Enhancing the <i>in vivo</i> bioavailability and absorption of Niclosamide with amorphous solid dispersion via solvent method

Abstract Objectives This research aims to prepare a superior amorphous solid dispersion (ASD) formulation via solvent method for the oral delivery of Niclosamide to enhance oral bioavailability and absorption. Methods Phase solubility tests were conducted to select an optimal carrier combination for Niclosamide solid dispersion (SD). The Niclosamide ASD was synthesized using a solvent rotary evaporation method and characterized through in vitro dissolution tests, differential scanning calorimetry (DSC), modulated DSC, powder X-ray diffraction, and scanning electron microscopy. In vivo oral pharmacokinetic studies were conducted in Sprague Dawley rats at a dose of 50 mg/kg. Key findings PEG6000 and poloxamer 188 combination was selected as an optimal carrier. ASD named ASD-5 was successfully prepared, encompassing a 25% drug loading, Niclosamide within ASD-5 remains amorphous and stable. 75% of Niclosamide in ASD-5 rapidly dissolved in 5 min, while below 5% of pure Niclosamide and physical mixture dissolved in a longer time. Amorphization of Niclosamide in ASD-5 notably contributes to its dissolution rate and extent. Furthermore, among reported Niclosamide SD formulations with drug loading above 25%, ASD-5 demonstrated the highest bioavailability, showing a 2.33-fold increase in plasma exposure and bioavailability compared to pure Niclosamide. Conclusions Amorphous ASD-5 prepared by the solvent method has higher drug loading and is scalable in pre-clinical stage preparation. Due to using PEG6000 and poloxamer 188 combination, ASD-5 had the highest bioavailability among reported Niclosamide SDs with a drug load exceeding 25%. Also, ASD-5 presented a simplified preparation procedure compared to other reported Niclosamide SD.