Dry Powder Inhaler Devices Research Articles

Pharmacokinetic Bioequivalence of Two Inhaled Tiotropium Bromide Formulations in Healthy Volunteers.

Background and ObjectiveA novel tiotropium bromide monodose capsule dry powder inhaler (DPI) formulation and device have been developed. The formulation was based on a spray-dried matrix that enhances the aerosolizaton properties, allowing a less active tiotropium metered dose (13 µg/capsule) while maintaining the same delivered dose (10 µg/actuation). This study describes the pharmacokinetic bioequivalence to the reference product.MethodsThis randomized, two-stage, crossover, semi-replicate (three-way) study was performed in healthy volunteers. In each study period, subjects received a single dose of two capsules (20 μg delivered dose) of the study medication, separated by a 14-day washout period: tiotropium 10 μg delivered dose (Laboratorios Liconsa, Spain) and Spiriva HandiHaler® (Boehringer Ingelheim Pharma GmbH & Co KG, Germany). Blood samples were obtained up to 48 h post-dose to evaluate the comparative bioavailability. Tiotropium was measured in plasma by means of dual stage liquid–liquid extraction followed by the two-dimensional ultra-high performance liquid chromatography sensitive sub-pg/mL bioanalytical method. The main pharmacokinetic parameters were maximum plasma concentration (C max), area under the concentration–time curve (AUC) from time zero hours to the last observed concentration at time t (AUCt), and AUC from time zero hours to 30 min (AUC0.5). Bioequivalence was accepted if the 90.20 % confidence interval (CI) for the ratio test/reference of the primary pharmacokinetic parameters lay within the acceptance range of 80–125 %. Safety assessment was a secondary endpoint.ResultsA total of 30 subjects were randomized and bioequivalence was demonstrated for all primary pharmacokinetic parameters: C max (CI 87.26–106.60 %), AUCt (CI 101.33–111.64 %), and AUC0.5 (CI 97.95–113.49 %). Both study treatments were well tolerated (four non-serious adverse events [AEs] were reported in four subjects: one AE before any product administration, two AEs after test product administration; and one AE after reference product administration).ConclusionsBoth products containing tiotropium 10 µg delivered-dose DPI were bioequivalent and showed good tolerability and a similar safety profile.

Solid Lipid Nanoparticle assemblies (SLNas) for an anti-TB inhalation treatment⿿A Design of Experiments approach to investigate the influence of pre-freezing conditions on the powder respirability

For direct intramacrophagic antitubercular therapy, pulmonary administration through Dry Powder Inhaler (DPI) devices is a reasonable option. For the achievement of efficacious aerosolisation, rifampicin-loaded Solid Lipid Nanoparticle assemblies (SLNas) were developed using the melt emulsifying technique followed by freeze-drying. Indeed, this drying method can cause freezing or drying stresses compromising powder respirability. It is the aim of this research to offer novel information regarding pre-freezing variables. These included type and concentration of cryoprotectants, pre-freezing temperature, and nanoparticle concentration in the suspension. In particular, the effects of such variables were observed at two main levels. First of all, on SLNas characteristics ⿿ i.e., size, polydispersity index, zeta-potential, circularity, density, and drug loading. Secondly, on powder respirability, taking into account aerodynamic diameter, emitted dose, and respirable fraction. Considering the complexity of the factors involved in a successful respirable powder, a Design of Experiments (DoE) approach was adopted as a statistical tool for evaluating the effect of pre-freezing conditions. Interestingly, the most favourable impact on powder respirability was exerted by quick-freezing combined with a certain grade of sample dilution before the pre-freezing step without the use of cryoprotectants. In such conditions, a very high SLNas respirable fraction (>50%) was achieved, along with acceptable yields in the final dry powder as well as a reduction of powder mass to be introduced into DPI capsules with benefits in terms of administered drug dose feasibility.

Understanding the Different Effects of Inhaler Design on the Aerosol Performance of Drug-Only and Carrier-Based DPI Formulations. Part 1: Grid Structure.

