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:
PHARMACEUTICAL COMPOSITION OF ENTACAPONE, LEVODOPA AND CARBIDOPA COMPRISING ENTACAPONE CO-MICRONIZED WITH SUGAR ALCOHOL
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D4-MIDC Area, Chikalthana,
Aurangabad - 431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a single oral dose pharmaceutical composition comprising, triple combination of entacapone, levodopa and carbidopa, or salts thereof along with one or more sugar alcohols wherein entacapone is co-micronized with sugar alcohol.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. Description
The present invention provides a single oral dose pharmaceutical composition comprising, triple combination of entacapone, levodopa and carbidopa, or salts thereof along with one or more sugar alcohols wherein entacapone is co-micronized with sugar alcohol.
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 C-14H15N3O5, 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 C10H-14N2O4H2O, and its structural formula is:

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 C9H-11NO4, and its structural formula is:

Entacapone being a BCS (Biopharmaceutics Classification system) class IV drug, it poses problems of low solubility, low dissolution rate and hence low bioavailability.
U.S. Patent No 4,963,590 provides a pharmaceutical composition comprising entacapone and pharmaceutically acceptable carrier.
U.S. Patent Nos. 6,500,867 and 6,797,732 disclose oral solid tablet compositions comprising entacapone, levodopa and carbidopa, or pharmaceutically acceptable salts or hydrates thereof, and a pharmaceutically acceptable excipient. Both these patents disclose that when carbidopa, levodopa and entacapone are mixed together, it results in stability problems and desired therapeutic effect is not achieved. On the other hand, when a substantial portion of carbidopa is separated from levodopa and entacapone, the formulation exhibits better stability and desired therapeutic effect is also achieved.
U.S. 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.


U.S. Application No. 20060222703 describes oral pharmaceutical compositions of entacapone, carbidopa and levodopa with microcrystalline cellulose and starch by simultaneous mixing of all the three actives. The composition is prepared by compaction granulation. The 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.
It is known that, even if the micronization or the grinding of a substance in the presence of a surfactant or of a sugar can increase its solubility, these parameters are not always adequate. For example, the bioavailability of micronized progesterone is not adequate and should be improved, for example by dispersion in camauba wax. Such a technique is described in application WO-89,02742. Thus, it appears that the properties of a substance treated by micronization or grinding, in particular its solubility and its bioavailability, are not predictable, it being possible to obtain contradictory results.
There are numerous prior art references, which quote use of sugar alcohols like mannitol, sorbitol etc as fillers in formulation or as sensory cue agents i.e which impart feeling of cooling in mouth in case of orally disintegrating tablets (WO2007080601, EP589981B1, EP906089B1, EP1109534B1, US6328994, WO2007001086, US20070196494, US20060240101, WO2006057912, US20060057199,). Sugar alcohols like mannitol are employed in most orally disintegrating formulations and not in conventional immediate release formulations as sensory cue agents because orally disintegrating tablets disintegrate in mouth instead of disintegrating in gastrointestinal tract as in case of conventional immediate release tablets.
The present inventors have noticed that sugar alcohols like mannitol or sorbitol when used along with other known water insoluble drugs like fenofibrate, irbesartan, aripiprazole, either as physical mixture or in the form of complex, does not result in any significant increase in solubility of above mentioned poorly


