Aerodynamic Size Research Articles

A Spray-Dried Combination of Capreomycin and CPZEN-45 for Inhaled Tuberculosis Therapy

Tuberculosis (TB) remains the single most serious infectious disease attributable to a single-causative organism. A variety of drugs have been evaluated for pulmonary delivery as dry powders: capreomycin sulfate has shown efficacy and was safely delivered by inhalation at high doses to human volunteers, whereas CPZEN-45 is a new drug that has also been shown to kill resistant TB. The studies here combine these drugs—acting by different mechanisms—as components of single particles by spray-drying, yielding a new combination drug therapy. The spray-dried combination powder was prepared in an aerodynamic particle size range suitable for pulmonary delivery. Physicochemical storage stability was demonstrated for a period of 6 months. The spray-dried combination powders of capreomycin and CPZEN-45 have only moderate affinity for mucin, indicating that delivered drug will not be bound by these mucins in the lung and available for microbicidal effects. The pharmacokinetics of disposition in guinea pigs demonstrated high local concentrations of drug following direct administration to the lungs and subsequent systemic bioavailability. Further studies are required to demonstrate the in vivo efficacy of the combination to confirm the therapeutic potential of this novel combination.

Carrier-free combination dry powder inhaler formulation of ethionamide and moxifloxacin for treating drug-resistant tuberculosis

This study aimed to develop a combination dry powder formulation of ethionamide and moxifloxacin HCl as this combination is synergistic against drug-resistant Mycobacterium tuberculosis (Mtb). L-leucine (20% w/w) was added in the formulations to maximize the process yield. Moxifloxacin HCl and/or ethionamide powders with/without L-leucine were produced using a Buchi Mini Spray-dryer. A next generation impactor was used to determine the in vitro aerosolization efficiency. The powders were also characterized for other physicochemical properties and cytotoxicity. All the spray-dried powders were within the aerodynamic size range of <5.0 µm except ethionamide-only powder (6.0 µm). The combination powders with L-leucine aerosolized better (% fine particle fraction (FPF): 61.3 and 61.1 for ethionamide and moxifloxacin, respectively) than ethionamide-only (%FPF: 9.0) and moxifloxacin-only (%FPF: 30.8) powders. The combination powder particles were collapsed with wrinkled surfaces whereas moxifloxacin-only powders were spherical and smooth and ethionamide-only powders were angular-shaped flakes. The combination powders had low water content (<2.0%). All the powders were physically stable at 15% RH and 25 ± 2 °C during 1-month storage and tolerated by bronchial epithelial cell-lines up to 100 µg/ml. The improved aerosolization of the combination formulation may be helpful for the effective treatment of drug-resistant tuberculosis. Further studies are required to understand the mechanisms for improved aerosolization and test the synergistic activity of the combination powder.

Safety, Tolerability, and Pharmacokinetics of a New Formulation of Nemiralisib Administered via a Dry Powder Inhaler to Healthy Individuals

PurposeNemiralisib, a phosphoinositide 3-kinase δ inhibitor, is being investigated as an immunomodulatory agent with anti-inflammatory properties in chronic obstructive pulmonary disease. This study evaluated the pharmacokinetic (PK) properties and safety of a new formulation of nemiralisib that contains 0.4% magnesium stearate. MethodsIn this randomized, double-blind, parallel-group study, healthy individuals received a single dose of 500 or 750 μg of nemiralisib administered via the Ellipta dry powder inhaler (DPI) (n = 6 in each treatment group). Aerodynamic particle size distribution (APSD) data comparing previous and new formulations were available before the study. Serial PK analyses for plasma exposure and safety assessments were performed during the first 24 h after dosing, with follow-up measurements on days 3 and 6 in clinic. FindingsAPSD had increases of approximately 6-fold and 2-fold in very fine particle mass and fine particle mass over the previous (Diskus) formulation. In humans, systemic exposure (AUC) was greater after inhalation of 750 versus 500 μg of nemiralisib (AUC0–t: 17,200 h∙pg/mL; 95% CI, 10,900–27,200 h∙pg/mL and 13,100; 95% CI, 8130–21,000 h∙pg/mL, respectively). A low frequency of individual adverse events and no serious adverse events were reported after both doses. ImplicationsAfter single-dose inhalation of 500 and 750 μg of nemiralisib from the Ellipta DPI in healthy individuals, plasma PK data were well defined, and as predicted based on previous PK and APSD data, exposure was increased with the new formulation. Nemiralisib was well tolerated with no new safety issues identified. These data supported progression of nemiralisib to a Phase IIb study in patients with chronic obstructive pulmonary disease. ClinicalTrials.gov identifier: NCT03189589.

