Title of Invention	NOVEL EXTENDED RELEASE FORMULATIONS OF LEVETIRACETAM
Abstract	The present invention relates to extended release formulation of levetiracetam comprising hydrophobic rate controlling polymer preferably ethyl cellulose and prepared by simple wet granulation method using water and isopropyl alcohol mixture as a granulating fluid.

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FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13] 1. Title of the invention: "Novel extended release formulations of Levetiracetam" 2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashtra, India. 3. The following specification particularly describes the invention and the manner in which it is to be performed. NOVEL EXTENDED RELEASE FORMULATION OF LEVETIRACETAM TECHNICAL FIELD OF INVENTION The present invention relates to extended release pharmaceutical composition of levetiracetam and processes for preparing the same. BACKGROUND OF THE INVENTION Levetiracetam is chemicaly known as (-)-(S)-α-ethyl-2-oxo-l -pyrrolidine acetamide. Its molecular formula is C8H14N2O2 and molecular weight is 170.21. Levetiracetam is chemically unrelated to existing antiepileptic drugs (AEDs). It has the following structural formula, Levetiracetam is a white to off-white crystalline powder with a faint odor and a bitter taste. It is very soluble in water (104.0 g/100 mL). Levetiracetam is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalization in patients from 16 years of age with newly diagnosed epilepsy and also as adjunctive therapy in the treatment of (a) partial onset seizures with or without secondary generalization in adults and children from 4 years of age with epilepsy; (b) myoclinic seizures in adults and adolescents from 12 years of age with Juvenile Myoclinic Epilepsy; and (c) primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic Generalized Epilepsy. Levetiracetam is available as an immediate release and extended release tablet in the United States of America under the brand name KEPPRA® (UCB Pharma.) and KEPPRA XR® (UCB Pharma.) respectively. KEPPRA® is available in 250, 500, 750 mg and lOOOmg strengths as the immediate release tablet formulation. KEPPRA tablets contain the labeled amount of levetiracetam, inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, polyethylene glycol 3350, polyethylene glycol 6000, polyvinyl alcohol, talc, titanium dioxide, and additional agents (250 mg tablets) FD&C Blue #2/indigo carmine aluminum lake, (500 mg tablets) iron oxide yello, (750 mg tablets) FD&C yellow #6/sunset yellow FCF aluminum lake, iron oxide red. KEPPRA XR tablets contain the labeled amount of levetiracetam, inactive ingredients: colloidal anhydrous silica, hypromellose, magnesium stearate, polyethylene glycol 6000, polyvinyl alcohol-partially hydrolyzed, titanium dioxide (E171), Macrogol/PEG3350, and talc. The imprinting ink contains shellac, FD&C Red #40, n-butyl alcohol, propylene glycol, titanium dioxide, ethanol, and methanol. Levetiracetam is rapidly and almost completely absorbed after oral administration. The pharmacokinetics are linear and time-invariant, with low intra-and inter-subject variability. The extent of bioavailability of levetiracetam is not affected by food. Levetiracetam is not protein-bound ( approximately 6-8 hours. It is increased in the elderly (primarily due to impaired renal clearance) and in subjects with renal impairment. Absorption of levetiracetam is rapid, with peak plasma concentrations occurring in about an hour following oral administration in fasted subjects. The oral bioavailability of levetiracetam tablets is 100% and food does not affect the extent of absorption of levetiracetam but it decreases Cmax by 20% and delays Tmax by 1.5 hours. The pharmacokinetics of levetiracetam are linear over the dose range of 500-5000 mg. Steady state is achieved after 2 days of multiple twice-daily dosing. Levetiracetam and its major metabolite are less than 10% bound to plasma proteins; clinically significant interactions with other drugs through competition for protein binding sites are therefore unlikely. The Physicians Desk Reference, 58th Edition (2004), p. 3230. Due to levetiracetam high degree of bioavailability and rapid metabolism, it would be advantageous to provide formulation that releases the active in an extended or controlled or delayed release profile. The prior art