The design of a dry powder inhaler device has significant influence on aerosol performance; however, such influence may be different between the drug-only and carrier-based formulations. The present study aims to examine the potential difference on the dispersion between these distinct types of formulations, using Aerolizer(®) as a model inhaler with the original or modified (cross-grid) designs. A coupled CFD-discrete element method analysis was employed to determine the flow characteristics and particle impaction. Micronized salbutamol sulphate as a drug-only formulation and three lactose carrier-based formulations with various drug-to-carrier weight ratios 1:5, 1:10 and 1:100 were used. The in vitro aerosolization performance was assessed by a next-generation impactor operating at 100L/min. Using the original device, FPFloaded was reduced from 47.5 ± 3.8% for the drug-only formulation to 31.8 ± 0.7%, 32.1 ± 0.7% and 12.9 ± 1.0% for the 1:5, 1:10 and 1:100 formulations, respectively. With the cross-grid design, powder-mouthpiece impaction was increased, which caused not only powder deagglomeration but also significant drug retention (doubling or more) in the mouthpiece, and the net result is a significant decrease in FPFloaded to 36.8 ± 1.2%, 20.9 ± 2.6% and 21.9 ± 1.5% for the drug-only, 1:5 and 1:10 formulations, respectively. In contrast, the FPFloaded of the 1:100 formulation remained the same at 12.1 ± 1.3%, indicating the increased mouthpiece drug retention was compensated by increased drug detachment from carriers caused by increased powder-mouthpiece impaction. In conclusion, this study has elucidated different effects and the mechanism on the aerosolization of varied dry powder inhaler formulations due to the grid design.

Advancements in Devices and Particle Engineering in Dry Powder Inhalation Technology.

Dry powder inhalers (DPI) attracted the attention of pharmaceutical field due to its enlarging market share in inhalable formulations. These formulations also pose patient compliance and good shelf life. Earlier DPI formulations were intended for local effect in lung (asthma and chronic obstructive pulmonary diseases), whereas 21(st) century witnessed formulations intended for systemic effect too. A better understanding of physiology of lung and fluidics of air flow helped in targeting alveoli using DPI technology. Modern characterization tools also accelerated the research pace. In addition to the synthetic molecules, DPI also was proved to be a better system for delivering biological molecules including vaccines. This review includes the mechanisms of drug deposition, advancements in the fields of DPI devices, various characterization tools and particle engineering. In this review we have related the chronological advancement of inhalational technology starting from 1788 AD to the present.

Budesonide inhaler device switch patterns in an asthma population in Swedish clinical practice (ASSURE).

Dry powder inhaler (DPI) device switch in asthma treatment could potentially increase with the entrance of new devices. We examined the switch patterns of budesonide (BUD) DPI analogues available in Sweden. This observational real-life study linked primary healthcare medical records data from the Västra Götaland region to national Swedish registries, and included asthma patients (ICD-10-CM J45) prescribed BUD in a multidose DPI. Index date: first dispense of BUD DPI. Switch date: prescription of another BUD DPI device. Study outcomes (switch vs. non-switch) were exacerbations and prescription of short-acting β2 -agonists. Study period was 1 July 2005 to 31 October 2013. Overall, 15,169 asthma patients were on treatment with BUD DPI; 1178 (7.35%) switched to another BUD DPI during the study. Pair-wise 1:1 matching of switchers vs. non-switchers resulted in two groups of 463 patients each (mean age 36 years, 55% female patients). A 25% higher exacerbation rate was seen postswitch (0.40 vs. 0.32; p = 0.047). Switchers were 4.5 year younger and had lower medication possession rate than non-switchers. Switch without primary healthcare visit did not differ between groups regarding consultations and exacerbations (no visit 4.96 and 0.90; visit 4.29 and 0.77, respectively). However, patients without primary healthcare visit at switch had significantly more outpatient hospital visits (2.01 vs. 0.81; p < 0.001). Considering the low switch rate, asthma patients and physicians in Swedish general practice seem reluctant to switch to another BUD DPI device. Switch, especially without primary healthcare visit, was associated with decreased asthma control resulting in higher exacerbation rate and more outpatient hospital visits.

A second-generation inhaled insulin for diabetes mellitus.

