Regional Lung Deposition Research Articles

IBCS: 3. A Biopharmaceutics Classification System for Orally Inhaled Drug Products.

In this article, we specify for the first time a quantitative biopharmaceutics classification system for orally inhaled drugs. To date, orally inhaled drug product developers have lacked a biopharmaceutics classification system like the one developed to navigate the development of immediate release of oral medicines. Guideposts for respiratory drug discovery chemists and inhalation product formulators have been elusive and difficult to identify due to the complexity of pulmonary physiology, the intricacies of drug deposition and disposition in the lungs, and the influence of the inhalation delivery device used to deliver the drug as a respirable aerosol. The development of an inhalation biopharmaceutics classification system (iBCS) was an initiative supported by the Product Quality Research Institute (PQRI). The goal of the PQRI iBCS working group was to generate a qualitative biopharmaceutics classification system that can be utilized by inhalation scientists as a "rule of thumb" to identify desirable molecular properties and recognize and manage CMC product development risks based on physicochemical properties of the drug and the deposited lung dose. Herein, we define the iBCS classes quantitatively according to the dose number and permeability. The proposed iBCS was evaluated for its ability to categorize marketed inhaled drugs using data from the literature. The appropriateness of the classification of each drug was assessed based on published development, clinical and nonclinical data, and mechanistic physiologically based biopharmaceutics modeling. The inhaled drug product development challenges for each iBCS classification are discussed and illustrated for different classes of marketed inhaled drugs. Finally, it is recognized that discriminatory laboratory methods to characterize regional lung deposition, dissolution, and permeability will be key to fully realizing the benefits of an iBCS to streamline and derisk inhaled drug development.

Performance and Feasibility of Therapeutic Vibrating Mesh Nebulizer for Ventilation Lung Scan

PurposeThis study aimed to evaluate the performance of a therapeutic vibrating mesh-type nebulizer for the pulmonary delivery of radioaerosols for lung scintigraphy in healthy subjects.MethodsSix healthy subjects (mean age of 28.7 ± 6.2 years) inhaled 2 mL Tc-99m diethylenetriaminepentaacetic acid and normal saline solution (20 mCi) via a therapeutic vibrating mesh-type nebulizer (DK010, DELBio, Taipei, Taiwan). The nebulizer’s mass median aerodynamic diameter was between 2.3 and 5.0 µm (3.47 ± 0.37 µm), and the nebulization rate was greater than 0.2 mL/min. Scintigraphy was performed to count radioaerosols in the regions of interest to determine the total and regional lung deposition and extrathoracic airway deposition of aerosols, penetration of aerosols, and radioactivity count balance (RCB).ResultsThe total lung depositions of aerosols were 21.2% ± 5.2% (% ex-valve dose), 27.4% ± 8.0% (% ex-device dose), and 13.8% ± 4.1% (% initial dose) in the nebulizer. The extrathoracic airway deposition was 4.8% ± 1.1%. The RCB was 5.4% ± 3.0%. The ratio of outer over inner lung deposition (O/I ratio, or penetration index) was 1.89 ± 0.55.ConclusionThe delivery efficiency and penetration of aerosols to the peripheral lung, which were achieved by the DELBio DK010 vibrating mesh-type nebulizer, were similar to the commercialized jet-type nebulizers dedicated for radioaerosol lung scintigraphy nebulizer. The therapeutic vibrating mesh-type nebulizer (DELBio DK010) is feasible for radionuclide lung ventilation scintigraphy.

Design of In Vivo Deposition and Clearance Experiments.

