FIELD OF THE INVENTION
This invention in general relates to a controlled release pharmaceutical composition
comprising Valproic acid or its pharmaceutically acceptable derivatives such as
esters, amides, salts, solvates, polymorphs, enantiomers or mixtures thereof. In
particular, but without restriction to the particular embodiments hereinafter described
in accordance with the best mode of practice, the present invention provides a
controlled release solid oral pharmaceutical composition comprising Divalproex
sodium wherein the process used for the preparation of pharmaceutical composition is
free of sticking during tablet compression.
BACKGROUND OF THE INVENTION
Valproic acid is a synthetic compound with anticonvulsant properties. Its derivatives
are generally used in the treatment of epilepsy. Divalproex sodium is a stable coordination
compound comprised of sodium valproate and Valproic acid in a 1:1 molar
relationship and is formed during partial neutralization of Valproic acid with 0.5
equivalent of sodium hydroxide. It is chemically designated as sodium hydrogen
bis(2-propylpentanoate) and is represented by the following formula:
CHgUrLuH^ — LH — LrUCH^CHo
HO — C ^ 0 N a ©
CHoCHoCHo *~" CH — CHnCHoCHgf n
It is an effective anti-epileptic, anti-migraine drug and is also used in management of
epilepsy, migraine and mania. The active moiety of Divalproex sodium is valproate
ion. Valproic acid and its derivatives have relatively short elimination half-life.
Frequent dosing is essential which reduces patient compliance. Thus, Divalproex
sodium is marketed as once daily extended release tablets in 250 and 500 mg
strengths under the brand name DEPAKOTE ER®. Inactive ingredients in the
DEPAKOTE ER® consist of FD&C Blue No. 1, hypromellose, lactose,
microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol,
silicon dioxide, titanium dioxide, and triacetin. In addition, 500 mg tablets contain
iron oxide and polydextrose.
Valproic acid and its derivatives are either liquid in nature or tend to liquefy quickly
and become sticky due to their hygroscopicity. Due to sticking tendency of Valproic
acid and its derivatives, various problems are encountered during manufacture of
pharmaceutical composition e.g. Divalproex sodium has been known to cause
sticking to die and punch surfaces during tablet compression process. Various
approaches have been employed to circumvent sticking and improve processability of
manufacturing process for preparation of solid oral formulations of Divalproex
sodium.
Patents No. US8980320 and US8652521 are assigned to Toray Industries and relate
to a film coating agent having excellent water vapor barrier properties. These
publications disclose a specialized film coating to overcome deliquescence of
Valproic acid or a pharmacologically acceptable salt thereof.
Patent No. US6419953 is assigned to Abbott Laboratories and discloses use of a
special grade silicon dioxide having a larger average particle size ranging from about
1 micron to about 10 microns to circumvent stickiness of Divalproex sodium.
Patent No. US5185159 is assigned to Sanofi and discloses an orally administrable
controlled release tablet pharmaceutical composition comprising a ratio of about one
mole of Valproic acid to about two moles of sodium valproate. The publication also
discloses addition of precipitated silica to the granules of Divalproex sodium before
compression to avoid sticking to the punches.
3
Patent publication US20080081069 discloses a controlled release formulation of
Divalproex sodium whereby the processing problems such as sticking, hardness or
capping are overcome by using smaller particle size silica having a particle size less
than about 1 micron and specific surface area not less than 70 m2/g.
Patent No. US5169642 is assigned to Abbott Laboratories and discloses a sustainedrelease
drug dosage form comprising granules of Divalproex sodium, Valproic acid or
amides or esters or salts thereof. The patent also discloses use of detackifying agent in
the coating composition to reduce the stickiness or adhesion of the coated drug
granules of Divalproex sodium, Valproic acid or amides or esters or salts thereof.
Patent No. US6752997 is assigned to Taro Pharmaceuticals and discloses a
combination of carbomer with a non-hygroscopic additive to prepare a
pharmaceutical composition comprising a hygroscopic salt of Valproic acid.
