to the maximum observed plasma concentration produced
by the
ingestion of the composition of the invention or the BID comparator.
f) "AUC" as used herein, means area under the plasma concentration-time curve,
as
calculated by the trapezoidal rule over the complete 24-hour interval for all
the
formulations.
g) "Degree of Fluctuation (DFL)" as used herein, is expressed as:
DFL=(Cmlx -Cmin)/Cavg produced by the ingestion of the composition of the
invention
or the BID comparator.
h) "Pharmaceutically acceptable" as used herein, means those salts, polymers,
and
excipients which are, within the scope of sound medical judgment, suitable for
use in
contact with the tissues of humans and lower animals without undue toxicity,
irritation, allergic response, and the like, in keeping with a reasonable
benefit/risk
ratio, and effective for their intended use in the treatment and prophylaxis
of
migraine, epilepsy, bipolar disorders, etc.
i) "Side effects" as used herein, means those physiological effects to various
systems in
the body such as cardiovascular, nervous, digestive, and the body as a whole,
which
cause pain and discomfort to the individual subject, and which are the direct
result of
the ingestion of the valproate compound.
j) "Decreased incidence of side effects" refers to a reduced incidence of side
effects in a
patient population, and not to a total absence of side effects, when measured
in a
comparable population consuming a valproate dosage form suitable for twice
daily
administration. As is well known to those skilled in the art, even placebo
dosage forms
made of sugar produce some measurable incidence of side effects. Thus an
improved
side effect profile must be interpreted in light of the relevant art.
k) " delayed release divalproex sodium tablets" refers to an enteric coated
dosage form
containing divalproex sodium intended to delay the release of the medication
until the
dosage form has passed through the stomach.
I) "bid" refers to the administration of a formulation twice during a 24 hour
period.
m) "qd" refers to the administration of a formulation once during a 24 hour
period.
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n) Any reference in the specification, or claims, to an in-vitro dissolution
profile should
be construed as referring to a dissolution test in which the total amount of
valproate
released is measured utilizing a Type 2 apparatus (paddle) at 100 rpm, a
temperature
of 37 + 0.5 C, a test solution of 500 ml of O.1N HC1 for the first 45 minutes,
followed
by a test solution of 900 ml of 0.05M phosphate buffer containing 75 mM sodium
laurel sulfate (pH5.5) for the remainder of the testing period, and utilizing
one tablet
(i.e. a single dosage form).
o) A statistical test is said to be "statistically significant" when the
resulting p-value is less
than or equal to 0.05, unless otherwise noted. "Equivalence" and "statistical
significance" are not synonoms.
As used in this application, the terms "Cm~~" and "trough levels", should be
considered
synonyms. Likewise, the terms "Cm~,'" and "peak levels" should also be
considered
synonyms. Any reference to a plasma concentration of valproate ion, and more
specifically to
any quantification thereof, such as, for example, Cmin, Cm:,X, AUC, DFL, etc.,
should be
considered to have been determined at steady state in a fasting population,
unless expressly
stated otherwise.
As is well known to those skilled in the art, in-vitro dissolution profiles
are routinely
used in the manufacture of pharmaceuticals. They serve as quality control
devices to insure
that different batches will have the same dissolution profile and thus produce
comparable
biological responses. Sometimes, dissolution profiles can serve as a reliable
predictor of in-
vivo blood levels. This is accomplished by establishing an in-vivo/in-vitro
correlation
(iv/ivc). Methods for carrying out such studies are described by the FDA at
ww~~~.usfda.gov.
The procedure outlined by the FDA in this website was utilized in developing
the dissolution
profiles described above and throughout this application.
Thus, the in-vitro dissolution profile described above is a reliable predictor
of the
pharmacokinetie profile of a hydrophilic matrix dosage form. Any valproate
containing
hydrophilic matrix formulation meeting the dissolution parameters above will
provide the
advantages of once daily dosing and a decreased incidence of side effects.
Such benefits will
be obtained regardless of the specific polymers or excipients contained within
the hydrophilic
matrix formulation.
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The dissolution testing described above is earned out as is known in the art.
A
detailed discussion of such techniques may be found in United States
Pharmacopeia (USP)
Vol. 23, pp. 1791-1793 (1995). It is important to note that all of the
compounds
encompassed by this invention disassociate within the gastrointestinal tract
to generate a
valproate ion, which is ultimately responsible for the biological activity.
Therefore, even
though a compound such as divalproex sodium is introduced into the dissolution
media, the
media is assayed for valproate content, not divalproex content, etc. Methods
for assaying
valproate content may be accomplished using a TDX fluoresence radioimmune
assay which
is available from Abbott Laboratories. Methods for carrying out this assay are
described in
the TDX system operation manual, List No: 9520-22 Abbott Laboratories,
Diagnostics
Division, Abbott Park, IL 60064 (19'92).
II. Dosage Forms
As noted above, a new valproate dosage form has been discovered that possess
significant advantages over the sustained release formulations of the prior
art. These
formulations provide zero (0) order release of valproate, minimizing the
variance between
peak and trough plasma levels of valproate. All of the formulations of this
invention are
matnx systems.
Matrix systems are well known in the art. In a matrix system, the drug is
homogenously dispersed in a polymer in association with conventional
excipients. This
admixture is typically compressed under pressure to produce a tablet. Drug is
released from
this tablet by diffusion and erosion. Matrix systems are described in detail
by (i) Handbook
of pharmaceutical controlled release technology, Ed. D. L. Wise, Marcel
Dekker, Inc. New
York, New York (2000), and (ii) Treatise on controlled drug delivery,
fundamentals,
optimization, applications, Ed. A. Kydonieus, Marcel Dekker, Inc. New York,
New York
( 1992).
The enhanced pharmacokinetic profile, described in detail below, can be
obtained by
the administration of a hydrophilic matrix formulation suitable for once-a-day
administration
comprising:
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a) a valproate compound, typically present in an amount sufficient to provide
the
required daily dose of said valproate compound, and;
b) said valproate compound is in admixture with a sufficient quantity of a
pharmaceutically acceptable polymer, so that said formulation exhibits the
following in-vitro dissolution profile, when measured in a type 2 dissolution
apparatus (paddle) at 100 rpm, at a temperature of 37 + 0.5 C, in 500m1 of 0.1
N
HCl for 45 minutes, followed by 900m1 of 0.05M phosphate buffer, containing 75
mNI sodium laurel sulfate (pH 5.5), for the remainder of the testing period:
i. no more than about 30 % of total valproate is released after 3 hours of
measurement in said apparatus;
ii. from about 40 to about 70% of total valproate is released after 9 hours
of measurement in said apparatus;
iii. from about 55% to about 95% of total valproate is released after 12
hour of measurement in said apparatus, and;
iv. not less than 85% of total valproate is released after 18 hours of
measurement in said apparatus.
In a more preferred embodiment, the formulation exhibits the following in-
vitro
dissolution profile, when tested under the same conditions:
a. from about 15% to about 30% of total valproate is released after 3 hours of
measurement in said apparatus;
b. from about 40% to about 70% of total valproate is released after 9 hours of
measurement in said apparatus;
c: from about 55% to about 90% of total valproate is released after 12 hours
of
measurement in said apparatus, and;
d. not less than 88% of total valproate is released after 18 hours of
measurement
in said apparatus.
