Influence of Air Flow on the Performance of a Dry Powder Inhaler Using Computational and Experimental Analyses

Purpose The aims of the study are to analyze the influence of air flow on the overall performance of a dry powder inhaler (Aerolizer^®) and to provide an initial quantification of the flow turbulence levels and particle impaction velocities that maximized the inhaler dispersion performance.Methods Computational fluid dynamics (CFD) analysis of the flowfield in the Aerolizer^®, in conjunction with experimental dispersions of mannitol powder using a multistage liquid impinger, was used to determine how the inhaler dispersion performance varied as the device flow rate was increased.Results Both the powder dispersion and throat deposition were increased with air flow. The capsule retention was decreased with flow, whereas the device retention first increased then decreased with flow. The optimal inhaler performance was found at 65 l min⁻¹ showing a high fine particle fraction (FPF) of 63 wt.% with low throat deposition (9.0 wt.%) and capsule retention (4.3 wt.%). Computational fluid dynamics analysis showed that at the critical flow rate of 65 l min⁻¹, the volume-averaged integral scale strain rate (ISSR) was 5,400 s⁻¹, and the average particle impaction velocities were 12.7 and 19.0 m s⁻¹ at the inhaler base and grid, respectively. Correlations between the device flow rate and (a) the amount of throat deposition and (b) the capsule emptying times were also developed.Conclusions The use of CFD has provided further insight into the effect of air flow on the performance of the Aerolizer^®. The approach of using CFD coupled with powder dispersion is readily applicable to other dry powder inhalers (DPIs) to help better understand their performance optimization.     

The Role of Capsule on the Performance of a Dry Powder Inhaler Using Computational and Experimental Analyses

Purpose To study the fundamental effects of the spinning capsule on the overall performance of a dry powder inhaler (Aerolizer®).Methods The capsule motion was visualized using high-speed photography. Computational fluid dynamics (CFD) analysis was performed to determine the flowfield generated in the device with and without the presence of different sized capsules at 60 l min^–1. The inhaler dispersion performance was measured with mannitol powder using a multistage liquid impinger at the same flowrate.Results The capsule size (3, 4, and 5) was found to make no significant difference to the device flowfield, the particle-device impaction frequency, or the dispersion performance of the inhaler. Reducing the capsule size reduced only the capsule retention by 4%. In contrast, without the presence of the spinning capsule, turbulence levels were increased by 65%, FPF_Em (wt% particles 6.8 m in the aerosol referenced against the amount of powder emitted from the device) increased from 59% to 65%, while particle-mouthpiece impaction decreased by 2.5 times. When the powder was dispersed from within compared to from outside the spinning capsule containing four 0.6 mm holes at each end, the FPF_Em was increased significantly from 59% to 76%, and the throat retention was dropped from 14% to 6%.Conclusions The presence, but not the size, of a capsule has significant effects on the inhaler performance. The results suggested that impaction between the particles and the spinning capsule does not play a major role in powder dispersion. However, the capsule can provide additional strong mechanisms of deagglomeration dependent on the size of the capsule hole.     

Influence of Humidity on the Electrostatic Charge and Aerosol Performance of Dry Powder Inhaler Carrier based Systems

Abstract To investigate the influence of storage relative humidity (RH) on the aerosolisation efficiency and tribo-electrification of carrier based dry powder inhaler (DPI) formulations using the next generation impactor (NGI) in vitro methodology and the electrostatic low pressure impactor (ELPI). Micronised salbutamol (d _0.5 1.48 ± 0.03 μm) was blended with 63–90 μm sieve fractioned α-lactose monohydrate carrier and stored at a range of humidities (0–84% RH). The aerosolisation efficiency after storage for 24 h periods was investigated using the NGI. The same experiment was conducted using the ELPI, with corona charger switched off, to measure the net charge vs. mass deposition profile. Significant variations in the aerosolisation efficiency of the formulation were observed with respect to storage RH. In general, the fine particle fraction aerosol performance measured by NGI and ELPI (fraction with mass median aerodynamic diameter <4.46 and 4.04 μm, respectively) followed a positive parabola with aerosol performance increasing over the range 0–60% RH before decreasing >60% RH. Analysis of the ELPI charge data suggested that the micronised salbutamol sulphate had an electronegative charge when aerosolised from lactose based carriers, which was most electronegative at low RH. Increased storage RH resulted in a reduction in net charge to mass ratio with the greatest reduction at RH >60%. The aerosol performance of this binary system is dependent on both electrostatic and capillary forces. The use of the ELPI allows a degree of insight into how these forces affect formulation performances after storage at different RH.     

