title: Effect of O-acylmenthol and salt formation on the skin permeation of diclofenac acid.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang, Liaoning, China.
authors.forename: Ligang
authors.initials: L
authors.lastname: Zhao
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Liang
authors.initials: L
authors.lastname: Fang
authors.forename: Changshun
authors.initials: C
authors.lastname: Ren
authors.forename: Yongnan
authors.initials: Y
authors.lastname: Xu
authors.forename: Zhonggui
authors.initials: Z
authors.lastname: He
mesh_terms: 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
chemical_list: D012492:Salts; D004008:Diclofenac; D008610:Menthol