Formulation Design For Improvement Of Performance Characteristics Of BCS IV Drug

Abstract

Abiraterone acetate has very low bioavailability and drastic food effect to warrant a dosing newlineregimen under fasting state only. Therefore, we aimed to develop and optimize a liquisolid newlinecompact formulation of abiraterone acetate to improve biopharmaceutical attributes aided by newlinepharmacokinetic modelling and achieve dose reduction with no food effect on the newlineformulation. Preliminary studies highlighted the importance of the selection of olive oil as a newlinecompatible vehicle. The pharmacokinetic model, integrated with gastrointestinal physiology, newlinewas used to predict fasted and fed state pharmacokinetic parameters. Optimization of the newlineliquisolid formulation containing abiraterone acetate was carried at more than five times newlinelower dose, i.e. 190 mg, compared to 1,000 mg. A central composite design (CCD) was used newlineto identify optimal levels of formulation factors, namely the amount of vehicle (olive oil), the newlineamount of coating agent (silicon dioxide), and the amount of surfactant (polysorbate 80). newlineGraphical optimization using the selected models in conjunction with maximization of the newlinedesirability was used to identify the optimized liquisolid formulation. The predicted newlinepharmacokinetic parameters (fasted C 901.83 ng/mL, fasted AUC 2723.82 ng·*h/mL, fed C newline1024.34 ng/mL, and fed AUC 3041.83 ng·h/mL) of the optimized formulation were newlineacceptable. Overall, the liquisolid compact formulation of abiraterone acetate was newlinesuccessfully developed and optimized. In vitro solubility and dissolution results aided by newlinepharmacokinetic modelling also showed improved predicted bioavailability with greater than newlinefive times reduction in dose and elimination of food effect. The optimized LS formulation is newlinestable for 6-months at accelerated (40°C/75% RH) and long-term (25°C/60% RH) stability newlinecondition. newlineIn conclusion, the study achieved more than 5-times dose reduction for abiraterone acetate, newlineeliminated the food effect, and improved the biopharmaceutical attributes of the formulation. newlineThe optimized formulation demonstrated stability under the recommende