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Introduction: The deposition of inhaled medications is the first step in the pulmonary pharmacokinetic process to produce a therapeutic response. Not only lung dose but more importantly the distribution of deposited drug in the different regions of the lung determines local bioavailability, efficacy, and clinical safety. Assessing aerosol deposition patterns has been the focus of intense research that combines the fields of physics, radiology, physiology, and biology., Areas Covered: The review covers the physics of aerosol transport in the lung, experimental, and in-silico modeling approaches to determine lung dose and aerosol deposition patterns, the effect of asthma, chronic obstructive pulmonary disease, and cystic fibrosis on aerosol deposition, and the clinical translation potential of determining aerosol deposition dose., Expert Opinion: Recent advances in in-silico modeling and lung imaging have enabled the development of realistic subject-specific aerosol deposition models, albeit mainly in health. Accurate modeling of lung disease still requires additional refinements in existing imaging and modeling approaches to better characterize disease heterogeneity in peripheral airways. Nevertheless, recent patient-centric innovation in inhaler device engineering and the incorporation of digital technology have led to more consistent lung deposition and improved targeting of the distal airways, which better serve the clinical needs of patients.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes CoronaVirus Disease 2019 (COVID-19), has resulted in a worldwide pandemic and currently represents a major public health crisis. It has caused outbreaks of illness through person-to-person transmission of the virus mainly via close contacts, and droplets produced by an infected person's cough or sneeze. Aerosolised inhaled therapy is the mainstay for treating obstructive airway diseases at home and in healthcare settings, but there is heightened particular concern about the potential risk for transmission of SARS-CoV-2 in the form of aerosolised respiratory droplets during the nebulised treatment of patients with COVID-19. As a consequence of this concern, the use of hand-held inhalers, especially pressurised metered dose inhalers, has risen considerably as an alternative to nebulisers, and this switch has led to inadequate supplies of inhalers in some countries. However, there is no evidence supporting an increased risk of viral transmission during nebulisation in COVID-19 patients. Furthermore, some patients may be unable to adequately use their new device and may not benefit fully from the switch to treatment via hand-held inhalers. Thus, there is no compelling reason to alter aerosol delivery devices for patients with established nebuliser-based regimens. The purpose of this paper is to discuss the current evidence and understanding of the use of aerosolised inhaled therapies during the SARS-CoV-2 pandemic and to provide some guidance on the measures to be taken to minimise the risk of transmitting infection, if any, during aerosol therapies., (© 2021. Società Italiana di Medicina Interna (SIMI).)

Inhalation therapy is one of the oldest approaches to the therapy of diseases of the respiratory tract. It is well recognised today that the most effective and safe means of treating the lungs is to deliver drugs directly to the airways. Surprisingly, the delivery of therapeutic aerosols has a rich history dating back more than 2,000 years to Ayurvedic medicine in India, but in many respects, the introduction of the first pressurised metered-dose inhaler (pMDI) in 1956 marked the beginning of the modern pharmaceutical aerosol industry. The pMDI was the first truly portable and convenient inhaler that effectively delivered drug to the lung and quickly gained widespread acceptance. Since 1956, the pharmaceutical aerosol industry has experienced dramatic growth. The signing of the Montreal Protocol in 1987 to reduce the use of CFCs as propellants for aerosols led to a surge in innovation that resulted in the diversification of inhaler technologies with significantly enhanced delivery efficiency, including modern pMDIs, dry powder inhalers and nebuliser systems. There is also great interest in tailoring particle size to deliver drugs to treat specific areas of the respiratory tract. One challenge that has been present since antiquity still exists, however, and that is ensuring that the patient has access to the medication and understands how to use it effectively. In this article, we will provide a summary of therapeutic aerosol delivery systems from ancient times to the present along with a look to the future.

