FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
STABLE PHARMACEUTICAL
COMPOSITIONS OF
LEVETIRACETAM AND PROCESS
FOR PREPARATION THEREOF
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near
Dinesh Hall, Ahmedabad 380 009,
Gujarat, India
The following specification describes the invention:
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FIELD OF THE INVENTION
The present invention relates to a stable pharmaceutical composition of levetiracetam and process for preparation thereof.
BACKGROUND OF THE INVENTION
Levetiracetam, chemically known as (S)-α-ethyl-2-oxo-1-pyrrolidineacetamide, is an antiepileptic drug which may be used as adjunctive therapy in the treatment of partial onset seizures in adults with epilepsy and also as adjunctive therapy in the treatment of myoclonic seizures with juvenile myoclonic epilepsy. Levetiracetam is a known compound and its preparation is disclosed in, for example, U.S. 4,943,639 and US 4,837,223. Oral solid pharmaceutical compositions, like tablets, of levetiracetam are also disclosed in the art. Levetiracetam oral tablets, sold under the brand name Keppra® by UCB SA, are available in strengths of 250 mg, 500 mg, 750 mg and 1000 mg. The tablets contain inactive ingredients maize starch, povidone K30, talc, colloidal anhydrous silica, magnesium stearate etc.
WO 2007/12439 A1, assigned to UCB SA, describes that pharmaceutical compositions comprising levetiracetam may present modified kinetics of release of the active ingredient as times goes along and this may lead to a slower release in time of the active ingredient and thus to reduced stability of the pharmaceutical composition. It is also described therein that existing pharmaceutical composition comprising levetiracetam are manufactured by a wet granulation process and such a wet granulation may cause degradation of the active ingredient upon contact with the liquid phase and that such compositions may show a decrease in the dissolution of levetiracetam upon storage. To overcome such problems, it discloses inter alia pharmaceutical composition of levetiracetam comprising 2.0 to 9.0 % by weight of a single super-disintegrant and roller compaction process for preparing such composition.
The compositions of levetiracetam have a high dose of the active ingredient which leads to an increased tablet size. Because of large tablet size it may be difficult to swallow tablets which may lead to reduced patient compliance. It is desirable to reduce the proportion of excipients in the higher dosed compositions
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to reduce size. This may, however, cause a problem in preparing compositions having desirable properties.
We have surprisingly found that compositions comprising levetiracetam which do not exhibit a substantial decrease in dissolution over time can be prepared by using a combination of two disintegrant. We have also found that. such compositions have a reduced tablet size, have desirable properties and can be manufactured without restriction to any particular process of preparation.
SUMMARY OF THE INVENTION
One embodiment discloses a stable pharmaceutical composition comprising (i) levetiracetam;
(ii) more than 9 % by weight disintegrant; and (iii) at least one pharmaceutical^ acceptable excipient.
Another embodiment discloses a stable pharmaceutical composition comprising (i) 60 % - 85 % by weight levetiracetam; (ii) 9.5 % - 20 % by weight disintegrant; and (iii) at least one pharmaceutically acceptable excipient.
Yet another embodiment discloses a stable pharmaceutical composition comprising
(i) 60 % - 85 % by weight levetiracetam;
(ii) 9.5 % - 20 % by weight of a combination of sodium starch glycolate
and maize starch; (iii) 0.5 % - 5 % by weight binder; and (iv) 0.5 % - 5 % by weight glidant/lubricant.
DETAILED DESCRIPTION OF THE INVENTION
The term "stable" as described herein refers to pharmaceutical compositions which do not exhibit a substantial decrease in dissolution upon storage over a
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period of at least 2 months, when kept at a temperature of 40°C and 75% relative humidity. It includes pharmaceutical compositions which do not exhibit a substantial decrease in dissolution upon storage over a period of six months.
Unless specified otherwise, the term "by weight" refers to the amount of levetiracetam, disintegrant and other excipients on basis of the total weight of the composition.
Disintegrant as described herein is intended to mean a combination of two disintegrants. Atleast one disintegrant of the combination belongs to the class of super-disintegrant and may be selected from sodium starch glycolate, croscarmellose sodium, pregelatinized starch, cross-linked polyvinylpyrrolidone or mixtures thereof. The other disintegrant of the combination is an auxiliary disintegrant and may be selected from powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, corn starch, maize starch, calcium carbonate, dextrose, kaolin, magnesium carbonate, magnesium oxide; sugars such as lactose or sucrose; sugar alcohols such as mannitol, sorbitol or erythritol; and the like. The auxiliary disintegrant may also function as a diluent. When the composition is prepared by granulation, the disintegrant may be present intragranularly or extragranularly or both. The disintegrant may be present in an amount of more than 9 % by weight of the composition, more particularly in an amount ranging from 9.5 % to 20 % by weight of the composition.
The pharmaceutical compositions as described herein may comprise of one or more pharmaceutical^ acceptable excipients selected from binder or glidant / lubricant.
Binder may be selected from hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, dextrin, ethyl cellulose, methylcellulose, gelatin, polymethacrylates, polyvinylpyrrolidone, sodium alginate, gums; or mixtures thereof. The binder may be present in an amount ranging from 0.1 % to 5 % by weight of the composition.
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Glidant / lubricant may be selected from talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, sodium stearyl fumarate, magnesium trisilicate; or mixtures thereof. The lubricant / glidant may be present in an amount ranging from 0.1 % to 5 % by weight of the composition.
The pharmaceutical composition may be in the form of a tablet, a capsule or granules. Tablet dosage form may be prepared by direct compression, dry granulation or wet granulation method.
Another embodiment discloses a stable pharmaceutical composition comprising (i) 60 % - 85 % by weight levetiracetam; (ii) 9.5 % - 20 % by weight disintegrant; and
(iii) at least one pharmaceutical^ acceptable excipient selected from binder or glidant/lubricant.
Another embodiment discloses a stable pharmaceutical composition comprising
(i) 60 % - 85 % by weight levetiracetam;
(ii) 9.5 % - 20 % by weight of a combination of sodium starch glycolate
and maize starch; (iii) 0.5 % - 5 % by weight binder; and (iv) 0.5 % - 5 % by weight glidant/lubricant.
Yet another embodiment discloses a process for preparing a stable pharmaceutical composition, wherein the process comprises:
(i) mixing levetiracetam, sodium starch glycolate and at least one
pharmaceutically acceptable excipent, (ii) granulating mixture of step (i) with a binder solution, (iii) drying the granules obtained in step (ii), (iv) optionally mixing the granules of step (iii) with sodium starch glycolate and
at least one pharmaceutically acceptable excipient, (v) lubricating the granules of step (iii) or mixture of (iv); and
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(vi) compressing the mixture of step (v) into tablets.
The tablets may be coated with polymers selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, ethyl cellulose, polyethylene oxide and the like.
The pharmaceutical compositions as described herein may be illustrated by the following example which is not to be construed as limiting the scope of the invention:
COMPARATIVE EXAMPLE

