Development and evaluation of inhalable composite niclosamide-lysozyme particles: A broad-spectrum, patient-adaptable treatment for coronavirus infections and sequalae

Abstract

Niclosamide (NIC) has demonstrated promising in vitro antiviral efficacy against SARS-CoV-2, the causative agent of the COVID-19 pandemic. Though NIC is already FDA-approved, administration of the currently available oral formulation results in systemic drug levels that are too low for the inhibition of SARS-CoV-2. We hypothesized that the co-formulation of NIC with an endogenous protein, human lysozyme (hLYS), could enable the direct aerosol delivery of the drug to the respiratory tract as an alternative to oral delivery, thereby effectively treating COVID-19 by targeting the primary site of SARS-CoV-2 acquisition and spread. To test this hypothesis, we engineered and optimized composite particles containing NIC and hLYS suitable for delivery to the upper and lower airways via dry powder inhaler, nebulizer, and nasal spray. The novel formulation demonstrates potent in vitro and in vivo activity against two coronavirus strains, MERS-CoV and SARS-CoV-2, and may offer protection against methicillin-resistance staphylococcus aureus pneumonia and inflammatory lung damage occurring secondary to SARS-CoV-2 infections. The suitability of the formulation for all stages of the disease and low-cost development approach will ensure rapid clinical development and wide-spread utilization.

SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals

“…A phase I clinical study of niclosamide has reported peak plasma concentrations ranging from 35.7-182 ng/ml (109-556 nM) 75 , which encompasses the IC 50 value of 0.13 μM reported here. Niclosamide is known to have limited resorption efficacy, which might be enhanced by improving the niclosamide formulation or by developing an inhalable derivate for local application 76 . Both MK-2206 and niclosamide might be promising candidates for clinical trials.…”

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

“…Thus, direct delivery of niclosamide to the lung could overcome the limitations of oral administration and achieve high drug concentration at the site of infection, i.e., the lungs. Brunaugh et al [ 76 ] engineered composite particles containing niclosamide and an endogenous protein, human lysozyme, for inhalation delivery to the lungs. This study demonstrated that the co-formulation of niclosamide with lysozyme is four-fold more potent against coronaviruses compared to niclosamide alone.…”

Drug delivery systems as immunomodulators for therapy of infectious disease: Relevance to COVID-19

“…Similarly, niclosamide has shown promising in vitro antiviral efficacy against SARS-CoV-2 [276] . A potential immunomodulatory response has also been observed, involving an up-regulation in IL-1β activity and decreased expression of IL-6, TNF-α [277] . However, in its oral dosage form, systemic drug levels are too low to inhibit SARS-CoV-2.…”