Comparative transdermal permeation disposition and enhancing effects of azone in human cadaver skin and hairless mouse skin



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The penetration kinetics and disposition of 1-dodecylazacycloheptan-2-one (AZ) were studied with full thickness human cadaver skin (HCS) and hairless mouse skin (HMS) as penetration barriers. In addition, the modification of penetration parameters of TA in HCS by AZ was established and compared with those in HMS. The effect of skin storage on AZ skin permeability were investigated. AZ was readily permeable in both HCS and HMS at concentrations 1-10[percent] (v/v). The presence of triamcinolone acetonide (TA) in the vehicle did not affect AZ permeation and disposition in both skin barriers. AZ exerted self enhancing effect in HMS in that permeability coefficient (Kp) increased significantly with increasing AZ concentrations due to the concentration dependent increase in diffusion constant (D). This AZ enhancing effect was more profound in HMS than in HCS. The Kp of AZ in HCS increased by 1.8 times when AZ increased from 1 to 10[percent] while that in HMS increased 4.3 times. The extent of AZ penetration at 1 to 10[percent] AZ increased from 4.60 to 9.0[percent] in HCS but 5.8 to 26.6[percent] in HMS. The lag time (T) of AZ in HCS were relatively constant 2.42-3.41 hr, but significantly shortened from 2.18 at 1[percent] to 0.73 hr at 10[percent] in HMS. AZ enhancing effect on TA skin permeation in HCS was evaluated with AZ concentrations of 2-10[percent]. AZ enhancing effect on TA skin permeation was found quantitatively smaller in HCS than in HMS. AZ significantly promoted the extent of TA penetration. Kp and the partition coefficient (Km) were significantly enhanced in HCS and HMS. The optimal concentration for AZ enhancing effects was at 2-5[percent] in HCS as compared with that of 2-3[percent] AZ in HMS. Penetration impedance was observed for AZ concentration above 5[percent] and 3[percent] in HCS and HMS respectively. AZ did not potentiate TA skin retention in HCS. Storage of the skin by cryopreservation resulted in increased permeability of skin after 3 days in HCS and after 7 days in HMS. As a result, the amount of AZ penetrated through the skin increased. Km was significantly increased in HCS after 3 days storage, and it was not appreciably affected by storage in HMS. D and T were not significantly affected by storage in HCS, but in HMS there was a significant increase in D and a shortening of T. The amount of AZ retained in the skin remained unchanged in HCS but was significantly reduced in HMS after 7 days of storage. These results suggested that with AZ, HMS overemphasized the accelerant activity compared to human skin. Therefore, there may be differences in the mechanism of AZ percutaneous permeation and enhancing effect in HCS and HMS. Hence the extrapolation of enhancer effects from HMS to HCS need to be done with caution. This study has contributed to the knowledge on AZ percutaneous penetration in two useful skin models for in vitro studies.



Skin absorption