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 Papp/absorptive Papp) of ACY across Caco-2 monolayers was determined to be 2.5 and in presence of 100 μM 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.