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Introduction: The manufacture of modern dry powder inhalers (DPIs), starting with the Spinhaler (Fisons) in 1967, was only possible thanks to a series of technological developments in the 20 th century, of which many started first around 1950. Not until then, it became possible to design and develop effective, cheap and mass-produced DPIs. The link between these technological developments and DPI development has never been presented and discussed before in reviews about the past and present of DPI technology., Areas Covered: The diversity of currently used DPIs with single dose, multiple-unit dose and multi-dose DPIs is discussed, including the benefits and drawbacks of this diversity for correct use and the efficacy of the therapy. No specific databases or search engines otherwise than PubMed and Google have been used., Expert Opinion: Considering the relatively poor efficacy regarding lung deposition of currently used DPIs, the high rates of incorrect inhaler use and inhalation errors and the poor adherence to the therapy with inhalers, much effort must be put in improving these shortcomings for future DPI designs. Delivered fine particle doses must be increased, correct inhaler handling must become more intuitive and simpler to perform, and the use of multiple inhalers must be avoided.

Introduction: Inhalation of herbs and other compounds has a long history but habits for medical treatment are intertwined with rituals to obtain hallucinatory effects and pleasurable sensations. Several examples of inhaled herbs, and the diseases they were used for, based on early translations of ancient manuscripts related to inhalation were found to be speculative and inconsistent with each other in literature. They needed to be reconsidered and verified with the original sources of information., Areas Covered: Examples of ancient inhalation and the development of early dry powder inhalers up to and including the first half of the twentieth century. Databases used for literature about historic events, ancient habits, and ancient science, included SmartCat, JSTOR, and ANDAT; various facts were verified via personal communication with historians and custodians of historic manuscripts and artifacts., Expert Opinion: Inhalation does not necessarily require active creation of inhalable aerosols, smokes or fumes. Inhaling 'healthy air' with volatile and gaseous components, or fine aerosols in pine forests, on volcano slopes and at the seaside must be considered as inhalation therapy too. From this viewpoint, inhalation therapy may have been much more common and widespread and have a longer history than is currently known from written evidence.

In recent years there is an increasing interest in the pulmonary delivery of large cohesive powder doses, i.e. drugs with a low potency such as antibiotics or drugs with a high potency that need a substantial fraction of excipient(s) such as vaccines stabilized in sugar glasses. The pulmonary delivery of high powder doses comes with unique challenges. For low potency drugs, the use of excipients should be minimized to limit the powder mass to be inhaled as much as possible. To achieve this objective the inhaler design should be adapted to the properties of the API in order to achieve a compatible combination of the drug formulation and inhaler device. The inhaler should have an appropriate powder dosing principle for which prefilled compartments seem most appropriate. The drug formulation should not only allow for accurate filling of these compartments but also enable efficient compartment emptying during inhalation. The dispersion principle must have the capacity to disperse considerable amounts of powder in a short time frame that allows the powder to reach the deep lung. Last, but not least, the inhaler should be simple and intuitive in use, be cost-effective and exhibit accurate and consistent, preferably patient independent, pulmonary delivery performance., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Correct inhalation technique is essential for effective use of dry powder inhalers (DPIs), as their effectiveness largely depends on the patient's inhalation manoeuvre. Children are an especially challenging target population for DPI development due to the large variability in understanding and inspiratory capacities. We previously performed a study in which we determined the prerequisites for a paediatric DPI in a mostly healthy paediatric population, for which we used an empty test inhaler with variable internal airflow resistance and mouthpiece. In the current study we investigated what specifications are required for a DPI for children with cystic fibrosis (CF), for which we expanded on our previous findings. We recorded flow profiles of 35 children with CF (aged 4.7-14.7 years) at three airflow resistances (0.031-0.045 kPa0.5.min.L-1) from which various inspiratory parameters were computed. Obstructions in the mouth during inhalation were recorded with a sinuscope. All children were able to perform a correct inhalation manoeuvre, although video analysis showed that children did not place the inhaler correctly in the mouth in 17% of the cases. No effect was found of medium to high airflow resistance on total inhaled volume, which implies that the whole resistance range tested is suitable for children with CF aged 4-14 years. No effect could be established of either mouthpiece design or airflow resistance on the occurrence of obstructions in the mouth cavity. This study confirms our previous conclusion that the development of DPIs specifically for children is highly desired. Such a paediatric DPI should function well at 0.5 L inhaled volume and a peak inspiratory flow rate of 20 to 30 L/min, depending on the internal airflow resistance. This resistance can be increased up to 0.045 kPa0.5.min.L-1 (medium-high) to reduce oropharyngeal deposition. A higher resistance may be less favourable due to its compromising effect on PIF and thereby on the energy available for powder dispersion.

There is increasing interest in the use of so-called 'extrafine' aerosols to target the small airways in the management of asthma and COPD. Using previously presented deposition data, we assessed whether submicron (<1μm) particles can improve central and deep lung deposition. Our data show instead that particles in the range 1-3μm are much more relevant in this respect. Based on this finding the Symbicort Turbuhaler, Seretide Diskus, Rolenium Elpenhaler and Foster (Fostair) NEXThaler ICS/LABA combination DPIs were tested in vitro as a function of the pressure drop (2, 4 and 6kPa) across the inhaler. Obtained fine particle fractions (FPFs) <5μm (as percent of label claim) were divided into subfractions <1, 1-3 and 3-5μm. Differences of up to a factor of 4 were found between the best (Turbuhaler) and worst performing DPI (Elpenhaler), particularly for the FPF in the size range 1-3μm. The NEXThaler, described as delivering 'extrafine' particles, did not appear to be superior in this size range. The marked differences in amount and size distribution of the aerosols between the devices in this study must cause significant differences in the total lung dose and drug distribution over the airways., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

