Browsing by Subject "SARS-CoV-2 enteric capsules"

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Repurposing niclosamide : oral and inhaled delivery of niclosamide using hot-melt extrusion and thin film freezing technologies
(2023-03-29) Jara Gonzalez, Miguel Orlando; Williams, Robert O., III, 1956-; Smyth, Hugh D; Zhang, Feng; Maniruzzaman, Mohammed; Morales, Javier O
This research aims to enable the repurposing of niclosamide as a viable pharmaceutical product for treating cancer and viral infections, including COVID-19. Niclosamide is a unique drug candidate because although it was approved for use over 60 years ago as an anthelmintic medication, several studies have shown its potential as a multi-targeted cancer therapy, broad-spectrum antiviral (including COVID-19), and antibacterial, among several others. There have previously been several attempts to repurpose niclosamide in clinical trials. Unfortunately, niclosamide is a poorly water-soluble molecule with low bioavailability, which has negatively affected the outcomes of these studies. To overcome this challenge, we developed two different niclosamide formulations based on the targeted disease state as well as the intended route of administration. We prepared an amorphous solid dispersion of niclosamide (Niclosamide ASD) as an oral therapy for prostate cancer and a dried powder inhaler to treat COVID-19 infection. Niclosamide ASD was manufactured using hot-melt extrusion. This ASD generates nanoparticles during its dissolution, increasing niclosamide’s apparent 5 solubility by more than 60-fold (i.e. from 6.6 ± 0.4 to 481.7 ± 22.2 μg/mL) and its oral bioavailability in Sprague–Dawley rats. This formulation generates amorphous nanoparticles during its dissolution, confirmed by cryo-TEM and Wide-angle X-ray scattering. Nevertheless, niclosamide ASD undergoes recrystallization in acidic media, and an enteric oral dosage form of niclosamide ASD was formulated without hindering the generation of nanoparticles while maintaining the increase in the niclosamide’s apparent solubility. The formulation successfully increased niclosamide’s plasma levels in dogs when compared to a niclosamide solution prepared using organic solvents. Niclosamide dried powder inhaler was prepared using the Thin Film Freezing technology (TFF). This formulation proved to be safe after an acute three-day, multi-dose pharmacokinetic study in rats, as evidenced by histopathology analysis. In addition, it achieved lung concentrations above the required IC90 levels of SARS-CoV-2 for at least 24 h after a single administration in Syrian golden hamsters. Efficacy studies confirmed that the formulation effectively reduces viral load in infected hamsters that had been inoculated 24 hours prior with intranasal SARS-CoV-2. This formulation was transferred to a pharmaceutical company and has successfully completed phase 1 clinical trials.