姚东刚 孙考祥 慕宏杰 周凤梅 陈慧慧 刘林军 梁娜. 环孢素mPEG-PLGA嵌段共聚物胶束的制备及大鼠药动学研究J. 药学学报, 2009,44(12): 1410-1415.
引用本文: 姚东刚 孙考祥 慕宏杰 周凤梅 陈慧慧 刘林军 梁娜. 环孢素mPEG-PLGA嵌段共聚物胶束的制备及大鼠药动学研究J. 药学学报, 2009,44(12): 1410-1415.
TAO Dong-Gang, SUN Kao-Xiang, MU Hong-Jie, ZHOU Feng-Mei, CHEN Hui-Hui, LIU Lin-Jun, LIANG Na. Preparation of cyclosporine A loaded mPEG-PLGA copolymer micelles and study its pharmacokinetics in ratsJ. 药学学报, 2009,44(12): 1410-1415.
Citation: TAO Dong-Gang, SUN Kao-Xiang, MU Hong-Jie, ZHOU Feng-Mei, CHEN Hui-Hui, LIU Lin-Jun, LIANG Na. Preparation of cyclosporine A loaded mPEG-PLGA copolymer micelles and study its pharmacokinetics in ratsJ. 药学学报, 2009,44(12): 1410-1415.

环孢素mPEG-PLGA嵌段共聚物胶束的制备及大鼠药动学研究

Preparation of cyclosporine A loaded mPEG-PLGA copolymer micelles and study its pharmacokinetics in rats

  • 摘要:

    为了开发不含Cremophor EL的环孢素注射制剂, 本文制备了环孢素 (cyclosporine A, CyA) 共聚物胶束并考察其体外释放行为和大鼠体内的药代动力学特征。采用开环聚合法合成聚乙二醇单甲-乳酸羟基乙酸嵌段共聚物。采用溶剂挥发法制备环孢素共聚物胶束 (CyA-PM), 并通过动态光散射技术、透射电镜、高效液相色谱法对其粒径、形态、包封率和载药量进行考察。体外释放和大鼠给药后的样品经处理后以高效液相色谱法测定。结果显示, 所制备CyA-PM呈核-壳球形结构, 粒径在136.1141.9 nm, 包封率可达62.3%CyA-PM在体外具有明显的缓释效果, 12 h内累计释放率为9.7%, 经拟合释放行为符合Higuchi方程; 与相同剂量的山地明溶液比较, CyA-PM在大鼠体内的半衰期延长, 相对生物利用度提高, 二者体内经时过程均符合二房室模型。CyA-PM增溶效果明显, 同时克服了山地明中增溶-聚氧乙烯蓖麻油的毒副作用, 有望开发成为环孢素的新一代制剂。

     

    Abstract:

    To prepare cyclosporine A (CyA) loaded block copolymer micelles and observe its release     behaviors in vitro and pharmacokinetics in rats, methoxylpoly (ethylene glycol)-poly (D, L-lactide-co-glycolide) (mPEG-PLGA) was synthesized by ring-opening copolymerization of lactide and glycolide in the presence    of methoxylpoly (ethylene glycol) (mPEG) as initiator.  The structure of the mPEG-PLGA copolymer was  confirmed with 1H NMR and FT-IR.  The cyclosporine A loaded micelles (CyA-PM) were prepared by solvent evaporation method and their morphology was observed by the transmission electron microscope (TEM).  The mean size and size distribution were determined by dynamic light scattering (DLS).  The release behaviors    in vitro and pharmacokinetics in rats were investigated by HPLC method using cyclosporine A injection    commercial agent, sandimmune, as the reference.  The obtained CyA-PM showed spherical shape with the core-shell structure, the mean particle sizes are in the range of 136.1−141.9 nm.  The drug loading amount and entrapment efficiency were increased and the particle size became smaller with decreasing the ratio of acetone  to water.  With the increasing of the amount of cyclosporine A fed the drug loading increased, entrapment   efficiency decreased and the particle size had no change.  CyA-PM showed significant sustained release behave in vitro compared with sandimmune and only 9.7% of encapsulated cyclosporine A was released after 12 hours, the release characteristics was well fitted with Higuchi equation (r = 0.999).  The Pharmacokinetics study at equal administration dosage (5 mg·kg−1) in rats showed the half-life (t1/2) of CyA-PM extended and the area  under concentration-time curve (AUC) increased compared to sandimmune.  The results also showed that   cyclosporine A concentration-time data were all in accord with two compartment model.  Cyclosporine A loaded mPEG-PLGA micelles showed obviously solubility enhancement, sustained release and overcome the side effect and toxicity of sandimmune resulted from solubiling agent-polyoxyethylene castor oil (Cremophor EL) and might be developed as a novel dosage form of cyclosporine A.

     

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