Inhalable Microparticles of TB Antibiotics Made by CAN-BD

Administration of TB antibiotics directly to the respiratory tract by inhalation offers the possibility of reduced systemic toxicity. CO 2-Assisted Nebulization with a Bubble Dryer® (CAN-BD) is a patented variant of spray-drying that forms micro-emulsions of carbon dioxide under pressure with solutions or suspensions containing antibiotics of interest in the treatment of tuberculosis, which are then rapidly decompressed and desolvated to form solid solutions or suspensions within inhalable dry microparticles. A stream of warm dry nitrogen was used to dilute, dry and protect the aerosol microparticles during processing and collection on a filter or in a cyclone. Temperatures between 20 °C and 60 °C are typically used in the drying. Aqueous solutions are typically used to solubilize drugs for CAN-BD processing, but organic solvents can be used as well. For example, rifampin was dissolved in ethyl acetate, while the other antibiotics were dissolved in water. Known and proposed antibiotics for TB treatment including capreomycin, amikacin, rifampin, ciprofloxacin, and moxifloxacin have been processed into inhalable dry powders consisting primarily of particles 1 to 5 μm in size. All of the antibiotics tested showed full retention of biological activity during formation of the dry microparticles. Additionally, these antibiotics may be combined with nanoparticulates embedded in dry microparticles. In other work, we have suspended nanoparticles of measles vaccine virus (ranging from 90 to 300 nm in diameter) in inhalable myo-inositol/excipient microparticles with mass median aerodynamic diameters of approximately 3 μm. These live-attenuated measles virus vaccine microparticles have been successfully administered by at-liberty inhalation to Cotton rats and Rhesus macaques, with subsequent demonstration of pulmonary delivery, viral replication, and a robust immune response.