Remdesivir exhibits in vitro activity against SARS-CoV-2 and was granted approval for Emergency Use. To maximize delivery to the lungs, the authors formulated remdesivir as a dry powder for inhalation using thin film freezing (TFF). TFF produces brittle matrix nanostructured aggregates that are sheared into respirable low-density microparticles upon aerosolization from a passive dry powder inhaler. In vitro aerodynamic testing demonstrated that drug loading and excipient type affected the aerosol performance of remdesivir. Remdesivir combined with optimal excipients exhibited desirable aerosol performance (up to 93.0% FPF; 0.82 micron MMAD). Remdesivir was amorphous after the TFF process, which benefitted drug dissolution in simulated lung fluid. TFF remdesivir formulations are stable after one-month storage at 25C/60%RH. In vivo pharmacokinetic evaluation in rats showed that TFF-remdesivir-leucine was poorly absorbed into systemic circulation while TFF-remdesivir-Captisol demonstrated increased systemic uptake compared to leucine. Remdesivir was hydrolyzed to the nucleoside analog GS-441524 in lung, and levels of GS-441524 were greater in lung with the leucine formulation compared to Captisol. In conclusion, TFF technology produces high potency remdesivir dry powder formulations for inhalation suitable to treat patients with COVID-19 on an outpatient basis and earlier in the disease course where effective antiviral therapy can reduce related morbidity and mortality.
- makes possible to deliver remdesivir direct to the primary site of infection, the lungs;
- inhalation route is the most promising route of administration to maximize direct delivery to the target site without first-pass metabolism, boost local antiviral activity in the lungs, and limit the potential for systemic side effects;
- lower dose required by inhalation as compared to injectable forms;
- reduced drug cost due to lower dose;
- reduced treatment cost due to no need of hostalization.
Sawittree Sahakijpijarn, Chaeho Moon, John J. Koleng, Dale J. Christensen, Robert O.
Williams III (2020) Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing. doi: https://doi.org/10.1101/2020.07.26.222109