In a more specific embodiment, the formulation exhibits the following in-vitro
dissolution profile, when tested under the same conditions:
from about 15% to about 27% of total valproate is released after 3 hours of
measurement in said apparatus;
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ii. from about 44% to about 69% of total valproate is released after 9 hours
of
measurement in said apparatus;
iii. from about 59% to about 90% of total valproate is released after 12 hours
of measurement in said apparatus, and;
iv. not less than 88% of total valproate is released after 18 hours of
measurement in said apparatus.
The matrix formulations of this invention comprise a valproate compound and a
pharmaceutically acceptable polymer. Preferably, the valproate compound is
divalproex
sodium. The amount of the valproate compound varies from about 40% to about
80% by
weight of the dosage form. Preferably, the dosage form comprises about 45% to
about 65%
by weight of the valproate compound.
The pharmaceutically acceptable polymer is a water-soluble hydrophilic
polymer, or a
water insoluble hydrophobic polymer (including waxes). Examples of suitable
water soluble
polymers include polyvinylpyrrolidine, hydroxypropyl cellulose,
hydroxypropylmethyl
cellulose, methyl cellulose, vinyl acetate copolymers, polysaccharides (such
as alignate,
xanthum gum, etc.) polyethylene oxide, methacrylic acid copolymers, malefic
anhydride/methyl vinyl ether copolymers and derivatives and mixtures thereof.
Examples of
suitable water insoluble hydrophobic polymers include acrylates, cellulose
derivatives such
ethylcellulose or cellulose acetate, polyethylene, methacrylates, acrylic acid
copolymers and
high molecular weight polyvinylalcohols. Examples of suitable waxes include
fatty acids
and glycerides.
Preferably, the polymer is selected from hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, and methyl cellulose. More preferably, the
polymer is
hydroxypropylmethyl cellulose. Most preferably, the polymer is a high
viscosity
hydroxypropylmethyl cellulose with viscosity ranging from about 4,000 cps to
about
100,000 cps. The most preferred high viscosity polymer is a
hydroxypropylmethyl cellulose
with a viscosity of about 15,000 cps, commercially available under the Trade-
mark,
Methocel, from The Dow Chemical C.'ampany.
The amount of the polymer in the dosage form generally varies from about 20%
to
about 50% by weight of the composition. Preferably, the amount of polymers
varies from
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about 25% to about 45% by weight of the dosage form. :Most preferably, the
amount of
polymer varies from about 30% to about 40% by weight of the dosage form.
The composition of the invention also typically includes pharmaceutically
acceptable
excipients. As is well known to those skilled in the art, pharmaceutical
excipients are
routinely incorporated into solid dosage forms. This is done to ease the
manufacturing
process as well as to improve the performance of the dosage form. Common
excipients
include diluents or bulking agents, lubricants, binders, etc. Such excipients
are routinely used
in the dosage forms of this invention.
Diluents, or fillers, are added in order to increase the mass of an individual
dose to a
size suitable for tablet compression. Suitable diluents include powdered
sugar, calcium
phosphate, calcium sulfate, microcrystalline cellulose, lactose, mannitol,
kaolin, sodium
chloride, dry starch, sorbitol, etc.
Lubricants are incorporated into a formulation for a variety of reasons. They
reduce
friction between the granulation and die wall during compression and ejection.
This prevents
the granulate from sticking to the tablet punches, facilitates its ejection
from the tablet
punches, etc. Examples of suitable lubricants include talc, stearic acid,
vegetable oil;
calcium stearate, zinc stearate, magnesium stearate, etc.
Glidant's are also typically incorporated into the formulation. A glidant
improves the
flow characteristics of the granulation. Examples of suitable glidant's
include talc, silicon
dioxide, and cornstarch.
Binders may be incorporated into the formulation. Binders are typically
utilized if the
manufacture of the dosage form uses a granulation step. Examples of suitable
binders include
povidone, polyvinylpyrrolidone, xanthan gum, cellulose gums such as
carboxymethylcellulose, methyl cellulose, hydroxypropylmethylcellulose,
hydroxycellulose,
gelatin, starch, and pregelatinized starch.
Other excipients that may be incorporated into the formulation include
preservatives,
antioxidants, or any other excipient commonly used in the pharmaceutical
industry, etc.
The amount of excipients used in the formulation will correspond to that
typically
used in a matrix system. The total amount of excipients, fillers and
extenders, etc. varies from
about 10% to about 40% by weight of the dosage form.
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The matrix formulations are generally prepared using standard techniques well
known
in the art. Typically, they are prepared by dry blending the polymer, filler,
valproate
compound, and other excipients followed by granulating the mixture using an
alcohol until
proper granulation is obtained. The granulation is done by methods known in
the art. The wet
granules are dried in a fluid bed dryer, sifted and ground to appropriate
size. Lubricating
agents are mixed with the dried granulation to obtain the final formulation.
The compositions of the invention can be administered orally in the form of
tablets,
pills, or the granulate may be loose filled into capsules. The tablets can be
prepared by
techniques known in the art and contain a therapeutically useful amount of the
valproate
compound and such excipients as are necessary to form the tablet by such
techniques.
Tablets and pills can additionally be prepared with enteric coatings and other
release-
controlling coatings for the purpose of acid protection, easing swallow
ability, etc. The
coating may be colored with a pharmaceutically accepted dye. 'the amount of
dye and other
excipients in the coating liquid may vary and will not impact the performance
of the extended
release tablets. The coating liquid generally comprises film fomning polymers
such as
hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose esters or
ethers such as
cellulose acetate or ethylcellulose, an acrylic polymer or a mixture of
polymers. The coating
solution is generally an aqueous solution or an organic solvent further
comprising propylene
glycol, sorbitan monoleate, sorbic acid, fillers such as titanium dioxide, a
pharmaceutically
acceptable dye.
A particularly preferred matrix system comprises: from about 50 weight percent
to
about 55 weight percent of a valproate compound; from about 20 weight percent
to about 40
weight percent of hydroxypropyl methylcellulose; from about 5 weight percent
to about 15
weight percent of lactose, from about 4 weight percent to about 6 weight
percent of
microcrystalline cellulose, and from about 1 weight percent to about 5 weight
percent of
silicon dioxide.
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In particular, the active ingredient, the hydroxypropylmethyl cellulose and
the lactose
may be in uniform admixture and form a hydrophilic matrix.
In especially preferred embodiments, silicon dioxide has an average particle
size
ranging between about 1 micron and about 10 microns.
All weight percentages are based upon the total weight of the dosage form.
This preferred embodiment of the invention also extends to a dry granular
composition suitable for compressing into a tablet dosage form, the granular
composition
comprising particles of a size smaller than about 1 mm and comprising from
about 50 weight
percent to about 55 weight percent of an active ingredient selected from the
group consisting
of valproic acid, a pharmaceutically acceptable salt or ester of valproic
acid, divalproex
sodium, and valpromide; from about 20 weight percent to about 40 weight
percent of
hydroxypropyl methylcellulose; from about 5 weight percent to about 15 weight
percent of
lactose, from about 4 weight percent to about 6 weight percent of
microcrystalline cellulose,
and from about 1 weight percent to about 5 weight percent of silicon dioxide.
