Clinical Pharmacology & TherapeuticsVolume 103, Issue 3 p. 395-395 Letter to the Editor Single Batch Bioequivalence Paradigm for Orally Inhaled Products: Time for Change Robert Hermann, Corresponding Author Robert Hermann robert.hermann@cr-appliance.de Clinical Research Appliance, Gelnhausen, GermanyCorrespondence: R. Hermann (robert.hermann@cr-appliance.de)Search for more papers by this authorBo Olsson, Bo Olsson Emmace Consulting, Lund, SwedenSearch for more papers by this authorLars Borgström, Lars Borgström Emmace Consulting, Lund, SwedenSearch for more papers by this authorDennis Sandell, Dennis Sandell S5 Consulting, Blentarp, SwedenSearch for more papers by this author Robert Hermann, Corresponding Author Robert Hermann robert.hermann@cr-appliance.de Clinical Research Appliance, Gelnhausen, GermanyCorrespondence: R. Hermann (robert.hermann@cr-appliance.de)Search for more papers by this authorBo Olsson, Bo Olsson Emmace Consulting, Lund, SwedenSearch for more papers by this authorLars Borgström, Lars Borgström Emmace Consulting, Lund, SwedenSearch for more papers by this authorDennis Sandell, Dennis Sandell S5 Consulting, Blentarp, SwedenSearch for more papers by this author First published: 14 December 2017 https://doi.org/10.1002/cpt.939Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume103, Issue3Breaking Down Barriers to Effective Patient CareMarch 2018Pages 395-395 RelatedInformation

Enhanced therapeutics are drug products derived from existing generic drugs that provide additional benefits to the patients and the healthcare system. Enhanced therapeutics are considered to be an important and relatively low risk source of innovation. Pulmonary drug delivery is the major delivery route to treat chronic respiratory diseases and has been proven as a potential delivery route for complex drugs that cannot be delivered orally. Development of dry powder inhalation systems targets the delivery of fine drug particles to the deep lung surface by a combination of drug formulation, primary packaging and a device, whereby each contributes to the overall performance. Various methodologies for the non-clinical and clinical performance testing of orally inhaled products have been proposed and applied with variable success. Regulatory pathways have been developed and applied since. Considerable efforts have been made during the past decade to understand and optimize pulmonary drug delivery including their efficient commercial manufacturing. Pulmonary drug delivery remains an area of future innovation in the effective treatment of pulmonary diseases as well as the systemic delivery of systemically active complex drugs.

Background: A validated method to predict lung deposition for inhaled medication from in vitro data is lacking in spite of many attempts to correlate in vitro and in vivo outcomes. By using an in vivo-like in vitro setup and analyzing inhalers from the same batches, both in vitro and in vivo, we wanted to create a situation where information from the in vitro and in vivo outcomes could be analyzed at the same time. Method: Nine inhalation products containing either budesonide or AZD4818 were evaluated. These comprised two pressurized metered dose inhalers (pMDIs), a pMDI plus a spacer, four dry powder inhalers, and two dosimetric nebulizers. In vitro, an in vivo-like setup consisting of anatomically correct inlet throats were linked to a flow system that could replay actual inhalation flow profiles through the throat to a filter or to an impactor. In vivo, total lung deposition was measured in healthy adults by pharmacokinetic methods. Results and Conclusion: We could show that the amount of drug escaping filtration in a realistic throat model under realistic delivery conditions predicts the typical total lung deposition in trained healthy adult subjects in the absence of significant exhaled mass. We could further show that by using combinations of throat models and flow profiles that represent realistic deviations from the typical case, variations in ex-cast deposition reflect between-subject variation in lung deposition. Further, we have demonstrated that ex-cast deposition collected either by a simple filter or by a cascade impactor operated at a fixed flow rate using a mixing inlet, to accommodate a variable flow profile through the inhaler, predicts equally well the lung deposited dose. Additionally, the ex-cast particle size distribution measured by this method may be relevant for predicting exhaled fraction and regional lung deposition by computational models.

Delivering therapeutic agents to the lungs requires a deep understanding of the kinetics and dynamics of drugs in this biologically and physiologically complex system. In this chapter these concepts are discussed and include drug dissolution rates in the airways, physical clearance mechanisms of the mucociliary escalator and cough, alveolar macrophage clearance, pulmonary metabolism, and pulmonary absorption. Finally, these aspects are considered together with drug and formulation aspects as determinants of duration of effects of inhaled products. The mechanisms of elimination of drug activity in the lungs by the various clearance processes described here are important factors to consider both in the development of new drugs and in understanding the relative merits of existing therapies.