Patent No. US5019398 is assigned to Sanofi and discloses a sustained release tablet,
comprising the complex formed between one mole of Valproic acid and one mole of
sodium valproate. The patent also discloses addition of a both lubricating and
absorbing excipient, such as hydrated silica known under the trade name Levilite®to
prevent sticking of Divalproex sodium.
Patent publication US20040037880 discloses an extended release pharmaceutical
composition of Divalproex sodium wherein sticking problem is surmounted by
manufacturing the composition at a temperature of from about 27° C to about 35° C
and a relative humidity of less than about 40%.
Patent publication WO2006011001 discloses an oral controlled release composition
of Divalproex sodium which is manufactured at a temperature of less than about
27°C, and a relative humidity of more than about 40%.
4
- • ft. T£.
- *4 £.
Patent publication US20080057118 discloses a modified release pharmaceutical
composition comprising a granulate comprising Valproic acid. The invention also
discloses improved processability with respect to reduced agglomerate formation
during drug loading by using a solvent mixture of isopropyl alcohol and methylene
chloride.
Most of the cited prior arts either involve use of specialized excipients or controlled
atmospheric conditions which add both to the cost and complexity of manufacturing
process. Furthermore, use of special grade of excipients is not able to overcome
sticking problem satisfactorily. Hence, there is an unmet need in the pharmaceutical
art for an alternate manufacturing process of developing a pharmaceutical
composition of Valproic acid and its derivatives wherein the developed composition
offers desirable formulation technical attributes.
The present inventors have developed an alternate manufacturing process for
pharmaceutical composition of Valproic acid or its pharmaceutically acceptable
esters, amides, salts, solvates, polymorphs, enantiomers or mixtures thereof, wherein
sticking and other manufacturing challenges associated with Valproic acid or its
pharmaceutically acceptable esters, amides, salts, solvates, polymorphs, enantiomers
or mixtures thereof are reduced. Further, the pharmaceutical compositions prepared
according to the manufacturing process of the present invention possess formulation
characteristics comparable to DEPAKOTE ER®.
OBJECTS AND SUMMARY OF THE INVENTION
It is a principal object of the present invention to provide a pharmaceutical
composition comprising Valproic acid or its pharmaceutically acceptable derivatives,
esters, amides, salts, solvates, polymorphs, enantiomers or mixtures thereof with one
or more pharmaceutically acceptable excipient and/or carrier and process for its
preparation.
It is another object of the present invention to provide a solid oral pharmaceutical
composition comprising Valproic acid or its pharmaceutical^ acceptable derivatives,
esters, amides, salts, solvates, polymorphs, enantiomers or mixtures thereof with one
or more pharmaceutical^ acceptable excipient and/or carrier and process for its
preparation.
It is another object of the present invention to provide a high drug load solid oral
pharmaceutical composition comprising Valproic acid or its pharmaceutical^
acceptable derivatives, esters, amides, salts, solvates, polymorphs, enantiomers or
mixtures thereof with one or more pharmaceutical^ acceptable excipient and/or
carrier and process for its preparation.
It is another object of the present invention to provide a solid oral pharmaceutical
composition in the form of a tablet comprising Valproic acid or its pharmaceutical^
acceptable derivatives, esters, amides, salts, solvates, polymorphs, enantiomers or
mixtures thereof with one or more pharmaceutical^ acceptable excipient and/or
carrier and process for their preparation.
It is another object of the present invention to provide a solid oral pharmaceutical
composition in the form of a controlled or modified release tablet comprising
Valproic acid or its pharmaceutical^ acceptable derivatives, esters, amides, salts,
solvates, polymorphs, enantiomers or mixtures thereof with one or more
pharmaceutically acceptable excipient and/or carrier like diluent, binder, disintegrant,
surfactant, lubricant, glidant and co-processed excipients.
