Commercial Inhaler Research Articles

Numerical study on the effect of the realistic mouth-inhaler positions on orally inhaled drug delivery in pediatric intersubject upper airways

The relative position between the pediatric upper airway and the inhalation device during real inhalation administration has significant effects on the delivery efficiency of orally inhaled drugs. Morphological variability plays an important role in this process. However, the mouth-throat differences between adults and children were usually neglected because most of the commercial inhalation devices currently are designed for adults or older adolescents. The main objective of this study is to investigate these effects by four realistic pediatric mouth-throat (RMT) geometries. In addition, an idealized mouth-throat (IMT) model was developed to validate the numerical model and to compare with the RMT models. Computational fluid dynamics (CFD) simulations were performed to investigate the flow pattern and deposition pattern in these models and the results were compared with the cascade impactor experiments, replica experiments and in vivo results. No significant correlation (p > 0.1) between the relative position parameters and inhaler insertion depth can be noticed among the RMT models. Notably, significant variability in the inhaler posture was observed in RMT models, especially for the S4 model. Airflow structure shows that the RMT model has a complex onset of turbulence, reverse flow and subsequently vortex formation when compared with the IMT model. The oral cavity is the region with the largest deposition fraction (DF) and deposition efficiency (DE). The DF and DE of the oral cavity are negatively correlated to the position parameter (Lm) when mass median aerodynamic diameter (MMAD) of indacaterol 150 μg was utilized as the input particle parameter. The relative position between the inhaler and oral cavity has significant effects on the particle transport and deposition. Furthermore, in silico results overestimated the lung deposition in comparison to the in vivo and experimental results when MMAD was used as input. To resolve the disparity between the in silico and in vivo results, a modified prediction method based on the cascade impactor and original in silico results was proposed and a good correlation of the relative contribution of pulmonary absorption to total systemic exposure (flung) was found between the predicted and observed results. The findings of present work will provide useful information in understanding the particle transport and deposition in the pediatric airways for the design of inhaler.

The effects of grid design on the performance of 3D-printed dry powder inhalers

The grid structure is an indispensable part of most dry powder inhalers, but the effects of grid geometry on inhaler performance are rarely reported. This study aims to systemically investigate the influence of grid design on the aerosolization performance of capsule-based inhalers through experiments and computational analysis. In-vitro aerosolization and deposition performance of commercial and 3D-printed customized inhalers with different grid mesh designs were experimentally studied using a Next Generation Impactor (NGI). Flow fields in the inhalers were generated, and average turbulence kinetic energy (TKE) and airstream trajectories were obtained through Computational Fluid Dynamics (CFD) analysis, delineating the effects of the different grid designs. Comparative studies using the commercial inhalers and the 3D-printed inhalers show a slightly better performance for the latter, probably due to the different materials used for the inhalers, confirming the suitability of 3D printing. Experimental results show that intensive grid meshes with a relatively small aperture size are beneficial to enhancing inhaler performance. Computational results illustrate that the intensive grid meshes can reduce vortexed airstreams and increase turbulent kinetic energy at the grids in general, which also supports the experimental results. In summary, inhalers with intensive grid meshes are preferred for capsule-based inhalers to enhance aerosolization performance. These findings have significant implications for the comprehensive understanding of how grid designs influence inhaler performance.

Effect of inflow conditioning for dry powder inhalers

The transport of pharmaceutical dry powder inside an optically accessible inhaler-like device is studied using both macro- and microscopic high-speed imaging. The investigation aims to systematically study the effect of inflow modifications on the dispersion characteristics of agglomerates inside a dry powder inhaler (DPI) geometry. An inhaler device was designed with geometrical features akin to commercial inhalers used in the current market and research oriented inhalers such as the Twincer®: two offset inlet channels (one with a powder pocket), a clockwise swirling chamber and a single outlet channel. At the device outlet, a vacuum pump was fitted with an actuator and calibrated to achieve a steady state inhalation with a peak flowrate of 85 and 125 L/min. Airflow conditions at the intake of the device were strategically perturbed in order to induce powder fluidisation and dispersion using turbulence grids and through physically obstructing channel streams in order to achieve changes in flow behaviour (e.g., flow separation). Complete fluidisation of the powder bed was observed with image processing enabling statistics on de-agglomerated fragment size and velocity. A range of behaviour was noted including local turbulence through introduction of a grid, bimodal fragment size behaviour for cohesive mannitol powder, as well as introduction of low velocity zones in the device through flow splitting. The geometry enables simple systematic study of inflow conditions into a DPI-like device with the data being useful for study of a given powder formulation (mannitol) and validation of computational models.

