# Targeted Delivery Strategies for Hydrophilic Phytochemicals
## 1 Introduction
### The Overview on the Phytochemicals Penetartions Rates: Discuss Factors Affecting Skin Penetration  
Skin is a large organ whose main role, aside from thermoregulation, is to protect the body from mechanical, biological, and chemical factors. Stratum corneum (SC), the outermost layer of the epidermis, acts as a barrier, which protects the skin from external factors including penetration of drugs or cosmetics. Active substances can penetrate the stratum corneum through several pathways. The most common is the transepidermal route, which includes two mechanisms: the intercellular route--used by the majority of compounds, and the transcellular route. Penetration can also occur through appendageal structures such as hair follicles and sweat glands. In the transepidermal pathway, compounds either pass directly through the corneocytes (transcellular) or move between them by crossing the intercellular lipid matrix--this intercellular route is the primary mode of penetration for most substances [11; 12; 13; 14; 15; 16; 17; 18; 19] (Figure 1). The penetration rate of active substances is determined by their hydrophobic nature. The octanol/water partition coefficient \(P\) (log\(P\)) is an important factor, which has an impact on membrane permeability. Positive values for log\(P\) indicates mo  
Figure 1: The main skin penetration routes of active substances. the compound. While hydrophilic compounds are characterized by negative values for log_P_, which determine its higher aqueous phase affinity following its low penetration [20; 21]. The molecules successful penetration is determined by the suitable balance between lipophilicity and hydrophilicity and also appropriate molecular mass of the compounds, which should be less than 500 Da. In addition to physicochemical properties, the formulation characteristics is equally important for effective skin penetration. For instance, formulations with greater viscosity delay the absorption of active compounds, because of the reduced diffusion coefficient. The pH of the cosmetic base is also crucial because it determines whether the active molecule is dissociated. Undissociated molecules penetrate more effectively, because of its better lipid dissolution compared to dissociated molecules, which easily separate into ions. Moreover, the presence of skin penetration enhancers (e.g., alcohols, amides, glycols) in the cosmetic base also have an influence by reducing the skins barrier resistance [11; 13; 14; 15; 16; 17; 18]. Furthermore, skin permeation is also affected by physiological factors (e.g., age, skin condition and metabolism), as well as sufficient physicochemical characteristics of drug carrier (e.g., size, shape or surface charge), which must be satisfied to guarantee the effective penetration deep into the skin [19; 20; 22; 23]. All the above-mentioned factors are extremely significant and relate to many active molecules. However, the primary focus reviewed here is on hydrophilic compounds and the additional factors, which affect its delivery efficiency. Challenges of Hydrophilic Phytochemical: Discuss Solubility, Stability, and Bioavailability Issues Associated with Hydrophilic Active Substances  
Considering the polar nature of hydrophilic phytochemicals, their effective penetration through the skin faces fundamental challenges. Since the stratum corneum extracellular lipid matrix predominantly contains lipids, e.g., cholesterol and ceramides, as well as free fatty acids, so it results on low solubility in nonpolar environments [19; 24]. Hydrophilic phytochemicals are often chemically unstable under environmental stressors such as temperature, pH, oxygen, and light. These weaknesses result in poor skin absorption and limited bioavailability. For instance, polyphenols, being the most abundant plant-derived compounds, are unstable, because of the presence of hydroxyl groups (-OH) attached to benzene ring, which are highly reactive. Therefore, with an increase of hydroxyl groups the stability of polyphenols is lowered.