Effect of O-acylmenthol and salt formation on the skin permeation of diclofenac acid.
OBJECTIVE
To enhance the transdermal delivery of diclofenac acid (DA) by using O-acylmenthol as a penetration enhancer and complexing with amines, or by a combination of the two methods.


METHODS
The skin permeability of diclofenac was tested in vitro across rat skin with each of the evaluated permeants in a saturated isopropyl myristate (IPM) donor solution.


RESULTS
A 4.5-fold increase in the flux of diclofenac was observed by ion-pair formation with diethylamine; however, the cations with hydroxyl groups had negative effects on the transdermal delivery of diclofenac. 2-isopropyl-5-methylcyclohexyl 2-hydroxypanoate and 2-isopropyl-5-methylcyclohexyl heptanoate produced significant increase in the permeation of diclofenac potassium (D-K); however, both of them were ineffective for the other diclofenac salts, including diclofenac diethylamine (D-DETA), diclofenac ethanolamine (D-EA), diclofenac diethanolamine (D-DEA), diclofenac triethanolamine, and diclofenac N-(hydroxylethyl) piperidine. 2-isopropyl-5-methylcyclohexyl tetradecanoate was effective on the penetration of D-K, D-DETA, D-EA, and D-DEA. Also, it is exciting to note that the combined use of diethylamine with 2-isopropyl-5-methylcyclohexyl tetradecanoate produced a 9.74-fold increase in accumulation amount of diclofenac compared with DA in IPM.


CONCLUSIONS
The use of ion pair in combination with O-acylmenthol is necessary to further increase the diclofenac flux to provide better compliance for the patients undergoing clinical therapy.
Zhao
Ligang
L
Department of Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang, Liaoning, China.
Li
Yan
Y
Fang
Liang
L
Ren
Changshun
C
Xu
Yongnan
Y
He
Zhonggui
Z
D000818:Animals; D002626:Chemistry, Pharmaceutical; D004008:Diclofenac / Q000737:chemistry* / Q000493:pharmacokinetics*; D008297:Male; D008610:Menthol / Q000737:chemistry* / Q000493:pharmacokinetics*; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012492:Salts / Q000737:chemistry / Q000493:pharmacokinetics; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D012869:Skin Absorption / Q000187:drug effects* / Q000502:physiology
D012492:Salts; D004008:Diclofenac; D008610:Menthol