自乳化微乳对9-硝基喜树碱内酯型的保护效应

Protection Effect of Self-Emulsifying Microemulsion on 9-Nitrocamptothecin Lactone Form

目的制备9-硝基喜树碱(9-nitrocamptothecin,9-NC)自乳化微乳(自微乳),并考察其对9-NC内酯型的体内外保护效应。方法以油酸乙酯为油相,Cremophor EL或Tween 80为乳化剂,PEG-400和无水乙醇为助乳化剂,制得2种9-NC自微乳。以9-NC溶液剂为对照,考察自微乳对9-NC内酯型结构的体内外保护效应。结果分别以Cremophor EL和Tween 80为乳化剂的自乳化油(油相-乳化剂-助乳化剂=20∶40∶40)在稀释倍数为20倍的水相中均可自发形成O/W型微乳液(9-NCME-C或9-NCME-T),粒径分别为(30.2±4.6)和(21.8±4.2)nm,Zeta电位分别为-(2.9±0.7)和-(8.1±0.9)mV,且具有良好的物理稳定性。与溶液剂(9-NCSol)相比,微乳能显著降低内酯型水解开环转变为羧酸盐型的速度,有利于提高体内9-NC活性结构(内酯型)的比例。大鼠静脉注射微乳(9-NCME-C和9-NCME-T)和溶液剂(9-NCSol)后血浆中内酯型9-NC的AUC0-∞分别为23072.24,20676.33和8954.97μg·min·L-1。结论自微乳对9-NC内酯型具有显著的体内外保护效应。

OBJECTIVE To prepare 9-nitrocamptothecin self-emulsifying microemulsion and investigate the protection effect of self-emulsifying microemulsion on 9-NC lactone form in vitro and in vivo. METHODS Two types of self-emulsifying microemulsion with Cremophor EL and Tween 80 as emulsifier respectively were prepared （SMEDDS-C and SMEDDS-T）. Comparing with 9-NC solution, the protection effects of self-emulsifying microemulsion on 9-NC lactone were evaluated. RESULTS When the two kinds of SMEDDS were diluted with saline during the dilution ratio of 1 ： 20, the diameters of microemulsions were （ 30. 2 ± 4. 6 ） and （21.8 ±4. 2） nm, and the potentials were - （2. 9 ± 0. 7） and - （8.1 ± 0. 3） mV for 9-NCME-C and 9-NCME-T, respectively. Microemulsion dramatically decreased the conversion rate of lactone form to carboxylate form and increased lactone form proportion. The AUC0-∞ of lactone form were 23 072. 24μg· min· L^-1for 9-NC SMEDDS-C, 20 676. 33 μg ·min· L^-1 for 9-NC SMEDDS-T and 8 954. 97 μg ·min · L^-1 for 9-NC solution after intravenous administration in rats. CONCLUSION The lactone form of 9-NC was significantly protected by self-emulsifying microemulsion.