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.

Ciprofloxacin Dry Powder for Inhalation: Inspiratory Flow in Patients with Non-cystic Fibrosis Bronchiectasis.

Background: As non-cystic fibrosis bronchiectasis (NCFB) progresses, patients suffer irreversible lung damage and deterioration in lung function. This study explored whether inhalational parameters (peak inspiratory flow [PIF, primary endpoint], inspiratory volume and time [secondary endpoints]) represent barriers to complete dosing in patients with poor lung function who are using Ciprofloxacin dry powder for inhalation (DPI) (a drug-device combination of the T-326 inhaler device and a Ciprofloxacin dry powder formulation). Methods: This open-label, multicenter study generated inspiratory flow rate data from patients with NCFB using the breath-actuated T-326 dry powder inhaler. These rates were compared against reference values to identify whether patients with all degrees of lung function impairment could generate sufficient flow rates to facilitate adequate drug delivery. Patients attended screening and a second visit 1 - 14 days later. Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), FEV1/FVC, and inspiratory capacity were measured via spirometry at both visits. Forty-two patients were screened for inclusion; 33 met eligibility criteria and were stratified into one of three groups based on their FEV1% predicted value (group 1: 25% ≤ FEV1% predicted <45%; group 2: 45% ≤ FEV1% predicted <70%; group 3: FEV1% predicted ≥70%). Results: No significant between-group differences occurred in PIF (mean flow rates 68.21, 66.01, and 65.18 L/min in groups 1, 2, and 3, respectively). Individual minimum PIFs of 46.0-49.0 L/min were observed across groups. These results all exceeded the reference value (minimum PIF 45 L/min for Ciprofloxacin DPI) indicating that regardless of the level of airflow obstruction, patients were capable of achieving sufficient PIFs to aerosolize and inhale Ciprofloxacin dry powder with the T-326 inhaler. Conclusions: Our data indicate that T-326 is suitable for use in the drug-device combination Ciprofloxacin DPI to provide targeted pulmonary delivery in patients with NCFB, including those with significantly impaired lung function.

Lung Deposition of the Dry Powder Fixed Combination Beclometasone Dipropionate Plus Formoterol Fumarate Using NEXThaler® Device in Healthy Subjects, Asthmatic Patients, and COPD Patients.

BACKGROUND: This study evaluated the lung deposition and the distribution pattern in the airways of a fixed combination of beclometasone dipropionate (BDP) and formoterol fumarate (FF) (100/6 µg) delivered as an extrafine dry powder formulation (mass median aerodynamic diameter, MMAD (µm) BDP = 1.5; FF = 1.4) through the NEXThaler® device in healthy subjects, asthmatics, and patients with COPD. METHODS: Healthy subjects (n = 10), asthmatic patients (n = 9; 30%≤FEV1 < 80%), and COPD patients (n = 9; FEV1/FVC ≤70%, 30%≤FEV1 < 50%) completed this open-label, single administration (inhalation of four actuations) parallel group study. After inhalation of 99mTc-radiolabeled BDP/FF combination (radiolabeled BDP + unlabeled FF), the drug deposition was assessed using a gamma-scintigraphy technique. Patients' lung function was assessed. RESULTS: No significant difference in drug deposition was observed between the three study groups. Mean lung deposition, extrathoracic deposition, and amount exhaled ranged, respectively, between 54.9% and 56.2%, between 41.8% and 43.2%, and between 1.6% and 3.3% of BDP emitted dose (71.7 ± 2.5 µg) for the three study groups. The central to peripheral ratio (reflecting the lung distribution pattern) ranged between 1.23 and 2.02 for the three study groups, indicating a distribution of the drug throughout the airways, including periphery. The study treatment produced a forced expiratory volume in one second (FEV1) increase over time, reaching a maximum improvement generally within 1-4 hours. CONCLUSIONS: The fixed extrafine dry powder combination BDP/FF (100/6 µg) administered through the DPI NEXThaler® achieved similar intrapulmonary deposition in healthy subjects, in asthmatic patients, and COPD patients (approximately 55% of emitted dose) irrespective of the underlying lung disease with a negligible amount of exhaled particles. The study showed high reliability of the device, reproducible dosing, and distribution throughout the lungs. The results supported the concept of efficient delivery of the combination to the target pulmonary regions, thanks to the extrafine formulation. FEV1 profile confirmed a relevant pharmacodynamic effect of the product.

