Laboratory Study Comparing Pharmacopeial Testing of Nebulizers with Evaluation Based on Nephele Mixing Inlet Methodology.

Determination of fine droplet dose with preparations for nebulization, currently deemed to be the metric most indicative of lung deposition and thus in vivo responses, involves combining two procedures following practice as described in the United States Pharmacopeia and the European Pharmacopeia. Delivered dose (DD) is established by simulating tidal breathing at the nebulizer, collecting the medication on a filter downstream of the nebulizer mouthpiece/facemask. Fine droplet fraction (FDF<x μm ) is determined separately using a cooled cascade impactor operated at 15 L/min. FDD<x μm is subsequently calculated as the product of DD and FDF<x μm . Development of the Nephele mixing inlet has allowed cascade impactor-based assessments to be made at a constant flow rate while simultaneously subjecting the nebulizer to the continuously varying flow profile associated with breath simulation. The study purpose was to investigate the feasibility of this approach, termed mixing inlet lung simulation (MILS), for direct determination of FDD<x μm . An optimal upper size limit for FDF is not given for nebulizers, but 5 μm was chosen since this limit is the European norm when testing other inhalation products. Vibrating membrane nebulizers (eFlow® Rapid) were used to deliver aqueous salbutamol sulfate, simulating an adult tidal-breathing pattern (inspiratory to expiratory ratio = 1:1, tidal volume = 500 mL, 15 breaths per minute, peak inspiratory flow rate = 24 L/min). The two procedures were inequivalent, as FDD<5 μm by the MILS approach was 72% of that obtained using the compendial "combination" method. Since the MILS methodology more closely mimics clinical use, we infer that the compendial approach likely overestimates the dose reaching the human lung.