WO2008062446A2

WO2008062446A2 - An extended release composition of levetiracetam, which exhibits no adverse food effect

Info

Publication number: WO2008062446A2
Application number: PCT/IN2007/000420
Authority: WO
Inventors: Rajesh Kshirsagar; Ashwin Rao; Nilesh Malaviya; Kaustubh Jinturkar
Original assignee: Alembic Limited
Priority date: 2006-09-14
Filing date: 2007-09-14
Publication date: 2008-05-29
Also published as: WO2008062446A3

Abstract

The present invention relates to extended release pharmaceutical compositions of Levetiracetam, which exhibits no adverse food effect, and processes for preparing the same. The extended release tablet of Levetiracetam is with a core comprising of Levetiracetam and 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. It provides extended therapeutically effective plasma levels over a twenty four hour period with diminished incidences of neuropsychiatric adverse events by eliminating the troughs and peaks of drug concentration in a patient's blood plasma.

Description

AN EXTENDED RELEASE COMPOSITION OF LEVETIRACETAM, WHICH EXHIBITS

NO ADVERSE FOOD EFFECT

FIELD OF INVENTION

This invention relates to an extended release pharmaceutical composition of Levetiracetam with once a day dosage regime and the process of preparing it.

BACKGROUND AND PRIOR ART

The use of high viscosity grade hydrophilic and the hydrophobic polymers to produce extended or controlled release pharmaceutical composition is known in the art. For extending the release, the tablet comprising the drug also comprises of high viscosity grade hydrophilic polymer. If required the tablets are coated with hydrophobic polymer and pore forming agent. As soon as the solid dosage form comes in contact with the surrounding media, pores are formed and the drug is diffused through these pores. The media enters the tablet core and results into the hydration of the polymer which also controls the release of the drug. Control of the rate of release benefits therapy by producing constant blood plasma levels of the active ingredient and by decreasing the frequency of administration, thereby improving the patient compliance to the dosage regimen. The present invention provides a pharmaceutical composition of extended release tablets of Levetiracetam suitable for once daily administration to human subjects.

It is known that the absorption and bioavailability of any particular therapeutic agent can be affected by numerous factors when dosed orally. Such factors include the presence of food in the gastrointestinal (Gl) tract because, in general, the gastric residence time of a drug is usually significantly longer in the presence of food than in the fasted state. If the bioavailability of a drug is affected beyond a certain point due to the presence of food in the Gl tract, the drug is said to exhibit a "food effect". Food effects are important in as much as, when a drug exhibits an adverse food effect, there is risk associated with administering it to a patient who has eaten recently. The risk derives from the potential that absorption into the bloodstream may be adversely affected to the point that the patient risks insufficient absorption to remediate the condition for which the drug was administered.

Levetiracetam is chemically named as (-)-(S)-α-ethyl-2-oxo-1 -pyrrolidine acetamide with molecular formula C₈H₁₄N₂O₂ and molecular weight 170.21. Levetiracetam is white to off white crystalline powder and has aqueous solubility of 1.04 gm/ml. It is freely soluble in chloroform (65.3 g/100 mL) and in methanol (53.6 g/100 mL), soluble in ethanol (16.5 g/100 mL), sparingly soluble in acetonitrile (5.7 g/100 mL) and practically insoluble in n-hexane. Levetiracetam is described in the U.S. Pat. Nos. 4,837,223, 4,943,639 and 6,107,492.

Levetiracetam is indicated as adjunctive therapy in the treatment of partial onset seizures in adults with epilepsy. The precise mechanism(s) by which Levetiracetam exerts its antiepileptic effect is unknown and does not appear to derive from any interaction with known mechanisms involved in inhibitory and excitatory neurotransmission. Levetiracetam is rapidly absorbed with the oral bioavailability of 100%. Food does not affect the extent of absorption of Levetiracetam but it decreases C_max by 20% and delays Tm_3x by 1.5 hours. The pharmacokinetics of Levetiracetam are linear over a dose range of 500-5000 mg, with steady state kinetics being achieved 2 days after multiple twice daily dosing. It is less than 10% bound to plasma proteins. Levetiracetam has plasma elimination half life of 7±1 hr with the volume of distribution of 0.6 L/Kg. The total body clearance is 0.9 ml/min/kg and the renal clearance is 0.6 ml/min/kg. Its elimination is correlated with creatinine clearance. There is no age, gender, race or circadian effect. Presently Levetiracetam is administered to adults as conventional immediate release tablets. The current dosing regimen includes twice daily administration. Levetiracetam is available as an immediate release and is approved for sale in various countries including the United States of America under the brand name KEPPRA™ (UCB Pharma.). KEPPRA™ is available in 250, 500 and 750 mg strengths as the immediate release tablet formulation. In the Biopharmaceutics Classification System, it belongs to Class I since it is highly soluble (1.04 g/ml), highly permeable (F>90%) and >85% of the tablet amount released in

15 minutes in three different pH media. Clinically, it does not belong to narrow therapeutic class because it has a relatively low order of toxicity and a relatively high therapeutic index.