The Influence of Electrostatic Controls on MDI Size Distribution Measurements

Cascade impactor testing is widely used to characterize the aerodynamic particle-size distribution of metered dose inhaler aerosols. Charge is often imparted to MDI aerosols by triboelectrification as formulation rapidly travels through the valve stem and actuator during atomization. The presence of charge on MDI aerosols can impact the accuracy and reproducibility of APSD measurements made using cascade impactors. The aerodynamic particle size distribution of three different experimental MDI formulations were evaluated using the Next Generation Impactor with and without incorporating static controls during testing. The static controls included grounding the analyst and the equipment, using an ionizing air blower and anti-static gun, rinsing and allowing the actuator to air dry prior to testing, and having the analyst not wear gloves or touch the USP throat during testing. For all three formulations, tests that used static controls had lower actuator and throat deposition and correspondingly higher deposition on the impactor stages. While static controls influenced the amount of drug entering into the impactor during testing, the static controls did not otherwise change the aerodynamic particle size distribution of these particles. Static controls had the greatest impact on the ethanol-free HFA-227 formulation. For this formulation, there was a 15% difference in throat deposition for the tests that did or did not incorporate static controls. These results demonstrated that electrostatic effects can lead to meaningful variability in cascade impactor test results. Static controls should be considered when developing cascade impactor test methods for MDI products in order to eliminate variability in test results.

Safety of Chinese Patent Medicine for treatment of caner: a review on randomized control trials published in Chinese

Nemiralisib, a phosphoinositide 3-kinase δ inhibitor, is being investigated as an immunomodulatory agent with anti-inflammatory properties in chronic obstructive pulmonary disease. This study evaluated the pharmacokinetic (PK) properties and safety of a new formulation of nemiralisib that contains 0.4% magnesium stearate.In this randomized, double-blind, parallel-group study, healthy individuals received a single dose of 500 or 750 μg of nemiralisib administered via the Ellipta dry powder inhaler (DPI) (n = 6 in each treatment group). Aerodynamic particle size distribution (APSD) data comparing previous and new formulations were available before the study. Serial PK analyses for plasma exposure and safety assessments were performed during the first 24 h after dosing, with follow-up measurements on days 3 and 6 in clinic.APSD had increases of approximately 6-fold and 2-fold in very fine particle mass and fine particle mass over the previous (Diskus) formulation. In humans, systemic exposure (AUC) was greater after inhalation of 750 versus 500 μg of nemiralisib (AUC0–t: 17,200 h∙pg/mL; 95% CI, 10,900–27,200 h∙pg/mL and 13,100; 95% CI, 8130–21,000 h∙pg/mL, respectively). A low frequency of individual adverse events and no serious adverse events were reported after both doses.After single-dose inhalation of 500 and 750 μg of nemiralisib from the Ellipta DPI in healthy individuals, plasma PK data were well defined, and as predicted based on previous PK and APSD data, exposure was increased with the new formulation. Nemiralisib was well tolerated with no new safety issues identified. These data supported progression of nemiralisib to a Phase IIb study in patients with chronic obstructive pulmonary disease. ClinicalTrials.gov identifier: NCT03189589.

Size distribution and chemical composition of indoor and outdoor particles in lab building

