Anti-melasma codrug of retinoic acid assists cutaneous absorption with attenuated skin irritation.
Melasma treatment with combined retinoic acid (RA) and hydroquinone (HQ) usually causes unsatisfactory outcomes and safety concerns. This study attempted to evaluate the cutaneous absorption and skin tolerance of the codrug conjugated with RA and HQ via ester linkage. The codrug's permeation of the pig skin was estimated using Franz diffusion cell. The codrug and parent drugs were comparatively examined for anti-inflammatory activity and tyrosinase inhibition. In vivo cutaneous irritation was assessed on nude mouse skin. Chemical conjugation of RA with HQ increased the lipophilicity and thus the skin absorption. The codrug absorption produced a 5.5- and a 60.8-fold increment compared to RA skin deposition at an equimolar (1.2mM) and saturated solubility dose, respectively. The cumulative amount of HQ derived from the codrug in the receptor was comparable to or less than that of topically applied HQ. The RA-HQ codrug was partly hydrolyzed on penetrating the skin. The hydrolysis rate in intact skin was significantly lower than that in esterase medium and skin homogenates. The codrug showed an interleukin (IL)-6 inhibition activity comparable to RA. A therapeutic index 6-fold greater than RA was obtained with the topical codrug. The tyrosinase inhibition percentage of the codrug and HQ was 13% and 21%, respectively. The skin tolerance test determined by transepidermal water loss (TEWL), redness, and histopathology had exhibited minor skin irritation caused by the codrug compared to the physical mixture of RA and HQ at an equivalent dose. Topical codrug delivery not only promoted RA absorption, but also diminished the adverse effects of the parent agents.
Medicinal Chemistry Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan; Research Center for Food and Cosmetic Safety and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan.
Pei-Wen
PW
Hsieh
School of Medicine, Fu Jen Catholic University, Hsinchuang, New Taipei City, Taiwan.
Chi-Feng
CF
Hung
Center for General Education, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan.
Chih-Hung
CH
Lin
Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan.
Chang-Wei
CW
Huang
Research Center for Food and Cosmetic Safety and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan; 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. Electronic address: fajy@mail.cgu.edu.tw.
Jia-You
JY
Fang
D000279:Administration, Cutaneous; D000818:Animals; D004338:Drug Combinations; D005260:Female; D006868:Hydrolysis; D006873:Hydroquinones / Q000008:administration & dosage* / Q000627:therapeutic use*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D007509:Irritants; D008548:Melanosis / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D012869:Skin Absorption / Q000187:drug effects*; D012995:Solubility; D013552:Swine; D014212:Tretinoin / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*
D004338:Drug Combinations; D006873:Hydroquinones; C508600:IL6 protein, human; D015850:Interleukin-6; D007509:Irritants; D014212:Tretinoin; C031927:hydroquinone
Codrug; Cutaneous absorption; Hydroquinone; Melasma; Retinoic acid