Pulmonary deposition of fluticasone propionate/formoterol in healthy volunteers, asthmatics and COPD patients with a novel breath-triggered inhaler.

INTRODUCTION: A combination of fluticasone propionate/formoterol fumarate (FP/FORM) has been incorporated within a novel, breath-triggered device, named K-haler®. This low resistance device requires a gentle inspiratory effort to actuate it, triggering at an inspiratory flow rate of approximately 30 L/min; thus avoiding the need for coordination of inhalation with manual canister depression. The aim of the study was to evaluate total and regional pulmonary deposition of FP/FORM when administered via the K-haler device. MATERIALS AND METHODS: Twelve healthy subjects, 12 asthmatics, and 12 COPD patients each received a single dose of 2 puffs 99mtechnetium-labelled FP/FORM 125/5 µg. A gamma camera was used to obtain anterior and posterior two-dimensional images of drug deposition. Prior transmission scans (using a99mtechnetium flood source) allowed the definition of regions of interest and calculation of attenuation correction factors. Image analysis was performed per standardised methods. RESULTS: Of 36 subjects, 35 provided evaluable post-dose scintigraphic data. Mean subject ages were 35.7 (healthy), 44.5 (asthma) and 61.7 years (COPD); mean FEV1% predicted values were 109.8%, 77.4% and 43.2%, respectively. Mean pulmonary deposition was 26.6% (healthy), 44.7% (asthma), 39.0% (COPD) of the delivered dose. The respective mean penetration indices (peripheral:central ratio normalised to a transmission lung scan) were 0.44, 0.31 and 0.30. CONCLUSION: FP/FORM administration via the K-haler device resulted in high lung deposition in patients with obstructive lung disease but somewhat lesser deposition in healthy subjects. Regional deposition data demonstrated drug deposition in both the central and peripheral regions in all subject populations. EUDRACT NUMBER: 2015-000744-42.

Ciprofloxacin Dry Powder for Inhalation in Patients with Non-Cystic Fibrosis Bronchiectasis or Chronic Obstructive Pulmonary Disease, and in Healthy Volunteers.

BACKGROUND: Ciprofloxacin dry powder for inhalation (Ciprofloxacin DPI) is in development as long-term intermittent therapy to reduce the frequency of acute exacerbations in non-cystic fibrosis bronchiectasis (NCFB) patients with respiratory bacterial pathogens. There is no approved therapy in this indication. Reliable, reproducible lung deposition is a prerequisite for inhaled drugs. METHODS: In this phase I study, six patients with NCFB, six with chronic obstructive pulmonary disease (COPD), and 12 healthy volunteers (HVs), received one dose of 99mTc-Ciprofloxacin DPI 32.5 mg to assess pulmonary drug deposition by quantitative scintigraphy. 81mKrypton ventilation scans were performed to map lung contours. Systemic exposure as mediated by absorption in the lung was measured using the charcoal block method. HVs ingested activated charcoal orally (20 g before and 2 × 10 g after inhalation) to block gastrointestinal absorption of drug swallowed during inhalation. Indirect determination of pulmonary drug deposition was based on plasma and urine pharmacokinetic (PK) data. RESULTS: Scintigraphic data revealed high, reproducible lung deposition in all participants (intrapulmonary deposition relative to nominal dose, mean [standard deviation; range]: NCFB, 53% [11%; 38%-64%]; COPD, 51% [10%; 34%-61%]; HVs, 51% [7%; 40%-64%] to 53% [8%; 44%-70%]). Similar ratios of central-to-peripheral airway deposition were seen across groups. Systemic exposure to ciprofloxacin was low. Relative bioavailability of Ciprofloxacin DPI was reduced by ∼60% after charcoal block, suggesting that systemic exposure was mainly caused by uptake via the lung. Lung deposition of 30% was estimated from PK data, but this may be an underestimation due to drug clearance from the lung and transintestinal secretion. Adverse events were no more frequent or severe in patients with lung diseases versus HVs, and no clinically relevant influence on vital signs or lung function was observed. CONCLUSION: This study supports the continued development of Ciprofloxacin DPI in NCFB patients with respiratory bacterial pathogens.

