Engineering a nifurtimox nanosuspension: toward improved pharmaceutical attributes

Nifurtimox (NFX) is one of the two approved drugs for the treatment of Chagas disease, a neglected parasitic infection caused by Trypanosoma cruzi. Classified as a biopharmaceutics classification system class II/IV drug, NFX exhibits poor aqueous solubility, which significantly limits its dissolution rate and results in erratic bioavailability. This study aimed to develop and characterize a novel nanosuspension of NFX (NFX-NS), composed of drug nanocrystals (NFX-NCs), as a strategy to enhance drug solubility and dissolution, while also enabling administration to pediatric patients. NFX-NS was prepared using a top-down, organic solvent-free wet milling approach, followed by lyophilization to obtain the solid-state formulation. A physicochemical characterization, solubility testing of NFX-NCs, and dissolution studies of NFX-NS were conducted, alongside in vitro biological evaluation. The resulting NFX-NS exhibited a particle size of approximately 200 nm, with a polydispersity index below 0.2 and demonstrated stability for at least 120 days. NFX retained its crystalline structure post-processing, with no significant changes in its physicochemical properties, indicating minimal interaction with the stabilizer. The aqueous solubility of NFX-NCs was enhanced tenfold compared to that of the raw drug, and a substantial improvement in the dissolution rate was observed. In vitro assays revealed significantly increased anti-T. cruzi activity for NFX-NCs, along with improved biocompatibility in human endothelial cells. These findings highlight the potential of NFX-NS as the first NCs-based formulation of NFX, offering a promising therapeutic alternative for pediatric use and addressing the solubility-related challenges associated with the drug.