Dry powder formulation of kanamycin with enhanced aerosolization efficiency for drug-resistant tuberculosis

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Background:Kanamycin, an injectable agent, is currently used to treat drug-resistant tuberculosis (TB). Parenteral kanamycin causes high systemic toxicity which could be avoided by direct delivery to the lungs. This study focused on producing a highly aerosolizable dry-powder of hygroscopic kanamycin by spray-drying with L-leucine.Methods:Kanamycin powders were prepared with different concentrations (0, 5, 10, 15 and 20% w/w) of L-leucine using the Buchi B-290 Mini Spray-Dryer. In vitro aerosolization efficiency, particle size, morphology, crystallinity, surface composition, drug-excipient interaction and moisture content of the powders were characterized by a Next Generation Impactor (NGI), laser diffraction, scanning electron microscopy, X-ray diffractometry, XPS, ATR-FTIR and thermogravimetric analysis. The physicochemical and aerosolization stability of the powders were investigated after one-month storage at 25 ± 2 °C/15% RH and 25 ± 2 °C/75% RH. The cytotoxicity on Calu-3 and A549 cells of the kanamycin powders was evaluated by MTT assay.Results:The spray-dried powder particles were in the inhalable size range (<6.1 μm). The powders with L-leucine were wrinkled in shape, amorphous in nature and had low moisture content (<5.0%). Kanamycin with 5% (w/w) of L-leucine showed the best aerosolization efficiency of 73.0 ± 2.5%. The powders remained stable during storage at 25 ± 2 °C/15% RH and tolerated by respiratory cell lines.Conclusion:L-leucine improved the aerosolization of kanamycin by surface modification, which may be helpful for the effective treatment of drug-resistant tuberculosis.Graphical abstract

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