Liu Kuo-Sheng, Huang Tse-Hung, Aljuffali Ibrahim A, Chen En-Li, Wang Jhi-Joung, Fang Jia-You
Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan; School of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan; School of Nursing, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan.
Int J Pharm. 2017 May 15;523(1):386-397. doi: 10.1016/j.ijpharm.2017.03.048. Epub 2017 Mar 23.
The purpose of this study was to evaluate the skin permeation of tricyclic antidepressants (TCAs) with propamine moiety to select candidates for the development of topical analgesics to treat cutaneous pain. We sought to establish the structure-permeation relationship (SPR) of topical TCAs. The lipophilicity, melting point, and aqueous solubility were determined to develop the physicochemical characterization. The TCA permeation into pig and nude mouse skins was estimated using Franz diffusion cell. TCAs and lidocaine were comparatively examined for cutaneous analgesia by pinprick assay. Cutaneous tolerance to TCAs was assessed using nude mouse skin. The skin deposition increased following the increase of lipophilicity after excluding the effect of solubility, with clomipramine exhibiting the highest skin retention. A contrary result was observed for TCA penetration into the receptor. Of the permeants tested, clomipramine demonstrated the best skin-targeting ability. Nortriptyline and clomipramine demonstrated selective uptake into the hair follicles, exhibiting a 2.5-fold higher follicular accumulation than desipramine. Replacement of nitrogen with carbon in the seven-member ring increased skin absorption. The tertiary amine TCAs demonstrated higher absorption than the secondary amine TCAs. The position of the double bond also affected skin transport. Topical clomipramine had a longer duration of analgesic action than lidocaine (240min versus 60min). Exploring the SPR revealed that clomipramine could be an analgesic candidate drug for future development.
本研究的目的是评估具有丙胺部分的三环类抗抑郁药（TCA）的皮肤渗透性，以筛选用于开发治疗皮肤疼痛的局部镇痛药的候选药物。我们试图建立局部TCA的结构-渗透关系（SPR）。测定了亲脂性、熔点和水溶性以进行物理化学表征。使用Franz扩散池评估TCA渗透进入猪和裸鼠皮肤的情况。通过针刺试验比较研究了TCA和利多卡因的皮肤镇痛效果。使用裸鼠皮肤评估对TCA的皮肤耐受性。在排除溶解度影响后，随着亲脂性增加，皮肤沉积量增加，氯米帕明的皮肤滞留量最高。观察到TCA渗透进入受体的结果则相反。在所测试的渗透剂中，氯米帕明表现出最佳的皮肤靶向能力。去甲替林和氯米帕明表现出对毛囊的选择性摄取，其毛囊蓄积量比地昔帕明高2.5倍。七元环中的氮被碳取代会增加皮肤吸收。叔胺类TCA比仲胺类TCA表现出更高的吸收。双键的位置也影响皮肤转运。局部应用氯米帕明的镇痛作用持续时间比利多卡因长（240分钟对60分钟）。探索SPR表明，氯米帕明可能是未来开发的一种镇痛候选药物。