Introduction: Exposure to toxic components in indoor PM is associated with a wide spectrum of adverse respiratory and cardiovascular health effects. The fine PM pollution in ambient air is currently a major health concern in Iran and is driving increasing research interest. Due to air pollution in Tehran met-ropolitan, it is necessary to study the concentration and size distribution of particles inside and outside the building. Materials and methods: Hence, for this study, concentration and size distribution of particles matter was calculated with diameters of PM≤0.4, PM0.4-0.7, PM0.7-1.1, PM1.1-2.1, PM2.1-3.3, PM3.3-4.7, PM4.7-7, PM7-11, PM≥11 and TSP during two seasons in the lab building in the Tehran. Measurements on the aerodynamic size of atmospheric aerosols carried with Anderson type 1-ACFM Cascade Impactor with six-stage. The length of each collection period was about 24 h. Results: The results show that the effect of outdoor air pollution on the con-centration of particles in the indoor environment is significant. According to these results, the lowest value is for particles with a diameter greater than 11 µm. the highest value of this ratio is dedicated to PM≤0.4 and with the increase of the aerodynamic diameter of the particles, the I/O decreases as well. A similar trend was recorded for concentration of TSP. The highest difference in the concentration of TSP in indoor and outdoor was 60.25 and 188.36 µg/ m3, respectively. Conclusion: This effect is due to factors such as the lack of standard ventilation, old doors and windows and the life of the building.

The impact of patients' real-life environmental temperature and humidity use conditions of tiotropium dry powder inhaler on its aerosol emission characteristics

IntroductionMany factors can affect dry powder inhalers' (DPIs) aerosol emission and lung deposition. The fluctuation of environmental temperature and relative humidity (RH) that inhalers experience in realistic daily use has not been extensively evaluated. This work aimed to evaluate the delivered dose (DD) and aerodynamic particle size distribution (APSD) of tiotropium Handihaler DPI (H) after exposure to patients' real-life use environments. MethodsEthical approval was obtained to enrol adult patients already using H. Patients who gave written consent were given new H to use and HygroLog temperature and RH data loggers to keep in the vicinity of the given inhaler. The H and HygroLog were returned after 2 weeks. Patient recruitment was done during the summer (HS) and winter (HW). As control, other HC were stored as per the leaflet storage instructions. The Next Generation Impactor was used to evaluate the inhalers. ResultsThe HC were stored under an average of 21.0 °C and 46.9% RH. The patients' HS and HW lived in an average (range) temperature (°C) 23.2 (18.3–38.2) and 17.8 (13.5–24.6), respectively, and RH 50.8% (24.3–65.3%) and 50.4% (30.6–72.4%), respectively. All H groups had comparable environments (p > 0.05). The HC, HS and HW gave similar tiotropium DD (μg) 7.60, 8.01 and 7.61, respectively (p > 0.05). Moreover, the fine particle dose μg (median diameter (μm)) were HC 2.41 (3.84), HS 2.55 (3.81) and HW 2.37 (3.83) (p > 0.05). ConclusionsThe aerosol emission behaviour of tiotropium Handihaler was tolerant to real-life retention environments of patients in Amman, Jordan.

A Laboratory Experiment for the Statistical Evaluation of Aerosol Retrieval (STEAR) Algorithms

We have developed a method for evaluating the fidelity of the Aerosol Robotic Network (AERONET) retrieval algorithms by mimicking atmospheric extinction and radiance measurements in a laboratory experiment. This enables radiometric retrievals that use the same sampling volumes, relative humidities, and particle size ranges as observed by other in situ instrumentation in the experiment. We use three Cavity Attenuated Phase Shift (CAPS) monitors for extinction and University of Maryland Baltimore County’s (UMBC) three-wavelength Polarized Imaging Nephelometer (PI-Neph) for angular scattering measurements. We subsample the PI-Neph radiance measurements to angles that correspond to AERONET almucantar scans, with simulated solar zenith angles ranging from 50 ∘ to 77 ∘ . These measurements are then used as input to the Generalized Retrieval of Aerosol and Surface Properties (GRASP) algorithm, which retrieves size distributions, complex refractive indices, single-scatter albedos, and bistatic LiDAR ratios for the in situ samples. We obtained retrievals with residuals less than 8% for about 90 samples. Samples were alternately dried or humidified, and size distributions were limited to diameters of less than 1.0 or 2.5 μ m by using a cyclone. The single-scatter albedo at 532 nm for these samples ranged from 0.59 to 1.00 when computed with CAPS extinction and Particle Soot Absorption Photometer (PSAP) absorption measurements. The GRASP retrieval provided single-scatter albedos that are highly correlated with the in situ single-scatter albedos, and the correlation coefficients ranged from 0.916 to 0.976, depending upon the simulated solar zenith angle. The GRASP single-scatter albedos exhibited an average absolute bias of +0.023–0.026 with respect to the extinction and absorption measurements for the entire dataset. We also compared the GRASP size distributions to aerodynamic particle size measurements, using densities and aerodynamic shape factors that produce extinctions consistent with our CAPS measurements. The GRASP effective radii are highly correlated (R = 0.80) and biased under the corrected aerodynamic effective radii by 1.3% (for a simulated solar zenith angle of θ ∘ = 50 ∘ ); the effective variance indicated a correlation of R = 0.51 and a relative bias of 280%. Finally, our apparatus was not capable of measuring backscatter LiDAR ratios, so we measured bistatic LiDAR ratios at a scattering angle of 173 degrees. The GRASP bistatic LiDAR ratios had correlations of 0.71 to 0.86 (depending upon simulated θ ∘ ) with respect to in situ measurements, positive relative biases of 2–10%, and average absolute biases of 1.8–7.9 sr.

