Amorphous Solid Dispersion of Niclosamide with Water-Soluble β-Cyclodextrins for Dissolution and Bioavailability Enhancement

Cyclodextrins (CDs) are cyclic oligosaccharides widely employed for the solubility enhancement of poorly water-soluble drugs. Niclosamide is a BCS class II drug for tapeworm infections and is currently under repurposing for various other indications, including COVID-19. Due to its low aqueous solubility, a high daily dose (2 g) is required for clinical efficacy. Herein, we investigate the potential of beta-cyclodextrin (beta-CD) and its sulfobutylether and hydroxypropyl derivatives for the dissolution enhancement of niclosamide. The solid dispersions were prepared by kneading the drug and cyclodextrins together by adding solvent, water: methanol (1 : 1 v/v). Among various CDs studied, 2-Hydroxypropyl-beta-cyclodextrin (HP-beta-CD) in the 1: 2 molar ratio (SB-IC-N4 batch) shows the most significant improvement in water solubility of niclosamide (6.3 vs. 182 mu g/ml), resulting in 2-fold improved in-vitro dissolution. The comparative oral pharmacokinetics in Wistar rats at 50 mg/ kg produced 1.69-fold higher plasma exposure of niclosamide. The spectral characterization provided molecular insights into interactions of niclosamide with HP-beta-CD. These results suggest that the dispersion of niclosamide with HP-beta-CD aid in faster dissolution and better drug bioavailability.

Automated summary

This study explores the potential of beta-cyclodextrin and its derivatives for enhancing the dissolution of niclosamide. Among the cyclodextrins studied, 2-Hydroxypropyl-beta-cyclodextrin in the 1:2 molar ratio shows the most significant improvement in water solubility and in-vitro dissolution of niclosamide. Oral administration of the niclosamide and HP-beta-CD complex in rats resulted in higher plasma exposure. Spectral characterization provides insights into the interactions between niclosamide and HP-beta-CD.