The pharmacologic properties of a recently approved inhaled insulin product, its unique delivery system, and the results of clinical safety and efficacy trials are reviewed. Afrezza (also called Technosphere Insulin, MannKind Corporation, Valencia, CA) is a novel ultrarapid-acting insulin formulation indicated for use in improving glycemic control in selected patients with type 1 or type 2 diabetes mellitus. Afrezza is not intended as a substitute for traditional basal therapy with injectable long-acting insulin but may be used to provide prandial insulin coverage; it must be used in combination with long-acting insulin in patients with type 1 diabetes. Administered before meals using a dry-powder inhalation device, Afrezza is formulated with a novel excipient (fumaryl diketopiperazine) that dissolves instantly in lung fluid and releases recombinant human insulin for absorption. In clinical trials, rates of hypoglycemia in Afrezza-treated patients were significantly lower than rates reported in comparator groups receiving injectable insulin products. The most commonly reported adverse effect of Afrezza is coughing, which tends to occur shortly after inhalation and is typically mild. Afrezza is not recommended for use in patients who smoke (or have recently stopped smoking) and those with a chronic lung disease such as asthma or chronic obstructive pulmonary disease. Afrezza is not recommended for the treatment of diabetic ketoacidosis. Afrezza is a safe and effective treatment for selected adults with type 1 or type 2 diabetes, potentially providing an alternative to injectable insulin for prandial blood glucose control.

70 Dry powder inhalation devices are a safe alternative to nebulizers regarding contamination with CF specific pathogenic germs

Objectives To assess the contamination risk with CF-relevant pathogens of the Tobi Podhaler dry powder inhaler (DPI) device compared to established nebulizers and to obtain real-world data from nebulizers of patients with chronic colonization of the lung with Gram-negative bacteria in the patient's usual inhalation setting, to learn more about patient's cleaning and inhalation habits. Methods Microbiological samples from the mouthpiece and medication reservoir were collected using an eSwab® from a device that was prepared in the patient's personal way before next inhalation. Results Microbiological analysis showed that the samples of 8/26 dry powder devices were sterile while the other 16 samples were contaminated with non-pathogenic bacteria of the human respiratory flora. Only 1/20 nebulizer devices were sterile. In 4 devices Staphylococcus aureus was detected. The other nebulizers were contaminated with a variety of bacterial species belonging to the human respiratory tract flora and bacteria typically found in humid sources (e.g. Pseudomonas fluorescens, Acinetobacter ursingii, Mycobacterium fortuitum ), indicating the potential transmission risk of CF-relevant species such as P. aeruginosa . Conclusion Tobi Podhaler is used 7 days twice daily. For cleaning it is supposed to be wiped with a dry and clean cloth. The cleaning procedure of a nebulizer is more time consuming and challenging. Under real-world conditions we found that the typical cleaning procedure of a nebulizer is failing to sterilize the device completely. Using a DPI with almost zero cleaning effort seems to be a satisfactory alternative regarding the hygienic requirements of an inhalation device.

Devices for dry powder drug delivery to the lung.

Dry powder inhalers (DPIs) are an important and increasingly investigated method of modern therapy for a growing number of respiratory diseases. DPIs are a promising option for certain patient populations, and may help to overcome several limitations that are associated with other types of inhalation delivery systems (e.g., accuracy and reproducibility of the dose delivered, compliance and adherence issues, or environmental aspects). Today, more than 20 different dry powder inhalers are on the market to deliver active pharmaceutical ingredients (APIs) for local and/or systemic therapy. Depending on the mechanism of deagglomeration, aerosolization, dose metering accuracy, and the interpatient variability, dry powder inhalers demonstrate varying performance levels. During development, manufacturers focus on improving aspects characteristic of their specific DPI devices, depending on the intended type of application and any particular requirements associated with it. With the wide variety of applications related to specific APIs, there exists a range of different devices with distinct features. In addition to the routinely used multi-use DPIs, several single-use disposable devices are under development or already approved. The recent introduction of disposable devices will expand the range of possible applications for use by including agents such as vaccines, analgesics, or even rescue medications. This review article discusses the performance and advantages of recently approved dry powder inhalers as well as disposable single-use inhalers that are currently under development.

The effects of loaded carrier mass and formulation mass on aerosolization efficiency in dry powder inhaler devices.

