Technical Field of the Invention
The present invention relates to tablet formulations which consist essentially of levetiracetam, binders and disinlegranis in specific concentrations. The resultant formulation is stable and can also be manufactured using conventional tablet manufacturing processes.
Background of the Invention
l.eveliiaceiam is an aniiepileptic drug which is chemically unrelated to existing antiepileptic drugs (AFDs) It is a single enantiomer, the S-form of the pyrrolidone etiracetam, chemically known as (-)-(S)-α-ethtl-2-o\o-l-pvrrolidineacetamide. The US Patent Number 4,943,639 discloses levetiracetam and also describes process for its preparation
Leveiiracelam is indicated as monotherapy in the treatment of partial onset seizures with or without sccondaiy 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. Commercially it is available in strengths of 250mg, 500mg, 750mg and 1000mg film-coated immediate release tablets; 100mg/mL oral solution and 100mg/mL concentrate for solution for infusion under the hi and name KEPPRA" by UCB S.A . Brussels, Belgium The US Patent Number 4,837,223 describes a pharmaceutical composition comprising a therapeutically effective amount of levetiracetam and a phaimacculicall) acceptable solid or liquid diluent or carrier therefor.
1 he prior an discusses different approaches for formulating solid dosage forms of levetiracetam.
The PC"! Application WO/2007/012439 relates to solid dosage forms with improved stability as compared to the conventional immediate release levetiracetam compositions, wherein the composition has
2 0 to 9 0% (w/w) of disintegrant, 0.0 to 3.0% (w/w) of gliding agent, 0.5% to 6.0% (w/w) of binder, and
() 0 to I 0% (w/w) of lubricant. It also teaches that such formulations are preferably not prepared by
conventional wet granulation process which may cause degradation of levetiracetam upon contact with
the liquid phase
I"he PC 1 application WO/2006/102750 discloses a process for the preparation of a solid oral composition of leveiiraeetam. wherein the process comprises wet granulation of a pharmaceutical blend comprising the drug and simultaneous fluid bed drying of the blend.
I he PCT application WO/2007/086891 relates to a stable and substantially glidant free levetiracetam composition.
The PCT application WO/2009/049642 teaches an improved formulation of levetiracetam comprising calcium dibasic phosphate, which improves the friability, harness and flow properties of the formulation.
The PCT application WO/2009/135646 relates to a stable immediate release levetiracetam composition which is free of a disintegrant
In the present case, the inventors have identified other methods of formulating levetiracetam into solid dosage formulations, particularly tablets which: are stable throughout the process of manufacturing as well as the shell' life of the dosage form; do not exhibit complexities from the manufacturing point of view, arc bioavailable and patient compliant.
Summary of the Invention
In one general aspect, it relates to a levetiracetam tablet consisting essentially of:
a) at least about 65% (w/w) of levetiracetam;
b) one or more binder(s) in an amount of > 6% (w/w) to about 25% (w/w); and
c) at least one disintegrant.
wherein all weights are based on total weight of the said tablet.
In another general aspect, it relates to a levetiracetam tablet consisting essentially of:
a) at least about 65% (w/w) of levetiracetam;
b) one or more binder(s) in an amount of < 6%(w/w); and
c) one or more dismtegrant(s) in an amount > 9% (w/w); wherein all weights are based on total weight of the said tablet
In one embodiment of the above aspects, the said binder(s) is present intragranularly, extragranularly, or as a combination thereof
In another embodiment of the above aspects, the said disintegrant(s) is present intragranularly, entagianulaily. or as a combination thereof.
In another embodiment of the above aspects, the said tablet is an immediate release tablet.
In one embodiment it relates to a process of preparation of a levetiracetam tablet as described in the above aspects
Detailed Description of the Invention
1 he term "tablet" as described herein includes without limitation, immediate release coated as well as uncoated tablets, caplets. minitablets and the like. One or more such tablets may further be filled into a capsule
The leeital of the term "consisting essentially of renders that the levetiracetam tablet described herein provides only for the inclusion of ingredients which would not materially affect the basic and novel charaetetisltes of the tablet defined in the present invention.
The said tablet composition according to the present invention is intended to deliver a therapeutically effective amount of levetiracetam to a patient, wherein the term "therapeutically effective amount" intends to describe an amount of the active agent which stops or reduces the progress of the condition to be treated or which otherwise completely or partly cures or acts palliatively on the condition. Alternately the lecommcnded dosage of KEPPRA may be considered as a standard dose. The amount of levethractam present in the said levetiracetam tablet is at least about 65% (w/w), particularly about 75% (\\/v\). more particular!) about 85 % (w/w), based on total weight of the tablet.
Bindeis are the adhesives that are added to the tablet formulation to provide the cohesiveness essential for the bonding of the solid particles (tor e.g. granules) under compaction to form a tablet. The use of binder in appropriate concentrations helps in formulating a tablet that would provide appropriate hardness and at the same time not hinder the release of the active agent.
