In this study, the development and validation of a novel modified version of the medium-sized Virginia Commonwealth University (VCU) mouth-throat (MT) and tracheal-bronchial (TB) realistic upper airway model, intended to evaluate total airway deposition and drug permeation behaviour for orally inhaled products (OIPs) in vitro, is presented. The VCU MT-TB model was modified to accommodate two Snapwell® permeable membrane inserts above the first TB airway bifurcation region to primarily collect deposited nebulised ciprofloxacinhydrochloride (CIP-HCL) droplets as a model drug aerosol system. Permeation characteristics were assessed by adapting the established Transwell® ‘fluid-capacity-limited’ dissolution test system. Firstly, the novel modified TB airway model resulted in significantly higher TB aerosol deposition compared with the original TB model. Secondly, the adapted Transwell permeation test system demonstrated reproducible and discriminatory permeation profiles for already-dissolved and nebulised CIP-HCL drug through a range of permeable membranes. Fundamentally, the rate and extent of CIP-HCL permeation depended on the permeable membrane material used, presence of a stirrer in the receptor compartment and, most importantly, the aerosol particle collection method. This novel hybrid in vitro approach, which incorporates a modified realistic airway model coupled with an adapted Transwell system holds great potential to evaluate other post-deposition characteristics, such as particle dissolution and cellular uptake of OIPs.