Long circulating emulsion carrier systems for highly lipophilic drugs.
Long circulating emulsion carrier systems for highly lipophilic drugs.
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用于高亲脂性药物的长循环乳剂载体系统。
DOI：
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发表时间：
1994
影响因子：
2
通讯作者：
M. Hashida
中科院分区：
文献类型：
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作者：
T. Takino;K. Konishi;Y. Takakura;M. Hashida
为了开发具有延长血液循环或肝靶向潜力的亲脂性药物乳剂载体系统，四种模型化合物的体内分布，即[3H]前列腺素E1、[3H]视黄酸、[14C]胆固醇和[14C]胆固醇油酸酯，计算出的log PC(oct)值为2.15、6.61、9.46和18.3 分别注射各种乳剂制剂，在小鼠中进行研究。将组成为鸡蛋磷脂酰胆碱(PC):大豆油=1:1(小PC乳)和PC:鸡蛋鞘磷脂(SM):大豆油=0.7:0.3:1(小SM乳)的直径约100 nm的小尺寸乳剂与直径约250 nm、组成为PC:大豆油=1:1(大PC乳)的常规乳剂进行比较。高亲脂性[14C]胆固醇油酸酯是乳液颗粒的标志物，表明了多种体内行为；即，小SM乳液在血液中产生延长的循环，小PC乳液紧随其后，而大PC乳液则迅速被肝脏吸收。因此，油滴表面尺寸的减小和 SM 涂层导致避开网状内皮系统 (RES)。其他测试化合物的处置特征不同，具体取决于它们的亲脂性：[14C]胆固醇在所有制剂中显示出与[14C]胆固醇油酸酯相似的处置模式，但中等亲脂性的[3H]前列腺素E1和[3H]视黄酸显示出共同的处置特征，无论乳液类型如何，表明它们从乳液载体中快速释放。这些结果表明，小SM乳剂和大PC乳剂可以分别作为log PC(oct)大于9的高亲脂性药物的长循环和肝靶向载体。
With the aim of developing of emulsion carrier systems for lipophilic drugs with the potential for prolonged circulation in the blood or hepatic targeting, the in vivo disposition of four model compounds, i.e., [3H]prostaglandin E1, [3H]retinoic acid, [14C]cholesterol, and [14C]cholesteryl oleate with calculated log PC(oct) values of 2.15, 6.61, 9.46, and 18.3, respectively, injected with various emulsion formulations, were studied in mice. Small sized emulsions of about 100 nm in diameters, with compositions of egg phosphatidylcholine (PC): soybean oil = 1:1 (small PC emulsion) and PC: egg sphingomyelin (SM): soybean oil = 0.7:0.3:1 (small SM emulsion), and a conventional emulsion with a diameter of about 250 nm and a composition of PC: soybean oil = 1:1 (large PC emulsion) were compared. Highly lipophilic [14C]cholesteryl oleate, a marker of emulsion particles, indicated diverse in vivo behaviors; i.e., the small SM emulsion produced prolonged circulation in the blood, and the small PC emulsion followed this, while the large PC emulsion was rapidly uptake by the liver. Thus, a reduction in size and coating with SM on the surface of oil droplets resulted in avoidance of the reticuloendothelial system (RES). Disposition profiles of other test compounds differed, depending on their lipophilicities: [14C]cholesterol showed disposition patterns in all formulations similar to those of [14C]cholesteryl oleate, but moderately lipophilic [3H]prostaglandin E1 and [3H]retinoic acid showed common disposition profiles, regardless of emulsion types, suggesting their rapid release from the emulsion carriers. These results suggest that small SM emulsion and large PC emulsion can act respectively as long circulating and liver targeting carriers for highly lipophilic drugs with log PC(oct) larger than 9.