Preparation and in vitro/in vivo evaluation of sustained release AZT-loaded microspheres

The main purpose of this work was to prepare and optimize a sustained release microsphere formulation of AZT that is suitable for oral administration.; The microspheres were prepared using an emulsification/solvent evaporation technique. The formulation was then optimized based on its in vitro characteristics, using response surface methodology (RSM). During the optimization process, three formulation variables were investigated for their effect on the in vitro release of AZT. Time for 85% release (t{dollar}sb{lcub}85{rcub}{dollar}) was selected as the response variable. A second order polynomial model was fitted to the t{dollar}sb{lcub}85{rcub}{dollar} data and the optimum region was located. An optimum formulation, with respect to in vitro release rate, was prepared and tested. This formulation released 85% of its AZT content in approximately 6 hours.; In the second part of this study, the microspheres were optimized for their overall in vitro performance. In addition to the t{dollar}sb{lcub}85{rcub}{dollar}, three other response variables were considered. These were: loading efficiency, yield and percentage of loose surface crystals. Each response was transformed into an individual desirability function. The four individual desirability functions were then combined into an overall desirability function. This was, in turn, optimized over the experimental range. The optimum formulation was prepared and tested for its in vitro performance. An excellent agreement between the experimental values and the corresponding predicted values was observed.; The optimized formulations were orally administered to four Beagle dogs. Plasma samples were assayed by HPLC and the data was analyzed by non-compartmental analysis. The mean residence time of AZT was almost doubled after administration of the microspheres (4.4 h) with respect to AZT powder (2.4 h). Moreover, the observed C{dollar}sb{lcub}rm max{rcub}{dollar} was lower (1.5 {dollar}mu{dollar}g/ml compared with 3.4 {dollar}mu{dollar}g/ml) and T{dollar}sb{lcub}rm max{rcub}{dollar} was longer (2.6 h compared with 1.1 h) after administration of the microspheres. A good in vitro/in vivo correlation was established.; In the last part of this study, the effect of gastrointestinal proteins on the release rate of AZT from ethyl cellulose microspheres was investigated at two different pH values that simulate gastric fluid and intestinal fluid. All the investigated proteins were found to slow the release of AZT from its microspheres. Protein adsorption that was observed by SDS-PAGE technique is believed to be responsible for this effect.