Inhaled therapies are the cornerstone of treatment in asthma and chronic obstructive pulmonary disease, and there are a multitude of devices available. There is, however, a distinct lack of evidence-based guidance for healthcare providers on how to choose an appropriate inhaler. This review aims to summarise recent updates on topics related to inhaler choice, and to offer practical considerations for healthcare providers regarding currently marketed devices. The importance of choosing the right inhaler for the right patient is discussed, and the relative merits of dry powder inhalers, pressurised metered dose inhalers, breath-actuated pressurised metered dose inhalers, spacers and soft mist inhalers are considered. Compiling the latest studies in the devices therapy area, this review focuses on the most common types of handling errors, as well as the comparative rates of incorrect inhalation technique between devices. The impact of device-specific handling errors on inhaler performance is also discussed, and the characteristics that can impair optimal drug delivery, such as inhalation flow rate, inhalation volume and particle size, are compared between devices. The impact of patient perceptions, behaviours and problems with inhalation technique is analysed, and the need for appropriate patient education is also highlighted. The continued development of technology in inhaler design and the need to standardise study assessment, endpoints and patient populations are identified as future research needs. The reviews of this paper are available via the supplemental material section .

Background: Patients with COPD may be prescribed multiple inhalers as part of their treatment regimen, which require different inhalation techniques. Previous literature has shown that the effectiveness of inhaled treatment can be adversely affected by incorrect inhaler technique. Prescribing a range of device types could worsen this problem, leading to poorer outcomes in COPD patients, but the impact is not yet known., Aims: To compare clinical outcomes of COPD patients who use devices requiring similar inhalation technique with those who use devices with mixed techniques., Methods: A matched cohort design was used, with 2 years of data from the Optimum Patient Care Research Database. Matching variables were established from a baseline year of follow-up data, and two cohorts were formed: a "similar-devices cohort" and a "mixed-devices cohort". COPD-related events were recorded during an outcome year of follow-up. The primary outcome measure was an incidence rate ratio (IRR) comparing the rate of exacerbations between study cohorts. A secondary outcome compared average daily use of short-acting beta agonist (SABA)., Results: The final study sample contained 8,225 patients in each cohort (mean age 67 [SD, 10], 57% males, 37% current smokers). Patients in the similar-devices cohort had a lower rate of exacerbations compared with those in the mixed-devices cohort (adjusted IRR 0.82, 95% confidence interval [CI] 0.80-0.84) and were less likely to be in a higher-dose SABA group (adjusted proportional odds ratio 0.54, 95% CI 0.51-0.57)., Conclusion: COPD patients who were prescribed one or more additional inhaler devices requiring similar inhalation techniques to their previous device(s) showed better outcomes than those who were prescribed devices requiring different techniques., Competing Interests: SBA has no shares in any pharmaceutical companies. She has received sponsorship to carry out studies, together with Board Membership, consultant agreements and honoraria for presentation, from several pharmaceutical companies that market inhaled products. These include AstraZeneca, GlaxoSmithKline, Meda, Mundipharma and Teva. HC has no shares in any pharmaceutical companies. He has received sponsorship to carry out studies, together with Board Membership, consultant agreements and honoraria for presentation, from several pharmaceutical companies that market inhaled products. These include Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Innovata Biomed, Meda, Napp Pharmaceuticals, Mundipharma, NorPharma, Norvartis, Orion, Sanofi, Teva, Truddell Medical International, UCB and Zentiva. Research sponsorship has also been received from grant awarding bodies (EPSRC and MRC). He is the owner of Inhalation Consultancy Ltd. He is also an employee of Research in Real Life Ltd, which conducted this study and which has conducted