Development of inhalable dry powders combining replication and protease inhibitors of SARS-CoV-2
Tushar Saha1, Shubhra Sinha2,3, Rhodri Harfoot2, Miguel E. Quiñones-Mateu2,4 & Shyamal C. Das1
1School of Pharmacy, University of Otago, Dunedin, 9016, New Zealand
2Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, 9016, New Zealand
3Current address: Department of Physiology, University of Otago, Dunedin, New Zealand;
4Current address: Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada
Summary
Respiratory drug delivery is considered the most logical approach to treating respiratory tract infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Delivering antiviral agents directly to the respiratory tract can ensure effective drug concentrations at the infection site with less exposure to the systemic circulation causing less side effects. The combination of replication (remdesivir) and protease (disulfiram/ebselen) inhibitors of SARS-CoV-2 can block virus production synergistically in vitro. This data gives an important insight that, suitable drug combinations will not only offer better antiviral effects but also restrain the chance of upcoming drug resistance against SARS-CoV-2, as it is harder to develop drug resistance against multiple drugs than a single drug. Considering this, inhalable dry powders containing remdesivir, in combination with disulfiram or ebselen, were developed utilizing spray-drying technology. The inhalable sized (1.6 –2.9 μm) combinational dry powders exhibited spherical shapes and were crystalline in nature. The emitted dose and fine particle fraction of the prepared combinational dry powders varied between 80–88% and 55–58% respectively. Furthermore, the dry powders were non-toxic to respiratory cell lines (CC50> 40 μM) and retained antiviral properties with EC50 values ranging from 4.43 – 8.04 μM.