Exploring the structure-permeation relationship of topical tricyclic antidepressants used for skin analgesia.
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.
Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
Kuo-Sheng
KS
Liu
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.
Tse-Hung
TH
Huang
Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Ibrahim A
IA
Aljuffali
Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan.
En-Li
EL
Chen
Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan. Electronic address: 400002@mail.chimei.org.tw.
Jhi-Joung
JJ
Wang
Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan; Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Kweishan, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan; Research Center for Industry of Human Ecology and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan. Electronic address: fajy@mail.cgu.edu.tw.
Jia-You
JY
Fang
D020003:1-Octanol / Q000737:chemistry; D000279:Administration, Cutaneous; D000698:Analgesia; D000700:Analgesics / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D066298:In Vitro Techniques; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009437:Neuralgia / Q000188:drug therapy*; D019946:Propylene Glycol / Q000737:chemistry; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption; D013552:Swine; D014867:Water / Q000737:chemistry
D000700:Analgesics; D000929:Antidepressive Agents, Tricyclic; D014867:Water; D019946:Propylene Glycol; D020003:1-Octanol
Analgesia; Cutaneous absorption; Propamine; Structure-permeation relationship; Tricyclic antidepressant