Experiments designed to image in vivo deposition of radiolabel-drug mixtures are useful for estimating inhaled drug delivery and for assessing bioequivalence of delivery devices. Validation of the radiolabel-drug mixture is vital to ensure that subsequent imaging is reflective of drug deposition. Application of gamma attenuation corrections allows both total and regional lung deposition of drug to be estimated by two-dimensional (2D) imaging. Imaging methods are also useful for measuring in vivo mucociliary clearance (MC) function. Such measures allow assessment of the efficacy of drugs designed to improve clearance of airway secretions in airway disease. MC rates can be measured by controlled inhalation and gamma camera monitoring of radiolabeled aerosols containing non-permeating tracers. While in vivo MC rates reflect the function of the mucociliary apparatus, they are also dependent on regional deposition patterns of the inhaled aerosol.

IBCS: 2. Mechanistic Modeling of Pulmonary Availability of Inhaled Drugs versus Critical Product Attributes.

This work is the second in a series of publications outlining the fundamental principles and proposed design of a biopharmaceutics classifications system for inhaled drugs and drug products (the iBCS). Here, a mechanistic computer-based model has been used to explore the sensitivity of the primary biopharmaceutics functional output parameters: (i) pulmonary fraction dose absorbed (Fabs) and (ii) drug half-life in lumen (t1/2) to biopharmaceutics-relevant input attributes including dose number (Do) and effective permeability (Peff). Results show the nonlinear sensitivity of primary functional outputs to variations in these attributes. Drugs with Do < 1 and Peff > 1 × 10–6 cm/s show rapid (t1/2 < 20 min) and complete (Fabs > 85%) absorption from lung lumen into lung tissue. At Do > 1, dissolution becomes a critical drug product attribute and Fabs becomes dependent on regional lung deposition. The input attributes used here, Do and Peff, thus enabled the classification of inhaled drugs into parameter spaces with distinctly different biopharmaceutic risks. The implications of these findings with respect to the design of an inhalation-based biopharmaceutics classification system (iBCS) and to the need for experimental methodologies to classify drugs need to be further explored.

In Vitro Estimation of Tracheobronchial and Alveolar Doses Using Filters

To date, in vitro estimation of doses delivered by an inhaler to the different major regions of the lung has required combining particle size measurements of the inhaled aerosol with in silico deposition models. Such a two step process is labor and time intensive. Here, we describe instead the development of an apparatus that allows direct estimation of regional lung deposition by measurement of doses collected on purpose-built metal grid filters that mimic tracheobronchial deposition efficiency. Placing these filters downstream of the Alberta Idealized Throat and upstream of a final filter allows collection of doses depositing in the extrathoracic, tracheobronchial and alveolar regions. Artificial electrostatic deposition on the metal tracheobronchial filters is prevented by a custom inline electrostatic neutralizer. We use the resulting apparatus to estimate regional deposition with a variety of dry powder inhalers during realistic, time-varying inhalation maneuvers and three pMDIs with a constant flow rate of 30 l/min. These results are compared to those obtained with the traditional two step approach that combines cascade impaction with a regional deposition model. Good agreement is found between the two approaches, indicating that the present direct method may be an efficient, time-saving alternative method for in vitro estimation of regional lung doses.

A scintigraphy study of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler in patients with moderate-to-very severe chronic obstructive pulmonary disease