Lung Deposition of Alpha1-Proteinase Inhibitor (Human) (A1-PI[H]) Inhalation Solution Using Two Inhalation Modes of the I-neb Adaptive Aerosol Delivery (AAD) System in Healthy Subjects and Subjects with Cystic Fibrosis.

BACKGROUND: In cystic fibrosis (CF) patients, inhalation of alpha1-proteinase inhibitor (A1-PI) can prevent or slow down persistent infections and reduce the massive ongoing inflammation and excessive levels of NE that destroy the airway epithelium, leading to progressive loss of pulmonary function and death. It is essential for an efficient treatment with inhaled A1-PI that an adequate and reproducible dose is deposited within all regions of the lung. The I-neb AAD System provides two inhalation modes: the Target Inhalation Mode (TIM) and the Tidal Breathing Mode (TBM). Both were compared in this study for their efficiency to deliver A1-PI to the lungs. METHODS: This was a randomized, open label, cross-over study to investigate the lung deposition of A1-PI in 6 healthy subjects (HS) and 15 CF subjects. The primary endpoint was to evaluate the total lung deposition relative to filling dose of A1-PI inhalation solution using the I-neb AAD System in TIM and in TBM. The main secondary endpoints were extra-thoracic deposition, exhaled drug fraction, nebulizer residue, C/P ratio, and variance of pixel counts. Additional exploratory endpoints were total treatment time and the inhalation time. Radiolabeling was performed considering GMP using a commercially available sterile labeling kit. Radiolabeling was validated using NGI data acquired by gamma scintillation and UV spectrometry. RESULTS AND CONCLUSIONS: The intrapulmonary deposition (mean ± SD) in CF subjects was 47.0% ± 6.6% and 46.7% ± 10.3% in TIM and TBM, respectively, and in healthy subjects, 50.0% ± 6.7% and 54.8% ± 7.0% in TIM and TBM, respectively. TIM resulted in an approximately 40% lower treatment time (HS 6.4 min vs. 10.3 min, CF 5.3 min vs. 10.7 min) and less extra-thoracic deposition compared to TBM, and showed a higher residue of drug in the nebulizer, compared to TBM. In both groups, inhalation of a single dose of 77 mg of A1-PI was efficient, safe, and well tolerated using TIM and TBM.

Standardization of techniques for using planar (2D) imaging for aerosol deposition assessment of orally inhaled products.

Two-dimensional (2D or planar) imaging with (99m)Tc radiolabels enables quantification of whole-lung and regional lung depositions for orally inhaled drug products. This article recommends standardized methodology for 2D imaging studies. Simultaneous anterior and posterior imaging with a dual-headed gamma camera is preferred, but imaging with a single-headed gamma camera is also acceptable. Correction of raw data for the effects of gamma ray attenuation is considered essential for accurate quantification, for instance, using transmission scanning with a flood-field source of (99m)Tc or (57)Co. Evidence should be provided of the accuracy of the quantification method, for instance, by determining "mass balance." Lung deposition may be expressed as a percentage of ex-valve or ex-device dose, but should also be given as mass of drug when possible. Assessment of regional lung deposition requires delineation of the lung borders, using X-ray computed tomography, radioactive gas scans ((133)Xe or (81m)Kr), or transmission scans. When quantifying regional lung deposition, the lung should be divided into outer (O) and inner (I) zones. A penetration index should be calculated, as the O/I ratio for aerosol, normalized to that for a radioactive gas or transmission scan. A variety of methods can be used to assess lung deposition and distribution. Methodology and results should be documented in detail, so that data from different centers may be compared. The use of appropriate methodology will provide greater confidence in the results of 2D imaging studies, and should allay concerns that such studies are qualitative or semiquantitative in nature.

Validation of radiolabeling of drug formulations for aerosol deposition assessment of orally inhaled products.

