The topical study of inhaled drug (salbutamol) delivery in idiopathic pulmonary fibrosis.

BACKGROUND: Our aim was to investigate total and regional lung delivery of salbutamol in subjects with idiopathic pulmonary fibrosis (IPF). METHODS: The TOPICAL study was a 4-period, partially-randomised, controlled, crossover study to investigate four aerosolised approaches in IPF subjects. Nine subjects were randomised to receive 99mTechnetium-labelled monodisperse salbutamol (1.5 µm or 6 µm; periods 1 and 2). Subjects also received radio-labelled salbutamol using a polydisperse nebuliser (period 3) and unlabelled salbutamol (400 µg) using a polydisperse pressurized metered dose inhaler with volumatic spacer (pMDI; period 4). RESULTS: Small monodisperse particles (1.5 µm) achieved significantly better total lung deposition (TLD, mean % ± SD) than larger particles (6 µm), where polydisperse nebulisation was poor; (TLD, 64.93 ± 10.72; 50.46 ± 17.04; 8.19 ± 7.72, respectively). Small monodisperse particles (1.5 µm) achieved significantly better lung penetration (mean % ± SD) than larger particles (6 µm), and polydisperse nebulisation showed lung penetration similar to the small particles; PI (mean ± SD) 0.8 ± 0.16, 0.49 ± 0.21, and 0.73 ± 0.19, respectively. Higher dose-normalised plasma salbutamol levels were observed following monodisperse 1.5 µm and 6 µm particles, compared to polydisperse pMDI inhalation, while lowest plasma levels were observed following polydisperse nebulisation. CONCLUSION: Our data is the first systematic investigation of inhaled drug delivery in fibrotic lung disease. We provide evidence that inhaled drugs can be optimised to reach the peripheral areas of the lung where active scarring occurs in IPF. TRIAL REGISTRATION: This trial was registered on clinicaltrials.gov ( NCT01457261 ).

Delivery and adherence with inhaled therapy in asthma.

The benefits of inhaled medication for the treatment of respiratory diseases are immense. Inhalers are unquestionably the most important medical devices for the treatment of asthma and in Europe today there are more than 230 different device and drug combinations of inhaled therapies many of which are available for the treatment of asthma. They are designed to alleviate the symptoms of asthma by controlling inflammation and minimizing exacerbations and are intended to be simple enough to operate by all patients regardless of their age and education. However, it is still a huge challenge for patients to use their inhaler correctly and consistently and achieving asthma control continues to be an elusive goal for most patients worldwide. The reality is that despite advances in the diagnosis of asthma, the availability of comprehensive asthma management guidelines and potent asthma medications combined with efficient delivery systems, uncontrolled disease is still linked to substantial morbidity and mortality. Despite the enormous benefits of delivering topically acting medication directly to the site of disease in the lungs adherence to treatment still remains one of the biggest challenges in asthma control. This current review looks at why patients have difficulty in using their inhalers and why adherence is so poor and how this may be improved through the use of innovation in inhaler design.

Inhaled aerosol dose distribution between proximal bronchi and lung periphery.

Modern inhaled drug discovery programs assess dose delivery to proximal and distal airways using rudimentary imaging indices, where relative deposition is estimated by generically defined 'central' and 'peripheral' lung regions. Utilizing recent data linking the proximal airway topology to a characteristic pattern of aerosol lung deposition, we provide a direct measure of dose distribution between the proximal bronchi and the distal lung. We analyzed scintigraphic lung images of twelve asthma patients following inhalation of 1.5-, 3- and 6-µm monodisperse drug particles at breathing flows of 30- and 60-L/min. We explicitly used the central hot-spots associated with each patient's specific bronchial topology to obtain a direct measure of aerosol deposition in the proximal bronchi, rather than applying standard templates of lung boundaries. Maximum deposition in the central bronchi (as % of lung deposition) was 52 ± 10(SD)% (6 µm;60 L/min). Minimum central deposition was 17 ± 2(SD)% (1.5 µm;30 L/min) where the 83% aerosol 'escaping' deposition in the central bronchi reached 75 ± 17(SD)% of the lung area that could be reached by Krypton gas. For all particle sizes, hot-spots appeared in the same patient-specific central airway location, with greatest intensity at 60 L/min. For a range of respirable aerosol sizes and breathing flows, we have quantified deposited dose in the proximal bronchi and their distal lung reach, constituting a platform to support therapeutic inhaled aerosol drug development.

