title: Synergistic effect of 1,4-cyclohexanediol and 1,2-hexanediol on percutaneous absorption and penetration of metronidazole.
abstract: The objective of this study was to investigate the percutaneous absorption of metronidazole (MTZ) in the topical formulations containing a combination of 1,4-cyclohexanediol and 1,2-hexanediol. Six formulations were studied in an in vitro hairless mouse skin model using Franz Diffusion Cell. MTZ was applied at infinite doses (50mg and 100mg of the formulations, which correspond to 375 and 750 μg of MTZ, respectively). Based on the flux values and retardation ratio (RR), a synergistic retardation effect on percutaneous absorption of MTZ was observed for the formulations containing a combination of 1,4-cyclohexanediol and 1,2-hexanediol (RRs are 0.40 for 375 μg dose and 0.69 for 750 μg dose, respectively). Interestingly, retention of MTZ in epidermis and dermis layer showed no significant differences (p>0.05) between the formulations containing the retardant combination and control formulations. In other words, the retardant combination in the formulation decreases MTZ fluxes while maintaining similar level of retention in epidermis and dermis layer when compared to the control formulations. These observations provide insight in formulating superior topical formulations with minimized potential systematic toxicity while maintaining therapeutic efficiency. A mechanistic explanation of the observed synergistic effect is proposed.
authors.affiliation: Tianjin Key Laboratory of Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 300072 Tianjin, PR China.
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.forename: Weibu
authors.initials: W
authors.lastname: Jia
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Fengping
authors.initials: F
authors.lastname: Tan
authors.forename: Jerry
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000277:Adjuvants, Pharmaceutic / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003511:Cyclohexanols / Q000737:chemistry / Q000494:pharmacology*; D003627:Data Interpretation, Statistical; D004357:Drug Synergism; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism; D006018:Glycols / Q000737:chemistry / Q000494:pharmacology*; D006586:Hexanes; D066298:In Vitro Techniques; D008297:Male; D008795:Metronidazole / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D051379:Mice; D008812:Mice, Hairless; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D012869:Skin Absorption / Q000187:drug effects*
chemical_list: D000277:Adjuvants, Pharmaceutic; D003511:Cyclohexanols; D006018:Glycols; D006586:Hexanes; D008795:Metronidazole; C064620:1,4-cyclohexanediol; C119102:1,2-hexanediol