BackgroundTriple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting β2-agonists (ICS/LAMA/LABA) is recommended for patients with chronic obstructive pulmonary disease (COPD) with continued symptoms or exacerbations, despite treatment with LAMA/LABA or ICS/LABA. The pulmonary, extrathoracic, and regional lung deposition patterns of a radiolabeled ICS/LAMA/LABA triple fixed-dose combination budesonide/glycopyrrolate/formoterol fumarate (BGF 320/18/9.6 μg), delivered via a single Aerosphere metered dose inhaler (MDI) were previously assessed in healthy volunteers and showed good deposition to the central and peripheral airways (whole lung deposition: 37.7%). Here, we report the findings assessing BGF in patients with moderate-to-very severe COPD.MethodsThis phase I, single-dose, open-label gamma scintigraphy imaging study (NCT03906045) was conducted in patients with moderate-to-very severe COPD. Patients received two actuations of BGF MDI (160/9/4.8 μg per actuation) radiolabeled with technetium‑99‑pertechnetate, not exceeding 5 MBq per actuation. Immediately following each inhalation, patients performed a breath-hold of up to 10 s, then exhaled into an exhalation filter. Gamma scintigraphy imaging of the anterior and posterior views of the lungs and stomach, and a lateral head and neck view, were performed immediately after exhalation. The primary objective of the study was to assess the pulmonary deposition of BGF. Secondary objectives assessed the deposited dose of radiolabeled BGF in the oropharyngeal and stomach regions, on the actuator, and on the exhalation filter in addition to regional airway deposition patterns in the lungs.ResultsThe mean BGF emitted dose deposited in the lungs was 32.1% (standard deviation [SD] 15.6) in patients with moderate-to-very severe COPD, 35.2% (SD 12.8) in patients with moderate COPD, and 28.7% (SD 18.4) in patients with severe/very severe COPD. Overall, the mean normalized outer/inner ratio was 0.55 (SD 0.19), while the standardized central/peripheral ratio was 2.21 (SD 1.64).ConclusionsRadiolabeled BGF 320/18/9.6 μg was efficiently delivered and deposited throughout the entire lung, including large and small airways, in patients with moderate-to-very severe COPD, with similar deposition in patients with moderate COPD and patients with severe/very severe COPD.Trial registration: ClinicalTrials.gov, NCT03906045. Registered 8 April 2019, https://clinicaltrials.gov/ct2/show/NCT03906045

Quantifying Uncertainty in the Residence Time of the Drug and Carrier Particles in a Dry Powder Inhaler

Abstract Dry powder inhalers (DPI), used as a means for pulmonary drug delivery, typically contain a combination of active pharmaceutical ingredients (API) and significantly larger carrier particles. The microsized drug particles—which have a strong propensity to aggregate and poor aerosolization performance—are mixed with significantly large carrier particles that cannot penetrate the mouth-throat region to deagglomerate and entrain the smaller API particles in the inhaled airflow. Therefore, a DPI's performance depends on the carrier-API combination particles' entrainment and the time and thoroughness of the individual API particles' deagglomeration from the carrier particles. Since DPI particle transport is significantly affected by particle-particle interactions, particle sizes and shapes present significant challenges to computational fluid dynamics (CFD) modelers to model regional lung deposition from a DPI. We employed the Particle-In-Cell method for studying the transport/deposition and the agglomeration and deagglomeration for DPI carrier and API particles in the present work. The proposed development will leverage CFD-PIC and sensitivity analysis capabilities from the Department of Energy laboratories: Multiphase Flow Interface Flow Exchange and Dakota UQ software. A data-driven framework is used to obtain the reliable low order statics of the particle's residence time in the inhaler. The framework is further used to study the effect of drug particle density, carrier particle density and size, fluidizing agent density and velocity, and some numerical parameters on the particles' residence time in the inhaler.

Differences between cigarette smoking and biomass smoke exposure: An in silico comparative assessment of particulate deposition in the lungs

Cigarette smoking and biomass smoke are the two main environmental risk factors of chronic obstructive pulmonary disease (COPD) worldwide. However, it remains unclear why these exposures result in two different disease phenotypes. In this study, we assessed the lung deposition from biomass and cigarette smoke exposures and examined whether differences due to inherently different particle size distributions and inhalation conditions may contribute to the differences between biomass- and tobacco-related COPD phenotypes. Using high-fidelity three-dimensional computational fluid-particle dynamics in a representative upper airway geometry, coupled to one-dimensional models of the lower airways, we computed total deposited doses and examined regional deposition patterns based on exposure data from a randomized control trial in Peru and from the literature for biomass and mainstream cigarette smoke, respectively. Our results showed that intrathoracic deposition was higher in cigarette smoking, with 36.8% of inhaled biomass smoke particles and 57.7% of cigarette smoke particles depositing in the intrathoracic airways. We observed higher fractions of cigarette smoke particles in the last few airway generations, which could explain why cigarette smoking is associated with more emphysema than biomass smoke exposure. Mean daily deposited dose was two orders of magnitude higher in cigarette smoking. Lobar distributions of the deposited dose also differed, with the left lower and right upper lobes receiving the highest doses of biomass and cigarette smoke particles, respectively. Our findings suggest that the differences between biomass- and tobacco-related COPD could, at least in part, be due to differences in total and regional lung deposition of biomass and cigarette smoke.