Another object of the present invention is to develop an extended release tablet
comprising Divalproex sodium by a manufacturing process which is consistent and
therefore feasible for industrial production, while maintaining stability and
pharmaceutical equivalence to the reference listed drug.
&£..&*£ ©S-- ****- &w± *• A *• - *+&
The following embodiments further describe the objects of the present invention in
accordance with the best mode of practice, however, disclosed invention is not
restricted to the particular embodiments hereinafter described.
One embodiment of the present invention relates to pharmaceutical compositions
comprising Valproic acid or its pharmaceutical^ acceptable derivatives, esters,
amides, salts, solvates, polymorphs, enantiomers or mixtures thereof.
In another embodiment, the present invention provides a process for the preparation
of pharmaceutical compositions of Valproic acid and its derivatives, wherein the
process does not require control of humidity conditions and can be carried out at
ambient atmospheric conditions.
Another embodiment of the present invention includes extended release solid oral
pharmaceutical compositions comprising Valproic acid and its derivatives wherein
the granules used for the composition do not exhibit sticking during compression.
In yet another embodiment, the process used for the manufacture of the
pharmaceutical composition of the present invention involves dry blending drug and
excipients, wet granulation (aqueous or non-aqueous) of the mass, drying the wet
granules to obtain dried granules, optionally milling of the dried granules, adding at
least one lubricant/glidant, swellable clay and optionally other pharmaceutical^
acceptable excipients to the dried milled granules, and compressing the lubricated
granules into tablets or filling in capsules.
In yet another embodiment, the invention relates to high drug load, controlled release
pharmaceutical compositions comprising a pharmacologically effective amount of
Valproic acid or its pharmaceutically acceptable derivatives, esters, amides, salts,
solvates, polymorphs, enantiomers or mixtures thereof present in an amount of from
7
'-JU ^l.©- - W HI - £> ^ A. P =& f- ' *+ £-
about 50% to about 80% by weight, preferably more than 54% by weight. In
particular, the amount of Valproic acid or its pharmaceutically acceptable derivatives,
esters, amides, salts, solvates, polymorphs, enantiomers or mixtures thereof may vary
from about 55% to about 80% by weight, based on the total weight of the
composition.
In yet another embodiment of the invention, controlled release pharmaceutical
composition comprises about 100 to about 1000 mg of Valproic acid or its
derivatives.
Another embodiment of the present invention encompasses a pharmaceutical
composition comprising Valproic acid or its derivatives and a pharmaceutically
acceptable excipient selected from at least one of diluent, binder, disintegrant,
surfactant, lubricant, glidant and co-processed excipients, wherein the granules used
for the composition do not exhibit sticking during compression.
In another embodiment, the present invention includes particle size of Valproic acid
or its derivatives, wherein D90 is less than about 100 ^m.
In further embodiment, present invention includes method of using the
pharmaceutical composition in the management of epilepsy, migraine and mania.
DETAILED DESCRIPTION OF THE INVENTION
The present invention can be more readily understood by reading the following
detailed description of the invention and study of the included examples.
As used herein, the term "composition", as in pharmaceutical composition, is
intended to encompass a drug product comprising Valproic acid or its
pharmaceutically acceptable derivatives, esters, salts, solvates, polymorphs,
8
enantiomers or mixtures thereof, and the other inert ingredient(s) (pharmaceutically
acceptable excipients). Such pharmaceutical compositions are synonymous with
"formulation" and "dosage form". Pharmaceutical compositions of the invention
include, but are not limited to, granules, tablets, capsules, powders and the like.
Preferably, the pharmaceutical composition refers to tablets and capsules. More
preferably, the pharmaceutical composition refers to tablets. Most preferably, the
pharmaceutical composition refers to extended release tablets.
Unless otherwise stated the weight percentages expressed herein are based on the
final weight of the composition or formulation.