Deposition and clearance studies are used during product development and in fundamental research. These studies mostly involve radionuclide imaging, but pharmacokinetic methods are also used to assess the amount of drug absorbed through the lungs, which is closely related to lung deposition. Radionuclide imaging may be two-dimensional (gamma scintigraphy or planar imaging), or three-dimensional (single photon emission computed tomography and positron emission tomography). In October 2009, a group of scientists met at the "Thousand Years of Pharmaceutical Aerosols" conference in Reykjavik, Iceland, to discuss future research in key areas of pulmonary drug delivery. This article reports the session on "Deposition, imaging and clearance." The objective was partly to review our current understanding, but more importantly to assess "what remains to be done?" A need to standardize methodology and provide a regulatory framework by which data from radionuclide imaging methods could be compared between centers and used in the drug approval process was recognized. There is also a requirement for novel radiolabeling methods that are more representative of production processes for dry powder inhalers and pressurized metered dose inhalers. A need was identified for studies to aid our understanding of the relationship between clinical effects and regional deposition patterns of inhaled drugs. A robust methodology to assess clearance from small conducting airways should be developed, as a potential biomarker for therapies in cystic fibrosis and other diseases. The mechanisms by which inhaled nanoparticles are removed from the lungs, and the factors on which their removal depends, require further investigation. Last, and by no means least, we need a better understanding of patient-related factors, including how to reduce the variability in pulmonary drug delivery, in order to improve the precision of deposition and clearance measurements.

