The present invention concerns a process for preparation of an extended release formulation
comprising valproic acid, a pharmaceutically acceptable salt, ester, or amide thereof or
divalproex sodium.
Valproic acid, 2-propylpentanoic acid, and its derivatives are widely used in the treatment of
mania, migraine and epilepsy. After ingestion, they dissociate into gastrointestinal tract to
valproate ion, which on absorption produce the desired effect.
Valproic acid and its derivative have few serious shortcomings associated with them. They are
either liquid or liquify rapidly and are sticky. Further, most of them are extremely hygroscopic in
nature. These physicochemical properties pose serious problems during manufacture of
pharmaceutical compositions, demanding well-defined approaches to overcome these
drawbacks.
Besides, they also suffer from relatively short elimination half-lives. For example, a short halflife
of 6-17 hours in adults and 4-14 hours in children for valproic acid has been reported.
Frequent dosing is thus necessary to maintain reasonably stable plasma concentrations.
However, it results in inconvenience to the patient, leading to poor compliance. Moreover,
widely fluctuating plasma concentrations of the drug also result in administration of erratic
amounts of drug.
A solution to the above problem is an extended release formulation of divalproex sodium that
permits once a day dosing and thereby helps in maintaining a reasonably stable plasma
concentration.
Abbott in its US patent 6,419,953 describes an extended release matrix tablet comprising a
valproate compound; hydroxypropyl methylcellulose; lactose, microcrystalline cellulose, and
silicon dioxide having an average particle size ranging between about 1 micron and about 10
microns. The patent further teaches that addition of either 1% silicon dioxide orland 5%
microcrystalline cellulose to the hydrophilic matrix formulations of the invention doubles tablet
hardness. However the problem of sticking still persists when conventionally used grades of
silicon dioxide are employed, and can be overcome only by the use of special grade silicon
dioxide (Syloid@ 244) having a smaller average particle size ranging from about 1 micron to
about 10 microns.
The inventors have developed a pharmaceutical composition for oral administration comprising
a drug capable of dissociating to produce valproate ion, and low and high viscosity grade
hydroxypropyl methylcellulose. The inventors have found out that low viscosity grade helps in
maintaining the integrity of the matrix, thereby playing an important role in controlling the
release of the drug from the matrix.
The extended release pharmaceutical composition provides the drug over a prolonged period of
time in such a manner as to provide substantial level of plasma concentrations of the drug
following once-a-day dosing.
In one general aspect, there is provided an extended release pharmaceutical composition
comprising
a) a drug capable of dissociating to produce valproate ion;
b) from 15-50% of a high viscosity grade hydroxypropyl methylcellulose ;
c) from 0.1-1 0% of a low viscosity grade hydroxypropyl methylcellulose.
In another general aspect, there is provided a process for the preparation of an extended
release pharmaceutical composition comprising the steps ofa)
blending a drug capable of dissociating as valproate ion, from 15-50% wlw of a high
viscosity grade hydroxypropyl methylcellulose and from 0.1-10% wlw of a low
viscosity grade hydroxypropyl methylcellulose,
b) optionally granulating the blend,
c) lubricating the blend of step a) or granules of step b), and
3
d) compressing into or filling into suitable size solid dosage form.
The process includes a) blending a drug capable of dissociating as valproate ion, high viscosity
grade hydroxypropyl rnethylcellulose and low viscosity grade hydroxypropyl rnethylcellulose, b)
optionally granulating the blend, c) lubricating the blend of step a) or granules of step b), and d)
compressing into or filling into suitable size solid dosage form.
In a yet another embodiment, there is provided a method of treating mania, migraine and
epilepsy using an extended release pharmaceutical composition comprising an extended
release pharmaceutical composition comprising
a) a drug capable of dissociating to produce valproate ion;
b) from 15-50% of high viscosity grade hydroxypropyl rnethylcellulose ;
c) from 0.1-1 0% of low viscosity grade hydroxypropyl methylcellulose.
In one general aspect, there is provided an extended release pharmaceutical composition
comprising
a) a drug capable of dissociating to produce valproate ion;
b) from 15-50% of a high viscosity grade hydroxypropyl rnethylcellulose ;
c) from 0.1-1 0% of a low viscosity grade hydroxypropyl methylcellulose
wherein the composition is free of microcrystalline cellulose.
In another general aspect, there is provided a process for the preparation of an extended
release pharmaceutical composition comprising
a) a drug capable of dissociating to produce valproate ion;
b) from 15-50% of high viscosity grade hydroxypropyl methylcellulose ;
c) from 0.1-1 0% of low viscosity grade hydroxypropyl methylcellulose
wherein the composition is free of microcrystalline cellulose.
