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Utility of the three-dimensional cultured human skin model as a tool to evaluate rapid determination of skin permeation of drag and skin irritation.

三维培养人体皮肤模型作为评估快速测定皮肤渗透性和皮肤刺激性的工具的实用性。

基本信息

批准号：
12672157
负责人：
SUGIBAYASHI Kenji
金额：
$ 1.98万
依托单位：
Josai University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

Three-dimensional cultured human skin model (LSE-high) was evaluated for prediction of skin permeation of drugs. Although the cumulative amount of drags that permeated through LSH-high was about 10-fold higher than those through the excised human and hairless rat skin, a good correlation was found the LSE-high and excised skin permeabilities. Effect of penetration enhancers on the permeation of drugs across LSE-high was also evaluated. Every enhancer showed a penetration-enhancing effect on the drug permeation through LSE-high as it did through the hairless rat skin. These findings suggest that LSE-high may be utilized as an alternative membrane when testing the promoting effect of penetration enhancers on the skin permeation of drugs. Additionally, a quartz crystal microbalance was tested for a rapid measuring method of permeation of drug through a living dermal model. The obtained values corrected by decomvolution were very closed to that by HPLC.A cytotoxicity assay using a LSE-high was evaluated. When the irritants were applied on the LSE-high, two first ordered decreasing phases, initial slow land following rapid phases, were found in the viability of LSE. The inflection time point from the slow to rapid rate was dependent on the kind and concentration of irritants applied, suggesting that the skin irritation rate is closely related by the barrier function of skin. LSE-high was also evaluated as an alternative to the Draize skin irritation using animals. Irritant concentration showing IC50 was similar for the MTT assay and Draize test. In contrast, IC50 for MTT assay in LSE was much lower than that using guinea pig skin. We than corrected the results for the MTT assay using a ratio of IC50 in gunea pig skin against LSE, resulting in a good relation between both MTT results in guinea pig skin and LSE-high.

评价了三维培养的人皮肤模型（LSE-high）用于药物经皮渗透的预测。尽管通过高LSH渗透的药物的累积量比通过切除的人和无毛大鼠皮肤的药物的累积量高约10倍，但发现高LSE和切除的皮肤渗透性具有良好的相关性。还评价了渗透促进剂对药物通过LSE-高的渗透的影响。每一种促进剂对药物通过LSE-高的渗透都表现出渗透促进作用，就像它通过无毛大鼠皮肤一样。这些结果表明，LSE-高可作为替代膜时，测试渗透促进剂对药物的皮肤渗透的促进作用。此外，石英晶体微天平是一种快速测定药物透过活体皮肤模型的方法。经去卷积校正后的测定值与HPLC测定值非常接近。当刺激物被施加在LSE高，两个第一顺序下降阶段，初始缓慢土地后快速阶段，被发现在LSE的生活力。皮肤刺激率由慢变快的拐点与所用刺激物的种类和浓度有关，提示皮肤刺激率与皮肤的屏障功能密切相关。还使用动物评价了高LSE作为Draize皮肤刺激的替代方法。MTT试验和Draize试验显示IC 50的刺激剂浓度相似。MTT法测定LSE的IC_（50）明显低于豚鼠皮肤。然后，我们使用豚鼠皮肤中对LSE的IC 50比率校正了MTT测定的结果，导致豚鼠皮肤中的MTT结果与LSE-高之间存在良好的相关性。