FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)

1. TITLE OF THE INVENTION:
PHARMACEUTICAL COMPOSITION COMPRISING PHENYTOIN OR SALTS THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D-4, MIDC, Chikalthana,
Aurangabad (M.S.) INDIA.
3.PREAMBLE TO THE DESCRIPTION
The present invention provides extended release pharmaceutical composition comprising Phenytoin or salt thereof, disintegrant and rate controlling material and the process of preparing the same by wet granulation.
The following specification particularly describes the invention and the manner in which it is to be performed.


4. DESCRIPTION
The present invention provides extended release pharmaceutical composition comprising Phenytoin or salt thereof, disintegrant and rate controlling material and the process of preparing the same by wet granulation.
Phenytoin is used mainly in the prophylactic management of tonic-clonic seizures and partial seizures with complex symptomatology. The drug is also effective in controlling autonomic seizures. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of posttetanic potentiation at synapses. Loss of post-tetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of tonic-clonic (grand mal) seizures. Chemically, it is designated as 5,5-diphenyl-2,4-imidazolidinedione, (Formula I). Commercially it is marketed as Dilantin® extended phenytoin sodium capsules.

Several formulations of phenytoin and phenytoin sodium have been reported in the prior art. Phenytoin sodium is a water soluble chemical moiety and several matrix based pharmaceutical formulations of this compound are disclosed in US


patent no. 4,996,047; 5,474,989; 6,346,270; 6,274,168; 6,620,432; US patent application no. 2002009494; 2006222713; 2006034910 and 2007185180.
Pharmaceutical compositions containing phenytoin sodium based on the osmotic drug deliver system are disclosed in prior art US patent no. 5,876,750; 5,876,750; 5,968,554; 6,110,499 and US application no. 2004191314.
Spheroidal pharmaceutical compositions having phenytoin are disclosed in US patent no. 4,867,985 and 5,516,531. Film coated pharmaceutical compositions of antiepileptic drugs are disclosed in US patent no. 5,863,558.
Despite the availability of different extended release pharmaceutical compositions of phenytoin known in the prior art, there is a need for better compositions that are simple, stable and can confer desired dissolution profile and can be manufactured by simple process.
The present inventors while working on extended release pharmaceutical compositions of phenytoin sodium have surprisingly found that extended release pharmaceutical compositions comprising 30 mg phenytoin or salts thereof, a disintegrant and a rate controlling material.
In one of the aspects of present invention there is provided, an extended release pharmaceutical composition comprising 30 mg of phenytoin or salts thereof in admixture with a disintegrant and rate controlling material.
In yet another aspect of the present invention there is provided, an extended release pharmaceutical composition comprising 30 mg of phenytoin sodium in admixture with a disintegrant and a rate controlling material, wherein the wherein 30% or less amount of phenytoin sodium is released within 30 minutes and 50% or more amount of phenytoin sodium is released after 1 hours and more than 70% of phenytoin sodium is release after 2 hours when the dissolution is


measured using USP Type I apparatus at 50 rpm and using 900 ml of water at 37°C±2.
In yet another aspect of the present invention there is provided, a process for preparing an extended release pharmaceutical composition wherein the said composition is prepared by wet granulating the blend of phenytoin sodium, disintegrant and rate controlling material.
The term "extended release pharmaceutical composition" used herein refers granules, spheroids, pellets, multiparticulates, capsules, tablets, sachets, extended release suspensions, or in any other suitable dosage form incorporating such granules, spheroids, pellets or multiparticulates.
The term "phenytoin or salts thereof" used herein refers to phenytoin sodium. The pharmaceutical composition of this invention contains 25 mg to 75 mg of phenytoin sodium.
The extended release pharmaceutical composition of phenytoin sodium may have dissolution of about 30% or less amount of phenytoin sodium is released within 30 minutes and 50% or more amount of phenytoin sodium is released after 1 hours and more than 70% of phenytoin sodium is release after 2 hours when the dissolution is measured using USP Type I apparatus at 50 rpm and using 900
ml of water at 37°C ±2.
The extended release pharmaceutical composition of phenytoin sodium may be prepared by granulating the blend of phenytoin sodium, disintegrant and rate controlling material using suitable pharmaceutically acceptable solvent. The granules are sized, dried and blended with extragranular excipients comprising glidant/s and lubricant/s. The granules may be formulated as granules, tablet, capsules, sachets and the like.