In another general aspect, there is provided a method of treating mania, migraine . and epilepsy
using an extended release pharmaceutical composition comprising
a) a drug capable of dissociating to produce valproate ion;
b) from 15-50% of high viscosity grade hydroxypropyl methylcellulose ;
c) from 0.1-1 0% of low viscosity grade hydroxypropyl methylcellulose
wherein the composition is free of microcrystalline cellulose.
The term 'pharmaceutical composition' as used herein includes solid dosage forms such as
tablet, capsule, pill and like. 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 releasecontrolling coatings for the purpose of acid protection,
easing swallow ability, etc.
The term 'drug capable of dissociating as valproate ion into the gastrointestinal tract' includes a
compound which dissociates within the gastrointestinal tract 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 below, and any of the prodrugs of valproic acid
described below.
Valproic acid is known for its activity as an antiepileptic compound as described in the
Physician Desk Reference, 52nd Edition, page 421, 1998. Upon oral ingestion within the
gastrointestinal tract, the acid moiety dissociates 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 Edition, page
1691, (1996).
Divalproex sodium, sodium hydrogen divalproate, is effective as an antiepileptic agent and is
also used for migraine and bipolar disorders. It is a stable co-ordination compound comprising
of sodium valproate and valproic acid in a 1:l ratio and formed during the partial neutralization
of valproic acid with 0.5 equivalent of sodium hydroxide may be used. The amount of drug may
vary from about 10% to about 90% by weight of the total pharmaceutical composition weight.
Like valproic acid, it also dissociates 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 might be functionalized in a variety of
ways. This includes forming compounds that 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 cations
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
cations 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 that retain, upon hydrolysis of the
ester bond, the biological effectiveness and properties of the carboxylic acid and are not
biologically or otherwise undesirable. The alcohol component of the ester will generally
comprise (i) a C2 -CI2 aliphatic alcohol that can or can not contain one or more double bonds
and can or can not contain branched carbons or (ii) a C, -CI2 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 that retain, upon hydrolysis of the
amide bond, the biological effectiveness and properties of the carboxylic acid and are not
biologically or otherwise undesirable. This invention also contemplates the use of those
compositions, which are both amides as described herein, and at the same time are the
pharmaceutically acceptable salts thereof.
The term 'extended release pharmaceutical composition' as used herein includes any
pharmaceutical composition that achieves the slow release of drug over an extended period of
time, and includes both prolonged and controlled release compositions.
The extended release pharmaceutical composition may be prepared by processes known in the
prior art for example, by comminuting, mixing, granulation, melting, sizing, filling, drying,
molding, immersing, coating, compressing etc.
The term 'high viscosity grade hydroxypropyl methylcellulose' used herein includes grades of
hydroxypropyl methylcellulose whose 2% wlw aqueous solution has nominal viscosity greater
than about 10,000 cP.
The term 'low viscosity grade hydroxypropyl methylcellulose' used herein includes grades of
hydroxypropyl methylcellulose whose 2% wlw aqueous solution has nominal viscosity less than
about 1,000 cP.
Hydroxypropyl rnethylcellulose polymers which are hydrophilic in nature and which may be
used in the present invention are of different viscosity grades such as those available under the
brand name Methocel TM available from Dow Chemical Co. and Metolose from Shin Etsu Ltd.
Examples of hydroxypropyl methylcellulose polymers having high viscosity include those
7
C
available under the brand names Methocel K15M, Methocel KIOOM, Methocel ElOM, Metolose
90SH 15000 and Metolose 90SH 39000 whose 2% by weight aqueous solution have viscosities
of 15,000 cP, 100,000 cP 10,000 cP, 15,000 cP and 39,000 cP, respectively. The high
viscosity grade of hydroxypropyl methylcellulose polymers may be used in the concentration
range of 15-50% wlw, in particular 20-40% wlw.
Examples of hydroxypropyl methylcellulose polymers of a low viscosity grade include those
available under the brand names Methocel E5, Methocel E-15 LV, Methocel E50 LV, Methocel
KlOO LV Methocel F50 LV, Methocel EGLV, Methocel A15LV and Metolose 60SH 50, whose
2% by weight aqueous solutions have viscosities of 5 cP, 15 cP, 50 cP, 100 cP, 50 cP, 6cP, 15
cP, and 50 cP, respectively. The low viscosity grade of hydroxypropyl methylcellulose polymers
may be used in the concentration range of 0.1-10% wlw, in particular 1-5% wlw.