Is there room for further innovation in inhaled therapy for airways disease?

Inhaled medication is the cornerstone in the treatment of patients across a spectrum of respiratory diseases including asthma and chronic obstructive pulmonary disease. The benefits of inhaled therapy have long been recognised but the most important innovations have occurred over the past 60 years, beginning with the invention of the pressurised metered dose inhaler. However, despite over 230 different device and drug combinations currently being available, disease control is far from perfect. Here we look at how innovation in inhaler design may improve treatments for respiratory diseases and how new formulations may lead to treatments for diseases beyond the lungs. We look at the three main areas where innovation in inhaled therapy is most likely to occur: 1) device engineering and design; 2) chemistry and formulations; and 3) digital technology associated with inhalers. Inhaler design has improved significantly but considerable challenges still remain in order to continually innovate and improve targeted drug delivery to the lungs. Healthcare professionals want see innovations that motivate their patients to achieve their goal of improving their health, through better adherence to treatment. Patients want devices that are easy to use and to see that their efforts are rewarded by improvements in their condition. KEY POINTS: The dictionary definition of innovation is the introduction of new things, ideas or ways of doing something. We show how this definition can be applied to inhaled therapy.We take a look at the past to see what drove innovation in inhaler design and how this has led to the current devices.We look at the current drivers of innovation in engineering, chemistry and digital technology and predict how this may translate to new devices.Can innovation help the healthcare professional manage their patients better?What does the patient expect from innovation in their device? EDUCATIONAL AIMS: To understand the importance of inhaled medication in the treatment of lung diseases.To understand how innovation has helped advance some of the devices patients use today from basic and inefficient designs.To understand the obstacles that prevent patients from receiving optimal treatment from their inhalers.To understand how innovation in inhaler design can lead to improved treatment for patients and widen the range of diseases that can be treated via the inhaled route.

Generating monodisperse pharmacological aerosols using the spinning-top aerosol generator.

Pharmacological aerosols of precisely controlled particle size and narrow dispersity can be generated using the spinning-top aerosol generator (STAG). The ability of the STAG to generate monodisperse aerosols from solutions of raw drug compounds makes it a valuable research instrument. In this paper, the versatility of this instrument has been further demonstrated by aerosolizing a range of commercially available nebulized pulmonary therapy preparations. Nebules of Flixotide (fluticasone propionate), Pulmicort (budesonide), Combivent (salbutamol sulphate and ipratropium bromide), Bricanyl (terbutaline sulphate), Atrovent(ipratropium bromide), and Salamol (salbutamol sulphate) were each mixed with ethanol and delivered to the STAG. Monodisperse drug aerosol distributions were generated with MMADs of 0.95-6.7 microm. To achieve larger particle sizes from the nebulizer drug suspensions, the STAG formed compound particle agglomerates derived from the smaller insoluble drug particles. These compound agglomerates behaved aerodynamically as a single particle, and this was verified using an aerodynamic particle sizer and an Andersen Cascade Impactor. Scanning electron microscope images demonstrated their physical structure. On the other hand using the nebulizer drug solutions, spherical particles proportional to the original droplet diameter were generated. The aerosols generated by the STAG can allow investigators to study the scientific principles of inhaled drug deposition and lung physiology for a range of therapeutic agents.

Inhaled Aerosol Distribution in Human Airways: A Scintigraphy-Guided Study in a 3D Printed Model.

