Carrier-free combination dry powder inhaler formulation of ethionamide and moxifloxacin for treating drug-resistant tuberculosis

Abstract

This study aimed to develop a combination dry powder formulation of ethionamide and moxifloxacin HCl as this combination is synergistic against drug-resistant Mycobacterium tuberculosis (Mtb). L-leucine (20% w/w) was added in the formulations to maximize the process yield. Moxifloxacin HCl and/or ethionamide powders with/without L-leucine were produced using a Buchi Mini Spray-dryer. A next generation impactor was used to determine the in vitro aerosolization efficiency. The powders were also characterized for other physicochemical properties and cytotoxicity. All the spray-dried powders were within the aerodynamic size range of <5.0 µm except ethionamide-only powder (6.0 µm). The combination powders with L-leucine aerosolized better (% fine particle fraction (FPF): 61.3 and 61.1 for ethionamide and moxifloxacin, respectively) than ethionamide-only (%FPF: 9.0) and moxifloxacin-only (%FPF: 30.8) powders. The combination powder particles were collapsed with wrinkled surfaces whereas moxifloxacin-only powders were spherical and smooth and ethionamide-only powders were angular-shaped flakes. The combination powders had low water content (<2.0%). All the powders were physically stable at 15% RH and 25 ± 2 °C during 1-month storage and tolerated by bronchial epithelial cell-lines up to 100 µg/ml. The improved aerosolization of the combination formulation may be helpful for the effective treatment of drug-resistant tuberculosis. Further studies are required to understand the mechanisms for improved aerosolization and test the synergistic activity of the combination powder.

Keywords: Carrier-free; combination; drug-resistant; dry powder inhaler; spray-drying; tuberculosis.