Can Pharmacokinetic Studies Assess the Pulmonary Fate of Dry Powder Inhaler Formulations of Fluticasone Propionate?

In the context of streamlining generic approval, this study assessed whether pharmacokinetics (PK) could elucidate the pulmonary fate of orally inhaled drug products (OIDPs). Three fluticasone propionate (FP) dry powder inhaler (DPI) formulations (A-4.5, B-3.8, and C-3.7), differing only in type and composition of lactose fines, exhibited median mass aerodynamic diameter (MMAD) of 4.5 μm (A-4.5), 3.8 μm (B-3.8), and 3.7 μm (C-3.7) and varied in dissolution rates (A-4.5 slower than B-3.8 and C-3.7). In vitro total lung dose (TLDin vitro) was determined as the average dose passing through three anatomical mouth-throat (MT) models and yielded dose normalization factors (DNF) for each DPI formulation X (DNFx = TLDin vitro,x/TLDin vitro,A-4.5). The DNF was 1.00 for A-4.5, 1.32 for B-3.8, and 1.21 for C-3.7. Systemic PK after inhalation of 500 μg FP was assessed in a randomized, double-blind, four-way crossover study in 24 healthy volunteers. Peak concentrations (Cmax) of A-4.5 relative to those of B-3.8 or C-3.7 lacked bioequivalence without or with dose normalization. The area under the curve (AUC0-Inf) was bio-IN-equivalent before dose normalization and bioequivalent after dose normalization. Thus, PK could detect differences in pulmonary available dose (AUC0-Inf) and residence time (dose-normalized Cmax). The differences in dose-normalized Cmax could not be explained by differences in in vitro dissolution. This might suggest that Cmax differences may indicate differences in regional lung deposition. Overall this study supports the use of PK studies to provide relevant information on the pulmonary performance characteristics (i.e., available dose, residence time, and regional lung deposition).

High resolution size characterization of particulate contaminants for radioactive metal waste treatment

To regulate the safety protocols in nuclear facilities, radioactive aerosols have been extensively researched to understand their health impacts. However, most measured particle-size distributions remain at low resolutions, with the particle sizes ranging from nanometer to micrometer. This study combines the high-resolution detection of 500 size classes, ranging from 6 nm to 10 μm, for aerodynamic diameter distributions, with a regional lung deposition calculation. We applied the new approach to characterize particle-size distributions of aerosols generated during the plasma arc cutting of simulated non-radioactive steel alloy wastes. The high-resolution measured data were used to calculate the deposition ratios of the aerosols in different lung regions. The deposition ratios in the alveolar sacs contained the dominant particle sizes ranging from 0.01 to 0.1 μm. We determined the distribution of various metals using different vapor pressures of the alloying components and analyzed the uncertainties of lung deposition calculations using the low-resolution aerodynamic diameter data simultaneously. In high-resolution data, the changes in aerosols that can penetrate the blood system were better captured, correcting their potential risks by a maximum of 42%. The combined calculations can aid the enhancement of high-resolution measuring equipment to effectively manage radiation safety in nuclear facilities.

Comparative lung distribution of radiolabeled tobramycin between nebulized and intravenous administration in a mechanically-ventilated ovine model, an observational study.