In one general aspect, the extended release pharmaceutical composition may be prepared by
wet granulation technique, comprising the steps of blending drug capable of dissociating as
valproate ion in gastrointestinal tract, extended release polymer and optionally pharmaceutically
inert excipient; granulating with a granulating fluid or solutionldispersion of binder; drying and
sizing the granules; optionally blending with pharmaceutically inert extragranular excipients;
lubricating the granuleslblend; compressing the lubricated blend into suitable sized tablets and;
optionally coating with film forming polymer and coating additives.
In one general aspect, the extended release pharmaceutical composition may be prepared by
dry granulation technique, comprising the steps of blending drug capable of dissociating as
valproate ion in gastrointestinal tract, extended release polymer and optionally pharmaceutically
inert excipient; dry granulating the blend by roller compactor or slugging; lubricating the
granuleslblend; compressing the lubricated blend into suitable sized tablets and; optionally
coating with film forming polymer and coating additives.
In another general aspect, the extended release pharmaceutical composition may be prepared
by direct compression technique, comprising the steps of blending drug capable of dissociating
as valproate ion in gastrointestinal tract, extended release polymer and optionally
pharmaceutically inert excipient; lubricating the blend; directly compressing the lubricated blend
into suitable sized tablets and; optionally coating with film forming polymer and coating
additives.
In another general aspect, the extended release pharmaceutical composition may be prepared
by melt extrusion technique, comprising the steps of blending drug capable of dissociating as
valproate ion into gastrointestinal tract, extended release polymer and optionally
pharmaceutically inert excipient; melting the blend followed by solidifying into a compact mass;
breaking the compact mass into granules; optionally blending with pharmaceutically inert
extragranular excipients; lubricating the granuleslblend; compressing the lubricated blend into
suitable sized tablets and; optionally coating with film forming polymer and coating additives.
The term "pharmaceutically acceptable inert excipients" as used herein includes all excipients
used in the art of manufacturing solid dosage forms. Examples include binders, diluents,
surfactants, lubricantslglidants, coloring agents, and the like.
Specific examples of binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol,
pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the
like.
Specific examples of diluents include calcium carbonate, calcium phosphate-dibasic, calcium
phosphate-tribasic, calcium sulfate, cellulose-microcrystalline, cellulose powdered, dextrates,
dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch
pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like.
Surfactants include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants
suitable for use in pharmaceutical dosage forms. These include polyethoxylated fatty acids and
its derivatives, for example polyethylene glycol 400 distearate, polyethylene glycol - 20
dioleate, polyethylene glycol 4 -1 50 mono dilaurate, polyethylene glycol -20 glyceryl stearate;
alcohol - oil transesterification products, for example polyethylene glycol - 6 corn oil;
polyglycerized fatty acids, for example polyglyceryl - 6 pentaoleate; propylene glycol fatty acid
esters,r for example propylene glycol monocaprylate; mono and diglycerides for example
glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives,
for example polyethylene glycol - 20 sorbitan monooleate, sorbitan monolaurate; polyethylene
glycol alkyl ether or phenols, for example polyethylene glycol - 20 cetyl ether, polyethylene
glycol - 10 - 100 nonyl phenol; sugar esters, for example sucrose monopalmitate;
polyoxyethylene - polyoxypropylene block copolymers known as "poloxamer"; ionic surfactants,
for example sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate,
propylene glycol alginate, octyl sulfosuccinate disodium, palmitoyl carnitine; and the like.
Specific examples of lubricants/glidants include colloidal silicon dioxide, stearic acid,
magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty
acid, microcrystalline wax, yellow beeswax, white beeswax, and the like.
Coloring agents include any FDA approved colors for oral use.
The pharmaceutical composition may optionally be coated with functional and/or non-functional
layers comprising film-forming polymers, if desired.
Examples of film-forming polymers include ethylcellulose, hydroxypropyl methylcellulose,
hydroxypropylcellulose, methylcellulose, carboxymethyl cellulose, hydroxymethylcellulose,
hydroxyethylcellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose
acetate phthalate, cellulose acetate trimellitate; waxes such as polyethylene glycol; methacrylic
acid polymers such as Eudragit 8 RL and RS; and the like. Alternatively, commercially
10
available coating compositions comprising film-forming polymers marketed under various trade
The invention is further illustrated by the following examples, which is for illustrative purpose
only and should not be considered as limiting the scope of invention in any way.
