Note: Descriptions are shown in the official language in which they were submitted.
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CONTROLLED RELEASE FORMULATION OF DIVALPROIC ACID AND ITS DERIVATIVES
FIELD OF TI3E INVENTION
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 tablet
formulation.
BACKGROUND OF THE INVENTION
2-Propylpentanoic acid, more commonly known as valproic acid (VPA), its amide,
valpromide (VPO), and certain salts and esters of the acid are effective in
the treatment of
epileptic seizures or as antipsychotic agents. Meade, U.S. Pat. No. 4,988,731,
describes an
oligomer having a 1:1 molar ratio of sodium valproate and valproic acid
containing 4 units,
and Meade, U.S. Pat. 5,212,326, describes a stable, non-hygroscopic solid form
of valproic
acid which comprises an oligomer having 1:1 molar ratio of sodium valproate
and valproic
acid and containing four to six units. Divalproex sodium (sodium hydrogen
divalproate) is
useful in the prophylaxis of migraine headaches in adults and may be used in
the treatment or
prophylaxis of seizures.
However, despite its efficacy in the treatment of epilepsy, valproic acid has
been
shown to exhibit an elimination half-life which is apparently shorter than
other commonly
used anti-epileptic agents. Half-lives for the drug of between six and
seventeen hours in
adults and between four and fourteen hours in children have been reported.
This can lead to
substantial fluctuations in the plasma concentration of the drug, especially
in chronic
admiiiistration. To maintain reasonably stable plasma concentrations, it is
perhaps 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.
To overcome this disadvantage valproic acid formulations which maintain more
constant plasma levels of the drug following administration have been
developed. The
ultimate goal is the development of a formulation which affords stable plasma
levels in an
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once-a-day dosing regimen. Efforts to accomplish this goal 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.
U.S. Pat. No. 4,369,172 (Schor, et al.) describes, for example, a prolonged
release
therapeutic composition based on mixtures of hydroxypropyl inethylcellulose,
ethyl cellulose
and/or sodium carboxymethyl cellulose. Schor et al provide a long list of
therapeutic agents
which they suggest can be incorporated into the formulation including sodium
valproate.
U.S. Pat. No. 4,913,906 (Friedman, et al.) appears to describe 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.
U.S. Pat. No. 5,009,897 (Brinker, et al.) describes 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.
U.S. Pat. No. 5,019,398 (Daste) describes a sustained-release tablet of
divalproex
sodium in a matrix of hydroxypropyl inethylcellulose and hydrated silica.
U.S. Pat. No. 5,055,306 (Barry, et al.) describes 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
patentees
suggest a list of therapeutic agents which may be used in the formulation of
the invention,
including sodium valproate.
U.S. Pat. No. 5,169,642 (Brinkler, et al.) appears to describe a sustained
release
dosage form comprising granules of divalproex sodium or amides or esters of
valproic acid
coated with a sustained release coinposition coinprising ethyl cellulose or a
methacrylic
methyl ester, a plasticizer, a detaclcifying agent, and a slow-release
polymeric viscosity agent.
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ar, t
U.S. Pat. No. 5,185,159 (Aubert, et al.) a formulation of valproic acid and
sodium
valproate which is prepared seemingly without the use of either a binder or a
granulating
solvent. The formulation optionally contains precipitated silica as an anti-
sticking or
detackifying agent.
U.S. Pat. No. 5,589,191 (Exigua, et al.) describes 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 (Ayer, et al.) describes a method for
control
of epilepsy by delivering a therapeutic composition of valproic acid or a
derivative in
combination with a poly(alkylene oxide).
Bialer, et al., "Metabolism of Antiepileptic Drugs," pp. 143-151, R. H. Levy,
Ed.,
Raven Press, New York, 1984; Int. J. Pharmaceutics, 20: 53-63 (1984); and
Biopharmaceutics and Drug Disposition, 6: 401-411 (1985); and Israel J. Med.