A Novel Adherence Sensor System for Valved Holding Chambers Suitable for Children and Adults With Asthma

Poor adherence to inhaled drug therapy is considered to be a major factor in asthma related morbidity and it has been shown, in a significant number of patients, that estimates of adherence by patients or parents of children is not accurate. Inaccurate reporting may lead to higher dose of drug or more potent drugs being prescribed. A number of adherence sensors are available for some commercial inhaler devices. However, existing adherence monitoring mainly focuses on how the hardware of an inhaler has been actuated and does not provide evidence of drug aerosol inhalation. Valved holding chambers are now first choice for aerosol drug delivery for young children, who inhale drug by breathing in and out of the device several times and are increasingly used by older children and adults who inhale drug aerosol by taking a single deep breath. To the best knowledge of the authors, there is no adherence sensor in the market that provides evidence of actuation of the drug into a valved holding chamber and evidence that it is inhaled by different age groups. We therefore developed a novel adherence sensor system embedded into a valved holding chambers to achieve this. Our customised algorithm ensures that correct use is recorded, and incorrect use flagged. It also distinguishes a deep breath from tidal breaths and in combination measurement of actuation into the device triggers different classifiers for registering usage as good technique or not. A good technique or poor technique is immediately fed back to users using a visual light signal, while the data recorded is Bluetoothed to a paired mobile device for historical recording and statistical analysis. The entire system, including battery, micro-controller, sensors and Bluetooth, is integrated on a 66 ×22 mm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> printed circuit board and weighs only 8 grams. The system has been evaluated on a custom-made artificial lung which mimics the breathing patterns confirming recognition of tidal and deep breaths. The low-power device operates from a 3.3 V, 560 mAh battery and lasts 14 months if used daily.

Integrated Continuous Crystallization and Spray Drying of Insulin for Pulmonary Drug Delivery

Pulmonary delivery of insulin in the form of a dry powder is an attractive alternative in comparison to conventional subcutaneous delivery. Insulin crystals have potential advantages such as sustained release and higher stability in comparison to amorphous particles. However, the design of crystallization processes that can reliably produce insulin crystals in a suitable size range for pulmonary delivery is challenging. A continuous process involving the integration of a tubular crystallizer and a spray dryer is characterized for the production of inhalable insulin. Supersaturation is created via cooling and a pH shift at the inlet of the crystallizer, aiming at a high nucleation rate. The recovery of insulin in the crystallizer exceeds 90%, and the insulin particles appear crystalline under most of the tested conditions. Integration with a spray dryer produces a dry powder with favorable properties for pulmonary drug delivery. The emitted fraction of insulin from a capsule in a commercial inhaler is in the range of 84.3–93.1%, which shows good powder dispersibility. Furthermore, the fine particle fraction of the insulin crystals ranges from 22.0% to 36.4%, which indicates a good potential for pulmonary delivery.