Measurement of Aerodynamic Particle Size Distribution of Orally Inhaled Products by Cascade Impactor: How to Let the Product Specification Drive the Quality Requirements of the Cascade Impactor.

The multi-stage inertial cascade impactor is used to determine the mass-weighted aerodynamic particle size distribution (APSD) as a critical quality attribute for orally inhaled products (OIPs). These apparatuses progressively size-fractionate the aerosol passing through a series of stages containing one or more nozzles, by increasing particle velocity. Nozzle sizes for a given multi-nozzle stage can be described collectively by effective diameter ([Formula: see text]), related to the cut-point size, providing the link to aerodynamic diameter. Users undertake stage mensuration periodically to assure that each stage [Formula: see text] remains within the manufacturer's tolerance, but there is no guidance on how frequently such checks should be made. We examine the philosophy that particle size-related specifications of the OIP should determine when an impactor is mensurated. Taking an example of a dry powder inhaler-generated aerosol sampled via a Next Generation Impactor with pre-separator, we find that there are only three critical stages that could have a material effect on the measured APSD specified as four groupings of stages following current regulatory practice. Furthermore, [Formula: see text] for the most critical stage having the smallest nozzle sizes could be relaxed by a factor of four or more before risking an inability to measure the mass fraction of API in the group containing the finest particles to a specification within ± 10% of nominal. We therefore conclude that users should consider letting the specification for APSD performance of an OIP in terms of accepted stage groupings drive the impactor quality requirements and frequency that stage mensuration is undertaken.

Quantification of Size Segregated Particulate Matter Deposition in Human Airways

Background: Air pollution has become a significant concern in both urban and rural sectors due to its catastrophic effect on human health and the environment. Particulate matter (PM) is crucial among criteria pollutants and is well correlated with human mortality and morbidity. Based on aerodynamic size, PM is classified into coarse (PM10) and fine (PM2.5 and PM1). A recent study by World Health Organization showed that PM has caused 7 million premature deaths globally. Also, the International Agency for Research on Cancer (IARC) identified PM as carcinogenic as it is directly related to lung cancer. Human airway is the primary pathway for PM to enter the human body. Hence the study on coarse and fine PM deposition in the human respiratory tract is essential for health risk assessments. Materials and Methods: Hourly measurements of PM10, PM2.5 and PM1 are measured during a winter using Grimm aerosol spectrometer near an arterial roadside in Chennai city of Tamil Nadu, India. PM deposition in the human airway is investigated using the Multiple-Path Particle Deposition Model (MPPD) version 3.04. In MPPD model, the stochastic structure which depicts the real human lung is considered. The deposition in MPPD model is assessed for three size fractions, i.e. PM10, PM2.5 and PM1 under different breathing scenarios viz. nasal, oral, and oronasal. Results: Highest total deposited mass rate obtained from the MPPD model for PM10, PM2.5, and PM1 are 942 ng min-1, 345 ng min-1, and 104 ng min-1, respectively. The maximum deposited mass rate is also assessed in the head (PM10 = 904 ng min-1; PM2.5 = 244 ng min-1; PM1 = 57 ng min-1), tracheobronchial (PM10 = 284 ng min-1; PM2.5 = 60 ng min-1; PM1 = 24 ng min-1) and pulmonary (PM10 = 32 ng min-1; PM2.5 = 89 ng min-1; PM1 = 27 ng min-1) regions. In the head region, maximum deposition is caused by nasal breathing; whereas, tracheobronchial (TB) and pulmonary regions, the oral breathing leads to higher deposition. Results also showed that for all PM sizes the lobe wise depositions are in the following order: right upper > left lower > left upper > right middle > right lower. Further, the airway clearance results indicated that PM removal is faster in the TB region than the alveolar region. Conclusion: PM10 has a higher deposition in the head region whereas PM2.5 and PM1 deposition is higher in the TB and pulmonary regions. This indicates that PM deposition inside lungs is influenced by its size and several other deposition mechanisms viz. inertial impaction, sedimentation, diffusion and interception. Further, this study results can be utilized for assessing health risks such as oxidative potential and toxicity of deposited PM.