"Controlled release composition" as used herein means a pharmaceutical composition
which releases the drug substance at a slower rate than from an immediate release
composition. The term "Controlled release composition" is used herein
interchangeably with prolonged release composition, extended release composition,
modified release composition, sustained release composition, retard release
composition and delayed release composition. Similarly, the material used to modify
the said release of the drug from composition are termed herein as extended release
material, modified release material, sustained release material, delayed release
material and the like, all having the same meaning.
The term "High drug load" as used herein, refers to more than 50% by weight of
Valproic acid or its pharmaceutically acceptable derivatives, esters, amides, salts,
solvates, polymorphs, enantiomers or mixtures thereof based on the total weight of
the composition. Preferably the amount of Valproic acid or its pharmaceutically
acceptable derivatives, esters, amides, salts, solvates, polymorphs, enantiomers or
mixtures thereof is more than 54% by weight. In particular, the amount of Valproic
acid or its pharmaceutically acceptable derivatives, esters, amides, salts, solvates,
9
polymorphs, enantiomers or mixtures thereof may vary from about 55% to about 80%
by weight, based on the total weight of the composition.
As used herein, the term "about" means ± approximately 20% of the indicated value,
such that "about 10 percent" indicates approximately 08 to 12 percent.
The term "excipient" means a pharmacologically inactive component such as a
diluent, binder, disintegrant, surfactant, lubricant, glidant and the like. The excipients
that are useful in preparing a pharmaceutical composition are generally safe, nontoxic
and are acceptable for veterinary as well as human pharmaceutical use.
Reference to an excipient includes both one and more than one such excipient. Coprocessed
excipients are also covered under the scope of present invention. Further,
excipient may be in the form of powders or in the form of dispersion. Combination of
excipients performing the same function may also be used to achieve desired
formulation characteristics.
The term "swellable clay" as used herein includes layered clays (such as smectites),
porous fibrous clay minerals, and synthetic clay materials related in structure to
layered clays and porous fibrous clays. Swellable clay may be used intragranularly or
extragranularly or in both. Preferably, the swellable clay is used extragranularly.
The term "layered clays" as used herein includes substantially homogeneous layered
clays and mixtures thereof, and interstratified or mixed layered clays. Substantially
homogeneous layered clays includes the smectite group for example dioctahedral and
trioctahedral types. Examples of dioctahedral smectites are the montmorillonite group
(montmorillonoids); magnesium and other (e.g. calcium) aluminium silicates such as
Veegum in its various grades e.g. Veegum, Veegum HV, Veegum F. and Veegum
WG); almasilate; fullers earth (e.g. Surrey finest); American fullers earth; bentonite;
beidellite; cheto montmorillonite, Wyoming montmorillonite, Utah montmorillonite;
10
Tatalia and Chambers montmonllomtes; and iron rich smectites such as nontrite (e.g.
Garfield nontronite) and ferrian smectites.
The term "interstratified or mixed layer clays", as used herein includes clays
involving different layers arranged in a regular or irregular structure. The most
common examples of such clays have generally two components in substantially
equal proportions and have been given mineral names such as rectorite (micasmectite),
hydrobiotite (biotite-vermiculite), corrensiten (chlorite-smectite) allettite
(talc-saponite). More irregular arrangements include illite-smectite, chlorite-smectite,
and kaolinite-smectite. Further examples of interstratified clays are tosudite,
tarasovite, allevardite, Japanese bentonite ("acid clays"), AWAZU acid clay, and
kaolinite-smectite. Other mixed layer clays may include one or more of the following
minerals: clinchlore, chamosite, nimite, thuringite, sudoite, and cookeite. Mixed layer
smectities are also known e.g. interdispersed montmorillonite and beidellite layers.
The layers of mixed layer clays may be homogeneous or non-homogeneous.
The term "porous fibrous clays" includes palygorskite and sepiolite such as, for
example attapulgite and American fuller's earth.
