Preformulation Studies and Enabling Formulation Selection for an Insoluble Compound at Preclinical Stage-From In Vitro, In Silico to In Vivo.

The objective of this work was to identify an enabling formulation for an insoluble compound ZL006 with potency of boosting leukocytes after chemotherapy. The low oral bioavailability (<1%) of its conventional suspension was the hurdle for the preclinical evaluation via oral administration. Preformulation studies including physical form screening and physicochemical properties determination were performed. Polymorphism was observed, and the more thermodynamically stable form was selected for further studies. ZL006 showed certain supersaturation solubility, although the thermodynamic solubility in FaSSIF was low, which indicated the supersaturating formulation might work. Parameter sensitivity analysis by in silico simulation predicted that in vivo exposure was sensitive to solubility, while particle size reduction would have limited impact on exposure. Based on in silico prediction and the understanding of the molecule from preformulation studies, solid dispersion approach was selected. A preliminary dose escalation pharmacokinetic study in rats demonstrated that in vivo exposure increased in dose-proportional manner from 12.5 mg/kg to 50 mg/kg with around 50% oral bioavailability after oral dosing of the solid dispersion. This work showed that combination of preformulation studies and in silico simulation could efficiently guide the selection of enabling formulation, which could save resources at preclinical stage.