Journal of Aerosol Medicine and Pulmonary Drug DeliveryVol. 23, No. S2 Special Supplement1000 Years of Pharmaceutical Aerosols: What Remains to Be Done?Reykjavik, Iceland, October 1–2, 2009Free AccessIntroduction 1000 Years of Pharmaceutical Aerosols: What Remains to Be Done?Lars Borgström, Andy Clark, and Bo OlssonLars BorgströmAstraZeneca R&D, Lund, Sweden.Search for more papers by this author, Andy ClarkNovartis Pharmaceutical Corp., San Carlos, California.Search for more papers by this author, and Bo OlssonAstraZeneca R&D, Lund, Sweden.Search for more papers by this authorPublished Online:6 Dec 2010https://doi.org/10.1089/jamp.2010.0848AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail In October 2010 a group of 38 scientists gathered in Reykjavik, Iceland, to discuss "What Remains to Be Done?" in the field of pharmaceutical aerosol science. The group included academics and industry scientists with a combined experience totaling 1,038 years. The purpose of the meeting was to use the wealth of knowledge represented by this group to speculate on, and recommend areas for, future research. To go with this forward-looking objective a novel approach to organization was taken. The session chairs and co-chairs were each invited to put together their sessions, and where given, both control of content and the speaker list. In order to make the meeting as interactive as possible, all the participants were expected to be part of a session and to give a presentation on their invited topic. The format of these presentations was a brief review of the state of the art, followed by suggestions for future research. Each topic was then discussed by the whole group. As a consequence of this approach the meeting naturally contained reviews of the current state of research in a given area, and this has been carried through to the articles published in this issue. The topics chosen for discussion were: Formulation and device design, Modeling and in vitro methods, Deposition and imaging, and Pulmonary biopharmaceutics. The manuscripts that follow in this issue contain summaries of these reviews and discussions, and highlight areas where the group believes there is still fruitful research to be done, and indeed, where our knowledge base is limited and research absolutely needs to be done!The formulation and device session was organized and chaired by Dr. Jeff Weers and Dr. Ian Smith. This session highlighted the many advances made over the last 5 decades, and concluded that future innovations most probably lie at the interface between formulation/device design and biology.Understanding, the interplay between particle clearance, cellular targeting, trafficking, and absorption was deemed to be the area that could be most fruitful and yield possible advances. In particular, pulmonary controlled release, which had much attention paid to it in the 1990s but failed to produce a viable technology, was deemed to be an area of much value if a viable approach could be found, particularly for topical antibiotic delivery. Targeting was another area highlighted, both in terms of formulations giving higher lung deposition, regional control, and reduced variability, as well as cellular targeting using active targeting moieties. The group still believed macromolecule delivery has its place in pulmonary delivery, and that improved systemic bioavailability should be an aspiration, as should improved transfection of pulmonary epithilieal cells with siRNA and DNA fragments. However, it was accepted that beyond the value of the scientific knowledge ultimately the market will decide on "the real value" of any of these areas.In the devices area, a better understanding of the patient interface has and continues to be the main concern for effective device development. Despite 50 years of work the industry is still regularly reminded that inhaler devices are less than adequate and in some cases are "patient unfriendly." Work in the area of patient psychology and device interactions is one area, although not strictly pharmaceutical in nature, that the group felt could produce major benefits to the patient. The group was very specific about what was needed in the short to medium term. For the pressurized metered dose inhaler (pMDI), development of a pMDI that delivers a consistent dose regardless of poor patient technique and, as part of this, a cost-effective breath actuation device to aid patient coordination is needed. For dry powder inhalers (DPIs), a simple open-inhale-close device was thought to be valuable (although some participants questioned if this would really help compliance or not). Also, a DPI device/formulation combination that delivers a consistent lung doses independent of a patient's inspiratory effort was thought to be a major advance if achieved. (It was noted that this is not the same as in vitro flow independence of delivered dose and aerosol particle size.)Session 2 was chaired by Dr. Stephen Newman and Dr. Gerhard Scheuch, and covered the areas of deposition, imaging, and clearance. Although it was agreed that huge progress has been made in imaging and analysis techniques since the early studies of the 1980s, there are some major areas that still need much development and understanding. One major area of agreement was the need to develop standards for image acquisition and data analysis techniques that all laboratories could/should use. The lack of standardization continues to prevent global meta-analysis of imaging studies, and as a consequence, limits the knowledge that can be obtained to the objectives of individual studies. However, although agreeing with the need, the group also understood the challenges involved in obtaining agreement between research centers each using techniques applicable to their particular study objectives. A second area highlighted, in line with the formulation and devices session, was developing an understanding of patient variability and how to reduce intrasubject variability in both lung and regional deposition. Imaging studies, appropriately conducted, can be used to investigate and understand variability but to do so the technique has to move beyond comparison of inhalers. An area of particular importance was to understand the relationship between regional deposition, pharmacokinetics, and clinical effect. In this regard the group felt that imaging was the only method currently available that could help in our understanding of these relationships and that 3D SPECT imaging may offer the best chance of understanding regional distributions. The third major area was understanding clearance of insoluble materials particularly nanoparticles. Although the relevance of this later point may seem questionable in the context of highly soluble pharmaceutical molecules currently being used therapeutically, it does have relevance in the context of controlled release formulations and the current trend of pharmaceutical research to produce more and more insoluble compounds.The third session was chaired by Dr. Peter Byron and Dr. Warren Finlay, and covered aspects of in vitro/in vivo correlations and predicting pulmonary drug deposition either from in vitro measurement or by mathematical modeling [one-dimensional semiempirical models and computational fluid dynamics (CFD) methods were both discussed]. Again, the tremendous progress that has been made both in developing more realistic models, assessing product performance using in vitro "sizing" methods, and modeling deposition was acknowledged. However, it was also pointed out that we are a very long way from regulators agreeing to approve significant changes to inhalers using any combination of in vitro testing and modeling, or indeed pharmaceutical scientists agreeing that they should. It was recognized by the group that prediction of total lung deposition was insufficient in itself as a characterization of a product and that measures, or predictions, of regional lung distribution are also required. This was felt particularly important for drugs with longer durations of action, although this perspective was felt to be an expression of the perceived lack of understanding of the relationship between regional deposition and clinical response rather than any currently available science.From the perspective of predicting device performance using modeling it was agreed that major work was needed before either adequate models or indeed the knowledge base was available to build them. The lack of a real understanding of how surface forces and fluid profiles interact to disperse powders was a fundamental missing piece in the modeling chain. For now it was felt that the combined approach of in vitro testing as an input boundary condition for the