Divalproex sodium, lactose, Methocel K-15M CR and Methocel E-5 were blended in a rapid
mixer granulator. The granules were prepared adding the granulation fluid (purified water) to
mixture of drug/polymer/lactose. The resulting granules were dried in a fluidized bed drier and
sieved through suitable sieves. The dried granules were blended with talc, colloidal silicon
dioxide and magnesium stearate and compressed into suitable sized tablets and coated with an
aqueous dispersion of PEG 400 and Opadry.
Table 1: Composition of extended release tablets of divalproex sodium.
In vitro dissolution study
In vitro release of extended release tablets of divalproex sodium as per composition of example
1 was done in 900 ml phosphate buffer (pH 6.8) with 1% sodium lauryl sulphate in USP type I1
apparatus at a paddle speed of 100 rpm. The tablets were kept in sinker basket of lo#. The
results are shown in table 2.
11
Table 2: Drug release profile of extended release formulation.
released from the formulation
While particular formulation has been described above, it will be apparent that various
modifications and combinations of the formulations detailed in the text can be made without
departing from the spirit and scope of the invention. For example, different concentration of
high viscosity grade and low viscosity grade polymers as given in Table 3.
Table 3: Composition of extended release tablets of divalproex sodium (example 2 & 3).
The extended 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.
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.

WE CLAIM:
1. A process for the preparation of an extended release pharmaceutical composition
comprising the steps ofa)
blending a drug capable of dissociating as valproate ion, from 15-50% wlw of a high
viscosity grade hydroxypropyl methylcellulose and from 0.1-10% wlw of a low
viscosity grade hydroxypropyl methylcellulose,
b) optionally granulating the blend,
c) lubricating the blend of step a) or granules of step b), and
d) compressing into or filling into suitable size solid dosage form.
2. The process according to claim 1 wherein drug capable of dissociating as valproate ion
is selected from valproic acid and its pharmaceutically acceptable salts, esters, amides
and the like.
3. The process according to claim 2 wherein valproic acid salt is divalproex sodium.
4. The process according to claim 3 wherein amount of divalproex sodium may vary from
about 10% to about 90% by weight of the total pharmaceutical composition weight.
5. The process according to claim 1 wherein pharmaceutical composition is suitable for
once a day dosing.
6. The process according to claim 1 wherein high viscosity grade hydroxypropyl
methylcellulose is one whose 2% aqueous solution has nominal viscosity greater than
about 10,000 cP.
7. The process according to claim 6 wherein the nominal viscosity is 10,000 to 100,000 cP.
8. The process according to claim 7 wherein the nominal viscosity is 15,000 cP.
9. The process according to claim 1 wherein high viscosity grade hydroxypropyl
methylcellulose is present in the concentration range of about 20-40% wlw.
10. The process according to claim 1 wherein low viscosity grade is one whose 2%
aqueous solution has nominal viscosity less than about 1, 000 cP.
11. The process according to claim 10 wherein the nominal viscosity is 5 to 100 cP.
12. The process according to claim 11 wherein the nominal viscosity is 5 cP.
13. The process according to claim 1 wherein low viscosity grade hydroxypropyl
methylcellulose is selected in the concentration range of 1-5% wlw.
14. The process according to claim 1 wherein pharmaceutical composition is selected from
tablet, capsule and the like.
15. The process according to claim 1 wherein pharmaceutical composition is tablet.
16. The process according to claim 1 wherein extended release pharmaceutical
composition further comprises pharmaceutically inert excipients.
17. The process according to claim 16 wherein pharmaceutically inert excipients is selected
from the group comprising of glidants, lubricants, diluents and binders, and the like.
18. The process according to claim 1 wherein granulation is carried out by a process
selected from wet granulation, dry granulation, melt extrusion techniques and the like.
19. The process according to claim 18 wherein granulation is carried out by wet granulation
technique.
20. The process for the preparation of an extended release pharmaceutical composition
according to claim 19 wherein wet granulation comprises the steps of
a) dry blending a mixture of a drug capable of dissociating as valproate ion, and
high viscosity grade hydroxypropyl methylcellulose and a low viscosity grade
hydroxypropyl methylcellulose;
b) wet granulating the blend from step a);
c) drying and sizing the wet granules;
d) lubricating the granules from step c);
e) compressing into or filling into suitable size solid dosage form; wherein all weight
percentages are based upon the total weight of the dosage form.
21. The process for the preparation of an extended release pharmaceutical composition
according to claim 20 wherein in step e) granules are compressed into solid dosage
form.
22. The process for the preparation of an extended release pharmaceutical composition
according to claim 20 and 21 wherein solid dosage form is tablet.
