Effect of Device Design on the In Vitro Performance and Comparability for Capsule-Based Dry Powder Inhalers

Self Cite

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.

Section: Electronic Supplementary Materialsmentioning

confidence: 79%

Section: Airflow Resistancementioning

confidence: 99%

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

Shur

Saluja

Lee

et al. 2015

Self Cite

“…& To ensure that the targeted patients can operate the Test DPI device effectively and receive proper medication without any significant change in their inspiratory effort compared to use of the Reference DPI, it is preferable that the device resistance of a Test DPI be comparable to that of the Reference DPI. It has also been suggested that the use of a Test DPI with a comparable air flow resistance to the Reference DPI is expected to increase the likelihood of establishing SAC and APSD equivalence at different flow rates [16].…”

Section: In Vitro Studiesmentioning

confidence: 99%

Regulatory Considerations for Approval of Generic Inhalation Drug Products in the US, EU, Brazil, China, and India

Lee

Saluja

García‐Arieta

et al. 2015

Abstract. This article describes regulatory approaches for approval of Bgeneric^orally inhaled drug products (OIDPs) in the United States, European Union, Brazil, China and India. While registration of a generic OIDP in any given market may require some documentation of the formulation and device similarity to the Boriginal^product as well as comparative testing of in vitro characteristics and in vivo performance, the specific documentation approaches, tests and acceptance criteria vary by the country. This divergence is due to several factors, including unique cultural, historical, legal and economic circumstances of each region; the diverse healthcare and regulatory systems; the different definitions of key terms such as Bgeneric^and Breference^drug; the acknowledged absence of in vitro in vivo correlations for OIDPs; and the scientific and statistical issues related to OIDP testing (such as how best to account for the batch-to-batch variability of the Reference product, whether to use average bioequivalence or population bioequivalence in the statistical analysis of results, whether to use healthy volunteers or patients for pharmacokinetic studies, and which pharmacodynamic or clinical end-points should be used). As a result of this discrepancy, there are ample opportunities for the regulatory and scientific communities around the world to collaborate in developing more consistent, better aligned, science-based approaches. Moving in that direction will require both further research and further open discussion of the pros and cons of various approaches.

“…Experimental studies coupled with computational fluid dynamics (CFD) analysis were employed in this series of studies to simulate the flow field generated in the device with the purpose to better understand the effect of device design on deagglomeration. Most recently, CFD analysis was also employed to investigate the effect of carrier properties on the aerosolization (8) and in vitro comparability of two capsule-based devices (9) for the carrier-based DPIs. However, CFD analysis can only simulate the air flow pattern and is unable to take particle interactions into account.…”

Section: Introductionmentioning

confidence: 99%

Effect of Device Design on the Aerosolization of a Carrier-Based Dry Powder Inhaler—a Case Study on Aerolizer® Foradile®

Zhou

Tong

Tang

et al. 2013

Abstract. The objective of this study is to investigate the effect of device design of the Aerolizer ® on the aerosolization of a carrier-based dry powder inhaler formulation (Foradile ® ). The Aerolizer was modified by reducing the air inlet size and mouthpiece length to 1/3 of the original dimensions, or by increasing the grid voidage. Aerosolization of the powder formulation was assessed on a multi-stage liquid impinger at air flow rates of 30, 60, and 100 L/min. Coupled CFD-DEM simulations were performed to investigate the air flow pattern and particle impaction. There was no significant difference in the aerosolization behavior between the original and 1/3 mouthpiece length devices. Significant increases in FPF total and FPF emitted were demonstrated when the inlet size was reduced, and the results were explained by the increases in air velocity and turbulence from the CFD analysis. No significant differences were shown in FPF total and FPF emitted when the grid voidage was increased, but more drugs were found to deposit in induction port and to a lesser extent, the mouthpiece. This was supported by the CFD-DEM analysis which showed the particle-device collisions mainly occurred in the inhaler chamber, and the cross-grid design increased the particle-device collisions on both mouthpiece and induction port. The air inlet size and grid structure of the Aerolizer ® were found to impact significantly on the aerosolization of the carrier-based powder.KEY WORDS: aerosolization; computational fluid dynamics; device design; discrete element method; dry powder inhalers.