Preparation of cyclosporine A loaded mPEG-PLGA copolymer micelles and study its pharmacokinetics in rats

To prepare cyclosporine A (CyA) loaded block copolymer micelles and observe its release     behaviors in vitro and pharmacokinetics in rats, methoxylpoly (ethylene glycol)-poly (D, L-lactide-co-glycolide) (mPEG-PLGA) was synthesized by ring-opening copolymerization of lactide and glycolide in the presence    of methoxylpoly (ethylene glycol) (mPEG) as initiator.  The structure of the mPEG-PLGA copolymer was  confirmed with ¹H NMR and FT-IR.  The cyclosporine A loaded micelles (CyA-PM) were prepared by solvent evaporation method and their morphology was observed by the transmission electron microscope (TEM).  The mean size and size distribution were determined by dynamic light scattering (DLS).  The release behaviors    in vitro and pharmacokinetics in rats were investigated by HPLC method using cyclosporine A injection    commercial agent, sandimmune, as the reference.  The obtained CyA-PM showed spherical shape with the core-shell structure, the mean particle sizes are in the range of 136.1−141.9 nm.  The drug loading amount and entrapment efficiency were increased and the particle size became smaller with decreasing the ratio of acetone  to water.  With the increasing of the amount of cyclosporine A fed the drug loading increased, entrapment   efficiency decreased and the particle size had no change.  CyA-PM showed significant sustained release behave in vitro compared with sandimmune and only 9.7% of encapsulated cyclosporine A was released after 12 hours, the release characteristics was well fitted with Higuchi equation (r = 0.999).  The Pharmacokinetics study at equal administration dosage (5 mg·kg⁻¹) in rats showed the half-life (t_1/2) of CyA-PM extended and the area  under concentration-time curve (AUC) increased compared to sandimmune.  The results also showed that   cyclosporine A concentration-time data were all in accord with two compartment model.  Cyclosporine A loaded mPEG-PLGA micelles showed obviously solubility enhancement, sustained release and overcome the side effect and toxicity of sandimmune resulted from solubiling agent-polyoxyethylene castor oil (Cremophor EL) and might be developed as a novel dosage form of cyclosporine A.