deposition models was the best approach.One of the major issues raised by the group was "validation" of either in vitro methods or modeling predictions. It was recognized that much work still remains to be done in these areas. The lack of dynamic models for the airways was recognized as a major limitation, and it was obvious that, despite recent progress, an understanding of the interactions between delivery devices and how these interactions affect airway geometry was sorely needed. The group also agreed that standardization of airway "geometries" needed to occur, both for oropharyngeal and lung casts used for in vitro testing as well as the spatial models used for deposition modeling. Standardization would result in an ability to make fairer comparison between data, models, and work carried out in different laboratories. Finally, the lack of good disease models of the lower respiratory tract was acknowledged in particular. The lack of an understanding of airway geometry variability, and hence its impact of deposition, was particularly troubling. Thus, the group felt that more work was needed in terms of the defining airway geometry and variability across the patient populations.The forth and final session was chaired by Dr. John Patton and Dr. Carsten Ehrhardt, and covered what was arguably the most difficult session: pulmonary biopharmaceutics, "The Particle has landed—Characterizing the fate of inhaled pharmaceuticals." The group concluded that despite "a modest body of literature" on the absorption of pharmaceutical compounds from the lung there is still a major lack of knowledge about any of the details. Although some basic principles of dissolution, absorption, metabolism, and distribution of compounds within the various lung tissue compartments were available the details and an understanding of how to control these aspects was definitely lacking. As a result, the lung biologists have many questions to answer both for large and small molecules. For example, what is the role of mucus clearance and movement in the redistribution and elimination of deposited drugs. What role does dissolution and spreading play in redistribution of deposited drug within the airway and what might the effect be on response? Finally, after these molecules have done their work in the airways, how do they get absorbed through the lung epithelium and enter the systemic circulation: transcellular or pericellular passive transport, or do drug transporters play a significant role? Also, although there are conjectures about the absorption and elimination of large moles, the mechanisms are still poorly understood. What is the role of proteases and peptidases in the lung; how are these molecules absorbed relative to small molecules? And of course, looming over all of these interesting puzzles is the question of how does disease affect transport and absorption. To quote the chairs of the session, "Essential questions are abundant; clever experimental designs to answer them are few."Although there were many suggestions in each session, there were a number of common themes across all of the discussions. First, both the modeling area and the deposition imaging areas needed some level of agreement and standardization. For the modeling group this was to agree on airways geometries both for normal and diseased lungs; for the imaging group it was agreeing on standard techniques for image acquisition and more important for processing of representation of data. In the formulation and biopharmaceutics areas there was a common need for better understanding of dissolution and clearance, driven primarily to enable more focused formulation development for objectives like controlled release or cell targeting. Finally, across all areas it was apparent that a much better understanding of interpatient variability was greatly needed. For formulation and device design this would bound the possibilities in terms of controlling lung dose and regional deposition; for modeling and imaging it would bring deposition data appropriately into context.Table 1 summarizes some of the key areas highlighted in each of the sessions that "need attention" from a research and understanding perspective. Although this summary facilitates understanding of the key points deemed by the group as important for future research, it should not be considered as all inclusive because, as always, judging areas for future research is at best a speculative endeavor. The main theme to these research questions can be seen as the intersections between inhalation products and the patient, both in terms of human interactions, basic biology, and overall variability. It is also clear that one of the areas that still holds many mysteries is lung biology and the phenomena of dissolution, metabolism, absorption, and clearance. A more comprehensive understanding of the biology may well lead to new treatments and new product forms. It was obvious from this meeting and the engaging and informative discussions that much "still remains to be done."Table 1. Summary of Some of the Key Areas Highlighted in Each of the Sessions That "Need Attention" from a Research and Understanding PerspectivePulmonary formulations and inhaler deviceIn vitro–in vivo correlations: Predicting drug depositionDeposition, imaging, and clearancePulmonary biopharmaceuticsNeed to understand the interplay between particle clearance, cellular targeting, trafficking, and absorption to enhance formulation development for controlled release and/or targetingNeed for standard geometries to facilitate comparisons between models and research groupsNeed for standardization of methods; image acquisition and data analysis to facilitate comparison and global analyses of dataNeed to understand the effects of mucocillary clearance of drug redistribution and eliminationNeed to understand how aerosol characteristics affect regional deposition and interpatient variability so as to facilitate formulation designNeed to understand the intersubject variability in airways geometric better and how this affects variability in lung and regional depositionNeed to understand intersubject variability in regional deposition and relationship between study means and population meansNeed to understand the factors controlling dissolution within the lung and the role of diffusional or transport driven redistributionNeed to develop device/product designs that give consistent lung dose and regional deposition patterns independent of a patient's inspiratory efforts/profileNeed better methods and studies to validate modeling prediction in a prospective wayNeed to develop a better understanding of relationship between deposition patterns and pulmonary pharmacokineticsNeed to understand absorption mechanisms for small molecules; pericellular/transcellular, active/passive and the role of transporters Need to develop dynamic models of the airways which take into account changes in geometry during inspiration and reflect the effects of diseaseNeed to understand clearance and redistribution caused by mucocillary clearanceNeed to understand the degradation/elimination and absorption mechanism for large molecules Need to understand factors affecting regional deposition, how to assess products, and how to predict outcomes Need knowledge of how disease affects on all of the aboveFinally, the organizers would like to thank the 38 participants for making the journey to Iceland, essentially at their own expense, and for contributing to both the meeting and this issue of the Journal of Aerosol Medicine and Pulmonary Drug Delivery. We would also like to thank AstraZeneca and Novartis Pharmaceuticals for sponsoring the meeting and this issue of the Journal. Hopefully, the contents that follow will be useful to researchers in the field and will inspire research for many years to come.Author Disclosure StatementThe authors declare that no conflicting financial interests, apart from being full-time employees, exist.FiguresReferencesRelatedDetailsCited byInhalation Biopharmaceutics10 December 2021Inhalation Toxicology StudiesIn Vitro Testing for Orally Inhaled Products: Developments in Science-Based Regulatory Approaches5 May 2015 | The AAPS Journal, Vol. 17, No. 4Priverzhennost' k ingalyatsionnoyterapii i kontrol' bronkhial'noy astmy15 March 2011 | Russian Journal of Allergy, Vol. 8, No. 1 Volume 23Issue S2Dec 2010 InformationCopyright 2010, Mary Ann Liebert, Inc.To cite this article:Lars Borgström, Andy Clark, and Bo Olsson.Introduction 1000 Years of Pharmaceutical Aerosols: What Remains to Be Done?.Journal of Aerosol Medicine and Pulmonary Drug Delivery.Dec 2010.S-1-S-4.http://doi.org/10.1089/jamp.2010.0848Published in Volume: 23 Issue S2: December 6, 2010PDF download