A homogenous nanoporous pulmonary drug delivery system based on metal-organic frameworks with fine aerosolization performance and good compatibility

Pulmonary drug delivery has attracted increasing attention in biomedicine, and porous particles can effectively enhance the aerosolization performance and bioavailability of drugs. However, the existing methods for preparing porous particles using porogens have several drawbacks, such as the inhomogeneous and uncontrollable pores, drug leakage, and high risk of fragmentation. In this study, a series of cyclodextrin-based metal-organic framework (CD-MOF) particles containing homogenous nanopores were delicately engineered without porogens. Compared with commercial inhalation carrier, CD-MOF showed excellent aerosolization performance because of the homogenous nanoporous structure. The great biocompatibility of CD-MOF in pulmonary delivery was also confirmed by a series of experiments, including cytotoxicity assay, hemolysis ratio test, lung function evaluation, in vivo lung injury markers measurement, and histological analysis. The results of ex vivo fluorescence imaging showed the high deposition rate of CD-MOF in lungs. Therefore, all results demonstrated that CD-MOF was a promising carrier for pulmonary drug delivery. This study may throw light on the nanoporous particles for effective pulmonary administration.

Dry powder inhaler aerosol deposition in a model of tracheobronchial airways: Validating CFD predictions with in vitro data.

Effective drug delivery into the lungs plays an important role in management of pulmonary diseases that affect millions all around the world. The main objective of this investigation is to study airflow structure, as well as transport and deposition of micron-size particles at different inhalation flow rates in a realistic model of human tracheobronchial airways. The airway model was developed based on computed tomography (CT) images of a healthy 48-years-old female, which includes extrathoracic, trachea, and bronchial airways up to fourth generations. Computational fluid dynamics (CFD) simulations were performed to predict transport and deposition of inhaled particles and the results were compared to our previous in vitro experiments. Airflow structure was studied through velocity contours and streamlines in the extrathoracic region, where the onset of turbulence, reverse flow and subsequently vortex formation, and laryngeal jet are found to be critical phenomenons in the formation of airflow and deposition patterns. The deposition data was presented by deposition efficiency (DE) and deposition fraction (DF) against impaction parameter and Stokes number. At all of the inhalation flow rates, highest values of deposition fractions were devoted to the mouth-throat (MT), tracheobronchial tree (TB), and trachea (Tra), respectively (At 60L/min: MT=6.7%, TB=5.3%, Tra=1.9%). The numerical deposition data showed a good agreement with the experimental deposition data in most of the airway regions (e.g. less than 10% difference between the deposition fractions in the tracheobronchial region). Enhancing inhalation flow rate in all of the airway regions led to an uptrend in deposition rate due to the increase of particles inertia and turbulence level. In addition, the increase of particle deposition with enhancing inhalation flow rate in all of the sections including extrathoracic, trachea, and tracheobronchial tree suggesting that inertial impaction is the dominant deposition mechanism due to the increase of inertial force. In conclusion, the validated CFD model provided an opportunity to cover the limitations of our previous experimental investigation on aerosol deposition of commercial inhalers and became an efficient method for further studies.

Development of an Aerosol Dose Collection Apparatus for In Vitro Dissolution Measurements of Orally Inhaled Drug Products

The aim of the study was to develop a robust and standardized in vitro dissolution methodology for orally inhaled drug products (OIDPs). An aerosol dose collection (ADC) system was designed to uniformly deposit the whole impactor stage mass (ISM) over a large filter area for dissolution testing. All dissolution tests were performed under sink conditions in a sodium phosphate buffered saline solution containing 0.2%w/w sodium dodecyl sulphate. An adapted USP Apparatus V, Paddle over Disk (POD), was used throughout the study. The dissolution characteristics of the ISM dose of a commercial metered-dose inhaler (MDI) and a range of dry powder inhaler (DPI) formulations containing inhaled corticosteroids were tested. The uniform distribution of the validated ISM dose considerably reduced drug loading effects on the dissolution profiles for both MDI and DPI formulations. The improvement in the robustness and discriminatory capability of the technique enabled characterization of dissolution rate differences between inhaler platforms and between different DPI product strengths containing fluticasone propionate. A good correlation between in vivo mean absorption time and in vitro dissolution half-life was found for a range of the inhaled corticosteroids. The ADC system and the reproducible in vitro POD dissolution measurements provided a quantitative-based approach for measuring the relationship between the influence of device and the dispersion characteristics on the aerosol dissolution of low solubility compounds. The in vitro dissolution method could potentially be applied as a dissolution methodology for compendial, quality control release testing, and during development of both branded orally inhaled drug products and their generic counterparts.