Suitable pharmaceutically acceptable solvent for the granulation of the blend of phenytoin sodium, disintegrant and rate controlling material may be selected from a group comprising water, isopropyl alcohol, methylene chloride, acetone, dichloromethane, chloroform and the like.
The extended release pharmaceutical composition of phenytoin sodium comprises an alkalizing agent, wherein the said alkalizing agent is capable of maintaining a pH of more than 8 of the 2% aqueous solution of pharmaceutical composition. The percentage w/w of alkalizing agent in the extended release pharmaceutical composition may vary from about 0.001% to about 10.00%. Phenytoin sodium can convert in various degrees to practically insoluble phenytoin within the pH ranges of 1 to 8 during manufacture of the dosage form, during storage of the finished product, and following administration of the pharmaceutical composition to a human. In this pH range, it is possible that a conversion occurs inside or at the surface of the pharmaceutical compositions, thereby retarding dissolution of the phenytoin sodium. The use of an alkaline pH modifier may make it less likely that conversion to insoluble phenytoin. Examples of alkaline pH modifiers may include magnesium oxide, calcium carbonate, magnesium aluminum silicates, and other mineral bases.
The extended release pharmaceutical composition of phenytoin sodium comprises rate-controlling material. The percentage w/w of rate controlling material in the extended release pharmaceutical composition may vary from about 40.00% to about 50.00%. Suitable rate controlling material include, but are not limited to: cellulose ethers (e.g. hydroxypropylmethylcellulose (HPMC), ethylcellulose, hydroxypropylcellulose (HPC), hydroxyethylcellulose and carboxymethylcellulose sodium); polysaccharides (e.g. carageenan, guar gum, xanthan gum, tragacanth and ceratonia); polymethacrylates (e.g. copolymers of acrylic and methacrylic acid esters containing quaternary ammonium groups); cellulose esters (e.g. cellulose acetate); acrylic acid polymers (e.g. carbomers);


waxes (e.g. hydrogenated castor oil, hydrogenated vegetable oil, carnauba wax and microcrystalline wax); alginates (e.g. alginic acid and sodium alginate); and fatty acid derivatives (e.g. glyceryl monostearate and glyceryl palmitostearate).
The extended release pharmaceutical composition of phenytoin sodium comprises a disintegrant. The percentage w/w of a disintegrant in the extended release pharmaceutical composition may vary from about 10.00% to about 15.00%. Suitable disintegrant may be one or more selected from a group of microcrystalline cellulose, croscarmellose sodium, crospovidone, alginic acid, carboxymethyicellulose calcium, carboxymethylcellulose sodium, guar gum, magnesium aluminium silicate, sodium alginate and starches.and the like.
The pharmaceutical composition comprises phenytoin sodium and pharmaceutically acceptable excipients comprising of diluent, binder, disintegrant, lubricant, glidant and the like.
The suitable diluents may be one or more of microcrystalline cellulose, mannitol, starch, lactose monohydrate, pregelatinized starch, sodium starch glycolate and the like.
Suitable binders may be one or more selected from a group of starch, sugars, gums, low molecular weight, polyvinylpyrrolidone and hydroxypropyl cellulose, calcium carbonate, calcium phosphate dibasic (anhydrous and dihydrate) and tribasic, microcrystalline cellulose, silicified microcrystalline cellulose, lactose (anhydrous and monohydrate), magnesium carbonate, maltitol, maltodextrin, maltose, mannitol, sorbitol and the like.
Suitable lubricants may be one or more talc, magnesium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate and sodium benzoate, calcium stearate, glyceryl behenate, glyceryl monostearate,


glyceryl palmitostearate, sodium stearyl fumarate, stearic acid, talc and zinc stearate and the like.
Suitable glidants may be one or more of, calcium phosphate tribasic, powdered cellulose, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate and talc, magnesium stearate and the like.
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 1
The pharmaceutical composition of phenytoin sodium is provided in Table 1.

