N-trimethylated chitosan chloride (TMC) improves the intestinal permeationof the peptide drug buserelin in vitro (Caco-2 cells) and in vivo (rats)

Purpose. To evaluate N-trimethyl chitosan chloride (TMC) of high degrees of substitution as intestinal permeation enhancers for the peptide drug buser elin in vitro using Caco-2 cell monolayers, and to investigate TMCs as enha ncers of the intestinal absorption of buserelin in vivo, in rats. Methods, TMCs were rested on Caco-2 cells for their efficiency to increase the paracellular permeability of the peptide buserelin. For the in vivo stu dies male Wistar rats were used and buserelin was administered with or with out the polymers intraduodenally. Both types of experiments were performed at pH 7.2. Results. Transport studies with Caco-2 cell monolayers confirmed that the i ncrease in buserelin permeation is dependent on the degree of trimethylatio n of TMC. In agreement with the in vitro results, in vivo data revealed hig hly increased bioavailability of buserelin following intraduodenal co-admin istration with 1.0% (w/v) TMCs. Intraduodenally applied buserelin resulted in 0.8% absolute bioavailability, whereas co-administrations with TMCs resu lted in mean bioavailability values between 6 and 13 %. Chitosan HCl(1.0%; pH = 7.2) did not significantly increase the intestinal absorption of buser elin. Conclusions. Both the in vitro and in vivo results indicate that TMCs are p otent mucosal permeation enhancers of the peptide drug buserelin at neutral pH values.