Inhalation Potential of Rifampicin-Loaded Novel Metal-Organic Frameworks for Improved Lung Delivery: Physicochemical Characterization, <i>In Vitro</i> Aerosolization and Antimycobacterial Studies.

<b><i>Background:</i></b> The aim of the current study was to examine the potential of a rifampicin-loaded metal-organic framework (RIF@ZIF-8) for management of tuberculosis. <b><i>Materials and Methods:</i></b> RIF@ZIF-8 was developed using a simple, economic, and environmentally friendly ultrasonication method. Furthermore, the developed metal-organic framework (MOF) formulations were subjected to physicochemical characterization analyses such as Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), powder X-ray diffractometry, thermogravimetric analysis, field emission-scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), and UV spectroscopy. In addition, <i>in vitro</i> release, powder flow characterization, <i>in vitro</i> lung deposition, and efficacy studies against the <i>Mycobacterium tuberculosis</i> (MTB) H37Rv strain were performed. <b><i>Results:</i></b> Physicochemical characterization confirms its spherical shape and drug loading, whereas <i>in vitro</i> release analysis shows 80.5 ± 5.5% release of the drug from the loaded formulation within 48 hours. Furthermore, powder flow properties suggested that the nature of MOFs is free flowing. Additionally, <i>in vitro</i> lung deposition studies indicated an emission fraction of 88.02 ± 10.23% for the emitted dose and circa 21% fine particle fraction. The mass median aerodynamic diameter and geometric standard deviation were found to be 4.42 ± 0.07 μm and 1.55 ± 01 μm, respectively. The <i>in vitro</i> aerosol performance study demonstrated higher deposition at stages 3, 4, and 5 of the cascade impactors, which simulate deep lung delivery in terms of the trachea-primary bronchus and secondary and terminal bronchi of the human lung, respectively. Moreover, RIF@ZIF-8 exhibited improved antimycobacterial activity (0.0125 mg/mL) <i>vis-à-vis</i> an unformulated drug (0.025 mg/mL) against the MTB H37Rv strain, using the BACTEC 460TB system. <b><i>Conclusions:</i></b> Therefore, MOFs could be promising nanocarriers for targeting lungs and overcoming the hepatotoxicity associated with antituberculosis drugs requiring inhalation administration.