Radiolabeling of inhaler formulations for imaging studies is an indirect method of determining lung deposition and regional distribution of drug in human subjects. Hence, ensuring that the radiotracer and drug exhibit similar aerodynamic characteristics when aerosolized, and that addition of the radiotracer has not significantly altered the characteristics of the formulation, are critical steps in the development of a radiolabeling method. The validation phase should occur during development of the radiolabeling method, prior to commencement of in vivo studies. The validation process involves characterization of the aerodynamic particle size distribution (APSD) of drug in the reference formulation, and of both drug and radiotracer in the radiolabeled formulation, using multistage cascade impaction. We propose the adoption of acceptance criteria similar to those recommended by the EMA and ISAM/IPAC-RS for determination of therapeutic equivalence of orally inhaled products: (a) if only total lung deposition is being quantified, the fine particle fraction ratio of both radiolabeled drug and radiotracer to that of the reference drug should fall between 0.85 and 1.18, and (b) if regional lung deposition (e.g., outer and inner lung regions) is to be quantified, the ratio of both radiolabeled drug and radiotracer to reference drug on each impactor stage or group of stages should fall between 0.85 and 1.18. If impactor stages are grouped together, at least four separate groups should be provided. In addition, while conducting in vivo studies, measurement of the APSD of the inhaler used on each study day is recommended to check its suitability for use in man.

Insulin lung deposition and clearance following Technosphere® insulin inhalation powder administration.

PURPOSE: To determine distribution and deposition of Technosphere® Insulin (TI) inhalation powder and the rate of clearance of fumaryl diketopiperazine (FDKP; major component of Technosphere particles) and insulin from the lungs. METHODS: Deposition and distribution of (99m)pertechnetate adsorbed onto TI immediately after administration using the MedTone® inhaler was quantified by gamma-scintigraphy. Clearance from the lungs was studied in a second experiment by serial bronchoalveolar lavage (BAL) after administration of TI inhalation powder and assay of the recovered fluid for FDKP and insulin. RESULTS: Following inhalation, ~60% of radioactivity (adsorbed on TI) emitted from the inhaler was delivered to the lungs; the remainder of the emitted dose was swallowed. Clearance from the lung epithelial lining fluid (ELF) of FDKP and insulin have a half-life of ~1 hour. CONCLUSION: TI inhalation powder administered via the MedTone inhaler was uniformly distributed throughout the lungs; ~40% of the initial cartridge load reached the lungs. Insulin and FDKP are quickly cleared from the lungs, mainly by absorption into the systemic circulation. The terminal clearance half-life from the lung ELF, estimated from sequential BAL fluid measurements for both components, was ~1 hour. Since there is an overnight washout period, the potential for accumulation on chronic administration is minimal.

Effects of formoterol and tiotropium bromide on mucus clearance in patients with COPD.

BACKGROUND: Lung mucociliary clearance is impaired in patients with chronic obstructive pulmonary disease (COPD). Treatment guidelines recommend that patients with COPD receive maintenance therapy with long-acting beta-agonists and anticholinergic agents. METHODS: Twenty-four patients with mild to moderate COPD received formoterol (12 µg, twice daily from Turbuhaler® dry powder inhaler (DPI)) or tiotropium (18 µg, once daily from Handihaler® DPI) for 14 days. They also received single doses of formoterol, tiotropium, salbutamol (200 µg) and placebo. A radioaerosol technique was used to assess the effects on mucus clearance of 14 days treatment with formoterol or tiotropium, as well as single doses of these drugs. RESULTS: The 4 h whole lung retention of radioaerosol was significantly higher after 14 days treatment with tiotropium (P = 0.016), but not after 14 days treatment with formoterol. However, patients bronchodilated after 14 days treatment with both drugs, so that the deposited radioaerosol may have had an increased distance to travel in order to be cleared by mucociliary action. A single dose of formoterol enhanced radioaerosol clearance significantly compared to other single dose treatments (P < 0.05). CONCLUSION: Formoterol (12 µg) enhances mucus clearance in patients with mild to moderate COPD when given as a single dose, and may do so when given for 14 days. Studies of longer duration would be needed in order to assess the effects of the study drugs on mucus clearance when they are used for long-term maintenance therapy.

