Comparison Between Pharmacopeial Testing and Testing Based on Mixing Inlet Methodology with Application to Nebuliser Testing: Part 2 – Main Study

Mårten Svensson, Elna Berg, Jolyon Mitchell, Dennis Sandell

The compendial approach to determine fine particle dose (FPD) of preparations for nebulisation when using a simulated patient breathing pattern, is to combine the results from two pharmacopeial methods. The delivered dose (DD) is collected on the inhalation filter during breathing simulation, while the fine particle fraction (FPF) is determined using the cooled Next Generation Impactor (NGI) operated at 15 L/min. FPD is then calculated as the product of DD and FPF. A recent advance in mixing inlet lung simulation (MILS) allows cascade impactor assessments to be made at constant flow rate whilst operating the nebuliser using a varying flow profile associated with breath simulation. The purpose of this study was to investigate the feasibility of the MILS approach for direct determination of FPD<5μm using a vibrating membrane nebulizer (eFlow® Rapid) delivering aqueous salbutamol sulphate with an adult tidal-breathing pattern (inspiratory:expiratory ratio = 1:1, tidal volume = 500 mL, 15 bpm, peak inspiratory flow rate (PIFR) = 24 L/min) as the model system. FPD<5μm obtained with the MILS was 72% of that obtained using the compendial method, showing that the two procedures were not equivalent for this particular comparison, although MILS methodology may be more pertinent. Whether this conclusion holds for other nebulizer types, drug products or alternate breathing patterns remains to be investigated. Regardless of the outcome of those studies, the present finding raises an important question as to which of the two methods provides the FPD<5μm that is more representative of the lung dose received by a patient.

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