records several documents describing levetiracetam sustained release formulations. U.S. Patent Application No. 2006165796 filed by Alembic Limited discloses an extended release tablet of Levetiracetam with the core comprising of Levetiracetam, water dispersible rate controlling polymer and the tablet core is optionally functional coated comprising a combination of water non-dispersible and/or water dispersible polymer. PCT Application WO 2006123357 filed by Sun Pharmaceutical Industries Limited discloses oral controlled release pharmaceutical composition in the form of a unit dosage form comprising levetiracetam and a rate controlling means comprising a rate-controlling agent and optionally coating selected form (i) an active ingredient permeable coating surrounding the unit dosage form, and (ii) an active ingredient impermeable coating covering one or more surfaces but not all the surfaces of the unit dosage form, wherein the composition is in the form of a compact tablet. U.S. Patent Application No. 20070298098 filed by Elan Pharma Int. Ltd. discloses a controlled release composition comprises an immediate release component and a modified release component or formulation. PCT Application WO 2007000778 filed by Panacea Biotec Limited discloses a novel modified release pharmaceutical composition comprising at least one active agent(s) selected from a group comprising HMG CoA reductase inhibitors, immunomodulators, oxcarbazepine, levetiracetam, quetiapine, tolterodine, famciclovir, and the like, or its pharmaceutically acceptable salts, hydrates, polymorphs, esters, and derivatives and the composition comprising at least two swellable pH independent polymers wherein at least one is hydrophilic; optionally other pharmaceutically acceptable excipients; wherein the composition provides therapeutic concentrations of active agent(s) for extended periods of time. U.S. Patent Application No. 20080014264 filed by Caroline Goffin et al. discloses a prolonged release formulation of levetiracetam with at least one hydrophilic matrix agent preferably hydroxypropyl methylcellulose. PCT Application WO 2008062446 filed by Alembic Limited discloses an extended release levetiracetam composition in the form of tablet which is coated with a functional coat of about 1% w/w to 15% w/w of the tablet weight comprising a combination of a water non - dispersible polymer and a water dispersible polymer. As levetiracetam is very highly soluble in water, different methods have been used in the prior art to prepare sustained release formulation. These are as follows: 1. by using high viscosity hydrophilic rate controlling polymer in the core along with levetiracetam, 2. by using hydrophobic rate controlling polymer coating over the core containing levetiracetam, 3. combination of 1 and 2 i.e. hydrophilic rate controlling polymer in the core along with levetiracetam and hydrophobic rate controlling coating over the core. Thus, it is evident from the prior art that due to high water solubility of levetiracetam it is difficult to formulate a sustained release formulation of levetiracetam. Thus, there is constant need to formulate a sustained release formulation of levetiracetam using suitable rate controlling polymer which will over come high water solubility problem of levetiracetam. SUMMARY OF THE INVENTION The present invention relates to extended release formulation of levetiracetam comprising hydrophobic rate controlling polymer and prepared by simple wet granulation method. The extended release formulation prepared according to the present invention showed comparatively similar in-vitro release profile as that of KEPPRA XR. DETAILED DESCRIPTION OBJECTIVE OF THE PRESENT INVENTION 1. Objective of the present invention is to formulate extended release formulation of levetiracetam using hydrophobic rate controlling polymer. 