In particular, the active ingredient, the hydroxypropylmethylcellulose and the
lactose
may be in uniform admixture.
In especially preferred embodiments, the silicon dioxide has an average
particle size
ranging between about 1 micron and about 10 microns.
All weight percentages are based upon the total weight of the granular
composition.
More specifically, a divalproex matrix may be prepared by a) dry blending a
mixture
of from about 50 weight percent to about 55 weight percent divalproex sodium,
from about
20 weight percent to about 35 weight percent hydroxypropylmethyl cellulose,
from about 5
weight percent to about 15 weight percent lactose to form a uniform mixture of
the dry
ingredients; b) wet granulating the dry uniform mixture from step a); c)
drying and sizing the
wet granules from step b) to select granules having an average size below 1
mm; d) dry
blending the granules with from about 4 weight percent to about 6 weight
percent
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microcrystalline cellulose, and from about 1 weight percent to about 5 weight
percent silicon
dioxide which conveniently may have an average particle size ranging between
about 1
micron and about 10 microns; and e) compressing the blended granules of step
h) under a
force ranging between about 2000 lbf (about 8.9 x 103 Newtons) and 10,000 lbf
(about 4.45 x
104 Newtons). In a similar manner, the microcrystalline cellulose can be dry
blended in step
(a) with the divalproex sodium, hydroxypropyl methylcellulose and lactose.
II. Pharmacokinetic Profile
As noted above, the invention resides in the discovery that a matrix
formulation
meeting the dissolution profile above will simultaneously accomplish two
results. First, it
will provide a dosage form of valproate that will maintain therapeutic levels
of the valproate
ion over a 24 hour dosing period, thus providing once daily dosing. Secondly,
it will reduce
the incidence of side effects associated with valproate therapy. Formulations
matching the
dissolutions profiles above, will provide the pharmacokinetic profile
described below.
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In order to obtain these beneLits, it is necessary for the once-a-day
valproate dosage
form to achieve certain pharmacokinetic parameters, when compared to a BID
valproate
dosage form. The qd dosage form rrmst reduce peak plasma levels of valproate
("CmaX")
without significantly impacting either trough levels {"Cm;"") or the extent of
valproate
absorption ("AUC"). Further, the qd dosage form will exhibit a Degree of
Fluctuation
("DFL") that is lower than that exhibited by a corresponding bid valproate
dosage form.
Cmax for the qd dosage form should be statistically significantly lower than
the CmaX
for a bid dosage form of the same valproate compound, when each is measured at
steady state
in a fasting population. For example, a once-a-day divalproex sodium dosage
form will
exhibit a Cn,aX that is statistically significantly lower than that produced
by a divalproex
sodium delayed release tablet, when each is measured at steady state in a
fasting population.
Typically, peak plasma levels of valvproate are reduced at least 10%. More
typically, these
peak plasma levels are reduced up to about 20%. This reduction must be
accomplished with
out any significant reduction in trough levels or total absorption of
valproate.
Cm;° for the qd dosage form should not be statistically significantly
different from that
obtained with a bid dosage form of the same valproate compound, when each is
determined
at steady state in a fasting population. More specifically, Cm;n for a once-
day divalproex
sodium dosage form should not be statistically significantly different from
that obtained with
a delayed release divalproex sodium tablet when each is measured at steady
state in a fasting
population. Maintaining comparable trough levels to those obtained with the
prior art bid
dosage forms is necessary to maintain the therapeutic efficacy of the
valproate compound.
Inadequate trough levels are associated with seizures in epileptic patients.
In addition to reducing peak valproate levels as described above, it is also
important
that the total amount of valproate absorbed from the qd dosage form not be
decreased
significantly, when compared to a bid dosage form of the same valproate
compound over a
24 hour dosing interval. Total drug absorption is also referred to as AUC
(area under the
curve). Methods for quantifying dnrg absorption are well known to those
skilled in the art
and have been standardized by the United States Food and Drug Administration
at
www.fda.~ov/cder/~uidanceistat-two.pdf.
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AUC for the qd dosage form will be equivalent to the AUC of the bid dosage
form of
the same valproate compound when each is measured at steady state in a fasting
population
over a 24 hour period. Equivalence of a pharmacokinetic parameter refers to
the 90%
confidence interval of the ratio of the central values of the pharmacokinetic
parameter of the
test formulation to the reference formulation being contained within 0.80 to
1.25. More
specifically, the AUC of qd divalproex sodium dosage form will be equivalent
to that
obtained with a delayed release divalproex sodium tablet when each is
determined at steady
state in a fasting population over a 24 hour dosing period.
An AUC of at least 80% should be achieved with the formulations of this
invention,
when compared to a bid dosage form over a 24 hour interval. Values below 80%
tend to
negatively impact trough levels leading to sub-therapeutic concentrations of
valproate and
loss of epileptic control, etc. AUG's in excess of 125°/a should also
be avoided. Thus with
respect to the extent of absorption, the formulations of this invention should
be considered
equivalent to the corresponding bid valproate dosage form.
Degree of Fluctuation is a measurement of how much plasma levels of a drug
vary
over the course of a dosing interval. The closer the DFL is to zero (0), the
less variance there
is over the course of a dosing period. Thus a reduced DFL signifies that the
difference in
peak and trough plasma levels has been reduced. The.DFL for a qd dosage form
of this
invention will be lower than that of the corresponding bid dosage form, for
the same
valproate compound, when each is evaluated at steady state in a fasting
population. In a
more specific embodiment, a qd divalproex sodium dosage form will have a DFL
that is lower
than that achieved with a bid delayed release divalproex sodium tablet when
each is
evaluated at steady state in a fasting population.
Despite the numerous therapeutic advantages of valproate therapy, certain
patients
consuming these medications experience side effects. For example, with
divalproex sodium
delayed release tablets, approximately 7% of patients report alopecia (hair
loss), PDR supra,
page 435-436. Up to 8% of patients report significant weight gain, PDR supra,
page 435-
436. Such side effects can have disasterous consequences for the self image of
patients,
especially for females, or younger patients. It is unknown whether this hair
loss or weight
gain is associated with obtaining or maintaining certain plasma levels of
valproate.
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Likewise, up to one-third of patients consuming divalproex sodium delayed
release
tablets complain of nausea. While such an event is certainly not life
threatening, it is
unpleasant for the patient. The nausea can lead to non-compliance and
subsequent
worsening of the patient's disease. Dizziness, tremor, asthenia, somnolence
are also common
with valproate therapy. The impact of plasma levels on these side effects is
also unknown.
For a more complete discussion of valproate side effects, please refer to PDR
supra, page 435-
436.
The incidence of these side effects can be reduced significantly by reducing
peak
plasma levels of valproate by approximately 10-20%. Further, therapeutic
control can be
maintained by meeting the Cm,~ DFL and AUC guidelines discussed above. Such a
finding
was totally unexpected. The literature clearly documents that the correlation
between side
effects and plasma valproate levels is unknown. Formulations meeting the
dissolution profiles
above will exhibit this reduced incidence of side effects.
The following examples are presented in order to further illustrate the
invention.
These examples should not be construed in any manner to limit the invention.
