Development and characterization of a solid self-microemulsifying drug delivery system (SMEDDS) of albendazole and evaluation of oral bioavailability in rabbits

Albendazole's (ABZ) poor aqueous solubility is a major determinant of its variable therapeutic response (20 to 50%). The primary objectives of the present work were, first, to develop, optimize and characterize the composition of a stable liquid and solid self-microemulsifying drug delivery system (SMEDDS) of ABZ and second, to evaluate its oral bioavailability in healthy rabbits. In this study, the process parameters of the fluid bed processes impacting the quality attribute of a solid SMEDDS system of ABZ were also evaluated. A D-optimal mixture design of experiments was used to select the levels of constraints of the liquid SMEDDS formulation variables. The predicted composition was optimized using four responses such as dispersion performance, droplet sizes, dissolution efficiency (DE) and time for 85% drug release ( t85%). The optimized liquid SMEDDS formulation of ABZ (5 mg/g) was characterized by its droplet size, zeta potential and viscosity. Based on the core liquid SMEDDS composition, a supersaturating solid SMEDDS formulation containing higher amount of ABZ (10 mg/g) was prepared by fluid-bed granulating the liquid SMEDDS using granular sorbitol as a carrier and acidified PEG 4000 as a supersaturating polymer. The in vitro dissolution studies were performed at pH 1.2--7.4. Solid state characterization of the solid SMEDDS was performed by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD). The chemical and thermodynamic stability of both liquid and solid SMEDDS formulations of ABZ was evaluated by stressing them at higher temperatures (up to 60°C) for 60 days. A randomized cross-over pharmacokinetic study was conducted using three rabbits by giving them an oral dose of 10 mg/kg of body weight. The relative bioavailability was calculated against a commercial suspension of ABZ (Zentel(TM), GlaxoSmithKline). A fractional factorial design (4x2) with four parameters (spray rate, inlet air temperature, inlet air flow and atomization air pressure) was used to evaluate the fluid bed process to manufacture solid SMEDDS particles. The optimal composition of ABZ-SMEDDS formulation of ABZ with approximately 5 mg/g drug loading was predicted to have Cremophor EL (30% w/w), Tween 80 (15% w/w), Capmul PG-8 (10% w/w) and acidified PEG 400 (45% w/w). When dispersed in water, it produced droplet sizes of 37.3 +/- 2.7 nm. The zeta potential was found to be neutral (-1.562 mV) whereas the initial viscosity was high (1244 cp at 24°C). The droplet size analysis of reconstituted microemulsion revealed no difference between liquid and solid SMEDDS formulation. The in vitro dissolution profiles were found to be pH independent for both SMEDDS formulations. The DSC theromogranms and XRD study revealed absence of crystallinity of ABZ in the solid SMEDDS formulations. The solid SMEDDS showed an improved chemical stability at higher temperature than its liquid counterpart, although both formulations were thermodynamically stable at room temperature. The same dose of ABZ in the solid SMEDDS and in the liquid SMEDDS resulted in similar AUC 0&rarr24h and Cmax values, but the maximum absorption was resulted by the solid SMEDDS. The AUC0&rarr24h and Cmax after oral administration of the solid SMEDDS were 1.86- and 1.64-fold higher, respectively, compared with those of the commercial suspension (ZentelRTM, GlaxoSmithKline, USA). For process development study, spray rate was found to increase the sauter-mean diameter (SMD). The effect of inlet air temperature on the peak moisture which is directly related to the mean particle size was found to be significant. This study demonstrated a strategy for the development of a supersaturated SMEDDS formulation and of a drug with low aqueous solubility. These results showed that the solid SMEDDS may produce an improved bioavailability with releasing microemulsion lipid droplets from the formulation in vivo.