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Spray freeze drying is a particle engineering technique that allows the production of porous particles of low density with excellent aerosol performance for inhalation. There are a number of operating parameters that can be manipulated in order to optimise the powder properties. In this study, a two-fluid nozzle was used to prepare spray freeze dried formulation of voriconazole, a triazole antifungal agent for the treatment of pulmonary aspergillosis. A full factorial design approach was adopted to explore the effects of drug concentration, atomisation gas flow rate and primary drying temperature. The aerosol performance of the spray freeze dried powder was evaluated using the next generation impactor (NGI) operated with different inhaler devices and flow rates. The results showed that the primary drying temperature played an important role in determining the aerosol properties of the powder. In general, the higher the primary drying temperature, the lower the emitted fraction (EF) and the higher the fine particle fraction (FPF). Formulations that contained the highest voriconazole concentration (80% w/w) and prepared at a high primary drying temperature (-10 °C) exhibited the best aerosol performance under different experimental conditions. The high concentration of the hydrophobic voriconazole reduced surface energy and cohesion, hence better powder dispersibility. The powders produced with higher primary drying temperature had a smaller particle size after dispersion and improved aerosol property, possibly due to the faster sublimation rate in the freeze-drying step that led to the formation of less aggregating or more fragile particles. Moreover, Breezhaler®, which has a low intrinsic resistance, was able to generate the best aerosol performance of the spray freeze dried voriconazole powders in terms of FPF., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Pulmonary delivery of short interfering RNA (siRNA) has been widely studied in both animal and clinical studies to treat various respiratory diseases by gene silencing through RNA interference. Some of these studies showed that the administration of naked siRNA (without the use of any delivery vectors) could achieve satisfactory gene silencing effect, a unique feature to pulmonary delivery. Liquid aerosols were mostly used with very limited studies on the use of powder aerosols for siRNA. In this study, siRNA was co-spray dried with mannitol and l-leucine, the latter being a dispersion enhancer. To the best of our knowledge, this is the first time that siRNA in its naked form was formulated into an inhalable dry powder using spray drying technology. The aerosol performance of the powder was evaluated by Next Generation Impactor (NGI). The presence of l-leucine in the formulation could improve the aerosolization of siRNA-containing powders. Results from the X-ray photoelectron spectroscopy (XPS) suggested that l-leucine was enriched on the particle surface and promote powder dispersion. Among the different siRNA formulations being examined, the one that contained 50% w/w of l-leucine exhibited the best aerodynamic performance, with a high emitted fraction (EF) of around 80% and a modest fine particle fraction (FPF) of 45%. Importantly, the integrity of siRNA was successfully retained as evaluated by gel retardation assay and high performance liquid chromatography (HPLC)., (Copyright © 2017 Elsevier B.V. All rights reserved.)