Effect of O-acylmenthol on transdermal delivery of drugs with different lipophilicity.
To develop more effective compounds as enhancers, O-acylmenthol derivatives which were expected to be enzymatically hydrolyzed into nontoxic metabolites by esterases in the living epidermis were synthesized from l-menthol and pharmaceutical excipient acids (lactic acid, cinnamic acid, salicylic acid and oleic acid) in this study. Their promoting activity on the percutaneous absorption of five model drugs, 5-fluorouracil (5-FU), isosorbide dinitrate (ISDN), lidocaine (LD), ketoprofen (KP), and indomethacin (IM), which were selected based on their lipophilicity represented by log K(O/W), were tested in vitro across full thickness rat skin with each of the evaluated drugs in saturated donor solution. 2-Isopropyl-5-methylcyclohexyl 2-hydroxypanoate (M-LA) provided the highest increase of accumulation of 5-FU (3.74-fold) and LD (4.19-fold) in the receptor phase while 2-isopropyl-5-methylcyclohexyl cinnamate (M-CA) was ineffective for most of the drugs; Both 2-isopropyl-5-methylcyclohexyl 2-hydroxybenzoate (M-SA) and (E)-2-isopropyl-5-methylcyclohexyl octadec-9-enoate (M-OA) had better promoting effects on the drugs with low water-solubility. The four O-acylmenthol enhancers produced parabolic relationship between the lipophilicity (log K(O/W)) of the model drugs (5-FU, ISDN, KP, IM) and their enhancement ratio of the permeation coefficient (ER(P)), indicating that the lipophilicity of the penetrants has significant effect on the permeation results, r = 0.989 (P=0.144) for M-LA, r = 0.965 (P = 0.216) for M-CA, r = 0.786 (P = 0.630) for M-SA, and r = 0.996 (P = 0.088) for M-OA.
Department of Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, China.
Ligang
L
Zhao
Liang
L
Fang
Yongnan
Y
Xu
Yanyan
Y
Zhao
Zhonggui
Z
He
D000146:Acids, Carbocyclic / Q000737:chemistry / Q000494:pharmacology*; D000279:Administration, Cutaneous; D000818:Animals; D002626:Chemistry, Pharmaceutical; D002934:Cinnamates / Q000494:pharmacology; D015194:Diffusion Chambers, Culture; D004339:Drug Compounding; D005472:Fluorouracil / Q000378:metabolism; D006868:Hydrolysis; D007213:Indomethacin / Q000378:metabolism; D007548:Isosorbide Dinitrate / Q000378:metabolism; D007660:Ketoprofen / Q000378:metabolism; D007700:Kinetics; D007773:Lactates / Q000494:pharmacology; D008012:Lidocaine / Q000378:metabolism; D008297:Male; D008610:Menthol / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D009829:Oleic Acids / Q000737:chemistry / Q000494:pharmacology*; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012459:Salicylates / Q000494:pharmacology; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D012869:Skin Absorption / Q000187:drug effects*; D013678:Technology, Pharmaceutical / Q000379:methods
D000146:Acids, Carbocyclic; D002934:Cinnamates; D007773:Lactates; D009829:Oleic Acids; D004364:Pharmaceutical Preparations; D012459:Salicylates; D008610:Menthol; D007660:Ketoprofen; D008012:Lidocaine; D007548:Isosorbide Dinitrate; D005472:Fluorouracil; D007213:Indomethacin