Improved Dissolution and Pharmacokinetics of Abiraterone through KinetiSol® Enabled Amorphous Solid Dispersions

Abstract

Abiraterone is a poorly water-soluble drug. It has a high melting point and limited solubility in organic solvents, making it difficult to formulate as an amorphous solid dispersion (ASD) with conventional technologies. KinetiSol® is a high-energy, fusion-based, solvent-free technology that can produce ASDs. The aim of this study was to evaluate the application of KinetiSol to make abiraterone ASDs. We developed binary KinetiSol ASDs (KSDs) using both polymers and oligomers. For the first time, we reported that KinetiSol can process hydroxypropyl-β-cyclodextrin (HPBCD), a low molecular-weight oligomer. Upon X-ray diffractometry and modulated differential scanning calorimetry analysis, we found the KSDs to be amorphous. In vitro dissolution analysis revealed that maximum abiraterone dissolution enhancement was achieved using a HPBCD binary KSD. However, the KSD showed significant abiraterone precipitation in fasted state simulated intestinal fluid (FaSSIF) media. Hence, hypromellose acetate succinate (HPMCAS126G) was selected as an abiraterone precipitation inhibitor and an optimized ternary KSD was developed. A pharmacokinetic study revealed that HPBCD based binary and ternary KSDs enhanced abiraterone bioavailability by 12.4-fold and 13.8-fold, respectively, compared to a generic abiraterone acetate tablet. Thus, this study is the first to demonstrate the successful production of an abiraterone ASD that exhibited enhanced dissolution and bioavailability.

Physical formulation approaches for improving aqueous solubility and bioavailability of ellagic acid: A review

“…Ea is the energy required to disrupt crystalline lattice of a drug in a conventional formulation; Ec is the energy required to disrupt the glass solution of a drug in an ASD formulation, Eb is the energy required for solvent cavitation in the solubilization of a crystalline solid and Ed is the energy required for solvent cavitation in the case of ASD solubilization. Reprint with permission from [56].…”

Selective Laser Sintering 3-Dimensional Printing as a Single Step Process to Prepare Amorphous Solid Dispersion Dosage Forms for Improved Solubility and Dissolution Rate

“…6,13 Innovative techniques (thin-film freezing, TFF; KinetiSol® Processing, KSD; and micro precipitated bulk powder, MBP; microwave based dielectric heating 14 ) have been developed as viable alternatives to creating ASDs, each also with their unique limitations. 15,16 Previously, the preparation of dosage forms using selective laser sintering three-dimensional printing (SLS-3DP) has employed the BCS class III drug acetaminophen (APAP), and the final product observes a partial amorphous conversion of the drug. 10 This phenomenon of partial amorphous conversion of BCS class III drugs can impact the formulation's release behavior, making it unpredictable, and the stability of the formulation is also compromised as the drug molecules become more reactive.…”

Innovations in Thermal Processing: Hot-Melt Extrusion and KinetiSol® Dispersing

“…The KSD produced ritonavir tablets exhibited similar performance characteristics, such as the permeation rate and in vivo pharmacokinetics, to those of Norvir®. Lastly, Gala et al demonstrated, for the first time, the ability of KSD to process short-chain cyclic oligomers with low molecular weights (e.g., Hydroxypropyl-β-cyclodextrin [HPBCD]) (163). In this study, improved formulations were made of the generic abiraterone acetate tablets by creating ternary KSD products.…”

“…This lead to the eventual incorporation of the pHdependent polymer HPMCAS 126 G, acting as a parachute to prevent abiraterone precipitation when transitioning to FaSSIF. The ternary ASD formulation selected (e.g., HPBCD/HPMCAS 126 G/Abiraterone [80/10/10]) for in vivo studies in male beagle dogs achieved a 13.8-fold increase in bioavailability compared to the commercially available generic product (163).…”