Co-drug strategy for promoting skin targeting and minimizing the transdermal diffusion of hydroquinone and tranexamic acid.
Hydroquinone and tranexamic acids (TXA) are skin-lightening agents with a hydrophilic nature and low skin absorption. A high dose is needed for clinical use, resulting in a high incidence of skin irritation. Co-drugs formed by conjugating hydroquinone and TXA were synthesized and their in vitro and in vivo skin absorption characteristics were evaluated. The two synthesized co-drugs were 4-hydroxyphenyl 4-(aminomethyl)cyclohexanecarboxylate (HAC) and 1,4- phenylene bis(aminomethyl)cyclohexanecarboxylate (BAC). The co-drugs were chemically stable in aqueous solution, but rapidly degraded to the respective parent drug in esterases and skin homogenates. Compared to hydroquinone application, 7.2- and 2.4-fold increments in the hydroquinone skin deposition were obtained with the in vitro application of HAC and BAC. HAC and BAC led to 3- and 2-fold enhancements of equivalent TXA deposition compared to TXA administration. The in vivo experiment showed a further enhancement of co-drugs compared to the in vitro setup. The transdermal penetration of co-drugs, especially BAC, was much lower than that of hydroquinone and TXA. This indicated high-level skin targeting by the co-drugs. HAC and BAC revealed strong affinities for the viable epidermis/dermis. Hair follicles are important reservoirs for co-drug delivery. Daily administration of co-drugs to the skin did not generate irritation for up to 7 days. Both co-drugs are superior candidates for treating skin hyperpigmentation.
Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, 259 Wen- Hwa 1st Road, Kweishan, Taoyuan 333, Taiwan. fajy@mail.cgu.edu.tw.
Pei-Wen
PW
Hsieh
Wei-Yu
WY
Chen
Ibrahim A
IA
Aljuffali
Chun-Che
CC
Chen
Jia-You
JY
Fang
D000279:Administration, Cutaneous; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004338:Drug Combinations; D016503:Drug Delivery Systems; D005260:Female; D018859:Hair Follicle / Q000737:chemistry; D006801:Humans; D006873:Hydroquinones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects; D008819:Mice, Nude; D017550:Spectroscopy, Fourier Transform Infrared; D014148:Tranexamic Acid / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
D004338:Drug Combinations; D006873:Hydroquinones; D014148:Tranexamic Acid; C031927:hydroquinone