Lung deposition of BDP/formoterol HFA pMDI in healthy volunteers, asthmatic, and COPD patients.

BACKGROUND: When inhaling medication, it is essential that drug particles are delivered to all sites of lung inflammation, including the peripheral airways. The aim of this study was to assess the lung deposition and lung distribution of beclomethasone dipropionate (BDP)/formoterol (100/6 microg), both dissolved in hydrofluoroalkane (HFA) and delivered by pressurized metered dose inhaler (pMDI) in healthy subjects, asthmatic, and chronic obstructive pulmonary disease (COPD) patients, to investigate how the in vitro characteristics of the formulation translate into the in vivo performance in diseases with different airway obstruction. METHODS: Healthy volunteers (n = 8), persistent asthmatics (n = 8), and patients with stable COPD (n = 8) completed this open-label, single-dose parallel-group study. Each patient received one single treatment of four puffs of (99 m)Tc-labeled BDP/formoterol formulation. The correlation between particle size distribution of radioactivity and of the drugs in the radiolabeled formulation was validated. Intra- and extrapulmonary deposition, amount of exhaled drug, and the central to peripheral ratio (C/P) were calculated immediately after inhalation. Patients' lung function and pharmacokinetic parameters were also assessed up to 24 h post-dose. RESULTS: The average lung deposition of BDP/formoterol was 34.08 +/- 9.30% (relative to nominal dose) in healthy subjects, 30.86 +/- 8.89% in asthmatics, and 33.10 +/- 8.90% in COPD patients. Extrathoracic deposition was 53.48% +/- 8.95, 57.64% +/- 9.92 and 54.98% +/- 7.01, respectively. C/P ratios of 1.42 +/- 0.32 in healthy subjects, 1.96 +/- 0.43 in asthmatics, and 1.94 +/- 0.69 for COPD patients confirmed drug distribution to all regions of the lungs. Forced expiratory volume in 1 sec (FEV(1)) increased in all groups after BDP/formoterol inhalation, but was more evident in the patient groups. No significant correlation between baseline lung function and drug deposition was observed. Formoterol, BDP, and beclomethasone 17 monopropionate (B17MP) plasma profiles were comparable between groups. CONCLUSION: Inhalation of BDP/formoterol HFA (100/6 microg) produces high and homogeneous deposition of BDP and formoterol in the airways, regardless of pathophysiological condition.

Deposition, retention, and translocation of ultrafine particles from the central airways and lung periphery.

RATIONALE: Little is known about clearance of ultrafine carbon particles from the different regions of the human lung. These particles may accumulate and present a health hazard because of their high surface area. OBJECTIVES: Technetium Tc 99m ((99m)Tc)-radiolabeled 100-nm-diameter carbon particles were inhaled by healthy nonsmokers, asymptomatic smokers, and by patients with chronic obstructive pulmonary disease (COPD). METHODS: Using a bolus inhalation technique, particle deposition was targeted either to the airways or to the lung periphery, and retention, clearance, and translocation were measured using retained radiotracer imaging. MEASUREMENTS AND MAIN RESULTS: In vitro studies revealed that mean leaching of soluble (99m)Tc-radiotracer from the carbon particles was 4.1 (2.6 [SD]) % after 24 hours. Cumulative (99m)Tc activity in urine at 24 hours was 1.1 (1.3) % of activity deposited in the lungs. In the lung periphery, particle retention was not affected by smoking or pulmonary disease; retention was 96 (3) % after 24 hours. The small amount of clearance could be attributed to leaching of the (99m)Tc label, suggesting negligible particle clearance. In healthy nonsmokers, retention of particles targeted to the airways was 89 (6) and 75 (10) % after 1.5 and 24 hours, respectively. Radiolabel activity did not accumulate in the liver. CONCLUSIONS: Within the limits of detection of our experimental system, most inhaled ultrafine carbon particles are retained in the lung periphery and in the conducting airways without substantial systemic translocation or accumulation in the liver at 48 hours. Repeated exposure may result in significant pulmonary accumulation of ultrafine particles.

