Hsieh Pei-Wen, Aljuffali Ibrahim A, Fang Chia-Lang, Chang Shu-Hao, Fang Jia-You
Medicinal Chemistry Laboratory, Graduate Institute of Natural Products, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan.
Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
J Dermatol Sci. 2014 Nov;76(2):120-31. doi: 10.1016/j.jdermsci.2014.08.013. Epub 2014 Sep 4.
Hydroquinone (HQ) and salicylic acid (SA) are drugs for treating melasma through the mechanisms of tyrosinase inhibition and chemical peeling, respectively. Their high frequency of causing skin irritation has led to limited use of both drugs.
We designed the new conjugates obtained by joining HQ and SA by the co-drug concept for evaluating cutaneous absorption capability.
Monoester (4-hydroxyphenyl 2-hydroxybenzoate, HPH) and diester (1,4-phenylene bis(2-hydroxybenzoate), PBH) forms of the conjugates were synthesized and physicochemically characterized. The enzymatic hydrolysis to the parent drugs was examined. Both an equimolar dose and a saturated solubility were utilized as the applied dose for testing cutaneous absorption via pig and nude mouse skins.
The conjugates had higher lipophilicity, less aqueous solubility, and a lower melting point/crystallinity than the parent drugs. Both conjugates showed a quick conversion into the parent drugs in esterases and skin homogenates, with PBH showing the greater hydrolysis. The hydrolysis level in skin after topical application was less as compared to that in esterases and homogenates. The tyrosinase inhibition (%) and molecular docking demonstrated that the conjugates possessed skin-lightening capability (3% for HPH and 7% for PBH) although this activity was lower than that of HQ (23%). The conjugates showed an increased skin deposition compared to the respective parent drugs. Total absorption of HPH and PBH led to a 13- and 19-fold enhancement in cutaneous retention compared to HQ alone. A similar increment of skin deposition was shown for the conjugates when compared to SA. Contrary to skin reservoir retention, transdermal transport across the skin was decreased by the conjugates, especially for PBH. This indicates the maximization of cutaneous targeting by the conjugates.
Topically applied HPH and PBH can be the new candidates for treating melasma due to efficient skin absorption and acceptable skin tolerance.
对苯二酚（HQ）和水杨酸（SA）分别是通过抑制酪氨酸酶和化学剥脱机制来治疗黄褐斑的药物。它们引起皮肤刺激的频率较高，导致这两种药物的使用受限。
我们通过共药概念将HQ和SA连接起来设计了新的偶联物，以评估皮肤吸收能力。
合成了偶联物的单酯（4-羟基苯基2-羟基苯甲酸酯，HPH）和二酯（1,4-亚苯基双（2-羟基苯甲酸酯），PBH）形式，并对其进行了物理化学表征。检测了其对母体药物的酶促水解。等摩尔剂量和饱和溶解度均被用作经猪和裸鼠皮肤测试皮肤吸收的给药剂量。
与母体药物相比，偶联物具有更高的亲脂性、更低的水溶性和更低的熔点/结晶度。两种偶联物在酯酶和皮肤匀浆中均显示出快速转化为母体药物的现象，PBH的水解程度更大。局部应用后皮肤中的水解水平低于酯酶和匀浆中的水解水平。酪氨酸酶抑制率（%）和分子对接表明，偶联物具有皮肤美白能力（HPH为3%，PBH为7%），尽管该活性低于HQ（23%）。与各自的母体药物相比，偶联物的皮肤沉积增加。与单独使用HQ相比，HPH和PBH的总吸收导致皮肤滞留增加了13倍和19倍。与SA相比，偶联物的皮肤沉积也有类似增加。与皮肤储库滞留相反，偶联物降低了经皮转运，尤其是PBH。这表明偶联物实现了皮肤靶向的最大化。
局部应用的HPH和PBH由于有效的皮肤吸收和可接受皮的肤耐受性，可成为治疗黄褐斑的新候选药物。
