Abstract  The purpose of the present study was to determinate the significance of ion pairing on the topical permeation of retinoic acid (R.A) using microemulsions as delivery vehicles. Phenylalanine methyl ester, phenylalanine ethylester, histidine methyl ester, tryptophan methyl ester and valine methyl ester were used as counter ions. Results of diffusion studies through polydimethylsiloxane membrane (PDMS) indicate that retinoic acid permeation from ethanol-pH 6.4 buffer mixture significantly increased in the presence of counter ions. A linear relationship was found between apparent partition coefficients and permeation coefficients. The highest values were with valine methyl ester and phenylalanine ethyl ester. In order to develop alternative formulations for topical administration of R.A, microemulsions were evaluated as delivery vehicles. Oil-in-water (O/W) and water-in-oil (W/O) microemulsion formulations were prepared using water, isopropyl myristate, lecithin, caprylyl-capryl glucoside and ethanol or 1,2 hexanediol. Experiments with PDMS membranes showed decreasing permeabilities of R.A from microemulsions in the presence of counter ions. This was related to the increased lipophilicity and different vehicle membrane affinity of the ion pairs The ability of the systems to deliver R.A through the skin was evaluated in vitro using pig-skin. R.A permeabilities were much lower with microemulsions than with solution, while a large increase in R.A skin deposition was observed only from O/W microemulsions in the presence of counter ions. The depth of skin accumulation was below 100 mum after 24 h application. The results suggest that O/W microemulsions containing a counter ion can be used to optimise drug targeting without a concomitant increase in systemic absorption. (C) 2002 Elsevier Science B.V. All rights reserved.

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.

Abstract  OBJECTIVE: This study was to investigate the topical skin targeting effects and mechanism of combination penetration modifiers of 1,2-hexanediol (or 1,2-heptanediol) and 1,4-cyclohexanediol on transdermal absorption of metronidazole (MTZ) in different skin models.

METHODS: Six formulations were applied to pig abdominal skin and pig ear skin models, respectively, and the results were compared with the previous data on hairless mouse skin worked out by our laboratory. Four parameters (flux, Tlag, Q24 and targeting ratio) were used to evaluate permeability and targeting effect in skin.

RESULTS: The combined penetration modifiers played a general role on decreasing permeability without reducing skin retention. The most significant skin permeability decrement to MTZ was pig abdominal skin (permeability decrement was ∼20% for hairless mouse skin, 60% for pig abdominal skin and 40% for pig ear skin, respectively) while the strongest skin targeting effect appeared in hairless mouse skin (targeting ratios were 1.79 for hairless mouse skin, 1.24 for pig abdominal skin and 1.05 for pig ear skin, respectively) under the role of penetration modifiers.

CONCLUSIONS: Thickness of stratum corneum (SC) was the major factor impact on skin targeting effect. Selection criteria of skin models also have been discussed in this study.