FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
BILAYER TABLET COMPOSITION OF MODAFINIL
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a bilayer tablet comprising modafinil or pharmaceutically acceptable salts thereof wherein the tablet comprises micronized and unmicronized modafinil particles.
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. Description
The present invention provides a bilayer tablet comprising modafinil or pharmaceutical^ acceptable salts thereof wherein the tablet comprises micronized and unmicronized modafinil particles.
Modafinil is a wakefulness-promoting agent indicated to improve wakefulness in patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder. It has molecular weight of 273.36. The chemical name of modafinil is (2-[(diphenylmethyl) sulfinyl] acetamide. Its empirical formula is C15H15NO2S, and its structural formula is:


O O
II II
CH—S-CH2—C-NH2

U.S. Patent No 4,927,855 discloses the levorotatory form of modafinil and the use of the levorotatory form for treating hypersomnia and Alzheimer's disease
U.S. Patent No 4,177,290 relates to modafinil drug used for the treatment of idiopathic hypersomnia and narcolepsy.
U.S. Patent No RE 37,516 provides a method of size reduction and a pharmaceutical composition that has at least 95% of the modafinil particles having a diameter of less than 200 mu.m.
U.S. Patent No 6,919,378 describes solid dispersion of modafinil.
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U.S. Patent No 6,489,363 relates to pharmaceutical compositions comprising a modafinil compound in solution, and in particular, to non-aqueous solutions comprising at least one organic solvent
U.S. Patent No. 7,115,281 relates to processes for preparing, and pharmaceutical compositions of, modafinil dosage forms for oral administration. The dosage forms include a mixture of coarse and fine particles of modafinil.
U.S. Patent No. 7,141,555 relates to complexes of a modafinil compound with a cyclodextrin.
U.S. Published Application Nos. 20030022940, 2003220403, 20040105891, 20050137264, 20040170683, 20040048931, 20070026507 describes pharmaceutical compositions of modafinil.
U.S. Published Application No 20040253308 relates to solid oral dosage form comprising surface-treated particles of modafinil.
U.S. Published Application No 2004116532. describes pharmaceutical unit dose of modafinil and method of treating ADHD by using modafinil.
U.S. Published Application No 2006024370 describes oral lyophilizate of modafinil.
U.S. Published Application No 20070065517 describes method of formulating a composition of modafinil.
International (PCT) Publication WO2007013962 describes pharmaceutical composition of modafinil comprising combination of d and l-enantiomers of modafinil and modafinil component is greater than 50% by weight d-modafinil.
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The present inventors while working on the modafinil formulation have developed a specialized tablet dosage form of modafinil i.e. bilayer tablet. The bilayer tablet of modafinil or pharmaceutically acceptable salts thereof comprises micronized and unmicronized modafinil particles and the tablets possess no stability problems. Also the present inventors noticed that the desired therapeutic effect is achieved with the tablet of the present invention.
One of the aspects of the present invention provides a bilayer tablet comprising modafinil or pharmaceutically acceptable salts thereof wherein the said tablet comprises micronized and unmicronized modafinil particles in admixture with one or more pharmaceutically acceptable excipients.
As used herein, "micronized" means modafinil is subjected to micronisation methods. The micronisation methods include conventional micronization equipment such as air jet milling and also include methods that are known to ordinary skilled in the art.
The micronized modafinil particles contain atleast about 90% of the particles having particle size less than 50pm and atleast about 50% of the particles having particle size less than 25pm. As used herein, "about" means plus or minus approximately ten percent of the indicated value, such that "about 90%" indicates approximately 81% to 99%.
As used herein, "unmicronized" means modafinil is not subjected to micronisation. The unmicronized modafinil particles contain atleast about 90% of the particles having particle size more than 250μm.
The pharmaceutical composition comprises of pharmaceutically acceptable excipients wherein excipients comprise one or more of binders, fillers, lubricants, disintegrants, surfactants and glidants.
Suitable binders comprise one or more of, povidone, starch, stearic acid, gums, hydroxypropylmethyl cellulose and the like. Suitable fillers comprise one or more
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of microcrystalline cellulose, lactose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar and the like. Suitable lubricants comprise one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil and the like. Suitable disintegrants comprise one or more of starch, pregelatinized starch, L-HPC, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
Suitable surfactants comprise one or more of anionic, cationic, non-ionic, amphoteric surfactants. Examples of such surfactants are sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or another ester of polyoxyethylene sorbitane, sodium dioctylsulfosuccinate (DOSS), lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamer. RTM., etc. Mixtures of surfactants are also suitable.
Suitable glidants comprise one or more of colloidal silicon dioxide, talc or cornstarch and the like.
In yet another aspect of the present invention there is provided a process for preparing bilayer tablet of modafinil or pharmaceutical^ acceptable salts thereof wherein the said process comprises preparation of:
a) Granules of micronized modafinil particles or pharmaceutically
acceptable salts thereof
i) blending micronized modafinil particles and optionally one or
more pharmaceutically acceptable excipients ii) granulating the blend of step i)
b) Granules of unmicronized modafinil particles or pharmaceutically
acceptable salts thereof
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i) blending unmicronized modafinil particles and optionally one or
more pharmaceutical^ acceptable excipients ii) granulating the blend of step i)
c) Granules of step a) and b) are compressed to form a bilayer tablet.
In the process of the present invention blending of micronized or unmicronized modafinil particles and optionally one or more pharmaceutically acceptable excipients can be done by methods known to ordinary skilled in the art.
In the process of the present invention granulation can be done by dry granulation or wet granulation. The composition of the present invention can also be prepared by direct compression method.
The pharmaceutical composition is prepared in two parts. First part comprises of mixing micronized modafinil particles with one or more fillers, disintegrant and granulating with binder solution and drying the granules. Dried granules are milled and mixed with suitable glidant. Modafinil granules are further lubricated with lubricant. Second part comprises of mixing unmicronized modafinil particles with one or more fillers, disintegrant, surfactant and granulating with binder solution and drying the granules. Dried granules are milled and mixed with suitable glidant. Modafinil granules are further lubricated with suitable lubricant. Finally, the first and the second parts are compressed in to bilayer tablet.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
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EXAMPLE 1
Table 1: Composition of modafinil tablets

