Enhancement of dissolution rate and bioavailability of Paliperidone by Hot Melt Extrusion technique

The purpose of the study was to increase the dissolution and bioavailability of BCS class II drug, paliperidone by amorphization. The technique that was evaluated for preparing amorphous paliperidone (PAL) was Hot Melt Extrusion (HME). In case of hot melt extrusion process, copovidone was used essentially as a hydrophilic polymer with plasticizers like PEG (6000 and 20000), stearic acid and cetosterayl alcohol. Melt extrusion process was carried out by using different concentrations of drug, polymer, and plasticizers. DSC studies showed that the crystalline nature of PAL was significantly reduced on melt extrude. Incorporation of the plasticizer resulted in faster drug release compared with extrudes without plasticizer. Out of the plasticizers studied extrudes prepared with 25% PEG 6000 showed rapid release, wherein more than 75% of drug release was achieved within 30 minutes. The pharmacokinetics of melt extruded composition (PAL with 25% PEG 6000) and pure PAL was evaluated following oral administration (0.8 mg/kg) in healthy female Sprague Dawley rats. The extent of the mean plasma exposures of PAL was 14-fold higher in animals treated with extruded mixture of PAL, compared to animals treated with PAL. Melt extruded of PAL with PEG, especially PEG 6000, reduced drug crystallinity, increased the rate and extent of dissolution, and improved bioavailability.