Formulating abiraterone acetate-HPMCAS-based amorphous solid dispersions: insights into in vitro and biorelevant dissolution assessments and pharmacokinetic evaluations

Abstract

Abiraterone acetate (ABTA) is used as a primary treatment for metastatic castration-resistant prostate cancer. Its low aqueous solubility results in inadequate dissolution and poor oral bioavailability (<10%), necessitating the consumption of large doses of ABTA (1000 mg per day) for desired efficacy. The aim of this study is to enhance the solubility, dissolution, and bioavailability of ABTA through amorphous solid dispersions (SDs). ABTA-SD was prepared via a solvent granulation method with different grades of hydroxypropyl methylcellulose acetate succinate (HPMCAS 716 and 912). The theoretical solubility parameter between ABTA and HPMCAS was below 7 MPa^1/2, indicating miscibility between the drug and the polymer according to the Hansen solubility parameter. HPMCAS showed a remarkable recrystallization inhibition of up to 180 min compared to the free drug (10 min), maintaining the soluble drug in supersaturation state and exhibiting the “spring and parachute” phenomenon. ABTA-SD exhibited a higher solubility (1.16-fold to 52-fold) in different media than free ABTA. The results of DSC, PXRD, ATR-FTIR, and FE-SEM indicated that the crystallinity of ABTA was completely transformed to an amorphous form and maintained in the SD formulation. In vitro and bio-relevant dissolution behavior of ABTA was studied in various dissolution media, indicating the higher dissolution of ABTA-SD than that of free ABTA. The pharmacokinetic study conducted in Wistar rats revealed that C_max and AUC_0–t of the optimized ABTA-SD formulation were significantly enhanced by 1.92-fold and 2.87-fold, respectively, compared to those of free ABTA.