(W1130-03-17) Effect of Bioadhesive Polymer Hydration on Mucociliary Clearance

Purpose: Mucociliary clearance within the nasal cavity results from the coordinated activity of cilia moving materials along the surface of the periciliary fluids, typically clearing materials from the nasal cavity within 15-30 min. Decreasing mucociliary clearance rates using bioadhesive materials can achieve longer residence times within the nasal cavity, and the potential to promote additional polymer-mucus interactions following polymer hydration was investigated using powders and spray-dried particles prepared from three families of polymers: polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), and sodium alginate.

Methods: PVP K12 (MW=4,000), sodium alginate (Manucol LKX, 1% = 60-170 cps and Manugel DMB, 1% = 300 cps) and HPMC E6 LV (Methocel E6 PREM LV, 2% = 6 cps) spray-dried microparticles were prepared from aqueous solutions using a Yamato ADL 311S mini spray-dryer equipped with a 0.7 mm spray nozzle. PVP K12 + maltodextrin and HPMC E6 LV + maltodextrin microparticles were prepared using the same method after mixing polymer and maltodextrin at a 1:4 (w/w) ratio. All of these polymers, along with samples of PVP K29/32 (MW=58,000) and K120 (MW=3,000,000), and HPMC E50 LV (Methocel E50 PREM LV, 2% = 50 cps) and K4M (Methocel K4M PREM, 2%=4,000 cps) were evaluated for their ability to adsorb water and to reduce mucociliary clearance. The hydration of each material was tested in triplicate using a 90-99% relative humidity desiccator chamber maintained at 31-35ºC to mimic the nasal cavity environment. Mucociliary transport rate (MTR) reduction was measured in triplicate using excised bovine trachea coated with 4% w/v mucin. The bioadhesive particles were labeled with activated charcoal for visual tracking. The movement of the charcoal particles was measured over a period of 5—60 min, and the MTR was normalized to the native clearance rate for each tissue, based on the clearance of a charcoal-loaded mucus gel.

Results: Each polymer family showed a unique relationship between MTR reduction and polymer hydration. For the PVP samples exposed to high humidity conditions, each reached a 40-45% water content after a 1 hour exposure, and their MTR reductions ranged between 60-98%. The sodium alginate samples all showed significant water sorption (39-50% water content after 1 h) and produced the highest MTR reductions (75-100%). The HPMC particles showed a good correlation between water sorption and MTR reduction. Storage of samples under humidification resulted in a 26% increase in water content and 79% reduction in MTR for the lowest viscosity polymer, E6 LV (2% = 6 cps). Humidified storage of the highest viscosity grade HPMC, K4M (2% = 4000 cps), resulted in a 34% increase in water content and a 97% decrease in MTR. Spray-dried polymer particles underwent similar testing procedures and most showed nearly identical hydrations and MTR reductions as the unprocessed materials. The HPMC E6 LV and PVP K12 were co-processed with maltodextrin to aid in solvent removal during spray-drying. Inclusion of 80% of the processing aid, however, resulted in limited or reduced hydration of both types of microparticles owing to the lower polymer content and the limited water sorption by both HPMC and maltodextrin. Neither type of spray-dried particle containing maltodextrin showed any reduction in MTR, suggesting the limited amount of polymer in the particle was insufficient to interact with the mucus layer and increase nasal residence time.

Conclusion: Bioadhesive polymers are able to slow mucociliary clearance across an excised segment of ciliated tracheal mucosa, and the distinct properties of each polymer family result in unique properties regarding their hydration rates, their ability to interact with mucus, and any resulting decrease in mucociliary clearance. Spray-drying the polymers did not alter their effects on mucociliary clearance compared to unprocessed polymer powders, but reducing the amount of polymer in the spray-dried particles with replacement by maltodextrin decreased the ability to resist mucociliary clearance. While spray-drying drug, excipient, and polymer mixtures offers significant advantages in dose reproducibility for nasally-administered powders, these results suggest a critical level of polymer is required to increase the nasal residence time via mucoadhesion.