BackgroundVentilator-associated pneumonia is common and is treated using nebulized antibiotics. Although adequate pulmonary biodistribution is important for antibiotic effect, there is a lack of data for both intravenous (IV) and nebulized antibiotic administration during mechanical ventilation. ObjectiveTo describe the comparative pulmonary regional distribution of IV and nebulized technetium-99m-labeled tobramycin (99mTc-tobramycin) 400 mg in a mechanically-ventilated ovine model. MethodsThe study was performed in a mechanically-ventilated ovine model. 99mTc-tobramycin 400 mg was obtained using a radiolabeling process. Computed tomography (CT) was performed. Ten sheep were given 99mTc-tobramycin 400 mg via either an IV (five sheep) or nebulized (five sheep) route. Planar images (dorsal, ventral, left lateral and right lateral) were obtained using a gamma camera. Blood samples were obtained every 15 min for 1 h (4 time points) and lung, liver, both kidney, and urine samples were obtained post-mortem. ResultsTen sheep were anesthetized and mechanically ventilated. Whole-lung deposition of nebulized 99mTc-tobramycin 400 mg was significantly lower than with IV (8.8% vs. 57.1%, P<0.001). For both administration routes, there was significantly lower deposition in upper lung zones compared with the rest of the lungs. Dorsal deposition was significantly higher with nebulized 99mTc-tobramycin 400 mg compared with IV (68.9% vs. 58.9%, P=0.003). Lung concentrations of 99mTc-tobramycin were higher with IV compared with nebulized administration. There were significantly higher concentrations of 99mTc-tobramycin in blood, liver and urine with IV administration compared with nebulized. ConclusionsNebulization resulted in lower whole and regional lung deposition of 99mTc-tobramycin compared with IV administration and appeared to be associated with low blood and extra-pulmonary organ concentrations.

Regional Lung Deposition: In Vivo Data.

The method section of this chapter on in vivo regional lung deposition highlights a nonradioactive method to measure regional deposition, which uses a photometer to quantify inhaled and exhaled particles and in that way is able to estimate the lung region from which the particles are exhaled and to what amount. The radioactive methods cover the measurement of clearance of the deposited particles as well as different imaging techniques to determine regional deposition. The result section reviews in vivo trials in human subjects. It also addresses different parameters that influence the regional deposition in the lungs: particle size, inhalation maneuver, carrier gas, disease, and inhalation device. All of these factors can affect regional deposition significantly. By choosing specific values of these parameters, it should be feasible to target different regions of the lungs for the therapy of different diseases.

EFFECT OF SWITCHING FROM MULTI-INHALER NON-EXTRA FINE TO SINGLE-INHALER EXTRA FINE TRIPLE THERAPHY ON REGIONAL BRONCHODILATION AND VENTILATION IN PATIENTS WITH SEVERE COPD

EFFECT OF SWITCHING FROM MULTI-INHALER NON-EXTRA FINE TO SINGLE-INHALER EXTRA FINE TRIPLE THERAPHY ON REGIONAL BRONCHODILATION AND VENTILATION IN PATIENTS WITH SEVERE COPD

On the Validation of Generational Lung Deposition Computer Models Using Planar Scintigraphic Images: The Case of Mimetikos Preludium.

