Co-Spray Dried Nafamostat Mesylate with Lecithin and Mannitol as Respirable Microparticles for Targeted Pulmonary Delivery: Pharmacokinetics and Lung Distribution in Rats

Abstract

Coronavirus disease 2019 (COVID-19), caused by a new strain of coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading rapidly worldwide. Nafamostat mesylate (NFM) suppresses transmembrane serine protease 2 and SARS-CoV-2 S protein-mediated fusion. In this study, pharmacokinetics and lung distribution of NFM, administered via intravenous and intratracheal routes, were determined using high performance liquid chromatography analysis of blood plasma, lung lumen using bronchoalveolar lavage fluid, and lung tissue. Intratracheal administration had higher drug delivery and longer residual time in the lung lumen and tissue, which are the main sites of action, than intravenous administration. We confirmed the effect of lecithin as a stabilizer through an ex vivo stability test. Lecithin acts as an inhibitor of carboxylesterase and delays NFM decomposition. We prepared inhalable microparticles with NFM, lecithin, and mannitol via the co-spray method. The formulation prepared using an NFM:lecithin:mannitol ratio of 1:1:100 had a small particle size and excellent aerodynamic performance. Spray dried microparticles containing NFM, lecithin, and mannitol (1:1:100) had the longest residual time in the lung tissue. In conclusion, NFM-inhalable microparticles were prepared and confirmed to be delivered into the respiratory tract, such as lung lumen and lung tissue, through in vitro and in vivo evaluations.

Nafamostat-Mediated Inhibition of SARS-CoV-2 Ribosomal Frameshifting Is Insufficient to Impair Viral Replication in Vero Cells. Comment on Munshi et al. Identifying Inhibitors of −1 Programmed Ribosomal Frameshifting in a Broad Spectrum of Coronaviruses. Viruses 2022, 14, 177

“…Importantly, Nafamostat has a short half-life time due to rapid hydrolysis by blood and liver esterases [ 25 , 26 , 27 ]. Therefore, it remains unclear whether Nafamostat concentrations suitable to block −1PRF can be attained in patients receiving Nafamostat via continuous infusion, the approved route of Nafamostat administration [ 28 , 29 ], or upon topical application, a recently pursued approach to COVID-19 therapy [ 30 ]. Nevertheless, although Nafamostat-mediated inhibition of −1PRF did not translate into reduced SARS-CoV-2 replication in our study, interference with SARS-CoV-2 −1PRF by more potent compounds could still represent a promising antiviral strategy.…”

A novel property of hexokinase inhibition by Favipiravir and proposed advantages over Molnupiravir and 2 Deoxy d glucose in treating COVID-19

“…Furthermore, because CES1 is known to exhibit genetic variation (Merali et al 2014 ), it is reasonable to predict that not every COVID-19 patient receiving Remdesivir or Molnupiravir will have the same CES1-mediated metabolism. Also, some herbal diet supplements, such as grapefruit juice, ginsenosides (Gao et al 2020 ), cannabinoids, lecithin (Kang et al 2021 ), and resveratrol, as well as plant extracts with active constituents such as naringenin, quercetin, luteolin, oleanolic acid, and asiatic acid, appear to have the highest CES1 inhibition potential (Qian and Markowitz 2020 ) which could alter the efficacy of the anti-viral drugs used.…”

Poly(Lactic Acid)-Based Microparticles for Drug Delivery Applications: An Overview of Recent Advances

“…The process is generally divided into three steps: (i) atomization of the feed into small droplets via an atomizer, (ii) drying of the droplets upon contact with the drying gas and particle formation, and (iii) separation of the dry particles from the drying medium [14]. Lately, the technique has been successfully employed for the preparation of inhalable formulations suitable for pulmonary drug delivery [15], [16]. However, adhering particles to the inner wall of the spray-dryer is the major drawback [13].…”