No Ingredients Quantity (mg) Quantity(%w/w)
1. Phenytoin Sodium 30.00 27.52
2. Magnesium Oxide Light 10.00 9.17
3. HPMC 47.00 43.12
4. Sodium starch glycolate 12.00 11.01
5. Isopropyl Alcohol q.s. -
6. Methylene Chloride q.s. -
7. Colloidal Silicon Dioxide 2.00 1.83
8. Talc 6.00 5.50
9. Magnesium Stearate 2.00 1.83
Total Weight 109.00
Table 1
Procedure:
Weighed accurately 30.00 mg of phenytoin sodium, 10.00 mg of magnesium
oxide and 47.00 mg of hydroxypropylmethylcellulose. A solvent mixture is


prepared by using isopropyl alcohol and methylene chloride. The above blend is granulated with this solvent mixture. The resulting granules are dried, milled and blended with 2.00 mg of colloidal silicon dioxide, 6.00 mg of talc, and 2.00 mg of magnesium stearate. The blended material was filled in size '4' hard gelatin capsules by using a capsule-filling machine.
Example 2
The dissolution profile of the pharmaceutical composition prepared according to the example 1 and commercially marketed extended phenytoin sodium capsule (Dilantin®) is measured using USP Type I apparatus at 50 rpm and using 900 ml of water at 37°C ±2. Table 2 provides the comparative dissolution profile of pharmaceutical composition of example 1 and commercially available formulation Dilantin®.

Cumulative percentage release of Phenytoin sodium
Time (minutes) Dilantin® Example 102751 74
0 30 0 38
60 120 58 76
Table 2


WE CLAIM:
1. An extended release pharmaceutical composition comprising 30 mg of phenytoin or salts thereof, in admixture with a disintegrant and a rate controlling material.
2. An extended release pharmaceutical composition comprising 30 mg of phenytoin or salts thereof, in admixture with a disintegrant and rate controlling material, wherein the wherein 30% or less amount of phenytoin sodium is released within 30 minutes and 50% or more amount of phenytoin sodium is released after 1 hours and more than 70% of phenytoin sodium is release after 2 hours when the dissolution is measured using USP Type I apparatus at 50 rpm and using 900 ml of water at 37°C±2.
3. A process for preparing an extended release pharmaceutical composition wherein the said composition is prepared by wet granulating the blend of phenytoin or salts thereof, disintegrant and rate controlling material.
4. The extended release pharmaceutical composition according to claim 1 and 2 and process according to claim 3, wherein phenytoin or salts thereof comprises phenytoin sodium.
5. The process for preparing an extended release pharmaceutical composition according to claim 3, wherein wet granulation is carried out using either aqueous or non-aqueous solvent system.
6. The extended release pharmaceutical composition according to claim 1 and 2 and process according to claim 3, wherein the pharmaceutical composition comprises an alkalizing agent.


7. The extended release pharmaceutical composition according to claim 1 and 2 and process according to claim 3, the rate controlling material is hydroxypropyl methylcellulose.
8. The extended release pharmaceutical composition according to claim 1 and 2 and process according to claim 3, the disintegrant is sodium starch glycolate.
9. The extended release pharmaceutical composition according to claim 1 and 2 and process according to claim 3, the pharmaceutical composition comprises pharmaceutically acceptable excipients.
10. The extended release pharmaceutical composition according to claim 1 and 2 and process according to claim 3, the pharmaceutical composition is in the form of tablet, capsule, granules, pellets, sachets meant for oral administration.






Abstract
The present invention relates to extended release pharmaceutical composition comprising Phenytoin or salt thereof, disintegrant and rate controlling material. The pharmaceutical composition of the present invention is prepared by wet granulating the blend of phenytoin sodium, disintegrant and rate controlling material.