paid research in respiratory disease on behalf of the following other organizations in the past 5 years: Aerocrine, AKL Ltd, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Meda, Mundipharma, Napp, Novartis, Orion, Takeda, Teva, and Zentiva, a Sanofi company. RC has a patent on an audio-based technology to assess response to inhaled medication. He currently has grants from GSK and Aerogen and receives speaker and Advertisement board fees from GSK Novartis, Boehringer and TEVA. FL has no shares in any pharmaceutical companies. FL reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla and Teva Pharmaceuticals. FL has board membership with Boehringer Ingelheim, Chiesi, Teva Pharmaceuticals. RRR reports grants and personal fees from Almirall, AstraZeneca, Boehringer Ingelheim, Ferrer Group, Mylan, Novartis, Pearl Therapeutics, Takeda, and TEVA and grants and personal fees from Menarini during the conduct of the study. He is member of the GOLD Board of Directors and of the Scientific Committee. SY is employed by Observational and Pragmatic Research Institute Pte Ltd, which receives funding from UK National Health Service, British Lung Foundation, Aerocrine, AKL Ltd, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Eli Lilly, GlaxoSmithKline, Meda, Merck, Mundipharma, Napp, Novartis, Orion, Pfizer, Respiratory Effectiveness Group, Takeda, Teva Pharmaceuticals and Zentiva. DP has board membership with Aerocrine, Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Meda, Mundipharma, Napp, Novartis and Teva Pharmaceuticals; consultancy with Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Meda, Mundipharma, Napp, Novartis, Pfizer and Teva Pharmaceuticals; grants and unrestricted funding for investigator-initiated studies (conducted through Research in Real-Life Ltd, which is subcontracted by Observational and Pragmatic Research Institute Pte Ltd, and OPRI) from UK National Health Service, British Lung Foundation, Aerocrine, AKL Ltd, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Eli Lilly, GlaxoSmithKline, Meda, Merck, Mundipharma, Napp, Novartis, Orion, Pfizer, Respiratory Effectiveness Group, Takeda, Teva Pharmaceuticals and Zentiva; payments for lectures/speaking from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Meda, Merck, Mundipharma, Novartis, Pfizer, Skyepharma, Takeda and Teva Pharmaceuticals; payment for manuscript preparation from Mundipharma and Teva Pharmaceuticals; patents (planned, pending or issued) from AKL Ltd; payment for the development of educational materials from GlaxoSmithKline and Novartis; stock/stock options from AKL Ltd which produces phytopharmaceuticals; owns 80% of Research in Real Life Ltd, which is subcontracted by OPRI, 75% of the social enterprise Optimum Patient Care Ltd and 75% of OPRI; received payment for travel/accommodations/meeting expenses from Aerocrine, Boehringer Ingelheim, Mundipharma, Napp, Novartis and Teva Pharmaceuticals; funding for patient enrolment or completion of research from Almirral, Chiesi, Teva Pharmaceuticals and Zentiva; and peer reviewer for grant committees of the Medical Research Council (2014), Efficacy and Mechanism Evaluation programme (2012), HTA (2014). The other authors report no conflicts of interest in this work.

Chronic obstructive pulmonary disease (COPD) is common in older people. Inhaled medications are the mainstay of pharmacological treatment of COPD, and are typically administered by handheld inhalers, such as pressurised metered-dose inhalers and dry powder inhalers, or by nebulisers. For each of the three major categories of aerosol delivery devices, several new inhalers have recently been launched, each with their own particularities, advantages and disadvantages. Consequently, broader availability of new drug-device combinations will increase prescription opportunities. Despite this, however, there is limited guidance available in published guidelines on the choice of inhalers, and still less consideration is given to elderly patients with COPD. The aim of this article is to provide a guide for healthcare professionals on device selection and factors to be considered for effective inhaled drug delivery in elderly COPD patients, including device factors (device type and complexity of use), patient factors (inspiratory capabilities, manual dexterity and hand strength, cognitive ability, co-morbidities) and considerations for healthcare professionals (proper education of patients in device use).

