Formulation Development and in vivo evaluation in rabbits of Stavudine extended-release pellets

Abstract

The stavudine pellets were prepared by extrusion and spheronization process. The influence of processing variables, including the spheronizer speed and the spheronization time on physical properties of the pellets, were studied. The sphericity of pellets were increased with increasing spheronizer speed during wet mass process. When spheronization time was increased, sphericity, smooth surface and mean particle size of pellets were increased. Pellets using Avicel® PH101 as a diluent at high spheronizer speed showed sphere shape, narrow size distribution and good flow characteristic. The pellets also have a low angle of repose, a low percent friability, and no difference between bulk density and tapped density. The suitable condition for preparing stavudine pellet consisted of 40 %w/w of stavudine, 60 %w/w of Avicel® PH101, 65%w/w of water and spheronizer speed of 860 rpm with spheronization time at 10 min. The stavudine controlled released pellets were prepared by coating core pellets with Surelease® containing HPMC E15 LV at different proportions of coating load. The Surelease® : HPMC E15 LV ratio had a major role in the release of drug. The release of the drug increased as the amount of HPMC E15 LV in coating solution was increased. This was thought to be due to the leakage of the soluble part of the film (HPMC E15 LV) during dissolution, which left pores for drug release. The combination of Surelease® and HPMC E15 LV of 95 : 5 at 20% coating level provided the drug release profile as requirement. The mechanism of drug release from coated pellets followed zero-order kinetic. The in vitro analytical method was validated and showed linearity, precision, accuracy and specificity. Both Zerit® IR and stavudine pellet were stable at least 6 months when products were stored at 30 0 C, 65 %RH and at 40 0 C, 75 %RH. The pharmacokinetic comparison of stavudine pellet and Zerit® IR was conducted in 12 White New Zealand rabbits. Each subject received a single dose of 100 mg stavudine pellet and 50 mg Zerit® IR in a randomized two way crossover design with 2 weeks washout period between dosing. Blood sample were collected at specified time intervals. Plasma was separated and analysed for stavudine concentrations using a developed and validated HPLC method. In this study, The AUClast values of stavudine pellet and Zerit® IR were 3,214.09 ± 364.42 and 1,504.79 ± 222.58 ng.hr/ml, respectively. The AUC0-∞ values were 33,585.96 ± 397.82 and 1,606.21 ± 237.46 ng.hr/ml for stavudine pellet and Zerit® IR, respectively. The Cmax values values of stavudine pellet and Zerit® IR were 598.83 ± 61.94 and 1,168.03 ± 74.38 ng/ml, respectively. The Tmax values of stavudine pellet and Zerit® IR were 3.29 ± 0.17 and 0.63 ± 0.12, respectively. Percentage relative bioavailability of stavudine pellet was 112.44 ± 8.92%. It was concluded that stavudine pellet can be completely absorbed and the extent of drug absorption depends on dose given. However, drug absorption rate of stavudine pellet was slower than that of Zerit® IR and drug from stavudine pellet can be maintained in plasma longer than Zerit® IR. Stavudine pellets which were prepared in this study can be an extended-release product.