Airway absorption and bioavailability of inhaled corticosteroids (ICSs) may0020be influenced by differences in pharmacokinetic properties such as lipophilicity and patient characteristics such as lung function. This study aimed to further investigate and clarify the distribution of budesonide and fluticasone in patients with severe chronic obstructive pulmonary disease (COPD) by measuring the systemic availability and sputum concentration of budesonide and fluticasone, administered via combination inhalers with the respective long-acting β2-agonists, formoterol and salmeterol.

To investigate whether dry powder inhalers (DPIs) function in a constrained situation, a literature analysis was performed to evaluate the use of DPIs compared with established therapies in the treatment of acute asthma and COPD, irrespective of rapid-acting β2-agonist used. The external databases Medline, Embase, Biosis and Current Contents and AstraZeneca's internal literature database Planet were searched up to April 2008. Only publications or congress abstracts describing clinical trials in patients treated at EDs or hospitals were considered, and then only those in which exacerbation severity (measured as FEV1) were included. Fifteen clinical studies met these criteria; twelve in acute asthma and three in acute COPD. For acute asthma, eight studies were double-blind, randomised studies (six in adults and two in children), two were open-label studies (one in adults and one in children), and two were investigational (methacholine challenge) studies. For the acute COPD studies, one was double-blind and randomised, one was single-blind and randomised, and one was open-label. This review found that administration of fast-acting bronchodilators via DPIs, the majority of which were Turbuhaler, is effective during an asthma or COPD worsening. Our literature review finds that DPIs function in patients with acute asthma or COPD equally well as established therapies with other inhaler devices. Patients can therefore rely upon DPIs in the same way that they rely upon other inhaler devices.

