Ji Ying, Liu Chen, Pei Yuan-Ying
Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 200032, China.
Acta Pharmacol Sin. 2007 May;28(5):744-50. doi: 10.1111/j.1745-7254.2007.00513.x.
The relative bioavailabilities and effects on lung injury alleviation of 4 insulin- artificial pulmonary surfactant (INS-APS) preparations were studied in normal rats. The relationship between the minimal surface tension (Gamma(min )) of INS-APS and the absorption of insulin was also investigated.
Four formulations of APS [1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)/lecithin/palmitic acid (PA), DPPC/1-hexadecanol (Hex)/tyloxapol (Tyl), DPPC/L-alpha-phosphatidyl-DL-glycerol sodium salt (PG), DPPC/Tyl] were prepared by thin-film sonication method and direct sonication. The Gamma(min ) of 4 APS dispersions was examined with and without INS by pulsating with a bubble surface tensiometer. In vivo experiments were performed in which serum glucose change and the insulin level were measured by an enzymatic glucose reagent kit and a radioimmunology assay kit after IT to rats. The reduction in lung injury by INS-APS following 7 d of consecutive administration was evaluated by the pulmonary edema index (the weight ratio of wet lung to dry lung) and histopathology examination.
The Gamma(min ) of all APS dispersions were below 10 mN/m. There was no significant difference (P> 0.05) between the Gamma(min ) of APS and the corresponding INS-APS. In vivo experiments showed a significant glucose level decrease and insulin absorption increase (P< 0.05) in the presence of APS, compared to the insulin solution alone. From the results, we found that the pulmonary edema index values of all the INSAPS groups were significant lower (P< 0.05) than that of the insulin solution group, and there were no significant differences (P> 0.05) between INS/DPPC/Tyl, INS/ DPPC/PG, and the control group. The pulmonary edema indices and histopathological observation indicated that INS-APS could alleviate lung injury.
The most potent hypoglycemic effect and insulin absorption increase in this study were obtained with INS/DPPC/Tyl. According to the results, there was a linear correlation between the Gamma(min ) and relative bioavailability of INS-APS, suggesting a possible effect of the Gamma(min ) of carriers on the in vivo absorption of insulin. APS, DPPC/Tyl, and DPPC/PG dispersions might be the most efficient insulin pulmonary delivery carriers in achieving a lower Gamma(min ), enhancing insulin absorption, and decreasing lung injury.
在正常大鼠中研究4种胰岛素 - 人工肺表面活性剂（INS - APS）制剂的相对生物利用度及其对减轻肺损伤的作用。同时研究INS - APS的最小表面张力（Gamma(min)）与胰岛素吸收之间的关系。
采用薄膜超声法和直接超声法制备4种APS制剂[1,2 - 二棕榈酰 - sn - 甘油 - 3 - 磷酸胆碱（DPPC）/卵磷脂/棕榈酸（PA）、DPPC/1 - 十六醇（Hex）/聚乙氧基月桂醇（Tyl）、DPPC/L - α - 磷脂酰 - DL - 甘油钠盐（PG）、DPPC/Tyl]。使用气泡表面张力仪通过脉动检测4种APS分散体在有和没有INS情况下的Gamma(min)。对大鼠进行经气管内给药（IT）后的体内实验，用酶法葡萄糖试剂试剂盒和放射免疫分析试剂盒测量血清葡萄糖变化和胰岛素水平。连续给药7天后，通过肺水肿指数（湿肺与干肺的重量比）和组织病理学检查评估INS - APS对肺损伤的减轻作用。
所有APS分散体的Gamma(min)均低于10 mN/m。APS的Gamma(min)与相应的INS - APS之间无显著差异（P>0.05）。体内实验表明，与单独的胰岛素溶液相比，在有APS存在时血糖水平显著降低，胰岛素吸收增加（P<0.05）。结果显示，所有INS - APS组的肺水肿指数值均显著低于胰岛素溶液组（P<0.05），INS/DPPC/Tyl、INS/DPPC/PG与对照组之间无显著差异（P>0.05）。肺水肿指数和组织病理学观察表明INS - APS可减轻肺损伤。
本研究中INS/DPPC/Tyl具有最强的降血糖作用和最大的胰岛素吸收增加量。结果表明，INS - APS的Gamma(min)与相对生物利用度之间存在线性相关性，提示载体的Gamma(min)可能对胰岛素的体内吸收有影响。APS、DPPC/Tyl和DPPC/PG分散体可能是最有效的胰岛素肺部给药载体，可实现较低的Gamma(min)，增强胰岛素吸收并减轻肺损伤。
