Optimization of proniosomal itraconazole formulation using Box Behken design to enhance oral bioavailability

摘要

The aim of our investigation was to study the combined impact of 3 independent variables on the development of itraconazole (ITR) proniosomes by using Box-Behnken design (BBD). BBD was implemented with 3 variable factors at 3 levels. The values of the factors and responses were exposed to multiple regressions to derive a second-order polynomial equation used to predict the values of optimized dependent variables (responses). The surfactant concentration, drug concentration and molar ratio (Span 60: cholesterol) were chosen as the independent variables. Fifteen proniosome formulae were prepared using the slurry method and estimated for drug entrapment efficiency (DEE), vesicle size (VZ) and % drug released after 8 h. The insignificant terms of the equation that showed the probability value (P 0.05), were excluded from the full-model equation to attain a reduced-model equation to ease expecting the different responses upon changing variables. The effect of the different variables was also shown by the construction of line and contour plots. Two optimized formulae; P1 (0.28, 0.91 and -0.91) for the maximized response of DEE and % drug released without restriction of VZ and P2 (0.5, -1, -1) with a minimum VZ were prepared and evaluated for ex-vivo permeation study. In-vivo pharmacokinetic study of the optimized selected formula P2was tested against the market product (sporonox (R)) in rabbits. ITR Proniosomal formula showed 1.95 fold, 1.3 fold and 1.4 fold increase in C-max, AUC(0-48), and AUC(0-infinity) when compared to ITR market product. Our investigation suggested the potential use of proniosome as a drug carrier to enhance the bioavailability of ITR.