Drug Delivery from an Innovative LAMA/LABA Co-suspension Delivery Technology Fixed-Dose Combination MDI: Evidence of Consistency, Robustness, and Reliability

Abstract

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).

A randomized study using functional respiratory imaging to characterize bronchodilator effects of glycopyrrolate/formoterol fumarate delivered by a metered dose inhaler using co-suspension delivery technology in patients with COPD

“…GFF MDI is formulated using co-suspension delivery technology that has demonstrated uniform delivery throughout the whole lung in vivo24 and consistent dose delivery in the presence of simulated patient-handling errors in vitro 27. This study, which evaluated the physiologic effects of GFF MDI drug delivery, evidenced bronchodilator distribution throughout the lung, resulting in improvements in airway volume, airway resistance, bronchodilation, and hyperinflation.…”

Pharmacokinetics of Co‐Suspension Delivery Technology Budesonide/Glycopyrronium/Formoterol Fumarate Dihydrate (BGF MDI) and Budesonide/Formoterol Fumarate Dihydrate (BFF MDI) Fixed‐Dose Combinations Compared With an Active Control: A Phase 1, Randomized, Single‐Dose, Crossover Study in Healthy Adults

“…Although only single doses were administered in the present study, the safety profile of BUD/FORM DPI is well established, [30][31][32] and the safety profile of doses of budesonide and formoterol considerably higher than those used in this study has been well documented. 17 The study was conducted in healthy volunteers rather than patients with COPD, which is typical for phase 1 studies and similar to other PK studies of budesonide/formoterol fixed-dose combinations. Similarly, a phase 1 study comparing PK parameters of BGF MDI with glycopyrrolate/formoterol fumarate MDI (Bevespi Aerosphere; AstraZeneca) found no evidence of within-combination PK drug-drug interactions when budesonide was formulated with glycopyrronium and formoterol, based on the equivalence of the PK parameters of glycopyrronium and formoterol between BGF MDI and glycopyrrolate/formoterol fumarate MDI using the same co-suspension delivery technology platform.…”

“…38 The absence of any drug-drug interactions in the current study among the individual components of BGF MDI incorporated into the triple fixed-dose combination is aligned with the consistent drug delivery seen across mono and dual bronchodilator MDI formulations incorporating co-suspension delivery technology. 17 The study was conducted in healthy volunteers rather than patients with COPD, which is typical for phase 1 studies and similar to other PK studies of budesonide/formoterol fixed-dose combinations. 27,39,40 A limitation of the study was the collection of blood samples for analysis of PK parameters only up to 12-hours after dosing.…”

“…[15][16][17] Glycopyrronium is a LAMA that binds to muscarinic receptors with high affinity and has a prolonged dissociation profile. BGF MDI has been formulated using innovative co-suspension delivery technology, which has been shown to provide consistent drug delivery with similar in vitro profiles, regardless whether a drug is administered alone or in combination with one or more other drugs.…”

“…BGF MDI has been formulated using innovative co-suspension delivery technology, which has been shown to provide consistent drug delivery with similar in vitro profiles, regardless whether a drug is administered alone or in combination with one or more other drugs. [15][16][17] Glycopyrronium is a LAMA that binds to muscarinic receptors with high affinity and has a prolonged dissociation profile. Inhaled glycopyrronium causes long-lasting bronchodilation in patients with COPD.…”