the inventors have now discovered that when entacapone having a particle size ( d 90 ) of 40 microns or less is used , it results in increased solubility , significant increase in percent drug release of entacapone and hence improved bioavailability of entacapone pharmaceutical compositions as compared to entacapone pharmaceutical compositions that contain large sized entacapone particles . the inventors have also discovered that the use of a wetting agent reduces the surface tension of water and therefore increases adhesion of water to the entacapone surface . improved wettability is observed as a lower contact angle between the entacapone and water , which in turn results in increased solubility , significant increase in percent drug release of entacapone and hence improved bioavailability . it was also discovered that the use of cyclodextrin also results in increased solubility , significant increase in percent drug release of entacapone and consequently improved bioavailability of entacapone . in general , the entacapone having a particle size ( d 90 ) of 40 microns or less may be prepared by chemical methods and / or mechanical methods . the chemical methods may include one or more of solvent crystallization , chemical synthesis , modified crystal engineering , freeze - drying or other suitable means . the mechanical methods to reduce the particle size of entacapone may include one or more of milling , ultrasonication or other suitable techniques . the milling may include conventional techniques like ball mill , fluid energy attrition mills , jet mills or other suitable means . alternatively , the particle size of entacapone may be reduced by dissolving entacapone of bigger size in a suitable solvent such as dimethylformamide optionally , with other pharmaceutically acceptable excipients and the resultant mass may be spray dried to get the desired particle size of entacapone . the resultant mass may optionally be spray dried over other excipients to form a film . the particle size of entacapone may also be reduced by co - melting entacapone with other pharmaceutically acceptable excipients and resultant mass may be cooled to get solid - solid dispersion . the pharmaceutical composition may be prepared by mixing entacapone ( d 90 particle size of 40 microns or less ) with other pharmaceutically acceptable excipients , compacting the pre - mix through a compactor , breaking flakes into granules of the desired size . the compacting and breaking may be carried out one or more times . the granules may be mixed with one or more of a lubricant , disintegrant , glidant , or a mixture thereof , and the mixture may be formulated into a suitable dosage form . the pharmaceutical composition may also be prepared by mixing entacapone with one or more wetting agents and other pharmaceutically acceptable excipients , compacting the pre - mix through a compactor , breaking flakes into granules of the desired size . the compacting and breaking may be carried out one or more times . the granules may be mixed with one or more of a lubricant , disintegrant , glidant or a mixture thereof , and the mixture may be formulated into a suitable dosage form . the “ wetting agent ” may be one or more of anionic , cationic or non - ionic surface - active agents or surfactants . the wetting agent may further include one or more of gum acacia , guar gum , xanthan gum , kaolin , bentonite , hectorite , tragacanth , sodium alginate , pectin , and the like . suitable anionic surfactants may include one or more of sodium dodecyl sulfate ( sds ), sodium lauryl sulfate ( sls ), sodium laurate , dialkyl sodium sulfosuccinates , sodium stearate , potassium stearate , sodium oleate , and the like . suitable cationic surfactants may include one or more of benzalkonium chloride , bis - 2 - hydroxyethyl oleyl amine , benzethonium chloride , cetrimide , and the like . suitable non - ionic surfactants may include one or more of polyoxyethylene sorbitan fatty acid esters , fatty alcohols such as lauryl , cetyl and stearyl alcohols ; glyceryl esters such as the naturally occurring mono -, di -, and tri - glycerides ; fatty acid esters of fatty alcohols and other alcohols such as propylene glycol , polyethylene glycol , sorbitan , cholesterol , and the like . the pharmaceutical composition may be prepared by mixing entacapone with cyclodextrin and other pharmaceutically acceptable excipients , compacting the pre - mix through a compactor , breaking flakes into granules of the desired size . the compacting and breaking may be carried out one or more times . the granules may be mixed with one or more of a lubricant , disintegrant , glidant or a mixture thereof , and the mixture may be formulated into a suitable dosage form . the complex of entacapone and cyclodextrin may be prepared by various processes including solvent evaporation , kneading , spray drying , colloidal milling , high speed mixing , trituration or simple mixing . the entacapone may be present in an amount relative to the cyclodextrin , such that a molar ratio between the entacapone and the cyclodextrin may be from about 1 : 1 to 1 : 10 . suitable water soluble cyclodextrin derivatives may include one or more of , β - cyclodextrin , α - cyclodextrin , γ - cyclodextrins , hydroxypropyl - α - cyclodextrin , hydroxypropyl - β - cyclodextrin , dimethyl - β - cyclodextrin , 2 - hydroxyethyl β - cyclodextrin , trimethyl - β - cyclodextrin , sulfonated cyclodextrins and the like . the pharmaceutical composition as described herein may include other pharmaceutically acceptable excipients . examples of other pharmaceutically acceptable as used herein include binders , fillers , lubricants , disintegrants , glidants , and the like . suitable binders may include one or more of povidone , starch , stearic acid , gums , hydroxypropylmethylcellulose , and the like . suitable fillers may include one or more of microcrystalline cellulose , lactose , mannitol , calcium phosphate , calcium sulfate , kaolin , dry starch , powdered sugar , and the like . suitable lubricants may include one or more of magnesium stearate , zinc stearate , calcium stearate , stearic acid , sodium stearyl fumarate , hydrogenated vegetable oil , and the like . suitable glidants may include one or more of colloidal silicon dioxide , talc or cornstarch , and the like . suitable disintegrants may include one or more of starch , croscarmellose sodium , crosspovidone , sodium starch glycolate , and the like . the pharmaceutical compositions of the invention may be formulated into monolayered tablets , bilayered tablets , tablet in a tablet , a caplet , minitablets , capsules , tablet in a capsule , granules in capsules , pellets , pellets in capsules , or powder . further , the powder or granules may be suspended to give a pharmaceutically acceptable oral suspension . the pharmaceutical composition as described herein may include granules of entacapone having a size of 900 microns or less . the pharmaceutical composition that includes the particles of entacapone having a size ( d 90 ) that is 40 microns or less may exhibit a dissolution profile such that within 30 minutes , at least 80 % of entacapone or salt thereof 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 . the invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention . certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention . procedure : entacapone ( d 90 particle size of 40 microns or less ), microcrystalline cellulose , mannitol , croscarmellose sodium and colloidal silicon dioxide were sieved and mixed together in a double cone blender . magnesium stearate was mixed with above pre - mix in a double cone blender . half of this mixture was compacted through a roll compactor and milling was carried out to break flakes in to granules using a multi mill . the remaining half of the mixture was also compacted through a roll compactor along with fines of first half and again milling was done using a multimill to obtain granules of desired size . the granules were mixed with hydrogenated vegetable oil , sodium starch glycollate , colloidal silicon dioxide and talc . the granules were then lubricated with magnesium stearate and the final blend was compressed in to tablets using suitable tooling and coated with aqueous dispersion of opadry . table 2 provides the comparative dissolution data for entacapone tablets ( d 90 particle size of 40 microns vis - à - vis d 90 particle size of 40 microns or less ) prepared as per the formula given in table 1 . 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 a medium . procedure : entacapone , mannitol and sodium dodecyl sulfate were co - sifted and mixed with microcrystalline cellulose , croscarmellose sodium and colloidal silicon dioxide in double cone blender . magnesium stearate was mixed with above pre - mix in a double cone blender . half of this mixture was compacted through a roll compactor and sizing was carried out to break flakes in to granules using a multi mill . the remaining half of the mixture was also compacted through a roll compactor along with fines of first half and sizing was done using a multimill to obtain granules of desired size . the granules were mixed with hydrogenated vegetable oil , sodium starch glycollate , colloidal silicon dioxide and talc . the granules were then lubricated with magnesium stearate and the final blend was compressed in to tablets using suitable tooling and coated with aqueous dispersion of opadry . procedure : entacapone , mannitol and beta cyclodextrin were co - sifted and mixed with microcrystalline cellulose , croscarmellose sodium and colloidal silicon dioxide in double cone blender . magnesium stearate was mixed with above pre - mix in a double cone blender . half of this mixture was compacted through a roll compactor and sizing was carried out to break flakes in to granules using a multi mill . the remaining half of the mixture was also compacted through a roll compactor along with fines of first half and sizing was done using a multimill to obtain granules of desired size . the granules were mixed with hydrogenated vegetable oil , sodium starch glycollate , colloidal silicon dioxide and talc . the granules were lubricated with magnesium stearate and the final blend was compressed in to tablets using suitable tooling and coated with aqueous dispersion of opadry . while the 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 invention .
the invention relates to pharmaceutical compositions comprising entacapone or pharmaceutically acceptable salts thereof . the invention also relates to processes for the preparation of such compositions .