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 CO-MICRONIZED WITH SUGAR ALCOHOLS
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 pharmaceutical composition comprising entacapone 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 pharmaceutical composition comprising entacapone 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 C14H-15N3O5, 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 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.


International Publication No. (PCT) WO2006/131591 discloses oral dosage forms of entacapone and methods of preparation thereof.
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 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 vis-a-vis the formulation wherein entacapone is not co-micronized with sugar alcohol.
Stalevo 200® releases about 70% of entacapone in 20 minutes, whereas pharmaceutical composition of the present invention releases almost 100% of entacapone in 20 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 entacapone or salts thereof along with one or more sugar alcohols, wherein entacapone is co-micronized with sugar alcohol.
In another aspect of the present invention there is provided a pharmaceutical composition comprising entacapone 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 or salt thereof s released, wherein the release rate is measured in Apparatus 2 (USP, Dissolution, paddle, 50 rpm) using 1000 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 co-micronizing entacapone or salts thereof with one or more sugar alcohols, mixing with other pharmaceutically acceptable excipients, and forming the mixture 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 by co-micronizing entacapone with suitable sugar alcohol, mixing, granulating with other pharmaceutically acceptable excipients. Granules are mixed with other suitable pharmaceutically acceptable excipients.
The pharmaceutical composition of the invention can be present in the form of one or 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 further 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 entacapone

No Ingredients % Composition
Entacapone Granules
1 Entacapone 15-65
2 Mannitol 5-50
3 Polyvinyl pyrrolidone 0.5-8
4 Crospovidone 2-10
5 Magnesium stearate 0.2-3
Procedure: Entacapone and mannitol were mixed and co-micronized through multimill. To the co-micronized mixture, crospovidone, povidone and magnesium stearate was added, mixed and granulated using roll compactor to obtain granules of suitable size. Crospovidone and magnesium stearate was added to granules and the resultant mixture was compressed into tablets using suitable tooling.


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

Time (min) % drug released (Comtan®) % drug released (Example-1)
10 35 93
20 70 100
30 78 100
45 91 100
For determination of drug release rate, USP Type 2 Apparatus (rpm 50) was used wherein 900 ml of pH 5.5 phosphate buffer at 37 °C ± 0.5°C was used as medium.


WE CLAIM:
1. A pharmaceutical composition comprising entacapone or salts thereof along with one or more sugar alcohols, wherein entacapone is co-micronized with sugar alcohol.
2. A pharmaceutical composition comprising entacapone 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 1000 ml of pH 5.5 phosphate buffer at 37 °C ± 0.5°C.
3. 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.
4. 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.
5. The composition as per any preceding claims, wherein the mean particle size of co-micronized entacapone and sugar alcohol mixture is less than 30u.

6. 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.
7. The composition as per any preceding claims further comprises of pharmaceutically acceptable excipients.


8. A process of preparing pharmaceutical composition which process comprises of co-micronizing entacapone or salts thereof with one or more sugar alcohols, mixing with other pharmaceutically acceptable excipients, and forming the mixture into pharmaceutical dosage form.
9. The process of claim 8, wherein pharmaceutical dosage form comprises one or more of tablet, capsule, powder, disc, caplet, granules, pellets, granules in capsule, minitablets, minitablets in capsule, pellets in capsule and sachet.

ABSTRACT
The present invention provides a pharmaceutical composition comprising entacapone or pharmaceutically 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.