2. Another objective of the invention is to formulate extended release formulation of levetiracetam using hydrophobic rate controlling polymer, which showed comparatively similar in-vitro release profile of KEPPRA XR. Due to very high water solubility of levetiracetam , suitable rate controlling polymer selection is important to develop an extended release formulation. According to the present invention hydrophobic rate controlling polymer is selected to prepare extended release formulation of levetiracetam. Hydrophobic polymer by its nature will retard the water penetration inside the core and thus can control the release of highly water soluble levetiracetam in better way. None of the prior art discloses the uses of hydrophobic rate controlling polymer in the core along with levetiracetam to prepare extended release formulation. It was now found that use of hydrophobic rate controlling polymer in core along with levetiracetam is suitable to formulate levetiracetam extended release matrix formulation which also provided comparatively similar in-vitro release profile as that of KEPPRA XR. In the present invention an extended release formulation is prepared by wet granulation method using water and isopropyl alcohol mixture as granulating fluid. The resulting tablets were then film coated (HPMC based), optionally followed by a wax polishing. According to the present invention an extended release formulation, may contain, in addition to levetiracetam, and one or more hydrophobic polymer such as ethyl cellulose, cellulose acetate, HPMC Phthalate, polyvinyl acetate phthalate. Even the commercially available Eudragit L-30D55, Eudragit NE 30D, Aquacoat ECD-30, Surelease E-7, Eudragit RS 30D, Eudragit RL 30D etc. may be used. One or more fillers such as microcrystalline cellulose, lactose, sugars, starches, modified starch, mannitol, sorbitol and other polyols, dextrin, dextran and maltodextran, calcium phosphate (dibasic and/or tribasic), calcium sulfate and the like. One or more binders such as starch, cellulose, sugars, polyethylene glycols, hydroxypropyl methylcellulose, ethylcellulose, hydroxyethyl cellulose, methylcellulose, carboxy methylcellulose, sodium carboxy methylcellulose, gelatin, acacia gum, tragacanth, polyvinylpyrrolidone, alginic acid, carbomer, dextrin, gelatin, guar gum, hydroxypropyl cellulose, maltose, polyethylene oxide and the like. One or more different glidants such as magnesium, calcium and zinc stearate, calcium behenate, sodium stearyl fumarate, talc, magnesium trisilicate, stearic acid, palmitic acid, camauba wax, silicon dioxide and the like. The present invention is illustrative but in no way limited by the following examples EXAMPLE 1: Manufacturing process: 1. Sift levetiracetam, microcrystalline cellulose, ethyl cellulose, Sodium citrate and pregelatinised starch through #40 mesh. 2. Dry mix the sifted materials of step 1 in RMG for 10 minutes. 3. Granulate the step 2 materials with purified water till to get uniform granules. 4. Dry the wet mass at 50 ± 5° c till to get LOD in the range of 1.0 to 2.0 % at 80° c using suitable moisture analyzer. 5. Sift the dried granules through #20 mesh. Mill the oversized granules in multi mill using 2.0 mm screen using knives forward at fast speed followed by 1.5 mm screen at medium speed. 6. Ensure all the materials should pass through #20 mesh. 7. Sift Magnesium stearate through # 40 mesh. 8. Add the sifted Magnesium stearate of step 7 to step 6 materials and mix for 5 minutes. 9. Compress the lubricated blend into tablets using suitable punches. 10. Disperse coating materials in suitable quantity of purified water under stirring for 45 minutes. 11. Coat the core tablets of step 9 with coating solution of step 10 for weight build up of 2-3 % w/w. EXAMPLE 2: Manufacturing process: 1. Sift levetiracetam, microcrystalline cellulose, ethyl cellulose, Sodium citrate and Glyceryl palmito stearate through #40 mesh. 2. Dry mix the sifted materials of step 1 in RMG for 10 minutes. 3. Granulate the step 2 materials with purified water till to get uniform granules. 4. Dry the wet mass at 50 ± 5° c till to get LOD in the range of 1.0 to 2.0 % at 80° c using suitable moisture analyzer. 5. Sift the dried granules through #20 mesh. Mill the oversized granules in multi mill using 2.0 mm screen using knives forward at fast speed followed by 1.5 mm screen at medium speed. 6. Ensure all the materials should pass through #20 mesh. 7. Sift Magnesium stearate through # 40 mesh. 8. Add the sifted Magnesium stearate of step 7 to step 6 materials and mix for 5 minutes. 9. Compress the lubricated blend into tablets using suitable punches. 10. Disperse coating materials in suitable quantity of purified water under stirring for 45 minutes. 11. Coat the core tablets of step 9 with coating solution of step 10 for weight build up of 2-3% w/w. EXAMPLE 3: Manufacturing process: 1. Sift levefiracetam, microcrystalline cellulose, ethyl cellulose, Sodium citrate and Hydrogenated vegetable oil through #40 mesh. 2. Dry mix the sifted materials of step 1 in RMG for 10 minutes. 