Enhanced solubility and oral bioavailability of niclosamide- sulfobutylether-β-cyclodextrin sodium inclusion complexes: An approach to improve its repurposing potential

Abstract

Niclosamide monohydrate (NCL) displays promising efficacy across diverse medical conditions, but its limited solubility (1.6 µg/mL at 20°C) and oral bioavailability (10%) hinder its translational potential. In this study, we investigate the complexation of NCL with sulfobutylether-β-cyclodextrin sodium (SBECD) as a strategy to enhance its solubility, dissolution rate and oral bioavailability. Molecular docking studies revealed weak binding (∆Gbind < 2.0 kcal/mole) between NCl and SBECD. The nitrophenyl ring inserted into the SBECD cavity, while the phenyl ring, housing Cl and OH groups, prominently extended outside. Phase solubility studies confirmed a 1:1 inclusion complex formation with a stability constant of 186 M−1. Inclusion complexes, prepared via co-grinding, kneading, solvent evaporation, and spray drying, significantly improved NCL dissolution. Specifically, the spray dried and kneaded complexes achieved complete drug release within 60 min, unlike pure NCL exhibiting only 16% dissolution at 90 min. Microscopic analysis showcased reduced particle surface area in the spray dried complex. Oral bioavailability assessments demonstrated an approximately1.6-fold increase for the spray dried and kneaded complexes compared to pure NCL. Our findings support the scalability and efficacy of NCL-SBECD complexation as a strategic approach for enhancing the repurposing potential of NCL in therapeutic applications.