FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
TITLE OF THE INVENTION:
PHARMACEUTICAL COMPOSITIONS OF DIVALPROEX SODIUM.
APPLICANT(S):
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh Hall, Ahmedabad 380 009,
Gujarat, India.
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a process for preparing a modified release pharmaceutical compositions of valproic acid and/or pharmaceutically acceptable salt thereof, with pharmaceutically acceptable excipients.
Divalproex sodium is a stable co-ordination compound having sodium valproate and valproic acid in a 1:1 molar ratio, formed by partially neutralizing valproic acid with sodium hydroxide. Divalproex sodium (shown in Formula I) is chemically designated as sodium hydrogen bis(2propylpentanoate).

Divalproex sodium is effective in treating epilepsy, migraine and mania in bipolar disorder. It dissociates within the gastrointestinal tract into valproate ion, which is responsible for eliciting the pharmacological response.
The marketed composition of DEPAKOTE® SPRINKLE CAPSULES (Divalproex sodium coated particles in capsules) comprises cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1 gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.
US Pat. No. 5,169,642 discloses a sustained release dosage form of divalproex sodium in which the drug granules are coated with a sustained-release coating of ethylcellulose and/or a methacrylic methylester together with a plasticizer and a detackifying agent.

US Patent application No. 20080057118 describes a modified release pharmaceutical composition comprising divalproex sodium granules coated with hydrophilic polymer. Further, the drug layer may be coated on inert cores with subsequent layers comprising modified release polymer. The divalproex sodium coated particles can be compressed into tablets or filled into capsules.
US Patent application No. 20080085304 discloses a sustained release formulation comprising divalproex sodium and a hydrophilic gum. Further it may be coated with a hydrophobic polymer and/or a plasticizer. The drug core described therein can be prepared by granulation or spheronizing mixed powders of drug and at least one spheronizing agent (like MCC).
US Patent application No. 20090004281 discloses a pharmaceutical composition comprising: at least one pellet comprising drug in the core which is at least partially coated with at least one osmotic subcoat, and at least one outer coat which at least partially coats the osmotic subcoat. The pellets can be manufactured by extrusion/spheronization, granulation or pelletization.
The prior art compositions result into irregular shaped particles and fail to present reproducible dissolution profiles. Prior art compositions also suffer from the problem of dose dumping and inadequate gastric-resistance.
The present inventors while working on the divalproex sodium compositions have surprisingly found that if the granulation step is followed by extrusion-spheronization of the wet mass, it results into uniform sized spherical pellets. These pellets possess better processability, handling characteristics and facilitate uniform coating.
Further, the inventors also have surprisingly found that if the pellets are coated with a rate-controlling polymer such as polyvinyl acetate (PVA) in the form of dispersion (Kollicoat SR 30D) the resulting coated pellets are bio-equivalent with Innovator product (DEPAKOTE® SPRINKLE CAPSULES).

In one aspect of the present invention there is provided a process for preparing a modified release pharmaceutical composition of divalproex sodium, comprising the steps of:
(a) Blending the divalproex sodium with a diluent and a binder;
(b) Granulating the dry mixture of step (a) with purified water;
(c) Subjecting the wet mass of step (b) to extrusion-spheronization process;
(d) Coating the pellets of step (c) with coating solution comprising a rate-controlling polymer;
(e) Optionally filling the coated pellets of step (d) into capsules.
Suitable diluents that provide good extrudability and aid in spheronization include spheronizing agents like microcrystalline cellulose, sodium carboxymefhyl cellulose, pregelatinized starch, glyceryl monostearate, glyceryl behenate, glyceryl dibehenate, glyceryl palmitostearate, hydrogenated castor oil, magnesium stearate, calcium stearate, mannitol, sorbitol, xylitol, stearic acid, palmitic acid, sodium lauryl sulfate, PEG-32 distearate, PEG-150 distearate, cetostearyl alcohol, carnauba wax, white wax, paraffin wax, povidone, a cellulose ether, a polyvinyl alcohol, and combinations thereof. The preferred diluent is microcrystalline cellulose.
Suitable binders may include, but not limited to celluloses such as hydroxypropyl cellulose, hydroxy ethyl cellulose, hydroxypropyl methylcellulose, methylcellulose, povidone, copovidone, starch, and other materials known to have cohesive and desirable binding properties. The preferred binder is copovidone (also known as Plasdone S630).
The wet granulation in the present invention can be carried out in a fluidized bed granulator or rapid mixer granulator or planetary mixer. The preferred granulating vehicle is purified water.
The rate-controlling polymers include water-insoluble polymers selected from, but are not limited to polyvinyl acetate, ethyl cellulose, cellulose acetate, methacrylic copolymers; the waxes selected from hydrogenated castor oil, hydrogenated vegetable oil, bees wax, carnauba wax, microcrystalline wax, fatty acid esters such as glyceryl monostearate; glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate, and the like. The preferred rate controlling polymer is polyvinyl acetate (PVA) in the form of dispersion (Kollicoat® SR 30 D).