3. Granulate the step 2 materials with purified water till to get uniform granules. 4. Dry the wet mass at 50 ± 5° c till to get LOD in the range of 1.0 to 2.0 % at 80° c using suitable moisture analyzer. 5. Sift the dried granules through #20 mesh. Mill the oversized granules in multi mill using 2.0 mm screen using knives forward at fast speed followed by 1.5 mm screen at medium speed. 6. Ensure all the materials should pass through #20 mesh. 7. Sift the extra granular materials (Glyceryl behenate and Aerosil) through #40 mesh and mix with the step 6 materials for 10 minutes in low shear blender. 8. Compress the lubricated blend into tablets using suitable punches. 9. Disperse coating materials in suitable quantity of purified water under stirring for 45 minutes. 10. Coat the core tablets of step 8 with coating solution of step 9 for weight build up of 2-3 % w/w. Results of Tablets prepared according to Examples 1, 2 and 3 Example 1, 2 and 3 of Levetiracetam Extended release formulation were designed with an objective of sustaining the release of levetiracetam for 12 hours. But the initial batches were failed to sustain the release of levetiracetam for 12 hours. The tablets prepared according to example released 90% of the levetiracetam within 3 to 4 hours. Following reasons may be responsible for the aforesaid observation, 1. Use of water as granulating fluid was not sufficient to hold hydrophobic rate controlling polymer ethyl cellulose and levetiracetam together so as to sustain the release of Levetiracetam. 2. Use Sodium citrate as a channel forming agent resulted in faster release of levetiracetam form ethylcellulose. 3. Use of pregelatinised starch as a binder in example 1 resulted in a granules with poor binding property and non uniform particle size, because of which flow problem was observed. 4. The tablets prepared using only magnesium stearate as a lubricant (example 1) provided smooth surface as compared to mixture glyceryl palmito stearate and magnesium stearate (example 2) and hydrogenated vegetable oil, glyceryl behenate Aerosil 200M (example 3). Further examples 4, 5 and 6 were designed with following changes: 1. Granulation fluid-isopropyl alcohol + water mixture. 2. Povidone K90 as binder EXAMPLE 4: q.s.: Manufacturing process: 1. Sift levetiracetam, microcrystalline cellulose, ethyl cellulose FP through #40 mesh. 2. Dry mix the sifted materials of step 1 in RMG for 10 minutes. 3. Granulate the step 2 materials with binder solution (Povidone dispersed in Isopropyl alcohol + water mixture) till to get uniform granules. 4. Dry the wet mass at 50 ± 5° c till to get LOD in the range of 1.0 to 2.0 % at 80° c using suitable moisture analyzer. 5. Sift the dried granules through #20 mesh. Mill the oversized granules in multi mill using 2.0 mm screen using knives forward at fast speed followed by 1.5 mm screen at medium speed. 6. Ensure all the materials should pass through #20 mesh. 7. Sift Magnesium stearate through # 40 mesh. 8. Add the sifted Magnesium stearate of step 7 to step 6 materials and mix for 5 minutes. 9. Compress the lubricated blend into tablets using suitable punches. 10. Disperse coating materials in suitable quantity of purified water under stirring for 45 minutes. 11. Coat the core tablets of step 9 with coating solution of step 10 for weight build up of 2-3 % w/w. Example 5: Manufacturing process: 1. Sift levetiracetam, microcrystalline cellulose, ethyl cellulose (FP) through #40 mesh. 2. Dry mix the sifted materials of step 1 in RMG for 10 minutes. 3. Granulate the step 2 materials with binder solution (Povidone dispersed in Isopropyl alcohol + water mixture) till to get uniform granules. 4. Dry the wet mass at 50 ± 5° c till to get LOD in the range of 1.0 to 2.0 % at 80° c using suitable moisture analyzer. 5. Sift the dried granules through #20 mesh. Mill the oversized granules in multi mill using 2.0 mm screen using knives forward at fast speed followed by 1.5 mm screen at medium speed. 6. Ensure ail the materials should pass through #20 mesh. 7. Sift Ethyl cellulose (N10) through # 30 mesh. 8. Add the sifted Ethyl cellulose (N10) of step 7 to step 6 materials and mix for 10 minutes. 