soluble drugs. It was observed that it does not make any significant difference either in solubility or percent release of these poorly soluble drugs, whether these drugs are present alone in formulation or along with sugar alcohols.
The present inventors while working on the entacapone, levodopa, carbidopa triple combination formulation have surprisingly found when entacapone is co-micronized with sugar alcohols, it results in significant increase in solubility of entacapone and percent drug release of entacapone from triple combination of entacapone, levodopa, carbidopa formulation vis-a-vis the formulation wherein entacapone is not co-micronized with sugar alcohol.
Stalevo 200® releases about 70% of entacapone in 30 minutes, whereas pharmaceutical composition of the present invention releases about 85% of entacapone in 30 minutes. This significant increase in percent release of entacapone leads to improved wettability, solubility, and hence increased percent release.
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 along with one or more sugar alcohols, wherein entacapone is co-micronized with sugar alcohol.
In one aspect there is provided a single oral dose pharmaceutical composition comprising triple combination of entacapone, levodopa and carbidopa, or salts thereof, along with one or more sugar alcohols wherein entacapone is co-micronized with sugar alcohol and wherein a substantial portion of entacapone or a salt thereof is separated from a mixture of 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 another aspect there is provided a single oral dose pharmaceutical composition comprising triple combination of entacapone, levodopa and carbidopa, or salts thereof, along with one or more sugar alcohols wherein entacapone is co-micronized with sugar alcohol and wherein a substantial portion of carbidopa or a salt thereof is separated from a mixture of entacapone and levodopa or salts thereof.
In another aspect of the present invention there is provided a single oral dose pharmaceutical composition comprising, triple combination of entacapone, levodopa and carbidopa, or salts thereof along with one or more sugar alcohols; wherein entacapone is co-micronized with sugar alcohol and wherein the composition exhibits a dissolution profile such that within 30 minutes at least 80% of entacapone is released, wherein the release rate is measured in Apparatus 2 (USP, Dissolution, paddle, 50 rpm) using 900 ml of pH 5.5 phosphate buffer at 37 °C ± 0.5°C.
In yet another aspect of the present invention, there is provided a process of preparing pharmaceutical composition which process comprises of a) co-micronizing entacapone or salts thereof with one or more sugar alcohols, mixing and granulating with other pharmaceutically acceptable excipients; b) mixing, granulating carbidopa and levodopa with other pharmaceutically acceptable excipients, c) mixing the mixture of step (a) and step (b); d) forming the mixture of step (c) into pharmaceutical dosage form.
Suitable sugar alcohols may include one or more of mannitol, maltitol, maltol, sorbitol, lactitol, xylitol and the like.
In the pharmaceutical composition of the present invention, entacapone can be present in an amount relative to the sugar alcohol, such that such that a molar ratio between the entacapone and the sugar alcohol is from about 1:1 to 10:1.


The co-micronization can be carried out by suitable means known in the art, which include but not limited to one or more of nano mill, ball mill, attritor mill, vibratory mill, sand mill, bead mill, jet mill, ultrasonication, and the like.
The mean particle size of entacapone and sugar alcohol obtained after co-micronization is less than 30u.
The pharmaceutical composition can be prepared in two parts. First part comprises of co-micronizing entacapone with suitable sugar alcohol, granulating with binder solution and drying the granules. Dried granules can be milled and mixed with other suitable pharmaceutically acceptable excipients.
Second part consists of mixing levodopa, carbidopa with suitable pharmaceutically acceptable excipients and granulating with binder solution. Granules can be dried. Dried granules can be milled and mixed with other suitable pharmaceutically acceptable excipients.
The above said granules of entacapone and granules of levodopa, carbidopa can be formulated in to suitable dosage form as monolayered tablets, bilayered tablets, tablet in tablet, caplet, minitablet, capsules, tablet in capsule, granules in capsules, pellets, pellets in capsules, powder. Further the powder or granules can be suspended to give pharmaceutically acceptable oral suspension.
The pharmaceutical composition comprises of pharmaceutically acceptable excipients wherein excipients may include binders, fillers, lubricants, disintegrants, and glidants.
Suitable binders may be selected from a group comprising one or more of, povidone, starch, stearic acid, gums, hydroxypropylmethylcellulose and the like.


Suitable fillers 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 disintegrants may be one or more of starch, croscarmellose sodium, crosspovidone, sodium starch glycolate and the like.
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.


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

No Ingredients % Composition
Entacapone Granules
1 Entacapone 20-45
2 Starch 2-15
3 Mannitol 2-25
4 Polyvinyl pyrrolidone 0.3-5
5 Purified Water q.s.
6 Croscarmellose sodium 1-6
7 Sodium starch glycollate 1-8
Levodopa, carbidopa Granules
8 Levodopa 5-40
9 Carbidopa 1-10.0
10 Starch 2-15
11 Croscarmellose sodium 2-5
12 Povidone 0.5-5
13 Purified Water q.s.
Extragranular portion
14 Mannitol 3-25
15 Sodium starch glycollate 1-8
16 Microcrystalline cellulose + Sodium carboxymethyl cellulose 4-20
17 Talc 0.1-2
18 Magnesium stearate 0.1-2
Film coating using Opadry 1-5%
Procedure: The pharmaceutical composition was prepared in two parts. First part comprised of mixing entacapone with mannitol and co-micronizing the pre-mix through one or more cycles. Starch, croscarmellose sodium, sodium starch glycollate were mixed in rapid mix granulator, granulated with aqueous povidone solution and the granules were dried in fluidized bed dryer.


