Co-spray drying of hygroscopic kanamycin with the hydrophobic drug rifampicin to improve the aerosolization of kanamycin powder for treating respiratory infections

Abstract

High dose delivery of drugs to the lung using a dry powder inhaler (DPI) is an emerging approach to combat drug-resistant local infections. To achieve this, highly aerosolizable powders are required. We hypothesized that co-spray-drying kanamycin, a hydrophilic hygroscopic antibiotic, with rifampicin, a hydrophobic antibiotic, would produce inhalable particles with surfaces enriched in rifampicin. Such particles would have higher aerosolization than kanamycin alone, and minimise the mass of powder for inhalation avoiding use of non-active excipients. Kanamycin was co-spray-dried with rifampicin using a Buchi Mini Spray-dryer. All powders were inhalable in size (1.1-5.9 µm) and noncrystalline. X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) showed the surface of the combination powder was enriched with rifampicin. In vitro aerosolization (fine particle fraction) determined by next generation impactor (NGI), dramatically improved from 29.5 ± 0.2% (kanamycin-only) to 78.2 ± 1.3% (kanamycin-rifampicin combination). The combination powder was flake-shaped in morphology, stable at 15% and 53% RH and 25 ± 2 °C during one-month storage in an open Petri dish, and non-toxic (up to 50 µg/mL) to human alveolar and bronchial cell-lines. Surface enrichment of kanamycin by hydrophobic rifampicin improves aerosolization, which may help to combat drug-resistant local infections by facilitating high dose delivery to deep lung.

Keywords: High dose; Hydrophobic; Kanamycin; Rifampicin; Spray-drying; Surface.