Abstract
The aim of this study was to further evaluate and optimize the Transwell® system for assessing the dissolution behavior of orally inhaled drug products (OIDPs), using fluticasone propionate as a model drug. Sample preparation involved the collection of a relevant inhalable dose fraction through an anatomical mouth/throat model, resulting in a more uniform presentation of drug particles during the subsequent dissolution test. The method differed from previously published procedures by (1) using a 0.4 µm polycarbonate (PC) membrane, (2) stirring the receptor compartment, and (3) placing the drug-containing side of the filter paper face downwards, towards the PC membrane. A model developed in silico, paired with the results of in vitro studies, suggested that a dissolution medium providing a solubility of about 5 µg/mL would be a good starting point for the method’s development, resulting in mean transfer times that were about 10 times longer than those of a solution. Furthermore, the model suggested that larger donor/receptor and sampling volumes (3, 3.3 and 2 mL, respectively) will significantly reduce the so-called “mass effect”. The outcomes of this study shed further light on the impact of experimental conditions on the complex interplay of dissolution and diffusion within a volume-limited system, under non-sink conditions.
Highlights
Accepted: 14 July 2021Differences in dissolution rates have shown to affect the pulmonary residence time of orally inhaled lipophilic drugs such as fluticasone propionate and mometasone furoate [1].Despite the relevance of the dissolution process for the local and systemic drug exposure of orally inhaled drug products (OIDPs), dissolution tests have not yet been incorporated into the arsenal of in vitro tests recommended by regulatory agencies, nor are fully validated methods available [2]
In a continuation of previously published work [21,22], we further optimized and evaluated the Transwell® system to assess the dissolution behavior of OIDPs
While dissolution tests have been performed on OIDPs with “unfractionated” material, applied via airbrush, dry powder insufflators or aerosol generators [6], most stake
Summary
Accepted: 14 July 2021Differences in dissolution rates have shown to affect the pulmonary residence time of orally inhaled lipophilic drugs such as fluticasone propionate and mometasone furoate [1].Despite the relevance of the dissolution process for the local and systemic drug exposure of OIDPs, dissolution tests have not yet been incorporated into the arsenal of in vitro tests recommended by regulatory agencies, nor are fully validated methods available [2]. The pulmonary efficacy of an inhaled drug and the extent of pulmonary targeting is affected by deposition-related properties, and by post-deposition events, such as dissolution and permeation [3]. While the need for biorelevant dissolution methods has been recently highlighted [4], stakeholders have not yet agreed on a standardized methodology. Such a method should allow for a study of the dissolution of the drug product’s respirable fraction, to adequately relate the physicochemical characteristics of the drug to its in vivo
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