BACKGROUND: While it is generally accepted that inertial impaction will lead to particle loss as aerosol is being carried into the pulmonary airways, most predictive aerosol deposition models adopt the hypothesis that the inhaled particles that remain airborne will distribute according to the gas flow distribution between airways downstream. METHODS: Using a 3D printed cast of human airways, we quantified particle deposition and distribution and visualized their inhaled trajectory in the human lung. The human airway cast was exposed to 6 µm monodisperse, radiolabeled aerosol particles at distinct inhaled flow rates and imaged by scintigraphy in two perpendicular planes. In addition, we also imaged the distribution of aerosol beyond the airways into the five lung lobes. The experimental aerosol deposition patterns could be mimicked by computational fluid dynamic (CFD) simulation in the same 3D airway geometry. RESULTS: It was shown that for particles with a diameter of 6 µm inhaled at flows up to 60 L/min, the aerosol distribution over both lungs and the individual five lung lobes roughly followed the corresponding distributions of gas flow. While aerosol deposition was greater in the main bronchi of the left versus right lung, distribution of deposited and suspended particles toward the right lung exceeded that of the left lung. The CFD simulations also predict that for both 3 and 6 µm particles, aerosol distribution between lung units subtending from airways in generation 5 did not match gas distribution between these units and that this effect was driven by inertial impaction. CONCLUSIONS: We showed combined imaging experiments and CFD simulations to systematically study aerosol deposition patterns in human airways down to generation 5, where particle deposition could be spatially linked to the airway geometry. As particles are negotiating an increasing number of airways in subsequent branching generations, CFD predicts marked deviations of aerosol distribution with respect to ventilation distribution, even in the normal human lung.

Characterization of the generation of radiolabeled monodisperse albuterol particles using the spinning-top aerosol generator.

UNLABELLED: Inhaled radiolabeled aerosols provide invaluable information about in vivo drug deposition. Here, we report our methodology for radiolabeling and imaging monodisperse pharmacologic aerosols in order to study basic aerosol science concepts of drug delivery within the human airways. METHODS: We used a spinning-top aerosol generator to produce (99m)Tc-labeled monodisperse albuterol sulfate aerosols of 1.5-, 3-, and 6- micro m mass median aerodynamic diameter. RESULTS: In vitro Andersen cascade validation data showed that technetium and albuterol were coassociated on each impactor stage for all 3 aerosols, and the radiolabeling process itself did not affect their particle size distributions. Good-quality gamma-camera scintigraphic images of lung and extrathoracic deposition were obtained within an asthmatic patient. CONCLUSION: We have successfully radiolabeled and imaged monodisperse albuterol aerosols within the human lungs. This novel technique provides an important tool to relate fundamental concepts of aerosol particle behavior, in vivo deposition, and therapeutic clinical response.

Effects of bronchodilator particle size in asthmatic patients using monodisperse aerosols.

Aerosol particle size influences airway drug deposition. Current inhaler devices are inefficient, delivering a heterodisperse distribution of drug particle sizes where, at best, 20% reaches the lungs. Monodisperse aerosols are the appropriate research tools to investigate basic aerosol science concepts within the human airways. We hypothesized that engineering such aerosols of albuterol would identify the ideal bronchodilator particle size, thereby optimizing inhaled therapeutic drug delivery. Eighteen stable mildly to moderately asthmatic patients [mean forced expiratory volume in 1 s (FEV1) 74.3% of predicted] participated in a randomized, double-blind, crossover study design. A spinning-top aerosol generator was used to produce monodisperse albuterol aerosols that were 1.5, 3, and 6 microm in size, and also a placebo, which were inhaled at cumulative doses of 10, 20, 40, and 100 microg. Lung function changes and tolerability effects were determined. The larger particles, 6 and 3 microm, were significantly more potent bronchodilators than the 1.5-microm and placebo aerosols for FEV1 and for the forced expiratory flow between exhalation of 25 and 75% of forced vital capacity. A 20-microg dose of the 6- and 3-microm aerosols produced FEV1 bronchodilation comparable to that produced by 200 microg from a metered-dose inhaler. No adverse effects were observed in heart rate and plasma potassium. The data suggest that in mildly to moderately asthmatic patients there is more than one optimal beta2-agonist bronchodilator particle size and that these are larger particles in the higher part of the respirable range. Aerosols delivered in monodisperse form can enable large reductions of the inhaled dose without loss of clinical efficacy.

