The molecular weight dependence of the absorption of polyethylene glycols in the nasal and gastrointestinal mucosa and its correlation to size dependent diffusion.

The optimization of non-parenteral routes of drug administration is important for therapeutic agents that are not effective when administered orally in order to increase patient compliance and therapeutic efficacy. The nasal cavity is an optimal site for such delivery since physiologically the mucosa present is designed for fast exchange heat and water in order to condition inspired air. The mechanisms of transnasal absorption are not well understood, and since molecular weight and size have been implicated as a controlling factors in absorption from other mucosal sites, the molecular weight-absorption profile of the nasal mucosa was investigated in rats and compared to that of the gastrointestinal tract using a range of polyethylene glycols (PEG) as marker molecules. Qualitatively, the molecular weight-absorption profiles from each site were similar, yet quantitatively, the gastrointestinal tract showed a steeper dependence on molecular weight and reached a limiting absorption of approximately one half that of the nasal mucosa. Several compounds with absorption promoting capabilities were also evaluated for their effect on the molecular weight-absorption profile in the nasal mucosa. The adjuvants appeared to affect the profile via multiple and unique mechanisms. Based on evidence from histologic examinations of the mucosa following exposure to the adjuvant/PEG mixture, one mechanism of adjuvant action identified was that of cellular disruption. The observed molecular weight dependency of absorption may be due to the hindered diffusion of the larger molecules through the mucus blanket, a hydrated polymeric solution, present in both the nasal cavity and the gastrointestinal tract. The degree of molecular weight dependency of diffusion through hydrated polymer solutions was studied in vitro using poly(hydroxyethyl methacrylate-co-methacrylic acid) hydrogels of varying hydrations. The molecular weight dependency of diffusion was found to be steeper in the hydrogel system than in aqueous solution. This suggests that hindered diffusion may indeed play a role in determining the molecular weight-permeability profiles of mucosal absorption.PhDPharmaceutical sciencesUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/162180/1/8920526.pd