FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
BILAYERED TABLET COMPOSITIONS OF ENTACAPONE, LEVODOPA AND CARBIDOPA
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 single oral dose bilayered tablet pharmaceutical composition comprising, triple combination of entacapone, levodopa and carbidopa, or pharmaceutically acceptable salts thereof along with other pharmaceutically acceptable excipients, wherein a "substantial portion" of entacapone or pharmaceutically acceptable salts thereof is separated from mixture of levodopa and carbidopa or pharmaceutically acceptable salts thereof.
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 single oral dose bilayered tablet pharmaceutical composition comprising, triple combination of entacapone, levodopa and carbidopa, or pharmaceutically acceptable salts thereof along with other pharmaceutically acceptable excipients, wherein a "substantial portion" of entacapone or pharmaceutically acceptable salts thereof is separated from mixture of levodopa and carbidopa or pharmaceutically acceptable salts thereof.
Entacapone, an inhibitor of catechol-O-methyltransferase (COMT), is a nitro-catechol-structured compound with a molecular weight of 305.3 used in the treatment of Parkinson's disease as an adjunct to levodopa/carbidopa therapy. The chemical name of entacapone is (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide. Its empirical formula is CM4H15N3O5, and its structural formula is:

Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 244.3. It is designated chemically as (-)-L-(a-hydrazino-(a-methyl-P-(3,4-dihydroxybenzene) propanoic acid monohydrate. Its empirical formula is CM0H14N2O4H2O, and its structural formula is:
2

HO
OH
Av^

Levodopa, an aromatic amino acid, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 197.2. It is designated chemically as (-)-L-a-amino-|3-(3,4-dihydroxybenzene) propanoic acid. Its empirical formula is C9H11NO4, and its structural formula is:


H NH2

US Patent No 4,963,590 provides a pharmaceutical composition comprising entacapone and pharmaceutically acceptable carrier.
US Patent No 5,112,861 provides method of treatment of Parkinson's disease using entacapone.
US Patent No 5,446,194 disclose entacapone or pharmaceutically acceptable salts or esters thereof.
US Patent No. 5,135,950 and European equivalent EP 426468B1 provides crystallographically essentially pure polymorphic form A of entacapone.
US Patent No 6,500,867 and 6,797,732 provide oral solid tablet composition comprising entacapone, levodopa and carbidopa, or pharmaceutically acceptable salts or hydrates thereof, and a pharmaceutically acceptable excipient. Both '867 patent and '732 patent describes that when carbidopa, levodopa and entacapone are mixed together, it resulted in stability problems and desired therapeutic effect
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is not achieved. On the other hand when substantial portion of carbidopa is separated from levodopa and entacapone, formulation exhibits better stability and desired therapeutic effect is also achieved.
US Patent No 6,599,530 provides an oral compacted composition in the form of a tablet, which comprises entacapone, nitecapone, or pharmaceutically acceptable salt of entacapone or nitecapone, and croscarmellose sodium in an amount of at least 6% by weight of the composition.
The present inventors have surprisingly found that when "substantial portion" of entacapone is separated from levodopa, carbidopa mixture, formulation poses no stability problems and also the desired therapeutic effect is achieved.
One of the aspects of the present invention provides a single oral dose bilayered tablet pharmaceutical composition comprising, triple combination of entacapone, levodopa and carbidopa, or pharmaceutically acceptable salts thereof along with other pharmaceutically acceptable excipients, wherein a "substantial portion" of entacapone or pharmaceutically acceptable salts thereof is separated from mixture of levodopa and carbidopa or pharmaceutically acceptable salts thereof.
The term "substantial portion" of entacapone or pharmaceutically acceptable salts thereof herein refers to the amount of entacapone or pharmaceutically acceptable salts thereof that do not interfere with stability and or dissolution and therapeutic effect or bioavailability thereof in a single oral dose triple combination of entacapone, levodopa and carbidopa.
The pharmaceutical composition is prepared in two parts. First part comprises of mixing entacapone with suitable fillers, granulating with binder solution and drying the granules. Dried granules are milled and mixed with suitable disintegrants and glidants. Entacapone granules are further lubricated with lubricant.
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Second part consists of mixing levodopa, carbidopa with suitable fillers and granulating with binder solution. Granules are dried. Dried granules are milled and mixed with suitable disintegrants and glidants. Levodopa and carbidopa granules are further lubricated with lubricant.
Finally, the above said entacapone layer and levodopa, carbidopa layer are compressed in to bilayered tablets.
The pharmaceutical composition comprises of pharmaceutically acceptable excipients wherein excipients may include binders, fillers, lubricants, disintegrants, and glidants.
Suitable binder may be selected from a group comprising one or more of, povidone, starch, stearic acid, gums, hydroxypropylmethyl cellulose and the like.
Suitable filler may be selected from a group comprising one or more of, microcrystalline cellulose, lactose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar and the like.
Suitable lubricants may be selected from a group comprising one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil and the like.
Suitable glidants may be one or more of colloidal silicon dioxide, talc or cornstarch and the like.
Suitable disintegrant may be one or more of starch, croscarmellose sodium, crosspovidone, sodium starch glycolate and the like.
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In yet another aspect of the invention there is provided a tablet in tablet dosage form comprising
a) an inner tablet comprising of levodopa, carbidopa or pharmaceutically acceptable salts thereof along with other pharmaceutically acceptable excipients.
b) an outer tablet comprising of granules of entacapone or pharmaceutically acceptable salts thereof along with other pharmaceutically acceptable excipients.
In yet another aspect of the invention there is provided a tablet in tablet dosage form comprising
c) an inner tablet comprising of entacapone or pharmaceutically acceptable salts thereof along with other pharmaceutically acceptable excipients.
d) an outer tablet comprising of granules of levodopa and carbidopa or pharmaceutically acceptable salts thereof along with other pharmaceutically acceptable excipients.
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 Levodopa, carbidopa and entacapone tablets