In 3 open‐label studies, the systemic bioavailability of budesonide and formoterol administered via pressurized metered‐dose inhaler (pMDI) or dry powder inhaler (DPI) formulations was evaluated in asthma (24 children, 55 adults) or chronic obstructive pulmonary disease (COPD; n =26) patients. Treatments were administered at doses high enough to estimate pharmacokinetic parameters reliably. Two of the studies included an experimental budesonide pMDI formulation. In study 1 (asthma, adults), budesonide area under the curve (AUC) was 32% and 31% lower and maximal budesonide concentration (Cmax) 45% and 56% lower after budesonide/formoterol pMDI and budesonide pMDI versus budesonide DPI. Formoterol AUC and Cmax were 13% and 39% lower after budesonide/formoterol pMDI versus formoterol DPI. In study 2 (asthma, children), budesonide AUC and Cmax were 27% and 41% lower after budesonide/formoterol pMDI versus budesonide DPI + formoterol DPI. In study 3 (COPD/asthma, adults), budesonide AUC and Cmax were similar and formoterol AUC and Cmax 18% and 22% greater after budesonide/formoterol pMDI versus budesonide pMDI + formoterol DPI (COPD). Budesonide and formoterol AUC were 12% and 15% higher in COPD versus asthma patients. In conclusion, systemic exposure generally is similar or lower with budesonide/formoterol pMDI versus combination therapy via separate DPIs or monotherapy and comparable between asthma and COPD patients.

Objective: To investigate the pharmacokinetics of budesonide and formoterol administered concomitantly in healthy adults.

Flexhaler is a multiple-dose, inspiratory flow-driven dry powder inhaler that is a newer version of Turbuhaler, and is identical to the Symbicort Turbuhaler. Sustained performance is of the utmost importance to ensure consistent drug delivery throughout the lifespan of the inhaler. We report functionality testing results of Flexhaler inhalers used in two large-scale 12-week studies of budesonide (Pulmicort) and returned for testing. Functionality tests included measurement of airflow resistance and inspection of vital parts for the mechanical functionality of the inhaler, including visual inspection of the indicator wheel and function check of dose loading. In addition, delivered dose, particle size distribution, moisture content, and microbial counts were evaluated. Seven hundred sixteen out of 720 units were returned. Airflow resistance was not affected by the handling of the Flexhaler inhalers during use (prior to use, average airflow resistance: 67 Pa(0.5)*s*L(-1); returned inhalers: 66 and 67 Pa(0.5)*s*L(-1) in each study, respectively. The average dose delivered remained as intended after prolonged clinical use [95% (range 88 -103%) vs. reference of 99% (range 93-104%) before issue]. Relative fine particle dose ( <5 mum) after use was 107% (range 96-111%) of the reference value before issue. Moisture content in the inhaler desiccant was 3-25%, suggesting variability in storage conditions. Among the 28 inhalers randomly selected for microbiological testing there was no or very limited microbial growth. All 14 inhalers returned with functionality issues operated as intended and no reported functionality issues could be confirmed. Flexhaler inhalers operated as intended during these two clinical trials. These results should reassure both clinicians and patients with respect to the consistent quality of this unit for the delivery of dry powder formulations for inhalation.

The role of airway clearance in inhaled drug therapy is complex. Disease-induced bronchoconstriction results in a central drug-deposition pattern where mucociliary clearance is most efficient. When drug-induced bronchodilation is achieved, deposition and uptake becomes more peripheral, and because there is less mucociliary clearance in the periphery, this will lead to an unintentional increase in lung exposure and enhance the risk of systemic side effects. In addition, mucociliary clearance is pathologically reduced in both asthma and chronic obstructive pulmonary disease. Among inhaled corticosteroids, rate of dissolution and lung uptake differs considerably. For the slowly dissolving, lipophilic steroids, the contribution of mucociliary clearance to these findings appears significant, and variability in lung and systemic exposure resulting from variable mucociliary function appears to be amplified. In addition, dose optimisation of non-stable asthma becomes more complex. The present review highlights the impact of mucociliary clearance on inhaled corticosteroid disposition and identifies critical areas where more research is needed.

