Title of Invention	"A PROCESS FOR PREPARING AN EXTENDED RELEASE FORMULATION OF PHENYTOIN SODIUM"
Abstract	The present invention relates to extended release pharmaceutical composition of phenytoin sodium comprising a blend of phenytoin sodium and hydrophilic polymer(s). It also relates to a process for preparing the extended release pharmaceutical composition.

Full Text

The present invention relates to a process for preparing extended release pharmaceutical composition comprising a blend of phenytoin sodium and hydrophilic polymer(s). Phenytoin sodium is a known antiepileptic compound. Phenytoin, phenytoin sodium and procedures for their manufacture are well known, for example Kao et al., US Patent No. 4,696,814; Fawzi et. Al., US Patent No. 4,642,316 and Henze et al., US Patent No. 2,409,754, all of which are incorporated herein by reference. Phenytoin sodium is commercially available as 30 mg and 100 mg capsules marketed by Parke Davis, sold under the brand name Dilantin®. These capsules contain lactose, confectioner's sugar, talc, magnesium stearate and phenytoin sodium as loose powder. The capsules are sealed with a band. Drug release problems associated with these pharmaceutical compositions have resulted in numerous recalls for failure to meet dissolution requirements. Moreover, Dilantin® requires multiple, repetitive dosing intervals. A dose of 100 mg of Dilantin requires a capsule size #3 (230 mg), therefore in order to incorporate a larger dose of the drug using Dilantin capsules, the size of the capsules would have to increased, thus making it patient incompliant. Extended release oral capsules containing 200mg and 300mg phenytoin sodium are also available commercially under the brand name Phenytek®. These capsules contain phenytoin sodium in an erodible matrix, comprising povidone, hydroxyethyl cellulose, microcrystalline cellulose, magnesium oxide, colloidal silicon dioxide and magnesium stearate as described in Mylan's US Patent No. 6,274,168 and its continuation in part application US 20010043945. These extended release oral capsules are prepared by mixing phenytoin sodium with diluents, binder(s), alkaline pH modifier(s), or a combination thereof, and then granulating with an aqueous solvent, which may or may not contain a binder(s). The dried granules are milled and finally blended with other excipients. The blend is filled into capsules or compressed into tablets. The tablets may then be additionally coated and/or filled into capsules. The present invention provides a simple, economical and easy process for manufacturing extended release phenytoin oral capsules. Thus, in the present invention extended-release capsules are formulated by employing a simple process, which does not involve extra steps of granulation, drying, milling, compression and band-sealing after filling in capsules and is still capable of imparting extended-release properties. Accordingly, it is an object of the present invention to provide an extended release formulation for phenytoin sodium that can deliver 100-300mg of the drug in a single unit dosage form without batch-to-batch variation. It is another object of the present invention to provide an extended release formulation for phenytoin sodium using a simple process, which can be easily adapted for lower or higher strengths. It is a further object of the present invention to provide an extended release formulation for phenytoin sodium that contains a high dose medicament and is of an acceptable size, convenient for oral administration. In the present invention the above objectives have been achieved by filling a blend of phenytoin sodium and hydrophilic polymer(s) as powder into hard gelatin capsules. Powder filling eliminates the steps of granulation, drying, milling and compaction thus making the process simple, cost effective and time saving. The use of hydrophilic polymers effectively controls the release rate of the drug without significant batch-to-batch variability initially as well as after a storage period of 3 months at accelerated conditions of temperature and humidity. Further, filling of blend of the present invention into capsules does not require an additional process of band sealing. Therefore, the extended release pharmaceutical composition of the present invention comprises a blend of phenytoin sodium and hydrophilic polymer(s), wherein the blend forms a matrix on coming in contact with aqueous media, and wherein said matrix retains at least about 20% phenytoin after 1 hour. The hydrophilic polymer is selected in such a way that it brings about batch-to-batch reproducibility in the dissolution profile of the pharmaceutical composition of the present invention. While not intending to be limited by any theory, it is believed that upon oral ingestion of the extended-release powder-filled capsules of the invention, in an acid aqueous