Dry powder formulation combining bedaquiline with pyrazinamide for latent and drug-resistant tuberculosis

Abstract

The purpose of this study was to develop an inhalable combination dry powder formulation of bedaquiline and pyrazinamide and study their physicochemical properties and safety since this combination acts synergistically against Mycobacterium tuberculosis while pyrazinamide alone is active against latent TB and bedaquiline alone is active against drug-resistant TB. The cospray-dried powder of bedaquiline and pyrazinamide with 20% w/w of L-leucine consisted of spherical, porous particles of inhalable size with a diameter ≤3.2 µm. The aerosolization efficiency of the combination powder (FPF: >66%) evaluated using a next generation impactor was higher than bedaquiline-only (FPF: 31.3%) and pyrazinamide-only (FPF: 5.1%) powders, which could be due to the differences in the morphology of the powders. The combination powder was stable during storage for one month in a desiccator and 75% RH and also safe to both Calu-3 and A549 cells up to 100 µg/ml. This is the first report on the development of an inhalable combination dry powder formulation of bedaquiline and pyrazinamide with high aerosolization efficiency. This formulation has the potential to improve the treatment of both latent and drug-resistant TB.