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

已经开发了几种改善经皮给药的方法，如渗透增强剂和前药。然而。目前尚无理论依据来优化这些方法增强药物吸收。因此，大多数方法都是通过试错来应用的，导致增强效果不足。本研究的目的是基于皮肤扩散模型，提出将前药衍生和增强剂应用相结合的皮肤渗透增强的合理设计。首先，我们基于皮肤扩散模型预测了增强剂对不同理化性质药物皮肤渗透的影响。然后，合成模型药物阿昔洛韦的前药，使其亲脂性达到增强剂作用的最佳水平。使用这些前药，我们使用流动型扩散细胞进行了体外皮肤渗透研究，这使我们能够获得足够精确的渗透剖面，以便进行详细的模型分析。我们发现，正如扩散模型所预测的那样，增强剂比母体药物更有效地增强了前药的皮肤渗透。最后，我们基于新建立的皮肤扩散/生物转化模型，分析了增强剂对前药的渗透，揭示了前药的扩散和生物转化速率与其理化性质的关系，以及渗透增强剂对前药的影响。总之，我们已经建立了一个理论框架来设计最佳的前药增强剂的沟通，以增强经皮给药。

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.