Galeterone, a novel
prostate cancer candidate treatment, was discontinued after a Phase III clinical trial due to lack of efficacy.
Galeterone is weakly basic and exhibits low solubility in biorelevant media (i.e., ~ 2 µg/mL in fasted simulated intestinal fluid). It was formulated as a 50-50 (w/w)
galeterone-
hypromellose acetate succinate spray-dried dispersion to increase its bioavailability. Despite this increase, the bioavailability of this formulation may have been insufficient and contributed to its clinical failure. We hypothesized that reformulating
galeterone as an amorphous solid dispersion by KinetiSol® compounding could increase its bioavailability. In this study, we examined the effects of composition and manufacturing technology (Kinetisol and spray drying) on the performance of
galeterone amorphous solid dispersions. KinetiSol compounding was utilized to create
galeterone amorphous solid dispersions containing the complexing agent hydroxypropyl-β-
cyclodextrin or
hypromellose acetate succinate with lower
drug loads that both achieved a ~ 6 × increase in dissolution performance versus the 50-50 spray-dried dispersion. When compared to a spray-dried dispersion with an equivalent
drug load, the KinetiSol amorphous solid dispersions formulations exhibited ~ 2 × exposure in an in vivo rat study.
Acid-base surface energy analysis showed that the equivalent composition of the KinetiSol amorphous solid dispersion formulation better protected the weakly basic
galeterone from premature dissolution in acidic media and thereby reduced precipitation, inhibited recrystallization, and extended the extent of supersaturation during transit into neutral intestinal media.