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:
TRIPLE COMBINATION 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 pharmaceutical composition comprising triple combination of entacapone, levodopa and carbidopa, or pharmaceutically acceptable salts thereof and microcrystalline cellulose in an amount of at least 5% by weight of the composition along with other pharmaceutically acceptable excipients.
The following specification particularly describes the invention and the manner in which it is to be performed.
1

4. Description
The present invention provides a single oral dose pharmaceutical composition comprising triple combination of entacapone, levodopa and carbidopa, or pharmaceutically acceptable salts thereof and microcrystalline cellulose in an amount of at least 5% by weight of the composition along with other pharmaceutically acceptable excipients.
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 C14H15N3O5, 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-b-(3,4-dihydroxybenzene) propanoic acid monohydrate. Its empirical formula is C10H14N2O4H2O, and its structural formula is:

2

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-b-(3,4-dihydroxybenzene) propanoic acid. Its empirical formula is C9H11NO4, and its structural formula is:

U.S. Patent No 4,963,590 provides a pharmaceutical composition comprising entacapone and pharmaceutically acceptable carrier.
U.S. Patent No 5,112,861 provides method of treatment of Parkinson's disease using entacapone.
U.S. Patent No 5,446,194 describes entacapone or pharmaceutically acceptable salts or esters thereof.
U.S. Patent No. 5,135,950 and European equivalent EP 426468B1 provides crystallographically essentially pure polymorphic form A of entacapone.
U.S. Patent Nos. 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 other than microcrystalline cellulose. Both '867 patent and '732 patent describes that microcrystalline cellulose destabilizes the formulations on long-term storage, when carbidopa, levodopa and entacapone are combined together.
US Application 20060222703 describes oral pharmaceutical compositions of entacapone, carbidopa and levodopa with microcrystalline cellulose and starch. This 703 application involves simultaneous mixing of all the three actives and
3

method of preparing the composition is compaction granulation. The 703 application describes the disadvantages associated with wet granulation technique which includes destabilization of composition and decreased dissolution of levodopa, carbidopa and entacapone due to use of water in wet
granulation method.
The present inventors while working on the entacapone, carbidopa, levodopa formulation have surprisingly found that when microcrystalline cellulose is used in triple combination of entacapone, carbidopa, levodopa, formulation poses no stability problems on long term storage. The present inventors have further found that use of wet granulation technique neither affects stability of formulation nor it affects the dissolution of the formulation comprising entacapone, levodopa and carbidopa.
One of the aspects of present invention provides a single oral dose pharmaceutical composition comprising triple combination of entacapone, levodopa and carbidopa, or salts thereof and microcrystalline cellulose in an amount of at least 5% by weight of the composition along with other pharmaceutically acceptable excipients.
Another aspect of the present invention provides a single oral dose pharmaceutical composition comprising triple combination of entacapone, levodopa and carbidopa, or salts thereof and microcrystalline cellulose in an amount of at least 5% by weight of the composition along with other pharmaceutically acceptable excipients, wherein the pharmaceutical composition is prepared by wet granulation method.
In yet another aspect of the invention, there is provided a single oral dose pharmaceutical composition comprising triple combination of entacapone, levodopa and carbidopa, or pharmaceutically acceptable salts thereof and microcrystalline cellulose in an amount of at least 5% by weight of the composition along with other pharmaceutically acceptable excipients, wherein a
4

"substantial portion" of entacapone or salts thereof is separated from levodopa and carbidopa or salts thereof.
The term "substantial portion" of entacapone or salts thereof herein refers to the amount of entacapone or 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.
In yet another aspect of the invention, there is provided a single oral dose pharmaceutical composition comprising triple combination of entacapone, levodopa and carbidopa, or pharmaceutically acceptable salts thereof and microcrystalline cellulose in an amount of at least 5% by weight of the composition along with other pharmaceutically acceptable excipients, wherein a "substantial portion" of carbidopa or salts thereof is separated from entacapone and levodopa or salts thereof.
The term "substantial portion" of carbidopa or salts thereof herein refers to the amount of carbidopa or 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 of the present invention can be present in the form of monolayered tablets, bilayered tablets, tablet in tablet, caplet, minitablet, capsules, tablet in capsule, granules in capsules, pellets, pellets in capsules, powder or any other suitable dosage form.
Microcrystalline cellulose is purified, partially depolymerized cellulose that occurs as white, odorless, tasteless powder composed of porous particles. It is commercially available in different particle sizes and grades, which have different properties and applications. It is widely used in pharmaceuticals primarily as a binder/diluent in oral tablet and capsule formulations. In addition to its use as a binder/diluent, it also has some lubricant and disintegrant properties. It is used as adsorbent in concentration of 20-90%, anti-adherent in 5-20%range, capsule
5