Adhesive mixtures for inhalation are the most widely used type of formulation in dry powder inhalation products. Although they have been the subject of active research, the relationships between properties of the starting materials, the mixing and dispersion processes, and the dispersion performance of this type of formulation are generally poorly understood. Interactions between relevant variables have been mentioned as an important cause. By reviewing the effects on mixture dispersion performance of the most widely studied formulation variables we try to find out whether or not the understanding of adhesive mixtures has improved in recent years. We furthermore propose an approach that may potentially accelerate the process of understanding. General conclusions concerning the effects of the variables considered cannot be drawn, because inconsistent findings are reported throughout the literature for all of them. These inconsistencies are indeed largely the result of interactions between variables of the formulation and dispersion processes. Mechanisms for most of the observed effects and interactions have been proposed, but they often remain unproven and, therefore, speculative. We have attempted to condense the knowledge from the literature into a theoretical framework that is intended to help explain the interplay between variables. According to this framework, only few mixture properties are key to understanding the effects of and interactions between formulation variables. Therefore, we suggest that the development or optimisation of techniques to accurately characterise these mixture properties could be an effective approach to further the fundamental understanding of adhesive mixtures for inhalation and enable their rational engineering.

Background: Although understanding of the scientific basis of aerosol therapy with dry powder inhalers (DPIs) has increased, some misconceptions still persist. These include the beliefs that high resistance inhalers are unsuitable for some patients, that extra fine (<1.0 μm) particles improve peripheral lung deposition and that inhalers with flow rate-independent fine particle fractions (FPFs) produce a more consistent delivered dose to the lungs., Objectives: This article aims to clarify the complex inter-relationships between inhaler design and resistance, inspiratory flow rate (IFR), FPF, lung deposition and clinical outcomes, as a better understanding may result in a better choice of DPI for individual patients., Methods: The various factors that determine the delivery of drug particles into the lungs are reviewed. These include aerodynamic particle size distribution, the inspiratory manoeuvre, airway geometry and the three basic principles that determine the site and extent of deposition: inertial impaction, sedimentation and diffusion. DPIs are classed as either dependent or independent of inspiratory flow rate and vary in their internal resistance to inspiration. The effects of these characteristics on drug deposition in the airways are described using data from studies directly comparing currently available inhaler devices., Results: Clinical experience shows that most patients can use a high resistance DPI effectively, even during exacerbations. Particles in the aerodynamic size range from 1.5-5 μm are shown to be optimal, as particles <1.0 μm are very likely to be exhaled again while those >5 μm may impact on the oropharynx. For DPIs with a constant FPF at all flow rates, less of the delivered dose reaches the central and peripheral lung when the flow rate increases, risking under-dosing of the required medication. In contrast, flow rate-dependent inhalers increase their FPF output at higher flow rates, which compensates for the greater impaction on the upper airways as flow rate increases., Conclusions: The technical characteristics of different inhalers and the delivery and deposition of the fine particle dose to the lungs may be important additional considerations to help the physician to select the most appropriate device for the individual patient to optimise their treatment., (Copyright © 2014. Published by Elsevier Ltd.)

Age appropriateness is a major concern of pulmonary delivery devices, in particular of dry powder inhalers (DPIs), since their performance strongly depends on the inspiratory flow manoeuvre of the patient. Previous research on the use of DPIs by children focused mostly on specific DPIs or single inspiratory parameters. In this study, we investigated the requirements for a paediatric DPI more broadly using an instrumented test inhaler. Our primary aim was to assess the impact of airflow resistance on children's inspiratory flow profiles. Additionally, we investigated children's preferences for airflow resistance and mouthpiece design and how these relate to what may be most suitable for them. We tested 98 children (aged 4.7-12.6 years), of whom 91 were able to perform one or more correct inhalations through the test inhaler. We recorded flow profiles at five airflow resistances ranging from 0.025 to 0.055 kPa0.5.min.L-1 and computed various inspiratory flow parameters from these recordings. A sinuscope was used to observe any obstructions in the oral cavity during inhalation. 256 flow profiles were included for analysis. We found that both airflow resistance and the children's characteristics affect the inspiratory parameters. Our data suggest that a medium-high resistance is both suitable for and well appreciated by children aged 5-12 years. High incidences (up to 90%) of obstructions were found, which may restrict the use of DPIs by children. However, an oblong mouthpiece that was preferred the most appeared to positively affect the passageway through the oral cavity. To accommodate children from the age of 5 years onwards, a DPI should deliver a sufficiently high fine particle dose within an inhaled volume of 0.5 L and at a peak inspiratory flow rate of 25-40 L.min-1. We recommend taking these requirements into account for future paediatric inhaler development.

Objectives: To use computational fluid dynamics (CFD) for evaluating and understanding the performance of the high-dose disposable Twincer™ dry powder inhaler, as well as to learn the effect of design modifications on dose entrainment, powder dispersion and retention behaviour., Methods: Comparison of predicted flow and particle behaviour from CFD computations with experimental data obtained with cascade impactor and laser diffraction analysis., Key Findings: Inhaler resistance, flow split, particle trajectories and particle residence times can well be predicted with CFD for a multiple classifier based inhaler like the Twincer™. CFD computations showed that the flow split of the Twincer™ is independent of the pressure drop across the inhaler and that the total flow rate can be decreased without affecting the dispersion efficacy or retention behaviour. They also showed that classifier symmetry can be improved by reducing the resistance of one of the classifier bypass channels, which for the current concept does not contribute to the swirl in the classifier chamber., Conclusions: CFD is a highly valuable tool for development and optimisation of dry powder inhalers. CFD can assist adapting the inhaler design to specific physico-chemical properties of the drug formulation with respect to dispersion and retention behaviour., (© 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.)