Formulation and Characterization of Lipid-Coated Tobramycin Particles for Dry Powder Inhalation

Purpose This study was conducted to develop and evaluate the physicochemical and aerodynamic characteristics of lipid-coated dry powder formulations presenting particularly high lung deposition. Methods Lipid-coated particles were prepared by spray-drying suspensions with different concentrations of tobramycin and lipids. The solid-state properties of the formulations, including particle size and morphology, were assessed by scanning electron microscopy and laser diffraction. Aerosol performance was studied by dispersing the powders into a Multistage Liquid Impinger and determining drug deposition by high-performance liquid chromatography. Results Particle size distributions of the formulations were unimodal, narrow with more than 90% of the particles having a diameter of less than 2.8 μm. All powder formulations exhibited mass median diameters of less than 1.3 and 3.2 μm, as determined by two different laser diffraction methods, the Malvern's Mastersizer? and Spraytec?, respectively. The fine particle fraction varied within a range of 50.5 and 68.3%. Conclusions Lipid coating of tobramycin formulations resulted in a reduced agglomeration tendency and in high fine particle fraction values, thus improving drug deposition. The very low excipients content (about 5% m/m) of these formulations offers the benefit of delivering particularly huge concentrations of antibiotic directly to the site of infection, while minimizing systemic exposure, and may provide a valuable alternative treatment of cystic fibrosis.     

Effect of Gender and Device Mouthpiece Shape on Bolus Insulin Aerosol Delivery Using the AERx Pulmonary Delivery System

PURPOSE: A study was designed to compare differences in insulin aerosol deposition profiles in healthy male and female subjects, as well as examine the effect of mouthpiece cross-sectional shape, volume, and taper on deposition profiles using a developmental AERx pulmonary delivery system. METHODS: Six mouthpieces were screened in the laboratory, and three were selected for clinical investigation: a cylindrical mouthpiece with constant-cross-sectional area, an elliptical mouthpiece with constant-cross-sectional area, and a tapered elliptical mouthpiece with an exit cross-sectional area equal to one half the entrance cross-sectional area. RESULTS: There was no significant difference in the lung dose or in the deposition pattern between males and females (p > 0.05, by ANOVA). The cross-sectional shape of the mouthpiece had no significant effect on the clinical lung dose or the deposition pattern (p > 0.05, by ANOVA), although in vitro testing showed lower emitted dose values with the tapered elliptical mouthpiece (by ANOVA and Duncan's multiple range test, alpha = 0.05). Using the tapered mouthpiece in the clinic resulted in significantly more deposition on the mouthpiece itself when compared to the nontapered mouthpieces. CONCLUSION: Inhalation of insulin using the AERx system was insensitive to differences in male and female respiratory tract geometry across all mouthpiece designs examined.     

Effect of Dosing Cup Size on the Aerosol Performance of High-Dose Carrier-Based Formulations in a Novel Dry Powder Inhaler

This study investigated how varying the dosing cup size of a novel reservoir dry powder inhaler (DPI) affects the detachment of a micronized active pharmaceutical ingredient from larger carrier particles, and the aerosol performance of a DPI carrier formulation. Three different-sized dosing cups were designed: 3D printed with cup volumes of 16.26 mm³, 55.99 mm³, and 133.04 mm³, and tested with five different carrier type formulations with beclomethasone dipropionate (BDP) concentrations between 1% and 30% (w/w). The morphology of the BDP attached to the carrier was investigated using scanning electron microscopy and the aerosol performance using the Next Generation Impactor. Increasing the volume of the dosing cup led to a reduction of BDP deposition in the Next Generation Impactor preseparator, and an increase in BDP detachment from the carrier was observed, leading to increased aerosol performance. The decreased amount of BDP attached to carrier after aerosolization was attributed to the increased dosing cup void volume. This may enable greater particle-particle and particle-wall collisions, with greater BDP detachment from the carrier and deagglomeration of smaller agglomerates. The dosing cup volume was observed to have significant influence on particle dispersion and the overall aerosol performance of a DPI.     

