Enhanced Selective Lymphatic Delivery of Cyclosporin A by Solubilizers and Intensified Immunosuppressive Activity Against Mice Skin Allograft

The absorption and lymphatic delivery of a new immunosuppressive drug, cyclosporin A (CsA), were studied in rats by administering CsA orally after solubilization with HCO-60 (polyoxyethylated hydrogenated castor oil), sugar ester, and oils. After the administration of solubilized CsA (7 mg/kg) to rats with thoracic lymph duct cannulas, both plasma and lymph CsA levels were measured over 6 hr. The lymph CsA levels were strongly affected by the solubilizers. The rank order of the solubilizers in enhancing lymph absorption was HCO-60 (57 µg/ml) > sugar ester (46 µg/ml) > sesame oil (3.5 µg/ml) > linoleic acid (0.4 µg/ml), where the parentheses show the maximum lymph CsA levels. Plasma CsA levels were below 2 µg/ml in each group of animals and were barely altered by the solubilizers. These results support the selective lymphatic delivery of CsA with solubilizers such as HCO-60 and sugar ester. The immunosuppressive activity of CsA (1 mg/kg) solubilized with HCO-60 was nearly equivalent to the sesame oil solution with 7 to 15 mg/kg CsA in the skin-allograft mice model.