Oral Absorption Enhancement of Hydrophobic Drugs by Chitosan Based Amphiphilic Polymers

Abstract

Poor physiochemical properties which lead to sub-optimal absorption and pharmacokinetic profiles have been estimated to be responsible for 40% of drug development failures. There is evidence that quaternary ammonium palmitoyl glycol chitosan (GCPQ) based nanoparticles enable the transport of hydrophobic drugs across biological barriers and improve bioavailability. The current project was aimed at identifying the mechanism of action of these bioavailability enhancing carbohydrate nanoparticles. Our working hypothesis states that the polymers increase drug solubility in the gastrointestinal fluid and improve drug permeability across the gut membrane and we sought to identify the polymer characteristics which promote drug absorption. Six amphiphilic glycol chitosan based polymers were synthesized. The quaternised polymers formed isotropic micellar liquids whereas the non quaternised polymers formed dense nanoparticles. These polymers possess very low CAC values (3-100μM) thus making them stable drug delivery systems which do not fall apart upon dilution in large volumes of biological fluids like the blood and the gastrointestinal fluids. The quaternary ammonium function in the chitosan amphiphiles directed the formation of highly stable micellar aggregates (100-500nm) with enhanced drug loading ability. Both the quaternised and non quaternised polymers enhanced the oral absorption of cyclosporine and griseofulvin in rats. The area under the plasma level versus time curve was increased up to six fold when the hydrophobic drug was administered with these polymers. The three mechanisms of oral absorption enhancement by these polymers are, a) by increasing the solubility of hydrophobic drugs, b) by increasing drug residence time at the absorptive membrane of the gut via mucoadhesion, and c) by promoting transcellular uptake of hydrophobic molecules