EFFECT OF 1-ALKYL- OR 1-ALKENYLAZACYCLOALKANONE DERIVATIVES ON THE PENETRATION OF DRUGS WITH DIFFERENT LIPOPHILICITIES THROUGH GUINEA-PIG SKIN

The percutaneous penetration-enhancing effects of 1-dodecyl- (azone), l-geranyl-, and 1-farnesylazacycloheptan-2-one were investigated using seven penetrants having a wide range of n-octanol-water partition coefficients. The penetration of the drugs from water vehicle (aqueous system) and ethanol vehicle (ethanolic system) through excised guinea pig skin was increased by pretreatment with the enhancers. Large enhancement was observed for the drugs, such as 5-fluorouracil and 6-mercaptopurine, with n-octanol-water partition coefficients of approximately unity. The penetration profiles were analyzed based on a one-layer skin model. Two parameters corresponding to the drug diffusivity and partitioning into the skin were obtained. In the aqueous system, the partitioning of drugs into the skin was increased by pretreatment with the enhancers. This led to an increase in drug penetration and accumulation in the skin; diffusivities were little affected. From these parameters, the drug amounts in the vehicle and the skin were well estimated for drugs having partition coefficients of <1. In the ethanolic system, the enhancement was far less than that observed in the aqueous system.