Previous studies have suggested that particle-particle impaction may influence aerosolization properties in carrier-based dry powder inhalers, through transfer of kinetic energy from large carriers to surface-deposited active drug. The importance of particle-particle collision has yet to be compared against other mechanisms that could lead to drug liberation, such as particle-wall impaction and turbulence. In particular, particle-particle collisions are difficult to model in silico due to computational restrictions. This study investigated the effects of dry powder inhaler particle-particle collisions in vitro using an established carrier-drug model dry powder inhalation formulation. Spherical polystyrene beads of median size 82.80 μm were chosen as a model carrier as they were of uniform size, shape, surface area, density, porosity and hardness and thus eliminated potential variables that would have conflicted with the study. This model carrier was geometrically blended with micronized salbutamol sulphate (loaded blend). The correlation between the mass of loaded blend (5-40 mg) in the Rotahaler® DPI device and resulting fine particle fraction (FPF) was examined at a constant flow rate of 60 L.min(-1). In a second experiment, the mass of loaded blend was kept constant and a variable amount of blank carrier particles were added to the Rotahaler® device to ascertain if additional "blank" carrier particles affected the final FPF. The efficiency of aerosolization remained constant with varying amounts of blank carrier particles as determined by the fine particle fraction of the emitted dose (FPFED) and fine particle fraction of the loaded dose (FPFLD). No statistical difference in FPFED and FPFLD values were observed for increasing masses of blank carrier. In addition, no statistical difference in FPFED and FPFLD between the two experiments was obtained. These observations suggest that particle-particle collisions are not a driving mechanism responsible for deaggregation of drug from carrier-based systems.

Bronchodilator Response to Salbutamol Delivered by Metered Dose Inhaler with Spacer and Dry Powder Inhaler in Acute Asthma In Children: A Comparative Study

Background: Salbutamol inhalation is the mainstay of treatment for acute exacerbation of asthma. A number of delivery systems for asthma medication have been developed for children, each having its own advantages and disadvantages. This study was done to compare the bronchodilator effect of salbutamol inhalation delivered through metered dose inhaler (MDI) with spacer and dry powder inhaler (DPI) in children presenting with mild and moderate acute asthma. Methodology: Children of 6 to 15 years of age with mild or moderate acute exacerbation of asthma were assessed primarily and randomly distributed into two groups having equal number of patients and received 400micro-gram of salbutamol delivered by either MDI with spacer or DPI device. The primary outcome variable was peak expiratory flow rate (PEFR) and secondary outcome variables were percent predicted PEFR, heart rate, respiratory rate, oxygen saturation, wheezing and accessory muscle scores. Changes in primary and secondary outcome variables, before and after drug intervention were recorded and subjected to statistical tests for significance. Separate analyses were done for mild and moderate asthma patients. Results: The changes in primary outcome variable (PEFR) in both groups before and after intervention was 179.19 ± 33.27 vs. 197.52 ± 57.01 liters/min and 184.81 ± 59.65 vs. 202.83 ± 64.76 liters/min respectively, which was statistically highly significant (P= 0.001). Similar significant changes were also observed in case of secondary outcome variables. Conclusion: Bronchodilator response to salbutamol in mild or moderate acute asthma in children is similar when equal amount of drug is delivered either through an MDI with spacer or a DPI DOI: http://dx.doi.org/10.3329/bjch.v38i2.21138 Bangladesh J Child Health 2014; VOL 38 (2) : 62-67

Effect of turbulent kinetic energy on dry powder inhaler performance

Dry powder inhalers (DPIs) have been extensively used for delivering medication to the lungs. Different designs of DPI devices affect the aerosolization processes of the drug particles. The processes cannot be easily visualized in experiments, thus computational fluid dynamics were used to investigate the turbulence kinetic energy and particle impaction. In this research, 3 size ranges of lactose carrier and the Cyclohaler® and Inhalator® devices were used as models for the computational simulations. The velocity vector, the turbulence kinetic energy (TKE) and particle trajectory were obtained. An aerosol dispersion experiment was performed using the Andersen Cascade Impactor. The TKE was directly related to the flow-rate. The TKE in the Cyclohaler® was lower than that in the Inhalator® due to its narrow geometry and this resulted in a high velocity air-flow. In the Cyclohaler® the probability of deagglomeration by impaction was high because of the cyclone-like design while the cross grid of the Inhalator® was an important factor for deagglomeration of the particles. The FPF varied from 7 to 30% and the FPF increased as the flow-rate increased. The MMAD was in the range of 4–6μm. The carrier size also affected the probability of deagglomeration at 60 and 90L/min, but not at 30L/min. In summary, maximizing the TKE and the particle impaction rate by adding a grid and providing a cyclone-like design was key factor to achieve a high deagglomeration of the particles.