The twice daily dosing regimen for immediate-release Levetiracetam tablets is well tolerated with few incidences of neuropsychiatric adverse events like, somnolence, fatigue, coordination difficulties and behavioral abnormalities. The adverse effects are proportionate to the drug plasma level and therefore for improving the therapeutic efficacy, reducing incidences of adverse events and enhancing patient compliance an extended release once- daily regimen is explored in the present invention. WO 01/51033 provides for a Solid pharmaceutical compound that can be administered orally, permitting controlled release of at least one active substance which can be Levetiracetam consisting of a homogeneous mixture comprising active substance, at least one matrix excipient between 5 and 95% by weight in relation to total weight of the compound, selected among the inert matrices, the hydrophilic, or lipid matrices, mixtures of inert and lipidic matrices mixture of hydrophilic and inert matrices; at least one entero- soluble polymer between 2 and 50% by weight in relation to the total weight of the compound and at least one alkalinizing agent soluble in a aqueous phase under conditions of physiological pH, of at least 0.5 to 50% by weight in relation to the total weight of the compound.

WO 03/101428 provides for a method for the manufacture of a pharmaceutical compound with retarded release of the active principle, which can be Levetiracetam. A mixture of active substance and the polymer that provides the retarded release are compressed by putting them through two rollers that have a temperature of more than 40° C and compaction force is exerted on it of more than 15 to 40 kN/cm roller width. The compressed mixture is powdered to the desired particle size and if required the process is repeated. US 20060165796 A1 discloses extended release pharmaceutical compositions of

Levetiracetam which comprise Levetiracetam, optionally a binder, hydrophilic rate controlling polymer and conventional pharmaceutically acceptable excipients. In preferred embodiment a blend comprising Levetiracetam and optionally a binder, a hydrophilic rate controlling polymer and conventional pharmaceutically acceptable excipients is compressed into tablets and the formed tablets can further be coated with a functional coating comprising a combination of water non-dispersible and/or water dispersible polymer. The composition may be further coated with a polymer based non-functional coating.

WO 01/51033 provides for a solid pharmaceutical compound that can be administered orally, permitting controlled release of at least one active substance which can be Levetiracetam consisting of a homogeneous mixture comprising active substance, at least one matrix excipient between 5 and 95% by weight in relation to total weight of the compound, selected among the inert matrices, the hydrophilic, or lipid matrices, mixtures of inert and lipidic matrices mixture of hydrophilic and inert matrices; at least one entero- soluble polymer between 2 and 50% by weight in relation to the total weight of the compound and at least one alkalinizing agent soluble in a aqueous phase under conditions of physiological pH, of at least 0.5 to 50% by weight in relation to the total weight of the compound. WO 03/101428 provides for a method for the manufacture of a pharmaceutical compound with retarded release of the active principle, which can be Levetiracetam. A mixture of active substance and the polymer that provides the retarded release are compressed by putting them through two rollers that have a temperature of more than 4O.degree. C. and compaction force is exerted on it of more than 15 to 40 kN/cm roller width. The compressed mixture is powdered to the desired particle size and if required the process is repeated.

There is a need in the art for extended release formulations of levetiracetam which do hot exhibit food effect. We have now found a specific embodiment of the generic disclosures of US 20060165796 A1 that does not exhibit a food effect.

OBJECTS OF INVENTION

The object of the present invention is to provide an extended release pharmaceutical composition of Levetiracetam, which upon ingestion results in blood plasma levels having plateau effect, for an extended period of time.

Another object of the present invention is to produce a pharmaceutical composition which releases Levetiracetam in predetermined manner.

Yet another object of the present invention is to provide extended release pharmaceutical composition of Levetiracetam for once daily dosage regimen. Yet another object of the present invention is to provide a extended release composition of Levetiracetam which does not exhibit food effect.

Yet another object of the present invention is to provide an extended release composition of Levetiracetam which shows reduced inter subject variability.

SUMMARY OF THE INVENTION

The present invention relates to compositions of and processes of preparing an extended release pharmaceutical composition of Levetiracetam which do not exhibit food effect, the composition comprising Levetiracetam, optionally a binder, hydrophilic rate controlling polymer and conventional pharmaceutically acceptable excipients, the blend is compressed into a tablet and the formed tablet is further coated with a functional coating comprising of a hydrophobic rate controlling polymer. The functional coating optionally comprises of a channeling agent which can be a hydrophilic polymer or a water soluble substance. The composition may be further coated with a polymer based non functional coating. The components are selected in such a way to give extended release of Levetiracetam in a predetermined manner.

Preferably, the present invention relates to the extended release formulation which comprises from about 30% w/w to about 85% w/w of Levetiracetam, from about 1% w/w to about 50% w/w of hydrophilic polymer and optionally from about 1% w/w to about 10% w/w binder. All these weights are in relation to the weight of the core tablets. The tablet is further functional coated with a hydrophobic polymer, which comprises of about 2% w/w to about

15% w/w of the weight of core tablet. The coating optionally comprises channeling agent from about 10% w/w to about 60% w/w of the total weight of the coating layer. Further the coated tablet is given a nonfunctional coating which comprises about 1 % w/w to 3% w/w of the total weight of the composition.

More preferably the present invention relates to the extended release formulation which comprises from about 50% w/w to about 75% w/w of Levetiracetam, from about 0.5% to about 5% Polyvinyl pyrrolidone, from about 20% w/w to about 45% w/w Hydroxypropyl Methylcellulose. The functional coating on the tablets comprises of from about 2% w/w to about 5% w/w of the total weight of the composition. The coating comprises from about 50% w/w to about 80% w/w ethyl cellulose as functional polymer and from about 15% w/w to about 35% w/w Hydroxypropyl Methylcellulose, as a channeling agent. According to the present invention, the extended release formulation is prepared by compression of a matrix tablet followed by functional coating, the said method comprising steps of: i. Blending Levetiracetam or its granules prepared by dry or wet granulation with the rate controlling polymer. ii. Lubricating the blended mixture and compressing into tablets of appropriate shape, iii. Coating the tablets with an aqueous dispersion of water insoluble and water soluble polymer. iv. Coating the tablets with an aqueous dispersion of the nonfunctional coating polymer. 3RIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a plot showing the drug release profile of Levetiracetam from four different compositions of the drug in matrices using USP I, 100 rpm and at 37° C.

