## 4 Discussion  
The topic of substances of natural origin, mainly derived from plants, and their use in dermatological preparations applied to the skin, such as in the form of ointments, creams, and hydrogels, has recently been increasingly discussed. Particularly noteworthy are hydrogels, whose semi-solid consistency, spreadability, good mechanical properties, and other physical characteristics are due to their internal structure. This is a structure that is a combination of a solid (rigid) phase and a continuous (liquid) phase. Hydrogels are a three-dimensional network in which the solid phase is formed by suitable polymers and the liquid phase by water with dissolved substances. Their chemical structure allows for a gradual release of the API from the hydrogel matrix, which translates into a prolonged pharmacological effect. Advantageous features of this drug formulation include high biocompatibility, transparency, and easy wash-off [70]. Unfortunately, when applied to the skin, it dries quickly and can be irritating as a result. To prevent rapid drying, glycerol or propylene glycol is added to these bases. The main barrier to the penetration of the active ingredient is the stratum corneum. In the case of topical administration, it is important to increase the passage of the API through the stratum corneum so that it is retained in the inner layers of the skin. The permeation of medicinal substances through the skin depends on many factors, such as the condition of the skin, the presence of absorption promoters, the physicochemical characteristics of the API, and the vehicle used in the dermatological preparation. Unfortunately, quercetin shows poor water solubility, higher metabolism, and poor bioavailability, which limits its therapeutic use. A number of works have addressed its topical delivery in the form of nanocarrier systems [71; 72]. Transdermal delivery of quercetin from formulations can be \begin{table}
\begin{tabular}{c c c} \hline \hline
**Formulation Code** & \
\begin{tabular}{c} **Cumulative Amount** \\ **of Flavonoid Permeated (\%)** \\ \end{tabular} &
\begin{tabular}{c} **Flavonoid Retention** \\ **(\(\mu\)g/cm2) \(\pm\) SD** \\ \end{tabular} \\ \hline
**F-AA** & 0.10 \(\pm\) 0.02 & 4.21 \(\pm\) 0.62 [FOOTNOTE:2]Footnote 2: \(p\leq 0.01\) as compared to F-AA, F-CA; \(p\leq 0.01\) as compared to F-AB, F-CB; \(p\leq 0.01\) as compared to F-MA, \({}^{d}\) \(p\leq 0.01\) as compared to F-MB. F-AA (SA; quercetin 0.4%), F-AB (SA; quercetin 0.7%), F-CA (CMC, quercetin 0.4%), F-CB (CMC, quercetin 0.7%), F-MA (MC, quercetin 0.4%), F-MB (MC, quercetin 0.7%). \\ \end{tabular}
\end{table} 
Table 6: Quercetin penetration (%) and retention (\(\mu\)g/cm2) into porcine ear skin from hydrogels. improved by the use of penetration enhancers such as dimethylformamide, L-menthol [73], diethylene glycol monoethyl ether [74], oxymatrine-fatty acid deep eutectic solvents [75], propylene glycol, and polyethylene glycol 400 [76]. In our study, DMSO was used as a transdermal quercetin transport enhancer. DMSO is a solvent with low toxicity and documented efficacy in the treatment of various skin injuries. It is also applied to enhancing the solubility of poorly soluble polar and non-polar molecules [77]. It is a potent penetrator of cell membranes and biological barriers, so it is used as a carrier to increase the permeability and absorption of actives substances. The target site of quercetin action is the epidermis and dermis, where the disease process is taking place. After application, the drug should be released slowly, and systemic absorption should be zero or minimized. Our ex vivo permeation and retention results showed that quercetin from CMC-based formulations crossed the stratum corneum to a significantly higher degree (\(p<0.01\)) compared to ALC- and MC-based formulations. Furthermore, the higher API content of the hydrogel substrate correlated with increased accumulation in the skin layers. [PERSON] et al.