Sci., 20: 46-
49 (1995) report the pharmacokinetic evaluation of several sustained release
formulations of
valproic acid.
U.S. Pat No. 6,419,953 (Qiu et al.) appears to describe a hydrophilic matrix
tablet
suitable for the once-a-day administration of valproate compounds such as
divalproex
sodium, with hydroxypropylmethyl cellulose in an amount from about 20 weight
percent to
about 40 weight percent.
U.S. Pat. No. 6,528,090 (Qiu et al.) allegedly describes an oral controlled
release
formulation suitable for the once-a-day administration of valproate compounds,
with a
pharmaceutically acceptable hydrophilic polymer in an amount from about 20% to
about 50%
by weight of the foriuulation.
There remains, however, the need for a sustained release formulation of
valproic acid
which will effectively maintain plasma concentrations of the drug at more
constant levels.
SUMMARY OF THE INVENTION
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The present invention provides a controlled release tablet dosage formulation
comprising a) about 40% to about 80% of a valproic acid compound such as
Divalproex
Sodium, and
b) at least two, preferably hydrophilic, polymers each in an amount of less
than about
20% of the tablet weight. Preferably the controlled release formulation
comprises two to four
polymers, more preferably 2 polymers. Preferably, the controlled release
formulation
comprises from about 45- about 55% of a valproic acid compound. Moreover, the
polymers
are preferably selected from the group consisting of hyproinellose
(Hydroxypropylmethyl
cellulose HPMC), hydroxyethyl cellulose, and Polyethylene Oxide.
In another aspect the present invention also provides a controlled release
tablet dosage
form comprising a valproic acid compound and at least two, preferably
hydrophilic, polymers
each in an amount of less than 20% by weight of the tablet, having a
dissolution profile in an
aqueous buffer at 37 C and pH 5.5 of
a) no more than about 30% of total valproate is released during or within 3
hours of
measurement in said apparatus;
b) from about 35% to about 70% of total valproate is released during or within
9
hours ofineasurement in said apparatus;
c) from about 50% to about 95% of total valproate is released during or within
12
hour of measurement in said apparatus, and;
d) not less than 75% of total valproate is released during or within 18 hours
of
measurement in said apparatus.
Further, there is provided a method of preparing a granular composition
suitable for
filling into capsules or pressing into controlled release tablets dosage form
comprising the
following steps of
a) dry blending a mixture of polymers comprising a valproic acid compound such
as
divalproex sodium, at least two, preferably two to four and more preferably
two, preferably
hydrophilic, polymers, preferably hypromellose, and hydroxyethylcellulose, and
a binder,
preferably pregelatinized starch;
b) wet granulating witll a hydro alcoholic solution, a mixture of an alcohol
and water,
in order to form a homogeneous mixture;
c) drying and sizing the wet granulate;
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d) surface'coating the dried granulate with a dispersion containing a
hydrophilic
polymer, preferably hypromellose, and talc, with purified water;
e) drying the coated granulate;
f) adding a glidant, preferably silicon dioxide, and sieving the coated
granulate;
5 g) dry blending the coated granulate with a filler, preferably
microcrystalline
cellulose, and a lubricant preferably stearic acid;
h) compressing the blended granules into tablets; and
i) coating the tablets with a cosmetic coat.
In the embodiment where the granules are filled into capsules this can occur
after step
e) the steps f) and g) above thus become optional and steps h) and i) are not
relevant.
In another aspect, the present invention provides a method of treating a
patient
suffering from a condition treated with a controlled release formulation of a
valproic acid
compound comprising administering once-a-day a therapeutically effective
amount of a
valproic acid compound in a controlled release tablet dosage formulation
comprising about
40% to about 80% of the valproic acid compound and at least two, preferably
hydrophilic,
polymers each in an amount of less than about 20% of the tablet weight.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the terins "sustained release," "prolonged release," and
"controlled
release" as applied to drug formulations have the meanings ascribed to them in
"Remington's
Pharmaceutical Sciences," 18th Ed., p. 1677, Mack Pub. Co., Easton, Pa.