EXAMPLES
Example 1
The following example provides a summary of the experimental work culminating
in
the formulation of the present invention. It also discloses a dissolution
method which does
not correlate with an in-vivo/in-vitro correlation profile.
One gram tablets containing 538 mg of divalproex sodium, magnesium stearate,
dicalcium phosphate, microcrystalline cellulose (Avicel~, FMC Corporation,
Philadelphia,
PA, USA) and/or lactose and various hydrophilic polymers were prepared.
Hydrophilic
polymers tested included hydroxypropyl methylcellulose, methylcellulose
(iVlethocel~ grades
K100LVP CR, K4MP CR, K15MP CR and K100MP CR, Dow Chemical, Midland, MI,
USA); hydroxypropyl cellulose (Klucel~ LF, Hercules, Inc., Wilmington, DE,
USA); and
alginate (Keltone~ grades LVCR and HVCR, Kelco Co., San Diego, GA, USA).
Bulk drug was milled prior to use and was sized to pass a 40 mesh sieve (0.42
mm
nominal mesh opening). The milled and sieved bulk drug was dry-mixed with
polymer and
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excipients in a Collette Gral 10 (T'rade-mark) high shear mixer for 5 min at a
high
chopper speed of 3000 rpm and impeller speed of 200 rpm. Granules were
prepared
by adding 70 ml/kg of granulation fluid (water or water/ethanol mixtures) to
the
polymer/drug/excipient powder mixture over a 1-2 minute period at high chopper
speed of 3000 rpm and impeller speed of 500 rpm. Additional fluid of 10-165 ml
was
added in one step as needed in order to reach granulation end-point. Total
granulation
time ranged from 2-18 min.
Tablet matrix ingredients included microcrystalline cellulose, lactose,
magnesium stearate, and silicon dioxide. The resulting granules were tray
dried at
50°C-55°C overnight under reduced pressure. The dried granules
were mixed with
lubricant (magnesium stearate) in a bag and then passed through a 20 mesh
(0.84 mm
nominal opening) sieve. Tablets weighing 1 g were pressed in a Model C Carver
Press (Trade-mark) tableting machine using a 0.747 inch ( 1.9 cm) x 0.360 inch
(0.91
cm) ovaloid die at a compression force between about 2000 lbf (about 8.9 x 103
Newtons) and about 10,000 lbf (about 4.45 x 104 Newtons), preferably between
about
2300 lbf (1.02 x 104 Newtons) to .about 5000 lbf (2.25 x 104 Newtons). The
tablet
compositions are presented in Table 1.
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Table 1
Test Divalproex Matrix Tablet Formulations
Ingredient' ~A B C D E F ~ H I
~
Divalproex 50 50 50 50 50 53.8 53.8 53.8 53.8
Sodium
Methocel~ 18 20 - - - - - - 10
K100LVPCR
Methocel~ 8 - - - - - - - -
K4MPCR
Klucel~LF - 20 - - - - - - -
Keltone - - 30 - - - - - -
HVCR
Methocel - - - - 30 26 35 - 16
K15MPCR
Methocel~ - - - 15 - - - 30 -
K100MPCR
Lactose 23 9.5 9.5 29.5 14.5 14.7 5.7 10.7 14.7
Avicel~ - 0 5 5 5 5 5 5 5
PH101
PVPZ - - 5 - - - - - -
Magnesium 1 0.5 0.5 0.5 0.5 ~ ~ ~ ~ 0.5
0.5 0.5 0.5
Stearate
Percent by weight, based upon the total tablet weight
' Poly(vinylpyrolidone)
Initial Formulation Screenin;=
Initial screening of the matrix tablet formulations was performed using a
number of tests. Tablet hardness for each formulation was measured using a
Model
VK2000 VanKel (Trade-mark) tablet hardness analyzer and recorded in units of
kiloPounds (kP) as the average of ten trials.
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Bulk density of the formulation granules was measured by carefully filling a
glass
graduated cylinder to the 100 ml mark. Tap density was determined following
100 taps of
the filled cylinder.
Determination of granule size distribution was performed by collecting
granules larger
than 140 mesh (about 0.105 mm nominal mesh opening) and 40 mesh (about 0.42 mm
nominal mesh opening) for evaluation of the percentage of fines and large
granules.
In ~ritro dissolution tests were conducted using Apparatus II described in the
United State
Pharmacopeicc XXI/National Formulary XVI. Samples aliquots of 1.5 ml were
withdrawn and
filtered through a 0.45 pm filter and assayed by TDX~ fluorescent polarization
immunoassay.
Upon withdrawal of each sample, an equal volume of medium was added to the
test mixture
to maintain constant volume. The test conditions were as follows:
Apparatus USP II, paddle
Medium 1 M HCl for one hour; remaining time
pH 6.8 buffer
Volume of medium 900 ml
Temperature 37C 0.5C
Paddle speed 100 rpm
Sampling volume 1.5 ml
Sampling times 0, 0.5, 1, 2, 4 ,6, 8, 13,
24 hours
The results of these tests are presented in Table 2.
Based upon these initial studies, and the data appearing in Table 2 above, the
following conclusions were drawn:
(1) Effects on tablet hardness: The use of ethanol as a granulation fluid
tends to
increase tablet hardness. There is a strong interaction between ethanol and
particle size of
the bulk drug. The increase in hardness was only observed for formulations
containing drug
of larger particle size. The opposite effect was found for drug of smaller
particle size.
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(2) Effects on friability: The use of drug having a small particle size
reduced
friability. However, this effect was significant only for formulations using
water as
granulation fluid:
(3) EfFects on density: The use of ethanol as a granulation fluid was shown to
decrease the density of the granules. However, significant interactions of
ethanol with the use
of Klucel~, and of ethanol with drug particle size were observed. Ethanol
decreased the
density only of formulations containing drug of larger particle size and/or
formulations
without Klucel~ present. The opposite effects were found for formulations
containing smaller
dr~.ig particles and/or Klucel~. The same conclusions were obtained with
either tap or bulk
density as response.
(4) Effects on size of granules: More granules of larger size were obtained
with the
use of drug having a larger particle size. Moreover, interaction between
ethanol
and Klucel~ was found to be significant i.e. use of ethanol tends to generate
larger granules
when there is no Klucel~ present in the formulation. No effect was observed
for formulations
containing 4% Klucel~. Factors that showed significant influences on
the percentage of fines in the granules included ethanol, drug particle size,
and their
interaction. Using smaller drug particles tended to yield more fines in the
granules. More
fines were generated when ethanol was used as a granulation fluid. The effect
of ethanol
was most significant for formulations containing drug of a small particle
size.
(5) Effects on granulation fluid volume: In order to obtain granulation end-
point,
more fluid volume was needed for formulations containing either drug of a
smaller particle
size or with the use of ethanol as granulation fluid.
(6) In vitro drug release: In vitro percent release of valproic acid from
controlled-
release tablets are shown in Figure 1. The difference in release profiles
among formulations
was small. In the study, percent release at 8 hours (~hr) was used to
represent release rate for
data analysis. It was found that the use of Klucel~ or drug of a larger
particle size in the
formulation resulted in an increase in release rate. Similar results were
obtained when ~Ohr
Or ~qhr was used to estimate the release rate.
