Niclosamide inhalation powder made by thin-film freezing: Multi-dose tolerability and exposure in rats and pharmacokinetics in hamsters

Abstract

In this work, we have developed and tested a dry powder form of niclosamide made by thin-film freezing (TFF) and administered it by inhalation to rats and hamsters to gather data about its toxicology and pharmacokinetics. Niclosamide, a poorly water-soluble drug, is an interesting drug candidate because it was approved over 60 years ago for use as an anthelmintic medication, but recent studies demonstrated its potential as a broad-spectrum antiviral with pharmacological effect against SARS-CoV-2 infection. TFF was used to develop a niclosamide inhalation powder composition that exhibited acceptable aerosol performance with a fine particle fraction (FPF) of 86.0% and a mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of 1.11 µm and 2.84, respectively. This formulation not only proved to be safe after an acute three-day, multi-dose tolerability and exposure study in rats as evidenced by histopathology analysis, and also was able to achieve lung concentrations above the required IC 90 levels for at least 24 h after a single administration in a Syrian hamster model. To conclude, we successfully developed a niclosamide dry powder inhalation that overcomes niclosamide’s limitation of poor oral bioavailability by targeting the drug directly to the primary site of infection, the lungs.

Inhalation Delivery for the Treatment and Prevention of COVID-19 Infection

“…This study demonstrated that the co-formulation of niclosamide with lysozyme is four-fold more potent against coronaviruses compared to niclosamide alone. In a recent study, Jara et al [ 77 ] developed a dry powder formulation of niclosamide in combination with hydrophilic excipients, mannitol and leucine, using a thin-film freezing method. These powders showed acceptable aerosol properties, with a fine particle fraction of 86%, suitable for deep lung delivery.…”

Small molecules in the treatment of COVID-19

“…Intranasal administration of niclosamide (0.24 mg·kg −1 ·day −1 ) to SARS-CoV-2-infected mice for 10 days improved survival and significantly reduced viral loads. 538 Darunavir, with a similar anti-HIV effect, belongs to the carbamates. 539 Computational evidence showed it may interact with the M pro pocket.…”

Inhaled therapy for COVID-19: Considerations of drugs, formulations and devices

“…Niclosamide, an anthelmintic drug that was repurposed for COVID-19 as a tablet, was reformulated for inhaled delivery for COVID-19. In one study, Jara et al ( Jara et al, 2021 ) developed niclosamide dry powder by TFF technology. Mannitol and L-leucine were in this study to enhance the aerosolization property of the prepared dry powder.…”