Biodistribution of cyclosporin encapsulated in liposomes modified with bioadhesive polymer.

Abstract

The purpose of this investigation was to study the possibility of renewing the immunosuppressive activity of cyclosporin by formulating the compound in liposomes modified with bioadhesive polymers. The liposomes prepared were evaluated both pharmacokinetically and pharmacodynamically. Tissue distribution and plasma pharmacokinetics of cyclosporin and model dye, sudan black, which is as hydrophobic as cyclosporin, were studied in rats after intravenous infusion (10 mg kg-1). The immunosuppressive efficacy of liposomal cyclosporin preparations was studied in the allogenic rat-heart-transplantation model, where cyclosporin therapy (10 mg kg-1) continued for one week. The entrapment of sudan black in liposomes modified with bioadhesive polymers resulted in higher sudan black delivery to the spleen and the liver than with standard sudan-black-loaded liposomes. Among the modified liposomes, those modified with carbopol 941 showed the most remarkable enhancing effect on the delivery of sudan black to these organs and total plasma clearance of sudan black decreased to 38.6 +/- 7.8 mL h-1 kg-1 (standard liposomes, 58.9 +/- 6.4 mL h-1 kg-1). Delivery of cyclosporin to the spleen and the liver was increased approximately twofold by modifying the liposomes with carbopol 941. In the preliminary study on the allogenic rat-heart-transplantation model, the mean survival days of the graft were 18.8 +/- 2.9 days for the group receiving cyclosporin liposomes modified with carbopol 941, 14.2 +/- 4.4 days for the group receiving standard cyclosporin liposomes and 7.6 +/- 0.5 days for the group receiving cyclosporin solution. The encapsulation of cyclosporin in liposomes modified with bioadhesive polymer enhanced the residence time of cyclosporin in the systemic circulation, resulting in approximately twofold greater delivery of cyclosporin to the spleen and liver. However, in the allogenic rat-heart-transplantation model no significant difference was detected between the immunosuppressive efficacy of cyclosporin encapsulated in bioadhesive polymer-modified liposomes and that encapsulated in standard liposomes.