Computational fluid dynamics (CFD) assisted performance evaluation of the Twincer™ disposable high-dose dry powder inhaler

Objectives To use computational fluid dynamics (CFD) for evaluating and understanding the performance of the high‐dose disposable Twincer? dry powder inhaler, as well as to learn the effect of design modifications on dose entrainment, powder dispersion and retention behaviour. Methods Comparison of predicted flow and particle behaviour from CFD computations with experimental data obtained with cascade impactor and laser diffraction analysis. Key findings Inhaler resistance, flow split, particle trajectories and particle residence times can well be predicted with CFD for a multiple classifier based inhaler like the Twincer?. CFD computations showed that the flow split of the Twincer? is independent of the pressure drop across the inhaler and that the total flow rate can be decreased without affecting the dispersion efficacy or retention behaviour. They also showed that classifier symmetry can be improved by reducing the resistance of one of the classifier bypass channels, which for the current concept does not contribute to the swirl in the classifier chamber. Conclusions CFD is a highly valuable tool for development and optimisation of dry powder inhalers. CFD can assist adapting the inhaler design to specific physico‐chemical properties of the drug formulation with respect to dispersion and retention behaviour.     

气流进入角度对干粉吸入器药物解聚效果的影响

以硫酸沙丁胺醇粉雾剂为模型药物，通过体外试验比较3种不同类型干粉吸入器的分散效果。结果表明，具有载体截留功能的切向进气和非切向进气吸入器及无载体截留功能的切向进气吸入器在一级瓶和二级瓶的药物沉积率分别为8．1％、10．5％、49．0％和31．5％、34．1％、15．8％。     

Effect of Relative Humidity on the Electrostatic Charge Properties of Dry Powder Inhaler Aerosols

Purpose

At present, there is no published data examining the effect of relative humidity on the electrostatic charges of dry powder inhaler aerosols. The charging behaviour of two commercial products, Pulmicort® and Bricanyl® Turbuhalers®, were investigated using an electrical low pressure impactor (ELPI).

Methods

ELPI was successfully modified to disperse the aerosols at 60 l/min. Four doses from each new inhaler were sampled at 15, 40, 65, and 90% RH. Particles deposited on the impactor stages according to their aerodynamic diameters and their charges were measured simultaneously by the electrometers. The drug in each size fraction was quantified using HPLC.

Results

Both products generated bipolar charges. The charging behaviour of the two types of inhaler showed different humidity dependence although the mass output was not significantly affected. The absolute specific charge of budesonide fine particles from Pulmicort® was the lowest at 40% RH but increased at lower and higher RHs. In contrast, the terbutaline sulfate fine particles from Bricanyl® followed the expected trend of charge reduction with increasing RH.

Conclusions

The distinct trends of charging of aerosols from Pulmicort® and Bricanyl® Turbuhalers® was explained by differences in hygroscopicity and other physicochemical factors between the two drugs.     

The Cohesive-Adhesive Balances in Dry Powder Inhaler Formulations II: Influence on Fine Particle Delivery Characteristics

PURPOSE: To investigate the influence of the cohesive-adhesive balances on dry powder formulation aerosolization and delivery characteristics. METHODS: De-agglomeration properties of pharmaceutical powders were investigated using an Aerosizer at various shear forces. Aerosol drug deposition properties of drug-only formulations and carrier-based formulations were investigated using a low-resistance device (Rotahaler) and a high-resistance device (Turbuhaler) via a twin-stage impinger. RESULTS: A paradoxical relationship between particle cohesive strength and de-agglomeration efficiencies of drug-only formulations was observed, where an increase in cohesive strength led to a higher fine particle fraction. A possible explanation for the variation in the fluidization and aerosolization properties between low and high cohesive particles was modeled on the relationship between cohesion, metastable agglomerate size, and the resulting aerodynamic drag force acting on the fluidized agglomerates. The addition of a fine particle lactose carrier influenced the drug deposition patterns in different ways depending on the relative cohesive and adhesive force balances within the formulation. CONCLUSIONS: The use of the colloid Atomic Force Microscrope (AFM) technique in combination with the cohesive-adhesive balance (CAB) system provides a novel preformulation tool for investigating the likely behavior of a dry powder formulation and a possible means of interpreting the possible de-aggregation and dispersion mechanisms of carrier-based formulations.     

