Development of a proliposomal pretomanid dry powder inhaler as a novel alternative approach for combating pulmonary tuberculosis.

ABSTRACT

Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) continue as public health concerns. Inhaled drug therapy for TB has substantial benefits in combating the causal agent of TB (Mycobacterium tuberculosis). Pretomanid is a promising candidate in an optional combined regimen for XDR-TB. Pretomanid has demonstrated high potency against M. tuberculosis in both the active and latent phases. Conventional spray drying was used to formulate pretomanid as dry powder inhalers (DPIs) for deep lung delivery using a proliposomal system with a trehalose coarse excipient to enhance the drug solubility. Co-spray drying with L-leucine protected hygroscopic trehalose in formulations and improved powder aerosolization. Higher amounts of L-leucine (40-50 % w/w) resulted in the formation of mesoporous particles with high percentages of drug content and entrapment efficiency. The aerosolized powders demonstrated both geometric and median aerodynamic diameters < 5 µm with > 90 % emitted dose and > 50 % fine particle fraction. Upon reconstitution in simulated physiological fluid, the proliposomes completely converted to liposomes, exhibiting suitable particle sizes (130-300 nm) with stable colloids and improving drug solubility, leading to higher drug dissolution compared to the drug alone. Inhalable pretomanid showed higher antimycobacterial activity than pretomanid alone. The formulations were safe for all broncho-epithelial cell lines and alveolar macrophages, thus indicating their potential suitability for DPIs targeting pulmonary TB.