The term "synthetic clay materials" as used herein includes materials related in
structure to layered clays and porous fibrous clays such as synthetic hectorite (lithium
magnesium sodium silicate) for example laponite®
As used in this specification, the singular forms "a", "an", and "the" include plural
references unless the context clearly dictates otherwise. Thus, for example, a
reference to "a process" includes one or more process, and/or steps of the type
described herein and/or which will become apparent to those persons skilled in the art
upon reading this disclosure and so forth.
11
The present invention relates to pharmaceutical composition of Valproic acid or its
pharmaceutically acceptable derivatives, esters, salts, solvates, polymorphs,
enantiomers or mixtures thereof Preferably, salt of Valproic acid is Divalproex
sodium.
In another embodiment the present invention includes particle size of Valproic acid or
its salt, wherein D9ois less than 100 urn. The particle size can be measured by suitable
techniques such as Laser light scattering (e.g. Malvern Light Scattering), Coulter
counter, microscopy and any other technique known in the art. This particle size can
be obtained either by the final step during the manufacture of the Divalproex sodium
or by the use of conventional micronizing techniques after the conventional
crystallization procedure(s).
In another embodiment of the invention, the pharmaceutical composition comprising
Valproic acid or its derivatives is prepared by using wet granulation. Any
pharmaceutically acceptable granulating agent can be used for wet granulation.
Suitable granulating agents include water, esters such as ethyl acetate; ketones such
as acetone; alcohols such as methanol, ethanol, isopropanol, butanol, and
combinations thereof. Preferably, the granulating agent used during wet granulation is
water.
In another embodiment of the invention, wet granulation can be performed using
Rapid mixer granulator, Fluid bed granulator, Planetary mixer and the like.
One embodiment of the invention encompasses a pharmaceutical composition
comprising Valproic acid or a salt thereof and a pharmaceutically acceptable
excipient selected from at least one of diluent, binder, disintegrant, surfactant,
lubricant, and glidant, wherein composition is prepared by using water as the
granulating agent.
12
Diluents are substances which usually provide bulk to the composition. Various
useful fillers or diluents include, but are not limited to calcium carbonate, calcium
phosphate, dibasic anhydrous, calcium phosphate, dibasic dihydrate, calcium
phosphate tribasic, calcium sulphate, cellulose powdered, silicified microcrystailine
cellulose, cellulose acetate, compressible sugar, confectioner's sugar, dextrates,
dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide,
maltodextrin, maltose, mannitol, microcrystailine cellulose, polydextrose,
simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelatinized starch,
sucrose, trehalose and xylitol, or mixtures thereof. The amount of diluent(s) may
vary within a range of from about 0% to about 50% by weight based on the total
weight of the composition.
Binders impart cohesiveness to formulation. Various useful binders include, but are
not limited to acacia, alginic acid, carbomer, carboxymethylcellulose sodium,
ceratonia, cottonseed oil, dextrin, dextrose, gelatin, guar gum, hydrogenated
vegetable oil type 1, hydroxyethyl cellulose, hydroxyethyhnethyl cellulose,
hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hypromellose,
magnesium aluminium silicate, maltodextrin, maltose, methylcellulose,
microcrystalline cellulose, polydextrose, polyethylene oxide, polymethacrylates,
povidone, sodium alginate, starch, pregelatinised starch, stearic acid, sucrose and
zein, or mixtures thereof. The amount of binder(s) may vary within a range of from
about 0% to 40% by weight based on the total weight of the composition.
Various useful disintegrants include, but are not limited to, alginic acid, calcium
phosphate, tribasic, carboxymethylcellulose calcium, carboxymethylcellulose sodium,
colloidal silicon dioxide, croscarmellose sodium, crospovidone, docusate sodium,
guar gum, low substituted hydroxypropyl cellulose, magnesium aluminun silicate,
methylcellulose, microcrystalline cellulose, povidone, sodium alginate, sodium starch
13
glycolate, polacrilin potassium, silicifled microcrystalline cellulose, starch or pregelatinized
starch, or mixtures thereof. The amount of disintegrant(s) may vary within
a range of from about 0% to 20% by weight based on the total weight of the
composition.