9. Sift Magnesium stearate through # 40 mesh. EXAMPLE 6: Manufacturing process: 1. Sift levetiracetam, microcrystalline cellulose, ethyl cellulose FP through #40 mesh. 2. Dry mix the sifted materials of step 1 in RMG for 10 minutes. 3. Granulate the step 2 materials with binder solution (Povidone dispersed in Isopropyl alcohol + water mixture) till to get uniform granules. 4. Dry the wet mass at 50 ± 5° c till to get LOD in the range of 1.0 to 2.0 % at 80° c using suitable moisture analyzer. 5. Sift the dried granules through #20 mesh. Mill the oversized granules in multi mill using 2.0 mm screen using knives forward at fast speed followed by 1.5 mm screen at medium speed. 6. Ensure all the materials should pass through #20 mesh. 7. Sift Magnesium stearate through # 40 mesh. 8. Add the sifted Magnesium stearate of step 7 to step 6 materials and mix for 5 minutes. 9. Compress the lubricated blend into tablets using suitable punches. 10. Disperse coating materials in suitable quantity of purified water under stirring for 45 minutes. 11. Coat the core tablets of step 9 with coating solution of step 10 for weight build up of 2-3 % w/w. Tablets prepared according to example 4 and 6 showed 101% and 102% drug release at the end of 12 hours. Tablets prepared according to example 5 wherein extra granular ethylcellulose was additionally added showed no significant difference in the dissolution profile. (Table 1 and 2). Further the tablets prepared according to example 4 and 6 were kept for stability at 40°C /75 % RH for 3 Months (Table 3 and 4). TABLE 1 - Comparative in-vitro dissolution data of tablets prepared according to example 6 with innovators KEPPRA XR: TABLE 2 - Comparative in-vitro dissolution data of tablets prepared according to example 4 and 5 with innovators KEPPRA XR: TABLE 3 - Stability data of tablets prepared according to example 6 at 40°C 115 % RH for 3 Months TABLE 4 - Stability data of tablets prepared according to example 4 at 40°C /75 % RH for 3 Months: Tablets prepared according to example 4 and 6 showed no significant changes with respect to assay and dissolution at 40° C /75 % RH for 3 Months (Table 3 and 4). CLAIMS: 1. An extended release pharmaceutical formulation comprising levetiracetam, a hydrophobic rate controlling polymer and at least one pharmaceuticaily acceptable excipient wherein the hydrophobic polymer is present within the core along with levetiracetam. 2. An extended release pharmaceutical formulation as claimed in claim 1, wherein one or more excipients are selected from the group consisting of binder, filler, disintegrant and the like. 3. An extended release pharmaceutical formulation as claimed in claim 2, wherein binder is Povidone. 4. An extended release pharmaceutical formulation of levetiracetam as claimed in claim 1, which shows comparatively similar in-vitro dissolution profile as that of KEPPRA XR, comprising hydrophobic rate controlling polymer and at least one pharmaceuticaily acceptable excipient. 5. A process for preparation of an extended release pharmaceutical formulation as claimed in claim 1 comprising wet granulation method. 6. A process for preparation of an extended release pharmaceutical formulation as claimed in claim 1 comprising wet granulation method using mixture of water & Isopropyl alcohol as a granulation fluid. 7. An extended release pharmaceutical formulation comprising levetiracetam as described in the examples. Dated this 03rd day of November, 2009

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2347-MUM-2008-ABSTRACT(04-11-2009).pdf

2347-mum-2008-abstract.doc

2347-MUM-2008-CLAIMS(04-11-2009).pdf

2347-MUM-2008-CLAIMS(AMENDED)-(11-1-2013 ).pdf

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2347-MUM-2008-CLAIMS(AMENDED)-(8-4-2014).pdf

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2347-MUM-2008-CORRESPONDENCE(04-11-2009).pdf

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2347-MUM-2008-DESCRIPTION(COMPLETE)-(04-11-2009).pdf

2347-mum-2008-description(provisional).doc

2347-mum-2008-description(provisional).pdf

2347-mum-2008-form 1.pdf

2347-MUM-2008-FORM 18(22-10-2010).pdf

2347-mum-2008-form 2(04-11-2009).pdf

2347-MUM-2008-FORM 2(TITLE PAGE)-(04-11-2009).pdf

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2347-MUM-2008-REPLY TO EXAMINATION REPORT(11-1-2013 ).pdf

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2347-MUM-2008-REPLY TO HEARING(8-4-2014).pdf