(W1130-07-44) Bioadhesive-Drug Powder Mixtures for Improved Local Delivery to the Nasal Mucosa

Purpose: Local delivery using nasal sprays or nasal drops can face challenges including short residence time due to mucociliary clearance (MCC). MCC is the result of coordinated activity of cilia moving materials along the mucosal surface, typically clearing materials from the nasal cavity within 15-30 min. Bioadhesive polymers, such as alginates, have been studied for their abilities to improve nasal delivery efficiency by slowing MCC, yet bioadhesive gels can also reduce the rate of drug release due to reduced diffusivity through the gel matrix. In addition, intermolecular interactions among the bioadhesive polymer, drug and mucin may result in drug binding to polymer components, which may also contribute to delays in drug transfer from the gel. Direct delivery of bioadhesive-drug powder mixtures may provide higher drug concentrations at the mucosal surface, leading to improved absorption. In this study, azelastine, an antihistamine used in nasal sprays to treat allergic symptoms of nose, was used to investigate the potential for improving local delivery to the nasal mucosa from alginate-containing bioadhesive-drug powder mixtures.

Methods: Five grades of sodium alginate (Manucol LKX: molecular weight (MW)=110 kDa, D-mannuronic acid to L-guluronic acid (M/G) ratio=1.5-2.3; Manugel DMB: MW=124 kDa, M/G ratio=0.6; A1112: MW=30-100 kDa, M/G ratio=1.56; 71238: MW=100-200 kDa, M/G ratio=0.43; and W201502: MW=12-40 kDa, M/G ratio=1.56) were investigated for their interactions with azelastine. Equilibrium dialysis was used to characterize drug binding to reconstituted mucus (4% w/v), alginate polymers (1% w/v), and mixtures of both. The rate and extent of azelastine transfer from azelastine-containing aqueous solutions (250 μg/mL), alginate gels (250 μg/mL azelastine, 1% w/v alginate), and physical mixtures of azelastine and alginate (1:40 w/w) were studied by measuring drug transfer across a cellulose membrane mounted in a Franz diffusion cell. Samples were analyzed by HPLC.

Results: Azelastine showed ~26% binding to 4% w/v reconstituted mucin while binding varied from 7% for A1112 and 71238 to 38% for Manugel DMB. Azelastine binding to alginate-mucin mixtures was greater than its binding to mucin alone, indicating polymer components contributed to additional drug binding. The amounts of drug transferred from azelastine solutions, alginate gels, and alginate-drug physical mixtures were compared, and Manucol LKX, Manugel DMB and 71238 showed more rapid transfer of drug across the cellulose membrane from the drug-polymer physical mixtures compared to drug solutions, likely due to the dissolution of azelastine in the small volume of mucus added to the membrane surface which provided a near-saturated solution able to maximize the concentration gradient for drug permeation across the membrane. The release of drug was slowed from the pre-formed alginate gels due to reduced diffusivity through the gel matrix and azelastine-alginate binding.

Conclusion: Azelastine binding to 1% w/v alginate gels varied based on molecular weight, M/G ratio, and viscosity of the gel. Drug-polymer binding and reduced diffusivity of drug through the polymer gel matrix slowed the release of drug molecules from the gel, resulting in a decrease in drug transfer across a synthetic membrane. Physical mixtures of drug with bioadhesive powders showed superior performance compared to traditional drug solutions and gels and present promising new formulation approaches for improved nasal delivery.