(616b) Surfactant Formulation Principles for Self-Dispersing Aerosol Drug Carriers Based On Marangoni Flow in the Pulmonary Airways

While inhaled aerosol drugs can deliver substantial doses of medication directly to the lungs, altered patterns of ventilation associated with obstructive lung diseases cause inhaled drugs to deposit non-uniformly. Some lung regions receive very high local doses of medication while other regions go untreated. This presentation concerns recent research suggesting that the addition of surfactant to the aerosol will disperse these drugs more effectively after deposition on the airway surface liquid (ASL). The enhanced dispersion results from the creation of surface tension gradients on the ASL. Surfactants in the deposited droplets adsorb and decrease surface tension locally. Marangoni stresses drive the droplet to spread outward over higher surface tension regions of the surrounding ASL. In this way, drug that initially deposits on mucus obstructions spread over the surface of the obstruction to reach poorly accessible targets. A considerable body of prior research exists concerning the influence of Marangoni stresses on the spreading of exogenous fluids administered in bolus form to the lungs of premature infants being treated for acute respiratory distress syndrome. That research focused on the driving force and initial dynamics of spreading. The current research focuses instead on the factors that determine the extent of spreading, as this is the variable to be optimized for aerosol drug delivery. Model systems are used to isolate the critical surfactant solution characteristics that control the extent of spreading. The relevant subphase for aerosol delivery to the conducting airways of patients with obstructive lung disease is mucus. Pulmonary mucus is an entangled solution of mucin glycoproteins with a variety of other solutes, the type and abundance of which depend on the physiological state of the individual lung. Mucins are surface active and decrease the surface tension of mucus relative to water, and chain entanglements make mucus rheologically complex. Here we use three model subphases that preserve these key features while offering greater simplicity for mechanistic studies: cultured monolayers of human bronchial epithelial cells that express mucus, entangled aqueous mucin solutions, and entangled aqueous solutions of polyacrylamide. We compare surfactants that represent canonical categories: the anionic surfactant sodium dodecyl sulfate (SDS), the cationic surfactant cetyltrimethylammonium bromide (CTAB), and the nonionic polyether surfactant Tyloxapol. These surfactants differ qualitatively in the strength of their interactions with the polymeric subphase and serve to isolate the potential importance of direct surfactant/polymer complexation. Dyes serve as model drugs that can be tracked visually on the subphase. Spreading of dissolved hydrophilic dyes is contrasted with the spreading of surfactant-solubilized hydrophobic dyes. Tracer particles placed on the subphase before droplet deposition allow the motion of the subphase to be tracked independent of the dye solution spreading. Results obtained to date confirm that Marangoni stresses are the principle driving force for surfactant-enhanced spreading. While the hydrophilic dye clearly marks the edges of the spread droplet, the trajectories of surface tracer particles are consistent with migration of surfactant ahead of the spreading droplet. There is strong evidence for a large separation in the time scales of the underlying processes in the spreading. The convective portion of the spreading event is complete before there is significant mixing of the droplet contents and the miscible subphase. Despite the miscibility of the aqueous droplet and subphase, the spreading occurs as if the subphase were immiscible, and the final spread droplet state is captured by a quasi-static interfacial tension balance on a flattened lens of the dosing fluid.