Evaluation of the Transwell System for Characterization of Dissolution Behavior of Inhalation Drugs: Effects of Membrane and Surfactant

Abstract

Assessing the dissolution behavior of orally inhaled drug products (OIDs) has been proposed as an additional in vitro test for the characterization of innovator and generic drug development. A number of suggested dissolution methods (e.g., commercially available Transwell or Franz cell systems) have in common a membrane which provides the separation between the donor compartment, containing nondissolved drug particles, and an acceptor (sampling) compartment into which dissolved drug will diffuse. The goal of this study was to identify and overcome potential pitfalls associated with such dissolution systems using the inhaled corticosteroids (ICS), viz., budesonide, ciclesonide, and fluticasone propionate, as model compounds. A respirable fraction (generally stage 4 of a humidity, flow, and temperature controlled Andersen Cascade Impactor (ACI) or a Next Generation Impactor (NGI)) was collected for the tested MDIs. The dissolution behavior of these fractions was assessed employing the original and an adapted Transwell system using dissolution media which did or did not contain surfactant (0.5% sodium dodecyl sulfate). The rate with which the ICS transferred from the donor to the acceptor compartment was assessed by HPLC. Only a modified system that incorporated faster equilibrating membranes instead of the original 0.4 μm Transwell membrane resulted in dissolution and not diffusion being the rate-limiting step for the transfer of drug from the donor to the acceptor compartment. Experiments evaluating the nature of the dissolution media suggested that the presence of a surfactant (e.g., 0.5% SDS) is essential to obtain rank order of dissolution rates (e.g., for budesonide, fluticasone propionate, and ciclesonide) that is in agreement with absorption rates of these ICS obtained in studies of human pharmacokinetics. Using the optimized procedure, the in vitro dissolution behavior of budesonide, ciclesonide, and fluticasone propionate agreed approximately with descriptors of in vivo absorption. The optimized procedure, using membranes with increased permeability and surfactant containing dissolution medium, represents a good starting point to further evaluate in vitro/in vivo correlations.

Scope and relevance of a pulmonary biopharmaceutical classification system AAPS/FDA/USP Workshop March 16-17th, 2015 in Baltimore, MD

“…The models resulted in plausible successes in fitting/ simulating and describing different PK profiles of poorly soluble fluticasone propionate (FP) formulated in various inhaler products, while yielding its lung regionindependent, dissolution-controlled slow absorption rate with a half-life of~3.5 h (Tayab & Hochhaus 2005;Sakagami 2014;Weber & Hochhaus 2015). In line with these results, a further study has now implied that in vitrobased mean dissolution times may be an indicator for the in vivo lung absorption rates of slowly-dissolving, lipophilic corticosteroids (e.g., FP, ciclesonide and budesonide) (Rohrschneider et al 2015). Meanwhile, PKlinked systemic PD modeling was found feasible for inhaled FP to predict the profiles of serum cortisol reduction, as potential systemic adverse outcomes (Meibohm et al 1999;Möllmann et al 1998).…”

Towards Standardized Dissolution Techniques for In Vitro Performance Testing of Dry Powder Inhalers

“…Diffusion controlled systems described in the literature are the horizontal diffusion cell, vertical diffusion cell, and Transwell setups (42,49,(56)(57)(58)(59)(60). The principle of these techniques differs from the approach used by Davies and Feddah.…”

The influence of lung surfactant liquid crystalline nanostructures on respiratory drug delivery

“…Impactor (May et al, 2012, Rohrschneider et al, 2015 or Next Generation Impactor (Son and McConville, 2009, Son et al, 2010, Son et al, 2011.…”