Is "Slow Inhalation" Always Suitable for Pressurized Metered Dose Inhaler?

To achieve adequate inhalation therapy, a proper inhalation technique is needed in clinical practice. However, there is limited information on proper inhalation flow patterns of commercial inhalers. Here, we quantitatively estimated airway deposition of two commercial pressurized metered dose inhalers (pMDIs) to determine their optimal inhalation patterns. Sultanol® inhaler (drug particles suspended in a propellant, suspension-pMDI) and QVAR™ (drug dissolved in a propellant with ethanol, solution-pMDI) were used as model pMDIs. Aerodynamic properties of the two pMDIs were determined using an Andersen cascade impactor with human inhalation flow simulator developed by our laboratory. As indices of peripheral-airway drug deposition, fine particle fractions (FPFPA) at different inhalation flow rates were calculated. The time-dependent particle diameters of sprayed drug particles were determined by laser diffraction. On aerodynamic testing, FPFPA of suspension-pMDI significantly decreased depending on the increasing inhalation flow rate, while solution-pMDI achieved higher and constant FPFPA in the range of the tested inhalation flow rates. The particle diameter of solution-pMDI markedly decreased from 5 to 3μm in a time-dependent manner. Conversely, that of suspension-pMDI remained at 4μm during the spraying time. Although "slow inhalation" is recommended for pMDIs, airway drug deposition via solution-pMDI (extra-fine particles) is independent of patients' inhalation flow pattern. Clinical studies should be performed to validate instruction for use of pMDIs for each inhaler for the optimization of inhalation therapy.

Amorphous pullulan trehalose microparticle platform for respiratory delivery

Spray drying biologics and small-molecule drugs can increase their thermal stability relative to liquid dosage forms and allow for widespread distribution to developing countries without cold chain infrastructure. In this study, pullulan trehalose powder is spray dried for inhalation. The powder is characterized in terms of manufacturability, physical stability, device compatibility, and aerosol performance. The manufacturability is demonstrated by reasonable spray drying yield and powder flowability. The powder has relatively low cohesiveness and high compressibility without semi-elastic deformation. Short-term physical stability for ambient temperature dry storage and 40 °C storage in commercial pressurized metered-dose inhaler propellants HFA 134a and HFA 227 is shown. A theoretical model predicts a high glass transition temperature near the surface of the microparticles where biologics are expected to reside. Emission from a commercial dry powder inhaler demonstrates high dispersibility, optimal size for inhalation, and adequate total lung dose, exceeding many commercial inhalation devices. The powder can be filled, stored, and actuated from a pressurized metered-dose inhaler without changes in particle morphology or solid phase. The pullulan trehalose platform thus appears promising for respiratory delivery.

Assessment of inhalation flow patterns of soft mist inhaler co-prescribed with dry powder inhaler using inspiratory flow meter for multi inhalation devices.

The patients’ inhalation flow pattern is one of the significant determinants for clinical performance of inhalation therapy. However, the development of inhalation flow meters for various inhalation devices has been unable to keep up with the increasing number of newly launched inhalation devices. In the present study, we developed simple attachment orifices for the inhalation flow pattern monitoring system, which are suitable for all commercial inhalers, and investigated the efficacy of the system on the clinical inhalation instruction for patients co-prescribed dry powder inhaler (DPI) and soft mist inhaler (SMI). First, we constructed simple attachment orifices that were adjusted for 13 commercial inhalers, and examined the correlation between orifice and inhalation device. Second, the inhalation flow patterns (peak inspiratory flow rate, PIFR; inhalation duration time, DT) of patients prescribed a combination of DPI and SMI were monitored before and after inhalation instruction. The inhalation resistance of commercial inhalers are listed in the following order; Twincaps® > Handihaler® > Swinghaler® = Clickhaler® > Twisthaler® > Turbuhaler® > Jenuair® > Diskus® = Ellipta® > Diskhaler® > Breezhaler® > Respimat® = pMDI. The pressure drop via orifice was significantly correlated with that via the commercial inhaler. For the confirmation, all participants achieved the DPI criterion of PIFR. On the other hand, 4 participants (6 clinical visits) of 10 experimented participants could not achieve the essential criterion of DT (> 1.5 sec) for SMI, but all participants improved their duration time after inhalation instruction by pharmacists (P<0.05). In the present study, we successfully developed simple attachment orifice suitable for 13 commercial inhalation devices. These data suggested that our simple attachment orifices for the inhalation flow pattern monitoring system can detect patients with inadequate inhalation patterns via SMI.