binder/diluent in 20-90% range, tablet disintegrant in 5-15% range and tablet binder/diluent in 20-90% concentration range.
The pharmaceutical composition comprises of pharmaceutically acceptable excipients wherein excipients may include binders, fillers, lubricants, disintegrants, and glidants.
Suitable binders may be one or more of, povidone, starch, stearic acid, gums, hydroxypropylmethylcellulose and the like.
Suitable fillers may be one or more of, microcrystalline cellulose, lactose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar and the like.
Suitable lubricants may be 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 disintegrants may be one or more of starch, croscarmellose sodium, crosspovidone, sodium starch glycolate and the like.
The pharmaceutical composition may be prepared in two parts. First part comprises of mixing entacapone with pharmaceutically acceptable excipients, granulating with binder solution and drying the granules. Dried granules are sized and mixed with other pharmaceutically acceptable excipients. Second part consists of mixing levodopa, carbidopa with pharmaceutically acceptable excipients and granulating with binder solution. Granules are dried. Dried granules are sized and mixed with other pharmaceutically acceptable excipients.
6

The above said entacapone granules and levodopa, carbidopa granules are lubricated and the blend is compressed.
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.
7

EXAMPLE 1
Table 1: Composition of Levodopa, carbidopa and entacapone

No | Ingredients %w/w
Entacapone Granules (Part-I)
1 Entacapone 28.57
2 Microcrystalline cellulose 5-15
3 Mannitol 5-25
4 Corn starch 7-30
5 Croscarmellose sodium 2-5
6 PVP 1-5
7 Purified Water q.s.
Levodopa, carbidopa Granules (Part-II)
8 Levodopa 21.43
9 Carbidopa 5.34
10 Corn Starch 5-40
11 PVP 1-7
12 Purified Water q.s.
13 Talc 0.5-3
14 Magnesium stearate 0.5-1.5
15 Opadry 2-3
Procedure: The pharmaceutical composition is prepared in two parts. First part comprises of mixing entacapone, microcrystalline cellulose, mannitol, cornstarch, croscarmellose sodium in double cone blender, granulating with aqueous polyvinyl pyrrolidone (PVP) solution and drying the granules. Second part consists of mixing levodopa, carbidopa with cornstarch, and granulating with aqueous polyvinyl pyrrolidone solution. Granules are dried. Dried granules of entacapone (part I) and carbidopa-levodopa granules (part II) are mixed together in double cone blender and further lubricated with talc and magnesium stearate in double cone blender. Granules thus obtained are compressed into tablets and coated with aqueous dispersion of Opadry.
8

WE CLAIM:
1) A single oral dose pharmaceutical composition comprising triple combination of entacapone, levodopa and carbidopa, or salts thereof and microcrystalline cellulose in an amount of at least 5% by weight of the composition along with other pharmaceutically acceptable excipients.
2) A single oral dose pharmaceutical composition comprising triple combination of entacapone, levodopa and carbidopa, or salts thereof and microcrystalline cellulose in an amount of at least 5% by weight of the composition along with other pharmaceutically acceptable excipients, wherein the pharmaceutical composition is prepared by wet granulation method.
3) A single oral dose pharmaceutical composition comprising triple combination of entacapone, levodopa and carbidopa, or pharmaceutically acceptable salts thereof and microcrystalline cellulose in an amount of at least 5% by weight of the composition along with other pharmaceutically acceptable excipients, wherein a "substantial portion" of entacapone or salts thereof is separated from levodopa and carbidopa or salts thereof.
4) A single oral dose pharmaceutical composition comprising triple combination of entacapone, levodopa and carbidopa, or pharmaceutically acceptable salts thereof and microcrystalline cellulose in an amount of at least 5% by weight of the composition along with other pharmaceutically acceptable excipients, wherein a "substantial portion" of carbidopa or salts thereof is separated from entacapone and levodopa or salts thereof.
5) The pharmaceutical composition as per any preceding claims comprises one or more of monolayered tablets, bilayered tablets, tablet in tablet, caplet, minitablet, capsules, tablet in capsule, granules in capsules, pellets, pellets in capsules, powder, disc, caplet and other dosage form suitable for oral administration.
9

6) The pharmaceutical composition of claim 1, 2, 3 and 4 wherein pharmaceutically acceptable excipients comprises one or more of binders, fillers, lubricants, disintegrants, glidants.
7) The pharmaceutical composition of claim 6, wherein binders comprises one or more of povidone, starch, stearic acid, gums, hydroxypropylmethylcellulose and the like.
8) The pharmaceutical composition of claim 6, wherein fillers comprises one or more of microcrystalline cellulose, lactose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, corn starch, powdered sugar and the like.
9) The pharmaceutical composition of claim 6, wherein lubricants comprises one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil and the like.
10) The pharmaceutical composition of claim 6, wherein disintegrants comprises one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycollate and the like.

Dated this 26TH day of February, 2007
For Wockhardt Limited
(Mandar Kodgule)
Authorized Signatory