title: 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.
authors.forename: Marc
authors.initials: M
authors.lastname: Rohrschneider
authors.affiliation: §College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: Sharvari
authors.initials: S
authors.lastname: Bhagwat
authors.affiliation: §College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: Raphael
authors.initials: R
authors.lastname: Krampe
authors.affiliation: §College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: Victoria
authors.initials: V
authors.lastname: Michler
authors.affiliation: ∥Heinrich Heine Universität Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Breitkreutz
authors.affiliation: §College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: Günther
authors.initials: G
authors.lastname: Hochhaus
mesh_terms: D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000493:pharmacokinetics; D019819:Budesonide / Q000008:administration & dosage / Q000493:pharmacokinetics; D002478:Cells, Cultured; D016568:Drugs, Generic / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000068298:Fluticasone / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D008566:Membranes / Q000187:drug effects / Q000502:physiology*; D058993:Oral Sprays; D011282:Pregnenediones / Q000008:administration & dosage / Q000493:pharmacokinetics; D012138:Respiratory Therapy / Q000379:methods; D065589:Respiratory Tract Absorption / Q000187:drug effects; D012995:Solubility; D013501:Surface-Active Agents / Q000494:pharmacology*; D046509:Tissue Culture Techniques / Q000295:instrumentation* / Q000379:methods
chemical_list: D000305:Adrenal Cortex Hormones; D016568:Drugs, Generic; D058993:Oral Sprays; D011282:Pregnenediones; D013501:Surface-Active Agents; D019819:Budesonide; D000068298:Fluticasone; C120481:ciclesonide
keywords: Transwell; dissolution medium; dissolution methods; inhalation; inhaled corticosteroids