Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing

Remdesivir, an investigational broad-spectrum antiviral agent, formulated with sulfobutyl beta-cyclodextrin, has shown in vitro activity against SARSCoV-2.

Currently, remdesivir is administered by injection into a vein as an infusion to treat patients with
COVID-19 only in hospitals. However, due to the pandemic, many patients are not able to be
hospitalized, and they do not have access to injectable administration of remdesivir. To provide
remdesivir for other patients besides those most severely ill, more convenient and accessible dosage
forms for different routes of administration must be quickly developed and tested so that patients have
more options to get treated.

Nebulization of the current IV formulation in a diluted form is a potential method of pulmonary
administration; however, the drug is prone to degrade by hydrolysis in aqueous solution to form the
nucleoside monophosphate, which has difficulty penetrating cell membranes, thereby minimizing the
antiviral activity in the lung cells.

To maximize direct delivery to the target site, the lungs, remdesivir as a dry powder for inhalation was developed using thin film freezing (TFF). TFF produces a brittle matrix of nanostructured aggregates that can be 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 (e.g. sulfobutyl ether beta-cyclodextrin, mannitol, lactose, leucine) exhibited suitable aerosol performance (up to 92.4% fine particle fraction and 0.86 µm mass median aerodynamic diameter). Remdesivir was amorphous after the TFF process, which we hypothesize will provide a benefit for drug dissolution once administered to the lungs. Neither the organic/water processing cosolvent or the rapid freezing rate used during the TFF process affected the chemical stability of remdesivir during processing. In conclusion, TFF is a suitable technology for producing remdesivir dry powder formulations suitable for pulmonary administration.

Sawittree Sahakijpijarn, Chaeho Moon, John J. Koleng, Robert O. Williams III: Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing. bioRxiv 2020.07.26.222109; 
doi: https://doi.org/10.1101/2020.07.26.222109