Pharmacokinetics and organ distribution of cyclosporin A incorporated in liposomes and mixed micelles

The commercially available intravenous dosage form of cyclosporin A (C-CsA) contains a solubilizing agent, polyoxyethylated castor oil, which has been reported to be toxic. To replace the toxic solubilizing agent present in C-CsA, liposomal and mixed micellar preparations were made to solubilize CsA by the proliposome method and characterized. Furthermore, pharmacokinetics and organ distributions of these preparations were evaluated in comparison to C-CsA, which is micellar. The mean size of liposomal preparation (L-CsA) composed of DPPC/PA (molar ratio 3/1) and CsA was 43.6 nm and that of mixed micellar preparation (M-CsA) composed of DMPC/DSPE-PEG (molar ratio 95/5) and CsA was 6.5 nm. The solubilization of CsA was 2-fold greater in mixed micellar solution than in liposomes (0.06 vs 0.03 mg of CsA/mg of lipid). L-CsA, M-CsA and C-CsA were intravenously administered into rats via the femoral vein to analyze pharmacokinetics and organ distribution of CsA. M-CsA was not significantly different from C-CsA in every pharmacokinetic parameter studied. However, L-CsA resulted in 30% decrease in AUC and 55% increase in Cl-t, compared with C-CsA (P < 0.05), without any significant differences in MRT, V-dss and t(1/2). In addition, the distributions of M-CsA and L-CsA in different organs were not significantly different from those of C-CsA (P < 0.05), except for a 51% decrease of M-CsA in the spleen at 4 h and a 33% increase of L-CsA in the liver at 4 h (P < 0.05). These findings demonstrate that the liposomal preparation composed of DPPC/PA and CsA shows slightly different pharmacokinetics and organ distribution patterns from C-CsA, whereas the mixed micellar preparation composed of DMPC/DSPE-PEG and CsA exhibits similar patterns to C-CsA, as expected. Furthermore, these results suggest that those mixed micellar and liposomal preparations can replace C-CsA containing the toxic solubilizing agent, thus providing useful alternative dosage forms for intravenous administration of CsA. (C) 1999 Elsevier Science B.V. All rights reserved.