Inhalable dry powder containing remdesivir and disulfiram: Preparation and in vitro characterization

Abstract

The respiratory tract, as the first and most afflicted target of many viruses such as SARS-CoV-2, seems to be the logical choice for delivering antiviral agents against this and other respiratory viruses. A combination of remdesivir and disulfiram, targeting two different steps in the viral replication cycle, has showed synergistic activity against SARS-CoV-2 in-vitro. In this study, we have developed an inhalable dry powder containing a combination of remdesivir and disulfiram utilizing the spray-drying technique, with the final goal of delivering this drug combination to the respiratory tract. The prepared dry powders were spherical, and crystalline. The particle size was between 1 and 5 μm indicating their suitability for inhalation. The spray-dried combinational dry powder containing remdesivir and disulfiram (RDSD) showed a higher emitted dose (ED) of >88% than single dry powder of remdesivir (RSD) (∼72%) and disulfiram (DSD) (∼84%), with a fine particle fraction (FPF) of ∼55%. Addition of L-leucine to RDSD showed >60% FPF with a similar ED. The in vitro aerosolization was not significantly affected after the stability study conducted at different humidity conditions. Interestingly, the single (RSD and DSD) and combined (RDSD) spray-dried powders showed limited cellular toxicity (CC50 values from 39.4 to >100 µM), while maintaining their anti-SARS-CoV-2 in vitro (EC50 values from 4.43 to 6.63 µM). In a summary, a combinational dry powder formulation containing remdesivir and disulfiram suitable for inhalation was developed by spray-drying technique which showed high cell viability in the respiratory cell line (Calu-3 cells) retaining their anti-SARS-CoV-2 property. In the future, in vivo studies will test the ability of these formulations to inhibit SARS-CoV-2 which is essential for clinical translation.