A study of jet-milling and spray-drying process for the physicochemical and aerodynamic dispersion properties of amiloride HCl

The aim of this investigation was to examine the effect of a jet-mill and spray-drying process on the physicochemical and aerodynamic dispersion properties of amiloride HCl particles. Micro-fine particles were prepared by a spiral air jet-mill Hosokawa 50 AS and Mini Spray-Dryer B-191. A 23-1 fractional factorial experimental design was implemented to screen three jet-mill process parameters. Possible changes in the physicochemical properties of the material due to spiral jet-milling were examined by the determination of the particle size distribution (PSD), powder true density, powder flowability, diffuse reflectance Fourier transform infrared spectroscopy (DRIFTS) and scanning electron microscopy (SEM). The effect of different jet-milling parameters and the spray-drying process on the aerosol dispersion characteristics was examined with a cascade impactor with a preseparator using the Aerolizer® dry powder inhaler device (Novartis, Switzerland). The results show that small changes in the particle size within the 1 to 5μm range had an impact on the physicochemical and aerosol dispersion properties of jet-milled and spray-dried particles.

Inspiratory Flows and Volumes in Subjects with Cystic Fibrosis Using a New Dry Powder Inhaler Device

Introduction:Drug inhalation via a dry-powder inhaler (DPI) is a convenient, time efficient alternative to nebulizers in the treatment of cystic fibrosis (CF). Efficient drug administration via DPIs depends on the device resistance and adequate (≥ 45L/min) inspiratory flows and volumes generated by individuals. Dry-powder mannitol is delivered using a RS01 breath-actuated device developed by Plastiape, for Pharmaxis. The study aim was to determine in vivo if CF patients’ inspiratory flows and volumes are adequate to use the RS01 DPI device.Materials and Methodology:An open, non-interventional study; enrolled 25 CF subjects, aged ≥ 6 years with FEV1 ≥ 30 to < 90‰ predicted. Inspiratory flows and volumes were measured when subjects inhaled in a controlled manner through the RS01 device in series with a spirometer.Results:The mean inspiratory volume (IV) of CF subjects was 1.83L ± 0.97. Their achieved mean ± SD peak inspiratory flow (PIF) was 75.5 ± 27.2L/min. Twenty-three subjects (92%) achieved PIF of > 45L/min with the inhaler device; eighteen of those subjects (78%) had a baseline FEV1 of > 1L.Conclusion:Use of the RS01 DPI device allowed adequate inspiratory flow and volume for dispersion of dry-powder mannitol in CF patients.

Inspiratory Flows and Volumes in Subjects with Non-CF Bronchiectasis Using a New Dry Powder Inhaler Device

Introduction:Drug inhalation via a dry-powder inhaler (DPI) is a convenient, time efficient alternative to nebulizers in the treatment of cystic fibrosis (CF) or non-CF bronchiectasis. Efficient drug administration via DPIs depends on the device resistance and adequate (≥45L/min) inspiratory flows and volumes generated by individuals. Drypowder mannitol is delivered using a RS01 breath-actuated device developed by Plastiape, for Pharmaxis. The study aim was to determine in vivo if non-CF bronchiectasis patients’ inspiratory flows and volumes are adequate to use the RS01 DPI device.Materials and Methodology:An open, non-interventional study; enrolled 17 subjects with non-CF bronchiectasis, 18 to 80 years, with baseline FEV1 ≥1.0L and ≥50‰ predicted. Inspiratory flows and volumes were measured when subjects inhaled in a controlled manner through the RS01 device in series with a spirometer.Results:The mean inspiratory volume (IV) of non-CF bronchiectasis subjects was 2.08 ± 0.5L and achieved a mean PIF of 78.6 ± 11.2L/min with the inhaler device.Conclusion:Use of the RS01 DPI device allowed adequate inspiratory flow and volume for dispersion of dry-powder mannitol in non-CF bronchiectasis patients.

