## 4 Discussion
The most widely used method for enhancing drug penetration through the cuticle employs chemical enhancers [44]. We used two chemical penetration enhancers: OA and azone. The ability of OA to enhance skin penetration has been widely recognized in various in vitro studies [45]. It disrupts highly stacked intercellular domain lipids in the cuticle [46]. Azone was the first compound specifically designed as a skin penetration enhancer, and its penetration-enhancing properties reflected the molecule's ability to reduce skin diffusion resistance [47; 48]. Due to the limited enhancement effect of a single chemical enhancer on skin permeability, the combined use of chemical enhancers may achieve more satisfactory therapeutic effects and safety owing to their synergistic effects [49]. This study evaluated the permeability of SIM-CAP transdermal patches using oleic acid and azone alone and in combination. The results showed that at the 16% concentration of OA/azone (1:1), the cumulative drug release was the highest and was selected as the enhancer for the SIM-CAP transdermal patches. Pressure-sensitive adhesives (PSAs) are viscoelastic materials that can adhere to various solid surfaces under slight pressure quickly [50]. They have the advantages of convenient use, good stability, simple manufacturing, and good appearance [51]. Polyacrylic acid resin II is a type of polyacrylic acid resin pressure-sensitive adhesive that can adhere to biological tissues and shows excellent sustained release effects in the skin [52]. We investigated the effect of different concentrations of polyacrylic acid resin II in SIM-CAP transdermal patches on drug release. The results showed that 2% polyacrylic acid resin II maintained the developed patch's moderate adhesive qualities and optimized the cumulative release of SIM-CAP from the sustained-release TDDS. The optimal formula for the SIM-CAP composite transdermal patch was determined by screening the skeletal material, penetration enhancer, and pressure-sensitive adhesive. The quality of the optimal formula was then evaluated, including quality indicators such as integrity, stability, and viscosity. SEM was used to inspect the integrity of the patch; the results showed that the surface of the prepared SIM-CAP composite transdermal patches was relatively smooth and uniform without solid particles or cracks. The SIM-CAP composite transdermal patches exhibited no significant changes in appearance and good stability under high-temperature, severe cold, and freeze-thaw conditions. The patches were also evaluated for their initial adhesion, adhesion retention, and peel strength. The results indicated that the SIM-CAP composite transdermal patch exhibited good adhesion. We conducted pharmacokinetic analysis of oral administration and the SIM-CAP TDDS using rabbits. Compared with oral medication, the maximum concentration of the SIM-CAP TDDS was reduced, which avoids the side effects caused by peak oral administration. The T\({}_{\max}\) of the SIM-CAP TDDS was prolonged to 4 h, showing that the speed at which drugs are absorbed into the body slows down. The extension of MRT from 5.34 h to 9.29 h indicated an increase in the duration of drug retention in the body. Compared with oral administration, the AUC(0-t) value of the SIM-CAP TDDS increased significantly, indicating that the patches had a longer duration of action and a more stable blood drug concentration. The AUC(0-t) ratio of the SIM-CAP TDDS and oral administration was compared. We found that the SIM-CAP TDDS gained a significant increase in relative bioavailability, reaching 235.16%. In summary, this pharmacokinetic parameter indicated that the SIM-CAP TDDS had a better absorption effect in vivo, longer action time, higher bioavailability, and more stable blood drug concentration and overcomes the first-pass effect of oral administration. However, skin reactions may still occur with transdermal medications [53].