environment, such as the stomach, water penetrates the capsule shell initiating surface hydration of the hydrophilic polymer blend to form a gel layer. Erosion of the gel layer gradually exposes more dry powder that hydrates to form a matrix. Drug is then released by diffusion through the matrix over an extended period of time. The matrix formed retains at least about 20% phenytoin after 1 hour. Preferably the said matrix retains at least about 30% phenytoin after 1 hour and more preferably, the said matrix retains at least about 60% phenytoin after I hour. The term about herein means ± 5 % of the given value. The pharmaceutically acceptable hydrophilic polymers used in according with the present invention comprise of carbohydrate gums, cellulose ethers, acrylic acid polymers or mixtures thereof. Carbohydrate gums may be selected from amongst xanthan gum, tragacanth gum, gum karaya, guar gum, acacia gellan gum, locust bean gum and the like. These gums upon contact with the gastrointestinal fluid form a viscous gel and sustain the release of the drug even when used in very small amounts. The cellulose ethers used in accordance with the present invention include methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl ethyl cellulose, hydroxypropyl butyl cellulose and the like. The acrylic acid polymers may be carboxyvinyl polymer such as those available under the brand name Carbopol (B.F. Goodrich, USA). The hydrophilic polymer(s) may be present in an amount from about 10% to 30% w/w of the composition. The use of small amounts of hydrophilic polymers ensures low total weight of the dosage form and therefore provides the therapeutic dosage of the drug in a single unit as compared to two or three units which need to be administered while using commercially available Dilantin® 100mg capsules. The present invention provides obvious benefits with respect to patient convenience and therefore better patient compliance. Phenytoin sodium is monosodium salt of 5,5-diphenyl hydantoinate, described on page 1259 of the Twelfth Edition of the Merck Index, which is incorporated herein by reference. It is useful as an anticonvulsant, effective for the treatment of generalized tonic-clonic seizures in adults and children and is also useful in the treatment of simple and complex partial seizures. Phenytoin sodium used in accordance with the present invention comprises about 40% to about 70% w/w of the total formulation weight. In addition to the active and hydrophilic polymer(s), the composition of the present invention may contain other excipients, which act in one or more capacities as diluents, lubricants or glidants. Diluents can be selected from any conventional diluents such as microcrystalline cellulose, powdered cellulose, lactose, starch, mannitol, calcium hydrogen phosphate and dextrose. Lubricants of the present invention may be selected from talc, magnesium stearate, calcium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate and sodium benzoate. Glidants may be selected from the colloidal silicon dioxide (Aerosil) or talc. The blend of active, polymer and excipient may be prepared using tumbler mixers, ribbon mixers, twin shell V-blenders, double cone blenders, planetary mixers or fluid bed mixers. This blend is then filled into hard gelatin capsules using either gravity wherein the powder blend is filled into the capsule due to its natural flow; or partial compression, so that weak slugs are formed inside a calibrated punch prior to being deposited into the capsule. Alternatively, the lubricants and glidants may be added after thorough blending of other components of the formulation. This blend is passed through No. 30 mesh screen and filled into hard gelatin capsules. Accordingly, the present invention relates to a process for preparing extended release pharmaceutical compositions of phenytoin sodium, comprising: a) blending 40 to 70% by weight of phenytoin sodium, 10 to 30% by weight of hydrophilic polymers selected from the group consisting of carbohydrate gum, cellulose ether, acrylic acid polymer or mixtures thereof and 5 to 12% of other pharmaceutically acceptable excipients as described herein, and b) filling the blend in capsules, wherein the blend forms a matrix on coming in contact with aqueous media, and wherein said matrix retains at least 20% of phenytoin after 1 hour. The extended release phenytoin capsules of the present invention release the drug both initially and after storage for 3 months at 40 degrees centigrade / 75% relative humidity over a two hour period when measured in vitro by dissolution testing. Dissolution is carried out in 900ml of water using USP Dissolution Apparatus I (basket) at 50 rpm (for 100 mg capsules) and 75 rpm (for 200/300 capsules). 