Good Things in Small Packages: an Innovative Delivery Approach for Inhaled Insulin.

The design development of a small, hand held, battery operated, breath actuated inhaler as a drug/device platform for inhaled insulin posed a number of technical challenges. Our goal was to optimize lung deposition and distribution with aerosol generators producing 3-6μm particle size distribution. In silico modeling with computational fluid dynamics (CFD) and in vitro testing of device components were assessed using an Alberta idealized adult airway (Copley, UK) to optimize mouthpiece and aerosol path design for dose delivered distal to the trachea. Human factors use testing was designed to determine the ability to perform inspiratory manuevers with LED guidance within target flow limits. In vivo testing with healthy normal subjects of radiolabeled aerosol compared 2 breathing patterns for lung deposition efficiency, distribution, and subject preference. CFD demonstrated that flows ≤5L/min and ≥15L/min reduced the delivery efficiencg. Prototypes tested with inspiratory flow of 10L/min provided up to 70% of dose delivered distal to the model throat with aerosols of 3 to 6μm. Users guided by LED were able to inhale for 8-24s with 5s breath hold. Lung dose >70% with peripheral to central ratios >2.0 were achieved, with subject preference for the longer inspiratory time with breath hold. The device design phase integration led to a novel design and inspiratory pattern with greater levels of peripheral deposition than previously reported with commercial inhalers. The rationale and process of the application of these methods are described with implications for use in future device development.

Optimization of a DPI Inhaler: A Computational Approach

Alternate geometries of a commercial dry powder inhaler (DPI, i.e., Turbuhaler; AstraZeneca, London, UK) are proposed based on the simulation results obtained from a fluid and particle dynamic computational model, previously developed by Milenkovic et al. The alternate DPI geometries are constructed by simple alterations to components of the commercial inhaler device leading to smoother flow patterns in regions where significant particle-wall collisions occur. The modified DPIs are investigated under the same conditions of the original studies of Milenkovic et al. for a wide range of inhalation flow rates (i.e., 30-70 L/min). Based on the computational results in terms of total particle deposition and fine particle fraction, the modified DPIs were improved over the original design of the commercial device.

Performance of fibrous filters during nanoparticle cake formation

ABSTRACTFibrous filters are highly efficient in removing micrometer particles, but their performance in the nanometer particle range is still little known. The aim of this study was to evaluate pressure drop and collection efficiency during nanoparticles cake formation using commercial fibrous filters. The filter media used were High Efficiency Particulate Air (HEPA) and polyester filters. The aerosols were generated by a commercial inhaler using a 5 g/L solution of NaCl and the particles produced were in the size range from 6 to 800 nm, with a peak at around 40 nm. A superficial velocity (vs) of 0.06 m/s was employed. During the filtration, the maximum pressure drop established was ∆P = ∆Pf +980Pa, where ∆Pf is the initial pressure drop of the filter. The collection efficiency was determined for a clean filter and for intermediate pressure drops. The filtration curves obtained showed that the HEPA filter provided greater surface filtration, compared to the polyester filter. Comparison of the collection efficiencies for clean filters revealed that the HEPA filter was highly efficient, even in the absence of cake, while the polyester filter showed initial collection efficiencies of between 20 and 40% for particles in the size range from 100 nm to 1000 nm. However, after formation of the filter cake, the collection efficiencies of both filters were almost 100% during the final stage of filtration. This shows that the fibrous filter can be applied in several industrial processes with highly efficient nanoparticle separation, after the formation of a thin layer cake filtration.

