(M1230-04-24) Comparison of Mucociliary Clearance Rates of Bioadhesive Gels, Powders and Spray-Dried Polymeric Microparticles

Purpose: Increasing the residence time of drugs applied locally to the nasal mucosa is complicated by the coordinated activity of cilia clearing materials from the surface. Bioadhesive materials, administered in a variety of forms, have been shown to transiently alter mucociliary clearance and increase residence time. The purpose of these investigations was to compare the retention of powders, spray-dried microparticles and pre-formed gels containing bioadhesive polymers on a ciliated mucosal surface to identify forms most suitable for drug delivery.

Methods: PVP and sodium alginate microparticles were prepared using a Yamato ADL 311S mini spray-dryer equipped with a 0.7 mm spray nozzle. An aqueous solution of polyvinyl pyrrolidone (PVP; Kollidon K12; MW=3,000 Da) was prepared by stirring the polymer, followed by immersion of samples in a room temperature ultrasonic bath for 3 h. Dissolution of two sodium alginates, Manucol LKX (1% = 60-170 cps) and Manugel DMB (1% = 300 cps) in deionized water was facilitated by 24 h of magnetic stirring. The Feret’s diameter for spray-dried microparticles was determined using an Olympus light microscope at 10× and 50× magnification with subsequent processing using ImageJ. Mucociliary transport rate (MTR) reduction was measured in triplicate using excised bovine trachea coated in 4% w/v mucin. The bioadhesive systems were labeled with activated charcoal to enable visualization and particle 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: Spray-drying resulted in PVP microparticles having a median particle diameter (d₅₀) of 29 mm, as determined by image analysis (n = 1878). Imaging of sodium alginate spray-dried microparticles showed that both grades had smaller d₅₀ = 9 mm (LKX n = 4946; DMB n = 4118). For PVP, the extent to which MTR was reduced was dependent on the form of PVP. A 3% PVP K12 solution gave an MTR reduction of 48% after 15 min, while PVP K12 solid showed an even more significant reduction in clearance rate of 93% after 15 min. The spray-dried PVP microparticles underwent almost no clearance over the measurement time (MTR reduction = 98% after 15 min). The reductions in MTR for a Manucol LKX powder and 3.5% gel were 100% and 69%, respectively, over a 15 min observation period. Similarly, the reductions in MTR at 15 min for both Manugel DMB powder and 2% gel were 96% and 91%, respectively. The MTR reduction for the spray-dried Manucol LKX particles was 75% after 15 min, while the MTR reduction for spray-dried Manugel DMB particles was 100% over the same time interval.

Conclusion: While bioadhesive polymer powders are able to increase retention by hydrating on the mucosal surface and limiting mucociliary clearance, it is unlikely that suitable polymer-drug physical mixtures can be successfully developed for delivery as dry solid powders. The spray-drying process allows for control over the particle size, size distribution, and morphology of the resulting microparticles, and direct encapsulation of an API in the particles will enable better control over sample homogeneity. The results of these experiments show that spray-dried microparticles can be highly effective in reducing mucociliary clearance, relative to powder mixtures or pre-formed gels, which demonstrates the potential for improved local or systemic bioavailability using spray-dried bioadhesive delivery systems.