(1990). Sustained
release drug systems include any drug delivery system which achieves the slow
release of
drug over an extended period of time, and include both prolonged and
controlled release
systems. If such a sustained release system is effective in maintaining
substantially constant
drug levels in the blood or target tissue, it is considered a controlled
release drug delivery
system. If, however, a drug delivery system extends the duration of action of
a drug over that
achieved by conventional delivery, without reference to whether it is
successful at achieving
substantially constant blood or tissue drug levels, it is considered a
prolonged release system.
The formulations of the present invention provide a controlled release
forinulation for
valproic acid coinpounds. The ten-n "valproic acid" is meant to encompass the
coinpound 2-
propylpentanoic acid per se, and its pharmaceutically acceptable salts, and
compounds which
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readily metabolize in vivb to produce valproic acid, such as valproic acid
amide
(valpromide), as well as other pharmaceutically acceptable ainides and esters
of the acid. A
particularly preferred form of valproic acid for the compositions of the
present invention is
the complex formed between 2-propylpentanoic acid and its sodium salt (2:1),
commonly
referred to as "divalproex sodium."
Divalproex Sodium may be represented by the following structure, wherein m is
an
integer from two to six:
H3C CH3 H3C CHs
O
o
nlH\
Na Na
H
) o 0
H3C CH3 H3C CH3
m
Methods for the synthesis of valproic acid 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, 12th Edition, page 1691 (1996). Further descriptions may be found
in the
Physician Desk Reference, 52"d Edition, page 417 (1998).
Divalproex sodium is effective as an anti-epileptic agent and is also used
for, migraine
and bipolar disorders. Methods for its preparation may be found in U.S. Pat.
Nos. 4,988,731
and 5,212,326, the contents of both which are hereby incorporated by
reference. Like
valproic acid, it apparently also disassociates within the gastrointestinal
tract to form a
valproate ion.
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Furthermore, as used herein:
a) any reference to "valproic acid 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) "Clnax " means maximum plasma concentration of the valproate ion, produced
by
the ingestion of the composition of the invention.
c) "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.
d) "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 various disorders.
Further, in-vitro dissolution profiles are often 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.
A new valproic acid compound dosage form is provided that possess significant
advantages over the sustained release formulations of the prior art. These
formulations
provide substantially zero (0) order release of valproate, minimizing the
variance between
peak and trough plasma levels of valproate. All of the formulations of this
invention comprise
a matrix system comprising at least two, preferably hydrophilic, polymers each
in an amount
less than 20% by tablet weight, and may further comprise a granulate matrix
surface coating.
In a matrix system, the drug or active pharmaceutical ingredient is
hoinogenously
dispersed in a polymer in association with conventional excipients. This
admixture may be
compressed under pressure to produce a tablet. The drug is released from this
tablet by
diffusion and erosion. Matrix systems are described in detail by (1) Handbook
of
pharmaceutical controlled release technology, Ed. D. L. Wise, Marcel Dekker,
Inc. New
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York, N.Y. (2000), and (2) Treatise on controlled drug delivery, fundamentals,
optimization,
applications, Ed. A. Kydonieus, Marcel Dekker, Inc. New York, N.Y. (1992),
both of which
are hereby incorporated by reference.
The enhanced pharmacokinetic profile, described in more detail below, can be
obtained by the administration of a matrix formulation of a valproic acid
compound
comprising at least two, preferably hydrophilic, polymers. In one einbodiment,
the controlled
release dosage form according to the invention comprises:
a) a valproic acid compound, present in an amount sufficient to provide the
required
daily dose of valproate, and
b) at least two, preferably two to four and more preferably two, preferably
hydrophilic, polymers, wherein each polymer is in an asnount less than about
20% of the
tablet in weight, preferably less than about 16% by tablet weight.
