Aerosol Mass Median Aerodynamic Diameter Research Articles

A Technical Feasibility of Aqueous Aerosol Generation Based on the Flashing Jet: Effects of Overheat Degree, Jetting Rate, Jetting Volume, and Liquid Type

AbstractA previously established flashing jet inhaler prototype (FJ prototype) can produce an aqueous aerosol but cannot steadily provide inhalable aerosol (2–5 μm). This study aims to optimize the atomization performance of the FJ prototype and generate inhalable aqueous aerosols. The effects of overheat degree, jetting rate, jetting volume, and liquid type on atomization performance were assessed by determining output aerosol's mass median aerodynamic diameter (MMAD) and aerodynamic particle size distribution. Drug distribution of active ingredients in different liquid types was also measured. A Pari nebulizer was used as a reference device. Our data suggested that MMAD is negatively correlated with the overheat degree and jetting rate, but has no significant relationship with the jetting volume. The effect of jetting rate is weaker than that of the overheat degree. When normal saline was used as the atomization liquid, output aerosol's MMAD at the FJ prototype and Pari nebulizer were 1.98 ± 0.18 and 2.50 ± 0.81 μm, respectively. The addition of a surfactant significantly decreases MMAD both in solution and in suspension, but the suspended particles had no effect on the residual level and atomization performance of the FJ prototype. When ventolin was used as the atomization liquid, the MMAD of the FJ prototype and Pari nebulizer was 2.1 ± 0.2 and 1.7 ± 0.2 μm, respectively, while the fine particle dosage (FPD) in percent of the nominal dose (%ND) was 50.4 ± 3.1 and 53.1 ± 7.2%, respectively. When pulmicort respules was used as the atomization liquid, the MMAD of the FJ prototype and Pari nebulizer was 2.5 ± 0.5 and 4.6 ± 0.2 μm respectively, while the FPD (%ND) was 30.1 ± 5.6 and 58.6 ± 5.1%, respectively. The FJ prototype not only delivers inhalable aqueous aerosol but also has a potential advantage in the atomization of suspension or poorly soluble drugs.

Evaluation and Selection of the Inhaler Device for Treprostinil Palmitil Inhalation Powder

Treprostinil palmitil (TP) is a prodrug of treprostinil that has been formulated as an inhaled powder, termed TPIP, for evaluation in patients with pulmonary arterial hypertension. In these characterization studies we investigated the aerosol performance of TPIP in response to changes in capsule fill, device resistance, and inspiratory flow rate to enable selection of an inhaler for clinical use. Capsules containing 8, 16 or 32 mg of TPIP (80, 160, or 320 μg TP, respectively) were evaluated using four commercially-available, breath-actuated RS01 devices (Plastiape, S. p.A., Osnago, Italy) with low, medium, high or ultra-high inspiratory resistances, creating 12 different capsule and device configurations for evaluation. Aerosol characterization was performed using the next generation impactor at compendial conditions of 23°C and 35% relative humidity and a flow rate corresponding to a 4 kPa pressure drop. The aerosol mass median aerodynamic diameter, geometric standard deviation, fine particle fraction, emitted dose and fine particle dose (FPD) were calculated from the in vitro impactor data. The TP emitted dose at 4 kPa exceeded 75% for all 12 capsule and device configurations. The FPD, an estimate of the respirable dose, varied between 61.0 and 70.6% of the loaded TP dose for all four devices with the 8 and 16 mg TPIP capsule dose. For the 32 mg TPIP capsule dose, the FPD remained above 61.0% for the high and ultra-high resistance devices but decreased to 48.5 and 52.6% for the low and medium resistance devices, respectively. Based on this initial data, the high resistance device was selected for additional characterization studies at 40 and 80 L/min corresponding to pressure drops of 1.4 and 5.4 kPa. The FPD was relatively insensitive to changes in flow rate, providing an expectation of a consistent total lung dose of TP under scenarios simulating variability in how the device is used. Based on these findings, the high resistance device was chosen for further development in human clinical trials.