Background: Mechanistic computer models for calculation of total and regional deposition of aerosols in the lungs are important tools for predicting or understanding clinical studies and for facilitating development of pharmaceutical inhalation products. Validation of such models must be indirect since generational in vivo data are lacking. Planar scintigraphy is probably the most common method addressing regional lung deposition in humans. Scintigraphic regions of interest (ROI) contain mixtures of airway generations and can therefore not be directly compared to model results. We propose a method to translate computed deposition per generation to deposition in scintigraphic ROI to be able to compare computed results with corresponding results obtained in humans. Methods: The total and regional lung deposition computed by the one-dimensional algebraic typical-path software Mimetikos Preludium was compared for 18 study legs in 14 published deposition studies involving 9 dry powder inhaler brands to the activity in planar scintigraphic ROIs (oropharyngeal, central [C], intermediate, and peripheral [P]) using for the computed regional lung distribution a generic mapping of the contribution of each airway generation to the ROIs. Results: The computed oropharyngeal and total lung deposition correlated with high significance (p < 0.0001) to the scintigraphic results with a near one-to-one relationship. For the regional lung distribution, computed C, P, and P/C results correlated with high significance (p < 0.01) to the corresponding scintigraphic measures. The computed C (P) deposition was on average about 28% lower (8% higher) than the mean scintigraphic results. The computed P/C ratio was on average 29% higher than the mean scintigraphic ratio. Conclusions: The results indicate that both the computational deposition model and the mapping algorithm are valid. The small underprediction of the C region merits further investigations. We believe that this method may prove useful also for the validation of computational fluid particle dynamic lung deposition models.

Pulmonary deposition of budesonide/glycopyrronium/formoterol fumarate dihydrate metered dose inhaler formulated using co-suspension delivery technology in healthy male subjects

This gamma scintigraphy imaging study assessed pulmonary, extrathoracic and regional lung deposition patterns of a radiolabelled inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β2-agonist triple fixed-dose combination budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF 320/14.4/10 μg), delivered by pressurised metered dose inhaler (pMDI) using innovative co-suspension delivery technology (Aerosphere™). In this Phase I, randomised, single-centre, single-dose, two-period, crossover study (NCT03740373), 10 healthy male adults received two actuations of BGF MDI (160/7.2/4.8 μg per actuation) radiolabelled with 99mTc, not exceeding 5 MBq per actuation. Immediately following each inhalation, subjects performed a 10- or 3-second breath-hold, then exhaled into an exhalation filter. The primary objective was to assess the pulmonary deposition of BGF MDI following the 10-second breath-hold. The secondary objectives were to assess deposition after the 3-second breath-hold and lung regional and extrathoracic deposition after each breath-hold length. Imaging of the lungs, stomach, head and neck was recorded by gamma scintigraphy immediately after exhalation. The mean BGF MDI emitted dose deposited in the lungs was 37.7% for the 10-second breath-hold and 34.5% for the 3-second breath-hold. Emitted dose detected in the exhalation filter was ≤0.4% for both breath-hold lengths. The mean normalised peripheral/central ratio was 0.65 and 0.75 for the 10- and 3-second breath-holds, respectively, while the standardised central/peripheral ratios were 1.79 and 1.40, respectively. There were no new or unexpected safety findings. In conclusion, BGF MDI was efficiently deposited in the central and the peripheral regions of the lungs, with similar regional deposition patterns following a 10- and 3-second breath-hold.

Maximizing Deep Lung Deposition in Healthy and Fibrotic Subjects During Jet Nebulization.

Background: In volunteers with idiopathic pulmonary fibrosis (IPF), inhaled Interferon-γ (IFN-γ) is safe and may improve pulmonary function. However, coughing, associated with upper airway deposition, is often reported. To address this problem, a small-particle, breath-enhanced jet nebulizer (i-NEB Mini; InspiRx, Inc., Somerset, NJ) was developed. Using gamma scintigraphy, this device was tested in healthy individuals and subjects with IPF to determine efficiency and regional deposition in lung and airways.Methods: Four healthy individuals and nine subjects with IPF were enrolled. The nebulizer was filled with 2 mL of saline with 99m Tc bound to diethylenetriaminepentaacetic acid (DTPA) powered continuously with 3.4 L/min of compressed air. Mass median aerodynamic diameter (MMAD) was measured by cascade impactor. To maximize deposition in alveoli, inspiratory flow was limited by an inspiratory resistance incorporated into the nebulizer, resulting in a deep inspiration ∼6 seconds. The treatment was run to completion (10 minutes), and each subject underwent deposition imaging. Mass balance and regions of interest determined upper airway (measured by calibrated stomach activity) and regional lung deposition as a percent of pretreatment nebulizer charge.Results: Subjects tolerated the device with no complaints. MMAD (mean [geometric standard deviation]) = 1.04 [1.92] μm. Lung deposition (mean ± standard error, % nebulizer charge) in healthy subjects was 26.2% ± 1.83 and in IPF individuals 23.4% ± 1.60 (p = 0.414). Upper airway deposition was 1.4% ± 0.83 and 2.3% ± 0.48, respectively (p = 0.351), and 20.1% was lost during expiration. Central/Peripheral ratios were consistent in both groups, showing high peripheral deposition (1.32 ± 0.050, vs. 1.28 ± 0.046, p = 0.912).Conclusion: The i-NEB Mini jet nebulizer with breath enhancement produced small particles, resulting in minimal upper airway deposition. Using slow and deep breathing, more than half of the emitted dose deposited in the peripheral lung in normal subjects and individuals with IPF. These data indicate that, for future clinical trials, controlled lung doses of small particles, designed to avoid coughing, are possible even in subjects with advanced disease.