FIG. 2 is a plot showing the comparative plasma level profile of Levetiracetam under Fed dosing in Healthy Human volunteers.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment of the present invention, the extended release tablet comprises of active ingredient and water soluble rate controlling polymer and optionally conventional excipients including a binder. These tablets are coated with a combination of water insoluble polymer. The coating optionally includes a water soluble polymer or substance as a channeling agent. The functional coated tablets are further coated with water soluble polymer as non functional coat.

According to the embodiment of the present invention the active ingredient is used as such, inclusive or exclusive of the binder, if the crystal morphology is favoring direct compression. However, if the particles are not favoring direct compression and granulation is required then it is carried out either as 'dry granulation¹ or as 'wet granulation'. The dry granulation process involves the mixing of drug with the binder or directly with the rate controlling hydrophilic polymer or both, followed by slug formation on tablet press or using the roll compactors. The process of wet granulation includes aqueous or non aqueous granulation. The wet granulation process comprises the admixing of the active ingredient with 'diluent' or mixture of 'diluent' and rate controlling hydrophilic polymer, and granulation of the blend with the binder mass to form the wet mass followed by drying and sizing. The binder may optionally be admixed with the dry blend and granulation performed with aqueous or non aqueous solvent. The solvent for the non aqueous granulation is selected from ethanol, isopropyl alcohol and dichloromethane.

According to the present invention, the pharmaceutical composition contains Levetiracetam as an active ingredient. The Levetiracetam may be present in an amount from about 40% to about 80%, more preferably from about 50% to about 75% by weight of extended release composition.

In the preferred embodiment of the present invention Levetiracetam is granulated using aqueous granulation with a binder solution. The binder used is essentially important to impart compressibility, flow property and strength/hardness. The binder can be selected from Polyvinyl pyrrolidone, Hydroxypropyl cellulose, Hydroxypropyl Methylcellulose (low viscosity grade), methyl cellulose, starch, pregelatinized starch, modified corn starch, polyacryl amide, poly-N-vinyl amide, sodium carboxymethyl cellulose, polyethylene glycol, gelatin, polyethylene oxide, poly propylene glycol, tragacanth, alginic acid, combinations there of and other materials known to one of ordinary skill in the art. The binder may be present in an amount from about 0.01% to about 10%, preferably from about 0.5% to about 5% by weight of the extended release composition.

According to the embodiment of the present invention the active granules are blended with hydrophilic rate controlling polymer of high viscosity grade as a part of the matrix system. The high viscosity grade is the one which provide viscosity greater than 15 cps in a 2% w/w solution. The hydrophilic rate controlling polymer in the matrix system includes Hydroxyethyl cellulose, Hydroxypropyl cellulose, sodium alginate, carbomer (Carbopol™), sodium carboxymethyl cellulose, xanthan gum, guar gum, locust bean gum, poly vinyl acetate, polyvinyl alcohol and Hydroxypropyl Methylcellulose (high viscosity grade). The matrix forming polymer comprises from about 1% to about 50%, preferably from about 20% to about 40% by weight of the coated extended release composition.

In yet another embodiment the present invention discloses an extended release pharmaceutical composition of levetiracetam which does not exhibit a food effect. The present invention provides an extended release compositions of Levetiracetam which can be administered to a mammal (including humans) in fed state and which exhibits a mean (AUC _fasti_ng)/(AUC _fed) of at least 0.80. In particular, the present invention provides an extended release compositions of Levetiracetam which can be administered to a mammal (including humans) in fed state and which exhibits a mean (AUC _fas_ting)/(AUC _fΘd) of at least 0.80 and/or with a lower 90% confidence limit of at least 0.75.

According to the embodiment of the present invention, for definitional purposes, and specifically with respect to Levetiracetam extended release compositions only, a dosage form of Levetiracetam exhibits a food effect if, after dosing a population, once fasted and once fed, the mean (AUC _fas_ting)/(AUC_feCι) is below the value 0.80 and/or the lower 90% confidence limit for this ratio is below 0.75. Conversely, a dosage form of Levetiracetam which does not exhibit a food effect is one which, when tested on a test population, exhibits a value for (AUC _fas_ting)/(AUC_fed) of at least 0.80 and/or a lower 90% confidence limit for this value is at least 0.75. The value for mean (AUC _fa_sting)/(AUC_feCι) can be any value above 0.80 and still be within the scope of this invention, though it is preferred that it can have an upper (mean) limit of 1.25, and/or an upper 90% confidence limit of 1.40 or below.

In addition to the above ingredients the extended release tablets as described here also contains the lubricant, anti adherent and a glidant. Antiadherents include, by way of example and without limitation, magnesium stearate, talc, calcium stearate, glyceryl behenate, Polyethylene glycols, hydrogenated vegetable oil, mineral oil, stearic acid and other materials known to one of ordinary skill in the art. Glidants include cornstarch, talc, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one of ordinary skill in the art. Lubricants include, by way of example and without limitation, calcium stearate, magnesium stearate, sodium stearyl fumerate, glyceryl palmitostearate, glyceryl stearate, mineral oil, stearic acid, and zinc stearate and other materials known to one of ordinary skill in the art. The glidants, lubricants and anti adherents are individually present in the range from about 0.01% to about 5% w/w of the coated tablets. Preferably the glidants, anti adherents and lubricants are present in the range from about 0.5% to about 4% weight of the coated tablets, either alone or in combination.