Characterization of a dextran-budesonide prodrug for inhalation therapy

Reducing the dosing frequency of corticosteroids may increase compliance and increase pulmonary targeting. The objective of this study was to evaluate whether a high molecular weight dextran-budesonide conjugate might be suitable for pulmonary slow release of the otherwise fast absorbed budesonide. An array of dextran-spacer-budesonide conjugates was prepared that differed in the molecular weight of dextran (20 kDa or 40 kDa) and the length of the dicarboxylic spacer (succinic, glutaric, and adipic anhydride). The conjugates were characterized for identity by proton nuclear magnetic resonance (1H NMR) and Fourier-transform infrared spectroscopy (FTIR), the degree of dextran-hydroxyl conjugation, purity, and physiological activation (release of budesonide). The 40 kDa dextran-succinate-budesonide conjugate was formulated as a dry powder for pulmonary delivery and characterized for particle size distribution, particle morphology, and aerodynamic particle size. The degree of substitution (grams of budesonide in 100 g of conjugate) ranged from 4 to 10% for all six dextran-spacer-budesonide conjugates. Incubation at 37 °C and pH 7.4 in phosphate buffered saline resulted in release of 25–75% of the conjugated budesonide over an 8-hour period with the rate of release increasing with molecular weight of dextran and the length of the spacer. Modeling of the concentration time profiles of the released budesonide and budesonide-21-hemisucinate in phosphate buffered saline, suggested that budesonide is generated either directly or via the budesonide-21-hemisucinate pre-cursor. Data also suggested that the rate of budesonide generation likely depends on the position of budesonide on the dextran molecule. Spray-drying the 40 kDa dextran-succinate-budesonide produced respirable particles of the conjugate with a mass median aerodynamic particle size (MMAD) of 4 μm. The slow generation of budesonide from the chemical delivery system might further improve the pharmacological profile of budesonide.

On the Effective Density and Fractal–Like Dimension of Diesel Soot Aggregates as a Function of Mobility Diameter

A new technique is proposed for the assessment of aggregate morphology based on combined information of aerodynamic and mobility size distributions. Instead of formulating a complex inverse problem having aggregate morphology as unknown, the actual problem is separated to two stages. The aerodynamic distribution is determined directly by the electric low pressure impactor (ELPI) data whereas the morphology is independently assessed by matching the distribution arises from ELPI and from scanning mobility particle sizer (SMPS). The advantage of this approach is that it can estimate different fractal dimension for different aggregate size. The approach is applied to soot aggregates from three different diesel engines. In all cases, a non-monotonic behavior of fractal dimension versus aggregate size is observed. In particular, the fractal dimension initially decreases and then increases (passing through a minimum) as the mobility diameter increases.