Lung deposition of formoterol HFA (Atimos/Forair) in healthy volunteers, asthmatic and COPD patients.

In this study, the influence of lung function on lung deposition of a radioactively labeled Formotoerol HFA MDI (Forair) was investigated. Eighteen subjects were measured: 6 healthy subjects (FEV(1) = 107% pred), 6 patients with Asthma (FEV(1) = 72% pred), and 6 patients with COPD (FEV(1) = 40% pred). The lung deposition of the radioactive-labeled drug was measured with a gamma camera. The lung deposition relative to the emitted dose was 31% for healthy subjects, 34% for asthmatics, and 35% for COPD patients. These data suggest a comparable lung deposition in the different populations. There was no significant correlation between lung function (FEV(1)) and lung deposition. The extrathoracic deposition was around 50%. The finding were that lung deposition of the inhaled Formoterol did not depend on lung function and the relative high values of lung deposition can be explained by the small particle size (0.8 microm) of the HFA-Formoterol-Formulation and the slow inhalation (30 L/min flow) used in this study. It can be concluded, that with this modern HFA drug formulation, the deposition is high, even in obstructed lungs.

In vitro comparison of two delivery devices for administering formoterol: Foradil P and formoterol ratiopharm single-dose capsule inhaler.

Formoterol, a long-acting beta (2)-agonist with a rapid onset of bronchodilation, is available in various delivery devices. However, differences in the size and uniformity of drug particles generated by different devices may result in variable clinical effects. The present study compared in vitro the aerodynamic particle size distribution, emitted dose and device resistance of formoterol delivered via Foradil Aerolizer (Foradil P) with those a non-proprietary single-dose capsule inhaler (ratiopharm), using an 8-stage Andersen Cascade Impactor set at a flow of 60 L/min. Relative to the formoterol ratiopharm capsule inhaler, Foradil Aerolizer produced particles with a smaller mass median aerodynamic diameter (3.5 vs. 4.1 microm, p = 0.018) and a smaller measured particle diameter distribution (geometric standard deviation 2.2 vs. 2.5, p = 0.048). The Foradil Aerolizer produced a 44% higher fine particle dose than the single-dose capsule inhaler (2.6 vs. 1.8 microg, p = 0.0001). Although the single-dose capsule inhaler produced a higher total emitted dose than that from Foradil Aerolizer (11.2 vs. 10.0 microg, p = 0.155, not significant), the respirable fraction from Foradil Aerolizer was 58% higher (25.7 vs. 16.3%, p = 2 x 10(8)). Both devices had a similarly low airflow resistance. These relative particle size profiles suggest that the Aerolizer may provide a more clinically effective delivery of formoterol to the lungs at the high inspiratory flows such as are typically achieved using this device.

Dose delivery characteristics of the AIR pulmonary delivery system over a range of inspiratory flow rates.

The purpose of this study was to evaluate the in vitro and in vivo dose delivery characteristics of the AIR pulmonary delivery system over a range of flow rates. A 5-mg placebo powder of engineered particles with low densities (<0.4 g/cc) and large geometric diameters (>5 microm) was delivered via a simple, capsule based, passive dry powder inhaler. The emitted dose, geometric and aerodynamic particle size distributions (aPSDs) were obtained over a range of flow rates (15-60 LPM). The in vitro results demonstrated improved powder dispersion with increasing flow rate through the inhaler. The in vivo dose delivery characteristics were obtained by gamma scintigraphy. Twelve healthy subjects performed the following three inhalation maneuvers: (i) a targeted peak inspiratory flow rate (PIFR) of 20 +/- 10 LPM, (ii) a deep comfortable inhalation, and (iii) a deep forced inhalation. PIFR and inhaled volume were obtained during the inhalation of the dose using a spirometer. In vivo dose delivery was characterized by high and reproducible emitted doses (mean = 87%; inter and intra-subject CV = 5%) and high lung deposition (mean = 51% of the total dose), with low inter and intra-subject CVs (18% and 13%, respectively) across a range of PIFRs (12-86 LPM). Lung deposition of the total dose was shown not to be dependent on PIFR by analysis of variance across the range of inspiratory flow rates (p = 0.29). This was due to the competing effects of smaller aPSDs, increased extrathoracic deposition and higher emitted doses with increasing PIFR. Fully characterizing the effect of inspiratory flow rate requires analysis of the therapeutic response, as well as in vitro dose delivery and lung deposition.