The formed extended release tablets are coated with a hydrophobic rate controlling polymeric coat and the rate controlling polymeric coat is composed of hydrophobic polymer, hydrophobic or hydrophilic plasticizer and/ hydrophilic pore forming polymer (channeling agent). The hydrophobic film forming polymer is selected from the group consisting of cellulose ether such as ethyl cellulose, cellulose acetate, polyvinyl acetate, methacrylic acid esters neutral polymer, polyvinyl alcohol-maleic anhydride copolymers and the like. Even the commercially available dispersion of film formers namely, Eudragit L-30D, Eudragit NE 30D₁ Aquacoat ECD-30, Surelease E-7, Eudragit RS 30D₁ Eudragit RL 3OD, etc. may be used for the purpose of providing rate controlling coat. The hydrophilic pore forming polymer in the rate controlling coat is said to be selected from copolyvidone, Polyvinyl pyrrolidone, polyethylene glycols, Hydroxyethyl cellulose, Hydroxypropyl Methylcellulose (low viscosity grade). In the current embodiment, the water insoluble polymer is present in an amount from 40% to about 90%, preferably from about 50% to about 80% by weight of the functional coating layer of extended release composition. The water soluble pore forming polymer is present in an amount from about 10% to about 60%, preferably from about 15% to about 35% by weight of the coating layer. Additionally the coating dispersion may also comprise of plasticizer to modify the properties and characteristics of the polymers used on the coat of the compressed tablets. Plasticizers useful in the invention can include, by way of example and without limitation, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multi-block polymers, single block polymers, low molecular weight poly(ethylene glycol), citrate ester-type plasticizers, triacetin, propylene glycol and glycerin. Such plasticizers can also include ethylene glycol, 1 ,2- butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and other poly(ethylene glycol) compounds, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl, ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutylsebacate, acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and allyl glycolate. Also the combination of the plasticizers can be used in the present formulation. The composition in the present embodiment preferably comprises 1.0 to 10.0% of hydrophobic polymer per weight of the coated tablets; optionally up to 5% per weight of hydrophilic pore forming polymer of the coated tablets and optionally up to 2% of plasticizer per weight of the coated tablets.

According to the present invention, the non-functional coating is selected from the group of ready to form dispersion such as OPADRY. The OPADRY comprises of the hydrophilic (low viscosity grade) film forming polymer, suitable colorant and the opacifying agent. Opacifying agent include by titanium dioxide and other materials known to one of ordinary skill in the art. Colorant include, by way of example and without limitation, FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel, and ferric oxide, red, other F.D. & C. dyes and natural coloring agents such as grape skin extract, beet red powder, beta-carotene, annato, carmine, turmeric, paprika, and other materials known to one of ordinary skill in the art.

It should be understood, that compounds used in the art of pharmaceutical formulation generally serve a variety of functions or purposes. Thus, if a compound named herein is mentioned only once or is used to define more than one term herein, its purpose or function should not be construed as being limited solely to that named purpose(s) or function(s). Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. The following examples are given to illustrate the present invention. It should be understood that the invention is not to be limited to the specific conditions or details described in these examples.

EXAMPLES 1-2

TABLE 1

Composition

Sr. Weiαht in mgs

No. Ingredient Ex. 1 Ex. 2

1 Levetiracetam 500.00 500.00

2 Povidone 05.00 05.00

3 Purified water q.s. q.s.

4 Hydroxypropyl Methylcellulose (HV) 300.00 300.00

5 Magnesium Stearate 10.00 10.00

6 Colloidal silicon dioxide 5.00 5.00

7 Aqueous dispersion of Ethyl cellulose (solid — 24.30 content)

Total 820 844.30 q.s. means quantity sufficient.

Levetiracetam 500 mg was sifted through s. s. sieve of mesh 40 and was then granulated with aqueous Polyvinyl pyrrolidone solution and the granulated mass was dried at 50° C. The dried granules were sized through s. s. sieve of 20 mesh and these granules were blended with Hydroxypropyl Methylcellulose, lubricated with magnesium stearate and colloidal silicon dioxide and the lubricated granules were compressed into tablets.

As mentioned in Table 1 the tablets of example 2 were further coated with aqueous dispersion of hydrophobic rate controlling ethyl cellulose to weight gain of 2.96% w/w of the compressed tablet. Following the functional coating the tablets were cured at 55° C for 1 hour.

EXAMPLE 3

TABLE 2

Composition

Sr. Weight in mgs

No. Ingredient Ex. 3

1 Levetiracetam 500.00

2 Povidone 05.00

3 Purified water q.s.

4 Hydroxypropyl Methylcellulose (HV) 300.00

5 Magnesium Stearate 10.00

6 Colloidal silicon dioxide 5.00

7 Aqueous dispersion of Ethyl cellulose (solid 35.82 content)

8 Opadry 42.98

Total 898.80 q.s. means quantity sufficient.

