Establishment of the theory based on a skin diffusion model for the optimal design of a new approach to enhanced trandermal drug delivery

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Several approaches to improving transdermal drug delivery, such as penetration enhancers and prodrugs, have been developed. However.there have been no theoretical bases for optimizing enhanced drug absorption by these approaches. Thereby, most of the approaches have been applied through trial and error, resulting in insufficient enhancement effects obtained. The purpose of this study is to propose rational design of skin penetration enhancement, in which prodrug derivation an enhancer application are combined, based on a skin diffusion model. At first, we predicted the effect of enhancers on skin penetration of drugs with various physicochemical properties based on a skin diffusion model. Next, prodrugs of acyclovir, a model drug, was synthesized to have the optimal lipophilicity for the enhancers' effect. Using these prodrugs, we carried out the in vitro skin permeation study using flow-through type diffusion cells which allowed us to obtain penetration profiles precise enough for detailed model analysis. We found that skin penetration of the prodrugs were more efficiently enhanced by the enhancers than that of the parent drug, as perdicted by the diffusion model. At last, we analyzed the penetration of the prodrugs with the enhancers based on a newly developed skin diffusion/bioconversion model, revealing the relationships of both diffusion and bioconversion rates of prodrugs with their physiochemical properties and the effect of penetration enhancers on them. In summary, we have established a theoretical framework to design the optimal prodrug-enhancer comvination for enhanced transdermal drug delivery.