Abstract
BackgroundThe pulmonary residence time of inhaled glucocorticoids as well as their rate and extend of absorption into systemic circulation are important facets of their efficacy-safety profile. We evaluated a novel approach to elucidate the pulmonary absorption of an inhaled glucocorticoid. Our objective was to monitor and compare the combined process of drug particle dissolution, pro-drug activation and time course of initial distribution from human lung tissue into plasma for two different glucocorticoid formulations.MethodsWe chose beclomethasone dipropionate (BDP) delivered by two different commercially available HFA-propelled metered dose inhalers (Sanasthmax®/Becloforte™ and Ventolair®/Qvar™). Initially we developed a simple dialysis model to assess the transfer of BDP and its active metabolite from human lung homogenate into human plasma. In a novel experimental setting we then administered the aerosols into the bronchus of an extracorporally ventilated and reperfused human lung lobe and monitored the concentrations of BDP and its metabolites in the reperfusion fluid.ResultsUnexpectedly, we observed differences between the two aerosol formulations Sanasthmax®/Becloforte™ and Ventolair®/Qvar™ in both the dialysis as well as in the human reperfusion model. The HFA-BDP formulated as Ventolair®/Qvar™ displayed a more rapid release from lung tissue compared to Sanasthmax®/Becloforte™. We succeeded to explain and illustrate the observed differences between the two aerosols with their unique particle topology and divergent dissolution behaviour in human bronchial fluid.ConclusionWe conclude that though the ultrafine particles of Ventolair®/Qvar™ are beneficial for high lung deposition, they also yield a less desired more rapid systemic drug delivery. While the differences between Sanasthmax®/Becloforte™ and Ventolair®/Qvar™ were obvious in both the dialysis and lung perfusion experiments, the latter allowed to record time courses of pro-drug activation and distribution that were more consistent with results of comparable clinical trials. Thus, the extracorporally reperfused and ventilated human lung is a highly valuable physiological model to explore the lung pharmacokinetics of inhaled drugs.
Highlights
Current asthma management guidelines recommend inhaled glucocorticoids as preferred therapy for control of mild persistent, moderate and severe asthma [1,2]
Lung tissue-plasma distribution of HFA-beclomethasone dipropionate (BDP) determined in a dialysis model The time course of distribution of two different HFA-BDP formulations from human lung tissue into human plasma was initially determined using a simple dialysis model
Equal doses of 500 μg BDP (2 × 250 μg Sanasthmax®/BecloforteTM and 5 × 100 μg Ventolair®/QvarTM) ex valve were applied to each 4.8 mL human lung tissue homogenate (Figure 1)
Summary
Current asthma management guidelines recommend inhaled glucocorticoids as preferred therapy for control of mild persistent, moderate and severe asthma [1,2]. Glucocorticoids are the most effective anti-inflammatory agents and inhalation is an efficient way to deposit the compound in the therapeutic target tissue. Prolonged residence of an inhaled glucocorticoid in the lung tissue is associated with an extended duration of action. The rate and extend of absorption of the glucocorticoid into systemic circulation might result in systemic adverse effects such as adrenal suppression or decreased bone mineral density [5]. Though the tissue residence time and the time course of distribution into systemic circulation significantly contribute to the risk-benefit value of inhaled corticosteroids [4,6] the precise determination of the pulmonary absorption is a challenge. The pulmonary residence time of inhaled glucocorticoids as well as their rate and extend of absorption into systemic circulation are important facets of their efficacy-safety profile. Our objective was to monitor and compare the combined process of drug particle dissolution, prodrug activation and time course of initial distribution from human lung tissue into plasma for two different glucocorticoid formulations
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