Levetiracetam 500 mg was sifted through s. s. sieve of mesh 40 and was then granulated with aqueous Polyvinyl pyrrolidone solution and the granulated mass was dried at 50° C. The dried granules were sized through s. s. sieve 20 mesh and these granules were blended with Hydroxypropyl Methylcellulose, lubricated with magnesium stearate and colloidal silicon dioxide and lubricated granules were compressed into tablets. The compressed tablets were coated with the mixture of aqueous dispersion of ethyl cellulose and Opadry to a weight gain of 9.60% w/w of the compressed tablets. Following the functional coating the tablets were cured at 55° C for 1 hour. EXAMPLE 4

TABLE 3

Composition

Sr. Weight in mgs

No. Ingredient Ex. 4

1 Levetiracetam 500.00

2 Povidone 10.00

3 Purified water q.s.

4 Hydroxypropyl Methylcellulose (HV) 285.00

5 Magnesium Stearate 10.00

6 Colloidal silicon dioxide 5.00

7 Opadry 16.30

8 Talc 5.00

Total 831.30 q.s. means quantity sufficient.

Levetiracetam 500 mg was sifted through s. s. sieve of mesh 40 and was then granulated with aqueous Polyvinyl pyrrolidone solution and the granulated mass was dried at 50°. The dried granules were sized through s. s. sieve of 20 mesh and these granules were blended with Hydroxypropyl Methylcellulose, lubricated with magnesium stearate, talc and colloidal silicon dioxide and lubricated granules were compressed into tablets. The compressed tablets were coated with Opadry to a weight gain of 2% w/w of the compressed tablets.

EXAMPLES 5-6

TABLE 4

Composition

Sr. Weiqht in mqs

No. Ingredient Ex. 5 Ex. 6

1 Levetiracetam 500.00 500.00

2 Povidone 10.00 10.00

3 Purified water q.s. q.s.

4 Hydroxypropyl Methylcellulose (HV) 285.00 285.00

5 Magnesium Stearate 10.00 10.00

6 Colloidal silicon dioxide 5.00 5.00

7 Aqueous dispersion of Ethyl cellulose (solid 15.28 30.56 content)

8 Opadry 16.71 17.12

9 Talc 5.00 5.00

10 Hydroxypropyl Methylcellulose (LV) 5.10 10.19

Total 852.09 872.87 q.s. means quantity sufficient.

Levetiracetam 500 mg was sifted through s.s. sieve of mesh 40 and was then granulated with aqueous Polyvinyl pyrrolidone solution and the granulated mass was dried at 50° C. The dried granules were sized through s. s. sieve of 20 mesh and these granules were blended with Hydroxypropyl Methylcellulose, lubricated with magnesium stearate, talc and colloidal silicon dioxide and the lubricated granules were compressed into tablets.

The tablets of example 5 and 6, as mentioned in the table 4, were coated with mixture of aqueous dispersion of ethyl cellulose and Hydroxypropyl Methylcellulose (LV; low viscosity) in the ratio of 75:25 (solid content). The tablets were coated to target weight gain of 2.5% w/w and 5.0% w/w of the compressed tablets for example 5 and example 6 respectively. Following the coating the tablet were cured at 65° C for 1 hr. The coated tablets were further coated with Opadry to a weight gain of 2% w/w of the functional coated tablet.

EXAMPLE 7

The extended release tablets of Examples 1 to Example 6 were tested for dissolution of Levetiracetam using 900 ml of pH 6.8 phosphate buffer as dissolution media at 37° C and in 40-mesh basket (USP Type 1) at 100 rpm

The dissolution profiles are recorded in Table 5.

TABLE 5

Dissolution Profile

Percentage Levetiracetam dissolved Time (hrs) Ex.1 Ex.2 Ex.3 Ex.4 Ex.5 Ex.6

1 26 0 16 30 16 10

2 40 3 30 43 30 23

3 51 7 41 53 41 34

4 60 14 51 61 51 43

6 75 27 67 74 66 58

8 88 41 81 83 80 69

10 98 54 94 90 90 78

12 105 66 103 94 99 85

EXAMPLE 8

TABLE 6

Composition

Sr. Weight in mgs

No. Ingredient Ex. 8

1 Levetiracetam 750.00

2 Povidone 15.00

3 Purified water q.s.

4 Hydroxypropyl Methylcellulose (HV) 316.00

5 Magnesium Stearate 12.00

6 Colloidal silicon dioxide 6.00

7 Talc 6.00

8 Aqueous dispersion of Ethyl cellulose (solid 16.58 content)

9 Opadry 22.54

10 Hydroxypropyl Methylcellulose (LV) 5.52

Total 1149.64 q.s. means quantity sufficient.

Levetiracetam 750 mg was sifted through s. s. sieve of mesh 40 and was then granulated with aqueous Polyvinyl pyrrolidone solution and the granulated mass was dried at 50° C. The dried granules are sized through s. s. sieve of 20 mesh and these granules were blended with Hydroxypropyl Methylcellulose and then lubricated with magnesium stearate, colloidal silicon dioxide and talc and the lubricated granules were compressed into tablets.

The tablets as mentioned in the table 6, were coated with mixture of aqueous dispersion of ethyl cellulose and Hydroxypropyl Methylcellulose LV in the ratio of 75:25 (solid content). The tablets were coated to target weight gain of 2.0% w/w. Following the coating the tablet were cured at 65⁰C for 1 hr. The coated tablets were further coated with Opadry to a weight gain of 2% w/w of the functional coated tablet.

EXAMPLE 9

TABLE 7

Composition

Sr. Weight in mgs

No. Ingredient Ex. 9

1 Levetiracetam 750.00

2 Carbopol (71 G) 330

3 Glyceryl Behenate 15

4 Colloidal silicon dioxide 5

5 Talc 5

Total 1105 q.s. means quantity sufficient.