Prescription cost-containment measures are increasing in many European countries and, as more inhaler devices become available, there may be pressure to switch patients from reference inhaled medication to cheaper generic inhaled drugs. Indeed, in some countries, such a substitution is mandated by current regulations, and patients who do not accept the substitution have to pay the difference in cost. Generic inhaled drugs are therapeutically equivalent to original branded options but may differ in their formulation and inhalation device. This new situation raises questions about the potential impact of switching from branded to generic inhaled medications in patients with asthma or chronic obstructive pulmonary disease (COPD), with or without their consent, in countries where this is permitted. Acquisition cost savings from a substitution could be offset by costs related to deterioration in asthma control or worsening in COPD outcomes if the patient is unable or unwilling to use the inhaler device properly. Non-adherence to therapy and incorrect inhaler usage are recognised as major factors in uncontrolled asthma and worsening of COPD outcomes. Switching patients to a different inhaler device may exacerbate these problems, particularly in patients who disagree to switch. Where switching is permitted or mandatory, it is crucial that the reason for switching has been properly explained to the patient and adequate instruction for operating correctly the inhaler have clearly been provided., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Inhaled therapy is the cornerstone of pharmacotherapy in patients with asthma and chronic obstructive pulmonary disease (COPD). Appropriate inhalation device selection is as important as drug choice but device-specific guidance appears to be lacking., Methods: To quantify the level of inhalation-device recommendations in clinical guidelines, a review was conducted by hand-searching national and international asthma and COPD guidelines (Global Initiative for Asthma [GINA] and Global initiative for chronic Obstructive Lung Disease [GOLD] guidelines) and an international guideline on device selection (the American College of Chest Physicians/American College of Asthma, Allergy, and Immunology [ACCP/ACAAI]). For each guideline, the number of pages, tables/figures and references relating to inhalation devices was identified., Results: GINA and GOLD guidelines contain very little inhalation device-specific guidance beyond recommendations for demonstrating and testing correct inhalation technique: <2% of pages or references and <3% of tables/figures are dedicated to devices. Device-related content in the ACCP/ACAAI device selection guideline was considerably higher with 54% of pages, 88% of tables/figures and 82% of references, respectively. Results in national guidelines reflect those on international guidelines., Conclusions: These results indicate that there is a considerable lack of clear and specific guidance regarding inhalation devices in current asthma/COPD guidelines. More robust studies on the impact of inhalation devices are needed to increase the number of evidence statements and recommendations regarding inhalation devices., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Drug delivery to the lungs is an effective way of targeting inhaled therapeutic aerosols and treating obstructive airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD). In the past 10 years, several new drugs for the management of asthma and COPD have been marketed and more are under development. These new therapeutic respiratory drugs have been furthered by innovations in all categories of pulmonary drug delivery systems to ensure optimal aerosolisation performance, consistency in efficacy and satisfactory patient adherence. In this review, we discuss the technological advances and innovations in recent inhaler devices and the evolving roles of pressurised metered-dose inhalers, dry powder inhalers and nebulisers, as well as their impact on patient adherence to treatment., (© 2014 S. Karger AG, Basel)

Inhaled medication is the cornerstone of the pharmacological treatment of patients with asthma and COPD. The major two classes of inhaled medication include corticosteroids (ICS) and bronchodilators. There is a wide diversity in molecules in both classes. Moreover, there is a wide variation in delivery systems. The correct use of inhalers is not granted and patients often incur in many mistakes when using pMDIs and DPIs, despite repeated instructions. A better matching between patient and device could be accomplished if the physician is aware of: (1) the patient characteristics (disease, severity, fluctuation in airflow obstruction, etc); (2) what class of medication is indicated; (3) where in the lung the medication should be delivered; and, (4) how this can be best achieved by a given device in this specific patient. We focus on the prescription of pMDIs and DPIs at the GP office or at the outpatient clinic of the hospital, and we propose an evidence based approach enabling the caregiver to make a rational choice in only a few minutes by just considering the following four simple questions: Who?, What? Where? and How? (the so-called 3W-H approach)., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To evaluate the retail sales of pressurised metered-dose inhalers (pMDIs), dry-powder inhalers (DPIs) and liquids for nebulisation in 16 European countries., Methods: Retail sales data relating to pMDIs, DPIs and liquids for nebulisation delivering short- and long-acting bronchodilators, corticosteroids and combinations between 2002 and 