A Study on the Stability of High Drug Solubility Characteristics of Hydroxyphenyl Adhesives under the Interference of CPEs.

Novel hydroxyphenyl adhesives (HP-PSAs) could significantly increase drug solubility and control drug release through a doubly ionic hydrogen bond (DIH bond) in the patch. However, chemical penetration enhancers (CPEs) always destroy the performance of most adhesives. As a result, this work investigated the stability of both the HP-PSA features and the DIH bond under the interference of the CPEs. Donepezil (DON) was chosen as the model drug, and CPEs with hydroxyl, carboxyl, amido, and ester groups were selected as model CPEs. Unlike the commonly used neutral H-bond, the DIH bond between DON and the HP-PSA was still stable under the interference of the CPEs, resulting in the 2-3-fold drug solubility in the HP-PSA, which was higher than that in the nonfunctional PSA, which reduced the drug crystallization risk and the difficulty of formulation design. FT-IR, ¹H NMR, XPS, dynamic simulation, and molecular docking revealed the mechanism of the stability feature of both the DIH bond and the high drug solubility of the HP-PSA, which was that the formed neutral H-bond interaction caused by CPEs is weaker than that of the DIH bond between DON and the HP-PSA. Furthermore, the drug release, skin permeation, and CPE release study showed that the newly formed weak H-bond and strong ionic H-bond interaction promoted or controlled both DON and CPE release, respectively, thereby influencing drug skin permeation, which provided a theoretical basis for drug release regulation. To summarize, besides the reversible, strong features of the DIH bond in our previous study, the stability of the interaction made the HP-PSA's high drug solubility potential to be applied in the TDDS.