Use of Computational Fluid Dynamics (CFD) Dispersion Parameters in the Development of a New DPI Actuated with Low Air Volumes.

To determine the predictive power of computational fluid dynamics (CFD)-based dispersion parameters in the development of a new inline DPI that is actuated with low volumes of air. Four new versions of a dose aerosolization and containment (DAC)-unit DPI were created with varying inlet and outlet orifice sizes and analyzed with results from five previous designs. A concurrent in vitro and CFD analysis was conducted to predict the emitted dose (ED; as a % of loaded dose) and aerosol mass median aerodynamic diameter (MMAD) produced by each device when actuated with 10ml air bursts. CFD simulations of device operation were used to predict flow field and particle-based dispersion parameters. Comparisons of experimental and CFD results indicated that multiple flow field and particle-based dispersion parameters could be used to predict ED (minimum RMS Error = 4.9%) and MMAD (minimum RMS Error = 0.04μm) to a high degree of accuracy. Based on experiments, the best overall device produced mean (standard deviation; SD) ED = 82.9(4.3)% and mean MMAD (SD) = 1.73(0.07)μm, which were in close agreement with the CFD predictions. A unique relationship was identified in the DAC-unit DPI in which reducing turbulence also reduced the MMAD.

Lipid nanocapsules: Ready-to-use nanovectors for the aerosol delivery of paclitaxel

Aerosol drug delivery permits the development of dose-intensification strategies in severe, malignant lung diseases. The aim of the study was to demonstrate that the encapsulation of paclitaxel in lipid nanocapsules (LNCs), a novel drug nanocarrier for lipophilic components, allows one to provide pulmonary drug delivery of paclitaxel by nebulisation, thereby allowing preclinical and clinical studies. LNC dispersions are made into aerosols with commercial nebulisers. The structure, drug payload and cytotoxicity of nebulised LNCs were compared to fresh LNCs. The results demonstrated that LNC dispersions could be made into aerosols by using mesh nebulisers without altering the LNC structure. Only eFlow rapid-produced aerosols are compatible with human use: the mean duration to nebulise 3 ml of LNC dispersion is less than 9 min, with an aerosol mass median aerodynamic diameter equal to 2.7+/-0.1 microm and a fine-particle fraction (between 1.0 and 5.0 microm) of 81.5+/-3.1%. No modifications of drug payload or cytotoxicity effects of paclitaxel-loaded LNC (PTX-LNC) were observed. In order to carry out preclinical studies, a scaled-up LNC formulation protocol was used. Chemical parameters, such as acidity and osmolarity, were optimised, and a storage procedure for PTX-LNC batches was set-up. Animal studies are now needed to determine the tolerance and therapeutic potential of LNC dispersion aerosols.

In vitro comparison of an electronic micropump and jet nebulizer with budesonide

RATIONALE: Budesonide was approved for use with jet nebulizers. The Aeroneb® Go Nebulizer (Aerogen, Inc.) generates aerosol using the OnQ™ electronic micropump. To determine capabilities of this newer technology, we compared nebulization of budesonide respules 0.5 mg / 2.0mL (AstraZeneca) with the Go and the LC Plus® (Pari, Inc.). METHODS: : Inhaled mass of budesonide was collected on a filter placed between the nebulizer and breathing simulator (Hans Rudolph; adult pattern). Aerosol mass median aerodynamic diameter (MMAD), Geometric Standard Deviation (GSD) and fine particle fraction less than 5.8 μm (FPF) were determined by cascade impaction (Anderson Mk II). Three units of each device were tested in triplicate. Drug deliuvery determined by HPLC. RESULTS: The MMAD (μm) ± GSD of the Go (3.1 ± 1.6) was less than the LC Plus (3.8 + 1.7). Inhaled mass for the Aeroneb Go was 115±13 μg (22±3% of dose) and 91± 14 (18 ± 3% of dose) for the LC Plus (p=0.03:ANOVA). Respirable mass (inhaled mass x FPF) was greater for the Go (20±2 %) than the LC Plus (13±1 %) (p=0.001). Treatment time was 6 min for the Go and 5 min for the LC Plus. CONCLUSIONS: Aerosol delivery of budesonide suspension by the electronic micropump (Aeroneb Go) was similar to the most efficient jet nebulizer (LC Plus). Although budesonide is approved only for use with jet nebulizers, the Aeroneb Go delivered higher inhaled and respirable mass in this in vitro model.