Inhaled Solid Lipid Microparticles to target alveolar macrophages for tuberculosis

The goal of the work was to evaluate an anti-tubercular strategy based on breathable Solid Lipid Microparticles (SLM) to target alveolar macrophages and to increase the effectiveness of the conventional tuberculosis (TB) therapy. Rifampicin loaded SLM composed of stearic acid and sodium taurocholate were characterized for aerodynamic diameter, surface charge, physical state of the components, drug loading and release as well as drug biological activity on Bacillus subtilis strain. Moreover, SLM cytotoxicity and cell internalization ability were evaluated on murine macrophages J774 cell lines by MTT test, cytofluorimetry and confocal laser microscopy. SLM exhibited aerodynamic diameter proper to be transported up to the alveolar epithelium, negative charged surface able to promote uptake by the macrophages and preserved drug antimicrobial activity. The negligible in vitro release of rifampicin indicated the capacity of the microparticle matrix to entrap the drug preventing its spreading over the lung fluid. In vitro studies on J774 cell lines demonstrated SLM non-cytotoxicity and ability to be taken up by cell cytoplasm. The microparticulate carrier, showing features suitable for the inhaled therapy and for inducing endocytosis by alveolar macrophages, could be considered promising in a perspective of an efficacious TB inhaled therapy by means of a Dry Powder Inhaler device.

Development of a High Efficiency Dry Powder Inhaler: Effects of Capsule Chamber Design and Inhaler Surface Modifications

The objective of this study was to explore the performance of a high efficiency dry powder inhaler (DPI) intended for excipient enhanced growth (EEG) aerosol delivery based on changes to the capsule orientation and surface modifications of the capsule and device. DPIs were constructed by combining newly designed capsule chambers (CC) with a previously developed three-dimensional (3D) rod array for particle deagglomeration and a previously optimized EEG formulation. The new CCs oriented the capsule perpendicular to the incoming airflow and were analyzed for different air inlets at a constant pressure drop across the device. Modifications to the inhaler and capsule surfaces included use of metal dispersion rods and surface coatings. Aerosolization performance of the new DPIs was evaluated and compared with commercial devices. The proposed capsule orientation and motion pattern increased capsule vibrational frequency and reduced the aerosol MMAD compared with commercial/modified DPIs. The use of metal rods in the 3D array further improved inhaler performance. Coating the inhaler and capsule with PTFE significantly increased emitted dose (ED) from the optimized DPI. High efficiency performance is achieved for EEG delivery with the optimized DPI device and formulation combination producing an aerosol with MMAD < 1.5 μm, FPF<5 μm/ED > 90%, and ED > 80%.

Characterization and aerosol dispersion performance of advanced spray-dried chemotherapeutic PEGylated phospholipid particles for dry powder inhalation delivery in lung cancer

Pulmonary inhalation chemotherapeutic drug delivery offers many advantages for lung cancer patients in comparison to conventional systemic chemotherapy. Inhalable particles are advantageous in their ability to deliver drug deep in the lung by utilizing optimally sized particles and higher local drug dose delivery. In this work, spray-dried and co-spray dried inhalable lung surfactant-mimic PEGylated lipopolymers as microparticulate/nanoparticulate dry powders containing paclitaxel were rationally designed via organic solution advanced spray drying (no water) in closed-mode from dilute concentration feed solution. Dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylethanolamine poly(ethylene glycol) (DPPE-PEG) with varying PEG chain length were mixed with varying amounts of paclitaxel in methanol to produce co-spray dried microparticles and nanoparticles. Scanning electron microscopy showed the spherical particle morphology of the inhalable particles. Thermal analysis and X-ray powder diffraction confirmed the retention of the phospholipid bilayer structure in the solid-state following spray drying, the degree of solid-state molecular order, and solid-state phase transition behavior. The residual water content of the particles was very low as quantified analytically Karl Fisher titration. The amount of paclitaxel loaded into the particles was quantified which indicated high encapsulation efficiencies (43–99%). Dry powder aerosol dispersion performance was measured in vitro using the Next Generation Impactor™ (NGI™) coupled with the Handihaler® dry powder inhaler device and showed mass median aerodynamic diameters in the range of 3.4–7μm. These results demonstrate that this novel microparticulate/nanoparticulate chemotherapeutic PEGylated phospholipid dry powder inhalation aerosol platform has great potential in lung cancer drug delivery.

