TY - JOUR
T1 - Niclosamide inhalation powder made by thin-film freezing
T2 - Multi-dose tolerability and exposure in rats and pharmacokinetics in hamsters
AU - Jara, Miguel O.
AU - Warnken, Zachary N.
AU - Sahakijpijarn, Sawittree
AU - Moon, Chaeho
AU - Maier, Esther Y.
AU - Christensen, Dale J.
AU - Koleng, John J.
AU - Peters, Jay I.
AU - Hackman Maier, Sarah D.
AU - Williams, Robert O.
N1 - Funding Information:
This research was funded by TFF Pharmaceuticals, Inc. through a sponsored research agreement with the University of Texas at Austin. Warnken is partially supported by this sponsored research agreement with TFF Pharmaceuticals Inc. Miguel O. Jara acknowledges the funding support from the Equal Opportunities Fulbright—CONICYT Scholarship 56170009.
Publisher Copyright:
© 2021 Elsevier B.V.
PY - 2021/6/15
Y1 - 2021/6/15
N2 - 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.
AB - 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.
KW - Dry powder inhaler
KW - Lung pharmacokinetics
KW - Niclosamide
KW - Pulmonary administration
KW - SARS-CoV-2
KW - Thin Film Freezing
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U2 - 10.1016/j.ijpharm.2021.120701
DO - 10.1016/j.ijpharm.2021.120701
M3 - Article
C2 - 33989748
AN - SCOPUS:85106966595
VL - 603
JO - International Journal of Pharmaceutics
JF - International Journal of Pharmaceutics
SN - 0378-5173
M1 - 120701
ER -