Background: Little is known about the impact of COPD on lung deposition of inhaled drugs and the relationship between lung-dose and response of pulmonary function measurements.Methods: Nineteen patients with varying degrees of COPD were randomized to inhale single doses of formoterol (Oxis((R))) Turbuhaler((R)) 4.5, 9, 18, and 36 mu g in a double blind, placebo-controlled, crossover design. Urinary excreted formoterol during 32 h was used to determine absolute lung deposition. Peak inspiratory flow (PIF) and inhaled volume (IV) were recorded to assess the patients' ability to use Turbuhaler. Efficacy was measured by spirometry, inspiratory capacity (IC), airway conductance (sG(AW)), and absolute lung volumes.Results: Mean pulmonary bioavailability of formoterol was about 24% of the nominal delivered dose after inhalation for the different treatments. No significant correlations between lung deposition and baseline FEV1, PIF or IV were shown. All formoterol doses produced statistically significant increases in FEV1, FVC, IC, and sG(AW) relative to placebo. Linear dose/response relationships were observed for these variables, with more narrow limits of the slopes for the lung-dose/response relationships than for the nominal-dose/ response relationships. Moreover, 36 and 18 mu g formoterol statistically significantly decreased functional residual capacity (FRC) and residual volume (RV) relative to placebo.Conclusions: This study could not show any difference in lung deposition of formoterol inhaled via Turbuhaler between patients with moderate and severe COPD. Moreover, the effect of formoterol on various pulmonary function measurements were more closely related to lung deposition than the inhaled nominal dose. (c) 2007 Elsevier Ltd. All rights reserved.

Magnetic resonance imaging (MRI) of the oropharyngeal region from 20 adult volunteers using four model inhalation devices (varying mouthpiece diameters, airflow resistances) and tidal breathing was carried out. Statistical analysis (convex hull method) selected 12 scans from 80 data sets representing the extremes of all dimensions in the population. Twelve physical mouth-throat models were made by stereolithography using the exact scan data. The aim was to produce models with varying dimensions to span the adult population, and to investigate if oropharyngeal dimensions affected throat retention for different delivery systems. In an in vitro analysis, the models were used to determine the retention effect of the oropharyngeal airspaces when drug aerosols were administered from four inhalation delivery systems: a pressurised metered dose inhaler (pMDI), two different dry powder inhalers (DPIs A and B), and a nebulizer. The aims of this work were to determine the key parameters governing mouth-throat retention and whether retention was dependent on the delivery system used. Characterizing the throat models by measuring 51 different dimensional variables enabled determination of the most influential variables for dose retention for each inhalation delivery system. Throat model retention was found to be dependent on the delivery system (pMDI approximately DPI(A) > DPI(B) > Neb.). The most influential variable was the total throat model volume. Throat models representing high, median, and low oropharyngeal filtration in healthy adults have been identified.

The dry-powder inhaler (DPI) Turbuhaler® has been on the market for nearly two decades. Products containing terbutaline, formoterol, budesonide, and the combination budesonide/formoterol are widely used by patients with asthma and COPD. Most patients and physicians find Turbuhaler® easy to use, and local side effects are rare. This is thought to arise from the lack of additives or only small amounts in the formulation, in addition to minimal deposition of the drug in the oropharynx and on the vocal cords during inspiration.The function of Turbuhaler® has frequently been questioned. This article aims to review and clarify some key issues that have been challenged in the literature (e.g. the effectiveness of Turbuhaler® in patients with more restricting conditions), to discuss the importance of lung deposition, and to explain the low in vivo variability associated with Turbuhaler® and the lack of correlation with the higher in vitro variability.Turbuhaler®, like other DPIs, is flow dependent to some degree. However, a peak inspiratory flow (PIF) through Turbuhaler® of 30 L/min gives a good clinical effect. These PIF values can be obtained by patients with conditions thought to be difficult to manage with inhalational agents, such as asthmatic children and adult patients with acute severe airway obstruction and COPD. Excellent clinical results with Turbuhaler® in large controlled studies in patients with COPD and acute severe airway obstruction provide indirect evidence that medication delivered via Turbuhaler® reaches the target organ.Due to the large amount of small particles and the moderate inbuilt resistance in Turbuhaler®, which opens up the vocal cords during inhalation, Turbuhaler® is associated with a high lung deposition (25–40% of the delivered dose) compared with pressurized metered-dose inhalers (pMDIs) and other DPIs. A good correlation has been found between lung deposition and clinical efficacy. A high lung deposition always results in the best ratio between clinical efficacy and risk of unwanted systemic activity. Studies with Turbuhaler® also show that the in vivo variation in lung deposition is significantly lower compared with a pMDI or, for example, the Diskus® inhaler, and much lower than the in vitro dose variability seen in laboratory tests.Turbuhaler® appears to be a reliable DPI which can be used with confidence by patients with airway diseases, including those with clinical conditions believed to be difficult to manage with inhalational therapy.

