Effect of Device Design and Formulation on the In Vitro Comparability for Multi-Unit Dose Dry Powder Inhalers

Abstract

Abstract. The focus of this investigation was to understand the design space to achieve comparable in vitro performance of two multi-unit dose dry powder inhalers (DPIs)-Flixotide® Accuhaler® (reference product) and MultiHaler® (test product). Flow field, pressure drop and particle trajectories within the test and reference DPI devices were modelled via computational fluid dynamics (CFD). Micronized fluticasone propionate (FP) was characterized to determine particle size distribution (PSD), specific surface area (SSA) and surface interfacial properties using cohesive-adhesive balance (CAB). CFD simulations suggested that the pressure drop and airflow velocity in the MultiHaler® were greater than Accuhaler®. Two modified test devices (MOD MH 1 and MOD MH 2) were manufactured with the introduction of by-pass channels in the airflow path, which achieved comparable specific resistance and airflow path between the test and reference devices. Assessment of reference product formulation in modified test devices suggested that MOD MH 2 achieved comparable in vitro performance to the reference product. CAB analysis suggested that adhesion of all FP batches to lactose was different, with batch D showing greatest and batch A least adhesion to lactose. Test DPI formulations were manufactured using four different batches of FP with milled or sieved lactose, and showed that batch A FP formulated with sieved lactose in MOD MH 2 device demonstrated the highest degree of similarity to the Accuhaler® in vitro deposition. Application of CFD modelling and material characterization of formulation raw materials enabled the modification of device and formulation critical material attributes to create an in vitro comparable device/formulation system to the reference product.KEY WORDS: aerosolization; computational fluid dynamics; device design; dry powder inhaler; in vitro comparability; in vitro performance.

In Silico Methods for Development of Generic Drug–Device Combination Orally Inhaled Drug Products

“…In addition to current work using a CFD‐DEM approach, several recent studies have used CFD with the more traditional Lagrangian approach for particle tracking to investigate DPI performance . The use of CFD with Lagrangian particle tracking for the investigation of DPI performance was also recently reviewed by Sommerfeld et al .…”

“…who also included some discussion on CFD‐DEM models. A good example of the utility of CFD with a Lagrangian approach comes from Shur et al . who made modifications to an existing RLD device, Multihaler (Cipla Limited, Mumbai, India), and tested eight different formulations of fluticasone propionate in the modified devices with the intent of producing a drug–device combination with comparable in vitro performance to an existing drug–device combination, Flixotide Accuhaler (GlaxoSmithKline UK Limited, Brentford, UK; fluticasone propionate DPI).…”

“…who made modifications to an existing RLD device, Multihaler (Cipla Limited, Mumbai, India), and tested eight different formulations of fluticasone propionate in the modified devices with the intent of producing a drug–device combination with comparable in vitro performance to an existing drug–device combination, Flixotide Accuhaler (GlaxoSmithKline UK Limited, Brentford, UK; fluticasone propionate DPI). A CFD method with Lagrangian particle tracking was used to characterize the differences in pressure drop, particle residence time, and normal particle velocity at the time of impact between Multihaler and Flixotide Accuhaler, where two modifications to Multihaler were designed based on these results . In vitro characterization of impactor sized mass, fine particle mass, and mass median aerodynamic diameter from the modified devices with the eight formulations showed that the second modified device when combined with the formulation that included sieved lactose and the API with the least adhesion to lactose was most similar to Flixotide Accuhaler .…”

“…A CFD method with Lagrangian particle tracking was used to characterize the differences in pressure drop, particle residence time, and normal particle velocity at the time of impact between Multihaler and Flixotide Accuhaler, where two modifications to Multihaler were designed based on these results . In vitro characterization of impactor sized mass, fine particle mass, and mass median aerodynamic diameter from the modified devices with the eight formulations showed that the second modified device when combined with the formulation that included sieved lactose and the API with the least adhesion to lactose was most similar to Flixotide Accuhaler . Suwandecha et al .…”

Current Scientific and Regulatory Approaches for Development of Orally Inhaled and Nasal Drug Products: Overview of the IPAC-RS/University of Florida Orlando Inhalation Conference

“…The following review papers in this issue provide an integrated view of talks and discussions related to a given topic: & Application of the modified chi-square ratio statistic in a stepwise procedure for cascade impactor equivalence testing (by Ben Weber et al) (6) & Effect of device design and formulation on the in vitro comparability for multi-unit dose dry powder inhalers (by Jag Shur et al) (7) & In vitro, pharmacokinetic, pharmacodynamic, and safety comparisons of single and combined administration of tiotropium and salmeterol in COPD patients using different dry powder inhalers (by Stephen Horhota et al) (8) & Safety of β2-agonists in asthma: linking mechanisms, meta-analyses, and regulatory practice (by Sanjeeva Dissanayake) (9).…”