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(ε-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 < 15 and 10% increase in diameter in SGF and SIF, respectively, within 24 h. PEO-b-PCL showed signs of minimal degradation when incubated for > 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 AUC0-∞ and tmax of CyA in the polymeric micellar formulation was comparable to that for Neoral®. However, the Cmax 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®.