Adenosine dry powder inhalation for bronchial challenge testing, part 1: Inhaler and formulation development and in vitro performance testing

Lexmond, Anne J.; Hagedoorn, Paul; Wiel, Erica van der; Hacken, Nick H. T. ten; Frijlink, Henderik W.; Boer, Anne H. de

doi:10.1016/j.ejpb.2013.06.027

Cited by 15 publications

(12 citation statements)

References 27 publications

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“…[14,15] Performance testing results, specifications of the inhaler in combination with dry powder adenosine, and the first clinical pilot in five asthma patients have been described by Lexmond and colleagues. [8,16]…”

Section: Methodsmentioning

confidence: 99%

Targeting the small airways with dry powder adenosine: a challenging concept

Wiel

Lexmond

Berge

et al. 2017

European Clinical Respiratory Journal

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Background: Small-particle inhaled corticosteroids (ICS) provide a higher small airway deposition than large-particle ICS. However, we are still not able to identify asthma patients who will profit most from small-particle treatment. Objective: We aimed to identify these patients by selectively challenging the small and large airways. We hypothesized that the airways could be challenged selectively using small- and large-particle adenosine, both inhaled at a high and a low flow rate. Design: In this cross-over study 11 asthma subjects performed four dry powder adenosine tests, with either small (MMAD 2.7 µm) or large (MMAD 6.0 µm) particles, inhaled once with a low flow rate (30 l min–1) and once with a high flow rate (60 l min–1). Spirometry and impulse oscillometry were performed after every bronchoprovocation step. We assumed that FEV1 reflects the large airways, and FEF25–75%, R5-R20 and X5 reflect the small airways. Results: The four adenosine tests were not significantly different with respect to the threshold values of FEV1 (p = 0.12), FEF25–75% (p = 0.37), R5-R20 (p = 0.60) or X5 (p = 0.46). Both small- and large-particle adenosine induced a response in the small airways in the majority of the tests. Conclusions: In contrast to our hypothesis, all four adenosine tests provoked a response in the small airways and we could not identify different large- or small-airway responders. Interestingly, even the test with large particles and a high flow rate induced a small-airway response, suggesting that selective challenging of the small airways is not necessary. Future studies should investigate the relation between particle deposition and the site of an airway response.

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Section: Methodsmentioning

confidence: 99%

Targeting the small airways with dry powder adenosine: a challenging concept

Wiel

Lexmond

Berge

et al. 2017

European Clinical Respiratory Journal

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“…On the application site, new dry powder bronchial challenge tests have recently been presented for methacholine and adenosine [110,166] in addition to the mannitol test [167].…”

Section: Miscellaneous Innovative Developmentsmentioning

confidence: 99%

Dry powder inhalation: past, present and future

Boer

Hagedoorn

Hoppentocht

et al. 2016

Expert Opinion on Drug Delivery

221

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Introduction: Early dry powder inhalers (DPIs) were designed for low drug doses in asthma and COPD therapy. Nearly all concepts contained carrier-based formulations and lacked efficient dispersion principles. Therefore, particle engineering and powder processing are increasingly applied to achieve acceptable lung deposition with these poorly designed inhalers. Areas covered: The consequences of the choices made for early DPI development with respect of efficacy, production costs and safety and the tremendous amount of energy put into understanding and controlling the dispersion performance of adhesive mixtures are discussed. Also newly developed particle manufacturing and powder formulation processes are presented as well as the challenges, objectives, and new tools available for future DPI design. Expert opinion: Improved inhaler design is desired to make DPIs for future applications cost-effective and safe. With an increasing interest in high dose drug delivery, vaccination and systemic delivery via the lungs, innovative formulation technologies alone may not be sufficient. Safety is served by increasing patient adherence to the therapy, minimizing the use of unnecessary excipients and designing simple and self-intuitive inhalers, which give good feedback to the patient about the inhalation maneuver. For some applications, like vaccination and delivery of hygroscopic formulations, disposable inhalers may be preferred. ARTICLE HISTORY

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“…Spray-dried powders of adenosine and AMP were prepared following the same procedure used for the adenosine powders that were tested clinically [11]. Aqueous solutions of adenosine or AMP at a concentration of 25 mg/mL were spray dried with a Büchi B290 Mini Spray Drier (Büchi Labortechnik, Switzerland) under the following conditions: compressed nitrogen flow rate 650 L/h, aspirator 100%, solution feed rate 2.5 mL/min, inlet temperature 120 °C, nozzle size 0.7 mm.…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, nebuliser solution AMP concentrations > 20 mg/mL have been shown to greatly affect aerosol formation, which may have implications for the test outcome, such as a shift in deposition site or disproportional dose increase [10]. Delivery of adenosine as a dry powder aerosol overcomes the issues identified above [11, 12], and bronchial challenge in subjects with asthma has demonstrated that adenosine and AMP appear to induce airway obstruction in a similar manner [13]. Based on these findings, we reasoned that if dry powder adenosine is useful clinically as an inducer of airway obstruction, this should be reverse translated into pre-clinical models to provide more relevant test systems for studying asthma pathophysiology and to aid in the development of novel drug treatments for affecting AHR.…”

Section: Introductionmentioning

confidence: 99%

A novel method for studying airway hyperresponsiveness in allergic guinea pigs in vivo using the PreciseInhale system for delivery of dry powder aerosols

Lexmond

Keir

Terakosolphan

et al. 2018

Drug Deliv. and Transl. Res.

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Inhaled adenosine receptor agonists induce bronchoconstriction and inflammation in asthma and are used as bronchial challenge agents for the diagnosis of asthma and in respiratory drug development. Recently developed dry powder aerosols of adenosine have several advantages over nebulised adenosine 5′-monophosphate (AMP) as bronchial challenge agents. However, reverse translation of this bronchial challenge technique to pre-clinical drug development is limited by the difficulty of administering powder aerosols to animals. The aim of the current study was to develop methods for delivering powder aerosols of adenosine receptor agonists to sensitised guinea pigs (as a model of allergic asthma) and evaluate their effect as challenge agents for the measurement of airway responsiveness. The PreciseInhale system delivered micronised AMP and adenosine powders, with mass median aerodynamic diameters of 1.81 and 3.21 μm and deposition fractions of 31 and 48% in the lungs, respectively. Bronchoconstrictor responses in passively sensitised, anaesthetised, spontaneously breathing guinea pigs were compared to responses to nebulised and intravenously administered AMP and adenosine. AMP- and adenosine-induced bronchoconstriction following all routes of administration with the magnitude of response ranking intravenous > dry powder > nebulisation, probably reflecting differences in exposure to the adenosine agonists delivered by the different routes. In conclusion, the PreciseInhale system delivered AMP and adenosine dry powder aerosols accurately into the lungs, suggesting this method can be used to investigate drug effects on airway responsiveness.

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Adenosine dry powder inhalation for bronchial challenge testing, part 1: Inhaler and formulation development and in vitro performance testing

Cited by 15 publications

References 27 publications

Targeting the small airways with dry powder adenosine: a challenging concept

Targeting the small airways with dry powder adenosine: a challenging concept

Dry powder inhalation: past, present and future

A novel method for studying airway hyperresponsiveness in allergic guinea pigs in vivo using the PreciseInhale system for delivery of dry powder aerosols

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