A system for the production and delivery of monodisperse salbutamol aerosols to the lungs.

An aerosol system is described for the generation and delivery of measured doses of monodisperse therapeutic drug particles to the human lungs. The system comprises a spinning top aerosol generator (STAG), aerosol chamber and inhalation control unit. Monodisperse aerosols allow drug particle size effects to be studied as the dose is within a narrow size distribution and when combined with controlled inhalation may lead to more precise targeting of therapeutic drug to the airways. Using the STAG, particles in the size range 1.5-12 microm were generated and their mass median aerodynamic diameter (MMAD) and concentration measured using an aerodynamic particle sizer (APS). The application and validation of the system with the bronchodilator drug salbutamol sulphate is described, and its potential use in the study of aerosol particle size effects is discussed.

The importance of imaging and physiology measurements in assessing the delivery of peripherally targeted aerosolized drugs.

Considerable recent effort has been directed towards developing new aerosol formulations and delivery devices that can target drugs to the lung periphery. In order to determine the efficacy of targeted drug therapy, it is essential that the peripheral lung region be adequately assessed. Imaging of the airways structure and pathology has greatly advanced in the last decade and this rate of growth is accelerating as new technologies become available. Lung imaging continues to play an important role in the study of the peripheral airways and, when combined with state-of-the-art lung function measurements and computational modeling, can be a powerful tool for investigating the effects of inhaled medication. This article focuses on recent strategies in imaging and physiological measurements of the lungs that allow the assessment of inhaled medication delivered to the periphery and discusses how these methods may help to further optimize and refine future aerosol delivery technology.

Comparing lung regions of interest in gamma scintigraphy for assessing inhaled therapeutic aerosol deposition.

BACKGROUND: Two-dimensional gamma scintigraphy is an important technique used to evaluate the lung deposition from inhaled therapeutic aerosols. Images are divided into regions of interest and deposition indices are derived to quantify aerosol distribution within the intrapulmonary airways. In this article, we compared the different approaches that have been historically used between different laboratories for geometrically defining lung regions of interest. We evaluated the effect of these different approaches on the derived indices classically used to assess inhaled aerosol deposition in the lungs. Our primary intention was to assess the ability of different regional lung templates to discriminate between central and peripheral airway deposition patterns generated by inhaling aerosols of different particle sizes. METHODS: We investigated six methods most commonly reported in the scientific literature to define lung regions of interest and assessed how different each of the derived regional lung indices were between the methods to quantify regional lung deposition. We used monodisperse albuterol aerosols of differing particle size (1.5, 3, and 6 µm) in five mild asthmatic subjects [forced expiratory volume in 1 sec (FEV(1)) 90% predicted] to test the different approaches of each laboratory. RESULTS: We observed the areas of geometry used to delineate central (C) and peripheral (P) lung regions of interest varied markedly between different laboratories. There was greater similarity between methods in values of penetration index (PI), defined as P/C aerosol counts normalized by P/C krypton ventilation counts, compared to nonnormalized C/P or P/C aerosol count-ratios. Normalizing the aerosol deposition P/C count-ratios by the ventilation P/C count-ratios, reduced the variability of the data. There was dependence of the regional lung deposition indices on the size of the P region of interest in that, as P increased, C/P count-ratios decreased and P/C count-ratios increased, whereas PI was less affected by variations in the P area. We found particle size, itself, strongly influenced the indices of regional aerosol deposition such that C/P count-ratios increased with increasing particle size for each method and conversely, P/C count-ratios and PI decreased. CONCLUSIONS: Different approaches used to determine pulmonary regions of interest and quantify aerosol deposition produce different results. Our research highlights a genuine need for a consensus to standardize the methodology to facilitate data comparison between laboratories on aerosol deposition.

