Thiolated chitosan:: Development and in vitro evaluation of an oral delivery system for acyclovir

The aim of the study was to develop a novel oral delivery system for the efflux pump substrate acyclovir (ACY) utilizing thiolated chitosan as excipient which is capable of inhibiting P-glycoprotein (P-gp). Three chitosan-4-thiobutylamidine (Chito-TBA) conjugates with increasing molecular mass (Chito-9.4 kDa-TBA, Chito-150 kDa-TBA and Chito-600 kDa-TBA) were synthesized and permeation studies on rat intestinal mucosa and Caco-2 monolayers were performed. Additionally, tablets comprising the conjugates and ACY were tested towards their drug release behaviour. The efflux ratio (secretory P-app/absorptive P-app) of ACY across Caco-2 monolayers was determined to be 2.5 and in presence of 100 mu M verapamil 1.1 which indicates ACY as P-gp substrate. In comparison to buffer only, the transport of ACY in presence of 0.5% (m/v) unmodified chitosan, 0.5% (m/v) Chito-150 kDa-TBA and 0.5% (m/v) Chito-150 kDa-TBA with 0.5% (m/v) reduced glutathione (GSH), was 1.3-, 1.6- and 2.1-fold improved, respectively. Transport studies across Caco-2 monolayers showed that P-gp inhibition is dependent on the average molecular mass of thiolated chitosan showing following rank order: 0.5% (m/v) Chito-150 kDa-TBA/GSH > 0.5% (m/v) Chito-9.4 kDa-TBA/GSH > 0.5% (m/v) Chito-600 kDa-TBA/GSH. The higher the molecular mass of Chito-TBA was, the more sustained was the release of ACY Chito-150 kDa-TBA/GSH might be an appropriate sustained release drug delivery system for ACY, which is able to enhance ACY transport due to efflux pump inhibition. (c) 2007 Elsevier B.V.. All rights reserved.