Solubility Enhancement and Inhalation Delivery of Cyclodextrin-Based Inclusion Complex of Delamanid for Pulmonary Tuberculosis Treatment.

Tuberculosis (TB) is a contiguous airborne disease caused by Mycobacterium tuberculosis (M.tb), primarily affecting the human lungs. The progression of drug-susceptible TB to drug-resistant strains, MDR-TB and XDR-TB, has become a global challenge toward eradicating TB. Conventional TB treatment involves frequent dosing and prolonged treatment regimens predominantly by an oral or invasive route, leading to treatment-related systemic adverse effects and patient's noncompliance. Pulmonary delivery is an attractive option as we could reduce dose, limit systemic side-effects, and achieve rapid onset of action. Delamanid (DLD), an antituberculosis drug, has poor aqueous solubility, and in this study, we aim to improve its solubility using cyclodextrin complexation. We screened different cyclodextrins and found that HP-β-CD resulted in a 54-fold increase in solubility compared to a 27-fold and 13-fold increase by SBE-β-CD and HP-ɣ-CD, respectively. The stability constant (265 ± 15 M) and complexation efficiency (8.5 × 10) suggest the formation of a stable inclusion complex of DLD and HP-β-CD in a 2:1 ratio. Solid-state characterization studies (DSC, PXRD, and NMR) further confirmed successful complexation of DLD in HP-β-CD. The nebulized DLD-CD complex solution showed a mass median aerodynamic diameter of 4.42 ± 0.62 μm and fine particle fraction of 82.28 ± 2.79%, suggesting deposition in the respiratory airways. In bacterial studies, minimum inhibitory concentration of DLD-CD complex was significantly reduced (four-fold) compared to free DLD in M.tb (H37Ra strain). Furthermore, accelerated stability studies confirmed that the inclusion complex was stable for 4 weeks with 90%w/w drug content. In conclusion, we increased the aqueous solubility of DLD through cyclodextrin complexation and improved its efficacy in vitro.