Levetiracetam 750 mg and carbopol were sifted through s. s. sieve of mesh 30 and were blended together. The blend was lubricated with glyceryl behenate, colloidal silicon dioxide and talc and the lubricated blend was compressed into tablets.

EXAMPLE 10

TABLE 8

Composition

Sr. Weight in mgs

No. Ingredient Ex. 10

1 Levetiracetam 750.00

2 Polyvinyl Acetate 275

3 Glyceryl Behenate 15

4 Colloidal silicon dioxide 5

5 Talc 5

6 Aqueous dispersion of Ethyl cellulose (solid 15.00 content)

7 Opadry 20

8 Hydroxypropyl Methylcellulose (LV) 5

Total 1145 q.s. means quantity sufficient.

Levetiracetam 750 mg and Kollidon SR (Polyvinyl Acetate: Polyvinyl Pyrolidone, 8:2) were sifted through s. s sieve of mesh 30 and blended together. The blend was lubricated with glyceryl behenate, colloidal silicon dioxide and talc and the lubricated blend was compressed into tablets. ' The tablets as mentioned in the table 8, were coated with mixture of aqueous dispersion ^'of ethyl cellulose and Hydroxypropyl Methylcellulose (LV) in the ratio of 75:25 (solid content). The tablets were coated to target weight gain of 1.90% w/w of the uncoated tablets. Following coating the tablet were cured at 65° C for 1 hr.

The functional coated tablets were further coated with Opadry to a weight gain of 1.87% w/w of the functional coated tablet. EXAMPLE 11

TABLE 9

Composition

Sr. Weight in mgs

No. Ingredient Ex. 11

1 Levetiracetam 750.00

2 Hydroxypropyl Methylcellulose (HV) 350

3 Magnesium stearate 12.00

4 Colloidal silicon dioxide 6.00

5 Talc 6.00

6 Aqueous dispersion of Ethyl cellulose (solid 15.00 content)

7 Opadry 20

8 Hydroxypropyl Methylcellulose (LV) 5

Total 1164 q.s. means quantity sufficient.

Levetiracetam 750 mg and hydroxyl propyl methyl cellulose (HV) were sifted through s. s. sieve of mesh 40 and blended together. The blend was compacted using a roll compactor (Chilsonator) to form slugs. The slugs were sized in an oscillating granulator using a s. s. sieve of mesh 20. Obtained granules were lubricated with magnesium stearate, colloidal silicon dioxide and talc. The lubricated blend was compressed into tablets.

The tablets as mentioned in the table 9 were coated with mixture of aqueous dispersion of ethyl cellulose and Hydroxypropyl Methylcellulose (LV) in the ratio of 75:25 (solid content). The tablets were coated to target weight gain of 1.78% w/w of the uncoated tablets. Following the coating the tablet were cured at 65° C for 1 hr.

The functional coated tablets were further coated with Opadry to a weight gain of 1.75% w/w of the functional coated tablet. EXAMPLE 12

TABLE 10

Composition

Sr. Weight in mgs

No. Ingredient Ex. 12

1 Levetiracetam 750.00

2 Hydroxypropyl Methylcellulose (HV) 271

3 Hydroxypropyl cellulose 45.00

4 Magnesium stearate 12.00

5 Colloidal silicon dioxide 6.00

6 Talc 6.00

7 Aqueous dispersion of Ethyl cellulose (solid 15.00 content)

8 Opadry 20

9 Hydroxypropyl Methylcellulose (LV) 5

Total 1164 q.s. means quantity sufficient.

Levetiracetam 750 mg and Hydroxylpropyl Methylcellulose (HV) were sifted through s. s. sieve of mesh 40 and blended together. The blend was granulated using nonaqueous granulation using Hydroxypropyl Cellulose as the binder. The granulated mass was dried at 45° C. The dried granules were sized through s. s. sieve of mesh 20 and the granules were lubricated with Magnesium Stearate, Talc and Colloidal Silicon dioxide. The lubricated blend was compressed into tablets.

The tablets as mentioned in the table 10 were coated with mixture of aqueous dispersion of ethyl cellulose and Hydroxypropyl Methylcellulose LV in the ratio of 75:25 (solid content). The tablets were coated to target weight gain of 1.78% w/w of the uncoated tablets. Following the coating the tablet were cured at 65° C for 1 hr.

The coated tablets were further coated with Opadry to a weight gain of 1.75% w/w of the functional coated tablet. EXAMPLE 13

TABLE 11

Composition

Sr. Weight in mgs

No. Ingredient Ex. 13

1 Levetiracetam 750.00

2 Hydroxypropyl cellulose 45.00

3 Hydroxyethyl cellulose (HV) 271

4 Magnesium stearate 12.00

5 Colloidal silicon dioxide 6.00

6 Talc 6.00

7 Aqueous dispersion of Ethyl cellulose (solid 15.00 content)

8 Opadry 20

9 Hydroxypropyl Methylcellulose (LV) 5

Total 1164 q.s. means quantity sufficient.

Levetiracetam 750 mg was sifted through s. s. sieve of mesh 40 and was then granulated with non aqueous Hydroxypropyl cellulose solution and the granulated mass was dried at 45° C. The dried granules are sized through s. s. sieve of mesh 20 and these granules were blended with Hydroxyethyl cellulose and lubricated with magnesium stearate, colloidal silicon dioxide and talc. The lubricated granules were compressed into tablets.