In another embodiment of the present invention there is provided a controlled
release
formulation comprising
a) a valproic acid compound, present in an amount sufficient to provide the
required
daily dose of valproate,
b) a pharmaceutical matrix granulate comprising at least two, preferably two
to four
and more preferably two, preferably hydrophilic, polymers, and
c) a granulate surface coating of the pharmaceutical matrix granulate
comprising a
polymer, , preferably a hydrophilic polymer, wherein the amount of each
individual type of
polymer in the formulation is less than about 20%, preferably less than about
16%, of the
composition.
In preferred embodiments this surface coated granulate is pressed into a
tablet core
which may be optionally coated with, preferably a cosmetic coat.
Preferably the valproic acid compound is divalproex sodium. The amount of a
valproic acid compound sufficient to provide the required daily dose of
valproate varies from
about 40% to about 80% by weight of the dosage form. More preferably, the
controlled
release dosage form of the present invention comprises about 45% to about 60%
by weight of
the valproic acid compound, most preferably about 45%-55% of the valproic aicd
compound.
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Suitable pr'eferred'hydrophilic polymers for use in the controlled release
dosage form
are selected from the group consisting of hypromellose (HPMC, such as for
example
Methocel K100, Methocel E15, and Pharmacoat 606), hydroxyethyl cellulose (HEC,
such as
for example Natrosol 250M), Polyethylene Oxide, polyvinylpyrrolidine,
hydroxypropyl
cellulose, methyl cellulose, vinyl acetate copolymers (such as for example
Kollicoat SR 30,
an aqueous dispersion of Polyvinyl acetate stabilized with
polyvinylpyrrolidone and sodium
lauryl sulfate), polysaccharides (such as alginate, xanthum gum, etc.),
methacrylic acid
copolymers, maleic anhydride/methyl vinyl ether copolymers and derivatives
thereof.
Preferably, the hydrophilic polymers are selected from hypromellose,
hydroxyethyl cellulose,
Polyethylene Oxide, and Kollicoat. Most preferably, the hydrophilic polymers
are
hypromellose and hydroxyethyl cellulose. Preferred hypromellose compounds
include the
commercially available Methocel K100, Methocel E15, and Phannacoat 606. A
preferred
commercially available hydroxyethyl cellulose is Natrosol 250M.
The amount of each polymer in the dosage formulation of the present invention
is less
than about 20% by weight of the composition. Preferably, the ainount of each
polymer is less
than about 16% by weight of the composition. More preferably, the amount of
each polymer
varies from about 10% to about 16% by weight of the dosage forin. Most
preferably, the
amount of each polymer varies from about 12% to about 16% by weight of the
dosage form.
The controlled release tablet dosage formulation of the present invention may
further
comprise a hydrophobic polyiner such as for example ethylcellulose. Preferred
commercially
available ethylcelluloses include Ethocel Premium 7cps and Ethocel Premium
100cps.
The composition of the invention also typically includes phannaceutically
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
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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
5 friction between the granulation and die wall during compression and
ejection. This prevents
the granulate from sticking to the tablet punches and dies, facilitates its
ejection from the
tablet punches, etc. Examples of suitable lubricants include talc, sodium
lauryl sulfate, stearic
acid, vegetable oil, calciuin stearate, zinc stearate, magnesium stearate,
sodium stearyl
fumarate, 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. Also, binders are often the same
polymers as the
polymers used to control the release of the active ingredient from the
formulation.
Other excipients that may be incorporated into the formulation include
preservatives,
antioxidants, or any other excipient commonly used in the pharmaceutical
industry, etc. The
optional tablet coat is preferably cosmetic and may be prepared from, for
example,
cominercially available powders for coating suspensions based on either
Hypromellose or
Polyvinyl alcohol, together with polyethylene Glycol and colorants etc.
In another embodiment of the present invention there is provided a controlled
release
tablet core dosage form comprising from about 47 to about 50 weight percent of
a valproic
acid compound; about 13 to 16 weight percent hypromellose; about 13 to 15
weight percent
hydroxyethylcellulose; about 8 to 9 weight percent pregelatinized starch;
about 4 to 10
weight percent microcrystalline cellulose; about 3 to 4 weight percent silicon
dioxide and
about 1 to 2 weight percent stearic acid; all weight percentages based upon
the total weight of
the tablet dosage form.
