Qi Tony Zhou, Dmitry Zemlyanov, Nivedita Shetty, Alex Cavallaro, Patricia Ahn, Sharad Mangal, Sonal V Bhujbal, Jian Li, Hee Jun Park, Shetty, Nivedita, Ahn, Patricia, Park, Heejun, Bhujbal, Sonal, Zemlyanov, Dmitry, Cavallaro, Alex, Mangal, Sharad, Li, Jian, and Zhou, Qi Tony
OBJECTIVE: This study aimed to develop dry powder inhaler (DPI) combination formulations of ciprofloxacin and colistin for use in respiratory infections. Effects of colistin on physical stability and aerosolization of spray-dried ciprofloxacin were examined. METHODS: The combination DPI formulations were produced by co-spray drying colistin and ciprofloxacin in mass ratios of 1:1, 1:3 and 1:9. Colistin and ciprofloxacin were also co-sprayed with L-leucine in the mass ratio of 1:1:1. The physical and aerosolization stability of the selected co-sprayed formulations stored at 20, 55 and 75% relative humidity (RH) were examined. Formulation characterizations were carried out using Powder X-ray diffraction (PXRD) for crystallinity, scanning electron microscopy (SEM) for morphology and particle size distribution, and Dynamic Vapor Sorption (DVS) for moisture sorption. Particle surface analysis was performed using X-ray Photoelectron Spectroscopy (XPS), Energy Dispersive X-ray Spectrometry (EDX) and Nano-Time-of-flight Secondary Ion Mass Spectrometry (Nano ToF-SIMS). Potential intermolecular interactions were studied using Fourier-transform infrared spectroscopy (FTIR). Aerosol performance was evaluated using a multi-stage liquid impinger (MSLI) with a RS01 Monodose inhaler device. RESULTS: PXRD diffractograms showed that the co-spray dried colistin-ciprofloxacin formulation in the mass ratio (1:1) was amorphous at 55% RH for up to 60 days; whereas the co-spray dried colistin-ciprofloxacin (1:3) and colistin-ciprofloxacin (1:9) crystallized after storage for 3 days at 55% RH. However, the extent of crystallization for the combination formulations was less as compared to the spray-dried ciprofloxacin alone formulation. Surface morphology of the co-spray dried formulations at different concentrations did not change even after storage at 55% RH for 60 days, unlike the spray-dried ciprofloxacin alone powder which became rougher after 3 days of storage at 55% RH. Surface analysis data indicated surface enrichment of colistin in the co-spray dried formulations. Increasing colistin concentration on the composite particles surfaces improved aerosol performance of ciprofloxacin. FTIR data demonstrated intermolecular interactions between colistin and ciprofloxacin, thereby delaying and/or preventing crystallization of ciprofloxacin when co-spray dried. Co-spray drying ciprofloxacin with colistin in the mass ratio (1:1) completely prevented crystallization of ciprofloxacin at 55% RH for up to 60 days. However, the colistin-ciprofloxacin formulation (1:1) began to fuse when stored at 75% RH due to moisture absorption resulting in compromised aerosol performance. However, the colistin-ciprofloxacin-leucine (1:1:1) formulation demonstrated no particles fusion, enabling a stable aerosol performance at 75% RH for 7 days. CONCLUSIONS: This study demonstrated that incorporation of colistin in the spray-dried formulations can improve physical stability and aerosolization of amorphous ciprofloxacin at 55% RH. At 75% RH for 7 days, further addition of L-leucine in the formulation prevents particle fusion and deterioration in aerosol performance, attributed to enrichment of non-hygroscopic L-leucine on the particle surface.