The skin has several layers, but drug penetration primarily occurs across the epidermis, particularly through the stratum corneum.
There are three primary pathways for dermal penetration:
Transcellular (Trans-epidermal) Route
Drugs pass directly through the keratinocytes (cells) of the stratum corneum.
Challenges: This route requires the drug to partition into and out of the lipid-rich cell membrane and the aqueous intracellular environment, which can be difficult depending on the physicochemical properties of the drug.
Example: Polar molecules may find this route challenging due to their need to traverse both hydrophobic and hydrophilic barriers.
Intercellular (Inter-epidermal) Route
The drug diffuses between the cells of the stratum corneum, primarily through the lipid-rich matrix.
Advantages: This is the more common route for many drugs, especially lipophilic (fat-soluble) molecules, which find it easier to diffuse through the lipid layers.
Example: Most lipophilic drugs follow this pathway, as it bypasses the intracellular space.
Transappendageal (Shunt) Route
Drugs penetrate through appendages such as hair follicles, sebaceous glands, and sweat ducts.
Advantages: This pathway provides an alternative route, especially for larger or more hydrophilic molecules that have difficulty penetrating the stratum corneum.
Example: Charged or large molecules may preferentially utilize this route, though it offers a smaller surface area compared to the other routes.