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 regimen under fasting state only. Therefore, we aimed to develop and optimize a liquisolid compact formulation of abiraterone acetate to improve biopharmaceutical attributes aided by pharmacokinetic modelling and achieve dose reduction with no food effect on the formulation. Preliminary studies highlighted the importance of the selection of olive oil as a compatible vehicle. The pharmacokinetic model, integrated with gastrointestinal physiology, was used to predict fasted and fed state pharmacokinetic parameters. Optimization of the liquisolid formulation containing abiraterone acetate was carried at more than five times lower dose, i.e. 190 mg, compared to 1,000 mg. A central composite design (CCD) was used to identify optimal levels of formulation factors, namely the amount of vehicle (olive oil), the amount of coating agent (silicon dioxide), and the amount of surfactant (polysorbate 80). Graphical optimization using the selected models in conjunction with maximization of the desirability was used to identify the optimized liquisolid formulation. The predicted pharmacokinetic parameters (fasted C 901.83 ng/mL, fasted AUC 2723.82 ng·*h/mL, fed C 1024.34 ng/mL, and fed AUC 3041.83 ng·h/mL) of the optimized formulation were acceptable. Overall, the liquisolid compact formulation of abiraterone acetate was successfully developed and optimized. In vitro solubility and dissolution results aided by pharmacokinetic modelling also showed improved predicted bioavailability with greater than five times reduction in dose and elimination of food effect. The optimized LS formulation is stable for 6-months at accelerated (40°C/75% RH) and long-term (25°C/60% RH) stability condition. In conclusion, the study achieved more than 5-times dose reduction for abiraterone acetate, eliminated the food effect, and improved the biopharmaceutical attributes of the formulation. The optimized formulation demonstrated stability under the recommended storage conditions (40°C/75% RH and 25°C/60% RH) in accordance with the requirements of regulatory agencies such as USFDA and ICH guidance. The formulation has been studied extensively and offers numerous benefits over conventional marketed immediate release products.