No Ingredients % Composition
Entacapone layer
1 Entacapone 28.78
2 Microcrystalline cellulose 15.54
3 Mannitol 7.19
4 Hydroxy propyl Methyl cellulose 1.73
5 Purified Water q.s.
6 Croscarmellose sodium 1.99
7 Colloidal silicon dioxide 0.86
8 Magnesium stearate 0.60
Levodopa, carbidopa layer
9 Levodopa 21.58
10 Carbidopa 5.40
11 Starch 1.73
12 Croscarmellose sodium 1.44
13 Povidone 0.86
14 Purified Water q.s.
15 Croscarmellose sodium 1.32
16 Colloidal silicon dioxide 0.58
17 Magnesium stearate 0.40
18 Opadry Red 2.88
Procedure: The pharmaceutical composition is prepared in two parts. First part comprises of mixing entacapone, microcrystalline cellulose and mannitol in double cone blender, granulating with aqueous hydroxypropylmethylcellulose solution and drying the granules. Dried granules are milled and mixed with croscarmellose sodium and colloidal silicon dioxide in double cone blender.
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Entacapone granules are further lubricated with magnesium stearate in double cone blender.
Second part consists of mixing levodopa, carbiodopa with starch, croscarmellose sodium and granulating with aqueous povidone solution. Granules are dried. Dried granules are milled and mixed with croscarmellose sodium and colloidal silicon dioxide in double cone blender. Levodopa and carbidopa granules are further lubricated with magnesium stearate in double cone blender.
Finally, the above said entacapone layer and levodopa, carbidopa layer are compressed in to bilayered tablets using suitable tooling and coated with dispersion of Opadry.
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WE CLAIM:
1. A single oral dose bilayered tablet pharmaceutical composition comprising, triple combination of entacapone, levodopa and carbidopa, or pharmaceutically acceptable salts thereof along with other pharmaceutically acceptable excipients, wherein a "substantial portion" of entacapone or pharmaceutically acceptable salts thereof is separated from mixture of levodopa and carbidopa or pharmaceutically acceptable salts thereof.
2. A tablet in tablet dosage form comprising
a) an inner tablet comprising of levodopa, carbidopa or pharmaceutically
acceptable salts thereof along with other pharmaceutically acceptable
excipients.
b) an outer tablet comprising of granules of entacapone or
pharmaceutically acceptable salts thereof along with other
pharmaceutically acceptable excipients.
3. A tablet in tablet dosage form comprising
a) an inner tablet comprising of entacapone or pharmaceutically acceptable salts thereof along with other pharmaceutically acceptable excipients.
b) an outer tablet comprising of granules of levodopa and carbidopa or pharmaceutically acceptable salts thereof along with other pharmaceutically acceptable excipients.
3. A pharmaceutical composition as per any preceding claims, wherein pharmaceutically acceptable excipients are binders, fillers, lubricants, disintegrants, glidants.
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4. A pharmaceutical composition of claim 3, wherein binders are selected from a group comprising one or more of povidone, starch, stearic acid, gums, hydroxypropylmethylcellulose and the like.
5. A pharmaceutical composition of claim 3, wherein fillers are selected from a group comprising one or more of microcrystalline cellulose, lactose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar and the like.
6. A pharmaceutical composition of claim 3, wherein lubricants are selected from a group comprising one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil and the like.
7. A pharmaceutical composition of claim 3, wherein disintegrants are selected from a group comprising one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycollate and the like.
8. A pharmaceutical composition of claim 3, wherein glidants are selected from a group comprising one or more of colloidal silicon dioxide, talc, cornstarch and the like.
Dated this So™ day of October, 2006 For Wockhardt Limited
(Mandartyodgule) Authorized Signatory
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