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本文以十八甲基炔诺酮(norgestrel,NG)为手性模型药物,研究其经离体大鼠皮肤渗透的对映体选择性以及手性促透剂芳樟醇和皮肤类脂对NG经皮渗透对映体选择性的影响。采用Valia-Chien双室渗透池进行离体皮肤渗透实验,手性HPLC法检测渗透液样品,考察了NG经完整皮肤和去类脂皮肤渗透的对映体选择性及芳樟醇的影响。结果表明,当dl-NG或l-NG于无水乙醇-水(2∶8,v/v)饱和溶液中,未观察到dl-NG经皮渗透的对映体选择性,但dl-NG的皮肤渗透速率是l-NG的2倍,这主要归因于l-NG和dl-NG间溶解度的差异;当加入dl-芳樟醇后,dl-NG出现对映体选择性渗透,l-NG的稳态渗透速率高出d-NG 22%,而采用去类脂的皮肤进行相同实验时对映体选择性现象消失;傅里叶变换红外光谱检测显示,经dl-芳樟醇处理的皮肤角质层类脂的亚甲基不对称伸缩振动在波数上与对照组相比发生了蓝移。结果提示,dl-芳樟醇引起dl-NG对映体选择性经皮渗透与其对皮肤类脂的作用有关。皮肤类脂50%以上由手性物质神经酰胺组成,推测手性促透剂芳樟醇、皮肤类脂手性物质神经酰胺和/或手性药物NG之间可能存在对映体选择性相互作用。
In this paper, norgestrel (norgestrel, NG) is used as a chiral model drug to study the enantioselectivity of percutaneous rat skin permeation and the effect of chiral anti-hypertensive agents linalool and skin lipids on NG Effect of skin permeation on enantioselectivity. In vitro skin permeation experiments were performed using a Valia-Chien dual-chamber infiltration cell. Penetration samples were examined by chiral HPLC to investigate the enantioselectivity and linalool effects of NG penetration on intact and de-lipidated skin. The results showed that no enantioselectivity of dl-NG transdermal penetration was observed when either dl-NG or l-NG was in a saturated solution of absolute ethanol-water (2: 8, v / v) Of the skin permeation rate is twice that of l-NG, which is mainly attributed to the difference in solubility between l-NG and dl-NG; enantioselective infiltration of dl-NG when dl-linalool is added, l The steady-state permeation rate of -NG was 22% higher than that of d-NG, while the enantioselectivity disappeared when the same experiment was carried out on the skin with de-lipidification. Fourier transform infrared spectroscopy showed that the dl-linalool treatment The asymmetric stretching vibration of the cuticular stratum corneum lipids in the wave number compared with the control group blue shift occurred. The results suggest that dl-linalool induced dl-NG enantioselective transdermal penetration is associated with its effect on cutaneous lipids. More than 50% of the skin lipids are composed of the chiral ceramides, suggesting that there may be an enantioselective interaction between the chiral lecithin linalool, the skin lipid chiral ceramide, and / or the chiral drug NG .