CZ48 Cosolvent Drug Delivery System And Its Pharmacokinetic Study In Rats

Camptothecin（CPT）is an indole alkaloid isolated from Camptotheca acuminata,which has broad spectrum antitumor activity and is mainly used in the treatment of colon cancer,ovarian cancer,liver cancer,bone cancer and leukemia.The clinical application of CPT was limited due to its poor water solubility and its instability under human physiological conditions.CZ48（camptothecin-20-O-propionate）,a designed ester derivative of CPT at the C20 hydroxyl group,which decreases the toxicity and protects the activity.In this dissertation,we designed CZ48cosolvent delivery systems for the pharmacokinetic studies of CZ48 after intravenous and oral administrations in rats,which provided the experimental data for further development of CZ48,and the main experimental results are as follows:Screening of suitable cosolvents for intravenous administration was performed using the FDA-approved database of drug inactive ingredients.PEG 400,polyoxyethylene 35 castor oil（Cr EL）and DMSO were selected as components of the cosolvent delivery system based on the preliminary solubility screening of CZ48 in cosolvents.The system was optimized by mathematical modeling and effect surface comparison using the central composite design-effect surface method,and the CZ48 cosolvent drug delivery system was determined as follows:F1（CZ48 0.1 mg/m L,Cr EL 6.5%,PEG 400 27.5%and DMSO 6%）,F2（CZ48 0.2 mg/m L,Cr EL 6.5%,PEG 400 37.5%and DMSO 6%）.The in vitro stability study showed that CZ48 was stable at 4°C for 30 days,began to decrease on the 11^th day at room temperature,and dropped sharply on the 4^th day at 40°C.In vitro hemolysis experiments showed that the CZ48 cosolvent deliver system did not induce hemolysis,and the hemolysis rates were all lower than 5%.The in vivo pharmacokinetic studies of CZ48 were performed after intravenous and oral administrations,and the results showed that the cosolvent delivery system of CZ48 was suitable for intravenous administration in rats,and the kinetic parameters were consistent with the characteristics of intravenous administration,with AUC_0-4h of CZ48 and CPT after administration were 120.65±30.52 h-ng-m L-1 and 5.73±0.81 h-ng-m L-1,respectively.The half-life and mean retention time were prolonged by oral administration of 200 mg/kg CZ48.The oral bioavailability of CZ48 was only 0.01%based on the calculated AUC_（0-t）in rats after intravenous administration as a reference.