Tuberculosis (TB), caused by aerosol inhalation of Mycobacterium tuberculosis, mainly localizes in the lungs. Rifampicin is a first line anti-TB drug used as a part of a multi-drug regimen via oral route. Since the maximum recommended oral dose of rifampicin is 10 mg/kg with a daily maximum of 600 mg, delivery of high concentration of drug to local target sites in the lung, via the oral route, is dose limited. Inhaled delivery can be an alternative route for rifampicin delivery to achieve high concentration in the lungs as well as the blood for effective TB treatment. In this study, inhalable rifampicin powder was prepared by spray drying and in vivo safety at a dose of 50 mg/kg was studied in Sprague Dawley rats. Lung safety of rifampicin delivered by intra-tracheal insufflation was determined by lung histopathology and hepatic effects were evaluated by liver histopathology as well as measurement of alanine transaminase (ALT) activity in serum at 24 hours post drug administration. It was observed that ALT activity was significantly lower after inhaled delivery when compared to the oral group and rifampicin concentration in rat plasma after intra-tracheal delivery was four times that from orally administered rifampicin. Similarly, histopathological evaluation of rat lung and liver confirmed no damage to the tissue structures after intra-tracheal delivery of rifampicin indicating intra-tracheal delivery of rifampicin powder at 50 mg/kg dose was safe and tolerable in rats.
Rifampicin delivered by intra-tracheal insufflation to rats was safe at 50 mg/kg. Compared to oral rifampicin, inhaled rifampicin led to lower ALT activity and higher rifampicin level in plasma at 24 hours post drug administration suggesting its potential to achieve high lung and blood concentrations with lower adverse hepatic effects.