**3. Stratum corneum structure**

Stratum corneum, an upper layer of the skin, is a lipid-rich matrix with embedded corneocyte cells, which are dead keratinocytes. Corneocytes are tied together by a protein called corneodesmosome (**Figure 1**). Renewal of stratum corneum occurs every 14 days [31]. This layer is the first barrier for transdermal drug delivery. Lipid-rich matrix is used for transdermal drug delivery (TDD)—intercellular pathway. The lipid-rich matrix is composed of hydrophilic domain—head of ceramides and lipophilic domain—tails (**Figure 1**). The lipids in stratum corneum include mostly ceramides (41%), cholesterol (27%), cholesteryl esters (10%) and fatty acids (9%) with a small fraction of cholesterol sulphate (2%) [32]. The presence of ceramides indicates that lipids will be structured [31].

The permeability of stratum corneum lipid membranes depends strongly on the ceramide composition of these membranes. Molecular dynamics simulations show that ceramides with shorter (four- to eight-carbon acyl chains) fatty acid chains increase skin permeability, whereas further shortening of the chain leads to increased resistance to penetration almost as good as that of ceramides from healthy skin (24 carbons long on average) [33]. In order to enhance skin permeability, mechanisms like alternation of lipids of stratum corneum and its fluidity or creation of the disordering effect between alkyl chains of lipids of stratum corneum have been proposed [34].

**Figure 1.** Stratum corneum layer with intercellular space [31].
