The present invention relates to an oral extended release multiple unit dosage form of phenytoin sodium in which individual units containing phenytoin sodium are coated with film forming polymer(s).
Phenytoin is 5,5-diphenyl-2, 4-imidazolidinedione. It is a well-known pharmaceutical agent having anti-convulsant and anti-epileptic activity. Due to phenytoin's poor solubility in water, phenytoin sodium, which is much more soluble, is employed in the dosage forms.
Phenytoin is available in a number of dosage forms. Oral dosage forms include an immediate release capsule, a sustained release capsule (Kapseal), a chewable tablet and an oral suspension. The sustained release capsules are available in two strengths, 30 mg and 100mg, under the brand name Dilantin. These capsules contain lactose, confectioner's sugar, talc, magnesium stearate and phenytoin sodium as loose powder and are band sealed. Drug release problems associated with these pharmaceutical compositions have resulted in numerous recalls because of failure to meet dissolution requirements. Moreover, due to its narrow therapeutic window, it is necessary for the patients to take this dosage form several times a day to maintain an effective therapeutic plasma level.
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 by Mylan's US Patent No. 6,274,168 and its continuation in part application US 20010043945.
Further, US Patent No. 5,968,554 assigned to Cascade Development Inc., discloses a sustained release drug delivery system, which comprises: a core of active ingredient, an enteric coating over the core, a second coating of the active ingredient and finally a coating, which is soluble in gastric juices. According to the specifications and examples of this patent, 305 mg of coated beads were required to deliver a dose of 100mg phenytoin sodium. Therefore, in order to incorporate a larger dose of the drug, the size of the capsules would have to be increased, making it patient incompliant.
US Patent No. 5,863,558 assigned to Alza Coporation, discloses a dosage form for controlled release of an antiepileptic drug, wherein the dosage form is characterized by a nonionic polymer film that protects the drug from fluid of the gastrointestinal environment that contacts the dosage form. The dosage form of this invention comprises at least one exit in the inert wall surrounding the internal compartment and the wall maintains its integrity during the release of the drug from the exit.
It is evident that there are a number of extended and sustained release dosage forms available for phenytoin but there is still a need for a dosage form which can incorporate a high dose of phenytoin as well as impart extended-release properties.
Numerous systems have been developed and marketed for the purpose of obtaining an extended release and for reducing the number of daily administrations. Examples of such are the matrix systems, reservoir systems, osmotic drug delivery systems and other monolithic systems.
For extended-release dosage forms containing very high quantities of active principle, an excessively rapid release (dose dumping) is particularly very critical as it can lead to toxic effects, which are undesirable. Moreover, such systems are dependent upon gastric emptying rates and transit times and are also associated with a lot of intra- and inter-individual variations.
These disadvantages have led to a shift in modified release technology, from the use of monolithic systems to multiple unit systems, wherein each individual unit is formulated with modified release characteristics. The final dosage form comprises a multiplicity of individual units contained in a formulation in such a form that individual units will be made available from the formulation in the gastrointestinal tract.
Multiple unit dosage forms possess large surface area, which promotes complete and uniform absorption, minimize peak plasma fluctuations and thus reduce the potential for systemic side effects. A further advantage of these dosage forms is that high local concentrations of the active substance in the gastrointestinal system is avoided, due to the units being distributed freely throughout the tract.
Hence, the multiple unit dosage form ensures incorporation of higher dose of phenytoin, resulting in a decreased dosing frequency and consequently better patient compliance.
Therefore, it is one general aspect to develop a dosage form for phenytoin, which is capable of incorporating a high dose.
In another general aspect it relates to a dosage form of phenytoin sodium, which provides extended release.
It is another general aspect to prepare multiple unit dosage form of phenytoin sodium using dry compaction; and applying a coating of film-forming polymers over these multiple units.
In yet another aspect, it relates to the multiple unit dosage forms of phenytoin sodium coated with film-forming polymer(s).
In another general aspect, extended release multiple unit systems are formulated by employing a simple process, which does not involve extra steps of layering, drying and band sealing after filing in capsules and are still capable of imparting extended release properties.
Accordingly, in one general aspect, the present invention provides an extended release formulation for phenytoin sodium that can deliver 30-300mg of the drug in a single administration without batch-to-batch variation.
