A facile one-step jet-milling approach for the preparation of proliposomal dry powder for inhalation as effective delivery system for anti-TB therapeutics.

Objective: Physicochemical characterization and assessment of aerosol dispersion performance of anti-TB proliposome dry powders for inhalation (DPIs) prepared using a single-step jet-milling (JM) approach.

Significance: Conventional tuberculosis (TB) treatment involves isoniazid and rifampicin as first-line agents in extended oral multi-drug regimes. Liposomal DPIs are emerging as promising alternatives for targeted delivery of anti-TB agents to alveolar macrophages harboring . However, traditional approaches for liposomal DPI preparation are tedious, time consuming and require sophisticated/expensive equipment. The proposed JM technique for preparation of proliposome DPIs could obviate these limitations and facilitate use of these drugs for more effective and safer treatment.

Methods: Proliposome DPIs containing isoniazid and/or rifampicin, cholesterol and cholesterol sulfate were successfully prepared via JM (injection pressure, 7.4 bar; milling pressure, 3.68 bar). Their physicochemical, content uniformity, and aerosol dispersion performance were assessed using scanning electron microscopy/energy-dispersive X-ray spectroscopy, transmission electron microscopy, dynamic light scattering/Zeta potential, X-ray diffraction spectroscopy, thermogravimetric analysis, high-performance liquid chromatography, and the Next-Generation Impactor.

Results: The DPIs exhibited consistent, spherically shaped, smooth particles. Drug particles were evenly distributed with acceptable content uniformity. Drug crystallinity was not significantly affected by milling and the formulations had minimal (<2.0%) water content. After reconstitution of the DPIs, the hydrodynamic size was about 370.9-556.2 nm and charge was -12.3 to -47.3 mV. Furthermore, the proliposome DPIs presented emitted dose (69.04-89.03%), fine particle fraction, <4.4 µm (13.7 - 57.8%), and mass median aerodynamic diameter (<3.0 µm), which satisfied the requirements for deep lung delivery.

Conclusion: The proposed approach was suitable for preparation of proliposome DPIs that could be deployed for local targeting of the lower respiratory tract for the treatment of TB.