Second part consisted of mixing levodopa, carbidopa with starch, granulating with aqueous povidone solution and drying granules in fluidized bed dryer. Dried granules of entacapone and levodopa, carbidopa were combined and mixed with sodium starch glycollate, mannitol, microcrystalline cellulose, talc in double cone blender and lubricated with magnesium stearate. Lubricated granules were compressed into tablets using suitable tooling and coated with aqueous dispersion of opadry.


Table 2: Comparative dissolution data of Stalevo 200® vs composition of the present invention prepared as per example 1

Time (min) % drug released (Stalevo 200®) % drug released (Example-1)
5 1 6
10 11 13
20 44 51
30 70 85
45 90 96
60 96 100
For determination of drug release rate, USP Type 2 Apparatus (rpm 50) was used wherein 1000 ml of pH 5.5 phosphate buffer at 37 °C ± 0.5°C was used as medium.


WE CLAIM:
1. A single oral dose pharmaceutical composition comprising, triple combination of entacapone, levodopa and carbidopa, or salts thereof along with one or more sugar alcohols, wherein entacapone is co-micronized with sugar alcohol.
2. A single oral dose pharmaceutical composition comprising triple combination of entacapone, levodopa and carbidopa, or salts thereof along with one or more sugar alcohols wherein entacapone is co-micronized with sugar alcohol and wherein a substantial portion of entacapone or a salt thereof is separated from a mixture of levodopa and carbidopa or salts thereof.
3. A single oral dose pharmaceutical composition comprising triple combination of entacapone, levodopa and carbidopa, or salts thereof, along with one or more sugar alcohols wherein entacapone is co-micronized with sugar alcohol and wherein a substantial portion of carbidopa or a salt thereof is separated from a mixture of entacapone and levodopa or salts thereof.
4. A single oral dose pharmaceutical composition comprising, triple combination of entacapone, levodopa and carbidopa, or salts thereof along with one or more sugar alcohols; wherein entacapone is co-micronized with sugar alcohol and wherein the composition exhibits a dissolution profile such that within 30 minutes at least 80% of entacapone is released, wherein the release rate is measured in Apparatus 2 (USP, Dissolution, paddle, 50 rpm) using 900 ml of pH 5.5 phosphate buffer at 37 °C ± 0.5°C.
5. The pharmaceutical composition as per any preceding claims, wherein
entacapone can be present in an amount relative to the sugar alcohol, such that
a molar ratio between the entacapone and the sugar alcohol is from about 1:1 to
10:1.


6. The pharmaceutical composition as per any preceding claims, wherein sugar alcohols comprise one or more of mannitol, maltitol, maltol, sorbitol, lactitol, xylitol and the like.
7. The composition as per any preceding claims, wherein the mean particle size of co-micronized entacapone and sugar alcohol mixture is less than 30u.

8. The pharmaceutical composition as per any preceding claims, wherein composition comprises one or more of tablet, capsule, powder, disc, caplet, granules, pellets, granules in capsule, minitablets, minitablets in capsule, pellets in capsule and sachet.
9. The composition as per any preceding claims further comprises of pharmaceutically acceptable excipients.
10. A process of preparing pharmaceutical composition which process comprises of a) co-micronizing entacapone or salts thereof with one or more sugar alcohols, mixing and granulating with other pharmaceutically acceptable excipients; b) mixing and granulating carbidopa and levodopa with other pharmaceutically acceptable excipients, c) mixing the mixture of step (a) and step (b); d) forming the mixture of step (c) into pharmaceutical dosage form.




ABSTRACT
The present invention provides a single oral dose pharmaceutical composition comprising, triple combination of entacapone, levodopa and carbidopa, or pharmaceutical^ acceptable salts thereof along with one or more sugar alcohols wherein entacapone is co-micronized with sugar alcohol. The invention also provides process of making such compositions.