Category: Manufacturing and Bioprocessing
Purpose: The objective of this study is to evaluate aerosolization of surface-modified high potency voriconazole nanoaggregates with commercially available dry powder inhalers. In this study we compared the aerodynamic properties of voriconazole nanoaggregates that were aerosolized by Plastiape low and high resistance RS00 and RS01 inhalers at different flow rates.
Methods: Voriconazole (95 % w/w) and mannitol (5 % w/w) were dissolved in water and acetonitrile binary solvent system. The solution was applied from a height of 10 cm onto a rotating cryogenically cooled stainless steel drum by using an 8-channel peristaltic pump (Cole-Parmer, Vernon Hills, IL) at a flow rate of 25 mL/min. The frozen samples were collected in a lyophilizer tray filled with liquid nitrogen, and stored in a freezer (−80 °C) until lyophilized. An Advantage Pro 3-shelf lyophilizer (SP Scientific, Gardiner, NY) was used to remove the solvent over 60 hours. The pressure was kept at 100 mTorr during the drying process.
Aerodynamic properties of the surface-modified high potency voriconazole nanoaggregates were measured by using a Next Generation Pharmaceutical Impactor (NGI) (MSP Co., Shoreview, MN). A #3 HPMC capsule (Vcaps® Puls, Capsugel®, Morristown, NJ) was filled with the powder formulation and placed into Plastiape dry powder inhalers (Plastiape, Osnago, Italy). The powder was dispersed into the NGI through the USP induction port with the total volume of 4 L of air. Copley Inhaler Testing Data Analysis Software (CITDAS) was used to calculate aerodynamic properties based on the amount of voriconazole collected from capsule, device, adapter, induction port, and stages 1 through micro-orifice collector (MOC). Fine particle fraction (FPF) was calculated as the percent metered dose with an aerodynamic diameter less than 5 µm.
Results: The maximum aerosol performance of voriconazole nanoaggregates was achieved by low resistance RS00 at 90 L/min with an FPF of 48.6% and mass median aerodynamic diameter (MMAD) of 3.22 µm. The range of FPF by low resistance RS00 was 27.0 – 48.6% at a flow rate between 30 – 90 L/min. High resistance RS00 presented FPFs of 30.7 – 34.7% at a flow rate between 30 – 60 L/min. FPFs obtained by low resistance and high resistance RS01 were 27.0 – 40.1% at a flow rate between 30 – 90 L/min, and 20.2 – 31.3% at a flow rate between 30 – 60 L/min respectively.
Conclusion: Overall, surface-modified high potency voriconazole nanoaggregates aerosolized better with RS00 devices than RS01 devices. While the low resistance RS00 device can provide the maximum aerosolization, the high resistance RS00 device resulted in more consistent aerosolization of surface-modified voriconazole nanoaggregates flow rates between 30 and 60 L/min.