College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China.
Int J Nanomedicine. 2012;7:3567-77. doi: 10.2147/IJN.S32860. Epub 2012 Jul 26.
Brucine was encapsulated into stealth liposomes using the ammonium sulfate gradient method to improve therapeutic index.
Four brucine stealth liposomal formulations were prepared, which were made from different phosphatidylcholines (PCs) with different phase transition temperatures (T(m)). The PCs used were soy phosphatidylcholine (SPC), dipalmitoyl phosphatidylcholine (DPPC), hydrogenated soy phosphatidylcholine (HSPC), and distearoyl phosphatidylcholine (DSPC). The stabilities, pharmacokinetics, and toxicities of these liposomal formulations were evaluated and compared.
Size, zeta potential, and entrapment efficiency of brucine-loaded stealth liposomes (BSL) were not influenced by PC composition. In vitro release studies revealed that drug release rate increased with decreased T(m) of PCs, especially with the presence of rat plasma. After intravenous administration, the area under the curve (AUC) values of BSL-SPC, BSL-DPPC, BSL-HSPC, and BSL-DSPC in plasma were 7.71, 9.24, 53.83, and 56.83-fold as large as that of free brucine, respectively. The LD(50) values of brucine solution, BSL-SPC, BSL-DPPC, BSL-HSPC, and BSL-DSPC following intravenous injection were 13.17, 37.30, 37.69, 51.18, and 52.86 mg/kg, respectively. It was found in calcein retention experiments that the order of calcein retention in rat plasma was SPC < DPPC << HSPC < DSPC stealth liposomes.
PC composition could exert significant influence on the stabilities, pharmacokinetics, and toxicities of brucine-loaded stealth liposomes. DSPC or HSPC with T(m) above 50°C should be used to prepare the stealth liposomal formulation for the intravenous delivery of brucine. However, it was found in the present paper that the pharmacokinetics and toxicity of BSL were not influenced by the PC composition when the T(m) of the PC was in the range of -20°C to 41°C.
采用硫酸铵梯度法将马钱子碱包封入隐形脂质体中，以提高治疗指数。
制备了 4 种马钱子碱隐形脂质体配方，它们由相变温度（Tm）不同的不同磷脂（PC）制成。所用的 PC 为大豆磷脂（SPC）、二棕榈酰磷脂酰胆碱（DPPC）、氢化大豆磷脂（HSPC）和二硬脂酰磷脂酰胆碱（DSPC）。评估和比较了这些脂质体配方的稳定性、药代动力学和毒性。
载马钱子碱隐形脂质体（BSL）的大小、Zeta 电位和包封效率不受 PC 组成的影响。体外释放研究表明，药物释放速率随 PC 的 Tm 降低而增加，特别是在存在大鼠血浆的情况下。静脉给药后，BSL-SPC、BSL-DPPC、BSL-HSPC 和 BSL-DSPC 在血浆中的 AUC 值分别是游离马钱子碱的 7.71、9.24、53.83 和 56.83 倍。静脉注射后马钱子碱溶液、BSL-SPC、BSL-DPPC、BSL-HSPC 和 BSL-DSPC 的 LD50 值分别为 13.17、37.30、37.69、51.18 和 52.86 mg/kg。在 calcein 保留实验中发现，大鼠血浆中 calcein 保留的顺序为 SPC < DPPC << HSPC < DSPC 隐形脂质体。
PC 组成对载马钱子碱隐形脂质体的稳定性、药代动力学和毒性有显著影响。应使用 Tm 高于 50°C 的 DSPC 或 HSPC 来制备用于静脉给药马钱子碱的隐形脂质体制剂。然而，本文发现，当 PC 的 Tm 在-20°C 至 41°C 范围内时，BSL 的药代动力学和毒性不受 PC 组成的影响。