The physical and biological doses of methacholine are different for Mefar MB3 and Jaeger APS sidestream nebulizers.

BACKGROUND: Within a study on respiratory symptoms in rural areas, we used the European Community Respiratory Health Survey methacholine challenge protocol. For quicker and more reliable handling, we had to change the nebulizer in the bronchial challenge system from Mefar model MB3 (Bovezzo, Italy) to Jaeger APS Sidestream (similar to Mefar; Würzburg, Germany). Therefore, we compared the physical properties of the two systems, adapted the challenge protocol, and compared the results of both systems in subjects with and without airway hyperresponsiveness to methacholine. METHOD: The physical properties of both systems were characterized by the residual method indicating a similar particle size distribution and an average output of 6 muL/s for Mefar MB3 and 1.25 muL/s for APS Sidestream. In the comparison study, 34 subjects were included. Airway responsiveness was quantified by provocative dose of methacholine causing a 20% fall in FEV(1). RESULTS: A significant difference was found between the two challenge systems (p =0.004, McNemar test). Nine subjects reached a 20% drop in FEV(1) with the APS Sidestream only. The FEV(1) dropped by > 20% using either system in eight subjects. In 17 subjects, none of the two systems caused a 20% decrease in FEV(1). CONCLUSION: Even if the physical dose is determined with elaborate methods, the biological dose may vary between two nebulizer systems, causing incomparable outcomes for subjects tested with different systems.

In vitro and in vivo dose delivery characteristics of large porous particles for inhalation.

The purpose of this study was to evaluate the in vitro and in vivo dose delivery characteristics of two large porous particle placebo formulations with different mass median aerodynamic diameters (MMAD approximately equal to 3 and 5 microm). In vitro dose delivery characteristics were measured using the multistage liquid impinger (MSLI). In vitro lung deposition was predicted by calculating the extrathoracic deposition using the ICRP model, with the remaining fraction assumed to deposit in the lungs. Healthy subjects were trained to inhale through the AIR delivery system at a target peak inspiratory flow rate (PIFR) of 60 l/min, The in vivo dose delivery of large porous particles were obtained by gamma-scintigraphy and was characterized by high ( approximately 90%), reproducible emitted doses for both the small and large MMAD powders. The mean in vivo lung deposition relative to the total metered dose were 59.0 and 37.3% for 3 and 5 microm MMAD powders, respectively. The AIR delivery system produced high in vivo lung deposition and low intersubject CVs (approximately 14%) across the range of PIFRs obtained in the study (50-80 l/min), This is relative to a variety of dry powder inhalers (DPI) that have been published in the literature, with in vivo lung deposition ranging from 13 to 35% with intersubject CVs ranging from 17 to 50%. The ICRP model provided a good estimate of the mean in vivo lung deposition for both powders. Intersubject variability was not captured by the ICRP model due to intersubject differences in the morphology and physiology of the oropharyngeal region. The ICRP model was used to predict the regional lung deposition, although these predictions were only considered speculative in the absence of experimental validation.

Targeting delivery of aerosols to different lung regions.

With the increasing use of aerosolized drugs, there is a need to understand the means by which these drugs can most effectively be targeted to desired regions of the lung. Several attempts have been made at targeting aerosols in the lung by changing particle sizes and breathing patterns with varying degrees of success. Recent use of such techniques as shallow, aerosol bolus delivery and extremely slow inhalations of aerosols in diagnostic lung tests may also prove beneficial for targeting drug delivery to the conducting airways. This review discusses the potential for utilizing aerosol delivery techniques for selectively targeting aerosol deposition along both serial and parallel pathways in the lung. Based on a review of previous studies concerning factors that determine aerosol and gas distribution in the lung, the potential for utilizing various breathing techniques in concert with variations in particle sizes are considered. Further research on the factors that determine distribution of aerosol in the diseased lung may help in designing successful targeting strategies for the future.