Studies On 9-nitrocamptothecin Self-microemulsifying Drug Delivery Systems

SMEDDS （Self-microemulsifying Drug Delivery Systems） are mixtures of drugs, oil, surfactants and co-surfactants, which form fine oil-in-water （O/W） microemulsion with a particle size of less than 100 run when exposed to aqueous media under conditions of gentle agitation. It has been developed to increase the solubility, dissolution rate, intestinal lymphatic transport and, ultimately, oral bioavailability of poorly water soluble drug. The objectives of the study were to develop optimum formulations of SMEDDS containing 9-Nitrocamptothecin（9-NC） which was model drug and assess their characteristics in vitro and in vivo.In the study of formulation, the equilibrium solubility of 9-NC in different oil, surfactants and co-surfactants and their compatibility was investigated and Pseudo-ternary Phase diagramswere constructed to evaluate the formulation effect. By determining the solubility of the formulations, the optimal formulations were optimized: ethyl oleate as oil phase （20%）, Cremophor EL or Tween 80 （40%） as surfactant, PEG400/dehydrated alcohol（40%） as co-surfactants. Compared with 9-NC solution, the solubility of the formulations increased about 400 times.Evaluation of the pharmaceutical property of self-microemulsifying formulations: the self-microemulsifying efficiency, the effect of dilution on the particle size, the stability of 9-NC in microemulsion and the stability of the self-microemulsifying preparations were investigated. The results indicated that self-microemulsifying preparations have favorable self-emulsification performance and physicochemical stability.Protection effect of lactone structure of 9-NC in microemulsions was determined in vitro. The hydrolyze t_1/2 of 9-NC SMEDDS-C/T and 9-NC Sol were 22.61±1.14、21.79±4.28、15.10±0.80 min respectively after incubation with pH7.4 PBS and 12.59±0.70、12.23±0.079、6.77±0.68 min after incubation with rat plasma. The results showed that SMEDDS could improve the stability of lactone 9-NC significantly in vitro. To testify if the self-made SMEDDS could improve the bioavailability of 9-NC, the pharmacokinetics study of self-made SMEDDS in rat was carried out. The AUC_0-∞ of lactone 9-NC were 23072.24±5209.34、20676.33±12445.00、8954.97±1918.45 ng·min·ml^-1 respectively after I.V. administration of 9-NC SMEDDS-C/T and 9-NC Sol; And the AUC_0-∞of lactone 9-NC of the preparations were 4182.20±1077.84、2659.32±559.40、1411.05±295.88 ng·min·ml^-1 respectively after oral administration. The results showed that self-made SMEDDS could improve the bioavailability of insoluble anticancer drugs significantly.Drug cytotoxicity efficacy of 9-NC SMEDDS-C/T、9-NC Sol on SKOV3 cells were investigated using the MTT assay, the 50% inhibition of growth （IC50） were 10.24+++++3.73、29.89±8.05、46.50±14.33 nM respectively. The results indicated that self-made SMEDDS could improve the cytotoxicity efficacy of 9-NC. The cell uptake characteristics of 9-NC SMEDDS-C/T、9-NC Sol was also studied in vitro. The cell uptake quantity of 9-NC SMEDDS-C/T was more than that of 9-NC sol.The anticancer efficacy of 9-NC SMEDDS-C/T、9-NC Su was determined using a SKOV3 experimental model in nude mice. Visible tumor grew slower in the 9-NC SMEDDS -treated groups than that in the 9-NC Su -treated groups （p<0.05）. But there was no difference on the weight of nude mice. The results demonstrated that 9-NC SMEDDS increased the anticancer efficacy and not the toxicity simultaneously.