The highly water-soluble monomethoxypoly(ethyleneglycol) (mPEG) prodrugs of cyclosporin A (CsA) were synthesized. These prodrugs were prepared by initially preparing intermediate in the form of carbonate at the 3'-positions of CsA with chloromethyl chloroformate, in the presence of a base to provide a 3'-carbonated CsA intermediate. Reaction of the CsA intermediate with mPEG derivative in the presence of a base provides the desired water-soluble prodrugs. As a model, we chose molecular weight 5 kDa mPEG in the reaction with CsA to give water soluble prodrugs. To prove that the prodrug is decomposed in the body to produce CsA, the enzymatic hydrolysis test was conducted using human liver homogenate at 37 degrees C. The prodrug was decomposed in human liver homogenate to produce the active material, CsA, and the hydrolysis half-life (t(1/2)) of the prodrug, KI-306 was 2.2 minutes at 37 degrees C. However, a demonstration of non-enzymatic conversion in pH 7.4 phosphate buffer was provided by the fact that the half-life (t(1/2)) is 21 hours at 37 degrees C. The hydrolysis test in rat whole blood was also conducted. The hydrolysis was seen with half-life (t(1/2)) of about 9.9, 65.0, 14.2, 3.4, 2.1 9.5, and 1.6 minutes for KI-306, 309, 312, 313, 315, 316, and 317, respectively. This is the ideal for CsA prodrug. The pharmacokinetic study of the prodrug, KI-306, in comparison to the commercial product (Sandimmune Neoral Solution) was also carried out after single oral dose. Each rat received 7 mg/kg of CsA equivalent dose. Especially, the prodrug KI-306 exhibits higher AUC and Cmax than the conventional Neoral. The AUC and Cmax were increased nearly 1.5 fold. The kinetic value was also seen with Tmax of about 1.43 and 2.44 hours for KI-306 and Neoral, respectively.
