Abstract.To ensure consistency of clinical outcomes, orally inhaled therapies must exhibit consistent delivered dose and aerosol properties at the time of manufacturing, throughout storage, and during various patient-use conditions. Achieving consistency across these scenarios has presented a significant challenge, especially for combination products that contain more than one drug. This study characterized the delivered dose and aerosol properties of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI; Bevespi Aerosphere™). GFF MDI, a fixed-dose combination (FDC) of a long-acting muscarinic antagonist, glycopyrrolate (18 μg, equivalent to glycopyrronium 14.4 μg), and a long-acting β 2 -agonist, formoterol fumarate (9.6 μg; equivalent to formoterol fumarate dihydrate 10 μg), is formulated using innovative co-suspension delivery technology, which suspends micronized drug crystals with spray-dried phospholipid porous particles in hydrofluoroalkane propellant. In this study, delivered dose uniformity was assessed through the labeled number of doses, and aerosol properties, such as percent fine particle fraction (FPF) and mass median aerodynamic diameter, were determined by cascade impaction. GFF MDI achieved reproducible dose delivery and an FPF greater than 55%, whether formulated and delivered as a monocomponent or dual FDC. The performance of GFF MDI was maintained across various manufacturing batches, under extended storage, and with variations in flow rate. Furthermore, unlike a GFF drug crystal-only suspension, drug delivery remained consistent for GFF MDI when simulated patient-handling errors were applied, such as reduced shake energy and delays between shaking and actuation. These results demonstrate that cosuspension delivery technology overcomes well-known sources of variability in MDI drug delivery.KEY WORDS: dose consistency; co-suspension delivery technology; respiratory drug delivery; metered dose inhaler (MDI); chronic obstructive pulmonary disease (COPD).

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IntroductionTo assure consistency of clinical outcomes, orally inhaled products must have consistent in vitro delivered dose and aerosol properties. Achieving this consistency has been challenging with MDIs, particularly those that combine multiple drugs. Co-Suspension™ delivery technology has been developed for in vitro drug-drug interaction-free delivery of multiple drugs from fixed-dose MDI combinations. This versatile technology suspends the micronised drugs with spray-dried phospholipid porous particles in hydrofluoroalkane propellant. The objective of this study was to determine whether BGF MDI, the triple Co-Suspension delivery technology formulation of BD/GP/FF, displays in vitro drug delivery comparable to its constituent single and dual drug formulations.MethodsSingle, dual and triple therapy MDIs of BD, GP and FF were prepared by suspending each drug’s microcrystals with phospholipid porous particles in HFA propellant. In vitro drug delivery was assessed by comparing delivered dose uniformity and aerodynamic particle size distribution.ResultsBD, GP and FF formed stable suspensions in the presence of phospholipid porous particles, despite differences in drug physicochemical properties and doses. A consistent and comparable delivered dose and aerodynamic particle size distribution was observed whether emitted from a single, dual or triple therapy MDI.ConclusionThe single, dual and triple drug MDI formulations demonstrated comparable aerosol characteristics which should enable patients to transition across the continuum of these MDI therapies without in vitro drug-drug interaction impacting drug delivery and clinical outcomes.