The coating solution in addition to rate-controlling polymer dispersion may further comprise other pharmaceutically acceptable excipients such as plasticizers, detackifying agents and vehicles.
Plasticizers useful in the coating composition can include castor oil, propylene glycol, polyethylene glycol, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, tributyl citrate. and the like. The preferred plasticizer is polyethylene glycol 400.
The detackifying agents that reduce the stickiness or adhesion in the coating composition, include magnesium stearate, talc, titanium dioxide, silica gel, and the like. The preferred detackifying agent is talc.
The vehicle used in the coating solution is preferably purified water.
The coated divalproex sodium pellets are lubricated with talc, and optionally filled into capsules.
The pharmaceutical composition of the present invention is meant for oral administration and it can be prepared as granules, pellets, beads, spheres, particulates and capsules.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLE

No. Ingredients %W/W
1. Divalproex Sodium 49.01
2. Microcrystalline cellulose 50.01
3. Copovidone 0.98
4. Purified Water q.S.
Theoretical Weight 100.00
COATING of DRUG PELLETS
5. Drug pellets 76.16
6. PVA dispersion (Kollicoat® SR 30 D) 15.23
7. Talc 6.09
8. Polyethylene Glycol 400 1.52
9. Purified Water q.s.
LUBRICATION
10. Talc q.s.
Theoretical Weight 100
The composition of above example can be prepared by a process comprising following steps:
(a) Blending the divalproex sodium with micro crystal line cellulose and copovidone;
(b) Granulating the dry mixture of step (a) with purified water;
(c) Subjecting the wet mass of step (b) to extrusion - spheronization process;
(d) Coating the pellets of step (c) with coating solution comprising PVA dispersion;
(e) Lubricating the coated pellets of step (d) with talc.

Claims:
1. A process for preparing a modified release pharmaceutical composition of divalproex sodium,
comprising the steps of:
(a) Blending the divalproex sodium with a diluent and a binder;
(b) Granulating the dry mixture of step (a) with purified water;
(c) Subjecting the wet mass of step (b) to extrusion - spheronization process;
(d) Coating the pellets of step (c) with coating solution comprising a rate-controlling polymer;
(e) Optionally filling the coated pellets of step (d) into capsules.

2. The process according to claim 1, wherein the diluent is microcrystalline cellulose.
3. The process according to claim 1, wherein the binder is copovidone.
4. The process according to claim 1, wherein the wet granulation is carried out in a fluidized bed granulator or a rapid mixer granulator or planetary mixer.
5. The process according to claim 1, wherein the rate-controlling polymer is polyvinyl acetate.
6. The process according to claim I, wherein the coating solution in addition to a rate-controlling polymer dispersion may further comprise other pharmaceutically acceptable excipients such as plasticizers, detackifying agents and vehicles.
7. A process for preparing a modified release pharmaceutical composition of divalproex sodium as substantially described and exemplified herein.