Particle Aerosolisation and Break-up in Dry Powder Inhalers 1: Evaluation and Modelling of Venturi Effects for Agglomerated Systems

Wong, William; Fletcher, David F.; Traini, Daniela; Chan, Hak‐Kim; Crapper, John; Young, Paul M.

doi:10.1007/s11095-010-0128-4

Cited by 50 publications

(35 citation statements)

References 29 publications

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“…The third CFD performance measure is used to characterize the nature of the impacts during carrier particleinhaler collisions, which were previously suggested to be one of the dominant factors in inducing deaggregation of drug particles from lactose carriers in DPI devices (15,30). These CFD performance measures, as summarized in Table II, are intended to illustrate important trends in the aerosolization performance of the DPI devices rather than to provide quantitative analysis.…”

Section: Discussionmentioning

confidence: 99%

“…Computational fluid dynamics (CFD) is an established methodology for predicting the flow properties and the fate of the particulate system in the respiratory tract and inhalation devices (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). For example, Coates et al demonstrated how CFD modeling of the DPI mouthpiece geometry, dispersion grid and air inlet size (11), airflow rate (12), and capsule properties (13) could be used to investigate aerosol performance.…”

Section: Introductionmentioning

confidence: 99%

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

Shur

Lee

Adams

et al. 2012

AAPS J

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Abstract. This study investigated the effect of modifying the design of the Cyclohaler on its aerosolization performance and comparability to the HandiHaler at multiple flow rates. The Cyclohaler and HandiHaler were designated as model test and reference unit-dose, capsule-based dry powder inhalers (DPIs), respectively. The flow field, pressure drop, and carrier particle trajectories within the Cyclohaler and HandiHaler were modeled via computational fluid dynamics (CFD). With the goal of achieving in vitro comparability to the HandiHaler, the CFD results were used to identify key device attributes and to design two modifications of the Cyclohaler (Mod 1 and Mod 2), which matched the specific resistance of the HandiHaler but exhibited different cyclonic flow conditions in the device. Aerosolization performance of the four DPI devices was evaluated by using the reference product's capsule and formulation (Spiriva capsule) and a multistage cascade impactor. The in vitro data showed that Mod 2 provided a closer match to the HandiHaler than the Cyclohaler and Mod 1 at 20, 39, and 55 l/min. The in vitro and CFD results together suggest that matching the resistance of test and reference DPI devices is not sufficient to attain comparable aerosolization performance, and the improved in vitro comparability of Mod 2 to the HandiHaler may be related to the greater degree of similarities of the flow rate of air through the pierced capsule (Q c ) and the maximum impact velocity of representative carrier particles (V n ) in the Cyclohaler-based device. This investigation illustrates the importance of enhanced product understanding, in this case through the CFD modeling and in vitro characterization of aerosolization performance, to enable identification and modification of key design features of a test DPI device for achieving comparable aerosolization performance to the reference DPI device.KEY WORDS: computational fluid dynamics; device design; dry powder inhaler; in vitro comparability; in vitro performance.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Shur

Lee

Adams

et al. 2012

AAPS J

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“…Thus, using the ICRP 66 model for predicting deposition patterns (in patients) after drug inhalation with a metered dose inhaler (MDI) or dry powder inhaler (DPI) led to overprediction of the pulmonary dose and underprediction of the mouth-throat fraction (82). Possible explanations for the constantly overpredicted pulmonary dose might be an inhaler spray momentum (ballistic effect; high aerosol velocity produced) of MDIs (83), turbulent inhaler jet effects (84), or coarse effects (particle deagglomeration dependent on inhalation flow) of DPIs (28,85). The lung deposition of a nebulizer without a strong ballistic or coarse effect was accurately predicted (82).…”

Section: Pulmonary Drug Deposition Patternsmentioning

confidence: 99%

Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs

Borghardt

Weber

Staab

et al. 2015

AAPS J

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Abstract. During the last decades, the importance of modeling and simulation in clinical drug development, with the goal to qualitatively and quantitatively assess and understand mechanisms of pharmacokinetic processes, has strongly increased. However, this increase could not equally be observed for orally inhaled drugs. The objectives of this review are to understand the reasons for this gap and to demonstrate the opportunities that mathematical modeling of pharmacokinetics of orally inhaled drugs offers. To achieve these objectives, this review (i) discusses pulmonary physiological processes and their impact on the pharmacokinetics after drug inhalation, (ii) provides a comprehensive overview of published pharmacokinetic models, (iii) categorizes these models into physiologically based pharmacokinetic (PBPK) and (clinical data-derived) empirical models, (iv) explores both their (mechanistic) plausibility, and (v) addresses critical aspects of different pharmacometric approaches pertinent for drug inhalation. In summary, pulmonary deposition, dissolution, and absorption are highly complex processes and may represent the major challenge for modeling and simulation of PK after oral drug inhalation. Challenges in relating systemic pharmacokinetics with pulmonary efficacy may be another factor contributing to the limited number of existing pharmacokinetic models for orally inhaled drugs. Investigations comprising in vitro experiments, clinical studies, and more sophisticated mathematical approaches are considered to be necessary for elucidating these highly complex pulmonary processes. With this additional knowledge, the PBPK approach might gain additional attractiveness. Currently, (semi-)mechanistic modeling offers an alternative to generate and investigate hypotheses and to more mechanistically understand the pulmonary and systemic pharmacokinetics after oral drug inhalation including the impact of pulmonary diseases.

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“…23 In general, the primary mannitol powder and agglomerated systems were characterised in terms of particle size, morphology, density, mass, and surface area. The primary particle size distribution was determined using laser diffraction (Malvern Mastersizer 2000; Malvern, Worcestershire, UK) by suspending the particles in chloroform.…”

Section: Physical Characterisation Of the Primary Mannitol Particles mentioning

confidence: 99%

“…Previous studies have utilised a combination of CFD and experimental entrainment tubes to study the break-up and aerosolisation of a model agglomerate system (containing micron-sized mannitol particles) as a function of airflow, turbulence level and impact force against the surface of an entrainment tube. 23,24 The initial study utilised a series of venturi tubes to induce turbulent flow with characteristics equivalent to commercial DPI devices whilst minimising other potential break-up mechanisms (such as wall or grid impaction), whereas the subsequent study utilised a series of impactors with different impaction angles to induce agglomerate collision upon the impact surface whilst reducing the effect of break-up in turbulent flow. Interestingly, these studies found agglomerate impaction to play a more dominant role in the aerosol performance.…”

Section: Introductionmentioning

confidence: 99%

Particle Aerosolisation and Break‐up in Dry Powder Inhalers: Evaluation and Modelling of the Influence of Grid Structures for Agglomerated Systems

Wong

Fletcher

Traini

et al. 2011

Journal of Pharmaceutical Sciences

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Particle Aerosolisation and Break-up in Dry Powder Inhalers 1: Evaluation and Modelling of Venturi Effects for Agglomerated Systems

Abstract: While this study focussed on the effect of turbulence on agglomerate break-up, the small amount of impaction, which inevitably occurs in the venturi assembly, appeared to dominate agglomerate break-up in this dry powder system.

Cited by 50 publications

References 29 publications

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

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

Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs

Particle Aerosolisation and Break‐up in Dry Powder Inhalers: Evaluation and Modelling of the Influence of Grid Structures for Agglomerated Systems

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