The term "extended release multiple units formulation" indicates a pharmaceutical formulation comprising a multiplicity of individual coated units contained in the formulation in such a form that the individual units will be available from the formulation upon disintegration of the formulation in the stomach. The multiple unit formulation may be a capsule or a tablet, which disintegrate in the stomach to give individual units.
Drug release from such extended release multiple units is controlled either by diffusion of a coating or by erosion of the coating by a process dependent on enzymes or pH. The erodible coatings involve the use of enteric polymers, which rapidly erode in the intestines.
There are a number of methods available for manufacturing these multiple units, which include:
(a) Extrusion-spheronization
(b) Wet granulation
(c) Dry granulation: These are two main processes for dry granulation:

1. Slugging
2. Roller compaction
Dry granulation or compaction has several advantages because of its low processing time and cost, production of uniform blends and uniform particle size range, improvements in flow properties, reduction in dust, better control of particle hardness and increase in the bulk density of the powder. Dry compaction is an efficient and useful method of granulation capable of handling a large amount of material. The compacted granules being denser than the parent powder, occupy less volume per unit weight. Therefore, high drug content can be incorporated in the dosage form using this technique.
One of the embodiments provides a process of preparing an oral pharmaceutical extended-release multiple unit dosage form of phenytoin sodium, wherein the process comprises:
1. Compacting or compressing Phenytoin sodium powder,
2. Screening the compacted material to form uniform sized multiple units, and
3. Coating the individual units with film-forming polymer(s).
Phenytoin sodium may constitute up to 90% w/w of the compacted units.
The multiple units of this invention may be designed as granules, pellets, compacts and beads.
Phenytoin sodium may be compressed/compacted alone or with atleast one component selected from lubricants, antiadherents or glidants
The coating applied to the multiple units of the present invention comprises film forming polymer(s).
The film forming polymers according to the present invention are substantially water insoluble, or sparingly water-soluble but, which permit water diffusion. These polymers may be selected from cellulose derivatives; vinyl polymers and copolymers; acrylic polymers and copolymers; and biodegradable polymers.
Suitable cellulose derivatives may include carboxymethyl cellulose, ethyl cellulose, cellulose acetate, cellulose propionate, cellulose triacetate, cellulose acetate butyrate, cellulose acetate phthalate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyl ethyl cellulose, hydroxyl methyl cellulose and the like.
Suitable vinyl polymers and copolymers may be selected from polyvinyl pyrrolidone, polypropylene, poly (vinyl) chloride, poly (vinyl) alcohol, poly (vinyl) acetate and the like.
Suitable acrylic polymers and copolymers may be selected from cross-linked polyacrylic acids like carbopols.
Suitable biodegradable polymers may be selected from polyamino acids, polylactic acid and copolymers.
The film-forming polymers may be admixed with various excipients such as plasticizers, lubricants, antiadherants and pigments.
Suitable examples of plasticizers include triacetin, glycerine, triethyl citrate, tributyl citrate, polyethylene glycol, propylene glycol, olive oil, sesame, oil, diethyl fumarate and mixtures thereof.
Suitable lubricants include magnesium stearate, calcium stearate, colloidal silica, stearic acid, sodium stearate, hydrogenated vegetable oil, waxes and mixtures thereof.
Anti-adherents may include talc, cornstarch, silicon dioxide, sodium lauryl sulphate and metallic stearates like magnesium stearate and the like.
The polymers may be applied as a solution or dispersion in a solvent. The solvent may be selected from water, alcohols like ethyl alcohol or isopropylalcohol; ketones like acetone or ethylmethylketone; halogenated hydrocarbons like dichloroethane and trichloroethane or mixtures thereof.
Any conventional coating equipment may be employed to facilitate coating such as centrifugal fluidized bed coating apparatus or a pan coating apparatus. The coating may be applied using a conventional coating pan, a spray coater, rotating perforated pan or an automated system. The coated multiple units may be dried in an oven or in a fluidized bed.
The coating may constitute about 10-20% w/w of the formulation.
The coated multiple units are filled into hard gelatin capsules or compressed into tablets,
which disintegrate in the stomach to make available a multiplicity of individually coated
units.
The extended-release formulation shows the following in vitro dissolution profile for phenytoin sodium in water when tested using USP Apparatus I at 50 rpm:
a. not more than 35 percent released in 30 minutes.
b. between 30 and 65 percent released in 60 minutes
c. not less than 60 percent released in 120 minutes.
The following examples illustrate various aspects of the present invention. These examples are for illustration only and should not be construed as limiting the scope of the invention.