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A particularly preferred controlled release formulation of the invention is
described in
Table 1 infra, wherein all weight percentages are based upon the total weight
of the dosage
form.
Table 1: Preferred Controlled Release Formulation of the Invention (Uncoated
Tablet Core)
Tn redient Formulation mg %o) tif tablet
CORE:
Divalproex Sodium 538.2 47.1-50.6
Starch 91.8 8.0-8.6
Hydroxypropylmethyl Cellulose (Methocel K - 90.0-150.0 8.0-13.1
Hydroxyethyl Cellulose NF 150.0 13.1-14.1
SURFACE COATING:
Hydroxypropylmethyl Cellulose (Methocel E-15) 24.0-84.0 2.2-7.4
Talc Extra Fine 28.0 2.5-2.6
DRY MIXING:
Silicon Dioxide (Syloid 244) 40.0 3.5-3.8
Microcrystalline Cellulose (Avicel PH 102) 50.0 4.6-8.8
Stearic Acid NF 20.0 1.8-1.9
Total 1064.0-1142.0 100
hi another embodiment of the present invention there is provided a controlled
release
tablet dosage formulation comprising at least two, preferably two to four and
more preferably
two, preferably hydrophilic, polymers, the formulation having a dissolution
profile of a) no
more than about 30% of the total valproic acid compound is released during or
within 3
hours; b) from about 35% to about 70% of the total valproic acid compound is
released
during or within 9 hours; c) from about 55% to about 95% of the total valproic
acid
compound is released during or within 12 hour; and d) not less than 75% of the
total valproic
acid compound is released during or within 18 hours. The dissolution profile
of the controlled
release tablet dosage form of the present invention is in an USP type II
apparatus at 100 rpm,
at a temperature of 37 C, in an acid stage of 500 ml of 0.1N HCl for 45
minutes, followed by
a basic stage of 900ml 0.05 M phosphate buffer with 75mM Sodiuin Lauryl
Sulfate (SLS) pH
5.5.
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In yet anbther ethbodiment of the present invention there is provided a
controlled
release tablet dosage formulation comprising a valproic acid compound and at
least two,
preferably two to four and more preferably two, preferably hydrophilic,
polymers, the
formulation having a relative pharmacokinetic profile in a mammal as compared
to the
pharmacokinetic profile of Depakote ER (a commercially available extended
release
Divalproex Sodium formulation), of a) an average AUC value in the range from
about 85% to
about 120% wherein the observed AUC value for the Depakote ER is set at 100%,
and b) a
C,,,ax value in the range from about 90% to about 160% wherein the observed
C,,,ax value for
the Depakote ER is set at 100%, wherein the controlled release tablet dosage
formulation is
administered to a non-fasting maininal. Moreover, in a fasting maminal the AUC
value
ranges from about 90 to about 130 and the Cmax value ranges from about 100 to
about 160.
In this pharmacokinetic profile the parameters for AUC and Cmax are presented
as 100 times
the ratio of the observed value for the dosage formulation of the present
invention versus the
observed value for Depakote ER. Preferably, the values for the pharmacokinetic
parameters
of the dosage forms of the present invention satisfy the 0.80-1.25 criterion
for equivalence
with Depakote ER. The dosage formulations of the present invention comprising
a valproic
acid compound and at least two, preferably hydrophilic, polymers in an amount
of less than
20%, preferably less than 16%, therefore have comparable pharmacokinetics in
comparison
to the commercially available Depakote ER formulation, and are preferably
bioequivalent.
The controlled release formulations are generally prepared using standard
techniques
well known in the art. Typically, they are prepared by dry blending the,
preferebly
hydrophilic, polylner, filler, valproic acid compound, and other excipients
followed by
granulating the mixture using a hydro alcoholic solution (a mixture of alcohol
and water)
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, and
may subsequently be surface coated with a dispersion containing a hydrophilic
polymer.
