Ranking In Vitro Dissolution Of Orally Inhaled Drug Substance Powders In A Time-Efficient Manner

Frans Franek¹, Linn Nilsson¹, Helena Thörn¹, Rebecca Fransson², Ulrika Tehler²

AstraZeneca R&D, Pepparedsleden 1, Mölndal, 43183, Sweden

¹Pharmaceutical Technology & Development Inhalation, Operations

²Pharmaceutical Sciences, IMED

Summary

For poorly soluble drug substances, dissolution is likely to be the rate-limiting step for absorption and an important parameter to consider when evaluating drug product performance. Currently, in vitro characterization of orally inhaled powder dissolution is time-consuming, often requiring separate (“off-line”) quantification of concentration. In this study, a time-efficient method to rank in vitro dissolution of poorly soluble orally inhaled drug substance powders was developed. Micronized budesonide, fluticasone propionate (FP), fluticasone furoate (FF) and a candidate drug (CD) were deposited onto filters, either by direct weighing onto filters or by being dispersed onto filters using a modified Andersen cascade impactor. Filter holders were designed and 3D-printed, which allow for drug powder placed on filters to be added into the µDiss, a dissolution apparatus with built-in UV-probes for “on-line” quantification of concentration. Dissolution started with addition of dissolution media (Phosphate buffer pH 6.8 with 0.5% SDS). Concentrations were quantified using the µDiss probe and via separate analysis using UPLC-UV. The dissolution profiles were fitted to a Weibull equation which allowed for statistical comparison of time when 63% of drug substance dose is dissolved (t63). All non-dispersed powders dissolved slower than dispersed powders and only the budesonide dissolution rate differed from the other substances. For dispersed powders a ranking was successfully established: budesonide (t63 (SD) = 11 (1) min) < FP (45 (27) min) = CD (55 (8) min) < FF (96 (12) min).The rank-order of dissolution for budesonide, FP and FF corresponded to the rank order of lung absorption expressed as mean absorption time (MAT) in man for the same substances formulated as drug products.