Inhalation is a mainstay for treatment of asthma, and lung deposition can be seen as a surrogate marker for the ensuing clinical effects. Not only absolute lung deposition, but also its variability is of interest, as it indicates the range of expected lung deposition in an individual patient when prescribing the drug and the expected day-to-day variability when using it. A literature survey found 71 studies with relevant information on lung deposition and its variability. Further characteristics of the studies, such as if the subjects were healthy or asthmatics, adults or children, and what device that was used, were noted. In all, 187 data points were included. Variability in lung deposition was depicted as a function of mean lung deposition; for the entire data set and for subsets thereof. Independent of device type or subject category high lung deposition was associated with low relative variability and vice versa. Using a published throat deposition model, the observed correlation of lung deposition variability to mean lung deposition could be explained as being determined largely by the extent of and variability in throat deposition. We hypothesize that throat deposition is the major determinant for lung deposition of an inhaled aerosol, and its absolute variability will largely be determined by the absolute variability in throat deposition. The relative variability in lung deposition will therefore tend to be high for low lung deposition and low for high lung deposition. Consequently, low relative variability in lung deposition can only be attained if high lung deposition is achieved.

Medication for the treatment of asthma and chronic obstructive pulmonary disease should be given locally by inhalation. There is, however, no such thing as an ideal inhaler, or ‘Idealhaler’, which has all desired properties with no drawbacks. In this short review, we have compared the relative merits of the two most commonly used dry powder inhalers – Turbuhaler® and Diskus™. Clinical effect is related to the amount of inhaled drug that reaches the lungs, and this in turn depends on the amount of fine particles generated at inhalation. Turbuhaler® is more than twice as effective as Diskus™ at generating fine particles, and the higher lung deposition with Turbuhaler® is accompanied by a lower variability in lung deposition. Compared with Diskus™, the lung deposition with Turbuhaler® is affected less by factors such as humidity.

In addition to aerosol particle size and mode of inhalation, the time-point of dose delivery during inhalation may be an important factor governing the intrapulmonary distribution of aerosolized drug. To generate different intrapulmonary deposition patterns of a drug model aerosol, a device with the capability of delivering small amounts of technetium-99m-labeled lactose dry powder at pre-set time-points during inhalation was developed. A single dose of the radioaerosol was delivered after inhalation of 20% (A) or 70% (B) of the vital capacity inhaled through the device. Twelve healthy subjects were studied in a randomized crossover fashion. Planar gamma scintigraphy was carried out, and the penetration index, PI, defined as the ratio of peripheral to central lung zone deposition of radioactivity, was estimated. A significant increase in PI from 3.0 (A) to 3.7 (B) was observed with the change from early to late delivery of the dose (p < 0.01). No difference in the total amount of radioactivity within the lungs could be detected. In conclusion, independent of total pulmonary deposition, deeper dry powder aerosol penetration into the lungs was found for the dose delivered at near end instead of at the beginning of inhalation. By computational modeling of the aerosol transport and deposition, that finding was mechanistically explained by differences in airway caliber as a consequence of the level of lung inflation at the time-point of dose delivery.

Dry powder inhalers (DPIs) are increasingly being used for the treatment of asthma and COPD. A potential drawback is that DPIs can be sensitive to humidity. Two DPIs, Symbicort Turbuhaler and Seretide Diskus, were stored 3 months at either 25 degrees C/30% RH or 40 degrees C/75% RH. After storage, delivered, as well as fine particle dose, FPD, were tested in vitro and lung deposition, of the steroid components, was assessed in vivo. After storage at 40 degrees C/75% RH, delivered dose as well as FPD from Symbicort Turbuhaler was virtually unchanged while FPD for Seretide Diskus decreased by about 50% despite no decrease in delivered dose. For both products, no difference in FPD was seen after storage at 25 degrees C/30% RH. These in vitro findings were confirmed in the in vivo part of the study. Lung deposition for Symbicort Turbuhaler was unaffected by 40 degrees C/75% RH storage, while for Seretide Diskus it was reduced with about 50%. The study extends previous in vitro observations of impaired performance of Seretide Diskus and demonstrates that this translates into decreased drug delivery to the site of action. The clinical importance of this finding has not been studied but could result in undertreatment.