No Ingredients % Composition
Layer I
1. Modafinil (Micronised) 26
2. Lactose Monohydrate 15
3. Microcrystalline cellulose 51.75
4. Croscarmellose Sodium 3
5. PVP K-30 3
6. Colloidal Silicon dioxide 0.5
7. Magnesium Stearate 0.75
Total 100
Layer II
1. Modafinil (Unmicronised) 35
2. Lactose Monohydrate 15
3. Microcrystalline cellulose 34.75
4. Poloxamer 10
5. Croscarmellose Sodium 2
6. PVP K-30 2
7. Colloidal Silicon dioxide 0.5
8. Magnesium Stearate 0.75
Total 100
Procedure: The pharmaceutical composition is prepared in two parts. First part comprises of mixing micronized modafinil, Lactose Monohydrate, Microcrystalline cellulose and Croscarmellose Sodium. Granulating the obtained blend in rapid mixer granulator using aqueous solution of PVP K-30 followed by drying the granules. Dried granules are milled and blended with colloidal silicon dioxide. The obtained modafinil granules are further lubricated with magnesium stearate. Second part comprises of mixing unmicronized modafinil, Lactose Monohydrate, Microcrystalline cellulose, poloxamer and Croscarmellose Sodium. Granulating the obtained blend in rapid mixer granulator using aqueous solution of PVP K-30 followed by drying the granules. Dried granules are milled and blended with colloidal silicon dioxide. The obtained modafinil granules are further lubricated with magnesium stearate. First and second part are compressed to form a bilayer tablet using suitable tooling and optionally coated with dispersion of Opadry.
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WE CLAIM:
1. A bilayer tablet comprising modafinil or pharmaceutically acceptable salts thereof wherein the said tablet comprises micronized and unmicronized modafinil particles in admixture with one or more pharmaceutically acceptable excipients.
2. A bilayer tablet of claim 1 is meant for oral administration.
3. A process for preparing bilayer tablet of modafinil or pharmaceutically acceptable salts thereof wherein the said process comprises preparation of:
a) Granules of micronized modafinil particles or pharmaceutically
acceptable salts thereof
i) blending micronized modafinil particles and optionally one or more
pharmaceutically acceptable excipients ii) granulating the blend of step i)
b) Granules of unmicronized modafinil particles or pharmaceutically
acceptable salts thereof
i) blending unmicronized modafinil particles and optionally one or more
pharmaceutically acceptable excipients ii) granulating the blend of step i)
c) Granules of step a) and b) are compressed to form a bilayer tablet.
4. A bilayer tablet of claim 1 and a process of claim 3, wherein
pharmaceutically acceptable excipients comprise one or more of binders,
fillers, lubricants, disintegrants, surfactants and glidants.
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5. A bilayer tablet and a process of claim 4 wherein binders comprise one or more of povidone, starch, stearic acid, gums, hydroxypropylmethyl cellulose.
6. A bilayer tablet and a process of claim 4 wherein fillers comprise one or more of microcrystalline cellulose, lactose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar.
7. A bilayer tablet and a process of claim 4 wherein lubricants comprise one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil.
8. A bilayer tablet and a process of claim 4 wherein disintegrants comprise one or more of starch pregelatinized starch, L-HPC, croscarmellose sodium, crospovidone, sodium starch glycolate.
9. A bilayer tablet and a process of claim 4 wherein surfactants comprise one or more of anionic, cationic, non-ionic, amphoteric surfactants.
10. A bilayer tablet and a process of claim 4 wherein glidants comprise one or more of colloidal silicon dioxide, talc or cornstarch.
Dated this 27TH day of April, 2007 For Wockhardt Limited

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