The Role of Fines in the Modification of the Fluidization and Dispersion Mechanism Within Dry Powder Inhaler Formulations

PURPOSE: To investigate the role of in situ generated fine excipient particles on the fluidization and aerosolization properties of dry powder inhaler (DPI) formulations. MATERIALS AND METHODS: Carrier based DPI formulations were prepared under low and high shear blending. Powder rheometery was utilized to measure bulk powder properties in a consolidated and aerated state. Powder fluidization and aerosolization characteristics were related to bulk powder properties using high speed imaging and inertial impaction measurements. RESULTS: High shear blending of formulations resulted in the in situ generation of excipient fines, which corresponded to an increase in aerosolization efficiency. The generation of fines were shown to increase the tensile strength and free volume of the carrier, which resulted in a characteristic change in the fluidization properties, as observed by high speed imaging. The increase in minimum fluidization velocity and aerodynamic drag forces required to aerate the powder may provide the source of energy for the increase in fine particle re-suspension. CONCLUSIONS: The in situ generation of excipient fines affect bulk powder properties of DPI formulations, which directly affects fluidization and aerosolization behaviour of DPI formulations. The study suggests an alternative mode of action by which fines increase DPI formulation performance.     

The Influence of Fine Excipient Particles on the Performance of Carrier-Based Dry Powder Inhalation Formulations

The inclusion of a small amount of fine particle excipient in a carrier-based dry powder inhalation system is a well researched technique to improve formulation performance and is employed in the pharmaceutical industry. The removal of intrinsic fines from a lactose carrier has been found to decrease formulation performance, whereas adding fines of many different materials into formulations increased performance. Changing the particle size of these fines, the amount added and the technique by which they were prepared also affected formulation behaviour. Despite this body of research, there is disagreement as to the mechanism by which fines improved formulation performance, with two main hypotheses presented in the literature. The first hypothesis suggested that fines prevent the drug from adhering to the strongest binding sites on the carrier, whilst the second proposed that fine particles of drug and excipient form mixed agglomerates that are more easily dispersed and deaggregated during aerosolisation. The evidence in support of each hypothesis is limited and it is clear that future research should aim to produce stronger mechanistic evidence. The investigation of interparticulate interactions using techniques such as atomic force microscopy and inverse gas chromatography may prove useful in achieving this aim.     

粉雾剂胶囊的穿刺特性与体外分散表现评价

本试验探究了粉雾剂(dry powder inhaler,DPI)装置中明胶和羟丙甲纤维素(hydroxypropyl methylcellulose,HPMC)2种材质胶囊在不同轴直径刺针及穿刺速度条件下的力学性能表现,及对药物体外分散沉积效果的影响。穿刺性能测试使用的是装有单根DPI刺针的质构仪,研究了不同轴直径(0.58、1.17和1.46 mm)刺针和穿刺速度(0.05和5 mm/s)对2种胶囊刺破力和穿刺效果的影响。此外,还在60 L/min的流速下,使用快速筛选撞击器进行了体外分散试验,研究胶囊材质和刺针尺寸对DPI体外分散行为的影响。结果显示,HPMC胶囊与明胶胶囊相比,所需的刺破力更小,不易产生胶囊壳碎片;穿刺速度对胶囊上穿刺形成的孔洞面积影响较小。分散试验结果表明,与明胶胶囊相比,马来酸氯苯那敏在HPMC胶囊内残余量更少,微细粒子剂量(fine particle dose,FPD)相对较大。本研究的3种刺针中,0.58 mm直径的刺针穿刺胶囊产生的孔洞最小,药物在预分离器中沉积量最少,所得的FPD值最大,说明适当减小刺孔的尺寸有可能更有利于药物分散,但明胶胶囊有可能产...     

