## 3 The Skin's Role  
The skin is the largest organ in the body, which covers an area of about 1.80 m\({}^{2}\), with a thickness of 2.97 \(\pm\) 0.28 mm and its main function is to protect the body from undesirable effects of the environment. The main characteristics of the skin are elasticity, strength, self-healing, and receiving one-third of the total blood circulation [30]. The isoelectric point of human skin is between 4-4.5, which is below its pH under normal conditions [23]. The skin protects from heat, light, injuries, and infections. Although the main role is protective, it also regulates body temperature, prevents water loss, and inhibits the entry of bacteria [11]. The skin consists of three different layers: epidermis, dermis, and hypodermis. The outer layer of the epidermis is formed by the stratum corneum (s.c.) and due to its high density and low hydration, it acts as a skin barrier. The dermis is the middle layer, located between the epidermis and subcutaneous tissues, being the thinnest layer of the skin. The dermis is a vascular network responsible for skin nutrition, repair, regulation, and immune response. The subcutaneous layer, the hypodermis, is the deepest layer, after the dermis and is mainly made up of fat. The hypodermis acts as a heat insulator, shock absorber and energy storage. Transdermal drug delivery requires considerable development in the field of research. The design needs for a topical compound requires primarily the interaction knowledge of what happens between the formulation and the skin [11; 31]. The topical drug delivery system is specially designed to pass active therapeutic substances through the skin. Since the skin is considered a multifunctional organ, it has a limitation of being less permeable when passing through the stratum corneum, constituting an effective barrier to the passage of substances, and several vehicle systems that surpass this barrier have been developed [11]. The stratum corneum is about 10-20 \(\upmu\)m thick and is composed of intercellular lipids and dead cells, the corneocytes, preventing the passage of macromolecules, so it is usually necessary to find improvement strategies for passive penetration (use of supersaturated and penetration enhance solutions) and physical (electroporation and iontophoresis) to overcome the barrier [32]. The methods for drug delivery and the processes for administering pharmaceutical compounds have been used to obtain therapeutic effects in both humans and animals. The transdermal drug delivery means the passage of a substance or drug through the skin in the form of a plaster, cream or lotion that passes through the skin and enters the bloodstream. This process depends on some factors, such as the nature of the skin barrier, the balance between the physicochemical properties of the membrane and the drug, application time, skin location, skin conditions, the vehicle's effect on the stratum corneum, properties and type of formulations and the available technologies, which facilitate transdermal transport [10]. The properties of the skin have an important role in the topical application of medicines or other substances. Pharmacokine studies, including in vivo microdialysis experiments with volunteers, have shown that vasodilation improves the system of assimilation and penetration of substances into tissues, while vasoconstriction has the opposite effect, causing accumulation in tissues. The compounds only reach the systemic circulation of the skin after being absorbed by the stratum corneum [31]. In an effective transdermal drug delivery system, the drug must infiltrate the skin tissues and go directly into the bloodstream without accumulating in the skin layers.