Discrete Modelling of Powder Dispersion in Dry Powder Inhalers - A Brief Review.

The performance of a dry powder inhaler (DPI) depends on powder properties as well as the air and particle flows in the device. The main principle of powder dispersion is to overcome the inter-particle cohesion using various dispersion/ de-agglomeration forces. While different dispersion mechanisms have been identified, their relative importance under different conditions is less clear. The lack of understanding of these mechanisms is a major obstacle to the advance of pharmaceutical powder aerosol technology. This paper briefly reviews our recent effort in developing a combined computational fluid dynamics (CFD) and discrete element method (DEM) approach to gain such pivotal information. Dispersions under various specifically designed conditions were simulated to exam the role of individual dispersion mechanism. The air and particle flows were analysed at the particle scale and linked to dispersion performance characterised by fine particle fraction (FPF). In addition, the dispersion mechanisms of both drug only and carrier based formulations in a commercial inhaler were studied. Our work shows that the approach has the potential to develop a theoretical framework for designing new DPIs.

De-agglomeration Effect of the US Pharmacopeia and Alberta Throats on Carrier-Based Powders in Commercial Inhalation Products.

The US pharmacopeia (USP) and Alberta throats were recently reported to cause further de-agglomeration of carrier-free powders emitted from some dry powder inhalers (DPIs). This study assessed if they have similar influences on commercially available carrier-based DPIs. A straight tube, a USP throat, and an Alberta throat (non-coated and coated) were used for cascade impaction testing. Aerosol fine particle fraction (FPF ≤ 5μm) was computed to evaluate throat-induced de-agglomeration. Computational fluid dynamics are employed to simulate airflow patterns and particle trajectories inside the USP and Alberta throats. For all tested products, no significant differences in the in vitro aerosol performance were observed between the USP throat and the straight tube. Using fine lactose carriers (<10μm), Symbicort(®) and Oxis(™) showed minimal impaction inside the Alberta throat and resulted in similar FPF among all induction ports. For products using coarse lactose carriers (>10μm), impaction frequency and energy inside the Alberta throat were significant. Further de-agglomeration was noted inside the non-coated Alberta throat for Seretide(®) and Spiriva(®), but agglomerates emitted from Relenza(®), Ventolin(®), and Foradil(®) did not further break up into smaller fractions. The coated Alberta throat considerably reduced the FPF values of these products due to the high throat retention, but they generally agreed better with the in vivo data. In conclusion, depending on the powder formulation (including carrier particle size), the inhaler, and the induction port, further de-agglomeration could happen ex-inhaler and create differences in the in vitro measurements.

Preparation and Characterization of Biocompatible Polymer Particles as Potential Nanocarriers for Inhalation Therapy

Aim.Investigation of the possibility of manufacturing biocompatible polymer particles which have the required properties for pulmonary delivery via inhalation and simultaneously act as vehicles of nanotherapeutics.Methods.Nanostructures were obtained from biocompatible polysaccharides by successive oxidation and reactive coiling in the aqueous phase. The resultant nanosuspensions of PAD (polyaldehyde dextran) and DACMC (dialdehyde carbomethylcellulose) were used as precursors in spray drying production of powders at variable process conditions. The resultant dry microparticles were characterized by SEM observations, and their properties related to delivery by inhalation were determined by laser diffraction spectrometry following the dispersion in the commercial inhaler. Finally, the possibility of the reconstitution of nanosuspensions by powders rehydration was evaluated.Results.Synthesized nanoparticles had size of 120–170 nm. Microparticles after drying had size of 0.5–5 µm and different surface morphology. Aerosolized particles obtained from powder dispersion in the inhaler had the volumetric median diameter of ~2 and ~1 µm for PAD and DACMC, respectively. Hydration of powders led to restoring the nanosuspensions with the average particle size similar to the precursor.Conclusions.PAD and DACMC can be used to obtain nanostructures which, after processing, take a form suitable for effective delivery to the lungs via inhalation.