Influence of Realistic Inspiratory Flow Profiles on Fine Particle Fractions of Dry Powder Aerosol Formulations

Purpose The purpose of the study was to determine how air flow profiles affect fine particle fractions (FPF) (<5 μm) from dry powder aerosol formulations and whether laser diffraction (LD) could be used to measure FPF of aerosols generated by variable flows. Materials and Methods Carrier-based formulations containing 1.5% w/w micronized salbutamol base blended with the 63–90 μm fraction of alpha-lactose monohydrate or sorbitol or maltose were aerosolised from a model glass device using either a constant flow rate or a predetermined flow profile. The FPFs of the same aerosolised particles were first measured by LD and then by a liquid impinger. Volunteer inhalation airflow profiles and 3-phase (acceleration, constant flow rate and deceleration) square wave airflow profiles were generated using the Electronic Lung™ and an Inhalation Profile Recorder. Similar experiments were conducted for a carrier-free formulation from the Bricanyl Turbohaler™. Results Salbutamol FPFs of all carrier-based formulations were found to increase by increasing the initial flow increase rate (FIR) from 200 to 600 l min⁻¹ s⁻¹ although they could be placed in an increasing order of maltose blend < sorbitol blend < lactose blend. A significant linear correlation was found between FPFs measured by LD and by inertial impaction (R ² = 0.95, p < 0.01, ANOVA). For the Bricanyl Turbohaler™, increasing FIR from 120 to 600 l min⁻¹ s⁻¹ for a constant peak flow rate (PFR) of 60 l min⁻¹ increased the mean Terbutaline FPF from 18.2% to 45.5%. For the volunteer inhalation profiles, a higher FIR tended to be associated with higher PFR, leading to a marked increase in drug FPF due to the combined effect of FIR and PFR. Conclusion Drug FPF from either carrier-free or carrier-based formulations is determined by both FIR and PFR. LD is a viable technique to measure the performance of dry powder aerosol formulations at realistic inspiratory flow profiles.     

Investigations on the Mechanism of Magnesium Stearate to Modify Aerosol Performance in Dry Powder Inhaled Formulations

The potential of the force control agent magnesium stearate (MgSt) to enhance the aerosol performance of lactose-based dry powder inhaled (DPI) formulations was investigated in this study. The excipient-blends were investigated with analytical techniques including time-of-flight secondary ion mass spectrometry and single particle aerosol mass spectrometry (SPAMS), and particle size, morphology, and surface properties were evaluated. Excipient-blends were manufactured either by high-shear or low-shear blending lactose carrier with different amounts of MgSt in the range from 0% to 10% (w/w). Fluticasone propionate (FP) and salmeterol xinafoate (SX) used as model active pharmaceutical ingredients were added by low-shear mixing. The in vitro aerosol performance in terms of aerodynamic particle size distribution and fine particle fraction (FPF) of the FP and SX DPI formulations was evaluated with the Next Generation Impactor and also with SPAMS using a Breezhaler^® inhalation device. The distribution of MgSt on the lactose carrier in the blends was visualized and found to depend strongly on the blending method. This affected drug particle detachment from the carrier and thus impacted aerosol performance for FP and SX. Compared with blends without force control agent, low-shear blending of MgSt increases the FPF of the model drug SX, whereas high-shear blending significantly increased FPF of both SX and FP. The interactions between drug and carrier particles were substantially affected by the choice of blending technique of MgSt with lactose. This allows detailed control of aerosol performance of a DPI by an adequate choice of the blending technique. SPAMS successfully demonstrated that it is capable to distinguish changes in DPI formulations blended with different amounts of MgSt, and additional information in terms of dispersibility of fine particles could be generated.     