DIM mediants and superdisintegrants are agents added to tablet formulations to promote the breakup of the tablet into smaller fragments in an aqueous environment thereby increasing the available surface area and
promoting a more rapid release of the drug substance. Basically, the purpose of the disintegrant is to oppose the efficiency of the tablet binder and the physical forces that act under compression to form a table The stronger the binder, more effective should be the disintegrating agent in order for the tablet to release the active ingredient.
There lore, it is obvious from the above that binders and disintegrants perform antagonistic functions in a tablet dosage form and the concentrations in which they are used are significant for the efficient release of the active ingredient from the tablet dosage form.
In one aspect of the invention described herein, the amount of binder is > 6% (vv/w) to about 25% (w/vv), pailicularlv in an amount of about 10% (w/vv) to about 20% (w/w), by total weight of the tablet.
In another aspect of the invention described herein,
- v\ hen the amount of binder is < 6% (w/w),
- the amount of disintegrant is in an amount of > 9% (w/w), wherein, all weights are based on the total weight of the tablet.
One or more of binders may be present extragranularly, intragranularly or as a combination thereof.
One or more of disintegrants ma> be present extragranularly, intragranularly or as a combination thereof.
Binders thai may be used encompasses, without limitation, starch and derivatives like corn starch and pregelatmized starch; microcrystalline cellulose, cellulose ethers such as carboxymethyl cellulose, methvlcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose; carboxy vinyl polymers like carbomers. acrylates such as Eudragits; polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolvmer anthan gum. guar gum and combinations thereof. Particularly, silicified microcrystalline cellulose and combinations of silicified microcrystalline cellulose with other excipients which are also commercially available under the trade name Prosolv® from JRS Pharma may be used. In one embodiment, silicified microcrystalline cellulose, corn starch and polyvinylpyrrolidone are used as binders In another embodiment, the binder used is hydroxypropyl methylcellulose.
Disintegiants and superdisinlegrants may be selected from the group consisting of alginic acid, earhowmeilnlcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, erosearmellose sodium, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, guar gum, magnesium
aluminium silicate, sodium starch glycolate, corn starch, potato starch, pregelatinized starch, low-substriuted hydroxypropylcellulose, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, and methacrylic acid divinylbenzene copolymer salts. In one embodiment the disintegrant is crosslinked polyvinylpyrrolidone. In another embodiment the disintegrant is croscarmellose sodium.
The tablets described may further comprise of other pharmaceutical ly acceptable excipient(s) which when used would not materially affect the basic and novel characteristics of the product defined in the present invention I he term "pharmaceutically acceptable excipients" as recited herein includes conventional pharmaceutical additives known in the art, such as diluent(s), lubricants(s), granulating solvent(s), glidants(s) or combinations thereof.
Diluents that may be used may be exemplified, but are not limited to, saccharides like lactose, dextrose, suciosc. fructose, maltose, sugars like mannitol. erythritol, sorbitol, xylitol and lactitol; cellulose derivatives like powdered cellulose, microcrystalline cellulose, and the like.
Lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, powdered stearic acid, magnesium oleate, calcium palmitate, potassium laureate, sodium suberate, vegetable oil. mineral oil and the like. Glidants may be selected from talc, colloidal silicon dioxide, corn starch and the like.
Suitable granulating solvents may be used which include without limitation, water, ethanol, methanol, isopropyI alcohol, methylene chloride, acetone and the like.
The levehracetam tablets as described herein may be formulated following any conventional techniques known in the art. namely aqueous or non-aqueous wet granulation.
The lewtiracelam tablets, as disclosed herein may optionally be coated using conventional non-functional coaling compositions, which are available under the trade name of Opadry, Opaspray, from Colorcon Limited. UK
In one embodiment, a levetiracetam tablet consists essentially of
a) about 66% (w/w) of levetiracetam;
b) about 9% (w/w) of binder; and
b) about 20% (w/w) of binder; and e) a disintegrant.
In one embodiment, a levetiracetam tablet consists essentially of: u) about 66% (w/w) of levetiracetam; b) about 2% (w/w) of binder; and e) about 10% (w/w) of disintegrant.
In one embodiment, a levetiracetam tablet consists essentially of:
a) about 85% (w/w) of levetiracetam;
b) about 2% (w/w) of bi nder; and
c) about 10% (w/w) of disintegrant.
In one aspect of the above embodiments, the said binder is present intragranularly, extragranularly, or as a combination thereof.
In one aspect of the above embodiments, the said disintegrant is present intragranularly, extragranularly, or as a combination thereof
In one aspect of the above embodiments, the binder is selected from hydroxypropyl methylcellulose. poly\m\lp\rrolidone, starch, silicified microcrystalline cellulose and combinations thereof.
In one aspect of the above embodiments, the disintegrant is selected from croscarmellose sodium, uosslinked polyvinylpyrrolidone and combinations thereof.
In one embodiment, the process of preparation of a levetiracetam tablet comprises the following steps:
(a) Levetiracetam is sifted and loaded in a rapid mixer granulator.
(b) The intiagranular binders) is dissolved in the granulating fluid to obtain the granulating solution.
(c) The levetiracetam in step (a) is granulated using the granulating solution in step (b).
(d) The wet mass obtained in step (c) is dried and sieved to obtain granules.