Cobalt-containing dust exposures: Prediction of whole blood and tissue concentrations using a biokinetic model

Biokinetic models estimating cobalt (Co) tissue burden can help assess the potential for systemic effects. Such models, however, have not been used to estimate remote tissue concentrations associated with inhalation exposure to Co-containing dust in general environments, work spaces, or animal toxicity tests. We have therefore updated a Co biokinetic model previously developed for oral dosing to include the inhalation pathway by incorporating the International Commission on Radiological Protection (ICRP) Human Respiratory Tract Model. Further, data from animal studies allowed for characterization of testes Co tissue concentration supplementing previous predictions for the liver, heart and blood. Reasonable agreement (within a factor of two) was found between modeled and measured blood, liver, testes and tissue concentrations when animal doses were modeled using human equivalent concentrations to account for species differences in regional lung deposition. We applied the updated model to occupational inhalation exposure scenarios, and found that upper-bound plausible human systemic body burden associated with Co ingestion is much higher than the burden associated with Co inhalation. Chronic ingestion of Co at a previously proposed oral reference dose (RfD) of 0.03 mg/kg-day resulted in predicted tissue levels of 22–54 μg/L (blood), 0.05–0.1 μg/g (heart), 0.01–0.02 μg/g (testes), and 0.2–0.5 μg/g (liver), which were at least 5-fold more than the systemic burden associated with various Co inhalation occupational exposure limits (OELs) of 0.1 mg/m3 or less (for 8 h/d and 5 d/w). Overall, our analysis indicated that Co-metal or dust induced systemic health effects, including myocardial damage, are unlikely for the inhalation pathway when personal exposures levels are below concentrations associated with local respiratory effects such as pulmonary fibrosis.

The degree of inhomogeneity of the absorbed cell nucleus doses in the bronchial region of the human respiratory tract

Inhalation of short-lived radon progeny is an important cause of lung cancer. To characterize the absorbed doses in the bronchial region of the airways due to inhaled radon progeny, mostly regional lung deposition models, like the Human Respiratory Tract Model (HRTM) of the International Commission on Radiological Protection, are used. However, in this model the site specificity of radiation burden in the airways due to deposition and fast airway clearance of radon progeny is not described. Therefore, in the present study, the Radact version of the stochastic lung model was used to quantify the cellular radiation dose distribution at airway generation level and to simulate the kinetics of the deposited radon progeny resulting from the moving mucus layer. All simulations were performed assuming an isotope ratio typical for an average dwelling, and breathing mode characteristic of a healthy adult sitting man. The study demonstrates that the cell nuclei receiving high doses are non-uniformly distributed within the bronchial airway generations. The results revealed that the maximum of the radiation burden is at the first few bronchial airway generations of the respiratory tract, where most of the lung carcinomas of former uranium miners were found. Based on the results of the present simulations, it can be stated that regional lung models may not be fully adequate to describe the radiation burden due to radon progeny. A more realistic and precise calculation of the absorbed doses from the decay of radon progeny to the lung requires deposition and clearance to be simulated by realistic models of airway generations.

