Medicinal Chemistry Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan.
Eur J Pharm Biopharm. 2012 Jun;81(2):369-78. doi: 10.1016/j.ejpb.2012.03.006. Epub 2012 Mar 24.
A co-drug of hydroquinone (HQ) and azelaic acid (AA), bis(4-hydroxyphenyl)nonanedioate (BHN), was synthesized and investigated as a topical prodrug with the aim of improving the dermal delivery of the parent drugs. Physicochemical parameters were ascertained, and the enzymatic hydrolysis was examined. Skin permeation of HQ, AA, and BHN was studied by determining the skin deposition and flux across nude mouse skin under equivalent doses with the same thermodynamic activity. The partition coefficient (log P) of the co-drug increased by up to 5.0 with HQ and AA conjugation, which had respective log P values of 0.5 and 1.4. In the skin absorption experiment, BHN in ethanol/pH 7 buffer resulted in a 2-fold enhancement of skin deposition compared to both HQ and AA. With permeation using polyethylene glycol 400/pH 7 buffer as the vehicle, the co-drug, respectively, exhibited 8.1- and 1.4-fold enhancements of skin uptake compared to HQ and AA alone. The transdermal flux from BHN was negligible compared to those with HQ and AA treatments. The results of a preliminary safety evaluation showed no signs of stratum corneum disruption or erythema by BHN application within 24h. The co-drug approach provides a viable option for the treatment of skin hyperpigmentation of HQ and AA.
将对苯二酚（HQ）和壬二酸（AA）的共药物，双（4-羟基苯基）壬二酸酯（BHN）进行合成和研究，作为一种局部前药，旨在改善母体药物的皮肤传递。确定了物理化学参数，并检查了酶水解。通过在相同热力学活性下用等量的 HQ、AA 和 BHN 测定皮肤沉积和通量，研究了 HQ、AA 和 BHN 的皮肤渗透。与 HQ 和 AA 共轭，共药物的分配系数（log P）增加了高达 5.0，其 log P 值分别为 0.5 和 1.4。在皮肤吸收实验中，BHN 在乙醇 /pH7 缓冲液中的皮肤沉积量比 HQ 和 AA 分别增加了 2 倍。使用聚乙二醇 400 /pH7 缓冲液作为载体进行渗透时，与 HQ 和 AA 单独使用相比，共药物分别使皮肤吸收增加了 8.1 倍和 1.4 倍。与 HQ 和 AA 处理相比，BHN 的透皮通量可以忽略不计。初步安全性评估结果表明，在 24 小时内 BHN 应用不会破坏角质层或引起红斑。共药物方法为 HQ 和 AA 治疗皮肤色素沉着提供了可行的选择。