Size Distribution of Chromate Paint Aerosol Generated in a Bench-Scale Spray Booth

Spray painters are potentially exposed to aerosols containing hexavalent chromium [Cr(VI)] via inhalation of chromate-based paint sprays. Evaluating the particle size distribution of a paint spray aerosol, and the variables that may affect this distribution, is necessary to determine the site and degree of respiratory deposition and the damage that may result from inhaled Cr(VI)-containing paint particles. This study examined the effect of spray gun atomization pressure, aerosol generation source and aerosol aging on the size distribution of chromate-based paint overspray aerosols generated in a bench-scale paint spray booth. The study also determined the effect of particle bounce inside a Marple personal cascade impactor on measured size distributions of paint spray aerosols. Marple personal cascade impactors with a modified inlet were used for sample collection. The data indicated that paint particle bounce did not occur inside the cascade impactors sufficiently to affect size distribution when using uncoated stainless steel or PVC substrate sampling media. A decrease in paint aerosol mass median aerodynamic diameter (MMAD) from 8.2 to 7.0 mum was observed as gun atomization pressure increased from 6 to 10 psi. Overspray aerosols were sampled at two locations in the spray booth. A downstream sampling position simulated the exposure of a worker standing between the painted surface and exhaust, a situation encountered in booths with multiple workers. The measured mean MMAD was 7.2 mum. The distance between the painted surface and sampler was varied to sample oversprays of varying ages between 2.8 and 7.7 s. Age was not a significant factor for determining MMAD. Overspray was sampled at a 90 degrees position to simulate a worker standing in front of the surface being painted with air flowing to the worker's side, a common situation in field applications. The resulting overspray MMAD averaged 5.9 mum. Direct-spray aerosols were sampled at ages from 5.3 to 11.7 s. Overspray and direct-spray results indicated that most of the change in aerosol size distribution occurred between the time the paint aerosol impacted the painted surface and the time the overspray became 2.8 s old. The overall mean MMAD of overspray in the study was 6.4 mum and may have been underestimated due to sampling efficiency biases. If inhaled by a worker, the overspray aerosols evaluated in this study would mostly deposit in the head airways region of the respiratory tract. Paint overspray aerosols contained Cr primarily in the Cr(VI) state.

In vitro comparison of an electronic micropump nebulizer with other high efficiency nebulizers

Rationale Nebulizers vary in available respirable mass and treatment times. The Aeroneb® Go Nebulizer (Aerogen, Inc.) has a novel design and generates aerosol using the OnQ™ electronic micropump. Its aerosol delivery characteristics were compared with those of the high efficiency MicroAir® (Omron, Inc.) and LC Star® (Pari Respiratory Equipment, Inc.) nebulizers using albuterol sulfate ampoules (2.5 mg in 3 mL). Methods Inhaled albuterol was collected on a filter placed between the nebulizer and breathing simulator (Hans Rudolph; adult pattern). Aerosol Mass Median Aerodynamic Diameter (MMAD) and fine particle fraction less than 5.8 μm (FPF) were determined by cascade impaction. The amount of drug deposited was determined by HPLC. Treatment time was measured to the end of aerosol generation or one minute past sputter. Results The MMAD of the Go (3.1 μm) fell between those of the MicroAir (5.2 μm) and LC Star (1.7 μm). Respirable mass (inhaled mass × FPF) trended greater for the LC Star (31 ± 6%) and the Go (31 ± 4%) vs. the MicroAir (27 ± 2%) (p=ns by ANOVA). Treatment time for the Go (6 min) was half that of the Micro Air (12 min) or the LC Star (14 min). Conclusion Aerosol delivery characteristics of the Aeroneb Go are consistent with those of the most efficient general-purpose nebulizers. The Aeroneb Go offers the advantage of a substantially shorter treatment time.