(e) The granules in step (d) are blended with diluent (s), extragranular binder(s), disintegrant(s), lubricant(s), glidant(s).
(I) The homogeneous blend of step (e) is compressed into tablets using appropriate tooling.
L) a disintegranl.
In one embodiment, a levetiracetam tablet consists essentially of
a) about 66% (w/w) of levetiracetam;
b) about l2%(\v/w)of binder; and
c) a dismtegrant
In one embodiment, a levetiracetam tablet consists essentially of .1) about 66% (w/w) of levetiracetam; b) about 15% (w/w) of binder; and u a disintegranl
In one embodiment, a levetiracetam tablet consists essentially of
a) about 66% (w/w) of levetiracetam;
b) about 20% (w/w) of binder; and
c) a disintegrant.
In one embodiment, a levetiracetam tablet consists essentially of:
a) about 85% (w/w) of levetiracetam;
b) about 9% (w/w) of binder; and
c) a disintegranl.
In one embodiment, a levetiracetam tablet consists essentially of
a) about 85% (w/w) of levetiracetam;
b) about 12% (w/w) of binder; and
c) a disintegrant
In one embodiment, a levetiracetam tablet consists essentially of
a) about 85% (w/w) of levetiracetam;
b) about 15% (w/w) of binder; and
c) a disintegrant
In one embodiment, a levetiracetam tablet consists essentially of a) about 85% (w/w) of levetiracetam;
In one embodiment, the process of preparation of a levetiracetam tablet comprises the following steps:
(a) Levetiracetam is mixed with intragranular disintegrant(s) in a rapid mixer granulator.
(b) The intragranular binder(s) is dissolved in the granulating fluid to obtain the granulating solution.
(c) The levetiracetam in step (a) is granulated using the granulating solution in step (b).
(d) The wet mass obtained in step (c) is dried and sieved to obtain granules.
(e) The granules in step (d) are blended with diluent (s), extragranular binders), extragranular dismtegrant(s), lubricant(s), glidant(s).
(0 The homogeneous blend of step (e) is compressed into tablets using appropriate tooling.
From the above it is apparent that various modifications and combinations of the formulations detailed in the tell ma\ be made without departing from the spirit and scope of the invention. The invention as described herein ma\ be illustrated by the following examples but is not to be construed to be limiting by them
Examples 1-3:
(Table Removed)

General Procedure for Examples 1.2 and 3:
Levetiracetam was per se (Example 1) or was mixed with intragranular excipient(s) other than the binder(s) (in case of Examples 2 and 3) in a rapid mixer granulator. The intragranular binder(s) (Polyvinylpyrrohdone and corn starch in Example 1 and Hydroxypropyl methylcellulose in Example 2) was/werc dissolved in the granulating fluid (water) to obtain the granulating solution. The granulating solution so obtained was used to granulate the sifted/blended levetiracetam. The resultant wet mass was dried in a fluidized bed dryer and sieved to obtain granules of appropriate size range. The sized granules so obtained were blended with the extragranular excipient(s), compressed into tablets using appropriate tooling, and further coated using Opadry solution.

We claim:
1) A levetiracetam tablet consisting essentially of:
a) at least about 65% (w/w) of levetiracetam;
b) one or more binder(s) in an amount of > 6% (w/w) to about 25% (w/w); and
c) at least one disintegrant;
wherein all weights are based on total weight of the said tablet.
2) A le\etiracetam tablet consisting essentially of:
a) at least about 65% (w/w) of levetiracetam;
b) one or more binder(s) in an amount of < 6% (w/w); and
c) one or more disintegrant(s) in an amount > 9% (w/w); wherein all weights are based on total weight of the said tablet.
3) A levetiracetam tablet according to claims 1 and 2, wherein the binder(s) is present intragranularly,
exlragranularly, or as a combination thereof.
4) A levetiracetam tablet according to claims 1 and 2, wherein the disintegrant(s) is present
inlragranularly. extragranularly, or as a combination thereof.
5) A levetiracelam tablet according to claims 1 and 2, wherein the tablet is an immediate release tablet.
6) A levetiracetam tablet according to claims 1 and 2, wherein the binder is selected from a group consisting of starch, pregelatinized starch, microcrystalline cellulose, silicified microcrystalline cellulose, carbox)methyl cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose; carboxy vinyl polymers, acrylates. polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, xanthan gum. guar gum. and combinations thereof.
7) A levetiracetam tablet according to claims 1 and 2, wherein the disintegrant is selected from a group consisting of alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, guar gum. magnesium aluminium silicate, sodium starch glycolate, corn starch, potato starch, pregelatinized starch, low-substituted hydroxypropylcellulose, methylcellulose, microcrystalline cellulose, polacrilin
potassium, powdered cellulose, pregelatinized starch, sodium alginate, methacrylic acid divinylbenzene copolymer salts and combinations thereof.
8) A process of preparation of a levetiracetam tablet according to claims 1 and 2, wherein the process
comprises of wet granulation.
9) A levetiracetam tablet and process for the preparation thereof substantially as described and illustrated
by examples herein.