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Formulations containing high load and high viscosity grades of polymers often
showed poor compressibility. This is believed to be the result of the increase
in polymer
order and elasticity with increasing molecular weight. Hardness of the tablets
remained
almost unchanged under compression forces ranging from about 3000 1b (1.3 x
104
Newtons) to about 10,000 1b (4.45 x 104 Newtons).
Table 2
Form- GranulatingHardnessFriability' Tap Bulk % GranuleFines' Qen.
ulationFluid (kP) (% Loss)DensityDensity Size (%)Z
Volume (g/ml)(glml) >40 Mesh
A 100 11.9 0.049 0.504 0.429 22.6 6.1 27.6
B 80 7.2 0.16 0.515 0.438 31.3 9.8 29.0
C 115 12.2 0.025 0.459 0.39 30.2 3.3 28.6
D 80 8.4 0.162 0.459 0.406 38.2 6.6 30.4
E 235 10.4 0.060 0.599 0.509 21.5 40.7 27.0
F 110 12.2 0.006 0.400 0.340 49.2 1.8 28.0
G 200 9.4 0.085 0.596 0.506 24.0 29.7 29.7
H 150 12.9 0.142 0.593 0.504 35.0 22.8 30.0
1 130 9:5 0.015 0.475 0.404 33.8 1.2 28.8
Uetmeo as percent granules passing a 0.105 mm nominal mesh opening
2 Defined as percent drug released in an 8-hour period under the in vitro test
conditions
In order to increase the hardness of tablets, microcrystalline cellulose and
colloidal
silicon dioxide were tested by externally adding small amounts to the granules
at levels of
1-5%. Table 3 shows the results from the test. It was found that external
addition of small
amounts of microcrystalline cellulose or colloidal silicon dioxide
significantly increased
tablet hardness.
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Table 3
Effect of External Addition of Microcrystalline
Cellulose or Silicon Dioxide
Hardness Test Additive Hardness
Formulation (kp)
la None 6.2
Ib 5% Avicel~ 9.6
Ic 5% Avicel~ and 1 13.8
% silicon
dioxide'
Ila None --
Ilb 1 % Silicon dioxide'10.9
Ilc 5% Avicel~ and 1 14.4
% silicon
dioxide'
Illa None 5.8
Illb 1% Silicon dioxide' 10.8
II Ic 5% Avicel~ and 1 14.8
% silicon
dioxide'
' Silicon dioxide was Cab-O-Sil M-5 fumed silica (Cabot Corp., Boyertown, PA,
USA) having
average partite size ofbetween about 0.2 and 0.3 microns
As shown by the data in Table 3, the addition of either 1% silicon dioxide or
5%
microcrystalline cellulose to the hydrophilic matrix formulations of the
invention almost
doubled tablet hardness, while adding both resulted in a greater than doubling
of tablet
hardness. However, although the results shown above demonstrated improvement
of tablet
hardness by the combined use of the external addition of Avicel~
microcrystalline cellulose
and Cab-o-sil~ silicon dioxide, problems of sticking and relatively low
density persisted.
The low bulk density (i.e. 40 g/1) of the small particle size Cab-O-Sil~ fumed
silica led to
the problem of not being able to load sufficient material into the tablet die.
In response to this problem, a different silicon dioxide having a larger
average
particle size ranging from about 1 micron to about 10 microns, preferably
ranging between
about 2 microns to about 5 microns, and most preferably about 2-3 microns was
used. One
such material is available as Syloid~ 244, available from W. R. Grace,
Lexington, NIA,
USA. When this material was used, initially intended as a de-tackifying and
hardening
agent for tableting, a surprising and unexpected benefit was conferred upon
the
formulation, as shown below. The material was added "externally" to the
formulation: that
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is, the active ingredient, polymers) and excipients were dry blended, wet
granulated, and
then dried and sized. The silicon dioxide was then added to the granular
formulation and
the resulting mixture blended prior to pressing into tablets.
On the basis of the above findings, preferred tablet formulations were chosen
for an
in uiUO absorption study in healthy human subjects. The ingredients of the
formulations and
in tritro release rates are shown in Table 4 and Figure 2, respectively. The
formulations were
designed to have different release rates by using high viscosity HPMC alone or
blended
with low viscosity HPNIC. The target in vitro release rates were chosen to
release drug in
vivo for 16-20 hours. Formulation B was subsequently used in the
pharmacokinteie studies
and clinical trail described in Examples 4-6 of this application.
Table 4
Preferred Controlled Release Formulations
of the Invention
Ingredient Preferred
Formulation Formulation
A B
Divalproex sodium 53.82%2 53.82%
(milled)'
Hydroxypropyl 8% 30%
methylcellulose
(Methocel~ K15M,
CR)
Methyl cellulose 18% ---
(Methocel~ K100L,
CR)
Anhydrous lactose 12.18% 8.18%
Microcrystalline 5% 5%
cellulose
(Avicel~ PH 101 )
Silicon dioxide 3% 3%
(Average particle
size
1 Nm< >10 ~Im)
(Syloid~ 244)
total tablet weight 1 g 1 g
1$ ' Bulk drug sized e (0.42 mm h opening
to pass a 40 mesh nominal
siev mes
Z All percentages as weight ased upon
in the Table expressedpercentages
b
the total weight
of the tablet
Example 2
This Example illustrate the manufacture of a preferred dosage form of the
present
invention at a larger scale.
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Divalproex sodium was milled through a 0.040" band with impact forward (flat
edge) using a Fluid Air Mill ('Trade-mark) operating at 50-75 rpm feed rate
and
3500 rpm mill speed. 81 kg of milled drug was vacuum loaded directly into the
Collette Gral-600 high shear mixer and mixed with 12.3 kg of lactose, 7.5 kg
of
microcrystalline cellulose and 45 kg of hydroxypropylmethycellulos for 5
minutes.
The mixture of drug and excipients was granulated using 18 kg of purified
water for
a total of 7 minutes and dried in a fluid bed dryer until the average moisture
content
of the granules, measured by a. gravimetric test, is below the in-process
control limit
of 1.0% w/w. The dried granules are sized using a speed sifter and the
oversize
granules are milled through a 0.078" band with impact forward (flat edge)
using a
Fluid Air Mill operating at 50 rpm feed rate and 3500 rpm mill rate. The two
fractions of granules are then recombined and blended with 4.5 kg of silicon
dioxide
in a twin-shell blender. The blended mixture is compressed into 1.00 gram
tablets
with approximately 0-12 kN precompression and 24 kN main compression force
using a rotary tableting machine (Fette 2090)(Trade-mark) operating at 35-50
rpm.
Example 3
Multiple Dose Study
The bioavailability and plasma concentration versus time profile of valproate
from an oral extended-release tablet formulation of divalproex sodium (made as
in
Example 2) determined under fasting and nonfasting conditions was compared to
those of a commercially available enteric coated divalproex sodium delayed-
release tablet
formulation (Depakote~, Abbott Laboratories; reference) determined under
fasting conditions in
healthy subjects. The study was conducted according to a multiple-dose, open-
label, three-period,
randomized, complete crossover design. In each period, a six-day regimen was
administered with a
minimum of 16 days separating the first doses of consecutive periods. The
three regimens were:
Regimen A: Extended-release formulation 1000 mg q24h administered under
fasting
conditions (testlinvention}
Regimen B: Extended-release formulation 1000 mg q24h administered 30 minutes
after breakfast was served (test/invention)
Regimen C: Depakotf.° enteric coated tablet 500 mg ql2h administered
under fasting
conditions (reference/bid comparator)
A schedule of the doses and meal times for the three regimens follows.