Investigation of a Novel Condensation Aerosol Generator: Solute and Solvent Effects

Part I of this article presents results of an experimental study on gas-phase nucleation for three model solutes and their solvent, propylene glycol (PG), with variables being solute concentration and the nature of the solute substance. A single manifestation of an aerosol generator, which forms condensation aerosols by cooling of hot vapor issuing from an electrically heated, pumped capillary, is described and used for all experiments. The effects of solute concentration and solute type were studied for deoxycorticosterone (DOC), benzil (BZ), and phenyl salicylate (PhS). Suppression of homogeneous nucleation and occurrence of heterogeneous condensation of the solvent was observed at different solute concentrations for BZ, PhS, and DOC. The nature and concentration of the solute dissolved in the solvent was shown to determine the final particle size distribution of the condensed aerosol. In the case of the least volatile solute, DOC, solute aerosol and total aerosol size distributions were identical at low solute concentrations. A transitional concentration region then existed in which a bimodal solute aerosol was formed, followed at high concentrations by increasing separation of the solvent-dominated aerosol size distribution and that of the solute. In Part II of this article, the effect of DOC dissolution in different solvents was studied at fixed solute concentration. The effects of six glycol solvents--i.e., PG, ethylene glycol (EG), dipropylene glycol (DPG), diethylene glycol (DEG), triethylene glycol (TEG), and tetraethylene glycol (TetEG)--and three nonglycol solvents--i.e., dimethyl sulfoxide (DMSO), formamide (FORM), and oleyl alcohol (OA)--were studied, as these affected the resultant aerosol sizes. Suppression of total aerosol mass median aerodynamic diameter (MMAD) was observed on dissolution of 0.5% w/w DOC in each solvent, although suppression occurred to different extents. It was shown that the boiling point or volatility of the solvent used to dissolve the less volatile DOC had an effect on the final particle size distribution of the condensed aerosol and whether the aerodynamic size distributions for the solute and the total aerosol were the same or different.

System for Precise Control of Volumetric Flow Rate during Sampling with a Cascade Impactor

Calculations were made with efficiency curves developed for the micro-orifice impactor (MOI) to estimate errors in mass collected on individual stages due to fluctuations in the flow rate during sampling of submicrometer particles. The sizes of these errors depend on the size distribution of the sampled aerosol and the level of flow rate fluctuation. For a log-normally distributed particle population, mass errors due to flow rate fluctuations were bimodally distributed about stages with cutpoints near the aerosol Mass Median Aerodynamic Diameter (MMAD). The largest errors occurred uniformly on the stage with the smallest cutpoint (here, 0.059 w m). These errors were asymmetric with respect to sign, which leads to a net error for a randomly fluctuating flow rate. In general, mass errors increased with decreasing geometric standard deviation ( † g ) and were substantially greater for populations with 0.5 w m MMADs than for those with 0.2 w m MMADs. The largest net errors for the former were 4, 110, and 560%...

Selecting an accessory device with a metered-dose inhaler: variable influence of accessory devices on fine particle dose, throat deposition, and drug delivery with asynchronous actuation from a metered-dose inhaler.