The tablets as mentioned in the table 11, were coated with mixture of aqueous dispersion of ethyl cellulose and Hydroxypropyl Methylcellulose (LV) in the ratio of 75:25 (solid content). The tablets were coated to target weight gain of 1.78% w/w. The coated tablet were cured at 65° C for 1 hr.

The functional coated tablets were further coated with Opadry to a weight gain of 1.75% w/w of the functional coated tablet. EXAMPLE 14

The extended release tablets of Examples 8 to Example 13 were tested for dissolution of Levetiracetam using 900 ml of pH 6.8 phosphate buffer as dissolution media at 37° C and in 40-mesh basket (USP Type 1) at 100 rpm The dissolution profiles are recorded in Table 12.

TABLE 12

Dissolution Profile

Percentage Levetiracetam dissolved Time (hrs) Ex.8 Ex.9 Ex.10 Ex.11 Ex.12 Ex.13

1 17 23 9 18 6 6

2 30 44 26 33 12 30

3 41 59 45 45 22 48

4 49 72 59 55 31 60

6 63 91 78 72 49 82

8 76 101 93 85 66 94

10 85 99 98 95 79 99

12 91 98 97 101 91 97

EXAMPLE 15 An in vivo study was conducted in healthy human volunteers to assess bioavailability of Levetiracetam formulated as the extended release tablets of Example 8 by comparison with a reference treatment with immediate release Levetiracetam tablets.

Method The study followed an open label, two-treatment, two-periods, comparative oral bioavailability study in healthy, adult, male, human subjects under fed conditions. The subjects received each of the two treatments during the course of the study, which was conducted at a single center. The subjects were given 1500 mg oral dose of Levetiracetam. In the case of the IR formulation, which was provided as Keppra^® tablets, two equally divided doses of 750 mg each were given at 12 hour interval beginning in the morning. In the case of the extended release formulation of Example 8, two tablets of 750 mg were given at a time in the morning. Plasma Levetiracetam concentrations were quantified by HPLC method. Samples were not diluted prior to analysis as all sample concentrations were within the limits of quantitation. Pharmacokinetic parameters for Levetiracetam were estimated by non compartmental methods. The parameters Tmax, Cmax, AUC_0→t, AUC₀-_*.= were estimated during the studies and recorded in Table 13.

Results

Mean plasma Levetiracetam concentrations over the 36 hour assessment period are shown in FlG. 2.

TABLE 13

Parameter Unit Formulation of Keppra Example 8 tablets 750 mg

Cmax μg/ml 17.194 ± 4.23 22.23 ± 5.44 Tmax Hrs 12-13 2-3 and 14-15 AUC (O →t) μg.h/mL 345.81 ± 105.45 375.267 ± 76.86 AUC (O →inf) μg.h/mL 383.855 ± 125.87 413.854 ± 91.50

EXAMPLE 16-18

TABLE 14

Composition

Sr. Weight in mgs No. Ingredient Ex. 16 Ex. 17 Ex. 18

1 Levetiracetam 750.00 500.00 1000 2 Povidone USP 10.00 10.00 20 (Piasdone K 90 D)

3 Purified water q.s. q.s. q.s. 4 Hypromellose 2208 (Methocel 250.00 167.00 333 KIOOM CR) USP

5 Hypromellose 2208 (Methocel 41.00 27.00 55 KIOO LV) USP

6 Colloidal silicon dioxide 6 4 8

7 Magnesium Stearate NF 12 8 16

8 Talc BP 6 4 8

9 Ethyl cellulose 7 cps 19.65 13.10 26.20

10 Polyethyleneglycol 4000 7.56 5.04 10.08

11 Methocel E-3 (Hypermellose 2910) 10.58 7.06 14.12

Total 1117.80 745.20 1490.4 q.s. means quantity sufficient.

Levetiracetam 750 mg was sifted through s. s. sieve of mesh 40 and was then granulated with aqueous Polyvinyl pyrrolidone solution and the granulated mass was dried at 45° C. The dried granules are sized through s. s. sieve of mesh 20 and these granules were blended with Hypermellose 2208 and lubricated with magnesium stearate, colloidal silicon dioxide and talc. The lubricated granules were compressed into tablets.

The tablets as mentioned in the table 14, were coated with mixture of aqueous dispersion of ethyl cellulose and Hydroxypropyl Methylcellulose (E-3) and polyethylene glycol. The tablets were coated to target weight gain of 3.5% w/w. The coated tablets were cured at 65° C for 1 hr.

The functional coated tablets were further coated with Opadry to a weight gain of 2.5% w/w of the functional coated tablet.

EXAMPLE 19

The extended release tablets of Examples 16-18 were tested for dissolution of Levetiracetam using 900 ml of pH 6.8 phosphate buffer as dissolution media at 37° C and in 40-mesh basket (USP Type 1) at 100 rpm

The dissolution profiles are recorded in Table 15. TABLE 15

Dissolution Profile

Percentaqe Levetiracetam dissolved

Time(hrs) Ex.16 Ex.17 Ex.18

1 20 16 14

2 35 31 29

3 46 44 39

4 55 53 49

6 69 67 63

8 79 77 72

10 87 86 80

12 93 91 86

A randomized two-treatment, two period, cross-over pharmacokinetic study was conducted in eighteen healthy, adult, male human subjects in both fast and fed conditions for the above formulations and the data obtained was compared with the data of Keppra^® tablets.