Lubricants are added to a pharmaceutical composition for ease in processing, to
prevent adhesion to the equipment during processing. Lubricants used in the
composition include lubricants commonly used in solid pharmaceutical compositions.
Lubricants used in the composition include, but are not limited to, calcium stearate,
glycerine monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated
castor oil, hydrogenated vegetable oil 0 type I, magnesium lauryl sulphate,
magnesium stearate, medium-chain triglycerides, poloxamer, polyethylene 5 glycol,
sodium benzoate, sodium chloride, sodium lauryl sulphate, sodium stearyl fumarate,
stearic acid, talc, sucrose stearate and zinc stearate or mixtures thereof. Preferably,
the amount of lubricant(s) may vary within a range of from about 0.1% to about 5%
by weight based on the total weight of the composition. The amount of lubricant(s)
may vary within a range of from about 0.1% to about 10% by weight based on the
total weight of the composition.
Glidants improve flowability and accuracy of dosing. Glidants used in the
composition include, but are not limited to, tribasic calcium phosphate, calcium
silicate, cellulose, powdered, colloidal silicon dioxide, magnesium silicate,
magnesium trisilicate, starch and talc or mixtures thereof. The amount of glidant may
vary within ranges of from about 0.1% to about 10% by weight based on the total
weight of the composition.
Various directly compressible grades of pharmaceutically acceptable excipients are
also contemplated within the scope of the present invention. Directly compressible
excipients include but are not limited to anhydrous lactose, spray dried lactose,
14
dibasic calcium phosphate dihydrate, silicified microcrystalline cellulose, powdered
cellulose, low substituted hydroxypropyl cellulose, dextrose, sucrose, modified
dextrin + sucrose, spray dried maltose, maltodextrin, mannitol, xylitol, sorbitol,
lactitol, starch, pregelatinized starch etc.
Pharmaceutically acceptable surfactants include, but are limited to both non-ionic and
ionic surfactants suitable for use in pharmaceutical dosage forms. Ionic surfactants
may include one or more of anionic, cationic or zwitterionic surfactants. Examples
include, but are not limited to, sodium lauryl sulfate, monooleate, monolaurate,
monopalmitate, monostearate or another ester of olyoxyethylene sorbitane, sodium
dioctylsulfosuccinate (DOSS), lecithin, stearyic alcohol, cetostearylic alcohol,
cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides,
poloxamer, or any other commercially available co-processed surfactant like
SEP1TRAP® 80 or SEPITRAP® 4000 and mixtures thereof.
In another embodiment of the invention, the pharmaceutical compositions are
formulated into solid oral pharmaceutical dosage forms. Solid oral pharmaceutical
dosage forms include, but are not limited to, tablets, capsules, powders, granules and
sachets. Preferably, the solid pharmaceutical dosage form is a tablet or capsule. More
preferably, the solid pharmaceutical dosage form is a tablet. Most preferably, the
solid pharmaceutical dosage form is an extended release tablet.
In yet another embodiment of the invention, the pharmaceutical compositions
comprise from about 100 to about 1000 mg of Valproic acid or its derivative such as
Divalproex sodium. Preferably, the pharmaceutical compositions comprise about 250
to about 500 mg of Valproic acid or its salt such as Divalproex sodium.
The final formulations may be coated or uncoated. For coating, additional excipients
such as film-forming polymers, plasticizers, antiadherents and opacifiers are used.
