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      New Mechanisms to Explain the Effects of Added Lactose Fines on the Dispersion Performance of Adhesive Mixtures for Inhalation

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          Abstract

          Fine excipient particles or ‘fines’ have been shown to improve the dispersion performance of carrier-based formulations for dry powder inhalation. Mechanistic formulation studies have focussed mainly on explaining this positive effect. Previous studies have shown that higher drug contents may cause a decrease in dispersion performance, and there is no reason why this should not be true for fines with a similar shape, size and cohesiveness as drug particles. Therefore, the effects on drug detachment of ‘fine lactose fines’ (FLF, X 50 = 1.95 µm) with a similar size and shape as micronised budesonide were studied and compared to those of ‘coarse lactose fines’ (CLF, X 50 = 3.94 µm). Furthermore, interactions with the inhalation flow rate, the drug content and the mixing order were taken into account. The observed effects of FLF are comparable to drug content effects in that the detached drug fraction was decreased at low drug content and low flow rates but increased at higher flow rates. At high drug content the effects of added FLF were negligible. In contrast, CLF resulted in higher detached drug fractions at all flow rates and drug contents. The results from this study suggest that the effects of fines may be explained by two new mechanisms in addition to those previously proposed. Firstly, fines below a certain size may increase the effectiveness of press-on forces or cause the formation of strongly coherent fine particle networks on the carrier surface containing the drug particles. Secondly, when coarse enough, fines may prevent the formation of, or disrupt such fine particle networks, possibly through a lowering of their tensile strength. It is recommended that future mechanistic studies are based on the recognition that added fines may have any effect on dispersion performance, which is determined by the formulation and dispersion conditions.

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

          Aerosol particle size influences the extent, distribution, and site of inhaled drug deposition within the airways. We hypothesized that targeting albuterol to regional airways by altering aerosol particle size could optimize inhaled bronchodilator delivery. 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. 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. 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.
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            A critical view on lactose-based drug formulation and device studies for dry powder inhalation: which are relevant and what interactions to expect?

            Many years of research have not led to a profound knowledge of the mechanisms involved in the formulation and dispersion of carrier based mixtures for inhalation. Although it is well understood that the mixing is a key process in DPI carrier based formulation, there remains a limited understanding of how blending processes affect in-process material properties and the resulting distribution of the drug in the final dosage form. A great number of variables are considered relevant to the interfacial forces in adhesive mixtures, but their effects have mostly been investigated individually, without taking account of the influence they may have on each other. Interactions may be expected and without proper choices made and definitions given for all the variables involved, conclusions from studies on adhesive mixtures are of less relevance. By varying any of the variables that are not subject of the study, an opposite effect may be obtained. Currently, there is a strong focus on exploring techniques for the characterisation of drug and carrier surface properties that are believed to have an influence on the interparticulate forces in adhesive mixtures. For a number of surface properties it may be questioned whether they are really the key parameters to investigate however. Their orders of magnitude are subordinate to the effects they are supposed to have on the drug-to-carrier forces. Therefore, they seem rather indicators of other variability and their influence may be dominated by other effects. Finally, the relevance of inhaler design is often ignored. By using powerful inhalers, the effect of many variables of current concern may become less relevant. Carrier properties that are considered disadvantageous at present may even become desirable when a more appropriate type of dispersion force is applied. This can be shown for the effect of carrier surface rugosity when inertial separation forces are applied instead of the more widely applied lift and drag forces. Therefore, inhaler design should be taken into consideration when evaluating studies on adhesive mixtures. It should also become an integral part of powder formulation for inhalation. Copyright © 2011 Elsevier B.V. All rights reserved.
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              Dry powder inhaler device influence on carrier particle performance.

              Dry powder inhalers (DPIs) are distinguished from one another by their unique device geometries, reflecting their distinct drug detachment mechanisms, which can be broadly classified into either aerodynamic or mechanical-based detachment forces. Accordingly, powder particles experience different aerodynamic and mechanical forces depending on the inhaler. However, the influence of carrier particle physical properties on the performance of DPIs with different dispersion mechanisms remains largely unexplored. Carrier particle trajectories through two commercial DPIs were modeled with computational fluid dynamics (CFD) and the results were compared with in vitro aerosol studies to assess the role of carrier particle size and shape on inhaler performance. Two percent (w/w) binary blends of budesonide with anhydrous and granulated lactose carriers ranging up to 300 μm were dispersed from both an Aerolizer® and Handihaler® through a cascade impactor at 60 L min(-1). For the simulations, carrier particles were modeled as spherical monodisperse populations with small (32 μm), medium (108 μm), and large (275 μm) particle diameters. CFD simulations revealed the average number of carrier particle-inhaler collisions increased with carrier particle size (2.3-4.0) in the Aerolizer®, reflecting the improved performance observed in vitro. Collisions within the Handihaler®, in contrast, were less frequent and generally independent of carrier particle size. The results demonstrate that the aerodynamic behavior of carrier particles varies markedly with both their physical properties and the inhalation device, significantly influencing the performance of a dry powder inhaler formulation. Copyright © 2011 Wiley Periodicals, Inc.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                28 January 2014
                : 9
                : 1
                : e87825
                Affiliations
                [1 ]Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands
                [2 ]Center for Aerosol and Nanomaterials Engineering, RTI International, Research Triangle Park, North Carolina, United States of America
                Massey University, New Zealand
                Author notes

                Competing Interests: AJH is employed by RTI International. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: AJL PH AJH AHdB. Performed the experiments: MvdN PH AJL FG. Analyzed the data: FG AHdB AJL MvdN PH AJH HWF. Wrote the paper: FG AJL MvdN PH AJH HWF AHdB.

                Article
                PONE-D-13-46253
                10.1371/journal.pone.0087825
                3905031
                24489969
                ca4b549b-9762-4323-9057-62812b627a42
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 5 November 2013
                : 31 December 2013
                Page count
                Pages: 11
                Funding
                The authors have no support or funding to report.
                Categories
                Research Article
                Chemistry
                Physical Chemistry
                Mixtures
                Aerosols
                Heterogeneous Mixtures
                Engineering
                Bioengineering
                Medical Devices
                Medicine
                Drugs and Devices
                Drug Research and Development
                Medical Devices
                Pulmonology
                Asthma
                Chronic Obstructive Pulmonary Diseases
                Physics
                Materials Physics

                Uncategorized
                Uncategorized

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