Results

The following are a tabulation of the results of the study in both fast and fed conditions. Comparison of data of the Tablet of Example 16 and Keppra tablets in fasting conditions

Table 16

Parameter Unit Keppra™ Example 16

Cmax ng/ml 31.49±5.34 20.46±2.08

Tmax Hrs 13.01±0.55 9.88±2.39

AUC (0-t) ng.h/mL 469.98±35.50 432.098+55.11

AUC (O-inf) ng.h/mL 516.99±46.03 462.93±65.25 Comparison of data of the invention of Example 16 and Keppra tablets in fed conditions

Table 17

Parameter Unit Keppra^® Example 16

Cmax ng/ml 27.22±3.43 20.50±3.32

Tm ax Hrs 12.59±4.48 13.22±2.81

AUC (0-t) ng.h/mL 461.31±57.66 450.12+62.65

AUC (O-inf) ng.h/mL 507.78±75.20 497.27±73.63

As can be seen from the above data, the AUC_fasted/AUC_feCι for example 16 is 0.96 for

AUC (O-D ^and °-⁹³ for AUC (o-inf). .

Although certain presently preferred embodiments of the invention have been specifically described herein, it will be apparent to those skilled in the art to which the invention pertains that variations and modifications of the various embodiments shown and described herein may be made without departing from the spirit and scope of the invention. Accordingly, it is intended that the invention be limited only to the extent required by the appended claims and the applicable rules of law.

Claims

1. An extended release composition of Levetiracetam, which exhibits no adverse food effect, comprising from about 30% w/w to about 85% w/w of Levetiracetam and about 1 % w/w to about 50% w/w of the composition of a water dispersible rate controlling polymer.

2. An extended release composition formulation according to claim 1, wherein the composition is in tablet form and wherein said tablet exhibiting a value of (AUC_fed)/(AUC_fasted) of at least 0.80 with a lower 90% confidence limit of at least 0.75.

3. An extended release composition formulation according to claim 1, wherein the composition is in tablet form and wherein said tablet 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.

4. An extended release composition formulation according to claim 1 , wherein when orally administered to a patient in need thereof provides a peak plasma level of Levetiracetam in from about eight to about sixteen hours and provides extended therapeutically effective plasma levels over a twenty four hour period with diminished incidences of neuropsychiatric adverse events by eliminating the troughs and peaks of drug concentration in vivo.

5. An extended release composition according to claim 1 , wherein the composition is in tablet form and wherein the tablet is comprised of from about 50% to 80% Levetiracetam w/w of the tablet and about 20% to about 40% w/w of the tablet hydroxypropyl methylcellulose.

6. An extended release composition according to claim 5, wherein the tablet further comprises about 1 % to about 5 % w/w of the tablet povidone.

7. An extended release composition according to claim 6, wherein the tablet is coated with a functional coat comprising of ethyl cellulose, hydroxypropyl methylcellulose and polyethylene glycol.

8. An extended release composition according to claim 1, wherein the composition is in tablet form and wherein the tablet is coated with a functional coat of about 1%w/w to about 12%w/w of the tablet weight, said functional coat comprising of from about 70% to about 80% w/w of the functional coat of ethyl cellulose, from about 20% to about 30% w/w of the functional coat of hydroxypropyl methylcellulose and from 10 to about 20% w/w of the functional coat of polyethylene glycol.

9. An extended release composition according to claim 1 wherein the composition is in tablet form and wherein the tablet is coated with a functional coat of about 1%w/w to about 12%w/w of the tablet weight, said functional coat comprising of from about 70% to about 80% w/w of the functional coat of ethyl cellulose and from about 20% to about 30% w/w of the functional coat of lactose.

10. An extended release composition according to claim 1 wherein the composition is in tablet form and has the following dissolution profile in USP Apparatus 1 (basket) at 100 rpm in purified water at 37° C:

Time (hours) Average % Levetiracetam released

2 <35

4 35-75

12 >75

11. An extended release composition according to claim 1 , wherein the composition is in tablet form and wherein the tablet is comprised of from about 61% to 73% w/w of the tablet Levetiracetam and about 25% to about 35% w/w. of the tablet of hydroxypropyl methylcellulose

12. An extended release composition according to claim 11 , wherein the tablet further comprises from about 1.1 % to about 1.5 % w/w of the tablet of povidone.

13. An extended release composition according to claim 11 , wherein the tablet is coated with a functional coat of about 1.0% to about 6.0 % w/w of the tablet, said functional coat comprising of about 75% w/w of the functional coat of ethyl cellulose and about 25% w/w of the functional coat of hydroxypropyl methylcellulose.

14. An extended release composition according to claim 11 , wherein the tablet is coated with a functional coat comprising of ethyl cellulose, hydroxypropyl methylcellulose and polyethylene glycol.

15. An extended release composition according to claim 1, wherein the composition is in tablet form and wherein said tablet is coated with a functional coat of about 1-6% w/w of the tablet.

16. An extended release composition according to Claim 15, wherein the functional coat comprises of ethyl cellulose having a 44.0-51.0% content of ethoxy groups and hydroxypropyl methylcellulose having viscosity of 2 - 6 cps at 2% aqueous solution with a methoxy content of 28.0-30.0% and a hydroxypropoxy group content of 7.0-12.0%.

17. An extended release composition according to claim 1, wherein the composition is in tablet form and wherein the tablet is prepared by wet granulation, dry granulation or direct compression.

18. An extended release composition according to claim 1 , wherein the composition is in tablet form and wherein the tablet is prepared by wet granulation, dry granulation or direct compression and the core is coated either in a coating pan or in a fluidized bed system.

19. The extended release composition of Claim 1 wherein the composition is in tablet form and wherein the hydrophilic polymer is in the form of Opadry ready mix.