100 mg capsules of present invention show the following in vitro dissolution profile (a) not more than 35 percent drug released in 30 minutes (b) not more than 75 percent drug released in 60 minutes, and (c) not less than 65 percent drug released in 120 minutes whereas 200/300 mg capsules show the following in vitro dissolution profile (a) not more than 40 percent drug released in 30 minutes (b) not more than 65 percent drug released in 60 minutes, and (c) not less than 75 percent drug released in 120 minutes. The examples given herein further illustrate the invention and are not intended to limit the scope of the invention. EXAMPLES 1-5 (Table Removed) Process: Phenytoin sodium, microcrystalline cellulose, hydroxypropyl cellulose, Xanthan gum and hydroxypropyl methylcellulose are loaded into a twin shell V-blender and blended. Talc, colloidal silicon dioxide and magnesium stearate are added to the blend and mixed. This blend is screened through No. 30 mesh and filled into size "0" hard gelatin capsules on automatic capsule filling machines. These capsules are then packed into high-density polyethylene bottles and stored for 3 months at 40°C / 75% relative humidity and tested for in-vitro dissolution. Table 1 shows the dissolution data of Phenytoin sodium 300mg capsules prepared as per composition of Example 3 initial and after storage for 3 months at 40°C/ 75% relative humidity. Table 1: In vitro dissolution profile of Phenytoin sodium capsules using USP Apparatus l/900ml water/75 rpm (Table Removed) EXAMPLE - 6 (Table Removed) Phenytoin sodium, microcrystalline cellulose, hydroxypropyl cellulose, Xanthan gum and hydroxypropyl methylcellulose are loaded into a twin shell V-blender and blended. Talc, colloidal silicon dioxide and magnesium stearate are added to the blend and mixed. This blend is screened through No. 30 mesh and filled into size "0" hard gelatin capsules on automatic capsule filling machines. These capsules are then packed into high-density polyethylene bottles and stored for 3 months at 40°C / 75% relative humidity and tested for in-vitro dissolution. Table 2 shows the dissolution data of Phenytoin sodium 100mg capsules prepared as per composition of Example 6 using USP Apparatus I, 900ml water at 50 and 75 RPM. Table 2: In vitro dissolution profile of Phenytoin sodium capsules using USP Apparatus l/900ml water. (Table Removed) WE CLAIM: 1 A process for preparing extended release pharmaceutical compositions of phenytoin sodium, comprising: a) blending 40 to 70% by weight of phenytoin sodium, 10 to 30% by weight of hydrophilic polymers selected from the group consisting of carbohydrate gum, cellulose ether, acrylic acid polymer or mixtures thereof and 5 to 12% of other.pharmaceutically acceptable excipients as described herein, and b) filling the blend in capsules, wherein the blend forms a matrix on coming in contact with aqueous media, and wherein said matrix retains at least 20% of phenytoin after 1 hour. 2 The process as claimed in claim 1 wherein the said matrix retains at least 30% of phenytoin after 1 hour. 3 The process as claimed in claim 1 wherein the said matrix retains at least 60% of phenytoin after 1 hour. 4 The process as claimed in claim 1 wherein the blend is filled as powder. 5 The process as claimed in claim 1 wherein the carbohydrate gum is selected from xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan gum, locust bean gum or mixtures thereof. 6 The process as claimed in claim 1 wherein the cellulose ether is selected from methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl butyl cellulose, carboxymethyl cellulose or combinations thereof. 7 The process as claimed in claim 1 wherein the hydrophilic polymer(s) is a combination of a cellulose ether and carbohydrate gum. 8 The process as claimed in claim 1 wherein the cellulose ether is a combination of hydroxypropyl cellulose and hydroxypropyl methylcellulose and carbohydrate gum is xanthan gum. 9 The process as claimed in claim 1 wherein the pharmaceutically acceptable excipients are selected from diluents, lubricants and glidants. 10 The process as claimed in claim 9 wherein the diluents may be selected from microcrystalline cellulose, powdered cellulose, lactose, starch, mannitol, calcium hydrogen phosphate and dextrose. 11 The process as claimed in claim 9 wherein the lubricant may be selected from talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol, sodium stearyl fumarate and sodium benzoate. 12 The process as claimed in claim 9, wherein the glidant may be selected from colloidal silicon dioxide and talc. 13 A process for preparing extended release pharmaceutical composition of phenytoin sodium as described and exemplified herein.

Documents:

1264-del-2002-abstract.pdf

1264-del-2002-claims.pdf

1264-del-2002-correspondence-others.pdf

1264-del-2002-correspondence-po.pdf

1264-del-2002-description (complete).pdf

1264-del-2002-form-1.pdf

1264-del-2002-form-2.pdf

1264-del-2002-petition-138.pdf