Accessory devices reduce common problems with metered-dose inhalers (MDIs), namely high oropharyngeal deposition of aerosol and incoordination between actuation and inhalation by the patient. The objective of this study was to systematically compare the performance of various accessory devices in vitro. MDIs were tested alone or in combination with four spacers (Toilet paper roll, Ellipse, Optihaler, Myst Assist) and five holding chambers (Aerochamber, Optichamber, Aerosol Cloud Enhancer, Medispacer, and Inspirease). An Anderson cascade impactor was used to measure aerosol mass median aerodynamic diameter (MMAD) and fine particle dose (MMAD < 4.7 microm). In separate experiments, the influence of asynchronous MDI actuation on drug delivery was determined with a simulated spontaneous breathing model. Compared with the MDI alone, all of the accessory devices reduced aerosol MMAD and increased lung-throat ratio (fine particle dose/throat impaction; p < 0.05 for both parameters). The fine particle dose of albuterol was 40% higher with the Ellipse (p < 0.01), was equivalent with the Toilet Paper Roll, Aerochamber, Optichamber, and Medispacer, and was 33-56% lower with the Optihaler, Myst Assist, Aerosol Cloud Enhancer, and Inspirease (p < 0.03). MDI actuation in synchrony with inspiration produced highest drug delivery; when MDI actuation occurred 1-sec before inspiration or during exhalation, decrease in drug delivery with holding chambers (10-40% reduction) was less than that with spacers (40-90% reduction). Accessory device selection is complicated by variability in performance between devices, and in the performance of each device in different clinical settings. In vitro characterization of a MDI and accessory device could guide appropriate device selection in various clinical settings.

Simulation Analysis of Inhalable Dust Sampling Errors Using a Multi-Component Error Model

Measurements to characterize inhalable aerosol exposure are subject to random error even after sources of systematic error have been eliminated. For a fixed aerosol sampler geometry the random errors are due to the variability of measured and unmeasured parameters including ambient variables, quantification technique, and operation parameters. In this discussion we apply a multi-component error estimation model to size selective aerosol sampling with the well-known Institute of Occupational Medicine (IOM) inhalable aerosol sampler. Random errors due to typical variations in sampler flow control, timing, and mass determination were small, being approximately 3%. Similarly, random errors due to variations in wind velocity were reasonably small at approximately 10%. However, the bias introduced by wind velocity was notable, ranging from peak values of 17 to 27% depending on aerosol mass median aerodynamic diameter and geometric standard deviation. This modeling indicated that the combined influence of variations in sampler flow control, timing, mass determination, and ambient wind velocity on IOM performance appeared to be less than approximately 10%; however, bias at moderate wind velocities was shown to be important for the IOM sampler as suggested by other studies. The effects of sampler placement, angle of incidence of ambient wind velocity on the sampler, and head orientation of the exposed person are unknown at this time and need additional research.

SULFURIC ACID AEROSOL INDUCES CHANGES IN ALVEOLAR SURFACE TENSION IN THE GUINEA PIG BUT NOT IN THE RAT

The purpose of this study was to investigate the effects of an acid aerosol, at high concentration, on the surface properties of the extracellular fluid lining the airways and alveolae. Guinea pigs and rats were exposed to 43 mg/m3 and 94 mg/m3 of sulfuric acid aerosol mass median aerodynamic diameter (MMAD) 0.9 mu m or water aerosol (control), respectively, for 4 hours in an exposure chamber. Surfactant material was extracted from bronchoalveolar lavage fluid (BAL) by centrifugation, and phospholipid, protein, and cell concentrations measured. The extract was reconstituted to 300 mu g/mL of phospholipid, and its surface properties assessed with a captive bubble surfactometer. The minimum surface tension for the acid-exposed guinea pig BAL was 12.1 +/- 8.48 (mean SD) mN/m, which was significantly higher than the control group, 2.0 +/- 0.43 (mean SD) mN/m, or the acid-exposed rats, 1.29 +/- 0.11 (mean SD). The change in film area obtained by compressing the film from equilibrium surface tension (25 mN/m) to its minimum value (gamma n) was 62.9 +/- 13.83 mi (meanSD)% for acid-exposed guinea pigs, compared to 16. 35.77 (meanSD)% for the control guinea pigs. The most sensitive index of surfactant inhibiion was found to be the maximum film compressibility (C) of the compression isotherm. This index was 119 times greater for the acid max exposed guinea pigs compared to control animals. These abnormalities were associated with an elevation of total protein (0.95 +/- 0.33 [mean SD] mg/mL compared to 0.13 +/- 0.03 [meanSD] mg/mL in controls) and polymorphonuclear leucocytes in the BAL. There was no change in total phospholipids. By contrast BAL retrieved from rats exposed to approximately twice the concentration of acid aerosol showed no cellular nor biochemical abnormalities and its surface tension properties were normal. We conclude that the abnormalities of surfactant activity in the acid- exposed guinea pigs result from the cellular and humoral responses of acute lung injury rather than a direct effect of acid.

