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. 2014 Aug;15(4):973-80.
doi: 10.1208/s12249-014-0125-8. Epub 2014 May 13.

Effect of hydroxyl groups and rigid structure in 1,4-cyclohexanediol on percutaneous absorption of metronidazole

Yan Zhang  1 , Fengping Tan, Weipu Jia, Nan Li, Jerry Zhang
Affiliations

Effect of hydroxyl groups and rigid structure in 1,4-cyclohexanediol on percutaneous absorption of metronidazole

Yan Zhang et al. AAPS PharmSciTech. 2014 Aug.

Abstract

In a previous study, a synergistic retardation effect of 1,4-cyclohexanediol and 1,2-hexanediol on percutaneous absorption and penetration of metronidazole (MTZ) was discovered. A complex formation between 1,4-cyclohexanediol and 1,2-hexanediol was proposed to be responsible for the observed effect. The objective of this study was to investigate the necessity of hydroxyl group and the ring structure in 1,4-cyclohexanediol on percutaneous absorption and penetration of MTZ. Eleven formulations were studied in an in vitro porcine skin model using glass vertical Frans Diffusion Cell. 1,4-Cyclohexanediol was changed into 1,4-cyclohexanedicarboxylic acid, trans (and cis)-1,2-cyclohexanediol and 1,6-hexanediol, respectively, to study if H-bonding or ring structure would influence the retardation effect. MTZ was applied at infinite dose (100 mg), which corresponded to 750 μg of MTZ. Based on modifier ratios (MR) calculated by the flux values, the retardation effect on percutaneous absorption and penetration of MTZ was found in the formulations containing 1,4-cyclohexanedicarboxylic acid or cis-1,2-cyclohexanediol (MR values were 0.47 for which only contains 1,4-cyclohexanedicarboxylic acid, 0.74 for the formulation containing both 1,4-cyclohexanedicarboxylic acid and 1,2-hexanediol, and 0.90 for the formulation containing cis-1,2-cyclohexanediol and 1,2-hexanediol, respectively). The results showed that the hydroxyl group and structure of 1,4-cyclohexanediol played a significant role in retardation effects and provided valuable insight on the mechanisms of retardation effect through structure-activity relationships.

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Figures

Fig. 1
Fig. 1
The model of the vertical Franz diffusion cell
Fig. 2
Fig. 2
a Percentage of epidermal retention of MTZ: comparison of F1, F4, and F5. Mean ± SD, n = 6. b Percentage of amount of MTZ in receptor medium: comparison of F1, F4, and F5. Mean ± SD, n = 6. c Percentage of epidermal retention of MTZ: comparison of F1, F6, F7, F8, and F9. Mean ± SD, n = 6. d Percentage of amount of MTZ in receptor medium: comparison of F1, F6, F7, F8, and F9. Mean ± SD, n = 6. e Percentage of epidermal retention of MTZ: comparison of F1, F10, and F11. Mean ± SD, n = 6. f Percentage of amount of MTZ in receptor medium: comparison of F1, F10, and F11. Mean ± SD, n = 6. SD standard deviation
Fig. 3
Fig. 3
Proposed hydrogen bonds interactions between ceramides and modifier molecules 1,2-hexanediol and 1,4-cyclohexanedicarboxylic acid. Dashed lines, H-bonding
Fig. 4
Fig. 4
Proposed hydrogen bonds interactions between ceramides and modifier molecules 1,2-hexanediol, trans-1,2-cyclohexanediol, and cis-1,2-cyclohexanediol. Dashed lines, H-bonding
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