23. The process for the preparation of an extended release pharmaceutical composition
according to claim 20 wherein in step e) granules are filled into suitable size solid
dosage form.
24. The process for the preparation of an extended release pharmaceutical composition
according to claim 20 and 23 wherein solid dosage form is a capsule.
25. The process for preparation of an extended release pharmaceutical composition
according to claim 1 wherein it is used for treatment of epilepsy, migraine and bipolar
disorders.
26. A process for the preparation of an extended release pharmaceutical composition
comprising the steps ofa)
blending a drug capable of dissociating as valproate ion, from 15-50% wlw of a high
viscosity grade hydroxypropyl methylcellulose and from 0.1-10% wlw of a low
viscosity grade hydroxypropyl methylcellulose,
b) optionally granulating the blend,
c) lubricating the blend of step a) or granules of step b), and
d) compressing into or filling into suitable size solid dosage form
wherein the composition is free of microcrystalline cellulose.
27. The process according to claim 26 wherein drug capable of dissociating as valproate ion
is selected from valproic acid and its pharmaceutically acceptable salts, esters, amides
and the like.
28. The process according to claim 27 wherein valproic acid salt is divalproex sodium.
29. The process according to claim 28 wherein amount of divalproex sodium may vary from
about 10% to about 90% by weight of the total pharmaceutical composition weight.
30. The process according to claim 26 wherein pharmaceutical composition is suitable for
once a day dosing.
31. The process according to claim 26 wherein high viscosity grade hydroxypropyl
methylcellulose is one whose 2% aqueous solution has nominal viscosity greater than
about 10,000 cP.
32. The process according to claim 31 wherein the nominal viscosity is 10,000 to 100,000
cP.
33. The process according to claim 32 wherein the nominal viscosity is 15,000 cP.
34. The process according to claim 26 wherein high viscosity grade hydroxypropyl
rnethylcellulose is present in the concentration range of about 20-40% wlw.
35. The process according to claim 26 wherein low viscosity grade is one whose 2%
aqueous solution has nominal viscosity less than about 1,000 cP.
36. The process according to claim 35 wherein the nominal viscosity is 5 to 100cP.
37. The process according to claim 36 wherein the nominal viscosity is 5 cP.
38. The process according to claim 26 wherein low viscosity grade hydroxypropyl
rnethylcellulose is selected in the concentration range of 1-5% wlw.
39. The process according to claim 26 wherein pharmaceutical composition is selected from
tablet, capsule and the like.
40. The process according to claim 26 wherein pharmaceutical composition is tablet.
41. The process according to claim 26 wherein extended release pharmaceutical
composition further comprises pharmaceutically inert excipients.
42. The process according to claim 41 wherein pharmaceutically inert excipients is selected
from the group comprising of glidants, lubricants, diluents and binders, and the like.
43. The process according to claim 26 wherein granulation is carried out by a process
selected from wet granulation, dry granulation, melt extrusion techniques and the like.
44. The process according to claim 43 wherein granulation is carried out by wet granulation
technique.
45. The process for the preparation of an extended release pharmaceutical composition
according to claim 44 wherein wet granulation comprises the steps of
a) dry blending a mixture of a drug capable of dissociating as valproate ion, and
high viscosity grade hydroxypropyl methylcellulose and a low viscosity grade
hydroxypropyl methylcellulose;
b) wet granulating the blend from step a);
c) drying and sizing the wet granules;
17
d) lubricating the granules from step c);
e) compressing into or filling into suitable size solid dosage form; wherein all weight
percentages are based upon the total weight of the dosage form.
46. The process for the preparation of an extended release pharmaceutical composition
according to claim 45 wherein in step e) granules are compressed into solid dosage
form.
47. The process for the preparation of an extended release pharmaceutical composition
according to claim 45 and 46 wherein solid dosage form is tablet.
48. The process for the preparation of an extended release pharmaceutical composition
according to claim 45 wherein in step e) granules are filled into suitable size solid
dosage form.
49. The process for the preparation of an extended release pharmaceutical composition
according to claim 45 and 48 wherein solid dosage form is a capsule.
50. The process for preparation of an extended release pharmaceutical composition
according to claim 26 wherein it is used for treatment of epilepsy, migraine and bipolar
disorders.
51. The process for preparation of extended release pharmaceutical composition as per the
examples and specifications described herein.
Dated 1 7da~y o~f F ebruary, 2004.
For Ranbaxy Laboratories Limited * (Sushil Kumar 6 a r i )
Company Secretary