1262. Investigation and Mitigation of a Multi-Species Outbreak of Invasive Fungal Infections on Two Oncology Wards

BackgroundWe investigated an increase in hospital-acquired invasive fungal infections (HA-IFI) among patients admitted to adjacent hematopoietic stem cell transplant (HSCT) and hematologic malignancy (HM) wards in the setting of a large construction project adjacent to the hospital.MethodsWe defined cases of HA-IFI as HSCT or HM patients who met criteria for probable or proven IFI with suspected inpatient acquisition. We hypothesized that outside construction increased internal particle/spore counts despite preconstruction prevention efforts. The environmental investigation included an evaluation of storage/distribution of supplies, air handler inspections, air particulate counts, and bioaerosol sampling of airborne fungal spores.ResultsFrom October 2017 to January 2018, 11 cases of probable/proven HA-IFI occurred (Figure 1). Infections caused by multiple pathogens (Figure 2) ranged from pneumonia and sinusitis to disseminated disease. Bioaerosol sampling and particulate counts were taken from unit corridors and rooms on both wards. Fungal species identified via bioaerosol sampling were primarily Penicillium and Cladosporium species, with rare Aspergillus identified. Geometric mean particulate counts of 1 μm aerodynamic size were reduced by 88% and 75% on the HM and HSCT wards, respectively (Figure 3). Interventions on these units occurred from January to February 2018 and included: limiting the frequency of outdoor air exchanges on air handler units, reinforcing seals around entrance doors, adjusting room pressurizations to be positive or neutral on HM ward (HSCT ward is already a positive pressure environment), eliminating cardboard associated with supplies, and requiring N95 respirators for HSCT patients when off unit. After implementing these environmental control measures, we have not identified additional cases of HA-IFI on these wards.ConclusionWe describe a multispecies outbreak of IFI in HM and HSCT patients potentially associated with new building construction that occurred despite implementation of multiple pre-construction control efforts. A multifaceted strategy to improve air quality and protect patients on and off high-risk units was needed to mitigate the outbreak. Disclosures All authors: No reported disclosures.

Drug Output and Aerosol Characteristics of Different Jet Nebulisers for Adults While Simulating the Nebulisation of Salbutamol

Successful inhalation therapy with nebulisers depends on the amount and quality of the aerosol. Choosing a nebuliser requires knowledge of relevant aerosol characteristics. We analysed the aerosol performance of 9 commercially available jet nebulisers in 2 in vitro simulation models by assessing the aerosol delivery of albuterol (Sultanol forte® Inhalation Solution 2.5 mg/2.5 ml; GSK) over 4 minutes. The output parameters were analysed with PARI Compas II breath simulator mimicking an adult breathing pattern (Ph.Eur.9.0; n = 5/6 nebulisation), and the aerodynamic particle size distribution was determined by the Next Generation Impactor (Ph.Eur.9.0, Copley Scientific; n = 3 nebulisation). The aerosol performance of the devices differed considerably. The DDR varied from 196 µg/min (PARI LC Sprint (blue)) to 67 µg/min (MIDINEB). The Respirable Drug Delivery Rate (RDDR), calculated from the DDR and the Fine Particle Fraction ≤ 5 µm, varied by a factor of 3.5 between the nebulisers tested. The results of the in vitro simulation studies can be utilised to select an appropriate nebuliser for the individual patient. In order to enhance therapeutic efficacy and patient compliance, a nebuliser with a high RDDR should be selected.

Intranasal Filtration of Inhaled Aerosol in Human Subjects as a Function of Nasal Pressure Drop.

Intersubject variability in nasal deposition of inhaled aerosol is significant because of the differences in nasal anatomy and breathing rate. The notable limitation of the majority of previously developed predictive correlations is including a limited number of subjects. A few recent studies have considered a wide age range of subjects, but the resulting correlations require the knowledge of the dimensions of the nasal airways and the properties of inhaled gas. In this study empirical correlations are proposed to predict aerosol deposition in nasal airways of subjects of different age as a function of intranasal pressure drop and the particle aerodynamic diameter. The experimental nasal deposition and pressure drop data in anatomically correct nasal replicas of 5 adults, 13 children aged 4-14 years, and 11 infants aged 3-18 months were reanalyzed. The range of aerodynamic diameter was 0.5-5.3 μm and physiological breathing at different activity levels was considered. Correlations between nasal deposition and a deposition parameter including the aerodynamic size of inhaled aerosol and nasal pressure drop were developed with nonlinear least-square algorithms. The general coefficient of determination r2 was used to evaluate the fitting accuracy for each correlation. New correlations were developed to predict the intranasal deposition of particles as a function of intranasal pressure drop and particle size for pediatric and adult subjects. The intranasal deposition fraction in adults and children can be calculated using the same correlation, whereas the intranasal deposition in infants followed a different trend line because of higher intranasal pressure drop in infants. This study was the first offering correlations to predict intranasal deposition in multiple age groups using only the aerodynamic size of inhaled aerosol and nasal pressure drop. These correlations include the effects of intersubject variability in nasal deposition within each age group and among different age groups.