Predicting the clinical effect of a short acting bronchodilator in individual patients using artificial neural networks.

Artificial neural networks were used in this study to model the relationships between in vitro data, subject characteristics and in vivo outcomes from N=18 mild-moderate asthmatics receiving monodisperse salbutamol sulphate aerosols of 1.5, 3 and 6 µm mass median aerodynamic diameter in a cumulative dosing schedule of 10, 20, 40 and 100 µg. Input variables to the model were aerodynamic particle size (APS), body surface area (BSA), age, pre-treatment forced expiratory volume in one-second (FEV(1)), forced vital capacity, cumulative emitted drug dose and bronchodilator reversibility to a standard salbutamol sulphate 200 µg dose MDI (REV(%)). These factors were used by the model to predict the bronchodilator response at 10 (T10) and 20 (T20) min after receiving each of the 4 doses for each of the 3 different particle sizes. Predictability was assessed using data from selected patients in this study, which were set aside and not used in model generation. Models reliably predicted ΔFEV(1)(%) in individual subjects with non-linear determinants (R(2)) of ≥ 0.8. The average error between predicted and observed ΔFEV(1)(%) for individual subjects was <4% across the cumulative dosing regimen. Increases in APS and drug dose gave improved ΔFEV(1)(%). Models also showed trends towards improved responses in younger patients and those having greater REV(%), whilst BSA was also shown to influence clinical effect. These data show that APS can be used to discriminate predictably between aerosols giving different bronchodilator responses across a cumulative dosing schedule, whilst patient characteristics can be used to reliably estimate clinical response in individual subjects.

Regional lung deposition and bronchodilator response as a function of beta2-agonist particle size.

RATIONALE: Aerosol particle size influences the extent, distribution, and site of inhaled drug deposition within the airways. OBJECTIVES: We hypothesized that targeting albuterol to regional airways by altering aerosol particle size could optimize inhaled bronchodilator delivery. METHODS: In a randomized, double-blind, placebo-controlled study, 12 subjects with asthma (FEV1, 76.8 +/- 11.4% predicted) inhaled technetium-99m-labeled monodisperse albuterol aerosols (30-microg dose) of 1.5-, 3-, and 6-microm mass median aerodynamic diameter, at slow (30-60 L/min) and fast (> 60 L/min) inspiratory flows. Lung and extrathoracic radioaerosol deposition were quantified using planar gamma-scintigraphy. Pulmonary function and tolerability measurements were simultaneously assessed. Clinical efficacy was also compared with unlabeled monodisperse albuterol (15-microg dose) and 200 microg metered-dose inhaler (MDI) albuterol. RESULTS: Smaller particles achieved greater total lung deposition (1.5 microm [56%], 3 microm [50%], and 6 microm [46%]), farther distal airways penetration (0.79, 0.60, and 0.36, respective penetration index), and more peripheral lung deposition (25, 17, and 10%, respectively). However, larger particles (30-microg dose) were more efficacious and achieved greater bronchodilation than 200 microg MDI albuterol (deltaFEV1 [ml]: 6 microm [551], 3 microm [457], 1.5 microm [347], MDI [494]). Small particles were exhaled more (1.5 microm [22%], 3 microm [8%], 6 microm [2%]), whereas greater oropharyngeal deposition occurred with large particles (15, 31, and 43%, respectively). Faster inspiratory flows decreased total lung deposition and increased oropharyngeal deposition for the larger particles, with less bronchodilation. A shift in aerosol distribution to the proximal airways was observed for all particles. CONCLUSIONS: Regional targeting of inhaled beta2-agonist to the proximal airways is more important than distal alveolar deposition for bronchodilation. Altering intrapulmonary deposition through aerosol particle size can appreciably enhance inhaled drug therapy and may have implications for developing future inhaled treatments.