Inhalation

INH0617

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will become more accurate and span a larger size range as device development continues. Conclusions and future work Although CI-based analysis stands as the only method currently approved for regulatory purposes, the labor times and high costs, as well as relatively large measurement biases, call for faster and more reliable methods for APSD estimation. Such meth- ods, despite lack of chemical specificity, may prove valuable for high throughput screening of devices and drugs during product development and serve as a complementary method for validation of existing measurement methods. For the first time, a proof-of-concept study has shown the feasibility of obtaining meaningful aerosol measurements from DPIs, in approximately 1 minute, using direct estimation of settling velocities with automatic image analysis. While only DPIs were used in this study, the method can, in princi- ple, be adapted for pressurized metered dose inhalers (pDMIs) as well as nebulizers by preventing droplet evaporation through humidification or cooling of the system. With further development, this method has the poten- tial to become a standard reference replacing or com- plementing current OIP characterization methods because this simple measurement method is inherently tolerant to minor changes in the design of the mea- surement system or in its operating conditions. In addition, the particle-by-particle measurement approach may prove useful for measuring very low drug doses (e.g., 5 or 10 mg). Furthermore, due to its simplicity, the system may serve as a cost-effective alternative to current OIP characterization techniques and even be assembled in a research laboratory setup from off-the-shelf materials. Future work includes further verification of the device capabilities, expanding its abilities towards measurement from various inhalation devices, intro- ducing a calibration scheme to correct for possible biases due to size-dependent detection rates and increasing the number of measured particles per measurement in order to increase the accuracy and the size range. Acknowledgments The authors would like to thank Wilbur de Kruijf (Medspray, The Netherlands) for helpful discus- sions, and acknowledge the support of the Uzi and Michal Halevi Fund for Innovative Applied Engineering (Technion). This work was supported in part by the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Program (Grant Agreement #677772). References 1. European Directorate for Quality in Medicines (EDQM): European Pharmacopeia 9.0, Monograph 2.9.18. Preparations for Inhalations: Aerodynamic Assessment of Fine Particles. Strasburg, France EDQM (2017). 2. US Pharmacopeial Convention: United States Pharmacopeia 39/National Formulary 34, Chapter <601> Aerosols, Nasal Sprays, Metered-Dose Inhalers, and Dry Powder Inhalers. Rockville, MD (2016). 3. Mitchell, J. P., Nagel, M. W., Wiersema, K. J. and Doyle, C. C. Aerodynamic Particle Size Analysis of Aerosols from Pressurized Metered-Dose Inhalers: Comparison of Andersen 8-Stage Cascade Impactor, Next Generation Pharmaceutical Impactor, and Model 3321 Aerodynamic Particle Sizer Aerosol Spectrometer. AAPS PharmSciTech 4, 425-433 (2003). 4. Taki, M., Marriott, C., Zeng, X.-M. and Martin, G. P. Aerodynamic Deposition of Combination Dry Powder Inhaler Formulations In Vitro: A Comparison of Three Impactors. Int. J. Pharm. 388, 40-51 (2010). 5. Kulkarni, P., Baron, P. A. and Willeke, K. Aerosol Measurement: Principles, Techniques, and Applications. (John Wiley and Sons, 2011). MMAD and GSD measurements for two drug/DPI combinations, compared to data from the literature Table 1 Inhaler Flow Rate (L/min) Mass Median Aerodynamic Diameter (MMAD) (µm) Geometric Standard Deviation (GSD) Cascade Impactor Time of Flight (ToF) Prototype Cascade Impactor Time of Flight (ToF) Prototype Symbicort® Turbuhaler® 60 2.6 2.4 2.5 ± 0.1 (n = 9) 2.1 1.7 1.5 ± 0.03 (n = 9) Seretide® Diskus® 60 4.1 ± 0.1 3.8 6.0 ± 0.7 (n = 9) 2.0 ± 0.03 1.8 1.7 ± 0.09 (n = 9) 24 JUNE 2017 Inhalation

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