(483e) Self-Dispersing Drug Carriers for Pulmonary Delivery: Spreading of Aqueous Surfactant Solutions On Model Airway Surface Liquid Subphases

Persistent pulmonary infections are a leading cause of mortality in cystic fibrosis lung disease. This condition is associated with over-secretion of abnormally viscoelastic mucus that creates pulmonary airway obstructions. Current aerosolized antibiotic delivery techniques rely entirely on aerodynamic mechanisms to disperse and distribute these medications inside the lung after inhalation. The elements of obstruction common to cystic fibrosis and other lung diseases can decrease ventilation in portions of the lung, preventing aerosol drugs from reaching these zones. The unusual aerodynamics associated with obstructive disease can also cause highly non-uniform aerosol deposition patterns, further limiting distribution of drug throughout the lung. Poor distribution ultimately limits their efficacy. The inhaled antibiotics used to treat bacterial infections associated with cystic fibrosis lung disease often provide successful suppression of infection but rarely provide eradication. Drug resistance has also been associated with these therapies, likely due to the consistent delivery of sub-therapeutic doses at sites of infection. This group is investigating the potential to develop self-dispersing aerosol medications to improve the uniformity of drug delivery to obstructed lungs. An active agent is formulated with aqueous surfactant solutions that harness surface tension gradients to promote spreading on the airway surface liquid after aerosols deposit. Experiments on model systems show that surfactants significantly enhance spreading relative to saline controls as expected. Surfactant-laden aqueous drops when placed on entangled aqueous polymer solutions spread to form static lenses that persist on top of the subphase for tens of minutes, despite their complete miscibility.  Our interests are focused on the relationship between formulation composition and the final spread area of deposited drops, a surrogate for the extent of drug dispersal after droplet deposition on the airway surface liquid. We use entangled aqueous poly(acrylamide) and porcine gastric mucin (PGM) solutions as subphases to mimic the physical properties of airway mucus plaques that are the main obstacles to uniform aerosol deposition in the lungs of patients with obstructive lung diseases. Solutions of the anionic surfactant sodium dodecyl sulfate (SDS), cationic surfactant cetyltrimethylammonium bromide (CTAB) or non-ionic surfactant tyloxapol contain dyes (absorptive or fluorescent) that serve as both model “drugs” and as tracers to measure the extent of drop spreading on the subphase. Regardless of the type of surfactant, when a drop of surfactant solution is placed on the polymer subphase, we observe that the dye spreads with the drop and that the surface tension of the subphase decreases in regions far outside the deposited drop, indicating that surfactant escapes across the drop contact line. This phenomenon is not observed with surfactant-free aqueous drops.  The spread drop forms a finite, static lens that exists for on the order of 10 minutes while its contents slowly diffuse into the subphase. While Marangoni stresses initiate flow, a capillary force balance terminates the convective spreading process, resulting in the confinement of the spread solution to a well-defined static area. Spreading times are on the order of tens of seconds, considerably shorter than the timescales for diffusion into the subphase bulk or for subphase disentanglement. Spreading of aerosolized surfactant solutions is compared to the extent of spreading of macroscopic surfactant solution drops. The final spread areas for a macroscopic drop and the same deposited volume of aerosolized surfactant solution (aerosol size 2-10 um) are comparable, suggesting a similar spreading trend for aerosolized surfactant solutions and surfactant-laden drops on entangled polymer subphases that model the airway surface liquid.