Polysaccharides for permeation enhancement of in-vitro models for nasal drug delivery studies

Introduction. This dissertation encompasses the work related to investigating the effect of a new polysaccharide in the form of colominic acid as a permeation enhancer to be utilized for nasal drug delivery. The results of preliminary research on nasal drug delivery and naturally occurring polysaccharides with mechanistic functions that are favorable in penetration of the nasal tight junction membranes or attaching to the epithelial surface membrane lead to pursuing this drug permeation development pathway. The goal of this dissertation is to understand how to develop, monitor an in vitro nasal model that will support the evaluation of the permeation effects that colominic acid may achieve in a nasal developed formulation.;Methods. An in vitro model was studied in both the Liquid / Liquid interface as well as the Air / Liquid interface to best represent the effect of the proposed permeation enhancing effects of colominic acid in a controlled 2 dimensional CALU-3 cell line monolayer model. Various formulations of the fluorescent marker drug and the colominic acid were developed in a solution format and dosed onto the Air / Liquid interface of the in-vitro model. Both controls (without enhancer) and reproducibility (N=3) were observed by examining results of the analysis against developed fluorescence responding analytical methods that would support the generation of P app values allowing for the comparison of permeation effects between different formulations. To achieve this Calu-3 cells were first cultured to near confluence and then transferred to individual in vitro support membrane wells that allowed the formation of a tight junction monolayer of cells represent the nasal epithelium (approximately 7 to 10 days) depending on seeding density. Individual formulations incorporating various concentrations of colominic acid were then tested on the in vitro monolayer to see how much drug transport occurred across the epithelial barrier layer via a model drug of FITC-dextran.;Results and conclusions. The Papp values for various colominic acid formulations were in the 2 to 3 X 10−8 cm/sec with similar enhancement ratios observed indicating negligible effects in the permeation enhancement effect compared to the control formulation. Based on these results colominic acid as a permeation enhancer in a liquid formulation has been ruled out, but could still be a viable enhancer as either a powder nasal drug formulation enhancer or utilized in combination with other polyelectrolyte permeation enhancers to create a more favorable polyelectrolyte permeation enhancing complex or by combining with a cationic polysaccharide to form micelles or nanoparticles.