2008 were obtained from the IMS sales database. The IMS database ensured that wholesalers' stock sales accurately matched that of retail pharmacies and included purchases by panel pharmacies directly from pharmaceutical manufacturers, specialist wholesalers and distribution cooperatives., Results: Mean inhaler retail sales (expressed as percentages of total sales) were 47.5% for pMDIs, 39.5% for DPIs and 13% for nebulisers. The distribution of inhaler sales differed significantly between the countries with pMDI sales greatest in the United Kingdom and Hungary compared to other countries, where DPI sales prevailed. Sales of nebulisation liquids were high in Italy. The pMDI was the most frequently prescribed inhaler for bronchodilators. In contrast, retail sales of DPIs were similar to those of pMDIs for inhaled corticosteroids, and higher in the case of inhalers with combined long-acting β(2)-agonist and corticosteroid., Conclusion: We found a high degree of variability in inhaler prescription between European countries. Differing health policies, costs, health insurance issues, pharmaceutical/commercial aspects and prescribers' and patients' preferences may explain this variation. We suggest a need for more uniform, outcome-led inhaler prescribing practice across Europe to improve the efficacy and cost effectiveness of the treatment of obstructive airways diseases., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Inhaled medications are the preferred therapies for patients with asthma and COPD, but their effectiveness is limited by the patient's ability to use the device properly, an issue often neglected when these medications are prescribed. Correct inhaler technique must be taught and learnt, and requires educational and motivational programs aimed at patients and healthcare providers alike. Written instructions alone are manifestly insufficient: education must include practical demonstration and periodic re-assessment and reeducation, since correct technique and motivation usually deteriorate with time. Several devices are available on the market, the purpose of which is to train patients to use inhalers correctly. They are often directed at particular devices or groups of devices and/or particular critical aspects of technique. This paper reviews the devices currently available for training patients in the correct use of both pressurised metered-dose inhalers (pMDIs) and dry powder inhalers (DPIs).

Aim: Spacer devices are inhalation aids of varying dimension and complexity, specifically designed to overcome problems with the use of pressurised metered dose inhalers (pMDIs). The aim of this review is to examine the current understanding about these inhalation devices and discuss their advantages and disadvantages., Methods: The pertinent literature concerning the characteristics and effects of spacers on delivery and lung deposition of inhaled medications, as well as their clinical efficacy in patients with reversible airway obstruction, is examined., Results: Spacers minimise problems of poor inhalation technique with pMDI, reduce oropharyngeal deposition and increase lung deposition. Spacers improve the clinical effect of inhaled medications, especially in patients unable to use a pMDI properly. Compared to both pMDIs and dry-powder inhalers, spacers may increase the response to beta-adrenergic bronchodilators, even in patients with correct inhalation technique. A pMDI plus spacer has proven to be viable lower cost alternative to the use of a nebuliser for delivering large bronchodilator doses in patients with severe acute asthma or chronic obstructive pulmonary disease. The use of large-volume spacers is recommended for delivering high doses of inhaled corticosteroids, and may permit a lower maintenance dose to be used., Conclusion: pMDIs may be routinely fitted with a spacer, especially in situations where correct pMDI use is unlikely.

Background: Incorrect usage of inhaler devices might have a major influence on the clinical effectiveness of the delivered drug. This issue is poorly addressed in management guidelines., Methods: This article presents the results of a systematic literature review of studies evaluating incorrect use of established dry powder inhalers (DPIs) by patients with asthma or chronic obstructive pulmonary disease (COPD)., Results: Overall, we found that between 4% and 94% of patients, depending on the type of inhaler and method of assessment, do not use their inhalers correctly. The most common errors made included failure to exhale before actuation, failure to breath-hold after inhalation, incorrect positioning of the inhaler, incorrect rotation sequence, and failure to execute a forceful and deep inhalation. Inefficient DPI technique may lead to insufficient drug delivery and hence to insufficient lung deposition. As many as 25% of patients have never received verbal inhaler technique instruction, and for those that do, the quality and duration of instruction is not adequate and not reinforced by follow-up checks., Conclusions: This review demonstrates that incorrect DPI technique with established DPIs is common among patients with asthma and COPD, and suggests that poor inhalation technique has detrimental consequences for clinical efficacy. Regular assessment and reinforcement of correct inhalation technique are considered by health professionals and caregivers to be an essential component of successful asthma management. Improvement of asthma and COPD management could be achieved by new DPIs that are easy to use correctly and are forgiving of poor inhalation technique, thus ensuring more successful drug delivery.