S/N Ingredients Quantity (mg/tablet)
1 Levetiracetam 250.0
2 Maize starch 67.6
3 Polyvinylpyrrolidone 6.0
4 Purified water q.s.
5 Colloidal Silicon Dioxide 10.0
6 Magnesium Stearate 8.0
Total weight 330.0
PROCEDURE: Levetiracetam and maize starch were mixed and the mixture was granulated with an aqueous dispersion of polyvinylpyrrolidone. The granules obtained were dried and mixed with colloidal silicon dioxide and magnesium stearate. The lubricated granules were compressed into tablets using appropriate tooling.
TABLE 1: Dissolution Profile of Comparative Example in 900 ml of water using USP Type II apparatus, paddle speed 50 rpm at 37 ± 0.5°C

Time (min) % drug dissolved
Storage at 40 °C/ 75 % RH
Initial 2 Month 3 Month
5 29.6 19.4 18.8
10 48.2 32.4 31.9
15 70.3 41.6 40.9
30 90.3 60.6 58.6

EXAMPLES 1 AND 2

S/N Ingredients Quantity (mg/tablet)
EXAMPLE 1 EXAMPLE 2
1 Levetiracetam 250.00 1000.00
2 Maize starch 25.67 102.67
3 Sodium starch glycolate 10.00 40.00
4 Colloidal silicon dioxide 1.67 6.67
5 Polyvinylpyrrolidone 6.00 24.00
6 Purified water q.s. q.s.
7 Sodium starch glycolate 10.00 40.00
8 Colloidal Silicon Dioxide 3.33 13.33
9 Talc 0.67 2.67
10 Magnesium Stearate 2.67 10.67
Coating
11 Hydroxypropyl methylcellulose (6 cps) 5.02 19.78
12 Titanium Dioxide 0.47 2.70
13 Polyethylene glycol 400 0.48 2.33
Purified water q.s. q.s.
Procedure: Levetiracetam, maize starch, sodium starch glycolate and colloidal silicon dioxide were mixed and the mixture was granulated with an aqueous dispersion of polyvinylpyrrolidone. The granules obtained were dried, mixed with sodium starch glycolate and colloidal silicon dioxide and the mixture was lubricated by addition of talc and magnesium stearate. The lubricated granules were compressed into tablets using appropriate tooling. Hydroxypropyl methylcellulose, titanium dioxide and polyethylene glycol were mixed and dispersed in purified water and the dispersion was coated on the tablets.
TABLE 2: Dissolution Profile of Example 1 and 2 in 900 ml of water using USP Type II apparatus, paddle speed 50 rpm at 37 ± 0.5°C

Time | % drug dissolved I

(min) EXAMPLE 1 EXAMPLE 2
Storage at 40 °C / 75 % RH Storage at 40 °C / 75 % RH
Initial 1 Month 2 Month Initial 1 Month 2 Month
5 45.0 41.9 39.7 27.9 22.0 24,0
15 95.4 96.8 94.6 89.7 86.3 88.0
30 100.0 102.3 98.7 101.2 99.1 99.9
As is evident from Table 2, the pharmaceutical compositions as described herein do not undergo substantial decrease in dissolution on storage.
Dated This 17th Day of March, 2007

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ABSTRACT
The present invention relates to a stable pharmaceutical composition of levetiracetam and process for preparation thereof.