Loading, release and activity of inhalable benzothiazinone-loaded human albumin nanocarriers for anti-tuberculosis therapy  

Ayasha Patel¹, Natalja Redinger⁴, Adrian Richter², Arcadia Woods¹, Peter Imming², Ulrich E. Schaible^4,5, Nick Childerhouse³, Ben Forbes¹  and Lea Ann Dailey²

¹Institute of Pharmaceutical Science, King’s College London, 150 Stamford Street, SE1 9NH, United Kingdom

²Department of Pharmacy, Martin Luther University of Halle-Wittenberg, Wolfgang-Langenbeck-Str.4, 06120 Halle, Germany

³Vectura Group plc, One Prospect West, Chippenham, Wiltshire, SN14 6FH, United Kingdom

⁴Leibniz Center for Medicine & Biosciences, Priority Area Infections, Dept. Cellular Microbiology, Parkallee 1, 23845 Borstel, Germany

⁵German Center for Infection Research, TTU TB, Parkallee 1, 23845 Borstel, Germany

Albumin nanoparticles are attractive candidates for enhancing drug delivery to the lungs. Previous studies have demonstrated their favourable biodistribution properties and their ability to incorporate therapeutically relevant compounds for pulmonary application. In this study the loading, release kinetics and therapeutic activity of two new antimycobacterial benzothiazinones (IR 20 and FG 2) incorporated within human serum albumin nanoparticles was investigated. Nanoparticles were manufactured with similar drug loading (5.5 ± 0.4 and 5.9 ± 0.4 µg/mg albumin for IR 20 & FG 2, respectively). Drug release studies into a lung lining fluid mimetic showed both nanoparticle systems to be stable without the enzyme, trypsin, however upon its addition a rapid initial release of drug was documented (~70% for IR 20 & ~50% for FG 2 in the first 8 hours) followed by slower release over the remaining 48 hour time period (total release ~87% for IR 20 and ~61% for FG 2). Pharmacological activity was tested in macrophages infected with the Mycobacterium tuberculosis H37Rv strain.  The more potent FG 2 was found to have slightly higher antimicrobial activity than IR 20, particularly when incorporated into albumin nanoparticles where >10-fold decrease in mycobacterial cell counts was observed. These studies demonstrate that 1) poorly soluble compounds can be formulated in albumin nanocarriers, 2) drug release rates in biologically relevant systems occur over a therapeutically relevant timeframe and 3) drug-loaded albumin nanoparticles can confer an enhanced therapeutic activity.