(M1430-06-38) Effects of Sodium Alginate Properties on Mucoadhesion and Mucociliary Clearance

Purpose: Nasal delivery has many benefits including rapid absorption, increased bioavailability and the potential for nose-to-brain delivery. It also faces challenges including short nasal residence time due to rapid mucociliary clearance (MCC). Bioadhesive gels have been studied for their abilities to improve nasal delivery efficiency by slowing MCC, but bioadhesive gel formulations have shown limited increases in bioavailability. Direct delivery of bioadhesive powders has been reported to have advantages over gels as a nasal formulation, including higher microbiological stability and patient compliance. More importantly, the dehydration of mucosal fluids following bioadhesive powder hydration may lead to stronger mucoadhesion and longer residence time. This study aims to evaluate the effects of alginate polymer properties, including molecular weight (MW), D-mannuronic acid to L-guluronic acid (M/G) ratio, particle size distribution (PSD) and hygroscopicity, on its interactions with cilia and mucociliary clearance.

Methods: Five grades of sodium alginate (Manucol LKX: MW=110 kDa, M/G=1.5-2.3; Manugel DMB: MW=124 kDa, M/G=0.6; A1112: MW=30-100 kDa, M/G=1.56; 71238: MW=100-200 kDa, M/G=0.43; and W201502: MW=12-40 kDa, M/G=1.56) were tested. A QICPIC was used to measure the PSD of the alginate powders before and after sieving using a 100 μm screen. Dynamic vapor sorption (DVS) was used to determine polymer hygroscopicity at 35°C and 90% RH of the sieved alginate powders. To investigate the alginates’ effects on MCC, the mucociliary transport rate (MTR) across a segment of bovine trachea, an easily accessible ciliated tissue, was compared among polymer powders and pre-formed alginate gels (2% w/v). Further evaluations of polymer interactions with cilia were studied by measuring the ciliary beat frequency (CBF) of cultured human airway cells following application of the sieved alginate powders to the apical surface.

Results: The Dv₅₀ of the alginate powders initially varied from 28-226 μm but was reduced to 28-76 μm following sieving. All of the alginate powders adsorbed considerable amounts of water vapor with 34-48% increases in weight over a 15 min exposure period. Application of alginate powders to the tracheal tissues reduced mucociliary transport rates to a greater extent than application of equivalent alginate-grade polymer gels or a control mucus solution. The relative reduction over 15 min for gels varied from 20% for the 71238 gel to 91% for the Manugel DMB gel, compared to that for powders from 76% for 71238 to 100% for Manucol LKX. Four of the alginate powders (Manucol LKX, Manugel DMB, A1112 and W201502), which resulted in slowed MTR, also showed significantly reduced ciliary motility, and the CBF rate showed good recovery to near baseline during the one-hour observation period suggesting minimal longer-term effects on the natural clearance activities in the nasal cavity. Alginates with high L-guluronic acid contents showed unfavorable CBF and MTR reductions, while alginate powders with smaller particle sizes enable more efficient gel formation on the tracheal tissues and resulted in greater reductions in MTR.

Conclusion: Alginate powders are able to hydrate rapidly when exposed to the high humidity conditions experienced in the nasal cavity. Hydrated alginate powders, especially those with Dv50 < 100 μm or M/G ratio > 1 are able to form an alginate-mucin matrix able to halt ciliary motility resulting in reduced mucociliary clearance compared to pre-formed bioadhesive gels administered to the mucosal surface.