Fillers and lubricating agents are mixed with the dried granulation to obtain
the final
formulation.
More specifically, a controlled release tablet dosage formulation comprising a
valproic acid compound and at least two, preferably hydrophilic, polylners may
be prepared
as in the following example. The method for preparing a granular composition
suitable for
pressing into controlled release tablets dosage form comprises the steps of,
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1) dry blending a tnixture of polymers comprising a valproic acid compound
such as
divalproex sodium, and a least two, preferably two to four and more preferably
two,
preferably hydrophilic, polymers, preferably hypromellose, and
hydroxyethylcellulose, and
binder, preferably pregelatinized starch;
2) wet granulating with a hydro alcoholic solution, a mixture of alcohol and
water, in
order to form a homogeneous mixture;
3) drying and sizing the wet granulate;
4) surface coating the dried granulate with a dispersion containing diluents
and a
polymer, preferably a hydrophilic polymer, more preferably hypromellose, and
talc, with
purified water;
5) drying the coated granulate;
6) adding a glidant, preferably silicon dioxide, and sieving the coated
granulate;
7) dry blending the coated granulate with a filler, preferably
microcrystalline
cellulose, and a lubricant preferably stearic acid;
8) compressing the blended granules into tablets; and
9) optionally coating the tablets with a cosmetic coat.
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
valproic acid
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 forming polymers such as
hydroxypropyl
cellulose, polyvinyl alcohol, 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 solution further
comprising
plasiticizer e.g. polyethylene glycol, propylene glycol, sorbitan monoleate,
sorbic acid,
colorants such as titaniuin dioxide, pharmaceutically acceptable dyes or
lacquers.
In another embodiment of the present invention there is provided a inethod of
treating
a patient suffering from a condition treated with a controlled release
formulation of a valproic
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14
acid compound Lompriging administering once-a-day a therapeutically effective
amount of a
valproic acid compound in a controlled release tablet dosage formulation
comprising about
40% to about 80% of the valproic acid compound and at least two, preferably
two to four and
more preferably two, preferably hydrophilic, polymers each in an amount of
less than about
20%, preferably less than 16%, of the tablet weight. The controlled release
tablet
formulations of the present invention provide an effective delivery system for
the once daily
administration of valproic acid compound (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.
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: Divalproex Sodium formulations.
Tablets containing a tablet core of 538 mg of divalproex sodium, starch, and
various
polymers were prepared. The tablet compositions are presented in Table 2.
Table 2: Divalproex Sodium controlled release formulations (mg/tablet)
1~1~tcCi,115 ~~<- ~~ li K K- L~ K~~ li- h-
~3((i5 3275' 33429 348GX 34')9) 3i9QQ 3500235U43 35b89 3(jl ;1) ir)143
Core
Divalproex Sodium 538.2 538.2 538.2 538.2 538.2 538.2 538.2 538.2 538.2 538.2
538.2
Starch 1500 55.0 90.0 149.8 89.8 91.8 91.8 91.8 91.8 91.8 91.8 91.8
Pol ox WSR N-12K 90.0 150.0
Polyox WSR 301 110.0
Hypromellose 150.0 150.0 150.0
(Methocel K-15M CR)
Hypromellose 90.0 90.0 150.0 150.0 90.0 90.0 150.0
(Methocel K-100M
CR)
