Inclusion complexes of bedaquiline fumarate with β-cyclodextrin and its derivatives: In silico, in vitro and in vivo evaluation

Abstract

Bedaquiline fumarate (BQF), a BCS class-II drug, shows dissolution rate-dependent absorption pattern, which results in poor biopharmaceutical performance. In this research, we formulated β-cyclodextrin (β-CD) and hydroxypropyl β-cyclodextrin (HP-β-CD) inclusion complexes (ICs) of BQF to improve its biopharmaceutical attributes. ICs were prepared by freeze drying method and characterized using NMR, FTIR, DSC, PXRD and polarised microscopy. These complexes were evaluated for in vitro dissolution and optimized BQF-HP-β-CD ICs was further evaluated for cytotoxicity, intestinal permeability, and in vivo pharmacokinetic studies. 1D and 2D NMR and FTIR confirmed hydrogen bonding between BQF and cyclodextrins. DSC, PXRD and polarised microscopy confirmed the amorphous nature of BQF in complexes. In vitro dissolution study showed 29.6 and 57.5-fold enhancement in dissolution efficiency (DE60) for BQF-β-CD and BQF-HP-β-CD IC, respectively, in comparison to BQF. The selected BQF-HP-β-CD IC was found to be compatible to Caco-2 cells and a 5-fold enhancement in the intestinal permeability. In vivo pharmacokinetic studies demonstrated an increase in Cmax and relative bioavailability of BQF with BQF-HP-β-CD IC in comparison to BQF suspension.