Evaluation of the Deposition of Nanoparticles in Fibrous Filter

This study aimed to evaluate the deposition of NaCl nanoparticles during filtration in a cellulose filter medium (HEPA). The diameter of the generated polydisperse particles was between 6 and 800nm. Deposition was evaluated with the curves of pressure drop as a function of time. The permeability of the filter medium was determined and, after the deposition of particles, specific resistance of the formed cake was obtained. Filter performance was evaluated by counting particles before and after the filter medium and the pressure drop was monitored in order to obtain the filtration curve. Filtration velocity was kept at 0.06 m/s, and the concentration of the solution generated at a rate of 0.0042 L /min in a commercial inhaler was of 5 g/L. The results showed that this filter showed two steps during the deposition of particles, an internal filtration stage and a surface filtration stage. Although this filter is highly efficient in removing particles in the range evaluated, roughly 100%, particle penetration was observed in the range between 50 and 200nm.

Transport and deposition of pharmaceutical particles in three commercial spacer–MDI combinations

Respiratory drug delivery has been under the research spotlight for the past few decades, mainly due to the high incidence of pulmonary diseases and the fact that this type of delivery offers the highest efficiency for treatment. Despite its invaluable benefits, there are some major drawbacks to respiratory drug delivery, the most important of which being poor delivery efficiency and relatively high drug deposition in undesirable regions, such as the mouth cavity. One way to improve the efficiency of respiratory drug delivery with metered-dose inhalers is placing a respiratory spacer between the inhaler exit and the mouth. It is argued that high drug deposition in the immediate airways of the respiratory system is strongly affected by relatively high initial momentum of pharmaceutical particles leaving the inhaler. A respiratory spacer, however, can provide an expansion region in which the initial momentum of particles can subside. As a result, particles enter the patient׳s oral cavity more gradually and are more likely to reach the desired regions. In this study, the effectiveness of using three commercial spacers paired with a commercial inhaler is examined through numerical investigation of fluid flow and particle transport phenomena. Particles ranging from 1 to 50µm in diameter are tracked using a Lagrangian point of view and fluid flow fields are resolved using the LRN k-ω turbulence model. A novel particle injection method is introduced and is demonstrated to be able to adequately capture the effects of particle initial momentum. Lastly, a few design suggestions are made.

Abstracts from The Aerosol Society Drug Delivery to the Lungs 22Edinburgh International Conference CentreEdinburgh, Scotland, UKDecember 7–9, 2011

Summary Background: In bronchial challenge testing lung deposition of the stimulus may be poorly controlled due to incorrect use of nebulisers. Furthermore, the need for freshly prepared solutions burdens personnel and budget. In this study we aim to develop a dry powder alternative with higher reproducibility, better stability and lower costs than the current nebulisation test. Methods: Different pharmacological stimuli in the solid state were characterised on physico-chemical properties to determine the optimal conditions for processing and storage and were tested on their potential for dry powder inhalation. Adenosine and methacholine were micronised and dispersed with the Twincer ™ dry powder inhaler (DPI). Laser diffraction technique was applied to measure particle size distributions in the aerosol clouds. Results: Adenosine allows processing under ambient conditions. It was mixed with a lactose carrier in various mass ratios to produce adhesive mixtures and nucleus agglomerates. With three formulations, almost the entire dose range could be delivered with the Twincer ™ DPI. However, the process of preparing nucleus agglomerates might not be suitable for upscaling. Currently, spherical pellets are investigated as a more robust alternative. Methacholine is very hygroscopic and should therefore not be exposed to a high relative humidity. The methacholine particles leaving the Twincer ™ had an appropriate particle size distribution for inhalation. However, inhaler retention was high and should be reduced by controlling processing and storage conditions. Conclusions: Dry powder adenosine and methacholine seem promising alternatives for nebulisation. Methacholine must be handled under dry conditions. The highest doses of adenosine require further fine tuning.