15
Various film forming agents include but are not limited to cellulose derivatives such
as soluble alkyl- or hydroalkylcellulose derivatives such as methylcellulose,
hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxymethylethyl cellulose, hydroxypropyl . methylcellulose, sodium
carboxymethyl cellulose, etc., acidic cellulose derivatives such as cellulose acetate
phthalate, cellulose acetate trimellitate, and methylhydroxypropylcellulose phthalate,
polyvinyl acetate phthalate, etc., insoluble cellulose derivative such as ethylcellulose
and the like, dextrins, starches and starch derivatives, polymers based on
carbohydrates and derivatives thereof, natural gums such as gum Arabic, xanthans,
alginates, polyacrylic acid, polyvinyl alcohol, polyvinyl acetate,
polyvinylpyrrolidone, polymethacrylates and derivatives thereof (Eudragit™),
chitosan and derivatives thereof, shellac and derivatives thereof, waxes and fat
substances. ,
If desired, the films may contain additional adjuvants for coating such as plasticizers,
polishing agents, colorants, pigments, antifoaming agents, opacifiers, antisticking
agents, and the like.
As an alternative to the above coating ingredients, pre-formulated coating products
such as Opadry™ may be used. The products that are sold in dry form require only
mixing with a liquid before use. These may also be available as ready to use coating
solutions.
Another embodiment of the present invention includes method of using the
pharmaceutical composition in the management of epilepsy, migraine and mania.
Having described the invention with reference to certain preferred embodiments,
other embodiments will become apparent to one skilled in the art from consideration
16
of the specification. The invention is further defined by reference to the following
examples describing in detail method for the preparation and testing of
pharmaceutical composition comprising Divalproex sodium. It will be apparent to
those skilled in the art that many modifications, both to materials and methods, may
be practiced without departing from the scope of the invention. Following examples
are set out to illustrate the invention and do not limit the scope of the present
invention.
EXAMPLES
The following examples are intended to further illustrate certain preferred
embodiments of the invention and are not limiting in nature.
Example I (Tablet composition)
Divalproex sodium extended release tablets (500 mg) were prepared by wet
granulation method by using quantitative formula as given in Table 1:
TABLE 1
Ingredients
Divalproex sodium
Lactose
HPMC
Silicon dioxide
Magnesium aluminum metasilicate
Microcrystalline cellulose
Talc
Magnesium stearate
Purified Water USP
Opadry
% (wAv)
66.00
1.50
23.00
1.00
1.50
6.00
0.50
0.50-
q.s.
2.50
The processing steps involved in the manufacturing of extended release tablet dosage
form are given below:
17
B'EL.fei-1 E*S - 8 - 4 - 2-S-A. # *#•-**&
fe-B
i) Divalproex sodium, Lactose and HPMC were sifted through a suitable sieve.
ii) The sifted blend of step i was mixed for a suitable time.
iii) Step ii blend was granulated using water as granulating medium.
iv) The granules of step iii were dried and the dried granules were sifted/milled
through a suitable sieve/mill.
v) Microcrystalline cellulose, Silicon Dioxide, Talc and Magnesium aluminum
metasilicate were sifted through a suitable sieve and added to step iv granules
and mixed for a suitable time.
vi) Magnesium stearate was sifted through a suitable sieve and mixed with step v
blend for a suitable time.
vii) The blend of step vi was compressed into tablets using suitable punches.
viii) The tablets of step vii were film coated using opadry coating solution.
Example II
The standardized method and equipment for testing dissolution time is provided in
United States Pharmacopeia (USP). The dissolution profile of 500 mg tablets
prepared using quantitative composition as given in Table 1 was measured using Test
2 in two stages. In acid stage, dissolution test was performed using 500 ml of 0.1 N
HC1 in United States Pharmacopeia (USP)-National Formulary (NF) (USP 40/NF 37),
chapter 711 in USP II apparatus (paddle, with helix sinker if necessary) at a
temperature of 37±0.5°C and a rotation speed of 100 revolutions per minute for forty
five minutes. In buffer stage: dissolution test was performed using 900 ml of pH 5.5
phosphate buffer having 75mM sodium lauryl sulphate in United States
Pharmacopeia (USP)-National Formulary (NF) (USP 40/NF 35), chapter 711 in USP
II apparatus (paddle, with helix sinker if necessary) at a temperature of 37±0.5°C and
a rotation speed of 100 revolutions per minute, sampling was performed at 3, 9, 12
and 21 hours. The dissolution test was also conducted on the reference formulation
DEPAKOTE ER® Tablets in comparison to a solid oral tablet dosage form prepared
using quantitative composition as given in Table 1. The results of the dissolution test
18
of DEPAKOTE ER® Tablets and solid oral tablet dosage form of the present
invention are tabulated in Table 2.
