Pharmacokinetics of Orally Administered Poly(Ethylene Oxide)-block-Poly(ε-Caprolactone) Micelles of Cyclosporine A in Rats: Comparison with Neoral®

PURPOSE: The aim of this study was to assess the pharmacokinetics of methoxy poly(ethylene oxide)- block -poly(e-caprolactone) (PEO- b -PCL) micellar formulation of cyclosporine A (CyA) following oral administration in rats making comparisons with its commercial microemulsion formulation, Neoral ® . METHODS: PEO- b -PCL copolymer was synthesized and used to form micelles encapsulating CyA. The release of CyA from Neoral ® and PEO- b -PCL as well as PEO- b -PCL degradation were assessed in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). Polymeric micellar CyA and Neoral ® were administered by oral gavage to healthy Wistar rats. At predetermined intervals, rats (n=5 for each time point) were euthanized, samples of blood and plasma were collected and analyzed for CyA using an LC-MS/MS assay. Blood and plasma pharmacokinetic parameters of CyA in its polymeric micellar formulation were compared to those of Neoral ® . RESULTS: Polymeric micelles of CyA showed 8 h in SGF, but was stable in SIF. Drug release in both SGF and SIF was comparable between the two formulations except for significantly higher release of CyA in SIF only at 24 h time point from Neoral ® . Following oral administration (10 mg/kg), the blood AUC 0-∞ and t max of CyA in the polymeric micellar formulation was comparable to that for Neoral ® . However, the C max of CyA-loaded PEO- b -PCL micelles was significantly ( p < 0.05) higher than that obtained with Neoral ® (2.10 ± 0.41 versus 1.40 ± 0.25 µg/mL, respectively). CyA had higher blood-to-plasma concentration ratios in polymeric micelles compared to Neoral ® , in vivo . CONCLUSION: Our results show that PEO- b -PCL micelles can serve as stable and good solubilizing carriers for oral delivery of CyA providing similar pharmacokinetic profile to that of Neoral ® .