Development of a novel digital breath-activated inhaler: Initial particle size characterization and clinical testing

BackgroundDelivery of inhaled respiratory medications have been associated with variable delivery of drug due to errors in device operations and have not been designed to monitor true delivery of medication. A fully digital breath-activated inhaled (DBAI) delivery platform has been developed with integrated firmware and software to address these limitations. Methodsthe device was designed to produce similar aerosol particle output to a marketed albuterol MDI and to the albuterol/ipratropium combination in a soft mist inhaler (SMI). Cascade impactor studies were conducted to demonstrate comparable aerodynamic particle size distribution (APSD) metrics. Efficacy was evaluated by pharmacodynamic studies involving spirometry in two separate protocols with adult subjects having COPD (albuterol DBAI vs. albuterol MDI – Study A, albuterol/ipratropium DBAI single arm – Study B). ResultsThe total emitted doses (TED) were 81.9 ± 10.3, 109.3 ± 15.0 and 121.9 ± 7.0 μg/actuation for the DBAI, SMI and MDI respectively, and the fine (respirable) particle doses (FPD) were 56.2 ± 6.0, 61.7 ± 5.5 and 79.4 ± 2.7 μg/actuation. MMADs for albuterol sulfate were 1.93 ± 0.11, 1.75 ± 0.19, and 2.65 ± 0.05 μm for the DBAI, Respimat soft mist inhaler (SMI) and MDI respectively. The corresponding GSDs were 1.96 ± 0.16, 2.79 ± 0.25, and 1.48 ± 0.02 μm. The corresponding respirable fractions were 68.7 ± 3.2%, 57.3 ± 10.5%, and 65.2 ± 2.4%. Spirometric study A enrolled 23 subjects (age 64 ± 7.3 years, 39% male, FEV1 45 ± 14% predicted). Study B enrolled 23 subjects (age 65 ± 8.6 years, 43% male, FEV1 47 ± 10% predicted). For Study A, FEV1 at 20 min post-dose improved by 120 (167) mL (p = 0.002) for the DBAI device and 109 (183) mL (p = 0.008) for the MDI device (p = 0.86 for between group differences). For Study B, FEV1 (20 min post-dose) improved by 216 (126) mL (p < 0.001). ConclusionThe DBAI generated highly respirable aerosols containing albuterol sulfate that were similar to the MDI and SMI in respirable fraction but lower in dose. Subsequent pharmacodynamic studies delivering albuterol sulfate alone and in combination with ipratropium bromide confirmed similar responses for the DBAI compared with the other inhalers, which could possibly be related to a response ceiling. The DBAI breath-activated capability combined with the ability to monitor actual delivery of medication may improve effectiveness by overcoming patient miscoordination.

Uncertainty Estimation in PM10 Mass Measurements

Mass measurements of particles in the atmosphere are important for regulatory and scientific purposes. In nearly all of the countries, particulates ≤ 10 µm in aerodynamic size (PM10) are one of the most significant parameters of National Ambient Air Quality Standards (NAAQS). In India, as given in NAAQS, the PM10 regulatory limit is 60 µg m−3 which is based on the annual mean weight of samples (minimum 104) annually at a specific site taken for two/three days in a week for 24 h. In this paper, the components of uncertainty involved in the filter-based sampling of PM10 along with the gravimetric determination of mass have been calculated. As per the EPA guidelines, PM10 mass was monitored for a year at NPL (National Physical Laboratory), New Delhi from January 2014 to January 2015. The 24-h time-weighted mean mass concentration (n = 104) for one-year measurement varied from 32.5 to 480.2 µg m−3.During the study, high mass loading was observed in the month of December to February. In general, the flow rate of the sampling has been reported to be major uncertainty component in size-segregated PM sampling. In this work, the flow rate of the sampling (90.4%) and charge effect of the filter (6.7%) had the major contribution in the total uncertainty budget of PM10 mass measurement. Rest of the uncertainty components, e.g., balances (0.39%) and conditioning of filter (2.39%), had the least contribution.

