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

Miguel O. Jara, Zachary N. Warnken, Sawittree Sahakijpijarn, Chaeho Moon, Esther Y. Maier, Dale J. Christensen, John J. Koleng, Jay I. Peters, Sarah D. Hackman Maier, Robert O. Williams

Research output: Contribution to journalArticlepeer-review

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 IC90 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.

Original languageEnglish (US)
Article number120701
JournalInternational Journal of Pharmaceutics
Volume603
DOIs
StatePublished - Jun 15 2021

Keywords

  • Dry powder inhaler
  • Lung pharmacokinetics
  • Niclosamide
  • Pulmonary administration
  • SARS-CoV-2
  • Thin Film Freezing

ASJC Scopus subject areas

  • Pharmaceutical Science

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