Advanced dissolution testing for inhalation products: functionalized membranes simulating pulmonary mucus

Dissolution is now recognized as a critical property for the development of pulmonary drug delivery systems. Numerous methods have been proposed to characterize the in vivo behaviour of these products. In this context, Respicell, an innovative dissolution apparatus developed by the University of Parma, has emerged as a valuable tool for directly analysing the dissolution profile of the respirable dose (<5 µm) of dry powder inhalers (DPIs). Respicell is a vertical diffusion cell comprising a donor compartment and a receptor compartment separated by a filter from a Fast Screening Impactor (FSI) [1]. The respirable fraction of the drug formulation is collected on the filter and exposed to the dissolution medium in the receptor compartment. While Respicell provides valuable insights, as the rest of proposed dissolution approaches, it does not fully replicate the complex in vivo environment, such as the influence of the nature and composition of respiratory tract lining fluids on drug dissolution and absorption [2]. To address this limitation, this research aimed to simulate the behavior at the interface of conductive airways and the dissolution process of inhaled drugs with low solubility by incorporating a simulant of the mucus barrier. A novel inhaled phosphodiesterase-4 inhibitor under development (molecule X), formoterol fumarate, and beclomethasone dipropionate were used as model drugs. Polycarbonate membranes ( coated with a mucus simulant composed of phosphate-buffered saline (PBS), polyethylene oxide (PEO), and phosphatidylcholine were developed to mimic the physiological pulmonary conditions. The membranes were coated with varying concentrations of the proposed mucus simulant and placed on the filter of the Fast Screening Impactor after the collection of the respirable drug fraction. The assembly was then exposed to the dissolution medium to rehydrate the mucus and initiate the dissolution process. The results demonstrated that the mucus-functionalized membranes significantly reduced the dissolution rate of all three drugs, highlighting the critical role of the mucus barrier in drug absorption. The dissolution profiles obtained with the mucus-functionalized membranes were comparable to those obtained with a biorelevant dissolution medium obtained by dilution (10 % v/v) in physiological solution a complex artificial pulmonary mucus (Biochemazone, Canada), confirming the effectiveness of the simulated mucus model in replicating the barrier offerd by respiratory lining fluid in the conductive airways. In conclusion, the use of mucus-functionalized polycarbonate membranes represents a valuable tool for investigating the dissolution behavior of inhaled drugs in the complex pulmonary environment. This approach provides insights into the factors influencing drug absorption and can aid in the development of more effective inhalation therapies