扫描电子显微镜-能谱仪在吸入式干粉制剂表征中的应用进展

目的 综述扫描电子显微镜-能谱仪在吸入式干粉制剂表征中的重要应用。方法 通过文献调研与归纳,扫描电子显微镜-能谱仪法表征吸入式干粉制剂,自动颗粒粒形粒径分析软件统计分析载体颗粒,对扫描电子显微镜在吸入式干粉制剂的研发过程中的4个广泛应用场景进行论证和总结。结果 吸入式干粉制剂学是高度依赖颗粒工程学的制剂类型,其性能和治疗功效很大程度上取决于原料药与辅料的微观特性。载体颗粒的尺寸、形状对高效肺部输送起决定性作用。而载体颗粒的表面粗糙度直接影响原料药与载体颗粒之间的黏附-脱附平衡,最终直接影响制剂雾化性能。扫描电子显微镜可以很直观地对颗粒的粒径、粒形以及表面粗糙情况进行快速评估。此外,也可通过扫描电子显微镜图像结合能谱分析判断原料药在载体颗粒上的负载情况,还可用来直接评估原料药颗粒的脱附能力。结论 扫描电子显微镜-能谱仪在吸入式干粉制剂的研发中具有广泛的应用意义,为该类型制剂的研发提供了先进的表征工具。     

干粉吸入剂空气动力学分散模型的建立和验证

在Weiler干粉粒子聚集体全分散理论模型基础上,以硫酸沙丁胺醇为模型药物,建立了一种更加深入的千粉吸入剂空气动力学分散模型.硫酸沙丁胺醇干粉吸入剂体外沉积试验表明,该模型可预测干粉粒子的空气动力学分散行为,并可结合计算流体动力学,估算干粉吸入剂在吸入装置中的分散及微细粒子分数.     

Preparation and <Emphasis Type="BoldItalic">in Vivo</Emphasis> Evaluation of a Dry Powder for Inhalation of Capreomycin

Purpose To develop an aerosol system for efficient local lung delivery of a tuberculostatic drug. Methods The antibiotic, capreomycin sulfate, was spray dried to form a dry powder aerosol. The chemical content and physical properties of resulting particles were assessed under various storage conditions. Plasma concentrations of capreomycin after insufflation into guinea pigs were evaluated at three doses, and compared to IV and IM administration of a capreomycin solution. Results Dry powder aerosols containing capreomycin were formulated to enable efficient delivery of large drug masses to the lungs of guinea pigs. Aerosols loaded with 73% CS were shown to possess good aerosolization properties and physical–chemical stability for up to 3 months at room temperature. Upon insufflation into guinea pigs, the amount of CS reaching the bloodstream was significantly lower compared to IV or IM administration, but resulted in a significantly longer drug half-life. Conclusions The results indicate that large doses of capreomycin in dry powder form can be efficiently delivered to the lungs of guinea pigs, which may result in high local drug exposure but significantly reduced systemic exposure as suggested by plasma concentrations in the present studies. These systems have considerable potential to provide more effective therapy for MDR-TB     

Characterisation of a Carrier-Free Dry Powder Aerosol Formulation Using Inertial Impaction and Laser Diffraction

Purpose The purpose of the study was to examine the suitability of using laser diffraction to measure the fine particle fraction (FPF) of drugs emitted from carrier-free dry powder aerosol formulations.Materials and Methods Particle size distribution of terbutaline sulphate from Bricanyl™ Turbohaler™, which contained loose agglomerates of drug particles only, was measured separately by laser diffraction apparatus equipped with a metal throat and a twin-stage, multi-stage liquid impingers, or Andersen cascade impactor at flow rates ranging from 28.3 to 100 l min⁻¹. In-line measurements were then conducted which allowed the same aerosolised particles to be measured first by laser diffraction then captured by an impactor or impinger for subsequent chemical analysis.Results A significant linear correlation (p < 0.001, R ² = 0.96, ANOVA) existed between the results obtained from two techniques when measurements were conducted independently. There was little difference in FPFs measured by inertial impaction and laser diffraction at the same flow rate. When in-line measurements were conducted, the FPFs measured by inertial impaction were approximately 0.7–0.9 times the aerosol FPFs measured by laser diffraction. This linear relationship was statistically significant and had a statistically insignificant y-intercept, regardless of inhaler batches, impinger types and measuring position of the laser beam.Conclusion Laser diffraction could prove to be a reliable technique for development, evaluation and quality control of carrier-free, dry powder aerosol formulations.