On topical application of a semisolid drug, the drug diffuses passively out of its vehicle and partitions into either the stratum corneum or the sebum-filled ducts of the pilosebaceous glands. Inward diffusive movements continue from these locations to the viable epidermal and dermal points of entry. Thus, a concentration gradient develops across the skin up to the outer reaches of the skin’s microcirculation, where the drug is swept away by the capillary flow and rapidly distributed throughout the body.

The following are the two principle absorption routes:

1. Transepidermal route involving diffusion of drug directly across the stratum corneum
2. Transfollicular route involving diffusion through the follicular pore

1. Transepidermal route: It is generally believed that the transepidermal pathway is responsible for diffusion across the skin. It involves direct partitioning into the stratum corneum. Majority of the drugs diffuse across the stratum corneum through the intercellular lipoidal route. There appears to be another microscopic path through the stratum corneum for extremely polar compounds and ions. During permeation through stratum corneum, the drug enters the epidermis. As the epidermis has no direct blood supply, the drug is forced to diffuse across to reach the underlying vasculature. The epidermal cell membranes are tightly joined, and there is little to no intercellular space for ions and polar nonelectrolyte molecules to diffuse through the membrane.
2. Transfollicular route: The skin appendages such as sebaceous glands and eccrine glands distributed over the entire body offer secondary avenues for drug permeation and are regarded as shunt pathways. The orifice of eccrine glands are tiny and up to a miniscule fraction of the body’s surface. They are either evacuated or so profusely active that the molecule cannot diffuse inwardly against the gland’s output. Hence, they are not considered as a significant route of percutaneous absorption. Follicular route still remains an important route for percutaneous absorption, since the opening of the follicular pore is relatively large and sebum assists in diffusion of penetrants.