Development of polydisperse aerosol generation and measurement procedures for wind tunnel evaluation of size-selective aerosol samplers

Accurate development and evaluation of inlets for representatively collecting ambient particulate matter typically involves use of monodisperse particles in aerosol wind tunnels. However, the resource requirements of using monodisperse aerosols for inlet evaluation creates the need for more rapid and less-expensive techniques to enable determination of size-selective performance in aerosol wind tunnels. The goal of recent wind tunnel research at the U.S. EPA was to develop and validate the use of polydisperse aerosols which provide more rapid, less resource-intensive test results which still meet data quality requirements necessary for developing and evaluating ambient aerosol inlets. This goal was successfully achieved through comprehensive efforts regarding polydisperse aerosol generation, dispersion, collection, extraction, and analysis over a wide range of aerodynamic particle sizes. Using proper experimental techniques, a sampler's complete size-selective efficiency curve can be estimated with polydisperse aerosols in a single test, as opposed to the use of monodisperse aerosols which require conducting multiple tests using several different particle sizes. While this polydisperse aerosol technique is not proposed as a regulatory substitute for use of monodisperse aerosols, the use of polydisperse aerosols is advantageous during an inlet's development where variables of sampling flow rate and inlet geometry are often iteratively evaluated before a final inlet design can be successfully achieved. Complete Standard Operating Procedures for the generation, collection, and analysis of polydisperse calibration aerosols are available from EPA as downloadable files. The described experimental methods will be of value to other researchers during development of ambient sampling inlets and size-selective evaluation of the inlets in aerosol wind tunnels.

Pharmacokinetics and pharmacodynamics of high doses of inhaled dry powder drugs

For many years, administration of drugs by inhalation has been the mainstay treatment for obstructive respiratory disorders such as asthma and chronic obstructive pulmonary disease. Antibiotics and other drugs have been administered for decades as aerosols to treat other pulmonary disease in a clinical setting, but it was until the early 1980’s that colistin was formally marketed as a solution for nebulization in Europe (Colomycin, Pharmax, Bexley). The solubility of other drugs and the size of the dose required to achieve therapeutic concentrations at the site of action, made treatment times long and difficult to be performed at home. High dose dry powder delivery is a potentially effective way to deliver low potency drugs such as antibiotics. There are three major barriers to achieving the desired pharmacodynamic effect with these compounds: aerosol delivery, lung deposition and clearance. The powder formulation and device technology influence aerosol generation and may influence the size of the dose that can be achieved by inhalation in one puff. The site of deposition in the lungs is dictated by mechanisms of deposition which are influenced by the aerosol properties, particularly aerodynamic particle size distribution and the anatomy and physiology of the lungs. Finally, mechanisms of clearance dictate the local and systemic disposition of the drug, which in turn affects its pharmacokinetics and ultimately the pharmacodynamic effect and efficacy of treatment. Each of these factors will be considered and the implications for antimicrobial agent delivery as a high dose delivery example will be given.

Ash cenosphere fragmentation during pulverised pyrite combustion: Importance of cooling

This paper as the first time in the field reports the direct experimental evidence for demonstrating the important role of cooling in ash cenosphere fragmentation using a simple but unique combustion system. The combustion system used pulverised pyrite (38–45 µm) for combustion in drop-tube furnace under designed conditions (gas temperature: 1000 °C; residence time: 1.2 s), which produced dominantly ash cenosphere particles or fragments. The combustion products were quenched under various cooling conditions (represented by nominal cooling rates of 6400–11,800 °C/s) for sampling. The results show that increasing cooling rate from 6400 to 11,800 °C/s substantially intensifies ash cenosphere fragmentation. Such enhanced ash cenosphere fragmentation leads to a significant shift in the particle size distribution of ash collected in the cyclone (>10 µm) to much smaller sizes. It also produces considerably more particulate matter (PM) with aerodynamic sizes less than 10 µm (i.e., PM10) that consists of dominantly PM with aerodynamic sizes between 1 and 10 µm (i.e., PM1–10) and some PM with aerodynamic sizes less than 1 µm (i.e., PM1). It is further noted that the PM1 is mainly PM with aerodynamic sizes between 0.1 and 1 µm (i.e., PM0.1–1) and to a considerably lesser extent PM with aerodynamic sizes less than 0.1 µm (i.e., PM0.1). Chemical analyses further show that both ash and PM samples contain only Fe2O3, indicating that complete consumption of sulphur and full oxidation of iron have been achieved during pulverised pyrite combustion under the conditions.