Flow and particle deposition in the Turbuhaler: A CFD simulation

In this work the steady-state flow in a commercial dry powder inhaler device, DPI (i.e., Turbuhaler) is described using computational fluid dynamics. The Navier-Stokes equations are solved using commercial CFD software considering different flow models, i.e., laminar, k-ε, k-ε RNG, and k-ω SST as well as large Eddy simulation. Particle motion and deposition are described using a Eulerian-fluid/Lagrangian-particle approach. Particle collisions with the DPI walls are taken to result in deposition when the normal collision velocity is less than a critical capture velocity. Flow and particle deposition, for a range of mouthpiece pressure drops (i.e., 800-8800 Pa), as well as particle sizes corresponding to single particles and aggregates (i.e., 0.5-20 μm), are examined. The total volumetric outflow rate, the overall particle deposition as well as the spatial distribution of deposition sites in the DPI are determined. The transitional k-ω SST model for turbulent flow was found to produce results most similar to a reference solution obtained with LES, as well as experimental results for the pressure drop in the DPI. Overall, the simulation results are found to be in agreement with the available experimental data for local and total particle deposition.

A Novel Continuous Powder Aerosolizer (CPA) for Inhalative Administration of Highly Concentrated Recombinant Surfactant Protein-C (rSP-C) Surfactant to Preterm Neonates

In pulmonary medicine, aerosolization of substances for continuous inhalation is confined to different classes of nebulizers with their inherent limitations. Among the unmet medical needs is the lack of an aerosolized surfactant preparation for inhalation by preterm neonates, to avoid the risks associated with endotracheal intubation and surfactant bolus instillation. In the present report, we describe a high-concentration continuous powder aerosolization system developed for delivery of inhalable surfactant to preterm neonates. The developed device uses a technique that allows efficient aerosolization of dry surfactant powder, generating a surfactant aerosol of high concentration. In a subsequent humidification step, the heated aerosol particles are covered with a surface layer of water. The wet surfactant aerosol is then delivered to the patient interface (e.g., nasal prongs) through a tube. The performance characteristics of the system are given as mass concentration, dose rate, and size distribution of the generated aerosol. Continuous aerosol flows of about 0.84 L/min can be generated from dry recombinant surfactant protein-C surfactant, with concentrations of up to 12 g/m(3) and median particle sizes of the humidified particles in the range of 3 to 3.5 μm at the patient interface. The system has been successfully used in preclinical studies. The device with its continuous high-concentration delivery is promising for noninvasive delivery of surfactant aerosol to neonates and has the potential for becoming a versatile disperser platform closing the gap between continuously operating nebulizers and discontinuously operating dry powder inhaler devices.

Aerosolization characteristics of dry powder inhaler formulations for the excipient enhanced growth (EEG) application: Effect of spray drying process conditions on aerosol performance

The aim of this study was to develop a spray dried submicrometer powder formulation suitable for the excipient enhanced growth (EEG) application. Combination particles were prepared using the Buchi Nano spray dryer B-90. A number of spray drying and formulation variables were investigated with the aims of producing dry powder formulations that were readily dispersed upon aerosolization and maximizing the fraction of submicrometer particles. Albuterol sulfate, mannitol, L-leucine, and poloxamer 188 were selected as a model drug, hygroscopic excipient, dispersibility enhancer and surfactant, respectively. Formulations were assessed by scanning electron microscopy and aerosol performance following aerosolization using an Aerolizer dry powder inhaler (DPI). In vitro drug deposition was studied using a realistic mouth-throat (MT) model. Based on the in vitro aerosolization results, the best performing submicrometer powder formulation consisted of albuterol sulfate, mannitol, L-leucine and poloxamer 188 in a ratio of 30:48:20:2, containing 0.5% solids in a water:ethanol (80:20%, v/v) solution which was spray dried at 70 °C. The submicrometer particle fraction (FPF(1 μm/ED)) of this final formulation was 28.3% with more than 80% of the capsule contents being emitted during aerosolization. This formulation also showed 4.1% MT deposition. The developed combination formulation delivered a powder aerosol developed for the EEG application with high dispersion efficiency and low MT deposition from a convenient DPI device platform.