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Table 5
Regimen Formulation Time of Dose Breakfast Lunch Dinner Snack
A Test ER 6:00 a.m. 8:00 a.m. 12 N 8:00 pm 10:30 pm
B Test ER 6:00 a.m. 5:30 a.m. 12 N 8:00 pm 10:30 pm
C Reference DR 6:00 a.m. 8:00 a.m. 12 N 8:00 pm 10:30 pm
6:00 p.m.
ER = Extended-Release; DR = Delayed Release (enteric-coated).
Fourteen healthy adult subjects (I 1 male and 3 female subjects) completed all
phases of the study. The mean age was 27 years (range 19 -- 51 years), mean
height was 69
inches (range 63 - 74 inches) and weight was 161 pounds (range 120 - 200
pounds).
Blood samples (7 mL) were collected at 0, 12, 24, 36, 48, 60, 72, 84, 96, 108,
120,
121, 122, 123, 124.5, 126, 127.5, 129, 130.5, 132, I33, 134, 135, 136.5, 138,
139.5, 141,
142.5 and 144 hours after the first dose of each period. Plasma samples were
analyzed for
valproic acid using a validated gas-liquid chromatographic method with flame
ionization
detection at Oneida Research Services, Inc., Whitesboro, New York.
Pharmacokinetic and Statistical Analyses
Pharmacokinetic parameters were estimated by noncompartmental techniques. For
Day 6 data, these included C,r,~, Tm~, C,,~in, AUCO_24, and degree of
fluctuation (DFL).
If Cn,a,,~ for the reference occurred after the second dose of Day 6, TI,1~
was taken to be the
time since the second dose rather than the time from the first dose.
Analyses of variance (ANOVAs) appropriate for crossover models were performed
for Tlr,~, DFL, and for the natural logarithms of C,;,;n, Clr,~,,~, and
AUCO_24. Within the
framework of the ANOVA; the regimens were compared pair-wise, each comparison
done
by a test at significance level of 0.05. Equivalence of the two formulations
with respect to
AUC was addressed by performing the two one-sided tests procedure at
significance level
0.05 within the framework of the ANOVA on the logarithm of AUC. As a further
aid for
assessing the characteristics of the ER formulation, 95% confidence intervals
for the ratios
of the ER formulation central values to the reference regimen central value
were obtained
from the ANOVAs for logarithms of C,r,;n and CI"~. In addition, a two one-
sided tests
procedure was carried out to compare the fasting and nonfasting extended-
release
formulation regimens.
The mean valproic acid plasma concentration-time profiles for the three
regimens
are shown in Figure 3.
The pharmacokinetic results for Day 6 of each regimen are summarized in the
following Table 6.
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Table 6
Mean ion),
(Standard n=14
Deviat
RegimenTmax Cmax Cmin AUCO_24 DFL
(hr) (Ng/mL) (Ng/mL) (Nghr/mL)
A 13.6 80.5 (18.6)*48.2 (17.0)1592 (402)0.523
(6.3)* (0.231)
B 15.9 85.0 (12.5)*55.1 (13.3)1709 (276)0.432
(4.5)* (0.127)*
C 3.6 (0.9)99.4 (15.7)54.1 (13.1)1789 (332)0.623
(0.160)
- ~rausucauy signmcanny airrerenr rrom rcegimen c.
Regimen A: Divalproex Sodium ER; 2x500 mg once daily, fasting.
Regimen B: Divalproex Sodium ER; 2x500 mg once daily, nonfasting.
Regimen C: Depakote Tablet; 500 mg twice daily, fasting.
The mean Tm~ for Regimens A and B were about three-fold longer than that of
Regimen C. The differences in Tm~,~ between Regimens A and C and between B and
C
were statistically significant. Regimens A and B tended to have lower Cm~,~
than that of
Regimen C, and these differences were statistically significant. The regimens
did not differ
statistically significantly with respect to Cm;~. The mean DFL for both ER
Regimens A and
B was lower than that of the reference, and the difference between Regimen B
and the
reference was statistically significant.
The 95% confidence intervals for bioavailability of the ER regimens relative
to the
reference for Gm~ and Cm;~ are given below. The point estimate for the ratio
of the central
values for both Cm~ and Cm;n for Regimen A, and Cm~ for Regimen B, were lower
than
1Ø The point estimate of the ratio for C~,;~ for Regimen B was approximately
unity.
25
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Table 7
Relative Bioavailability
Regimen Cmax Cmin
95% 95%
Confidence Confidence
Test Reference Point Estimate Interval Point Estimate Interval
A C 0.811 0.742 - 0.887 0.847 0.672 - 1.067
B C 0.861 0.788 - 0.941 1.026 0.814 - 1.293
Regimen A: Divalproex Sodium ER; 2x500 mg once daily, fasting.
Regimen B: Divalproex Sodium ER; 2x500 mg once daily, nonfasting.
Regimen C: Depakote Tablet; 500 mg twice daily, fasting.
The results for the two one-sided tests procedure for equivalence assessment
of the
regimens via a 90% confidence interval based on the natural logarithm of
AUCp_24 are
given below.
Table 8
Two One-Sided Tests Procedure for Equivalence Assessment, Day 6 AUC
Relative Bioavailability
Test Reference Point Estimate 90% Confidence
Interval
A C 0.891 0.817 - 0.971
B C 0.970 0.890 - 1.058
A B 0.918 0.842 - 1.001
Regimen A: Divalproex Sodium ER; 2x500 mg once daily, fasting.
Regimen B: Divalproex Sodium ER; 2x500 mg once daily, nonfasting.
Regimen C: Depakote Tablet; 500 mg twice daily, fasting.
The 90% confidence intervals for AUC on Day 6 for the test ER formulation
administered under fasting (A) and nonfasting (B) conditions versus the
reference fasting (C),
both satisfied the 0.80 - 1.25 criterion for equivalence. Additionally, the
90% confidence
interval for the ratio of central values of AUC for the test ER formulation
fasting:nonfasting
regimens also satisfied the equivalence criterion.
The extended-release formulation performs well. The extended-release regimens
are equivalent to the reference regimen with respect to extent of absorption
as
characterized by AUC. The two test regimens did not differ statistically
significantly from
the reference regimen with respect to Cmi~. The lower CmyY and later T maa
central values
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of the extended-release regimens compared the reference regimen suggest that
the ER
formulation provides extended release of valproic acid in viUO under fasting
and nonfasting
conditions. The mean DFL for the extended-release formulation administered
under
nonfasting conditions is lower (~31 %) than that of the reference regimen
(observed means
of 0.432 and 0.623, p<0.05). The mean DFL for the extended-release formulation
administered under fasting conditions was also lower (~ 16°'0) than
that of the reference
regimen although statistical significance was not attained (observed means of
0.523 and
0.623, p=0.126).
