A comparative study on in vitro and in vivo characteristics of enzalutamide nanocrystals versus amorphous solid dispersions and a better prediction for bioavailability based on "spring-parachute" model

Abstract

This study systematically compared enzalutamide (ENZ) nanocrystals and amorphous formulation (Xtandi® Tablets) and proposed an effective method for predicting pharmacokinetic behavior. ENZ nanosuspensions were prepared by anti-solvent precipitation (ENZ/NS-AS) and wet milling (ENZ/NS-WM) under optimal conditions and were solidified by spray drying and further tableting. Spray dried ENZ/NS-WM was confirmed to exist in crystalline state by DSC and PXRD, while spray dried ENZ/NS-AS was amorphous form. The dissolution testing revealed that ENZ/NS-WM tablets exhibited significantly faster dissolution rate than the physical mixture of untreated ENZ and HPMCAS-HG (1:1) prepared by gently grinding with a mortar and pestle for 2 min and were comparable to Xtandi® Tablets. However, the pharmacokinetic study in beagle dogs indicated that ENZ/NS-WM tablets displayed 0.43-fold lower C_max and area under the curve from 0 d to 14 d (AUC_{0-14 d}) than Xtandi® Tablets. This difference was well explained by the "spring-parachute" testing, where ENZ/NS-WM tablets exhibited a worse supersaturation performance with 0.46-fold lower supersaturated level (C_spring) and 0.42-fold lower area under the curve of "spring-parachute" process in pH6.8 (AUSPC_2-24h) compared to Xtandi® Tablets, indicating that C_spring and AUSPC_2-24h obtained from "spring-parachute" testing were better indicators for predicting in vivo behavior than the dissolution rate. Overall, despite the fact that the current nanocrystal formulation did not exhibit advantageous bioavailability, the study provided valuable information and direction for oral drug delivery system based on nano-technology.

Keywords: Amorphous solid dispersions; Anti-solvent precipitation; Enzalutamide nanocrystals; Spring-parachute model; Wet-milling.