Abstract
Remdesivir exhibits in vitro activity against SARS-CoV-2 and was granted approval for emergency use. To maximize delivery to the lungs, we 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< 5 µm; 0.82 µm mass median aerodynamic diameter). Remdesivir was amorphous after the TFF process, which benefitted drug dissolution in simulated lung fluid. TFF remdesivir formulations are stable after one month of storage at 25 °C/60% relative humidity. An in vivo pharmacokinetic evaluation 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 the lung, and levels of GS-441524 were greater in the lung with leucine formulation compared to Captisol®. In conclusion, TFF technology produces high-potency remdesivir dry powder formulations for inhalation that are 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.
Highlights
IntroductionAs of September 2020, laboratory-confirmed cases have been reported in 213 countries and territories with more than 30 million reported cases and close to one million reported deaths [1]
The coronavirus disease 2019 (COVID-19) is an ongoing worldwide pandemic
Another study evaluated the performance of different models of the monodose dry powder inhaler (DPI) (RS01 and RS00) on the aerosol performance of brittle matrix powders containing voriconazole nanoaggregates prepared by thin film freezing (TFF) [42]
Summary
As of September 2020, laboratory-confirmed cases have been reported in 213 countries and territories with more than 30 million reported cases and close to one million reported deaths [1]. This disease is asymptomatic to mild in most people, in some cases, it can develop into pneumonia, acute respiratory distress syndrome (ARDS) and multi-organ dysfunction [2]. While effective treatments for COVID-19 are urgently needed, including therapeutics and vaccines, currently no drugs are approved to treat COVID-19. Additional therapeutics and routes of administration are needed to treat this respiratory virus
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