Engineering rifampicin-encapsulated inhalable microparticles for precision tuberculosis therapy: in vivo distribution and therapeutic evaluation.

Tuberculosis (TB) continues to cause significant global mortality, highlighting the need for improved drug delivery systems. The objective of this paper focuses in describing the formulation, optimisation and in vivo assessment of rifampicin encapsulated PLGA microparticles for site-specific inhalation therapy. Microparticles for inhalation were produced by spray drying, and the DoE methodology was applied to reach the most suitable aerodynamic properties (mass median aerodynamics diameter (MMAD) 2.5 µm, fine particle fraction (FPF) 62%). Microparticles encapsulation of rifampicin led to prolongation of the pulmonary residence time both in BALB/c mice and Wistar rats and was 2.4 times higher than the concentration of the free oral rifampicin. Further, via Computational Fluid Dynamics (CFD) simulations and the use of AI-determined predictive modelling, aerosol deposition was maximised at an inhalation flow rate of 30 L/min targeting the alveolar region indicated by having 52.8% of the aerosol deposition at this region. The TB-infected mice, which showed the lung tissue bacterial load was reduced to 3.2 log colony forming unit (CFU) and the levels of TNF-α were decreased while IL-10 levels were increased. With this kind of accelerated stability testing it was ascertained that the type of formulation had a shelf-life of 24 months.