The skin itself has two main layers, the epidermis, which is the outermost layer of the skin, covers the dermis and is the active part of the skin, holding the hair muscles, blood supply, sebaceous glands, and nerve receptors. There is a fat layer underneath the dermis. The skin is a very heterogeneous membrane and has a variety of cell types, but the layer that controls the penetration of drugs is called the stratum corneum and, despite its thickness of only 15–20 µm, it provides a very effective barrier to penetration. The permeation of the drug through the skin has several routes: transcellular, intercellular, and appendageal (through eccrine (sweat) glands or hair follicles).
Fig: Schematic representation of the
different possible routes of penetration through the skin.
Since the appendages occupy a very low
surface area, this means of permeation is less significant under normal
conditions. Nevertheless, in iontophoretic delivery, this route is more significant.
The intercellular spaces consist of a mixture of lipids–ceramides, free fatty
acids and their esters, and cholesterol and its sulfates that are structured in
bilayers. Recent developments in spectroscopic techniques give interesting
insights at the molecular level that may explain the impermeability of the skin
by repeated partition and diffusion across structured bilayers. Transdermal
drug permeability is influenced mainly by three factors: the mobility of the
drug in the vehicle, the release of the drug from the vehicle, and drug
permeation through the skin. Therefore, the researchers are challenged to come
up with formulations that increase the permeability of the drug without
irreversibly changing the skin barrier function. Various potential mechanisms
to enhance drug penetration through the skin include directly affecting the
skin and modifying the formulation so the partition, diffusion, or solubility
are altered. Here we will present briefly these potential mechanisms that are interconnected
with each other.
1. Direct Effect on the Skin
(a) Denaturation of intracellular
keratin or modification of its conformation causes swelling and increased
hydration.
(b) Affection of desmosomes (known as
macula adherens- cell structures specialized for cell-to-cell adhesion) that
maintain cohesion between corneocytes (dead cells of the stratum corneum).
(c) Modification of lipid bilayers
reduces resistance to penetration.
(d) Altering the solvent properties of
the stratum corneum to modify drug partitioning.
(e) Use of solvent that can extract
the lipids in the stratum corneum and decrease its resistance to penetration.
2. Modification of the Formulation
(a) Supersaturation state produced by a
volatile solvent that leaves the active substance in a more thermodynamically
active state.
(b) Choosing the enhancer molecules in
the vehicle that are good solvents for the active ingredient and which enhance
permeation through the skin; this way the partition of the drug into the
stratum corneum will be improved.
(c) The diffusion of the active
ingredient through the skin may be facilitated by using enhancers that create
liquid pools within the bilayers like oleic acid, or disturb the bilayers
uniformly as do the Azone® molecules (1-dodecyl aza cyclo heptan-2-one or Lauro
capram) is the first molecule specifically designed as a skin permeation enhancer.
Azone® serves as a surfactant and enhances the skin transport of a wide variety
of drugs including steroids, antibiotics, and antiviral agents.