EXAMPLES 1-2

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Process:
Phenytoin sodium and magnesium stearate (in case of Example 2) are loaded into a twin shell V-blender and blended. This blend is screened and compacted to form pellets. The compacted pellets are coated with a dispersion of ethyl cellulose. These coated pellets are filled into hard gelatin capsules on automatic capsule filling machines.
Table 1 shows the dissolution data of Phenytoin sodium 300mg capsules prepared as per composition of Example 2.
Table 1: Comparative in vitro release of phenytoin sodium extended release capsules of Example 2 and Phenytek capsules (300 mg; marketed by Mylan) using USP Apparatus l/900ml water/50 rpm

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WE CLAIM:
1. A process of preparing an extended release multiple unit dosage form of phenytoin sodium, wherein individual units comprising phenytoin sodium are coated with film forming polymer(s).
2. The process according to claim 1 wherein the units comprise up to 90%w/w of phenytoin sodium.
3. The process according to claim 1 wherein the individual units are pellets, beads, granules or compacts.
4. The process according to claim 1 wherein the individual units may be prepared by roller compaction, slugging or extrusion-spheronization.
5. The process according to claim 4 wherein the multiple units are prepared by roller compaction.
6. The process according to claim 1 wherein the individual units further comprise at least one component selected from the group consisting of lubricants/ antiadherents and glidants.
7. The process according to claim 6 wherein the lubricant/antiadherent is selected from talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol, sodium stearyl fumarate and sodium benzoate.
8. The process according to claim 7 wherein the lubricant/antiadherent is magnesium stearate.
9. The process according to claim 6, wherein the glidant may be selected from colloidal silicon dioxide and talc.
10. The process according to claim 1 wherein the film forming polymer(s) may be selected from cellulose derivatives; vinyl polymers and copolymers; acrylic polymers and copolymers; and biodegradable polymers.
11. The process according to claim 10 wherein the cellulose derivatives may be selected from carboxymethylcellulose, ethyl cellulose, cellulose acetate, cellulose propionate, cellulose triacetate, cellulose acetate butyrate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose and the like.
12. The process according to claim 11 wherein the cellulose derivative is ethyl cellulose.
13. The process according to claim 10 wherein vinyl polymers may be selected from polyvinyl pyrrolidone, poly (vinyl) acetate and the like.
14. The process according to claim 10 wherein acrylic polymers may be selected from cross-linked polyacrylic acids such as carbopols.
15. The process according to claim 10 wherein biodegradable polymers may be selected from polyamino acids, polylactic acid and the like.
16. The process according to claim 1 wherein the coating may comprise 10-20% w/w of the composition.
17. The process according to claim 1 wherein the coating composition may additionally comprise other pharmaceutically acceptable excipients selected from plasticizers, lubricants, anti-adherents and pigments.
18. The process according to claim 17 wherein the plasticizer may be selected from triacetin, triethylcitrate, tributyl citrate, propylene glycol, polyethylene glycol, olive oil, sesame oil, diethyl fumarate and mixtures thereof.
19. The process according to claim 17 wherein the lubricant may be selected from magnesium stearate, calcium stearate, colloidal silica, hydrogenated vegetable oil, stearic acid, waxes and mixtures thereof.
20. The process according to claim 19 wherein the lubricant is colloidal silica.
21. The process according to claim 17 wherein the anti-adherent may be selected from talc, corn starch, silicon dioxide, sodium lauryl sulfate, magnesium stearate and mixtures thereof.
22. The process according to claim 21 wherein the anti-adherent is talc.
23. The process according to claim 1 wherein the multiple unit dosage form is constituted as tablets or capsules.
24. The process according to claim 1 wherein phenytoin sodium is directly compressed into pellets, the pellets are coated with ethyl cellulose and filled into hard gelatin capsules.
25. The process according to claim 1 wherein said multiple unit dosage form has the following in vitro dissolution profile for phenytoin sodium when tested using USP Apparatus I in water at 50 rpm:
a. not more than 35 percent released in 30 minutes.
b. between 30 and 65 percent released in 60 minutes
c. not less than 60 percent released in 120 minutes.
26. A process for preparing extended release phenytoin sodium capsule comprising
compacting phenytoin sodium into pellets; coating pellets with ethyl cellulose and
filling the coated pellets into capsules, as exemplified and described herein.