Ethocel Premium 7cps 30.8 100.0
Hydroxyethylcellulose 150.0 150.0 150.0 150.0 150.0 150.0 150.0 150.0 150.0
atrosol 250M)
Calcium Phosphate 40.0
Dibasic
Surface coatin
Hypromellose 6cps 56.0
(Pharmacoat 606
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Hypromellose 56.0 56.0 84.0 24.0
(Methocel E-15 CR)
Ethylcellulose 56.0
(Ethocel Premium
7cps)
Ethylcellulose 56.0
(Ethocel Premium
100c s
Dibutyl Sebacate 7.0 7.0
PEG 400 7.0 7.0
Kollicoat SR 30D 46.0 50.0 40.0
TEC 17.3 18.75 15.0
Talc 15.6 16.25 13.0 28.0 28.0 28.0 28.0 28.0
Dry Mixin
Syloid 60.0 40.0 40.0 40.0 40.0 40.0 40.0 40.0 40.D 40.0 40.0
Avicel PH-102 70.0 50.0 50.0 50.0 50.0 50.0 50.0 50.0 50.0 100.0 50.0
Magnesium Stearate 10.0
Stearic acid 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0 20.0
Coating of Tablet
Talc 7.8
Pharmacoat 606 7.8
Kollicoat SR 30D 31.2
PEG 6000 3.2
Ethylcellulose 3.0
(Ethocel Prem. 7cps)
TEC 13.5
Tate 3,0
Opadry 31F32870 25.0 35.0 - 10.5
Yellow
Opadry H 85F27675 29,0 30.0
Grey
Total 1029.0 1152.1 1233.0 1265.0 1064.0 1064.0 1110.0 1110.0 1094.0 1142.0
1092.0
% Hydroxyethyl 13.02 11.86 14.10 14.10 13.51 13.51 13.71 13.1 13.7
cellulose(HEC) vs.
tablet weight
% Hypromellose 13.02 12.16 11.86 13.72 13.72 13.51 13.51 13,35 15.2 15.9
(HPMC) vs. tablet
weight
% Polyox vs. tablet 19.40 12.16
weight
% Kollicoat SR 30D 4.00 6.58 3.16
% Ethylcellulose 3.00 8.14 5.06 5.06
Example 2: Preparation of Divalproex Sodium controlled release fonnulation.
This Example illustrate the manufacture of a preferred dosage form of the
present
5 invention on a scale of 2500 tablets.
Divalproex sodium was milled through in Quadro comill equipped with an 0.187
inch
aperture screen. 2.691 kg of milled drug was loaded directly into a mixer and
mixed with 230
g of starch NF, 225 g of Methocel K-100M (Hypromellose NF) and 375 g Natrosol@
250M
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(Hydroxyethylc'ellulose NF) for 4 minutes. This mixture was granulated using
150 g of 95%
Alcohol USP for 1 ininute and a mixture of 25 g purified water and 25 g 95%
Alcohol for
another 30 seconds, and subsequently dried. The dried granules were milled
through a 1 mm
aperture screen. The granules were then granulate coated in a fluidized bed
drier using a
suspension prepared from 1350 g purified water and 280g Methocel E-15
(Hypromellose 15
cps NF) and140 g talc. The coated granules were blended with 100 g of silicon
dioxide
(Syloid 244) and 125 g of microcrystalline cellulose (Avicel PH 102) in a
mixer for 10
ininutes. 50 g of Stearic Acid was added and mixed for another 5 minutes The
blended
mixture was compressed into 1.00 gram tablet cores.
Example 3: Dissolution tests with Dilvaproex Sodium controlled release
tablets.
Dissolution tests with the controlled release divalproex sodium tablet
formulations
were performed. These in vitro dissolution tests were conducted using an
Apparatus II
described in the United State Pharmacopeia XXI/National Formulary XVI. A
comparative
dissolution test in release medium was conducted under the following
conditions. Divalproex
Sodium ER tablets were dissolved in an USP type II apparatus at 100 rpm, at a
temperature of
37 C, in an acid stage of 500 ml of 0.1N HCI for 45 minutes, followed by a
basic stage of
900m10.05 M phosphate buffer with 75mM Sodium Lauryl Sulfate (SLS) pH 5.5.
Sampling
times in the basic stage were at 3, 9, 12, and 18 hours. The results of this
dissolution test are
presented in Table 3.
Table 3: Percentage of labeled dose dissolved in a comparative dissolution
test at the
sampling times indicated in hours.