Aims: This study aimed at evaluating changes in airway patency, lung volumes and perception of breathing discomfort intensity following salbutamol administration via the Diskus dry-powder inhaler (DPI) or a pressurized metered-dose inhaler with the Volumatic valved holding chamber (pMDI + Volumatic) in asthmatic patients with methacholine-induced bronchoconstriction., Methods: On six different study days, 18 patients inhaled methacholine until forced expiratory volume in 1 s (FEV(1)) decreased by approximately 35% of baseline. Following placebo, 200 and 400 microg of salbutamol through the pMDI + Volumatic or the Diskus, changes in FEV(1), volume-adjusted mean forced expiratory flow from 25 to 75% of the forced vital capacity (isoFEF(25-75)), lung volumes and breathing discomfort intensity, assessed by visual analogue scale (VAS) score, were repeatedly measured over a 60-min observation period., Results: Induced bronchoconstriction was accompanied by obvious reductions in lung volumes and increases in VAS score. After salbutamol administration, FEV(1) and VAS score changes were similar in all experimental conditions. However, following 400 microg salbutamol via pMDI + Volumatic, isoFEF(25-75) values increased up to 4.48 l s(-1) (95% confidence interval 4.06, 4.90), a significantly (P < 0.01) higher value than those attained in all other experimental conditions. Independently of the salbutamol dose, lung volumes rose to significantly (P < 0.01) higher levels in pMDI + Volumatic than in Diskus trials. The low salbutamol dose via the pMDI + Volumatic and the high dose via the DPI increased isoFEF(25-75) and lung volumes to similar extents., Conclusions: Salbutamol via the pMDI + Volumatic provides greater isoFEF(25-75) and lung volume increases in asthmatic patients with induced bronchoconstriction; salbutamol-induced changes in VAS scores poorly reflect those in small airway patency. The lack of differences in FEV(1) increases observed after 200 and 400 microg salbutamol may reflect attainment of the flat portion of the dose-response curve using either device.

The effects of spacer devices on the magnitude and velocity of large and small airway bronchodilator responses in asthmatic patients who can correctly operate a metered dose inhaler (MDI) remain unclear. According to a double-blinded, randomized, crossover protocol, 14 asthmatic patients were studied on seven separate occasions. On each occasion, patients inhaled doubling methacholine concentrations until forced expiratory volume in 1 second (FEV1) had fallen by 20% of baseline. Changes in forced expiratory flow between 25% and 75% of vital capacity (FEF25-75) were also evaluated. Subsequently, patients were administered 20 or 50 micrograms of procaterol from an MDI either alone or in conjunction with a small- or large-volume spacer device. Changes in FEV1 and FEF25-75 corrected for baseline forced vital capacity (isoFEF25-75) were assessed at 3-minute intervals for 15 minutes and at 30 minutes. Spontaneous recovery was similarly evaluated. The time required to attain significant increases in both FEV1 and isoFEF25-75 was calculated in bronchodilator trials. With 20 micrograms of procaterol, both spacers allowed larger and faster FEV1 increases than the MDI alone (P < 0.01); with 50 micrograms, the velocity and magnitude of FEV1 increases were further enhanced in trials with the MDI alone. The lower procaterol dose via the large-volume spacer determined larger and faster isoFEF25-75 increases than the higher dose via both the small-volume spacer and the MDI alone (P < 0.01). Spacers enhance bronchodilation even in patients using MDIs optimally. Compared with both the small-volume device and the MDI alone, the large-volume spacer allows faster and larger small airway dilation with less than half of the procaterol dose.