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Example 4
Multiple Dose Stndy
The bioavailability and plasma concentration-time profile of valproic acid
from a
new oral extended-release tablet formulation of divalproex sodium (invention,
made as in
Example 2) was compared to that from the currently marketed divalproex sodium
enteric
coated delayed-release tablet (Depakote~ Abbott Laboratories; reference) under
multiple-
dose conditions.
Sixteen subjects enrolled in the study. They had a mean age of 34 years (range
19
55 years), mean height of 69 inches (range 65 - 75 inches), and mean weight of
180 pounds
(range 148 - 209 pounds). This was a multiple-dose, open-label, 2-period,
crossover study
with no washout between periods in healthy adult male and female subjects
comparing the
extended-release (ER/invention) test formulation (2 x 500 mg qd) with the
delayed-release
(DR/bid/prior art) Depakote enteric-coated tablet (500 mg ql2h) as the
reference. In one
part of the study (Groups I and II), 4 subjects started on the ER test tablet
in the morning
and switched over to the 500 mg DR tablet bid on Day 7 (end of Period I) and
continued
on it through Day 12 (Period 2). The other four subjects (Group II) started
with the DR
tablet and switched over to the ER test tablet in the morning of Day 7 and
continued
through Day 12. The second part of the study (Groups III and I~ was a repeat
of the first
part except that the test formulation was given in the evening instead of in
the morning.
The ER formulation was administered after a meal, and thc° DR tablet
was given under
fasting conditions.
A schematic of the formulations administered and the meal times follows.
Table 9
Formulation Time of BreakfastLunch Dinner Snack
Dose
Morning Dose for ER
Formulations
ER 6 am 5:30 am 12 5:30 pm 10:30
N pm
DR 6 am, 6 pm 8:00 am 12 8:00 pm 10:30
N pm
Evening Dose for ER
Formulations
ER 6 pm 5:30 am 12 5:30 pm 10:30
N pm
DR 6 pm, 6 am 8:00 am 12 8:00 pm 10:30
N pm
ER = Extended-Release (invention); DR = Delayed-Release (prior art)
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Regimens: The regimens administered were as follows.
A: Divalproex sodium extended-release tablets, 500 mg valproic acid
equivalents; 2 x 500 mg tablets once every 24 hours starting with a
morning dose. (invention)
B: Divalproex sodium enteric-coated delayed-release tablets (same as
Depakote, Abbott Laboratories, reference); one 500 mg tablet once
every 12 hours starting with a morning dose.
C: Divalproex sodium extended-release tablets, 500 mg valproic acid
equivalents; 2 x 500 mg tablets once every 24 hours starting with an
evening dose. (invention)
D: Divalproex sodium enteric-coated delayed-release tablets (same as
Depakote, Abbott Laboratories, reference; one 500 mg tablet once
every 12 hours starting with an evening dose.
Blood samples (7 mL) were taken at 0, 12, 24, 36, 48, 60, 72, 84, 96, 108,
120, 121,
122, 123, 124.5, 126, 127.5, 129, 130.5, 132, 133, 134, 135, 136.5, 138,
139.5, 141, 142.5
and 144 hours from the f rst dose of each period. Blood samples were taken on
the same
schedule for Groups III and IV except that they were 12 hours later than for
Groups I and
II (i.e., first blood sample at 6 p.m. instead of 6 a.m.). Plasma samples were
analyzed for
valproic acid using a validated gas-liquid chromatographic method with flame
ionization
detection at Oneida Laboratories, New York.
Pharmacokinetic and Statistical Analyses
Pharmacokinetic parameters were estimated by noncompartmental techniques. For
Day 6 and 12 data, Cr,.,~, Tr,.,~, Cn,in, AUCo_24 and DFL were calculated. If
Tr,.,~
occurred after the second dose of Day 6 or 12, T,.r,~ was taken to be the time
since the
second dose rather than the time from the first dose.
Analyses of variance (ANOVAs) were performed for TI,.,~, DFL, and for the
natural logarithms of Cmin~ Cmax~ and AUCp_24. The model had effects for time
(whether
subject received ER formulation in morning or evening), formulation sequence,
subjects
nested within time by formulation sequence, formulation period, and the
interaction of time
with each of formulation sequence, formulation and period. Subject effects
were random
and all other effects were fixed. Equivalence of the two formulations with
respect to AUC
was addressed by performing the two one-sided tests procedure within the
framework of the
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ANOVA on the logarithm of AUC. This confidence interval for relative
bioavailability
was obtained by exponentiating the endpoints of a 90% confidence interval for
the
difference of logarithm means (difference of formulation main effects). As a
further aid for
assessing the characteristics of the ER formulation, 95% confidence intervals
for
bioavailability relative to that of the reference formulation were obtained
from the
ANOVAs for logarithms of C""n and CT"~.
The mean plasma-valproic acid concentrations following administration of the
1000
mg test formulation once every 24 hours (Regimens A and C) or the 500 mg
reference
formulation once every 12 hours (Regimens B and D) for Days 6 and 12 are shown
in
10 Figure 4.
The pharmacolinetic results for Day 6 of each regimen are summarized in the
following table.
Table 10
Mean
(%
Coefficient
of
Variation)
Cmax Cmin AUCO_24
Regimen (Ng/mL)(Ng/mL) (Nghr/mL)DFL
ER formulation in
morning (n=8)
A 0-24 hr 87 (17.3)55.5 1771 0.46
(38.7} (22.8) (55.9)
B 0-24 hr 102 53.3 1798 0.67
(10.5) (26.2) (16.6) (31.2)
ER formulation in
evening (n=8)
C 0-24 hr
85 (10.0)57.4 1728 0.39(19.7)
(14.9) (12.5)
D 0-24 hr
98 (10.2)54.7 1747 0.60
(13.9) (10.5) (12.3)
All groups combined 86 (13.8)56.4 1749 0.42
(28.1) (17.9) (44.3)
A and C 0-24 hr
100 54.0 1773 0.64
B and D 0-24 hr (10.3) (20.2) (13.6) (24.8)
Regimen A: Divalproex Sodium ER; 2x500 mg in a.m., nonfasting.
Regimen B: Depakote DR Tablet; 500 mg in a.m. and 500 mg in p.m., fasting.
Regimen C: Divalproex Sodium ER; 2x500 mg in p.m., nonfasting.
Regimen D: Depakote DR Tablet; 500 mg in p.m. and 500 mg iri a.m., fasting.
There were no statistically significant differences in the pharmacokinetic
results
between subjects who received the ER formulation in the morning and those who
received
the ER formulation in the evening. Hence, the conclusions are based on the
combined
data of the groups.
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The mean DFL of the ER formulation was statistically significantly lower than
that
of the reference. The two formulations differed statistically significantly
with respect to
C,.,1~,,~, but not with respect to Cn,;n and AUC. For Cn,~ and Cl,,in, the 95%
confidence
interval for bioavailability of the ER formulation relative to that of the
reference was 0.80
to 0.91 and 0.89 to I .18, respectively. The 90% confidence interval by which
the two one-
sided tests procedure was performed for AUC was 0.924 to 1.041, being entirely
within the
equivalence range of 0.80 to 1.25.
Nlean C,,.,2,,~ for the test formulation on Day 6 for both periods, when the
plasma
valproic acid concentrations were characterized, was lower than the reference
formulation
and was statistically significantly different. Mean AUCp_2.~ for Day 6 of each
period was
not significantly different between the test and reference formulations.