Tilnte, hours K-30965 K-32752 K-33429 K-33861 K-34999 K-35002 K-359$9 K-36076
0 0 0 0 0 0 0 0 0
0.75 4 2 1 2 3 2 2 3
3.75 20 13 25 23 22 17 29 19
9.75 59 39 60 52 58 42 59 47
12.75 98 51 80 64 68 58 67 55
18.75 102 87 95 81 85 84 81 71
24.75 96 102
Based upon these dissolution studies, the results appearing in Table 3 above,
the
following conclusions were drawn: a) no more than about 30% of total valproate
is released
during or within 3 hours of measurement in said apparatus; b) from about 35%
to about 70%
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17
of total valproate is released during or within 9 hours of measurement in said
apparatus; c)
from about 55% to about 95% of total valproate is released during or within 12
hour of
measurement in said apparatus, and; d) not less than 75% of total valproate is
released during
or within 18 hours of measurement in said apparatus.
Example 4: In vivo pharmacokinetic study
In three in-vivo biostudies pharmacokinetics were coinpared between preferred
formulations and a reference drug. The bioavailability and plasma
concentration versus time
profile of valproate from oral controlled release tablet formulations of
divalproex sodium (I,'--
34999, K-35002, and K-35689 described in Table 2) determined under fasting and
non-
fasting conditions were compared to those of a commercially available extended
release
divalproex sodium tablet formulation (Depakote ER) under the same conditions
in healthy
subjects (15 subjects in a non-fasting study and 13 in a fasting study).
Pharmacokinetic parameters were obtained for C,,,aX and AUCO-24 in both the
fasted
and non-fasted (fed) biostudy. Analyses of variance (ANOVAs) were obtained for
these
parameters as well. The pharmacokinetic results for each formulation as
coinpared to the
reference formulation are summarized in the Table 5.
Table 5: Comparative Pharmacokinetics of formulation versus reference
formulation
l~aaIn2~lation l'a~~anae.ter 100 Si' .lt<~~e of ~~f~"~~ Cl oii T~~o
g i'~,~ u~-af ANT~VAP~r~luc Geolzictric 7"racisfornled fur L..og
Tratisforzriedtn4arls Data Dat1 K-34999 (fasted) AUC 105 93.4 - 118 0.79234
0.4793
G"inax 113 101 - 126 0.84891 0.0733
K-35002 (fasted) AUC 115 102 - 130 0.79234 0.0500
C,,,aX 140 126- 157 0.84891 0.0001
K-35689 (fasted) AUC 107 98 - 117
CmaX 121.6 113.7 - 129.9
K-34999 (fed) AUC 94 88.1 - 100 0.99828 0.1128
C,nax 103 94.1 - 112 0.96475 0.6119
K-35002 (fed) AUC 106 98.9- 113 0.99754 0.1670
Cinax 141 129- 154 0.95639 0.0001
K-35689 (fed) AUC 108 98.3 - 117.9
Cinax 117.5 110.6 - 124.8
The 90% confidence intervals for the AUC values for the test formulations
administered under fasting and non-fasting conditions versus the reference
fasting and non-
fasting, would satisfy the criterion for bioequivalence when the values are in
the range from
0.80-1.25 times the reference value. Additionally, the 90% confidence interval
for the ratio of
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central values of C,,,aX forthe test formulations under fasting and non-
fasting regimens would
also be satisfied by the same bioequivalence criterion.
The controlled release tablet dosage formulations perform well. The controlled
release
regimens are either similar or bioequivalent to the reference regimen with
respect to extent of
absorption as characterized by AUC. The two test regiinens did not differ
statistically
significantly from the reference regimen with respect to Cmax values of the
controlled release
regimens compared the reference regimen suggest that the controlled release
tablet dosage
formulation provides controlled release of valproic acid in vivo under fasting
and non-fasting
conditions.
Moreover, the results demonstrate the controlled release characteristics of
the test
formulations and their similarity in bioavailability based on AUC when
compared to the
reference forinulation.
