Koyama Y, Bando H, Yamashita F, Takakura Y, Sezaki H, Hashida M
Faculty of Pharmaceutical Science, Kyoto University, Japan.
Pharm Res. 1994 Mar;11(3):377-83. doi: 10.1023/a:1018904802566.
Percutaneous absorption-enhancing effects of d-limonene and oleic acid were investigated using three model drugs with different lipophilicities in in vitro diffusion experiments with guinea pig skin. Pretreatment of the skin with d-limonene resulted in a large penetration enhancement for the lipophilic butylparaben (BP) and amphiphilic 6-mercaptopurine (6-MP) but had little effect on the hydrophilic mannitol (MT). Oleic acid caused a large effect only on 6-MP penetration. The penetration profiles were analyzed with a two-layer skin diffusion model consisting of stratum corneum with polar and nonpolar routes and viable epidermis plus dermis. Through curve-fitting, six parameters corresponding to drug diffusivity and partitioning in these three regions of the skin were obtained, and the mechanisms of enhancers were assessed in comparison with those of 1-geranylazacycloheptan-2-one (GACH) reported previously. Increased penetration was caused mainly by modification of the barrier property of the nonpolar route in the stratum corneum in all cases. In the nonpolar route, d-limonene increased mainly drug diffusivity, while GACH enhanced predominantly drug partitioning. On the other hand, oleic acid moderately increased both parameters.
在豚鼠皮肤的体外扩散实验中，使用三种具有不同亲脂性的模型药物研究了d - 柠檬烯和油酸的经皮吸收增强作用。用d - 柠檬烯预处理皮肤后，亲脂性的对羟基苯甲酸丁酯（BP）和两亲性的6 - 巯基嘌呤（6 - MP）的渗透显著增强，但对亲水性的甘露醇（MT）影响很小。油酸仅对6 - MP的渗透有较大影响。采用由角质层的极性和非极性途径以及活性表皮加真皮组成的两层皮肤扩散模型分析渗透曲线。通过曲线拟合，获得了与药物在皮肤这三个区域的扩散系数和分配相关的六个参数，并与先前报道的1 - 香叶基氮杂环庚烷 - 2 - 酮（GACH）的作用机制进行了比较，评估了增强剂的作用机制。在所有情况下，渗透增加主要是由于角质层中非极性途径屏障特性的改变。在非极性途径中，d - 柠檬烯主要增加药物扩散系数，而GACH主要增强药物分配。另一方面，油酸适度增加了这两个参数。