Relative
bioavailability based on the ratio (test:reference) of mean logarithm of
AUCp_24 (90%
confidence interval) was 0.981 (0.924 to 1.041). The degree of fluctuation was
statistically
significantly smaller for the test formulation (0.42) than for the reference
(0.64). The results
demonstrate the extended-release characteristics of the test formulation and
its similarity in
bioavailability based on ALTC when compared to the reference formulation.
Example 5
Based on the results of one multicenter, randomized, double-blind, placebo-
controlled clinical trial, the formulation of Example 2 (hereinafter "Depakote
ER") was
well tolerated in the prophylactic treatment of migraine headache. Of the 122
patients
exposed to Depakote ER in the placebo-controlled study, 8% discontinued for
adverse
events, compared to 9% for the 115 placebo patients.
a. Invention
The study below describes the side effect profile of a qd divalproex sodium
dosage
form according to this invention.
Table 11 includes those adverse events reported for patients in the placebo-
controlled
trial where the incidence rate in the Depakote ER-treated group was greater
than 5% and
was greater than that for placebo patients.
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Table 11
Adverse Events Reported by >5% of Depakote Extended Release (ER/lnvention)
Patients During the Migraine Placebo-Extended Trial with a Greater
Incidence than Patients Taking Placebo'
S
Body System Depakote ER Placebo
Event (N=122) (N=115)
Gastrointestinal
Nausea 15% 9%
Dyspepsia 7% 4%
Diarrhea 7% 3%
Vomiting 7% 2%
Abdominal Pain 7% 5%
Nervous System
Somnolence 7% 2%
Other
Infection 15% 14%
' The following adverse events occurred in greater than 5% of Depakote ER-
treated
patients and at a greater incidence for placebo than for Depakote ER: asthenia
and flu
syndrome.
The following additional adverse events were reported by greater than 1% but
not
more than 5% of Depakote ER-treated patients and with a greater incidence than
placebo
in the placebo-controlled clinical trial for migraine prophylaxis:
Body as a Whole: Accidental injury, viral infection.
Digestive System: Increased appetite, tooth disorder.
Metabolic and Nutritional Disorders: Edema, weight gain.
Nervous System: Abnormal gait, dizziness, hypertonia, insomnia, nervousness,
tremor, vertigo.
Respirator,~ystem: Pharyngitis, rhinitis.
Skin and Appendages: Rash.
Special Senses: Tinnitus.
b. Prior Art
The study below describes the side effect profile of Depakote DR.
Based on two placebo-controlled clinical trials and their long term extension,
Depakote DR tablets were generally well tolerated with most adverse events
rated as mild
to moderate in severity. Of the 202 patients exposed to Depakote DR tablets in
the
placebo-controlled trials, 17% discontinued for intolerance. This is compared
to a rate of
5% for the 81 placebo patients. The adverse events reported as the primary
reason for
discontinuation by greater than or equal to 1 % of 248 Depakote DR-treated
patients were
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alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%),
somnolence
( 1 %), elevated SGOT and/or SGPT ( 1 %), and depression ( 1 %).
Table 12 includes those adverse events reported for patients in the placebo
controlled trials where the incidence rate in the Depakote DR-treated group
was greater
than 5% and was greater than that for placebo patients.
Table 12
Adverse Events Reported by >5% of Depakote DELAYED-RELEASE (DR/priorart)
Patients During Migraine Placebo-Extended Trials with a Greater
slncidence than Patients Taking Placebo'
Body System Depakote DR Placebo
Event (N=202) (N=81 )
Gastrointestinal System
Nausea 31 % 10%
Dyspepsia 13%
9%
Diarrhea 12% 7%
Vomiting 11 % 1
Abdominal Pain 9% 4%
Increased Appetite 6% 4%
Nervous System
Asthenia 20% 9%
Somnolence 17% 5%
Dizziness 12% 6%
Tremor 9% 0%
Other
Weight Gain 8% 2%
Back Pain 8% 6%
Alopecia 7% 1
'The following adverse events occurred in greater than 5% of Depakote DR-
treated patients
and at a greater incidence for placebo than for Depakote DR: flu syndrome and
pharyngitis.
The following additional adverse events not referred to above were reported by
greater than 1 % but not more than 5% of Depakote DR-treated patients and with
a greater
incidence than placebo in the placebo-controlled clinical trials:
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Body as a Whole: Chest pain.
Cardiovascular Svstem: Vasodilatation.
Digestive Svstem: Constipation, dry mouth, flatulence, stomatitis.
Hemic and L,~phatic SXstem: Ecchymosis.
Metabolic and Nutritional Disorders: Peripheral edema.
Musculoskeletal System: Leg cramps.
Nervous Svstem: Abnormal dreams, confusion, paresthesia, speech disorder,
thinking abnormalities.
Respiratory S, sue: Dyspnea, sinusitis.
Skin and Appendages: Pruritus.
Uro~enital System: lVletrorrhagia.
Although the safety of ER and DR formulations were not assessed in the same
study, a cross-study comparison of the data presented in Tables 11 and 12
suggest that the
rate of adverse events were similar in the placebo-treated patients of the
three well-
controlled randomized studies. It is evident from Tables 11 and 12 that while
the adverse
events in the placebo-treated subjects were similar, Depakote ER-treated
patients had
lower number of adverse events compared to the Depakote DR-treated patients.
It can be
deduced that the reduced adverse events seen with Depakote ER treatment
compared to
Depakote DR treatment is probably due to the expected lower maximal plasma
concentrations (CI,1~ and DFL that would be achieved, as illustrated in
Examples 3 & 4,
following administration of equal doses of two the formulations. It is
reasonably believed
that the reduced adverse effects, as well as lower frequency of dosing (once-a-
day) dosing
achieved with Depakote ER, would lead to better compliance.
The controlled release tablet formulations of the present invention thus
provide an
effective delivery system for the once daily administration of valproic acid
(divalproex
sodium) to patients in need of such treatment. The formulations of the
invention provide
substantially level plasma concentrations of valproic acid falling within the
therapeutic
range of the drug over a period which permits administration once daily.
Further the
incidence of side effects associated with valproate therapy has been reduced
with this new
formulation.
Example 6
Dissolution method and data
The following example illustrates the dissolution method of this application
carried
out on a tablet prepared as in Example 2.
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Dissolution of tablet was tested using USP dissolution apparatus 2 operating
at 37
°C with a paddle rotating speed of 100 rpm. The tablet was tested in
500 ml of O.1N HC1
for the first 45 minutes, followed by 900 ml of 0.05M phosphate buffer
containing 75 mlVl
SLS at pH 5.5. Samples were taken at 1, 3, 5, 9, 12 and 18 hours and assayed
using TDx
fluorescence polarization immunoassay (FPIA) technology.
Dissolution data of commercial tablet:
ime(hr) 1.00 3.00 5.00 9.00 12.00 18.00
L/odissolved 3.60 17.90 29.00 48.40 71.30 101.10
While there have been shown and described what are the preferred embodiments
of
the invention, one skilled in the pharmaceutical formulation art will
appreciate that various
modifications in the formulations and process can be made without departing
from the
scope of the invention as it is defined by the appended claims.
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