TABLE 2
Time (Hours)
1
3
9
12
21
f2 value
% drug released
DEPAKOTE ER® tablets
2
21
63
83
97
—
Example I
6
23
57
74
102
65.00
Dissolution profile of tablets prepared using quantitative composition as given in
Table 1 was similar to dissolution profile of DEPAKOTE ER ® tablets with f2 value
of 65.
Many modifications of this invention can be made without departing from its spirit
and scope, as will be evident to those skilled in the art. The specific embodiments
described herein are provided by way of example only, and the invention is to be
limited only by the terms of the appended claims, along with the full scope of
equivalents to which such claims are entitled.

WE CLAIM:
1. A high drug load controlled release pharmaceutical composition comprising
Valproic acid or its pharmaceutically acceptable derivatives, esters, amides, salts,
solvates, polymorphs, enantiomers or mixtures thereof, wherein:
a) the composition comprises swellable clay
b) granules used for the composition do not exhibit sticking during compression.
2. The pharmaceutical composition as claimed in claim 1, wherein swellable clay is
selected from the group consisting of magnesium aluminium silicate, calcium
aluminium silicate, lithium magnesium sodium silicate, bentonite, Kaolin and
attapulgite.
3. The pharmaceutical composition as claimed in claim 2, wherein Valproic acid or
its pharmaceutically acceptable derivatives, esters, amides, salts, solvates,
polymorphs, enantiomers or mixtures thereof is present in an amount ranging from
about 100 mg to about 500 mg.
4. The pharmaceutical composition as claimed in claim 3, wherein Valproic acid or
its pharmaceutically acceptable derivatives, esters, amides, salts, solvates,
polymorphs, enantiomers or mixtures thereof is present in an amount of more than
about 54% by weight.
5. The pharmaceutical composition as claimed in claim 4, wherein Valproic acid or
its pharmaceutically acceptable derivatives, esters, amides, salts, solvates,
polymorphs, enantiomers or mixtures thereof is present in an amount of from about
55% to about 80% by weight.
6. The pharmaceutical composition as claimed in claim 5, wherein Valproic acid or
its pharmaceutically acceptable derivatives, esters, amides, salts, solvates,
polymorphs, enantiomers or mixtures thereof has a particle size distribution such that
D90 is less than about 100 ^im.
7. The pharmaceutical dosage form as claimed in claim 1-6, wherein the derivative of
Valproic acid is Divalproex sodium.
8. The pharmaceutical composition as claimed in claim 1-7, wherein the composition
comprises at least one or more pharmaceutically acceptable excipient.
9. The pharmaceutical composition as claimed in claim 8, wherein the
pharmaceutically acceptable excipient is selected from diluent, binder, disintegrant,
surfactant, lubricant, and glidant.
10. A process for the preparation of a high drug load controlled release
pharmaceutical composition comprising Valproic acid or its pharmaceutically
acceptable derivatives, esters, amides, salts, solvates, polymorphs, enantiomers or
mixtures thereof, the process comprising:
(a) blending the drug and at least one pharmaceutically acceptable excipient;
(b) wet granulating the blend of step (a);
(c) drying the wet granules to obtain dried granules;
(d) optionally milling the dried granules;
(e) lubricating the granules obtained in step (d) with at least one lubricant/glidant
and swellable clay
(f) compressing the lubricated granules into tablets or filling in capsules