Experimental Measurements of Regional Lung Deposition in Taiwanese

ABSTRACT Inhalation is the most important route of entry for aerosol particles. Deposition in the respiratory tract is affected by many factors, such as particle size, shape, charge, density, breathing pattern and physical tract structure. However, most of the currently available lung deposition data are on Caucasians, with very limited data on Taiwanese. Therefore, it is essential to clarify whether there is a significant difference in respiratory tract deposition between Caucasian and Taiwanese individuals. This work is thus aimed at characterizing regional lung deposition in Taiwanese. A rapid method of measuring regional lung deposition was employed in the present study. The experimental system consisted of an aerosol chamber, a mouthpiece, a pneumotachograph flow meter, and a particle counter. A cylinder-piston type breathing machine was used to generate a series of “standard” breathing patterns for subjects to follow. In addition to oral breathing, nasal breathing was also conducted. A special respirator was employed to facilitate measurements of the nasal route deposition. The regional lung deposition data obtained in this work showed good agreement with previous studies based on the bolus technique, indicating that the difference in lung deposition between Taiwanese and Caucasian individuals is negligible. The local deposition efficiency increased with the penetration volume. This increased trend was particularly prominent in the deep lungs, which was likely due to the dilution effect caused by the relatively clean air in the functional residual capacity. When a fixed fraction of the forced vital capacity was used to replace the fixed tidal volume, the total lung deposition became less dependent on the tidal volume. Primarily due to nostril hairs and the complex configuration of the nasal turbinate, the local deposition efficiency of the nasal route was higher than that of the oral route but only in the early stage of penetration (200 mL).

Gamma scintigraphic pulmonary deposition study of glycopyrronium/formoterol metered dose inhaler formulated using co-suspension delivery technology

This gamma scintigraphy imaging study was the first to assess pulmonary and extrathoracic deposition and regional lung deposition patterns of a radiolabelled long-acting muscarinic antagonist/long-acting β2-agonist fixed-dose combination glycopyrronium/formoterol fumarate dihydrate (GFF) 14.4/10μg (equivalent to glycopyrrolate/formoterol fumarate 18/9.6μg), delivered by pressurized metered dose inhaler (pMDI) using novel co-suspension delivery technology. In this Phase I, randomized, single-centre, single-blind, single-dose, two-treatment, crossover, placebo-controlled study (PT003020), 10 healthy male adults received two actuations of GFF pMDI (7.2/5.0μg per actuation) and placebo pMDI (containing phospholipid-based porous particles without active pharmaceutical ingredient), both radiolabelled with 99mTc, up to 5MBq per actuation. Gamma scintigraphy images of lungs, stomach, head and neck were recorded. In addition, images of the actuators after use, collected mouth washings and exhalation filters were acquired. On average, 38.4% of the emitted dose of radiolabelled GFF pMDI, and 32.8% of radiolabelled placebo pMDI, was deposited in the lungs. The percentage emitted dose detected in the oropharyngeal and stomach regions was 61.4% and 66.9% for radiolabelled GFF pMDI and placebo pMDI, respectively. For both treatments, ≤0.25% of the emitted dose was detected in the exhalation filter. The normalized outer/inner ratio was 0.57 and 0.59 for radiolabelled GFF pMDI and placebo pMDI, respectively, and the standardized central/peripheral ratio was 1.85 and 1.94 respectively, indicating delivery of both co-suspension delivery technology formulations throughout the airways. There were no new or unexpected safety findings. In conclusion, both formulations were efficiently and uniformly deposited in the lungs with similar regional deposition patterns, oropharyngeal and stomach deposition, exhalation fraction and actuator-recovered dose.