张磊, 潘弘, 刘敏, 陆伟跃. 阿霉素的不同盐型对其脂质体体外药物泄漏和体内长循环的影响J. 药学学报, 2004, 39(12): 1018-1022.
引用本文: 张磊, 潘弘, 刘敏, 陆伟跃. 阿霉素的不同盐型对其脂质体体外药物泄漏和体内长循环的影响J. 药学学报, 2004, 39(12): 1018-1022.
ZHANG Lei, PAN Hong, LIU Min, LU Wei-yue. Influence of different doxorubicin-salt aggregates on the leakage of liposomal doxorubicin in vitro and long circulation in vivoJ. Acta Pharmaceutica Sinica, 2004, 39(12): 1018-1022.
Citation: ZHANG Lei, PAN Hong, LIU Min, LU Wei-yue. Influence of different doxorubicin-salt aggregates on the leakage of liposomal doxorubicin in vitro and long circulation in vivoJ. Acta Pharmaceutica Sinica, 2004, 39(12): 1018-1022.

阿霉素的不同盐型对其脂质体体外药物泄漏和体内长循环的影响

Influence of different doxorubicin-salt aggregates on the leakage of liposomal doxorubicin in vitro and long circulation in vivo

  • 摘要: 目的探讨阿霉素不同盐型对脂质体体内外稳定性的影响。方法以薄膜分散-挤压法制备含有不同缓冲对的空白脂质体,用pH梯度和化学梯度法包载阿霉素,对其在脂质体内状态进行观察,测定了阿霉素脂质体理化性质;用透析法检测阿霉素脂质体在不同介质中的药物泄漏;用HPLC法研究不同盐型阿霉素脂质体在大鼠体内药代动力学行为。结果甘氨酸盐缓冲液、柠檬酸盐缓冲液和硫酸铵溶液作内水相制得的空白脂质体的平均粒径分别为(103±8),(102±12)和(97±8) nm,zeta电位分别为(-21.3±0.5),(-21.7±0.4)和(-20.9±0.7) mV,对阿霉素的包封率分别为47.8%,96.7%和98.6%。甘氨酸盐制得的脂质体体外泄漏最快,硫酸铵制得的脂质体泄漏最慢;甘氨酸盐缓冲液、柠檬酸盐缓冲液和硫酸铵溶液作内水相制得的阿霉素脂质体大鼠体内平均滞留时间分别为12.13,23.31和29.79 h。结论阿霉素在脂质体内水相中不同盐型影响其脂质体的体内外稳定性,以硫酸铵为内水相制得的阿霉素脂质体最稳定,其稳定次序与内水相中酸的强度有关,酸性越弱其脂质体稳定性越高。

     

    Abstract: AimTo develop liposomes containing doxorubicin with different salts and to investigate their influence on the stability of liposomal doxorubicin in vitro and in vivo. MethodsLiposomes were prepared by the film method, treated further by extruded through nuclear membrane. The entrapment efficiency was determined by column chromatography. In vitro drug release experiments were carried out with a dialysis bag (mw cut-off 12 000-14 000). Reverse-phase HPLC was used to study the pharmacokinetics of liposomal doxorubicin. ResultsThe particle size of liposomes with glycinate buffer, citrate buffer and ammonium sulfate as the inner water phase were (103±8), (102±12) and (97±8) nm. The ζ potential and the encapsulation ratio were (-21.3±0.5), (-21.7±0.4), (-20.9±0.7) mV and 47.8%, 96.7%, 98.6%, respectively. The leaking rate of doxorubicin from liposomes was related to the pH value of the release medium. The leaking rate increased at lowered pH. Pharmacokinetic study showed that the MRT(mean retention time)of liposomes with glycinate buffer, citrate buffer and ammonium sulfate as the inner water phase were 12.13, 23.31 and 29.79 h, respectively. Conclusion Doxorubicin showed different stability in liposomes with different inner water phases, the weaker the acid in the inner water phase, the stabler the liposome.

     

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