A quality-by-design strategic approach for the development of bedaquiline-pretomanid nanoparticles as inhalable dry powders for TB treatment.

Tuberculosis (TB) is caused by Mycobacterium tuberculosis (M.tb) and is the second leading cause of death from an infectious disease globally. The disease mainly affects the lungs and forms granulomatous lesions that encapsulate the bacteria, making treating TB challenging. The current treatment includes oral administration of bedaquiline (BDQ) and pretomanid (PTD); however, patients suffer from severe systemic toxicities, low lung drug concentration, and non-adherence. In this study, we developed BDQ-PTD loaded nanoparticles as inhalable dry powders for pulmonary TB treatment using a Quality-by-Design (QbD) approach. The BDQ-PTD combination showed an additive/synergistic effect for M.tb inhibition in vitro, and the optimized drug ratio (1:4) was successfully loaded into polymeric nanoparticles (PLGA NPs). The QbD approach was implemented by identifying the quality target product profile (QTPPs), critical quality attributes (CQAs), and critical process parameters (CPPs) to develop efficient design space for dry powder preparation using spray drying. The three-factorial and three-level Box-Behnken Design was used to assess the effect of process parameters (CPPs) on product quality (CQAs). The Design of Experiments (DoE) analysis showed different regression models for product quality responses and helped optimize process parameters to meet QTPPs. The optimized dry powder showed excellent yield (72 ± 2 % w/w), high drug (BDQ-PTD) loading, low moisture content (<1% w/w), and spherical morphology. Further, aerosolization performance revealed the suitability of powder for deposition in the respiratory airways of the lungs (MMAD 2.4 µm and FPF > 75 %). In conclusion, the QbD approach helped optimize process parameters and develop dry powder with a suitable quality profile for inhalation delivery in TB patients.