Submicrometer Aerosol Generator Development for the U.S. Environmental Protection Agency's Human Exposure Laboratory

A submicrometer aerosol generation unit was developed for use in the U.S. Environmental Protection Agency's new air pollution exposure chambers located on the campus of the University of North Carolina at Chapel Hill. The aerosol mass median aerodynamic diameter and mass concentration are operator-selected, ranging from 0.1 to 1.0 μm and from 0 to 2 mg/m3, respectively. The aerosol was to have a geometric standard deviation (GSD) of < 1.5. Two-fluid nebulization was selected to generate water-soluble aerosols. Multiple Collison-type nozzles are used to create a polydisperse droplet cloud. Aerosol uniformity is improved by removing the large droplets from the original distribution by passing the aerosol through an external impaction device. Variations in the solvent-solute ratio, nebulizer driving pressure, impactor cut-point size, and number of nozzles are used to control the final aerosol size and mass concentration. Aerosol size distributions were determined with an electrical aerosol analyzer and a low-pressure impactor. By means of data obtained by testing several experimental nebulizers, a 48-nozzle prototype submicrometer aerosol generator was designed, constructed, and tested. The GSD of the aerosol produced ranged from 1.4 to 1.6 and the mass output, upon generator replication, can satisfy maximum exposure chamber demands.

Particle size study of nine metered dose inhalers, and their deposition probabilities in the airways

This study deals with the particle size measurement of nine aerosol metered dose inhalers. Calibration was made possible by the use of a laser particle velocimeter (aerodynamic Particle Sizer from TSI). The count median aerodynamic diameters (CMAD) show little variation, from 0.63 to 0.73 micron, with standard deviations (sigma g) between 1.2 and 1.8. Aerodynamic diameter aerosol diagram analysis showed multimodal mass distribution for all the tested dose inhalers. Calculations for the airway deposition probabilities (extrathoracic, tracheobronchial and alveolar) refer to the studies made by W. Stahlhofen and co-workers. As most aerosol metered dose inhalers have a predominantly bronchial therapeutic destination, the deposition at the bronchial level could be enhanced with the following parameters: inspired volume of 1500 ml, inspiratory time of 2 sec, aerosol mass median aerodynamic diameter (MMAD) of 7.5 microns, with a monodispersed distribution. The respective influences of the excipients and propellents used for the aerosolization of these dose metered inhalers are also discussed.

Relationship between fluid bed aerosol generator operation and the aerosol produced.

The relationships between bed operation in a fluid bed aerosol generator and aerosol output were studied. A two-inch diameter fluid bed aerosol generator (FBG) was constructed using stainless steel powder as a fluidizing medium. Fly ash from coal combustion was aerosolized and the influence of FBG operating parameters on aerosol mass median aerodynamic diameter (MMAD), geometric standard deviation (sigma g) and concentration was examined. In an effort to extend observations on large fluid beds to small beds using fine bed particles, minimum fluidizing velocities and elutriation constant were computed. Although FBG minimum fluidizing velocity agreed well with calculations, FBG elutriation constant did not. The results of this study show that the properties of aerosols produced by a FBG depend on fluid bed height and air flow through the bed after the minimum fluidizing velocity is exceeded.